USOO8673881B2

(12) United States Patent (10) Patent No.: US 8,673,881 B2 Gjorstrup et al. (45) Date of Patent: Mar. 18, 2014

(54) COMPOSITIONS AND METHODS FOR THE (52) U.S. Cl. TREATMENT OF USPC ...... 514/63; 514/475; 514/549; 514/560; 549/561; 554/77: 554/219 (75) Inventors: Per Gjorstrup, Cambridge, MA (US); (58) Field of Classification Search C. Eric Schwartz, Wakefield, MA (US) USPC ...... 549/561; 514/63, 475,549, 560; 554/77, 219 (73) Assignee: A.T. Resolve Sarl, St-Legier (CH) See application file for complete search history. (*) Notice: Subject to any disclaimer, the term of this (56) References Cited patent is extended or adjusted under 35 U.S.C. 154(b) by 88 days. U.S. PATENT DOCUMENTS 4,172,896 A 10, 1979 Uno et al. (21) Appl. No.: 13/264,155 4,346,227 A 8/1982 Terahara et al. 4,444,784. A 4, 1984 Hoffman et al. (22) PCT Filed: Apr. 13, 2010 4,681,893 A 7, 1987 Roth 5,354,772 A 10, 1994 Kathawala (86). PCT No.: PCT/US2O1 O/O3O813 5,427,7985,358,970 A 10,6/1995 1994 LudwigRuffet al. et al. S371 (c)(1), 5,541,231 A 7/1996 Ruffet al. (2), (4) Date: Dec. 23, 2011 (Continued) (87) PCT Pub. No.: WO2010/120719 FOREIGN PATENT DOCUMENTS PCT Pub. Date: Oct. 21, 2010 WO WO-2009/038671 3, 2009 65 Prior Publication D WO WO-2010/039531 4/2010 (65) rior Publication Data OTHER PUBLICATIONS US 2012/0101.061 A1 Apr. 26, 2012 Becker, et al., Hydrolyse von Carbonsaurederivaten, Organikum, pp. 414-415 (1990) (No translation available). Related U.S. Application Data (Continued) (60) Sl applits No. RS ill , s: Primary Examiner — Deborah D Carr s prov1s1onal application No. sy V ws (74) Attorney, Agent, or Firm — Kilpatrick Townsend & filed on May 1, 2009. Stockton LLP (51) Int. Cl. (57) ABSTRACT AOIN 55/00 (2006.01) The invention relates to novel compounds and phar A6CO7D IK3I/695 303/2 (2006.01) maceuucaltical preparauonstions unereoI.thereof. TheiIne 1nvenuon tion furtherCaLS relat C07C 59/00 (2006.01) tof methodsthe i ofti treatment using the novel resolvin compounds C07F 7/02 (2006.01) O1V1O. C07F II/00 (2006.01) 19 Claims, 7 Drawing Sheets

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(56) References Cited Mexican Office Action dated Sep. 14, 2012 in related Mexican Patent Appl Serial No. MX/a/2011/010827 (With English Translation). U.S. PATENT DOCUMENTS New Zealand Examination Report dated Aug. 29, 2012 in related New Zealand Patent Appl Serial No. 596228. 5,731,000 A 3, 1998 Ruffet al. 5,763,493 A 6, 1998 Ruffet al. Billman, et al., “Prevention of Sudden Cardiac Death by Dietary Pure 6,110,973 A 8/2000 Young w-3 Polyunsaturated Fatty Acids in Dogs.” Circulation, (1999), RE37,314 E 8, 2001 Hirai et al. 99:2452-2457. 6,583,124 B2 6/2003 Asgharian Henkel-Hanke, et al., “Artificial oxygen carriers: a current review.” 2005, 0004074 A1 1/2005 Lyons et al. AANA.J. (2007), 75(3):205-211. 2005/OO31697 A1 2/2005 Vehige et al. Iigo, et al., “Inhibitory effects of on colon 2005/0059744 A1 3/2005 Donello et al. carcinoma 26 metastasis to the lung.” Br. J. Cancer, (1997), 2005, 0080056 A1 4, 2005 Horn 75(5):650-655. 2005/0228042 A1 10, 2005 Friswad et al. International Search Reportdated Jun. 29, 2010 in related PCT Appli 2005/0228047 A1* 10, 2005 Petasis ...... 514,560 cation Serial No. PCT/US2010/030813. 2009,0294347 A1 12, 2009 Wochele et al. Simopoulous, et al., “Workshop on the Essentiality of and Recom OTHER PUBLICATIONS mended Dietary Intakes for Omega-6 and Omega-3 Fatty Acids.” (1999), J. Am. Coll. Nutr., 18(5):487-489. European Search Report dated Jul. 26, 2012 in related European Patent Appl No. 10764985.7. * cited by examiner U.S. Patent Mar. 18, 2014 Sheet 1 of 7 US 8,673,881 B2

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(~~~~~~~~~~*~~~~~~~~~.~~~~~~~~~~~~~--~~~~~~~*~~~~~~~~~~4…--~~~~~~~~!···: US 8,673,881 B2 1. 2 COMPOSITIONS AND METHODS FOR THE SUMMARY OF INVENTION TREATMENT OF INFLAMMATION The present invention provides a compound of formula I, (I) RELATED APPLICATIONS Ri Rh ORe O This application claims the benefit of priority to U.S. Pro visional Patent Application No. 61/168,739, filed Apr. 13, 2009, and U.S. Provisional Patent Application No. 61/174, 806, filed May 1, 2009, which applications are hereby incor 10 porated by reference in their entirety. and pharmaceutically acceptable salts thereof, wherein: the stereochemistry of the carbon qq to carbon rr double bond is cis or trans; the stereochemistry of the carbon ss' to carbon tt'double bond 15 is cis or trans; BACKGROUND Re and Rfare independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl (e.g., alkoxyacyl, Supplementation of dietary omega-3 polyunsaturated fatty aminoacyl), aminocarbonyl, alkoxycarbonyl, or silyl; E is a branched alkoxy Such as isopropoxy, isobutoxy, sec acids (“c)-3 PUFAs) such as , a com butoxy, tert-butoxy, 3-methylbutoxy, 2,2-dimethylpro ponent of fish oils, may have beneficial effects in diseases poxy, or 1.1.2-trimethylpropoxy. Such as arteriosclerosis, , and cancer, which Rh and Ri are independently selected from hydrogen, alkyl, may be mediated by antithrombotic, immunoregulatory and alkenyl, alkynyl, perfluoroalkyl, aryl or heteroaryl; anti-inflammatory responses De Caterina, R. S. Endres, S. Rs is selected from i-iv as follows: i) CHCH(R)CH, where 25 R is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, D. Kristensen, and E. B. Schmidt, editors. (1993). n-3 Fatty aryl, heteroaryl, fluoro, hydroxyl or alkoxy; ii) CHC Acids and Vascular Disease. Springer-Verlag, London; (RR)CH2, where RandR, are each independently alkyl, Lands, W. E. M., editor. (1987). Proceedings of the AOCS alkenyl, alkynyl, perfluoroalkyl, aryl, or fluoro, or R and Short Course on Polyunsaturated Fatty Acids and R, are connected together to form a carbocyclic or hetero cyclic ring; iii) CHOCH, CHC(O)CH, or CHCH; or . American Oil Chemists’ Society, Champaign, 30 iv) Rs is a carbocyclic, heterocyclic, aryl or heteroaryl ring; Ill.: Iigo, M. et al. (1997) Br. J. Cancer 75:650. The potential and of c)-3 PUFAs for preventative actions in cardiovascular dis Rs and Ro are independently selected from hydrogen, alkyl, eases was recently supported by the finding that major dietary alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or heteroaryl, c)-3 PUFAs, such as eicosapentaenoic acid (C20:5 co-3; EPA) 35 or Rs and Ro are connected together to form a carbocyclic or heterocyclic ring. and docosahexaenoic acid (C22:6 co-3; DHA), have a dra In certain embodiments, a compound of formula I is rep matic effect on ischemia-induced ventricular fibrillation resented by formula II, Billman, G. E. et al. (1999) Circulation. 99:2452. Emer gence of Such possible preventative and/or therapeutic 40 actions of c)-3 PUFA supplementation in infant nutrition, (II) cardiovascular diseases, and mental health has led to a call for recommended dietary intakes by an international workshop Simopoulous, A. P. et al. (1999).J. Am. Coll. Nutr. 18:487. The Gruppo Italiano per lo Studio della Sopravvivense nell 45 Infarto Miocardio (GISSI) Prevenzione trial evaluated the effects of c)-3 PUFA supplementation with 11,300 patients and pharmaceutically acceptable salts thereof, wherein: surviving myocardial infarction taking ~1 g of c)-3 PUFA the stereochemistry of the carbon qq to carbon rr double daily (n=2,836) along with recommended preventive treat 50 bond is cis or trans; ments including , and reported a significant benefit the stereochemistry of the carbon ss' to carbon tt'double bond with a decrease in cardiovascular death Marchioloi, R. et al. is cis or trans; (1999). Lancet. 354:447. However, the mechanisms under Re, Rf, Rs, and E are as defined above. lying the protective action of dietary (D-3 PUFAs in these In certain embodiments, a compound of formula I or II is 55 represented by formula III, studies and other studies including those concerned with dis eases of the skin, bowel, and neural tissues are not currently understood. One of the many hypothesized elements of the (III) mechanism(s) of action of c)-3 PUFAs is that naturally occur ORf ORe O ring metabolites, formed from these PUFAs, may act as 60 mediators that provide important biological functions, but these metabolites may have relatively short half-lives in vivo. There remains a need for new analogues which may have greater in vivo stability than naturally occurring ()-3 PUFA 65 metabolites for settings where a longer half-life may be and pharmaceutically acceptable salts thereof, wherein: advantageous. Re, Rf, and E are as defined above. US 8,673,881 B2 3 4 In certain embodiments, the present invention provides a Re and Rfare independently selected from hydrogen, alkyl, pharmaceutical preparation Suitable for use in a human alkenyl, alkynyl, aryl, heteroaryl, acyl (e.g., alkoxyacyl, patient, comprising an effective amount of any of the com aminoacyl), aminocarbonyl, alkoxycarbonyl, or silyl, pref pounds shown above (e.g., a compound of the invention, Such erably from hydrogen, acyl (e.g., alkoxyacyl, aminoacyl), as a compound of any of formulae I-III), and one or more aminocarbonyl, and alkoxycarbonyl, most preferably pharmaceutically acceptable excipients. In certain embodi hydrogen; ments, the pharmaceutical preparations may be for use in E is a branched alkoxy Such as isopropoxy, isobutoxy, sec treating or preventing a condition or disease as described butoxy, tert-butoxy, 3-methylbutoxy, 2,2-dimethylpro herein. In certain embodiments, the pharmaceutical prepara poxy, or 1.1.2-trimethylpropoxy, preferably isopropoxy. tions have a low enough pyrogen activity to be suitable for 10 Rh and Ri are independently selected from hydrogen, alkyl, intravenous use in a human patient. alkenyl, alkynyl, perfluoroalkyl, aryl or heteroaryl, prefer The present invention further provides methods of treating ably hydrogen or alkyl, most preferably hydrogen; or preventing bone metabolism, mucositis, cardiovascular Rs is selected from i-iv as follows: i) CHCH(R)CH, where disease, inflammatory diseases, metabolic diseases, oph 15 R is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, thalmic conditions, immune function, pulmonary conditions, aryl, heteroaryl, fluoro, hydroxyl or alkoxy; ii) CHC gastrointestinal conditions, rheumatological conditions, der (RR)CH2, where RandR, are each independently alkyl, matological conditions, neurological conditions, cancer, alkenyl, alkynyl, perfluoroalkyl, aryl, or fluoro, or R and infectious conditions, degenerative conditions, gerontologi R, are connected together to form a carbocyclic or hetero cal conditions, and apoptotic conditions, reducing, prevent cyclic ring; iii) CHOCH, CHC(O)CH, CH, or ing or reversing organ damage, reducing and/or preventing CHCH, or iv) Rs is a carbocyclic, heterocyclic, aryl or stem cell damage and/or death, enhancing organ preservation heteroaryl ring, preferably (CH2); and and/or Survival, or enhancing stem cell preservation and/or Rs and Ro are independently selected from hydrogen, alkyl, Survival, as described herein, comprising administering a alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or heteroaryl, compound of the invention. 25 or Rs and Ro are connected together to form a carbocyclic or heterocyclic ring, preferably from hydrogen and alkyl, DETAILED DESCRIPTION OF THE DRAWINGS most preferably hydrogen. For example, the present invention provides a compound of FIG. 1 shows that comparable levels of compound 1003 formula Ia, were observed in the aqueous humor (FIG.1a), the vitreous 30 (FIG. 1b), and the (FIG. 1c) upon topical ocular administration of compounds 1001 and 1002 to rabbits. (Ia) FIG. 2 shows data from measurements of ocular discom Ro ORf Rh ORe 2 fort on day 28 of a human dry eye study after topical admin istration of vehicle or compound 1001 at dose A, B, or C. 35 Rs 21N 21 E Rsul E, FIG. 3 shows data from measurements of ocular discom fort on day 29 (approximately one day after last treatment) of a human dry eye study after topical administration of vehicle or compound 1001 at dose A, B, or C. FIG. 4 shows measurements of grittiness and dryness on 40 and pharmaceutically acceptable salts thereof, wherein: day 28 of a human dry eye study after topical administration Re and Rfare independently selected from hydrogen, alkyl, of vehicle or compound 1001 at dose A, B, or C. alkenyl, alkynyl, aryl, heteroaryl, acyl (e.g., alkoxyacyl, FIG.5 shows the "H NMR spectrum for compound 1001 in aminoacyl), aminocarbonyl, alkoxycarbonyl, or silyl, pref CDC1. erably from hydrogen, acyl (e.g., alkoxyacyl, aminoacyl), FIG. 6 shows the "H NMR spectrum for compound 1002 in 45 aminocarbonyl, and alkoxycarbonyl, most preferably CDC1. hydrogen; FIG. 7 shows the "H NMR spectrum for compound Z in E is a branched alkoxy Such as isopropoxy, isobutoxy, sec D.O. butoxy, tert-butoxy, 3-methylbutoxy, 2,2-dimethylpro poxy, or 1.1.2-trimethylpropoxy, preferably isopropoxy. DETAILED DESCRIPTION OF THE INVENTION 50 Rh and Ri are independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or heteroaryl, prefer The present invention provides a compound of formula I, ably hydrogen or alkyl, most preferably hydrogen; Rs is selected from i-iv as follows: i) CHCH(R)CH, where 55 R is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, (I) aryl, heteroaryl, fluoro, hydroxyl or alkoxy; ii) CHC (RR)CH2, where RandR, are each independently alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, or fluoro, or R and R, are connected together to form a carbocyclic or hetero 60 cyclic ring; iii) CHOCH, CHC(O)CH, CH, or CHCH, or iv) Rs is a carbocyclic, heterocyclic, aryl or heteroaryl ring, preferably (CH2); and and pharmaceutically acceptable salts thereof, wherein: Rs and R are independently selected from hydrogen, alkyl, the stereochemistry of the carbon qq to carbon rr double alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or heteroaryl, bond is cis or trans; 65 or Rs and Ro are connected together to form a carbocyclic the stereochemistry of the carbon ss' to carbon tt'double bond or heterocyclic ring, preferably from hydrogen and alkyl, is cis or trans; most preferably hydrogen. US 8,673,881 B2 5 6 In certain preferred embodiments of formula Ia, the stere Exemplary compounds of formulae I, II, and III include ochemistry of the carbons bearing —ORf and —ORe are as compound 1001 shown in formula Ia',

1001

OH OH O

OiPr, 10

and pharmaceutically acceptable salts thereof. In certain embodiments, a compound of formula I is rep In certain embodiments, the present invention provides a resented by formula II, 15 pharmaceutical preparation Suitable for use in a human patient, comprising an effective amount of any of the com pounds shown above (e.g., a compound of the invention, such as a compound of any of formulae I-III), and one or more (II) pharmaceutically acceptable excipients. In certain embodi ments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical prepara tions have a low enough pyrogenactivity to be suitable for use in a human patient. Compounds of any of the above structures may be used in 25 the manufacture of medicaments for the treatment of any and pharmaceutically acceptable salts thereof, wherein: diseases or conditions disclosed herein. the stereochemistry of the carbon qq to carbon rr double Bone Metabolism bond is cis or trans; The present invention provides methods of treating or pre the stereochemistry of the carbon ss' to carbon tt'double bond venting bone loss in a patient comprising administering a 30 compound of the invention. In certain embodiments, condi is cis or trans; tions with which the bone loss is associated include, for Re, Rf, Rs, and E are as defined above. example, but are not limited to any one or more of ankylosing For example, the present invention provides a compound of spondylitis, renal osteodystrophy (e.g., in patients undergo formula IIa, ing dialysis), osteoporosis, glucocorticoid-induced 35 osteoporosis, Paget’s disease, abnormally increased bone turnover, periodontitis, , bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, (IIa) osteogenesis imperfecta, metastatic bone disease, hypercal ORf cemia of malignancy, multiple myeloma, bone loss associ ated with microgravity, Langerhan's Cell Histiocytosis 41\4N- Rg E, 40 (LHC), bone loss associated with renal tubular disorders, or bone loss associated with bed-ridden conditions. The present invention provides a method of treating or preventing osteoporosis in a patient comprising administer ing a compound of the invention. In certain embodiments, the and pharmaceutically acceptable salts thereof, wherein: 45 osteoporosis is medicine-induced osteoporosis. In certain Re, Rf, Rs, and E are as defined above. embodiments, the medicine-induced osteoporosis is gluco corticoid-induced osteoporosis. In certain embodiments, a compound of formula I or II is The present invention provides a method of treating or represented by formula III, preventing diabetic osteopenia in a patient comprising admin 50 istering a compound of the invention. The present invention provides a method of treating or (III) preventing metastatic bone disease in a patient comprising ORf ORe administering a compound of the invention. The present invention provides a method of decreasing the incidence of 55 bone metastasis in a patient comprising administering a com pound of the invention. The present invention further pro vides a method of delaying the onset of bone metastasis in a patient comprising administering a compound of the inven and pharmaceutically acceptable salts thereof, wherein: tion. In certain embodiments, a compound of the invention is 60 administered conjointly with chemotherapy or radiation Re, Rf, and E are as defined above. therapy. In certain embodiments of Formulae I-III, E represents The present invention provides a method of treating or O—R, where R represents an alkyl group, preferably a lower preventing periodontitis in a patient comprising administer alkyl group, that is branched at the position bonded to the ing a compound of the invention. oxygen atom. Exemplary Such R moieties include —CH 65 The present invention provides a method of treating or (CH) (isopropyl), —CH(CHCH), —CH(CH) preventing in a patient comprising administering a (CHCH) (sec-butyl), and —C(CH) (tert-butyl). compound of the invention. US 8,673,881 B2 7 8 The present invention provides a method of treating or teniposide, testosterone, thioguanine, thiotepa, titanocene preventing ankylosing spondylitis in a patient comprising dichloride, topotecan, trastuzumab, tretinoin, vinblastine, administering a compound of the invention. Vincristine, vindesine, and vinorelbine. The present invention provides a method of treating or Many combination therapies have been developed for the preventing renal osteodystrophy (e.g., in patients undergoing treatment of cancer. In certain embodiments, compounds of dialysis) in a patient comprising administering a compound the invention may be conjointly administered with a combi of the invention. nation therapy. Examples of combination therapies with In one embodiment, the method of treating or preventing which compounds of the invention may be conjointly admin bone loss may comprise administering a compound of the istered are included in Table 1. invention conjointly with an additional agent useful in the 10 treatment of bone loss. In certain embodiments, the com TABLE 1 pound of the invention may be conjointly administered with a bisphosphonate (e.g., ibandronate, Zolendronate, risedronate, Exemplary combinatorial therapies for the treatment of cancer. etidronate, or alendronate), a steroid, Such as an anabolic Name Therapeutic agents steroid (e.g., testosterone, quinbolone, oxymetholone, nan 15 ABV Doxorubicin, Bleomycin, Vinblastine drolone hexylphenylpropionate, Oxandrolone, testosterone ABVD Doxorubicin, Bleomycin, Vinblastine, Dacarbazine undecanoate, mibolerone, danozol, nandrolone decanoate, AC (Breast) Doxorubicin, Cyclophosphamide trenbolone cyclohexylmethylcarbonate, methenolone AC (Sarcoma) Doxorubicin, Cisplatin acetate, methenolone enanthate, mesterolone, dihydrotest AC Cyclophosphamide, Doxorubicin (Neuroblastoma) osterone, methandrostenolone, nandrolone undecanoate, ACE Cyclophosphamide, Doxorubicin, Etoposide boldenone undecylenate, formebolone, trenbolone acetate, ACe Cyclophosphamide, Doxorubicin fluoxymesterone, nandrolone laureate, drostanolone propi AD Doxorubicin, Dacarbazine AP Doxorubicin, Cisplatin onate, clostebol acetate, trestolone acetate, methandriol ARAC-DNR Cytarabine, Daunorubicin dipropionate, methyltestosterone, furazabol, bolasterone, B-CAWe Bleomycin, Lomustine, Doxorubicin, Vinblastine norethandrolone, mepitioStane, tetrahydrogestrinone, tren 25 BCVPP Carmustine, Cyclophosphamide, Vinblastine, bolone enanthate, and stanozolol), an estrogen (e.g., estra Procarbazine, Prednisone diol, estriol, estrone, equilin, or equilenin), a Substance hav BEACOPP Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, ing estrogenic activity (e.g., Xenoestrogens, phytoestrogens, Prednisone, Filgrastim or mycoestrogens), a selective estrogen BEP Bleomycin, Etoposide, Cisplatin (e.g., raloxifene), or treatment (e.g., calcitonin or 30 BIP Bleomycin, Cisplatin, Ifosfamide, Mesna BOMP Bleomycin, Vincristine, Cisplatin, Mitomycin teriparitide). In certain embodiments, the compound of the CA Cytarabine, Asparaginase invention may be conjointly administered with growth factors CABO Cisplatin, Methotrexate, Bleomycin, Vincristine or other therapeutic agents that have a positive effect on the CAF Cyclophosphamide, Doxorubicin, Fluorouracil growth of bone or connective tissue. Such as osteoprotegerin, CAL-G Cyclophosphamide, Daunorubicin, Vincristine, interleukins, MMP inhibitors, beta glucans, integrin antago 35 Prednisone, Asparaginase CAMP Cyclophosphamide, Doxorubicin, Methotrexate, nists, calcitonin, proton pump inhibitors, protease inhibitors, Procarbazine insulin-like growth factor-1, -derived growth factor, CAP Cyclophosphamide, Doxorubicin, Cisplatin epidermal growth factor, inhibitors of transforming growth CaT Carboplatin, Paclitaxel factor-alpha, transforming growth factor-beta, bone morpho CAV Cyclophosphamide, Doxorubicin, Vincristine CAVE ADD CAV and Etoposide genetic protein, parathyroid hormone, osteoprotegerin, a 40 CA-VP16 Cyclophosphamide, Doxorubicin, Etoposide growth factor, Vitamin D, vitronectin, plasmino CC Cyclophosphamide, Carboplatin gen-activator inhibitor, or a protease inhibitor Such as a met CDDP VP-16 Cisplatin, Etoposide CEF Cyclophosphamide, Epirubicin, Fluorouracil alloprotease inhibitor, or elements known to be beneficial to CEPP(B) Cyclophosphamide, Etoposide, Prednisone, with or bone formation, such as calcium, fluoride, magnesium, without Bleomycin boron, or a combination thereof. 45 CEV Cyclophosphamide, Etoposide, Vincristine In one embodiment, the method of treating or preventing CF Cisplatin, Fluorouracil or Carboplatin Fluorouracil metastatic bone disease may comprise administering a com CHAP Cyclophosphamide or Cyclophosphamide, Altretamine, Doxorubicin, Cisplatin pound of the invention conjointly with a chemotherapeutic ChIVPP Chlorambucil, Vinblastine, Procarbazine, Prednisone agent. Chemotherapeutic agents that may be conjointly CHOP Cyclophosphamide, Doxorubicin, Vincristine, administered with compounds of the invention include: ami 50 Prednisone noglutethimide, amsacrine, anastroZole, asparaginase, bcg, CHOP-BLEO Add Bleomycin to CHOP CISCA Cyclophosphamide, Doxorubicin, Cisplatin bicalutamide, bleomycin, buserelin, buSulfan, campothecin, CLD-BOMP Bleomycin, Cisplatin, Vincristine, Mitomycin capecitabine, carboplatin, carmustine, chlorambucil, cispl CMF Methotrexate, Fluorouracil, Cyclophosphamide atin, cladribine, clodronate, colchicine, cyclophosphamide, CMFP Cyclophosphamide, Methotrexate, Fluorouracil, cyproterone, cytarabine, dacarbazine, dactinomycin, dauno 55 Prednisone CMFVP Cyclophosphamide, Methotrexate, Fluorouracil, rubicin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, Vincristine, Prednisone epirubicin, estradiol, estramustine, etoposide, exemestane, CMV Cisplatin, Methotrexate, Vinblastine filgrastim, fludarabine, fludrocortisone, fluorouracil, flu CNF Cyclophosphamide, Mitoxantrone, Fluorouracil oxymesterone, , gemcitabine, genistein, goserelin, CNOP Cyclophosphamide, Mitoxantrone, Vincristine, Prednisone hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, 60 COB Cisplatin, Vincristine, Bleomycin irinotecan, ironotecan, letrozole, leucovorin, leuprolide, CODE Cisplatin, Vincristine, Doxorubicin, Etoposide levamisole, lomustine, mechlorethamine, medroxyprogester COMLA Cyclophosphamide, Vincristine, Methotrexate, one, megestrol, melphalan, mercaptopurine, mesna, methotr Leucovorin, Cytarabine COMP Cyclophosphamide, Vincristine, Methotrexate, exate, mitomycin, mitotane, mitoxantrone, nilutamide, Prednisone nocodazole, octreotide, Oxaliplatin, paclitaxel, pamidronate, 65 Cooper Regimen Cyclophosphamide, Methotrexate, Fluorouracil, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, Vincristine, Prednisone rituximab, Streptozocin, Suramin, tamoxifen, temozolomide, US 8,673,881 B2 9 10 TABLE 1-continued TABLE 1-continued Exemplary combinatorial therapies for the treatment of cancer. Exemplary combinatorial therapies for the treatment of cancer. Name Therapeutic agents Name Therapeutic agents COP Cyclophosphamide, Vincristine, Prednisone MP (prostate Mitoxantrone, Prednisone COPE Cyclophosphamide, Vincristine, Cisplatin, Etoposide cancer) COPP Cyclophosphamide, Vincristine, Procarbazine, MTXF6-MO Methotrexate, Mercaptopurine Prednisone MTX6-MPVP Methotrexate, Mercaptopurine, Vincristine, Prednisone CP(Chronic Chlorambucil, Prednisone MTX-CDDPAdr Methotrexate, Leucovorin, Cisplatin, Doxorubicin lymphocytic 10 MV (breast Mitomycin, Vinblastine leukemia) cancer) CP (Ovarian Cyclophosphamide, Cisplatin MV (acute Mitoxantrone, Etoposide Cancer) myelocytic CT Cisplatin, Paclitaxel leukemia) CVD Cisplatin, Vinblastine, Dacarbazine M-VAC Vinblastine, Doxorubicin, Cisplatin CV Carboplatin, Etoposide, Ifosfamide, Mesna 15 Methotrexate CVP Cyclophosphamide, Vincristine, Prednisome MVP Mitomycin Vinblastine, Cisplatin CVPP Lomustine, Procarbazine, Prednisone MVPP Mechlorethamine, Vinblastine, Procarbazine, CYVADIC Cyclophosphamide, Vincristine, Doxorubicin, Prednisone Dacarbazine NFL Mitoxantrone, Fluorouracil, Leucovorin DA Daunorubicin, Cytarabine NOVP Mitoxantrone, Vinblastine, Vincristine DAT Daunorubicin, Cytarabine, Thioguanine OPA Vincristine, Prednisone, Doxorubicin DAV Daunorubicin, Cytarabine, Etoposide OPPA Add Procarbazine to OPA. DCT Daunorubicin, Cytarabine, Thioguanine PAC Cisplatin, Doxorubicin DHAP Cisplatin, Cytarabine, Dexamethasone PAC-I Cisplatin, Doxorubicin, Cyclophosphamide DI Doxorubicin, Ifosfamide PA-CI Cisplatin, Doxorubicin DTICFTamoxifen Dacarbazine, Tamoxifen PC Paclitaxel, Carboplatin or Paclitaxel, Cisplatin DVP Daunorubicin, Vincristine, Prednisone PCV Lomustine, Procarbazine, Vincristine EAP Etoposide, Doxorubicin, Cisplatin 25 PE Paclitaxel, Estramustine EC Etoposide, Carboplatin PFL Cisplatin, Fluorouracil, Leucovorin EFP Etoposie, Fluorouracil, Cisplatin POC Prednisone, Vincristine, Lomustine ELF Etoposide, Leucovorin, Fluorouracil ProMACE Prednisone, Methotrexate, Leucovorin, Doxorubicin, EMA 86 Mitoxantrone, Etoposide, Cytarabine Cyclophosphamide, Etoposide EP Etoposide, Cisplatin ProMACE Prednisone, Doxorubicin, Cyclophosphamide, EVA Etoposide, Vinblastine 30 cytaBOM Etoposide, Cytarabine, Bleomycin, Vincristine, FAC Fluorouracil, Doxorubicin, Cyclophosphamide Methotrexate, Leucovorin, Cotrimoxazole FAM Fluorouracil, Doxorubicin, Mitomycin PROMACE Prednisone, Doxorubicin, Cyclophosphamide, FAMTX Methotrexate, Leucovorin, Doxorubicin MOPP Etoposide, Mechlorethamine, Vincristine, FAP Fluorouracil, Doxorubicin, Cisplatin Procarbazine, Methotrexate, Leucovorin F-CL, Fluorouracil, Leucovorin Cisplatin, Teniposide FEC Fluorouracil, Cyclophosphamide, Epirubicin 35 Prednisone, Vincristine, Asparaginase FED Fluorouracil, Etoposide, Cisplatin Cisplatin, Vinblastine, Bleomycin FL Flutamide, Leuprolide Prednisone, Vincristine, Daunorubicin, Asparaginase FZ Flutamide, Goserelin acetate implant Streptozocin, Mitomycin, Fluorouracil HDMTX Methotrexate, Leucovorin Mechlorethamine, Doxorubicin, Vinblastine, Hexa-CAF Altretamine, Cyclophosphamide, Methotrexate, Vincristine, Bleomycin, Etoposide, Prednisone Fluorouracil TCF Paclitaxel, Cisplatin, Fluorouracil CE-T fosfamide, Carboplatin, Etoposide, Paclitaxel, Mesna 40 TIP Paclitaxel, Ifosfamide, Mesna, Cisplatin DMTXF6-MP Methotrexate, Mercaptopurine, Leucovorin TTT Methotrexate, Cytarabine, Hydrocortisone E fosfamide, Etoposie, Mesna Topo/CTX Cyclophosphamide, Topotecan, Mesna foVP fosfamide, Etoposide, Mesna VAB-6 Cyclophosphamide, Dactinomycin, Vinblastine, PA fosfamide, Cisplatin, Doxorubicin Cisplatin, Bleomycin M-2 Vincristine, Carmustine, Cyclophosphamide, WAC Vincristine, Dactinomycin, Cyclophosphamide Prednisone, Melphalan 45 WACAdr Vincristine, Cyclophosphamide, Doxorubicin, MAC-III Methotrexate, Leucovorin, Dactinomycin, Dactinomycin, Vincristine Cyclophosphamide WAD Vincristine, Doxorubicin, Dexamethasone MACC Methotrexate, Doxorubicin, Cyclophosphamide, WATH Vinblastine, Doxorubicin, Thiotepa, Flouxymesterone Lomustine WBAP Vincristine, Carmustine, Doxorubicin, Prednisone MACOP-B Methotrexate, Leucovorin, Doxorubicin, VBCMP Vincristine, Carmustine, Melphalan, Cyclophosphamide, Vincristine, Bleomycin, 50 Cyclophosphamide, Prednisone Prednisone VC Vinorelbine, Cisplatin MAID Mesna, Doxorubicin, Ifosfamide, Dacarbazine VCAP Vincristine, Cyclophosphamide, Doxorubicin, m-BACOD Bleomycin, Doxorubicin, Cyclophosphamide, Prednisone Vincristine, Dexamethasone, Methotrexate, VD Vinorelbine, Doxorubicin Leucovorin WeIP Vinblastine, Cisplatin, Ifosfamide, Mesna MBC Methotrexate, Bleomycin, Cisplatin 55 VIP Etoposide, Cisplatin, Ifosfamide, Mesna MC Mitoxantrone, Cytarabine VM Mitomycin, Vinblastine MF Methotrexate, Fluorouracil, Leucovorin VMCP Vincristine, Melphalan, Cyclophosphamide, MICE fosfamide, Carboplatin, Etoposide, Mesna Prednisone MINE Mesna, Ifosfamide, Mitoxantrone, Etoposide VP Etoposide, Cisplatin mini-BEAM Carmustine, Etoposide, Cytarabine, Melphalan WTAD Etoposide, Thioguanine, Daunorubicin, Cytarabine MOBP Bleomycin, Vincristine, Cisplatin, Mitomycin 5 - 2 Cytarabine, Daunorubicin, Mitoxantrone MOP Mechlorethamine, Vincristine, Procarbazine 60 7 - 3 Cytarabine with?, Daunorubicin or Idarubicin or MOPP Mechlorethamine, Vincristine, Procarbazine, Mitoxantrone Prednisone 8 in 1 Methylprednisolone, Vincristine, Lomustine, MOPPABV Mechlorethamine, Vincristine, Procarbazine, Hydroxyurea, Cisplatin, Cytarabine, Procarbazine, Dacarbazine Prednisone, Doxorubicin, Bleomycin, Vinblastine MP (multiple Melphalan, Prednisone 65 myeloma) In certain embodiments, a compound of the invention may be conjointly administered with non-chemical methods of US 8,673,881 B2 11 12 cancer treatment. In certain embodiments, a compound of the The present invention provides a kit comprising: invention may be conjointly administered with radiation a) a first pharmaceutical formulation (e.g., one or more therapy. In certain embodiments, a compound of the inven single dosage forms) comprising a chemotherapeutic tion may be conjointly administered with Surgery, with ther agent as mentioned above; and moablation, with focused ultrasound therapy, or with cryo- 5 b) instructions for the administration of the first pharma therapy. ceutical formulation with a compound of the invention In certain embodiments, different compounds of the inven for treating or preventing bone loss, treating or inhibit tion may be conjointly administered with one or more other ing the development of osteoporosis, treating or inhib compounds of the invention. Moreover, Such combinations iting the development of periodontitis, treating or inhib may be conjointly administered with other therapeutic 10 agents, such as other agents suitable for the treatment of a iting the development of metastatic bone disease, bone metabolism condition, Such as the agents identified decreasing the incidence of bone metastasis, or delaying above. the onset of bone metastasis. In certain embodiments, the present invention provides a Mucositis kit comprising: a) one or more single dosage forms of a 15 The present invention provides a method of treating or compound of the invention; b) one or more single dosage preventing mucositis comprising administering a compound forms of a chemotherapeutic agent as mentioned above; and of the invention. Mucositis, for the purposes of this applica c) instructions for the administration of the compound of the tion, refers to mucosal injury induced by or associated with invention and the chemotherapeutic agent. the administration of radiation or drugs (chemotherapy) for The present invention provides a kit comprising: 2O the treatment of cancer and related diseases. Mucositis typi a) a pharmaceutical formulation (e.g., one or more single cally manifests itself as ulcerations, tissue necrosis, and atro dosage forms) comprising a compound of the invention; phy of the mucous membranes anywhere along the digestive and tract, from the mouth to the anus. For example, the present b) instructions for the administration of the pharmaceutical methods may be used to treat ulcerations and tissue necrosis formulation, e.g., for treating or preventing any of the 25 associated with radiation therapy and/or chemotherapy. conditions discussed above, e.g., bone loss. The present invention provides a method of preventing the In certain embodiments, the kit further comprises instruc development of chemotherapy or radiation therapy-induced tions for the administration of the pharmaceutical formula mucositis comprising administering a compound of the tion comprising a compound of the invention conjointly with invention. In certain embodiments, a compound of the inven an agent Suitable for the treatment or prevention of bone loss 30 tion is administered conjointly with chemotherapy or radia (e.g., a bisphosphonate) as mentioned above. In certain tion therapy. embodiments, the kit further comprises a second pharmaceu The present invention provides a method of improving tical formulation (e.g., as one or more single dosage forms) Survival rates by reducing the incidence of therapy-induced comprising an agent Suitable for the treatment or prevention mucositis comprising administering a compound of the of bone loss (e.g., a bisphosphonate) as mentioned above. 35 invention. The rate of life-threatening severe mucositis, grade The present invention provides a kit comprising: 4 on WHO scale, would be expected to be reduced from an a) a pharmaceutical formulation (e.g., one or more single average incidence of 60% in untreated patients, to 20% or less dosage forms) comprising a compound of the invention; in patents receiving a subject treatment. and In one embodiment, the method of treating or preventing b) instructions for the administration of the pharmaceutical 40 mucositis may comprise administering a compound of the formulation for treating or inhibiting the development of invention conjointly with an additional agent useful in the osteoporosis, treating or inhibiting the development of treatment of mucositis. In certain embodiments, the com periodontitis, treating or inhibiting the development of pound of the invention may be conjointly administered with metastatic bone disease, decreasing the incidence of an antimicrobial agent. In certain embodiments, the com bone metastasis, or delaying the onset of bone metasta 45 pound of the invention may be conjointly administered with a S1S. growth factor. In certain embodiments, the compound of the In certain embodiments, the kit further comprises instruc invention may be conjointly administered with an agent that tions for the administration of the pharmaceutical formula inhibits the synthesis of ceramide, an agent that blocks the tion comprising a compound of the invention conjointly with activity of ceramide, or an agent that degrades ceramide. a chemotherapeutic agent as mentioned above. In certain 50 In one embodiment, the method of treating or preventing embodiments, the kit further comprises a second pharmaceu mucositis may comprise administering a compound of the tical formulation (e.g., as one or more single dosage forms) invention conjointly with a chemotherapeutic agent. Chemo comprising a chemotherapeutic agent as mentioned above. therapeutic agents that may be conjointly administered with The present invention provides a kit comprising: compounds of the invention include any Suitable chemothera a) a first pharmaceutical formulation (e.g., one or more 55 peutic agent or combination therapy as set forth above. single dosage forms) comprising an agent Suitable for In certain embodiments, different compounds of the inven the treatment or prevention of bone loss (e.g., a bispho tion may be conjointly administered with one or more other sphonate) as mentioned above; and compounds of the invention. Moreover, Such combinations b) instructions for the administration of the first pharma may be conjointly administered with other therapeutic ceutical formulation and a second pharmaceutical for 60 agents, such as other agents suitable for the treatment or mulation comprising a compound of the invention for prevention of mucositis, Such as the agents identified above. treating or preventing bone loss, treating or inhibiting In certain embodiments, the present invention provides a the development of osteoporosis, treating or inhibiting kit comprising: a) one or more single dosage forms of a the development of periodontitis, treating or inhibiting compound of the invention; b) one or more single dosage the development of metastatic bone disease, decreasing 65 forms of a chemotherapeutic agent as mentioned above; and the incidence of bone metastasis, or delaying the onset of c) instructions for the administration of the compound of the bone metastasis. invention and the chemotherapeutic agent. US 8,673,881 B2 13 14 The present invention provides a kit comprising: disorders of the heart muscle (cardiomyopathy or myocardi a) a pharmaceutical formulation (e.g., one or more single tis) such as idiopathic cardiomyopathy, metabolic cardiomy dosage forms) comprising a compound of the invention; opathy which includes diabetic cardiomyopathy, alcoholic and cardiomyopathy, drug-induced cardiomyopathy, ischemic b) instructions for the administration of the pharmaceutical cardiomyopathy, and hypertensive cardiomyopathy; formulation e.g., for treating or preventing mucositis, atheromatous disorders of the major blood vessels (mac preventing the development of chemotherapy or radia rovascular disease) Such as the aorta, the coronary arteries, tion therapy-induced mucositis, or improving Survival the carotid arteries, the cerebrovascular arteries, the renal rates by reducing the incidence of therapy-induced arteries, the iliac arteries, the femoral arteries, and the mucositis. 10 popliteal arteries; In certain embodiments, the kit further comprises instruc toxic, drug-induced, and metabolic (including, but not limited tions for the administration of the pharmaceutical formula to, hypertensive and/or diabetic) disorders of small blood tion comprising a compound of the invention conjointly with vessels (microvascular disease) Such as the retinal arterioles, an agent Suitable for the treatment or prevention of mucositis 15 the glomerular arterioles, the Vasa nervorum, cardiac arteri (e.g., an antimicrobial agent, a growth factor, an agent that oles, and associated capillary beds of the eye, the , the inhibits the synthesis of ceramide, an agent that blocks the heart, and the central and peripheral nervous systems; and, activity of ceramide, or an agent that degrades ceramide) as plaque rupture of atheromatous lesions of major blood ves mentioned above. In certain embodiments, the kit further sels such as the aorta, the coronary arteries, the carotid arter comprises a second pharmaceutical formulation (e.g., as one ies, the cerebrovascular arteries, the renal arteries, the iliac or more single dosage forms) comprising an agent Suitable for arteries, the fermoral arteries and the popliteal arteries. the treatment of mucositis (e.g., an antimicrobial agent, a Yet other disorders that may be treated with compounds of growth factor, an agent that inhibits the synthesis of ceramide, the invention include restenosis, e.g., following coronary an agent that blocks the activity of ceramide, or an agent that intervention, and disorders relating to an abnormal level of degrades ceramide) as mentioned above. 25 high density and low density cholesterol. In certain embodiments, the kit further comprises instruc In certain embodiments, the present invention provides tions for the administration of the pharmaceutical formula methods of treating a vascular disease or disorder. In certain tion comprising a compound of the invention conjointly with embodiments, the vascular disorder may include any vascular a chemotherapeutic agent as mentioned above. In certain disease or disorder which comprises an autoimmune element, embodiments, the kit further comprises a second pharmaceu 30 tical formulation (e.g., as one or more single dosage forms) for example one which is caused by an autoimmune response. comprising a chemotherapeutic agent as mentioned above. Exemplary vascular disorders include one or more of The present invention provides a kit comprising: Raynaud's disease and phenomenon, anterior uveitis, vascu a) a first pharmaceutical formulation (e.g., one or more litis, obliterative vascular disorder, atheroma formation, arte single dosage forms) comprising an agent Suitable for 35 riosclerosis, arteritis (e.g., Takayasu arteritis, temporal arteri the treatment or prevention of mucositis (e.g., an anti tis/giant cell arteritis), myointimal hyperplasia (natural or microbial agent, a growth factor, an agent that inhibits following angioplasty), inflammatory and autoimmune thick the synthesis of ceramide, an agent that blocks the activ ening of the intima and/or muscular layer of blood vessels, ity of ceramide, or an agent that degrades ceramide) as inflammatory blood vessel lesions, atherosclerotic heart dis mentioned above; and 40 ease, reperfusion injury, cardiac conduction disturbances, b) instructions for the administration of the first pharma myocarditis, and myocardial infarction. ceutical formulation with a compound of the invention, In certain embodiments, the present invention provides a e.g., for treating or preventing mucositis, preventing the method of treating or preventing heart attack or dysrhythmia development of chemotherapy or radiation therapy-in in a patient comprising administering to said patient a com duced mucositis, or improving Survival rates by reduc 45 pound of the invention. In certain embodiments, the present ing the incidence of therapy-induced mucositis. invention provides a method of preventing cardiac death in a The present invention provides a kit comprising: patient comprising administering to said patient a compound a) a first pharmaceutical formulation (e.g., one or more of the invention. In certain embodiments, the method com single dosage forms) comprising a chemotherapeutic prises optional conjoint administration with a statin. agent as mentioned above; and 50 Compounds of the invention are capable of resolving b) instructions for the administration of the first pharma inflammation. Several aspects of cardiovascular disease, in ceutical formulation with a compound of the invention, particular the formation of atherosclerotic vessel wall e.g., for treating or preventing mucositis, preventing the plaques, are believed to be intimately related to inflammation. development of chemotherapy or radiation therapy-in Today it is believed that serum markers of inflammation such duced mucositis, or improving Survival rates by reduc 55 as CRP may be as predictive of risk of cardiovascular disease ing the incidence of therapy-induced mucositis. as elevated levels of LDL. Thus, compounds of the invention Cardiovascular Disease are useful in treating or preventing cardiovascular disease. In The present invention provides a method of treating or certain embodiments, compounds of the invention are useful preventing cardiovascular disease in a patient comprising for the treatment or prevention of arterial inflammation and/or administering to said patient a compound of the invention. In 60 artherosclerosis. certain embodiments, the method comprises optional con Another mechanism by which compounds of the invention joint administration with a statin. may be effective in treating or preventing cardiovascular dis Cardiovascular disease refers to one or more disease States ease is by inhibiting the structural and functional modifica of the cardiovascular tree (including the heart). Diseases of tions of HDL that are an immediate effect of the acute phase the cardiovascular tree and diseases of dependent organs 65 response commonly seen in cardiovascular disease with include, for example, but are not limited to any one or more active atherosclerotic vessel wall plaques. Thus, compounds of: of the invention may increase HDL levels (or prevent the US 8,673,881 B2 15 16 decrease of HDL levels) and restore the LDL scavenging For example, statins suitable for use in the methods of this effects of HDL. This may lead to a lower and improved serum invention include statins of formula 200: LDL/HDL ratio. In addition to increasing HDL levels, statins also demon strate anti-inflammatory activity which contributes to their 200 ability to lower cardiovascular disease risk and treat cardio vascular disease. However, the full anti-inflammatory poten tial of statins cannot be utilized clinically as a monotherapy due to the high doses required, which can lead to an increased rate and severity level of treatment-limiting adverse events, 10 notably liver toxicity. Advantageously and Surprisingly, treatment or prevention of cardiovascular disease with a combination of a statin and a compound of the invention leads to a mutual enhancement of both the anti-inflammatory properties and the serum HDL 15 elevating properties of the two classes of compounds while avoiding the risks associated with high doses of statins alone. In methods of the invention, wherein a compound of the wherein invention is administered conjointly with a statin (i.e., an Ro is selected from alkyl, alkenyl, alkynyl, cycloalkyl or HMG-CoA reductase inhibitor), the statin may be chosen aralkyl; from any statin known in the art. Statins suitable for said Rao, Rao and R2 are independently selected from hydro conjoint administration include, but are not limited to, meV gen, halogen, alkyl, alkenyl or alkynyl: astatin ((2S)-2-methylbutanoic acid (1S,7S,8S,8aR)-1,2,3,7, Ros and Roe are independently selected from hydrogen, 8.8a-hexahydro-7-methyl-8-2-(2R,4R)-tetrahydro-4-hy halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, droxy-6-OXO-2H-pyran-2-yl)ethyl-1-naphthalenyl ester), 25 alkoxy or aralkoxy; and atorvastatin (BR, 8R)-2-(4-fluorophenyl)-3,6-dihydroxy-5- Rao is selected from hydrogen, R or M: (1-methylethyl)-3-phenyl-4-(phenylamino)carbonyl)-1H R is a physiologically acceptable and hydrolyzable ester Pyrrole-1-heptanoic acid), fluvastatin ((3R,5S,6E)-rel-7-3- group; and (4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)-3,5- M is a pharmaceutically acceptable cation; dihydroxy-6-heptenoic acid), lovastatin (2CS)-2-methyl 30 butanoic acid (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3, or enantiomers or salts or hydrates thereof. 7-dimethyl-8-2-(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H Other statins suitable for use in the methods of this inven pyran-2-ylethyl-1-naphthalenyl ester), pravastatin (BR,öR, tion include statins of formula 201: 1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-B.B.6- trihydroxy-2-methyl-8-(2S)-2-methyl-1-oxobutoxy-1- 35 wherein naphthaleneheptanoic acid), simvastatin (2,2-dimethyl A is selected from butanoic acid (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3, 7-dimethyl-8-2-(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H pyran-2-ylethyl-1-naphthalenyl ester), rosuvastatin ((3R, 5S,6E)-7-4-(4-fluorophenyl)-6-(1-methylethyl)-2-methyl 40 (methylsulfonyl)amino-5-pyrimidinyl-3,5-dihydroxy-6- heptenoic acid), eptastatin, pitavastatin ((3R,5S,6E)-7-2- cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl-3,5- dihydroxy-6-heptenoic acid), cerivastatin ((3R,5S,6E)-7-4- (4-fluorophenyl)-5-(methoxymethyl)-2,6-bis(1- 45 methylethyl)-3-pyridinyl-3,5-dihydroxy-6-heptenoic acid), berivastatin ((R*.S*-(E)-7-(4-(4-fluorophenyl)spiro (2H-1- benzopyran-2,1'-cyclopentan)-3-yl)-3,5-dihydroxy-ethyl ester), dalvastatin ((4R,6S)-rel-6-(1E)-2-[2-(4-fluoro-3-me thylphenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl)ethenyl 50 tetrahydro-4-hydroxy-, 2H-Pyran-2-one), glenvastatin ((4R, 6S)-6-(1E)-2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6- phenyl-3-pyridinylethenyltetrahydro-4-hydroxy-2H Pyran-2-one), RP 61969 (2S-2a(E),4|B-: fluorophenyl)-2-(1-methylethyl)-3-2-(tetrahydro-4- 55 hydroxy-6-oxo-2H-pyran-2-yl)ethenyl-1(2H)- isoquinolinone), SDZ-265859, BMS-180431 ((3R,5S,6E)- rel-9.9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H tetrazol-5-yl)-6,8-Nonadienoic acid), CP-83101 ((3R,5S, 6E)-rel-3,5-dihydroxy-9,9-diphenyl-6,8-Nonadienoic acid 60 methyl ester), dihydromevinolin (2S)-2-methyl-butanoic acid (1S,3S4aR,7S,8S,8aS)-1,2,3,4,4a,7,8,8a-octahydro-3, 7-dimethyl-8-2-(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H pyran-2-yl)ethyl-1-naphthalenyl ester), and L-669262 (2.2- dimethyl-butanoic acid (1S,7R,8R,8aR)-1,2,6,7,8,8a 65 hexahydro-3,7-dimethyl-6-oxo-8-2-(2R,4R)-tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl)ethyl-1-naphthalenyl ester). US 8,673,881 B2 17 18 -continued R216 R222 \ / X

