(12) United States Patent (10) Patent No.: US 7,250,518 B2 Magee Et Al

US007250518B2

(12) United States Patent (10) Patent No.: US 7,250,518 B2 Magee et al. (45) Date of Patent: Jul. 31, 2007

(54) NICOTINAMIDE ACIDS, AMIDES, AND WO WO O157O25 8, 2001 THER MIMETCS ACTIVE AS INHIBITORS WO WO O157.036 8, 2001 OF PDE4 ISOZYMES (75) Inventors: Thomas V. Magee, Mystic, CT (US); OTHER PUBLICATIONS Anthony Marfat, Mystic, CT (US); Trophy, Theodore J. et al., “Phosphodiesterase IV Inhibitors as Robert J. Chambers, Mystic, CT (US) Therapy for Eosinophil-induced Lung Injury in Asthma, Environ mental Health Perspectives, vol. 102 Suppl. 10, Dec. 1994, pp. (73) Assignee: Pfizer Inc., New York, NY (US) 79-84. Duplantier, Allen J., et al., "Biarylcarboxylic Acids and -amides: (*) Notice: Subject to any disclaimer, the term of this Inhibition of PhosphodiesteraseType IV versus HIRolipram Bind patent is extended or adjusted under 35 ing Activity and Their Relationship to Emetic Behavior in the U.S.C. 154(b) by 340 days. Ferret, Journal of Medicinal Chemistry.” 1996, vol. 39, No. 1, pp. 120-125. (21) Appl. No.: 10/781,062 Schneider, Herbert H. et al., “Dicriminative Stimulus Properties of the Stereoisomers of the Phosphodiesterase Inhibitor Rolipram.” Pharmacology Biochemistry and Behavior, vol. 50, No. 2, 1995, pp. (22) Filed: Feb. 17, 2004 211-217. (65) Prior Publication Data Banner, Katherine H., et. al., “Acute versus chronic administration of phosphodiesterase inhibitors on allergen-induced pulmonary cell US 2004/0171798 A1 Sep. 2, 2004 influx in sensitized guinea-pigs, British Journal of Pharmacology, 114, 1995, pp. 93-98. Related U.S. Application Data Barnette, Mary S., et. al., “The Ability of Phosphodiesterase IV Inhibitors to Suppress Superoxide Production in Guinea Pig (63) Continuation of application No. 10/062,811, filed on Eosinophils Is Correlated with Inhibition of Phosphodiesterase IV Jan. 31, 2002, now abandoned. Catalytic Activity.” The Journal of Pharmacology and Experimental Therapeutics, 273, 1995 pp. 674-679. (60) Provisional application No. 60/265.240, filed on Jan. Wright, Kathryn, F., et al., “Differential in vivo and in vitro 31, 2001. bronchorelaxant activities of CP-80,633, a selective phosphodiesterase 4 inhibitor, 'Can. J. Physiol. Pharmacol. 75. (51) Int. Cl. 1997, pp. 1001-1008. CO7D 405/2 (2006.01) Manabe, Haruhiko, “Anti-inflammatory and Bronchodilator Prop CO7D 213/64 (2006.01) erties of KF19514, a Phosphodiesterase 4 and 1 Inhibitor.” Euro (52) U.S. Cl...... 546/284.1; 546/291; 546/290; pean Journal of Pharmacology, 332, 1997, pp. 97-107. 546/269.1:546/268.4 Ukita, Tatsuzo, et. al., Novel, Potent, and Selective (58) Field of Classification Search ...... 514/345, Phosphodiesterase-4 Inhibitors as Antiasthmatic Agents: Synthesis 514/346; 546/290, 291, 268.4, 269.1, 284.1 and Biological Activities of a Series of 1-Pyridylnaphthalene See application file for complete search history. Derivatives, J. Med. Chem, 48, 1999, pp. 1088-1099. (56) References Cited (Continued) U.S. PATENT DOCUMENTS Primary Examiner Charanjit S. Aulakh (74) Attorney, Agent, or Firm—Charles W. Ashbrook; Paul 4,157,395 A 6, 1979 Hitzel et al...... 424,266 M. Misiak; Rosanne Goodman 4,181,658 A 1, 1980 Hitzel et al. . ... 424/266 4,692, 185 A 9, 1987 Michaely ...... T1.94 (57) ABSTRACT 4,861,891 A 8, 1989 Saccomano et al...... 546/194 5,552,438 A 9/1996 Christensen, IV ...... 514/520 5,602,157 A 2/1997 Christensen, IV . ... 514,362 Compounds of the formula: 5,614,540 A 3/1997 Christensen, IV ...... 514,362 5,863,926 A 1/1999 Christensen, IV et al. .. 514/277 5,922,557 A 7, 1999 Pon ...... 435/21 6,380,218 B1 4/2002 Marfat et al...... 514/326

FOREIGN PATENT DOCUMENTS EP OO23569 6, 1983 EP O550900 12/1992 l

EP O661274 7, 1995 EP OSOO989 12/1998 FR 214O772 1, 1973 (O) GB 2327675 2, 1999 JP 7304775 11, 1995 WO WO95OO139 1, 1995 WO WO 98.18796 5, 1998 useful as inhibitors of PDE4 in the treatment of diseases WO WO9845268 10, 1998 WO WO9918793 4f1999 regulated by the activation and degranulation of eosinophils. WO WO992028O 4f1999 WO WO992O625 4f1999 7 Claims, No Drawings US 7.250,518 B2 Page 2

OTHER PUBLICATIONS Perrier, Helene, et. al., “Substituted Furans as Inhibitors of the PDE4 Enzyme.” Bioorganic & Medicinal Chemistry Letters 9, Compton, CH, et. al., The Efficacy of ArifloTM (SB 207499. A 1999, pp. 323-326. Second Generation, Oral PDE4 Inhibitor, In Patients with COPD, Am. J. Respir. Crit. Care Med., 159, 1999. Groneberg, Robert D., et al., “Dual Inhibition of Phosphodiesterase Leeman, Marc M.D., et al., “Reduction in Pulmonary Hypertension 4 and Matrix Metalloproteinases by an (Arylsulfonyl)hydroxamic and in Airway Resistances by Enoximone (MDL 17,043) in Acid Template.” Journal of Medicinal Chemistry, 1999, vol. 42, No. Decompensated COPD*,” Chest, 91, 1987, pp. 662-666. 4, 541-544. Rabe, K.F., et al., “Identification of PDE Isozymes in Human Fujimura, Masaki, et. al., Bronchoprotective Effects of KF-19514 Pulmonary Artery and Effect of Selective PDE Inhibitors.” Am. J. and Cliostazol in Guinea Pigs In Vivo, European Journal of Phar Physiol, 266 (LCMP 10), 1994, pp. L536-L543. macology, 327, 1997, pp. 57-63. Hughes, Bernadette, et. al., PDE 4 Inhibitors: the use of molecular cloning in the design and development of novel drugs, Drug Manabe, Haruhiko, et. al., “KF19514, a Phosphodiesterase 4 and 1 Discovery Today, Science Direct, 2(3), 1997 pp. 89-101. Inhibitor, Inhibits PAF-Induced Lung Inflammatory Responses by Banner, K.H., et al., “The Effect of Selective Phosphodiesterase Inhaled Administration in Guinea Pigs.” International Archives of Inhibitors in Comparison with other Anti-asthma Drugs on Aller Allergy-Immunology, 1997. 114, pp. 389-399. gen-induced Eosinophilia in Guinea-pig Airways.” Pulmonary Suzuki, Fumio, et. al., “New Bronchodilators, 3. Imidazo4.5- Pharmacology, 8, 1995, pp. 37-42. c1.8 naphthyridin-4(5H)-ones,” Journal of Medicinal Chemistry, Raebum, David, et al., “Anti-inflammatory and bronchodilator 1992, vol. 35, No. 26, pp. 4866-4874. properties of RP 73401, a novel and selective phosphodiesterase Matsuura, Akihiro, et. al., “Substituted 1.8-Naphthyridin-2(1H)- typed IV inhibitor.” Br, J. Pharmacol., 113, 1994, pp. 1423-1431. ones as Selective Phosphodiesterase IV Inhibitors.” Biol. Pharm. Karlsson, J.A., et. al., “Anti-Inflammatory Effects of the Novel Phosphodiesterase IV Inhibitor RP 73401.” Int. Arch Allergy Bull. vol. 17(4), 1994, pp. 498-503. Immunol. 107, 1995, pp. 425-426. Manabe, Haruhiko, et. al., “Pharmacological properties of a New Escott, K.J., et. al., Pharmacological Profiling of Phosphodiesterase, Bronchodilator, KF17625.” Jpn. J. Pharmacol., 58 (Suppl 1)., 1992 4 (PDE4) Inhibitors and Analysis of the Therapeutic Ratio in Rats pp. 238. and Dogs, Br. J. Pharmacol. 123 (Proc suppl.) 1998 40P. Montana, John G., et. al., “PDE4 Inhibitors: New Xanthine Ana Landells, L.J., et. al., “Oral Administration of the Phosphodiesterase logues.” Bioorganic & Medicinal Chemistry Letters 8, 1998, pp. (PDE) 4 Inhibitor, V11294A Inhibits Ex-Vivo Agonist-induced Cell 2925-2930. Activation.” Eur, Resp. J., 12 (Suppl. 28), 362s, 1998, P2393. Gale, D.D., et. al., “Pharmacodynamic-Pharmacokinetic (PD/PK) Merz, Karl-Heinz, et. al., “Synthesis of 7-Benzylamino-6-chloro Profile of the Phosphodiesterase (PDE)4. Inhibitor, V11294A, in 2-piperazino-4-pyrrolidinopteridine and Novel Derivatives Free of Human Volunteers.” Am. J. Respir. Crit Care Med., 159, A611, Positional Isomers. Potent Inhibitors of cAMP-Specific 1999, pp. A108. Phosphodiesterase and of Malignant Tumor Cell Growth.” Journal Montana, J., et. al., “Activity of D4418. A Novel Phosphodiesterase of Medicinal Chemistry, vol. 41, No. 24, 1998, pp. 4733–4743. 4 (PDE4) Inhibitor, Effects in Cellular and Animal Models of Danhaive, P. et al., “UCB29936, A Selective Phosphodiesterase Asthma and Early Clinical Studies,” Am. J. Respir. Crit., Care Med., Type IV Inhibitor, Therapeutic Potential In Endotoxic Shock.” Am. 159, A108, 1999, pp. A624. J. Respir, Crit. Care Med., 159, A611, 1999. Cavalla, D., et al., “Activity of V11294A, A Novel Tian, Gaochao, et. al., “Dual Inhibition of Human Type 4 Phosphodiesterase 4 (PDE4) Inhibitor. In Cellular and Animal Phosphodiesterase Isostates by (R,R)-(+)-Methyl 3-Acetyl-4-3- Models of Asthma.” Am. J. Respir. Crit. Care Med. 155, 1997, pp. (cyclopentyloxy)-4-methoxyphenyl-3-methyl-1-pyr A660. Pascal.Y., et. al., “Synthesis and Structure.-activity Relationships of rolindinecarboxylate.” Biochemistry, 37(19), 1998 pp. 6894-6904. 4-oxo-1 pheyl-3,4,5,7-Tetrahydro-14Diazepino.6.7.1- Norman, Peter, “PDE4 Inhibitors 1999.” Exp. Opin. Ther. Patents HIIndolines: Novel PDE4 Inhibitors,” 215 ACS, MEDI, 50, 1998. 9(8) 1999, pp. 1101-1118. Bumouf, C., et. al., “Pharmacology of the Novel Phosphodiesterase Dyke, Hazel J. & Montana, John G., “The Therapeutic Potential of Type 4 Inhibitor, CI-1018, 215th ACS, MEDL 008, 1998. PDE4 Inhibitors.” Expert Opinion on Investigational Drugs, 8(9), Mueller, George W., et. al., N-Phthaloyl-B-Aryl-B-Amino Deriva 1999, pp. 1301-1325. tives Potent TNF-O. And PDE4 Inhibitors, MEDI, 299, 1999. Mueller, George W., et. al., “Thalidomide Analogs and PDE4 XP-002066969, Vinivk, Fredric J., et. al., “Nicotinamide Ethers: Inhibition.” Bioorganic & Medicinal Chemistry Letters, 8, 1998 pp. Novel Inhibitors of Calcium-Independent Phosphodiesterase and 2669-2674. 3H]Rolipram Binding.” Journal of Medicinal Chemistry, vol. 34. Takayama, K., “Synthetic Studies on Selective Type IV No. 1, 1991, pp. 86-89. Phosphodiesterase (PDE IV) Inhibitors,” MEDI 245, 1997. Pruniaux, M.P., et. al., “The novel phosphodiesterase 4 inhibitor Gordon, T., et. al., “Anti-Inflammatory Effects of a PDE4 Inhibitor C1-1018 inhibits antigen-induced lung eosinophilia in sensitized in a Rat Model of Chronic Bronchitis.” Am. J. Respir. Crit. Care brown-norway rats—comparison with rollipram.' Mediators of Med., 159, A33, 1999. Inflammation, vol. 8, Supplement 1, 1999, S-04-6, pp. S10. US 7,250,518 B2 1. 2 NICOTINAMIDE ACIDS, AMIDES, AND disease models. See, e.g., Torphy et al., Environ. Health THER MIMETCS ACTIVE AS INHIBITORS Perspect. 102 Suppl. 10, 79-84, 1994; Duplantier et al., J. OF PDE4 ISOZYMES Med. Chem. 39 120-125, 1996; Schneider et al., Pharmacol. Biochem. Behav. 50 211-217, 1995: Banner and Page, Br. J. This application is a continuation of U.S. patent applica Pharmacol. 11493-98, 1995; Barnette et al., J. Pharmacol. tion Ser. No. 10/062,811, filed Jan. 31, 2002, now aban Exp. Ther. 273 674-679, 1995; Wright et al. “Differential in doned which claims the benefit of Provisional Application vivo and in vitro bronchorelaxant activities of CP-80633, a No. 60/265,240, filed Jan. 31, 2001. selective phosphodiesterase 4 inhibitor.” Can. J. Physiol. Pharmacol. 75 1001-1008, 1997: Manabe et al. “Anti 1.O REFERENCE TO COPENDING 10 inflammatory and bronchodilator properties of KF19514, a APPLICATIONS phosphodiesterase 4 and 1 inhibitor.' Eur: J. Pharmacol. 332 97-107, 1997; and Ukita et al. “Novel, potent, and selective Reference is made to International application and US phosphodiesterase-4 inhibitors as antiasthmatic agents: Syn application based thereon, Serial No. PCT/IB98/00315, both thesis and biological activities of a series of 1-pyridyinaph filed Mar. 10, 1998, and published as WO 98/.45268 on Oct. 15 thalene derivatives,” J. Med. Chem. 42 1088–1099, 1999. 15, 1998; claiming priority from application Ser. No. Accordingly, there continues to be considerable interest in 60/043403 filed Apr. 4, 1997, now abandoned; which dis the art with regard to the discovery of further selective closes nicotinamide derivatives having biological activity as inhibitors of PDE4S. inhibitors of PDE4 isozymes, and thus being useful in the The present invention is also concerned with the use of treatment of inflammatory, respiratory and allergic diseases selective PDE4 inhibitors for the improved therapeutic treat and conditions. Nothing that is disclosed in the above ment of a number of inflammatory, respiratory and allergic mentioned applications would teach the person of ordinary diseases and conditions, but especially for the treatment of skill in the pertinent art the novel compounds of the present asthma; chronic obstructive pulmonary disease (COPD) invention or their unexpectedly high level of inhibitory including chronic bronchitis, emphysema, and bronchiecta selectivity for PDE 4 isozymes. 25 sis; chronic rhinitis; and chronic sinusitis. Heretofore in the Reference is also made to application Ser. No. 09/345,185 art, however, the first-line therapy for treatment of asthma filed Jun. 30, 1999 now abandoned claiming priority from and other obstructive airway diseases has been the nonse application Ser. No. 60/105,120 filed Oct. 21, 1998, which lective PDE inhibitor theophylline, as well as pentoxifylline discloses compounds and processes for preparing N-Substi and IBMX, which may be represented by Formulas (0.0.1), tuted nicotinamide derivatives. However, the disclosed com 30 (0.0.2), and (0.0.3), respectively: pounds and processes are not the same as those of the present invention. Reference is further made to copending applications filed (0.0.1) of even date with the instant application, Ser. Nos. 60/265, 531; 60/265,250; 60/265,491; 60/265,486; 60/265,304; and 35 60/265,492 which involve other classes of nicotinamide derivatives useful as inhibitors of PDE4 isozymes. The try disclosures of all of said copending applications are incor porated herein by reference in their entireties. 40 --- CH 2.O. BACKGROUND OF THE INVENTION Theophylline The 3',5'-cyclic nucleotide phosphodiesterases (PDEs) comprise a large class of enzymes divided into at least 45 (0.0.2) eleven different families which are structurally, biochemi O O cally and pharmacologically distinct from one another. The CH enzymes within each family are commonly referred to as isoenzymes, or isozymes. A total of more than fifteen gene --~~ N/ products is included within this class, and further diversity H3C N X results from differential splicing and post-translational pro 50 1. N cessing of those gene products. The present invention is primarily concerned with the four gene products of the CH fourth family of PDEs, i.e., PDE4A, PDE4B, PDE4C, and Pentoxifylline PDE4D. These enzymes are collectively referred to as being isoforms or subtypes of the PDE4 isozyme family. Further 55 below will be found a more detailed discussion of the genomic organization, molecular structure and enzymatic activity, differential splicing, transcriptional regulation and (0.0.3) phosphorylation, distribution and expression, and selective N inhibition of the PDE4 isozyme subtypes. 60 S. CH3 The PDE4s are characterized by selective, high affinity O hydrolytic degradation of the second messenger cyclic N CH3 nucleotide, adenosine 3',5'-cyclic monophosphate (cAMP), / HC and by sensitivity to inhibition by rolipram. A number of O selective inhibitors of the PDE4s have been discovered in 65 recent years, and beneficial pharmacological effects result IBMX ing from that inhibition have been shown in a variety of US 7,250,518 B2 3 Theophylline, which has the PDEs as one of its biochemi cal targets, in addition to its well characterized bronchod -continued ilatory activity, affects the vasculature of patients with (0.0.6) increased pulmonary artery pressure, Suppresses inflamma HC-O O-CH tory cell responses, and induces apoptosis of eosinophils. Theophylline's adverse events, most commonly cardiac dysrhythmias and nausea, are also mediated by PDE inhi bition, however, leading to the search for more selective inhibitors of PDEs that are able to suppress both immune 10 cell functions in vitro and allergic pulmonary inflammation N-CH in vivo, while at the same time having improved side-effect profiles. Within the airways of patients suffering from Benafeintrine asthma and other obstructive airway diseases, PDE4 is the most important of the PDE isozymes as a target for drug 15 However, benafentrine results in bronchodilation only discovery because of its distribution in airway smooth when administered by inhalation, and Zardaverine produces muscle and inflammatory cells. Several PDE4 inhibitors only a modest and short-lived bronchodilation. Milrinone, a introduced to the art thus far have been designed to have an cardiotonic agent, induces short-lived bronchodilation and a improved therapeutic index concerning the cardiovascular, slight degree of protection against induced bronchoconstric gastrointestinal, and central nervous system side effects of tion, but has marked adverse events, e.g., tachycardia and the above-mentioned nonselective Xanthines. hypotension. Unsatisfactory results have also been obtained Airflow obstruction and airway inflammation are features with a weakly selective PDE4 inhibitor, tibenelast, and a of asthma as well as COPD. While bronchial asthma is selective PDE5 inhibitor, Zaprinast, which may be repre predominantly characterized by an eosinophilic inflamma 25 sented by Formulas (0.0.7) and (0.0.8): tion, neutrophils appear to play a major role in the patho genesis of COPD. Thus, PDEs that are involved in smooth (0.0.7) muscle relaxation and are also found in eosinophils as well as neutrophils probably constitute an essential element of the 30 progress of both diseases. The PDEs involved include c OH PDE3s as well as PDE4s, and bronchodilating inhibitors He1 No O have been discovered which are selective PDE3 inhibitors Tibenelast and dual PDE3/4 selective inhibitors. Examples of these are milrinone, a selective PDE3 inhibitor, as well as Zardaverine 35 and benafentrine, both dual PDE3/4 selective inhibitors, (0.0.8) O which may be represented by Formulas (0.0.4), (0.0.5), and H (0.0.6), respectively: N 40 \N-4 N (0.0.4) CH3 O H c1\1 N N N \ o Zaprinast O N 45 / \ / More relative success has been obtained in the art with the discovery and development of selective PDE4 inhibitors. NC In vivo, PDE4 inhibitors reduce the influx of eosinophils to the lungs of allergen-challenged animals while also reduc Millrinone 50 ing the bronchoconstriction and elevated bronchial respon siveness occurring after allergen challenge. PDE4 inhibitors also suppress the activity of immune cells, including CD4" T-lymphocytes, monocytes, mast cells, and basophils; reduce pulmonary edema; inhibit excitatory nonadrenergic (0.0.5) 55 noncholinergic neurotransmission (eNANC); potentiate FHC inhibitory nonadrenergic noncholinergic neurotransmission (iNANC); reduce airway Smooth muscle mitogenesis; and O induce bronchodilation. PDE4 inhibitors also suppress the activity of a number of inflammatory cells associated with N 60 the pathophysiology of COPD, including monocytes/mac O 2NN rophages, CD8" T-lymphocytes, and neutrophils. PDE4 inhibitors also reduce vascular Smooth muscle mitogenesis CH3 N and, and potentially interfere with the ability of airway O epithelial cells to generate pro-inflammatory mediators. Zardaverine 65 Through the release of neutral proteases and acid hydrolases from their granules, and the generation of reactive oxygen species, neutrophils contribute to the tissue destruction US 7,250,518 B2 5 6 associated with chronic inflammation, and are further impli enoXimone and motapizone may be represented by Formulas cated in the pathology of conditions such as emphysema. (0.0.10) and (0.0.11), respectively: Selective PDE4 inhibitors which have been discovered thus far that provide therapeutic advantages include SB-207, 499, identified as ARIFLOR), which may be represented by (0.0.10) Formula (0.1.9): H N (0.1.9) H3C 10 y V H3C O COOH S HC N Enoximone NC (0.0.11) C 15 SB-207,499 HC H O / 7 SB-207,499, administered orally at dosages of 5, 10, and 15 N -N S mg b.id., has produced significant increases in trough FEV1 H (forced expiratory volume in 1 second) from placebo at week 2 of a study involving a large number of patients. Motapizone Another potent, selective PDE4 inhibitor, CDP840, has shown Suppression of late reactions to inhaled allergen after The effects of PDE4 inhibitors on various inflammatory 9.5 days of oral administration at doses of 15 and 30 mg in 25 cell responses can be used as a basis for profiling and a group of patients with bronchial asthma. CDP840 may be selecting inhibitors for further study. These effects include represented by Formula (0.0.9): elevation of cAMP and inhibition of superoxide production, degranulation, chemotaxis, and tumor necrosis factor alpha 30 (0.0.9) (TNFC) release in eosinophils, neutrophils and monocytes. PDE4 inhibitors may induce emesis, i.e., nausea and Vom iting, which, as expected, is an adverse effect. The emesis adverse effect became apparent when PDE4 inhibitors were first investigated for CNS indications such as depression, 35 when rolipram and denbufylline were used in clinical trials. Rolipram and denbufylline may be represented by Formulas (0.0.12) and (0.0.13), respectively: CDP840 40 (0.0.12) PDEs have also been investigated as potential therapy for obstructive lung disease, including COPD. In a large study of SB-207,499 in patients with COPD, the group of patients O)- O receiving 15 mg b.i.d. has experienced a progressive 45 O improvement in trough FEV, reaching a maximum mean M NH difference compared with placebo of 160 mL at week 6, H3C which represents an 11% improvement. See Compton et al., Rollipram “The efficacy of Ariflo (SB207499), a second generation, (0.0.13) oral PDE4 inhibitor, in patients with COPD, Am. J. Respir: 50 Crit. Care Med. 159, 1999. Patients with severe COPD have been observed to have pulmonary hypertension, and decreases in mean pulmonary artery pressure under clinical conditions have been achieved by oral administration of the 55 selective PDE3 inhibitors milrinone and enoximone. Enoxi mone has also been shown to reduce airway resistance in patients hospitalized with decompensated COPD. See Lee Denbufylline man et al., Chest 91 662-6, 1987. Using selective PDE3 inhibition by motapizone and selective PDE5 inhibition by 60 Zaprinast, it has been shown that combined inhibition of The mechanism(s) by which PDE4 inhibitors may poten PDE 3 and 5 exerts a relaxation of pulmonary artery rings tially induce emesis is/are uncertain, but a study of the PDE4 which corresponds broadly to the pattern of PDE isozymes inhibitor Ro-20-1724 Suggests that nausea and vomiting are found in the pulmonary artery smooth muscle. See Rabe et at least partially mediated by the emesis centers in the brain. al., Am. J. Physiol. 266 (LCMP 10): L536-L543, 1994. The 65 Gastrointestinal adverse events may be caused by local structures of milrinone and Zaprinast are shown above as effects, e.g., rolipram is a very potent stimulator of acid Formulas (0.0.4) and (0.0.8), respectively. The structures of secretion from gastric parietal cells, and the resulting excess US 7,250,518 B2 7 8 acid, by producing local irritation, may exacerbate gas It has been known for some time that rolipram had the trointestinal disturbances. Ro-20-1724 may be represented ability to interact with a high-affinity binding site on brain by Formula (0.0.14): membranes, and it was later established in the art that this high-affinity rolipram binding site (S), which is distinct from the catalytic site (S), exists in a truncated recombinant (0.0.14) PDE4A and a full-length recombinant PDE4B. More recently, S, has been identified on all four PDE4 subtypes. See Hughes et al., Drug Discovery Today 2(3) 89-101, 1997. O- NH 10 The presence of S. appears to have a profound effect on the ability of certain inhibitors such as rolipram and RS-25.344 O to inhibit the catalytic activity of PDE4 isozymes. W H3C The impact of residues on inhibitor binding is also sig nificant. A single amino acid substitution (alanine for aspar Ro-20-1724 15 tate) in the catalytic region of PDE4B has been shown to be critical for inhibition by rolipram, and this appears to be a Efforts to minimize or eliminate the above-mentioned class effect because related inhibitors RP-73,401 and Ro-20 adverse events sometimes associated with PDE4 inhibitors 1724 also lose potency on the mutant enzyme. However, the have included creating inhibitors which do not penetrate the role of binding of inhibitors to the S or to the S., in terms central nervous system, and administering PDE4 inhibitors of elevation of cAMP and inhibition of cell responses, is not by inhalation rather than orally. fully understood at the present time. With regard to the PDE4 subtypes, A, B, C, and D, it has RP-73,401, in guinea-pig studies, has been found to be been found that PDE4C is usually less sensitive to all active in (1) the inhibition of antigen-induced lung eosino inhibitors; whereas, with respect to the subtypes A, B, and 25 philia and eosinophil peroxidase (EPO), Banner, K. H., “The D, there is as yet no clear evidence of inhibitor specificity, effect of selective phosphodiesterase inhibitors in compari which is defined as a 10-fold difference in ICs values. While most inhibitors, especially RS-25,344, are more potent son with other anti-asthma drugs on allergen-induced eosi against PDE4D, this does not amount to selectivity. RS-25, nophilia in guinea-pig airways.” Pulm. Pharmacol. 837-42, 344 may be represented by Formula (0.0.15): 30 1995; (2) antigen-induced bronchoalveolar lavage (BAL) eosinophilia, Raeburn et al., “Anti-inflammatory and bron chodilator properties of RP73401, a novel and selective (0.0.15) phosphodiesterase Type IV inhibitor. Br. J. Pharmacol. 113 O 1423-1431, 1994; (3) antigen-induced airway eosinophilia 35 and platelet activating factor- (PAF)- and ozone-induced N N N airway hyper-responsiveness (AHR), Karlsson et al., “Anti inflammatory effects of the novel phosphodiesterase IV N 4 1.1N N - inhibitor RP73401, ' Int. Arch. Allergy Immunol. 107425 40 426, 1995; and (4) IL-5 induced pleural eosinophila. Devel opment of RP-73,401, piclamilast, has been discontinued. Piclamilast may be represented by Formula (0.0.17): NO RS-25,344 45 (0.0.17) C

On the other hand, there is a stereoselective effect on the O- H )- elevation of cAMP in a range of cell types, which has been N \ / O demonstrated with the results of an investigation of 50 M CDP840, shown above as Formula (0.0.9), and its less active H3C O Cl enantiomer CT-1731, which is represented by Formula (0.0.16): Piclami last (ROP-73.401)

55 (0.0.16) A related series of compounds is represented by RPR 132294 and RPR-132703, which have been demonstrated in rat studies to have activity in the inhibition of antigen / induced bronchospasm; Escott et al., “Pharmacological pro CO 60 filing of phosphodiesterase 4 (PDE4) inhibitors and analysis of the therapeutic ratio in rats and dogs.” Br. J. Pharmacol. CH3 123(Proc. Suppl.) 40P, 1998; and Thurairatnam et al., “Bio logical activity and side effect profile of RPR-132294 and CT-1731 65 RPR-132703 novel PDE4 inhibitors,” XV' EFMC Int. Symp. Med. Chem., 1998. The structure of RPR-132294 may be represented by Formula (0.0.18): US 7,250,518 B2 10

-continued (0.0.18) (0.1.12)

O O)- NH 7 O H e-N N O N / HC HC 1. -NH. 10 O N N RPR-132294

Another compound whose development has been discon tinued is WAY-PDA-641, filaminast, which in studies in the 15 dog, has been found to be active in the inhibition of Cipamfylline (BRL-61,063) seratonin-induced bronchoconstriction. Filaminast may be represented by Formula (0.0.19): Another compound which is in development is LAS 31025, arofylline, which in guinea-pig studies, has been found to be active in the inhibition of antigen-induced (0.0.19) bronchoconstriction; Beleta, B. J., “Characterization of LAS31025: a new selective PDE IV inhibitor for bronchial asthma.” Third Int. Conf. On Cyclic Nucleotide Phosphodi N-O 25 esterase. From Genes to Therapies, Glasgow, UK, 1996, y / X-Nil, Abstract 73. LAS-31025, arofylline, may be represented by CH, O Formula (0.0.21):

Filaminast (WAY-PDA-641) 30 (0.0.21)

It has been suggested in the art that PDE4 inhibitors that H have a high affinity at the S, can be correlated with emesis N and increased gastric acid secretion. RS-23.544, RP-73,401, 35 and CP-80,633 elicit emesis and have a high affinity at the S. CDP840 and SB-207,499 have a comparatively low es 2 affinity at the S, but CDP840 has a significantly higher potency at the S than does SB-207,499. CDP840 has been demonstrated to provide significant inhibition of late-phase 40 response in the treatment of asthma without any adverse events of nausea or headache. Another PDE4 inhibitor that has been shown to have adverse events of nausea and vomiting is BRL-61,063, also referred to as cipamfylline, Arofylline (LAS-31025) which is described further below. The development of 45 CDP840 has been discontinued, while CP-80,633, atizoram, continues in development. CP-80.633 and BRL-61,063 may A number of PDE4 inhibitors have been advanced in be represented by Formulas (0.0.20) and (0.1.12), respec development. For example, the effects of V-11294A on tively: LPS-stimulated ex vivo TNF release and PHA induced 50 lymphocyte proliferation have been determined in a ran domized, double-blind placebo-controlled study which has (0.0.20) found that an oral dose of 300 mg is effective in reducing TNF levels and lymphocyte proliferation; Landells et al., 55 “Oral administration of the phosphodiesterase (PDE) 4 inhibitor, V11294A inhibits ex-vivo agonist-induced cell activation.” Eur: Resp.J. 12(Suppl. 28) 362s, 1998; and Gale et al., “Pharmacodynamic-pharmacokinetic (PD/PK) profile 60 of the phosphodiesterase (PDE) 4 inhibitor, V11294A, in human volunteers, Am. J. Respir: Crit. Care Med. 159A611, 1s. 1999. H The compound D4418 has been administered to healthy Atizoram (CP-80,633) 65 Volunteers in a single escalating dose, randomized, placebo controlled Phase I study; Montana et al., “Activity of D4418. a novel phosphodiesterase 4 (PDE4) inhibitor, effects in US 7,250,518 B2 11 12 cellular and animal models of asthma and early clinicalstud ies.” Am. J. Respir: Crit. Care Med. 159 A108, 1999. D4418 is a moderately potent PDE4 inhibitor with an ICs of 200 (0.0.24) nM. It has good oral absorption; a 200 mg dose provides a plasma C of 1.4 g/ml. D4418 has been discontinued 5 from development due to its moderate potency, and has been replaced by the preclinical development candidate D4396. V-11294A and D4418 may be represented by Formulas (0.0.22) and (0.0.23), respectively: 10

(0.0.22) HN1 Nchi, 15 The above-mentioned compounds have also been evalu N CH3 ated in animal models which demonstrate their PDE4 inhi bition activity. For example, V-11294A, in guinea-pig stud ies, has been found to be active in the inhibition of antigen Nls NX-( CH induced bronchoconstriction: Cavalla et al., “Activity of V11294A, a novel phosphodiesterase 4 (PDE4) inhibitor, in O cellular and animal models of asthma.” Amer. J. Respir: Crit. Care Med. 155 A660, 1997. D4418, in guinea-pig studies, has been found to be active in the inhibition of antigen OCH induced early and late phase bronchoconstriction and BAL 25 eosinophilia; Montana, et al., Ibid. CI-1018, in rat studies, W-11294A has been found to be active in the inhibition of antigen induced eosinophilia; Burnouf, et al., “Pharmacology of the novel phosphodiesterase Type 4 inhibitor, CI-1018,” 215" ACS Nat. Meeting, MEDI 008, 1998. 30 Other compounds which have been advanced in devel opment include CDC-3052, D-22888, YM-58997, and rof (0.0.23) lumilast, which may be represented by Formulas (0.0.27), N (0.0.28), (0,0.29), and (0.0.30), respectively:

HCO 21 C 35 (0.0.27) O-CH N

O C 2N 40 O V CH D4418 N O

45 O-CH

Another compound, CI-1018, has been evaluated in 54 CDC-3052 Subjects and no adverse events were reported at doses up to 400 mg. Pruniaux et al., “The novel phosphodiesterase inhibitor CI-1018 inhibits antigen-induced lung eosinophilia 50 in sensitized brown-norway rats—comparison with rollip ram.” Inflammation S-04-6, 1999. CI-1018 has been dem (0.0.28) onstrated to have good oral bioavailability (57% in the rat) CH3 and good oral potency of with an EDs of 5 mg/kg in that 55 same species. CI-1018 is a relatively weak PDE4 inhibitor with an ICs of 1.1 uM in U937 cells. CI-1018 has also been N O identified as, or associated with as closely related in struc ture to, PD-168787, which in rat studies has been demon r strated to have activity in the inhibition of antigen-induced 60 H3C No N 2 N1 N-CH eosinophilia; Pascal et al., “Synthesis and structure-activity relationships of 4-oxo-1-phenyl-3,4,6,7-tetrahydro-1,4-di sN azepino 6,7,1-hi indolines: novel PDE4 inhibitors,” 215" H3C ACS, Dallas, USA, MEDI 50, 1998. Inferred structures for 65 D-22888 CI-1018 and PD-168787 belong to a diazepinone class whose nucleus may be represented by Formula (0.0.24): US 7,250,518 B2 13

-continued -continued (0.0.32) (0.0.29) O-CH

O O

N O 10

O NH2

Br 15 CDC-801 YM-58977

The compound of Formula (0.0.32) is reported to have IC values of 42 pM and 130 nM as an inhibitor of PDE4 and TNF production, respectively; Muller et al., “N-Phthaloyl beta-aryl-beta-amino derivatives: Potent TNF-alpha and (0.0.30) PDE4 inhibitors,” 217" American Chemical Society, Annheim, Germany, MEDI 200, 1999; and Muller et al., 25 “Thalidomide analogs and PDE4 inhibition.” Bioorg. Med. Chem. Letts. 82669-2674, 1998. CDC-801 is from a series of compounds based on thali domide and has been developed primarily to improve the TNF-C. inhibitory activity of thalidomide for the treatment of 30 autoimmune diseases. Thalidomide may be represented by Formula (0.0.33):

O NH (0.0.33) O C 21 C 35

N N O N N H Roflumilast 40 O O Thalidomide

CDC-801 has also been studied for the treatment of Crohn's 45 disease, a chronic granulomatous inflammatory disease of CDC-3052 has been discontinued from development, but unknown etiology commonly involving the terminal ileum, has been succeeded by very potent inhibitors of PDE4 such with scarring and thickening of the bowel wall which as the compound represented by Formula (0.0.31), and by frequently leads to intestinal obstruction and fistula and the anti-inflammatory compound CDC-801 represented by 50 abscess formation. Crohn's disease has a high rate of recur Formula (0.0.32), respectively: rence after treatment. YM-58997 has an ICs value of 1.2 nM against PDE4; Takayama et al., “Synthetic studies on selective Type IV (0.0.31) phosphodiesterase (PDE IV) inhibitors,” 214" American O-CH 55 Chemical Society, Las Vegas, USA, MEDI 245, 1997. YM-58997 has a 1.8-naphthyridin-2-one structure, as does /-ch YM-976. O O Roflumilast has been studied for the treatment of both COPD and asthma, and has an ICs value of 3.5 nM in 60 standard in vitro guinea-pig models of asthma. The use of N O roflumilast and a surfactant for the treatment of adult res piratory distress syndrome (ARDS) has also been described. O NH AWD-12,281, which is now designated as loteprednol, / has been shown to be active in a rat model of allergic HO 65 rhinitis, as described further below in a section which deals with allergic rhinitis and the use of PDE4 inhibitors to treat it. AWD-12,281 may be represented by Formula (0.0.34): US 7,250,518 B2 15 16 -continued (0.0.34) (0.0.37) HO

Ne- h CIO F N N N H C 10 O Loteprednol (AWD-12,281)

Compounds related in structure to CDP840, shown fur 15 ther above as Formula (0.0.9), include L-826,141, which has been reported to have activity in a rat model of bronchitis; Gordon et al., “Anti-inflammatory effects of a PDE4 inhibi tor in a rat model of chronic bronchitis. Am. J. Respir: Crit. Care Med. 159 A33, 1999. Another such compound is (0,0.38) related in structure to those reported in Perrier et al., “Substituted furans as inhibitors of the PDE4 enzyme.” Bioorg. Med. Chem. Letts. 9 323-326, 1999, and is repre CH sented by Formula (0.0.35): 25 (0.0.9) e HC3 No O O O

f O CH 30 NCH, 3 O Compounds have been created which combine PDE4 and H3C matrix metalloproteinase (MMP) inhibitory activity in a No single molecule; Groneberg et al., “Dual inhibition of phos 35 phodiesterase 4 and matrix metalloproteinases by an (aryl CDP840 sulfonyl)hydroxamic acid template.” J. Med. Chem. 42(4) (0.0.35) 541-544, 1999. Two examples of such compounds are represented by Formulas (0.0.39) and (0.0.40):

40 O Y-/S O \ Z N (0.0.39) HC No 45 YoH

Other compounds which been found to be very potent s Sa O PDE4 inhibitors are those represented by Formulas (0.0.36), no (0.0.37), and (0.038): HC 50 No (0.0.36) O YCH,

55 (0.0.4.0) CH3 60 YoH On S n O No

65 HC No O CH US 7,250,518 B2 17 18 The respective ICs values for the compounds of Formulas (0.1.36) and (0.1.37) using a guinea-pig macrophage PDE4 (0.043) assay were 1 nM and 30 nM. R The compounds identified as KF19514 and KF 17625 have been shown in guinea-pig studies to have activity in the inhibition of the following: histamine-induced and antigen induced bronchoconstriction; PAF-induced lung eosino philia and antigen-induced BAL eosinophilia; acetylcholine O-o (ACh)-induced AHR; PAF-induced BAL eosinophilia and 10 O O neutrophilia, and AHR; antigen-induced bronchospasm; and anaphylactic bronchoconstriction; Fujimura et al., “Bron N o1 CH choprotective effects of KF-19514 and cilostazol in guinea pigs in vivo.” Eur: J. Pharmacol. 32757-63, 1997: Manabe 2 et al., Ibid.: Manabe et al., “KF19514, a phosphodiesterase 15 N R = benzyloxy 4 and 1 inhibitor, inhibits PAF-induced lung inflammatory (0.0.44) responses by inhaled administration in guinea-pigs.” Int. R = 14-piperidinyl-1'-carbonyloxy Arch. Allergy Immunol. 114389-399, 1997: Suzuki et al., The PDE4 inhibitors that have been created heretofore fall “New bronchodilators. 3. Imidazo[4,5-c.18 naphthyridin into a significant number of different classes in terms of their 4(5H)-ones,” J. Med. Chem. 35 4866-4874, 1992: Matsuura chemical structures. Such classes have been as diverse as et al., “Substituted 1.8-naphthyridin-2(1H)-ones as selective phenanthridines and naphthyridines. One class of PDE4 phosphodiesterase IV inhibitors. Biol. Pharm. Bull. 17(4) inhibitors are lignans such as T440, which has been dem 498-503, 1994; and Manabe et al., “Pharmacological prop onstrated to have activity in the inhibition of the following: erties of a new bronchodilator, KF17625, 'Jpn. J. Pharma 25 early phase bronchoconstriction induced by antigen, hista mine, LTD4, U46619, Ach, neurokinin A, and endothelin-1, col. 58(Suppl. 1) 238P, 1992. KF19514 and KF17625 may allergen-induced early phase and late phase bronchocon be represented by Formulas (0.0.41) and (0.0.42): striction and BAL eosinophilia; and ozone-induced AHR and airway epithelial injury. Optimization of the PDE4 30 inhibitory potency of Such compounds has led to the dis (0.0.41) covery of T-2585, one of the most potent PDE4 inhibitors described to date with an ICs value of 0.13 nM against N=\eer S N guinea-pig lung PDE4. T-440 and T-2585 may be repre sented by Formulas (0.0.45) and (0.0.46): 35 (0.0.45) HC O 2 CN N O N1 O OH He1 No 40 21

KF19514 O N 45 N- O NCH, T-440 (0.0.42) Ne (0.0.46) H3C O S1S 50 N1 O OH 2 OH CN N O He1 No 55 21 O

KF17625 N 60 NS The reported potency and lack of emesis in a series of indandiones suggests that the hypothesis that has related 21 side-effects such as emesis to the ratio of affinity for the N-N PDE4 enzyme relative to that for the high affinity rolipram 65 binding site (HARBS) is erroneous. Such indandiones may T-2585 be represented by Formulas (0.0.43) and (0.0.44): US 7,250,518 B2 19 20 Another class of PDE4 inhibitors consists of benzofurans and benzothiophenes. In particular, furan and chroman rings (0.0.50) have been utilized as surrogates for the cyclopentylether of O O the rolipram pharmacophore. An example of Such a com 5 pound is one that is apparently related in structure to BAY FC N1 NN 19-8004, and which may be represented by Formula H (0.0.47): C N

10 (0.0.47) - O (0.0.51) O O HN ls NH2 FC 15 N O H N HC O)O - (0.0.52) c-( ) O O FC N H 25 Another benzofuran-type compound has been reported to N 21 have an ICs value of 2.5 nM, and may be represented by N Formula (0.0.48): CH N 30

(0.0.48) Purines, Xanthines, and pteridines represent yet further classes of chemical compounds to which PDE4 inhibitors described heretofore in the art belong. The compound V-1 35 1294A described further above and represented by Formula (0.0.22), is a purine. A PDE4 inhibitor which is a xanthine compound, the class of compounds to which theophylline belongs, has been described in the art; Montana et al., “PDE4 inhibitors, new xanthine analogues.” Bioorg. Med. 40 Chem. Letts. 82925-2930, 1998. The xanthine compound may be represented by Formula (0.0.54): A compound with a related Structure, which is not, however, a benzofuran, is characterized by a fused dioxicin ring and is reported to produce almost complete inhibition of (0.0.54) canine tracheal PDE4 at 100 nM. This compound may be 45 represented by Formula (0.0.49):

(0.0.49) 50 cror) CH3

55 A potent PDE4 inhibitor belonging to the pteridine class N-- (O) of compounds has been demonstrated to have an ICso value of 16 nM against a PDE4 derived from tumor cells and to C inhibit the growth of tumor cells at micromolar concentra 60 tions; Merz et al., “Synthesis of 7-Benzylamino-6-chloro 2-piperazino-4-pyrrolidinopteridine and novel derivatives Quinolines and quinolones are a further class of PDE4 free of positional isomers. Potent inhibitors of cAMP inhibitor structures, and they serve as Surrogates for the specific phosphodiesterase and of malignant tumor cell catechol moiety of rolipram. This compound and two com 65 growth,” J. Med. Chem. 41(24) 4733-4743, 1998. The pounds of similar structure may be represented by Formulas pteridine PDE4 inhibitor may be represented by Formula (0.0.50), (0,0.51), and (0.0.52): (0.0.55): US 7,250,518 B2 21 22

(0.0.55) (0.0.58) C F

N O C

H HN C. 21DOJO N Triazines represent a still further class of chemical com 15 O pounds to which PDE4 inhibitors belong that have been described in the artheretofore. Two such triazines have been described which display bronchodilator activity and are 2 (0.0.59) potent relaxant agents in a guinea-pig trachea model. These compounds, which may be represented by Formulas (0.0.56) and (0.0.57) below, are also moderately potent PDE4 inhibi r tors with ICs values of 150 and 140 nM, respectively: 1s1's (0.0.56) 25 1

