US007129241B2

(12) United States Patent (10) Patent No.: US 7,129,241 B2 Eggenweiler et al. (45) Date of Patent: Oct. 31, 2006

(54) PYRIDAZINE DERIVATIVES (58) Field of Classification Search ...... 544/224, 544/238, 182, 215, 235, 237; 514/247, 241, (75) Inventors: Hans-Michael Eggenweiler, Darmstadt 514/248, 249, 252.02, 252.03, 252.04, 252.05; (DE); Michael Wolf, Darmstadt (DE) 206/570 See application file for complete search history. (73) Assignee: Merck Patent Gesellschaft, Darmstadt (DE) (56) References Cited (*) Notice: Subject to any disclaimer, the term of this U.S. PATENT DOCUMENTS patent is extended or adjusted under 35 6,417,188 B1 7/2002 Jonas et al. U.S.C. 154(b) by 0 days. 6.479,494 B1 1 1/2002 Rochus et al. (21) Appl. No.: 10/S16,876 FOREIGN PATENT DOCUMENTS y x- - - 9 WO WO9806704 2, 1998 (22) PCT Filed: May 12, 2003 WO WO996588O 12/1999 WO WO O157O25 8, 2001 (86). PCT No.: PCT/EP03/04930 Primary Examiner Kahsay Habte S 371 (c)(1), (74) Attorney, Agent, or Firm Millen, White, Zelano & (2), (4) Date: Dec. 3, 2004 Branigan, P.C. (87) PCT Pub. No.: WO03/104204 (57) ABSTRACT Pyridazine derivatives of the formula (I) act as phosphodi PCT Pub. Date: Dec. 18, 2003 esterase IV inhibitors and can be employed for the treatment 65 Prior Publication Dat of osteoporosis, tumours, cachexia, atherosclerosis, rheuma (65) O DO toid arthritis, multiple sclerosis, diabetes mellitus, inflam US 2005/0176714 A1 Aug. 11, 2005 matory processes, allergies, asthma, autoimmune diseases, myocardial diseases and AIDS (30) Foreign Application Priority Data Jun. 5, 2002 (DE) ...... 102 24 888 (I) (51) Int. Cl. R4 \ 3 CO7D 403/2 (2006.01) s \ R C07D 237/04 (2006.01) R2 V- N-N N-R A6 IK3I/50 I (2006.01) A6 IK3I/50 (2006.01) A6 IP II/06 (2006.01) O x-G) (52) U.S. Cl...... 514/241; 544/182:544/215; 544/224: 544/238; 514/247; 514/248: 514/249; 514/252.02: 514/252.03: 514/252.04: 514/252.05; 206/570 17 Claims, No Drawings US 7,129,241 B2 1. 2 PYRIDAZINE DERVATIVES 1–7 H atoms may be replaced by F and/or Cl, and/or 1 H atom may be replaced by R. The invention relates to compounds of the formula I R'' is H, A, COOA"R, CONH, CONHA"R, CONCA"R) (A"R), NH, NHA"R, N(A"R)(A"R), NCOA"R, NCOOA"R, OH or OA"R, R" is H, A, COOA"R, CONH CONHA"R or CON R (A"R)(A"R), 3 \ V Y is alkylene having 1–10 carbon atoms or alkenylene R4 V N-N N-R having 2-8 carbon atoms, 10 in which one, two or three CH groups may be replaced by O, S, SO, SO, NH or NR'' and/or 1–7 H atoms may be replaced by F and/or Cl, KO A and A' are each, independently of one another, alkyl having 1-10 carbon atoms or alkenyl having 2-8 carbon 15 atoms, in which in which one, two or three CH groups may be replaced R" and R are each, independently of one another, H, OH, by O, S, SO, SO, NH or NR'' and/or OR, SR, SOR, -SOR or Hal, 1–7 H atoms may be replaced by F and/or C1, or R" and R together are alternatively —OCHO or aryl or Het, –OCHCHO , A and A' together are alternatively an alkylene chain having R is H, A"R, COA"R, COOA"R, CONH CONHA"R, 2–7 carbon atoms, in which one, two or three CH groups CONCA"R)(A"R), NH, NHA"R, N( "R)(A"R), may be replaced by O, S, SO, SO, NH, NR', NCOR' NCOA"R or NCOOA"R, or NCOOR, R is H, A"R, COA"R, COOA"R, CONH CONHA"R A" and A" are each, independently of one another, absent, or CONCA"R)(A"R), 25 alkylene having 1-10 carbon atoms, alkenylene having B is an aromatic isocyclic or heterocyclic radical, which may 2-8 carbon atoms or cycloalkylene having 3–7 carbon be unsubstituted or monosubstituted, disubstituted or atoms, trisubstituted by R. Rand/or R', in which one, two or three CH groups may be replaced X is alkylene having 1-10 carbon atoms or alkenylene by O, S, SO, SO, NH or NR'' and/or having 2-8 carbon atoms, 30 1–7 H atoms may be replaced by F and/or Cl, in which one, two or three CH2 groups may be replaced A" and A" together are alternatively an alkylene chain by O, S, SO, SO, NH or NA"R. having 2–7 carbon atoms, in which one, two or three CH 1–7 H atoms may be replaced by F and/or Cl, groups may be replaced by O, S, SO, SO, NH, NR', and/or 1 or 2H atoms may be replaced by R'' and/or R', NCOR' or NCOOR, R. R. and R7 are each, independently of one another, H. 35 aryl is phenyl, naphthyl, fluorenyl or biphenyl, each of A"R, OH, OA"R, NH, NHA"R, N(A"R)(A"R), which is unsubstituted or monosubstituted, disubstituted NHCOA"R, NHCOOA"R, NHCONH, or trisubstituted by Hal, R', OR, N(R'), NO, CN, NHCONHA"R, NHCON(A"R)(A"R), Hal, COOH, COOR, CONCR), NRCOR, NRCONCR), COOA"R, CONH CONHA"R, CONCA"R)(A"R), NR'SOA, COR', SON(R'), or S(O).R'', 40 R" is H or alkyl having 1–6 carbon atoms, R'' is alkyl having 1–6 carbon atoms, Het is a monocyclic or bicyclic Saturated, unsaturated or aromatic heterocyclic ring having 1 to 2 N, O and/or S o ^ s atoms, which may be unsubstituted or monosubstituted or 45 disubstituted by carbonyl oxygen, Hal, R'', OR', N(R'), NO, CN, COOR, CONCR), NRCOR', \, NR'CON(R'), NRSOR, COR', SONR' and/or N N S(O).R'', / / Hal is F, Cl, Br or I, Y- Y 50 m is 0, 1 or 2, N N n is 0, 1, 2, 3 or 4, O, or its W \ and pharmaceutically usable derivatives, Solvates and Ste 2 NN eN, reoisomers thereof, including mixtures thereof in all ratios. N 55 1-Benzoyltetrahydropyridazines as progesterone receptor ligands are described, for example, in J. Med. Chem. 38. R is A, cycloalkyl having 3–7 carbon atoms or alkylenecy 4878 (1995). Further arylalkanoylpyridazines are disclosed, cloalkyl having 4-8 carbon atoms, for example, in EP 0 922 036, EP 1 124 809 or WO R is H, COOH, COOA, CONH, CONHA, CONAA, NH, O1/O4O99. NHA, NAA', NCOA, NCOOA, OH, OA, (CH)-aryl or 60 The invention had the object of finding novel compounds (CH), Het, having valuable properties, in particular those which can be R" is alkyl having 1-10 carbon atoms, cycloalkyl having used for the preparation of medicaments. 3-7 carbon atoms, alkylenecycloalkyl having 4-8 carbon It has been found that the compounds of the formula I and atoms or alkenyl having 2-8 carbon atoms, salts and Solvates thereof have very valuable pharmacologi in which one, two or three CH2 groups may be replaced 65 cal properties and are well tolerated. by O, S, SO, SO, NH, NMe, NEt and/or by The compounds of the formula I exhibit selective phos —CH=CH groups, phodiesterase IV inhibition which is associated with an US 7,129,241 B2 3 4 intracellular increase of cAMP (N. Sommer et al., Nature Reference is made to WO 01/57025 which discloses Medicine, 1, 244-248 (1995)). The PDE IV inhibition can special pyrimidine derivatives as PDE IV inhibitors, the use be detected, for example, analogously to C. W. Davis in thereof for the treatment of diseases and combinations with Biochim. Biophys. Acta 797, 354-362 (1984). other medicaments. The affinity of the compounds according to the invention 5 Accordingly, the invention relates in particular to the use for phosphodiesterase IV is determined by measuring their of compounds of the formula I and physiologically accept ICso values (concentration of the inhibitor that is required in able salts and solvates thereof for the preparation of a order to achieve 50% inhibition of the enzyme activity). medicament for the treatment of a patient Suffering from a The compounds according to the invention can be disease or condition mediated by the PDE IV isozyme in its employed for the treatment of asthmatic diseases. The 10 role of regulating the activation and degranulation of human anti-asthmatic action of the PDE IV inhibitors is described, eosinophils. for example, by T. J. Torphy et al. in Thorax, 46, 512-523 WO 01/57025 discloses various in-vitro assays and ani (1991), and can be determined, for example, by the method mal model experiments, which are capable of providing data of T. Olsson, Acta allergologica 26, 438447 (1971). sufficient to define and demonstrate therapeutic utility of Since cAMP inhibits osteoclastic cells and stimulates 15 compounds of the formula I. osteogenetic cells (S. Kasugai et al., M. 681, and K. Miya Compounds of the formula I inhibit the PDE IV isozyme moto, M 682, in Abstracts of the American Society for Bone and are therefore suitable for a wide range of therapeutic and Mineral Research, 18" Annual Meeting, 1996), the applications, because of the essential role which the PDE IV compounds according to the invention can be employed for family of isozymes plays in the physiology of all mammals. the treatment of osteoporosis. The enzymatic role performed by the PDE IV isozymes is In addition, the compounds exhibit an antagonistic action the intracellular hydrolysis of adenosine 3',5'-monophos to the production of TNF (tumour necrosis factor) and are phate (cAMP) within pro-inflammatory leukocytes. cAMP. therefore suitable for the treatment of allergic and inflam in turn, is responsible for mediating the effects of numerous matory diseases, autoimmune diseases, such as, for example, hormones in the body, and as a consequence, PDE IV rheumatoid arthritis, multiple Sclerosis, Crohn's disease, 25 inhibition plays a significant role in a variety of physiologi diabetes mellitus or ulcerative colitis, transplant rejection cal processes. There is extensive literature in the art describ reactions, cachexia and sepsis. ing the effects of PDE inhibitors on various inflammatory cell responses, which in addition to cAMP elevation, also The anti-inflammatory action of the Substances according include inhibition of Superoxide production, degranulation, to the invention and their effectiveness for the treatment of 30 for example, autoimmune disorders. Such as multiple scle chemotaxis and tumour necrosis factor (TNF) release in rosis or rheumatoid arthritis, can be determined analogously eosinophils, neutrophils and monocytes. to the methods of N. Sommer et al., Nature Medicine 1, The invention therefore relates to the compounds of the 244-248 (1995), or L. Sekutet al., Clin. Exp. Immunol. 100, formula I and to a process for the preparation of compounds 126-132 (1995). 35 of the formula I and salts and solvates thereof, characterised The compounds can be employed for the treatment of in that cachexia. The anticachectic action can be tested in TNF a) a compound of the formula II dependent models of cachexia (P. Costelli et al., J. Clin. Invest. 95, 2367ff. (1995); J. M. Argiles et al., Med. Res. II Rev. 17, 477 ff. (1997)). 40 PDE IV inhibitors can also inhibit the growth of tumour cells and are therefore suitable for tumour therapy (D. Marko et al., Cell Biochem. Biophys. 28, 75 ff. (1998)). The action of PDE IV inhibitors in the treatment of tumours is described, for example, in WO9535 281, WO 95 17399 or 45 WO 96 OO 215 in which PDE IV inhibitors can prevent mortality in models of sepsis and are therefore suitable for the therapy of sepsis (W. R" and Rare as defined in claim 1, Fischer et al., Biochem. Pharmacol. 45, 2399ff. (1993)). is reacted with a compound of the formula III They can furthermore be employed for the treatment of 50 memory disorders, atherosclerosis, atopic dermatitis and III AIDS. The action of PDE IV inhibitors in the treatment of asthma, inflammatory diseases, diabetes mellitus, atopic dermatitis, psoriasis, AIDS, cachexia, tumour growth or 55 tumour metastases is described, for example, in EP 7792.91. The compounds of the formula I can be employed as medicament active ingredients in human and Veterinary medicine. They can furthermore be employed as intermedi 60 ates for the preparation of further medicament active ingre in which dients. L is Cl, Br, I or a free or reactively functionally modified OH Furthermore, the invention relates to the use of type 4 group, and R. R. X and B are as defined in claim 1, phosphodiesterase inhibitors (PDE IV inhibitors) of the with the proviso that any further OH and/or amino group formula I for the treatment of diseases and relates to com 65 present is protected, binations of compounds of the formula I with other medi and Subsequently, if desired, a protecting group is removed, Caments. O US 7,129,241 B2 5 6 b) one or more radicals R', R , R, R and/or B in a compound of the formula I are converted into one or more -continued other radicals R', R. R. R. and/or B by DMF dimethylformamide i) cleaving an ether or ester, EDCI N-ethyl-N,N'-(dimethylaminopropyl)carbodiimide ii) alkylating or acylating an OH function, E ethyl iii) reductively alkylating an amino group, FCA fluoresceincarboxylic acid FITC fluorescein isothiocyanate and/or in that a basic compound of the formula I is converted Fmoc 9-fluorenylmethoxycarbonyl into one of its salts by treatment with an acid. FTH fluoresceinthiourea HOBt 1-hydroxybenzotriazole In addition, the invention relates to the optically active 10 Me methyl forms (stereoisomers), the enantiomers, the racemates, the MBHA 4-methylbenzhydrylamine diastereomers and the hydrates and Solvates of these com Mitr 4-methoxy-2,3,6-trimethylphenylsulfonyl pounds. The term Solvates of the compounds is taken to HONS N-hydroxysuccinimide OBut tert-butyl ester mean adductions of inert solvent molecules onto the com Oct octanoyl pounds which form owing to their mutual attractive force. 15 OMe methyl ester Solvates are, for example, monohydrates, dihydrates or OEt ethyl ester alcoholates. POA phenoxyacetyl Sal Salicyloyl The term pharmaceutically usable derivatives is taken to TFA trifluoroacetic acid mean, for example, the salts of the compounds according to Trt trityl (triphenylmethyl). the invention and so-called prodrug compounds. The term prodrug derivatives is taken to mean, for example, compounds of the formula I which have been The meanings of all radicals which occur more than once modified, for example, with alkyl or acyl groups, Sugars or are in each case independent of one another. oligopeptides and which are rapidly cleaved in the organism Above and below, the radicals R', R. R. R. X., B and and thus release the active ingredients according to the 25 L are as defined in the formulae I, II and III, unless expressly invention. stated otherwise. These also include biodegradable polymer derivatives of Alkyl having 1-10 carbon atoms is alkyl having 1, 2, 3, the compounds according to the invention, as described, for 4, 5, 6, 7, 8, 9 or 10 carbon atoms, is branched or example, in Int. J. Pharm. 115, 61-67 (1995). unbranched, and is preferably alkyl having 1, 2, 3, 4, 5 or 6 The abbreviations given above and below for amino-acid 30 carbon atoms and is, for example, methyl, ethyl, trifluorom radicals represent the radicals of the following amino acids: ethyl, pentafluoroethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl. Particular prefer Abu 4-aminobutyric acid ence is given to methyl, ethyl, trifluoromethyl, propyl. Aha 6-aminohexanoic acid, 6-aminocaproic acid 35 Ala alanine isopropyl, butyl, n-pentyl, n-hexyl or n-decyl. ASn asparagine Cycloalkyl preferably has 3–7 carbon atoms and is pref Asp aspartic acid Arg arginine erably cyclopropyl or cyclobutyl, furthermore preferably Cys cysteine cyclopentyl or cyclohexyl, furthermore also cycloheptyl: Dab 2,4-diaminobutyric acid 40 particular preference is given to cyclopentyl. Dap 2,3-diaminopropionic acid Gln glutamine Alkenyl is preferably vinyl, allyl, 2- or 3-butenyl, isobute Glp pyroglutamic acid nyl or sec-butenyl; preference is furthermore given to 4-pen Glu glutamic acid tenyl, isopentenyl or 5-hexenyl. Gly glycine Alkylene is preferably unbranched and is preferably His histidine 45 homo-Phe homo-phenylalanine methylene or ethylene, furthermore preferably propylene or Ile isoleucine butylene. Leu eucine Lys ysine Alkylenecycloalkyl is, for example, cyclohexylmethyl or Met methionine cyclopentylethyl. Nle norleucine Alkyl having 1–6 carbon atoms is alkyl having 1, 2, 3, 4, Orn ornithine 50 Phe phenylalanine 5 or 6 carbon atoms, is branched or unbranched, and is, for Phg phenylglycine example, methyl, ethyl, trifluoromethyl, pentafluoroethyl or 4-Hal-Phe 4-halophenylalanine propyl, furthermore preferably isopropyl, butyl, isobutyl, Pro proline sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopen Ser serine tyl or n-hexyl. Particular preference is given to methyl, Thr hreonine 55 Trp tryptophan ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl or Tyr tyrosine n-hexyl. Wall valine. Hal is preferably F, C1 or Br, furthermore also I. The radicals R and R may be identical or different and The following abbreviations are also used below: 60 are preferably in the 3- or 4-position of the phenyl ring. They are, for example, independently of one another, H., hydroxyl, —S—CH. —SO CH, -SOCH, F, Cl, Br or I or together are methylenedioxy. However, they are preferably Ac acetyl BOC tert-butoxycarbonyl each methyl, ethyl, propyl, methoxy, ethoxy, propoxy, iso CBZ or Z benzyloxycarbonyl 65 propoxy, benzyloxy, or alternatively fluoro-, difluoro- or DCCI dicyclohexylcarbodiimide trifluoromethoxy or 1-fluoro-, 2-fluoro-, 1.2-difluoro-, 2.2- difluoro-, 1.2.2-trifluoro- or 2.2.2-trifluoroethoxy.