R220 R218 R219 C Do 10 O N wherein

N R is selected from n 15 HO O HO CO OH ;

F .F 25 R is selected from OH, CHCO or RCO: R is a branched or straight C-C alkyl, C-C alkenyl, or C-C alkynyl: R7Rs and Rare independently selected from H. C-Cs alkyl, C-C alkenyl, C-C alkynyl or C-Cs acyl; and 30 Ro is selected from H or CH. / N Other statins suitable for use in the methods of this inven NA tion include statins of formula 203:

All 35 2O3 OH B is selected from

40

R207 or

45 wherein CH, CH, CH R is 1-naphthyl: 2-naphthyl, cyclohexyl, norbornenyl: 2-, 50 3-, or 4-pyridinyl; phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl trifluoromethyl; alkyl, alk enyl, oralkynyl of from one to four carbonatoms, alkoxy of C1 and C2 are joined by a single or a double bond; from one to four carbon atoms, or alkanoyloxy of from two Ro, is selected from CORs, CONRR or CHOR, to eight carbon atoms; 55 Either R22 or R22s is —CONR22sR229 where R22s and R229 or Rao, and Roo can form a lactone; are independently hydrogen; alkyl, alkenyl, or alkynyl of Rs is selected from Horacationic salt moiety, or CORs from one to six carbonatoms; 2-, 3-, or 4-pyridinyl; phenyl: forms a pharmaceutically acceptable ester moiety; phenyl Substituted with fluorine, chlorine, bromine, cyano, Ros, Roo and Rao are independently selected from H. C(O) trifluoromethyl, or carboalkoxy of from three to eight car R-1 or C(O)NR2 R22. 60 bonatoms; and the other of R or Rs is hydrogen; alkyl, R and R2 are independently selected from H. alkyl, alk alkenyl, or alkynyl of from one to six carbonatoms; cyclo enyl or alkynyl: propyl, cyclobutyl, cyclopentyl; cyclohexyl, phenyl; or phenyl substituted with fluorine, chlorine, bromine, R is selected from H or C(O)Ra; and hydroxyl; trifluoromethyl; alkyl, alkenyl, or alkynyl of Ra is selected from alkyl, alkenyl or alkynyl. 65 from one to four carbon atoms, alkoxy of from one to four Other statins suitable for use in the methods of this inven carbon atoms, or alkanoyloxy of from two to eight carbon tion include statins of formula 202: atoms; and US 8,673,881 B2 19 R is alkyl, alkenyl, or alkynyl of from one to six carbon Rs is selected from atoms; cyclopropyl; cyclobutyl, cyclopentyl; cyclohexyl, or trifluoromethyl; or the hydroxyl acids, and pharmaceu tically acceptable salts thereof, derived from the opening of R239 the lactone ring. 5 H H2 H2 Other statins suitable for use in the methods of this inven C-C ––c -COR240 O tion include statins of formula 204: OH OH

OH 204 10 R239: R232 R230 O X N N R- RN38 237 O 15 R2334N Y.

Ro is selected from hydrogen, or C. alkyl, C-C alkenyl, wherein or C-C alkynyl: one of R2so and R2 is Rao is selected from hydrogen, R or M: R is a physiologically acceptable and hydrolyzable ester 25 group; and V-R234 M is a pharmaceutically acceptable cation. / SSs. Other statins suitable for use in the methods of this inven ==/ R235 tion include statins of formula 205: R236 30

205 OH HOC and the other is primary or secondary Calkyl, alkenyl, or HO alkynyl not containing an asymmetric carbon atom, C 35 cycloalkyl or phenyl-(CH) : R is selected from hydrogen, C alkyl, C-C alkenyl, C-C alkynyl. n-butyl, i-butyl, t-butyl, C- alkoxy, n-bu toxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or 40 R242 benzyloxy; Rs is selected from hydrogen, C alkyl, C-C alkenyl, wherein C-C alkynyl, Calkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R is selected from 45 R is selected from hydrogen, C alkyl, Calkenyl, C. alkynyl, Calkoxy, fluoro or chloro; m is selected from 1, 2 or 3, with the provisos that both Rs and R2 must be hydrogen when R2 is hydrogen, R2 50 must be hydrogen when Rs is hydrogen, not more than O one of R and Rs is trifluoromethyl, not more than one of R and Rs is phenoxy, and not more than one of R2 and Rs is benzyloxy; R is selected from hydrogen, C alkyl, C-C alkenyl, HO C-C alkynyl. n-butyl, i-butyl, t-butyl, C. cycloalkyl, 55 C. alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; R is selected from hydrogen, C alkyl, C-C alkenyl, C-C alkynyl, Calkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R must be 60 hydrogen when R is hydrogen, not more than one of OH RandR is trifluoromethyl, not more than one of R2 and R2 is phenoxy, and not more than one of R22 and R2s is benzyloxy: 65 or ring-closed lactones, salts or esters thereof. Rs7 is selected from —(CH), or —CH=CH-, wherein Other statins suitable for use in the methods of this inven n is 0, 1, 2 or 3: tion include statins of formula 206: US 8,673,881 B2 21 22 Rao is Sulfur, oxygen, or Sulfonyl, or imino which may have a Substituent; and HO O the dotted line represents the presence or absence of a double bond; or the corresponding ring-closed lactone. The synthesis of various statins is set forth in U.S.

RE37314 E., U.S. Pat. No. 4444,784, U.S. Pat. No. 4,346, us 227, U.S. Pat. No. 5,354,772, U.S. Pat. No. 4,681,893 and US 2005/0228.042. 10 In another embodiment, the invention provides a method of raising serum HDL concentration (or preventing a decrease in serum HDL concentration) or decreasing the serum LDL/ HDL ratio in a patient, said method comprising administering to said patient a compound of the invention, optionally in 15 combination with a statin. The patient to be treated in this wherein method may have a total serum cholesterol level of greater R is selected from H or CH: than 189 mg/dl., preferably higher than 200 mg/dl and most Ra is selected from 1,1-dimethylpropyl; Cocycloalkyl; preferably higher than 240 mg/dl; and/or a serum LDL con Coalkenyl; CCF-Substituted alkyl; phenyl: centration of greater than 130 mg/dl., preferably greater than halophenyl; phenyl-C-alkyl; Substituted phenyl-C- 160 mg/dl., and most preferably higher than 189 mg/dl. In alkyl in which the substituent is halo, Calkyl or addition to serum cholesterol and/or LDL levels, other factors Calkoxy. to be considered are the presence or absence of coronary the dotted lines at X,Y and Zrepresent possible double bonds, disease and risk factors, such as age (45 or over for men, 55 or said double bonds, when any are present, being either X over for women), family history of coronary heart disease, and Z in combination or X, Y or Zalone; 25 Smoking, high blood pressure, serum HDL cholesterol level. or the corresponding dihydroxy acid of formula 206a or presence of diabetes. In certain embodiments, the invention provides a method of lowering triglyceride levels in a patient, said method com 206a HO prising administering to said patient a compound of the inven CO2H 30 tion, optionally in combination with a statin. In certain embodiments, the patient to be treated in this OH method of the invention may already be receiving a choles terol-lowering drug. In one preferred embodiment, the patient is already taking a statin, Such as one of the statins described us 35 above; and will continue to take that drug conjointly with a compound of the invention. Alternatively, the compound of the invention may be used as a replacement for the previously administered cholesterol-lowering drug. In a related embodiment, the invention provides a method R243 40 of reducing the dose of a statin required to achieve a desired increase in serum HDL, a decrease in serum LDL/HDL ratio or a pharmaceutically acceptable salt of said acid, a Calkyl or serum total cholesterol level, and/or a decrease in triglyc ester of said acid or a phenyldimethylamino-, or acety eride level. Reducing the dose of statins while maintaining lamino-Substituted-Calkyl ester of said acid. potent serum lipid-reducing properties is highly desirable due Other statins suitable for use in the methods of this inven 45 to side effects associated with certain statins. Well-known tion include statins of formula 207: side effects include, deleterious changes in liver function, muscle pain, weakness, muscle tenderness, myopathy. Other side effects of statins include reduced cognition, memory impairment, depression, irritability, non-muscle pain, periph 50 eral neuropathy, sleep disorders, sexual dysfunction, fatigue, dizziness, Swelling, shortness of breath, vision changes, CO2R 248 changes in temperature regulation, weight change, hunger, N breast enlargement, blood Sugar changes, dry skin, rashes, blood pressure changes, nausea, upset stomach, bleeding, and - - 55 ringing in ears or other noises. R245 R340 N In this embodiment, the dose of a statin is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, wherein at least 30%, at least 40%, at least 50%, at least 60%, at least Ras is lower alkyl, alkenyl, alkynyl, aryl or aralkyl, each of 70%, or more. The actual reduction in statin dose will depend which may have one or more substituents; 60 upon the nature of the compound of the invention being Rae and Ra, independently are selected from hydrogen, administered, the amount of compound of the invention being lower alkyl, alkenyl, alkynyl, oraryl, and each of said lower administered, and the reduction in serum lipid and/or triglyc alkyl, alkenyl, alkynyl and aryl may have one or more eride level desired, as well as other factors set forth elsewhere Substituents; in this application that are typically considered in treating a Ras is hydrogen, lower alkyl, alkenyl, alkynyl, or a cation 65 disease or condition. The amount of compound of the inven capable of forming a non-toxic pharmaceutically accept tion administered in this method will also depend upon the able salt; factors set forth above, as well as the nature and amount of US 8,673,881 B2 23 24 statin being administered. In certain embodiments, the streptokinase activator complex (APSAC, Eminase, Bee amount of compound of the invention administered in this cham Laboratories), animal salivary gland plasminogen acti method is less than 5%, less than 10%, less than 15%, less vators, and nasaruplase. than 20%, less than 25%, less than 30%, less than 40%, less Examples of the antihypertensive drug include angiotensin than 50%, less than 60%, less than 70%, less than 80%, or less converting enzyme inhibitors (such as captopril, alacepril, than 90% of the dose of compound of the invention required lisinopril, imidapril, quinapril, temocapril, delapril, to produce an anti-inflammatory effect. In other embodi benazepril, cilaZapril, trandolapril, enalapril, ceronapril, fosi ments, the amount of compound of the invention adminis nopril, imadapril, mobertpril, perindopril, ramipril, spirapril, tered is over 110%, over 120%, over 130%, over 140%, over Zofenopril, pentopril, randolapril and salts of Such com 10 pounds), angiotensin II antagonists (such as losartan, cande 150%, over 160%, over 170%, over 180%, over 190%, or Sartan, Valsartan, eprosartan, and irbesartan), calcium chan even over 200% of the dose of compound of the invention nel blocking drugs (such as aranidipine, efonidipine, required to produce an anti-inflammatory effect. nicardipine, bamidipine, benidipine, manidipine, cilnidipine, In one embodiment, the method of treating or preventing nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, cardiovascular disease according to this invention may com 15 amlodipine, diltiazem, bepridil, clentiazem, phendilin, galo prise the additional step of conjointly administering to the pamil, mibefradil, prenylamine, Semotiadil, terodiline, Vera patient another agent suitable for treating cardiovascular dis pamil, cilnidipine, elgodipine, isradipine, lacidipine, lercani ease, Such as, for example, a cyclooxygenase inhibitor, a dipine, nimodipine, cinnarizine, flunarizine, lidoflazine, , a mimetic, a lomerizine, bencyclane, etafenone, and perhexyline), phosphodiesterase inhibitor, a vasodilator, a cerebral protect B-adrenaline receptor blocking drugs (propranolol, pindolol. ing drug, a brain metabolic stimulant, an anticoagulant, an indenolol, carteolol, bunitrolol, atenolol, acebutolol, meto antiplatelet drug, a thrombolytic drug, an antihypertensive prolol, timolol, nipradillol, penbutolol, nadolol, tilisolol, agent, a calcium channel blocker, an antianginal drug, a carvedilol, bisoprolol, betaxolol, celiprolol, bopindolol, diuretic, a cardioplegic Solution, a cardiotonic agent, an anti bevantolol, labetalol, alprenolol, amoSulalol, arotinolol. arrhythmic drug, a fibrinolytic agent, a Sclerosing solution, a 25 befunolol, bucumolol, bufetolol, buferalol, buprandolol, vasoconstrictoragent, a donor, a potassium chan butylidine, butofilolol, carazolol, cetamolol, cloranolol, dil nel blocker, a sodium channel blocker, an antihyperlipidemic evalol, epanolol, levobunolol, mepindolol, metipranolol. drug, an immunosuppressant, or a natriuretic agent. moprolol, nadoxolol, nevibolol, Oxprenolol, practol, pron Examples of a cyclooxygenase inhibitor include, but are etalol, Sotalol, Sufinalol, talindolol, tertalol, toliprolol, 30 Xybenolol, and esmolol), C.-receptor blocking drugs (such as not limited to, celecoxib, rofecoxib, meloxicam, Valdecoxib, amosulalol, praZosin, teraZosin, doxazosin, bunaZosin, urapi aspirin or indomethacin. dil, phentolamine, arotinolol, dapiprazole, fenspiride, An example of a thromboxane receptor antagonist is indoramin, labetalol, naftopidil, nicergoline, tamsulosin, ifetroban. tolazoline, trimaZosin, and yohimbine), sympathetic nerve Examples of vasodilators include, e.g., bencyclane, cin 35 inhibitors (such as clonidine, guanfacine, guanabenZ, meth narizine, citicoline, cyclandelate, cyclonicate, ebumamonine, yldopa, and reserpine), hydralazine, todralazine, budralazine, phenoxeZyl, flunarizine, ibudilast, ifenprodil, lomerizine, and cadralazine. naphlole, nikamate, noSergoline, nimodipine, papaverine, Examples of the antianginal drug include nitrate drugs pentifylline, nofedoline, Vincamin, Vinpocetine, Vichizyl. (such as amyl nitrite, nitroglycerin, and isosorbide), pentoxifylline, prostacyclin derivatives (such as prostaglan 40 B-adrenaline receptor blocking drugs (exemplified above), din E1 and I2), an endothelin receptor blocking calcium channel blocking drugs (exemplified above) tri drug (such as bosentan), diltiazem, nicorandil, and nitroglyc metazidine, dipyridamole, etafenone, dilaZep, trapidil, nic erin. orandil, enoxaparin, and aspirin. Examples of the cerebral protecting drug include radical Examples of the diuretic include thiazide diuretics (such as Scavengers (such as edaravone, vitamin E, and vitamin C), 45 hydrochlorothiazide, methyclothiazide, bendrofluazide, glutamate antagonists, AMPA antagonists, kainate antago chlorothiazide, trichlormethiazide, benzylhydrochlorothiaz nists, NMDA antagonists, GABA agonists, growth factors, ide, flumethiazide, hydroflumethiazide, bendroflumethiaz opioid antagonists, precursors, seroto ide, methylchlorthiazide, polythiazide, benzthiazide and pen nin agonists, Na"/Ca" channel inhibitory drugs, and K" flutizide), loop diuretics (such as furosemide, etacrynic acid, channel opening drugs. 50 bumetanide, piretanide, azosemide, and torasemide), K" Examples of the brain metabolic stimulants include aman sparing diuretics (spironolactone, triamterene, amiloride, and tadine, tiapride, and gamma-aminobutyric acid. potassium canrenoate), osmotic diuretics (such as isosorbide, Examples of the anticoagulant include heparins (such as D-mannitol, and glycerin), nonthiazide diuretics (such as heparin Sodium, heparin potassium, dalteparin sodium, dalte meticrane, tripamide, chlorthalidone, and mefruside), and parin calcium, heparin calcium, parnaparin Sodium, reviparin 55 acetazolamide. Sodium, and danaparoid sodium), warfarin, enoxaparin, arga Examples of the cardiotonic include digitalis formulations troban, batroXobin, and Sodium citrate. (such as digitoxin, digoxin, methyldigoxin, deslanoside, Examples of the antiplatelet drug include ticlopidine Vesnarinone, lanatoside C, and proscillaridin), Xanthine for hydrochloride, dipyridamole, ciloStaZol, ethyl icosapentate, mulations (such as aminophylline, choline , Sarpogrelate hydrochloride, dilaZephydrochloride, trapidil, a 60 , and proxyphylline), catecholamine formula nonsteroidal antiinflammatory agent (such as aspirin), bera tions (such as dopamine, dobutamine, and docarpamine), prostSodium, , and indobufene. PDE III inhibitors (such as amrinone, olprinone, and mil Examples of the thrombolytic drug include urokinase, tis rinone), denopamine, ubidecarenone, pimobendan, levosim Sue plasminogenactivator (tPA), recombinant tEPA, issue-type endan, aminoethylsulfonic acid, Vesnarinone, carperitide, plasminogen activators (such as alteplase, tisokinase, 65 and colforsin daropate. nateplase, pamiteplase, monteplase, and rateplase), Streptoki Examples of the antiarrhythmic drug include ajmaline, nase, urokinase, prourokinase, anisoylated plasminogen pirmenol, procainamide, cibenzoline, disopyramide, quini US 8,673,881 B2 25 26 dine, aprindine, mexiletine, lidocaine, phenyloin, pilsicain tion may include conjointly administering one or more of the ide, propafenone, flecainide, atenolol, acebutolol, Sotalol, above agents either as a separate dosage form or as part of a propranolol, metoprolol, pindolol, amiodarone, nifekalant, composition that also comprises a statin, a compound of the diltiazem, bepridil, moricizine, tocainide, encainide, pro invention, and optionally further comprising a statin. More pafenone, esmolol, artilide, bretylium, clofilium, isobutilide, over, the use of a composition comprising both a statin and a Sotalol, azimilide, dofetilide, dronedarone, ersentilide, ibutil compound of the invention according to this invention in the ide, tedisamil, trecetilide, digitalis, adenosine, nickel chlo treatment of cardiovascular disease, does not preclude the ride, and magnesium ions and Verapamil. separate but conjoint administration of another statin. Examples of the antihyperlipidemic drug include atorvas The method of increasing serum HDL concentration, tatin, simvastatin, pravastatin Sodium, fluvastatin Sodium, cli 10 reducing serum LDL/HDL ratio, reducing total serum cho nofibrate, clofibrate, simfibrate, fenofibrate, bezafibrate, lesterol concentration, and/or lowering the triglyceride level colestimide, colestyramine, mevastatin ((2S)-2-methyl in a patient according to this invention may additionally com butanoic acid (1S,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-7-me prise administering to said patient another active ingredient thyl-8-2-(2R-4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran other than a statin. Such additional active ingredient may be 2-yl)ethyl-1-naphthalenyl ester), fluvastatin ((3R,5S,6E)- 15 selected from a non-statin cholesterol lowering reagent. Such rel-7-3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2- as bile acid sequestrants (colesevelam, cholestyramine and yl-3,5-dihydroxy-6-heptenoic acid), lovastatin (2(S)-2- colestipol), niacin, fibrates (gemfibrozil, probucol and clofi methyl-butanoic acid (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a brate). hexahydro-3,7-dimethyl-8-2-(2R,4R)-tetrahydro-4- In certain embodiments, different compounds of the inven hydroxy-6-oxo-2H-pyran-2-yl)ethyl-1-naphthalenyl ester), tion may be conjointly administered with one or more other pravastatin ((BR.6R,1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahy compounds of the invention. Moreover, Such combinations dro-3,3,6-trihydroxy-2-methyl-8-(2S)-2-methyl-1-oxobu may be conjointly administered with other therapeutic toxy-1-naphthaleneheptanoic acid), rosuvastatin ((3R,5S, agents, such as other agents suitable for the treatment or 6E)-7-4-(4-fluorophenyl)-6-(1-methylethyl)-2-methyl prevention of cardiovascular disease, such as the agents iden (methylsulfonyl)amino-5-pyrimidinyl-3,5-dihydroxy-6- 25 tified above. heptenoic acid), eptastatin, pitavastatin ((3R,5S,6E)-7-2- In certain embodiments, the present invention provides a cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl-3,5- kit comprising: dihydroxy-6-heptenoic acid), cerivastatin ((3R,5S,6E)-7-4- a) one or more single dosage forms of a compound of the (4-fluorophenyl)-5-(methoxymethyl)-2,6-bis(1- invention; methylethyl)-3-pyridinyl-3,5-dihydroxy-6-heptenoic acid), 30 b) one or more single dosage forms of a statin as mentioned berivastatin ((R*.S*-(E)-7-(4-(4-fluorophenyl)spiro (2H-1- above; and benzopyran-2,1'-cyclopentan)-3-yl)-3,5-dihydroxy-ethyl c) instructions for the administration of the compound of ester), dalvastatin ((4R,6S)-rel-6-(1E)-2-[2-(4-fluoro-3-me the invention and the statin. thylphenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl)ethenyl The present invention provides a kit comprising: tetrahydro-4-hydroxy-, 2H-Pyran-2-one), glenvastatin ((4R, 35 a) a pharmaceutical formulation (e.g., one or more single 6S)-6-(1E)-2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6- dosage forms) comprising a compound of the invention; phenyl-3-pyridinylethenyltetrahydro-4-hydroxy-2H and Pyran-2-one), RP 61969 (2S-2a(E),4|B-: b) instructions for the administration of the pharmaceutical fluorophenyl)-2-(1-methylethyl)-3-2-(tetrahydro-4- formulation e.g., for treating or preventing cardiovascu hydroxy-6-oxo-2H-pyran-2-yl)ethenyl-1(2H)- 40 lar disease, raising serum HDL concentration (or pre isoquinolinone), SDZ-265859, BMS-180431 ((3R,5S,6E)- venting a decrease in serum HDL concentration), rel-9.9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H decreasing the serum LDL/HDL ratio, and/or lowering tetrazol-5-yl)-6,8-Nonadienoic acid), CP-83101 ((3R,5S, triglyceride levels. 6E)-rel-3,5-dihydroxy-9,9-diphenyl-6,8-Nonadienoic acid In certain embodiments, the kit further comprises instruc methyl ester), dihydromevinolin (2S)-2-methyl-butanoic 45 tions for the administration of the pharmaceutical formula acid (1S,3S4aR,7S,8S,8aS)-1,2,3,4,4a,7,8,8a-octahydro-3, tion comprising a compound of the invention conjointly with 7-dimethyl-8-2-(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H an agent Suitable for treating or preventing cardiovascular pyran-2-yl)ethyl-1-naphthalenyl ester), and L-669262 (2.2- disease, raising serum HDL concentration (or preventing a dimethyl-butanoic acid (1S,7R,8R,8aR)-1,2,6,7,8,8a decrease in serum HDL concentration), decreasing the serum hexahydro-3,7-dimethyl-6-oxo-8-2-(2R,4R)-tetrahydro-4- 50 LDL/HDL ratio, and/or lowering triglyceride levels (e.g., a hydroxy-6-oxo-2H-pyran-2-yl)ethyl-1-naphthalenyl ester). statin or another agent Suitable for treating cardiovascular Examples of the immunosuppressant include azathioprine, disease. Such as, for example, a cyclooxygenase inhibitor, a mizoribine, cyclosporine, tacrolimus, gusperimus, and meth thromboxane receptor antagonist, a prostacyclin mimetic, a Otrexate. phosphodiesterase inhibitor, a vasodilator, a cerebral protect In one embodiment, the method of treating or preventing 55 ing drug, a brain metabolic stimulant, an anticoagulant, an cardiovascular disease according to this invention may com antiplatelet drug, a thrombolytic drug, an antihypertensive prise administering a compound of the invention conjointly agent, a calcium channel blocker, an antianginal drug, a with non-chemical means for the treatment or prevention of diuretic, a cardioplegic Solution, a cardiotonic agent, an anti cardiovascular disease. Such as part of a regimen including arrhythmic drug, a fibrinolytic agent, a Sclerosing solution, a physical intervention (e.g., percutaneous transluminal coro 60 vasoconstrictoragent, a nitric oxide donor, a potassium chan nary angioplasty, coronary Surgery, or vascular Surgery). In nel blocker, a sodium channel blocker, an antihyperlipidemic certain Such embodiments, the regimen including physical drug, an immunosuppressant, or a natriuretic agent) as men intervention may further include conjointly administering tioned above. In certain embodiments, the kit further com another agent Suitable for the treatment or prevention of car prises a second pharmaceutical formulation (e.g., as one or diovascular disease, such as the agents listed above. 65 more single dosage forms) comprising an agent Suitable for It should be understood that the methods of treatment or treating or preventing cardiovascular disease, raising serum prevention of cardiovascular disease according to this inven HDL concentration (or preventing a decrease in serum HDL US 8,673,881 B2 27 28 concentration), decreasing the serum LDL/HDL ratio, and/or conditions which may be treated by the present invention lowering triglyceride levels (e.g., a statin or another agent include inflammation caused by infectious agents, including, Suitable for treating cardiovascular disease. Such as, for but not limited to, viruses, bacteria fungi and parasites. example, a cyclooxygenase inhibitor, a thromboxane receptor Inflammatory lung conditions include, but are not limited antagonist, a prostacyclin mimetic, a phosphodiesterase 5 to, asthma, adult respiratory distress syndrome, bronchitis, inhibitor, a vasodilator, a cerebral protecting drug, a brain pulmonary inflammation, pulmonary fibrosis, and cystic metabolic stimulant, an anticoagulant, an antiplatelet drug, a fibrosis (which may additionally or alternatively involve the thrombolytic drug, an antihypertensive agent, a calcium gastro-intestinal tract or other tissue(s)). Inflammatory joint channel blocker, an antianginal drug, a diuretic, a cardiople conditions include rheumatoid arthritis, rheumatoid gic solution, a cardiotonic agent, an antiarrhythmic drug, a 10 spondylitis, juvenile rheumatoid arthritis, osteoarthritis, fibrinolytic agent, a Sclerosing solution, a vasoconstrictor gouty arthritis and other arthritic conditions. Eye diseases agent, a nitric oxide donor, a potassium channel blocker, a with an inflammatory component include, but are not limited Sodium channel blocker, an antihyperlipidemic drug, an to, uveitis (including iritis), conjunctivitis, Scleritis, kerato immunosuppressant, or a natriuretic agent) as mentioned conjunctivitis sicca, and retinal diseases, including, but not above. 15 limited to, diabetic retinopathy, retinopathy of prematurity, The present invention provides a kit comprising: retinitis pigmentosa, and dry and wet age-related macular a) a first pharmaceutical formulation (e.g., one or more degeneration. Inflammatory bowel conditions include single dosage forms) comprising an agent Suitable for Crohn's disease, ulcerative and distal proctitis. treating or preventing cardiovascular disease, raising Inflammatory skin diseases include, but are not limited to, serum HDL concentration (or preventing a decrease in conditions associated with cell proliferation, such as psoria serum HDL concentration), decreasing the serum LDL/ sis, eczema and , (e.g., eczematous dermatitides, HDL ratio, and/or lowering triglyceride levels (e.g., a topic and seborrheic dermatitis, allergic or irritant contact statin or another agent Suitable for treating cardiovascu dermatitis, eczema craquelee, photoallergic dermatitis, pho lar disease. Such as, for example, a cyclooxygenase totoxic dermatitis, phytophotodermatitis, radiation dermati inhibitor, a thromboxane receptor antagonist, a prosta 25 tis, and stasis dermatitis). Other inflammatory skin diseases cyclin mimetic, a phosphodiesterase inhibitor, a vasodi include, but are not limited to, Scleroderma, ulcers and ero lator, a cerebral protecting drug, a brain metabolic sions resulting from trauma, burns, bullous disorders, or stimulant, an anticoagulant, an antiplatelet drug, a ischemia of the skin or mucous membranes, several forms of thrombolytic drug, an antihypertensive agent, a calcium ichthyoses, epidermolysis bullosae, hypertrophic scars, kel channel blocker, an antianginal drug, a diuretic, a car 30 oids, cutaneous changes of intrinsic aging, photoaging, fric dioplegic Solution, a cardiotonic agent, an antiarrhyth tional blistering caused by mechanical shearing of the skin mic drug, a fibrinolytic agent, a Sclerosing solution, a and cutaneous atrophy resulting from the topical use of cor vasoconstrictor agent, a nitric oxide donor, a potassium ticosteroids. Additional inflammatory skin conditions include channel blocker, a sodium channel blocker, an antihy inflammation of mucous membranes, such as cheilitis, perlipidemic drug, an immunosuppressant, or a natri 35 chapped lips, nasal irritation, mucositis and Vulvovaginitis. uretic agent); and Inflammatory disorders of the endocrine system include, b) instructions for the administration of the first pharma but are not limited to, autoimmune thyroiditis (Hashimoto's ceutical formulation with a compound of the invention, disease). Type I diabetes, and acute and chronic inflammation e.g., for treating or preventing cardiovascular disease, of the adrenal cortex. Inflammatory conditions of the cardio raising serum HDL concentration (or preventing a 40 vascular system include, but are not limited to, coronary decrease in serum HDL concentration), decreasing the infarct damage, peripheral vascular disease, myocarditis, vas serum LDL/HDL ratio, and/or lowering triglyceride lev culitis, revascularization of Stenosis, artherosclerosis, and els. vascular disease associated with Type II diabetes. The present invention provides a kit comprising: Inflammatory condition of the kidney include, but are not a) a first pharmaceutical formulation (e.g., one or more 45 limited to, , interstitial nephritis, lupus single dosage forms) comprising a statin as mentioned nephritis, nephritis secondary to Wegener's disease, acute above; and renal failure secondary to acute nephritis, Goodpasture’s Syn b) instructions for the administration of the first pharma drome, post-obstructive syndrome and tubular ischemia. ceutical formulation with a compound of the invention, Inflammatory conditions of the liver include, but are not e.g., for treating or preventing cardiovascular disease, 50 limited to, hepatitis (arising from viral infection, autoimmune raising serum HDL concentration (or preventing a responses, drug treatments, toxins, environmental agents, or decrease in serum HDL concentration), decreasing the as a secondary consequence of a primary disorder), biliary serum LDL/HDL ratio, and/or lowering triglyceride lev atresia, primary biliary cirrhosis and primary Sclerosing cho els. langitis. General Inflammatory Diseases 55 Inflammatory conditions of the central nervous system The present invention provides a method of treating or include, but are not limited to, multiple Sclerosis and neuro preventing inflammatory disease in a patient comprising degenerative diseases such as Alzheimer's disease, Parkin administering to said patient a compound of the invention. son's disease, or dementia associated with HIV infection. Examples of inflammatory conditions, which may be Other inflammatory conditions include periodontal dis treated or prevented by the administration of a compound of 60 ease, tissue necrosis in chronic inflammation, endotoxin the invention include, but are not limited to, inflammation of shock, Smooth muscle proliferation disorders, graft versus the lungs, joints, connective tissue, eyes, nose, bowel, kidney, host disease, tissue damage following ischemia reperfusion liver, skin, central nervous system, Vascular system and heart. injury, and tissue rejection following transplant Surgery. In certain embodiments, inflammatory conditions which may The present invention further provides a method of treating be treated by the current invention include inflammation due 65 or preventing inflammation associated with post-Surgical to the infiltration of leukocytes or other immune effector cells wound in a patient comprising administering to said into affected tissue. Other relevant examples of inflammatory patient a compound of the invention. US 8,673,881 B2 29 30 It should be noted that compounds of the current invention tolone, difluprednate, fluclorolone, fludroxycortide, may be used to treat or prevent any disease which has an flumetaSone, flunisolide, fluocinolone acetonide, fluocinon inflammatory component, such as those diseases cited above. ide, fluocortin, fluocortolone, fluorometholone, fluperolone, Further, the inflammatory conditions cited above are meant to fluprednidene, fluticasone, formocortal, halcinonide, halom be exemplary rather than exhaustive. etaSone, hydrocortisonefcortisol, hydrocortisone aceponate, Those skilled in the art would recognize that additional hydrocortisone buteprate, hydrocortisone butyrate, lotepred inflammatory conditions (e.g., systemic or local immune nol, medrysone, meprednisone, methylprednisolone, methyl imbalance or dysfunction due to an injury, an insult, infection, prednisolone aceponate, mometasone furoate, parametha inherited disorder, or an environmental intoxicant or pertur Sone, prednicarbate, prednisone/prednisolone, prednylidene, bant to the subject's physiology) may be treated or prevented 10 rimexolone, tiXocortol, triamcinolone, ulobetasol, mometa by compounds of the current invention. Thus, the methods of Sone, fluticasone propionate, beclomethasone dipropionate, the current invention may be used to treat or prevent any fluocinolone, flunisolide hemihydrate, mometasone furoate disease which has an inflammatory component, including, monohydrate, desoxymethasone, diflorasone diacetate, but not limited to, those diseases cited above. hydrocortisone acetate, difluorocortolone, fluorocortisone, The present invention also provides methods for treating or 15 flumethasone, flunisolide, fluorocortolone, prednisolone, preventing arthritis, inflammatory bowel disease, uveitis, prednisone, cortisol. 6a-methylprednisolone, alclometasone ocular inflammation, asthma, pulmonary inflammation, cys dipropionate, fluclorolone acetonide, fluocinolone acetonide, tic fibrosis, psoriasis, arterial inflammation, cardiovascular betamethasone benzoate, fluocoritin butyl, betamethasone diseases, multiple Sclerosis, or neurodegenerative disease by dipropionate, fluocortolone preparations, betamethasone val administering an effective amount of a compound of the erate, fluprednidene acetate, flurandrenolone, clobetasol pro invention. pionate, clobetasol butyrate, hydrocortisone, hydrocortisone The present invention also provides methods for treating butyrate, methylprednisolone acetate, diflucortolone Valer ischemia by administering an effective amount of a com ate, flumethasone pivalate, or triamcinolone acetonide, or pound of the invention. In certain embodiments, the ischemia pharmaceutically acceptable salts thereof. is cardiac ischemia, cerebral ischemia, bowel ischemia (e.g., 25 In certain embodiments, the patient to be treated by a ischemic colitis or mesenteric ischemia), or cutaneous method of the invention may already be receiving an anti ischemia. inflammatory drug (other than a glucocorticoid). In one pre The present invention provides a method of treating or ferred embodiment, the patient is already taking a glucocor preventing inflammatory disease in a patient comprising ticoid, such as one of the glucocorticoids described above, administering to said patient a compound of the invention 30 and will continue to take that drug conjointly with a com conjointly with a glucocorticoid. pound of the invention. Alternatively, the compound of the The present invention provides a method of treating or invention may be used as a replacement for the previously preventing an inflammatory condition (e.g., any of the inflam administered anti-inflammatory drug. matory conditions described above) comprising administer In a related embodiment, the invention provides a method ing to said patient a compound of the invention conjointly 35 of reducing the dose of a glucocorticoid required to achieve a with a glucocorticoid. desired anti-inflammatory effect. Reducing the dose of glu Compounds of the invention are capable of resolving cocorticoid while maintaining potent anti-inflammatory inflammation. Glucocorticoids are also known for their role properties is highly desirable due to side effects associated in treating inflammation. However, the full anti-inflammatory with certain glucocorticoids. Side effects of glucocorticoids potential of glucocorticoids is often clinically constrained as 40 include increased appetite and weight gain, deposits offat in a monotherapy due to the rate and severity of treatment the chest, face, upperback, and stomach, water and salt reten limiting adverse events that accompany high or prolonged tion leading to Swelling and edema, high blood pressure, dosing regimens. For example, the administration of gluco diabetes, slow healing of wounds, osteoporosis, cataracts, corticoids can result in side effects that mimic Cushings acne, muscle weakness, thinning of the skin, increased Sus disease. These side effects and others associated with gluco 45 ceptibility to infection, stomach ulcers, increased Sweating, corticoid use include increased appetite and weight gain, mood Swings, psychological problems such as depression, deposits of fat in the chest, face, upper back, and stomach, and adrenal Suppression and crisis. water and salt retention leading to Swelling and edema, high In this embodiment, the dose of a glucocorticoid is reduced blood pressure, diabetes, slow healing of wounds, osteoporo by at least 5%, at least 10%, at least 15%, at least 20%, at least sis, cataracts, acne, muscle weakness, thinning of the skin, 50 25%, at least 30%, at least 40%, at least 50%, at least 60%, at increased Susceptibility to infection, Stomach ulcers, least 70%, at least 80%, at lest 90%, or more. The actual increased Sweating, mood Swings, psychological problems reduction in glucocorticoid dose will depend upon the nature Such as depression, and adrenal Suppression and crisis. and amount of the compound of the invention being admin Advantageously, treatment of inflammatory disease with a istered, the reduction in inflammation desired, and other fac combination of a glucocorticoid and a compound of the 55 tors set forth elsewhere in this application that are typically invention enhances the anti-inflammatory properties of both considered in treating a disease or condition. The amount of classes of compounds while reducing the effects associated the compound of the invention administered in this method with high doses of glucocorticoids alone. will also depend upon the factors set forth above, as well as In methods of the invention, wherein a glucocorticoid is the nature and amount of glucocorticoid being administered. administered conjointly with a compound of the invention, 60 In certain embodiments, the amount of the compound of the the glucocorticoid may be chosen from any glucocorticoid invention administered in this method is less than 5%, less known in the art. Glucocorticoids suitable for said conjoint than 10%, less than 15%, less than 20%, less than 25%, less administration include, but are not limited to, alclometaSone, than 30%, less than 40%, less than 50%, less than 60%, less amcinonide, beclometasone, betamethasone, budesonide, than 70%, less than 80%, or less than 90% of the dose of the ciclesonide, clobetasol, clobetaSone, clocortolone, clopred 65 compound of the invention required to produce an anti-in nol, cortisone, cortivaZol, deflazacort, desonide, desoximeta flammatory effect without conjoint administration with a glu Sone, desoxycortone, dexamethasone, diflorasone, diflucor cocorticoid. US 8,673,881 B2 31 32 In one embodiment, the method of treating or preventing The present invention provides a kit comprising: inflammatory disease according to this invention may com a) a first pharmaceutical formulation (e.g., one or more prise the additional step of conjointly administering to the single dosage forms) comprising a glucocorticoid as patient another anti-inflammatory agent, Such as, for mentioned above; and example, a non-steroidal anti-inflammatory drug (NSAID), a b) instructions for the administration of the first pharma mast cell stabilizer, or a modifier. ceutical formulation with a compound of the invention, In certain embodiments, the use of a composition compris e.g., for treating or preventing inflammatory disease. ing a compound of the invention and a glucocorticoid accord Metabolic Diseases ing to this invention in the treatment of inflammatory disease, The present invention provides a method of treating or does not preclude the separate but conjoint administration of 10 preventing complex disorders having an inflammatory com another corticosteroid. ponent in a patient comprising administering to said patient a In certain embodiments, the use of a composition compris compound of the invention. In certain embodiments, the com ing both a compound of the invention and a glucocorticoid plex disorder having an inflammatory component is type 2 according to this invention in the treatment of inflammatory 15 diabetes or obesity. disease, does not preclude the separate but conjoint adminis The present invention provides a method of treating or tration of another glucocorticoid. preventing metabolic disorders in a patient comprising In certain embodiments, different compounds of the inven administering to said patient a compound of the invention. In tion may be conjointly administered with one or more other certain embodiments, the metabolic disorder is selected from compounds of the invention while conjointly administering a an eating disorder, dyslipidemia, hypertriglyceridemia, glucocorticoid. Moreover, Such combinations may be con hypertension, or metabolic syndrome. jointly administered with other therapeutic agents, such as The present invention further provides a method of treating other anti-inflammatory agents. or preventing type 1 diabetes in a patient, comprising admin In certain embodiments, the present invention provides a istering to said patient a compound of the invention. In certain kit comprising: a) one or more single dosage forms of a 25 embodiments, the present invention provides a method of compound of the invention; b) one or more single dosage treating a patient at risk of developing type 1 diabetes com forms of a glucocorticoid as mentioned above; and c) instruc prising administering to said patient a compound of the inven tions for the administration of the compound of the invention tion. In certain embodiments, the present invention provides and the glucocorticoid. a method of treating a patient exhibiting one or more warning The present invention provides a kit comprising: 30 signs of type 1 diabetes, such as extreme thirst, frequent urination; drowsiness or lethargy; Sugar in urine; Sudden a) a pharmaceutical formulation (e.g., one or more single vision changes; increased appetite; sudden weight loss; dosage forms) comprising a compound of the invention; fruity, sweet, or wine-like odor on breath; heavy, labored and breathing; stupor; or unconsciousness, comprising adminis b) instructions for the administration of the pharmaceutical 35 tering to said patient a compound of the invention. formulation e.g., for treating or preventing a disorder or The present invention further provides a method of treating condition as discussed above, e.g., inflammatory dis or preventing type 2 diabetes in a patient, comprising admin CaSC. istering to said patient a compound of the invention. In certain In certain embodiments, the kit further comprises instruc embodiments, the present invention provides a method of tions for the administration of the pharmaceutical formula 40 treating a patient at risk of developing type 2 diabetes com tion comprising a compound of the invention conjointly with prising administering to said patient a compound of the inven a glucocorticoid as mentioned above. In certain embodi tion. In certain embodiments, the present invention provides ments, the kit further comprises a second pharmaceutical a method of treating a patient exhibiting one or more warning formulation (e.g., as one or more single dosage forms) com signs of type 2 diabetes, such as extreme thirst, frequent prising a glucocorticoidas mentioned above. 45 urination; drowsiness or lethargy; Sugar in urine; Sudden In certain embodiments, the kit further comprises instruc vision changes; increased appetite; Sudden weight loss; tions for the administration of the pharmaceutical formula fruity, sweet, or wine-like odor on breath; heavy, labored tion comprising a compound of the invention conjointly with breathing; stupor; or unconsciousness, comprising adminis an agent Suitable for the treatment or prevention of inflam tering to said patient a compound of the invention. matory disease (e.g., a non-steroidal anti-inflammatory drug 50 The present invention further provides a method for pro (NSAID), a mast cell stabilizer, or a leukotriene modifier) as tecting, e.g., promoting the growth and/or Survival of beta mentioned above. In certain embodiments, the kit further cells of Islets of Langerhans from lipid- or glucose-triggered comprises a second pharmaceutical formulation (e.g., as one toxicity in a patient comprising administering to the patient a or more single dosage forms) comprising an agent Suitable for compound of the invention. the treatment or prevention of inflammatory disease (e.g., a 55 In certain embodiments, the methods of treating or pre non-steroidal anti-inflammatory drug (NSAID), a mast cell venting a complex disorder having an inflammatory compo stabilizer, or a leukotriene modifier) as mentioned above. nent, such as type 2 diabetes, or of treating type 1 diabetes The present invention provides a kit comprising: according to this invention may comprise the additional step a) a first pharmaceutical formulation (e.g., one or more of conjointly administering to the patient another treatment single dosage forms) comprising an agent Suitable for 60 for diabetes including, but not limited to, Sulfonylureas (e.g., the treatment or prevention of inflammatory disease chlorpropamide, tolbutamide, glyburide, glipizide, aceto (e.g., a non-steroidal anti-inflammatory drug (NSAID), hexamide, tolaZamide, gliclazide, gliquidone, or glime a mast cell stabilizer, or a leukotriene modifier) as men piride), medications that decrease the amount of glucose pro tioned above; and duced by the liver (e.g., metformin), meglitinides (e.g., b) instructions for the administration of the first pharma 65 repaglinide or nateglinide), medications that decrease the ceutical formulation with a compound of the invention, absorption of carbohydrates from the intestine (e.g., alpha e.g., for treating or preventing inflammatory disease. glucosidase inhibitors such as acarbose), medications that US 8,673,881 B2 33 34 effect glycemic control (e.g., pramlintide or exenatide), DPP In certain embodiments, the kit further comprises instruc IV inhibitors (e.g., Sitagliptin), insulin treatment, or combi tions for the administration of the pharmaceutical formula nations of the above. tion comprising a compound of the invention conjointly with In certain embodiments, the methods of treating or pre an agent Suitable for the treatment or prevention of obesity, as venting a complex disorder having an inflammatory compo mentioned above. In certain embodiments, the kit further nent. Such as obesity, according to this invention may com comprises a second pharmaceutical formulation (e.g., as one prise the additional step of conjointly administering to the or more single dosage forms) comprising an agent Suitable for patient another treatment for obesity including, but not lim the treatment or prevention of obesity, as mentioned above. ited to, orlistat, Sibutramine, phendimetrazine, phentermine, The present invention provides a kit comprising: 10 a) a first pharmaceutical formulation (e.g., one or more diethylpropion, benzphetamine, mazindol, dextroamphet single dosage forms) comprising an agent Suitable for amine, rimonabant, cetilistat, GT 389-255, APD356, pram the treatment or prevention of obesity as mentioned lintide/AC137, PYY3-36, AC 162352/PYY3-36, oxynto above; and modulin, TM 30338, AOD 9604, oleoyl-estrone, b) instructions for the administration of the first pharma bromocriptine, ephedrine, leptin, pseudoephedrine, or phar 15 ceutical formulation with a compound of the invention, maceutically acceptable salts thereof. e.g., for treating or preventing complex disorders having In certain embodiments, different compounds of the inven an inflammatory component (e.g., type 2 diabetes or tion may be conjointly administered with one or more other obesity), treating or preventing metabolic disorders compounds of the invention. Moreover, Such combinations (e.g., eating disorder, dyslipidemia, hypertriglyceri may be conjointly administered with other therapeutic demia, hypertension, or metabolic syndrome), treating agents, such as other agents Suitable for the treatment or or preventing type 1 diabetes, treating a patient at risk of prevention of metabolic disorders, such as the agents identi developing type 1 diabetes, treating a patient exhibiting fied above. warning signs of type 1 diabetes, or protecting (e.g., The present invention provides a kit comprising: promoting the growth and/or survival of) beta cells of a) a pharmaceutical formulation (e.g., one or more single 25 Islets of Langerhans from lipid- or glucose-triggered dosage forms) comprising a compound of the invention; toxicity. and The present invention provides a kit comprising: b) instructions for the administration of the pharmaceutical a) a first pharmaceutical formulation (e.g., one or more formulation e.g., for treating or preventing complex dis single dosage forms) comprising an agent Suitable for orders having an inflammatory component (e.g., type 2 30 the treatment or prevention of diabetes as mentioned diabetes or obesity), treating or preventing metabolic above; and disorders (e.g., eating disorder, dyslipidemia, hypertrig b) instructions for the administration of the first pharma lyceridemia, hypertension, or metabolic syndrome), ceutical formulation with a compound of the invention, treating or preventing type 1 diabetes, treating a patient e.g., for treating or preventing complex disorders having at risk of developing type 1 diabetes, treating a patient 35 an inflammatory component (e.g., type 2 diabetes or exhibiting warning signs of type 1 diabetes, or protect obesity), treating or preventing metabolic disorders ing (e.g., promoting the growth and/or Survival of) beta (e.g., eating disorder, dyslipidemia, hypertriglyceri cells of Islets of Langerhans from lipid- or glucose demia, hypertension, or metabolic syndrome), treating triggered toxicity. or preventing type 1 diabetes, treating a patient at risk of In certain embodiments, the kit further comprises instruc 40 developing type 1 diabetes, treating a patient exhibiting tions for the administration of the pharmaceutical formula warning signs of type 1 diabetes, or protecting (e.g., tion comprising a compound of the invention conjointly with promoting the growth and/or survival of) beta cells of an agent suitable for the treatment or prevention of diabetes Islets of Langerhans from lipid- or glucose-triggered (e.g., Sulfonylureas (e.g., chlorpropamide, tolbutamide, gly toxicity. buride, glipizide, acetohexamide, tolaZamide, gliclazide, 45 Ophthalmic Conditions gliquidone, or glimepiride), medications that decrease the The present invention provides a method of treating or amount of glucose produced by the liver (e.g., metformin), preventing an ophthalmic condition in a patient, comprising meglitinides (e.g., repaglinide or nateglinide), medications administering to said patient a compound of the invention that decrease the absorption of carbohydrates from the intes (e.g., a compound of any one of formula I-III as shown tine (e.g., alpha glucosidase inhibitors such as acarbose), 50 above). medications that effect glycemic control (e.g., pramlintide or The present invention further provides a method of treating exenatide), DPP-IV inhibitors (e.g., sitagliptin), insulin treat or preventing an ophthalmic condition (such as dry eye) in a ment, or combinations of the above) as mentioned above. In patient, comprising administering to said patient a compound certain embodiments, the kit further comprises a second phar of formula IV. maceutical formulation (e.g., as one or more single dosage 55 forms) comprising an agent Suitable for the treatment or pre vention of diabetes (e.g., Sulfonylureas (e.g., chlorpropamide, (IV) tolbutamide, glyburide, glipizide, acetohexamide, tolaza mide, gliclazide, gliquidone, or glimepiride), medications that decrease the amount of glucose produced by the liver 60 (e.g., metformin), meglitinides (e.g., repaglinide or nateglin ide), medications that decrease the absorption of carbohy drates from the intestine (e.g., alpha glucosidase inhibitors Such as acarbose), medications that effect glycemic control or a pharmaceutically acceptable salt thereof, wherein: (e.g., pramlintide or exenatide), DPP-IV inhibitors (e.g., sita 65 X is selected from -C=C , —C(R)=C(R) -, -(cy gliptin), insulin treatment, or combinations of the above) as clopropyl)-, -(cyclobutyl)-, -(cyclopentyl)-, and -(cyclo mentioned above. hexyl)-; US 8,673,881 B2 35 36 R" is selected from OR, N(R) SO. R. and In certain embodiments, R and R' together are - N(R)(R), wherein each of R and R is indepen dently selected from H. C-C-alkyl, aryl, aralkyl, het eroaryl, and heteroaralkyl, and R is selected from C-C-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; N R. R is selected from —CH2—, —C(O) , -SO. , PO C/ (OR)—, and tetrazole; NO-N R is selected from hydrogen and alkyl: R is selected from a carbocyclic ring, a heterocyclic ring, 10 —(CH), , CHC(O)CH2, and —CH2—O—CH2, wherein: In certain embodiments, X is —C=C . In certain n is an integer from 1 to 3: embodiments, X is C(R)=C(R)-, -(cyclopropyl)-, any hydrogen atom in R is optionally and indepen -(cyclobutyl)-, -(cyclopentyl)-, or -(cyclohexyl)-. In certain dently replaced by halo, (C-C)-alkyl, perfluoro 15 alkyl, aryl, heteroaryl, hydroxy, or O—(C-C)-alkyl; embodiments, X is C(R)=C(R)-. In certain embodi and ments, X is —C=C-, -(cyclopropyl)-, -(cyclobutyl)-, -(cy clopentyl)-, or -(cyclohexyl)-. In certain embodiments, X is any two hydrogen atoms bound to a common carbon atom in R are optionally taken together with the -(cyclopropyl)-. In certain embodiments, X is —C=C- or carbon atom to which they are bound to form a car —C(R)=C(R)-. In certain embodiments wherein X is bocyclic or heterocyclic ring; -(cyclopropyl)-, -(cyclobutyl)-, -(cyclopentyl)-, or -(cyclo each of R“and R' is independently selected from hydro hexyl)-, the olefin and the carbon bearing R“are attached to gen, halo. —OH, -O-(C-C)-alkyl, —O-aryl, O-het adjacent carbons on the -(cyclopropyl)-, -(cyclobutyl)-, -(cy eroaryl, —O—C(O)—(C-C)-alkyl, —O—C(O)-aryl, 25 clopentyl)-, or -(cyclohexyl)-ring system. —O C(O)-heteroaryl, - O C(O)—O (C-C)- In certain embodiments, R' is hydrogen. In certain alkyl, —O—C(O)—O-aryl, —O C(O)—O-het embodiments, R' is halo, OH, O (C-Cs)-alkyl, -O- eroaryl, and O C(O) N(R)(R), wherein any aryl, O-heteroaryl, —O—C(O)—(C-C)-alkyl, —O C alkyl, aryl or heteroaryl is optionally substituted with up (O)-aryl, —O C(O)-heteroaryl, —O C(O)—O—(C- 30 Cs)-alkyl, - O C(O)—O-aryl, O C(O)—O-heteroaryl, to 3 substituents independently selected from halo, (C- or —O C(O) N(R)(R'), wherein any alkyl, aryl or het Cs)-alkyl, O—(C-C)-alkyl, hydroxyl, carboxyl, ester, eroaryl is optionally substituted with up to 3 substituents alkoxycarbonyl, acyl, thioester, thioacyl, thioether, independently selected from halo, (C-C)-alkyl, O—(C- amino, amido, acylamino, cyano, and nitro, Cs)-alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, each of RandR is independently selected from hydro 35 thioester, thioacyl, thioether, amino, amido, acylamino, gen, halo, (C-C)-alkyl, perfluoroalkyl, aryl, and het cyano, and nitro. In certain embodiments, R' is fluoro. In eroaryl, preferably hydrogen, halo and (C-C)-alkyl, certain embodiments, R' is hydrogen, OH, - O (C- R is selected from -phenyl, -(C-Cs)-alkyl, -(C-C,)- Cs)-alkyl, -O-aryl, O-heteroaryl, —O—C(O)—(C-Cs)- cycloalkyl, -C=C-phenyl, -C=C-(C-C2)-cy alkyl, —O C(O)-aryl, - O C(O)-heteroaryl, —O—C cloalkyl, -C=C-(C-C)-alkyl, and —O-phenyl, 40 (O)—O—(C-C)-alkyl, —O C(O)—O-aryl, —O C wherein phenyl is optionally substituted with up to 3 (O)-O-heteroaryl, or -O-C(O) N(R)(R), wherein Substituents independently selected from halo, (C-C)- any alkyl, aryl or heteroaryl is optionally substituted with up alkyl, O—(C-C)-alkyl, hydroxyl, carboxyl, ester, to 3 substituents independently selected from halo, (C-Cs)- alkoxycarbonyl, acyl, thioester, thioacyl, thioether, alkyl, O—(C-C)-alkyl, hydroxyl, carboxyl, ester, alkoxy 45 carbonyl, acyl, thioester, thioacyl, thioether, amino, amido, amino, amido, acylamino, cyano, and nitro, acylamino, cyano, and nitro. In certain embodiments, R' is and R is additionally selected from -C=CH when: selected from —OH, - O (C-C)-alkyl, O-aryl, O-het a) X is C(R)=C(R) - or -(cyclopropyl)-; or eroaryl, —O—C(O)—(C-C)-alkyl, O C(O)-aryl, O C b) each of R“ and R' is hydrogen or halo; or (O)-heteroaryl, and —O C(O) N(R)(R). In certain 50 embodiments, R' is hydrogen, halo, O C(O) O (C- c) each of RandR is halo; or Cs)-alkyl, —O C(O) O-aryl, or —O C(O)—O-het d) R is —CH2—, eroaryl, wherein any alkyl, aryl or heteroaryl is optionally each R" is independently selected from hydrogen and (C- substituted with up to 3 substituents independently selected Cs)-alkyl, or two occurrences of R7 may optionally be from halo, (C-C)-alkyl, O—(C-C)-alkyl, hydroxyl, car taken together with the carbons to which they are 55 boxyl, ester, alkoxycarbonyl, acyl, thioester, thioacyl, thioet attached to form a 5- or 6-membered ring: her, amino, amido, acylamino, cyano, and nitro. In certain each of R'' and R' is independently selected from embodiments, R' is selected from hydrogen, halo, OH, or hydrogen, (C-C)-alkyl, perfluoroalkyl, O—(C-C)- —O (C-Cs)-alkyl. In certain embodiments, R' is O alkyl, aryl and heteroaryl, or R'" and R'' are taken aryl, O-heteroaryl, —O—C(O)—(C-C)-alkyl, —O—C 60 (O)-aryl, —O C(O)-heteroaryl, —O C(O)—O—(C- together with the carbonatom to which they are bound to Cs)-alkyl, —O—C(O)—O-aryl, —O C(O)—O- form a carbocyclic or heterocyclic ring; heteroaryl, or - O C(O) N(R)(R), wherein any alkyl, and each double bond is independently in an E- or a Z-con aryl or heteroaryl is optionally substituted with up to 3 sub figuration. stituents independently selected from halo, (C-C)-alkyl, In certain embodiments, R' is —OM, where M is a cation 65 O—(C-C)-alkyl, hydroxyl, carboxyl, ester, alkoxycarbo selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, nyl, acyl, thioester, thioacyl, thioether, amino, amido, acy and Zn. lamino, cyano, and nitro. In certain embodiments, R” is US 8,673,881 B2 37 38 selected from —OH, - O (C-Cs)-alkyl, —O-aryl, O-het In certain embodiments, R" is in an (S) configuration. In eroaryl. —O—C(O)—(C-C)-alkyl, —O—C(O)-aryl, certain embodiments, R“ is in an (R) configuration. —O C(O)-heteroaryl, —O C(O)—O—(C-Cs)-alkyl, In certain embodiments wherein R“ is -OH, R is —O C(O)—O-aryl, —O C(O)—O-heteroaryl, and selected from hydrogen or (C-C)-alkyl. In certain embodi —O C(O) N(R)(R), wherein any alkyl, aryl or het ments wherein R* is selected from —OH, - O (C-Cs)- eroaryl is optionally substituted with up to 3 substituents alkyl, —O-aryl, O-heteroaryl, —O C(O)—(C-Cs)-alkyl, independently selected from halo, (C-C)-alkyl, O—(C- —O—C(O)-aryl, —O C(O)-heteroaryl, —O—C(O)— Cs)-alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, O—(C-C)-alkyl, —O C(O)—O-aryl, —O C(O)—O- thioester, thioacyl, thioether, amino, amido, acylamino, heteroaryl, and - O C(O) N(R)(R), R is selected 10 from hydrogen or (C-C)-alkyl. In certain embodiments, R' cyano, and nitro. In certain embodiments, R' is selected from is fluoro. In certain embodiments, R is selected from hydro hydrogen or halo. gen and (C-C)-alkyl. In certain embodiments, R' is in an (R) configuration. In In certain embodiments wherein R' is -OH, R is certain embodiments, R' is in an (S) configuration. selected from hydrogen or (C-C)-alkyl. In certain embodi In certain embodiments, R“ is hydrogen. In certain 15 ments wherein R' is selected from OH, - O (C-Cs)- embodiments, R" is halo, -OH,-O-(C-Cs)-alkyl, -O- alkyl, —O-aryl, O-heteroaryl, - O C(O)—(C-C)-alkyl, aryl, O-heteroaryl, —O—C(O)—(C-C)-alkyl, —O—C —O—C(O)-aryl, —O C(O)-heteroaryl, —O—C(O)— (O)-aryl, - O C(O)-heteroaryl, —O C(O)—O—(C- O—(C-C)-alkyl, —O C(O)—O-aryl, —O C(O)—O- Cs)-alkyl, —O—C(O)—O-aryl, —O C(O)—O- heteroaryl, and - O C(O) N(R)(R), R is selected heteroaryl, or - O C(O) N(R)(R), wherein any alkyl, from hydrogen or (C-C)-alkyl. In certain embodiments, R aryl or heteroaryl is optionally substituted with up to 3 sub is fluoro. In certain embodiments, R is selected from hydro stituents independently selected from halo, (C-C)-alkyl, gen and (C-C)-alkyl. O—(C-C)-alkyl, hydroxyl, carboxyl, ester, alkoxycarbo In certain embodiments, R is —CH . In certain embodi nyl, acyl, thioester, thioacyl, thioether, amino, amido, acy ments, R is —C(O)—. lamino, cyano, and nitro. In certain embodiments, R" is 25 In certain embodiments, R is selected from Hand C-C- fluoro. In certain embodiments, R“ is hydrogen, OH, alkyl. In certain embodiments, R is selected from aryl, —O—(C-C)-alkyl, —O-aryl, O-heteroaryl, —O—C(O)— aralkyl, heteroaryl, and heteroaralkyl. (C-C)-alkyl, —O—C(O)-aryl, —O C(O)-heteroaryl, In certain embodiments, R is selected from Hand C-C- —O—C(O)—O—(C-C)-alkyl, —O C(O)—O-aryl, alkyl. In certain embodiments, R is selected from aryl, —O C(O)-O-heteroaryl, or - O C(O) N(R)(R), 30 aralkyl, heteroaryl, and heteroaralkyl. wherein any alkyl, aryl or heteroaryl is optionally substituted In certain embodiments, R is C-C-alkyl, aryl, or het with up to 3 substituents independently selected from halo, eroaryl. In certain embodiments, R is selected from aryl, (C-C)-alkyl, O—(C-C)-alkyl, hydroxyl, carboxyl, ester, aralkyl, heteroaryl, and heteroaralkyl. alkoxycarbonyl, acyl, thioester, thioacyl, thioether, amino, In certain embodiments wherein R is selected from a car amido, acylamino, cyano, and nitro. In certain embodiments, 35 bocyclic ring, a heterocyclic ring, —(CH) , and CHC(O) R" is selected from -OH, - O (C-C)-alkyl, O-aryl, CH2, any hydrogen atom in R is optionally and indepen O-heteroaryl, —O C(O)—(C-Cs)-alkyl, O C(O)-aryl, dently replaced by halo, (C-C)-alkyl, perfluoroalkyl, aryl, O–C(O)-heteroaryl, and —O-C(O) N(R)(R). In cer heteroaryl, hydroxy, or O—(C-C)-alkyl. In certain embodi tain embodiments, R“ is hydrogen, halo, O C(O)-O- ments wherein R is —CH2—O—CH2, any hydrogen atom (C-C)-alkyl, —O C(O)—O-aryl, or—O C(O)—O-het 40 in R is optionally and independently replaced by halo, (C- eroaryl, wherein any alkyl, aryl or heteroaryl is optionally Cs)-alkyl, perfluoroalkyl, aryl, heteroaryl, or O—(C-Cs)- substituted with up to 3 substituents independently selected alkyl. In certain embodiments, R is selected from from halo, (C-C)-alkyl, O—(C-C)-alkyl, hydroxyl, car —(CH), and —CH2—O—CH2, wherein n is an integer boxyl, ester, alkoxycarbonyl, acyl, thioester, thioacyl, thioet from 1 to3, and up to two hydrogenatoms in Rare optionally her, amino, amido, acylamino, cyano, and nitro. In certain 45 and independently replaced by (C-C)-alkyl. In certain embodiments, R" is selected from hydrogen, halo, OH, or embodiments, R is selected from a carbocyclic ring, a het —O (C-C)-alkyl. In certain embodiments, R“ is —O- erocyclic ring, and CHC(O)CH, wherein n is an integer aryl, O-heteroaryl, —O—C(O)—(C-C)-alkyl, —O—C from 1 to 3; any hydrogen atom in R is optionally and (O)-aryl, - O C(O)-heteroaryl, —O C(O)—O—(C- independently replaced by halo, (C-C)-alkyl, perfluoro Cs)-alkyl, —O—C(O)—O-aryl, —O C(O)—O- 50 alkyl, aryl, heteroaryl, hydroxy, or O—(C-C)-alkyl; and heteroaryl, or - O C(O) N(R)(R), wherein any alkyl, any two hydrogen atoms bound to a common carbon atom in aryl or heteroaryl is optionally substituted with up to 3 sub R are optionally taken together with the carbon atom to stituents independently selected from halo, (C-C)-alkyl, which they are bound to form a carbocyclic or heterocyclic O—(C-C)-alkyl, hydroxyl, carboxyl, ester, alkoxycarbo r1ng. nyl, acyl, thioester, thioacyl, thioether, amino, amido, acy 55 In certain embodiments, R" is hydrogen. In certain lamino, cyano, and nitro. In certain embodiments, R" is embodiments, R' is selected from (C-C)-alkyl, perfluo selected from —OH, - O (C-Cs)-alkyl, —O-aryl, O-het roalkyl, O (C-C)-alkyl, aryl and heteroaryl, or R' is eroaryl, —O—C(O)—(C-C)-alkyl, -O-C(O)-aryl, taken together with R', and the carbon atom to which they —O C(O)-heteroaryl, —O C(O)—O—(C-Cs)-alkyl, are bound to form a carbocyclic or heterocyclic ring. —O C(O)—O-aryl, —O C(O)—O-heteroaryl, and 60 In certain embodiments, R' is hydrogen. In certain —O C(O) N(R)(R), wherein any alkyl, aryl or het embodiments, R' is selected from (C-C-)-alkyl, perfluo eroaryl is optionally substituted with up to 3 substituents roalkyl, O (C-Cs)-alkyl, aryl and heteroaryl, or R' is independently selected from halo, (C-C)-alkyl, O—(C- taken together with R'' and the carbon atom to which they Cs)-alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, are bound to form a carbocyclic or heterocyclic ring. thioester, thioacyl, thioether, amino, amido, acylamino, 65 In certain embodiments, R' is —OR". In certain embodi cyano, and nitro. In certain embodiments, R“ is selected from ments, R is selected from N(R) SO R and N(R) hydrogen or halo. (R'). In certain embodiments, R is N(R) SO. R. US 8,673,881 B2 39 40 In certain embodiments, R' is selected from —OR" and -continued -N(R)(R). In certain embodiments, R is N(R)(R). In certain embodiments, R' is selected from —OR, and (302) N(R) SO, R. OH In certain embodiments, R is hydrogen. In certain embodi ments, R is (C-C)-alkyl or two occurrences of R may O'Na', optionally be taken together with the carbons to which they are attached to form a 5- or 6-membered ring. In certain embodiments, X is -C=C- and R' is hydro 10 gen. In certain embodiments, X is -C=C- and R" is hydro (303) gen. OH OH In certain embodiments, X is -C=C , R“ is fluoro, and 15 R is fluoro. O'Na', In certain embodiments, X is -C=C R' is fluoro, and R is fluoro. In certain embodiments, X is -C=C , and each of R' and R' is independently selected from OH, - O (C- Cs)-alkyl, O-aryl, O-heteroaryl, —O C(O)—(C-C)- alkyl, O—C(O)-aryl, O C(O)-heteroaryl, and —O—C (O) N(R)(R). (304) 25 In certain embodiments, X is -C=C- and R is OH OH —CH2—. In certain embodiments, X is -(cyclopropyl)-, -(cyclobu tyl)-, -(cyclopentyl)-, and -(cyclohexyl)-. In certain embodi O'Na', ments, X is -(cyclopropyl)-. 30 In certain embodiments, X is C(R)=C(R)—. In certain embodiments, each of R and R is indepen dently selected from Hand C-C-alkyl; R is C1-Co-alkyl; R (305) is selected from —(CH), and —CH2—O—CH, wherein OH OH n is an integer from 1 to 3, and up to two hydrogenatoms in R 35 are optionally and independently replaced by (C-C)-alkyl; each of RandR' is independently selected from hydrogen, O'Na', halo, OH, O (C-C)-alkyl; and each of R" and R' is hydrogen. 40 In certain embodiments, each double bond is in an E-con (306) figuration. In certain embodiments, each double bond is in a OH OH Z-configuration. In certain embodiments, one double bond is in an E-configuration and one double bond is in a Z-configu O'Na', ration. 45 In certain embodiments, the invention contemplates any combination of the foregoing. Those skilled in the art will recognize that all specific combinations of the individual possible residues of the variable regions of the compounds as disclosed herein, e.g., R. R. R. R. R. R. R. R. R7, 50 R", R', R. R. R., n and X, are within the scope of the invention. As an example, any of the various particular recited embodiments for R* may be combined with any of the vari ous particular recited embodiments of X. In certain embodiments, the compound is selected from 55 (307) any one of OH OH