Another nicotinamide compound has been described in (0.0.57) the art which may be useful in the treatment of CNS diseases 35 such as multiple sclerosis; GB-2327675; and a rolipram derivative has been described in the art which is a PDE4 inhibitor which binds with equal affinity to both the catalytic and the HARB sites on human PDE4B2B: Tian et al., “Dual inhibition of human Type 4 phosphodiesterase isostates by 40 (R,R)-(+/-)-methyl-3-acetyl-4-3-(cyclopentyloxy)-4-meth oxyphenyl-3-methyl-1-pyrrolidine carboxylate.” Biochem istry 37(19) 6894-6904, 1998. The nicotinamide derivative and the rolipram derivative may be represented by Formulas 45 (0.0.60) and (0.0.61), respectively: A triazine having a structure assumed to be closely related to that of the compounds of Formulas (0.0.56) and (0.0.57) (0.0.60) is UCB-29936, which has been demonstrated to have activ ity in a murine model of Septic shock; Danhaive et al., 50 “UCB29936, a selective phosphodiesterase Type IV inhibi N O tor: therapeutic potential in endotoxic shock. Am. J. Respir: N Crit. Care. Med. 159 A611, 1999. H Efforts have also been made in the art to improve the 2 N N selectivity of PDE4 inhibitors with respect to the A through 55 D subtypes described further above. There are presently four O 2N known isoforms (subtypes) of the PDE4 isozyme, encom (0.0.61) passing seven splice variants, also described further above. CH3 The PDE4D isoform mRNA is expressed in inflammatory O cells such as neutrophils and eosinophils, and it has been 60 suggested in the art that D-selective inhibitors of PDE4 will provide good clinical efficacy with reduced side-effects. A ()- O nicotinamide derivative displaying selectivity for inhibition -( of the PDE4D isoform has been described; WO98/.45268; as HC-O O-CH well as a naphthyridine derivative reported to be a PDE4D 65 selective inhibitor; WO 98/18796. These compounds may be represented by Formulas (0.0.58) and (0.0.59), respectively: US 7,250,518 B2 23 24 Further background information concerning selective PDE4 isozymes may be found in publications available in the art, e.g., Norman, “PDE4 inhibitors 1999, 'Exp. Opin. (0.1.3) Ther. Patents 9(8) 1101-1118, 1999 (Ashley Publications Ltd.); and Dyke and Montana, “The therapeutic potential of 5 PDE4 inhibitors.” Exp. Opin. Invest Drugs 8(9) 1301-1325, N 1999 (Ashley Publications Ltd.). 2 3.O DESCRIPTION OF THE STATE OF THE ART 10

WO 98/45268 (Marfat et al.), published Oct. 15, 1998, discloses nicotinamide derivatives having activity as selec tive inhibitors of PDE4D isozyme. These selective inhibitors are represented by Formula (0.1.1): 15 CF

(0.1.1) where R is (C-C)alkyl, (C-C)haloalkyl, or halo. EP550 900 (Jeschke et al.) discloses herbicides and plant nematicides of Formula (0.1.4): l qYRI

(0.1.4) O R4 25 RI

U.S. Pat. No. 4,861,891 (Saccomano et al.), issued Aug. C N N 29, 1989, discloses nicotinamide compounds which function 4N 2. as calcium independent c-AMP phosphodiesterase inhibitors 30 useful as antidepressants, of Formula (0.1.2): k

where n is 0-3; R is selected from numerous groups, but is 35 (0.1.2) usually H, 6-CH, or 5-Cl; R is alkyl, alkenyl, alkynyl, O cycloalkyl, aryl or aralkyl; R1 and R2 is halo, CN, NO, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalky RI N N1 lthio, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, or H arylthio; and R is alkyl. 2 40 N R2 EP 500 989 (Mollner et al.) discloses ACE inhibitors of Formula (0.1.5): 45 The nicotinamide nucleus of a typical compound disclosed in this patent is bonded directly to the R' group, which is defined as 1-piperidyl, 1-(3-indolyl)ethyl, C-C alkyl, phe (0.1.5) nyl, 1-(1-phenylethyl), or benzyl optionally mono-Substi ( R3)n 2 tuted by methyl, methoxy, chloro or fluoro. The R substitu 50 ent is bicyclo[2.2.1]hept-2-yl or N JN - CON CoN R COR 55

where n is 0-3; R is OH, SH, COOH, NH, halo, OR, SR, 60 COOR NHR or N(R), where R is lower alkyl, option ally substituted aryl, or acyl: R is OH, lower alkoxy, where Y is H. F or Cl; and X is H. F. C1, OCH, CF, CN, optionally substituted aryl lower alkoxy, aryloxy, or disub COOH, -C(=O)(C-C)alkoxy, NH(CH)C(=O)-(meth stituted amino; R is lower alkyl or amino lower alkyl, and ylcarbamoyl) or N(CH),C(=O)-(dimethylcarbamoyl). 65 R1 and R2 is halo, NO, lower alkyl, halo lower alkyl, aryl U.S. Pat. No. 4,692,185 (Michaely et al.) discloses her lower alkyl, or aryl. Specific embodiments disclosed include bicides such as those of Formula (0.1.3): compounds such as that of Formula (0.1.6): US 7,250,518 B2 25 26 agent identified as ARIFLOR), which is a compound of Formula (0.1.9) and named as indicated below: (0.1.6) O CH3 5 (0.1.9) N H3C N N V H /NCH, O COOH 2 O O N O O NC 10 C ARIFLOOR) cis-4-cyano-4-(3-cyclopentyl-oxy-4- methoxyphenyl)cyclo-hexane-1-carboxylic acid 15 FR 2.140.772 (Aries) discloses compounds asserted to have utility as analgesics, tranquilizers, antipyretics, anti The compound of Formula (0.1.9) falls within the scope of U.S. Pat. No. 5,552,438 which discloses a genus of inflammatories, and antirheumatics, of Formula (0.1.7): compounds of Formula (0.1.10): 2O (0.1.7) O (0.1.10) RX R A2 N X4 N N SÁ 2 21 R" 25 X ax N O O1 X3

21 where R= -(CRRs).R. where r–0 and RFC - R 30 cycloalkyl; X=YR where Y=O and R= -CH: X-O; S X-H; and X a moiety of partial Formula (0.1.10.1) where R is 1 or 2 substituents chosen from lower alkyl, (0.1.10.1) trihalomethyl, alkoxy, and halo; R is H or alkyl; and R" is 35 Z hydrogen or alkyl. JP 07304775 (Otsuka et al.) discloses naphthyridine and pyridopyrazine derivatives which have anti-inflammatory, X immunomodulating, analgesic, antipyretic, antiallergic, and antidepressive action. Also disclosed are intermediates of 40 Formula (0.1.8): where X=H; s=0; R1 and R2=CN; and Z=C(O)OR where RH. The disclosures of U.S. Pat. No. 5,602,157 and U.S. (0.1.8) Pat. No. 5,614,540 differ from that of U.S. Pat. No. 5,552, COOR 45 438 and each other as to the definition of the R group, which in the case of the ARIFLOR) compound, is CN. A preferred salt form of the ARIFLOR) compound is disclosed to be the tris(hydroxymethyl)ammonium methane salt. U.S. Pat. No. 5,863,926 (Christensen et al.) discloses 50 analogs of the ARIFLOR) compound, e.g., that of Formula (0.1.11): where X may be CH, and R and R' are each lower alkyl. (0.1.11) With regard to the disclosures of the above-identified HC patents and published patent applications, it will be appre- ss V ciated that only the disclosure of WO 98/.45268 (Marfat et O COOH al.) concerns the inhibition of PDE4 isozymes. The state of C the art also contains information regarding compounds wholly dissimilar in chemical structure to those of Formula (1.0.0) of the present invention, but which, on the other 60 c C hand, possess biological activity similar to that of the compounds of Formula (1.0.0). Representative patents and published patent applications disclosing said information are WO 99/18793 (Webb et al.) discloses a process of making illustrated further below. the ARIFLOR) and related compounds. WO95/00139 (Bar U.S. Pat. No. 5,552,438: U.S. Pat. No. 5,602,157; and 65 nette et al.) claims a compound which has an ICso ratio of U.S. Pat. No. 5,614,540 (all to Christensen), which all share about 0.1 or greater as regards the ICs for the PDE IV the same Apr. 2, 1992 priority date, relate to a therapeutic catalytic form which binds rolipram with a high affinity, US 7,250,518 B2 27 28 divided by the ICs for the form which binds rolipram with compounds of Formula (1.0.0). Such compounds disclosed a low affinity; but in a dependent claim restricts the scope in the prior art do, nevertheless, often have therapeutic thereof to a compound which was not known to be a PDE4 utility similar to that possessed by the compounds of For inhibitor prior to Jun. 21, 1993. mula (1.0.0), i.e., in the treatment of inflammatory, respira WO99/20625 (Eggleston) discloses crystalline polymor tory and allergic diseases and conditions. In particular this is phic forms of cipamfylline for treatment of PDE and TNF applicable to certain inhibitors of enzymes and antagonists mediated diseases, of Formula (0.1.12): of receptors in the so-called leukotriene pathway. This is especially the case with regard to the leukotrienes LTB and (0.1.12) 10 LTD. Accordingly, representative patents and published patent applications disclosing further information of this O type are described below. H N Arachidonic acid is metabolized by cyclooxygenase-1 N and by 5-lipoxygenase. The 5-lipoxygenase pathway leads 1. M NH2 15 to the production of leukotrienes (LTs) which contribute to O N N the inflammatory response through their effect on neutrophil aggregation, degranulation and chemotaxis; vascular perme ability; Smooth muscle contractility; and on lymphocytes. The cysteinyl leukotrienes, LTC LTD, and LTE, play an important role in the pathogenesis of asthma. The compo Cipamfylline nents of the leukotriene pathway which afford targets for therapeutic intervention are illustrated in the following dia gram: WO 99/20280 (Griswold et al.) discloses a method of treating pruritis by administering an effective amount of a 25 PDE4 inhibitor, e.g., a compound of Formula (0.1.13): Enzyme 5-lipoxygenase

(0.1.13) O 30 ARACHIDONIC ACID la NH

1. R3 Enzyme LTA4 Hydrolase LTC Synthase O N N 35 R2 5-Lipoxygenase Activating Protein (FLAP) U.S. Pat. No. 5,922,557 (Pon) discloses a CHO-K1 cell line which stably expresses high levels of a full length 40 low-Km cAMP specific PDE4A enzyme, which has, in turn, been used to examine potent PDE4 enzyme inhibitors and Leukotriene GO GD) CD compare the rank order of their potencies in elevating cAMP in a whole-cell preparation with their ability to inhibit y phosphodiesterase activity in a broken-cell preparation. It is 45 Cys-LT1 Cys-LT2 further said to be found that the soluble enzyme inhibition Receptor assay described in the prior art does not reflect behavior of the inhibitors acting in vivo. An improved soluble enzyme whole-cell assay is then disclosed which is said to reflect the Accordingly, agents which are able to intervene in any of behavior of inhibitors acting in vivo. It is further disclosed 50 the steps of the 5-lipoxygenase pathway afford an opportu that there exist at least four distinct PDE4 isoforms or nity for therapeutic treatment. An example of one such agent Subtypes, and that each Subtype has been shown to give rise is the 5-lipoxygenase inhibitor, Zileuton, a therapeutic agent to a number of splice variants, which in themselves can exhibit different cellular localization and affinities for inhibi identified as ZYFLOR) which may be represented by For tOrS. 55 mula (0.1.14): With regard to the disclosures of the above-identified patents and published patent applications, it will be appre (0.1.14) ciated that the compounds involved possess the same bio S CH logical activity as the compounds of Formula (1.0.0). At the O same time, however, the artisan will observe that the chemi 60 cal structures of said compounds disclosed in the prior art are not only diverse from each other but dissimilar to that of S/ HO NH2 the novel compounds of the present invention as well. The state of the art contains still further information regarding ZYFLOR) compounds which are dissimilar in chemical structure to 65 Zileuton those of Formula (1.0.0), and which, moreover, do not possess PDE4 inhibitory activity similar to that of the US 7,250,518 B2 29 Another Such agent is the LTD receptor antagonist Zafirlukast, a therapeutic agent identified as ACCOLATER which may be represented by Formula (0.1.15): (0.1.18) CH, O NH OCH H3C NH2 (0.1.15) H3C CH3 O 1n 1a1n O A.CH3 O N 10 CGS-25019.c O N l H M C H Nothing in the above-described state of the art discloses So 15 or would suggest to the artisan the novel compounds of the H3CO , O present invention or their PDE4 inhibitory activity and the resulting significant improvement in therapeutic utility and ACCOLATEGR) therapeutic index in the treatment of inflammatory, respira Zafirlukast tory and allergic diseases and conditions.

4.O SUMMARY OF THE INVENTION A further such LTD receptor antagonist is montelukast, a therapeutic agent identified as SINGULAIR(R) which may be represented by Formula (0.1.16): The present invention is concerned with novel compounds 25 which have biological activity as inhibitors of the phos phodiesterase so-called “Type IV” isoenzyme (“PDE4 isozyme'). Embodiments of the novel compounds of the (0.1.16) present invention are active as non-selective inhibitors of the PDE4 isozyme. Other embodiments of said novel com 30 pounds have PDE4 isozyme substrate specificity, especially for the D Subtype. Said novel compounds having non selective or D-selective PDE4 inhibitor activity are gener ally useful in the therapeutic treatment of various inflam matory, allergic, and respiratory diseases and conditions, and they afford in particular a significant improvement in the therapeutic treatment of obstructive respiratory diseases, especially asthma and chronic obstructive pulmonary dis ease (COPD). 40 SINGULAIRR) The present invention relates to a compound of Formula Montelukast (1.0.0):

Another type of the above-mentioned therapeutic targets (1.0.0) is the LTB receptor, and an example of an antagonist for 45 said receptor is BIIL-260, a therapeutic agent which may be represented by Formula (0.1.17):

50 (0.1.17) oul 55

—wherein—

60 j is 0 or 1; provided that when j is 0, n must be 2: BIIL-260 k is 0 or 1 m is 0, 1, or 2: n is 1 or 2; Another example of a therapeutic agent which is an LTB 65 A has the following meanings: receptor antagonist is CGS-25019c which may be repre (a) a member selected from the group consisting of partial sented by Formula (0.1.18): Formulas (1.1.1) through (1.1.5): US 7,250,518 B2 31 32 benzyl, or pyridyl is substituted by 0 to 3 substituents selected from the group consisting of —F. —Cl, —F. (1.1.1) —CN, and —(C-C)alkyl, O (3) —(CH2), (C-C)cycloalkyl where u is 0, 1 or 2; and R7 further where said (C-C7)cycloalkyl is substituted by 0 to --- 3 substituents R' where R' has the same meaning as O O (1.1.2) defined above; —and usul (4) phenyl or benzyl, where said phenyl or benzyl is inde : o1 10 pendently substituted by 0 to 3 substituents R' where R' R9 has the same meaning as defined above; O (1.1.3) R is a member independently selected from the group consisting of R7 15 —the following:— --- (1) tetrazol-5-yl: 1,2,4-triazol-3-yl: 1,2,4-triazol-3-on-5-yl; R9 1,2,3-triazol-5-yl; imidazol-2-yl; imidazol-4-yl; imidazo (1.1.4) lidin-2-on-4-yl: 1.3,4-oxadiazolyl: 1.3,4-oxadiazol-2-on O 5-yl: 1,2,4-oxadiazol-3-yl: 1,2,4-oxadiazol-5-on-3-yl: R8 1,2,4-oxadiazol-5-yl: 1,2,4-oxadiazol-3-on-5-yl: 1.2.5- : N thiadiazolyl: 1.3,4-thiadiazolyl; morpholinyl; parathiazi nyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; pyrrolyl, R9 pyrazolyl; Succinimidyll; glutarimidyl, pyrrolidonyl: 2-pi (1.1.5) peridonyl: 2-pyridonyl, 4-pyridonyl; pyridazin-3-onyl: O 25 pyridyl; pyrimidinyl; pyrazinyl; pyridazinyl; —and : ls O1 (C)d Yw3 (2) indolyl; indolinyl: isoindolinyl; benzobfuranyl; 2.3- H dihydrobenzofuranyl: 1,3-dihydroisobenzofuranyl; 2H-1- benzopyranyl: 2-H-chromenyl; chromanyl; benzothienyl: 30 1H-indazolyl; benzimidazolyl; benzoxazolyl; benzisox azolyl; benzothiazolyl; benzotriazolyl; benzotriazinyl: —wherein— phthalazinyl: 1.8-naphthyridinyl; quinolinyl; isoquinoli “*” indicates the point of attachment of each partial Formula nyl; quinazolinyl; quinoxalinyl; pyrazolo 3,4-dipyrimidi (1.1.1) through (1.1.5) to the remaining portion of For nyl; pyrimido4.5-dpyrimidinyl, imidazol-2-alpyridi mula (1.0.0); 35 nyl; pyridopyridinyl; pteridinyl; and 1H-purinyl: q is 1, 2, or 3, provided that where q is 2 or 3, R has the meaning of —H in at least one instance, or two instances, —where— respectively; any moiety recited in (1) or (2) above is optionally substi v 0 or 1; tuted with respect to (i) any one or more carbon atoms W is —O—; N(R) , where R has the same meaning 40 thereof by a substituent R'" where R' has the same as defined below; or —OC(=O)—; meaning as defined below; (ii) any one or more nitrogen R’ is a member independently selected from the group atoms thereof that is not a point of attachment of said consisting of moiety, by a substituent R' where R' has the same meaning as defined below, and all tautomer forms, and —the following:— 45 optionally N-oxide forms thereof; and (iii) any sulfur (1) —H; atom thereof that is not a point of attachment of said (2) —(C-C)alkyl; —(C-C)alkenyl; or —(C-C)alkynyl: moiety, by 0, 1, or 2 oxygen atoms; where said alkyl, alkenyl or alkynyl is substituted by 0 to —and further where— 3 substituents R': R" is a member selected from the group consisting of —where— 50 —(C-C)alkyl; —(C-C)cycloalkyl, phenyl; benzyl, R" is a member selected from the group consisting of pyridyl; and quinolinyl; where said alkyl, cycloalkyl, phenyl, benzyl, pyridyl, or quinolinyl is substituted by 0. 1, or 2 substituents —F. - C1, —CH, OR, NO, —CN, or—NR'R'': and said R'' group further consists 55 of-F:-Cl:—CF; oxo (=O); OR':-NO; –CN: C(=O)CR: O C(=O)R'; C(=O)NR'R'7; O C(=O)NR'R'7; NR'R'7; NRC(=O)R7; NRC(=O)CR7; NRS(=O).R'7; and —where— S(=O), NR'R'7; R'' is F: –Cl; CF; CN; NO; OH: —(C-C) 60 alkoxy; —(C-C)alkyl: or NR'R'': —and still further where— R" is a member independently selected from the group —and— consisting of H; NR'R'7: C(=O)R'; OR; R'' and R'' are each a member independently selected from —(C-C)alkyl-OR'': –C(=O)CR'': —(C-C)alkyl-C the group consisting of —H; —(C-C)alkyl; —(C-C) 65 (=O)CR': C(=O)NR'R'': (C-C)alkyl; (C- alkenyl; —(C-C)cycloalkyl, phenyl; benzyl; and C.)alkenyl; —(CH2) - (C-C)cycloalkyl where u is 0. pyridyll; wherein said alkyl, alkenyl, cycloalkyl, phenyl, 1 or 2; phenyl; benzyl, pyridyl; and quinolinyl; wherein US 7,250,518 B2 33 34 said alkyl, alkenyl, alkoxy, cycloalkyl, phenyl, benzyl, —CHCHCHCH, -CH(CH)CHCH. —CHCH pyridyl or quinolinyl is substituted with 0 to 3 substituents (CH), —C(CH), cyclopropyl, cyclobutyl, or cyclo R'; where R'' and R' have the same meanings as pentyl: defined above; and R" and Rare each a member independently selected from 5 the group consisting of H; —F. —CF; —(C-C)alkyl: —where— —(C-C)cycloalkyl; phenyl; and benzyl, wherein said R'' is a member independently selected from the group cycloalkyl, phenyl, and benzyl moieties are each inde consisting of —F; –Cl; -COR': —OR'; –CN: pendently substituted with 0 to 3 substituents R' where C(=O)NR'R''. NR'R'': NRC(=O)R'; R" has the same meaning as defined above: NRC(=O)CR'; NR's(=O).R', S(=O), 10 NR'R'', where p is 1 or 2: —(C-C)alkyl; and —(C- —O— C.)alkoxy, where R' has the meaning of —OR'' above R" and Rare taken together, but only in the case where m and R' is defined as —(C-C)alkyl; wherein said alkyl is 1, to form a spiro moiety of Formula (1.2.0): and alkoxy are each independently substituted with 0 to 3 substituents independently selected from —F: —Cl; 15 —(C-C)alkoxycarbonyl; —(C-C)alkylcarbonyl; and (1.2.0) —(C-C)alkylcarbonyloxy; : : —where— (H3CQ (CH3), R" and R'' are independently selected from the group XA consisting of —H; —(C-C)alkyl; and phenyl: R is a member selected from the group consisting of H; —(C-C)alkyl; —(C-C)cycloalkyl, phenyl; benzyl, —where— pyridyl: C(=O)CR': C(=O)R': OR: –(C- rands are independently 0 to 4 provided that the sum of r+s is at least 1 but not greater than 5: C.)alkyl-OR': and —(C-C)alkyl-C(=O)CR'; where 25 R has the same meaning as defined above; —and —or A has the meaning— X is —CH2—, —CH(R') , or C(R') where each (b) a moiety comprising a member selected from the group R'' is selected independently of the other and each has the consisting of —O P(=O)(OH), (phosphoric); —PH same meaning as defined above; NR' , where R' (=O)CH (phosphinic); —P(=O)(OH) (phosphonic); 30 has the same meaning as defined above; —O—; or —P(=O)(OH)—O(C-C)alkyl)(alkylphosphono); —S(=O), where t is 0, 1, or 2; and said spiro moiety is —P(=O)(OH)—O(C-C)alkyl)(alkylphosphinyl); substituted as to any one or more carbon atoms thereof by —P(=O)(OH)NH, (phosphoramido), -P(=O)(OH)NH 0 to 3 substituents R'', where R'' has the same meaning (C-C)alkyl and - P(=O)(OH)NHR' (substituted as defined above; as to a nitrogen atom thereof by 0 or 1 phosphoramido); - O S(=O)OH (sulfuric); 35 substituent R', and as to a sulfur atom thereof by 0 or 2 —S(=O), OH (sulfonic); -S(=O)NHR' (arylsul OXygen atoms; fonamido); S(=O)NHR'; and acylsulfonamido R and R' have the same meaning as defined above for R' selected from the group consisting of —C(=O)NHS and R except that one of them must be —H, and they are (=O).R.: C(=O)NHS(=O)NH: C(=O)NHS selected independently of each other and of R and R' 40 R" and R may individually or together appear on any ring (=O)(C-C)alkyl: C(=O)NHS(=O)NH(C-C) or rings comprising a meaning of the moiety B as defined below, and R' and R are each a member independently selected from the group consisting of —H; —F. —Cl; —CN; —NO. —(C-C)alkyl; —(C-C)alkynyl; fluori 45 nated-(C-C)alkyl; —OR'; and –C(=O)NR'R'',: where R', and R', have the same meanings as defined above; R is —H; —(C-C)alkyl; phenyl; benzyl; or —OR', where R' has the same meaning as defined above; —where— 50 R, R and R may individually or together appear on any R’ is -H; —(C-C)alkyl; phenyl: or -OR', where R' ring or rings comprising a meaning of the moiety B' as has the same meaning as defined above; defined below, and R, R and R6 are each a member W is —O—; —S(=O), , where t is 0, 1, or 2; or independently selected from the group consisting of - N(R)— where R has the same meaning as defined below: 55 —the following:— Y is =C(R')—, where R', has the same meaning as defined below; or —N->(O)— where k is 0 or 1; —where— R", is a member selected from the group consisting of H; 60 —F. —Cl; —CN; —NO. —(C-C)alkyl; —(C-C) alkynyl: fluorinated-(C-C)alkyl; fluorinated-(C-C) alkoxy; OR'; and C(=O)NR'R'',:

—where— 65 R'' and R', are each independently —H: —CH: —CHCH: —CH2CH2CH: —CH2(CH), US 7,250,518 B2 35 36 —where— p is 0, 1, or 2; and R', R', and R'7 have the same -continued meanings as defined above; (1.3.5) (b) —(C-C)alkyl; and —(C-C)alkoxy in the case where one or more of R. R. or R has the meaning of OR under (a) above and R' is defined as —(C-C)alkyl: wherein said alkyl and alkoxy are each independently AirR20 Substituted with 0 to 3 substituents —F or —Cl; or 0 or 1 substituent (C-C)alkoxycarbonyl-, (C-C)alkylcar 10 bonyl-, or (C-C)alkylcarbonyloxy-, (1.3.6) —and— (c) an aryl or heterocyclyl moiety selected from the group 15 consisting of phenyl; benzyl; furanyl, tetrahydrofura R2 O nyl, oxetanyl; thienyl; tetrahydrothienyl; pyrrolyl; pyr rolidinyl, oxazolyl: oxazolidinyl; isoxazolyl; isoxazo A. lidinyl; thiazolyl; thiazolidinyl: isothiazolyl; isothiazolidinyl, pyrazolyl; pyrazolidinyl, oxadiazolyl; (1.3.7) thiadiazolyl; imidazolyl; imidazolidinyl; pyridinyl: pyrazinyl; pyrimidinyl; pyridazinyl; piperidinyl; piper azinyl; triazolyl; triazinyl; tetrazolyl; pyranyl; azetidi nyl; morpholinyl, parathiazinyl; indolyl; indolinyl; R benzobfuranyl: 2,3-dihydrobenzofuranyl: 2-H- 25 chromenyl: chromanyl; benzothienyl: 1-H-indazolyl; HO R20 2OHO benzimidazolyl; benzoxazolyl; benzisoxazolyl; benz thiazolyl; quinolinyl; isoquinolinyl; phthalazinyl; quinazolinyl; quinoxalinyl; and purinyl; wherein said (1.3.8) aryl and heterocyclyl moieties are each independently 30 substituted with 0 to 2 substituents R' where R has the same meaning as defined above; 2 —or in the case where B' is phenyl Mr. (d) Rand Rare taken together to form a moiety which is 35 (1.3.9) a member selected from the group consisting of partial Formulas (1.3.1) through (1.3.15):

(1.3.1) 40 * (1.3.10) b-I-R 45 R20 (1.3.2) (1.3.11)

50 O R21 R20 (1.3.3.) (1.3.12) 55

1. R2 N R21 / S A R20 r (1.34) 60 (1.3.13) f O R21 NFN Sls 65 A V R20 US 7,250,518 B2 37 38

-continued (1.3.14) (1.1.11)

(1.3.15) 10

(1.1.12)

R 15 1,2,4-triazol-3-yl —wherein— R" and R' are each a member independently selected from (1.1.13) the group consisting of —H; —F. —Cl; —CH; —CHF: : N O —CHF: —CF; —OCH; and —OCF; N Y R° and R'' are each independently —H; —CH; —OCH: 25 N-N —CHCH; —OCHCH: —CH2CHCH; —CH R15 Y is (CH); —CHCHCHCH; —CH(CH)CHCH: 1,2,4-triazol-3-on-5-yl —CH2CH(CH), —C(CH), or absent, in which case (1.1.14) the dashed line ---- represents a double bond; 30 B' is a moiety comprising a saturated or unsaturated carbon ring system that is 3- to 7-membered monocyclic, or that is 7- to 12-membered, fused or discontinuous, polycyclic; wherein optionally one carbon atom of said carbon ring system may be replaced by a heteroatom selected from N. 35 1,2,3-triazol-5-yl O, and S; and where N is selected, optionally a second (1.1.15) carbon atom thereof may be replaced by a heteroatom : N selected from N, O, and S: YN 40 A —wherein— R 15 said moiety defining B' is substituted on any ring or rings thereof by R, R and R, which have the same meaning imidazol-2-yl as defined above; (1.1.16) B is a moiety comprising a Saturated or unsaturated carbon 45 ring system that is 3- to 7-membered monocyclic, or that is 7- to 12-membered, fused or discontinuous, polycyclic; V 15 wherein optionally one carbon atom of said carbon ring imidazol-4-yl system may be replaced by a heteroatom selected from N. 50 O, and S; and where N is selected, optionally a second (1.1.17) carbon atom thereof may be replaced by a heteroatom selected from N, O, and S:

—wherein— 55 said moiety defining B is substituted on any ring or rings thereof by R' and R, which have the same meaning as defined above;

—O— 60 (1.1.18) a pharmaceutically acceptable salt thereof. The present invention is concerned in particular with a compound of Formula (1.0.0) as above-recited wherein A is of partial Formula (1.1.4) where v is 0 or 1, and R is a 65 1,3,4-oxadiazolyl member selected from the group consisting of partial For mulas (1.1.1 1) through (1.1.38): US 7,250,518 B2 39 40

-continued -continued y (1.1.19) (1.1.28) V R 15 SY 1,3,4-oxadiazol-2-on-5-yl Succinimidyl 10

(1.1.20) (1.1.29)

NS 15 N-O

1,2,4-oxiadazol-3-yl (1.1.21) R15 (1.1.30) YY 25 1,2,4-oxadiazol-5-on-3-yl (1.1.22) : ne N 5 (1.1.31) O-N 30 1,2,4-oxadiazol-5-yl (1.1.23) : N O 35 ne Y (1.1.32) O-N Y is 1,2,4-oxadiazol-3-on-5-yl (1.1.24) 40 2-pyridonyl (1.1.33) R 15 45 N (1.1.25) : V 50 O isoxazolyl 4-pyridonyl (1.1.26) (1.1.34)

(1.1.27) 60 (1.1.35)

- M 65 pyrazolyl US 7,250,518 B2 41 42

-continued -continued (1.1.36) (1.1.14) r 5 Y. N- N-N R 15 pyrimidinyl 1,2,3-triazol-5-yl 10 (1.1.37) N (1.1.15) : % D : e lsN 15 YN f pyrazinyl R A15 (1.1.38) % N NN Imidazol-2-wlmidazol-2-y : 2O (1.1.16) : N Pyridazinyltsu (\ )N Y is 25 —wherein— imidazol-4-yl “*” indicates the point of attachment of each partial Formula (1.1.17) (1.1.11) through (1.1.38) to the remaining portion of Formula (1.0.0); 30 : N O —and wherein— YY each carbon atom of partial Formulas (1.1.11) through N (1.1.38) is optionally substituted by a substituent R''; and R15 where R'' and R' have the same meaning as defined 35 imidazolidin-2-on-4-yl above; and all tautomer forms, and optionally N-oxide (1.1.19) forms, thereof. : O O The present invention is further concerned more particu- Sk Y larly with a compound of Formula (1.0.0) as above-recited N-N wherein A is of partial Formula (1.1.4) where v is 0 or 1, and 40 Yis R is a member selected from the group consisting of the following partial Formulas: 1,3,4-oxadiazol-2-on-5-yl (1.1.21) 15 45 R (1.1.11) N : N O a N// y\ y N-N N-O A R 15 50 1,2,4-oxadiazol-5-on-3-yl Tetrazol-5-yl (1.1.27) (1.1.12) R15 : N

Yy 55 N N AN-N -\ N R 15 1,2,4-triazol-3-yl pyrazolyl (1.1.13) 60 (1.1.28) : N NY O N O R?.N-N Y is SY 65 1,2,4-triazol-3-on-5-yl Succinimidyl US 7,250,518 B2 43 44

-continued -continued (1.1.32) (1.5.2)

O H 2-pyridonyl (1.1.33) 10 R 15

N (1.5.3) 15 FF O 4-pyridonyl OO OH (1.1.34)

(1.5.4)

(1.1.35) O H

(1.5.5) 30 F2 pyridyl OO O H The present invention is still further concerned with a 35 compound of Formula (1.0.0) characterized as to the right hand side thereof, where m is 1, by partial Formula (1.1.7): (1.5.6) C H3 O 1. (1.1.7) 40

OH 45

(1.5.7) where 66: is a symbol representing the point of attachment of the group of partial Formula (1.1.7) to the remaining portion of a compound of Formula (1.0.0), from and includ 50 ing the phenyl group forward; and where R and Rare both —H, or one is —H and the other is —CH, or both are —CH, or both are taken together to form spiro-cyclopropyl OH or spiro-cyclobutyl; R' is -H, - OCH, or 2'-F; R is H: (1.5.8) and the moiety -A is selected Such that, said group of partial 55 Formula (1.1.7) is a member selected from the group con sisting of partial Formulas (1.5.1) through (1.5.16): OH (1.5.9) (1.5.1) 60

OH 65 OH CH3 US 7,250,518 B2 45 46 selected, optionally a second carbon atom thereof may be -continued replaced by a heteroatom selected from N, O, and S. The (1.5.10) present invention is further concerned with a compound of : Formula (1.0.0) wherein B' comprises especially a member selected from the group consisting of phenyl; pyrrolyl, pyrrolidinyl; furanyl; thienyl; pyridyl; pyrimidinyl; piperidi nyl; piperazinyl; imidazolyl; imidazolidinyl, oxazolyl; isox azolyl; morpholinyl; thiazolyl; indolyl; quinolinyl; isoquino 10 linyl; benzimidazolyl; benzoxazolyl; quinuclidinyl; and (1.5.11) azabicyclo3.3.0 octanyl; a monocyclic —(C-C7)cy cloalkyl moiety; a monocyclic —(Cs-C7)cycloalkenyl moi ety that is a member selected from the group consisting of cyclopentenyl, cyclohexenyl, and cycloheptenyl; and a bicy 15 clic —(C7-Co)cycloalkyl or —(C7-Co)cycloalkenyl moi (1.5.12) ety that is a member selected from the group consisting of norbornanyl, norbornenyl, bicyclo2.2.2]octanyl, bicyclo 3.2.1]octanyl, bicyclo[3.3.0 octanyl, bicyclo[2.2.2]oct-5- enyl, bicyclo[2.2.2]oct-7-enyl, bicyclo[3.3.1 nonanyl, cyclodecanyl, and adamantanyl. The present invention is still further concerned especially (1.5.13) with a compound of Formula (1.0.0) wherein particularly B' and the substituents R. R. and R are selected in such a 25 way that the left-hand terminus of said compound of For mula (1.0.0) is represented by the following partial Formulas (1.8.1) through (1.8.72): CH (1.5.14) 30 (1.8.1) :

35 CH3 F (1.5.15) (1.8.2) : 40

CH3 F (1.5.16) 45 F (1.8.3) :

F (1.8.4) : —wherein— 55 “*” indicates the point of attachment of each said group of partial Formula (1.1.7) represented by partial Formulas (1.5.1) through (1.5.16) to the remaining portion of For mula (1.0.0); N The present invention has been defined above as being 60 C (1.8.5) concerned with a compound of Formula (1.0.0) wherein B' : has the meaning defined above as a moiety comprising a saturated or unsaturated carbon ring system that is 3- to 7-membered monocyclic, or that is 7- to 12-membered, fused or discontinuous, polycyclic; wherein optionally one 65 carbon atom of said carbon ring system may be replaced by O N a heteroatom selected from N, O, and S; and where N is US 7,250,518 B2 47 48

-continued -continued (1.8.6) : (1.8.13)

10 o1O:N C H3 (1.8.7)

15 (1.8.14)

N s (1.8.8) O

25 (1.8.15)

30 C /N1N. N s O (1.8.9) 35 (1.8.1.6) :

40 (1.8.10) 1SN211'SN21neaSS Ne. (1.8.17) S

N 2 (1.8.18) (1.8.11) 50

N Z 55 l (1.8.12) O (1.8.19)

N 65 YYs N N US 7,250,518 B2 49 50

-continued -continued (1.8.20) (1.8.29)

10 (1.8.30)

(1.8.21)

15 (1.8.31) N (1.8.22)

25 (1.8.32)

(1.8.23)

(1.8.24) (1.8.33) 35

40 (1.8.34) (1.8.25)

45 (1.8.35)

(1.8.26)

50 (1.8.36)

(1.8.27) 55

(1.8.37)

60 (1.8.28) 2 f -, O CH3 65 US 7,250,518 B2 51 52

-continued -continued (1.8.38) A (1.8.49) 10 (1.8.50) (1.8.39)

15 Atz (1.8.40) (1.8.51) : A, (1.8.52) (1.8.41)

(1.8.42) (1.8.53)

(1.8.43) CO (1.8.54) 35 A , (1.8.44) (1.8.55) : 40 G (1.8.56) (1.8.45) as

(1.8.46) 50 (1.8.57) :

55 19 (1.8.47) (1.8.58) :

60 YCH, (1.8.48) (1.8.59)

65 Nu CH US 7,250,518 B2 53 54

-continued -continued (1.8.60) (1.8.70) : X FC N (1.8.71) : N

(1.8.61) 10

OH (1.8.72) :

15 (1.8.62) CH

(1.8.63) The present invention has been defined above as being concerned with a compound of Formula (1.0.0) wherein B has the meaning defined above as a moiety comprising a 25 saturated or unsaturated carbon ring system that is 3- to 7-membered monocyclic, or that is 7- to 12-membered, fused or discontinuous, polycyclic; wherein optionally one carbon atom of said carbon ring system may be replaced by (1.8.64) 30 a heteroatom selected from N, O, and S; and where N is selected, optionally a second carbon atom thereof may be replaced by a heteroatom selected from N, O, and S. The present invention is further concerned with a compound of Formula (1.0.0) wherein B comprises especially a member 35 selected from the group consisting of phenyl; pyrrolyl, (1.8.65) pyrrolidinyl; furanyl; thienyl; pyridyl; pyrimidinyl; piperidi nyl; piperazinyl; imidazolyl; imidazolidinyl, oxazolyl; isox azolyl; thiazolyl; indolyl; quinolinyl; isoquinolinyl; benz 40 imidazolyl; benzoxazolyl; morpholinyl; quinuclidinyl; and aZabicyclo3.3.0 octanyl; a monocyclic —(C-C)cy cloalkyl moiety; a monocyclic —(Cs-C7)cycloalkenyl moi (1.8.66) ety that is a member selected from the group consisting of cyclopentenyl, cyclohexenyl, and cycloheptenyl; and a bicy 45 clic —(C7-Co)cycloalkyl or —(C7-Co)cycloalkenyl moi ety that is a member selected from the group consisting of norbornanyl, norbornenyl, bicyclo2.2.2]octanyl, bicyclo (1.8.67) 3.2.1]octanyl, bicyclo[3.3.0 octanyl, bicyclo[2.2.2]oct-5- 50 enyl, bicyclo[2.2.2]oct-7-enyl, bicyclo[3.3.1 nonanyl, cyclodecanyl, and adamantanyl. The present invention is also further concerned especially with a compound of Formula (1.0.0) wherein particularly B and the substituents R' and Rare selected in such away that 55 this portion of the right-hand terminus of said compound of (1.8.68) Formula (1.0.0) is represented by the following partial Formulas (3.0.1) through (3.0.40) set out below.