US 7,129,241 B2 9 10 Accordingly, the compound relates, in particular, to the B is phenyl which is unsubstituted or monosubstituted by compounds of the formula I in which at least one of the said OR', N(R'), O-alkylene-N(R') or O-alkylene-OH, radicals has one of the preferred meanings given above. or unsubstituted pyridyl: Some preferred groups of compounds may be expressed by the following sub-formulae Ia to Ik, which conform to the 5 in Ik R' and R are each, independently of one another, formula I and in which the radicals not denoted in greater methoxy, ethoxy, propoxy or isopropoxy, detail are as defined for the formula I, but in which R is H. fluorenylmethyloxycarbonyl, acetyl, tert-buty in la R' and R are each, independently of one another, H. loxycarbonyl, benzyloxycarbonyl, N,N-dimethylami methoxy, ethoxy, benzyloxy, propoxy, isopropoxy, difluo noethyl, benzyl or pyridylmethyl, romethoxy, F, Cl, cyclopentyloxy, cyclohexyloxy or 10 cycloheptyloxy; R is H, in Ib R and R are each, independently of one another, X is methylene, ethylene, propylene or butylene, methoxy, ethoxy, propoxy, isopropoxy, cyclopentyloxy or R" is H or alkyl having 1–6 carbon atoms, F; Het is pyridyl, in Ic R' is 4-methoxy, 15 R is 3-ethoxy: B is phenyl which is unsubstituted or monosubstituted by in Id R is H; OR', N(R'), O-alkylene-N(R') or O-alkylene-OH, in Ie R is H, COO(CH)-aryl, COA"H, COOA"H, A"NM', or unsubstituted pyridyl: A"-aryl or A"Het: in If X is methylene, ethylene, propylene or butylene; and pharmaceutically usable derivatives, Solvates and Ste in Ig B is phenyl, pyridyl, pyridyl N-oxide, thienyl, furyl, reoisomers thereof, including mixtures thereof in all ratios. pyrrolyl pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, The compounds of the formula I and also the starting isoxazolinyl, oxazolinyl, thiazolinyl, pyrazolinyl, imida materials for their preparation are, in addition, prepared by Zolinyl, naphthyl, quinolinyl, isoquinolinyl, cinnolinyl, methods known per se, as described in the literature (for phthalazinyl, quinazolinyl or quinoxalinyl, each of which 25 example in the standard works, such as Houben-Weyl, is unsubstituted or may be monosubstituted, disubstituted Methoden der organischen Chemie Methods of Organic or trisubstituted by OH, OA, NH, NAA', O-alkylene NAA' or O-alkylene-OH: Chemistry, Georg-Thieme-Verlag, Stuttgart), to be precise in Ih B is phenyl which is unsubstituted or monosubstituted under reaction conditions which are known and suitable for by OR, N(R'), O-alkylene-N(R'), or O-alkylene 30 the said reactions. Use can also be made here of variants OH, or unsubstituted pyridyl; which are known per se, but are not mentioned here in in Ii R' and Rare each, independently of one another, H, greater detail. methoxy, ethoxy, benzyloxy, propoxy, isopropoxy, difluo In the compounds of the formulae II and III, R', R. R. romethoxy, F, Cl, cyclopentyloxy, cyclohexyloxy or R. X and B have the meanings indicated, in particular the cycloheptyloxy, 35 R" and R together are alternatively —OCHO or preferred meanings indicated. —OCHCH O , Some of the starting materials of the formula II are R is H, A"R, COA"R, COOA"R, CONH, known. If they are not known, they can be prepared by CONHA"R, CONCA"R)(A"R), NH, NHA"R, methods known per se. N(A"R)(A"R), NCOA"R or NCOOA"R, 40 In the compounds of the formula II, L is preferably Cl, Br, R is H, I or a free or reactively modified OH group, such as, for X is methylene, ethylene, propylene or butylene, example, an activated ester, an imidazolide or alkylsulfony A" and A" are each, independently of one another, absent loxy having 1–6 carbon atoms (preferably methylsulfony or alkylene having 1, 2, 3 or 4 carbon atoms, loxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy hav R is H. (CH)-aryl or (CH), Het; 45 in I R' and R are each, independently of one another, H. ing 6–10 carbon atoms (preferably phenyl- or methoxy, ethoxy, benzyloxy, propoxy, isopropoxy, difluo p-tolylsulfonyloxy). romethoxy, F, Cl, cyclopentyloxy, cyclohexyloxy or Radicals of this type for activation of the carboxyl group cycloheptyloxy, in typical acylation reactions are described in the literature R" and R together are alternatively —OCHO or 50 (for example in the standard works, such as Houben-Weyl, —OCHCH O , Methoden der organischen Chemie Methods of Organic R is H, A"R, COA"R, COOA"R, CONH, Chemistry, Georg-Thieme-Verlag, Stuttgart). CONHA"R, CONCA"R)(A"R), NH, NHA"R, N(A"R)(A"R), NCOA"R or NCOOA"R, Activated esters are advantageously formed in situ, for R is H, 55 example by addition of HOBt or N-hydroxysuccinimide. X is methylene, ethylene, propylene or butylene, If desired, the starting materials can also be formed in situ A" and A" are each, independently of one another, absent by not isolating them from the reaction mixture, but instead or alkylene having 1, 2, 3 or 4 carbon atoms, immediately converting them further into the compounds of R is H. (CH)-aryl or (CH), Het, the formula I. aryl is phenyl, naphthyl, fluorenyl or biphenyl, each of 60 On the other hand, it is possible to carry out the reaction which is unsubstituted or monosubstituted by OR', stepwise. R" is H or alkyl having 1–6 carbon atoms, Het is pyridyl, pyridyl N-oxide, thienyl, furyl, pyrrolyl, The compounds of the formula I can preferably be pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isox obtained by reacting compounds of the formula II with aZolinyl, oxazolinyl, thiazolinyl, pyrazolinyl, imida- 65 compounds of the formula III. Zolinyl, naphthyl, quinolinyl, isoquinolinyl, cinnolinyl, Compounds of the formula I are preferably prepared, for phthalazinyl, quinazolinyl or quinoxalinyl, example, in accordance with the following reaction scheme: US 7,129,241 B2 11 12