(301) 60 OH O

2n-4 ONa",

65

US 8,673,881 B2 43 44 -continued -continued (319) (330) OH F F O O

o 5 o 21 Ne. OEt, 21 Nea OMe,

(320) 10 (331) OH OH F F O o an e = O 21 Ne- O'Na', | 15 | OEt, (321) (332)332 OH O OH OH O 2O 2n 2 = ouls 21 Ne- O'Na', OEt,

(322) (333) OH OH OH OH O eae = OEt, 21\21N O'Na', 30 | H3C | O

(326) OH OH O 35 21N 21 OEt,

F 40 (334) OH OH an ea = OEt, F (327)327 is O OH OH O an e- = (336) OEt, OH OH O

50 o 21 Ne. OEt, (328) OH OH O | 21-21 E OEt, 55 (337) OH OH O (329) 60 OH O 21 Nea OEt,

21Ne. OEt, | 65 US 8,673,881 B2 45 46 -continued -continued (338) (342) OH OH O OH OH O 5 OEt, 21 Na OEt,

10

C 15 C

(339) (343) O H O OH OH O 2O 21Ne. OEt, OMe,

25 (344) HO, HC CH3 O

30 HO 2 OMe, N1 N.

(340) O 35 OH OH O

OEt,

40 F

(345) O H OH O 45 21 21 OMe, and

50 (346) (341) OH OH O OH OH O afnan OEt, 55 -----H3C 60

The present invention further provides a method of treating as or preventing an ophthalmic condition (such as dry eye) in a OCH patient, comprising administering to said patient a compound of the formula V. US 8,673,881 B2 48 In certain embodiments, R and R' together are (V) OR8 OR S. 5 RIa R2, Ra R2 21\e o R31 NR R10b s R6 or formula VI, " In certain embodiments, R is C(O)—. In certain embodiments, R is —OR", wherein R is hydrogen or C-C- (VI) gR8 OR9 alkyl. In certain embodiments, Ris-(CH2), , whereinnis O Ras Rii, 2 3. In certain embodiments, R is -C=CH. In certain RS R embodiments, R is hydrogen. In certain embodiments, R. S R31 NRI 15 is hydrogen. In certain embodiments, R" is hydrogen. In R10b s certain embodiments, R' is hydrogen. In certain embodi ments, R is —C(O)—, R' is —OR", wherein R is C-C- alkyl, R is —(CH), , wherein n is 3, R is -C=CH, R or a pharmaceutically acceptable salt of either of the forego is hydrogen, R is hydrogen, R" is hydrogen, and R' is ing, wherein: hydrogen. R" is selected from OR, N(R) SO. R. and - N(R)(R), wherein each of R and R is indepen In certain embodiments, the compound is selected from dently selected from H. C-C-alkyl, aryl, aralkyl, het any one of eroaryl, and heteroaralkyl, and R is selected from 25 C-C-alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; (323)

R is selected from C(O) , -SO. , —PO(OR) , and tetrazole; R is selected from hydrogen and alkyl: R is selected from —(CH), and —CH2—O—CH2, 30 O'Na', wherein n is an integer from 1 to 3; and optionally up to two hydrogenatoms in Rare independently replaced by halo, (C-C)-alkyl, or O—(C-C)-alkyl; each of RandR is independently selected from hydro (324) gen, (C-C)-alkyl, perfluoroalkyl, aryl, and heteroaryl, 35 preferably hydrogen and (C-C)-alkyl; R is selected from -C=CH, -phenyl, -(C-Cs)-alkyl, ONa, —(C-C)-cycloalkyl, -C=C-phenyl, -C=C-(C- Cz)-cycloalkyl, -C=C-(C-C)-alkyl, and —O-phe 40 nyl, wherein phenyl is optionally substituted with up to 3 substituents independently selected from halo, (C- (325)

Cs)-alkyl, O—(C-C)-alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, thioester, thioacyl, thioether, amino, amido, acylamino, cyano, and nitro, 45 each of Rand Rare independently selected from hydro OEt, or gen, —(C-C)-alkyl, -aryl, -heteroaryl, —C(O)—(C- Cs)-alkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)— O—(C-C)-alkyl, —C(O)—O-aryl, —C(O)—O- heteroaryl, and C(O) N(R)(R), wherein any alkyl, 50 aryl or heteroaryl is optionally substituted with up to 3 Substituents independently selected from halo, (C-Cs)- (335) alkyl, O—(C-C)-alkyl, hydroxyl, carboxyl, ester, alkoxycarbonyl, acyl, thioester, thioacyl, thioether, amino, amido, acylamino, cyano, and nitro, 55 each of R'' and R' is independently selected from hydrogen, (C-C)-alkyl, perfluoroalkyl, O—(C-C)- alkyl, aryland heteroaryl, or R" and R'' are taken together with the carbon atom to which they are bound to form a carbocyclic or hetero 60 cyclic ring; and wherein each double bond is independently in an E- or a Z-configuration. The present invention further provides a method of treating In certain embodiments, R' is —OM, where M is a cation as or preventing an ophthalmic condition (such as dry eye) in a selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, patient, comprising administering to said patient a compound and Zn. of formula VII, US 8,673,881 B2 49 50 wherein: (VII) each of W' and Y is a bond or a linker independently R, R ORf Rh ORe Q selected from a ring containing up to 20 atoms or a chain of up to 20 atoms, provided that W and Y can independently Rs 41\41\– Rgul E, include one or more nitrogen, oxygen, Sulfur orphosphorous atoms, further provided that W and Y can independently include one or more substituents independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, and pharmaceutically acceptable salts thereof, wherein: 10 amino, alkylamino, dialkylamino, acylamino, carboxamido, Re and Rfare independently selected from hydrogen, alkyl, cyano, oxo, thio, alkylthio, arylthio, acylthio, alkylsulfonate, alkenyl, alkynyl, aryl, heteroaryl, acyl (e.g., alkoxyacyl, arylsulfonate, phosphoryl, or sulfonyl, further provided that aminoacyl), aminocarbonyl, alkoxycarbonyl, or silyl; W' and Y can independently contain one or more fused car E is a hydroxyl, alkoxy, aryloxy, amino, alkylamino, dialky bocyclic, heterocyclic, aryl or heteroaryl rings, and further lamino, or arylamino; 15 provided that when o' is 0, and V is Rh and Ri are independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or heteroaryl; Rs is selected from i-iv as follows: i) CHCH(R)CH, where R1001 Ra' R is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro, hydroxyl or alkoxy; ii) CHC 21 (RR)CH, where R and R7 are each independently alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, or fluoro, or R and R7 are connected together to form a carbocyclic or hetero cyclic ring; iii) CHOCH, CHC(O)CH, or CHCH; or Y" is connected to V via a carbon atom; iv) Rs is a carbocyclic, heterocyclic, aryl or heteroaryl ring; 25 V is selected from and Rs and R are independently selected from hydrogen, alkyl, R1001 Ra' R1001 Ra' alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or heteroaryl, or Rs and R are connected together to form a carbocyclic or heterocyclic ring. 30 In certain embodiments, a compound of formula VII is R1001 Ra' represented by formula VIII,

35 (VIII) WX-XR Rb ORf ORul RI 002 21-21 E Rs E, , or 40 A-KX1001 Rb" R1002 and pharmaceutically acceptable salts thereof, wherein: Re, Rf, Rs, and E are as defined above. 2n-4 In certain embodiments, a compound of formula VII or 45 Ra' R1001 VIII is represented by formula IX, wherein when q is 0 and V is a bond, n' is 0 or 1; otherwise (IX) n' is 1: 50 V is selected from a bond, ORf ORe O

21N 21 R1001 Ra' , or 55 Rb' R1002 and pharmaceutically acceptable salts thereof, wherein: 21 21 O Re, Rf, and E are as defined above. n Additional compounds suitable for use in methods and 60 Ra' R1001 compositions of the invention include those of Formula A, R1002 Rib'

65 R1001 US 8,673,881 B2 51 52 wherein: mido or a detectable label molecule, wherein any alkyl-, aryl L' is selected from C(R')(R') , wherein each of or heteroaryl-containing moiety is optionally Substituted with R'' and R'' is independently selected from hydro up to 3 independently selected substituents; gen, alkyl, alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or heteroaryl, or R'' and R'' are connected together s o' is 0, 1, 2, 3, 4, or 5: to form a carbocyclic or heterocyclic ring; when V is p' is 0, 1, 2, 3, 4, or 5: q' is 0, 1, or 2; and R1001 Ra' o'+p'+q' is 1, 2, 3, 4, 5 or 6: 10 wherein: N s if V is a bond, then q is 0, and V is a bond; if V is L' is additionally selected from W'; and n' is 0 or 1; V is selected from a bond or 15 R1001 Ra' R 1001 Ra' A-X->,

2O A-X >, then o' is 0, V is wherein: each R'' and R' is independently for each occurrence R1001 Ra' Selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkoxy, orhalo, wherein said alkyl- 25 or aryl-containing moiety is optionally Substituted with up to 3 independently selected substituents; each of R'' and R is independently for each occurrence selected from —OR' or N(R'), or adjacent RandR are taken togetherto forman ring having a cis or 30 p' is 1 and V2 is trans configuration, wherein each R' is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl, aminoacyl, aminocar R1001 Ra' bonyl, alkoxycarbonyl, or a protecting group; or when V is 35 A-X->,

Rb" R1002 any acyclic double bond may be in a cis or a trans configu ration or is optionally replaced by a triple bond; and 2^4 n 40 either one Ra' R1001 and V2 is N 21 Nea 45

R1001 Ra' portion of the compound, if present, is optionally replaced by N s 50 R'' and Rare both hydrogen; X is selected from-CN, C(NH)N(R") (R"), C(S)-A', 21 C(S)R", C(O)-A", C(O) R", C(O). SR", Q'-- C(O) NH S(O). R", S(O)-A', S(O). R", 55 N S(O)N(R") (R"), -P(O)-A", PO(OR")-A', -tetrazole, alkyltetrazole, or —CH2OH, wherein A is selected from OR", N(R")(R") or - OM': each R" is independently selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or a detect- 60 Oi Oile able label molecule, wherein any alkyl-, aryl- or het eroaryl-containing moiety is optionally Substituted with up to 3 independently selected substituents; and M" is a cation; G' is selected from hydrogen, halo, hydroxy, alkyl, aryl, 65 arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, aryloxy, car boxy, amino, alkylamino, dialkylamino, acylamino, carboxa US 8,673,881 B2 53 54 portion of the compound, if present, is optionally replaced by In certain embodiments, if V is

R1001 Ra' 21 A-X-> then o' is 3,4 or 5, p' is 0, 1 or 2, o'+p' is 4 or 5, and V is a bond. 10 In certain embodiments, if V is a bond, then o' is 0, 3, 4 or 5; p' is 0, 1, 2 or 5, o'+p' is 4 or 5, q' is 0, and V is a bond. wherein Q' represents one or more substituents and each Q' is In certain embodiments, each of WandY" is independently independently selected from halo, alkyl, alkenyl, alkynyl, selected from a bond or lower alkyl or heteroalkyl optionally cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, alkylcarbonyl, substituted with one or more substituents independently arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, 15 selected from alkenyl, alkynyl, aryl, chloro, iodo, bromo, hydroxy, cyano, carboxyl, alkoxycarbonyloxy, aryloxycarbo fluoro, hydroxy, amino, or oxo. nyloxy or aminocarbonyl. Additional compounds Suitable for use in methods and In certain embodiments, V is selected from compositions of the invention include those of Formula 1,

RI OO Ra' R1001 Ra' A-X->, WX-y O 25 R1001 Ra' N N R1002 Rib' 30 wherein: Carbons a' and b' are connected by a double bond or a triple In certain embodiments, V is selected from a bond, bond; Carbons c' and d'are connected by a double bond or a triple bond; R1001 Ra' 35 Re, Rf, and Rg are independently selected from hydrogen, s O alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl (e.g., alkoxya A-X C, cyl, aminoacyl), aminocarbonyl, alkoxycarbonyl, or silyl; Rb' R1002 Rh, Ri and Rj are independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or heteroaryl; 2^4 n 40 I is selected from —C(O)-E, —SO-E, —PO(OR)-E, where E is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialky Ra' RI OO lamino, or arylamino; and R is hydrogen or alkyl; J. L and H are linkers independently selected from a ring In certain embodiments, when q' is 0 and V is a bond, n' is 45 containing up to 20 atoms or a chain of up to 20 atoms, 0 or 1; otherwise n' is 1. provided that J. L and H can independently include one or In certain embodiments, p' is 0, 1, 2, 3, or 5. more nitrogen, oxygen, Sulfur or phosphorous atoms, and further provided that J. L and H can independently include In certain embodiments, q' is 0 or 1. one or more substituents selected from hydrogen, alkyl, In certain embodiments, if V is 50 alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alky lamino, dialkylamino, acylamino, carboxamido, cyano, R1001 Ra' oXo, thio, alkylthio, arylthio, acylthio, alkylsulfonate, aryl Sulfonate, phosphoryl, and Sulfonyl, and further provided N N 55 that J. L and H can also contain one or more fused carbocy R1002 Rb' clic, heterocyclic, aryl or heteroaryl rings, and provided that linker J is connected to the adjacent C(R)OR group via a carbon atom; then o' is 0 or 1, p' is 1 or 2, o'+p' is 1 or 2, V is G is selected from hydrogen, alkyl, perfluoroalkyl, alkenyl, 60 alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, R1001 Ra' dialkylamino, acylamino, or carboxamido; or pharmaceutically acceptable salts thereof. A-X->, In certain embodiments, a pharmaceutically acceptable 65 salt of the compound is formed by derivatizing E, wherein E is —OM, where M is a cation selected from ammonium, and V is a bond. tetra-alkyl ammonium, Na, K, Mg, and Zn. US 8,673,881 B2 55 56 In certain embodiments, a compound of formula 1 is rep and compound 3b, resented by formula 2. 2 ORf ORe O (3.b) 5 OH afn21N E OH O 21 41 y \ 4 OCH3. ORg 10 OH wherein: E. Re, Rf, and Rg are as defined above. Further exemplary compounds of formula 1 include Com In certain embodiments, a pharmaceutically acceptable 15 pound X, salt of the compound is formed by derivatizing E, wherein E is —OM, where M is a cation selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn. (X) Exemplary compounds of formula 2 include compound 2a: OH OH O (2a) OH OH O OH, 21\afn OCH3. 25 \ 4 OH OH and pharmaceutically acceptable salts and esters thereof. 30 Additional compounds Suitable for use in methods and In certain embodiments, a compound of formula 1 is rep compositions of the invention include those of Formula 4. resented by formula 3,

ORf ORe O 35 21 2 S E, \ 4 40 ORg wherein: A is H or —OP: wherein: P, P and Peach individually is a protecting group or hydro E. Re, Rf, and Rg are as defined above. 45 gen atom; In certain embodiments, a pharmaceutically acceptable R and Reach individually is a substituted or unsubstituted, salt of the compound is formed by derivatizing E, wherein E branched or unbranched alkyl, alkenyl, or alkynyl group, is —OM, where M is a cation selected from ammonium, substituted or unsubstituted aryl group, substituted or tetra-alkyl ammonium, Na, K, Mg, and Zn. unsubstituted, branched or unbranched alkylaryl group, Exemplary compounds of formula 3 include compound 3a, 50 halogen atom, hydrogen atom; (3a) Zis C(O)OR, C(O)NRR, C(O)H, C(NH)NRR, —C(S)H, -C(S)OR, C(S)NRR, CN, preferably a pict C(CH3)3 carboxylic acid, ester, amide, thioester, thiocarboxamide NS -Si or a nitrile; f 55 each R', if present, is independently selected from hydrogen, O O O (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5 41S21)— OCH C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 mem bered heteroalkyl, 3-8 membered heterocyclyl, morpholi \ 4 60 nyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered heterocyclylalkyl, 5-10 membered heteroaryl O and 6-16 membered heteroarylalkyl: each R', if present, is a suitable group independently selected -- from =O, —OR", (C1-C3) haloalkyloxy, —OCF, =S, C(CH3)3 65 - SR", =NR", =NOR, NRR, halogen, CF, CN, NC, OCN, -SCN, NO, NO. —N, —N, -S(O)R', -S(O),R, -S(O),OR', -S(O) US 8,673,881 B2 57 58 NRR, S(O)NR'R, OS(O)R, OS(O).R, OS Exemplary compounds of formula 5 include compound 5a, (O).OR - OS(O)NR'R'', C(O)R, C(O)OR, C(O)NR'R'', C(NH)NR'R'', C(NR)NR'R'',

C(NOH)R, C(NOH)NR'R'', OC(O)R, OC(O) (5a) OR, OC(O)NR'R'', OC(NH)NR'R'', OC(NR) NRR, -NHC(O)I.R, NRC(O)I.R, -NHC (O)IOR, NRC(O)IOR, NHC(O)NRR, -NRC(O)I.NRR, -NHC(NH)NR'R'' and NRC(NR) NRR): 10 each R, if present, is independently a protecting group or R', or, alternatively, two R taken together with the nitrogen atom to they are bonded form a 5 to 8-membered hetero cyclyl or heteroaryl which optionally including one or compound 5b, more additional heteroatoms and optionally substituted 15 with one or more of the same or different R or suitable R” groups; (5b) each n independently is an integer from 0 to 3: OH each Rindependently is a protecting group or R', or pharmaceutically acceptable salts thereof. Exemplary compounds of formula 4 include compound 4a, HG 25 (4a) and pharmaceutically acceptable salts and esters thereof. Additional compounds Suitable for use in methods and compositions of the invention include those of Formula 6, 30

compound 4b. 35

(4b)

40 or pharmaceutically acceptable salts thereof, wherein: the stereochemistry of the carbongg to carbonhh' bond is cis or trans; 45 each X represents hydrogen or taken together both X groups and pharmaceutically acceptable salts and esters thereof. represent one Substituted or unsubstituted methylene, an Additional compounds suitable for use in methods and oxygen atom, a Substituted or unsubstituted Natom, or a compositions of the invention include those of Formula 5, Sulfur atom Such that a three-membered ring is formed; and P. P. P. R. and Z are as defined above. 50 In certain embodiments, the stereochemistry of the carbon gg to carbon hh' bond is trans. Exemplary compounds of formula 6 include compound 6a,

55 (6a) HO OH

or pharmaceutically acceptable salts thereof, wherein: 60 the stereochemistry of the carbonii' to carboni' bond is cis or trans; Ps is a protecting group or hydrogen atom; and

P. P., R and Z are as defined above in formula 4. 65 In certain embodiments, the stereochemistry of the carbon ii' to carboni' bond is trans. US 8,673,881 B2 59 60 compound 6b, Exemplary compounds of formula 7 include compound 7a,

(7a)

COH,

10 HO compound 7b, and pharmaceutically acceptable salts and esters thereof. 15 Additional compounds suitable for use in methods and (7b) compositions of the invention include those of Formula 7.