60 (3.0.1) (1.8.69)

65 US 7,250,518 B2 55 56

-continued -continued (3.0.2) (3.0.12) : F

F : (3.0.13) : 10 (3.0.3) F N O : (3.0.14) : d 15 (3.0.4) N : 2 (3.0.15) CH3

: n N 2 CH (3.0.5) 3 NO 25 (3.0.16) HC CH

30 NN (3.0.6) CH

(3.0.17) S. 35 (3.0.7) CF3 40 (3.0.18)

(3.0.8) 45 y (3.0.19)

50 (3.0.9) (3.0.20)

o 55 (3.0.10) * NH2 (3.0.21)

(3.0.22) (3.0.11)

65 US 7,250,518 B2 57 58

-continued -continued (3.0.23) (3.0.34) O CHF (3.0.24) A 10 (3.0.35) (3.0.25) 15 : Zy (3.0.36) (3.0.26)

: Gl 25 (3.0.37) (3.0.27)

: : H3--> 30 (3.0.28) : (3,0.38)

NwYY - 35 (3.0.29) : (3.0.39) N 40 1N n O : (3.0.30)

: 45

(3.0.4.0) C : (3.0.31) 50

(3.0.41) 55 (3.0.32) : nanN1s-1NNN211-4nan -N

: 60 (3.0.33) (3.0.42) O H

: o 65 US 7,250,518 B2 59 60 chronic bronchitis, pulmonary emphysema or dyspnea -continued associated therewith: COPD that is characterized by (3.0.43) irreversible, progressive airways obstruction; adult res piratory distress syndrome (ARDS), and exacerbation of airways hyper-reactivity consequent to other drug therapy; Ol pneumoconiosis of whatever type, etiology, or pathogen (3.0.44) esis; or pneumoconiosis that is a member selected from the group consisting of aluminosis or bauxite workers’ 10 disease; anthracosis or miners asthma, asbestosis or Oy steam-fitters asthma, chalicosis or flint disease; ptilo (3.0.45) sis caused by inhaling the dust from ostrich feathers; siderosis caused by the inhalation of iron particles; silicosis or grinders disease; byssinosis or cotton-dust 15 asthma, and talc pneumoconiosis; C O bronchitis of whatever type, etiology, or pathogenesis; or bronchitis that is a member selected from the group (3.0.46) consisting of acute bronchitis; acute laryngotracheal CHF bronchitis; arachidic bronchitis; catarrhal bronchitis; o1 2 croupus bronchitis; dry bronchitis; infectious asthmatic bronchitis; productive bronchitis; staphylococcus or streptococcal bronchitis; and vesicular bronchitis; bronchiectasis of whatever type, etiology, or pathogen esis; or bronchiectasis that is a member selected from 25 the group consisting of cylindric bronchiectasis; sac (3.0.47) culated bronchiectasis; fusiform bronchiectasis; capil lary bronchiectasis; cystic bronchiectasis; dry bron chiectasis; and follicular bronchiectasis; seasonal allergic rhinitis; or perennial allergic rhinitis; or 30 sinusitis of whatever type, etiology, or pathogenesis; or The present invention is further concerned with a method sinusitis that is a member selected from the group of treating a subject suffering from a disease or condition consisting of purulent or nonpurulent sinusitis; acute or mediated by the PDE4 isozyme in its role of regulating the chronic sinusitis; and ethmoid, frontal, maxillary, or activation and degranulation of human eosinophils, com sphenoid sinusitis; prising administering to said Subject in need of said treat 35 rheumatoid arthritis of whatever type, etiology, or patho ment a therapeutically effective amount of a compound of genesis; or rheumatoid arthritis that is a member Formula (1.0.0) as described above. Similarly, the present Selected from the group consisting of acute arthritis; invention is also concerned with a pharmaceutical compo acute gouty arthritis; chronic inflammatory arthritis; sition for use in Such a therapeutic treatment, comprising a degenerative arthritis; infectious arthritis; Lyme arthri compound of Formula (1.0.0) as described above together 40 tis; proliferative arthritis; psoriatic arthritis; and verte with a pharmaceutically acceptable carrier. bral arthritis; The present invention relates to PDE4 isozyme inhibitors gout, and fever and pain associated with inflammation; comprising a compound of Formula (1.0.0) as described an eosinophil-related disorder of whatever type, etiology, above which is useful in treating or preventing one or or pathogenesis; or an eosinophil-related disorder that members selected from the groups of diseases, disorders, 45 is a member selected from the group consisting of and conditions consisting of eosinophilia; pulmonary infiltration eosinophilia; Lof asthma of whatever type, etiology, or pathogenesis; or fler's syndrome; chronic eosinophilic pneumonia; asthma that is a member selected from the group tropical pulmonary eosinophilia; bronchopneumonic consisting of atopic asthma; non-atopic asthma, aller aspergillosis; aspergilloma; granulomas containing gic asthma, atopic, bronchial, IgE-mediated asthma, 50 eosinophils; allergic granulomatous angiitis or Churg bronchial asthma, essential asthma; true asthma; intrin Strauss syndrome; polyarteritis nodosa (PAN); and sic asthma caused by pathophysiologic disturbances; systemic necrotizing vasculitis; extrinsic asthma caused by environmental factors; atopic dermatitis; or allergic dermatitis; or allergic or essential asthma of unknown or inapparent cause; non atopic eczema: atopic asthma; bronchitic asthma, emphysematous 55 urticaria of whatever type, etiology, or pathogenesis; or asthma, exercise-induced asthma, occupational urticaria that is a member selected from the group asthma; infective asthma caused by bacterial, fungal, consisting of immune-mediated urticaria; complement protozoal, or viral infection; non-allergic asthma, mediated urticaria; urticariogenic material-induced incipient asthma, wheezy infant syndrome; urticaria; physical agent-induced urticaria; stress-in chronic or acute bronchoconstriction; chronic bronchitis; 60 duced urticaria; idiopathic urticaria; acute urticaria; Small airways obstruction; and emphysema; chronic urticaria; angioedema; cholinergic urticaria; obstructive or inflammatory airways diseases of whatever cold urticaria in the autosomal dominant form or in the type, etiology, or pathogenesis; or an obstructive or acquired form; contact urticaria; giant urticaria; and inflammatory airways disease that is a member selected papular urticaria; from the group consisting of asthma; pneumoconiosis: 65 conjunctivitis of whatever type, etiology, or pathogenesis; chronic eosinophilic pneumonia; chronic obstructive or conjunctivitis that is a member selected from the pulmonary disease (COPD); COPD that includes group consisting of actinic conjunctivitis; acute US 7,250,518 B2 61 62 catarrhal conjunctivitis; acute contagious conjunctivi consisting of depression; Parkinson's disease; learning tis; allergic conjunctivitis; atopic conjunctivitis; and memory impairment; tardive dyskinesia; drug chronic catarrhal conjunctivitis; purulent conjunctivi dependence; arteriosclerotic dementia; and dementias tis; and Vernal conjunctivitis that accompany Huntington's chorea, Wilson's disease, uveitis of whatever type, etiology, or pathogenesis; or 5 paralysis agitans, and thalamic atrophies; uveitis that is a member selected from the group infection, especially infection by viruses wherein Such consisting of inflammation of all or part of the uvea; viruses increase the production of TNF-C. in their host, anterior uveitis; iritis; cyclitis; iridocyclitis; granulo or wherein Such viruses are sensitive to upregulation of matous uveitis; nongranulomatous uveitis; phacoanti TNF-C. in their host so that their replication or other genic uveitis; posterior uveitis; choroiditis; and chori 10 vital activities are adversely impacted, including a virus oretinitis; which is a member selected from the group consisting psoriasis; of HIV-1, HIV-2, and HIV-3; cytomegalovirus, CMV: multiple Sclerosis of whatever type, etiology, or patho influenza; adenoviruses; and Herpes viruses, including genesis; or multiple Sclerosis that is a member selected Herpes Zoster and Herpes simplex: from the group consisting of primary progressive mul- 15 yeast and fungus infections wherein said yeast and fungi tiple Sclerosis; and relapsing remitting multiple Sclero are sensitive to upregulation by TNF-C. or elicit TNF-C. sis; production in their host, e.g., fungal meningitis; par autoimmune/inflammatory diseases of whatever type, eti ticularly when administered in conjunction with other ology, or pathogenesis; or an autoimmune/inflamma drugs of choice for the treatment of systemic yeast and tory disease that is a member selected from the group fungus infections, including but are not limited to, consisting of autoimmune hematological disorders; polymixins, e.g., Polymycin B; imidazoles, e.g., clot hemolytic anemia; aplastic anemia; pure red cell ane rimazole, econazole, miconazole, and ketoconazole; mia; idiopathic thrombocytopenic purpura; systemic triazoles, e.g., fluconazole and itranazole; and ampho lupus erythematosus; polychondritis; Scleroderma; tericins, e.g., Amphotericin B and liposomal Amphot Wegner's granulomatosis; dermatomyositis; chronic 25 ericin B. active hepatitis; myasthenia gravis; Stevens-Johnson ischemia-reperfusion injury; autoimmune diabetes; reti syndrome; idiopathic sprue; autoimmune inflammatory nal autoimmunity; chronic lymphocytic leukemia; HIV bowel diseases; ulcerative colitis; Crohn's disease; infections; lupus erythematosus; kidney and ureter dis endocrin opthamopathy; Grave's disease; sarcoidosis: ease; urogenital and gastrointestinal disorders; and alveolitis; chronic hypersensitivity pneumonitis; pri 30 prostate diseases. mary biliary cirrhosis; juvenile diabetes or diabetes In particular, the compounds of Formula (1.0.0) are useful mellitus type I: anterior uveitis; granulomatous or pos int the treatment of (1) inflammatory diseases and conditions terior uveitis; keratoconjunctivitis sicca, epidemic comprising: joint inflammation, rheumatoid arthritis, rheu keratoconjunctivitis; diffuse interstitial pulmonary matoid spondylitis, osteoarthritis, inflammatory bowel dis fibrosis or interstitial lung fibrosis; idiopathic pulmo 35 ease, ulcerative colitis, chronic glomerulonephritis, derma nary fibrosis; cystic fibrosis; psoriatic arthritis; glom titis, and Crohn's disease; (2) respiratory diseases and erulonephritis with and without nephrotic syndrome; conditions comprising: asthma, acute respiratory distress acute glomerulonephritis; idiopathic nephrotic Syn syndrome, chronic pulmonary inflammatory disease, bron drome; minimal change nephropathy; inflammatory/ chitis, chronic obstructive airway disease, and silicosis; (3) hyperproliferative skin diseases; psoriasis; atopic der 40 infectious diseases and conditions comprising: sepsis, septic matitis; contact dermatitis; allergic contact dermatitis; shock, endotoxic shock, gram negative sepsis, toxic shock benign familial pemphigus; pemphigus erythematosus; syndrome, fever and myalgias due to bacterial, viral or pemphigus foliaceus; and pemphigus Vulgaris; fungal infection, and influenza; (4) immune diseases and prevention of allogeneic graft rejection following organ conditions comprising: autoimmune diabetes, systemic transplantation; 45 lupus erythematosis, graft vs. host reaction, allograft rejec inflammatory bowel disease (IBD) of whatever type, tions, multiple Sclerosis, psoriasis, and allergic rhinitis; and etiology, or pathogenesis; or inflammatory bowel dis (5) other diseases and conditions comprising: bone resorp ease that is a member selected from the group consist tion diseases; reperfusion injury: cachexia secondary to ing of ulcerative colitis (UC); collagenous colitis; coli infection or malignancy; cachexia secondary to human tis polyposa; transmural colitis; and Crohn's disease 50 acquired immune deficiency syndrome (AIDS), human (CD); immunodeficiency virus (HIV) infection, or AIDS related septic shock of whatever type, etiology, or pathogenesis; complex (ARC), keloid formation; Scar tissue formation; or septic shock that is a member selected from the type 1 diabetes mellitus; and leukemia. group consisting of renal failure; acute renal failure; The present invention still further relates to the combi cachexia; malarial cachexia; hypophysial cachexia; 55 nation of a compound of Formula (1.0.0) together with one uremic cachexia; cardiac cachexia; cachexia Suprarena or more members selected from the group consisting of the lis or Addison's disease; cancerous cachexia; and following: (a) leukotriene biosynthesis inhibitors: 5-lipoxy cachexia as a consequence of infection by the human genase (5-LO) inhibitors and 5-lipoxygenase activating pro immunodeficiency virus (HIV); tein (FLAP) antagonists selected from the group consisting liver injury; 60 of zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175: pulmonary hypertension; and hypoxia-induced pulmo Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfona nary hypertension; mides of Formula (5.2.8); 2,6-di-tert-butylphenol hydra bone loss diseases; primary osteoporosis. and secondary Zones of Formula (5.2.10); the class of methoxytetrahydro osteoporosis: pyrans which includes Zeneca ZD-2138 of Formula central nervous system disorders of whatever type, etiol 65 (5.2.11); the compound SB-210661 of Formula (5.2.12) and ogy, or pathogenesis; or a central nervous system the class to which it belongs; the class of pyridinyl-substi disorder that is a member selected from the group tuted 2-cyanonaphthalene compounds to which L-739,010 US 7,250,518 B2 63 64 belongs; the class of 2-cyanoquinoline compounds to which nase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 L-746,530 belongs; the classes of indole and quinoline (MMP-10), and stromelysin-3 (MMP-11); (pp) transforming compounds to which MK-591, MK-886, and BAY x 1005 growth factor (TGFB); (qq) platelet-derived growth factor belong; (b) receptor antagonists for leukotrienes LTB, (PDGF); (rr) fibroblast growth factor, e.g., basic fibroblast LTC LTD, and LTE selected from the group consisting of growth factor (bFGF), (SS) granulocyte macrophage colony the phenothiazin-3-one class of compounds to which L-651, 392 belongs; the class of amidino compounds to which stimulating factor (GM-CSF); (tt) capsaicin cream; (uu) CGS-25019c belongs; the class of benzoxaolamines to Tachykinin NK and NK receptor antagonists selected from which ontaZolast belongs; the class of benzenecarboximi the group consisting of NKP-608C; SB-233412 (talnetant); damides to which BIIL 284/260 belongs; and the classes of 10 and D-4418; and (VV) elastase inhibitors selected from the compounds to which Zafirlukast, ablukast, montelukast, group consisting of UT-77 and ZD-0892. pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAYX 7195 belong; (c) PDE4 DETAILED DESCRIPTION OF THE inhibitors; (d) 5-Lipoxygenase (5-LO) inhibitors; or 5-li INVENTION poxygenase activating protein (FLAP) antagonists; (e) dual 15 inhibitors of 5-lipoxygenase (5-LO) and antagonists of platelet activating factor (PAF), (f) leukotriene antagonists 5.0 Compounds (LTRAS) including antagonists of LTB, LTC, LTD, and The present invention is concerned with novel compounds LTE, (g) antihistaminic H receptor antagonists including which may be represented by Formula (1.0.0) as follows: cetirizine, loratadine, desloratadine, fexofenadine, astemi Zole, azelastine, and chlorpheniramine; (h) gastroprotective He receptor antagonists: (i) C- and C2-adrenoceptor agonist vasoconstrictor sympathomimetic agents administered (1.0.0) orally or topically for decongestant use, including propyl hexedrine, phenylephrine, phenylpropanolamine, pseu 25 doephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, Xylometazo line hydrochloride, and ethylnorepinephrine hydrochloride: l

(i) C- and C2-adrenoceptor agonists in combination with inhibitors of 5-lipoxygenase (5-LO); (k) anticholinergic 30 agents including ipratropium bromide, tiotropium bromide; (O) oxitropium bromide: pirenzepine; and telenzepine: (1) B- to fa-adrenoceptor agonists including metaproterenol, isopro terenol, isoprenaline, albuterol, salbutamol, formoterol, sal meterol, terbutaline, orciprenaline, bitolterol mesylate, and 35 pirbuterol; (m) methylxanthanines including theophylline The broadest scope of the compounds of the present and aminophylline; (n) sodium cromoglycate; (o) muscar invention is circumscribed above under Section 4.0 relating inic receptor (M1, M2, and M3) antagonists; (p) COX-1 to the Summary of the Invention. A further description of inhibitors (NSAIDs); COX-2 selective inhibitors including said compounds is provided hereafter in terms of a range of rofecoxib; and nitric oxide NSAIDs; (q) insulin-like growth 40 different types and groups of embodiments, as well as factor type I (IGF-1) mimetics; (r) ciclesonide: (s) inhaled specific embodiments which characterize and exemplify the glucocorticoids with reduced systemic side effects, includ compounds of Formula (1.0.0). Preferred and more pre ing prednisone, prednisolone, flunisolide, triamcinolone ferred embodiments of said compounds are also set forth, acetonide, beclomethasone dipropionate, budesonide, fluti but it will be understood that the recital of such preferences casone propionate, and mometaSone furoate; (t) tryptase 45 inhibitors; (u) platelet activating factor (PAF) antagonists; is in no way intended to, and does not limit the scope of the (v) monoclonal antibodies active against endogenous present invention with regard to said compounds. inflammatory entities; (w) IPL 576; (x) anti-tumor necrosis One significant component of the embodiments of the factor (TNFC) agents including Etanercept, Infliximab, and compounds of Formula (1.0.0) is the terminal moiety A, one D2E7: (y) DMARDs including Leflunomide: (Z) TCR pep 50 of the meanings of which is that of a member selected from tides: (aa) interleukin converting enzyme (ICE) inhibitors: a group of phosphorous and Sulfur acid side chains, and (bb) IMPDH inhibitors; (cc) adhesion molecule inhibitors derivatives thereof, e.g., phosphoric, phosphinic, phospho including VLA-4 antagonists; (dd) cathepsins; (ee) MAP nic, phosphoramido, Sulfuric, Sulfonic, and Sulfonamido kinase inhibitors, (f) glucose-6 phosphate dehydrogenase forms thereof. These meanings of A are defined in detail inhibitors; (gg) kinin-B- and B-receptor antagonists; (hh) 55 gold in the form of an aurothio group together with various above. hydrophilic groups; (ii) immunosuppressive agents, e.g., The other meaning of the terminal moiety A set forth in cyclosporine, azathioprine, and methotrexate; (ii) anti-gout detail above is that of a member independently selected from agents, e.g., colchicine; (kk) Xanthine oxidase inhibitors, the group consisting of partial Formulas (1.1.1) through e.g., allopurinol; (Il) uricosuric agents, e.g., probenecid, 60 (1.1.5): Sulfinpyrazone, and benzbromarone; (mm) antineoplastic agents, especially antimitotic drugs including the Vinca alkaloids Such as vinblastine and Vincristine; (nn) growth (1.1.1) hormone secretagogues; (oo) inhibitors of matrix metallo proteases (MMPs), i.e., the stromelysins, the collagenases, 65 and the gelatinases, as well as aggrecanase; especially us 1 collagenase-1 (MMP-1), collagenase-2 (MMP-8), collage US 7,250,518 B2 65 66 R" and R7 are - H or -CH; or R' is - F - C1, CF, -continued CN, OCH, NO, C(=O)CR', NR'R'7, or (1.1.2) S(=O)?NR'R'7 where R'' and R7 are H or CH: O O {} {} R is - H or -CH; () () W is -O-, () () Y is =C(R)-; () () R' is -H, or F: or () () R' and Rare usul independently —H or —CH; or R' and R are taken together to form a —(C-C7)cycloalkyl-spiro moiety; () () (1.1.3) one of R and RP is H and the other is —H or —CH: O () () R' and R are -H, -F, or - OCH; ) {} R is H 10 or -CH; and () () R, R and Rare - H provided that R R7 and R are not both – H at the same time, F, Cl, --- OCH, CN: NO, or C(=O)R or C(=O)CR where R is —CH; or Rand Rare taken together to form (1.1.4) a moiety of partial Formula (1.3.1), (1.3.2), 1.3.3), (1.3.11), 15 (1.3.12), or (1.3.15). (ii) Preferred embodiments of the type described in the paragraph immediately above are those wherein R is H: R is —H; R and Rare both —CH, or taken together are a cyclopropyl-spiro moiety; R and RP are both —H; R is (1.1.5) -H; R is —H: R is -H, -F, - C1, CN, OCH, O f —C(=O)CH, or - NO; R is -H, provided that R and Rare not both – H at the same time, or —F; or Rand R' us (C) are taken together to form a moiety of partial Formula : o1 Yw3 (1.3.1), or partial Formula (1.3.11) where R and R are H 25 both absent. (iii) Further embodiments of the present invention include a compound of Formula (1.0.0) wherein B and B are where 66: indicates the point of attachment of each partial independently phenyl or pyridyl: m is 1: () () n is 1: () () Formula (1.1.1) through (1.1.5) to the remaining portion of A is a moiety of partial Formula (1.1.3) where R is -H, or Formula (1.0.0). 30 —CH or phenyl independently substituted by 0 or 1 R' The substituents R. R. and R of the above enumerated where R' is pyridyl or phenyl substituted by 0-2 of F, partial Formulas, as well as their sub-substituents R', R', C1, OCH CN, NO, or NR'R'' where R'' and R", R. R. R'7, R', and R', are defined above and R7 are - H or -CH; or R' is - F - C1, CF –CN, provide a clear delineation of the intended scope of the OCH, NO, C(=O)CR', NR'R'', or compounds of the present invention. Particular embodi 35 - S(=O)NR'R'7 where R and R7 are H or CH: ments within said scope comprise particular meanings of the {} {} R is - H or -CH; () () W is -O-, () () Y is substituents R. R. and R, as well as of the other substitu =C(R)-; () () R' is -H; or F: () () R' and R are ents that form a part of Formula (1.0.0). Said embodiments independently —H or —CH; or R' and R are taken include, but are not limited to those set forth in paragraphs together to form a —(C-C)cycloalkyl-spiro moiety; () () 40 one of R and RP is —H and the other is —H or —CH: (i) through (vi) further below. () () R' and Rare -H, -F, or - OCH; ) {} R is H In order to assist the person of ordinary skill in consid or -CH; and () () R, R and Rare - H provided that R ering the scope and extent of the description of the present and R are not both – H at the same time, F, Cl, invention set forth hereafter, certain terms and expressions OCH, CN: NO, or C(=O)R or C(=O)CR used herein are defined in the paragraphs immediately 45 where R is —CH; or Rand Rare taken together to form below. a moiety of partial Formula (1.3.1), (1.3.2), (1.3.3), (1.3.11), As used herein, the expressions “—(C-C)alkyl. (1.3.12), or (1.3.15), where for partial Formulas (1.3.11), “—(C-C)alkyl, and “ (C-C)alkyl, are intended to (1.3.12), and (1.3.13), R and Rare both absent. include branched as well as Straight chain conformations of (iv) Preferred embodiments of the type described in the these aliphatic groups. Thus, the above-quoted expressions 50 paragraph immediately above are those wherein R is H: include, in addition to the straight chain entities methyl, R is H; R and R are taken together to form a cyclo ethyl, n-propyl. n-butyl, n-pentyl, and n-hexyl, the branched propyl-spiro or cyclobutyl-spiro moiety; R and Rare both chain entities iso-propyl, isobutyl, sec-butyl, tert-butyl, iso -H; R is H: R* and Rare both -H, and R is F; or pentane (2-methylbutane), 2-methylpentane, 3-methylpen R and R are taken together to form a moiety of partial tane, 1-ethylpropane, and 1-ethylbutane. The meanings of 55 Formula (1.3.1) or (1.3.11). the above-quoted expressions are also intended to apply to (v) Still further embodiments of the present invention said expressions whether or not they are substituted. Thus, comprise a compound of Formula (1.0.0) wherein B' and B2 the expression “fluorinated-(C-C)alkyl is intended to are independently phenyl or pyridyl, m is 1: () () n is 1: encompass the various fluorinated species of the n-propyl () () A is a moiety of partial Formula (1.1.4) where V is 0 and iso-propyl aliphatic groups. 60 or 1, and R is tetrazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol (i) Embodiments of the present invention include those 3-on-5-yl, 1,2,3-triazol-5-yl, imidazol-2-yl, imidazol-4-yl, that are a compound of Formula (1.0.0) wherein B' and Bf imidazolidin-3-on-4-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadia are independently phenyl or pyridyl, m is 1: () () n is 1: Zol-5-on-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-on-5- () () A is a moiety of partial Formula (1.1.1) where R is yl, 1,3,4-oxadiazolyl, 1,3,4-oxadiazol-2-on-5-yl, oxazolyl, —H, or —CH or phenyl independently substituted by 0 or 65 isoxazolyl pyrrolyl pyrazolyl. Succinimidyl, glutarimidyl, 1 R' where R' is phenyl or pyridyl substituted by 0-2 of pyrrolidonyl, 2-piperidonyl, 2-pyridonyl, 4-pyridonyl, —F. - C1, OCH –CN, NO, or - NR'R'7 where pyridazin-3-onyl, thiadiazolyl, parathiazinyl, pyridyl, pyri US 7,250,518 B2 67 68 midinyl, pyrazinyl, or pyridazinyl, all of which are indepen However, it is preferred that the R', substituent of the dently substituted by 0 or 1 R' where R' is —(C-C)alkyl, =C(R') moiety have the meaning of H; —F; Cl; phenyl, or pyridyl, each of which is independently Substi —CHs: —OCHs; or -(C-C)alkynyl; more preferably R', tuted by 0-2 of —F. —Cl, —OCH, —CN, NO, or is —F or —H. NR'R'7 where R' and R7 are H or CH or R' is 5 It will be noted that R has several substituent definitions, F. —Cl, —CF, —CN, OCH —NO, or —C(=O) especially —F, in common with those for the R' and R' OR, NR'R'', or S(=O)NR'R'7 where R and substituents on the B moiety. In the embodiments of the Rare-H or -CH; () () Ris-H or -CH; () () W is compounds of Formula (1.0.0) where Y is =C(R')—, and -O-, () () Y is =C(R)-; () () R' is -H; or - F; both the B' moiety and the B moiety have the preferred () () R' and Rare independently - Hor—CH; or R and 10 meaning of phenyl, the Substituents at the 5-position of the R” are taken together to form a —(C-C,)cycloalkyl-spiro nicotinamide core nucleus and at the 2'-position, of the moiety; () () one of R and RP is —H and the other is —H benzyl group attached to the amide portion thereof, are or —CH; () () R' and Rare -H, -F, or —OCH; ) {} selected from the same group of definitions, although on an R is - H or -CH; and () () R, R and R are H independent basis. The embodiments of the present inven provided that Rand Rare not both - H at the same time, 15 tion wherein such substituents are involved, and where j is F, - C1, OCH, CN, NO, or C(=O)R’ or 1, k is 0, n is 1, both R and RP are -H, and Y is —C(=O)CR where R is —CH; or R and R are taken =C(R') , may be illustrated by generic Formula (1.0.2a) together to form a moiety of partial Formula (1.3.1), (1.3.2), and sub-generic Formula (1.0.2b) as follows: (1.3.3), (1.3.11), (1.3.12), or (1.3.15). (vi) Preferred embodiments of the type described in the paragraph immediately above are those wherein v is 0, R is (1.0.2a) tetrazol-5-yl, 1,2,3-triazol-5-yl, or pyridyl; R and RP are both - H: R is H: R* and Rare both -H, and R is F; or R and Rare taken together to form a moiety of partial Formula (1.3.1) or (1.3.11). 25 A portion of the core nucleus of the compounds of Formula (1.0.0) is that of a nicotinamide of Formula (1.0.1):

(1.0.1) 30 (1.0.2b) Y | 35 N -

derived from nicotinic acid. This portion of the core nucleus 40 is then elaborated by defining the Y moiety as being =C(R')—, or —N->(O), where k is 0 or 1, and where the symbol->(O) indicates a nitrogen heteroatom in the form of its N-oxide when k is 1. It should be noted that in the N-containing heterocyclyl moieties which define R, it is 45 provided that optionally one or more of the N-heteroatoms comprising said heterocyclyl moieties may be in the form of In such embodiments of the present invention, the 5-po the N-oxide of said N-heteroatoms. Accordingly, the con sition (R') and 2'-position (R') substituents serve the same siderations concerning N-oxides just described also apply to function of modulating the properties of the overall com Such N-oxide-containing moieties defining R. 50 pound of Formula (1.0.0) with respect to its pharmacological Where Y has the meaning of —N->(O) — the com and pharmacokinetic properties such as potency, Substrate pounds of the present invention are pyrimidines. The pyri specificity (selectivity), and physico-chemical properties. In midine group of compounds of Formula (1.0.0) is a signifi preferred embodiments of the compounds of the present cant part of the scope of the present invention. It is preferred, invention of this type, both the R' and R', substituents will nevertheless, that the compounds of Formula (1.0.0) have 55 have the same meaning, which will be —H or —F. the Y moiety defined as =C(R)— where the substituent R1 is selected independently from the other substituents that 5.1 Linkage (W) and the R* , R , and R-Substituted form the compounds of Formula (1.0.0). Moiety B' In addition to H. R', of the =C(R')— moiety is The nicotinamide core nucleus is further elaborated by defined as a member selected from the group consisting of 60 allowing the 2-carbon atom in the pyridyl or pyrimidinyl —F. —Cl; —CN; —NO; —(C-C)alkyl; —(C-C)alky ring of the nucleus of Formula (1.0.1) to form a linkage to nyl; fluorinated-(C-C)alkyl; fluorinated-(C-C)alkoxy: a ring comprising the moiety B'. In preferred embodiments, OR'; and C(=O)NR'R'': where R', and R', are the moiety B' has the meaning of a phenyl ring which is each independently —H. —CH; —CH2CH: para-substituted by a moiety R', meta-substituted by a —CH2CH2CH; —CH2(CH), —CH2CH2CHCH; —CH 65 moiety R. or substituted on any of the remaining positions (CH)CHCH; —CHCH(CH), —C(CH), cyclopropyl; by a moiety R', resulting in a moiety of partial Formula cyclobutyl; or cyclopenty1. (1.0.3): US 7,250,518 B2 70 quickly and facilely synthesizing a very large number of chemically very similar compounds based on the Substituent

(1.0.3) choices outlined above, and of thereafter testing the relative effectiveness of the resulting molecules in rapid in vitro testing methods. Combinatorial chemistry synthesis and testing procedures currently available in the art have even more considerably expanded the number of substituent combinations which can be rapidly evaluated. The informa 10 tion which has thereby been produced through use of these techniques permits a reasonable prediction herein of certain preferences which exist as to various embodiments of the present invention. Such preferred embodiments are described in detail herein. 15 Preferred embodiments of the present invention further include those wherein both Rand Rare both —F; wherein where W has the meaning —O : —S(=O), , where t is R is – H and R is F; and wherein R is – H and R is 0, 1, or 2; or N(R)— where R is H; —(C-C)alkyl: —F. -OR', e.g., OCH –OCHF, —OCHF, or phenyl; benzyl; or —OR'; and is preferably —H or —CH. OCF, CN; COOH: COOCH; CONH; In other embodiments of the present invention, W has the —OCOCH; or NH. The most preferred embodiments are meaning —S(=O), , where t is 0, 1, or 2; and preferably those wherein Ris-H and R is F; R is –CN and R' has the meaning —S - whereby a thioether linkage is is —H; and R is NO, CN, OCH, or—C(=O)CH, formed. Where the sulfur atom of the thioether linkage is and R is H. oxygenated, a Sulfinyl or a Sulfonyl linkage results. In still 25 further embodiments, where W has the meaning of R and R may also be selected from substituents com —N(R)—, an amino linkage is formed, which preferably prising —(C-C)alkyl and —(C-C)alkoxy wherein said will be —NH-. Nevertheless, the nitrogen atom may be alkyl and alkoxy are substituted with 0 to 3 substituents —F substituted and where this is the case, it is preferred that said or —Cl; or 0 or 1 substituent (C-C)alkoxycarbonyl-: substituent be —CH. 30 (C-C)alkylcarbonyl-, or (C-C)alkylcarbonyloxy-. The meanings of the R, R and R substituents are selected from the same set of definitions, but it will be 5.2.0 B' is Phenyl and R and Rare Taken Together understood that said meanings are selected on an indepen Where the moiety B has the preferred meaning of a dent basis from each other. R and R may also be —H phenyl ring, R and R may also be taken together to form provided that they are not both —H at the same time. 35 Accordingly, where the moiety B' has the meaning of a a moiety which is a member selected from the group phenyl ring, the para-(R), meta-(R), or ortho-(R)-position consisting of partial Formulas (1.3.1) through (1.3.15): of the phenyl ring may be substituted, or all three positions may be substituted, or any combination of said positions may be substituted. It is preferred, however, in the com 40 (1.3.1) pounds of Formula (1.0.0) that the para- and/or meta positions be substituted, rather than the ortho-position. Where the moiety B' has the preferred meaning of a phenyl ring, R and R may also be taken together to form 4; R21 a member selected from a group of partial formulas 45 described in more detail further below. Some of these meanings of R and R taken together also constitute pre (1.3.2) ferred embodiments of the compounds of Formula (1.0.0) R and R may be —H provided that both are not – H at the same time; accordingly, a Substituent will always be 50 present at one or both of the positions occupied by R and O R21 R. In addition to H. R and R may, inter alia, be —F; R20 Cl; CN; NO: C(=O)R’; OR: C(=O) (1.3.3.) OR: or NR'R'7. Where R is H and R is F, preferred embodiments of the present invention result. In a 55 further preferred embodiment of the present invention, R .*. and R may also be —OR', where R' is hydrogen; (C- R21 C.)alkyl, or (C-C)cycloalkyl, wherein said alkyl and A O cycloalkyl are substituted by 0 to 3 substituents selected from the group consisting of —F and —Cl. Other preferred 60 (1.34) embodiments are those wherein R' is methyl; difluorom ethyl; ethyl; or cyclopentyl. O The medicinal chemist will appreciate that the choice of substituents from those described above will be influenced R2 by the effect which such substituents have in turn on the 65 s physico-chemical properties of the overall molecules which R20 result. The present state of the art provides the capability of US 7,250,518 B2 71 72

-continued -continued (1.3.5) (1.3.14) - w N1 R23 2 N A. AirR20 R24 O (1.3.15) 10

(1.3.6)

15 R2 O

wherein R' and R'' are each a member independently selected from the group consisting of —H; —F. —Cl; (1.3.7) CH; —CHF: —CHF: CF; —OCH; and —OCF; and R and R are each independently —H; —CH: —OCH; —CHCH; —OCHCH. —CHCHCH: —CH2(CH), —CH2CHCHCH; —CH(CH)CHCH: R 25 —CH-CH(CH), —C(CH); or absent, in which case the HO R20 2OHO dashed line ---- represents a double bond. For the moiety of (1.3.8) partial Formula (1.3.13) the nitrogen atom components thereof are represented as —N(->O)—and thus comprise optional nitrogen oxide forms of said nitrogen atoms, 30 selected independently of each other. It will be appreciated 2 that said nitrogen oxide form may also be represented as Mr.HO R20 —N(->O),— where j is 0 or 1, as in Formula (1.0.0). (1.3.9) Where the moiety B has the preferred meaning of a 35 phenyl ring, and where RandR are taken together to form O the moiety of partial Formula (1.3.1) and R'' and R are both hydrogen, there is formed together with the phenyl R21 group to which it is attached, a 1,3-benzodioxole group. Analogously, the structure of partial Formula (1.3.2) forms O R20 40 a 1,4-benzodioxan group. (1.3.10) Where the moiety B' has the preferred meaning of a OH phenyl ring, and where RandR are taken together to form the moieties of partial Formulas (1.3.9) through (1.3.13) and R21 R° and Rare as defined, benzofurazan, triazole and other 45 analogous groups, as well as Substituted derivatives thereof O R20 are formed, including, inter alia, the following moieties of (1.3.11) partial Formulas: (2.1.1) through (2.1.20):

Y R2 N r 4. 50 (2.1.1) R24 - (1.3.12) WN-O 55 (2.1.2) Y R2 N r S R24 60 (1.3.13) (2.1.3)

65 US 7,250,518 B2 73 74

-continued -continued (2.1.14) ... (2.1.4) - N-S

(2.1.15) (2.1.5) 10 -- CH3 / HC-N-N N S H 15 (2.1.16) (2.1.6)

(2.1.17) (2.1.7) 25

(2.1.8) (2.1.18) 30

(2.1.9) 35 (2.1.19)

40 (2.1.10)

(2.1.20) 45

(2.1.11)

(2.1.12) wherein the dashed line ---- in partial Formulas (2.1.18), 55 (2.1.19), and (2.1.20) represents a double bond where no oxygen atom is attached to the corresponding nitrogen atom, and represents a single bond where an oxygen atom is attached to said corresponding nitrogen atom. The artisan of ordinary skill in the preparation of organic (2.1.13) 60 molecules will appreciate that the compounds of Formula (1.0.0) wherein R and R are taken together to form moi eties of the above-illustrated partial Formulas (2.1.2). (2.1.3), (2.1.7), (2.1.8), (2.1.10), (2.1.12), and (2.1.14) exist 65 in tautomeric form, and each moiety of said partial Formulas (2.1.2), (2.1.3), (2.1.7), (2.1.8), (2.1.10), (2.1.12), and (2.1.14) has a tautomer counterpart. These tautomers are US 7,250,518 B2 75 76 related by the shift of a hydrogen and one or more L-bonds, and whenever necessary, the skilled artisan will be able to -continued (1.0.16) readily discern or determine which tautomeric form is O present or is the most stable. Preferred embodiments of the present invention result directly from the definition of RandR as taken together to ---, form a moiety which is a member selected from the group 2 CrsN W consisting of partial Formulas (1.3.1), (1.3.11), (1.3.12), and (1.3.15): 10

(1.3.1) Y. 15 (1.0.17) O

R20 1N ’, 2 CrsN W (1.3.11) S-R23 / 25 - O M R24 N-yY.

30 (1.0.18) (1.3.12) O 23 1N %. 'W --/ N-S 35 2 A CrsN W R24

40 (1.3.15) NY. Yes -o where R is —H or —CH; and W has the meaning of N-N 45 —O ; S(=O), where t is 0, 1, or 2; or N(R)— / Yes where R is as defined herein and is preferably —H or (O) —CH. In preferred compounds of Formula (1.0.0), W has the meaning of —O— whereby an ether linkage is created Accordingly, there further results moieties of partial For 50 to attach the benzo-fused, bicyclic heterocycle to the nico mulas (1.0.15) through (1.0.18): tinamide core nucleus. In preferred embodiments of the compounds of Formula (1.0.0), R and Rare both absent, except in compounds of the type illustrated by partial Formula (1.3.11), where only (1.0.15) one of R or R* may be absent. It will be recognized that 55 where R and Rare both absent, and the dashed lines: --- accordingly represent double bonds, that the phenyl portion of the resulting benzo-fused bicyclic heterocycles depicted cannot have all of the double bonds depicted in said partial Formulas, since the result would be prohibited pentavalent 60 carbon atoms in said phenyl portion. Accordingly, where R and R are both absent, the resulting compounds are characterized by Such structures as those shown in partial Formulas (1.0.16) and (1.0.17) above. In other embodiments of the compounds of Formula 65 (1.0.0) the substituents R'' and R on the benzo-fused, bicyclic heterocycles represented by partial Formula (1.3.1) are —H. —F. —Cl, —CH, -CHF, —CHF, or —CF. US 7,250,518 B2 77 78 Preferably, R' and R are both -H or –F, in which case the resulting compounds are characterized by the structure -continued (1.8.2) shown in partial Formula (1.0.15) above, or its correspond : ing difluoro analog (not shown). The substituents R* and R on the benzo-fused, bicyclic heterocycles represented by 5 the moieties of partial Formulas (1.3.9) through (1.3.13) are each independently —H; —CH; —OCH; or absent in which case the dashed line ---- represents a double bond. It will be understood, of course, that where R and R* are 10 C.F absent; there are no pentavalent carbon atoms in the phenyl portion of said benzo-fused, bicyclic heterocyles. The result ing benzo-fused, bicyclic heterocyclic structures are shown (1.8.3) in partial Formulas (1.0.15) through (1.0.18) above. 15 5.2.1 B' is other than Phenyl In addition to those embodiments of the present invention where B has the preferrred meaning of phenyl, the present invention has also been defined above as being concerned with a compound of Formula (1.0.0) wherein B has the meaning defined above as a moiety comprising a saturated or unsaturated carbon ring system that is 3- to 7-membered (1.8.4) monocyclic, or that is 7- to 12-membered, fused or discon tinuous, polycyclic; wherein optionally one carbon atom 25 thereof may be replaced by a heteroatom selected from N, O, or S, and where N is selected, optionally a second carbon atom thereof may be replaced by a heteroatom selected from N, O, or S. The present invention is further concerned with (1.8.5) a compound of Formula (1.0.0) wherein B comprises espe 30 cially a member selected from the group consisting of phenyl; pyrrolyl; pyrrolidinyl; furanyl; thienyl; pyridyl; pyrimidinyl; piperidinyl; piperazinyl; imidazolyl; imidazo lidinyl, oxazolyl; isoxazolyl; morpholinyl; thiazolyl; 35 indolyl; quinolinyl; isoquinolinyl; benzimidazolyl; benzox (1.8.6) azolyl; quinuclidinyl; and azabicyclo3.3.0 octanyl; a mono cyclic —(C-C7)cycloalkyl moiety; a monocyclic —(Cs-C7) cycloalkenyl moiety that is a member selected from the group consisting of cyclopentenyl, cyclohexenyl, and cyclo 40 heptenyl; and a bicyclic —(C7-Co)cycloalkyl or —(C7-Co) cycloalkenyl moiety that is a member selected from the C group consisting of norbornanyl, norbornenyl, bicyclo[2.2 (1.8.7) .2]octanyl, bicyclo[3.2.1]octanyl, bicyclo3.3.0 octanyl, 45 bicyclo[2.2.2]oct-5-enyl, bicyclo[2.2.2]oct-7-enyl, bicyclo 3.3.1 nonanyl, cyclodecanyl, and adamantanyl. The present invention is still further concerned especially with a compound of Formula (1.0.0) wherein particularly B' and the substituents R. R. and R are selected in such a 50 way that the left-hand terminus of said compound of For (1.8.8) mula (1.0.0) is represented by the following partial Formulas : (1.8.1) through (1.8.72): 55

(1.8.1)

60 (1.8.9)

65 US 7,250,518 B2 79 80

-continued -continued (1.8.10) : (1.8.18) :

O y CF 10 N (1.8.11)

(1.8.19)

(1.8.12) N W N H (1.8.20)

CH 25

N (1.8.13) C.W 30 V CH3 (1.8.21)

(1.8.14) (1.8.22) 40

(1.8.15) (1.8.23)

(1.8.24) (1.8.1.6) 55

(1.8.17) 60 C. (1.8.25)

65 CH3 US 7,250,518 B2 81 82

-continued -continued (1.8.26) (1.8.35)

(1.8.36) (1.8.27) 10

(1.8.37) 15 (1.8.28)

(1.8.29) H3C (1.8.38) 25 :

O ( 1.8.30 30 NCH, O (1.8.39) : S

35 (1.8.31) (1.8.40)

40 (1.841)

(1.8.32) 45 (1.842)

(1.843) 50

(1.8.33) (1.8.44) 55

(1.8.34) 60 (1.845)

65 US 7,250,518 B2 83 84

-continued -continued (1.8.46) : (1.8.57)

: (1.8.47) (1.8.58) 10 :

) N YCH, O (1.8.48) 15 : Out (1.8.59) (1.8.49) 20 : (1.8.60)

At : 25 OlCH3 (1.8.50) : (1.8.61)

CH : o1 3 (1.8.51) (1.8.6.2)

: I 35 : lCH3 (1.8.52) O : 40 (1.8.63)

(1.8.53) : 45 Š (1.8.64) : N n (1.8.54) 50 21

: F F (1.8.65) (1.8.55) 55 NN G 2 60 NO (1.8.56) (1.8.66) -ch : N pi, a COXN US 7,250,518 B2 85 86 nyl, a benzyl group which is substituted by substituents R' -continued and R. Preferably, only a single substituent, R' or R is (1.8.67) present, the single substituent R' or R is in the 2'-position, and the benzyl group is substituted in the 4-position by the moiety containing the substituents R. R. and A. This preferred right-hand-side of the compound of Formula OS9 (O (1.0.0) may be represented by Formula (1.0.4): CH3 10

(1.0.4) (1.8.68) : O

X 15 FC N

(1.8.69) F 5.3.0 B is Phenyl Substituted by R' and R' The R' and R substituents are each a member indepen dently selected from the group consisting of H; —F. —Cl; O (C-C)alkyl; fluorinated- and/or chlorinated-(C-C)alkyl: 25 fluorinated- and/or chlorinated-(C-C)alkoxy; (C-C)alky (1.8.70) nyl: –CN: NO: OR; and C(=O)NH2. Where R' : O and/or R is —H, there will be no substituent at any position, especially the 2-position of the phenyl group, attached to the X 30 remainder of the left-hand side of the molecule of Formula FC N (1.0.0). Such embodiments are not as preferred as those compounds of the present invention which have a substitu ent, especially one at the 2-position of the phenyl group. (1.8.71) : N Thus, in some preferred embodiments of the compounds of 35 the present invention, the meaning of R' and R is defined as —H; —Cl; —F; chlorinated- and/or fluorinated-(C-C) OH alkyl, chlorinated- and/or fluorinated-(C-C)alkoxy; or (C- (1.8.72) C.)alkynyl. It is preferred to have a halogen group at the point of the 40 CH3 molecule occupied by the R' or R substituent, since it usually results in improved inhibitory activity. It is contem plated to be within the scope of the present invention that R' O or R is a small lipophilic group comprising —Cl or —F; 45 chlorinated- and/or fluorinated-(C-C)alkyl; or chlorinated The character of the nicotinamide nucleus with an ether, and/or fluorinated-(C-C)alkoxy. Thus, the meaning of the thioether or Sulfonyl linkage to a Substituted phenyl group, R' or R substituent, as well as of any other substituent of a which forms the left-hand-side of the compound of Formula compound of Formula (1.0.0) that includes the definitions (1.0.0), has been discussed above. The right-hand-side of the —C1 or —F; chlorinated- and/or fluorinated-(C-C)alkyl: compound of Formula (1.0.0) comprises, in preferred or chlorinated- and/or fluorinated-(C-C)alkoxy, is selected embodiments where B has the preferrred meaning of phe from the group consisting of the following: US 7,250,518 B2 87 88 The selectivity of the overall molecule which is achieved by utilizing a moiety of this type as the R' and R substituent -continued may be due to the conformational alignment of the lipophilic (3.0.3) moiety with a corresponding lipophilic Zone in the PDE4 isozyme Substrate, or it may be due to the change in the lipophilicity of the overall molecule which results. Whatever the actual mechanism by which Such selectivity is achieved, all such embodiments are contemplated to be within the Scope of the present invention. 10 (3.0.4) 5.3.1 B is Other than Phenyl Y SaS1F N Nn. The present invention has also been defined above as being concerned with a compound of Formula (1.0.0) wherein B has the meaning defined above as a moiety 15 comprising a saturated or unsaturated carbon ring system that is 3- to 7-membered monocyclic, or that is 7- to 12-membered, fused or discontinuous, polycyclic; wherein (3.0.5) optionally one carbon atom thereof may be replaced by a NO 2 heteroatom selected from N, O, or S, and where N is selected, optionally a second carbon atom thereof may be replaced by a heteroatom selected from N, O, or S. The present invention is further concerned with a compound of o Formula (1.0.0) wherein B comprises especially a member 25 (3.0.6) selected from the group consisting of phenyl; pyrrolyl, 1. C H3 pyrrolidinyl; furanyl; thienyl; pyridyl; pyrimidinyl; piperidi O nyl; piperazinyl; imidazolyl; imidazolidinyl, oxazolyl; isox : azolyl; thiazolyl; indolyl; quinolinyl; isoquinolinyl; benz imidazolyl; benzoxazolyl; morpholinyl; quinuclidinyl; and 30 azabicyclo3.3.0 octanyl; a monocyclic —(C-C)cy cloalkyl moiety; a monocyclic —(Cs-C7)cycloalkenyl moi (3.0.7) ety that is a member selected from the group consisting of : cyclopentenyl, cyclohexenyl, and cycloheptenyl; and a bicy 35 clic —(C7-Co)cycloalkyl or —(C7-Co)cycloalkenyl moi ety that is a member selected from the group consisting of norbornanyl, norbornenyl, bicyclo2.2.2]octanyl, bicyclo 3.2.1]octanyl, bicyclo[3.3.0 octanyl, bicyclo[2.2.2]oct-5- (3.0.8) enyl, bicyclo2 .2.2]oct-7-enyl, bicyclo[3.3.1 nonanyl, 40 cyclodecanyl, and adamantanyl. The present invention is also further concerned especially with a compound of Formula (1.0.0) wherein particularly B : and the substituents R' and Rare selected in such a way that 45 this portion of the right-hand terminus of said compound of (3.0.9) Formula (1.0.0) is represented by the following partial Formulas (3.0.1) through (3.0.47) set out below. 50 o : (3.0.1) (3.0.10)

: (3.0.11) : S :

(3.0.2) 60 : F \ f (3.0.12) : 2

65 US 7,250,518 B2 89 90

-continued -continued (3.0.13) (3.0.24)

(3.0.14) A (3.0.25) 10 :

(3.0.15)

15 (3.0.26) :

Gl : (3.0.27) (3.0.16) : H3-As : 25 (3.0.28) : :

(3.0.17)

30 (3.0.29)

(3.0.18) 35 Ol : (3.0.30)

40 o : (3.0.19) (3.0.31) :

45 (3.0.20) N-l-M

(3.0.32) 50 :

(3.0.21) N21N21NN1s-1N : (3.0.33) 55 H

: (3.0.22) Na-1.O n.