O O HO O Os. EN - - -No C's St.

1. NH" O H2N HO O NH LiALH4 y He N1 N K- No

N - NH N (1)

O O= CI-CHCH-N"MeCI N NH N-19 N N1 S No O OH

o={O NH O N S

N-1 N- O \-()- O N O \ , N / US 7,129,241 B2 13 14

-continued

N-19

In detail, the reaction of the compounds of the formula II amino-protecting groups are removed after the desired reac with the compounds of the formula III is carried out in the 15 tion (or reaction sequence), their type and size is furthermore presence or absence of an inert solvent at temperatures not crucial; however, preference is given to those having between approximately -20 and approximately 150', pref 1–20, in particular 1–8, carbon atoms. The term “acyl erably between 20 and 100°. group' is to be understood in the broadest sense in connec Examples of suitable inert solvents are hydrocarbons, tion with the present process. It includes acyl groups derived Such as hexane, petroleum ether, benzene, toluene or Xylene; from aliphatic, araliphatic, aromatic or heterocyclic car chlorinated hydrocarbons, such as trichloroethylene, 1.2- boxylic acids or Sulfonic acids, and, in particular, alkoxy dichloroethane, tertachloromethane, chloroform or dichlo carbonyl, aryloxycarbonyl and especially aralkoxycarbonyl romethane; alcohols, such as methanol, ethanol, isopro groups. Examples of Such acyl groups are alkanoyl. Such as panol, n-propanol, n-butanol or tert-butanol; ethers, such as acetyl, propionyl and butyryl, aralkanoyl. Such as pheny diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or 25 dioxane; glycol ethers, such as ethylene glycol monomethyl lacetyl; aroyl. Such as benzoyl and tolyl: aryloxyalkanoyl, or monoethyl ether, ethylene glycol dimethyl ether (dig Such as POA; alkoxycarbonyl. Such as methoxycarbonyl, lyme), ketones. Such as acetone or butanone; amides, such as ethoxycarbonyl, 2.2.2-trichloroethoxycarbonyl, BOC (tert acetamide, dimethylacetamide or dimethylformamide butoxycarbonyl) and 2-iodoethoxycarbonyl: aralkoxycarbo (DMF): nitriles, such as acetonitrile; sulfoxides, such as 30 nyl, such as CBZ ('carbobenzoxy”), 4-methoxybenzyloxy dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic carbonyl and FMOC; and arylsulfonyl, such as Mtr. acids, such as formic acid or acetic acid; nitro compounds, Preferred amino-protecting groups are BOC and Mitr, fur Such as nitromethane or nitrobenzene, esters, such as ethyl thermore CBZ., Fmoc, benzyl and acetyl. acetate, or mixtures of the said solvents. The term “hydroxyl-protecting group' is likewise known Compounds of the formula I can furthermore be obtained 35 in general terms and relates to groups which are Suitable for by liberating compounds of the formula I from one of their protecting a hydroxyl group against chemical reactions, but functional derivatives by treatment with a solvolysing or can easily be removed after the desired chemical reaction hydrogenolysing agent. has been carried out elsewhere in the molecule. Typical of Preferred starting materials for the solvolysis or hydro 40 Such groups are the above-mentioned unsubstituted or Sub genolysis are those which conform to the formula I, but stituted aryl, aralkyl or acyl groups, furthermore also alkyl contain corresponding protected amino and/or hydroxyl groups. The nature and size of the hydroxyl-protecting groups instead of one or more free amino and/or hydroxyl groups is not crucial since they are removed again after the groups, preferably those which carry an amino-protecting desired chemical reaction or reaction sequence; preference is group instead of an H atom bonded to an N atom, in 45 given to groups having 1-20, in particular 1–10, carbon particular those which carry an R' N group, in which R" is atoms. Examples of hydroxyl-protecting groups are, inter an amino-protecting group, instead of an HN group, and/or alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluene those which carry a hydroxyl-protecting group instead of the sulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl H atom of a hydroxyl group, for example those which are particularly preferred. conform to the formula I, but carry a COOR" group, in 50 The compounds of the formula I are liberated from their which R" is a hydroxyl-protecting group, instead of a functional derivatives—depending on the protecting group —COOH group. used—for example using strong acids, advantageously using Preferred starting materials are also the oxadiazole deriva TFA or perchloric acid, but also using other strong inorganic tives, which can be converted into the corresponding ami acids, such as hydrochloric acid or Sulfuric acid, strong dino compounds. 55 organic carboxylic acids. Such as trichloroacetic acid, or It is also possible for a plurality of identical or differ Sulfonic acids, such as benzene- or p-toluenesulfonic acid. ent protected amino and/or hydroxyl groups to be present The presence of an additional inert solvent is possible, but in the molecule of the starting material. If the protecting is not always necessary. Suitable inert Solvents are prefer groups present are different from one another, they can in ably organic, for example carboxylic acids, such as acetic many cases be cleaved off selectively. 60 acid, ethers. Such as tetrahydrofuran or dioxane, amides, The term "amino-protecting group' is known in general such as DMF, halogenated hydrocarbons, such as dichlo terms and relates to groups which are Suitable for protecting romethane, furthermore also alcohols, such as methanol, (blocking) an amino group against chemical reactions, but ethanol or isopropanol, and water. Mixtures of the above can easily be removed after the desired chemical reaction mentioned solvents are furthermore suitable. TFA is prefer has been carried out elsewhere in the molecule. Typical of 65 ably used in excess without addition of a further solvent, and Such groups are, in particular, unsubstituted or Substituted perchloric acid is preferably used in the form of a mixture of acyl, aryl, aralkoxymethyl or aralkyl groups. Since the acetic acid and 70% perchloric acid in the ratio 9:1. The US 7,129,241 B2 15 16 reaction temperatures for the cleavage are advantageously Pharmaceutical Salts and Other Forms between about 0 and about 50°, preferably between 15 and The said compounds according to the invention can be 30° (room temperature). used in their final, non-salt form. On the other hand, the The BOC, Obut and Mitr groups can, for example, pref present invention also covers the use of these compounds in erably be cleaved off using TFA in dichloromethane or using the form of their pharmaceutically acceptable salts which approximately 3 to 5N HCl in dioxane at 15–30°, and the can be derived from various organic and inorganic acids and FMOC group can be cleaved off using an approximately 5 bases by procedures known in the art. Pharmaceutically to 50% solution of dimethylamine, diethylamine or piperi acceptable salt forms of the compounds of the formula I are dine in DMF at 15–30°. prepared for the most part by conventional means. If the Protecting groups which can be removed hydrogenolyti 10 compound of the formula I contains a carboxyl group, a cally (for example CBZ., benzyl or the liberation of the suitable salt thereof can be formed by reacting the com amidino group from its oxadiazole derivative)) can be pound with a suitable base to give the corresponding base cleaved off, for example, by treatment with hydrogen in the addition salt. Examples of Such bases are alkali metal presence of a catalyst (for example a noble-metal catalyst, hydroxides, including potassium hydroxide, Sodium hydrox Such as palladium, advantageously on a Support, such as 15 ide and lithium hydroxide; alkaline earth metal hydroxides, carbon). Suitable solvents here are those indicated above, in Such as barium hydroxide and calcium hydroxide; alkali particular, for example, alcohols, such as methanol or etha metal alkoxides, for example potassium ethoxide and nol, or amides, such as DMF. The hydrogenolysis is gener Sodium propoxide; and various organic bases, such as pip ally carried out at temperatures between about 0 and 100° eridine, diethanolamine and N-methylglutamine. Also and pressures between about 1 and 200 bar, preferably at included are the aluminium salts of the compounds of the 20–30° and 1–10 bar. Hydrogenolysis of the CBZ group formula I. In the case of certain compounds of the formula succeeds well, for example, on 5 to 10% Pd/C in methanol I, acid-addition salts can be formed by treating these com or using ammonium formate (instead of hydrogen) on Pd/C pounds with pharmaceutically acceptable organic and inor in methanol/DMF at 20–30°. ganic acids, for example hydrogen halides, such as hydrogen Examples of suitable inert solvents are hydrocarbons, 25 chloride, hydrogen bromide or hydrogen iodide; other min Such as hexane, petroleum ether, benzene, toluene or Xylene; eral acids and the corresponding salts thereof. Such as chlorinated hydrocarbons, such as trichloroethylene, 1.2- Sulfate, nitrate or phosphate, etc., and alkyl- and monoaryl dichloroethane, tetrachloromethane, trifluoromethylben Sulfonates, such as ethanesulfonate, toluenesulfonate and Zene, chloroform or dichloromethane; alcohols, such as benzenesulfonate, and other organic acids and the corre methanol, ethanol, isopropanol, n-propanol, n-butanol or 30 sponding salts thereof. Such as acetate, tartrate, maleate, tert-butanol; ethers, such as diethyl ether, diisopropyl ether, Succinate, citrate, benzoate, Salicylate, ascorbate, etc. tetrahydrofuran (THF) or dioxane: glycol ethers, such as Accordingly, the pharmaceutically acceptable acid-addition ethylene glycol monomethyl or monoethyl ether or ethylene salts of the compounds of the formula I include, but are not glycol dimethyl ether (diglyme), ketones, such as acetone or limited to, the following: acetate, adipate, alginate, arginate, butanone; amides, such as acetamide, dimethylacetamide, 35 aspartate, benzoate, benzenesulfonate (besylate), bisulfate, N-methylpyrrolidone (NMP) or dimethylformamide bisulfite, bromide, butyrate, camphorate, camphorsulfonate, (DMF): nitriles, such as acetonitrile; sulfoxides, such as caprylate, chloride, chlorobenzoate, citrate, cyclopen dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic tanepropionate, digluconate, dihydrogenphosphate, dini acids, such as formic acid or acetic acid; nitro compounds, trobenzoate, dodecylsulfate, ethanesulfonate, fumarate, Such as nitromethane or nitrobenzene, esters, such as ethyl 40 galacterate (from mucic acid), galacturonate, glucohep acetate, or mixtures of the said solvents. tanoate, gluconate, glutamate, glycerophosphate, hemisuc Esters can be saponified, for example, using acetic acid or cinate, hemisulfate, heptanoate, hexanoate, hippurate, using NaOH or KOH in water, water/THF or water/dioxane, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy at temperatures between 0 and 100°. ethanesulfonate, iodide, isethionate, isobutyrate, lactate, lac Free amino and/or hydroxyl groups can furthermore be 45 tobionate, malate, maleate, malonate, mandelate, metaphos acylated in a conventional manner using an acid chloride or phate, methanesulfonate, methylbenzoate, anhydride or alkylated using an unsubstituted or Substituted monohydrogenphosphate, 2-naphthalenesulfonate, nicoti alkyl halide or reacted with CH C(=NH)—OEt, advan nate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, tageously in an inert solvent, such as dichloromethane or phenylacetate, 3-phenylpropionate, phosphate, phosphonate THF and/or in the presence of a base, such as triethylamine 50 and phthalate. or pyridine, at temperatures between -60 and +30°. Furthermore, the