COH,

25 and pharmaceutically acceptable salts and esters thereof. Additional compounds Suitable for use in methods and compositions of the invention include those of Formula 8, 30

or pharmaceutically acceptable salts thereof, wherein: Carbons e' and fare connected by a double bond or a triple bond, and when carbon e' is connected to carbon f through a double bond the stereochemistry is cis or trans; 35 Carbons g and h' are connected by a double bond or a triple bond and when carbong" is connected to carbon h' through a double bond the stereochemistry is cis or trans; OP m is 0 or 1; 40 T is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) or pharmaceutically acceptable salts thereof, wherein: alkynyl, (C5-C14) aryl, (C6-C16) arylalkyl, 5-14 mem the stereochemistry of the carbon i' to carboni' bond is cis or bered heteroaryl, 6-16 membered heteroarylalkyl, or trans; -CH=CHCHCH: m is 0 or 1; D' is CH, -CH=CHCHU or -CH=CHCHCHA; T is -(CH2) - or -(CH2). O—, where q is an integer 45 U is a branched or unbranched, substituted or unsubstituted from 0 to 6; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkoxy, aryloxy, Z is (C1-C6) alkylene optionally substituted with 1, 2, 3, 4, 5 alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycar or 6 of the same or different halogen atoms, -(CH2) - bonyl, alkoxycarbonyloxy, and aryloxycarbonyloxy O—CH2—, or —(CH2), S-CH , where p is an inte group; ger from 0 to 4: 50 A is H or —OP: R. R. and Rs each individually is substituted or unsubsti P. P. P. R. R. and Z are as defined above. tuted, branched or unbranched alkyl, alkenyl, or alkynyl In certain embodiments, the stereochemistry of the carbon group, Substituted or unsubstituted aryl group, Substituted i' to carboni' bond is cis. or unsubstituted, branched or unbranched alkylaryl group, Exemplary compounds of formula 8 include compound 8a, Calkoxy, halogen atom, —CHR —CHRR, 55 —CRRR, or a hydrogen atom; Ra is independently for each occurrence selected from (8a)

—CN, NO, or halogen; P. P. P., and Z are as defined above. 60 In certain embodiments, carbons e' and fare connected by COH, a cis double bond. In certain embodiments, carbons gandh' are connected by a double bond. In certain embodiments, carbons e' and fare connected by 65 a cis double bond and carbons g and h' are connected by a double bond. US 8,673,881 B2 61 62 compound 8b, compound 9b,

(8b) (9b) OH 21a 21 COH, OH 10 N 4

OH

(8c) and pharmaceutically acceptable salts and esters thereof. 15 Additional compounds Suitable for use in methods and compositions of the invention include those of Formula 10,

10 and pharmaceutically acceptable salts and esters thereof. Additional compounds suitable for use in methods and 25 compositions of the invention include those of Formula 9.

X OP 30

S OP

R OP3 or pharmaceutically acceptable salts thereof, wherein: 35 P. P. P. R. and Z are as defined above; and Q represents one or more Substituents and each Q individu or pharmaceutically acceptable salts thereof, wherein: ally, if present, is a halogen atom or a branched or Carbons k" and 1' are connected by a double bond or a triple unbranched, substituted or unsubstituted alkyl, alkenyl, bond, and when carbonk' is connected to carbon 1' through alkynyl, cycloalkyl, aryl, alkoxy, aryloxy, alkylcarbonyl, a double bond the stereochemistry is cis or trans; 40 arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, the stereochemistry of the carbon m' to carbon n' double bond hydroxy, cyano, carboxyl, alkoxycarbonyloxy, aryloxycar is cis or trans; bonyloxy or aminocarbonyl group. Additional compounds Suitable for use in methods and m is 0 or 1; compositions of the invention include those of Formula 1 1, D is CH or -CH=CHCHCH: 45 P. P. P. R. X., and Z are as defined above. 11 In certain embodiments, the stereochemistry of the carbon m' to carbon n' double bond is cis. In certain embodiments, carbons k and 1' are connected by 50 a cis double bond. In certain embodiments, the stereochemistry of the carbon m' to carbon n' double bond is cis and carbons k" and 1' are connected by a cis double bond. 55 Exemplary compounds of formula 9 include compound 9a, (9a) OH

COH, R OP

or pharmaceutically acceptable salts thereof, wherein:

65 P. P., P, R, and Z areas defined above. Additional compounds Suitable for use in methods and compositions of the invention include those of Formula 12, US 8,673,881 B2 63 64

12 15

10 or pharmaceutically acceptable salts thereof, wherein: P. P., and Z are as defined above. Additional compounds Suitable for use in methods and 15 compositions of the invention include those of Formula 16,

16 or pharmaceutically acceptable salts thereof, wherein: P. P., P, Q, R, and Z are as defined above. Additional compounds suitable for use in methods and compositions of the invention include those of Formula 13, 25 or pharmaceutically acceptable salts thereof, wherein:

13 P and Z are as defined above. Additional compounds Suitable for use in methods and compositions of the invention include those of Formula 17, 30

17

35

40 or pharmaceutically acceptable salts thereof, wherein: Carbons o' and p' are connected by a single or a double bond or pharmaceutically acceptable salts thereof, wherein: (e.g., a cis or trans double bond): Carbons q' and r" are connected by a single or a double bond P. P. R. R. U, and Z are as defined above. (e.g., a cis or trans double bond); and Additional compounds suitable for use in methods and 45 P. P., and Z are as defined above. compositions of the invention include those of Formula 14, Additional compounds Suitable for use in methods and compositions of the invention include those of Formula 18,

14 50 18

55

OP

60 or pharmaceutically acceptable salts thereof, wherein: the stereochemistry of the carbons' to carbon t' double bond is cis or trans; or pharmaceutically acceptable salts thereof, wherein: the stereochemistry of the carbonu' to carbon v' double bond is cis or trans; and P. P. R. R. Q, and Z are as defined above. 65 P. P. R. R. and Z are as defined above. Additional compounds suitable for use in methods and Additional compounds Suitable for use in methods and compositions of the invention include those of Formula 15, compositions of the invention include those of Formula 19, US 8,673,881 B2 65 66 Formula 23, 23

19

Formula 24, OP 10

or pharmaceutically acceptable salts thereof, wherein: 24 Carbons w' and X’ are connected by a single or a double bond; Carbons y' and z are connected by a single or a double bond; 15 and P. P., and Z are as defined above. In certain embodiments of formulae 4 to 19, each R', if present, is a suitable group independently selected from =O. Formula 25, —OR', (C1-C3) haloalkyloxy, OCF =S, SR, =NR, =NOR, NRR, halogen, -CF, CN, NC, OCN, —SCN, NO,-NO =N - N - S(O)R, S(O).R. 25 S(O), OR, S(O)NR'R', S(O)NRR, OS(O)R’, OS(O).R, OS(O), OR, OS(O)NRR, C(O)R’, 25 C(O)OR, C(O)NR'R'', C(NH)NR'R'', C(NR) NRR, C(NOH)R, C(NOH)NR'R'', OC(O)R, OC(O)OR, OC(O)NR'R'', OC(NH)NR'R'', OC (NR)NR'R'', NHC(O)I.R., INRC(O)I.R., INHC Formula 26, (O)IOR, NHC(O)NRR, NRC(O)NRR, 30 -NHC(NH)NRR and NRC(NR)NR'R''. Additional compounds suitable for use in methods and 26 compositions of the invention include those of Formula 20, 35

2O

40 Formula 27, or

27

Formula 21, 45

21

50 Formula 28,

28

Formula 22, 55

22 PO OP 60 or pharmaceutically acceptable salts of any of the above, N S COR, wherein: each P is individually selected from Hora protecting group; 2 and R is H. Calkyl (e.g., methyl, ethyl, ), Calkenyl or OP 65 Calkynyl. Exemplary compounds of formula 21 include compound 21a, US 8,673,881 B2 67 68 =NR', NONR', NR'R'', halogen, CF, CN, (21a) NC, OCN, -SCN, NO, NO =N. N. S(O)R', S(O).R', S(O),OR', S(O)NR'R'', OS(O)R', OS(O).R', OS(O),OR', OS(O), NR'R'', C(O)R, C(O)OR, C(O)NR'R'', C(NH)NR'R, OC(O)R', OC(O)OR', OC (O)NR'R'', OC(NH)NR'R'', NHC(O)R', NHC(O)OR', NHC(O)NR'R'' and NHC(NH) and pharmaceutically acceptable salts and esters thereof. NRel Rel; Additional compounds suitable for use in methods and 10 each R' is independently selected from hydrogen, (C1-C4) compositions of the invention include those of Formula 29, alkyl, (C2-C4) alkenyl or (C2-C4) alkynyl; and each R" is independently an R' or, alternatively, RR taken together with the nitrogenatom to which it is bonded 29 15 forms a 5 or 6 membered ring. R102 OH R101 l In certain embodiments of Formula 29, when X—Y is —CH2CH, then at least one of Rio, Rio or Ros is other 2 21 21 D-E. 5 A1 W than hydrogen. Fl 18 - XI In certain embodiments, a compound of Formula 29 is NG; S Ny. represented by Formula 30, R103 OH 30 and pharmaceutically acceptable salts, hydrates and Solvates thereof, wherein: 25 R102 OH VJ D-E and F-G are independently are cis or trans-C=C- an 21 D-E, A1 W or —C=C : Ro, Ro and Ros are independently selected from hydro F1 NG N X Ny. gen, (C1-C4) straight-chained or branched alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) alkoxy, —CHR, 30 R103 OH —CHRio Rio and —CRio RoRo; each Roa is independently selected from CN, NO, and and pharmaceutically acceptable salts, hydrates and Solvates halogen; thereof, wherein: W is selected from —Rios —ORios —SRios and D-E and F-G are independently are cis or trans-C=C- —NRos Rios: 35 or —C=C- and each Ros is independently selected from hydrogen, (C1-C6) Rio, Ro2, Rios. Ro4. W. Rios: A1, X1, n. Y1, Roo R', and alkyl, (C2-C6) alkenyl or (C2-C6) alkynyl optionally sub R" are as defined above. stituted with one or more of the same or different R groups, (C5-C14) aryl optionally substituted with one or more of Additional compounds Suitable for use in methods and the same or different R groups, phenyl optionally Substi 40 compositions of the invention include those of Formulae 31 to tuted with one or more of the same or different R groups, 37 (C6-C16) arylalkyl optionally substituted with one or more of the same or different R groups, 5-14 membered het eroaryl optionally substituted with one or more of the same 31 or different R groups, 6-16 membered heteroarylalkyl 45 optionally substituted with one or more of the same or different R groups and a detectable label molecule: A is selected from (C1-C6) alkylene optionally substituted with 1,2,3,4, 5 or 6 of the same or different halogenatoms, —(CH), O—CH2— and —(CH2), S-CH2—, 50 where m is an integer from 0 to 4: 32 X is selected from —(CH), and —(CH), O—, where n is an integer from 0 to 6: Y is selected from hydrogen, (C1-C6) alkyl, (C2-C6) alk enyl, or (C2-C6) alkynyl, optionally substituted with one or 55 more of the same or different Roo groups, (C5-C14) aryl optionally substituted with one or more of the same or different Roo groups, phenyl, optionally substituted with one or more of the same or different Roo groups, (C6-C16) 33 arylalkyl optionally substituted with one or more of the 60 same or different Roo groups, 5-14 membered heteroaryl optionally substituted with one or more of the same or different Roo groups, 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different Roo groups and a detectable label molecule: 65 each Roo is independently selected from an electronegative group, =O. —OR'', (C1-C3) haloalkyloxy, =S, SR', US 8,673,881 B2 69 70 -continued E is hydroxyl, alkoxy, aryloxy, amino, alkylamino, dialky

34 lamino, or arylamino; Rh, Ri and Rj are independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or heteroaryl; R is selected from hydrogen, alkyl, perfluoroalkyl, alkenyl, alkynyl, aryl, heteroaryl, fluoro, hydroxyl, alkoxy, aryloxy; Rs is selected from i-iv as follows: i) CHCH(R)CH, where R is hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, 35 10 aryl, heteroaryl, fluoro, hydroxyl or alkoxy; ii) CHC (RR)CH2, where RandR, are each independently alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, or fluoro, or R and R, are connected together to form a carbocyclic or hetero cyclic ring; iii) CHOCH, CHC(O)CH, or CHCH; or 15 iv) Rs is a carbocyclic, heterocyclic, aryl or heteroaryl ring: and Rs and Ro are independently selected from hydrogen, alkyl, 36 alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or heteroaryl, or Rs and Ro are connected together to form a carbocyclic or heterocyclic ring; or pharmaceutically acceptable salts thereof. In certain embodiments Rs and Ro are hydrogen. In certain embodiments, a pharmaceutically acceptable 25 salt of the compound is formed by derivatizing E, wherein E 37 is —OM, where M is a cation selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn. Additional compounds Suitable for use in methods and compositions of the invention include those of Formulae 30 39-44,

S. -Sk 39

ORf ORe O and pharmaceutically acceptable salts, hydrates and Sol 35 vates thereof, wherein: E, Ro is —OH, - OCH —OCH(CH), or - NHCHCH: and Rioz is 40 ORf ORe O 21N 21 S E,

--()- O { / ( ) 45 \ SiR Additional compounds suitable for use in methods and 41 compositions of the invention include those of Formula 38. ORf 50

38 ~- Rs E, 42 ORf 55 -- Rg E, 60 SiR wherein 43 Carbons aa' and bb' are connected by a double bond or a triple R9 Ri ORf ORe O bond; Carbons cc' and dd' are connected by a double bond or a triple bond; Re, Rf, and Rg are independently selected from hydrogen, 65 alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl (e.g., alkoxya \ X----- E, cyl, aminoacyl), aminocarbonyl, alkoxycarbonyl, or silyl; US 8,673,881 B2 71 72 -continued independently designates a double or triple bond; 44 R", R, and R are each independently OR, OX', SR, SX, R9 Ri ORf ORe Q N(R), NHX, NRC(O)R, NRC(O)N(R), C(O)OR, C(O) Rs ul N(R), SOR, NRSOR, C(O)R, or SON(R): 41S21)- Rs E, each Ris independently selected from hydrogen oran option ally substituted group selected from Caliphatic, a 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitro SiR3 gen, oxygen, or Sulfur, or, 10 two R on the same nitrogen are taken together with the nitro gento form a 5-8 membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitro gen, oxygen, or Sulfur, and pharmaceutically acceptable salts thereof, wherein: 15 each X is independently a suitable hydroxyl protecting Re, Rf, E., Ri, Rs. Rs and R are as defined above. group; Exemplary compounds of formulae 39, 41, and 43 include: each X is independently a suitable thiol protecting group; each X is independently a suitable amino protecting group; and 45 R is NRC(O)R, NRC(O)N(R), C(O)CR, C(O)N(R), OH SOR, NRSOR, C(O)R, or SON(R). Additional compounds Suitable for use in methods and OH, compositions of the invention include those of Formula 47: 25

(47) and pharmaceutically acceptable salts and esters thereof. 30 In certain embodiments, a pharmaceutically acceptable salt of the compound is formed by derivatizing E, wherein E is —OM, where M is a cation selected from ammonium, tetra-alkyl ammonium, Na, K. Mg, and Zn. Examples of Such 35 compounds include compound Z.

40 OH OH O or a pharmaceutically acceptable salt or prodrug thereof, ONa. wherein: the stereochemistry of the carbonkk to carbon 11 double bond 45 is cis or trans; the stereochemistry of the carbon mm' to carbon nin' double bond is cis or trans; the stereochemistry of the carbon oo' to carbon pp' double Additional compounds suitable for use in methods and 50 bond is cis or trans; compositions of the invention include those of Formula 46, Y' is a bond or a linker selected from a ring containing up to 20 atoms or a chain of up to 20 atoms, provided that Y can include one or more nitrogen, oxygen, Sulfur or phospho 46 rous atoms, further provided that Y can include one or 55 more Substituents independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, Oxo, thio, alkylthio, arylthio, acylthio, alkylsul 60 fonate, arylsulfonate, phosphoryl, or Sulfonyl, further pro vided that Y can contain one or more fused carbocyclic, heterocyclic, aryl or heteroaryl rings; Z is selected from –CN, -C(NH)N(R") (R"), C(S)-A', C(S)R", C(O)-A", C(O) R", C(O) SR", 65 —C(O) NH S(O). R", S(O)-A', -S(O). R", or a pharmaceutically acceptable salt or prodrug thereof, S(O)N(R") (R"), -P(O)-A'. -PO(OR")-A', -tetrazole, wherein: alkyltetrazole, or —CH2OH, wherein US 8,673,881 B2 73 74 A is selected from OR", N(R")(R") or - OM': compound 48b. each R" is independently selected from hydrogen, alkyl, (48b) aryl, arylalkyl, heteroaryl, heteroarylalkyl or a detect able label molecule, wherein any alkyl-, aryl- or het eroaryl-containing moiety is optionally Substituted with up to 3 independently selected substituents; and M" is a cation. In certain embodiments, a compound of formula 47 is represented by formula 48, 10

(48)

15

compound 48c,

(48c)

25 or pharmaceutically acceptable salts and esters thereof, wherein: 30 the stereochemistry of the carbonkk' to carbon ll' double bond is cis or trans; the stereochemistry of the carbon mm' to carbon nin' double bond is cis or trans; the stereochemistry of the carbon oo' to carbon pp' double 35 bond is cis or trans. or pharmaceutically acceptable salts and esters thereof. In certain embodiments, the stereochemistry of the carbon In certain embodiments, a compound of formula 47 is kk" to carbon 11 double bond is trans. represented by formula 48d, In certain embodiments, the stereochemistry of the carbon 40 mm' to carbon nin' double bond trans.

(48d) In certain embodiments, the stereochemistry of the carbon oo' to carbon pp' double bond is cis. In certain embodiments, the stereochemistry of the carbon 45 kk' to carbon ll' double bond is trans, the stereochemistry of the carbon mm' to carbon nin' double bond trans, and the stereochemistry of the carbon oo' to carbon pp'double bond is C1S. In certain embodiments, a compound of formula 47 is 50 represented by compound 48a, (48a) 21 N

HO 55

2 COH, or pharmaceutically acceptable salts and esters thereof, wherein: the stereochemistry of the carbonkk to carbon 11 double bond 60 N OH is cis or trans; the stereochemistry of the carbon mm' to carbon nin' double N N bond is cis or trans; the stereochemistry of the carbon oo' to carbon pp' double 65 bond is cis or trans. Additional compounds Suitable for use in methods and compositions of the invention include those of Formula 49, US 8,673,881 B2 76 or pharmaceutically acceptable salts and esters thereof. (49) The compounds above (e.g., compounds of formula A or formulae 1 to 49) are known to be useful in the treatment or prevention of inflammation or inflammatory disease. Examples of Such compounds are disclosed in the following patents and applications: US 2003/0191184, WO 2004/ 0.14835, WO 2004/078143, U.S. Pat. No. 6,670,396, US 2003/023.6423, US 2005/0228047, US 2005/023.8589 and US2005/0261255. These compounds are suitable for use in 10 or a pharmaceutically acceptable salt or prodrug thereof, methods and compositions of the present invention. Additional compounds Suitable for use in methods and wherein: compositions of the invention are compounds that are chemi Y' is a bond or a linker selected from a ring containing up to cally similar variants to any of the compounds of formula A or 20 atoms or a chain of up to 20 atoms, provided that Y can formulae 1-49 or I-III set forth above. The term “chemically include one or more nitrogen, oxygen, Sulfur or phospho 15 similar variants' includes, but is not limited to, replacement rous atoms, further provided that Y can include one or of various moieties with known biosteres; replacement of the more Substituents independently selected from hydrogen, end groups of one of the compounds above with a correspond alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, ing end group of any other compound above, modification of bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino, the orientation of any double bond in a compound, the alkylamino, dialkylamino, acylamino, carboxamido, replacement of any double bond with a triple bond in any cyano, oxo, thio, alkylthio, arylthio, acylthio, alkylsul compound, and the replacement of one or more Substituents fonate, arylsulfonate, phosphoryl, or Sulfonyl, further pro present in one of the compounds above with a corresponding vided that Y can contain one or more fused carbocyclic, Substituent of any other compound. heterocyclic, aryl or heteroaryl rings; compounds Suitable for use in the methods and Z is selected from –CN, -C(NH)N(R") (R"), C(S)-A', 25 compositions of this invention include those of formula 50: C(S)R", C(O)-A", C(O) R", C(O). SR", —C(O) NH-S(O). R", S(O)-A', S(O). R", S(O)N(R")(R"), -P(O)-A'. -PO(OR")-A', -tetrazole, QH R302 alkyltetrazole, or —CHOH, wherein A is selected from OR", N(R")(R") or - OM': 30 each R" is independently selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or a detect able label molecule, wherein any alkyl-, aryl- or het eroaryl-containing moiety is optionally Substituted with 35 up to 3 independently selected substituents; and R306 Y301 M" is a cation; and each of R'' and R is independently for each occurrence selected from OR', or adjacent R and R'' are taken wherein: together to form an epoxide ring having a cis or trans X is Rso, OR so, or SR-so: configuration, wherein each R' is independently selected 40 from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, Rao is acyl, silyl alkoxyacyl, aminoacyl, aminocarbonyl, alkoxy (a) a hydrogen atom; carbonyl, or a protecting group. (b) an alkyl of 1 to 8 carbonatoms, inclusive, which may be Exemplary compounds of formula 49 include compound straight chain or branched; 49a, 45 (c) a cycloalkyl of 3 to 10 carbon atoms: (d) an aralkyl of 7 to 12 carbon atoms; (e) phenyl, (49a) (f) substituted phenyl 50

Zii 55 compound 49b, Z Ziv

(49b) 60 wherein Z, Z, Z, Z, and Z are each independently selected from —NO. —CN, —C(=O)—Ro, —SOH, a hydrogen atom, halogen, methyl, —OR, wherein R is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl, 65 wherein when any of Z, Z, Z, Z, or Z is C(=O)— Roi, said Z, Z, Z, Z or Z is not substituted with another C(=O)—Ro. US 8,673,881 B2 77 78 (g) a detectable label molecule; or -continued (h) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive; Q is (C=O), SO or (CN), provided when Q is CN, then X is absent; Q and Q are each independently O, S or NH; one of Ro and Ros is a hydrogen atom and the other is: (a) H: (b) an alkyl of 1 to 8 carbonatoms, inclusive, which may be 10 a straight chain or branched; (c) a cycloalkyl of 3 to 6 carbon atoms, inclusive; (d) analkenyl of 2 to 8 carbonatoms, inclusive, which may be straight chain or branched; or 15 (e) RQR, wherein Q is —O— or —S—, wherein R is alkylene of 0 to 6 carbons atoms, inclusive, which may wherein: be straight chain or branched and wherein R, is alkyl of each Ro, is independently selected from hydrogen and 0 to 8 carbon atoms, inclusive, which may be straight straight, branched, cyclic, Saturated, or unsaturated alkyl hav chain or branched, provided when R is 0, then R is a ing from 1 to 20 carbon atoms; hydrogen atom; Raos, R-soo. Rao, Rs 19, and R320 are independently selected Rao.4 is from: (a) H: (a) hydrogen; (b) an alkyl of 1 to 6 carbonatoms, inclusive, which may be (b) straight, branched, cyclic, Saturated, or unsaturated 25 alkyl having from 1 to 20 carbon atoms: a straight chain or branched; (c) substituted alkyl having from 1 to 20 carbon atoms, Raos is wherein the alkyl is substituted with one or more sub stituents selected from halo, hydroxy, lower alkoxy, ary loxy, amino, alkylamino, dialkylamino, acylamino, ary 30 lamino, hydroxyamino, alkoxyamino, alkylthio. arylthio, carboxy, carboxamido, carboalkoxy, aryl, and heteroaryl; (d) substituted aryl or heteroaryl, wherein the aryl or het eroaryl is substituted with one or more substituents 35 Selected from alkyl, cycloalkyl, alkoxy, halo, aryl, het eroaryl, carboxyl, and carboxamido; and (e) Z Y, wherein: wherein Z, Z, Z,Z. Z, and Z are defined as above: Z is selected from a straight, branched, cyclic, Saturated, or R-soo is unsaturated alkyl having from 1 to 20 carbon atoms; Substi (a) H: 40 tuted lower alkyl, wherein the alkyl is substituted with one or (b) an alkyl from 1 to 4 carbon atoms, inclusive, straight more Substituents selected from halo, hydroxy, lower alkoxy, chain or branched; aryloxy, amino, alkylamino, dialkylamino, acylamino, ary wherein Yo is —OH, methyl, -SH, an alkyl of 2 to 4 lamino, hydroxyamino, alkoxyamino, alkylthio, arylthio, car carbonatoms, inclusive, straight chain or branched, analkoxy boxy, carboxamido, carboalkoxy, aryl, and heteroaryl; and 45 substituted aryl or heteroaryl, wherein the aryl or heteroaryl is of 1 to 4 carbonatoms, inclusive, or (CH),(Z), wherep+q 3. substituted with one or more substituents selected from alkyl, p–0 to 3, q 0 to 3 and Z is cyano, nitro or a halogen; and cycloalkyl, alkoxy, halo, aryl, heteroaryl, carboxyl, and car T is O or S, and pharmaceutically acceptable salts thereof. boxamido; and Lipoxin compounds Suitable for use in the methods and Y is selected from hydrogen; alkyl, cycloalkyl; carboxyl: compositions of this invention include those of formulae 51, 50 carboxamido: aryl; heteroaryl; substituted aryl or heteroaryl, 52, 53 or 54: wherein the aryl or heteroaryl is substituted with one or more Substituents selected from alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaryl, carboxyl, and carboxamido; and R to Rs are independently selected from: (a) hydrogen; (b) halo: (c) straight, branched, cyclic, Saturated, or unsaturated alkyl having from 1 to 20 carbon atoms: (d) substituted alkyl having from 1 to 20 carbon atoms, wherein the alkyl is substituted with one or more sub stituents selected from halo, hydroxy, lower alkoxy, ary loxy, amino, alkylamino, dialkylamino, acylamino, ary lamino, hydroxyamino, alkoxyamino, alkylthio. arylthio, carboxy, carboxamido, carboalkoxy, aryl, and heteroaryl; (e) substituted aryl or heteroaryl, wherein the aryl or het eroaryl is substituted with one or more substituents US 8,673,881 B2 79 80 Selected from alkyl, cycloalkyl, alkoxy, halo, aryl, het -continued eroaryl, carboxyl, and carboxamido; or Ros to Ro are independently a bond that forms a carbon carbon double bond, a carbon-carbon triple bond, or a ring (forms ring) with the lipoxin backbone; or

any two of Ro, to Ro are taken together with the atoms to e which they are bound and optionally to 1 to 6 oxygen atoms, 1 to 6 nitrogen atoms, or both 1 to 6 oxygen atoms and 1 to 6 nitrogen atoms, to form a ring containing 3 to 20 atoms. 10 Xois R41, OR41, or SR41: Lipoxin compounds Suitable for use in the methods and Rail is compositions of this invention include those of formula 55: (a) a hydrogen atom; (b) an alkyl of 1 to 8 carbonatoms, inclusive, which may be (55) straight chain or branched; 15 (c) a cycloalkyl of 3 to 10 carbon atoms: (d) an aralkyl of 7 to 12 carbon atoms; r R401 (e) phenyl, R402 (f) substituted phenyl wherein: Rao is selected from: Ziii HO 25 Z Ziv

wherein Z, Z, Z, Z, and Z are each independently 30 selected from —NO. —CN, —C(=O)—R. —SOH, a hydrogen atom, halogen, methyl, —OR, wherein R is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl, wherein when any of Z, Z, Z, Z, or Z is C(=O)— 35 R, said Z, Z, Z, Z, or Z is not substituted with another C(=O)—R. (g) a detectable label molecule; or (h) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive; 40 (CH2)ls OR421; Q is (C=O), SO, or (CN); 2. Q is O, S or NH; R. R.4135 one of R and R is a hydrogen atom and the other is selected from: (a) H: Rao is selected from: 45 (b) an alkyl of 1 to 8 carbonatoms, inclusive, which can be straight chain or branched;

(c) a cycloalkyl of 3 to 6 carbon atoms, inclusive; (d) an alkenyl of 2 to 8 carbon atoms, inclusive, which can be straight chain or branched; or 50 (e) RQR wherein Q is —O— or —S—, wherein e 2. R4 1."Y40 Y402 nY40 Y402 Ra is alkylene of 0 to 6 carbons atoms, inclusive, which can be straight chain or branched and wherein R is (forms ring) alkyl of 0 to 8 carbon atoms, inclusive, which can be straight chain or branched; 55 Ras, and Ras, are each independently: (a) H: (b) an alkyl of 1 to 8 carbonatoms, inclusive, which can be straight chain or branched; (c) a cycloalkyl of 3 to 6 carbon atoms, inclusive; 60 (d) an alkenyl of 2 to 8 carbon atoms, inclusive, which can be straight chain or branched; or (e) Ras Q-Ras wherein Ras, Q2, and R4s are as defined above; R44 is 65 (a) H: (b) an alkyl of 1 to 6 carbon atoms, inclusive, can be straight chain or branched; US 8,673,881 B2 81 82 R4s is R22 and R42s are each independently: (a) an alkyl of 1 to 9 carbon atoms which can be straight (a) H: chain or branched; (b) a hydroxyl, or a thiol: (b) —(CH)—R, (c) a methyl or a halomethyl; wherein n=0 to 4 and R, is 5 (d) a halogen; or (i) a cycloalkyl of 3 to 10 carbon atoms, inclusive: (e) an alkoxy of 1 to 3 carbon atoms; (ii) a phenyl; or R424 and R42s are each independently: (iii) substituted phenyl (a) H: (b) a hydroxyl, or a thiol: 10 (c) a methyl or a halomethyl; (d) a halogen; (e) an alkoxy of 1 to 3 carbon atoms; or (f) an alkyl or haloalkyl of 2 to 4 carbon atoms inclusive, which can be straight chain or branched; and 15 R426 is (a) a Substituted phenyl

wherein Z, through Zare as defined above: (b) Ras Q-Ras, wherein Ras, Q2, and Ras are as defined above; (c) —C(R)(R)-R, wherein R, and Rare each independently: (i) a hydrogen atom; (ii) (CH),(Z), wherein Z. p, and q are as defined above: 25 (e) a haloalkyl of 1 to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, straight chain or branched; wherein Z, through Zare as defined above: Rao is (b) a substituted phenoxy (a) H: 30 (b) an alkyl from 1 to 4 carbon atoms, inclusive, straight Zi Zii chain or branched; (c) a halogen; one of Yao or Yao is —OH, methyl, or—SH, and wherein the other is selected from: 35 (a) H: – O -- Ziii (b)(CH), (Z), where p+q3, p=0 to 3, q=0 to 3 and each Z. Z Ziv independently, is cyano, nitro or a halogen; (c) an alkyl of 2 to 4 carbonatoms, inclusive, straight chain wherein Z, through Z are as defined above; or or branched; or 40 (c) (d) an alkoxy of 1 to 4 carbon atoms, inclusive, or Yao and Yao taken together are: (d) —NH; or Zi Zii (e)=O: one of Yao or Yao is —OH, methyl, or—SH, and wherein 45 the other is selected from: (a) H: (b) (CH),(Z), wherein Z. p, and q are as defined above; --Z Ziv (c) an alkyl of 2 to 4 carbonatoms, inclusive, straight chain or branched; or 50 (d) an alkoxy of 1 to 4 carbon atoms, inclusive, wherein Z, through Zare as defined above. or Yao and Yao taken together are: Lipoxin compounds Suitable for use in the methods and (a)=NH; or compositions of this invention include those of formula 56: (b)=O; one of Yaos or Yao is —OH, methyl, or—SH, and wherein 55 the other is selected from: (56) (a) H (b) (CH),(Z), wherein Z. p, and q are as defined above; (c) an alkyl of 2 to 4 carbonatoms, inclusive, straight chain or branched; or 60 (d) an alkoxy of 1 to 4 carbon atoms, inclusive, or Yao and Yao taken together are: (a)=NH; or (b)=O; R42 is 65 (a) H; or (b) alkyl of 1 to 8 carbon atoms: US 8,673,881 B2 83 84 wherein: ents selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, E is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialky heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, ary lamino or —OM, where M is a cation selected from ammo loxy, carboxy, amino, alkylamino, dialkylamino, acylamino, nium, tetra-alkyl ammonium, and the cations of Sodium, carboxamido, cyano, Oxo, thio, alkylthio, arylthio, acylthio. potassium, magnesium and Zinc; alkylsulfonate, arylsulfonate, phosphoryl, and Sulfonyl, and W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, further provided that J and K" can also contain one or more halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, fused carbocyclic, heterocyclic, aryl or heteroaryl rings, and dialkylamino, acylamino, carboxamido, or Sulfonamide; provided that linkers J and K" are connected to the adjacent each of Rso-Rs are independently selected from hydro C(R)OR group via a carbon atom or a C-heteroatom bond gen, alkyl, aryl, acyl or alkoxyacyl: 10 where the heteroatomis oxygen, Sulfur, phosphorous or nitro n is 0, 1 or 2; gen, m is 1 or 2; and G is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, the two Substituents on the phenyl ring are ortho, meta, or heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, ary para. loxy, carboxy, amino, alkylamino, dialkylamino, acylamino, Lipoxin compounds Suitable for use in the methods and 15 and carboxamido. compositions of this invention include those of formula 57: Re, Rf and Rg, are independently selected from hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl: Roo, Rao and Roos are independently selected from (57) hydrogen, alkyl, aryland heteroaryl, provided that Rao, Rao and Reo can independently be connected to linkers J or K'; R604 Rao and Roos are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, fluoro, and provided that Reo and Roos can be joined together to form a carbocy R605 clic, heterocyclic or aromatic ring, and further provided that 25 Roa and Ros can be replaced by a bond to form a triple bond. Other compounds suitable for use in the methods and com positions of the invention are the oxylipins described in inter wherein: national applications WO 2006055965, WO 2007090162, I is selected from: C(O)-E, -SO-E, PO(OR)-E, and WO2008103753 the compounds in which are incorpo where E is hydroxy, alkoxy, aryloxy, amino, alkylamino, 30 rated herein by reference. Examples of Such compounds are dialkylamino, or —OM, where M is a cation selected from those of formulae 58-132, as shown in Table 2. These com ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn; and pounds include long chain omega-6 fatty acids, docosapen R is hydroxyl or alkoxy taenoic acid (DPAn-6) (compounds 58-73) and docosatet J and K" are linkers independently selected from a chain of raenoic acid (DTAn-6) (compounds 74-83), and the omega-3 up to 20 atoms and a ring containing up to 20 atoms, provided 35 counterpart of DPAn-6, docosapentaenoic acid (DPAn-3) that J'and K" can independently include one or more nitrogen, (compounds 84-97). Further compounds are the docosanoids oxygen, Sulfur or phosphorous atoms, and further provided 98-115, the Y-linolenic acids (GLA) (compounds 116-122), that J'and K" can independently include one or more substitu and the stearidonic acids (SDA) (compounds 123-132). TABLE 2 10,17-Dihydroxy DPAn-6 (58) CO2H

16,17-Dihydroxy DPAn-6 o o o CO2H (59) \ 4

HO OH

4,5-Dihydroxy DPAn-6 HO OH (60) o 21 N CO2H

7,17-Dihydroxy DPAn-6 OH (61) o 21 o CO2H 1s

OH

US 8,673,881 B2 95 96 TABLE 2-continued

10.11 epoxy DPA (112) CO2H

19.20 epoxy DPA CO2H (113)

7-hydroxy DHA (114) CO2H

13,14 epoxy DPA CO2H (115)

6-hydroxy GLA (116)

10-hydroxy GLA (117)

7-hydroxy GLA (118)

12-hydroxy GLA (119)

9-hydroxy GLA (120)

13-hydroxy GLA (121) US 8,673,881 B2 97 98 TABLE 2-continued

6.13 dihydroxy GLA (122)

6-hydroxy SDA (123)

10-hydroxy SDA (124)

7-hydroxy SDA (125)

12-hydroxy SDA (126)

9-hydroxy SDA (127)

13-hydroxy SDA (128)

15-hydroxy SDA (129)

16-hydroxy SDA (130)

6.13 dihydroxy SDA (131) US 8,673,881 B2 99 100 TABLE 2-continued 6.16 dihydroxy SDA (132)