: 60 (3.0.34) CHF (3.0.23) : 65 o US 7,250,518 B2 91 92

-continued -continued (3.0.35) (3.0.45) o1 CF O

: : (3.0.46) (3.0.36) 10 o1 CHF

15 : (3.0.47) (3.0.37)

5.4.0 The R and R. Substituents The group of partial Formula (1.0.4) above is substituted (3,0.38) in the 4-position by a moiety containing the Substituents A, 25 R", and R, which may be represented by partial Formula (1.1.7):

(1.1.7) 30 (3.0.39)

35 where m is 0, 1, or 2. In the more preferred embodiments of the compounds of the present invention, m has the meaning (3.0.40) of 0 or 1. When m is 1 the moiety —R C R is 40 present, and R' and R are preferably each a member independently selected from the group consisting of —H; and (C-C)alkyl. In other preferred embodiments of the present invention (3.0.41) 45 R and R may be taken together, but only in the case where m is 1, to form a spiro moiety of Formula (1.2.0):

(1.2.0) : : 50 (3.0.42) (HC) N / (CH), XA

55 where rands are independently 0 to 4 provided that the sum of r+s is at least 1, but not greater than 5: X" is —CH2, (3.0.43) —CHR, or -C(R'), where each R' is selected inde pendently of the other and each R' has the same meaning 60 as defined herein; NR' where R' has the same mean ing as defined herein; —O—; or —S(=O), where t is 0, 1, or 2; and said spiro moiety is Substituted as to any one or (3.0.44) more carbon atoms thereof by 0 to 3 substituents R', as to a nitrogen atom thereof by 0 or 1 substituent R', and as to 65 a Sulfur atom thereof by 0 or 2 oxygen atoms. Accordingly, there results, inter alia, the moieties illustrated by partial Formulas (1.2.1) through (1.2.12): US 7,250,518 B2 93 94

-continued (1.2.11) (1.2.1) : : R4 R 14

(1.2.2) i 10 (O) (1.2.12) : :

R 14 15 1. (1.2.3) R 15-N y

where t is 0, 1, or 2; and R'' and R' have the same meaning as defined herein. (1.2.4) Preferred meanings of the R'' substituent include —F; - Cl; =O; OH: —CH: —CHOH, -CH(CH)OH: —C(CH)OH: —OCH; C(=O)CH; –C(=O)NH; 25 NH; NHCH(CH); NHC(=O)CH: NHC(=O) "t OCHCH, -NHS(=O)CH; and -S(=O)NH, result X. ing in moieties such as those of partial Formulas (3.1.1) (1.2.5) through (3.1.34): : : 30 (3.1.1)

reO (1.2.6) 35 NF (3.1.2)

40 HO1 (3.1.3) (1.2.7)

CH 45 (3.1.4) (1.2.8) HN 50 (3.1.5)

(1.2.9)

55 O (3.1.6)

(1.2.10) 60 X) (3.1.7)

R 14 N R 14 65 R15 US 7,250,518 B2 95

-continued -continued (3.1.8) (3.1.17) : : : : H OCH 5 N." (3.1.9) O : : (3.1.18) 10 : :

K / NH2 F F S (3.110) 15 W. : : (3.1.19) : :

O H O 2O () (3.1.11) OH : : 25 : : (3.1.20)

O 2X

30 : : (3.1.21)

(3.1.12) -N HC CH (3.1.22) 35 : :

NH H3CO OCH (3.113) : : 40 O (3.1.23) : : y C H3 X) 45 S (3.1.14) : (3.1.24) : :

50 H O c)OH (3.1.25) (3.1.15) : : : : 55 H3C O

SO HO (3.1.16) 60 (3.1.26) : :

65 N US 7,250,518 B2 97 98 preferred embodiments of the compounds of Formula (1.0.0) -continued detailed above with regard to the R and R substituents, are (3.1.27) for the most part also particular and preferred embodiments : : of the compounds of Formula (1.0.0) with regard to the R and RP substituents. 5.5 The Moiety —N(R)- The subscript has the meaning of 0 or 1. Where has the *H (3.1.28) meaning of 1, which is the preferred meaning, the moiety : : N(R)— is present and the compounds of Formula (1.0.0) 10 are essentially nicotinamides in structure. The nitrogen atom substituent R is preferably selected from H; —(C-C) alkyl, and —(C-C)alkoxy; and is more preferably —H; N —CH; or —OCH. In the most preferred embodiments of H the compounds of Formula (1.0.0), R has the meaning of 15 —H. O (3.1.29) Where B' and B both have the preferred meaning of : : phenyl; and j has the meaning of 0, which is a less preferred meaning than where j is 1; the moiety - N(R)— is absent and the compounds of Formula (1.0.0) are essentially nico tinoyl moieties, i.e., ketones in structure. This ketone struc ture of the compounds of Formula (1.0.0) is represented by (lH Formuls (1.0.7): (3.1.30) : : 25

(1.0.7)

O H C NCH, 30 O

g g (3.1.31)

H ( O (3.1.32) : : 40

where all of the substituents and components thereof, ie., A. 45 W: Y: k, m, and n: R. R. R. R., and R; and R. R. R. HO CH and R', have, for the most part, the same particular and (3.1.33) : : preferred meanings described in detail herein, as where j is 1 and the compounds are nicotinamides in structure. 5.6.0 The Moiety A 50 A is a member selected from the group of moieties defined by partial Formulas (1.1.1) through (1.1.5) illustrated further HO-/ above. The moieties which define the A group are typically (3.1.34) : : but not necessarily acids, amides, and heterocyclyl groups that act as acid and amide mimetics, but they are not limited 55 to these types of functional groups. Other moieties as described herein may be employed at the right-hand-side of the compounds of Formula (1.0.0). These moieties are bioisostereic in that they permit the compounds of Formula (1.0.0) containing them to achieve PDE4 inhibition essen CCH 60 tially equivalent to that achieved by other moieties, espe cially acid and amide moieties. 5.4.1 The R and RP Substituents 5.6.1 A is a Moiety of Partial Formulas (1.1.1), (1.1.2) or As already described, R and R' have the same meaning (1.1.3) as defined above for RandR, except that one of them must 65 Embodiments of the present invention wherein the defi be —H, and they are selected independently of each other nition of the A group is illustrated by partial Formulas and of R and R. Accordingly, all of the particular and (1.1.1); (1.1.2); and (1.1.3), are as follows: US 7,250,518 B2 99 100

-continued (1.1.1) (3.5.3)

(1.1.2)

(3.5.4) (1.1.3) O

15 : ls,1Net,

(3.5.5) One of a number of preferred moieties for defining the A O CH3 group is that of partial Formula (1.1.1) where R has the ul N meaning of —H, which is a preferred meaning of this : 1N1,No. 3 substituent. Where R is hydrogen and m is 0 in Formula (3.5.6) (1.0.0), a simple carboxylic acid —COOH results, and the O group of partial Formula (1.0.5) becomes a benzoic acid. 25 CH3 Benzoic acid as a meaning of the A group, however, is a less : r preferred embodiment of the present invention. OH R' is an optional substituent of the moieties that define (3.5.7) R7, and there may be up to three such substituents when O present. The meaning of the R' substituent includes phenyl 30 or pyridyl where said phenyl or pyridyl is in turn optionally lsO substituted by up to 3 substituents R' where R'' is F. Cl, —CN. —NO. —OH, -(C-C)alkoxy, —(C-C) alkyl, or NR'R''. In preferred embodiments that include 35 such R' substitution, there will be 1 or 2 substituents R' C F that have the meaning of —F. —Cl, —CH, —OCH, (3.5.8) —OH, -CN, or N(CH). The meaning of the R' O substituent further includes —F. —Cl, —CF, oxo (=O), OR, NO, CN, C(=O)CR', O C(=O)R', 40 O C(=O)NR'R'7, O C(=O)NR'R'7, NR'R'7, NR'C(=O)R'7, NRC(=O)CR'7, NRS(=O), R7, or S(=O)NR'R'7. The sub-substituents R'' and R' comprise —H; —(C- 45 C.)alkyl, preferably —CH; —(C-C)alkenyl: —(C-C) cycloalkyl, preferably cyclopropyl; phenyl; benzyl; or c N (3.5.9) pyridyl. Said alkyl, alkenyl, cycloalkyl, phenyl, benzyl, or O pyridyl groups are in turn optionally Substituted by up to 3 50 substituents —F. —Cl, or —CN. : ul These and other preferred embodiments of the compounds of Formula (1.0.0) comprising the moieties of partial For C mula (1.1.1) based on the preferred meanings of R and R' as described above, include, interalia, the following groups 55 illustrated by partial Formulas (3.5.1) through (3.5.15): C (3.5.10) O

(3.5.1) O : ls, -- 60 (3.5.2) O HC1 CH 65 --- H3 US 7,250,518 B2 101 102

-continued -continued (3.5.11) O (4.1.3) O O

lsO 5 ulls

CH, CH (4.1.4) 10 O O NY (3.5.12) O 15 A (4.1.5) O2. CH3 CH3 (3.5.13) O

2s Those embodiments wherein the definition of A is that of N 2 (3.5.14) an amide group, are illustrated by partial Formula (1.1.3): O

lsO CF (1.1.3) 30 O

(3.5.15) 35 O These and other preferred embodiments of the compounds usO of Formula (1.0.0) comprising moieties of partial Formula (1.1.3), based on the meanings of R and R described HC l CH3 40 above, include, interalia, the following groups illustrated by CH3 partial Formulas (4.5.1) through (4.5.20):

The A group is represented by partial Formula (1.1.2) in (4.5.1) which the nitrogen atom is substituted by R where R has the meaning of —H; —(C-C)alkyl; —(C-C)cycloalkyl: 45 ul phenyl; benzyl; —OR'; –(C-C)alkyl-OR'; and —(C- : NH C.)alkyl-C(=O)CR'; where R' is - Hor—(C-C)alkyl. (4.5.2) R" is preferably – H or -CH. O Accordingly, embodiments of the present invention where 50 CH the A group is represented by partial Formula (1.1.2) may be H illustrated as follows by partial Formulas (4.1.1) through (4.5.3) (4.1.5): O

55 : ls NH (4.1.1) O O s (4.5.4) H 60 O (4.1.2) --

65 ---,CH3 US 7,250,518 B2 103 104

-continued -continued (45.5) (4.5.15) O

(4.5.6) O OH 10 (4.5.16) O ls, F (45.7) H 15 F (45.17) C O

(4.5.8) H C (4.5.18) O 25

(4.5.9) H O YCH, (4.5.19) 30

usO N -Cl O (4.5.10) H 35 CH3 (4.5.20) O

40 H (4.5.11) O NH2

45 5.6.2 A is a Moiety of Partial Formula (1.1.4) Preferred embodiments of the present invention also (4.5.12) comprise those compounds of Formula (1.0.0) wherein the heterocycle-containing terminal moiety A falls within the Scope of partial Formula (1.1.4), i.e., embodiments of this 50 type are encompassed within the scope of the Amoiety when it has the meaning of partial Formula (1.1.4):

(4.5.13) (1.1.4) 55

60 (4.5.14) wherein v is 0 or 1; and wherein R is a monocyclic or bicyclic heterocyclyl which is a member selected from the group consisting of tetrazol-5-yl: 1,2,4-triazol-3-yl: 1,2,4- 65 triazol-3-on-5-yl: 1,2,3-triazol-5-yl; imidazol-2-yl; imida OH Zol-4-yl; imidazolidin-2-on-4-yl: 1,2,4-oxadiazol-3-yl: 1.2, 4-oxadiazol-5-on-3-yl: 1,2,4-oxadiazol-5-yl; 1,2,4- US 7,250,518 B2 105 106 oxadiazol-3-on-5-yl: 1,3,4-oxadiazolyl: 1.3,4-oxadiazol-2- NRC(=O)R'7, NRC(=O)CR'7, NRS(=O), on-5-yl, oxazolyl; isoxazolyl; pyrrolyl; pyrazolyl; R'7, or -S(=O)NR'R''. In addition to those preferred Succinimidyll; glutarimidyl; pyrrolidonyl: 2-piperidonyl: embodiments indicated above, when R'' is present it is also 2-pyridonyl, 4-pyridonyl; pyridazin-3-onyl; pyridazin-3- preferred that it have the meaning of —F. —Cl, —CF, onyl; thiazolyl; isothiazolyl; thiadiazolyl; morpholinyl; par —OCH, —CN, or - NO. athiazinyl; pyridyl, pyrimidinyl; pyrazinyl; pyridazinyl: Any one or more of the nitrogen atoms, which it will be indolyl; indolinyl: isoindolinyl; benzobfuranyl: 2,3-dihy appreciated occur only in the case of the heterocyclyl drobenzofuranyl: 1,3-dihydroisobenzofuranyl; 2H-1-ben moieties, and which are not a point of attachment of said Zopyranyl: 2-H-chromenyl; chromanyl; benzothienyl: heterocyclyl moiety, are optionally substituted by up to 3 1H-indazolyl; benzimidazolyl; benzoxazolyl; benzisox 10 azolyl; benzothiazolyl; benzotriazolyl; benzotriazinyl: substituents R'. Any sulfur atom which happens to occur in phthalazinyl: 1.8-naphthyridinyl, quinolinyl; isoquinolinyl: a heterocyclyl moiety, that is not a point of attachment of quinazolinyl; quinoxalinyl; pyrazolo 3,4-dipyrimidinyl: said heterocyclyl moiety, is Substituted by 0, 1, or 2 oxygen pyrimidoA,5-dipyrimidinyl; imidazol-2-alpyridinyl; pyri atOmS. dopyridinyl: pteridinyl; and 1H-purinyl. 15 The optional nitrogen heterocyclyl substituent R' com Partial Formulas (1.1.3) and (1.1.4) are similar and the prises H; C(=O)CR': C(=O)NR'R'':-(C-C) distinction between them should, therefore, be noted. Partial alkyl, preferably —CH; —(C-C)alkenyl: —(C-C) Formulas (1.1.3) and (1.1.4) are as follows: alkoxy, preferably —OCH; —(C-C)cycloalkyl, preferably cyclopropyl; phenyl: or benzyl, wherein said alkyl, alkenyl, alkoxy, cycloalkyl, phenyl, or benzyl are (1.1.3) optionally substituted with up to 2 substituents R''. O The sub-substituent R' comprises —F; Cl; CO.R': R7 OR; CN; C(=O)NR'R'': NR'R'': NRC --- (=OR'; NR'C(=O)CR'; NRS(=O).R'; 25 —S(=O)NR'R'', where p is 1 or 2, preferably 2; (C- C.)alkyl, preferably -CHs; and -(C-C)alkoxy, where (1.1.4) R has the meaning of —OR'' above and R' is defined as —(C-C)alkyl, preferably —OCH; where said alkyl and alkoxy are in turn optionally substituted with up to 3 30 Substituents —F. —Cl; —(C-C)alkoxycarbonyl; —(C- C.)alkylcarbonyl; and —(C-C)alkylcarbonyloxy. The R' and R' substituents comprise —H; or —(C-C)alkyl, pref erably —CH optionally substituted with up to 3 —F; or Where v is 0, R is linked in a direct fashion to the —Cl. remaining portion of a compound of Formula (1.0.0) and it 35 No R substituents are shown in partial Formulas (1.1.11) is, accordingly, readily distinguishable from a moiety of through (1.1.38) above, as well as further below, because the partial Formula (1.1.3) in which R7 is linked to the remain R substituent is attached only to a nitrogen atom that does ing portion of a compound of Formula (1.0.0) through the not form an integral, component part of an attached hetero amide bridging moiety —C(=O)NR -. Where v is 1, on cyclic moiety. The R substituent is optional in character in the other hand, both the Rand the R moieties are linked to 40 that “ H” is included as a definition of the R substituent, the remaining portion of a compound of Formula (1.0.0) and in many of the embodiments of the compounds of through the amide bridging moiety —C(=O)NR -. In this Formula (1.0.0) this is the preferred meaning of R. Another instance, the distinction between the moieties of partial preferred meaning of R is —CHs. Formulas (1.1.3) and (1.1.4) comprises the difference 45 There is also pointed out the distinction between the between the meanings of the R and the R moieties. This substituents R and R', both of which are attached only to difference has already been described above in detail. nitrogen atoms in any of the meanings of the moiety A. The In order to facilitate the following description, the mono substituent R' is attached only to a nitrogen atom that is an cyclic heterocyclyl moieties and the bicyclic heterocyclyl integral, component part of any heterocyclic moiety that moieties are first treated together and thereafter are dis 50 may be defined via the R substituent of partial Formula cussed as separate groups. (1.1.4) and in particular with reference to the more specific Any one or more of the carbon atoms of the phenyl, heterocyclic moieties of partial Formulas (1.1.11) through benzyl, or heterocyclyl moiety is substituted by 0 to 3 (1.1.38), shown above as well as further below. The R substituents R''. Consequently, R'' is an optional substitu Substituent, on the other hand, is attached only to a nitrogen ent of any one or more of the carbon atoms of the moieties 55 atom that in turn is attached to, but is not an integral, that define R, and said R'' substituent comprises —(C- component part of any of the heterocyclic moieties that is C.)alkyl, preferably —CH; —(C-C)cycloalkyl, prefer defined by partial Formulas (1.1.2), (1.1.3), and (1.1.5). The ably cyclopropyl; phenyl; benzyl, pyridyl; or quinolinyl: R" substituent may be attached to one or more nitrogen where said alkyl, cycloalkyl, phenyl, benzyl, pyridyl, or atoms and said nitrogen atoms may be present in any quinolinyl moiety is in turn optionally Substituted by 1 or 2 60 moieties falling within the scope of partial Formula (1.1.4) substituents —F, —Cl, —CH, OCH, -OR', —CN, or that can be characterized as containing or comprising a -NR'R''. In preferred embodiments R'' and R'' are nitrogen-containing heterocyclic moiety. independently —H or —CH. When R'' is substituted, it is As an illustration of preferred subgeneric embodiments of preferred that the substituent be - F or - C1. The R'' the present invention wherein the A group has the meaning substituent further comprises —F: —Cl; —CF; oxo (=O); 65 of a moiety of partial Formula (1.1.4) and V is 0 or 1, there OR: CN; NO, C(=O)CR', O C(=O)R', is set out below monocyclic heterocyclic groups which C(=O)NR'R'7, O C(=O)NR'R'7, NR'R'7, define R, of partial Formulas (1.1.11) through (1.1.38):

US 7,250,518 B2 109 110

-continued -continued (1.1.36) (1.1.28) N

: %

pyrimidinyl (1.1.37) 10 N : r (1.1.29) sN pyrazinyl 15 (1.1.38)

(1.1.30) pyridazinyl

As a further illustration of preferred subgeneric embodi ments of the present invention wherein the A group has the 25 meaning of a moiety of partial Formula (1.1.4) and V is 0 or 1, there is set out below more preferred monocyclic hetero (1.1.31) cyclic groups which define the moiety R', selected from the above-recited partial Formulas (1.1.11) through (1.1.38): 30 (1.1.11) aN N / 35 N-N (1.1.32) A R 15 Tetrazol-5-yl (1.1.12) : N 40 Yy 2-pyridonyl N-N A (1.1.33) R 15 R 15 45 1,2,4-triazol-3-yl N (1.1.13) : N N YO N-N A V O 50 R15 R 15 4-pyridonyl 1,2,4-triazol-3-on-5-yl

(1.1.34) (1.1.14) 55 Y.W N-N A R 15 1,2,3-triazol-5-yl 60 (1.1.15) (1.1.35) y A R 15 65 Imidazol-2-yl US 7,250,518 B2 111 112

-continued -continued

(1.1.16) (1.1.34)

V 15

imidazol-4-yl 10 pyridazin-3-onyl (1.1.17)

(1.1.35)

15 imidazolidin-2-on-4-yl sy (1.1.19) (1.1.38) V R 15 25 pyridazinyl 1,3,4-oxadiazol-2-on-5-yl (1.1.21) As a still further illustration of preferred subgeneric embodiments of the present invention wherein the A group 30 has the meaning of a moiety of partial Formula (1.1.4) and V is 0 or 1, there is set out below still more preferred monocyclic heterocyclic groups which define the moiety R, selected from the above-recited partial Formulas (1.1.11) through (1.1.38): 1,2,4-oxadiazol-5-on-3-yl 35 (1.1.27) R15 (1.1.11) a NN N 40 // N-N - ? R 15 pyrazolyl Tetrazol-5-yl (1.1.28) 45 (1.1.12)

R 15 50 1,2,4-triazol-3-yl (1.1.32) (1.1.13)

2-pyridonyl

(1.1.33) 60 (1.1.15) an 5 21 R 15 65 4-pyridonyl imidazol-2-yl US 7,250,518 B2 113 114 sisting of partial Formulas (4.8.1) through (4.8.80) from -continued which the R moiety is selected in such preferred embodi (1.1.16) ments: : N \ 5 N (4.8.1) Yis : a N NN Imidazol-4-yl \- (1.1.17) 10 H (4.8.2) : N : N O 2 YN Yy\ -N/ N 15 H3C R15 (4.8.3) : N imidazolidin-2-on-4-yl (1.1.27) N2 5 f 2O N-N N (4.84) ( YN : e CH3 - M. ne f N-N pyrazolyl 25 H (4.8.5)

(1.1.28) : N CF N y 3 N-N 30 H (4.8.6) (1.1.32) :N N -O 35 N-N H (4.8.7) Na 40 : Ney-\lN (1.1.34) N-Nf H (4.8.8) : N O 45 NY N-N H. H. (4.8.9) : N O N (1.1.35) 2 % 50 : N-N S. H3C (4.8.10) pyridyl : N O (1.1.38) 55 N Y % N N N-N : tru H VCH3 (4.8.11) pyridazinyl 60 : N N YO N-N In order to provide another demonstration of preferred H embodiments of the compounds of Formula (1.0.0) with reference to the A group where it is a moiety of partial 6s Formula (1.1.4) and v is 0 or 1, and R is a monocyclic heterocyclic group, there is set out below the groups con US 7,250,518 B2 115 116

-continued -continued (4.8.12) (4.8.23) : N H NY N N-N H

10 (4.8.24) (4.8.13) : NYN N-N N H 15 s (4.8.25)

(4.8.14) 2O ^^// (4.8.26) (4.8.15) : N 25

Y.N H (4.8.1.6) : N 30

Y.N (48.27) M (4.8.17 35

(4.8.18) 40 (4.8.28)

(4.8.19) 45

(4.8.20) 50 (4.8.29)

(48.21) (48.30)

60 (48.22) (48.31)

65 US 7,250,518 B2 117 118

-continued -continued (48.32) (4.842) :N N YO O N

O (48.33) H 10 : N HOS-C (4.843) N.Y." N N-O O (48.34) N Y. 15 O N

(4.8.35) 20 C (4.8.44)

(4.845) 25

(48.36) HO (4.846) 30

(4.8.47) (48.37) 35 :

CF 40 (4.848) (48.38) O O

45 : (4.849) H O O (48.39) 50 : (4.8.50) (4.8.40) : HwN 55

(48.51)

(4.8.41) OO 60

: (48.52)

65 : C US 7,250,518 B2 119 120

-continued -continued (48.53) (48.63) HC O V N OH \ : \ / \,

10 (48.64) (48.54) O H N O NS M V / N / CCCF 15 (48.55) : (48.65)

(4.8.56) (48.66)

25 N N-1s (48.67) (48.57) "Ne 30 N (48.68) 2

35 (48.58) N (48.69)

M 40 N (4.8.70) O (4.8.59) H N / Y-0 45

CF (4.8.71) : N O (48.60) s : N HC S 21 N (4.8.72) N Cl O (48.61) N 21 N (4.8.73) N : -Cl O 60 (48.62) N a NN (4.8.74) N O 65 : US 7,250,518 B2 121 122

-continued -continued (4.8.75) (5.0.2) : N R15 A N y t N D SX : (4.8.76) : N CH 10 indolinyl N cN (5.0.3) (4.8.77) : 15 N-R15 NM {N->O isolindolinyl (4.8.78) : N 21 NN (5.0.4) N (4.8.79) N 21 NN 25 OC. benzobfuranyl : N (5.0.5) (4.8.80) 30 y : / \ N SS : - N 2,3-dihydrobenzo-furanyl (5.0.6) : Preferred embodiments of the present invention where the 35 group A is a moiety of partial Formula (1.1.4) and V is 0 or 1, also include those wherein the moiety R is a bicyclic heterocyclic group selected from the group consisting of 1,3-dihydroisobenzo-furanyl; phthalanyl indolyl; indolinyl: isoindolinyl; benzobfuranyl: 2,3-dihy 40 drobenzofuranyl: 1,3-dihydroisobenzofuranyl; 2H-1-ben (5.0.7) Zopyranyl: 2-H-chromenyl; chromanyl; benzothienyl: O 1H-indazolyl; benzimidazolyl; benzoxazolyl; benzisox N : azolyl; benzothiazolyl; benzotriazolyl; benzotriazinyl: 2 phthalazinyl: 1.8-naphthyridinyl, quinolinyl; isoquinolinyl: 45 2H-1-benzopyranyl quinazolinyl; quinoxalinyl; pyrazolo 3,4-dipyrimidinyl: pyrimidoA,5-dipyrimidinyl; imidazol-2-alpyridinyl; pyri (5.0.8) dopyridinyl: pteridinyl; and 1H-purinyl. In order to provide a still further demonstration of pre 50 ferred embodiments of the compounds of Formula (1.0.0) with reference to the A group where it is a moiety of partial Formula (1.1.4), V is 0 or 1, and R is a bicyclic heterocyclic (5.0.9) group, there is set out below the groups consisting of partial Formulas (5.0.1) through (5.0.28) from which the R moiety 55 is selected in such preferred embodiments: 2.Q. Benzothienyl (5.0.10) (5.0.1) 60

65 1H-indazolyl US 7,250,518 B2 123 124

-continued -continued (5.0.11) R15 (5.0.21) A N s : X- : 2. N Quinazolinyl benzimidazolyl 10 (5.0.22) (5.0.12) OX N Benzoxazolyl 15 quinoxalinyl (5.0.23) (5.0.13) R15 N N A N M N-y : Null-/ Benzisoxazolyl (5.0.14) 1H-pyrazolo 3,4-d-pyrimidinyl S 25 (5.0.24) X N N 1N1 is - benzothiazolyl N els2 5.0.15 15 ( 30 Pyrimido5,4-d-pyrimidinyl (5.0.25) CC 21 NN- : 2H-1,2-benzothiazinyl 35 N s s (5.0.16) Imidazo-1,2-a-pyridinyl (5.0.26) N 21 NN 40 N-- (5.0.17) pyridopyridinyl 45 (5.0.27)

Quinolinyl CC4. 2N (5.0.18 so n N pteridinyl (5.0.28) R15 2 : M isoquinolinyl (5.0.19) 55 2 Nl CO Nu 1H-purinyl 1,8-naphthyridinyl 60 (5.0.20) where indicates the point of attachment to the remaining s : 2N portion of Formula (1.0.0); and where each carbon atom is 65 optionally substituted by a substituent R'; and where R'' Phthalazinyl and R' have the same meaning as defined above; and all tautomer forms, and optionally N-oxide forms, thereof. US 7,250,518 B2 125 126 5.6.3 A is a Moiety of Partial Formula (1.1.5) 2-4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo There are further embodiments of the compounds of nyl-amino-methyl)-phenyl)-2-methyl-propionic acid Formula (1.0.0) in which the A group comprises moieties of methyl ester of Formula (6.0.31); partial Formula (1.1.5): 2-4-(2-(4-Fluoro-phenoxy)-pyridine-3-carbonyl amino-methyl)-phenyl)-2-methyl-propionic acid methyl ester of Formula (6.0.32): (1.1.5) 3-Fluoro-4-({2-(4-fluoro-phenoxy)-pyridine-3-carbo O nyl- amino-methyl)-phenyl)-acetic acid methyl ester of Formula (6.0.35); : us O1 (C) "Yws 10 1-4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo H nyl-amino-methyl)-3-fluoro-phenyl-cyclobutanecar R7 boxylic acid ethyl ester of Formula (6.0.36): 1-4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo wherein q is 1, 2, or 3, provided that where q is 2 or 3, R nyl-amino-methyl)-3-fluoro-phenyl-cyclobutanecar has the meaning of —H in at least one instance, or two 15 boxylic acid ethyl ester of Formula (6.0.36): instances, respectively; W is —O ; N(R)-; or —OC 1-4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo (=O)— where R has the same meaning as defined above; nyl-amino-methyl)-3-fluoro-phenyl-cyclopropanecar and R has the same meaning as defined above. boxylic acid ethyl ester of Formula (6.0.37): In preferred embodiments of the compounds of partial 4-(2-(Benzo. 1.3dioxol-5-yloxy)-5-fluoro-pyridine-3- Formula (1.1.5), q is typically 1 or 2, R is typically -H, or carbonyl-amino-methyl)-3-fluoro-phenyl)-acetic acid —CH; Wis-O-, -O(C=O) , or -NH-; and R7 is methyl ester of Formula (6.0.38); typically one of the preferred moieties already described 1-4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo above. nyl-amino-methyl)-phenyl-cyclopropanecarboxylic acid Representative embodiments of the compounds of For ethyl ester of Formula (6.0.39); mula (1.0.0) in which the A groups fall within the scope of 25 2-4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo partial Formula (1.1.5) are those illustrated by partial For nyl-amino-methyl)-phenyl)-2-methyl-propionic acid of Formula (6.5.1); mulas (7.0.1) through (7.0.6): 2-4-(2-(4-Fluoro-phenoxy)-pyridine-3-carbonyl amino-methyl)-phenyl)-2-methyl-propionic acid of For 30 (7.0.1) mula (6.5.2): O O 1-4-(2-(Benzo1.3dioxol-5-yloxy)-pyridine-3-carbo nyl-amino-methyl)-3-fluoro-phenyl-cyclobutanecar ----- boxylic acid of Formula (6.5.3); (7.0.2) 2-4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo O 35 nyl-amino-methyl)-3-fluoro-phenyl)-2-methyl-propionic acid of Formula (6.5.4): : ls 1N-1 O YCH, 2-3-Fluoro4-((2-(4-fluoro-phenoxy)-pyridine-3-carbo (7.0.3) nyl-amino-methyl)-phenyl)-2-methyl-propionic acid of Formula (6.5.5); O st 40 1-4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo : ls 1N1 N YCH, nyl-amino-methyl)-phenyl-cyclopropanecarboxylic acid (7.0.4) of Formula (6.5.6): O 2-4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo 45 nyl-amino-methyl)-3-fluoro-phenyl-propionic acid of : ls 1N1 NH 2 Formula (6.5.7); (7.0.5) 2-4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo O CH, O nyl-amino-methyl)-3-methoxy-phenyl-2-methyl-propi onic acid of Formula (6.5.8); -s-s-s 50 2-4-(2-(Benzo. 1.3dioxol-5-yloxy)-5-fluoro-pyridine (7.0.6) 3-carbonyl-amino-methyl)-3-methoxy-phenyl-2-methyl O propionic acid of Formula (6.5.9): 2-4-(2-(4-Fluoro-phenoxy)-pyridine-3-carbonyl : 1N1 O r H amino-methyl)-3-methoxy-phenyl)-2-methyl-propionic 55 acid of Formula (6.5.10); O 3-Fluoro-4-({2-(4-fluoro-phenoxy)-pyridine-3-carbo nyl-amino-methyl)-phenyl-acetic acid of Formula In the above description various preferred aspects of the (6.5.11); compounds of Formula (1.0.0) have been set forth. As a 4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo further demonstration of the scope and content of the present 60 nyl-amino-methyl)-phenyl-acetic acid of Formula invention, specific compounds comprising embodiments of (6.5.12); the compounds of Formula (1.0.0) are presented. Such 1-4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo species of Formula (1.0.0) include, but are not limited to the nyl-amino-methyl)-3-fluoro-phenyl-cyclopropanecar following: boxylic acid of Formula (6.5.13): 4-({2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo 65 4-(2-(Benzo. 1.3dioxol-5-yloxy)-pyridine-3-carbo nyl-amino-methyl)-phenyl-acetic acid methyl ester of nyl-amino-methyl)-3-fluoro-phenyl-acetic acid of For Formula (6.0.30); mula (6.5.14): US 7,250,518 B2 127 128 4-(2-(3-Cyano-phenoxy)-pyridine-3-carbonyl 2-(Benzo. 1.3dioxol-5-yloxy)-N-4-(1-ethylcarbamoyl amino-methyl)-3-fluoro-phenyl-acetic acid of Formula 1-methyl-ethyl)-benzyl-nicotinamide of Formula (6.5.26); (6.5.15): 2-(4-Fluoro-phenoxy)-N-4-(1H-tetrazol-5-yl)-benzyl 4-({2-(Benzo. 1.3dioxol-5-yloxy)-5-fluoro-pyridine-3- nicotinamide of Formula (6.5.27); carbonyl-amino-methyl)-3-fluoro-phenyl-acetic acid of 5 2-(4-Fluoro-phenoxy)-N-(4-1-methyl-1-(1H-tetrazol-5- Formula (6.5.16); yl)-ethyl-benzyl-nicotinamide of Formula (6.5.28); 2-4-(2-(Benzo[2.1.3oxadiazol-5-yloxy)-pyridine-3- N-2-Fluoro-4-1-methyl-1-(1H-tetrazol-5-yl)-ethyl carbonyl-amino-methyl)-phenyl)-2-methyl-propionic acid benzyl-2-(4-fluoro-phenoxy)-nicotinamide of Formula of Formula (6.5.17): (6.5.29); 2-(Benzo. 1.3dioxol-5-yloxy)-N-4-(1-carbamoyl-1-me 10 5-Chloro-2-(4-fluoro-phenoxy)-N-(4-1-methyl-1-(1H thyl-ethyl)-benzyl-nicotinamide of Formula (6.5.18); tetrazol-5-yl )-ethyl-benzyl-nicotinamide of Formula 2-(Benzo. 1.3dioxol-5-yloxy)-N-(4-carbamoylmethyl (6.5.30); benzyl)-nicotinamide of Formula (6.5.19); 2-(Benzo1.3dioxol-5-yloxy)-5-chloro-N-(4-1-methyl N-(4-Carbamoylmethyl-2-fluoro-benzyl)-2-(4-fluoro 1-(1H-tetrazol-5-yl)-ethyl-benzyl-nicotinamide of For phenoxy)-nicotinamide of Formula (6.5.20): 15 mula (6.5.31); and 2-(Benzo. 1.3dioxol-5-yloxy)-N-4-(1-carbamoyl-1-me 2-(Benzo1.3dioxol-5-yloxy)-N-(4-1-methyl-1-(1H-tet thyl-ethyl )-2-fluoro-benzyl-nicotinamide of Formula razol-5-yl)-ethyl-benzyl-nicotin-amide of Formula (6.5.21); (6.5.32). N-4-(1-Carbamoyl-1-methyl-ethyl)-2-fluoro-benzyl-2- (4-fluoro-phenoxy)-nicotinamide of Formula (6.5.22); DETAILED DESCRIPTION OF THE 2-(4-Fluoro-phenoxy)-N-2-fluoro-4-(1H-tetrazol-5-ylm INVENTION ethyl)-benzyl-nicotinamide of Formula (6.5.23); 2-(Benzo. 1.3dioxol-5-yloxy)-N-4-(1-methyl-1-methyl 6.0 Processes for Making the Compounds of Formula (1.0.0) carbamoyl-ethyl)-benzyl-nicotinamide of Formula A method suitable for preparing the right-hand side of the (6.5.24); 25 compounds of Formula (1.0.0) where the A group is a 2-(Benzo1.3dioxol-5-yloxy)-N-(4-1-(cyclopropylm carboxyl moiety is illustrated in Synthesis Scheme (10.0.0) ethyl-carbamoyl)-1-methyl-ethyl-benzyl-nicotinamide of below, in which reference is made to Preparations which are Formula (6.5.25): presented still further below.

SYNTHESIS SCHEME (10.0.0) Reaction 1 R1 (Preparations 7) HO S4 O Reaction 2 (Preparation 8a) R1 21 HO nSy OR Yas O (10.0.2)

2 OH (10.0.1)

RI R1 TfG) S4 O Reaction 1 (Preparation 2) Ir,l- Clu21 OR RI OR (10.0.3) Br (10.0.5)

Reaction 3 CU2 OH / (Preparation 3) Reaction 3 Reaction 4 (Preparation 8b) (10.0.4) (Preparation 5) US 7,250,518 B2 129 130

-continued N RI | R1 Br SA O SAC O RA 2 OR 21 OR NH2 (10.0.6) R1 RB as %. RA O (10.0.7) Reaction 4 2 OR \ (Preparations 10, 11, and 19) B Reaction 3 R (Preparation 6) (10.0.9)

Reaction 5 (Preparations 4 and 9)

(10.0.8)

Reaction 1. The carboxylic acid (10.0.1) is dissolved in The left-hand side of the compounds of Formula (1.0.0) alcohol, typically either methanol or ethanol, and treated may be prepared and then coupled to the right-hand side with concentrated Sulfuric acid under refluxing conditions to prepared as described above, in accordance with SYNTHE yield the corresponding ester (10.0.2). 30 SIS SCHEME (10.1.0) set out below. Reaction 2. The phenolic ester (10.0.2) is dissolved in anhydrous dichloromethane and treated with 4-dimethy laminopyridine and triethylamine or N,N-diisopropylethy lamine under an inert atmosphere, then cooled (typically in SYNTHESIS SCHEME (10.1.0) a dry ice/acetone bath) before adding trifluoromethane 35 O OH sulfonic anhydride. The mixture is subsequently allowed to R1 warm to ambient temperature, whereupon water is added 3. N O and the organic layer extracted to yield crude trifluorosul -- fonate intermediate (10.0.3). This intermediate is carried on 2 5 N C CH R to the next step without purification. 40 Reaction 3. Under an inert atmosphere either the trifluo R6 romethanesulfonate (10.0.3) or the bromo compounds (10.1.1) (10.1.2) (10.0.5) and (10.0.7) are dissolved in a polar, anhydrous Solvent such as dimethylformamide, dioxane, or tetrahydro Reaction 6 furan, mixed with Zinc cyanide and a catalytic amount of (Preparations 1, tetrakis(triphenylphosphine)palladium(0) before heating (50 45 16, 17, 18, and 25a) to 100° C., typically 80° C.) for 2 to 8 hrs, typically 4 hrs, to yield the intermediates (10.0.6) or (10.0.8). Reaction 4. Dialkylations on phenyl acetic esters such as (10.0.5) and (10.0.6) are carried out under an inert atmo O sphere with an excess of a suitable base (preferably sodium 50 (Examplessis. 1a and 2a) N R 3. n OH hydride in mineral oil) in an anhydrous polar solvent Such (10.1.5, R = H) tetrahydrofuran or dioxane, addition of an appropriate alky lating agent (methyl iodide for gem-dimethylation, 1.3- O dibromoethane for spiro-cyclopropanation, or 1,4-dibro 55 mopropane for spiro-cyclobutanation), followed by addition R" n of ester. After heating the resulting slurry for 5 to 30 minutes from between 50° and 75° C., the reaction is complete. N O Monoalkylation is achieved under typical kinetic conditions, and is best exemplified by Preparation 19 below. 60 Reaction 5. Nitrile reductions of (10.0.8) are carried out Reaction 7 under either hydrous conditions, in ammonium hydroxide/ R5 (Preparation 13) methanol solvent (Preparation 4), or under anhydrous con R6 ditions in ethanol (Preparation 9) in the presence of molecu lar sieves. Palladium hydroxide (Pearlman's catalyst) is used 65 (10.1.4, R = alkyl) in either case, with an atmosphere of hydrogen (30 to 60 psi, typically 50 psi) to yield amine compound (10.0.9). US 7,250,518 B2 131 132 Reaction 6. Ethyl 2-chloronicotinates (10.1.1) are reacted anhydrous polar solvent, typically dichloromethane, dimeth with the appropriate phenol in the presence of inorganic base ylformamide, or tetrahydrofuran. After approximately 0.5 (preferably cesium carbonate) in an anhydrous polar solvent, hr, the amine (10.0.9) is added, and the resulting mixture is preferably dioxane, dimethylformamide, or dimethylsulfox stirred at ambient temperature for 12 to 24 hrs to yield ide, with heating (80° to 120° C.) for 12 to 168 hrs. coupled ester (10.1.4). Saponification of the resulting coupled products is carried Reaction 8. The coupled ester (10.1.4) is saponified in out with aqueous base, typically lithium hydroxide, either refluxing t-butanol with aqueous Sodium hydroxide, or in added to the coupling reaction mixture or in a separate step tetrahyrdrofuran with aqueous lithium hydroxide at ambient after isolating the coupled ester. Acidification of the Saponi temperature, and Subsequently acidified with concentrated fied esters yields the carboxylic acids (10.1.3). 10 hydrochloric acid to yield carboxylic acid (10.1.5). Reaction 7. Standard amide coupling conditions are used Once a compound of Formula (1.0.0) has been prepared for this reaction. A typical method involves mixing the in accordance with SYNTHESIS SCHEMES (10.0.0) and carboxylic acid (10.1.3) with 1-3-(dimethylamino)propyl (10.1.0) described above, further embodiments of the com 3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole pounds of Formula (1.0.0) may be prepared as is shown in hydrate, and N,N-diisopropylethylamine or triethylamine in SYNTHESIS SCHEME (10.2.0) below:

SYNTHESIS SCHEME (10.2.0)

Reaction 9 Examples - N. 3a, 5a, and 5b O R1 RI sas 3. N N 4. O fi || RA 7 2 21 -R N O RB R8

R5 (10.2.2)

(10.2.1) Reaction 10 Preparations 20 and 21

O R R1 Sás N R^ || - 2 2 Reaction 12 C.N O Examples 4, and 7a-c RB (10.2.3)