base salts of the compounds according It is furthermore possible to convert a compound of the to the invention include, but are not limited to, aluminium, formula I into another compound of the formula I by ammonium, calcium, copper, iron(III), iron(II), lithium, converting one or more radical(s) R', R, R and/or R' into magnesium, manganese(III), manganese(II), potassium, one or more other radicals R', R. Rand/or R', for example 55 Sodium and Zinc salts. Of the above-mentioned salts, pref by erence is given to ammonium; the alkali metal salts sodium reducing nitro groups (for example by hydrogenation on and potassium, and the alkaline earth metal salts calcium and Raney nickel or Pd/carbon in an inert solvent, such as magnesium. Salts of the compounds of the formula I derived methanol or ethanol) to amino groups and/or from pharmaceutically acceptable organic non-toxic bases converting bromine Substituents into cyano groups by reac 60 include, but are not limited to, salts of primary, secondary tion with, for example, copper cyanide and/or and tertiary amines, Substituted amines, also naturally occur hydrolysing cyano groups to COOH groups and/or ring Substituted amines, cyclic amines and basic ion esterifying carboxyl groups by reaction with alcohols and/or exchanger resins, for example arginine, betaine, caffeine, alkylating nitro groups under hydrogenolytic conditions, chloroprocaine, choline, N,N'-dibenzylethylenediamine giving alkylated amines, 65 (benzathine), dicyclohexylamine, diethanolamine, diethy and/or reductively alkylating amines by reaction with alde lamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, hydes and complex hydrides. ethanolamine, ethylenediamine, N-ethylmorpholine, N-eth US 7,129,241 B2 17 18 ylpiperidine, glucamine, glucosamine, histidine, hydrabam the active ingredient that has been used earlier. It may also ine, isopropylamine, lidocaine, lysine, meglumine, N-me be the case that only the pharmaceutically acceptable salt thyl-D-glucamine, morpholine, piperazine, piperidine, form of the active ingredient provides this active ingredient polyamine resins, procaine, purines, theobromine, trietha with a desired pharmacokinetic property which it did not nolamine, triethylamine, trimethylamine, tripropylamine previously possess, and may even have a positive effect on and tris-(hydroxymethyl)-methylamine (tromethamine). the pharmacodynamics of this active ingredient with respect Compounds of the present invention which contain basic to its therapeutic activity in the body. nitrogen-containing groups may be quaternised using The pharmacokinetic properties of the active ingredient agents, such as (C-C)alkyl halides, for example methyl, which may be favourably affected include, for example, the ethyl, isopropyl and tert-butyl chlorides, bromides and 10 manner in which this active ingredient is transported through iodides; di(C-C)alkyl Sulfates, for example dimethyl, cell membranes, which in turn can have a direct and positive diethyl and diamyl Sulfates; (Co-Cs)alkyl halides, for effect on the absorption, distribution, biotransformation and example decyl, dodecyl, lauryl, myristyl and Stearyl chlo excretion of this active ingredient. Although the method of rides, bromides and iodides; and aryl-(C-C)alkyl halides. administration of the pharmaceutical composition is impor for example benzyl chloride and phenethyl bromide. Such 15 tant, and various anatomical, physiological and pathological salts enable the preparation of both water-soluble and oil aspects can crucially affect bioavailability, the solubility of soluble compounds according to the invention. the active ingredient is usually dependent on the nature of The preferred pharmaceutical salts mentioned above the particular salt form thereof which is being used. Fur include, but are not limited to, acetate, besylate, citrate, thermore, it is clear to the person skilled in the art that an fumarate, gluconate, hemisuccinate, hippurate, hydrochlo aqueous Solution of the active ingredient provides the fastest ride, hydrobromide, isethionate, mandelate, meglumine, absorption of the active ingredient into the body of a patient nitrate, oleate, phosphonate, pivalate, Sodium phosphate, being treated, while lipid solutions and Suspensions, as well Stearate, Sulfate, Sulfosalicylate, tartrate, thiomalate, tosylate as Solid dosage forms, result in less rapid absorption of the and tromethamine. active ingredient. The acid-addition salts of basic compounds of the formula 25 I are prepared by bringing the free base form into contact Oral ingestion of an active ingredient of the formula I is with a sufficient amount of the desired acid, giving the salt the most preferred method of administration for reasons of in a conventional manner. The free base can be regenerated safety, convenience and economy, but absorption of an oral in a conventional manner by bringing the salt form into dosage form of this type may be adversely affected by contact with a base and isolating the free base. The free base 30 physical properties, such as polarity, vomiting caused by forms differ to a certain extent from the corresponding salt irritation of the gastrointestinal mucous membrane, degra forms thereof in certain physical properties, such as solu dation by digestive enzymes and low pH, irregular absorp bility in polar solvents; otherwise, however, the salts are tion or propulsion in the presence of food or other medica equivalent to their respective free base forms for the pur ments, and metabolism by enzymes of the mucous poses of the present invention. 35 membrane, the intestinal flora, or the liver. Formulation of As mentioned, the pharmaceutically acceptable base the active ingredient as different pharmaceutically accept addition salts of the compounds of the formula I are formed able salt forms may be effective in overcoming or alleviating with metals or amines, such as alkali metals and alkaline one or more of the above-mentioned problems in connection earth metals, or organic amines. Preferred metals are with the absorption of oral dosage forms. Sodium, potassium, magnesium and calcium. Preferred 40 A compound of the formula I prepared by the processes organic amines are N,N'-dibenzylethylenediamine, chloro described herein can be separated from the reaction mixture procaine, choline, diethanolamine, ethylenediamine, N-me in which it is ultimately prepared by any desired conven thyl-D-glucamine and procaine. tional method that is familiar to the chemist in the area of The base-addition salts of acidic compounds according to organic synthesis. The separated-off compounds can be the invention are prepared by bringing the free acid form 45 purified by known methods. Various methods and tech into contact with a sufficient amount of the desired base, niques can be used for the separation and purification, giving the salt in a conventional manner. The free acid can including, for example, distillation, recrystallisation, column be regenerated in a conventional manner by bringing the salt chromatography, ion-exchange chromatography, gel chro form into contact with an acid and isolating the free acid. matography, affinity chromatography, preparative thin-layer The free acid forms differ to a certain extent from the 50 chromatography and solvent extraction. corresponding salt forms thereof in certain physical proper ties, such as Solubility in polar solvents; otherwise, however, Stereoisomers the salts are equivalent to their respective free acid forms for A compound which conforms to the formula I may be of the purposes of the invention. Such a nature that its constituent atoms are capable of being If a compound according to the invention contains more 55 arranged spatially in two or more ways, despite having than one group which is capable of forming pharmaceuti identical bonds. As a consequence, this compound exists in cally acceptable salts of this type, the invention also covers the form of stereoisomers. Cis/trans isomerism is only one multiple salts. Typical multiple salt forms include, but are type of Stereoisomerism. If the stereoisomers are image and not limited to, bitartrate, diacetate, difumarate, dimeglu mirror image which cannot be Superimposed, they are enan mine, diphosphate, disodium and trihydrochloride. 60 tiomers which have chirality or handedness since one or In view of the above, it can be seen that the expression more asymmetric carbon atoms are present in the structure “pharmaceutically acceptable salt in the present connection forming them. Enantiomers are optically active and there is intended to mean an active ingredient which comprises a fore distinguishable since they rotate the plane of polarised compound of the formula I in the form of one of its salts, in light to an equal extent, but in opposite directions. particular if this salt form provides the active ingredient with 65 If two or more asymmetric carbon atoms are present in a improved pharmacokinetic properties compared with the compound of the formula I, two possible configurations free form of the active ingredient or any other salt form of exist at each of these carbon atoms. US 7,129,241 B2 19 20 If two asymmetric carbon atoms are present, four possible occurs naturally. Examples of isotopes which are readily stereoisomers exist, for example. Furthermore, these four commercially available and which can be incorporated into possible stereoisomers can be divided into six possible pairs a compound of the formula I by well-known methods of stereoisomers that differ from each other. In order for a include isotopes of hydrogen, carbon, nitrogen, oxygen, pair of molecules with more than one asymmetric carbon to 5 phosphorus, fluorine and chlorine, for example H. H. C. be enantiomers, they must have different configurations at “C, N, O, 7O, P, PSS, F and C1, respectively. each asymmetric carbon. Those pairs that do not behave as A compound of the formula I, a prodrug thereof or a enantiomers have a different stereochemical relationship, pharmaceutically acceptable salt of either which contains which is known as a diastereomeric relationship. Stereoiso one or more of the above-mentioned isotopes and/or other mers that are not enantiomers are known as diastereoiso 10 isotopes of other atoms is intended to be part of the present mers, or, more frequently, diastereomers. invention. An isotope-labelled compound of the formula I All of these well-known aspects of the stereochemistry of can be used in a number of beneficial ways. the compounds of the formula I are considered to be part of For example, an isotope-labelled compound of the for the present invention. The present invention therefore covers mula I into which, for example, a radioisotope, such as H compounds of the formula I which are stereoisomers, and, if 15 or "C, has been incorporated is suitable for medicament these are enantiomers, the individual enantiomers, racemic and/or Substrate tissue distribution assays. These radioiso mixtures of these enantiomers, and artificial, i.e. synthetic, topes, i.e. tritium (H) and carbon-14 (''C), are particularly mixtures comprising proportions of these enantiomers preferred owing to their simple preparation and excellent which are different from the proportions of these enanti detectability. Incorporation of heavier isotopes, for example omers observed in a racemic mixture. If a compound of the deuterium (H), into a compound of the formula I has formula I has stereoisomers that are diastereomers, this therapeutic advantages owing to the higher metabolic sta compound includes the individual diastereomers as well as bility of this isotope-labelled compound. Higher metabolic mixtures of any two