Other oxylipin compounds that are suitable for use in a compound of any one of formulae 1-49, a lipoxin com methods and compositions of the invention include analogs of pound, oran oxylipincompound) per treated eye per day, e.g., the compounds shown in Table 2. Such compounds include up to 100, 150, 200, 250, 300, 400, or even up to 550 nano but are not limited to those analogs wherein one or more 15 moles per treated eye per day. For example, the methods of double bonds are replaced by triple bonds, those wherein one treating or preventing an ophthalmic condition comprise or more carboxy groups are derivatized to form esters, amides administering from 7 to 550 nanomoles of any of the com or salts, those wherein the hydroxyl-bearing carbons are fur pounds described above (e.g., a compound of any of formulae ther derivatized (with, for example, a substituted or unsubsti I-IX, a compound of formula A, a compound of any one of tuted, branched or unbranched alkyl, alkenyl, or alkynyl formulae 1-49, a lipoxin compound, or an oxylipin com group, Substituted or unsubstituted aryl group, Substituted or pound) per treated eye per day, such as from 7 to 400 nano unsubstituted, branched or unbranched alkylaryl group, halo moles, from 7 to 300 nanomoles, from 7 to 250 nanomoles, gen atom) to form tertiary (or ethers, esters, or other from 7 to 200 nanomoles, from 7 to 150, or from 7 to 100 derivatives thereof), those wherein one or more hydroxyl nanomoles of any of the compounds described above (e.g., a groups are derivatized to form esters or protected alcohols, or 25 compound of any of formulae I-IX, a compound of formula A, those having combinations of any of the foregoing modifica a compound of any one of formulae 1-49, a lipoxin com tions. pound, or an oxylipin compound) per treated eye per day. In Further oxylipin compounds suitable for use in methods certain embodiments, the methods of treating or preventing and compositions of the invention include the following: an ophthalmic condition comprise administering from 10 to isolated docosanoids of docosapentaenoic acid (DPAn-6); 30 550 nanomoles of any of the compounds described above monohydroxy, dihydroxy, and trihydroxy derivatives of (e.g., a compound of any of formulae I-IX, a compound of DPAn-6; isolated docosanoids of docosapentaenoic acid formula A, a compound of any one of formulae 1-49, a lipoxin (DPAn-3); monohydroxy, dihydroxy, and trihydroxy deriva compound, oran oxylipin compound) per treated eye per day, tives of DPAn-3; isolated docosanoids of docosapentaenoic such as from 10 to 400 nanomoles, from 10 to 300 nanomoles, acid (DTAn-6); or monohydroxy, dihydroxy, and trihydroxy 35 from 10 to 250 nanomoles, from 10 to 200 nanomoles, from derivatives of DTAn-6. 10 to 150, or from 10 to 100 nanomoles of any of the com In certain embodiments, the present invention provides pounds described above (e.g., a compound of any of formulae methods of treating or preventing an ophthalmic condition I-IX, a compound of formula A, a compound of any one of (such as dry eye), comprising administering an effective formulae 1-49, a lipoxin compound, or an oxylipin com amount of any one or more of the compounds described above 40 pound) per treated eye per day. In certain embodiments, the (e.g., a compound of any of formulae I-IX, a compound of methods of treating or preventing an ophthalmic condition formula A, a compound of any one of formulae 1-49, a lipoxin comprise administering from 15 to 550 nanomoles of any of compound, or an oxylipin compound), e.g., as an aqueous the compounds described above (e.g., a compound of any of Solution as described herein, such as topically to the eye, e.g., formulae I-IX, a compound of formula A, a compound of any as eye drops. In certain Such embodiments, the methods of 45 one of formulae 1-49, a lipoxin compound, or an oxylipin treating or preventing an ophthalmic condition comprise compound) per treated eye per day, such as from 15 to 400 administering greater than 6 nanomoles of any of the com nanomoles, from 15 to 300 nanomoles, from 15 to 250 nano pounds described above (e.g., a compound of any of formulae moles, from 15 to 200 nanomoles, from 15 to 150, or from 15 I-IX, a compound of formula A, a compound of any one of to 100 nanomoles of any of the compounds described above formulae 1-49, a lipoxin compound, or an oxylipin com 50 (e.g., a compound of any of formulae I-IX, a compound of pound) per treated eye per day, e.g., up to 550 nanomoles per formula A, a compound of any one of formulae 1-49, a lipoxin treated eye per day, such as from 6 to 400 nanomoles, from 6 compound, oran oxylipin compound) per treated eye per day. to 300 nanomoles, from 6 to 250 nanomoles, from 6 to 200 In certain embodiments, the methods of treating or preventing nanomoles, from 6 to 150, or from 6 to 100 nanomoles of any an ophthalmic condition may comprise administering the of the compounds described above (e.g., a compound of any 55 dosages of any of the compounds described above (e.g., a of formulae I-IX, a compound of formula A, a compound of compound of the invention, such as a compound of any of any one of formulae 1-49, a lipoxin compound, oran oxylipin formulae I-IX, a compound of formula A, a compound of any compound) per treated eye per day. In certain Such embodi one of formulae 1-49, a lipoxin compound, or an oxylipin ments, the methods of treating or preventing an ophthalmic compound) as set forth above over the course of a day through condition comprise administering greater than 7 nanomoles 60 any Suitable dosing regimen. Suitable dosing regimens may of any of the compounds shown above (e.g., a compound of include once daily dosing, twice daily dosing, three times any of formulae I-IX, a compound of formula A, a compound daily dosing, four times daily dosing, and any other Suitable of any one of formulae 1-49, a lipoxin compound, or an dosing regimen Such that the net effect throughout the course oxylipin compound) per treated eye per day, Such as greater of the day is administering the total dosages per eye per day as than 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 65 set forth above. In certain embodiments, Suitable dosing regi nanomoles of any of the compounds shown above (e.g., a mens further include once every two days dosing, Such as compound of any of formulae I-IX, a compound of formula A, every other day, or once every three days dosing, such as US 8,673,881 B2 101 102 every third day, such that the net effect throughout the course In certain embodiments, the present invention provides a of the day of dosing is administering at least the total dosages pharmaceutical preparation Suitable for treating or preventing per eye per day as set forth above. an ophthalmic condition (such as dry eye) in a human patient, As a particular example, the present invention provides comprising any one or more of the compounds shown above methods of treating or preventing an ophthalmic condition (e.g., a compound of any of formulae I-IX, a compound of (such as dry eye), comprising administering an effective formula A, a compound of any one of formulae 1-49, a lipoxin amount of compound 1001, e.g., as an aqueous solution as compound, or an oxylipin compound), and one or more phar described herein, such as topically to the eye, e.g., as eye maceutically acceptable excipients, e.g., as an aqueous solu drops. In certain Such embodiments, the methods of treating tion Suitable for topical administration to the eye. Such as eye or preventing an ophthalmic condition comprise administer 10 drops. In certain embodiments, the pharmaceutical prepara tion has a concentration over 90 micromolar of any of the ing greater than 2 micrograms of compound 1001 per treated compounds described above (e.g., a compound of any of eye per day, e.g., up to 175 micrograms per treated eye per formulae I-IX, a compound of formula A, a compound of any day, such as from 2 to 150 micrograms, from 2 to 125 micro one of formulae 1-49, a lipoxin compound, or an oxylipin grams, from 2 to 100 micrograms, from 2 to 75 micrograms, 15 compound), e.g., from 90 micromolar to 7000 micromolar, from 2 to 50 micrograms, or from 2 to 25 micrograms of such as from 90 to 5000 micromolar, 90 to 3000 micromolar, compound 1001 per treated eye per day. In certain such 90 to 2000 micromolar, or 90 to 1000 micromolar of any of embodiments, the methods of treating or preventing an oph the compounds described above (e.g., a compound of any of thalmic condition comprise administering greater than 2.5 formulae I-IX, a compound of formula A, a compound of any micrograms of compound 1001 per treated eye per day. Such one of formulae 1-49, a lipoxin compound, or an oxylipin as greater than 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9,9.5, compound). In certain embodiments, the a pharmaceutical 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, preparation has a concentration of greater than 100 micromo 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 micrograms of com lar of any of the compounds described above (e.g., a com pound 1001 per treated eye per day, e.g., up to 25, 50, 75, 100, pound of any of formulae I-IX, a compound of formula A, a 125, 150, or even up to 175 micrograms per treated eye per 25 compound of any one of formulae 1-49, a lipoxin compound, day. In certain embodiments, the methods of treating or pre or an oxylipin compound). Such as greater than 150 micro venting an ophthalmic condition comprise administering molar, greater than 200 micromolar, greater than 250 micro from 2.5 to 175 micrograms of compound 1001 per treated molar, greater than 300 micromolar, greater than 350 micro eye per day, such as from 2.5 to 150 micrograms, from 2.5 to molar, greater than 400 micromolar, greater than 450 125 micrograms, from 2.5 to 100 micrograms, from 2.5 to 75 30 micromolar, greater than 500 micromolar, greater than 550 micrograms, from 2.5 to 50 micrograms, or from 2.5 to 25 micromolar, greater than 600 micromolar, greater than 650 micrograms of compound 1001 per treated eye per day. In micromolar, greater than 700 micromolar, greater than 750 certain embodiments, the methods of treating or preventing micromolar, or greater than 800 micromolar of any of the an ophthalmic condition comprise administering from 3 to compounds described above (e.g., a compound of any of 175 micrograms of compound 1001 per treated eye per day, 35 formulae I-IX, a compound of formula A, a compound of any Such as from 3 to 150 micrograms, from 3 to 125 micrograms, one of formulae 1-49, a lipoxin compound, or an oxylipin from 3 to 100 micrograms, from 3 to 75 micrograms, from 3 compound), e.g., up to 1000 micromolar, up to 2000 micro to 50 micrograms, or from 3 to 25 micrograms of compound molar, up to 3000 micromolar, up to 5000 micromolar, or 1001 per treated eye per day. In certain embodiments, the even up to 7000 micromolar. For example, the pharmaceuti methods of treating or preventing an ophthalmic condition 40 cal preparation may have a concentration from 100 micromo comprise administering from 4 to 175 micrograms of com lar to 7000 micromolar of any of the compounds described pound 1001 per treated eye per day, such as from 4 to 150 above (e.g., a compound of any of formulae I-IX, a compound micrograms, from 4 to 125 micrograms, from 4 to 100 micro of formula A, a compound of any one of formulae 1-49, a grams, from 4 to 75 micrograms, from 4 to 50 micrograms, or lipoxin compound, or an oxylipin compound). Such as from from 4 to 25 micrograms of compound 1001 per treated eye 45 100 to 5000 micromolar, 100 to 3000 micromolar, 100 to per day. In certain embodiments, the methods of treating or 2000 micromolar, or 100 to 1000 micromolar of any of the preventing an ophthalmic condition comprise administering compounds described above (e.g., a compound of any of from 5 to 175 micrograms of compound 1001 per treated eye formulae I-IX, a compound of formula A, a compound of any per day, such as from 5 to 150 micrograms, from 5 to 125 one of formulae 1-49, a lipoxin compound, or an oxylipin micrograms, from 5 to 100 micrograms, from 5 to 75 micro 50 compound). In certain embodiments, the pharmaceutical grams, from 5 to 50 micrograms, or from 5 to 25 micrograms preparation has a concentration from 150 micromolar to 7000 of compound 1001 per treated eye per day. In certain embodi micromolar of any of the compounds described above (e.g., a ments, the methods of treating or preventing an ophthalmic compound of any of formulae I-IX, a compound of formula A, condition may comprise administering the dosages of com a compound of any one of formulae 1-49, a lipoxin com pound 1001 as set forth above over the course of a day through 55 pound, or an oxylipin compound), such as from 150 to 5000 any suitable dosing regimen. Suitable dosing regimens may micromolar, 150 to 3000 micromolar, 150 to 2000 micromo include once daily dosing, twice daily dosing, three times lar, or 150 to 1000 micromolar of any of the compounds daily dosing, four times daily dosing, and any other Suitable described above (e.g., a compound of any of formulae I-IX, a dosing regimen, such that the net effect throughout the course compound of formula A, a compound of any one of formulae of the day is administering the total dosages per eye per day of 60 1-49, a lipoxin compound, or an oxylipin compound). In compound 1001 as set forth above. In certain embodiments, certain embodiments, the pharmaceutical preparation has a Suitable dosing regimens further include once every two days concentration from 90 micromolar to 7000 micromolar of any dosing, Such as every other day, or once every three days of the compounds described above (e.g., a compound of any dosing, Such as every third day, such that the net effect of formulae I-IX, a compound of formula A, a compound of throughout the course of the day of dosing is administering at 65 any one of formulae 1-49, a lipoxin compound, oran oxylipin least the total dosages per eye per day of compound 1001 as compound), such as 250 to 5000 micromolar, 250 to 3000 set forth above. micromolar, 250 to 2000 micromolar, or 250 to 1000 micro US 8,673,881 B2 103 104 molar of any of the compounds described above (e.g., a com pharmaceutical preparations (e.g., any of the pharmaceutical pound of any of formulae I-IX, a compound of formula A, a preparations described above comprising a compound of any compound of any one of formulae 1-49, a lipoxin compound, of formulae I-IX, a compound of formula A, a compound of or an oxylipin compound). any one of formulae 1-49, a lipoxin compound, oran oxylipin As a particular example, the present invention provides a 5 compound, Such as compound 1001, and one or more phar pharmaceutical preparation Suitable for treating or preventing maceutically acceptable excipients), the pharmaceutical an ophthalmic condition (such as dry eye) in a human patient, preparation is an aqueous solution Suitable for topical admin comprising compound 1001 and one or more pharmaceuti istration to the eye wherein the solution has a pH in the range cally acceptable excipients, e.g., as an aqueous solution Suit of 5.0 to 7.4, such as from 5.0 to 7.0, or from 5.0 to 6.5, such able for topical administration to the eye, Such as eye drops. In 10 as from 5.0 to 6.0, or from 5.0 to 5.5. In certain embodiments certain embodiments, the pharmaceutical preparation has a of the foregoing, the Solution further comprises one or more concentration over 30 micrograms/milliliter (ug/mL) of com Surfactants, one or more demulscents, and/or one or more pound 1001, e.g., from 30 ug/mL to 2000 ug/mL, such as emulsifiers, such as polysorbate 80, pluronic F-147, tylox from 30 ug/mL to 1500 g/mL, 30 ug/mL to 1000 g/mL, 30 apol, polyvinylpyrrolidone (such as polyvinylpyrrolidone ug/mL to 750 ug/mL, 30 ug/mL to 500 ug/mL, 30 g/mL to 15 having an average molecular weight of 360,000, e.g., polyvi 400 ug/mL, or 30 ug/mL to 350 g/mL of compound 1001. In nylpyrrolidone K-90, Chemical Abstracts Service Registry certain embodiments, the pharmaceutical preparation has a No. 9003-39-8), mineral oil or castor oil. In certain embodi concentration of greater than 40 ug/mL of compound 1001, ments, the pharmaceutical preparation is substantially free of Such as greater than 50 ug/mL, greater than 60 ug/mL, greater preservatives. than 70 ug/mL, greater than 75 ug/mL, greater than 100 20 In certain embodiments of the present invention, a phar ug/mL, greater than 125 g/mL, greater than 150 ug/mL, maceutical preparation as set forth above (e.g., having a con greater than 175ug/mL, greater than 200 ug/mL, greater than centration as set forth above), may be administered using any 225 ug/mL, or greater than 250 ug/mL of compound 1001, Suitable dosing regimen for the treatment or prevention of an e.g., up to 350 ug/mL, up to 400 g/mL, up to 500 g/mL, up ophthalmic condition. Suitable dosing regimens for an aque to 750 ug/mL, up to 1000 ug/mL, up to 1500 g/mL, or even 25 ous eye drop Solution include administering the pharmaceu up to 2000 g/mL. For example, the pharmaceutical prepara tical preparation once, twice, three times, or four times per tion may have a concentration from 40 ug/mL to 2000ug/mL day to an affected eye. In certain embodiments, Suitable dos of compound 1001, such as from 40 ug/mL to 1500 g/mL, 40 ing regimens for an aqueous eye drop solution further include ug/mL to 1000 g/mL, 40 ug/mL to 750 ug/mL, 40 ug/mL to once every two days dosing, such as every other day, or once 500 g/mL, 40 ug/mL to 400 ug/mL, or 40 ug/mL to 350 30 every three days dosing, such as every third day, to an affected ug/mL of compound 1001. In certain embodiments, the phar eye. In certain embodiments, any particular incidence of maceutical preparation has a concentration from 50 ug/mL to administration of a pharmaceutical preparation as set forth 2000 ug/mL of compound 1001, such as from 50 lug/mL to above (e.g., having a concentration as set forth above), may 1500 ug/mL, 50 ug/mL to 1000 ug/mL, 50 ug/mL to 750 comprise administering one or more drops of the pharmaceu ug/mL, 50 ug/mL to 500 g/mL, 50 ug/mL to 400 ug/mL, or 35 tical preparation to an affected eye. In certain Such embodi 50 ug/mL to 350 ug/mL of compound 1001. In certain ments, any particular incidence of administration of a phar embodiments, the pharmaceutical preparation has a concen maceutical preparation as set forth above (e.g., having a tration from 60 g/mL to 2000 ug/mL of compound 1001, concentration as set forth above), may comprise administer such as from 60 ug/mL to 1500 lug/mL, 60 lug/mL to 1000 ing two, three, four, or five drops of the pharmaceutical prepa ug/mL, 60 g/mL to 750Lig/mL, 60 ug/mL to 500 g/mL, 60 40 ration to an affected eye. The present invention further con ug/mL to 400 g/mL, or 60 g/mL to 350 ug/mL of com templates any and all combinations of the foregoing. pound 1001. In certain embodiments, the pharmaceutical Examples of ophthalmic conditions that may be treated by preparation has a concentration from 75 g/mL to 2000 administration of a compound or formulation of the inven ug/mL of compound 1001, such as from 75 lug/mL to 1500 tion, include, but are not limited to, AIDS-related retinal ug/mL, 75ug/mL to 1000 ug/mL, 75ug/mL to 750 ug/mL, 75 45 disorders; age-related macular degeneration; alkaline erosive ug/mL to 500 ug/mL, 75ug/mL to 400 g/mL, or 75ug/mL to keratoconjunctivitis; allergic keratitis; anterior ischemic 350 g/mL of compound 1001. optic neuropathy; anterior uveitis (iridocyclitis); Behcet’s In certain embodiments of the methods of treating or pre disease; blepharitis; seborrheic blepharitis; canaliculitis; venting an ophthalmic condition (Such as dry eye), compris cataract; central serous chorioretinopathy; chorioiditis; ing administering an effective amount of any one or more of 50 chronic uveitis; Coats disease; conjunctivitis (e.g., infectious the compounds described above (e.g., a compound of any of conjunctivitis, neonatal conjunctivitis, non-infectious con formulae I-IX, a compound of formula A, a compound of any junctivitis, and allergic conjunctivitis); contact lens-induced one of formulae 1-49, a lipoxin compound, or an oxylipin keratoconjunctivitis; contact eczema, corneal ulcer (e.g., compound), e.g., as an aqueous Solution as described herein, Mooren’s ulcer, corneal ulcer Subsequent to chronic rheuma Such as topically to the eye, e.g., as eye drops, compound 55 toid arthritis or collagen disease, Terrien’s marginal degen 1001 is the preferred compound. eration, catarrhal corneal ulcer, infectious corneal ulcer); In certain embodiments of any of the foregoing pharma crystalline retinopathy; cyclitis; edema (e.g., cystoid macular ceutical preparations (e.g., any of the pharmaceutical prepa edema), dacryoadenitis, dacryocystitis; degenerative myo rations described above comprising a compound of any of pia; degenerative retinoschisis; diabetic keratophathy; dia formulae I-IX, a compound of formula A, a compound of any 60 betic macular edema; diabetic retinopathy; dry eye disease one of formulae 1-49, a lipoxin compound, or an oxylipin (e.g., dry eye of the lacrimal system or dry eye of the cornea): compound, Such as compound 1001, and one or more phar dry age-related macular degeneration; endophthalmitis; epis maceutically acceptable excipients), the pharmaceutical cleritis; exudative macular edema; Fuchs’ Dystrophy, giant preparation is an aqueous Solution Suitable for topical admin cell arteritis; giant papillary conjunctivitis; glaucoma (e.g., istration to the eye wherein the solution has a pH in the range 65 primary open angle glaucoma, primary angle closure glau of 5.5 to 7.4, such as from 5.5 to 7.0, or from 5.5 to 6.5, or from coma, secondary open angle glaucoma, secondary angle clo 5.5 to 6.0. In certain embodiments of any of the foregoing Sure glaucoma, and childhood glaucoma); glaucoma Surgery US 8,673,881 B2 105 106 failure; graft versus host disease of the eye (often a form of tosa, and glaucoma. Compounds as described herein may also dry eye); herpes Zoster (shingles); hypertensive retinopathy; induce increases in tear production and density of Superficial inflammation after cataract Surgery; iridocorneal endothelial epithelial cells, two endpoints relevant to the treatment of dry syndrome; iridocytis; iritis; keratitis (e.g., infectious keratitis, eye. non-infectious keratitis, and neuroparalytic keratitis); kerato Compounds as described herein may also reduce vascular conjunctiva sicca, keratoconjunctival inflammatory disease; leakage. Accordingly, these compounds may be useful in the keratoconus; keratopathy; lattice dystrophy; map-dot-finger treatment of age-related macular degeneration. print dystrophy, necrotic keratitis; neovascular diseases Compounds as described herein may also inhibit CD11b+ involving the retina, uveal tract or cornea Such as neovascular cells. Animal models of dry eye show an increase in CD11b+ glaucoma, corneal neovascularization (inflammatory, trans 10 cells Suggesting the increased presence of leukocytes in cor plantation, developmental hypoplasia of the iris), neovascu neas. Accordingly, these compounds may be useful in the larization resulting following a combined vitrectomy and treatment of dry eye by decreasing the arrival of leukocytes lensectomy, neovascularization of the optic nerve, and induced by dry eye. neovascularization due to penetration of the eye or contusive Compounds as described herein may also prevent pig ocular injury; non-infectious uveitis; ocular herpes; ocular 15 mented retinal destruction. Accordingly, these rosacea; ophthalmic infections (e.g., corneal herpes, bacterial compounds may be useful in the treatment of age-related keratitis, bacterial conjunctivitis, mycotic keratitis, acan macular degeneration, retinopathy of prematurity, retinitis thamebic keratitis, infectious endophthalmitis, infectious pigmentosa, and glaucoma. corneal ulcer, inflammation of the conjunctiva or cornea by In certain embodiments, different compounds of the inven staphylococci, Streptococci, enterococci, euterococci, bacil tion may be conjointly administered with other agents Suit lus, Corynebacterium, chlamydia, and neisseria); ophthalmic able for the treatment or prevention of an ophthalmic condi pemphigoid, optic disc drusen; optic neuritis; panuveitis; tion. For example, the following agents or classes of agents papilledema; papillitis; pars planitis; persistent macular may be conjointly administered with a compound of the edema; phacoanaphylaxis; posterior uveitis (chorioentinitis); invention: doxycycline; decosahexanoic acid; angiogenesis post-operative inflammation (e.g., post-LASIK inflammation 25 inhibitors, e.g., VEGF inhibitors, such as pegaptainib Sodium, of the cornea); proliferative diabetic retinopathy; prolifera bevacizumab, ranibizumab, AV-951, Vandetanib, semaxanib, tive sickle cell retinopathy; proliferative vitreoretinopathy; CBO-P11, axitinib, Sorafenib, Sunitinib, pazopanib, and retinal artery occlusion; retinal detachment; retinal vasculitis; TIMP3; anesthetics and pain killing agents such as lidocaine retinal vein occlusion; retinitis pigmentosa; retinopathy of and related compounds and benzodiazepam and related com prematurity; rubeosis iritis; Scleritis; Stevens-Johnson syn 30 pounds; anti-cancer agents such as 5-fluorouracil, adriamycin drome (erythema multiforme major); sympathetic oph and related compounds; anti-inflammatory agents such as thalmia; temporal arteritis; toxic retinopathy: uveitis (e.g., 6-mannose phosphate; anti-fungal agents such as fluconazole anterior uveitis or posterior uveitis); Vernal conjunctivitis; and related compounds; anti-viral agents such as trisodium Vitamin A insufficiency-induced keratomalacia; vitreitis; and phosphomonoformate, trifluorothymidine, acyclovir, ganci wet age-related macular degeneration. 35 clovir, DDI, DDC, and AZT cell transport/mobility impend Diseases causing dry eye include Riley-Day Syndrome, ing agents such as colchicine, Vincristine, cytochalasin B, and Shy-Drager syndrome, Sjogren syndrome, sarcoidosis, amy related compounds; antiglaucoma drugs such as beta-block loidosis, sequela of radiotherapy, lagophthalmia, avitamino ers: timolol, betaxol, atenalol, etc.; such as sis A, Stevens-Johnson syndrome, ocular pemphigoid, mar and , etc.; immunological response ginal blepharitis, meibomitis, sequela of intraocular Surgery, 40 modifiers such as muramyldipeptide and related compounds; contact-lens affection, diabetic corneal epitheliopathy, dry peptides and proteins such as cyclosporin, insulin, growth eye due to VDT operation, graft versus host disease, and the , insulin related growth factor, nerve growth factor like. Disorders caused by corneal infective disease include, (optionally in further combination with decosahexanoic for example, viral epitheliopathy and the like. Stem cell acid), heat shock proteins and related compounds; estrogen depletion syndromes include Stevens-Johnson syndrome, 45 treatments; corticosteroids Such as dexamethasone, dexam ocular pemphigoid, thermal or chemical burn, drug toxicity ethasone 21-phosphate, fluorometholone, medrysone, of idoxuridine (IDU) and therapeutic agents for glaucoma, betamethasone, triamcinolone, triamcinolone acetonide, and the like. triminolone, prednisone, prednisolone, prednisolone The present invention provides a method of inhibiting 21-phosphate, prednisolone acetate, hydrocortisone, hydro COX-2 or TNF in the eye in a patient comprising administer 50 cortisone acetate, prednicarbate, deflazacort, halomethasone, ing to said patient a compound of the invention. The present tiXocortol, prednylidene (21-diethylaminoacetate), predni invention further provides a method of protecting against val, paramethasone, prednisolone, methylprednisolone, goblet cell loss in the eye in a patient comprising administer meprednisone, maZipredone, isoflupredone, halopredone ing to said patient a compound of the invention. acetate, halcinonide, formocortal, flurandrenolide, flupred Compounds as described herein may also inhibit inflam 55 nisolone, flurprednidine acetate, fluperolone acetate, fluocor matory mediators in the cornea, such as TNF, IL-1a, IL-1b. tolone, fluocortin butyl, fluocinonide, fluocinolone, fluocino IL-6, and IL-8. Accordingly, these compounds may be useful lone acetonide, flunisolide, flumethasone, fludrocortisone, in the treatment of dry eyes diseases, age-related macular fluclorinide, fluoromethalone, enoxolone, difluprednate, degeneration, retinopathy of prematurity, uveitis, and glau diflucortolone, diflorasone diacetate, desoximetasone (des COa. 60 oxymethasone), desonide, descinolone, cortivaZol, corticos Compounds as described herein may also inhibit COX-2 in terone, cortisone, cloprednol, clocortolone, clobetaSone, clo the cornea. Accordingly, these compounds may be useful in betasol, chloroprednisone, cafestol, budesonide, the treatment of dry eyes diseases. beclomethasone, amcinonide, allopregnane acetonide, Compounds as described herein may also guard against alclometaSone, 21-acetoxypregnenolone, tralonide, diflo goblet cell loss. Accordingly, these compounds may be useful 65 rasone acetate, deacylcortivazol, RU-26988, budesonide, and in the treatment of dry eye diseases, age-related macular deacylcortivazol oxetanone. All of the above-cited corticos degeneration, retinopathy of prematurity, retinitis pigmen teroids are known compounds. Further information about the US 8,673,881 B2 107 108 compounds may be found, for example, in The Merck Index, laser treatment (e.g., photocoagulation or photodynamic Thirteenth Edition (2001), and the publications cited therein, therapy), macular translocation Surgery or with devices (e.g., the entire contents of which are hereby incorporated herein by brimonidine tartrate implant). reference. In certain embodiments, the corticosteroid is In certain embodiments, different compounds of the inven selected from fluocinolone acetonide, triamcinolone tion may be conjointly administered with one or more other acetonide, dexamethasone, and related compounds, or any compounds of the invention. Moreover, Such combinations combination thereof; and carbonic anhydaze inhibitors. may be conjointly administered with other therapeutic Further examples of agents or classes of agents may be agents, such as other agents suitable for the treatment or conjointly administered with a compound of the invention prevention of an ophthalmic condition, Such as the agents include: DE-104; PF-04217329; PF-03187207; AL 37807; 10 identified above. OPC-12759; chemotherapeutic agents such as mitomycin C: In certain embodiments, the present invention provides a synthetic structural analogs of prostaglandin Such as bimato kit comprising: a) one or more single dosage forms of a prost; alpha 2 agonists such as brimonidine; carbonic anhy compound of the invention; b) one or more single dosage drase inhibitors such as dorZolamide HCl; prostaglandin forms of an agent suitable for the treatment or prevention of derivatives and analogs such as and travoprost; 15 an ophthalmic condition or an agent suitable for administra NMDA antagonists such as memantine; hyaluronic acid (e.g., tion to the eye and its Surrounding tissues to produce a local or Sodium hyaluronate); corticosteroids such as loteprednoleta a systemic physiologic or pharmacologic beneficial effect as bonate, difluprednate and rimexolone; antibiotics such as mentioned above; and c) instructions for the administration of doxycycline; agents that increase mucin Such as ecabet and the compound of the invention and the agent suitable for the rebamipide; lubricants such as the combination of carboxym treatment or prevention of an ophthalmic condition or agent ethylcellulose Sodium and glycerin; A3 adenosine receptor Suitable for administration to the eye and its surrounding agonists such as CF-101; immunomodulators such as thali tissues to produce a local or a systemic physiologic or phar domide, TNFC. antagonists such as etanercept; protein kinase macologic beneficial effect. C-b inhibitors such as ruboxistaurin; immunosuppressants The present invention provides a kit comprising: such as sirolimus; PARP inhibitors such as AG-014699; neu 25 a) a pharmaceutical formulation (e.g., one or more single roprotective thrombolytic agents such as microplasmin, dosage forms) comprising a compound of the invention; hyaluronidase; oxidizing agents such as carbamide: Soma and to statin analogs such as Octreotide acetate; angiotensin II b) instructions for the administration of the pharmaceutical receptor antagonists such as candesartan cilexetil: disease formulation e.g., for treating or preventing an oph modifying antirheumatic drugs such as leflunomide; 30 thalmic condition, inhibiting COX-2 or TNF in the eye, AEB071; TNF antagonists such as adalimumab: CD11 or protecting against goblet cell loss in the eye. antagonists such as efalizumab; calcineurin inhibitors such as In certain embodiments, the kit further comprises instruc LX211; interferons such as interferon C-2a, and human alpha tions for the administration of the pharmaceutical formula fetoproteins such as MM-093. tion comprising a compound of the invention conjointly with In addition to the above agents, other agents are suitable for 35 an agent Suitable for the treatment or prevention of an oph administration to the eye and its Surrounding tissues to pro thalmic condition, an agent suitable for administration to the duce a local or a systemic physiologic or pharmacologic eye and its surrounding tissues to produce a local or a sys beneficial effect. Such agents may be conjointly administered temic physiologic orpharmacologic beneficial effect, or non with a compound of the invention. Examples of Such agents chemical methods suitable for the treatment or prevention of include neuroprotectants, such as nimodipine and related 40 an ophthalmic condition as mentioned above. In certain compounds; antibiotics. Such as tetracycline, chlortetracy embodiments, the kit further comprises a second pharmaceu cline, bacitracin, neomycin, polymyxin, gramicidin, oxytet tical formulation (e.g., as one or more single dosage forms) racycline, chloramphenicol, gentamycin, and erythromycin; comprising an agent Suitable for the treatment or prevention antibacterials, such as Sulfonamides, Sulfacetamide, Sulfame of an ophthalmic condition or an agent Suitable for adminis thizole, and Sulfisoxazole; antivirals, such as, idoxuridine; 45 tration to the eye and its Surrounding tissues to produce a local other antibacterial agents, such as nitrofuraZone and sodium or a systemic physiologic or pharmacologic beneficial effect propionate; antiallergenics, such as antazoline, methapy as mentioned above. riline, chlorpheniramine, pyrilamine, and prophenpy The present invention provides a kit comprising: ridamine; decongestants, such as phenylephrine, naphazo a) a first pharmaceutical formulation (e.g., one or more line, and tetrahydrazoline; miotics and anti-cholinesterase, 50 single dosage forms) comprising an agent Suitable for Such as pilocarpine, eserine salicylate, carbachol, di-isopro the treatment or prevention of an ophthalmic condition pyl fluorophosphate, phospholine iodine, and demecarium or an agent Suitable for administration to the eye and its bromide; mydriatics, such as atropine Sulfate, cyclopentolate, Surrounding tissues to produce a local or a systemic homatropine, Scopolamine, tropicamide, eucatropine, and physiologic or pharmacologic beneficial effect as men hydroxyamphetamine; sympathomimetics, such as epineph 55 tioned above; and rine; and prodrugs, such as those described in Design of b) instructions for the administration of the first pharma Prodrugs, edited by Hans Bundgaard, Elsevier Scientific Pub ceutical formulation with a compound of the invention, lishing Co., Amsterdam, 1985. Reference may be made to any e.g., for treating or preventing an ophthalmic condition, standard pharmaceutical textbook Such as Remington's Phar inhibiting COX-2 or TNF in the eye, or protecting maceutical Sciences (Remington's Pharmaceutical Sciences. 60 against goblet cell loss in the eye. Mack Publishing Company, Easton, Pa., USA 1985) for the The present invention further provides a packaged phar identity of other agents. maceutical for delivering eyedrops comprising a compound In certain embodiments, different compounds of the inven of any one of formulae I-IX, a compound of formula A, a tion may be conjointly administered with non-chemical compound of any one of formulae 1-49, a lipoxin compound, methods suitable for the treatment or prevention of an oph 65 oran oxylipin compound to an eye in need of treatment for an thalmic condition. In certain embodiments, different com ophthalmic condition. In certain Such embodiments, the pounds of the invention may be conjointly administered with packaged pharmaceutical is configured to deliver the eye US 8,673,881 B2 109 110 drops in any of the daily doses (e.g., any of the molar or 1000 g/mL, or 30 lug/mL to 350 g/mL of compound 1001, weight quantities) set forth above by administering one, two, as an aqueous formulation Suitable for topical administration three, four, or five eyedrops per eye, either once, twice, three to an eye. times, or four times daily, or even administering once every In further embodiments, the packaged pharmaceutical two days, Such as every other day, or once every three days, comprises an aqueous preservative-free solution comprising such as every third day. One of skill in the art will recognize a compound of any one of formulae I-IX, a compound of how to vary the drop Volume (e.g., by altering the Surface formula A, a compound of any one of formulae 1-49, a lipoxin tension and/or viscosity of the Solution and/or by modifying compound, or an oxylipin compound (e.g., eye drops) pack the physical configuration of the drop-dispensing portion of aged in a container Suitable for multidose administration to an the package), the concentration of the solution, and the dos 10 age regimen (e.g., the number drops and frequency of admin eye in need of treatment for an ophthalmic condition. In istration) to provide the desired dosage. certain such embodiments, the container suitable for multi In certain embodiments, the packaged pharmaceutical dose administration of a preservative-free solution is comprises an aqueous Solution (e.g., eye drops) packaged in designed such that sterility of the solution is maintained a sealed single-use container, e.g., each container comprising 15 between successive uses. Suitable dispensing devices include at least 1.5 nanomoles of a compound of any of formulae I-IX, those disclosed in United States Patent Application 2009/ a compound of formula A, a compound of any one of formu 294347. lae 1-49, a lipoxin compound, oran oxylipin compound. Such Immune Function as at least 2, 3, or 6 nanomoles of a compound of any of The present invention provides a method of inhibiting formulae I-IX, a compound of formula A, a compound of any immune function and/or Suppressing an immune response in one of formulae 1-49, a lipoxin compound, or an oxylipin a patient, comprising administering to said patient a com compound, in an aqueous formulation Suitable for topical pound of the invention. administration to an eye. In certain such embodiments, each The present invention provides a method of treating or container comprises from 1.5 nanomoles to 550 nanomoles, preventing an autoimmune disease or an autoimmune disor such as from 1.5 to 400 nanomoles, or 1.5 to 100 nanomoles 25 der in a patient, comprising administering to said patient a of a compound of any of formulae I-IX, a compound of compound of the invention. formula A, a compound of any one of formulae 1-49, a lipoxin In certain embodiments, the autoimmune disease or compound, or an oxylipin compound, in an aqueous formu autoimmune disorder is of the type where the patients own lation Suitable for topical administration to an eye. In certain immune system damages one or more of the patient's tissues. embodiments, the packaged pharmaceutical comprises an 30 In certain embodiments, the autoimmune disease or autoim aqueous solution (e.g., eye drops) packaged in a sealed mune disorder may be triggered by something within the Single-use container, e.g., each container comprising at least patient or something within the patient’s environment. 0.5 micrograms of compound 1001, such as at least 0.7. 1, or In certain embodiments, the autoimmune disease or 2 micrograms of compound 1001 in an aqueous formulation autoimmune disorder of the present invention may be one Suitable for topical administration to an eye. In certain Such 35 which follows an initiating cause. For example, the autoim embodiments, each container comprises from 0.5 micro mune disease or autoimmune disorder may be one which is grams to 150 micrograms of compound 1001, Such as from caused by an infection and/or some other initiating cause. 0.5 to 100 micrograms, or 0.5 to 25 micrograms of compound Potential initiating causes may include old age, infection 1001 in an aqueous formulation suitable for topical adminis (such as parasitic infection), treatment with steroids, repeated tration to an eye. In certain embodiments, the packaged phar 40 vaccination with alum, pregnancy and/or cancers. maceutical comprises an aqueous solution (e.g., eye drops) In certain embodiments, the autoimmune disease or packaged in a sealed single-use container, e.g., each container autoimmune disorder may be organ-specific or non-organ comprising a solution with a concentration over 90 micromo specific. Examples of Such autoimmune diseases or autoim lar of a compound of any of formulae I-IX, a compound of mune disorders include multiple Sclerosis, arthritis (e.g., formula A, a compound of any one of formulae 1-49, a lipoxin 45 rheumatoid arthritis or juvenile arthritis), Crohn's disease, compound, oran oxylipin compound. Such as a concentration colitis ulcerosa and aplastic anemia systemic lupus erythe over 100, 150, 200, or 250 micromolar of a compound of any matosus (SLE or lupus), dermatomyositis, pernicious ane of formulae I-IX, a compound of formula A, a compound of mia, Addison's disease, ankylosing spondylitis, antiphospho any one of formulae 1-49, a lipoxin compound, oran oxylipin lipid syndrome, Churg-Strauss Syndrome, discoid lupus, compound, as an aqueous formulation Suitable for topical 50 fibromyalgia, Grave's Disease, myasthenia gravis, psoriasis, administration to an eye. In certain such embodiments, each Reiter's Syndrome, rheumatic , sarcoidosis, sclero container comprises a solution with a concentration from 90 derma, Sjogren's Syndrome, stiff-man syndrome, thyroiditis, micromolar to 7000 micromolar, such as from 90 micromolar uveitis, vitiligo, Wegener's granulomatosis, graft rejection, to 2000 micromolar, or 90 micromolar to 1000 micromolar of and vascular disorders. a compound of any of formulae I-IX, a compound of formula 55 In certain embodiments wherein the autoimmune disease A, a compound of any one of formulae 1-49, a lipoxin com or autoimmune disorder is graft rejection, the graft rejection pound, or an oxylipin compound, as an aqueous formulation may be chronic graft rejection. In certain embodiments of the Suitable for topical administration to an eye. For example, in present invention wherein a compound of the invention is certain embodiments, the packaged pharmaceutical com administered for the treatment of graft rejection, the admin prises an aqueous solution (e.g., eye drops) packaged in a 60 istration of a compound of the invention modulates immune sealed single-use container, e.g., each container comprising a responses to grafts (e.g., allografts or Xenografts) where Solution with a concentration over 30 g/mL of compound untreated rejection would otherwise lead to graft loss. Thus, a 1001, such as a concentration over 40, 50, 60, or 75ug/mL of compound of the invention may be used as a replacement for compound 1001, as an aqueous formulation Suitable for topi or in addition to the conventional immunosuppressant admin cal administration to an eye. In certain such embodiments, 65 istered prior to, during and/or after transplantation. In certain each container comprises a solution with a concentration embodiments, the graft rejection is in response to transplant from 30 ug/mL to 2000 ug/mL, such as from 30 ug/mL to ing natural or artificial cells, islet cells, tissues (e.g., natural or US 8,673,881 B2 111 112 artificial skin tissue), , , organs (e.g. kid disease or autoimmune disorder, or treating or preventing a ney, liver, pancreas, lung, or heart), lenses, or pacemakers. disease, sequela or pathological condition mediated by an The present invention further provides a method of treating activation of the immune system as mentioned above. In or preventing a disease, sequela or pathological condition certain embodiments, the kit further comprises a second phar mediated by an activation of the immune system in a patient, maceutical formulation (e.g., as one or more single dosage comprising administering to said patient a compound of the forms) comprising an agent Suitable for modulating immune invention. In certain embodiments, diseases, sequelae and function, Suppressing immune response, treating or prevent pathological conditions mediated by an activation of the ing an autoimmune disease or autoimmune disorder, or treat immune system include, but are not limited to, capillary leak ing or preventing a disease, sequela or pathological condition age, pulmonary failure, , endotoxic shock, or sequelae 10 of tissue damage. mediated by an activation of the immune system as men In certain embodiments, different compounds of the inven tioned above. tion may be conjointly administered with other agents Suit The present invention provides a kit comprising: able for modulating immune function, Suppressing immune a) a first pharmaceutical formulation (e.g., one or more response, treating an autoimmune disease or autoimmune 15 single dosage forms) comprising an agent Suitable for disorder, or treating a disease, sequela or pathological condi modulating immune function, Suppressing immune tion mediated by an activation of the immune system. For response, treating or preventing an autoimmune disease example, the following immunosuppressive agents may be or autoimmune disorder, or treating or preventing a dis conjointly administered with a compound of the invention: ease, sequela or pathological condition mediated by an cyclosporin, cyclosporin A, tacrolimus, rapamycin, everoli activation of the immune system as mentioned above; mus, FK-506, cyclophosphamide, azathioprene, methotrex and ate, brequinar, leflunomide, mizoribine, mycophenolic acid, b) instructions for the administration of the first pharma mycophenolate mofetil, 15-deoxyspergualine, triamcinolone ceutical formulation with a compound of the invention, acetonide, decadron, daclizumab, basiliximab, glatiramer e.g., for inhibiting immune function, Suppressing an acetate, infliximab, muromonab, Octreotide, muramylic acid 25 immune response, treating or preventing an autoimmune dipeptide derivatives, levamisole, niridazole, oxysuran, disease or an autoimmune disorder, or treating or pre flagyl, and sirolimus. venting a disease, sequela or pathological condition In certain embodiments, different compounds of the inven mediated by an activation of the immune system. tion may be conjointly administered with one or more other Pulmonary Conditions compounds of the invention. Moreover, Such combinations 30 The present invention provides a method of treating or may be conjointly administered with other therapeutic preventing a pulmonary condition in a patient comprising agents, such as other agents suitable for modulating immune administering a compound of the invention. In certain function, Suppressing immune response, treating or prevent embodiments, the pulmonary condition may be selected from ing an autoimmune disease or autoimmune disorder, or treat pulmonary inflammation, airway inflammation, asthma, ing or preventing a disease, sequela or pathological condition 35 chronic bronchitis, bronchiectasis, non--related mediated by an activation of the immune system, Such as the bronchiectasis, cystic fibrosis, eosinophilic lung diseases agents identified above. (e.g., parasitic infection, idiopathic eosinophilic pneumonias, In certain embodiments, the present invention provides a and Churg-Strauss vasculitis), allergic bronchopulmonary kit comprising: a) one or more single dosage forms of a aspergillosis, allergic inflammation of the respiratory tract compound of the invention; b) one or more single dosage 40 (e.g., rhinitis and sinusitis), bronchiolitis, bronchiolitis oblit forms of an agent Suitable for modulating immune function, erans, bronchiolitis obliterans with organizing pneumonia, Suppressing immune response, treating or preventing an eosinophilic granuloma, Wegener's granulomatosis, sarcoi autoimmune disease or autoimmune disorder, or treating or dosis, hypersensitivity pneumonitis, idiopathic pulmonary preventing a disease, sequela or pathological condition medi fibrosis, pulmonary manifestations of connective tissue dis ated by an activation of the immune system as mentioned 45 eases, acute or chorionic lung injury, adult respiratory distress above; and c) instructions for the administration of the com syndrome, pneumonia, emphysema, pulmonary disorders, or pound of the invention and the agent Suitable for modulating chronic obstructive pulmonary disease. immune function, Suppressing immune response, treating or In certain embodiments, different compounds of the inven preventing an autoimmune disease or autoimmune disorder, tion may be conjointly administered with one or more other or treating or preventing a disease, sequela or pathological 50 compounds of the invention. Moreover, Such combinations condition mediated by an activation of the immune system. may be conjointly administered with other therapeutic The present invention provides a kit comprising: agents, such as other agents suitable for the treatment or a) a pharmaceutical formulation (e.g., one or more single prevention of a pulmonary condition, Such as the conditions dosage forms) comprising a compound of the invention; disclosed herein. Exemplary agents suitable for the treatment and 55 of pulmonary conditions include corticosteroids (e.g., pred b) instructions for the administration of the pharmaceutical nisone, beclomethasone dipropionate, fluticasone propi formulation, e.g., for inhibiting immune function, Sup onate, and other Suitable corticosteroids), beta-agonists (e.g., pressing an immune response, treating or preventing an albuterol, metaproterenol, pirbuterol, formoterol, terbutaline, autoimmune disease or an autoimmune disorder, or isoetharine, levalbuterol, salmeterol Xinafoate, and other suit treating or preventing a disease, sequela or pathological 60 able beta-agonists), and anti-cholinergic agents (e.g., ipratro condition mediated by an activation of the immune sys pium bromide, tiotropium bromide, and other suitable anti tem. cholinergic agents). In certain embodiments, the kit further comprises instruc In certain embodiments, the present invention provides a tions for the administration of the pharmaceutical formula kit comprising: a) one or more single dosage forms of a tion comprising a compound of the invention conjointly with 65 compound of the invention; b) one or more single dosage an agent Suitable for modulating immune function, Suppress forms of an agent Suitable for the treatment or prevention of a ing immune response, treating or preventing an autoimmune pulmonary condition; and c) instructions for the administra US 8,673,881 B2 113 114 tion of the compound of the invention and the agent Suitable forms of an agent Suitable for the treatment or prevention of a for the treatment or prevention of a pulmonary condition. gastrointestinal condition; and c) instructions for the admin The present invention provides a kit comprising: istration of the compound of the invention and the agent a) a pharmaceutical formulation (e.g., one or more single Suitable for the treatment or prevention of a gastrointestinal dosage forms) comprising a compound of the invention; condition. and The present invention provides a kit comprising: b) instructions for the administration of the pharmaceutical a) a pharmaceutical formulation (e.g., one or more single formulation, e.g., for treating or preventing a condition dosage forms) comprising a compound of the invention; as discussed above, e.g., a pulmonary condition. and In certain embodiments, the kit further comprises instruc 10 b) instructions for the administration of the pharmaceutical tions for the administration of the pharmaceutical formula formulation, e.g., for treating or preventing a condition tion comprising a compound of the invention conjointly with as discussed above, e.g., a gastrointestinal condition. an agent Suitable for the treatment or prevention of a pulmo In certain embodiments, the kit further comprises instruc nary condition. In certain embodiments, the kit further com tions for the administration of the pharmaceutical formula prises a second pharmaceutical formulation (e.g., as one or 15 tion comprising a compound of the invention conjointly with more single dosage forms) comprising an agent Suitable for an agent Suitable for the treatment or prevention of a gas the treatment or prevention of a pulmonary condition. trointestinal condition. In certain embodiments, the kit fur In certain embodiments, the kit further comprises instruc ther comprises a second pharmaceutical formulation (e.g., as tions for the administration of the one or more single dosage one or more single dosage forms) comprising an agent Suit forms each comprising a compound of the invention con able for the treatment or prevention of a gastrointestinal con jointly with an agent Suitable for the treatment or prevention dition. of a pulmonary condition. In certain embodiments, the kit The present invention provides a kit comprising: further comprises one or more single dosage forms of an a) a first pharmaceutical formulation (e.g., one or more agent Suitable for the treatment or prevention of a pulmonary single dosage forms) comprising an agent Suitable for condition. 25 the treatment or prevention of a gastrointestinal condi The present invention provides a kit comprising: tion; and a) a first pharmaceutical formulation (e.g., one or more b) instructions for the administration of the first pharma single dosage forms) comprising an agent Suitable for ceutical formulation with a compound of the invention, the treatment or prevention of a pulmonary condition; e.g., for treating or preventing a condition as discussed and 30 above, e.g., a gastrointestinal condition. b) instructions for the administration of the first pharma Rheumatological Conditions ceutical formulation with a compound of the invention, The present invention provides a method of treating or e.g., for treating or preventing a condition as discussed preventing a rheumatological condition in a patient compris above, e.g., for treating or preventing a pulmonary con ing administering a compound of the invention. In certain dition. 35 embodiments, the rheumatological condition may be selected Gastrointestinal Conditions from rheumatic diseases, rheumatoid arthritis, osteoarthritis, The present invention provides a method of treating or inflammatory conditions of joints (e.g., rheumatoid arthritis, preventing a gastrointestinal condition in a patient compris rheumatoid spondylitis, osteoarthritis, gouty arthritis), anky ing administering a compound of the invention. In certain losing spondylitis, lupus, psoriatic arthritis, myalgias, or embodiments, the gastrointestinal condition may be selected 40 chronic low back pain. from gastrointestinal inflammation, ulcerative colitis, In certain embodiments, different compounds of the inven clostridium difficile colitis, microscopic or lymphocytic coli tion may be conjointly administered with one or more other tis, collagenous colitis, Crohn's disease, irritable bowel syn compounds of the invention. Moreover, Such combinations drome, infectious enteritis, antibiotic associative diarrhea, may be conjointly administered with other therapeutic colon polyps, familial polyps, familial polyposis syndrome, 45 agents, such as other agents suitable for the treatment or Gardner's syndrome, helicobacter pylori, nonspecific diar prevention of a rheumatological condition, Such as the con rheal illnesses, intestinal cancers, distal proctitis, inflamma ditions disclosed herein. Exemplary agents suitable for the tory states associated with abnormal colonic muscular con treatment or prevention of rheumatological conditions traction (e.g., spastic colon and mucous colitis), allergic include non-steroidal anti-inflammatory drugs such as Sali bowel disease (e.g., coeliac disease), esophogitis, or pancre 50 cylates (e.g., aspirin, amoxiprin, benorilate, choline magne atitis. sium salicylate, diflunisal, faislamine, methyl salicylate, In certain embodiments, different compounds of the inven magnesium salicylate, Salicyl salicylate), arylalkanoic acids tion may be conjointly administered with one or more other (e.g., diclofenac, aceclofenac, acemetacin, bromfenac, etod compounds of the invention. Moreover, Such combinations olac, indometacin, nabumetone, Sulindac, and tolmetin), may be conjointly administered with other therapeutic 55 2-arylpropionic acids (e.g., ibuprofen, carprofen, fenbufen, agents, such as other agents Suitable for the treatment or fenoprofen, flurbiprofen, ketoprofen, ketorolac, loxoprofen, prevention of a gastrointestinal condition, such as the condi naproxen, oxaprozin, tiaprofenic acid, and Suprofen), N-ary tions disclosed herein. Exemplary agents Suitable for the lanthranilic acids (e.g., mefenamic acid and meclofenamic treatment or prevention of gastrointestinal conditions include acid), pyrazolidine derivatives (e.g., phenylbutaZone, aza immunosuppressive agents (e.g., corticosteroids), hista 60 propaZone, metamizole, oxyphenbutaZone, and Sulfinpyra mine-2 receptor antagonists (e.g., cimetidine, famotidine, Zone), oxicams (e.g., piroXicam, lornoxicam, meloxicam, and nizatidine, and ranitidine), Sucralfate, prostaglandins (e.g., tenoxicam), COX-2 inhibitors (e.g., celecoxib, etoricoxib, misopostol), and proton pump inhibitors (e.g., omeprazole, lumiracoxib, parecoxib, rofecoxib, and Valdecoxib) and Sul lansoprazole, esomeprazole, pantoprazole, and rabeprazole). phonanilides (e.g., nimeSulide), corticosteroids (e.g., pred In certain embodiments, the present invention provides a 65 nisone, cortisone, Solumedrol, and hydrocortisone), disease kit comprising: a) one or more single dosage forms of a modifying anti-rheumatic drugs (e.g., leflunomide, oral gold, compound of the invention; b) one or more single dosage Sulfasalazine, mycophenolate, cyclophosphamide, azathio US 8,673,881 B2 115 116 prine, chlorambucil, rheumatrex, minocycline, gold shots, onate), antihistamines (e.g., diphenhydramine, hydroxy Zine, cuprimine, and quineprox), pain medication (e.g., acetami and cyproheptadine), salicyclic acid, anthroline, calcipot nophen, codeine, propoxyphene, fentanyl, hydromorphone, riene, and tazarotene. morphine, oxycodone, pentazocine, tramadol, and hydroc In certain embodiments, the present invention provides a odone) and biologic response modifiers (e.g., etanercept, kit comprising: a) one or more single dosage forms of a adalimumab, anakinra, abatacept, efalizumab, infliximab. 1 compound of the invention; b) one or more single dosage rituximab, and natalizumab) forms of an agent Suitable for the treatment or prevention of a In certain embodiments, the present invention provides a dermatological condition; and c) instructions for the admin kit comprising: a) one or more single dosage forms of a istration of the compound of the invention and the agent 10 suitable for the treatment or prevention of a dermatological compound of the invention; b) one or more single dosage condition. forms of an agent Suitable for the treatment or prevention of a The present invention provides a kit comprising: rheumatological condition; and c) instructions for the admin a) a pharmaceutical formulation (e.g., one or more single istration of the compound of the invention and the agent dosage forms) comprising a compound of the invention; suitable for the treatment or prevention of a rheumatological 15 and condition. b) instructions for the administration of the pharmaceutical The present invention provides a kit comprising: formulation, e.g., for treating or preventing a condition a) a pharmaceutical formulation (e.g., one or more single as discussed above, e.g., a dermatological condition. dosage forms) comprising a compound of the invention; In certain embodiments, the kit further comprises instruc and tions for the administration of the pharmaceutical formula b) instructions for the administration of the pharmaceutical tion comprising a compound of the invention conjointly with formulation, e.g., for treating or preventing a condition an agent Suitable for the treatment or prevention of a derma as discussed above, e.g., a rheumatological condition. tological condition. In certain embodiments, the kit further In certain embodiments, the kit further comprises instruc comprises a second pharmaceutical formulation (e.g., as one tions for the administration of the pharmaceutical formula 25 or more single dosage forms) comprising an agent Suitable for tion comprising a compound of the invention conjointly with the treatment or prevention of a dermatological condition. an agent suitable for the treatment or prevention of a rheuma The present invention provides a kit comprising: tological condition. In certain embodiments, the kit further a) a first pharmaceutical formulation (e.g., one or more comprises a second pharmaceutical formulation (e.g., as one single dosage forms) comprising an agent Suitable for or more single dosage forms) comprising an agent Suitable for 30 the treatment or prevention of a dermatological condi the treatment or prevention of a rheumatological condition. tion; and The present invention provides a kit comprising: b) instructions for the administration of the first pharma a) a first pharmaceutical formulation (e.g., one or more ceutical formulation with a compound of the invention, single dosage forms) comprising an agent Suitable for e.g., for treating or preventing a condition as discussed the treatment or prevention of a rheumatological condi 35 above, e.g., a dermatological condition. tion; and Neurological Conditions b) instructions for the administration of the first pharma The present invention provides a method of treating or ceutical formulation with a compound of the invention, preventing a neurological condition in a patient comprising e.g., for treating or preventing a condition as discussed administering a compound of the invention. In certain above, e.g., a rheumatological condition. 40 embodiments, the neurological condition may be selected Dermatological Conditions from neurodegeneration or dementia associated with HIV The present invention provides a method of treating or infection, depression, Alzheimer's disease, Parkinson's dis preventing a dermatological condition inapatient comprising ease, addiction, -related disorders, decision analysis, administering a compound of the invention. In certain degenerative neurological disorders, dementia, neurological embodiments, the dermatological condition may be selected 45 disorders, neuromuscular disorders, psychiatric disorders, from Scleroderma, psoriasis, urticaria, Vasculitis, seborrheic brain injury, trauma, neuronal inflammation, or multiple scle dermatitis, pustular dermatosis, eczema, dermatitis, ulcers rosis. and erosions resulting from trauma, burns, bullous disorders, In certain embodiments, different compounds of the inven or ischemia of the skin or mucous membranes, ichthyoses, tion may be conjointly administered with one or more other epidermolysis bullosae, hypertrophic scars and keloids, cuta 50 compounds of the invention. Moreover, Such combinations neous changes of intrinsic aging and photoaging, frictional may be conjointly administered with other therapeutic blistering caused by mechanical shearing of the skin, cutane agents, such as other agents suitable for the treatment or ous atrophy resulting from the topical use of corticosteroids, prevention of a neurological condition, such as the conditions inflammation to mucous membranes (e.g., cheilitis, chapped disclosed herein. Exemplary agents suitable for the treatment lips, nasal irritation, or Vulvovaginitis), dandruff. Sunburn, 55 of neurological conditions include thyroid hormone replace poison ivy, atopic dermatitis, acne, or rosacea. ment, cholinesterase inhibitors (e.g., donepezil and tacrine), In certain embodiments, different compounds of the inven antipsychotic drugs (e.g., clozapine, olanzapine, quetiapine, tion may be conjointly administered with one or more other risperidone, Ziprasidone, aripiprazole, trifluoperazine, flu compounds of the invention. Moreover, Such combinations penthixol, loxapine, perphenazine, chlorpromazine, halo may be conjointly administered with other therapeutic 60 peridol, fluphenazine decanoate, and thioridazine), anxiolyt agents, such as other agents Suitable for the treatment or ics, such as benzodiazepines (e.g., lorazepam, clonazepam, prevention of a dermatological condition, Such as the condi alprazolam, and diazepam) and non-benzodiazepines (e.g., tions disclosed herein. Exemplary agents Suitable for the buspirone), drugs for the treatment of Alzheimer's disease, treatment or prevention of dermatological conditions include Such as acetylcholinesterase inhibitors (e.g., donepezil, immunosuppressive agents, such as cyclosporine or cal 65 rivastigmine, and galantamine) or NMDA receptor antago cineurin inhibitors (e.g., tacrolimus or pimecrolimus), corti nists (e.g., memantine), antidepressants, such as selective costeroids (e.g., prednisone and betamethasone dipropi serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine, US 8,673,881 B2 117 118 escitalopram, citalopram, and Sertraline), serotonin and nore with radiation therapy. In certain embodiments, a compound pinephrine reuptake inhibitors (e.g., Venlafaxine and dulox of the invention may be conjointly administered with Surgery, etine), noradrenergic and specific serotonergic antidepres with thermoablation, with focused ultrasound therapy, or sants (e.g., mirtazapine), norepinephrine reuptake inhibitors with cryotherapy. (e.g., reboxetine), norepinephrine and dopamine reuptake The present invention provides a kit comprising: inhibitors (e.g., bupropion), tricyclic antidepressants (e.g., a) a pharmaceutical formulation (e.g., one or more single amitriptyline and desipramine), and monoamine oxidase dosage forms) comprising a compound of the invention; inhibitors (e.g., phenelzine, moclobemide, and selegiline), and drugs for the treatment of multiple Sclerosis, Such as interfer b) instructions for the administration of the pharmaceutical ons (e.g., interferon beta-1a and interferon beta-1b), glati 10 formulation, e.g., for treating or preventing cancer. ramer acetate, mitoxantrone, natalizumab, and corticoster In certain embodiments, the kit further comprises instruc oids (e.g., methylprednisolone or any of the corticosteroids tions for the administration of the pharmaceutical formula referenced above), and drugs for the treatment of Parkinson's tion comprising a compound of the invention conjointly with disease. Such as levodopa, carbidopa, benserazide, tolcapone, a chemotherapeutic agent, as described above. In certain entacapone; dopamine agonists, such as bromocriptine, per 15 embodiments, the kit further comprises a second pharmaceu golide, pramipexole, ropinirole, cabergoline, apomorphine, tical formulation (e.g., as one or more single dosage forms) and lisuride: MAO-B inhibitors, such as selegiline and rasa comprising a chemotherapeutic agent, as described above. giline, or combinations thereof. The present invention provides a kit comprising: In certain embodiments, the present invention provides a a) a first pharmaceutical formulation (e.g., one or more kit comprising: a) one or more single dosage forms of a single dosage forms) comprising a chemotherapeutic compound of the invention; b) one or more single dosage agent; and forms of an agent Suitable for the treatment or prevention of a b) instructions for the administration of the first pharma neurological condition; and c) instructions for the adminis ceutical formulation with a compound of the invention, tration of the compound of the invention and the agent Suit e.g., for treating or preventing cancer. able for the treatment or prevention of a neurological condi 25 Infectious Conditions tion. The present invention provides a method of treating or The present invention provides a kit comprising: preventing an infectious condition in a patient comprising a) a pharmaceutical formulation (e.g., one or more single administering a compound of the invention. In certain dosage forms) comprising a compound of the invention; embodiments, the infectious condition may be selected from and 30 a bacterial infection, parasitic diseases, a gram negative bac b) instructions for the administration of the pharmaceutical terial infection, salmonella typhimurium infection, an oral formulation, e.g., for treating a condition as discussed infection, a fungal infection, or a viral infection. above, e.g., a neurological condition. The present invention further provides a method of treating In certain embodiments, the kit further comprises instruc or preventing inflammation associated with infection in a tions for the administration of the pharmaceutical formula 35 patient comprising administering a compound of the inven tion comprising a compound of the invention conjointly with tion. In certain Such embodiments, compounds of the inven an agent Suitable for the treatment or prevention of a neuro tion may stimulate and increase production of anti-microbial logical condition. In certain embodiments, the kit further peptides expressed by human epithelial cells (e.g., bacteri comprises a second pharmaceutical formulation (e.g., as one cidal permeability increasing protein). or more single dosage forms) comprising an agent Suitable for 40 In certain embodiments, different compounds of the inven the treatment or prevention of a neurological condition. tion may be conjointly administered with one or more other The present invention provides a kit comprising: compounds of the invention. Moreover, Such combinations a) a first pharmaceutical formulation (e.g., one or more may be conjointly administered with other therapeutic single dosage forms) comprising an agent Suitable for agents, such as other agents suitable for the treatment or the treatment or prevention of a neurological condition; 45 prevention of an infectious condition, such as the conditions and disclosed herein. Exemplary agents suitable for the treatment b) instructions for the administration of the first pharma or prevention of infectious conditions include aminoglyco ceutical formulation with a compound of the invention, sides (e.g., amikacin, gentamicin, kanamycin, neomycin, e.g., for treating or preventing a condition as discussed netilmicin, Streptomycin, tobramycin, and paromomycin), above, e.g., a neurological condition. 50 ansamycins (e.g., geldanamycin and herbimycin), carba Cancer cephem (e.g., loracarbef), carbapenems (e.g., ertapenem, The present invention provides a method of treating or doripenem, imipenem, and meropenem), cephalosporins preventing cancer in a patient comprising administering a (e.g., cefadroxil, cefazolin, cefalotin, cephalexin, cefaclor, compound of the invention. In certain embodiments, the can cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cef cer may be selected from breast cancer, colon cancer, leuke 55 dinir, cefditoren, cefoperaZone, cefotaxime, cefpodoxime, mia, lymphoma, lung cancer, or prostate cancer. ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefdinir, In certain embodiments, different compounds of the inven and cefepime), glycopeptides (e.g., Vancomycin), macrollides tion may be conjointly administered with one or more other (e.g., azithromycin, clarithromycin, dirithromycin, erythro compounds of the invention. Moreover, Such combinations mycin, roXithromycin, troleandomycin, tellithromycin, and may be conjointly administered with other therapeutic 60 spectinomycin), monobactams (e.g., aztreonam), penicillins agents, such as other agents Suitable for the treatment or (e.g., amoxicillin, amplicillin, azlocillin, carbenicillin, clox prevention of cancer, Such as the chemotherapeutic agents or acillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, the combination therapies as disclosed above. penicillin, piperacillin, and ticarcillin), polypeptides (e.g., In certain embodiments, a compound of the invention may bacitracin, colistin, and polymyxin B), quinolones (e.g., be conjointly administered with non-chemical methods of 65 ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lom cancer treatment or prevention. In certain embodiments, a efloxacin, moxifloxacin, norfloxacin, ofloxacin, and trova compound of the invention may be conjointly administered floxacin), Sulfonamides (e.g., mafenide, prontosil, Sulfaceta US 8,673,881 B2 119 120 mide, Sulfamethizole, Sulfanilimide, Sulfasalazine, b) instructions for the administration of the pharmaceutical Sulfisoxazole, and trimethoprim), tetracyclines (e.g., deme formulation, e.g., for inhibiting or treating or clocycline, doxycycline, minocycline, Oxytetracycline, and preventing a condition arising from apoptosis. tetracycline), arsphenamine, chloramphenicol, clindamycin, In certain embodiments, the kit further comprises instruc lincoamycin, ethambutol, fosfomycin, fusidic acid, furazoli 5 tions for the administration of the pharmaceutical formula done, isoniazid, lineZolid, metronidazole, mupirocin, nitro tion comprising a compound of the invention conjointly with furantoin, platensimycin, pyrazinamide, quinuprisin, dalfo an agent Suitable for inhibiting apoptosis or for the treatment pristin, rifampin, and tinidazole. or prevention of a condition arising from apoptosis. In certain In certain embodiments, the present invention provides a embodiments, the kit further comprises a second pharmaceu kit comprising: a) one or more single dosage forms of a 10 tical formulation (e.g., as one or more single dosage forms) compound of the invention; b) one or more single dosage comprising an agent Suitable for inhibiting apoptosis or for forms of an agent suitable for the treatment or prevention of the treatment or prevention of a condition arising from apo an infectious condition; and c) instructions for the adminis ptosis. tration of the compound of the invention and the agent Suit The present invention provides a kit comprising: able for the treatment or prevention of an infectious condition. 15 a) a first pharmaceutical formulation (e.g., one or more The present invention provides a kit comprising: single dosage forms) comprising an agent Suitable for a) a pharmaceutical formulation (e.g., one or more single inhibitingapoptosis or for the treatment or prevention of dosage forms) comprising a compound of the invention; a condition arising from apoptosis; and and b) instructions for the administration of the first pharma b) instructions for the administration of the pharmaceutical ceutical formulation with a compound of the invention, formulation, e.g., for treating or preventing a condition e.g., for inhibitingapoptosis or for treating or preventing as discussed above, e.g., an infectious condition. a condition arising from apoptosis. In certain embodiments, the kit further comprises instruc Angiogenesis tions for the administration of the pharmaceutical formula The present invention provides a method of inhibiting tion comprising a compound of the invention conjointly with 25 angiogenesis in a patient comprising administering a com an agent Suitable for the treatment or prevention of an infec pound of the invention. In certain embodiments, compounds tious condition. In certain embodiments, the kit further com of the present invention limitangiogenesis necessary for Solid prises a second pharmaceutical formulation (e.g., as one or tumor metastasis. Since angiogenesis and neovascularization more single dosage forms) comprising an agent Suitable for are essential steps in Solid tumor growth, inhibition of angio the treatment or prevention of an infectious condition. 30 genesis is very useful to prevent the further growth, retard, or The present invention provides a kit comprising: even regress Solid tumors. Exemplary neoplasias which may a) a first pharmaceutical formulation (e.g., one or more be treated with compounds of the present invention include, single dosage forms) comprising an agent Suitable for but are not limited to, gastrointestinal tumors and gliomas. the treatment or prevention of an infectious condition; In certain embodiments, additional disorders or diseases and 35 that may be treated or prevented by inhibition of angiogenesis b) instructions for the administration of the first pharma (e.g., by administering a compound of the present invention) ceutical formulation with a compound of the invention, include, but are not limited to, retinopathy associated with e.g., for treating or preventing a condition as discussed diabetes, rheumatoid arthritis, osteoarthritis, macular degen above, e.g., an infectious condition. eration, glaucoma, Keloid formation, ulcerative colitis, Apoptotic Conditions 40 Krohn's disease, and psoriasis. The present invention provides a method of inhibitingapo In certain embodiments, different compounds of the inven ptosis in a patient comprising administering a compound of tion may be conjointly administered with one or more other the invention. The present invention further provides a compounds of the invention. Moreover, Such combinations method of treating or preventing a condition arising from may be conjointly administered with other therapeutic apoptosis in a patient comprising administering a compound 45 agents, such as other agents suitable for inhibiting angiogen of the invention. In certain embodiments, the condition aris esis or for the treatment or prevention of a condition arising ing from apoptosis may be selected from coronary infarct from angiogenesis, such as angiogenesis inhibitors including, damage, tissue necrosis in chronic inflammation, Smooth but not limited to, siRNAs, aptamers, angiostatin, endosta muscle proliferation disorders (e.g., restenosis following tin, and bevacizumab. angioplasty), inflammatory states associated with arterial 50 In certain embodiments, the present invention provides a Smooth muscle constriction (e.g., coronary spasm, ischemia kit comprising: a) one or more single dosage forms of a induced myocardial injury, cerebral spasm, or cerebral compound of the invention; b) one or more single dosage ischemia and related disorders, such as stroke), conditions forms of an agent Suitable for inhibiting angiogenesis or for associated with thrombosis (e.g., coronary thrombosis, phle the treatment or prevention of a conditionarising from angio bitis, or phlebothrombosis), and neurodegenerative diseases. 55 genesis; and c) instructions for the administration of the com In certain embodiments, the present invention provides a pound of the invention and the agent Suitable for inhibiting kit comprising: a) one or more single dosage forms of a angiogenesis or for the treatment or prevention of a condition compound of the invention; b) one or more single dosage arising from angiogenesis. forms of an agent Suitable for the treatment or prevention of a The present invention provides a kit comprising: condition arising from apoptosis; and c) instructions for the 60 a) a pharmaceutical formulation (e.g., one or more single administration of the compound of the invention and the dosage forms) comprising a compound of the invention; agent Suitable for inhibiting apoptosis or for the treatment or and prevention of a condition arising from apoptosis. b) instructions for the administration of the pharmaceutical The present invention provides a kit comprising: formulation, e.g., for inhibiting angiogenesis or treating a) a pharmaceutical formulation (e.g., one or more single 65 or preventing a condition arising from angiogenesis. dosage forms) comprising a compound of the invention; In certain embodiments, the kit further comprises instruc and tions for the administration of the pharmaceutical formula US 8,673,881 B2 121 122 tion comprising a compound of the invention conjointly with of a liver, a lung or part of a lung, a portion of pancreas, a an agent Suitable for inhibiting angiogenesis or for the treat portion of intestine, a heart, a cornea or tissue (e.g., skin, ment or prevention of a condition arising from angiogenesis. blood, bone marrow, blood stem cells, or umbilical cord In certain embodiments, the kit further comprises a second blood). pharmaceutical formulation (e.g., as one or more single dos In certain embodiments, the method for reducing or pre age forms) comprising an agent Suitable for inhibiting angio venting stem cell damage and/or death or enhancing stem cell genesis or for the treatment or prevention of a condition Survival and/or preservation comprises administering a com arising from angiogenesis. pound of the invention to a stem cell donor patient prior to The present invention provides a kit comprising: removal of the stem cells further comprises the step of remov a) a first pharmaceutical formulation (e.g., one or more 10 single dosage forms) comprising an agent Suitable for ing the stem cells from the stem cell donor patient. inhibiting angiogenesis or for the treatment or preven In certain embodiments, the organ and/or stem cell donor tion of a condition arising from angiogenesis; and patient is any suitable organ and/or stem cell donor patient. In b) instructions for the administration of the first pharma certain embodiments, the organ and/or stem cell donor patient ceutical formulation with a compound of the invention, 15 is a non-human animal. For example, the organ and/or stem e.g., for inhibiting angiogenesis or for treating or pre cell donor patient may be a pig or primate, such as a geneti venting a condition arising from angiogenesis. cally altered animal. In certain Such embodiments, the organ When administered alone or as part of a therapeutic regi and/or stem cell donor patient is an animal that has been men, in certain embodiments, the invention contemplates genetically modified Such that proteins on the Surface of the administration of compounds of the present invention to treat animals organs and/or cells are recognised as compatible by or prevent a particular primary disease, injury, disorder, or a human immune system. For example, the organ and/or stem condition. In certain embodiments, the invention contem cell donor patient may be an animal that has been genetically plates administration of compounds of the present invention modified such that proteins on the surface of the animals to treat or prevent symptoms secondary to the primary dis organs and/or cells are recognised as human by the human ease, injury, disorder, or conditions. 25 immune system, so the organs and/or cells are not attacked Organ Preservation when transplanted. In certain embodiments, the organ donor The present invention provides methods for reducing, pre patient is a pig. Venting or reversing organ damage or enhancing organ pres The present invention provides methods for reducing, pre ervation and/or Survival comprising administering a com Venting or reversing organ damage or enhancing organ pres pound of the invention to an organ donor patient prior to 30 ervation and/or Survival comprising administering a com removal of the organ. The present invention provides methods pound of the invention to an organ recipient prior to organ for reducing or preventing stem cell damage and/or death or transplantation. enhancing stem cell Survival and/or preservation comprising In certain embodiments, the method for reducing, prevent administering a compound of the invention to stem cell donor ing or reversing organ damage or enhancing organ preserva patient prior to removal of the stem cells. In certain embodi 35 tion and/or Survival comprising administering a compound of ments, the compound of the invention is administered to the the invention to an organ recipient prior to organ transplan organ and/or stem cell donor patient less than 24 hours prior tation further comprises the step of removing one or more to removal of the organ, Such as less than 12, eight, six, four organs from the organ recipient. In certain Such embodi or two hours prior to removal of the organ and/or stem cells. ments, the compound of the invention is administered to the In certain embodiments, the compound of the invention is 40 organ recipient at any point during the organ removal process. administered to the organ and/or stem cell donor patient In certain Such embodiments, the step of removing the one or immediately prior to removal of the organ and/or stem cells more organs from the organ recipient occurs prior to admin (e.g., less than one hour prior to removal of the organ and/or istering a compound of the invention to the organ recipient. In stem cells, such as less than 30, 15, or 10 minutes prior to certain embodiments, the step of removing the one or more removal of the organ and/or stem cells). In certain embodi 45 organs from the organ recipient occurs simultaneously to ments, the organ and/or stem cell donor patient is a human. administering a compound of the invention to the organ In certain embodiments, the organ and/or stem cell donor recipient. In certain embodiments, the step of removing the patient is characterized by brain death. In certain embodi one or more organs from the organ recipient occurs Subse ments, “brain death’ is defined as the total cessation of brain quent to administering a compound of the invention to the function, including brain stem function, e.g., wherein there is 50 organ recipient. no oxygen or blood flow to the brain, or wherein the brain no In certain embodiments, the method for reducing, prevent longer functions in any manner and will never function again. ing or reversing organ damage or enhancing organ preserva In certain embodiments, the organ and/or stem cell donor tion and/or Survival comprising administering a compound of patient is not diagnosed as having a chronic, transmissible, or the invention to an organ recipient prior to organ transplan infectious physical ailment, e.g., for which pharmacological 55 tation further comprises the step of transplanting one or more intervention is or would have been suitable. In certain organs into the organ recipient. embodiments, the organ and/or stem cell donor patient is not The present invention further provides methods for reduc currently and/or has not been diagnosed with diabetes, can ing or preventing stem cell damage and/or death or enhancing cer, high blood pressure, kidney disease, or cardiovascular stem cell preservation and/or Survival comprising administer disease, e.g., atherosclerosis or heart disease. 60 ing a compound of the invention to a stem cell recipient prior In certain embodiments, the method for reducing, prevent to stem cell transplantation. ing or reversing organ damage or enhancing organ preserva In certain embodiments, the method for reducing or pre tion and/or Survival comprises administering a compound of venting stem cell damage and/or death or enhancing stem cell the invention to an organ donor patient prior to removal of the preservation and/or Survival comprising administering a organ further comprises the step of removing the organ from 65 compound of the invention to a stem cell recipient prior to the organ donor patient. In certain such embodiments, the stem cell transplantation further comprises the step of trans organis selected from one or more of a kidney, a liver or a lobe planting stem cells into the stem cell recipient. US 8,673,881 B2 123 124 The present invention further provides methods for reduc In certain embodiments, the organ preservation Solution com ing, preventing or reversing organ damage or enhancing prises a perfluorocarbon, such as a perfluorohydrocarbon or organ preservation and/or Survival comprising contacting the a perfluoroalkylamine. Exemplary perfluorocarbons are organ with a compound of the invention. described in Transplantation, 74(12), 1804-1809, Dec. 27. In certain embodiments, the organis contacted ex vivo with 5 2002 and Am. Assoc. of Nurse Anesthetists Journal, 74(3): a compound of the invention. In certain embodiments, the 205-211, June 2007, the compounds in which are incorpo organ is contacted with a compound of the invention in a rated herein by reference. manner other than directly through the organ's blood Supply In certain embodiments wherein the method of the present (e.g., the organis contacted with a compound of the invention invention comprises reducing, preventing or reversing organ outside of its circulatory system). In certain embodiments, the 10 damage or enhancing organ preservation and/or Survival organis contacted with a compound of the invention while the organ is still in a Subject’s body, during the removal of the comprising contacting the organ with a preservation Solution organ from a Subject's body, after the organ is removed from wherein the preservation solution comprises a compound of a subject’s body, while the organ is being transplanted into a the invention, the preservation solution may be any Suitable recipient, immediately after the organ is transplanted into a 15 preservation solution known in the art. Examples of Such recipient, or any combination thereof. preservation solutions include, but are not limited to, Univer The present invention further provides methods for reduc sity of Wisconsin solution, Krebs-Henseleit solution, Celsior ing or preventing stem cell damage and/or death or enhancing Solution, St. Thomas Hospital 2 solution, Ringer-lactate solu stem cell preservation and/or Survival comprising contacting tion, Collins solution, Euro-Collins solution, Stanford solu the stem cells with a compound of the invention. tion, Ross-Marshall citrate solution, phosphate-buffered In certain embodiments, the stem cells are contacted with a sucrose solution, Kyoto ET solution, or Bretschneider histi compound of the invention ex vivo (e.g., during a period of ex dine ketoglutarate (HTK) solution. Vivo culture and/or manipulation, for example ex vivo culture The organ may be contacted with (or administered) the and/or manipulation for cell expansion and/or differentiation, preservation solution comprising the compound of the inven during the process of cryopreservation of the stem cells, dur 25 tion at any point during the transplantation process. For ing the process of thawing cryopreserved stem cells, or any example, the preservation Solution comprising a compound combination thereof). In certain Such embodiments, the com of the invention may be administered by flushing the organ, pound of the invention is present as a component of a Suitable continuously perfusing the organ, or intermittently perfusing culture medium (e.g., any culture medium suitable forex vivo through the blood vessels of the organ while the organ is still culture and/or manipulation, cryopreservation of stem cells, 30 in a Subject’s body, during the removal of the organ from a or the thawing of cryopreserved stem cells). subject’s body, after the organ is removed from a subjects In certain embodiments, the stem cells are contacted with a body, while the organ is being transplanted into a recipient, compound of the invention while the stem cells are still in a immediately after the organ is transplanted into a recipient, or subjects body, during the removal of the stem cells from a any combination thereof. In certain embodiments, the organ subjects body, after the stem cells are removed from a sub 35 preservation solution comprising the compound of the inven jects body, during the process of ex vivo culture and/or tion is administered directly into the organ's blood Supply manipulation (e.g., for expansion and/or differentiation) dur while the organ is being blood-perfused by a cardiovascular ing the process of cryopreservation of the stem cells, during system, which can be within the body of the organ donor or the process of thawing cryopreserved stem cells, while the organ recipient. stem cells are being transplanted into a recipient, immediately 40 In certain embodiments, the organ may be any organ Suit after the stem cells are transplanted into a recipient, or any able for transplantation, Such as a kidney, liver or lobe of a combination thereof. liver, heart, lung or part of a lung, skin, intestine or portion of The present invention further provides methods for reduc an intestine, cornea, pancreas or portion of a pancreas, tissue ing, preventing or reversing organ damage or enhancing (e.g., blood, bone marrow, blood stem cells, or umbilical cord organ preservation and/or Survival comprising contacting the 45 blood), or any combination thereof. organ with a preservation solution wherein the preservation In certain embodiments of methods of the invention, the Solution comprises a compound of the invention. stem cell is selected from adult stem cells or embryonic stem In certain embodiments, the preservation Solution com cells. Exemplary stem cells include, but are not limited to, prises a compound of the invention in an amount Sufficient for totipotent stem cells, pluripotent stem cells, multipotent stem reducing, preventing or reversing organ damage or enhancing 50 cells, unipotent stem cells, hematopoietic stem cells, adipose organ preservation and/or Survival. In certain embodiments, derived stem cells, endothelial stem cells, muscle stem cells, the preservation Solution comprises a compound of the inven bone marrow stromal cells (e.g., mesenchymal stem cells), tion at a concentration of 1 nM to 1 M, e.g., from 1 uM to 1 neural stem cells, skin stem cells, and follicular stem cells. mM. In certain embodiments, the organ preservation Solution Embryonic stem cells include embryonic stem cells made further comprises potassium, Sodium, magnesium, calcium, 55 using somatic cell nuclear transfer, as well as embryonic stem phosphate, Sulphate, glucose, citrate, mannitol, histidine, cells derived from the inner cell mass of embryos produced by tryptophan, alpha-ketoglutaric acid, lactobionate, raffinose, fertilization. Suitable stem cells also include induced pluri adenosine, allopurinol, , glutamate, insulin, dex potent stem cells, regardless of whether the induced pluripo amethasone, hydroxyethyl starch, bactrim, trehalose, glucon tent stem cells are produced using integrative or non-integra ate, or combinations thereof. In certain embodiments, the 60 tive vectors to express one or more reprogramming factors, organ preservation solution comprises sodium, potassium, and/or whether the induced pluripotent stem cells are pro magnesium, or combinations thereof. In certain embodi duced using Small molecules that mimic the effects of over ments, the organ preservation Solution is free or Substantially expressing one or more reprogramming factors. free of cells, coagulation factors, nucleic acids Such as DNA, In certain embodiments, compounds of the present inven and/or plasma proteins. In certain embodiments, the organ 65 tion reduce, prevent or reverse organ damage or enhance preservation solution is sterile. In certain embodiments, the organ preservation by protecting the organ against reperfu organ preservation Solution comprises an aqueous solution. sion injury. US 8,673,881 B2 125 126 In certain embodiments, compounds of the present inven may be measured by a delayed need for Subsequent transplan tion reduce, prevent or reverse organ damage, reduce or pre tation and/or other therapeutic intervention(s)). The presence vent stem cell damage and/or death, enhance organ preserva of any of the foregoing may be viewed as an enhancement in tion, or enhance stem cell preservation and/or Survival by the Success of an organ and/or stem cell transplant procedure. decreasing or protecting against apoptosis. 5 The present invention provides a method of prolonging The present invention provides a method of promoting organ viability ex vivo, comprising Survival of an organ transplant recipient, comprising administering a compound of the invention to an organ administering a compound of the invention to an organ donor patient prior to removal of the organ; donor patient prior to removal of the organ; contacting the organ ex vivo with a compound of the inven administering a compound of the invention to an organ 10 tion; recipient prior to organ transplantation; contacting the organ ex vivo with a preservation solution contacting the organ ex vivo with a compound of the inven wherein the preservation Solution comprises a com tion; pound of the invention; contacting the organ ex vivo with a preservation Solution or any combination thereof. wherein the preservation Solution comprises a com 15 The present invention provides a method of prolonging pound of the invention; stem cell viability ex vivo, comprising or any combination thereof. administering a compound of the invention to a stem cell The present invention provides a method of promoting donor patient prior to removal of the stem cells; Survival of a stem cell transplant recipient, comprising contacting the stem cells ex vivo (e.g., in vitro in a Suitable administering a compound of the invention to a stem cell culture medium, Such as during the process of cyro donor patient prior to removal of the stem cells; preservation and/or thawing of cryopreserved stem cells administering a compound of the invention to a stem cell or during ex vivo culture and/or manipulation, such as recipient prior to stem cell transplantation; for stem cell expansion and/or differentiation) with a contacting the stem cells ex vivo (e.g., in a suitable culture compound of the invention; medium) with a compound of the invention; 25 or any combination thereof. or any combination thereof. The present invention provides a method of enhancing the The present invention provides a method of facilitating an Success of stem cell cryopreservation and/or thawing cryo organ transplant procedure and/or enhancing the Success of preserved stem cells, comprising one or more steps of an organ transplant procedure, comprising administering a compound of the invention to a stem cell administering a compound of the invention to an organ 30 donor patient prior to removal of the stem cells; and donor patient prior to removal of the organ; contacting the stem cells ex vivo (e.g., in vitro in a Suitable administering a compound of the invention to an organ culture medium, such as during the process of cryo recipient prior to organ transplantation; preservation of the stem cells and/or thawing of cryo contacting the organ ex vivo with a compound of the inven preserved stem cells) with a compound of the invention. tion; 35 A patient’s body, as a whole, can typically only tolerate contacting the organ ex vivo with a preservation Solution much lower levels of chemo-, bio- and radiation therapy than wherein the preservation Solution comprises a com many particular organs. As such, prolonged and reliable ex pound of the invention; vivo organ viability would provide benefits outside the con or any combination thereof. text of organ transplantation, including providing opportuni The present invention provides a method of facilitating a 40 ties for ex vivo therapy. Accordingly, the Subject methods stem cell transplant procedure and/or enhancing the Success may be used to permit an organ to be removed from the body of a stem cell transplant procedure, comprising and treated in isolation, reducing the risk of damage to other administering a compound of the invention to a stem cell parts of the body. donor patient prior to removal of the stem cells; The present invention provides an organ infused with a administering a compound of the invention to a stem cell 45 compound of the invention. In certain embodiments, the recipient prior to stem cell transplantation; organ is ex vivo. For example, the present invention provides contacting the stem cells ex vivo (e.g., in vitro in a Suitable an ex vivo organ infused with a compound of the invention. In culture medium, Such as during the process of cyro certain embodiments, the organ comprises a concentration of preservation and/or thawing of cyropreserved stem cells greater than 1 nM of a compound of the invention, such as 1 or during ex vivo culture and/or manipulation) with a 50 nM to 1 M, 1 mM to 1 M, or 10 mM to 1 M. In certain compound of the invention; embodiments, alumen of an organ comprises a fluid having a or any combination thereof. concentration of greater than 1 nM of a compound of the The Success of an organ and/or a stem cell transplant pro invention, such as 1 nM to 1 M, 1 mM to 1 M, or 10 mM to 1 cedure may be evaluated, for example, by the reduction of M. side effects and/or symptoms associated with the transplan 55 The present invention further provides an organ in contact tation procedure, by a reduction in hospitalization time fol with, and preferably partially or wholly submersed in, an lowing the organ and/or stem cell transplant procedure, by a organ preservation solution, wherein the organ preservation reduction in the time between organ and/or stem cell trans Solution comprises a compound of the invention. In certain plantation and resumption of normal bodily functions and embodiments, the organ preservation solution further com processes (e.g., cessation of the need for dialysis, artificial 60 prises potassium, Sodium, magnesium, calcium, phosphate, respiration, the use of a cardiopulmonary bypass machine or Sulphate, glucose, citrate, mannitol, histidine, tryptophan, other prosthetic devices, such as artificial hearts, etc.) or by an alpha-ketoglutaric acid, lactobionate, raffinose, adenosine, increased life expectancy following organ and/or stem cell allopurinol, glutathione, glutamate, insulin, dexamethasone, transplantation. In certain embodiments, the Success of an hydroxyethyl starch, bactrim, trehalose, gluconate, or com organ transplant procedure may be evaluated, for example, as 65 binations thereof. In certain embodiments, the organ preser enhanced organ viability and/or functional longevity follow Vation solution comprises sodium, potassium, magnesium, or ing transplantation as compared to an untreated organ (e.g., as combinations thereof. In certain embodiments, the organ US 8,673,881 B2 127 128 preservation solution is free or substantially free of cells, preventing stem cell damage and/or death or enhancing coagulation factors, DNA, and/or plasma proteins. In certain stem cell preservation and/or Survival. embodiments, the organ preservation Solution is sterile. In In certain embodiments, the kit further comprises instruc certain embodiments, the organ preservation Solution com tions for the administration of the pharmaceutical formula prises a compound of the invention at a concentration of 5 tion (e.g., one or more single dosage forms) comprising a greater than 1 nM, such as greater than 10 nM, 100 nM, 1 mM, compound of the invention conjointly with a second thera 10 mM or 100 mM. In certain embodiments, the organ pres peutic agent, such as those mentioned above. In certain ervation Solution comprises an aqueous Solution. In certain embodiments, the kit further comprises a second pharmaceu embodiments, the organ preservation solution comprises a tical formulation (e.g., one or more single dosage forms) perfluorocarbon. 10 comprising a second therapeutic agent, such as those men tioned above. In certain embodiments, the kit further com The present invention provides an organ preservation solu prises a second pharmaceutical formulation (e.g., one or more tion comprising a compound of the invention. In certain single dosage forms) comprising a second agent Suitable for embodiments, the organ preservation solution further com reducing, preventing or reversing organ damage or enhancing prises potassium, Sodium, magnesium, calcium, phosphate, 15 organ preservation and/or Survival. In certain embodiments, Sulphate, glucose, citrate, mannitol, histidine, tryptophan, the kit further comprises a second pharmaceutical formula alpha-ketoglutaric acid, lactobionate, raffinose, adenosine, tion (e.g., one or more single dosage forms) comprising a allopurinol, glutathione, glutamate, insulin, dexamethasone, second agent Suitable for reducing or preventing stem cell hydroxyethyl starch, bactrim, trehalose, gluconate, or com damage and/or death or enhancing stem cell preservation binations thereof. In certain embodiments, the organ preser and/or survival. Vation solution comprises sodium, potassium, magnesium, or The present invention provides a kit comprising: combinations thereof. In certain embodiments, the organ a) a first pharmaceutical formulation (e.g., one or more preservation solution is free or substantially free of cells, single dosage forms) comprising a therapeutic agent coagulation factors, DNA, or plasma proteins. In certain Suitable for modulating immune function, Suppressing embodiments, the organ preservation Solution is sterile. In 25 immune response, treating an autoimmune disease or certain embodiments, the organ preservation Solution com autoimmune disorder, or treating a disease, sequela or prises a compound of the invention at a concentration of pathological condition mediated by an activation of the greater than 1 nM, such as greater than 10 nM, 100 nM, 1 mM, immune system, such as those mentioned above, or an 10 mM or 100 mM. In certain embodiments, the organ pres agent Suitable for reducing, preventing or reversing ervation Solution comprises an aqueous Solution. In certain 30 organ damage or enhancing organ preservation and/or embodiments, the organ preservation solution comprises a Survival, or an agent Suitable for reducing or preventing perfluorocarbon. stem cell damage and/or death or enhancing stem cell The present invention provides a kit comprising: preservation and/or Survival; and a) a pharmaceutical formulation (e.g., one or more single b) instructions for the administration of the first pharma dosage forms) comprising a compound of the invention; 35 ceutical formulation (e.g., one or more single dosage and forms) and a second pharmaceutical formulation (e.g., b) instructions for the administration of the pharmaceutical one or more single dosage forms) comprising a com formulation to an organ donor patient prior to removal of pound of the invention for reducing, preventing or the organ for reducing, preventing or reversing organ reversing organ damage or enhancing organ preserva damage or enhancing organ preservation and/or Sur 40 tion and/or Survival, and/or instructions for the admin vival, and/or instructions for the administration of the istration of the first pharmaceutical formulation (e.g., pharmaceutical formulation to a stem cell donor patient one or more single dosage forms) and a second pharma prior to removal of the stem cells for reducing or pre ceutical formulation (e.g., one or more single dosage venting stem cell damage and/or death or enhancing forms) comprising a compound of the invention for stem cell preservation and/or Survival. 45 reducing or preventing stem cell damage and/or death or The present invention provides a kit comprising: enhancing stem cell preservation and/or Survival. a) a pharmaceutical formulation (e.g., one or more single In certain embodiments, the invention relates to a method dosage forms) comprising a compound of the invention; for conducting a pharmaceutical business, by manufacturing and a formulation of a compound of the invention, or a kit as b) instructions for the administration of the pharmaceutical 50 described herein, and marketing to healthcare providers the formulation to an organ recipient prior to organ trans benefits of using the formulation or kit for reducing, prevent plantation for reducing, preventing or reversing organ ing or reversing organ damage or enhancing organ preserva damage or enhancing organ preservation and/or Sur tion and/or Survival, or for reducing or preventing stem cell vival, and/or instructions for the administration of the damage and/or death or enhancing stem cell preservation pharmaceutical formulation to a stem cell recipient prior 55 and/or survival. to stem cell transplantation for reducing or preventing In certain embodiments, the invention relates to a method stem cell damage and/or death or enhancing stem cell for conducting a pharmaceutical business, by providing a preservation and/or Survival. distribution network for selling a formulation of a compound The present invention provides a kit comprising: of the invention, or kit as described herein, and providing a) a pharmaceutical formulation (e.g., one or more single 60 instruction material to patients or physicians for using the dosage forms) comprising a compound of the invention; formulation for reducing, preventing or reversing organ dam and age or enhancing organ preservation and/or Survival, or for b) instructions for contacting an organ with the pharma reducing or preventing stem cell damage and/or death or ceutical formulation for reducing, preventing or revers enhancing stem cell preservation and/or Survival. ing organ damage or enhancing organ preservation and/ 65 In certain embodiments, the invention comprises a method or Survival, and/or instructions for contacting stem cells for conducting a pharmaceutical business, by determining an with the pharmaceutical formulation for reducing or appropriate formulation and dosage of a compound of the US 8,673,881 B2 129 130 invention for reducing, preventing or reversing organ damage The term “acyloxy” is art-recognized and refers to a group or enhancing organ preservation and/or Survival, or for reduc represented by the general formula hydrocarbylC(O)O—, ing or preventing stem cell damage and/or death or enhancing preferably alkylC(O)O—. stem cell preservation and/or Survival, conducting therapeu The term “alkoxy' refers to an alkyl group, preferably a tic profiling of identified formulations for efficacy and toxic lower alkyl group, having an oxygen attached thereto. Rep ity in animals, and providing a distribution networkfor selling resentative alkoxy groups include methoxy, ethoxy, propoxy, an identified preparation as having an acceptable therapeutic tert-butoxy and the like. profile. In certain embodiments, the method further includes The term “alkoxyalkyl refers to an alkyl group substituted providing a sales group for marketing the preparation to with an alkoxy group and may be represented by the general healthcare providers. 10 formula alkyl-O-alkyl. In certain embodiments, the invention relates to a method The term “alkenyl', as used herein, refers to an aliphatic for conducting a pharmaceutical business by determining an group containing at least one double bond and is intended to appropriate formulation and dosage of a compound of the include both “unsubstituted alkenyls' and “substituted alk invention for reducing, preventing or reversing organ damage enyls', the latter of which refers to alkenyl moieties having or enhancing organ preservation and/or Survival, or for reduc 15 Substituents replacing a hydrogen on one or more carbons of ing or preventing stem cell damage and/or death or enhancing the alkenyl group. Such Substituents may occur on one or stem cell preservation and/or Survival, and licensing, to a third more carbons that are included or not included in one or more party, the rights for further development and sale of the for double bonds. Moreover, such substituents include all those mulation. contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of DEFINITIONS alkenyl groups by one or more alkyl, carbocyclyl, aryl, het erocyclyl, or heteroaryl groups is contemplated. Angiogenesis” is defined as any enhancement of an exist The term “alkyl refers to the radical of saturated aliphatic ing vascular bed or the formation of new vasculature which groups, including straight-chain alkyl groups, branched benefits tissue perfusion. This includes the formation of new 25 chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-sub vessels by sprouting of endothelial cells from existing blood stituted cycloalkyl groups, and cycloalkyl-substituted alkyl vessels or the remodeling of existing vessels to alter size, groups. In preferred embodiments, a straight chain or maturity, direction or flow properties to improve blood per branched chain alkyl has 30 or fewer carbon atoms in its fusion of tissue. backbone (e.g., C-Clso for straight chains, C-Clso for As used herein, the term “corticosteroid’ refers to any of 30 branched chains), and more preferably 20 or fewer. Likewise, the adrenal corticosteroid hormones isolated from the adrenal preferred cycloalkyls have from 3-10 carbon atoms in their cortex or produced synthetically, and derivatives thereof that ring structure, and more preferably have 5, 6 or 7 carbons in are used for treatment of inflammatory diseases, as described the ring structure. herein. Corticosteroids include those that are naturally occur Moreover, the term “alkyl (or “lower alkyl) as used ring, synthetic, or semi-synthetic in origin, and Such com 35 throughout the specification, examples, and claims is pounds are characterized by the presence of a steroid nucleus intended to include both “unsubstituted alkyls' and “substi of four fused rings, e.g., as found in cholesterol, dihydroxy tuted alkyls', the latter of which refers to alkyl moieties cholesterol, Stigmasterol, and lanosterol structures. having Substituents replacing a hydrogen on one or more The term “LASIK', as used herein, is an acronym for carbons of the hydrocarbon backbone. Such substituents, if LAser in SItu Keratomileusis. This is a type of refractive 40 not otherwise specified, can include, for example, a halogen, Surgery in which the cornea is reshaped to change its optical a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbo power. Specifically, a disc of cornea is raised as a flap, then an nyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, excimer laser is used to reshape the middle layer of corneal a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a tissue, producing Surgical flattening. LASIK surgery may be phosphate, a phosphonate, a phosphinate, an amino, an used for correcting myopia, hyperopia, and astigmatism. 45 amido, an amidine, an imine, a cyano, a nitro, an azido, a As used herein, “immunosuppressive agent” refers to Sulfhydryl, an alkylthio, a sulfate, a Sulfonate, a Sulfamoyl, a agents that Suppress the body's ability to elicit an immuno Sulfonamido, a Sulfonyl, a heterocyclyl, an aralkyl, or an logical response to the presence of an antigenfallergen. For aromatic or heteroaromatic moiety. It will be understood by example, the ability to fight off disease or reject a transplanted those skilled in the art that the moieties substituted on the organ. Another term for these agents is anti-rejection agents. 50 hydrocarbon chain can themselves be substituted, if appro Not only are they are used to treat organ rejection after trans priate. For instance, the substituents of a substituted alkyl plantation, but many other diseases of immunological etiol may include Substituted and unsubstituted forms of amino, ogy Such as Crohn's disease, rheumatoid arthritis, lupus, azido, imino, amido, phosphoryl (including phosphonate and multiple Sclerosis, psoriasis, and other diseases and disorders phosphinate), Sulfonyl (including Sulfate, Sulfonamido, Sul as described herein. 55 famoyl and Sulfonate), and silyl groups, as well as ethers, The term 'graft, as used herein, refers to a body part, alkylthios, carbonyls (including ketones, aldehydes, car organ, tissue, or cells. Grafts may comprise all or part of one boxylates, and esters), —CF, CN and the like. Exemplary or more organs such as liver, kidney, heart or lung; body parts substituted alkyls are described below. Cycloalkyls can be Such as bone or skeletal matrix; tissue Such as skin, intestines, further substituted with alkyls, alkenyls, alkoxys, alkylthios, endocrine glands; or progenitor stem cells of various types. 60 aminoalkyls, carbonyl-substituted alkyls, —CF, —CN, and The term “acyl is art-recognized and refers to a group the like. represented by the general formula hydrocarbylC(O)—, pref The term “C” when used in conjunction with a chemical erably alkylC(O)—. moiety, Such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or The term “acylamino' is art-recognized and refers to an alkoxy is meant to include groups that contain from X to y amino group Substituted with an acyl group and may be 65 carbons in the chain. For example, the term "Calkyl” refers represented, for example, by the formula hydrocarbylC(O) to Substituted or unsubstituted Saturated hydrocarbon groups, NH including straight-chain alkyl and branched-chain alkyl US 8,673,881 B2 131 132 groups that contain from X toy carbons in the chain, including The term “carbamate' is art-recognized and refers to a haloalkyl groups such as trifluoromethyl and 2.2.2-trifluoro group ethyl, etc. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms “Calk enyl” and “Calkynyl” refer to substituted or unsubstituted 5 O O unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at ls R10 ls R10 least one double or triple bond respectively. A. r A. O1 The term “alkylamino', as used herein, refers to an amino R9 O R9 group Substituted with at least one alkyl group. 10 The term “alkylthio', as used herein, refers to a thiol group wherein R and R' independently represent hydrogen or a substituted with an alkyl group and may be represented by the hydrocarbyl group, such as an alkyl group, or R and R' general formula alkylS-. taken together with the intervening atom(s) complete a het The term “alkynyl', as used herein, refers to an aliphatic erocycle having from 4 to 8 atoms in the ring structure. group containing at least one triple bond and is intended to 15 include both “unsubstituted alkynyls' and “substituted alky The terms “carbocycle”, “carbocyclyl', and “carbocyclic”. nyls', the latter of which refers to alkynyl moieties having as used herein, refers to a non-aromatic saturated or unsatur Substituents replacing a hydrogen on one or more carbons of ated ring in which each atom of the ring is carbon. Preferably the alkynyl group. Such substituents may occur on one or a carbocycle ring contains from 3 to 10 atoms, more prefer more carbons that are included or not included in one or more ably from 5 to 7 atoms. triple bonds. Moreover, such substituents include all those The term "carbocyclylalkyl, as used herein, refers to an contemplated for alkyl groups, as discussed above, except alkyl group Substituted with a carbocycle group. where stability is prohibitive. For example, substitution of The term “carbonate” is art-recognized and refers to a alkynyl groups by one or more alkyl, carbocyclyl, aryl, het group —OCO. R", wherein R' represents a hydrocarbyl erocyclyl, or heteroaryl groups is contemplated. 25 group. The term "amide', as used herein, refers to a group The term “carboxy’, as used herein, refers to a group represented by the formula—CO.H. The term “ester', as used herein, refers to a group —C(O) OR' wherein R' represents a hydrocarbyl group. R10 M 30 The term “ether', as used herein, refers to a hydrocarbyl N group linked through an oxygen to another hydrocarbyl V group. Accordingly, an ether substituent of a hydrocarbyl R10 group may be hydrocarbyl-O-. Ethers may be either sym metrical or unsymmetrical. Examples of ethers include, but wherein each R' independently represent a hydrogen or 35 are not limited to, heterocycle-O-heterocycle and aryl-O- hydrocarbyl group, or two R' are taken together with the N heterocycle. Ethers include “alkoxyalkyl groups, which may atom to which they are attached complete a heterocycle hav be represented by the general formula alkyl-O-alkyl. ing from 4 to 8 atoms in the ring structure. The terms “halo' and “halogen as used herein means The terms “amine' and “amino” are art-recognized and halogen and includes chloro, fluoro, bromo, and iodo. refer to both unsubstituted and substituted amines and salts 40 The terms “hetaralkyl and "heteroaralkyl, as used herein, thereof, e.g., a moiety that can be represented by refers to an alkyl group Substituted with a hetaryl group. The term "heteroalkyl, as used herein, refers to a saturated or unsaturated chain of carbonatoms and at least one heteroa R10 R10 tom, wherein no two heteroatoms are adjacent. N Nt-R10 45 The terms "heteroaryland “hetaryl' include substituted or V V unsubstituted aromatic single ring structures, preferably 5- to R10 O R10 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, pref wherein each R' independently represents a hydrogen or a erably one to four heteroatoms, more preferably one or two hydrocarbyl group, or two R' are taken together with the N 50 heteroatoms. The terms "heteroaryl and “hetaryl also atom to which they are attached complete a heterocycle hav include polycyclic ring systems having two or more cyclic ing from 4 to 8 atoms in the ring structure. rings in which two or more carbons are common to two The term "aminoalkyl, as used herein, refers to an alkyl adjoining rings wherein at least one of the rings is heteroaro group Substituted with an amino group. matic, e.g., the other cyclic rings can be cycloalkyls, cycloalk The term “aralkyl, as used herein, refers to an alkyl group 55 enyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Substituted with an aryl group. Heteroaryl groups include, for example, pyrrole, furan, The term “aryl' as used herein include substituted or thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, unsubstituted single-ring aromatic groups in which each atom pyrazine, pyridazine, and pyrimidine, and the like. of the ring is carbon. Preferably the ring is a 5- to 7-membered The term "heteroatom' as used herein means an atom of ring, more preferably a 6-membered ring. The term “aryl 60 any element other than carbon or hydrogen. Preferred het also includes polycyclic ring systems having two or more eroatoms are nitrogen, oxygen, and Sulfur. cyclic rings in which two or more carbons are common to two The terms "heterocyclyl', "heterocycle', and "heterocy adjoining rings wherein at least one of the rings is aromatic, clic” refer to substituted or unsubstituted non-aromatic ring e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, structures, preferably 3- to 10-membered rings, more prefer cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl 65 ably 3- to 7-membered rings, whose ring structures include at groups include benzene, naphthalene, phenanthrene, phenol, least one heteroatom, preferably one to four heteroatoms, aniline, and the like. more preferably one or two heteroatoms. The terms "hetero US 8,673,881 B2 133 134 cyclyl and "heterocyclic” also include polycyclic ring sys heteroatoms. Substituents can include any Substituents tems having two or more cyclic rings in which two or more described herein, for example, a halogen, a hydroxyl, a car carbons are common to two adjoining rings wherein at least bonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, oran one of the rings is heterocyclic, e.g., the other cyclic rings can acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroar 5 thioformate), an alkoxyl, a phosphoryl, a phosphate, a phos yls, and/or heterocyclyls. Heterocyclyl groups include, for phonate, a phosphinate, an amino, an amido, an amidine, an example, piperidine, piperazine, pyrrolidine, morpholine, imine, a cyano, a nitro, an azido, a Sulfhydryl, an alkylthio, a lactones, lactams, and the like. Sulfate, a Sulfonate, a sulfamoyl, a Sulfonamido, a Sulfonyl, a The term "heterocyclylalkyl, as used herein, refers to an heterocyclyl, an aralkyl, or an aromatic or heteroaromatic alkyl group Substituted with a heterocycle group. 10 moiety. It will be understood by those skilled in the art that the The term “hydrocarbyl, as used herein, refers to a group moieties substituted on the hydrocarbon chain can them that is bonded through a carbonatom that does not have a =O selves be substituted, if appropriate. Unless specifically or =S Substituent, and typically has at least one carbon stated as “unsubstituted, references to chemical moieties hydrogen bond and a primarily carbon backbone, but may herein are understood to include substituted variants. For optionally include heteroatoms. Thus, groups like methyl, 15 example, reference to an “aryl group or moiety implicitly ethoxyethyl 2-pyridyl, and trifluoromethyl are considered to includes both substituted and unsubstituted variants. be hydrocarbyl for the purposes of this application, but sub The term "sulfate' is art-recognized and refers to the group stituents such as acetyl (which has a =O substituent on the —OSOH, or a pharmaceutically acceptable salt thereof. linking carbon) and ethoxy (which is linked through oxygen, The term "sulfonamide' is art-recognized and refers to the not carbon) are not. Hydrocarbyl groups include, but are not group represented by the general formulae limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof. The term “hydroxyalkyl, as used herein, refers to an alkyl O R10 group Substituted with a hydroxy group. O R10 S.C. The term “lower when used in conjunction with a chemi 25 cal moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or \ \ no V V alkoxy is meant to include groups where there are ten or fewer O R or R9 non-hydrogen atoms in the Substituent, preferably six or fewer. A “lower alkyl, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or 30 wherein R and R' independently represents hydrogen or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, hydrocarbyl, such as alkyl, or RandR' taken together with alkynyl, oralkoxy substituents defined herein are respectively the intervening atom(s) complete a heterocycle having from 4 lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower to 8 atoms in the ring structure. alkynyl, or lower alkoxy, whether they appear alone or in The term “sulfoxide' is art-recognized and refers to the combination with other Substituents, such as in the recitations 35 group—S(O) R', wherein R' represents a hydrocarbyl. hydroxyalkyl and aralkyl (in which case, for example, the The term “sulfonate' is art-recognized and refers to the atoms within the aryl group are not counted when counting group SOH, or a pharmaceutically acceptable salt thereof. the carbon atoms in the alkyl substituent). The term “sulfone' is art-recognized and refers to the The terms “polycyclyl', 'polycycle', and “polycyclic' group - S(O) R', wherein R' represents a hydrocarbyl. refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, 40 The term “thioalkyl, as used herein, refers to an alkyl cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in group Substituted with a thiol group. which two or more atoms are common to two adjoining rings, The term “thioester', as used herein, refers to a group e.g., the rings are “fused rings'. Each of the rings of the —C(O)SR'or-SC(O)R' wherein R' represents a hydro polycycle can be substituted or unsubstituted. In certain carbyl. embodiments, each ring of the polycycle contains from 3 to 45 The term “thioether, as used herein, is equivalent to an 10 atoms in the ring, preferably from 5 to 7. ether, wherein the oxygen is replaced with a Sulfur. The term “silyl refers to a silicon moiety with three hydro The term “urea' is art-recognized and may be represented carbyl moieties attached thereto. by the general formula The term “substituted” refers to moieties having substitu ents replacing a hydrogen on one or more carbons of the 50 backbone. It will be understood that “substitution' or “sub O stituted with includes the implicit proviso that such substi tution is in accordance with permitted valence of the substi ul tuted atom and the substituent, and that the substitution A. r R9 R9 results in a stable compound, e.g., which does not spontane 55 ously undergo transformation Such as by rearrangement, cyclization, elimination, etc. As used herein, the term "sub wherein R and R' independently represent hydrogen or a stituted” is contemplated to include all permissible substitu hydrocarbyl, such as alkyl, or either occurrence of R taken ents of organic compounds. In a broad aspect, the permissible together with R'' and the intervening atom(s) complete a Substituents include acyclic and cyclic, branched and 60 heterocycle having from 4 to 8 atoms in the ring structure. unbranched, carbocyclic and heterocyclic, aromatic and non “Protecting group' refers to a group of atoms that, when aromatic Substituents of organic compounds. The permissible attached to a reactive functional group in a molecule, mask, substituents can be one or more and the same or different for reduce or prevent the reactivity of the functional group. Typi appropriate organic compounds. For purposes of this inven cally, a protecting group may be selectively removed as tion, the heteroatoms such as nitrogen may have hydrogen 65 desired during the course of a synthesis. Examples of protect Substituents and/or any permissible Substituents of organic ing groups can be found in Greene and Wuts, Protective compounds described herein which satisfy the valences of the Groups in Organic Chemistry, 3" Ed., 1999, John Wiley & US 8,673,881 B2 135 136 Sons, NY and Harrison et al., Compendium of Synthetic transdermal delivery system, e.g., a skin patch. The compo Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, sition can also be present in a solution Suitable for topical NY. Representative nitrogen protecting groups include, but administration, Such as an eye drop. are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, ben A pharmaceutically acceptable carrier can contain physi Zyloxycarbonyl (“CBZ), tert-butoxycarbonyl (“Boc'), trim ologically acceptable agents that act, for example, to stabilize ethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl or to increase the absorption of a compound such as a com (“TES), trity1 and substituted trityl groups, alkyloxycarbo pound of the invention. Such physiologically acceptable nyl, 9-fluorenylmethyloxycarbonyl (“FMOC), nitro-vera agents include, for example, carbohydrates, such as glucose, tryloxycarbonyl (“NVOC) and the like. Representative Sucrose or dextrans, antioxidants. Such as ascorbic acid or hydroxyl protecting groups include, but are not limited to, 10 glutathione, chelating agents, low molecular weight proteins those where the hydroxyl group is either acylated (esterified) or other stabilizers or excipients. The choice of a pharmaceu or alkylated such as benzyl and trityl ethers, as well as alkyl tically acceptable carrier, including a physiologically accept ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., able agent, depends, for example, on the route of administra TMS or TIPS groups), glycol ethers, such as ethylene glycol tion of the composition. The pharmaceutical composition and propylene glycol derivatives and allyl ethers. 15 (preparation) also can be a liposome or other polymer matrix, The term “healthcare providers' refers to individuals or which can have incorporated therein, for example, a com organizations that provide healthcare services to a person, pound of the invention. Liposomes, for example, which com community, etc. Examples of “healthcare providers' include prise phospholipids or other lipids, are nontoxic, physiologi doctors, hospitals, continuing care retirement communities, cally acceptable and metabolizable carriers that are relatively skilled nursing facilities, Subacute care facilities, clinics, mul simple to make and administer. tispecialty clinics, freestanding ambulatory centers, home The phrase “pharmaceutically acceptable' is employed health agencies, and HMOs. herein to refer to those compounds, materials, compositions, The term “treating refers to: preventing a disease, disorder and/or dosage forms which are, within the scope of Sound or condition from occurring in a cell, a tissue, a system, medical judgment, Suitable for use in contact with the tissues animal or human which may be predisposed to the disease, 25 of human beings and animals without excessive toxicity, irri disorder and/or condition but has not yet been diagnosed as tation, allergic response, or other problem or complication, having it; stabilizing a disease, disorder or condition, i.e., commensurate with a reasonable benefit/risk ratio. arresting its development; and relieving one or more symp The phrase “pharmaceutically acceptable carrier as used toms of the disease, disorder or condition, i.e., causing regres herein means a pharmaceutically acceptable material, com sion of the disease, disorder and/or condition. 30 position or vehicle. Such as a liquid or solid filler, diluent, As used herein, a therapeutic that “prevents” a disorder or excipient, solvent or encapsulating material. Each carrier condition refers to a compound that, in a statistical sample, must be “acceptable” in the sense of being compatible with reduces the occurrence of the disorder or condition in the the other ingredients of the formulation and not injurious to treated sample relative to an untreated control sample, or the patient. Some examples of materials which can serve as delays the onset or reduces the severity of one or more symp 35 pharmaceutically acceptable carriers include: (1) Sugars, toms of the disorder or condition relative to the untreated Such as lactose, glucose and Sucrose; (2) starches, such as control sample. corn starch and potato starch; (3) cellulose, and its deriva As used herein, a "complex disorder having an inflamma tives, such as Sodium carboxymethyl cellulose, ethyl cellu tory component' is a disease where the initial pathology/ lose and cellulose acetate; (4) powdered tragacanth; (5) malt, dysfunction in a particular tissue or organ that is vital for the 40 (6) gelatin; (7) talc.; (8) excipients, such as cocoa butter and systems biology function of an individual will secondarily Suppository waxes; (9) oils, such as peanut oil, cottonseed oil, lead to systemic metabolic derangement and/or tissue stress safflower oil, sesame oil, olive oil, corn oil and Soybean oil; causing, or further enhancing, activation of the immune sys (10) glycols, such as propylene glycol, (11) polyols, such as tem leading to dysfunction in several organs vital for body glycerin, Sorbitol, mannitol and polyethylene glycol; (12) homeostasis. 45 esters, such as ethyl oleate and ethyl laurate; (13) agar, (14) Pharmaceutical Compositions buffering agents, such as and alumi The compositions and methods of the present invention num hydroxide: (15) alginic acid, (16) pyrogen-free water; may be utilized to treat an individual in need thereof. In (17) isotonic saline: (18) Ringer's solution; (19) ethyl alco certain embodiments, the individual is a mammal Such as a hol; (20) phosphate buffer solutions; and (21) other non-toxic human, or a non-human mammal. When administered to an 50 compatible Substances employed in pharmaceutical formula animal. Such as a human, the composition or the compound is tions. preferably administered as a pharmaceutical composition A pharmaceutical composition (preparation) can be comprising, for example, a compound of the invention and a administered to a subject by any of a number of routes of pharmaceutically acceptable carrier. Pharmaceutically administration including, for example, orally (for example, acceptable carriers are well known in the art and include, for 55 drenches as in aqueous or non-aqueous Solutions or Suspen example, aqueous solutions such as water or physiologically sions, tablets, capsules (including sprinkle capsules and gela buffered saline or other solvents or vehicles such as glycols, tin capsules), boluses, powders, granules, pastes for applica glycerol, oils such as olive oil or injectable organic esters. In tion to the tongue); absorption through the oral mucosa (e.g., a preferred embodiment, when such pharmaceutical compo Sublingually); anally, rectally or vaginally (for example, as a sitions are for human administration, the aqueous solution is 60 pessary, cream or foam); parenterally (including intramuscu pyrogen free, or Substantially pyrogen free. The excipients larly, intravenously, Subcutaneously or intrathecally as, for can be chosen, for example, to effect delayed release of an example, a sterile solution or Suspension); nasally; intraperi agent or to selectively target one or more cells, tissues or toneally; Subcutaneously; transdermally (for example as a organs. The pharmaceutical composition can be in dosage patch applied to the skin); and topically (for example, as a unit form Such as tablet, capsule (including sprinkle capsule 65 cream, ointment or spray applied to the skin, or as an eye and gelatin capsule), granule, powder, syrup, Suppository, drop). The compound may also be formulated for inhalation. injection or the like. The composition can also be present in a In certain embodiments, a compound may be simply dis US 8,673,881 B2 137 138 solved or suspended in sterile water. Details of appropriate milk Sugars, as well as high molecular weight polyethylene routes of administration and compositions Suitable for same glycols and the like. can be foundin, for example, U.S. Pat. Nos. 6,110,973, 5,763, A tablet may be made by compression or molding, option 493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172, ally with one or more accessory ingredients. Compressed 896, as well as in patents cited therein. tablets may be prepared using binder (for example, gelatin or The formulations may conveniently be presented in unit hydroxypropylmethyl cellulose), lubricant, inert diluent, pre dosage form and may be prepared by any methods well servative, disintegrant (for example, sodium starch glycolate known in the art of pharmacy. The amount of active ingredient or cross-linked sodium carboxymethyl cellulose), Surface which can be combined with a carrier material to produce a active or dispersing agent. Molded tablets may be made by single dosage form will vary depending upon the host being 10 molding in a suitable machine a mixture of the powdered treated, the particular mode of administration. The amount of compound moistened with an inert liquid diluent. active ingredient that can be combined with a carrier material The tablets, and other solid dosage forms of the pharma to produce a single dosage form will generally be that amount ceutical compositions, such as dragees, capsules (including of the compound which produces a therapeutic effect. Gen 15 sprinkle capsules and gelatin capsules), pills and granules, erally, out of one hundred percent, this amount will range may optionally be scored or prepared with coatings and from about 1 percent to about ninety-nine percent of active shells. Such as enteric coatings and other coatings well known ingredient, preferably from about 5 percent to about 70 per in the pharmaceutical-formulating art. They may also be for cent, most preferably from about 10 percent to about 30 mulated so as to provide slow or controlled release of the percent. active ingredient therein using, for example, hydroxypropy Methods of preparing these formulations or compositions lmethyl cellulose in varying proportions to provide the include the step of bringing into association an active com desired release profile, other polymer matrices, liposomes pound. Such as a compound of the invention, with the carrier and/or microspheres. They may be sterilized by, for example, and, optionally, one or more accessory ingredients. In gen filtration through a bacteria-retaining filter, or by incorporat eral, the formulations are prepared by uniformly and inti 25 ing sterilizing agents in the form of sterile Solid compositions mately bringing into association a compound of the present that can be dissolved in sterile water, or some other sterile invention with liquid carriers, or finely divided solid carriers, injectable medium immediately before use. These composi or both, and then, if necessary, shaping the product. tions may also optionally contain opacifying agents and may Formulations of the invention suitable for oral administra be of a composition that they release the active ingredient(s) tion may be in the form of capsules (including sprinkle cap 30 only, or preferentially, in a certain portion of the gastrointes Sules and gelatin capsules), cachets, pills, tablets, lozenges tinal tract, optionally, in a delayed manner. Examples of (using a flavored basis, usually Sucrose and acacia or traga embedding compositions that can be used include polymeric canth), powders, granules, or as a solution or a Suspension in Substances and waxes. The active ingredient can also be in an aqueous or non-aqueous liquid, or as an oil-in-water or 35 micro-encapsulated form, if appropriate, with one or more of water-in-oil liquid emulsion, or as an elixir or syrup, or as the above-described excipients. pastilles (using an inert base. Such as gelatin and glycerin, or Liquid dosage forms useful for oral administration include Sucrose and acacia) and/or as mouth washes and the like, each pharmaceutically acceptable emulsions, microemulsions, containing a predetermined amount of a compound of the Solutions, Suspensions, syrups and elixirs. In addition to the present invention as an active ingredient. Compositions or 40 active ingredient, the liquid dosage forms may contain inert compounds may also be administered as a bolus, electuary or diluents commonly used in the art, Such as, for example, water paste. or other solvents, Solubilizing agents and emulsifiers, such as To prepare solid dosage forms for oral administration (cap ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl Sules (including sprinkle capsules and gelatin capsules), tab acetate, benzyl alcohol, benzyl benzoate, propylene glycol, lets, pills, dragees, powders, granules and the like), the active 45 1,3-butylene glycol, oils (in particular, cottonseed, ground ingredient is mixed with one or more pharmaceutically nut, corn, germ, olive, castor and sesame oils), glycerol, tet acceptable carriers, such as sodium citrate or dicalcium phos rahydrofuryl alcohol, polyethylene glycols and fatty acid phate, and/or any of the following: (1) fillers or extenders, esters of sorbitan, and mixtures thereof. Such as starches, lactose. Sucrose, glucose, mannitol, and/or Besides inert diluents, the oral compositions can also silicic acid; (2) binders, such as, for example, carboxymeth 50 include adjuvants such as wetting agents, emulsifying and ylcellulose, alginates, gelatin, polyvinyl pyrrolidone. Sucrose Suspending agents, Sweetening, flavoring, coloring, perfum and/or acacia; (3) humectants, such as glycerol; (4) disinte ing and preservative agents. grating agents. Such as agar-agar, calcium carbonate, potato Suspensions, in addition to the active compounds, may or tapioca starch, alginic acid, certain silicates, and sodium contain Suspending agents as, for example, ethoxylated isos carbonate; (5) Solution retarding agents, such as paraffin; (6) 55 tearyl alcohols, polyoxyethylene Sorbitol and Sorbitan esters, absorption accelerators, such as quaternary ammonium com microcrystalline cellulose, aluminum metahydroxide, bento pounds; (7) wetting agents, such as, for example, cetyl alco nite, agar-agar and tragacanth, and mixtures thereof. hol and glycerol monostearate; (8) absorbents, such as kaolin Formulations of the pharmaceutical compositions for rec and bentonite clay; (9) lubricants, such a talc, calcium Stear 60 tal, vaginal, or urethral administration may be presented as a ate, magnesium Stearate, Solid polyethylene glycols, sodium Suppository, which may be prepared by mixing one or more lauryl Sulfate, and mixtures thereof, and (10) coloring agents. active compounds with one or more Suitable nonirritating In the case of capsules (including sprinkle capsules and gela excipients or carriers comprising, for example, cocoa butter, tin capsules), tablets and pills, the pharmaceutical composi polyethylene glycol, a Suppository wax or a salicylate, and tions may also comprise buffering agents. Solid compositions 65 which is solid at room temperature, but liquid at body tem of a similar type may also be employed as fillers in Soft and perature and, therefore, will melt in the rectum or vaginal hard-filled gelatin capsules using Such excipients as lactose or cavity and release the active compound. US 8,673,881 B2 139 140 Formulations of the pharmaceutical compositions for buffers, bacteriostats, solutes which render the formulation administration to the mouth may be presented as a mouth isotonic with the blood of the intended recipient or suspend wash, or an oral spray, or an oral ointment. ing or thickening agents. Alternatively or additionally, compositions can be formu Examples of suitable aqueous and nonaqueous carriers that lated for delivery via a catheter, stent, wire, or other intralu may be employed in the pharmaceutical compositions of the minal device. Delivery via such devices may be especially invention include water, ethanol, polyols (such as glycerol, useful for delivery to the bladder, urethra, ureter, rectum, or propylene glycol, polyethylene glycol, and the like), and Suit intestine. able mixtures thereof, vegetable oils, such as olive oil, and Formulations which are suitable for vaginal administration injectable organic esters, such as ethyl oleate. Proper fluidity also include pessaries, tampons, creams, gels, pastes, foams 10 can be maintained, for example, by the use of coating mate rials, such as lecithin, by the maintenance of the required or spray formulations containing Such carriers as are known particle size in the case of dispersions, and by the use of in the art to be appropriate. Surfactants. Dosage forms for the topical or transdermal administration These compositions may also contain adjuvants such as include powders, sprays, ointments, pastes, creams, lotions, 15 preservatives, wetting agents, emulsifying agents and dis gels, Solutions, patches and inhalants. The active compound persing agents. Prevention of the action of microorganisms may be mixed under sterile conditions with a pharmaceuti may be ensured by the inclusion of various antibacterial and cally acceptable carrier, and with any preservatives, buffers, antifungal agents, for example, paraben, chlorobutanol, phe or propellants that may be required. nol sorbic acid, and the like. It may also be desirable to The ointments, pastes, creams and gels may contain, in include isotonic agents. Such as Sugars, sodium chloride, and addition to an active compound, excipients, such as animal the like into the compositions. In addition, prolonged absorp and vegetable fats, oils, waxes, paraffins, starch, tragacanth, tion of the injectable pharmaceutical form may be brought cellulose derivatives, polyethylene glycols, silicones, bento about by the inclusion of agents that delay absorption Such as nites, silicic acid, talc and Zinc oxide, or mixtures thereof. aluminum monostearate and gelatin. Powders and sprays can contain, in addition to an active 25 In some cases, in order to prolong the effect of a drug, it is compound, excipients such as lactose, talc, silicic acid, alu desirable to slow the absorption of the drug from subcutane minum hydroxide, calcium silicates and polyamide powder, ous or intramuscular injection. This may be accomplished by or mixtures of these Substances. Sprays can additionally con the use of a liquid Suspension of crystalline or amorphous tain customary propellants, such as chlorofluorohydrocar material having poor water solubility. The rate of absorption bons and volatile unsubstituted hydrocarbons, such as butane 30 of the drug then depends upon its rate of dissolution, which, in and propane. turn, may depend upon crystal size and crystalline form. Transdermal patches have the added advantage of provid Alternatively, delayed absorption of a parenterally adminis ing controlled delivery of a compound of the present inven tered drug form is accomplished by dissolving or Suspending tion to the body. Such dosage forms can be made by dissolv the drug in an oil vehicle. ing or dispersing the active compound in the proper medium. 35 Injectable depot forms are made by forming microencap Absorption enhancers can also be used to increase the flux of Suled matrices of the Subject compounds in biodegradable the compound across the skin. The rate of such flux can be polymers such as polylactide-polyglycolide. Depending on controlled by either providing a rate controlling membrane or the ratio of drug to polymer, and the nature of the particular dispersing the compound in a polymer matrix or gel. polymer employed, the rate of drug release can be controlled. Ophthalmic formulations, eye ointments, powders, solu 40 Examples of other biodegradable polymers include poly tions and the like, are also contemplated as being within the (orthoesters) and poly(anhydrides). Depot injectable formu Scope of this invention. Exemplary ophthalmic formulations lations are also prepared by entrapping the drug in liposomes are described in U.S. Publication Nos. 2005/0080056, 2005/ or microemulsions that are compatible with body tissue. 0059744, 2005/003 1697 and 2005/004074 and U.S. Pat. No. For use in the methods of this invention, active compounds 6,583,124, the contents of which are incorporated herein by 45 can be given perse or as a pharmaceutical composition con reference. If desired, liquid ophthalmic formulations have taining, for example, 0.1 to 99.5% (more preferably, 0.5 to properties similar to that of lacrimal fluids, aqueous humor or 90%) of active ingredient in combination with a pharmaceu vitreous humor or are compatable with such fluids. A pre tically acceptable carrier. ferred route of administration is local administration (e.g., Methods of introduction may also be provided by recharge topical administration, such as eye drops, or administration 50 able or biodegradable devices. Various slow release poly via an implant). meric devices have been developed and tested in vivo in The phrases “parenteral administration' and “adminis recent years for the controlled delivery of drugs, including tered parenterally as used herein means modes of adminis proteinacious biopharmaceuticals. A variety of biocompat tration other than enteral and topical administration, usually ible polymers (including hydrogels), including both biode by injection, and includes, without limitation, intravenous, 55 gradable and non-degradable polymers, can be used to form intramuscular, intraarterial, intrathecal, intracapsular, an implant for the Sustained release of a compound at a intraorbital, intracardiac, intradermal, intraperitoneal, tran particular target site. stracheal, Subcutaneous, Subcuticular, intraarticular, Subcap Actual dosage levels of the active ingredients in the phar Sular, Subarachnoid, intraspinal and intrasternal injection and maceutical compositions may be varied so as to obtain an infusion. 60 amount of the active ingredient that is effective to achieve the Pharmaceutical compositions suitable for parenteral desired therapeutic response for a particular patient, compo administration comprise one or more active compounds in sition, and mode of administration, without being toxic to the combination with one or more pharmaceutically acceptable patient. sterile isotonic aqueous or nonaqueous Solutions, disper The selected dosage level will depend upon a variety of sions, Suspensions or emulsions, or sterile powders which 65 factors including the activity of the particular compound or may be reconstituted into sterile injectable solutions or dis combination of compounds employed, or the ester, Salt or persions just prior to use, which may contain antioxidants, amide thereof, the route of administration, the time of admin US 8,673,881 B2 141 142 istration, the rate of excretion of the particular compound(s) ammonium salts. In certain embodiments, contemplated Salts being employed, the duration of the treatment, other drugs, of the invention include, but are not limited to, L-arginine, compounds and/or materials used in combination with the benenthamine, benzathine, betaine, calcium hydroxide, cho particular compound(s) employed, the age, sex, weight, con line, deanol, diethanolamine, diethylamine, 2-(diethylamino) dition, general health and prior medical history of the patient ethanol, ethanolamine, ethylenediamine, N-methylglucam being treated, and like factors well known in the medical arts. ine, hydrabamine, 1H-imidazole, lithium hydroxide, A physician or veterinarian having ordinary skill in the art L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)mor can readily determine and prescribe the therapeutically effec pholine, piperazine, potassium hydroxide, 1-(2-hydroxy tive amount of the pharmaceutical composition required. For ethyl)pyrrolidine, Sodium hydroxide, triethanolamine, example, the physician or veterinarian could start doses of the 10 pharmaceutical composition or compound at levels lower tromethamine, and Zinc hydroxide salts. In certain embodi than that required in order to achieve the desired therapeutic ments, contemplated salts of the invention include, but are not effect and gradually increase the dosage until the desired limited to, Na, Ca, K, Mg., Zn or other metal salts. effect is achieved. By “therapeutically effective amount” is The pharmaceutically acceptable acid addition salts can meant the concentration of a compound that is Sufficient to 15 also exist as various Solvates, such as with water, methanol, elicit the desired therapeutic effect. It is generally understood ethanol, dimethylformamide, and the like. Mixtures of such that the effective amount of the compound will vary accord Solvates can also be prepared. The source of Such solvate can ing to the weight, sex, age, and medical history of the Subject. be from the solvent of crystallization, inherent in the solvent Other factors which influence the effective amount may of preparation or crystallization, or adventitious to Such sol include, but are not limited to, the severity of the patients Vent. condition, the disorder being treated, the stability of the com Wetting agents, emulsifiers and lubricants, such as Sodium pound, and, if desired, another type of therapeutic agent being lauryl Sulfate and magnesium Stearate, as well as coloring administered with the compound of the invention. A larger agents, release agents, coating agents, Sweetening, flavoring total dose can be delivered by multiple administrations of the and perfuming agents, preservatives and antioxidants can agent. Methods to determine efficacy and dosage are known 25 also be present in the compositions. to those skilled in the art (Isselbacher et al. (1996) Harrison's Examples of pharmaceutically acceptable antioxidants Principles of Internal Medicine 13 ed., 1814-1882, herein include: (1) water soluble antioxidants, such as ascorbic acid, incorporated by reference). hydrochloride, Sodium bisulfate, sodium met In general, a suitable daily dose of an active compound abisulfite, sodium sulfite and the like; (2) oil-soluble antioxi used in the compositions and methods of the invention will be 30 dants, such as ascorbyl palmitate, butylated hydroxyanisole that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will (BHA), butylated hydroxytoluene (BHT), lecithin, propyl generally depend upon the factors described above. gallate, alpha-tocopherol, and the like; and (3) metal chelat If desired, the effective daily dose of the active compound ing agents, such as citric acid, ethylenediamine tetraacetic may be administered as one, two, three, four, five, six or more 35 acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the Sub-doses administered separately at appropriate intervals like. throughout the day, optionally, in unit dosage forms. In cer In certain embodiments, the invention relates to a method tain embodiments of the present invention, the active com for conducting a pharmaceutical business, by manufacturing pound may be administered two or three times daily. In pre a formulation of a compound of the invention, or a kit as ferred embodiments, the active compound will be 40 described herein, and marketing to healthcare providers the administered once daily. benefits of using the formulation or kit for treating or prevent The patient receiving this treatment is any animal in need, ing any of the diseases or conditions as described herein. including primates, in particular humans, and other mammals In certain embodiments, the invention relates to a method Such as equines, cattle, Swine and sheep; and poultry and pets for conducting a pharmaceutical business, by providing a in general. 45 distribution network for selling a formulation of a compound In certain embodiments, compounds of the invention may of the invention, or kit as described herein, and providing be used alone or conjointly administered with another type of instruction material to patients or physicians for using the therapeutic agent. As used herein, the phrase "conjoint formulation for treating or preventing any of the diseases or administration” refers to any form of administration of two or conditions as described herein. more different therapeutic compounds such that the second 50 In certain embodiments, the invention comprises a method compound is administered while the previously administered for conducting a pharmaceutical business, by determining an therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, appropriate formulation and dosage of a compound of the which may include synergistic effects of the two com invention for treating or preventing any of the diseases or pounds). For example, the different therapeutic compounds 55 conditions as described herein, conducting therapeutic pro can be administered either in the same formulation or in a filing of identified formulations for efficacy and toxicity in separate formulation, either concomitantly or sequentially. In animals, and providing a distribution network for selling an certain embodiments, the different therapeutic compounds identified preparation as having an acceptable therapeutic can be administered within one hour, 12 hours, 24 hours, 36 profile. In certain embodiments, the method further includes hours, 48 hours, 72 hours, or a week of one another. Thus, an 60 providing a sales group for marketing the preparation to individual who receives such treatment can benefit from a healthcare providers. combined effect of different therapeutic compounds. In certain embodiments, the invention relates to a method This invention includes the use of pharmaceutically for conducting a pharmaceutical business by determining an acceptable salts of compounds of the invention in the com appropriate formulation and dosage of a compound of the positions and methods of the present invention. In certain 65 invention for treating or preventing any of the disease or embodiments, contemplated salts of the invention include, conditions as described herein, and licensing, to a third party, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl the rights for further development and sale of the formulation. US 8,673,881 B2 143 144 EXAMPLES 1003 Example 1 Ocular PK (Distribution) Study in Dutch-Belted Rabbits OM, The ocular distribution of compound 1001,