R 6 US 7,250,518 B2 133 134 -continued N Reaction 11 Preparation 27a

O / RI SA fi || RA 2 2 OH N O RB

R5 (10.2.5) (10.2.4) R5 R6

Preparations 26a and 26b -/

Reaction 9. Activation of the acid (10.2.1) is achieved by 25 addition of 1-3-(dimethylamino)propyl-3-ethylcarbodiim SYNTHESIS SCHEME (10.3.0) ide hydrochloride, 1-hydroxybenzotriazole hydrate, and oHCI N,N-diisopropylethylamine or triethylamine in anhydrous NH2 polar solvent, typically tetrahydrofuran, dichloromethane, or Reaction -N RI dimethylformamide. After stirring at ambient temperature 30 Preparation 14 for 0.5 to 18 hr, preferably 16 hr, excess amine (HNRR) is added (as a gas or solution, depending upon the Volatility of the amine), and concentrated to yield crude amide (10.2.2). Alternatively, acid (10.2.1) activation is achieved by disso 35 lution in dichloromethane with a catalytic amount of dim Reaction 14 ethylformamide added, or in pure dimethylformamide, fol Preparation 22 lowed by oxalyl chloride. After stirring at ambient temperature for 0.5 to 18 hr, preferably 1 hr., excess amine (HNR'R') is added (as a gas or solution, depending upon the 4\o volatility of the amine), and concentrated to yield crude 40 (10.3.1) amide (10.2.2). O Reaction 10. Conversion of amide (10.2.2) to nitrile RI (10.2.3) is achieved with excess neat phosphorus oxychlo R as ride (as solvent and reagent) and heating from 60 deg C. to 110 deg C., typically 90 deg C., for 0.5 to 12 hr., preferably 45 1 to 2 hr. 4. O 2 OH Reaction 11. An alternative source of the nitrile (10.2.3) is accessible through replacement of the tertiary alcohol (10.2.4) using trimethylsilyl cyanide and tin(IV) chloride in anhydrous dichloromethane, as described in detail in Prepa 50 ration 27a. Reaction 12. Tetrazole (10.2.5) is made from the nitrile (10.3.3) C. (10.2.3) by reacting with sodium azide and trimethylamine R6 hydrochloride in anhydrous toluene or benzene, followed by heating in a sealable tube (90-130 deg C., preferably 110 55 O Reaction 15 120 deg C.) for 5 to 18 hr. Alternatively, the nitrile (10.2.3) RI Preparation 23 is reacted with trimethylsilyl azide and catalytic dialkyltin R N N S4 oxide (alkyl is typically methyl or butyl) in anhydrous fi | H toluene or benzene in a sealable tube, with heating from 2 O 2 N 90-130 deg C. (preferably 95-110 deg C.), for 10 to 24 hr. 60 N \ f Compounds of Formula (1.0.0) where n is 0 and group A N N is attached directly to the remainder of the nucleus may be prepared as illustrated in SYNTHESIS SCHEME (10.3.0) below. The intermediate in that preparation may also be used (10.3.5) to make further compounds of Formula (1.0.0) where group 65 A has different meanings. US 7,250,518 B2 135 136 -continued salts such as Sulfate, nitrate, phosphate, etc.; and alkyl- and mono-arylsulfonates Such as ethanesulfonate, toluene O R1 Sulfonate, and benzenesulfonate; and other organic acids and RI 3. N N sa% YS their corresponding salts such as acetate, tartrate, maleate, fi || 5 Succinate, citrate, benzoate, salicylate, ascorbate, etc. 2 2 Accordingly, the pharmaceutically acceptable acid addi N O tion salts of the compounds of Formula (1.0.0) include, but Reaction 16 are not limited to: acetate, adipate, alginate, arginate, aspar Example 6 N tate, benzoate, benzenesulfonate (besylate), bisulfate, 10 bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopen N R5 tanepropionate, digluconate, dihydrogenphosphate, dini trobenzoate, dodecylsulfate, ethanesulfonate, fumarate, (10.3.4) R6 galacterate (from mucic acid), galacturonate, glucohep 15 tanoate, gluconate, glutamate, glycerophosphate, hemisuc Reaction 13. Nitrile (10.3.1) reduction to amine hydro cinate, hemisulfate, heptanoate, hexanoate, hippurate, chloride (10.3.2) is achieved in anhydrous alcohol (typically hydrochloride, hydrobromide, hydroiodide, 2-hydroxy ethanol) with addition of concentrated aqueous hydrochloric ethanesulfonate, iodide, isethionate, iso-butyrate, lactate, acid under hydrogen gas (30-60 psi, typically 50 psi) in a lactobionate, malate, maleate, malonate, mandelate, meta Parr shaker for 0.5 to 10 hr. preferably 1 to 3 hr. phosphate, methanesulfonate, methylbenzoate, monohydro Reaction 14. Two equivalents of carboxylic acid (10.1.3) genphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, are first activated by reaction with oxalyl chloride in dichlo oxalate, oleate, pamoate, pectinate, persulfate, phenylac romethane and catalytic dimethylformamide to form the etate, 3-phenylpropionate, phosphate, phosphonate, phtha corresponding acid chloride, and the reaction is cooled in a late. dry ice/acetone bath. One equivalent of amine hydrochloride 25 Further, base salts of the compounds of the present (10.3.2) and excess trimethylamine or N,N-disopropylethy invention include, but are not limited to aluminum, ammo lamine are then added and the reaction is allowed to warm nium, calcium, copper, ferric, ferrous, lithium, magnesium, to ambient temperature for 10 tp 24 hr (typically 18 hr). The manganic, manganous, potassium, Sodium, and Zinc salts. crude intermediate obtained is saponified with standard Preferred among the above-recited salts are ammonium; the conditions, for example aqueous lithium hydroxide in tet 30 alkali metal salts sodium and potassium; and the alkaline rahydrofuran, to yield amide (10.3.3) after acidification. earth metal salts calcium and magnesium. Salts of the Reaction 15. The same as Reactions 2 and 3 in Scheme compounds of Formula (1.0.0) derived from pharmaceuti (10.0.0) above. cally acceptable organic non-toxic bases include, but are not Reaction 16. The same as Reaction 12 in Scheme (10.2.0) limited to salts of primary, secondary, and tertiary amines, above. 35 Substituted amines including naturally occurring Substituted amines, cyclic amines, and basic ion exchange resins, e.g., DETAILED DESCRIPTION OF THE arginine, betaine, caffeine, chloroprocaine, choline, N,N'- INVENTION dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 40 2-dimethylaminoethanol, ethanolamine, ethylenediamine, 7.0 Pharmaceutical Salts and Other Forms N-ethylmorpholine, N-ethylpiperidine, glucamine, glu The above-described compounds of the present invention cosamine, histidine, hydrabamine, iso-propylamine, may be utilized in their final, non-salt form. On the other lidocaine, lysine, meglumine, N-methyl-D-glucamine, mor hand, it is also within the scope of the present invention to pholine, piperazine, piperidine, polyamine resins, procaine, utilize those compounds in the form of their pharmaceuti 45 purines, theobromine, triethanolamine, triethylamine, trim cally acceptable salts derived from various organic and ethylamine, tripropylamine, and tris-(hydroxymethyl)-me inorganic acids and bases in accordance with procedures thylamine (tromethamine). well known in the art. Compounds of the present invention which comprise Pharmaceutically acceptable salt forms of the compounds basic nitrogen-containing groups may be quaternized with of Formula (1.0.0) are prepared for the most part by con 50 Such agents as (C-C)alkyl halides, e.g., methyl, ethyl, ventional means. Where the compound of Formula (1.0.0) iso-propyl and tert-butyl chlorides, bromides and iodides: contains a carboxylic acid group, a suitable salt thereof may di (C-C)alkyl Sulfate, e.g., dimethyl, diethyl and diamyl be formed by reacting the compound with an appropriate Sulfates; (Co-Cs)alkyl halides, e.g., decyl, dodecyl, lauryl, base to provide the corresponding base addition salt. myristyl and Stearyl chlorides, bromides and iodides; and Examples of such bases are alkali metal hydroxides includ 55 aryl-(C-C)alkyl halides, e.g., benzyl chloride and phen ing potassium hydroxide, Sodium hydroxide, and lithium ethyl bromide. Such salts permit the preparation of both hydroxide: alkaline earth metal hydroxides such as barium water-soluble and oil-soluble compounds of the present hydroxide and calcium hydroxide; alkali metal alkoxides, invention. e.g., potassium ethanolate and Sodium propanolate; and Among the above-recited pharmaceutical salts those various organic bases such as piperidine, diethanolamine, 60 which are preferred include, but are not limited to acetate, and N-methylglutamine. Also included are the aluminum besylate, citrate, fumarate, gluconate, hemisuccinate, hippu salts of the compounds of Formula (1.0.0). rate, hydrochloride, hydrobromide, isethionate, mandelate, For certain compounds of Formula (1.0.0) acid addition meglumine, nitrate, oleate, phosphonate, pivalate, sodium salts may be formed by treating said compounds with phosphate, Stearate, Sulfate, Sulfosalicylate, tartrate, thioma pharmaceutically acceptable organic and inorganic acids, 65 late, tosylate, and tromethamine. e.g., hydrohalides such as hydrochloride, hydrobromide, The acid addition salts of basic compounds of Formula hydroiodide; other mineral acids and their corresponding (1.0.0) are prepared by contacting the free base form with a US 7,250,518 B2 137 138 sufficient amount of the desired acid to produce the salt in oral dosage form can be adversely affected by physical the conventional manner. The free base may be regenerated characteristics Such as polarity, emesis caused by irritation by contacting the salt form with a base and isolating the free of the gastrointestinal mucosa, destruction by digestive base in the conventional manner. The free base forms differ enzymes and low pH, irregular absorption or propulsion in from their respective salt forms somewhat in certain physi the presence of food or other drugs, and metabolism by cal properties such as solubility in polar solvents, but enzymes of the mucosa, the intestinal flora, or the liver. otherwise the salts are equivalent to their respective free Formulation of said active ingredient into different pharma base forms for purposes of the present invention. ceutically acceptable salt forms may be effective in over As indicated, the pharmaceutically acceptable base addi coming or alleviating one or more of the above-recited tion salts of the compounds of Formula (1.0.0) are formed 10 problems encountered with absorption of oral dosage forms. with metals or amines, such as alkali metals and alkaline A compound of Formula (1.0.0) prepared in accordance earth metals, or organic amines. Preferred metals are with the methods described herein can be separated from the Sodium, potassium, magnesium, and calcium. Preferred reaction mixture in which it is finally produced by any organic amines are N,N'-dibenzylethylenediamine, chloro ordinary means known to the chemist skilled in the prepa procaine, choline, diethanolamine, ethylenediamine, N-me 15 ration of organic compounds. Once separated said com thyl-D-glucamine, and procaine pound can be purified by known methods. Various methods The base addition salts of acidic compounds of the present and techniques can be used as the means for separation and invention are prepared by contacting the free acid form with purification, and include, e.g., distillation; recrystallization; a sufficient amount of the desired base to produce the salt in column chromatography; ion-exchange chromatography; the conventional manner. The free acid form may be regen gel chromatography; affinity chromatography; preparative erated by contacting the salt form with an acid and isolating thin-layer chromatography; and solvent extraction. the free acid form in the conventional manner. The free acid forms differ from their respective salt forms somewhat in 7.1 Stereoisomers physical properties Such as Solubility in polar solvents, but A compound within the scope of Formula (1.0.0) may be otherwise the salts are equivalent to their respective free acid 25 Such that its constituent atoms are capable of being arranged forms for purposes of the present invention. in space in two or more different ways, despite having Multiple salts forms are included within the scope of the identical connectivities. As a consequence, said compound present invention where a compound of the present inven exists in the form of stereoisomers. Sys-trans isomerism is tion contains more than one group capable of forming Such but one type of stereoisomerism. Where the stereoisomers pharmaceutically acceptable salts. Examples of typical mul 30 are nonsuperimposable mirror images of each other, they are tiple salt forms include, but are not limited to bitartrate, enantiomers which have chirality or handedness, because of diacetate, difumarate, dimeglumine, diphosphate, disodium, the presence of one or more asymmetric carbon atoms in and trihydrochloride. their constituent structure. Enantiomers are optically active In light of the above, it can be seen that the expression and therefore distinguishable because they rotate the plane “pharmaceutically acceptable salt as used herein is 35 of polarized light by equal amounts, but in opposite direc intended to mean an active ingredient comprising a com tions. pound of Formula (1.0.0) utilized in the form of a salt Where two or more asymmetric carbon atoms are present thereof, especially where said salt form confers on said in a compound of Formula (1.0.0), there are two possible active ingredient improved pharmacokinetic properties as configurations at each said carbon atom. Where two asym compared to the free form of said active ingredient or some 40 metric carbon atoms are present, for example, there are four other salt form of said active ingredient utilized previously. possible stereoisomers. Further, these four possible stereoi The pharmaceutically acceptable salt form of said active Somers may be arranged into six possible pairs of Stereoi ingredient may also initially confer a desirable pharmaco somers that are different from each other. In order for a pair kinetic property on said active ingredient which it did not of molecules with more than one asymmetric carbon to be previously possess, and may even positively affect the 45 enantiomers, they must have different configurations at pharmacodynamics of said active ingredient with respect to every asymmetric carbon. Those pairs that are not related as its therapeutic activity in the body. enantiomers have a different stereochemical relationship The pharmacokinetic properties of said active ingredient referred to as a diastereomeric relationship. Stereoisomers which may be favorably affected include, e.g., the manner in that are not enantiomers are called diastereoisomers, or more which said active ingredient is transported across cell mem 50 commonly, diastereomers. branes, which in turn may directly and positively affect the All of these well known aspects of the stereochemistry of absorption, distribution, biotransformation and excretion of the compounds of Formula (1.0.0) are contemplated to be a said active ingredient. While the route of administration of part of the present invention. Within the scope of the present the pharmaceutical composition is important, and various invention there is thus included compounds of Formula anatomical, physiological and pathological factors can criti 55 (1.0.0) that are stereoisomers, and where these are enanti cally affect bioavailability, the solubility of said active omers, the individual enantiomers, racemic mixtures of said ingredient is usually dependent upon the character of the enantiomers, and artificial, i.e., manufactured mixtures con particular salt form thereof which it utilized. Further, as the taining proportions of said enantiomers that are different artisan will appreciate, an aqueous solution of said active from the proportions of said enantiomers found in a racemic ingredient will provide the most rapid absorption of said 60 mixture. Where a compound of Formula (1.0.0) comprises active ingredient into the body of a patient being treated, Stereoisomers that are diastereomers, there is included while lipid solutions and Suspensions, as well as Solid within the scope of said compound the individual diastere dosage forms, will result in less rapid absorption of said omers as well as mixtures of any two or more of said active ingredient. diastereomers in any proportions thereof. Oral ingestion of an active ingredient of Formula (1.0.0) 65 By way of illustration, in the case where there is a single is the most preferred route of administration for reasons of asymmetric carbon atom in a compound of Formula (1.0.0), safety, convenience, and economy, but absorption of such an resulting in the (-)(R) and (+)(S) enantiomers thereof; there US 7,250,518 B2 139 140 is included within the scope of said compound all pharma dosage requirements, which under most circumstances ceutically acceptable salt forms, prodrugs and metabolites would constitute a preferred embodiment of the present thereof which are therapeutically active and useful in treat invention. An isotopically-labelled compound of Formula ing or preventing the diseases and conditions described (1.0.0) can usually be prepared by carrying out the proce further herein. Where a compound of Formula (1.0.0) exists 5 dures disclosed in the Synthesis Schemes and related in the form of (-)(R) and (+)(S) enantiomers, there is also description, Examples, and Preparations herein, Substituting included within the scope of said compound the (+)(S) a readily available isotopically-labelled reagent for its cor enantiomer alone, or the (-)(R) enantiomer alone, in the case responding non-isotopically-labelled reagent. where all, substantially all, or a predominant share of the therapeutic activity resides in only one of said enantiomers, 10 Deuterium, H, can also be incorporated into a compound and/or unwanted side effects reside in only one of said of Formula (1.0.0) for the purpose of manipulating the enantiomers. In the case where there is Substantially no oxidative metabolism of said compound by way of the difference between the biological activities of both enanti primary kinetic isotope effect. The primary kinetic isotope omers, there is further included within the scope of said effect is a change of rate for a chemical reaction that results compound of Formula (1.0.0) the (+)(S) enantiomer and the 15 from Substitution of isotopic nuclei, which in turn is caused (-) (R) enantiomer present together as a racemic mixture or by the change in ground State energies required for covalent as a non-racemic mixture in any ratio of proportionate bond formation Subsequent to said isotopic Substitution. amounts thereof. Substitution of a heavier isotope will usually result in a For example, the particular biological activities and/or lowering of the ground state energy for a chemical bond, physical and chemical properties of a pair or set of enanti thereby causing a reduction in rate for a rate-limiting bond omers of a compound of Formula (1.0.0) where such exist, breaking step. If the bond-breaking event occurs on or near may suggest use of said enantiomers in certain ratios to a saddle-point region along the coordinate of a multi-product constitute a final therapeutic product. By way of illustration, reaction, the product distribution ratios can be altered sub in the case where there is a pair of enantiomers, they may be stantially. By way of illustration, when deuterium is bound employed in ratios such as 90% (R)-10% (S); 80% (R)- 25 to a carbon atom at a non-exchangeable site, rate differences 20% (S); 70% (R)-30% (S); 60% (R)-40% (S); 50% (R)- of k/k, 2-7 are typical. This difference in rate, applied 50% (S); 40% (R)-60% (S); 30% (R)-70% (S); 20% (R)- successfully to an oxidatively labile compound of Formula 80% (S); and 10% (R)-90% (S). After evaluating the prop (1.0.0), can dramatically affect the profile of said compound erties of the various enantiomers of a compound of Formula in vivo and result in improved pharmacokinetic properties. (1.0.0) where such exist, the proportionate amount of one or 30 In discovering and developing therapeutic agents, the more of said enantiomers with certain desired properties that skilled artisan seeks to optimize pharmacokinetic param will constitute the final therapeutic product can be deter eters while retaining desirable in vitro properties. It is a mined in a straightforward manner. reasonable Surmise that many compounds with poor phar 7.2 Isotopes 35 macokinetic profiles suffer from a lability to oxidative There is further contemplated to be included within the metabolism. In vitro liver microsomal assays now available scope of a compound of Formula (1.0.0) isotopically-la provide valuable information about the course of this oxi belled forms thereof. An isotopically-labelled form of a dative metabolism, which in turn permits the rational design compound of Formula (1.0.0) is identical to said compound of deuterated compounds of Formula (1.0.0) with improved but for the fact that one or more atoms of said compound 40 stability through resistance to Such oxidative metabolism. have been replaced by an atom or atoms having an atomic Significant improvements in the pharmacokinetic profiles of mass or mass number different from the atomic mass or mass compounds of Formula (1.0.0) are thereby obtained, and can number of said atom which is usually found in nature. be expressed quantitatively in terms of increases in in vivo Examples of isotopes which are readily available commer half-life (t/2), concentration at maximum therapeutic effect cially and which can be incorporated into a compound of 45 (C), area under the dose response curve (AUC), and F: Formula (1.0.0) in accordance with well established proce and in terms of decreases in clearance, dose, and cost-of dures, include isotopes of hydrogen, carbon, nitrogen, oxy goods. gen, phosphorous, fluorine and chlorine, e.g., H., H 'C, By way of illustration of the above, a compound of “C, N, O, 7O, P, 2P, 5S, F, and C1, respectively. Formula (1.0.0) which has multiple potential sites for oxi A compound of Formula (1.0.0), a prodrug thereof, or a 50 dative metabolism, e.g., benzylic hydrogen atoms and pharmaceutically acceptable salt of either which contains hydrogen atoms a to a nitrogen atom, is prepared as a series one or more of the above-mentioned isotopes and/or other of analogs in which various combinations of hydrogen isotopes of other atoms is contemplated to be within the atoms are replaced by deuterium atoms So that some, most Scope of the present invention. or all of said hydrogen atoms are replaced with deuterium An isotopically-labelled compound of Formula (1.0.0) 55 atoms. Half-life determinations provide an expedient and may be used in a number of beneficial ways. For example, accurate determination of the extent of improvement in an isotopically-labelled compound of Formula (1.0.0), e.g., resistance to oxidative metabolism. In this manner it is one in which a radioactive isotope such as H or ''C has determined that the half-life of the parent compound can be been incorporated, will be useful in drug and/or substrate extended by as much as 100% as the result of such deute tissue distribution assays. These radioactive isotopes, i.e., 60 rium-for-hydrogen Substitution. tritium, H, and carbon-14, ''C, are especially preferred for Deuterium-for-hydrogen Substitution in a compound of their ease of preparation and eminent detectability. Incor Formula (1.0.0) can also be used to achieve a favorable poration of heavier isotopes, e.g., deuterium, H, into a alteration in the metabolite profile of the parent compound compound of Formula (1.0.0) will provide therapeutic as a way of diminishing or eliminating unwanted toxic advantages based on the greater metabolic stability of said 65 metabolites. For example, where a toxic metabolite arises isotopically-labelled compound. Greater metabolic stability through an oxidative carbon-hydrogen, C-H bond Scis translates directly into increased in vivo half-life or reduced Sion, the deuterated analog is reasonably expected to greatly US 7,250,518 B2 141 142 diminish or eliminate production of the unwanted metabo esterase in inflammatory leukocytes. The four subtypes of lite, even in the case where the particular oxidation is not a PDE4, i.e., PDE4A, PDE4B, PDE4C, and PDE4D, are rate-determining step. widely distributed in human tissues, as determined by the Further information concerning the state of the art with presence of their mRNAs. PDE4D is expressed in kidney, respect to deuterium-for-hydrogen Substitution may be 5 thymus, Small intestine, and colon tissues, and is strongly found, e.g., in Hanzlik et al., J. Org. Chem. 55 3992-3997, expressed in brain, lung, skeletal muscle, prostate, and 1990; Reider et al., J. Org. Chem. 52 3326-3334, 1987: peripheral blood leukocyte (PBL) tissues. It is only weakly Foster, Adv. Drug Res. 14 1-40, 1985; Gillette et al. , expressed in heart, placenta, liver, pancreas, spleen, testes, Biochemistry 33(10) 2927-2937, 1994; and Jarman et al. and ovary tissues. PDE4A and PDE4B are also strongly Carcinogenesis 16(4) 683-688, 1993. 10 expressed in brain and skeletal muscle tissues, and only weakly expressed in placenta, liver, and ovary tissues. DETAILED DESCRIPTION OF THE PDE4C is strongly expressed in skeletal muscle tissue as INVENTION well, and is also weakly expressed in ovary tissue. PDE4C is usually not detectable in the majority of the above 15 mentioned tissues. 8.0 Therapeutic Applications and Clinical Endpoints The PDE4 family of isozymes is the predominant form of The description which follows concerns the therapeutic phosphodiesterase found in cell types implicated in chronic applications to which the compounds of Formula (1.0.0) inflammatory diseases, and among bone-marrow derived may be put, and where applicable an explanation of the cell types, only platelets do not express PDE. PDE4 is the clinical endpoints associated with Such therapeutic applica major cAMP-metabolizing enzyme in immune and inflam tions. There is also set forth a disclosure of various in vitro matory cells, and is one of two major cAMP-metabolizing assays and animal model experiments, which are capable of enzymes in airway smooth muscle. PDE4 is exclusively providing data Sufficient to define and demonstrate the present in neutrophils, eosinophils, basophils, and mono therapeutic utility of the compounds of Formula (1.0.0). cyctes, while in macrophages PDE3 and PDE 1 activity, and The therapeutic utility of the compounds of Formula 25 in T lymphocytes PDE7 activity has also been demonstrated. (1.0.0) is applicable to a patient or subject afflicted with a The beneficial anti-inflammatory effects of inhibitors of disease or condition as herein set forth and therefore in need PDE have been demonstrated heretofore using in vitro of such treatment. The beneficial results are therapeutic experiments, which have established that Such compounds whether administered to animals or humans. As used herein inhibit Superoxide generation in human monocytes, eosino the terms “animal’ and “animals” is used merely for the 30 phils, and neutrophils; mediator release in basophils, mac purpose of pointing out human beings as opposed to other rophages, and neutrophils; and TNFC. release in monocytes members of the animal kingdom. The compounds of For and macrophages. PDE inhibitors also inhibit mediator mula (1.0.0) have therapeutic applicability in the treatment release of inflammatory cells like monocytes and monocyte of mammals, and in particular of humans. All of the major derived macrophages, lung mast cells, T lymphocytes, B Subdivisions of the class of mammals (Mammalia) are 35 lymphocytes, alveolar macrophages, and eosinophils. included within the scope of the present invention with Beneficial anti-inflammatory effects have also been regard to being recipients of therapeutic treatment as observed in vivo heretofore, including inhibition of described herein. Mammals have value as pets to humans microvascular leakage into the lungs of sensitized guinea and are therefore likely to be subjects of treatment. This pigs, and reduction of bronchial hyper-reactivity and eosi applies especially to the canine and feline groups of mam 40 nophilia in cynomolgus monkeys following repeated antigen mals. Other mammals are valued as domesticated animals challenge. It has also been demonstrated heretofore that and their treatment in accordance with the present invention PDE4 inhibitors potently suppress TNFC. release from is likely in view of the adverse economic impact of not mononuclear phagocytes. treating the diseases and conditions described herein. This applies especially to the equine, bovine, porcine, and ovine 45 8.1 Asthma groups of mammals. One of the most important respiratory diseases treatable The compounds of Formula (1.0.0) inhibit the PDE4 with PDE4 inhibitors of the type within the scope of the isozyme and thereby have a wide range of therapeutic compounds of Formula (1.0.0) is asthma, a chronic, increas applications, as described further below, because of the ingly common disorder encountered worldwide and charac essential role which the PDE4 family of isozymes plays in 50 terized by intermittent reversible airway obstruction, airway the physiology of all mammals. The enzymatic role per hyper-responsiveness and inflammation. The cause of formed by the PDE4 isozymes is the intracellular hydrolysis asthma has yet to be determined, but the most common of adenosine 3',5'-monophosphate (cAMP) within pro-in pathological expression of asthma is inflammation of the flammatory leukocytes. cAMP in turn, is responsible for airways, which may be significant even in the airways of mediating the effects of numerous hormones in the body, and 55 patients with mild asthma. Based on bronchial biopsy and as a consequence, PDE4 inhibition plays a significant role in lavage studies it has been clearly shown that asthma a variety of physiological processes. There is extensive involves infiltration by mast cells, eosinophils, and T-lym literature in the art describing the effects of PDE inhibitors phocytes into a patient’s airways. Bronchoalveolar lavage on various inflammatory cell responses, which in addition to (BAL) in atopic asthmatics shows activation of interleukin cAMP elevation, include inhibition of superoxide produc 60 (IL)-3, IL-4, IL-5 and granulocyte/macrophage-colony tion, degranulation, chemotaxis and tumor necrosis factor stimulating factor (GM-CSF) that suggests the presence of a (TNF) release in eosinophils, neutrophils and monocytes. T-helper 2 (Th-2)-like T-cell population. PDE4 was first identified in 1985, NemoZ. et al. Biochem. Compounds of Formula (1.0.0) inhibit PDE4 in human Pharmaco. 34 2997-3000, 1985, and the PDE4 inhibitors eosinophils and are therefore useful in the treatment of rolipram and denbufylline were studied early on in clinical 65 atopic and non-atopic asthma. The term "atopy refers to a trials for CNS indications such as depression. Subsequently, genetic predisposition toward the development of type I it was established that PDE4 is the principal phosphodi (immediate) hypersensitivity reactions against common US 7,250,518 B2 143 144 environmental antigens. The most common clinical mani It is also possible to evaluate the ability of the PDE4 festation is allergic rhinitis, while bronchial asthma, atopic inhibitory compounds of Formula (1.0.0) to increase cAMP dermatitis, and food allergy occur less frequently. Accord accumulation in intact tissues by using U-937 cells, a human ingly, the expression "atopic asthma’ as used herein is monocyte cell line that has been shown to contain a large intended to be synonymous with “allergic asthma’, i.e., amount of PDE4. In order to assess the level of PDE4 bronchial asthma which is an allergic manifestation in a inhibitory activity in intact cells, nondifferentiated U-937 sensitized person. The term “non-atopic asthma’ as used cells (approximately 10 cells/reaction tube) are incubated herein is intended to refer to all other asthmas, especially with various concentrations (0.01-1000 uM) of PDE inhibi essential or “true' asthma, which is provoked by a variety of tors for 1 m and 1 LM prostaglandin E for an additional 4 factors, including vigorous exercise, irritant particles, psy 10 m. The cells are lysed 5 m after initiating the reaction by the chologic stresses, etc. addition of 17.5% perchloric acid, the pH is brought to a The use of the compounds of Formula (1.0.0) to treat neutral level by the addition of 1 M KCO, and cAMP atopic asthma or non-atopic asthma is established and dem content is assessed by RIA. A general protocol for this assay onstrated by the models of PDE inhibition, inhibition of is described in Brooker et al., “Radioimmunoassay of cyclic eosinophil activation, and cell infiltration models described 15 AMP and cyclic GMP Adv. Cyclic Nucleotide Res. 10 below. 1-33, 1979. PDE Isozyme Inhibition. The ability of the compounds Pulmonary Inflammation in Allergic Cynomolgus Mon of Formula (1.0.0) to selectively inhibit PDE4 is demon keys—The ability of the compounds of Formula (1.0.0) to strated by the human PDE inhibition assay. In this assay all inhibit Ascaris antigen induced increases in the inflamma isoenzyme preparations are derived from human Sources. tory cell content of bronchial alveolar lavage fluid from PDE3 and PDE4 preparations are obtained by taking advan cynomolgus monkey subjects is evaluated in this method. tage of the predominance of PDE3 isozymes in platelets and Using a cross-over design, 8-10 Ascaris-sensitive cynomol PDE4 isozymes in neutrophils. The following techniques are gus monkeys are treated with vehicle or drug. At appropriate utilized. Citrated human blood is collected and neutrophils pretreatment time, each monkey is anesthetized (ketamine are separated by dextran sedimentation, density gradient 25 10 m/kg+xylazine 1 mg/kg, i.m.) and intubated with a cuffed centrifugation, and hypotonic lysis of erythrocytes. Human endotracheal tube. Bronchoalveolar lavage (BAL) is per platelets from the same source are washed with PBS (NaCl formed using one 15 ml wash of phosphate buffered saline 140 mM, KC1 2.7 mM, KHPO4 1.5 mM, Na HPO, 8.1 (PBS) delivered through a pediatric fiberoptic bronchoscope mM, pH 7.4). Neutrophils and platelets are suspended in 10 inserted through the endotracheal tube and wedged into a ml of buffer (0.24 M sucrose, 1 mM EDTA, 1 mM dithio 30 third to fifth generation bronchus. Lavage fluid is gently threitol, 10 mM tris HCl, pH 7.4) containing the following aspirated and collected in a syringe. After BAL is complete, protease inhibitor solutions: 5ul/ml of phenylmethylsulpho each animal receives a 2 min exposure to a concentration of nylfluoride (7 mg/ml in 2-propanol), 1 L/ml leupeptin and Ascaris Suum aerosol which doubles respiratory system pepstatin A (1 mg/ml each, in ethanol). After Sonication for resistance determined in previous experiments. Each mon 15 sec at 4°C., homogenates are centrifuged (2200 g). The 35 key is returned to its cage and 24 hr later a second lavage is pellet is resuspended in 10 ml of buffer and the sonication is performed, using 15 ml PBS, on the opposite side of the repeated. Pooled supernatants are stored at -20° C. lung. One week after the first trial, control and treated Other isoenzymes are partially purified employing chro monkeys are reversed and the experiment repeated. To matographic methods as described in the art, with PDE1 and determine the percent composition of each leukocyte type, PDE5 being obtained from human lung, and PDE2 being 40 two slides from each monkey BAL sample is obtained by obtained from human platelets. PDE activity is assayed in centrifuging 2x150 ul lavage fluid for 2 min (a) 500 rpm in the presence and absence of a test Substance of Formula Cytospin centrifuge. Slides are stained in Diff-Quick for (1.0.0) at varying concentrations, using the ion-exchange differential cell count and cells identified by standard mor column method described by Thompson et al., Nucleotide phological criteria. Total leukocyte numbers per milliliter of Res., 10 69-92, 1979; with 1 uMH-cyclic AMP as sub 45 BAL fluid are determined by diluting 20 ul of sample in 20 strate (PDE3 and PDE4), or 0.5 uM calcium, 0.125 uM ml Isoton, adding 3 drops of Zapoglobin to lyse erythrocytes calmodulin and 1.0 uMH-cyclic AMP (PDE1), or 100 and reading the sample using a Coulter Counter. Compari uMH-cyclic AMP (PDE2), or 1.0 MH-cyclic GMP sons are made between the ratio of increase in bronchial (PDE5). alveolar lavage eosinophil, cytokine or mediator levels, In this test method, compounds of Formula (1.0.0) pre 50 pre-antigen challenge versus 24 hours post antigen chal dominantly inhibit PDE4 isozymes, having relatively little lenge, with and without drug treatment. inhibitory effect on PDE1, PDE2, PDE3, and PDE5. In the above test model the combinations of therapeutic The selective PDE4 inhibitory activity of the compounds agents of the present invention exhibit anti-inflammatory of Formula (1.0.0) can also be determined using a battery of activity at dosages in the range of from 0.001 to 0.1 mg/kg five distinct PDE isozymes in accordance with procedures 55 iv. or 0.01 to 10.0 mg/kg p.o. or 0.001 to 0.1 mg/kg it. known in the art. The tissues used as sources of the different Another useful assay, based on the use of primates, is that isozymes can include the following: PDE1B porcine aorta; described in Turner et al., “Characterization of a primate PDE1C guinea-pig heart; PDE3 guinea-pig heart; model of asthma using anti-allergy/anti-asthma agents.” PDE4 human monocyte; and PDE5—canine tracheole. Inflammation Research 45 239-245, 1996. PDEs 1B, 1C, 3, and 5 are partially purified using conven 60 Anti-inflammatory Activity—The anti-inflammatory tional chromatographic techniques; Torphy and Cieslinski, activity of the compounds of Formula (1.0.0) is demon Mol. Pharmacol. 37 206-214, 1990. PDE4 is purified to strated by the inhibition of eosinophil activation as measured kinetic homogeneity by the sequential use of anion-ex by Sephadex bead stimulated LTE4 production in whole change followed by heparin-Sepharose chromatography; human blood. Whole Blood Assay for LTE4 using Sephadex Torphy et al., J. Biol. Chem. 267 1798-1804, 1992. PDE 65 Beads as Stimulant. On the day before the assay, siliconize activity is assayed using the protocol of Torphy and Cies glass tubes with Sigmacote (Sigma, Catil SL-2). Before linski described in the above-recited paper. Drawing the blood, dilute compounds in DMSO 1000x, add US 7,250,518 B2 145 146 1 ul of either DMSO or compound to each respective tube, tion of airways hyper-reactivity consequent to other drug and place rack of tubes in 37° C. water bath. Have Blood therapy, e.g., aspirin or B-agonist therapy. drawn into heparinized Vacutainer tube #6480 (143USP The compounds of Formula (1.0.0) are useful in the units sodium heparin, 10 ml), 10 tubes=100 ml blood. Pool treatment of asthma of whatever type, etiology, or patho Blood tubes in two 50 ml conical tubes. Add 1 ml of whole genesis; including intrinsic asthma attributed to pathophysi blood to each siliconized tube containing DMSO or com pound VORTEX and then incubate at 37° C. for 15 minutes. ologic disturbances, extrinsic asthma caused by some factor To prepare the Sephadex G-15 beads (Pharmacia, Cath in the environment, and essential asthma of unknown or 17-0020-01) suspension, add 3.3g. of Sephadex G-15, mix inapparent cause. The compounds of Formula (1.0.0) are with 20 mls of PBS in a 100 ml beaker then mix with a 10 useful in the treatment of allergic (atopic/bronchial/IgE magnetic stir bar. After 15 minutes, add 100 ul of Sephadex mediated) asthma; and they are useful as well in the treat G-15 beads to each tube except the Sephadex tubes which ment of non-atopic asthma, including e.g. bronchitic, will provide the baseline value for LTE4 release. Vortex and emphysematous, exercise-induced, and occupational incubate for 90 minutes at 37° C. At the end of 90 minutes asthma; infective asthma that is a sequela to microbial, incubation, add 20 ul of 15% EDTA, VORTEX and centri 15 especially bacterial, fungal, protozoal, or viral infection; and fuge for 5 minutes at 1000 rpm. Then remove and save the other non-allergic asthmas, e.g., incipient asthma (wheezy plasma sample for analysis. LTE4 levels are determined by infant syndrome). Cayman’s Cysteinyl-LT ELISA kit (Cat # 520501). Percent The compounds of Formula (1.0.0) are further useful in inhibition is calculated as 100x1-(LTE4 concentration in the the treatment of pneumoconiosis of whatever type, etiology, drug treated sample divided by the LTE4 concentration in or pathogenesis; including, e.g., aluminosis (bauxite work the non-drug treated control samples). ers disease); anthracosis (miners asthma); asbestosis Compounds of Formula (1.0.0) are active in the above test (steam-fitters asthma); chalicosis (flint disease); ptilosis method at concentrations in the range of from 0.0001 uM to caused by inhaling the dust from ostrich feathers; siderosis 0.5 LM, with preferred embodiments being active at con caused by the inhalation of iron particles; silicosis (grinders centrations in the range of from 0.5 nM to 20 nM. 25 From the above it may be seen that compounds of disease); byssinosis (cotton-dust asthma); and talc pneumo Formula (1.0.0) are useful for the treatment of inflammatory coniosis. or obstructive airways diseases or other conditions involving airways obstruction. In particular they are useful for the 8.2 Chronic Obstructive Pulmonary Disease (COPD) treatment of bronchial asthma. 30 The compounds of Formula (1.0.0) are still further useful In view of their anti-inflammatory activity, their influence in the treatment of COPD or COAD including chronic on airways hyper-reactivity, and their profile in relation to bronchitis, pulmonary emphysema or dyspnea associated PDE isoenzyme inhibition, in particular as selective PDE4 therewith. COPD is characterized by irreversible, progres inhibitors, the compounds of Formula (1.0.0) are useful for sive airways obstruction. Chronic bronchitis is associated the treatment, in particular prophylactic treatment, of 35 with hyperplasia and hypertrophy of the mucus secreting obstructive or inflammatory airways diseases. Thus, by glands of the Submucosa in the large cartilaginous airways. continued and regular administration over prolonged periods Goblet cell hyperplasia, mucosal and Submucosal inflam of time the compounds of Formula (1.0.0) are useful in matory cell infiltration, edema, fibrosis, mucus plugs and providing advance protection against the recurrence of bron increased Smooth muscle are all found in the terminal and choconstriction or other symptomatic attack consequential 40 respiratory bronchioles. The small airways are known to be to obstructive or inflammatory airways diseases. The com a major site of airway obstruction. Emphysema is charac pounds of Formula (1.0.0) are also useful for the control, terized by destruction of the alveolar wall and loss of lung amelioration or reversal of the basal status of Such diseases. elasticity. A number of risk factors have also been identified Having regard to their bronchodilator activity the com as linked to the incidence of COPD. The link between pounds of Formula (1.0.0) are useful as bronchodilators, 45 tobacco smoking and COPD is well established. Other risk e.g., in the treatment of chronic or acute bronchoconstric factors include exposure to coal dust and various genetic tion, and for the symptomatic treatment of obstructive or factors. See Sandford et al., “Genetic risk factors for chronic inflammatory airways diseases. obstructive pulmonary disease.” Eur: Respir: J. 10 1380 The words “treatment' and “treating as used throughout 1391, 1997. The incidence of COPD is increasing and it the present specification and claims in relation to obstructive 50 represents a significant economic burden on the populations or inflammatory airways diseases are to be understood, of the industrialized nations. COPD also presents itself accordingly, as embracing both prophylactic and symptom clinically with a wide range of variation from simple chronic atic modes of therapy. bronchitis without disability to patients in a severely dis In light of the above description, it may be seen that the abled state with chronic respiratory failure. present invention also relates to a method for the treatment 55 COPD is characterized by inflammation of the airways, as of airways hyper-reactivity in mammals; to a method of is the case with asthma, but the inflammatory cells that have effecting bronchodilation in mammals; and in particular, to been found in the bronchoalveolar lavage fluid and sputum a method of treating obstructive or inflammatory airways of patients neutrophils rather than eosinophils. Elevated diseases, especially asthma, in a mammal Subject in need levels of inflammatory mediators are also found in COPD thereof, which method comprises administering to said 60 patients, including IL-8, LTB, and TNF-C., and the surface Subject mammal an effective amount of a compound of epithelium and sub-epithelium of the bronchi of such Formula (1.0.0). patients has been found to be infiltrated by T-lymphocytes Obstructive or inflammatory airways diseases to which and macrophages. Symptomatic relief for COPD patients the present invention applies include asthma, pneumoconio can be provided by the use of 3-agonist and anticholinergic sis; chronic eosinophilic pneumonia; chronic obstructive 65 bronchodilators, but the progress of the disease remains airways or pulmonary disease (COAD or COPD); and adult unaltered. COPD has been treated using theophylline, but respiratory distress syndrome (ARDS), as well as exacerba without much success, even though it reduces neutrophil US 7,250,518 B2 147 148 counts in the sputum of COPD patients. Steroids have also facilitate release from monocytes of the anti-inflammatory failed to hold out much promise as satisfactory treatment cytokine IL-10, which in turn is capable of decreasing the agents in COPD. generation of TNF-C., IL-1B, and GM-CSF by synovial fluid Accordingly, the use of the compounds of Formula (1.0.0) mononuclear cells, thereby augmenting the overall anti to treat COPD and its related and included obstructed airways diseases, represents a significant advance in the art. inflammatory profile of the PDE4 inhibitors of Formula The present invention is not limited to any particular mode (1.0.0); Schudt et al., “PDE isoenzymes as targets for of action or any hypothesis as to the way in which the anti-asthma drugs.” Eur: Respir: J. 8 1179-1183, 1995; and desired therapeutic objectives have been obtained by utiliz Kambayashi et al., “Cyclic nucleotide phosphodiesterase ing the compounds of Formula (1.0.0). However, it is 10 Type IV participates in the regulation of IL-10 and the recognized in the art that PDE4 is the predominant PDE in subsequent inhibition of TNF-alpha and IL-6 release by neutrophils and macrophages; Cheng et al., “Synthesis and endotoxin-stimulated macrophages,” J. Immunol. 155 4909 in vitro profile of a novel series of catechol benzimidazoles. 4916, 1995. The discovery of potent, selective phosphodiesterase Type The application of PDE4 inhibitors to the treatment of IV inhibitors with greatly attenuated affinity for the 3H 15 rolipram binding site. Bioorg. Med. Chem. Lett. 5 1969 COPD in human patients has been demonstrated in clinical 1972, 1995; Wright et al. “Differential inhibition of human trials. Treatment with SB-207,499, represented by Formula neutrophil functions: role of cyclic AMP-specific, cyclic (0.1.9) above, at a dose of 15 mg twice a day for six weeks GMP-insensitive phosphodiesterase. Biochem. Pharmaco. has been shown to result in increrases in FEV, and forced 40 699-707, 1990; Schudt et al., “Influence of selective vital capacity (FVC); Brown, W. M., “SB-207499, ' Anti phosphodiesterase inhibitors on human neutrophil functions inflamm. Immunomodulatory Invest. Drugs 1 39-47, 1999. and levels of cAMP and Cai, Naunyn Schmiedebergs Arch. The clinical efficacy of SB-207,499 has also been demon Pharmacol. 344 682-690, 1991; and Tenor et al., “Cyclic strated in a four week trial that has provided evidence of nucleotide phosphodiesterase isoenzyme activities in human improved FEV; and in a six week study in COPD patients alveolar macrophages.” Clin. Exp. Allergy 25 625-633, 25 1995. receiving 15 mg twice a day that has also provided evidence In order to provide a better understanding of the present of improved FEV; Brown, Ibid. SB-207,499 has already invention, the inference is made here that the compounds of been described further above and represented by Formula Formula (1.0.0) inhibit PDE4s in neutrophils, resulting in (0.1.9): reduced chemotaxis, activation, adherence, and degranula 30 tion; Schudt et al., Ibid.; Nelson et al., “Effect of selective (0.1.9) phosphodiesterase inhibitors on the polymorphonuclear leu COOH kocyte respiratory burst.” J. Allergy Clin. Immunol. 86 801-808, 1990; and Bloeman et al., “Increased cAMP levels in stimulated neutrophils inhibit their adhesion to human 35 bronchial epithelial cells.” Am. J. Physiol. 272 L580-587, CN 1997. It is also inferred that the compounds of Formula (1.0.0) reduce superoxide anion production mediated by PDE4s in peripheral blood neutrophils, and that they regulate leukot 40 riene synthesis mediated by PDE4s; Wright et al., Ibid.; Schudt et al., Ibid.; Bloeman et al., Ibid.; Al Essa, et al., “Heterogeneity of circulating and exudated polymorpho nuclear leukocytes in Superoxide-generating response to SB-207,499 cyclic AMP and cyclic AMP-elevating agents: investigation 45 of the underlying mechanism.” Biochem. Pharmaco. 49 315-322, 1995: Ottonello et al., “Cyclic AMP-elevating 8.3 Bronchitis and Bronchiectasis agents down-regulate the oxidative burst induced by granu In accordance with the particular and diverse inhibitory locyte-macrophage colony Stimulating factor (GM-CSF) in activities described above that are possessed by the com adherent neutrophils.” Clin. Exp. Immunol. 101 502-506, 50 pounds of Formula (1.0.0), they are useful in the treatment 1995; and Ottonello et al., “Tumor necrosis factor alpha of bronchitis of whatever type, etiology, or pathogenesis, induced oxidative burst in neutrophils adherent to fibronec including, e.g., acute bronchitis which has a short but severe tin: effects of cyclic AMP-elevating agents. Br. J. Haema course and is caused by exposure to cold, breathing of tol. 91 566-570, 1995. irritant Substances, or an acute infection; acute laryngotra It is further inferred that the compounds of Formula 55 (1.0.0) inhibit CD11b/CD18 expression: Berends et al., cheal bronchitis which is a form of nondiphtheritic croup: “Inhibition of PAF-induced expression of CD11b and shed arachidic bronchitis which is caused by the presence of a ding of L-selectin on human neutrophils and eosinophils by peanut kernel in a bronchus; catarrhal bronchitis which is a the type-IV selective PDE inhibitor, rolipram.' Eur: Respir: form of acute bronchitis with a profuse mucopurulent dis J. 10 1000-1007, 1997; and Derian et al., “Inhibition of 60 charge; chronic bronchitis which is a long-continued form of chemotactic peptide-induced neutrophil adhesion to vascu bronchitis with a more or less marked tendency to recur lar endothelium by cAMP modulators. J. Immunol. 154 rence after stages of quiescence, due to repeated attacks of 308-317, 1995. acute bronchitis or chronic general diseases, characterized It is still further inferred that the compounds of Formula by attacks of coughing, by expectoration either scanty or (1.0.0) inhibit alveolar macrophage PDE4s, thereby reduc 65 profuse, and by secondary changes in the lung tissue; ing the release of chemotactic factors and TNF-C.; and that croupus bronchitis which is characterized by violent cough the compounds of Formula (1.0.0) increase synthesis and and paroxysms of dyspnea; dry bronchitis which is charac US 7,250,518 B2 149 150 terized by a scanty secretion of tough sputum; infectious The anti-inflammatory activity of the combinations of asthmatic bronchitis which is a syndrome marked by the therapeutic agents of the present invention is demonstrated development of symptoms of bronchospasm following res by the inhibition of TNFC. production in human whole blood piratory tract infections in persons with asthma, productive stimulated with Lipopolysacharide (LPS). Compounds are bronchitis which is bronchitis associated with a productive analyzed in the presence of beta agonist (10 ng/ml) and cough; staphylococcus or streptococcal bronchitis which are Indomethacin (1 uM). Prepare 250 ml assay buffer 200 mM caused by Staphylococci or streptococci; and vesicular bron HEPES in RPMI 1640 filtered. The following are performed chitis in which the inflammation extends into the alveoli, at room temperature at the bench. Prepare “IP” cocktail in 50 which are sometimes visible under the pleura as whitish ml polypropylene tube by adding 0.4 ml of Indomethacin yellow granulations like millet seeds. 10 (stock 4 mM) and 0.4 ml of beta agonist (stock 0.04 mg/ml) Bronchiectasis is a chronic dilatation of the bronchi for fiv. 40 ml with assay buffer. Prepare compounds from marked by fetid breath and paroxysmal coughing with the powder stocks into DMSO to either 200 or 60 mM stock expectoration of mucopurulent matter. It may affect the tube Solutions. Make eight-point half-log serial dilutions in glass uniformly, in which case it is referred to as cylindric vials or microtubes. Add 0.01 ml of each compound dilution bronchiectasis, or it may occur in irregular pockets, in which 15 to the 5 ml polypropylene tubes where 0.490 ml assay buffer case it is called sacculated bronchiectasis. When the dilated and 0.50 ml “IP” cocktail is added for fiv. 1.0 ml. (The bronchial tubes have terminal bulbous enlargements, the compounds assay fic. 100-0.1 uM.) Prepare LPS solution term fusiform bronchiectasis is used. In those cases where such that 0.08 ml LPS (stock 1 mg/ml) is added to 40 ml the condition of dilatation extends to the bronchioles, it is assay buffer for fc. 2 ug/ml. 6. Prepare a 2% DMSO solution referred to as capillary bronchiectasis. If the dilatation of the by adding 200 ul DMSO to 9.8 ml assay buffer. Add 10 ml bronchi is spherical in shape, the condition is referred to as of IP cocktail to the 2% DMSO Solution. This cocktail is cystic bronchiectasis. Dry bronchiectasis occurs where the used for control wells such that Indomethacin assay fic. is 1 infection involved is episodic and it may be accompanied by uM and beta agonist fic. is 10 ng/ml. The following are hemoptysis, the expectoration of blood or of blood-stained performed under the tissue culture hood. Add 0.0125 ml of sputum. During quiescent periods of dry bronchiectasis, the 25 diluted compound to appropriate well in U-bottom sterile coughing which occurs is nonproductive. Follicular bron Costar 96-well plate #3790. Add 0.0125 ml LPS to all wells chiectasis is a type of bronchiectasis in which the lymphoid (fic. 0.1 ug/ml) except negative control wells. Fresh human tissue in the affected regions becomes greatly enlarged, and whole blood is drawn (-22 ml per 96-well plate) usually four by projection into the bronchial lumen, may seriously distort green tops per donor into sterile heparin tubes kept at 37°C. and partially obstruct the bronchus. Accordingly, the com 30 Add 0.225 ml of whole blood to the plates. Cover, incubate pounds of Formula (1.0.0) are useful in the beneficial at 37° C., and rock for four hours. Centrifuge the plates at treatment of the various above-described types of bron 2000 rpm for 10 minutes. Prepare ELISA standards. Remove chiectasis as a direct result of their inhibition of PDE4 100 ul serum into flat bottom plate. Dilute 1:20 by removing isozymes. 15ul and adding 285 ul RD6 diluent. Freeze (a) -20° C. For 35 analysis, thaw and add 200 ul to R & D Systems TNFC. The utility of the compounds of Formula (1.0.0) as ELISA. Process the plates according to R & D Systems bronchodilaors or bronchospasmolytic agents for treating protocol. Read plate at 450 nm using SoftMax Pro. Analyze bronchial asthma, chronic bronchitis and related diseases and disorder described herein, is demonstrable through the and interpret with Java Fitter in order to determine IC50 use of a number of different in vivo animal models known values. A dose response curve of data expressed as percent 40 control is plotted. A minimum of six triplicate points are in the art, including those described in the paragraphs below. generated for each compound. The IC50 values are calcu Bronchospasmolytic Activity In Vitro. The ability of the lated using the Java Fitter curve-fitting program under the compounds of Formula (1.0.0) to cause relaxation of guinea “IC50 fix both parameter. pig tracheal Smooth muscle is demonstrated in the following In the above test model, combinations of therapeutic test procedure. Guinea-pigs (350-500 g) are killed with 45 agents of the present invention produce concentration-re Sodium pentothal (100 mg/kg i.p.). The trachea is dissected lated inhibition of TNFOproduction at concentrations in the and a section 2-3 cm in length is excised. The trachea is range of from 0.001 to 1.0 uM. transected in the transverse plane at alternate cartilage plates 8.4 Allergic and Other Types of Rhinitis; Sinusitis So as to give rings of tissue 3-5 mm in depth. The proximal Allergic rhinitis is characterized by nasal obstruction, and distal rings are discarded. Individual rings are mounted 50 itching, watery rhinorrhea, Sneezing and occasional vertically on stainless steel Supports, one of which is fixed anoSmia. Allergic rhinitis is divided into two disease cat at the base of an organ bath, while the other is attached to an egories, seasonal and perennial, in which the former is isometric transducer. The rings are bathed in Krebs solution attributed to pollen or outdoor mould spores, while the latter (composition uM: NaHCO, 25; NaCl 113: KCl 4.7: is attributed to common allergens Such as house dust mites, MgSO4.7H2O 1.2: KHPO 1.2: CaCl2.5; glucose 11.7) at 55 animal danders, and mould spores. Allergic rhinitis gener 37° C. and gassed with O/CO (95:5, V/v). Rings prepared ally exhibits an early phase response and a late phase in this manner, preloaded to 1 g, generate spontaneous tone response. The early phase response is associated with mast and, after a period of equilibration (45-60 m), relax consis cell degranulation, while the late phase response is charac tently on addition of spasmolytic drugs. To ascertain spas terized by infiltration of eosinophils, basophils, monocytes, molytic activity, test compounds of Formula (1.0.0) are 60 and T-lymphocytes. A variety of inflammatory mediators is dissolved in physiological saline and added in increasing also released by these cells, all of which may contribute to the inflammation exhibited in the late phase response. quantities to the organ bath at 5 m intervals to provide a A particularly prevalent form of seasonal allergic rhinitis cumulative concentration-effect curve. is hay fever, which is marked by acute conjunctivitis with In the above test model, compounds of Formula (1.0.0) lacrimation and itching, Swelling of the nasal mucosa, nasal produce concentration-related relaxation of guinea-pig tra 65 catarrh, Sudden attacks of Sneezing, and often with asthmatic cheal ring preparations at concentrations in the range of symptoms. The compounds of Formula (1.0.0) are espe from 0.001 to 1.0 uM. cially useful in the beneficial treatment of hay fever. US 7,250,518 B2 151 152 Other types of rhinitis for which the compounds of Sinusitis is related to rhinitis in terms of anatomical Formula (1.0.0) may be used as therapeutic agents include proximity as well as a shared etiology and pathogenesis in acute catarrhal rhinitis which is a cold in the head involving Some cases. Sinusitis is the inflammation of a sinus and this acute congestion of the mucous membrane of the nose, marked by dryness and followed by increased mucous condition may be purulent or nonpurulent, as well as acute secretion from the membrane, impeded respiration through or chronic. Depending upon the sinus where the inflamma the nose, and some pain; atrophic rhinitis which is a chronic tion is located, the condition is known as ethmoid, frontal, form marked by wasting of the mucous membrane and the maxillary, or sphenoid sinusitis. The ethmoidal sinus is one glands; purulent rhinitis which is chronic rhinitis with the type of paranasal sinus, located in the ethmoid bone. The formation of pus; and vasomotor rhinitis which is a non allergic rhinitis in which transient changes in vascular tone 10 frontal sinus is one of the paired paranasal sinuses located in and permeability with the same symptoms as allergic rhini the frontal bone. The maxillary sinus is one of the paired tis, are brought on by Such stimuli as mild chilling, fatigue, paranasal sinuses located in the body of the maxilla. Accord anger, and anxiety. ingly, the compounds of Formula (1.0.0) are useful in the There is a recognized link between allergic rhinitis and beneficial treatment of acute or chronic sinusitis, but espe asthma. Allergic rhinitis is a frequent accompaniment to 15 cially of chronic sinusitis. asthma, and it has been demonstrated that treating allergic rhinitis will improve asthma. Epidemiologic data has also 8.5 Rheumatoid Arthritis, Osteoarthritis, Pain, Fever, and been used to show a link between severe rhinitis and more Gout severe asthma. For example, the compound D-22888, under preclinical development for the treatment of allergic rhinitis, Arthritis is defined as inflammation of the joints, and has been shown to exhibit a strong anti-allergic affect and to rheumatoid arthritis is a chronic systemic disease primarily inhibit rhinorrhea in the antigen-challenged pig. See, Marx of the joints, usually polyarticular, marked by inflammatory et 30 all “D-22888 a new PDE4 inhibitor for the treatment changes in the synovial membranes and articular structures, of allergic rhinitis and other allergic disorders. J. Allergy and by muscular atrophy and rarefaction of the bones. Late Clin. Immunol. 99 S444, 1997. Another experimental com 25 stages of rheumatoid arthritis are marked by ankylosis and pound, AWD-12.281 has been shown to be active in a rat deformity. Rheumatoid arthritis is a crippling autoimmune model of allergic rhinitis. See Poppe et al “Effect of AWD disease of unknown etiology which affects over 1% of the 12-281, a new selective PDE-4 inhibitor, loteprednol and population. beclomethasone in models of allergic rhinitis and airway inflammation in brown norway-rats. Am. J. Respir: Crit. 30 As used herein, the term "rheumatoid arthritis” is Care Med. A95, 1999. The compounds D-22888 and AWD intended to include within its scope where applicable related 12.281 have already been described further above and and associated forms of arthritis well known in the art, since represented by Formulas (0.0.28) and (0.0.34), respectively: these may also be treated with the compounds of Formula