or more of these diastereomers in any stability translates directly into an increased in-vivo half-life desired proportions. or lower dosages, which under most circumstances would The following is intended to serve for explanation: if a 25 represent a preferred embodiment of the present invention. single asymmetric carbon atom exists in a compound of the An isotope-labelled compound of the formula I can usually formula I that results in the (-)(R) and (+)(S) enantiomers be prepared by carrying out the procedures disclosed in the thereof, this compound includes all pharmaceutically synthesis schemes and the related description, in the acceptable salt forms, prodrugs and metabolites thereof example part and in the preparation part in the present text, which are therapeutically active and useful for the treatment 30 replacing a non-isotope-labelled reactant with a readily of or preventing the diseases and conditions described available isotope-labelled reactant. further herein. If a compound of the formula I exists in the form of (-) (R) and (+)(S) enantiomers, this compound also Deuterium (H) can also be incorporated into a compound includes the (+)(S) enantiomer alone or the (-)(R) enanti of the formula I in order to manipulate the oxidative metabo omer alone if all, Substantially all or a predominant share of 35 lism of the compound by way of the primary kinetic isotope the therapeutic activity resides in only one of these enanti effect. The primary kinetic isotope effect is a change in the omers or undesired side effects reside in only one of these rate of a chemical reaction that results from exchange of enantiomers. If essentially no difference exists between the isotopic nuclei, which in turn is caused by the change in biological properties of the two enantiomers, this compound ground State energies necessary for covalent bond formation of the formula I furthermore includes the (+)(S) enantiomer 40 after this isotopic exchange. Exchange of a heavier isotope and the (-)(R) enantiomer together as a racemic mixture or usually results in a lowering of the ground state energy for non-racemic mixture in any desired ratio of corresponding a chemical bond and thus causes a reduction in the rate in proportions. rate-limiting bond breakage. If the bond breakage occurs in The specific biological effects and/or physical and chemi or in the vicinity of a saddle-point region along the coordi cal properties of a pair or set of enantiomers of a compound 45 nate of a multi-product-reaction, the product distribution of the formula I—if present—may make it obvious to use ratios can be altered substantially. For explanation: if deu these enantiomers in certain ratios, for example to form a terium is bonded to a carbon atom in a non-exchangeable final therapeutic product. The following is intended to serve position, rate differences of k/k, 2-7 are typical. If this for illustration: if a pair of enantiomers exists, the enanti rate difference is Successfully applied to a compound of the 50 formula I that is susceptible to oxidation, the profile of this omers can be used in ratios such as 90% (R)-10% (S), 80% compound in vivo can thereby be drastically modified and (R)-20% (S), 70% (R)-30% (S), 60% (R)-40% (S), 50% result in improved pharmacokinetic properties. (R)-50% (S), 40% (R)-60% (S), 30% (R)-70% (S), 20% (R)-80% (S), and 10% (R)-90% (S). After evaluation of the When discovering and developing therapeutic agents, the properties of the various enantiomers of a compound of the person skilled in the art attempts to optimise pharmacoki formula I if they exist—the corresponding amount of one 55 netic parameters while retaining desirable in-vitro proper or more of these enantiomers having certain desired prop ties. It is reasonable to assume that many compounds with erties which form the final therapeutic product can be poor pharmacokinetic profiles are susceptible to oxidative determined in a simple manner. metabolism. In-vitro liver microsomal assays currently available provide valuable information on the course of Isotopes 60 oxidative metabolism of this type, which in turn permits the It is furthermore intended that a compound of the formula rational design of deuterated compounds of the formula I I includes isotope-labelled forms thereof. An isotope-la with improved stability through resistance to such oxidative belled form of a compound of the formula I is identical to metabolism. Significant improvements in the pharmacoki this compound apart from the fact that one or more atoms of netic profiles of the compounds of the formula I are thereby the compound have been replaced by an atom or atoms 65 obtained and can be expressed quantitatively in terms of having an atomic mass or mass number which differs from increases in the in-vivo half-life (T/2), concentration at the atomic mass or mass number of the atom which usually maximum therapeutic effect (C), area under the dose US 7,129,241 B2 21 22 response curve (AUC), and F; and in terms of reduced The formation of this species has been demonstrated in clearance, dose and costs of materials. human patients with myocardial ischaemia. Animal models The following is intended to illustrate the above: a com show that cytokine production correlates with the invasion pound of the formula I which has multiple potential sites of of peripheral macrophages and neutrophils, enabling the attack for oxidative metabolism, for example benzylic 5 damage to spread into the still intact myocardium. hydrogen atoms and hydrogen atoms bonded to a nitrogen The main factor in the cytokine response, however, is atom, is prepared as a series of analogues in which various TNF-C., which combines inflammatory and pro-apoptotic combinations of hydrogen atoms are replaced by deuterium responses and additionally has a direct negative ionotropic atoms, so that some, most or all of these hydrogen atoms effect on cardiac myocytes (Ceconi C, Curello S. Bachetti T. have been replaced by deuterium atoms. Half-life determi 10 Corti A, Ferrari R. Tumor necrosis factor in congestive heart nations enable favourable and accurate determination of the failure: a mechanism of disease for the new millennium? extent to which the improvement in resistance to oxidative Prog. Cardiovasc. Dis. 1998 41: 25–30. metabolism has improved. In this way, it is determined that Mann D. L.: The effect of tumor necrosis factor-alpha on the half-life of the parent compound can be extended by up cardiac structure and function: a tale of two cytokines. J. to 100% as the result of deuterium-hydrogen exchange of 15 Card. Fail. 1996 2: S165-S172. this type. Squadrito F. Altavilla D, Zingarelli B, et al: Tumor Deuterium-hydrogen exchange in a compound of the necrosis factor involvement in myocardial ischaemia-reper formula I can also be used to achieve a favourable modifi fusion damage. Eur. J. Pharmacol. 1993 237: 223–230). cation of the metabolite spectrum of the starting compound It has been shown in animal models of myocardial inf in order to diminish or eliminate undesired toxic metabo arction that TNF-C. is released rapidly during the reperfusion lites. For example, if a toxic metabolite arises through phase (Herskowitz, A. Choi S, Ansari A A. Wesselingh S: oxidative carbon-hydrogen (C-H) bond cleavage, it can Cytokine mRNA expression in postischemic/reperfused reasonably be assumed that the deuterated analogue will myocardium. Am. J. Pathol. 1995 146: 419–428) and that greatly diminish or eliminate production of the undesired the protective effects of medicaments, such as dexametha metabolite, even if the particular oxidation is not a rate 25 sone (Arras M. Strasser R, Mohri M. et al.: Tumor necrosis determining step. Further information on the state of the art factor-alpha is expressed by monocytes/macrophages fol with respect to deuterium-hydrogen exchange is given, for lowing cardiac microembolisation and is antagonised by example in Hanzlik et al., J. Org. Chem. 55, 3992–3997, cyclosporine. Basic. Res. Cardiol. 1998 93: 97-107), 1990, Reider et al., J. Org. Chem. 52, 3326–3334, 1987, cyclosporin A (Arras M. Strasser R. Mohri M. et al.: Tumor Foster, Adv. Drug Res. 14, 1–40, 1985, Gillette et al., 30 necrosis factor-alpha is expressed by monocytes/macroph Biochemistry 33(10), 2927–2937, 1994, and Jarman et al., ages following cardiac microembolisation and is antago Carcinogenesis 16(4), 683–688, 1993. nised by cyclosporine. Basic. Res. Cardiol. 1998 93: 97–107. Squadrito F. Altavilla D, Squadrito G, et al.: Therapeutic Applications Cyclosporin-A reduces leukocyte accumulation and protects The invention furthermore relates to the use of com 35 against myocardial ischaemia reperfusion injury in rats. Eur. pounds of the formula I for the treatment of myocardial J. Pharmacol. 1999 364: 159–168) or clorichromene diseases. (Squadrito F. Altavilla D. Zingarelli B, et al.: The effect of Coronary heart diseases represent the most frequent cause cloricromene, a coumarine derivate, on leukocyte accumu of death in the Western world. If the coronary vessel is lation, myocardial necrosis and TNF-alpha production in critically narrowed, a decrease of blood flow may result in 40 myocardial ischaemia-reperfusion injury. Life Sci. 1993 53: myocardial ischaemia. Initiation of reperfusion results, 341–355), are accompanied by a reduction of circulating depending on the severity of the preceding ischaemic period, TNF-C. in a reversibly or irreversibly damaged myocardium, which PDE IV inhibitors of the formula I are effective antago is characterised by long-lasting depression or an irreversible nists of macrophage and T-cell cytokine production. They loss of contractile function. Depending on the size of the 45 also inhibit the proliferation of T cells. PDE IV inhibition affected myocardial area, acute or chronic heart failure may may therefore have a beneficial effect in myocardial diseases develop. which are causally linked to cytokine production and inflam A particular clinical problem in the above-described case matory processes. is the development of restenosis after initially successful Compared with PDE III inhibitors and the early PDE IV reperfusion by PTCA, even after stent implantation, after 50 inhibitor rolipram, preferred PDE IV inhibitors have no thrombolysis or after transplantation of an aorto-coronary haemodynamic side effects, which can result in a restriction bypass. From experimental animal studies and clinical stud of the dose in the treatment of most cardiovascular disorders. ies, there is evidence that inflammatory processes play a The invention had the object of finding novel potential casual role in the various heart diseases mentioned above, uses of compounds having valuable properties, especially i.e. coronary heart disease itself, reversible or irreversible 55 those which can be used for the preparation of medicaments. myocardial ischaemia/reperfusion damage, acute or chronic It has been found that the compounds of the formula I and heart failure and restenosis, including in-stent restenosis and salts thereof both have extremely valuable pharmacological stent-in-stent restenosis. These inflammatory processes properties and are well tolerated for the treatment of myo involve resident and invading macrophages as well as neu cardial diseases. trophils and TH and TH helper cells. This leukocyte 60 The invention preferably proposes the use of the com response produces the characteristic cytokine pattern involv pounds of the formula I for the preparation of a medicament ing TNF-C., IL-1B, IL-2 and IL-6, as well as IL-10 and IL-13 for the treatment of myocardial diseases, where these myo (Pulkki KJ: Cytokines and cardiomyocyte death. Ann. Med. cardial diseases have inflammatory and immunological fea 1997 29: 339. 