10 1 OO1 wherein M is H (compound 45) or a pharmaceutically accept able cation, Such as ammonium, tetra-alkyl ammonium, Na OH OH O (compound Z), K, Mg, and Zn. Without wishing to be bound 21N 2° S OiPr, by theory, it is believed that compound 1003 or its metabo 15 lite(s) is primarily responsible for the biological activity asso ciated with compound 1001. Compound 1003 was extracted from ocular tissues (cornea, retina) by homogenization fol lowed by protein precipitation with 4 parts acetonitrile con and the corresponding methyl ester compound 1002, taining IS. The resulting Supernatant was dried under nitrogen and reconstituted as a concentrated solution in Mobile Phase A. Compound 1003 was extracted from aqueous/vitreous 10O2 humor by protein precipitation with 5 parts acetonitrile con OH OH O taining IS. The resulting Supernatant was dried under nitrogen and reconstituted as a concentrated solution in Mobile Phase 41 y\– OMe, 25 A. Mobile Phase A was added to rabbit cornea (~80 mg) to achieve a final w/v concentration of 5% solids. Corneas were homogenized until a homogenous Suspension was obtained. For blank homogenate, multiple corneas were pooled and in the ocular tissues of Dutch-belted rabbits when adminis 30 homogenized. tered topically to the surface of the eye was evaluated. Mobile Phase A was added to rabbit retina (-75 mg) to Healthy, young adult Dutch-belted rabbits (male/female; at achieve a final w/v concentration of 7% solids. Retinas were least 1.5 kg) were acclimated for at least 7 days prior to homogenized until a homogenous Suspension was obtained. initiation of the study. Prior to the initiation of the study, the For blank homogenate, multiple retinas were pooled and eyes of the rabbits were examined to ensure that the eyes were 35 homogenized. free of any defects that may affect the integrity of the study. Spiking solutions for standards were prepared by diluting Examinations were performed by a qualified observer. compound 1003 as its sodium salt (e.g., M is Na) (dissolved Animals were dosed via the topical ocular route using a in ethanol) in ethanol spanning the concentration range of pipettor system which delivered a 30 uL dose to each eye. 0.100 to 4000 ng/mL of compound 1003. Two standard Each animal was dosed at T=0. The right eye received a dose 40 curves were extracted and Subsequently analyzed one before concentration of 300 ug/mL of compound 1001 and the left and one after the samples. eye received a dose concentration of 300 g/mL of compound To 1 volume homogenate (100 uL), /10" volume (10 uL) of 1002. At the intervals noted in Table 3, the animals were ethanol was added to samples and blanks, and Mo' volume sacrificed. (10 uL) of spiking solution was added to standards. 4 Volumes 45 of acetonitrile containing 12.5 ng/mL IS (400 uL) were TABLE 3 added, and the samples were gently mixed for ~ 1 minute and Test Test centrifuged for 10 min at 3200 rcf. The supernatant was # of Dose Substance Substance Sacrifice removed (~400 uL), dried under nitrogen at 60° C. and recon Group Animals Volume Right Eye Left Eye Time stituted in 100 uL of 5 mMAmmonium Acetate. 1 2 30 L 1001 10O2 0.25hrs 50 Alternatively, standards were prepared by diluting com 2 2 30 L 1001 10O2 0.50 hrs pound 1003 as its sodium salt (e.g., M is Na) directly in blank 3 2 30 L 1001 10O2 1 hr homogenate spanning the concentration range of 0.0100 to 4 2 30 L 1001 10O2 2hrs 400 ng/mL of compound 1003. This eliminated the addition 5 2 30 L 1001 10O2 6 hrs of /10" volume (10 uL) of ethanol to samples and blanks in 55 the Subsequent extraction. Animals were euthanized with an overdose of an injectable Compound 1003 in the homogenized/extracted/dried/re barbiturate, and the eyes were retrieved from each animal. constituted samples was analyzed by LC/MS/MS using Using new or newly cleaned instruments for each eye, the D4-PGE2 as the internal standard. Detection was performed eyes were dissected and the following tissues isolated for on an Applied Biosystems API-4000 Mass Spectrometer analysis: conjunctiva, aqueous humor, cornea, lens, vitreous, 60 using the following method: iris/ciliary body, retina/choroid, optic nerve, and Sclera. Each LCGuard Column: Aqua C184x2.0 mm, 3 um, Phenomenex tissue was Snap frozen in liquid nitrogen and stored at -80°C. HAJO-7510 for further analysis. Column: Luna C18(2) 30x2.0 mm, 3 um, Phenomenex Analysis of Ocular Tissues: HOOA-4251-BO Without wishing to be bound by theory, it is expected that 65 Mobile Phase A: 5 mMAmmonium Acetate in water both compounds 1001 and 1002 are metabolized to their Mobile Phase B: 5 mMAmmonium Acetate in 95.5 aceto corresponding carboxylic acid, compound 1003, nitrile: water US 8,673,881 B2 145 Gradient: -continued t = 2.75 min 100% B t = 4.15 min 100% B t = O 59% t = 4.25 min 5% B t = 1 min 59% t = 4.75 min 5% B t = 1.5 min 40% t = 2.0 min 40% t = 2.75 min 100% Flow Rate: 0.5 mL/min t = 4.15 min 100% Injection Volume: 50 uL t = 4.25 min 59% MS Detection Scan Type: MRM t = 4.75 min 59% 10 Polarity: Negative Ion Source Electrospray Flow Rate: 0.5 mL/min Analyte Transition: m/z. 260.95 to 114.9 Injection Volume: 50 uL IS Transition: m/z. 355.0 to 275.3 MS Detection Scan Type: MRM 15 The linear standard curve of area ratio to compound 1003 Polarity: Negative concentration was generated using 1/x weighting. Ion Source Electrospray FIG. 1 shows that comparable levels of compound 1003 Analyte Transition: m/z. 260.95 to 114.9 were observed in the aqueous humor (FIG.1a), the vitreous IS Transition: m/z. 355.0 to 275.3 (FIG. 1b), and the cornea (FIG. 1c) upon administration of The linear standard curve of area ratio to compound 1003 compounds 1001 and 1002 using the protocol described concentration was generated using 1/x weighting. above. Analysis of Ocular Fluids: Ocular pharmacokinetic parameters (for the measured Compound 1003 was extracted from aqueous/vitreous compound 1003) following administration of either prodrug humor by protein precipitation with 5 parts acetonitrile con compound 1001 or 1002 are shown in Table 4. Peak levels of taining IS. Resulting Supernatant was dried under nitrogen 25 compound 1003 following administration of compound 1001 and reconstituted as a concentrated solution in Mobile Phase were ~12 mM in cornea with a half-life of ~1 hour and in the A. Spiking solutions for standards were prepared by diluting vitreous peak levels were ~15 nM with a slightly longer compound 1003 as its sodium salt (e.g., M is Na) (dissolved half-life of 1.3 hours. in ethanol) in ethanol spanning the concentration range of 30 0.040 to 4000 ng/mL of compound 1003. Two standard TABLE 4 curves were extracted and subsequently analyzed one before Aq Humor Cornea Vitreous and one after the samples. To 1 volume aqueous or vitreous humor (120 uD), '4' Compound 1001 volume (30 uL) of ethanol was added to samples and blanks, 35 T/2. (h) 1.18 1.OS 1.3 and '4" volume (30 ul) of spiking solution was added to AUC (h * ng/mL) or 2756 5.53 6.61 standards. 5 Volumes of acetonitrile containing 25 ng/mL IS (h ng/mg) Cmax (ng/mL) or (nging) 1055 3.56 4.36 (600 uL) were added, and the samples were gently mixed for Tmax (h) O.25 O.25 O.25 ~ 1 minute and centrifuged for 10 min at 3200 rcf. The super Compound 1002 natant was removed (~450 LL), dried under nitrogen at 60° C. 40 and reconstituted in 90 uL of 5 mMAmmonium Acetate. T/2. (h) 1.3 1.17 1.35 AUC (h * ng/mL) or 3.146 3.02 3.74 Alternatively, standards were prepared by diluting com (h ng/mg) pound 1003 as its sodium salt (e.g., M is Na) directly in blank Cmax (ng/mL) or (nging) 1337 3.35 1.64 aqueous or vitreous humor spanning the concentration range Tmax (h) O.25 O.25 O.25 of 0.01.00 to 1000 ng/mL of compound 1003. This eliminated 45 the addition of '4" volume (30 uD) of ethanol to samples and blanks in the Subsequent extraction. Example 2 Compound 1003 in the extracted/dried/reconstituted samples was analyzed by LC/MS/MS using D4-PGE2 as the internal standard. Detection was performed on an Applied 50 Chemical Stability Study Biosystems API-4000 Mass Spectrometer using the follow ing method: The chemical stability of compounds 1001 and 1002 was LCGuard Column: Aqua C184x2.0 mm, 3 um, Phenomenex measured via HPLC analysis of the purity of these com HAJO-7510 pounds over time. The purity assay of active components Column: Luna C18(2) 30x2.0 mm, 3 um, Phenomenex 55 using percent area (% area) and impurities reported as percent HOOA-4251-BO area (% area) were measured by HPLC using the following Mobile Phase A: 5 mMAmmonium Acetate in water conditions: Mobile Phase B: 5 mMAmmonium Acetate in 95.5 aceto Column: ACE 3, Cs, 3 um, 100x2.1 mm nitrile: water Column Temperature: 35°C. Gradient: 60 Autosampler Temperature: 5°C. Detection: UV at 272 nm Injection Volume: 30 ul Flow Rate: 0.5 mL/min t = O 59% t = 1 min 59% Run Time: 20 minutes t = 1.5 min 40% 65 Needle Wash: 100% Methanol with extended needle wash t = 2.0 min 40% Mobile Phase: A) Water/Trifluoroacetic acid (100/0.05 V/v), pH 3.0 US 8,673,881 B2 147 148 B) Acetonitrile?Trifluoroacetic acid (100/0.05 V/v) TABLE 6 Chemical Stability of Compound 1002