(0.0.28) (1.0.0). Accordingly, the term "rheumatoid arthritis' 35 includes acute arthritis, which is arthritis marked by pain, heat, redness, and Swelling due to inflammation, infection, or trauma; acute gouty arthritis, which is acute arthritis associated with gout, chronic inflammatory arthritis, which is inflammation of the joints in chronic disorders such as 40 rheumatoid arthritis; degenerative arthritis, which is osteoar thritis; infectious arthritis, which is arthritis caused by bacteria, rickettsiae, mycoplasmas, viruses, fungi, or para sites; Lyme arthritis, which is arthritis of the large joints 45 associated with Lyme 20 disease; proliferative arthritis, D-22888 which is inflammation of the joints with proliferation of the (0.0.34) synovium, seen in rheumatoid arthritis; psoriatic arthritis, F which is a syndrome in which psoriasis occurs in association with inflammatory arthritis; and vertebral arthritis, which is 50 inflammation involving the intervertebral disks. The three major pathological features of rheumatoid arthritis that are responsible for progressive joint destruction are inflammation, abnormal cellular and humoral responses, N and synovial hyperplasia. The particular cellular pathology 55 of rheumatoid arthritis includes the presence of T-cells and monocytes. The T-cells, which are predominantly memory HO T-cells, constitute up to 50% of the cells recovered from the O O synovial tissue of rheumatoid arthritis patients; and of the C 60 monocytes found in the same tissue, 30-50% are antigen NH presenting cells, which is indicative of the autoimmune s character of the disease. Pro-inflammatory cytokines, e.g., IL-1, IL4, IL-5, IL-6, IL-9, IL-13, and TNF-C., are the major N C contributors to joint tissue damage, inflammation, hyperpla 65 sia, pannus formation and bone resorption. See Firestein, G. S. and Zvaifier, W. J., “How important are T-cells in chronic Loteprednol (AWD-12,281) rheumatoid synovitis?' Arth. Rheum. 33 768-773, 1990. US 7,250,518 B2 153 154 This has been demonstrated, e.g., by the fact that mono After the cessation of treatment the test animals developed clonal antibodies (Mabs) to TNF-C. have shown promise in arthritis and reached the same arthritis top score as the RA clinical trials; Maini el al, "Beneficial effects of tumor control group. In the same study rolipram was also admin necrosis factor-alpha (TNF-C. blockade in rheumatoid arthri istered at 3 mg/kg twice daily at the time point when arthritis tis (RA), Clin. Exp. Immunol. 101 207-212, 1995. was apparent. This treatment drastically changed the devel The PDE4 inhibitors of Formula (1.0.0) are useful in the opment of the disease whereby progression of severity was treatment of rheumatoid arthritis as a result of their ability to halted and even after the cessation of treatment, the arthritis Suppress the activity of a variety of inflammatory cells, score did not reach the levels observed in untreated animals. including basophils, eosinophils, and mast cells. These The investigators were also able to demonstrate a strong inhibitory activities of the compounds of Formula (1.0.0) 10 down-regulation of TNF-C. and IFN-Y mRNA expression in have already been described further above, as has their wide regional lymph nodes, which Suggests that the major effect range of in vitro anti-inflammatory action via the release of of rolipram is exerted in the effector phase of the inflam reactive oxygen species, prostaglandins, and inflammatory matory process. Nyman et al., Ibid. Inhibition of TNF-C. Production by Human Monocytes In cytokines, e.g., IL-5. IFN-y, and TNF-C. See further Cohan 15 et al., “In vitro pharmacology of the novel phosphodiesterase Vitro The inhibitory effect of the compounds of Formula Type IV inhibitor, CP-80,633, 'J. Pharm. Exp. Ther. 278 (1.0.0) on in vitro TNF-C. production by human monocytes 1356-1361, 1996; and Barnette et al. “SB207499 (Arifio), a may be determined in accordance with the protocol potent and selective second generation phosphodiesterase 4 described in EP 411 754 (Badger et al) and WO 90/15534 inhibitor: in vitro anti-inflammatory actions. J. Pharm. Exp. (Hanna). The referenced publications also describe two Ther. 284 420-426, 1998. The PDE4 inhibitors of Formula models of endotoxic shock which may be used to determine (1.0.0) are also useful in the treatment of rheumatoid arthri in vivo inhibitory activity of the compounds of Formula tis as a result of their effectiveness in inhibiting T-cell (1.0.0). The protocols used in these models are detailed and proliferation mediated via a number of different agents, test compounds demonstrate a positive result by reducing serum levels of TNF-C. induced by the injection of endot including antigens such as house dust mite, which has been 25 demonstrated in the art; Barnette elal, Ibid. The ability of the OX1 compounds of Formula (1.0.0) to facilitate the release of Selective PDE4 inhibitors Such as RP73401 have been cytokine IL-10 from monocytes, which in turn is capable of shown to exhibit significant amelioration of disease, espe decreasing the generation of TNF-C., IL-1, IL-4, IL-5, IL-6, cially improvements in joint destruction, synovitis, and IL-9, IL-13, and GM-CSF by synovial fluid mononuclear 30 fibrosis, in animal models such as those involving strepto cells, further augments the overall anti-inflammatory profile coccal cell wall (SCW)-induced arthritis; Souness et al. of the PDE4 inhibitors of Formula(1.0.0); Kambayashielal, “Potential of phosphodiesterase Type IV inhibitors in the Ibid. Further, the ability of the compounds of Formula treatment of rheumatoid arthritis.” Drugs 1541-553, 1998. (1.0.0) to inhibit TNF-C. release from stimulated monocytes Of particular interest to the treatment of rheumatoid can be correlated with animal models of inflammation in 35 arthritis is the observation that PDE4 inhibitors have posi which anti-inflammatory effects can be shown to correspond tive effects at the site of action of the disease. For example, to Suppression of TNF-C. accumulation. One such animal RP73401 has been demonstrated to decrease TNF-C. mRNA model involves inhibition of LPS induced TNF-C. release in expression at the pannus/cartilage interface of paw joints of mice by oral administration of a PDE4 inhibitor; Cheng et al. collagen II treated mice. Souness et al., Ibid. RP73401 has “The phosphodiesterase Type 4 (PDE4) inhibitor CP-80,633 40 also been studied clinically in rheumatoid arthritis patients elevates cyclic AMP levels and decreases TNF-C. production in a placebo-controlled, double-blind Phase II study of 35 in mice: effect of adrenalectomy,” J. Pharm. Exp. Ther. 280 rheumatoid arthritis patients administered 400 pg of the 621-626, 1997. Another such animal model involves the compound t.i.d. The compound was able to induce a positive inhibition of rat paw edema, induced by carageenan, by oral trend towards clinical improvement associated with a reduc administration of rolipram; Singh el al. “Synovial fluid 45 tion in C-reactive protein and IL-6 serum levels. Chikanza levels of tumor necrosis factor a in the inflamed rat knee: et al., “The clinical effects of RP73401 phosphodiesterase Modulation by dexamethasone and inhibitors of matrix Type 4 inhibitor in patients with rheumatoid arthritis. Br. J. metalloproteinases and phosphodiesterases.” Inflamm. Res. Rheumatol. 36: Abstr. Suppl. I, 186, 1997. 46(Suppl. 2) S153-S154, 1997. Assaying Increased cAMPAccumulation in Intact Tissues Animal models of rheumatoid arthritis have also been 50 Using U-937 cells—Another assay suitable for demonstrat used in the art for the purpose of demonstrating the corre ing the PDE4 inhibiting activity of the compounds of lation between in vivo modulation of TNF-C. by PDE4 Formula (1.0.0) is one which utilizes U-937 cells from a inhibitors and their utility in the treatment of rheumatoid human monocyte cell line that has been shown to contain a arthritis. The activity of rolipram in animal models of acute large amount of PDE4. In order to assess the inhibition of inflammation Such as the mouse adjuvant arthritis model, 55 PDE4 activity in intact cells, non-differentiated U-937 cells has been demonstrated in the art; Sekut et al., “Anti-inflam at a density of approximately 10 cells per reaction tube are matory activity of phosphodiesterase (PDE) IV inhibitors in incubated with concentrations ranging from 0.01 to 1000 acute and chronic models of inflammation.” Olin. Exp. pM of test compound for one minute, and with 1 uM of Immunol. 100(1) 126-132, 1995. The ability of rolipram to prostaglandin E2 for an additional four minutes. Five min reduce disease severity in the collagen II induced arthritis 60 utes after initiating the reaction, cells are lysed by the (CIA) model after Sc. or ip. injection has been demonstrated addition of 17.5% perchloric acid, after which the pH is in the art; Nyman et al., “Amelioration of collagen II induced brought to neutral by the addition of 1 M potassium car arthritis in rats by Type IV phosphodiesterase inhibitor bonate. The cAMP content of the reaction tube is measured rolipram, Olin. Exp. Immunol. 108 415-419, 1997. In this using RIA techniques. A detailed protocol for carrying out study the dosing regimen for rolipram was 2 mg/kg twice 65 this assay is described in Brooker et al., “Radioimmunoassay daily for five days before the onset of arthritis, and it of cyclic AMP and cyclic GMP Adv. Cyclic Nucleotide Res. significantly delayed the appearance of arthritic symptoms. 10 1-33, 1979. US 7,250,518 B2 155 156 Gout refers to a group of disorders of purine metabolism, Such a collection of modified macrophages resembling epi and fully developed gout is manifested by various combi thelial cells, usually Surrounded by a rim of lymphocytes, nations of hyperuricemia, recurrent, characteristic acute with fibrosis commonly seen around the lesion. Some granu inflammatory arthritis induced by crystals of monosodium lomas contain eosinophils. Granuloma formation represents urate monohydrate, tophaceous deposits of said crystals in a chronic inflammatory response initiated by various infec and around the joints of the extremities, which may lead to tious and noninfectious agents. A number of Such granulo joint destruction and severe crippling, and uric acid uroli matous conditions are treatable using a compound of For thiasis. Rheumatic gout is another name for rheumatoid mula (1.0.0), e.g., allergic granulomatous angiitis, also arthritis. Tophaceous gout is gout in which there are tophi or called Churg-Strauss syndrome, which is a form of systemic chalky deposits of Sodium urate. Some therapeutic agents 10 necrotizing vasculitis in which there is prominent lung are useful in treating both gout and its attendant inflamma involvement, generally manifested by eosinophilia, granu tion, e.g., phenylbutaZone and colchicine; while other thera lomatous reactions, and usually severe asthma. A related peutic agents possess only uricoSuric properties, e.g., Sulfin disorder is polyarteritis nodosa (PAN), which is marked by pyrazone and benzbromarone multiple inflammatory and destructive arterial lesions and is Fever, or pyrexia, may be the result of any one of a large 15 a form of systemic necrotizing vasculitis involving the Small number of different factors, but with regard to the present and medium-sized arteries with signs and symptoms result invention Such fever is either that manifested in pharyngo ing from infarction and scarring of the affected organ conjunctival fever or rheumatic fever, or that manifested system, in particular the lungs. Other eosinophil-related during inflammation. A concomitant of inflammation is pain, disorders which may be treated in accordance with the especially that experienced in the joints and connective present invention are those affecting the airways which are tissue of those Suffering from rheumatoid arthritis and gout. induced or occasioned by a reaction to a therapeutic agent Accordingly, the PDE4 inhibitory compounds of Formula unrelated to any compound of Formula (1.0.0). (1.0.0) provide beneficial results in the treatment of gout, and fever and pain associated with inflammation. 8.7 Atopic Dermatitis, Urticaria, Conjunctivitis, and Uveitis 25 Atopic dermatitis is a chronic inflammatory skin disorder 8.6 Eosinophil-related Disorders seen in individuals with a hereditary predisposition to a The ability of the PDE4 inhibitory compounds of Formula lowered cutaneous threshold to pruritis, that is often accom (1.0.0) to inhibit eosinophil activation as part of their overall panied by allergic rhinitis, hay fever, and asthma, and that is anti-inflammatory activity has been described above. principally characterized by extreme itching. Atopic derma Accordingly, the compounds of Formula (1.0.0) are useful in 30 titis is also called allergic dermatitis, and allergic or atopic the therapeutic treatment of eosinophil-related disorders. CCZCa. Such disorders include eosinophilia, which is the formation Atopic dermatitis (AD) is the most common chronic and accumulation of an abnormally large number of eosi inflammatory skin disease in young children, and it affects nophils in the blood. The name of the disorder derives from from 10% to 15% of the population during childhood. “eosin', a rose-colored stain or dye comprising a bromine 35 Atopic dermatitis is frequently associated with asthma and derivative offiuorescein which readily stains “eosinophilic allergies and it has therefore become known as a component leukocytes' in the blood of patients who are thus readily of the so-called "atopic triad, since it occurs frequently in identified. A particular eosinophilic disorder that can be individuals with asthma and/or allergic rhinitis. See Leung treated in accordance with the present invention is pulmo Dym, Atopic Dermatitis. From Pathogenesis To Treatment, nary infiltration eosinophilia, which is characterized by the 40 R. G. Landes Co., Austin, Tex., 1-226, 1996. Accordingly, infiltration of the pulmonary parenchyma by eosinophils. the immune dysfunction associated with atopic dermatitis is This disorder includes especially Loffler's syndrome, which treatable with therapeutic agents that are inhibitors of PDE4. is a condition characterized by transient infiltrations of the For example, rolipram, Ro-201724, and denbufylline have lungs, accompanied by cough, fever, dyspnea, and eosino been reported to produce a concentration-related inhibition philia. 45 of the proliferation of human peripheral blood mononuclear Other eosinophilic disorders include chronic eosinophilic cells (HPBM) from normal patients as well as from subjects pneumonia, which is a chronic interstitial lung disease with atopic dermatitis. See, respectively, Torphy et al., characterized by cough, dyspnea, malaise, fever, night Drugs and the Lung, Eds. Page and Metzger, Raven Press, Sweats, weight loss, eosinophilia, and a chest film revealing New York, 1994; and O’Brien, Mol. Medicine Today, 369, non-segmental, non-migratory infiltrates in the lung periph 50 1997. These studies also determined that the proliferative ery; tropical pulmonary eosinophilia, which is a Subacute or response of HPBM from atopic dermatitis patients was more chronic form of occult filariasis, usually involving Brugia sensitive to PDE4 inhibition than was the proliferation malayi, Wuchereria bancrofti, or filariae that infect animals, observed in HPBM from normal subjects. occurs in the tropics, and is characterized by episodic Th2 type cytokine secreting T-cells expressing the cuta nocturnal wheezing and coughing, strikingly elevated eosi 55 neous lymphocyte associated antigen play a central role in nophilia, and diffuse reticulonodular infiltrations of the the induction of local IgE responses and the recruitment of lungs; bronchopneumonic aspergillosis, which is an infec eosinophils in this disease. The chronic inflammation seen in tion of the bronchi and lungs by Aspergillus fungi resulting atopic dermatitis is considered to be the result of several in a diseased condition marked by inflammatory granulo interdependent factors, such as repeated or persistent aller matous lesions in the nasal sinuses and lungs, but also in the 60 gen exposure, which can lead to Th2 cell expansion. It has skin, ear, orbit, and sometimes in the bones and meninges, been demonstrated that there is an increased frequency of and leading to aspergilloma, the most common type of allergen specific T-cells producing increased IL4, IL-5, and fungus ball formed by colonization of Aspergillus in a IL-3 levels in the blood of atopic dermatitis patients. See bronchus or lung cavity. Leung Dym et al., “Allergic and immunological skin disor The term 'granulomatous' means containing granulomas, 65 ders,” JAMA 278(22) 1914-1923, 1997. This is significant and the term 'granuloma’ refers to any Small nodular because IL-4 and IL-3 induce the expression of vascular delimited aggregation of mononuclear inflammatory cells or adhesion molecule-1 (VCAM-1), an adhesion molecule US 7,250,518 B2 157 158 involved in the migration of mononuclear cells and eosino nologic or nonimmunologic mechanisms, urticariogenic phils into sites of tissue inflammation. Further, IL-5 is a key material-induced, physical agent-induced, stress-induced, or mediator of eosinophil activation, which is a common fea idiopathic. The condition may also be designated acute or ture of atopic disease. chronic depending on the duration of an attack. Angioedema Increased concentration of cAMP in lymphocytes and is the same response in the deep dermis or Subcutaneous or basophils has long been known to be associated with Submucosal tissues. decreased mediator release from those cells, and more The most common types of urticaria which are treatable recently it has been reported that histamine acting on H2 with the compounds of Formula (1.0.0) are cholinergic receptors increases cAMP levels and inhibits IL-4 produc urticaria which is characterized by the presence of distinc tion in murine Th2 cells. It is Surmised, accordingly, that 10 tive punctate wheals Surrounded by areas of erythema, there is present in atopic diseases Such as atopic dermatitis, thought to be a nonimmunologic hypersensitivity reaction in impaired B-adrenergic responses or enhanced PDE4 activity which acetylcholine released from parasympathetic or motor of leukocyte inflammatory responses. A diminished cAMP nerve terminals induces release of mediators from mast response may result from an enhanced PDE4 activity that cells, and evoked by conditions of exertion, stress, or has a genetic basis or that is an acquired condition. 15 increased environmental heat; cold urticaria which is urti Studies have been carried out which compare different caria precipitated by cold air, water, or objects, occurring in cell types from atopic patients with those from healthy two forms: In the autosomal dominant form which is asso Volunteers, and the results have shown that increased ciated with fevers, arthralgias, and leukocytosis, the lesions cAMP-PDE activity in atopic cells correlates with abnormal present are erythematous, burning papules and macules, and inflammatory and immune cell function in atopic dermatitis. in the more common acquired form which is usually idio Further, the PDE4 enzyme from atopic leukocytes is more pathic and self-limited; contact urticaria which is a localized sensitive to PDE4 inhibitors than the PDE4 enzyme from or generalized transient wheal-and-flare response elicited by normal leukocytes, and up to a 14-fold difference has been exposure to rapidly absorbable urticariogenic agents; giant demonstrated. See Chan and Hanifin, “Differential inhibi urticaria which is angioedema; and papular urticaria which tory effects of cAMP phosphodiesterase isoforms in atopic 25 is a persistent cutaneous eruption representing a hypersen and normal leukocytes. J. Lab. Clin. Med., 121(1) 44-51, sitivity reaction to insect bites. 1993. An increased sensitivity can also be seen in the Accordingly, the PDE4 inhibitors of Formula (1.0.0) are inhibition of proliferation of peripheral blood mononuclear useful for the beneficial treatment of the various types of cells from atopic donors on treatment with PDE4 inhibitors. urticaria as described above. A related area of therapeutic For example, rolipram has been found to be more effective 30 application for which the compounds of Formula (1.0.0) also at inhibiting PHA stimulated atopic dermatitis PBMC pro produce beneficial results is in various ophthalmic uses, in liferation than at inhibiting PHA stimulated normal PBMC particular in the treatment of conjunctivitis and uveitis. proliferation, with an ICso 280 nM compared to an The conjunctiva is a delicate membrane that lines the ICso 2600 nM, respectively. eyelids and covers the exposed surface of the sclera. Con Further, it has been shown that a structurally diverse range 35 junctivitis is an inflammation of the conjunctiva that gener of selective PDE4 inhibitors are effective in reducing skin ally consists of conjunctival hyperemia associated with a eosinophilia in the guinea pig which has been mediated via discharge. The most common types of conjunctivitis, which a range of agents such as PAF, arachidonic acid, Zymosan are treatable with the compounds of Formula (1.0.0), are activated plasma, and protein of cutaneous anaphylaxis. See actinic conjunctivitis produced by ultraviolet light; acute Beasley et al., “Synthesis and evaluation of a novel series of 40 catarrhal conjunctivitis which is an acute, infectious con phosphodiesterase 4 inhibitors. A potential treatment for junctivitis associated with cold or catarrh and characterized asthma,” Bioorg. Med. Chem. Letts. 8. 2629-2634, 1998. by vivid hyperemia, edema, loss of translucence, and Such data shows the utility of PDE4 inhibitors in treating mucous or mucopurulent discharge; acute contagious con eosinophil driven skin diseases. Such treatment is by means junctivitis which is a mucopurulent, epidemic conjunctivitis of topical administration, e.g., topical atizoram applied 45 caused by Haemophilus aegyptius that has the same symp bilaterally over eight days to twenty patients in a clinical toms as acute catarrhal conjunctivitis and is also called trial has been found to effectively inhibit all of the inflam "pinkeye'; allergic conjunctivitis which is a component of matory parameters tested, showing both qualitative and hay fever, atopic conjunctivitis which is allergic conjunc quantitative improvements with no adverse effects. See tivitis of the immediate type caused by airborne allergens, Hanifin et al., “Type 4 phosphodiesterase inhibitors have 50 e.g., pollens, dusts, spores, and animal dander; chronic clinical and in vitro anti-inflammatory effects in atopic catarrhal conjunctivitis which is a mild, chronic conjunc dermatitis.' J. Invest. Dermatol. 107 51-56, 1996; and also tivitis with only slight hyperemia and mucous discharge; see Turner et al., “The in vivo pharmacology of CP-80,633, purulent conjunctivitis which is an acute conjunctivitis a selective inhibitor of phosphodiesterase 4, 'J. Pharmacol. caused by bacteria or viruses, particularly gonococci, men Exp. Ther. 278(3) 1349-1355, 1996. 55 ingococci, pneumococci, and streptococci, and character Accordingly, the PDE4 inhibitors of Formula (1.0.0) are ized by severe inflammation of the conjunctiva and copious useful for the beneficial treatment of atopic dermatitis as discharge of pus; and Vernal conjunctivitis which is a described above. A related area of therapeutic application for bilateral conjunctivitis of seasonal occurrence, of unknown which the compounds of Formula (1.0.0) also produce cause, affecting children especially boys and characterized beneficial results is in the treatment of urticaria. Urticaria is 60 by flattened papules and a thick, gelatinous exudate. Accord a vascular reaction, usually transient, involving the upper ingly, the PDE4 inhibitors of Formula (1.0.0) are useful for dermis, representing localized edema caused by dilatation the beneficial treatment of the various types of conjunctivitis and increased permeability of the capillaries, and marked by as described above. A related area of therapeutic application the development of wheals or hives. Many different stimuli for which the compounds of Formula (1.0.0) also produce are capable of inducing an urticarial reaction, and it may be 65 beneficial results is in the treatment of uveitis. classified according to precipitating causes, as: immune The uvea is the vascular middle coat or tunic of the eye, mediated, complement-mediated which may involve immu comprising the iris, ciliary body, and choroid. Uveitis is an US 7,250,518 B2 159 160 inflammation of all or part of the uvea and commonly from increased formation of connective tissue and in dis involves the other tunics of the eye, i.e., the sclera and the eases of the interstitial substance. The term "sclerosis” is cornea, and the retina as well. The most common types of used chiefly for Such a hardening of the nervous system due uveitis, which are treatable with the compounds of Formula to the deposition of connective tissue, or to designate (1.0.0), are anterior uveitis which is uveitis involving the hardening of the blood vessels. Multiple sclerosis (MS) is a structures of the iris and/or ciliary body, including iritis, disease in which there are foci of demyelination of various cyclitis, and iridocyclitis; granulomatous uveitis which is sizes throughout the white matter of the central nervous uveitis of any part of the uveal tract but particularly of the system, sometimes extending into the gray matter, resulting posterior portion, characterized by nodular collections of in weakness, incoordination, paresthesias, speech distur epithelioid cells and giant cells Surrounded by lymphocytes; 10 bances, and visual complaints. Multiple Sclerosis is a disease nongranulomatous uveitis which is inflammation of the of unknown etiology with a prolonged course involving anterior portion of the uveal tract, i.e., the iris and ciliary many remissions and relapses. body; phacoantigenic uveitis which is one of the lens Multiple Sclerosis is an autoimmune disease that in addi induced uveitides is a severe anterior uveitis similar to tion to chronic inflammation and demyelination, also results sympathetic ophthalmia, observed weeks or even months 15 in gliosis within the central nervous system. There are after extracapsular lens Surgery or other trauma to the several disease Subtypes, including primary progressive capsule; and posterior uveitis which is uveitis involving the multiple Sclerosis, and relapsing remitting multiple Sclero posterior segment of the eye, including choroiditis and sis. These disease Subtypes may be distinguished from each chorioretinitis. Accordingly, the PDE4 inhibitors of Formula other on the basis of the course of the disease, of the type of (1.0.0) are useful for the beneficial treatment of the various inflammation involved, and through the use of magnetic types of unveitis as described above. resonance imaging (MRI). It is also possible for the basic 8.8 Psoriasis disease mechanism to change during the course of multiple Psoriasis is a common chronic, squamous dermatosis with Sclerosis, with an inflammation-based process being polygenic inheritance and a fluctuating course that is char replaced later by one which involves demyelination and acterized by microabscesses and spongiform pustules, as 25 axonal damage. See Weilbach and Gold, “Disease modify well as erythematous, dry, Scaling patches of various sizes. ing treatments for multiple sclerosis. What is on the hori Psoriasis is a common skin disease that affects approxi zon?” CNS Drugs 11 133-157, 1999. mately 2% of the population, and more than 1/2 million In multiple Sclerosis inflammatory lesions are localized patients in the US annually consult physicians for treatment. to, but prevalent throughout the white matter of the central Psoriasis is usually recurrent and in some instances can be 30 nervous system, although sclerotic plaques characterized by very debilitating. The etiology of psoriasis is unknown, but demyelination are a hallmark of the disease. The develop it appears to be an autoimmune disease with genetic pre ment of demyelination, in turn, is caused by the necrosis of disposition. oligodendrocytes, and demyelination is associated with an Psoriasis involves a large T-cell infiltration in the affected infiltrate composed mainly of T-cells and macrophages, regions of the skin, with CD4+ lymphocytes in the dermis 35 which together with local cells such as astrocytes, microglia and CD8+ lymphocytes in the epidermis. These lympho and microvascular brain endothelial cells, express major cytes secrete IL-2, IFNY, and TNF-C., which alter kerati histocompatibility complex (MHC) class II. These cells are nocyte proliferation and differentiation. Further, from 5% to thus implicated in antigen presentation and an inflammatory 10% of psoriasis patients develop psoriatic arthritis, the response, and a number of pro-inflammatory cytokines, symptoms of which are very similar to those of rheumatoid 40 including TNF-C, TNF-B, IL-1, IL-6 and IFN-Y have been arthritis. The broad spectrum of anti-inflammatory activities identified in the brain tissue of multiple sclerosis patients displayed by PDE4 inhibitors, already discussed above, and their presence is generally associated with active enables such inhibitors to be used beneficially in the treat lesions. TNF-C. in particular has been the focus of attention ment of psoriasis. because it mediates myelin and oligodendrocyte damage in 45 vitro, induces astrocytes to express Surface adhesion mol It has been demonstrated that treatment of epidermal basal ecules, and is associated with disruption of the blood-brain cells, in primary culture, with the PDE4 inhibitor Ro barrier. 20-1724 leads to a three-fold increase in cAMP concentra tions. It has also been shown that treatment of psoriatic Animal models have been used to demonstrate the role of epidermal slices and keratomed psoriatic epidermal slices TNF-C. in multiple Sclerosis, e.g., in experimental allergic with Ro 20-1724 results in a very marked elevation of cAMP 50 encephalomyelitis (EAE) administration of anti-TNF anti concentrations over controls. Specifically, a 1395% increase bodies or soluble TNF receptors has been shown to provide in cAMP concentration in keratomed psoriatic epidermis has a protective effect. See Selmajet al., “Prevention of chronic been observed. PDE4 inhibitors have also been shown to relapsing experimental autoimmune encephalomyelitis by inhibit the inflammatory response of a number of mediators soluble tumor necrosis factor, J. Neuroimmunol. 56 135 via either topical or systemic administration. For example, 55 141, 1995. A direct correlation between the level of TNF-C. rolipram has been shown to inhibit croton oil-induced ear mRNA and progression of EAE has also been reported. See inflammation in the mouse at topical doses as low as 0.03 mg Reeno et al., “TNF-alpha expression by resident microglia per ear. The selective PDE4 inhibitor Ro 20-1724 has also and infiltrating leukocytes in the central nervous system of been investigated in two double-blind studies comparing its mice with experimental allergic encephalomyelitis: regula 60 tion by the Th1 cytokines,” J. Immunol. 154944-953, 1995. effectiveness to vehicle, where it has been shown to improve Further evidence demonstrating that TNF-C. is a mediator of psoriatic lesions without adverse systemic or cutaneous multiple sclerosis is the increased concentration of TNF-C. in effects. the cerebrospinal fluid of multiple sclerosis patients during 8.9 Multiple Sclerosis and Other Inflammatory Autoimmune the course of the disease. Further, a transgenic mouse Diseases 65 overexpressing TNF-C. in the central nervous system has A Sclerosis is an induration, or hardening, and refers shown signs of spontaneous demyelination, while a trans especially to hardening of a part from inflammation, and genic TNF-C. knockout mouse has shown a protective effect. US 7,250,518 B2 161 162 See Probert et al., “Spontaneous inflammatory demyelinat neic graft rejection following organ transplantation, where ing disease in transgenic mice showing central nervous Such organs typically include tissue from bone marrow, system-specific expression of tumor necrosis factor alpha, bowel, heart, kidney, liver, lung, pancreas, skin and cornea. Proc. Natl. Acad. Sci. USA 92 11294-11298, 1995; and Liu et al., “TNF is a potent anti-inflammatory cytokine in 8.10 Inflammatory Bowel Disease autoimmune-mediated demyelination.” Nature Med. 4 Ulcerative colitis (UC) is a chronic, recurrent ulceration in 78-83, 1998. the colon, chiefly of the mucosa and Submucosa, which is of Since PDE4 inhibitors also reduce TNF-C., they are ben unknown cause, and which is manifested clinically by eficial in the treatment of multiple sclerosis because TNF-C. cramping abdominal pain, rectal bleeding, and loose dis plays a key role in mediating multiple Sclerosis, as discussed 10 charges of blood, pus, and mucus with scanty fecal particles. above. For example, in a marmoset model of experimental Related diseases of the bowel include collagenous colitis, allergic encephalomyelitis rolipram has been found to Sup which is a type of colitis of unknown etiology that is press the appearance of clinical signs and abolish abnor characterized by deposits of collagenous material beneath malities in MRI imaging. In another study of the effects of the epithelium of the colon, and marked by crampy abdomi rolipram on chronic relapsing experimental allergic 15 nal pain with a conspicuous reduction in fluid and electrolyte encephalomyelitis in SJL mice, it has been shown that absorption that leads to watery diarrhea; colitis polyposa, rolipram ameliorates clinical signs and pathological changes which is ulcerative colitis associated with the formation of in this model. See Genain et al., “Prevention of autoimmune pseudopolyps, i.e., edematous, inflamed islands of mucosa demyelination in non-human primates by a cAMP-specific between areas of ulceration; and transmural colitis, which is phosphodiesterase.” Proc. Natl. Acad. Sci. USA. 92 3601 inflammation of the full thickness of the bowel, rather than 3605, 1995; and Sommer et al., “Therapeutic potential of mucosal and Submucosal disease, usually with the formation phosphodiesterase Type 4 inhibition in chronic autoimmune of noncaseating granulomas, that clinically resembles ulcer demyelinating disease.” J. Neuroimmunol. 79 54-61, 1997. ative colitis but in which the ulceration is often longitudinal In addition to inhibiting PDE4 activity and the production or deep, the disease is often segmental, stricture formation is of TNF-C., the compounds of Formula (1.0.0) also possess 25 common, and fistulas, particularly in the perineum, are a activity as immunosuppressive agents and are especially frequent complication. useful for treating autoimmune diseases in which inflam Crohn's disease (CD) is a chronic granulomatous inflam mation is a component part of the autoimmune disease, or in matory disease of unknown etiology involving any part of which inflammation is part of the etiology of the autoim the gastrointestinal tract, but commonly involving the ter mune disease, or in which inflammation is otherwise 30 minal ileum with Scarring and thickening of the bowel wall, involved with the autoimmune disease. Alternatively, the frequently leading to intestinal obstruction, and fistula and compounds of Formula (1.0.0) are anti-inflammatory agents abscess formation, and having a high rate of recurrence after useful in the treatment of inflammatory diseases in which treatment. Ulcerative colitis, Crohn's disease and the related autoimmune reactions are a component part of the inflam diseases discussed above are collectively referred to as matory disease, or in which autoimmune reactions are part 35 inflammatory bowel disease (IBD). These diseases are of the etiology of the inflammatory disease, or in which chronic, spontaneously relapsing disorders of unknown autoimmune reactions are otherwise involved with the cause that are immunologically mediated and whose patho inflammatory disease. Accordingly, the compounds of For genesis has been established through the use of animal mula (1.0.0) are useful in the treatment of multiple sclerosis, models and advanced immunological techniques. See Bick as discussed in detail further above. 40 ston and Caminelli, “Recent developments in the medical Other autoimmune/inflammatory diseases that can be therapy of IBD. Curr. Opin. Gastroenterol. 146-10, 1998: treated by therapeutic agents comprising the compounds of and Murthy et al., “Inflammatory bowel disease: A new Formula (1.0.0) include, but are not limited to, autoimmune wave of therapy.” Exp. Opin. Ther. Patents 8(7) 785-818, hematological disorders such as hemolytic anemia, aplastic 1998. While the incidence of ulcerative colitis has remained anemia, pure red cell anemia, and idiopathic thrombocy 45 relatively stable, the incidence of Crohn's disease has topenic purpura; systemic lupus erythematosus; polychon increased significantly. dritis; Scleroderma; Wegner's granulomatosis; dermatomyo Current therapy for inflammatory bowel disease includes sitis; chronic active hepatitis; myasthenia gravis; Stevens 5-aminosalicylic acid, corticosteroids, and immunomodula Johnson syndrome; idiopathic sprue, autoimmune tors such as azathioprine, 6-mercaptopurine, and methotr inflammatory bowel diseases such as ulcerative colitis and 50 exate. These agents have a wide range of adverse side effects Crohn's disease; endocrin opthamopathy; Grave's disease; and do not modify the disease itself, and there is thus an sarcoidosis; alveolitis; chronic hypersensitivity pneumoni ongoing need for more effective treatment agents. The tis; primary biliary cirrhosis; juvenile diabetes (diabetes compounds of Formula (1.0.0) are able to beneficially treat mellitus type I); anterior uveitis and granulomatous (poste inflammatory bowel diseases as a result of their ability to rior) uveitis; keratoconjunctivitis sicca and epidemic kera 55 inhibit the production of TNF-C., because TNF-C. causes toconjunctivitis; diffuse interstitial pulmonary fibrosis (in immune cell activation, proliferation, and mediator release terstitial lung fibrosis); idiopathic pulmonary fibrosis; cystic in inflammatory bowel disease. See Radford-Smith and fibrosis; psoriatic arthritis; glomerulonephritis with and Jewell, “Cytokines and inflammatory bowel disease.” without nephrotic syndrome, including acute glomerulone Baillieres Clin. Gasteroenterol. 10 151-164, 1996. TNF-C. phritis, idiopathic nephrotic syndrome, and minimal change 60 has also been detected in the stools and intestinal mucosa of nephropathy; inflammatory/hyperproliferative skin diseases patients with inflammatory bowel disease. Further, early including psoriasis and atopic dermatitis discussed in detail clinical studies in Crohn's disease using TNF monoclonal further above, contact dermatitis, allergic contact dermatitis, antibodies have shown significant promise. benign familial pemphigus, pemphigus erythematosus, pem As already detailed further above, selective PDE4 inhibi phigus foliaceus, and pemphigus Vulgaris. 65 tors have a marked effect on the inhibition of TNF-C. release Further, the compounds of Formula (1.0.0) may be used from peripheral blood mononuclear cells after those cells as immunosuppressant agents for the prevention of alloge have been stimulated with a wide range of mediators, both US 7,250,518 B2 163 164 in vitro and in vivo. The selective PDE4 inhibitor arofylline described activities of selective PDE4 inhibitors, it has been has been shown to provide beneficial effects when tested in demonstrated that selective PDE4 inhibitors are useful in the models of colitis in the rat. Further, in a dextran sulfate treatment of renal failure, especially acute renal failure. See induced colitis model in the rat, rolipram and the selective Begany et al., “Inhibition of Type IV phosphodiesterase by PDE4 inhibitor LAS31025 have demonstrated beneficial Ro-20-1724 attenuates endotoxin-induced acute renal fail effects comparable to prednisolone. Both test compounds ure.” J. Pharmacol Exp. Thera.278 37-41, 1996. See also have been shown to ameliorate bleeding and inflammatory WO 98/00135 assigned to the University of Pittsburgh. markers. See Puig et al. “Curative effects of phosphodi Accordingly, the compounds of Formula (1.0.0) are useful in esterase 4 inhibitors in dextran sulfate sodium induced the treatment of renal failure, particularly acute renal failure. colitis in the rat. Gastroenterology 114(4) A1064, 1998. 10 Cachexia is a profound and marked State of constitutional Other workers have used additional models to demonstrate disorder characterized by general ill health and malnutrition. the ability of selective PDE4 inhibitors to provide gas Cachexia may be the end result of a number of causative trointestinal protection. For example, it has been shown that factors, e.g., it may result from infection by any one of a lipopolysaccharide induced erythrocyte extravasation in rats number of different unicellular organisms or microorgan and intestinal hypoperfusion in dogs can be attenuated with 15 isms including bacteria, viruses, fungi, and protozoans. the selective PDE4 inhibitors rolipram and denbufylline. See Malarial cachexia is representative and comprises a group of Cardelus et al., “Inhibiting LPS induced bowel erythrocyte signs of a chronic nature that result from antecedent attacks extravasation in rats, and of mesenteric hypoperfusion in of severe malaria, the principal signs being anemia, sallow dogs, by phosphodiesterase inhibitors.” Eur: J. Pharmacol. skin, yellow Sclera, splenomegaly, and hepatomegaly. 299 153-159, 1996; and Cardelus et al., “Protective effects Another cause of cachexia is the deprivation or deterioration of denbufylline against endotoxin induced bowel hyperpla of humoral or other organic functions, e.g., hypophysial sia.” Met. Find. Exp. Clin. Pharmacol. 17(Suppl. A) 142, cachexia comprises a train of symptoms resulting from total 1995. deprivation of function of the pituitary gland, including phthisis, loss of sexual function, atrophy of the pituitary 8.11 Septic Shock, Renal Failure, Cachexia, and Infection 25 target glands, bradycardia, hypothermia, apathy, and coma. Septic shock is shock associated with overwhelming Uremic cachexia is cachexia associated with other systemic infection, most commonly infection with gram negative symptoms of advanced renal failure. Cardiac cachexia com bacteria, although it may be produced by other bacteria, prises the emaciation due to heart disease. Cachexia viruses, fungi and protozoa. Septic shock is deemed to result Suprarenalis, or Addison's disease, is a disorder character from the action of endotoxins or other products of the 30 ized by hypotension, weight loss, anorexia, and weakness, infectious agent on the vascular system, causing large Vol caused by adrenocortical hormone deficiency. It is due to umes of blood to be sequestered in the capillaries and veins. tuberculosis- or autoimmune-induced destruction of the Activation of the complement and kinin systems and the adrenal cortex that results in deficiency of aldosterone and release of histamine, cytokines, prostaglandins, and other cortisol. mediators is also involved. 35 Cachexia may also be the result of disease states of It has been shown in a model of endotoxin-induced acute various types. Cancerous cachexia comprises the weak, renal failure in rats that the selective PDE4 inhibitor, emaciated condition seen in cases of malignant tumor. Ro-201724, given as a post-treatment at 10 ug/kg/min Cachexia can also be a consequence of infection by the significantly increases urinary cAMP excretion, markedly human immunodeficiency virus (HIV), and comprises the attenuates endotoxin-induced increases in renal vascular 40 symptoms commonly referred to as acquired immune defi resistance and decreases in renal blood flow and glomerular ciency syndrome (AIDS). The compounds of Formula filtration rate. Ro-201724 has also been shown to improve (1.0.0) are useful in treating cachexia of the different types survival rates for endotoxin-treated rats. See Carcillo et al., described above as a result of their ability to provide Pharmacol. Exp. Ther. 279 1197, 1996. Pentoxifylline has down-regulation or inhibition of TNF-C. release. The selec also been studied in patients suffering from septic shock. In 45 tive PDE4 inhibitors of the present invention have a marked this study twenty-four individuals fulfilling the criteria for effect on the inhibition of TNF-C. release from peripheral septic shock have been selected, twelve of which have blood mononuclear cells after those cells have been stimu received pentoxifylline at 1 mg/kg/hr over a 24-hour period, lated with a wide range of mediators. TNF-C. release is while the other twelve have served as a control group. After implicated or plays a mediating role in diseases or condi 24 hours it has been found that the TNF-C. levels in the 50 tions whose etiology involves or comprises morbid, i.e., therapy group have been significantly lowered, while the unhealthy, excessive or unregulated TNF-C. release. IL-6 levels have been significantly increased. The PDE4 inhibitory compounds of Formula (1.0.0) are In another study, it has been shown that pretreatment with further useful in the treatment of infection, especially infec pentoxifylline at 5 to 50 mg/kg i.p. 3x, or with the selective tion by viruses wherein Such viruses increase the production PDE4 inhibitors rolipram at 10 to 30 mg/kg i.p. 3x, and 55 of TNF-C. in their host, or wherein such viruses are sensitive debufylline at 0.1 to 3 mg/kg i.p. 3x, reduces lipopolysac to upregulation of TNF-C. in their host so that their replica charide-induced bowel erythrocyte extravasation in rats, and tion or other vital activities are adversely impacted. Such that denbufylline is 100-fold more potent than pentoxifylline viruses include, e.g., HIV-1, HIV-2, and HIV-3; cytomega in inhibiting lipopolysaccharide-induced mesenteric blood lovirus, CMV; influenza; adenoviruses; and Herpes viruses, flow fall, without affecting renal blood flow or cardiac index. 60 especially Herpes Zoster and Herpes simplex. See Cardelus et al., Ibid., Eur: J. Pharmacol. The PDE4 inhibitory compounds of Formula (1.0.0) are Renal failure is the inability of the kidney to excrete further useful in the treatment of yeast and fungus infections metabolites at normal plasma levels under conditions of wherein said yeast and fungi are sensitive to upregulation by normal loading, or the inability to retain electrolytes under TNF-C. or elicit TNF-C. production in their host. A particular conditions of normal intake. In the acute form, it is marked 65 disease which is treatable in this way is fungal meningitis. by uremia and usually by oliguria or anuria, with hyper The compounds of Formula (1.0.0) also provide beneficial kalemia and pulmonary edema. On the basis of the above effects when combined with, i.e., administered in conjunc US 7,250,518 B2 165 166 tion with other drugs of choice for the treatment of systemic 8.14 Bone Loss Disease yeast and fungus infections. Such drugs of choice include, Bone loss disease, more commonly referred to as but are not limited to polymixins, e.g., Polymycin B; imi osteoporosis, is a condition of low bone mass and microar dazoles, e.g., clotrimazole, econazole, miconazole, and keto chitectural disruption that results in fractures with minimal conazole; triazoles, e.g., fluconazole and itranazole; and trauma. Secondary osteoporosis is due to systemic illness or amphotericins, e.g., Amphotericin B and liposomal Ampho medications such as glucocorticoids. Primary osteoporosis, tericin B. The term “co-administration' as used herein with it has been contended, should be viewed as comprising two reference to the compounds of Formula (1.0.0) and drugs of conditions: Type I osteoporosis which is loss of trabecular choice for the treatment of systemic yeast and fungus bone due to estrogen deficiency at menopause, and Type II infections, is intended to mean and include (a) simultaneous 10 osteoporosis which is loss of cortical and trabecular bone administration of such compound(s) and drug(s) to a subject due to long-term remodeling inefficiency, dietary inad when formulated together into a single dosage form; (b) equacy, and activation of the parathyroid axis with age. The Substantially simultaneous administration of Such primary regulators of adult bone mass include physical compound(s) and drug(s) to a subject when formulated apart activity, reproductive endocrine status, and calcium intake, from each other into separate dosage forms; and (c) sequen 15 and optimal maintenance of bone requires sufficiency in all tial administration of Such compound(s) and drug(s) to a three areas. Subject when formulated apart from each other and admin It has been demonstrated that selective PDE4 inhibitors istered consecutively with some significant time interval are useful in the beneficial treatment of bone loss disease, between. particularly osteoporosis. The effect of denbufylline on bone loss in Walker 256/S-bearing rats and on mineralized nodule 8.12 Liver Injury formation and osteoclast-like cell formation has been stud In addition to the above-described adverse effects of ied in bone marrow culture systems. It has been discovered TNF-C., it also causes hepatic failure in humans, a phenom that serial oral administrations of denbufylline inhibit the enon which has been shown in a number of animal models. decrease in the bone mineral density of femurs from Walker For example, in an acute model of T-cell mediated hepatic 25 256/S-bearing rats, and restore the bone mass and the failure, rolipram administered at 0.1 to 10 mg/kg i.p. 30 number of osteoclasts and osteoblasts per trabecular surface minutes before challenge with either concanavalin A or in the femur metaphysis. The administration of denbufylline staphylococcal enterotoxin B, has been shown to signifi has also been found to result in an increase in the number of cantly reduce plasma TNF-C. and INF-Y concentrations, mineralized nodules and a decrease in the number of osteo whereas it also significantly elevates IL-10 levels. See 30 clast-like cells in the in vitro bone marrow culture system. Gantneret al., J. Pharmacol. Exp. Ther. 280 53, 1997. In this These beneficial effects are specific for PDE4 inhibition and same study, rolipram has also been shown to suppress are mimicked by dibutyryl cAMP, demonstrating that the concanavalin A-induced IL-4 release. The plasma activities PDE4 isozyme plays an important role in bone turnover of the liver specific enzymes ALT, AST, and SDH have also through cAMP. See Miyamoto et al., Biochem. Pharmacol. been assessed in this study, since any increase in their levels 35 54 613, 1997; Waki et al., “Effects of XT-44, a phosphodi would indicate massive liver cell destruction. It has been esterase 4 inhibitor, in osteoblastgenesis and osteoclastgen found that in pretreatment of naive mice receiving con esis in culture and its therapeutic effects in rat osteopenia canavalin A, or galactosamine-sensitized mice receiving models.” Jpn. J. Pharmacol. 79 477-483. 1999; and JP galactosamine/staphylococcal enterotoxin B, with rolipram 9169665 assigned to Miyamoto (1997). Consequently, the at 0.1 to 10 mg/kg i.p., that rolipram has dose-dependently 40 selective PDE4 inhibitors of Formula (1.0.0) are useful in inhibited the above-mentioned plasma enzyme activities. the treatment of diseases involving bone loss, especially Accordingly, the compounds of Formula (1.0.0) are useful in osteoporosis. the treatment of T-cell disorders such as liver failure. 8.15 CNS Disorders 8.13 Pulmonary Hypertension 45 The PDE4 selective inhibitor rolipram was initially devel It is known that the activity of phosphodiesterases, which oped as an antidepressant and continues to be studied in hydrolyze the vasodilatory second messengers cAMP and clinical trials for that indication. Further, it has been dem cGMP, may be increased by hypoxia-induced pulmonary onstrated that selective PDE4 inhibitors provide beneficial hypertension (HPH). Hypoxia is a reduction of oxygen effects in other central nervous system disorders, including Supply to tissue below physiological levels despite adequate 50 Parkinson's disease, Hulley et al., “Inhibitors of Type IV perfusion of the tissue by blood. The resulting pulmonary phosphodiesterases reduce the toxicity of MPTP in substan hypertension is characterized by increased pressure, i.e., tia nigra neurons in vivo.' Eur: J. Neurosci. 7 2431-2440. above 30 mm Hg systolic and above 12 mm. Hg diastolic, 1995; as well as learning and memory impairment, Egawa et within the pulmonary arterial circulation. Using a model al., “Rolipram and its optical isomers, phosphodiesterase 4 which utilizes isolated pulmonary artery rings from normal 55 inhibitors, attenuate the Scopolamine-induced impairments rats and from rats with hypoxia-induced pulmonary hyper of learning and memory in rats,” Jpn. J. Pharmacol. 75 tension, it has been shown that the selective PDE4 inhibitor 275-281, 1997: Imanishi et al., “Ameliorating effects of rolipram potentiates the relaxant activities of isoproterenol rolipram on experimentally induced impairments of learning and forskolin. The same effect has been observed with and memory in rodents.” Eur: J. Pharmacol. 321 273-278, milrinone, which is a selective PDE3 inhibitor, thereby 60 1997; and Barad et al., “Rolipram, a Type IV-specific supporting inhibition of both PDE3 and PDE4 in order to phosphodiesterase inhibitor, facilitates the establishment of significantly improve pulmonary artery relaxation in long-lasting long-term potentiation and improves memory.” hypoxia-induced pulmonary hypertension. See Wagner et Proc. Natl. Acad. Sci. USA 95 15020-15025, 1998. al., J. Pharmacol. Exp. Ther. 282 1650, 1997. Accordingly, The use of PDE4 inhibitors to treat tardive dyskinesia and the compounds of Formula (1.0.0) are useful in the treatment 65 drug dependence has also been disclosed in the art, WO of pulmonary hypertension, especially hypoxia-induced pull 95/28.177 and JP 92221423 (1997), both assigned to Meiji monary hypertension. Seika Kaisha Ltd. The PDE4 isozyme has been found to play US 7,250,518 B2 167 168 a major role in controlling dopamine biosynthesis in mes sic asthma caused by pathophysiologic disturbances; encephalic neurons; accordingly PDE4 inhibitors are useful extrinsic asthma caused by environmental factors; in the treatment of disorders and diseases which are asso essential asthma of unknown or inapparent cause; non ciated with or mediated by dopamine within and around atopic asthma; bronchitic asthma, emphysematous mesencephalic neurons, Yamashita et al., “Rolipram, a 5 asthma, exercise-induced asthma, occupational selective inhibitor of phosphodiesterase Type 4, pro asthma; infective asthma caused by bacterial, fungal, nouncedly enhances the forskolin-induced promotion of protozoal, or viral infection; non-allergic asthma, dopamine biosynthesis in primary cultured rat mesencepha incipient asthma, wheezy infant syndrome; lic neurons,” Jpn. J. Pharmacol. 75 91-95, 1997. chronic or acute bronchoconstriction; chronic bronchitis; The PDE4 inhibitory compounds of Formula (1.0.0) are 10 Small airways obstruction; and emphysema; further useful in the treatment of arteriosclerotic dementia obstructive or inflammatory airways diseases of whatever and Subcortical dementia. Arteriosclerotic dementia, also type, etiology, or pathogenesis; or an obstructive or called vascular dementia and multi-infarct dementia, is a inflammatory airways disease that is a member selected dementia with a stepwise deteriorating course in the form of from the group consisting of asthma; pneumoconiosis: a series of Small strokes, and an irregular distribution of 15 chronic eosinophilic pneumonia; chronic obstructive neurological deficits caused by cerebrovascular disease. pulmonary disease (COPD); COPD that includes Subcortical dementia are caused by lesions affecting Sub chronic bronchitis, pulmonary emphysema or dyspnea cortical brain structures and are characterized by memory associated therewith: COPD that is characterized by loss with slowness in processing information or making irreversible, progressive airways obstruction; adult res intellectual responses. Included are dementias that accom piratory distress syndrome (ARDS), and exacerbation pany Huntington's chorea, Wilson's disease, paralysis agi of airways hyper-reactivity consequent to other drug tans, and thalamic atrophies. therapy; 8.16 Other Therapeutic Applications pneumoconiosis of whatever type, etiology, or pathogen esis; or pneumoconiosis that is a member selected from It has been demonstrated that PDE4 inhibitors are useful 25 the group consisting of aluminosis or bauxite workers’ in the treatment of ischemia-reperfusion injury, Block et al., disease; anthracosis or miners asthma, asbestosis or "Delayed treatment with rolipram protects against neuronal steam-fitters asthma, chalicosis or flint disease; ptilo damage following global ischemia in rats.” NeuroReport 8 sis caused by inhaling the dust from ostrich feathers; 3829-3832, 1997 and Belayev et al. “Protection against siderosis caused by the inhalation of iron particles; blood-brain barrier disruption in focal cerebral ischemia by 30 the Type IV phosphodiesterase inhibitor BBB022: a quan silicosis or grinders disease; byssinosis or cotton-dust titative study,” Brain Res. 787 277-285, 1998; in the treat asthma, and talc pneumoconiosis; ment of autoimmune diabetes, Liang et al., “The phosphodi bronchitis of whatever type, etiology, or pathogenesis; or bronchitis that is a member selected from the group esterase inhibitors pentoxifylline and rolipram prevent consisting of acute bronchitis; acute laryngotracheal diabetes in NOD mice. Diabetes 47 570-575, 1998; in the 35 treatment of retinal autoimmunity, Xu et al., “Protective bronchitis; arachidic bronchitis; catarrhal bronchitis; effect of the Type IV phosphodiesterase inhibitor rolipram in croupus bronchitis; dry bronchitis; infectious asthmatic EAU: protection is independent of the IL-10-inducing activ bronchitis; productive bronchitis; staphylococcus or ity.” Invest Ophthalmol. Visual Sci. 40942-950, 1999; in the streptococcal bronchitis; and vesicular bronchitis; treatment of chronic lymphocytic leukemia, Kim and 40 bronchiectasis of whatever type, etiology, or pathogen Lerner, “Type 4 cyclic adenosine monophosphate phos esis; or bronchiectasis that is a member selected from phodiesterase as a therapeutic agent in chronic lymphocytic the group consisting of cylindric bronchiectasis; sac leukemia, Blood 92 2484-2494, 1998; in the treatment of culated bronchiectasis; fusiform bronchiectasis; capil HIV infections, Angel et al., “Rolipram, a specific Type IV lary bronchiectasis; cystic bronchiectasis; dry bron phosphodiesterase inhibitor, is a potent inhibitor of HIV-1 45 chiectasis; and follicular bronchiectasis; replication.” AIDS 91137-1144, 1995 and Navarro et al., seasonal allergic rhinitis; or perennial allergic rhinitis; or “Inhibition of phosphodiesterase Type IV suppresses human sinusitis of whatever type, etiology, or pathogenesis; or immunodeficiency virus Type 1 replication and cytokine sinusitis that is a member selected from the group production in primary T cells: involvement of NF-kappaB consisting of purulent or nonpurulent sinusitis; acute or and NFAT. J. Virol. 72 4712-4720, 1998; in the treatment 50 chronic sinusitis; and ethmoid, frontal, maxillary, or of lupus erythematosus, JP 10067682 (1998) assigned to sphenoid sinusitis; Fujisawa Pharm. Co. Ltd.; in the treatment of kidney and rheumatoid arthritis of whatever type, etiology, or patho ureter disease, DE 4230755 (1994) assigned to Schering genesis; or rheumatoid arthritis that is a member AG; in the treatment of urogenital and gastrointestinal Selected from the group consisting of acute arthritis; disorders, WO 94/06423 assigned to Schering AG; and in 55 acute gouty arthritis; chronic inflammatory arthritis; the treatment of prostate diseases, WO 99/02161 assigned to degenerative arthritis; infectious arthritis; Lyme arthri Porssmann and WO 99/02161 assigned to Stief. tis; proliferative arthritis; psoriatic arthritis; and verte In accordance with the above descriptions, it will be bral arthritis; understood that the compounds of Formula (1.0.0) are useful gout, and fever and pain associated with inflammation; in the beneficial treatment of any one or more members 60 an eosinophil-related disorder of whatever type, etiology, selected from the group consisting of the following diseases, or pathogenesis; or an eosinophil-related disorder that disorders, and conditions: is a member selected from the group consisting of asthma of whatever type, etiology, or pathogenesis; or eosinophilia; pulmonary infiltration eosinophilia; Lof asthma that is a member selected from the group fler's syndrome; chronic eosinophilic pneumonia; consisting of atopic asthma; non-atopic asthma, aller 65 tropical pulmonary eosinophilia; bronchopneumonic gic asthma, atopic, bronchial, IgE-mediated asthma, aspergillosis; aspergilloma; granulomas containing bronchial asthma, essential asthma; true asthma; intrin eosinophils; allergic granulomatous angiitis or Churg US 7,250,518 B2 169 170 Strauss syndrome; polyarteritis nodosa (PAN); and ing of ulcerative colitis (UC); collagenous colitis; coli systemic necrotizing vasculitis; tis polyposa; transmural colitis; and Crohn's disease atopic dermatitis; or allergic dermatitis; or allergic or (CD). atopic eczema: septic shock of whatever type, etiology, or pathogenesis; urticaria of whatever type, etiology, or pathogenesis; or or septic shock that is a member selected from the urticaria that is a member selected from the group group consisting of renal failure; acute renal failure; consisting of immune-mediated urticaria; complement cachexia; malarial cachexia; hypophysial cachexia; mediated urticaria; urticariogenic material-induced uremic cachexia; cardiac cachexia; cachexia Suprarena urticaria; physical agent-induced urticaria; stress-in lis or Addison's disease; cancerous cachexia; and duced urticaria; idiopathic urticaria; acute urticaria; 10 cachexia as a consequence of infection by the human chronic urticaria; angioedema; cholinergic urticaria; immunodeficiency virus (HIV); cold urticaria in the autosomal dominant form or in the liver injury; acquired form; contact urticaria; giant urticaria; and pulmonary hypertension; and hypoxia-induced pulmo papular urticaria; 15 conjunctivitis of whatever type, etiology, or pathogenesis; nary hypertension; or conjunctivitis that is a member selected from the bone loss diseases; primary osteoporosis; and secondary group consisting of actinic conjunctivitis; acute osteoporosis: catarrhal conjunctivitis; acute contagious conjunctivi central nervous system disorders of whatever type, etiol tis; allergic conjunctivitis; atopic conjunctivitis; ogy, or pathogenesis; or a central nervous system chronic catarrhal conjunctivitis; purulent conjunctivi disorder that is a member selected from the group tis; and Vernal conjunctivitis consisting of depression; Parkinson's disease; learning uveitis of whatever type, etiology, or pathogenesis; or and memory impairment; tardive dyskinesia; drug uveitis that is a member selected from the group dependence; arteriosclerotic dementia; and dementias consisting of inflammation of all or part of the uvea; 25 that accompany Huntington's chorea, Wilson's disease, anterior uveitis; iritis; cyclitis; iridocyclitis; granulo paralysis agitans, and thalamic atrophies; matous uveitis; nongranulomatous uveitis; phacoanti infection, especially infection by viruses wherein Such genic uveitis; posterior uveitis; choroiditis; and chori viruses increase the production of TNF-C. in their host, oretinitis; or wherein Such viruses are sensitive to upregulation of psoriasis; 30 TNF-C. in their host so that their replication or other multiple Sclerosis of whatever type, etiology, or patho vital activities are adversely impacted, including a virus genesis; or multiple Sclerosis that is a member selected which is a member selected from the group consisting from the group consisting of primary progressive mul of HIV-1, HIV-2, and HIV-3; cytomegalovirus, CMV: tiple Sclerosis; and relapsing remitting multiple Sclero 35 influenza; adenoviruses; and Herpes viruses, including sis; Herpes Zoster and Herpes simplex: autoimmune/inflammatory diseases of whatever type, eti ology, or pathogenesis; or an autoimmune/inflamma yeast and fungus infections wherein said yeast and fungi tory disease that is a member selected from the group are sensitive to upregulation by TNF-C. or elicit TNF-C. consisting of autoimmune hematological disorders; production in their host, e.g., fungal meningitis; par hemolytic anemia; aplastic anemia; pure red cell ane 40 ticularly when administered in conjunction with other mia; idiopathic thrombocytopenic purpura; systemic drugs of choice for the treatment of systemic yeast and lupus erythematosus; polychondritis; Scleroderma; fungus infections, including but are not limited to, Wegner's granulomatosis; dermatomyositis; chronic polymixins, e.g., Polymycin B; imidazoles, e.g., clot active hepatitis; myasthenia gravis; Stevens-Johnson rimazole, econazole, miconazole, and ketoconazole; syndrome; idiopathic sprue; autoimmune inflammatory 45 triazoles, e.g., fluconazole and itranazole; and ampho bowel diseases; ulcerative colitis; Crohn's disease; tericins, e.g., Amphotericin B and liposomal Amphot endocrin opthamopathy; Grave's disease; sarcoidosis: ericin B. alveolitis; chronic hypersensitivity pneumonitis; pri ischemia-reperfusion injury; autoimmune diabetes; reti mary biliary cirrhosis; juvenile diabetes or diabetes 50 nal autoimmunity; chronic lymphocytic leukemia; HIV mellitus type I: anterior uveitis; granulomatous or pos infections; lupus erythematosus; kidney and ureter dis terior uveitis; keratoconjunctivitis sicca, epidemic ease; urogenital and gastrointestinal disorders; and keratoconjunctivitis; diffuse interstitial pulmonary fibrosis or interstitial lung fibrosis; idiopathic pulmo prostate diseases. nary fibrosis; cystic fibrosis; psoriatic arthritis; glom erulonephritis with and without nephrotic syndrome; 55 DETAILED DESCRIPTION OF THE acute glomerulonephritis; idiopathic nephrotic Syn INVENTION drome; minimal change nephropathy; inflammatory/ hyperproliferative skin diseases; psoriasis; atopic der 9.0 Combination with Other Drugs and Therapies matitis; contact dermatitis; allergic contact dermatitis; 60 The present invention contemplates embodiments in benign familial pemphigus; pemphigus erythematosus; which a compound of Formula (1.0.0) is the only therapeutic pemphigus foliaceus; and pemphigus Vulgaris; agent which is employed in a method of treatment described prevention of allogeneic graft rejection following organ herein, whether used alone or more commonly, together with transplantation; a pharmaceutically acceptable carrier to produce a suitable inflammatory bowel disease (IBD) of whatever type, 65 dosage form for administration to a patient. Other embodi etiology, or pathogenesis; or inflammatory bowel dis ments of the present invention contemplate a combination of ease that is a member selected from the group consist a compound of Formula (1.0.0) together with one or more US 7,250,518 B2 171 172 additional therapeutic agents to be co-administered to a “5-Lipoxygenase.” Ann. Rev. Biochem. 63 383417, 1994: patient to obtain some particularly desired therapeutic end Weitzel and Wendel, “Selenoenzymes regulate the activity result. The second, etc. therapeutic agent may also be one or of leukocyte 5-lipoxygenase via the peroxide tone.” J. Biol. more compounds of Formula (1.0.0), or one or more PDE4 Chem. 268 6288-92, 1993: Björnstedt et al. “Selenite incu inhibitors known in the art and described in detail herein. bated with NADPH and mammalian thioredoxin reductase More typically, the second, etc. therapeutic agent will be yields selenide, which inhibits lipoxygenase and changes the selected from a different class of therapeutic agents. These electron spin resonance spectrum of the active site iron.” selections are described in detail below. Biochemistry 35 851 1-6, 1996; and Stewart et al., “Struc As used herein, the terms “co-administration”, “co-ad ture-activity relationships of N-hydroxyurea 5-lipoxygenase ministered, and “in combination with', referring to the 10 inhibitors, J. Med. Chem. 40 1955-68, 1997: compounds of Formula (1.0.0) and one or more other (b) alkylating agents and compounds which react with SH therapeutic agents, is intended to mean, and does refer to and groups have been found to inhibit leukotriene synthesis in include the following: (a) simultaneous administration of vitro; see Larsson et al., “Effects of 1-chloro-2,4,6-trini Such combination of compound(s) and therapeutic agent(s) trobenzene on 5-lipoxygenase activity and cellular leukot to a patient in need of treatment, when Such components are 15 riene synthesis,” Biochem. Pharmacol. 55863-71, 1998; and formulated together into a single dosage form which releases (c) competitive inhibitors of 5-lipoxygenase, based on said components at Substantially the same time to said thiopyranoindole and methoxyalkyl thiazole structures patient; (b) Substantially simultaneous administration of which may act as non-redox inhibitors of 5-lipoxygenase; Such combination of compound(s) and therapeutic agent(s) see Ford-Hutchinson et al., Ibid.; and Hamel et al., “Sub to a patient in need of treatment, when Such components are stituted (pyridylmethoxy)naphthalenes as potent and orally formulated apart from each other into separate dosage forms active 5-lipoxygenase inhibitors—synthesis, biological pro which are ingested at Substantially the same time by said file, and pharmacokinetics of L-739,010, 'J. Med. Chem. 40 patient, whereupon said components are released at Substan 2866-75, 1997. tially the same time to said patient; (c) sequential adminis The observation that arachidonoyl hydroxyamate inhibits tration of such combination of compound(s) and therapeutic 25 5-lipoxygenase has led to the discovery of clinically useful agent(s) to a patient in need of treatment, when Such selective 5-lipoxygenase inhibitors such as the N-hydrox components are formulated apart from each other into yurea derivatives zileuton and ABT-761, represented by separate dosage forms which are ingested at consecutive Formulas (0.1.14) and (5.2.1): times by said patient with a significant time interval between each ingestion, whereupon said components are released at 30 (0.1.14) Substantially different times to said patient; and (d) sequen tial administration of such combination of compound(s) and therapeutic agent(s) to a patient in need of treatment, when S pi Such components are formulated together into a single 2 s NH2 dosage form which releases said components in a controlled 35 manner whereupon they are concurrently, consecutively, CH3 O and/or overlappingly ingested at the same and/or different times by said patient. Zileuton 9.1 With Leukotriene Biosynthesis Inhibitors: 5-Lipoxyge 40 (5.2.1) nase (5-LO) Inhibitors and 5-Lipoxygenase Activating Pro tein (FLAP) Antagonists One or more compounds of Formula (1.0.0) is used in combination with leukotriene biosynthesis inhibitors, i.e., 5-lipoxygenase inhibitors and/or 5-lipoxygenase activating 45 protein antagonists, to form embodiments of the present invention. As already adverted to above, 5-lipoxygenase (5-LO) is one of two groups of enzymes that metabolize arachidonic acid, the other group being the cyclooxygena ses, COX-1 and COX-2. The 5-lipoxygenase activating 50 protein is an 18 kDa membrane-bound, arachidonate-bind ABT-761 ing protein which stimulates the conversion of cellular arachidonic acid by 5-lipoxygenase. The arachidonic acid is Another N-hydroxyurea compound is fenleuton (Abbott converted into 5-hydroperoxyeicosatetraenoic acid 76745) which is represented by Formula (5.2.2): (5-HPETE), and this pathway eventually leads to the pro 55 duction of inflammatory leukotrienes; consequently, block ing the 5-lipoxygenase activating protein or the 5-lipoxyge (5.2.2) nase enzyme itself provides a desirable target for F beneficially interfering.with that pathway. One such 5-li poxygenase inhibitor is Zileuton represented by Formula 60 (0.1.14) above. Among the classes of leukotriene synthesis Ol OH inhibitors which are useful for forming therapeutic combi nations with the compounds of Formula (1.0.0) are the O Šs t following: CH, O (a) redox-active agents which include N-hydroxyureas: 65 N-alkythydroxamid acids; selenite; hydroxybenzofurans; Fenleuton hydroxylamines; and catechols; see Ford-Hutchinson et al., US 7,250,518 B2 173 174 Zileuton is covered by U.S. Pat. No. 4,873.259 (Summers et al.) assigned to Abbott Laboratories, which discloses indole, benzofuran, and benzothiophene containing lipoxy (5.24) genase inhibiting compounds which may be represented by H3CO Formula (5.2.3): 5 R3 O N (5.2.3) NV N NR4 Z S. Šs Nn 10 OH Y ris's R R2 "N-4'Nx OM RI (5.2.5) 15 where R is H. (C-C)alkyl: (C-C)alkenyl; or NRR HCO where R and R are H; (C-C)alkyl; or OH: X is O: S; SO; 5 or NR where R is H., (C-C)alkyl, (C-C)alkanoyl; aroyl; NV s' or alkylsulfonyl: A is (C-C)alkylene; or (C-C)alk 2O S/ N enylene; n is 1-5; and Y is H; halo; OH: CN; halo substituted OH alkyl, (C-C)alkyl, (C-C)alkenyl; (C-C)alkoxy; (C- R2 Cs)cycloalkyl, (C-C)thioalkyl, aryl; aryloxy; aroyl; (C- C.)arylalkyl, (C-C)arylalkenyl; (C-C)arylalkoxy: 25 R (C-C)arylthioalkoxy; or substituted derivatives of aryl; where R' through R" are H. Cl; CH; ethyl: iso-propyl; or aryloxy: aryoyl: (C-C)arylalkyl: (C-C)arylalkenyl: n-propyl: or R and R together are (CH) or (CH)O (C-C)arylalkoxy; (C-C)arylthioalkoxy; where said (CH); and R is methyl; ethyl; iso-propyl: methoxy; trif luoromethyl, chloromethyl; ethyl propionate; phenyl: substituent is halo: NO, CN; or (C-C)-alkyl-alkoxy and 30 -halosubstitutedalkyl; Z is O or S; and M is H; pharmaceu 2-furanyl: 3-pyridyll; or 4-pyridyl. See Connolly et al., tically acceptable cation; aroyl: or (C-C)alkanoyl. “N-Hydroxyurea and hydroxamic acid inhibitors of cyclooxygenase and 5-lipoxygenase.” Bioorganic & Medici Related compounds are disclosed in U.S. Pat. No. 4,769, nal Chemistry Letters 9979-984, 1999. 387 (Summers et al.); U.S. Pat. No. 4,822,811 (Summers): U.S. Pat. No. 4,822,809 (Summers and Stewart); U.S. Pat. 35 Another N-hydroxyurea compound is Abbott-79175 No. 4,897,422 (Summers); U.S. Pat. No. 4,992.464 (Sum which is represented by Formula (5.2.6): mers et al.); and U.S. Pat. No. 5,250,565 (Brooks and Summers); each of which is incorporated herein by refer (5.2.6) ence in its entirety as though fully set out herein. 40 Zileuton or any of the above-described derivatives thereof are combined with the compounds of Formula (1.0.0) to form embodiments of the present invention. Fenleuton is disclosed in U.S. Pat. No. 5,432,194; U.S. Pat. No. 5,446,062; U.S. Pat. No. 5,484,786; U.S. Pat. No. 5,559,144;U.S. Pat. No. 5,616,596; U.S. Pat. No. 5,668,146; U.S. Pat. No. 5,668, 150; U.S. Pat. No. 5,843,968; U.S. Pat. Abbott-791.75 No. 5,407,959; U.S. Pat. No. 5,426,111; U.S. Pat. No. Abbott-79175 has a longer duration of action than zileuton; 5,446,055; U.S. Pat. No. 5,475,009; U.S. Pat. No. 5,512,581; 50 Brooks et al., J. Pharm. Exp. Therapeut. 272 724, 1995. U.S. Pat. No. 5,516,795: U.S. Pat. No. 5,476,873; U.S. Pat. A still further N-hydroxyurea compound is Abbott-85761 No. 5,714,488; U.S. Pat. No. 5,783,586: U.S. Pat. No. which is represented by Formula (5.2.7): 5,399,699; U.S. Pat. No. 5,420,282: U.S. Pat. No. 5,459,150; (5.2.7) and U.S. Pat. No. 5,506.261; each of which is incorporated herein by reference in its entirety as though fully set out 55 F herein. Further descriptions of such N-hydroxyurea and related inhibitors of 5-lipoxygenase and the synthesis of W \ pi inflammatory leukotrienes may be found in WO95/30671; S Šs N NH2 WO 96/02507; WO 97/12865; WO 97/12866; WO 60 r 97/12867; WO 98/04555; and WO 98/14429. ÖH, 5 Tepoxalin is a dual COX/5-LO inhibitor with short-lived Abbott-85761 in vivo activity that has led to the development of two series of hybrid compounds which are N-hydroxyureas and 65 hydroxamic acids of Formulas (5.2.4) and (5.2.5), respec Abbott-85761 is delivered to the lung by aerosol adminis tively: tration of a homogeneous, physically stable and nearly US 7,250,518 B2 175 176 monodispersed formulation; Gupta et al., “Pulmonary deliv ery of the 5-lipoxygenase inhibitor, Abbott-85761, in beagle (5.2.10) dogs.” International Journal of Pharmaceutics 147 207 CH 218, 1997. Fenleuton, Abbott-79175, Abbott-85761 or any of the H3C CH, () above-described derivatives thereof or of tepoxalin, are N-N combined with the compounds of Formula (1.0.0) to form HO / H embodiments of the present invention. Since the elucidation of the 5-LO biosynthetic pathway, 10 H3C there has been an ongoing debate as to whether it is more CH advantageous to inhibit the 5-lipoxygenase enzyme or to CH3 antagonize peptido- or non-peptido leukotriene receptors. Inhibitors of 5-lipoxygenase are deemed to be superior to LT-receptor antagonists, since 5-lipoxygenase inhibitors 15 where “Het' is benzoxazol-2-yl; benzothizazol-2-yl; pyri block the action of the full spectrum of 5-LO products, din-2-yl; pyrazin-2-yl; pyrimidin-2-yl, 4-phenylpyrimidin whereas LT-antagonists produce narrower effects. Neverthe 2-yl; 4,6-diphenylpyrimidin-2-yl, 4-methylpyrimidin-2-yl; 4,6-dimethylpyrimidin-2-yl 4-butylpyrimidin-2-yl; 4.6- less, embodiments of the present invention include combi dibutylpyrimidin-2-yl; and 4-methyl-6-phenylpyrimidin-2- nations of the compounds of Formula (1.0.0) with LT y1. antagonists as well as 5-LO inhibitors, as described below. The N-(5-substituted)-thiophene-2-alkylsulfonamides of Inhibitors of 5-lipoxygenase having chemical structures that Formula (5.2.8), or the 2,6-di-tert-butylphenol hydrazones differ from the classes of N-hydroxyureas and hydroxamic of Formula (5.2.10), or any of the above-described deriva acids described above are also used in combination with the tives thereof, are combined with the compounds of Formula compounds of Formula (1.0.0) to form further embodiments 25 (1.0.0) to form embodiments of the present invention. of the present invention. An example of such a different class A further distinct class of 5-lipoxygenase inhibitors is that is the N-(5-substituted)-thiophene-2-alkylsulfonamides of of methoxytetrahydropyrans to which Zeneca ZD-2138 Formula (5.2.8): belongs. ZD-2138 is represented by Formula (5.2.11): 30 (5.2.8) (5.2.11) ^ - F 35 where X is O or S.; R is methyl, iso-propyl. n-butyl, n-octyl, O or phenyl; and R is n-pentyl, cyclohexyl, phenyl, tetrahydro 21 cles 1-naphthyl, 1- or 2-naphthyl, or phenyl mono- or di-substi OCH tuted by C1, F, Br, CH, OCH SCH, SOCH, CF, or 40 iso-propyl. A preferred compound is that of Formula (5.2.9): or CH