343. tures. Birks E. J. Yacoub M H: The role of nitric oxide and 65 The invention most preferably proposes the use of the cytokines in heart failure. Coron. Artery. Dis. 1997 8: compounds of the formula I for the preparation of a medi 389 402). cament for the treatment of coronary heart diseases, revers US 7,129,241 B2 23 24 ible or irreversible myocardial ischaemia/reperfusion dam an eosinophil-related pathological disorder of whatever age, acute or chronic heart failure and restenosis, including type, etiology or pathogenesis, or an eosinophil-related in-stent restenosis and stent-in-stent restenosis. pathological disorder selected from the group consist The invention preferably proposes the use of the com ing of eosinophilia, pulmonary infiltration eosinophilia, pounds of the formula I for the preparation of a medicament Löffler's syndrome, chronic eosinophilic pneumonia, for the treatment or prevention of one or more of the tropical pulmonary eosinophilia, bronchopneumonic diseases, pathological disorders and conditions from the aspergillosis, aspergilloma, eosinophilic granuloma, following group: allergic granulomatous angiitis or Churg-Strauss Syn asthma of whatever type, etiology or pathogenesis, or drome, polyarteritis nodosa (PAN) and systemic necro asthma selected from the group consisting of atopic 10 tising vasculitis; asthma, non-atopic asthma, allergic asthma, atopic, atopic dermatitis, allergic dermatitis, or allergic or atopic IgE-mediated asthma, bronchial asthma, essential eCZema, asthma, true asthma, intrinsic asthma caused by patho urticaria of whatever type, etiology or pathogenesis, or physiological disturbances, extrinsic asthma caused by urticaria selected from the group consisting of immune environmental factors, essential asthma of unknown or 15 mediated urticaria, complement-mediated urticaria, inapparent cause, non-atopic asthma, bronchitic urticariogenic material-induced urticaria, physical asthma, emphysematous asthma, exercise-induced stimulus-induced urticaria, stress-induced urticaria, asthma, occupational asthma, infective asthma caused idiopathic urticaria, acute urticaria, chronic urticaria, by bacterial, fungal, protozoal or viral infection, non angiooedema, cholinergic urticaria, cold urticaria in the allergic asthma, incipient asthma, wheezy infant syn autosomal dominant form or in the acquired form, drome; contact urticaria, giant urticaria and papular urticaria; chronic or acute bronchoconstriction, chronic bronchitis, conjunctivitis of whatever type, etiology or pathogenesis, Small air-way obstruction and emphysema; or conjunctivitis selected from the group consisting of obstructive or inflammatory airway disease of whatever actinic conjunctivitis, acute catarrhal conjunctivitis, type, etiology or pathogenesis, or an obstructive or 25 acute contagious conjunctivitis, allergic conjunctivitis, inflammatory airway disease selected from the group atopic conjunctivitis, chronic catarrhal conjunctivitis, consisting of asthma; pneumoconiosis, chronic eosino purulent conjunctivitis and Vernal conjunctivitis; philic pneumonia; chronic obstructive pulmonary dis uveitis of whatever type, etiology or pathogenesis, or ease (COPD), COPD including chronic bronchitis, pull uveitis selected from the group consisting of inflam monary emphysema or dyspnoea associated therewith, 30 mation of all or part of the uvea, anterior uveitis, iritis, COPD that is characterised by irreversible, progressive cyclitis, iridocyclitis, granulomatous uveitis, nongranu airway obstruction, acute respiratory distress syndrome lomatous uveitis, phacoantigenic uveitis, posterior (ARDS), and exacerbation of airway hypersensitivity uveitis, choroiditis and chorioretinitis; consequent to other medicament therapy: psoriasis; pneumoconiosis of whatever type, etiology or pathogen 35 multiple Sclerosis of whatever type, etiology or pathogen esis, or pneumoconiosis selected from the group con esis, or multiple Sclerosis selected from the group sisting of aluminosis, anthracosis (asthma), asbestosis, consisting of primary progressive multiple Sclerosis chalicosis, ptilosis caused by inhaling the dust from and relapsing remitting multiple Sclerosis: ostrich feathers, siderosis caused by the inhalation of 40 autoimmune/inflammatory diseases of whatever type, eti iron particles, silicosis, byssinosis or cotton-dust pneu ology or pathogenesis, or an autoimmune/inflammatory moconiosis and talc pneumoconiosis: disease selected from the group consisting of autoim bronchitis of whatever type, etiology or pathogenesis, or mune haematological disorders, haemolytic anaemia, bronchitis selected from the group consisting of acute aplastic anaemia, pure red cell anaemia, idiopathic bronchitis, acute laryngotracheal bronchitis, arachidic 45 thrombocytopenic purpura, Systemic lupus erythema bronchitis, catarrhal bronchitis, croupus bronchitis, dry tosus, polychondritis, Scleroderma, Wegner's granulo bronchitis, infectious asthmatic bronchitis, productive matosis, dermatomyositis, chronic active hepatitis, bronchitis, staphylococcal or Streptococcal bronchitis; myasthenia gravis, Stevens-Johnson syndrome, idio and vesicular bronchitis; pathic sprue, autoimmune inflammatory bowel dis bronchiectasis of whatever type, etiology or pathogenesis, 50 eases, ulcerative colitis, Crohn's disease, endocrine or bronchiectasis selected from the group consisting of ophthamopathy, Basedow's disease, sarcoidosis, alveo cylindric bronchiectasis, Sacculated bronchiectasis, litis, chronic hypersensitivity pneumonitis, primary bil fusiform bronchiectasis, capillary bronchiectasis, cys iary cirrhosis, juvenile diabetes or type 1 diabetes tic bronchiectasis, dry bronchiectasis and follicular mellitus, anterior uveitis, granulomatous or posterior bronchiectasis; 55 uveitis, keratoconjunctivitis sicca, epidemic keratocon seasonal allergic rhinitis, perennial allergic rhinitis, or junctivitis, diffuse interstitial pulmonary fibrosis or sinusitis of whatever type, etiology or pathogenesis, or interstitial pulmonary fibrosis, pulmonary cirrhosis, sinusitis selected from the group consisting of purulent cystic fibrosis, psoriatic arthritis, glomerulonephritis or nonpurulent sinusitis, acute or chronic sinusitis, and with and without nephrotic syndrome, acute glomeru ethmoid, frontal, maxillary, or sphenoid sinusitis; 60 lonephritis, idiopathic nephrotic syndrome, minimal rheumatoid arthritis of whatever type, etiology or patho change nephropathy, inflammatory/ hyperproliferative genesis, or rheumatoid arthritis selected from the group skin diseases, psoriasis, atopic dermatitis, contact der consisting of acute arthritis, acute gouty arthritis, pri matitis, allergic contact dermatitis, benign familial mary chronic arthritis, osteoarthrosis, infectious arthri pemphigus, pemphigus erythematosus, pemphigus tis, Lyme arthritis, progressive arthritis, psoriatic arthri 65 foliaceus and pemphigus Vulgaris; tis and spondylarthritis; prevention of foreign transplant rejection following organ gout, and fever and pain associated with inflammation; transplantation; US 7,129,241 B2 25 26 inflammatory bowel disease (IBD) of whatever type, erythematosis, GvH reaction, rejection of foreign trans etiology or pathogenesis, or inflammatory bowel dis plants, multiple Sclerosis, psoriasis and allergic rhinitis, and ease selected from the group consisting of ulcerative (5) other diseases and conditions, including bone absorption colitis (UC), collagenous colitis, colitis polyposa, trans diseases, reperfusion damage, cachexia secondary to infec mural colitis and Crohn's disease (CD); tion or malignancy, cachexia secondary to human acquired septic shock of whatever type, etiology or pathogenesis, immune deficiency syndrome (AIDS), human immunodefi or septic shock selected from the group consisting of ciency virus (HIV) infection, or AIDS related complex renal failure, acute renal failure, cachexia, malarial (ARC), keloid formation, Scar tissue formation, type 1 cachexia, hypophysial cachexia, uremic cachexia, car diabetes mellitus and leukaemia. diac cachexia, cachexia Suprarenalis or Addison's dis 10 The present invention furthermore relates to the combi ease, cancerous cachexia, and cachexia as a conse nation of a compound of the formula I together with one or quence of infection by the human immunodeficiency more members selected from the group consisting of the virus (HIV): following: liver damage: (a) leukotriene biosynthesis inhibitors: 5-lipoxygenase pulmonary hypertension and hypoxia-induced pulmonary 15 (5-LO) inhibitors and 5-lipoxygenase activating protein hypertension; (FLAP) antagonists selected from the group consisting of bone loss diseases, primary osteoporosis and secondary zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79.175, osteoporosis: Abbott-85761, N-(5-substituted)-thiophene-2-alkylsulfona pathological disorders of the central nervous system of mides, 2,6-di-tert-butylphenol hydrazones, the class of the whatever type, etiology or pathogenesis, or a patho methoxytetrahydropyrans, including Zeneca ZD-2138, the logical disorder of the central nervous system selected compound SB-210661 and the class to which it belongs, the from the group consisting of depression, Parkinson's class of the pyridinyl-substituted 2-cyanonaphthalene com disease, learning and memory disorders, tardive dys pounds, including L 739,010, the class of the 2-cyanoquino kinesia, drug dependence, arteriosclerotic dementia, line compounds, including L-746.530, the classes of the and dementias that accompany Huntington's chorea, 25 indole and quinoline compounds, including MK-591, Wilson's disease, paralysis agitans and thalamic atro MK-886 and BAY x 1005; (b) receptor antagonists for the phies; leukotrienes LTB, LTC, LTD and LTE selected from the infections, especially viral infections, where these viruses group consisting of the class of the phenothiazin-3-one increase the production of TNF-C. in their host or where compounds, including L-651,392, the class of the amidino these viruses are sensitive to up-regulation of TNF-C. in 30 compounds, including CGS-25019c, the class of the ben their host so that their replication or other vital activi ZOxazolamines, including ontazolast, the class of the ben ties are adversely affected, including viruses selected Zenecarboximideamides, including BIIL 284/260, and the from the group consisting of HIV-1, HIV-2 and HIV-3, classes of compound to which Zafirlukast, ablukast, mon cytomegalovirus, CMV, influenza, adenoviruses and telukast, pranlukast, Verlukast (MK-679), RG-12525, Herpes viruses, including Herpes Zoster and Herpes 35 Ro-245913, iralukast (CGP 45715A) and BAY x 7195 simplex: belong; (c) PDE IV inhibitors; (d) 5-lipoxygenase inhibitors yeast and fungal infections, where these yeasts and fungi (5-LO); or 5-lipoxygenase activating protein (FLAP) are sensitive to up-regulation by TNF-C. or elicit TNF-C. antagonists; (e) dual inhibitors of 5-lipoxygenase (5-LO) production in their host, for example fungal meningitis, and antagonists of platelet activating factor (PAF), (f) leu particularly when administered in conjunction with 40 kotriene antagonists (LTRAS) including LTB, LTC, LTD other medicaments of choice for the treatment of sys and LTE antagonists; (g) antihistamine H receptor antago temic yeast and fungal infections, including, but not nists, including cetirizine, loratadine, desloratadine, fex limited to, polymycins, for example polymycin B, ofenadine, astemizole, azelastine and chlorpheniramine; (h) imidazoles, for example clotrimazole, econazole, gastroprotective H receptor antagonists: (i) C- and miconazole and ketoconazole, triazoles, for example 45 C2-adrenoreceptor agonist vasoconstrictor sympathomi fluconazole and itranazole, and amphotericins, for metic agents administered orally or topically for deconges example amphotericin B and liposomal amphotericin tant use, including propylhexedrine, phenylephrine, phenyl B; propanolamine, pseudoephedrine, naphazoline ischaemia-reperfusion damage, autoimmune diabetes, hydrochloride, oxymetazoline hydrochloride, tetrahydrozo retinal autoimmunity, chronic lymphocytic leukaemia, 50 line hydrochloride, Xylometazoline hydrochloride and eth HIV infections, lupus erythematosus, kidney and ureter ylnorepinephrine hydrochloride; ) C- and C2-adrenorecep diseases, pathological urogenital and gastrointestinal tor agonists in combination with inhibitors of disorders and prostate diseases. 