% Area Time (min) % A % B Compound % Area O 8O 2O Time Point 10O2 Impurity 2 8O 2O 12 60 40 Initial 98.29 1.71 12.01 8O 2O 1 week 97.58 2.43 2O 8O 2O 2 weeks 97.46 2.55 10 4 weeks 96.54 3.46 8 weeks 94.95 5.05 Retention Times: Compound 1002, 6.3 minutes Compound 1001, 11.0 minutes Compound 1003, 2.3 minutes Example 3 A sample diluent was prepared with water/absolute ethanol 15 (90/10 v/v). Study of Compound 1001 in Dry Eye Reference solutions of compounds 1001 and 1002 were prepared by weighing approximately 10 mg (t2 mg) of a 1 The objective of this study was to compare the efficacy of mg/mL stock solution of compound 1001 or 1002 into a 1 mL compound 1001 to placebo (vehicle minus active) for the amber volumetric flask. Approximately 0.5 mL of sample treatment of the signs and symptoms of dry eye, in a multi diluent was added and the solution swirled to mix. The sample center, double-masked, randomized, placebo-controlled was diluted to volume with sample diluent and mixed well. study in which 100 human patients were equally randomized The reference solution for compound 1001 was stable for up into one of three active treatment groups or placebo and all to 7 days stored at 5° C.-3°C., protected from light. The treatment groups were exposed to identical humidity, tem 25 perature, and wind conditions which exacerbated the Symp reference solution for compound 1002 was stable for up to 3 toms of dry eye. days stored at 5°C.-3°C., protected from light. During a 14 day study run-in period prior to randomization Ophthalmic formulations of compounds 1001 (0.994 g of a (e.g., day -14 to day 0), all patients received placebo bilater 52 mg/mL Solution in propylene glycol) or compound 1002 ally two times per day (BID). At the time of treatment ran (1.034 g of a 50 mg/mL Solution in propylene glycol) were 30 domization (e.g., day 0), patients were exposed to 90 minutes prepared at 500 g/mL dose strength in potassium phosphate of identical humidity, temperature, and wind conditions buffer (25 mM, pH 5.5, 0.34g) with 0.2M sodium hydroxide which exacerbated the symptoms of dry eye after which solution (q.s.), sodium chloride (0.327 g), polysorbate 80 patients were stratified based on the following criterion: Cen (0.5% w/v), and purified water (q.s. to 100). Sample solutions tral corneal staining post-exposures2.5 or >3.0. Patients eli of compounds 1001 and 1002 were each prepared by accu 35 gible to be randomized received one of the following treat rately weighing approximately 20 mg of the 500 g/mL com ments to be administered as approximately a 30 ul, drop to pound formulation into a 1 mL amber Volumetric flask. both eyes BID: 1) Compound 1001 at dose A (26.4 g/mL) Approximately 0.5 mL of sample diluent was added and the Ophthalmic Solution; 2) Compound 1001 at dose B (87.8 solution gently swirled to mix. The solution was diluted to ug/mL) Ophthalmic Solution; 3) Compound 1001 at dose C volume with sample diluent and mixed well. 40 (275.6 g/mL) Ophthalmic Solution; 4) Placebo Ophthalmic The following equation was used to calculate the com Solution (Vehicle minus active). pound 1001 or compound 1002 purity assay (% area) in each Brief Summary of Visit Schedule. 5 visits over the course sample: of approximately 6 weeks were scheduled as follows: Visit 1=Day -14+1 day; Visit 2-Day 0; Visit 3-Day 14+2 days; Analogue Content(% area)=(Area of analog Total area 45 Visit 4-Day 28+2 days; Visit 5-Day 29-1 hour. of all peakse0.10% area)x100. The primary endpoint of mean ocular discomfort in the conditions for exacerbating the symptoms of dry eye using Impurities 0.10% area were integrated and reported as % the ORA Ocular Discomfort Scale (during the 90 minute area to 2 decimal places. exposure) was Summarized statistically (m, mean, standard Tables 5 and 6 show the results of the chemical stability 50 deviation, median, min and max), and analyzed with 1-sided study of compounds 1001 and 1002, respectively, over the t-tests comparing the best dose to placebo with a course of 8 weeks at 5° C. Compound 1001 displayed better p-values 0.025 considered significant. chemical stability than compound 1002, as shown by a At visit 4 (e.g., day 28), patients were exposed to 90 min greater percent purity over time (with less impurities). utes of identical humidity, temperature, and wind conditions 55 which exacerbated the symptoms of dry eye. Ocular discom TABLE 5 fort during this exposure period was measured using the ORA Ocular Discomfort Scale with the ocular discomfort score Chemical Stability of Compound 1001 being the average of all time points during exposure. Ocular % Area discomfort was measured again at visit 5 (e.g., day 29). Compound % Area 60 Scores on the ORAOcular Discomfort Scale areas follows: a Time Point 1001 Impurity score of 0 indicates no discomfort; a score of 1 indicates Initial 99.55 O45 intermittent awareness; a score of 2 indicates constant aware 1 week Not Tested Not Tested 2 weeks 99.03 0.97 ness; a score of 3 indicates intermittent discomfort; and a 4 weeks 99.39 O.61 score of 4 indicates constant discomfort. 8 weeks 99.31 O.69 65 FIG. 2 shows ocular discomfort as measured on environ mental day 28 after topical administration of vehicle or com pound 1001 at doses A, B, or C. The change in ocular dis US 8,673,881 B2 149 comfort as compared to vehicle showed approximately a 27% improvement when compound 1001 was administered at Scheme 1. Preparation of Compound 2005 dose C. TMS o TMS FIG. 3 shows ocular discomfort as measured on environ AlCl3, DCM mental day 29 (e.g., 24 hours after last treatment) after topical He administration of vehicle or compound 1001 at doses A, B, or C. The change in ocular discomfort as compared to vehicle O O O showed approximately a 36% improvement when compound 2001 O O 1001 was administered at dose C, indicating that the effect 10 TsOH (0.1 equiv) seen upon administration of compound 1001 persists 24 IPA, 659 C. hours after the last treatment. 2 OH --> 21 86% over 2 steps Symptoms of grittiness, dryness were measured on envi TMS ronmental day 28 on a visual analog scale of 0-5. FIG. 4 2002 15 shows a significant change in both grittiness and dryness, as O O compared to vehicle, when compound 1001 was topically administered at dose C. Noyori catalyst 221 Oi-Pr - i-ProH, 100% > Example 4 TMS 99% ee 2003 OH O Synthetic Protocols 2 Oi-Pr TBAF 21 84% All nonaqueous reactions were carried out under an atmo 25 sphere of dry nitrogen. Reagents were purchased from com TMS mercial sources and used as received. Solvents for reactions 2004 were reagent-grade unless otherwise noted in the text. Proton OH O and carbon nuclear magnetic resonance (NMR) spectra were obtained on a Bruker AV-300 spectrometer at 300 MHz for 30 2 O-Pr proton and 75 MHz for carbon, using CDC1, DMSO-de, or H CDOD as the solvent. Tetramethylsilane was used as an internal reference for proton spectra and the solvent peak was 2005 used as the reference peak for carbon spectra. Mass spectra were obtained on a Finnigan LCQ Duo LC-MS ion trap 35 electrospray ionization (ESI) mass spectrometer. Thin-layer chromatography (TLC) was performed on Whatman No. Synthesis of Compound 2002: To a clean, dry, 100-Ljack 4500-101 silica-gel plates (250 um layer thickness). Visual eted reactor equipped with a condenser, an addition funnel, ization of TLC plates was performed using ultraviolet light 40 (254 nm) or iodine staining. Corning pH meter 430 apparatus and a temperature probe was cautiously added aluminum was used to determine pH. chloride (1285g, 9.64 mol) followed by dichloromethane (55 L). The mixture was stirred and cooled to 0-5°C. A solution HPLC Conditions: Method A of glutaric anhydride (1000 g, 8.76 mol) and bis(trimethylsi Column: Zorbax SB-CN, 4.6x250 mm, 5um 45 lyl)acetylene (1643 g, 9.64 mol) in dichloromethane (10 L) Column Temp: Ambient was cautiously added to the mixture dropwise while main Sample Temp: Ambient taining the temperature between 0 and 5°C. After the addition Detection: UV at 254 nm was complete, the reaction mixture was stirred at room tem perature overnight. After 12-20h, the reaction mixture was Mobile Phase A: HPLC water with 0.1% formic acid 50 assayed to check for the presence of glutaric anhydride by 'H Mobile Phase B: HPLC acetonitrile with 0.1% formic acid NMR (CDC1). The sample was prepared for "H NMR analy Diluent: 50:50 waterfacetonitrile sis by adding dichloromethane (0.5 mL) and 1 M HCl (0.25 Flow Rate: 1 mL/min mL) to a sample (0.25 mL) of the reaction mixture in a vial: 55 the dichloromethane was separated and removed under TABLE 7 vacuum. The residue was diluted with CDC1 and submitted for "H NMR analysis. The reaction was deemed complete Gradient when less than 3% by wt of glutaric anhydride remained. The reaction mixture was then slowly added to a 1M HCl solution Time (min) % A % B 60 (12 L) while maintaining the temperature below 10°C. The mixture was stirred for 30-60 min until a clear solution was O 90 10 2O O 100 observed. Two phases were separated and the organic phase 22 90 10 was washed with brine (12 L), dried over sodium sulfate, 25 90 10 65 filtered over a packed bed of Celite on a glass fritted funnel, and washed thoroughly with dichloromethane. The filtrate was concentrated under vacuum at 35-40°C. to give com US 8,673,881 B2 151 152 pound 2002 (1,700 g, 91%) as a dark brown oil which was -continued used in the next step without further purification. i-Pir Synthesis of Compound 2003: To a clean, dry, 12-L, four neck, round-bottom flask equipped with a condenser and a Me C1 CI W temperature probe were charged crude acid 2002 (1000 g), S. p-TsOH.HO (89.5 g., 0.1 equiv), and 2-propanol (6 L). The ) W {{Cl Cl {Me reaction mixture was heated at 65° C. for 24hat which point the conversion was about 90% by HPLC. The reaction mix ture was cooled and 2-propanol was concentrated under 10 -Pr KOH vacuum at 50-55° C. The resulting residue was added to 2007 DCM 91%