(5.2.9) 45 ZD-2138 is highly selective and highly active orally in a number of species and has been evaluated in the treatment of asthma and rheumatoid arthritis by oral admininstration. Further details concerning ZD-2138 and derivatives thereof are disclosed in Crawley et al., J. Med. Chem., 35 2600, 50 1992; and Crawley et al., J. Med. Chem. 36295, 1993. Another distinct class of 5-lipoxygenase inhibitors is that to which the SmithKline Beecham compound SB-210661 N-- belongs. SB-210661 is represented by Formula (5.2.12): 55

A further description of these compounds may be found in (5.2.12) Beers et al., “N-(5-substituted) thiophene-2-alkylsulfona mides as potent inhibitors of 5-lipoxygenase.” Bioorganic &

Medicinal Chemistry 5(4) 779-786, 1997. 60 Another distinct class of 5-lipoxygenase inhibitors is that of the 2,6-di-tert-butylphenol hydrazones described in Cuadro et al., “Synthesis and biological evaluation of 2.6- di-tert-butylphenol hydrazones as 5-lipoxygenase inhibi tors.” Bioorganic & Medicinal Chemistry 6 173-180, 1998. 65 Compounds of this type are represented by Formula (5.2.10): US 7,250,518 B2 177 178 Two further distinct and related classes of 5-lipoxygenase from indole and quinoline structures; see Ford-Hutchinson inhibitors comprise a series of pyridinyl-substituted 2-cy et al., Ibid.: Rouzer et al. “MK-886, a potent and specific anonaphthalene compounds and a series of 2-cyanoquino leukotriene biosynthesis inhibitor blocks and reverses the line compounds discovered by Merck Frosst. These two membrane association of 5-lipoxygenase in ionophore-chal classes of 5-lipoxygenase inhibitors are exemplified by lenged leukocytes. J. Biol. Chem. 265 1436-42, 1990; and L-739,010 and L-746,530, represented by Formulas (5.2.13) Gorenne et al., “{(R)-2-quinolin-2-yl-methoxy)phenyl)-2- and (5.2.14) respectively: cyclopenty1 acetic acid (BAY x 1005), a potent leukotriene synthesis inhibitor: effects on anti-IgE challenge in human airways,” J. Pharmacol. Exp. Ther. 268 868-72, 1994 (5.2.13) 10

MK-591, which has been designated quiflipon sodium, is represented by Formula (5.2.15):

15 (5.2.15) CH N H3C NCH, S 2 O \ . N L-739,010 N O (5.2.14) N F O Nat 25

HO N CN O O n 30 O 21 The above-mentioned indole and quinoline classes of compounds and the specific compounds MK-591, MK-886, and BAY x 1005 to which they belong, or any of the above-described derivatives of any of the above-mentioned \ . classes, are combined with the compounds of Formula L-746,530 (1.0.0) to form embodiments of the present invention. 9.2 With Receptor Antagonists for Leukotrienes LTB, Details concerning L-739,010 and L-746,530 are disclosed 40 LTC LTD, and LTE in Dubé et al., “Quinolines as potent 5-lipoxygenase inhibi One or more compounds of Formula (1.0.0) is used in tors: synthesis and biological profile of L-746.530, 'Bioor combination with receptor antagonists for leukotrienes ganic & Medicinal Chemistry 8 1255-1260, 1998; and in LTB, LTC LTD, and LTE. The most significant of these WO95/03309 (Friesen et al.). leukotrienes in terms of mediating inflammatory response, The class of methoxytetrahydropyrians including Zeneca 45 are LTB and LTD. Classes of antagonists for the receptors ZD-2138 of Formula (5.2.11); or the lead compound of these leukotrienes are described in the paragraphs which SB-210661 of Formula (5.2.12) and the class to which it follow. belongs; or the series of pyridinyl-substituted 2-cyanonaph 4-Bromo-2,7-diemethoxy-3H-phenothiazin-3-ones, thalene compounds to which L-739,010 belongs, or the including L-651,392, are potent receptor antagonists for series of 2-cyanoquinoline compounds to which L-746,530 LTB, that are described in U.S. Pat. No. 4,939,145 (Guindon belongs; or any of the above-described derivatives of any of et al.) and U.S. Pat. No. 4,845,083 (Lau et al.). L-651,392 is the above-mentioned classes, are combined with the com represented by Formula (5.2.16): pounds of Formula (1.0.0) to form embodiments of the present invention. In addition to the 5-lipoxygenase enzyme, the other 55 (5.2.16) endogenous agent which plays a significant role in the Br biosynthesis of the leukotrienes is the 5-lipoxygenase acti vating protein (FLAP). This role is an indirect one, in contrast to the direct role of the 5-lipoxygenase enzyme. Nevertheless, antagonists of the 5-lipoxygenase activating 60 r protein are employed to inhibit the cellular synthesis of s' leukotrienes, and as such are also used in combination with O CH3 the compounds of Formula (1.0.0) to form embodiments of NCH, the present invention. Compounds which bind to the 5-lipoxygenase activating 65 L-651,392 protein and thereby block utilization of the endogenous pool of archidonic acid which is present have been synthesized US 7,250,518 B2 179 180 A class of amidino compounds that includes CGS-25019c 963: U.S. Pat. No. 5,583,152 (Bernstein et al.); and U.S. Pat. is described in U.S. Pat. No. 5,451,700 (Morrissey and Suh): No. 5,612,367 (Timko et al.). Zafirlukast is represented by U.S. Pat. No. 5.488,160 (Morrissey); and U.S. Pat. No. Formula (5.2.20): 5,639,768 (Morrissey and Suh). These receptor antagonists for LTB are typified by CGS-25019c, which is represented 5 by Formula (5.2.17): (5.2.20) O-CH (5.2.17) O H O CH, O NH 10 ( V )-( ) N-O H3C 'Nchi, NH2 &O N f SC) O HC CH o1n 11no CH3 N 15 CH CGS-25O19C

Zafirlukast OntaZolast, a member of a class of benzoxaolamines that are receptor antagonists for LTB, is described in EP535 521 (Anderskewitz et al.); and is represented by Formula Ablukast is a receptor antagonist for LTD that is desig (5.2.18): nated Ro 23-3544/001, and is represented by Formula (5.2.21):

(5.2.18) 25 (5.2.21) O

On 11-10 O OH 30 H HC HC

O OH O CH

35 Ablukast Ontazolast

The same group of workers has also discovered a class of Montelukast is a receptor antagonist for LTD which is benzenecarboximidamides which are receptor antagonists sold commercially under the name Singulair R and is for LTB, described in WO97/21670 (Anderskewitz et al.); 40 and WO 98/11119 (Anderskewitz et al.); and which are described in U.S. Pat. No. 5,565,473. Montelukast is repre typified by BIIL 284/260, represented by Formula (5.2.19): sented by Formula (5.2.22):

(5.2.19)

HO O O

H3C CH

BIIL 284,260

Zafirlukast is a receptor antagonist for LTC, LTD, and LTE which is sold commercially under the name Acco lateR). It belongs to a class of heterocyclic amide derivatives described in U.S. Pat. No. 4,859,692 (Bernstein et al.); U.S. Pat. No. 5,319,097 (Holohan and Edwards); U.S. Pat. No. 5,294,636 (Edwards and Sherwood); U.S. Pat. No. 5,482, US 7,250,518 B2 181 182 formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; (5.2.22) (k) Theophylline and aminophylline; O Na (1) Sodium cromoglycate; 5 (m) Muscarinic receptor (M1, M2, and M3) antagonists; (n) COX-1 inhibitors (NSAIDs); COX-2 selective inhibitors including rofecoxib; and nitric oxide NSAIDs:

C (o) Insulin-like growth factor type I (IGF-1) mimetics: (p) Ciclesonide; 10 (q) Inhaled glucocorticoids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticaSone propionate, and mometasone Montelukast 15 furoate: (r) Tryptase inhibitors; Other receptor antagonists for LTD include pranlukast, (s) Platelet activating factor (PAF) antagonists; verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP (t) Monoclonal antibodies active against endogenous 45715A), and BAY x 7.195. inflammatory entities; The above-mentioned phenothiazin-3-one class of com (u) IPL 576; pounds, including L-651,392; the class of amidino com (v) Anti-tumor necrosis factor (TNFC) agents including pounds that includes CGS-25019c; the class of benzoxaola Etanercept, Infliximab, and D2E7; mines which includes Ontazolast; the class of (w) DMARDs including Leflunomide: benzenecarboximidamides which is typified by BIIL 284/ (x) TCR peptides; 260; the heterocyclic amide derivatives including 25 Zafirlukast, Ablukast and Montelukast and the classes of (y) Interleukin converting enzyme (ICE) inhibitors; compounds to which they belong; or any of the above (z) IMPDH inhibitors; described derivatives of any of the above-mentioned classes, (aa) Adhesion molecule inhibitors including VLA-4 antago are combined with the compounds of Formula (1.0.0) to nists; form embodiments of the present invention. 30 (bb) Cathepsins: 9.3 With Other Therapeutic Agents to Form Further Com (cc) MAP kinase inhibitors; binations (dd) Glucose-6 phosphate dehydrogenase inhibitors; One or more compounds of Formula (1.0.0) are used (ee) Kinin-B- and B-receptor antagonists; together with other therapeutic agents as well as non 35 (f) Gold in the form of an aurothio group together with therapeutic agents to form combinations that are further various hydrophilic groups; embodiments of the present invention and that are useful in (gg) Immunosuppressive agents, e.g., cyclosporine, azathio the treatment of a significant number of different diseases, prine, and methotrexate; disorders, and conditions described herein. Said embodi (hh) Anti-gout agents, e.g., colchicine; ments comprise one or more compounds of Formula (1.0.0) 40 (ii) Xanthine oxidase inhibitors, e.g., allopurinol; together with one or more of the following: (ii) UricoSuric agents, e.g., probenecid, Sulfinpyrazone, and (a) PDE4 inhibitors; benzbromarone; (b) 5-Lipoxygenase (5-LO) inhibitors; or 5-lipoxygenase (kk) Antineoplastic agents, especially antimitotic drugs activating protein (FLAP) antagonists; including the Vinca alkaloids such as vinblastine and (c) Dual inhibitors of 5-lipoxygenase (5-LO) and antagonists 45 Vincristine; of platelet activating factor (PAF); (Tl) Growth hormone secretagogues; (d) Leukotriene antagonists (LTRAS) including antagonists (mm) Inhibitors of matrix metalloproteases (MMPs), i.e., the of LTB, LTC LTD and LTE: stromelysins, the collagenases, and the gelatinases, as (e) Antihistaminic H receptor antagonists including cetiriz 50 well as aggrecanase; especially collagenase-1 (MMP-1), ine, loratadine, desloratadine, fexofenadine, astemizole, collagenase-2 (MMP-8), collagenase-3 (MMP-13), aZelastine, and chlorpheniramine; stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and (f) Gastroprotective H receptor antagonists; stromelysin-3 (MMP-11): (g) C- and C-adrenoceptor agonist vasoconstrictor sym (nn) Transforming growth factor (TGF-B); pathomimetic agents administered orally or topically for decongestant use, including propylhexedrine, phenyleph 55 (oo) Platelet-derived growth factor (PDGF); rine, phenylpropanolamine, pseudoephedrine, naphazo (pp) Fibroblast growth factor, e.g., basic fibroblast growth line hydrochloride, oxymetazoline hydrochloride, tet factor (bFGF); rahydrozoline hydrochloride, Xylometazoline (qq) Granulocyte macrophage colony stimulating factor hydrochloride, and ethylnorepinephrine hydrochloride; 60 (GM-CSF); (h) C- and C2-adrenoceptor agonists in combination with (rr) Capsaicin; inhibitors of 5-lipoxygenase (5-LO); (ss) Tachykinin NK and NK receptor antagonists selected (i) Anticholinergic agents including ipratropium bromide; from the group consisting of NKP-608C; SB-233412 tiotropium bromide; oxitropium bromide: pirenzepine; (talnetant); and D-4418; and telenzepine; 65 (tt) Elastase inhibitors selected from the group consisting of () - to B-adrenoceptor agonists including metaproter UT-77 and ZD-0892; and enol, isoproterenol, isoprenaline, albuterol, Salbutamol, (uu) Adenosine A2a receptor agonists. US 7,250,518 B2 183 184 DETAILED DESCRIPTION OF THE while lipid solutions and Suspensions, as well as Solid INVENTION dosage forms, will result in less rapid absorption of said active ingredient. Oral ingestion of said active ingredient is 10.0 Pharmaceutical Compositions and Formulations the most preferred route of administration for reasons of 5 safety, convenience, and economy, but absorption of Such an The description which follows concerns the manner in oral dosage form can be adversely affected by physical which the compounds of Formula (1.0.0), together with characteristics Such as polarity, emesis caused by irritation other therapeutic agents or non-therapeutic agents where of the gastrointestinal mucosa, destruction by digestive these are desired, are combined with what are for the most enzymes and low pH, irregular absorption or propulsion in part conventional pharmaceutically acceptable carriers to 10 the presence of food or other drugs, and metabolism by form dosage forms suitable for the different routes of admin enzymes of the mucosa, the intestinal flora, or the liver. istration which are utilized for any given patient, as well as Formulation of said active ingredient into different pharma appropriate to the disease, disorder, or condition for which ceutically acceptable salt forms may be effective in over any given patient is being treated. coming or alleviating one or more of the above-recited The pharmaceutical compositions of the present invention 15 problems encountered with absorption of oral dosage forms. comprise any one or more of the above-described inhibitory Among the pharmaceutical salts recited further above, compounds of the present invention, or a pharmaceutically those which are preferred include, but are not limited to acceptable salt thereof as also above-described, together acetate, besylate, citrate, fumarate, gluconate, hemisucci with a pharmaceutically acceptable carrier in accordance nate, hippurate, hydrochloride, hydrobromide, isethionate, with the properties and expected performance of Such car mandelate, meglumine, nitrate, oleate, phosphonate, piv riers which are well-known in the pertinent art. alate, Sodium phosphate, Stearate, Sulfate, Sulfosalicylate, The amount of active ingredient that may be combined tartrate, thiomalate, tosylate, and tromethamine. with the carrier materials to produce a single dosage form Multiple salts forms are included within the scope of the will vary depending upon the host treated, and the particular present invention where a compound of the present inven mode of administration. It should be understood, however, 25 tion contains more than one group capable of forming Such that a specific dosage and treatment regimen for any par pharmaceutically acceptable salts. Examples of typical mul ticular patient will depend upon a variety of factors, includ tiple salt forms include, but are not limited to bitartrate, ing the activity of the specific compound employed, the age, diacetate, difumarate, dimeglumine, diphosphate, disodium, body weight, general health, sex, diet, time of administra and trihydrochloride. tion, rate of excretion, drug combination, and the judgment 30 The pharmaceutical compositions of the present invention of the treating physician and the severity of the particular comprise any one or more of the above-described inhibitory disease being treated. The amount of active ingredient may compounds of the present invention, or a pharmaceutically also depend upon the therapeutic or prophylactic agent, if acceptable salt thereof as also above-described, together any, with which the ingredient is co-administered. with a pharmaceutically acceptable carrier in accordance The above-described compounds of the present invention 35 with the properties and expected performance of Such car may be utilized in the form of acids, esters, or other chemical riers which are well-known in the pertinent art. classes of compounds to which the compounds described The term “carrier as used herein includes acceptable belong. It is also within the scope of the present invention to diluents, excipients, adjuvants, vehicles, solubilization aids, utilize those compounds in the form of pharmaceutically Viscosity modifiers, preservatives and other agents well acceptable salts derived from various organic and inorganic 40 known to the artisan for providing favorable properties in acids and bases in accordance with procedures described in the final pharmaceutical composition. In order to illustrate detail above and well known in the art. An active ingredient such carriers, there follows a brief survey of pharmaceuti comprising a compound of Formula (1.0.0) is often utilized cally acceptable carriers that may be used in the pharma in the form of a salt thereof, especially where said salt form ceutical compositions of the present invention, and thereaf confers on said active ingredient improved pharmacokinetic 45 ter a more detailed description of the various types of properties as compared to the free form of said active ingredients. Typical carriers include but are by no means ingredient or some other salt form of said active ingredient limited to, ion exchange compositions; alumina; aluminum utilized previously. The pharmaceutically acceptable salt Stearate; lecithin; serum proteins, e.g., human serum albu form of said active ingredient may also initially confer a min; phosphates; glycine; Sorbic acid; potassium Sorbate; desirable pharmacokinetic property on said active ingredient 50 partial glyceride mixtures of Saturated vegetable fatty acids; which it did not previously possess, and may even positively hydrogenated palm oils; water; salts or electrolytes, e.g., affect the pharmacodynamics of said active ingredient with prolamine Sulfate, disodium hydrogen phosphate, potassium respect to its therapeutic activity in the body. hydrogen phosphate, Sodium chloride, and Zinc salts; col The pharmacokinetic properties of said active ingredient loidal silica, magnesium trisilicate; polyvinyl pyrrolidone; which may be favorably affected include, e.g., the manner in 55 cellulose-based substances; e.g., Sodium carboxymethylcel which said active ingredient is transported across cell mem lulose; polyethylene glycol; polyacrylates; waxes; polyeth branes, which in turn may directly and positively affect the ylene-polyoxypropylene-block polymers; and wool fat. absorption, distribution, biotransformation and excretion of More particularly, the carriers used in the pharmaceutical said active ingredient. While the route of administration of compositions of the present invention comprise various the pharmaceutical composition is important, and various 60 classes and species of additives which are members inde anatomical, physiological and pathological factors can criti pendently selected from the groups consisting essentially of cally affect bioavailability, the solubility of said active those recited in the following paragraphs. ingredient is usually dependent upon the character of the Acidifying and alkalizing agents are added to obtain a particular salt form thereof which it utilized. Further, as the desired or predetermined pH and comprise acidifying artisan understands, an aqueous solution of said active 65 agents, e.g., acetic acid, glacial acetic acid, malic acid, and ingredient will provide the most rapid absorption of said propionic acid. Stronger acids such as hydrochloric acid, active ingredient into the body of a patient being treated, nitric acid and Sulfuric acid may be used but are less US 7,250,518 B2 185 186 preferred. Alkalizing agents include, e.g., edetol, potassium tretinoin, isotretinoin, etretinate, acitretin, and arotinoid; carbonate, potassium hydroxide, sodium borate, sodium mild antibacterial agents for treating skin infections, e.g., carbonate, and sodium hydroxide. Alkalizing agents which resorcinol, Salicylic acid, benzoyl peroxide, erythromycin contain active amine groups, such as diethanolamine and benzoyl peroxide, erythromycin, and clindamycin; antifun trolamine, may also be used. 5 gal agents for treating tinea corporis, tinea pedis, candidiasis Aerosol propellants are required where the pharmaceuti and tinea versicolor, e.g., griseofulvin, azoles Such as cal composition is to be delivered as an aerosol under miconazole, econazole, itraconazole, fluconazole, and keto significant pressure. Such propellants include, e.g., accept conazole, and allylamines Such as naftifine and terfinafine; able fluorochlorohydrocarbons such as dichlorodifluo antiviral agents for treating cutaneous herpes simplex, her romethane, dichlorotetrafluoroethane, and trichloromonof- 10 pes Zoster, and chickenpox, e.g., acyclovir, famciclovir, and luoromethane; nitrogen; or a volatile hydrocarbon Such as Valacyclovir, antihistamines for treating pruritis, atopic and butane, propane, isobutane or mixtures thereof. contact dermatitis, e.g., diphenhydramine, terfenadine, Antimicrobial agents including antibacterial, antifungal astemizole, loratadine, cetirizine, acrivastine, and temelas and antiprotozoal agents are added where the pharmaceuti tine; topical anesthetics for relieving pain, irritation and cal composition is topically applied to areas of the skin 15 itching, e.g., benzocaine, lidocaine, dibucaine, and pramox which are likely to have suffered adverse conditions or ine hydrochloride; topical analgesics for relieving pain and Sustained abrasions or cuts which expose the skin to infec inflammation, e.g., methyl salicylate, camphor, menthol, and tion by bacteria, fungi or protozoa. Antimicrobial agents resorcinol; topical antiseptics for preventing infection, e.g., include Such compounds as benzyl alcohol, chlorobutanol, benzalkonium chloride and povidone-iodine; and vitamins phenylethyl alcohol, phenylmercuric acetate, potassium Sor- 20 and derivatives thereof such as tocopherol, tocopherol bate, and Sorbic acid. Antifungal agents include Such com acetate, retinoic acid and retinol. pounds as benzoic acid, butylparaben, ethylparaben, meth Dispersing and Suspending agents are used as aids for the ylparaben, propylparaben, and Sodium benzoate. preparation of stable formulations and include, e.g., poli Antimicrobial preservatives are added to the pharmaceu geenan, povidone, and silicon dioxide. tical compositions of the present invention in order to 25 Emollients are agents, preferably non-oily and water protect them against the growth of potentially harmful soluble, which soften and soothe the skin, especially skin microorganisms, which usually invade the aqueous phase, that has become dry because of excessive loss of water. Such but in Some cases can also grow in the oil phase of a agents are used with pharmaceutical compositions of the composition. Thus, preservatives with both aqueous and present invention which are intended for topical applica lipid solubility are desirable. Suitable antimicrobial preser- 30 tions, and include, e.g., hydrocarbon oils and waxes, trig Vatives include, e.g., alkyl esters of p-hydroxybenzoic acid, lyceride esters, acetylated monoglycerides, methyl and other propionate salts, phenoxyethanol, methylparaben sodium, alkyl esters of Co-Co fatty acids, Co-Co fatty acids, propylparaben Sodium, sodium dehydroacetate, benzalko C-Co fatty alcohols, lanolin and derivatives, polyhydric nium chloride, benzethonium chloride, benzyl alcohol, alcohol esters such as polyethylene glycol (200-600), poly hydantoin derivatives, quaternary ammonium compounds 35 oxyethylene Sorbitan fatty acid esters, wax esters, phospho and cationic polymers, imidazolidinyl urea, diazolidinyl lipids, and sterols; emulsifying agents used for preparing urea, and trisodium ethylenediamine tetracetate (EDTA). oil-in-water emulsions; excipients, e.g., laurocapram and Preservatives are preferably employed in amounts ranging polyethylene glycol monomethyl ether, humectants, e.g., from about 0.01% to about 2.0% by weight of the total Sorbitol, glycerin and hyaluronic acid; ointment bases, e.g., composition. 40 petrolatum, polyethylene glycol, lanolin, and poloxamer; Antioxidants are added to protect all of the ingredients of penetration enhancers, e.g., dimethyl isosorbide, diethyl the pharmaceutical composition from damage or degrada glycol-monoethylether, 1-dodecylazacycloheptan-2-one, tion by oxidizing agents present in the composition itself or and dimethylsulfoxide (DMSO); preservatives, e.g., benza the use environment, e.g., anoXomer, ascorbyl palmitate, lkonium chloride, benzethonium chloride, alkyl esters of butylated hydroxyanisole, butylated hydroxytoluene, hypo- 45 p-hydroxybenzoic acid, hydantoin derivatives, cetylpyri phosphorous acid, potassium metabisulfite, propyl octyl and dinium chloride, propylparaben, quaternary ammonium dodecyl gallate, sodium metabisulfite, Sulfur dioxide, and compounds Such as potassium benzoate, and thimerosal; tocopherols. sequestering agents comprising cyclodextrins; Solvents, e.g., Buffering agents are used to maintain a desired pH of a acetone, alcohol, amylene hydrate, butyl alcohol, corn oil, composition once established, from the effects of outside 50 cottonseed oil, ethyl acetate, glycerin, hexylene glycol, agents and shifting equilibria of components of the compo isopropyl alcohol, isostearyl alcohol, methyl alcohol, meth sition. The buffering may be selected from among those ylene chloride, mineral oil, peanut oil, phosphoric acid, familiar to the artisan skilled in the preparation of pharma polyethylene glycol, polyoxypropylene 15 Stearyl ether, ceutical compositions, e.g., calcium acetate, potassium propylene glycol, propylene glycol diacetate, Sesame oil, metaphosphate, potassium phosphate monobasic, and tar- 55 and purified water, stabilizers, e.g., calcium saccharate and taric acid. thymol; Surfactants, e.g., lapyrium chloride; laureth 4, i.e., Chelating agents are used to help maintain the ionic C-dodecyl-(1)-hydroxy-poly(oxy-12-ethanediyl) or polyeth strength of the pharmaceutical composition and bind to and ylene glycol monododecyl ether. effectively remove destructive compounds and metals, and Emulsifying agents, including emulsifying and stiffening include, e.g., edetate dipotassium, edetate disodium, and 60 agents and emulsion adjuncts, are used for preparing oil-in edetic acid. water emulsions when these form the basis of the pharma Dermatologically active agents are added to the pharma ceutical compositions of the present invention. Such emul ceutical compositions of the present invention where they Sifying agents include, e.g., non-ionic emulsifiers such as are to be applied topically, and include, e.g., wound healing C-Cao fatty alcohols and said fatty alcohols condensed with agents such as peptide derivatives, yeast, panthenol, hexy- 65 from 2 to 20 moles of ethylene oxide or propylene oxide, lresorcinol, phenol, tetracycline hydrochloride, lamin and (C-C)alkyl phenols condensed with from 2 to 20 moles of kinetin; retinoids for treating skin cancer, e.g., retinol, ethylene oxide, mono- and di-Co-Co fatty acid esters of US 7,250,518 B2 187 188 ethylene glycol, Co-Co fatty acid monoglyceride, diethyl ylene chloride, mineral oil, peanut oil, phosphoric acid, ene glycol, polyethylene glycols of MW 200-6000, polypro polyethylene glycol, polyoxypropylene 15 Stearyl ether, pylene glycols of MW 200-3000, and particularly sorbitol, propylene glycol, propylene glycol diacetate, Sesame oil, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbi and purified water. tan, hydrophilic wax esters, cetostearyl alcohol, oleyl alco hol, lanolin alcohols, cholesterol, mono- and di-glycerides, Stabilizers which are suitable for use include, e.g., cal glyceryl monostearate, polyethylene glycol monostearate, cium saccharate and thymol. mixed mono- and distearic esters of ethylene glycol and Stiffening agents are typically used in formulations for polyoxyethylene glycol, propylene glycol monostearate, and topical applications in order to provide desired viscosity and hydroxypropyl cellulose. Emulsifying agents which contain 10 handling characteristics and include, e.g., cetyl esters wax, active amine groups may also be used and typically include myristyl alcohol, parafin, synthetic parafin, emulsifying anionic emulsifiers such as fatty acid soaps, e.g., Sodium, wax, microcrystalline wax, white wax and yellow wax. potassium and triethanolamine soaps of Co-Co fatty acids; Sugars are often used to impart a variety of desired alkali metal, ammonium or substituted ammonium (Co characteristics to the pharmaceutical compositions of the Cao)alkyl Sulfates, (Co-Cao)alkyl Sulfonates, and (Co-Cso) 15 present invention and in order to improve the results alkyl ethoxy ether sulfonates. Other suitable emulsifying obtained, and include, e.g., monosaccharides, disaccharides agents include castor oil and hydrogenated castor oil; leci and polysaccharides such as glucose, Xylose, fructose, reose, thin; and polymers of 2-propenoic acid together with poly mers of acrylic acid, both cross-linked with allyl ethers of ribose, pentose, arabinose, allose, tallose, altrose, mannose, Sucrose and/or pentaerythritol, having varying viscosities galactose, lactose. Sucrose, erythrose, glyceraldehyde, or and identified by product names carbomer 910, 934, 934P. any combination thereof. 940, 941, and 1342. Cationic emulsifiers having active Surfactants are employed to provide stability for multi amine groups may also be used, including those based on component pharmaceutical compositions of the present quaternary ammonium, morpholinium and pyridinium com invention, enhance existing properties of those composi pounds. Similarly, amphoteric emulsifiers having active 25 tions, and bestow desirable new characteristics on said amine groups, such as cocobetaines, lauryl dimethylamine compositions. Surfactants are used as wetting agents, anti oxide and cocoylimidazoline, may be used. Useful emulsi foam agents, for reducing the Surface tension of water, and fying and stiffening agents also include cetyl alcohol and as emulsifiers, dispersing agents and penetrants, and include, Sodium Stearate; and emulsion adjuncts such as oleic acid, e.g., lapyrium chloride; laureth 4, i.e., C.-dodecyl-(o-hy Stearic acid, and Stearyl alcohol. 30 droxy-poly(oxy-12-ethanediyl) or polyethylene glycol Excipients include, e.g., laurocapram and polyethylene monododecyl ether; laureth9, i.e., a mixture of polyethylene glycol monomethyl ether. glycol monododecyl ethers averaging about 9 ethylene oxide Where the pharmaceutical composition of the present groups per molecule; monoethanolamine; nonoxynol 4, 9 invention is to be applied topically, penetration enhancers and 10, i.e., polyethylene glycol mono(p-nonylphenyl) may be used, which include, e.g., dimethyl isosorbide, 35 ether; nonoxynol 15, i.e., C.-(p-nonylphenyl)-()-hydroxy diethyl-glycol-monoethylether, 1-dodecylazacycloheptan-2- penta-decacoxyethylene); nonoxynol 30, i.e., C.-(p-non one, and dimethylsulfoxide (DMSO). Such compositions ylphenyl)-()-hydroxytriaconta(oxyethylene); poloxalene, will also typically include ointment bases, e.g., petrolatum, i.e., nonionic polymer of the polyethylene-polypropylene polyethylene glycol, lanolin, and poloxamer, which is a glycol type, MW-approx. 3000; poloxamer, referred to in block copolymer of polyoxyethylene and polyoxypropylene, 40 the discussion of ointment bases further above; polyoxyl 8, which may also serve as a Surfactant or emulsifying agent. 40 and 50 Stearate, i.e., poly(oxy-1,2-ethanediyl), C.-hydro Preservatives are used to protect pharmaceutical compo ()-hydroxy-, octadecanoate; polyoxyl 10 oleyl ether, i.e., sitions of the present invention from degradative attack by poly(oxy-12-ethanediyl). C-(Z)-9-octadecenyl-(o-hy ambient microorganisms, and include, e.g., benzalkonium droxy-, polysorbate 20, i.e., Sorbitan, monododecanoate, chloride, benzethonium chloride, alkyl esters of p-hydroxy 45 poly(oxy-12-ethanediyl); polysorbate 40, i.e., Sorbitan, benzoic acid, hydantoin derivatives, cetylpyridinium chlo monohexadecanoate, poly(oxy-12-ethanediyl); polysorbate ride, monothioglycerol, phenol, phenoxyethanol, meth 60, i.e., Sorbitan, monooctadecanoate, poly(oxy-1,2- ylparagen, imidazolidinyl urea, sodium dehydroacetate, ethanediyl); polysorbate 65, i.e., Sorbitan, trioctadecanoate, propylparaben, quaternary ammonium compounds, espe poly(oxy-12-ethanediyl); polysorbate 80, i.e., Sorbitan, cially polymers such as polixetonium chloride, potassium 50 mono-9-monodecenoate, poly(oxy-12-ethanediyl); polysor benzoate, Sodium formaldehyde Sulfoxylate, Sodium propi bate 85, i.e., Sorbitan, tri-9-octadecenoate, poly(oxy-1,2- onate, and thimerosal. ethanediyl); Sodium lauryl Sulfate; Sorbitan monolaurate; Sequestering agents are used to improve the stability of Sorbitan monooleate; Sorbitan monopalmitate; Sorbitan the pharmaceutical compositions of the present invention monostearate; Sorbitan sesquioleate; Sorbitan trioleate; and and include, e.g., the cyclodextrins which are a family of 55 sorbitan tristearate. natural cyclic oligosaccharides capable of forming inclusion The pharmaceutical compositions of the present invention complexes with a variety of materials, and are of varying may be prepared using very straightforward methodology ring sizes, those having 6-, 7- and 8-glucose residues in a which is well understood by the artisan of ordinary skill. ring being commonly referred to as C-cyclodextrins, B-cy Where the pharmaceutical compositions of the present clodextrins, and Y-cyclodextrins, respectively. Suitable 60 invention are simple aqueous and/or other solvent Solutions, cyclodextrins include, e.g., C-cyclodextrin, B-cyclodextrin, the various components of the overall composition are Y-cyclodextrin, Ö-cyclodextrin and cationized cyclodextrins. brought together in any practical order, which will be Solvents which may be used in preparing the pharmaceu dictated largely by considerations of convenience. Those tical compositions of the present invention include, e.g., components having reduced water solubility, but Sufficient acetone, alcohol, amylene hydrate, butyl alcohol, corn oil, 65 solubility in the same co-solvent with water, may all be cottonseed oil, ethyl acetate, glycerin, hexylene glycol, dissolved in said co-solvent, after which the co-solvent isopropyl alcohol, isostearyl alcohol, methyl alcohol, meth solution will be added to the water portion of the carrier US 7,250,518 B2 189 190 whereupon the solutes therein will become dissolved in the rectum to release the drug. Such materials include cocoa water. To aid in this dispersion/solution process, a Surfactant butter, beeswax and polyethylene glycols. may be employed. The pharmaceutical compositions of the present invention Where the pharmaceutical compositions of the present may also be administered topically, especially when the invention are to be in the form of emulsions, the components target of treatment includes areas or organs readily acces of the pharmaceutical composition will be brought together sible by topical application, including diseases of the eye, in accordance with the following general procedures. The the skin, or the lower intestinal tract. Suitable topical for continuous water phase is first heated to a temperature in the mulations are readily prepared for each of these areas or range of from about 60° C. to about 95°C., preferably from Organs. about 70° to about 85°C., the choice of which temperature 10 Topical application for the lower intestinal tract can be to use being dependent upon the physical and chemical effected in a rectal Suppository formulation, as described properties of the components which make up the oil-in above, or in a suitable enema formulation. Topically active water emulsion. Once the continuous water phase has transdermal patches may also be used. reached its selected temperature, the components of the final For topical applications, the pharmaceutical compositions composition to be added at this stage are admixed with the 15 may be formulated in a suitable ointment containing the water and dispersed therein under high-speed agitation. active component Suspended or dissolved in one or more Next, the temperature of the water is restored to approxi carriers. Carriers for topical administration of the com mately its original level, after which the components of the pounds of this invention include, but are not limited to, composition which comprise the next stage are added to the mineral oil, liquid petrolatum, white petrolatum, propylene composition mixture under moderate agitation and mixing glycol, polyoxyethylene, polyoxypropylene compound, continues for from about 5 to about 60 minutes, preferably emulsifying wax and water. Alternatively, the pharmaceuti about 10 to about 30 minutes, depending on the components cal compositions can be formulated in a Suitable lotion or of the first two stages. Thereafter, the composition mixture cream containing the active components suspended or dis is passively or actively cooled to from about 20° to about 55° Solved in one or more pharmaceutically acceptable carriers. C. for addition of any components in the remaining stages, 25 Suitable carriers include, but are not limited to, mineral oil, after which water is added in sufficient quantity to reach its Sorbitan monostearate, polysorbate, cetyl esters wax, cet original predetermined concentration in the overall compo earyl alcohol, 2-octyldodecanol, benzyl alcohol and water. sition. Pharmaceutical compositions within the scope of the According to the present invention, the pharmaceutical present invention include those wherein the therapeutically compositions may be in the form of a sterile injectable 30 effective amount of an active ingredient comprising a com preparation, for example a sterile injectable aqueous or pound of the present invention required for treating or oleaginous suspension. This suspension may be formulated preventing diseases, disorders, and conditions mediated by according to techniques known in the art using Suitable or associated with modulation of PDE4 activity as described dispersing or wetting agents and Suspending agents. The herein, is provided in a dosage form Suitable for systemic sterile injectable preparation may also be a sterile injectable 35 administration. Such a pharmaceutical composition will Solution or Suspension in a non-toxic parenterally-accept contain said active ingredient in Suitable liquid form for able diluent or solvent, for example as a solution in 1,3- delivery by: (1) injection or infusion which is intraarterial, butanediol. Among the acceptable vehicles and solvents that intra- or transdermal, Subcutaneous, intramuscular, intraspi may be employed are water, Ringer's solution and isotonic nal, intrathecal, or intravenous, wherein said active ingre sodium chloride solution. In addition, sterile, fixed oils are 40 dient: (a) is contained in Solution as a solute; (b) is contained conventionally employed as a solvent or Suspending in the discontinuous phase of an emulsion, or the discon medium. For this purpose, any bland fixed oil may be tinuous phase of an inverse emulsion which inverts upon employed including synthetic mono- or di-glycerides. Fatty injection or infusion, said emulsions containing Suitable acids, Such as oleic acid and its glyceride derivatives are emulsifying agents; or (c) is contained in a Suspension as a useful in the preparation of injectables, as do natural phar 45 Suspended solid in colloidal or microparticulate form, said maceutically-acceptable oils, such as olive oil or castor oil, Suspension containing Suitable Suspending agents; (2) injec especially in their polyoxyethylated versions. These oil tion or infusion into Suitable body tissues or cavities as a Solutions or Suspensions may also contain a long-chain depot, wherein said composition provides storage of said alcohol diluent or dispersant, such as Rh, HCIX or similar active ingredient and thereafter delayed-, Sustained-, and/or alcohol. 50 controlled-release of said active ingredient for systemic The pharmaceutical compositions of the present invention distribution; (3) instillation, inhalation or insufflation into may be orally administered in any orally acceptable dosage Suitable body tissues or cavities of said pharmaceutical form including, but not limited to, capsules, tablets, aqueous composition in Suitable solid form, where said active ingre Suspensions or Solutions. In the case of tablets for oral use, dient: (a) is contained in a solid implant composition pro carriers which are commonly used include lactose and corn 55 viding delayed-, Sustained-, and/or controlled-release of said starch. Lubricating agents, such as magnesium Stearate, are active ingredient; (b) is contained in a particulate composi also typically added. For oral administration in a capsule tion to be inhaled into the lungs; or (c) is contained in a form, useful diluents include lactose and dried corn starch. particulate composition to be blown into suitable body When aqueous Suspensions are required for oral use, the tissues or cavities, where said composition optionally pro active ingredient is combined with emulsifying and Suspend 60 vides delayed-, Sustained-, and/or controlled-release of said ing agents. If desired, certain Sweetening, flavoring or col active ingredient; or (4) ingestion of said pharmaceutical oring agents may also be added. Alternatively, the pharma composition in suitable solid or liquid form for peroral ceutical compositions of this invention may be administered delivery of said active ingredient, where said active ingre in the form of suppositories for rectal administration. These dient is contained in a solid dosage form; or (b) is contained can be prepared by mixing the agent with a suitable non 65 in a liquid dosage form. irritating excipient which is solid at room temperature but Particular dosage forms of the above-described pharma liquid at the rectal temperature and therefore will melt in the ceutical compositions include (1) Suppositories as a special US 7,250,518 B2 191 192 type of implant, comprising bases which are solid at room delayed-, Sustained-, and/or controlled-release of said active temperature but melt at body temperature, slowly releasing ingredient to said local site. For ophthalmic use, the phar the active ingredient with which they are impregnated into maceutical compositions may be formulated as micronized the Surrounding tissue of the body, where the active ingre Suspension in isotonic, pH adjusted Sterile saline, or, pref dient becomes absorbed and transported to effect systemic erably, as Solutions in isotonic, pH adjusted Sterile saline, administration; (2) Solid peroral dosage forms selected from either with our without a preservative such as benzylalko the group consisting of (a) delayed-release oral tablets, nium chloride. Alternatively, for ophthalmic uses, the phar capsules, caplets, lozenges, troches, and multiparticulates; maceutical compositions may be formulated in an ointment (b) enteric-coated tablets and capsules which prevent release Such as petrolatum. and absorption in the stomach to facilitate delivery distal to 10 the stomach of the patient being treated; (c) Sustained The pharmaceutical compositions of the present invention release oral tablets, capsules and microparticulates which may also be administered by nasal aerosol or inhalation provide systemic delivery of the active ingredient in a through the use of a nebulizer, a dry powder inhaler or a controlled manner up to a 24-hour period; (d) fast-dissolving metered dose inhaler. Such compositions are prepared tablets; (e) encapsulated Solutions; (f) an oral paste; (g) a 15 according to techniques well-known in the art of pharma granular form incorporated in or to be incorporated in the ceutical formulation and may be prepared as solutions in food of a patient being treated; and (h) liquid peroral dosage saline, employing benzyl alcohol or other Suitable preser forms selected from the group consisting of solutions, Sus Vatives, absorption promoters to enhance bioavailability, pensions, emulsions, inverse emulsions, elixirs, extracts, hydrofluorocarbons, and/or other conventional solubilizing tinctures, and concentrates. or dispersing agents. Pharmaceutical compositions within the scope of the As already mentioned, the active ingredients of Formula present invention include those wherein the therapeutically (1.0.0) of the present invention may be administered sys effective amount of an active ingredient comprising a com temically to a patient to be treated as a pharmaceutical pound of the present invention required for treating or composition in Suitable liquid form by injection or infusion. preventing diseases, disorders, and conditions mediated by 25 or associated with modulation of PDE4 activity as described There are a number of sites and organ systems in the body herein is provided in a dosage form suitable for local of the patient which will allow the properly formulated administration to a patient being treated, wherein said phar pharmaceutical composition, once injected or infused, to maceutical composition contains said active ingredient in permeate the entire body and all of the organ system of the suitable liquid form for delivering said active ingredient by: 30 patient being treated. An injection is a single dose of the (1) injection or infusion into a local site which is intraarte pharmaceutical composition forced, usually by a Syringe, rial, intraarticular, intrachondrial, intracostal, intracystic, into the tissue involved. The most common types of injec intra- or transdermal, intrafasicular, intraligamentous, tions are intramuscular, intravenous, and Subcutaneous. By intramedulary, intramuscular, intranasal, intraneural, contrast, an infusion is the gradual introduction of the intraocular, i.e., opthalmic administration, intraosteal, 35 pharmaceutical composition into the tissue involved. The intrapelvic, intrapericardial, intraspinal, intrasternal, intra most common type of infusion is intravenous. Other types of synovial, intratarsal, or intrathecal; including components injection or infusion comprise intraarterial, intra- or trans which provide delayed-release, controlled-release, and/or dermal (including Subcutaneous), or intraspinal especially Sustained-release of said active ingredient into said local intrathecal. In these liquid pharmaceutical compositions, the site; where said active ingredient is contained: (a) in Solution 40 active ingredient may be contained in solution as the solute. as a solute; (b) in the discontinuous phase of an emulsion, or This is the most common and most preferred type of Such the discontinuous phase of an inverse emulsion which composition, but requires an active ingredient in a salt form inverts upon injection or infusion, said emulsions containing that has reasonably good aqueous solubility. Water (or Suitable emulsifying agents; or (c) in a suspension as a saline) is by far the most preferred solvent for such com Suspended solid in colloidal or microparticulate form, said 45 positions. Occasionally Supersaturated solutions may be Suspension containing Suitable Suspending agents; or (2) utilized, but these present stability problems that make them injection or infusion as a depot for delivering said active impractical for use on an everyday basis. ingredient to said local site; wherein said composition If it is not possible to obtain a form of some compound of provides storage of said active ingredient and thereafter Formula (1.0.0) that has the requisite degree of aqueous delayed-, Sustained-, and/or controlled-release of said active 50 solubility, as may sometimes occur, it is within the skill of ingredient into said local site, and wherein said composition the artisan to prepare an emulsion, which is a dispersion of also includes components which ensure that said active Small globules of one liquid, the discontinuous or internal ingredient has predominantly local activity, with little sys phase, throughout a second liquid, the continuous or external temic carryover activity; or wherein said pharmaceutical phase, with which it is immiscible. The two liquids are composition contains said active ingredient in Suitable Solid 55 maintained in an emulsified state by the use of emulsifiers form for delivering said inhibitor by: (3) instillation, inha which are pharmaceutically acceptable. Thus, if the active lation or insufflation to said local site, where said active ingredient is a water-insoluble oil, it can be administered in ingredient is contained: (a) in a solid implant composition an emulsion of which it is the discontinuous phase. Also which is installed in said local site, said composition option where the active ingredient is water-insoluble but can be ally providing delayed-, Sustained-, and/or controlled-re 60 dissolved in a solvent which is immiscible with water, an lease of said active ingredient to said local site; (b) in a emulsion can be used. While the active ingredient would particulate composition which is inhaled into a local site most commonly be used as the discontinuous or internal comprising the lungs; or (c) in a particulate composition phase of what is referred to as an oil-in-water emulsion, it which is blown into a local site, where said composition could also be used as the discontinuous or internal phase of includes components which will ensure that said active 65 an inverse emulsion, which is commonly referred to as a ingredient has predominantly local activity, with insignifi water-in-oil emulsion. Here the active ingredient is soluble cant systemic carryover activity, and optionally provides in water and could be administered as a simple aqueous US 7,250,518 B2 193 194 Solution. However, inverse emulsions invert upon injection routes. In particular, transdermal patches prepared in accor or infusion into an aqueous medium Such as the blood, and dance with well known drug delivery technology may be offer the advantage of providing a more rapid and efficient prepared and applied to the skin of a patient to be treated, dispersion of the active ingredient into that aqueous medium whereafter the active agent by reason of its formulated than can be obtained using an aqueous solution. Inverse solubility characteristics migrates across the epidermis and emulsions are prepared by using Suitable, pharmaceutically into the dermal layers of the patient’s skin where it is taken acceptable emulsifying agents well known in the art. Where up as part of the general circulation of the patient, ultimately the active ingredient has limited water solubility, it may also providing systemic distribution of the active ingredient over be administered as a Suspended solid in colloidal or micro a desired, extended period of time. Also included are particulate form in a suspension prepared using Suitable, 10 implants which are placed beneath the epidermal layer of the pharmaceutically acceptable Suspending agents. The Sus skin, i.e. between the epidermis and the dermis of the skin pended solids containing the active ingredient may also be of the patient being treated. Such an implant will be formu formulated as delayed-, Sustained-, and/or controlled-release lated in accordance with well known principles and mate compositions. rials commonly used in this delivery technology, and may be While systemic administration will most frequently be 15 prepared in Such a way as to provide controlled-, Sustained carried out by injection or infusion of a liquid, there are and/or delayed-release of the active ingredient into the many situations in which it will be advantageous or even systemic circulation of the patient. Such subepidermal (sub necessary to deliver the active ingredient as a solid. Sys cuticular) implants provide the same facility of installation temic administration of Solids is carried out by instillation, and delivery efficiency as transdermal patches, but without inhalation or insufllation of a pharmaceutical composition in the limitation of being Subject to degradation, damage or Suitable Solid form containing the active ingredient. Instil accidental removal as a consequence of being exposed on lation of the active ingredient may entail installing a solid the top layer of the patient’s skin. implant composition into Suitable body tissues or cavities. In the above description of pharmaceutical compositions The implant may comprise a matrix of bio-compatible and containing an active ingredient of Formula (1.0.0), the bio-erodible materials in which particles of a solid active 25 equivalent expressions: “administration', 'administration ingredient are dispersed, or in which, possibly, globules or of, "administering, and “administering a have been used isolated cells of a liquid active ingredient are entrapped. with respect to said pharmaceutical compositions. As thus Desirably, the matrix will be broken down and completely employed, these expressions are intended to mean providing absorbed by the body. The composition of the matrix is also to a patient in need of treatment a pharmaceutical compo preferably selected to provide controlled-, sustained-, and/or 30 sition of the present invention by any of the routes of delayed release of the active ingredient over extended peri administration herein described, wherein the active ingredi ods of time, even as much as several months. ent is a compound of Formula (1.0.0) or a prodrug, deriva The term “implant’ most often denotes a solid pharma tive, or metabolite thereof which is useful in treating a ceutical composition containing the active ingredient, while disease, disorder, or condition mediated by or associated the term "depot' usually implies a liquid pharmaceutical 35 with modulation of PDE4 activity in said patient. Accord composition containing the active ingredient, which is ingly, there is included within the scope of the present deposited in any Suitable body tissues or cavities to form a invention any other compound which, upon administration reservoir or pool which slowly migrates to Surrounding to a patient, is capable of directly or indirectly providing a tissues and organs and eventually becomes systemically compound of Formula (1.0.0). Such compounds are recog distributed. However, these distinctions are not always rig 40 idly adhered to in the art, and consequently, it is contem nized as prodrugs, and a number of established procedures plated that there is included within the scope of the present are available for preparing Such prodrug forms of the invention liquid implants and solid depots, and even mixed compounds of Formula (1.0.0). Solid and liquid forms for each. Suppositories may be The dosage and dose rate of the compounds of Formula regarded as a type of implant, since they comprise bases 45 (1.0.0) effective for treating or preventing a disease, disor which are solid at room temperature but melt at a patients der, or condition mediated by or associated with modulation body temperature, slowly releasing the active ingredient of PDE4, will depend on a variety of factors, such as the with which they are impregnated into the Surrounding tissue nature of the inhibitor, the size of the patient, the goal of the of the patient’s body, where the active ingredient becomes treatment, the nature of the pathology to be treated, the absorbed and transported to effect systemic administration. 50 specific pharmaceutical composition used, and the observa Systemic administration can also be accomplished by tions and conclusions of the treating physician. inhalation or insufflation of a powder, i.e., particulate com For example, where the dosage form is oral, e.g., a tablet position containing the active ingredient. For example, the or capsule, Suitable dosage levels of the compounds of active ingredient in powder form may be inhaled into the Formula (1.0.0) will be between about 0.1 ug/kg and about lungs using conventional devices for aerosolizing particulate 55 50.0 mg/kg of body weight per day, preferably between formulations. The active ingredient as a particulate formu about 5.0 g/kg and about 5.0 mg/kg of body weight per day, lation may also be administered by insufflation, i.e., blown more preferably between about 10.0 ug/kg and about 1.0 or otherwise dispersed into suitable body tissues or cavities mg/kg of body weight per day, and most preferably between by simple dusting or using conventional devices for aero about 20.0 ug/kg and about 0.5 mg/kg of body weight per Solizing particulate formulations. These particulate compo 60 day of the active ingredient. sitions may also be formulated to provide delayed-, Sus Where the dosage form is topically administered to the tained-, and/or controlled-release of the active ingredient in bronchia and lungs, e.g., by means of a powder inhaler or accordance with well understood principles and known nebulizer, suitable dosage levels of the compounds of For materials. mula (1.0.0) will be between about 0.001 ug/kg and about Other means of systemic administration which may utilize 65 10.0 mg/kg of body weight per day, preferably between the active ingredients of the present invention in either liquid about 0.5 g/kg and about 0.5 mg/kg of body weight per day, or Solid form include transdermal, intranasal, and opthalmic more preferably between about 1.0 ug/kg and about 0.1 US 7,250,518 B2 195 196 mg/kg of body weight per day, and most preferably between Preparation 1 about 2.0 ug/kg and about 0.05 mg/kg of body weight per 2-(Benzo. 1.3dioxol-5-yloxy)-nicotinic acid of Formula day of the active ingredient. (6.0.1): Using representative body weights of 10 kg and 100 kg in 5 order to illustrate the range of daily oral dosages which might be used as described above, suitable dosage levels of (6.0.1) the compounds of Formula (1.0.0) will be between about 1.0-10.0 ug and 500.0-5000.0 mg per day, preferably N OH between about 500-500.0 ug and 50.0-500.0 mg per day, 10 more preferably between about 100.0-1000.0 ug and 10.0- 2 100.0 mg per day, and most perferably between about 200.0-2000.0 ug and about 5.0-50.0 mg per day of the active ingredient comprising a compound of Formula (1.0.0). These ranges of dosage amounts represent total dosage 15 amounts of the active ingredient per day for a given patient. O The number of times per day that a dose is administered will depend upon Such pharmacological and pharmacokinetic factors as the half-life of the active ingredient, which reflects its rate of catabolism and clearance, as well as the minimal 2-Chloro-nicotinic acid ethyl ester (10 g), benzo. 1.3dioxol and optimal blood plasma or other body fluid levels of said 5-ol (Sesamol, 8.2 g), and cesium carbonate (21 g) were active ingredient attained in the patient which are required mixed in anhydrous dioxane (40 mL) and the resulting slurry for therapeutic efficacy Numerous other factors must also be heated to reflux for 16 h. In a separate flask, lithium considered in deciding upon the number of doses per day 25 hydroxide (12.9 g) was dissolved in water (80 mL) with warming and then added to the refluxing mixture, which was and the amount of active ingredient per dose that will be heated for an additional 4 h. The mixture was cooled to administered. Not the least important of such other factors is ambient temperature and concentrated in vacuo to remove the individual respsonse of the patient being treated. Thus, the dioxane. Concentrated hydrochloric acid was added for example, where the active ingredient is used to treat or 30 dropwise until the pH-3. The acidified solution was then prevent asthma, and is administered topically via aerosol extracted with ethyl acetate (7x100 mL) to yield crude inhalation into the lungs, from one to four doses consisting product, which was recrystallized from ethyl acetate to yield of acuations of a dispensing device, i.e., "puffs' of an the purified title compound (10.8 g). inhaler, will be administered each day, each dose containing H NMR (CDOD): 8 8.28 (dd, J=8 and 2 Hz, 2H), 7.13 from about 50.0 ug to about 10.0 mg of active ingredient. 35 (m. 1H), 6.79 (d. J=8 Hz, 1H) 6.62 (s, J-2 Hz, 1H), 6.53 (dd. J=8 and 2 Hz, 1H), 5.95 (s. 2H). The following compounds were prepared in a similar DETAILED DESCRIPTION OF THE manner using the corresponding phenol: INVENTION 2-(3-Cyano-phenoxy)-nicotinic acid of Formula (6.0.2): 40 11.0 Preparations and Working Examples O OH (6.0.2) There follows a description of numerous Preparations by 2 N which intermediates used in preparing specific compounds O 2 of Formula (1.0.0) were made. There also follows numerous 45 21 Examples showing preparation of specific compounds of Formula (1.0.0). These Preparations and Examples are N-N intended to further illustrate the compounds of the present invention and processes in accordance with which they may MS m/z 239 (M-H)" be readily prepared by the artisan. The artisan will be aware 50 2-(4-Fluoro-phenoxy)-nicotinic acid of Formula (6.0.3): of many other Suitable processes that are also available, as well as acceptable variations in the processes described (6.0.3) below. O The description which follows is for the purpose of 55 illustrating the present invention and is not intended to in N OH any way create limitations, express or implied, upon the 2 Scope of the present invention. The claims appended hereto N O are for the purpose of reciting the present invention, of expressing the contemplated Scope thereof, and of pointing 60 out particulars thereof. In the following Preparations, analytical characterizations of the compounds prepared were made by mass spectral F analyses determined by GCMS, AMPI, APCI or thermo 65 spray methods. All H NMR spectra were taken on a 400 MHz instrument. MS m/z 232 (M-H)"