5-lipoxygenase (5-LO); (k) anticholinergic agents, including In particular, compounds of the formula I are suitable for ipratropium bromide, tiotropium bromide, oxitropium bro the treatment of (1) inflammatory diseases and conditions, 55 mide, pirenzepine and telenzepine; (1) B- to B adrenore including joint inflammation, rheumatoid arthritis, rheuma ceptor agonists, including metaproterenol, isoproterenol, toid spondylitis, osteoarthritis, inflammatory bowel disease, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, ulcerative colitis, chronic glomerulonephritis, dermatitis and terbutaline, orciprenaline, bitolterol mesylate and pirbuterol: Crohn's disease, (2) respiratory tract diseases and condi (m) methylxanthanines, including theophylline and amino tions, including asthma, acute respiratory distress syndrome, 60 phylline; (n) sodium cromoglycate; (o) muscarinic receptor chronic pulmonary inflammatory disease, bronchitis, (M1, M2 and M3) antagonists; (p) COX-1 inhibitors chronic obstructive airway disease and silicosis, (3) infec (NSAIDs); COX-2 selective inhibitors, including rofecoxib, tious diseases and conditions, including sepsis, septic shock, and nitric oxide NSAIDs; (q) insulin-like growth factor type endotoxic shock, Gram-negative sepsis, toxic shock Syn I (IGF-1) mimetics; (r) ciclesonide: (s) inhalation glucocor drome, fever and myalgias due to bacterial, viral or fungal 65 ticoids with reduced systemic side effects, including pred infection, and influenza, (4) immune diseases and condi nisone, prednisolone, flunisolide, triamcinolone acetonide, tions, including autoimmune diabetes, systemic lupus beclomethasone dipropionate, budesonide, fluticasone pro US 7,129,241 B2 27 28 pionate and mometasone furoate; (t) tryptase inhibitors; (u) these components are formulated separately from one platelet activating factor (PAF) antagonists; (V) monoclonal another as separate dosage forms which are taken by the antibodies against endogenous inflammatory entities; (w) patient at Successive times with a clear time interval IPL 576; (x) antitumour necrosis factor (TNFC.) agents, between each taking, and the components are released to including etanercept, infliximab and D2E7; (y) DMARDs, the patient at essentially different times; and including leflunomide: (Z) TCR peptides: (aa) interleukin (d) sequential administration of Such a combination of one converting enzyme (ICE) inhibitors; (bb) IMPDH inhibitors: or more compound(s) and a therapeutic agent or a plu (cc) adhesion molecule inhibitors, including VLA-4 antago rality of therapeutic agents to a patient in need of treat nists; (dd) cathepsins; (ee) MAP kinase inhibitors; (f) ment if these components are formulated jointly as a glucose 6-phosphate dehydrogenase inhibitors; (gg) kinin 10 single dosage form which releases these components in a B and B receptor antagonists; (hh) gold in the form of an controlled manner, and the components are taken by the aurothio group together with various hydrophilic groups; (ii) patient simultaneously, Successively and/or in an overlap immunosuppressive agents, for example cyclosporine, aza ping manner at the same time and/or at different times. thioprine and methotrexate; (ii) anti-gout agents, for example colchicine; (kk) Xanthine oxidase inhibitors, for 15 Combinations with Leukotriene Biosynthesis Inhibitors: example allopurinol; (Il) uricosuric agents, for example 5-Lipoxygenase (5-LO) Inhibitors and 5-Lipoxygenase probenecide, Sulfinpyrazone and benzbromarone; (mm) Activating Protein (FLAP) Antagonists antineoplastic agents, especially antimitotic medicaments, In order to form embodiments according to the invention, including the Vinca alkaloids, such as vinblastine and Vin one or more of the compounds of the formula I is (are) used cristine; (nn) agents for promoting the Secretion of growth in combination with leukotriene biosynthesis inhibitors, i.e. hormone; (OO) inhibitors of matrix metalloproteases 5-lipoxygenase inhibitors or 5-lipoxygenase activating pro (MMPs), i.e. the stromelysins, collagenases and gelatinases, tein antagonists. 5-Lipoxygenase (5-LO) is one of two as well as aggrecanase, especially collagenase-1 (MMP-1), groups of enzymes which metabolise arachidonic acid, the collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromel other group being the cyclooxygenases, COX-1 and COX-2. ysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromel 25 5-lipoxygenase activating protein is a membrane-bound, ysin-3 (MMP-11); (pp) transforming growth factor (TGFB); arachidonate-binding protein with a size of 18 kDa which (qq) platelet-derived growth factor (PDGF); (rr) fibroblast stimulates the conversion of arachidonic acid in the cell by growth factor, for example basic fibroblast growth factor 5-lipoxygenase. The arachidonic acid is converted into 5-hy (bFGF), (SS) granulocyte macrophage colony stimulating droperoxyeicosatetraenoic acid (5-HPETE), and this route factor (GM-CSF); (tt) capsaicin; (uu) tachykinin NK, and 30 ultimately leads to the production of inflammatory leukot NK receptor antagonists selected from the group consisting rienes; blocking of 5-lipoxygenase activating protein or the of NKP-608C; SB233412 (talnetant) and D4418; and (vv) enzyme 5-lipoxygenase itself therefore represents a desir elastase inhibitors selected from the group consisting of able aim for favourably influencing this route. One of these UT-77 and ZD-0892. 5-lipoxygenase inhibitors is zileuton. The classes of leukot The present invention relates to a combination of a 35 riene synthesis inhibitors which are suitable for the forma compound of the formula I together with one or more tion of therapeutic combinations with the compounds of the additional therapeutic agents for joint administration to a formula I include the following: patient in order to obtain a particularly desired therapeutic (a) redox-active agents, including N-hydroxyureas, N-alky end result. The second, etc. therapeutic agent may likewise lhydroxamide acids, selenite, hydroxybenzofurans, be one or more compounds as described above or one or 40 hydroxylamines and catechol, see Ford-Hutchinson et al., more PDE IV inhibitors known in this art and described in “5-Lipoxygenase'. Ann. Rev. Biochem. 63. 383-417. greater detail here. In particular, the second, etc. therapeutic 1994: Weitzel and Wendel, “Selenoenzymes regulate the agent is selected from a different class of therapeutic agents. activity of leukocyte 5-lipoxygenase via the peroxide These selected combinations are described in greater detail tone'. J. Biol. Chem. 268, 6288–92, 1993: Björnstedt et below. 45 al. “Selenite incubated with NADPH and mammalian In the present connection, the terms joint administra thioredoxin reductase yields selenide, which inhibits tion', 'jointly administered and “in combination with', if lipoxygenase and changes the electron spin resonance they refer to the compounds of the formula I and one or more spectrum of the active site iron, Biochemistry 35, other therapeutic agents, should be taken to mean the 851 1-6, 1996, and Stewart et al., “Structure-activity rela following and do refer to and include the following: 50 tionships of N-hydroxyurea 5-lipoxygenase inhibitors'. J. (a) simultaneous administration of Such a combination of Med. Chem. 40, 1955–68, 1997: one or more compound(s) and a therapeutic agent or a (b) alkylating agents and compounds which react with SH plurality of therapeutic agents to a patient in need of groups have been found to inhibit leukotriene synthesis in treatment if these components are formulated jointly as a vitro; see Larsson et al., “Effects of 1-chloro-2,4,6-trini single dosage form which releases these components to 55 trobenzene on 5-lipoxygenase activity and cellular leu the patient at essentially the same time, kotriene synthesis, Biochem. Pharmacol. 55, 863–71, (b) essentially simultaneous administration of Such a com 1998; and bination of one or more compound(s) and a therapeutic (c) competitive inhibitors of 5-lipoxygenase based on thi agent or a plurality of therapeutic agents to a patient in opyranoindole and methoxyalkyl thiazole structures need of treatment if these components are formulated 60 which act as non-redox inhibitors of 5-lipoxygenase; see separately as separate dosage forms which are taken by Ford-Hutchinson et al., ibid.; and Hamel et al., “Substi the patient at essentially the same time, and the compo tuted (pyridylmethoxy)naphthalenes as potent and orally nents are released to this patient at essentially the same active 5-lipoxygenase inhibitors—synthesis, biological time; profile and pharmacokinetics of L-739,010, J. Med. (c) sequential administration of such a combination of one or 65 Chem. 40, 2866 75, 1997. more compound(s) and a therapeutic agent or a plurality The observation that arachidonic acid hydroxamate inhib of therapeutic agents to a patient in need of treatment if its 5-lipoxygenase has led to the discovery of clinically US 7,129,241 B2 29 30 useful selective 5-lipoxygenase inhibitors, such as the N-hy Abbott-85761 is delivered to the lung by aerosol admin droxyurea derivatives Zileuton and ABT-761, which are istration of a homogeneous, physically stable and virtually shown below: monodisperse formulation; Gupta et al., “Pulmonary deliv ery of the 5-lipoxygenase inhibitor, Abbott-85761, in beagle dogs’, International Journal of Pharmaceutics 147, 207-218, S pi 1997. For the formation of embodiments according to the inven tion, fenleuton, Abbott-79175, Abbott-85761 or any of the 2 N. 10 O above-described derivatives thereof or tepoxalin derivatives are combined with the compounds of the formula I. Zileuton Since the elucidation of the 5-LO biosynthetic pathway, 15 there has been an ongoing debate as to whether it is more advantageous to inhibit the 5-lipoxygenase enzyme or to use antagonists for the peptido- or non-peptidoleukotriene receptors. Inhibitors of 5-lipoxygenase are thought to be Superior to LT receptor antagonists, since 5-lipoxygenase inhibitors. block the action of the entire range of 5-LO r products, whereas the action of LT antagonists is narrower. ABT-761 Nevertheless, embodiments according to the invention include combinations of the compounds of the formula I not 25 Another N-hydroxyurea compound is fenleuton (Abbott only with 5-LO inhibitors, but also with LT antagonists, as 76745): described below. Inhibitors of 5-lipoxygenase having chemi cal structures which differ from the classes of N-hydrox yureas and hydroxamic acids described above are likewise F 30 combined with the compounds of the formula I and thus form further embodiments according to the invention. An example of a different class of this type comprises the O OH N-(5-substituted)-thiophene-2-alkylsulfonamides of the for O Šs s NH2. mula 35 O Fenleuton