MTBE (3 L) and washed with saturated NaHCO, (3x500 mL). The organic layer was dried over NaSO filtered over a packed bed of Celite on a glass fritted funnel, and washed 15 thoroughly with MTBE. The filtrate was concentrated under vacuum at 40-45° C. to give crude ester 2003 (1,160 g, 96%) as a dark brown oil, which was used in the next step without further purification. Synthesis of Compound 2005: To a clean, nitrogen 2009 flushed, 12-L, round-bottom flask equipped with a mechani Ts Me cal stirrer, temperature probe, and nitrogen inlet were charged compound 2003 (433 g, 1.7 mol), anhydrous isopropyl alco 25 ^ - N - hol (4.3 L), and compound 2010 (20.4 g., 0.034 mol). After stirring at ambient temperature for 1 h, the conversion to N. RutS. compound 2004 was deemed complete by TLC analysis (20% H EtOAc/heptane). Ammonium chloride (109 g, 2.03 mol) was i-Pir 30 added followed by the streamwise addition of tetrabutylam 2010 monium fluoride (2.03 L, 1 M solution in THF). After over Noyori catalyst night stirring, the conversion to compound 2005 was deemed complete by TLC analysis. The reaction mixture was concen Synthesis of Compound 2007: To a nitrogen-flushed, 2-L. trated under vacuum to approximately /10 of the original 35 three-neck, round-bottom flask were added ruthenium chlo volume and the material was partitioned between MTBE (4.3 ride hydrate (12 g, 0.058 mol) and absolute ethanol (0.6 L) L) and Saturated aqueous ammonium chloride (2 L). Phases followed by p-mentha-1,5-diene (96 mL). The mixture was were separated and the aqueous was extracted with MTBE (2 stirred at reflux for 4 h. The suspension was cooled, stirred at L). The combined organics were washed with brine (2 L). 0-5°C. for 30 min, and filtered; the solids were washed with 40 absolute ethanol (3x1 bed volume) to yield compound 2007 dried over Sodium sulfate, and concentrated to a dark oil. (10.4 g 58%) as a dark red solid. The filtrate was concentrated Chromatographic purification gave compound 2005 (216 g. to 75 mL and was stored in the refrigerator overnight. The 70% as pure fractions and 28 g.9% as mixed fractions) as an solids were filtered and washed with absolute ethanol (3x1 orange oil. bed volume) to give compound 2007 (2g, 11%) as a dark red 45 solid. Synthesis of Compound 2009: To a 2-L, three-neck, round bottom flask equipped with a temperature probe, magnetic stir bar, nitrogen inlet, and addition funnel were added (1S, Scheme 2. Preparation of Noyori Catalyst 2S)-(-)-1,2-diphenylethylenediamine (20g, 0.094 mol) and RuCl3 50 dichloromethane (160 mL). The mixture was cooled to 0-3 C. and a 1 M solution of sodium hydroxide (160 mL) was -- added dropwise while maintaining the temperature below 5° -Pr Me FOH C. To this mixture was added a solution of toluenesulfonyl 61% chloride (17.9 g, 0.094 mol) in dichloromethane (320 mL) 55 dropwise over a 2-h period. The biphasic mixture was stirred 2006 at 0-5°C. for an additional 1 h and the reaction was deemed complete by TLC (50% EtOAc/heptane, UV). Phases were separated and the organic phase was washed with water 4, NH2 (2x320 mL) and brine (320 mL), dried over sodium sulfate 60 and concentrated to a crude solid. The solid was dissolved in TsC1, NaOH -e- toluene (200 mL) at 70-80° C. and heptane (300 mL) was H2O, DCM added portionwise while maintaining this temperature. The NH 88% resulting slurry was cooled and stirred at 20-25°C. for 1 hand then cooled and stirred at 0-5°C. for 10 min. The solids were 65 filtered and washed with a 50% solution of toluene in heptane 2008 (3x1 bed volume) to give compound 2009 (30.24g, 88%) as a white powder. US 8,673,881 B2 153 154 Synthesis of Compound 2010: To a 1-L, nitrogen-flushed, tion was complete. The reaction mixture was purified by three-neck, round-bottom flask equipped with a temperature silica-gel plugin two bathes (silicagel: 6kg each) using DCM probe, mechanical stirrer, addition funnel and nitrogen inlet as eluent to afford the desired product as a colorless oil (2.2 were added compound 2007 (10.4g, 0.017 mol), compound kg, 86% yield). The H NMR spectrum was consistent with 2009 (12.5g, 0.034 mol), potassium hydroxide (14.14 g. the assigned structure of compound 2012. 0.252 mol), and anhydrous dichloromethane (217 mL). This Synthesis of Compound 2013: A multiple-neck, 72-L. mixture was stirred at 20-25° C. for 10 min and then water round-bottom flask equipped with a mechanical stirrer, a (217 mL) was added dropwise while maintaining the tem temperature probe, and an addition funnel with a nitrogen perature below 30°C. The resulting mixture was stirred for 15 inlet was charged with THF (5.5 L). n-Hexyl lithium (2.3 M min and the phases separated. The organic phase was washed 10 in hexane, 5.3 L, 12.3 mol) was added while maintaining the with water (217 mL), dried over sodium sulfate, and filtered. internal temperature below 30°C. The solution was cooled to The filtrate was dried over calcium hydride (4.2 g) portion -20°C. and TMS acetylene (1.98 L, 1.2 equiv) was added at wise and the solids were filtered over Celite and washed with <-50° C. The reaction was stirred at <-55° C. for 1 h and a anhydrous dichloromethane. The filtrate was concentrated solution of compound 2012 (2.2 kg, 11.66 mol) was added under vacuum to give compound 2010 (20g.98%) as a purple 15 over 75 min at <-55° C., followed by the addition of solid. BF.EtO (1.44 L, 1.0 equiv) over 110 min at <-55° C. The reaction was stirred at <-60° C. for 16 hand TLC analysis (9:1 heptane/EtOAc) indicated that the reaction was com Scheme 3. Preparation of Compound 2018 plete. It was quenched with 75% saturated brine solution (11 L., 5 vol) and diluted with MTBE (11 L, 5 vol). The organic O TBDMSCI, imidazole layer was concentrated to dryness to afford a colorless oil OH -> (3.43 kg, >100% yield). The "H NMR spectrum was consis DMAP, CHCl2, 90% tent with the assigned structure of compound 2013. 2011 Synthesis of Compound 2014: A multiple-neck, 72-L. O 25 round-bottom flask equipped with a mechanical stirrer, a o TMS, n-hexLi OTBS --- temperature probe, and an addition funnel with a nitrogen BFEtO, THF inlet was charged with crude 2013 (3.43 kg) and DCM (6.6 2012 L). Imidazole (1.19 kg, 17.5 mol) and DMAP (70 g, 580 TMS OH mmol) were added and the reaction was cooled to 0° C. 30 Šs OTBS -->TBDPSCI, imidazole TBDPSC1 (4.17 kg, 15.2 mol) was added while maintaining CH2Cl2, >80% over 2-steps the internal temperature below 10°C. The reaction was stirred 2013 at ambient temperature for 18 h and analyzed by TLC (9:1 TMS OTBDPS heptane/EtOAc) which indicated that the reaction was com CSA plete. The reaction mixture was concentrated to dryness, Suluons He 35 diluted with heptanes (11 L), and washed with water (2x11 2014 L). The organic layer was concentrated to dryness to afford TMS OTBDPS the desired product 2014 as a pale brown oil (8.21 kg, >100 DMSO, py-SO3, Et3N yield). The H NMR spectrum was consistent with the H -> assigned structure of compound 2014. CH2Cl2, 70% over 2 steps 40 Synthesis of Compound 2015: A multiple-neck, 72-L. round-bottom flask equipped with a mechanical stirrer, a TMS OTBDPS temperature probe, and a nitrogen inlet was charged with PhP=CHCHO O - He crude compound 2014 (8.21 kg, approximately 11.7 mol) and DCM (15.3 L). The reaction mixture was cooled to 0°C. and 45 a solution of CSA (2.72 kg, 11.7 mol) in MeOH (15.3 L) was H added at <10°C. The reaction was stirred at 0°C. for 2 hand 2016 analyzed by TLC (9:1 heptane/EtOAc) which indicated that TMS OTBDPS the reaction was complete. The reaction was quenched with CHI, H TEA (1.18 kg, 11.7 mol) and concentrated to dryness. The Null-N- CrCl 50 residue was diluted in heptanes (18.5 L) and washed with 2017 water (2x18.5 L). The organic layer was purified by silica-gel TMS OTBDPS plug in four bathes (silica gel: 5 kg each) using heptanes to eluent the impurities and 4:1 heptanes/EtOAc to eluent the Šs 4N4N desired product. The fraction containing the product was 55 concentrated to dryness to afford a pale brown oil (3.38 kg, 2018 70% yield over three steps). The "H NMR spectrum was consistent with the assigned structure of compound 15. Synthesis of Compound 2012: A three-neck, 22-L, round Synthesis of Compound 2016: A multiple-neck, 72-L. bottom flask equipped with a magnetic stirrer, a temperature round-bottom flask equipped with a magnetic stirrer, a tem probe, and an addition funnel with a nitrogen inlet was 60 perature probe, a heating mantle, and a nitrogen inlet was charged with (S)-(-)-glycidol (1.0 kg, 13.5 mol) and DCM charged with compound 2015 (3.38 kg, 8.2 mol) and DCM (3.0 L). Imidazole (1.01 kg, 14.8 mol) and DMAP (84g, 680 (16 L). It was cooled to 0°C. and DMSO (1.93 L) and TEA mmol) were added and the reaction was cooled to 0°C. A (3.79 L) were added. SOspyr (3.93 kg, 24.6 mol) was added solution of TBDMSC1 (2.04 kg, 13.5 mol) in DCM (2.0 L) while maintaining the internal temperature below 10°C. The was added while maintaining the internal temperature below 65 reaction was stirred at 0°C. for 3 hand analyzed by TLC (9:1 10°C. The reaction was stirred at 0°C. for 2 hand analyzed heptane/EtOAc) which indicated that the reaction was com by TLC (9:1 heptane/EtOAc) which indicated that the reac plete. The reaction was washed with 10% citric acid (2x5 Vol) US 8,673,881 B2 155 and the organic layer was concentrated to dryness. The resi -continued due was purified in four batches with a silica-gel plug (silica OTBDPS OH O TBAF, gel: 7 kg each) using 2% EtOAc in heptanes as eluent to afford eae = NHCI Oi-Pr -> the desired product as a yellow oil (2.0 kg, 59% yield). The 84% mixed fractions were combined and concentrated to dryness to afford a yellow oil (0.38 kg, 11% yield). The H NMR spectrum was consistent with the assigned structure of com pound 2016. TMS 2019 Synthesis of Compound 2017: A three-neck, 22-L, round 10 OH OH O bottom flask equipped with a magnetic stirrer, a temperature probe, aheating mantle, and a nitrogen inlet was charged with 21N 21 O-Pr compound 2016 (2.0 kg, contained 1.42 kg of 2017 by weight assay, 3.48 mol) and ACN (7.1 L). The reaction mixture was heated to 30° C. and PhPCHCHO (1.38 kg, 68.6 mmol) was 15 added in portions while maintaining the internal temperature H at <35° C. The reaction was heated at 30° C. for 15 h and 1 OO1 analyzed by H NMR which indicated that the reaction was complete. It was concentrated to dryness and the residue was dissolved in DCM (0.71 mL). The resulting solution was Synthesis of Compound 2019: A 3-L, three-neck, round diluted with heptanes (1.42 L) and purified by silica-gel plug bottom flask was degassed and purged under nitrogen. To the in two batches using 10:1 heptane/EtOAc as eluent to afford flask was added tetrakis(triphenylphosphine)palladium(0) the desired product as a pale yellow oil (1.87 kg, 88% yield). (7.4 g. 6 mmol) and copper iodide (2.5 g., 13 mmol). A The "H NMR spectrum was consistent with the assigned degassed solution of compound 2005 (24 g. 131 mol) in 25 anhydrous tetrahydrofuran (55 mL) was added under nitro structure of compound 2017. gen by cannula at ambient temperature. A degassed solution Synthesis of Compound 2018: A 5-L, three-neck, round of compound 2018 (0.131 mol) in diethylamine (400 mL) and bottom flask was heated with a heat gun under vacuum (1-10 anhydrous tetrahydrofuran (800 mL) was then added under torr) three times and purged under argon. Anhydrous chro nitrogen by cannula. The reaction mixture was allowed to stir mium chloride (100 g, 0.814 mol) was added and the flask 30 at ambient temperature overnight. At this point the reaction was again heated under vacuum three times. Anhydrous tet was complete by HPLC analysis. The reaction was quenched rahydrofuran (1000 mL) was added and the resulting slurry with Saturated aqueous ammonium chloride (20 mL) and then was stirred for 2 hat ambient temperature. The slurry gave an concentrated to a residue. MTBE (700 mL) was added and the exotherm to about 30-35°C. during this period and turned a mixture was slurried for 10 min; the solids were filtered over greenish color. In a separate flask, compound 2017 (57 g. 35 a packed bed of Celite on a glass fritted funnel. The filtrate 0.131 mol) was azeotroped with toluene three times. Iodo was washed with saturated aqueous ammonium chloride (300 form (102 g, 0.273 mol) and anhydrous tetrahydrofuran (700 mL), dried over magnesium Sulfate, filtered, and concentrated mL) were added to compound 2017 under nitrogen forming a to give 2019 (89 g, D100%) as a crude brown oil which had an yellow solution. The solution was then added to the slurry of 40 E/Z-ratio of 6.3:1 by HNMR analysis which was purified by chromium chloride by cannula under nitrogen over 30 min column chromatography on silica gel followed by Combi while maintaining the internal temperature below 5°C. After Flash chromatography. 30 min, TLC showed completion of reaction. The reaction was quenched portionwise with a mixture of Sodium thiosul Synthesis of Compound 1001: A 5-L, three-neck, round fate (10 wt %, 570 mL) and saturated sodium bicarbonate bottom flask was charged with intermediate 2019 (284.4g, (570 mL) while maintaining the temperature below 15° C. 45 0.46 mol), ammonium chloride (74.2g, 1.39 mol), and THF MTBE (2000 mL) was added; two phases were separated and (850 mL). The mixture was stirred and cooled to 5°C. using the organic phase was washed with brine (1140 mL), dried an ice bath. To the stiffing mixture was added 1 Mtetrabuty over magnesium sulfate, filtered, and concentrated to give lammonium fluoride in THF (1.4 L) via an addition funnel crude 2018 as agreen residue with an E/Z-ratio of 8.8:1 by 'H over 15 min such that the reaction temperature remained NMR analysis. The crude material was stored in diethylamine 50 below 10°C. The mixture was stirred for 2 hat which point (400 mL) in the freezer overnight. TLC analysis (40% ethyl acetate?heptanes) showed no start ing material remained. The reaction mixture was diluted with tert-butyl methyl ether (1.4 L) and saturated ammonium chlo Scheme 4. Preparation of Compound 1001 55 ride (1.4 L) and the layers separated. The organic layer was TMS OTBDPS washed with saturated ammonium chloride (1.4L), dried over Sodium Sulfate, and concentrated to afford an oil (271.4 g). The oil was suspended in 20% heptanes/ethyl acetate (200 Nu --> -- mL) and dichloromethane was slowly added until a solution 2018 60 was formed (approximately 20 mL). The mixture was puri OH O fied on silica gel (2 kg) eluting with 20% ethyl acetate?hep Pd(PPh3)4, CuI, EtNH tanes (16 L), 30% ethyl acetate?heptanes (8 L), 40% ethyl 2 O-Pr -e- acetate?heptanes (20 L), and 50% ethyl acetate?heptanes (16 2 56% over 2 steps from H compound 2017 L). The pure fractions were combined and concentrated to 65 afford 1001 (128.3 g, 91% yield): HPLC 97.7% (AUC), 2005 t=13.3 min; the "H NMR spectrum was consistent with the assigned structure of compound 1001 as is shown in FIG. 5. US 8,673,881 B2 157 158 HCl (900 mL). It was extracted with MTBE (6x5 vol) and the Scheme 5. Preparation of Compound 1002 combined organic layers were washed with water (5 Vol), dried over NaSO4, diluted with ethanol (10 vol), and con centrated to five volumes. The resulting ethanol solution was OH OH O 1s cooled to 0° C. and 6 N NaOH (1 equiv) was added. The E p-TsOH reaction was stirred for 1 h, concentrated to dryness, and dried under vacuum for 18 h to afford a brown oil (277 g. 88% yield): HPLC 99.2% (AUC), t-10.1 min; the "H NMR spec --- MeOH trum was consistent with the assigned structure of compound H 10 Z and indicated the presence of residual ethanol. The brown 1001 oil (277 g) was dissolved in water (2 vol), concentrated to OH OH O dryness at 40°C., and further dried under vacuum for 18 h to afford the desired product compound Zas a brown oil (279 g): HPLC 99.0% (AUC), t-9.9 min; the "H NMR spectrum was enue F o1 15 consistent with the assigned structure of compound Z as shown in FIG. 7. | INCORPORATION BY REFERENCE H All publications and patents mentioned herein are hereby 10O2 incorporated by reference in their entirety as if each indi vidual publication or patent was specifically and individually Synthesis of Compound 1002: Ta a solution of 1001 (35 g, indicated to be incorporated by reference. In case of conflict, 115 mmol) in MeOH (350 mL) was added p-TsOH.H.O(4.38 the present application, including any definitions herein, will g, 23 mmol). The resulting solution was stirred at room tem 25 control. perature for 22 h and diluted with EtOAc (700 mL). The EQUIVALENTS mixture was washed with 5% aqueous sodium bicarbonate (3x100 mL). The combined aqueous were extracted with While specific embodiments of the subject invention have EtOAc (3x200 mL). The organics were combined and 30 been discussed, the above specification is illustrative and not washed with brine (150 mL), dried over sodium sulfate, and restrictive. Many variations of the invention will become concentrated under vacuum. The oil residue was purified by apparent to those skilled in the art upon review of this speci column chromatography (2:3 EtOAc/n-heptane) to give 1002 fication and the claims below. The full scope of the invention (22.8 g., 71.7%,98.1% (AUC) by HPLC) as a light yellow oil. should be determined by reference to the claims, along with The "H NMR spectrum was consistent with the assigned 35 their full scope of equivalents, and the specification, along structure of compound 1002 as is shown in FIG. 6. with Such variations. The invention claimed is: Scheme 6. Preparation of Compound Z 1. A compound of formula I, 40 OH OH O 1) LiOH, R (I) 21N21 E THF/H2O Oi-Pr -- ORf 2) 2 Naq HCI 21N 21 45 1001 OH OH O NaOH, \ E EtOH/H2O 21N21 OH -- or a pharmaceutically acceptable salt thereof, wherein: 50 Re and Rf are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, ami 45 nocarbonyl, alkoxycarbonyl, or silyl; OH OH O E is a branched alkoxy: Rh and Ri are independently selected from hydrogen, an ea = ONa 55 alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or het eroaryl; Rs is selected from i-iv as follows: i) CH-CH(R)CH, where R is hydrogen, alkyl, alk Compound Z enyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, 60 fluoro, hydroxyl or alkoxy; Synthesis of Compound Z: A 5-L, three-neck, round-bot ii) CHC(RR)CH, where R and R are each inde tom flask was charged with 1001 335 g, 1.1 mol, THF (5 pendently alkyl, alkenyl, alkynyl, perfluoroalkyl, Vol), and water (5 vol). LiOH (52.7g, 2.2 mol) was added and aryl, or fluoro, or R and R, are connected together the reaction was stirred at ambient temperature for 4 hand to form a carbocyclic or heterocyclic ring; analyzed by TLC which indicated that the reaction was com 65 iii) CHOCH, CHC(O)CH, or CHCH; or plete. The reaction mixture was extracted with MTBE (2x5 iv) Rs is a carbocyclic, heterocyclic, aryl or heteroaryl Vol) and the aqueous layer was adjusted to pH 4.4 using 2 N ring; and US 8,673,881 B2 159 160 Rs and Ro are independently selected from hydrogen, 10. A pharmaceutical composition comprising the com alkyl, alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or pound heteroaryl, or Rs and Ro are connected together to form a carbocyclic or heterocyclic ring. 2. The compound of claim 1, wherein E is selected from 1001 isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, 3-methylbu toxy, 2,2-dimethylpropoxy, or 1,1,2-trimethylpropoxy. OH 3. The compound of claim 1, wherein the compound is represented by formula II, OiPr, 10 (II) ORf of claim 5, 21N 21 E Rs E, or a pharmaceutically acceptable salt thereof. 15 11. The pharmaceutical composition of claim 10, wherein the composition is an aqueous solution Suitable for topical administration to an eye, the solution having a concentration or a pharmaceutically acceptable salt thereof. of at least 30 micrograms/milliliter of the compound. 4. The compound of claim 3, wherein the compound is 12. The pharmaceutical composition of claim 11, having a represented by formula III, concentration from 30 micrograms/milliliter to 2000 micro grams/milliliter of the compound. 13. The pharmaceutical composition of claim 10, wherein (III) the composition is used for treating or preventing an oph 25 thalmic condition. ORf ORe O 14. A method of treating an ophthalmic condition, said method comprising administering topically to an eye a phar maceutical composition of claim 10. 15. The method of claim 14, wherein the pharmaceutical 30 composition is administered once, twice, three times, or four times daily. or a pharmaceutically acceptable salt thereof. 16. The method of claim 14, wherein the ophthalmic con 5. The compound of claim 4, wherein the compound is dition is dry eye. represented by formula 1001, 17. A packaged pharmaceutical for delivering eyedrops to 35 an eye in need of treatment for an ophthalmic condition, wherein the eyedrops comprise the compound 1 OO1

OH OH O 1001 40 OiPr, OH OH O

OiPr

or a pharmaceutically acceptable salt thereof. 45 6. A method of treating or preventing an ophthalmic con dition, said method comprising administering a compound of claim 5, or a pharmaceutically acceptable salt thereof. 18. The pharmaceutical composition of claim 10, wherein the composition is an aqueous solution having a pH of 5.5 to 1 OO1 50 7.4, Suitable for treating or preventing an ophthalmic condi tion in a human patient, said composition further comprising OH one or more pharmaceutically acceptable excipients wherein the composition is characterized in that OiPr a) the compound is present in a concentration over 90 55 micromolar, b) the composition optionally further comprises one or more demulscents, and/or of claim 5, c) the composition optionally further comprises one or more surfactants, and/or or a pharmaceutically acceptable salt thereof. 60 7. The method of claim 6, wherein at least 2 micrograms of d) the composition optionally further comprises one or the compound is administered to an eye per day. more emulsifiers. 8. The method of claim 7, wherein from 2 to 175 micro 19. The pharmaceutical composition of claim 18, wherein grams of the compound is administered to an eye per day. the pharmaceutical composition is Substantially free of pre 9. The method of claim 6, wherein the compound is admin servatives. istered once, twice, three times, or four times daily. UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,673,881 B2 Page 1 of 1 APPLICATIONNO. : 13/264155 DATED : March 18, 2014 INVENTOR(S) : Gjorstrup et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

On the Title Page:

The first or Sole Notice should read --

Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 160 days.

Signed and Sealed this Twenty-first Day of July, 2015 74-4-04- 2% 4 Michelle K. Lee Director of the United States Patent and Trademark Office