Another N-hydroxyurea compound is Abbott-79175 40 ^ -

F in which X is O or S.; R' is methyl, isopropyl. n-butyl, n-octyl or phenyl, and R is n-pentyl, cyclohexyl, phenyl, tetrahydro Oulu 45 1-naphthyl, 1- or 2-naphthyl, or phenyl which is monoSub O O Šs s NH2. stituted or disubstituted by C1, F, Br, CH, OCH SCH, SOCH, CF, or isopropyl. A preferred compound is O Abbott-791.75 50 H N-SO-CH Abbott-79175 has a longer duration of action than zileu ton; S Brooks et al., J. Pharm. Exp. Therapeut 272–724, 1995. S. Yet another N-hydroxyurea compound is Abbott-85761 55 O A more precise description of these compounds is given in Beers et al., “N-(5-substituted) thiophene-2-alkylsulfona 60 mides as potent inhibitors of 5-lipoxygenase'. Bioorganic & Medicinal Chemistry 5(4), 779-786, 1997. Another different class of 5-lipoxygenase inhibitors is the r class of the 2,6-di-tert-butylphenol hydrazones which is 65 described in Cuadro et al., “Synthesis and biological evalu Abbott-85761 ation of 2,6-di-tert-butylphenol hydrazones as 5-lipoxyge nase inhibitors’, Bioorganic & Medicinal Chemistry 6, US 7,129,241 B2 31 32 173–180, 1998. Compounds of this type conform to the aphthalene compounds and various 2-cyanoquinoline com formula pounds which were discovered by Merck Frosst. These two classes of 5-lipoxygenase inhibitors are illustrated by L-739, 010 and L-746,530, respectively:

L-739,010

HO 10 2

15 in which “Het' is benzoxazol-2-yl, benzothiazol-2-yl, pyri din-2-yl, pyrazin-2-yl, pyrimidin-2-yl 4-phenylpyrimidin \ N 2-yl 4,6-diphenylpyrimidin-2-yl 4-methylpyrimidin-2-yl, O 4,6-dimethylpyrimidin-2-yl 4-butylpyrimidin-2-yl, 4.6- L-746,530 dibutylpyrimidin-2-yl and 4-methyl-6-phenylpyrimidin-2- F y1. The N-(5-substituted)-thiophene-2-alkylsulfonamides or the 2,6-di-tert-butylphenol hydrazones or any of the above OH N. described derivatives thereof are combined with the com N a pounds of the formula I mentioned above and thus form 25 O O n embodiments according to the invention. A further different class of 5-lipoxygenase inhibitors is O 2 that of the methoxytetrahydropyrians to which Zeneca ZD-2138 belongs 30 \ N O F Further details concerning L-739,010 and L-746,530 are 35 O. given in Dubé et al., “Quinolines as potent 5-lipoxygenase inhibitors: synthesis and biological profile of L-746.530. Bioorganic & Medicinal Chemistry 8, 1255-1260, 1998, and in WO95/03309 (Friesen et al.). O COr -O The class of the methoxytetrahydropyrans, including Zen 40 eca ZD-2138, or the lead compound SB-210661 and the class to which it belongs, or the series of pyridinyl-substi ZD-2138 tuted 2-cyanonaphthalene compounds, including L-739,010, or the series of 2-cyanoquinoline compounds, including ZD-2138 is highly selective and highly active on oral 45 L-746,530, or any of the above-described derivatives of any administration in various species and has been evaluated in of the above-mentioned classes, are combined with the the treatment of asthma and rheumatoid arthritis by oral compounds of the formula I and thus form embodiments administration. Further details concerning ZD-2138 and according to the invention. derivatives thereof are given in Crawley et al., J. Med. The other endogenous substance which, besides the 5-li Chem., 35, 2600, 1992, and Crawley et al., J. Med. Chem. 50 poxygenase enzyme, plays a significant role in leukotriene 36, 295, 1993. biosynthesis is 5-lipoxygenase activating protein (FLAP). In Another different class of 5-lipoxygenase inhibitors is that contrast to the direct role of the 5-lipoxygenase enzyme, this comprising the SmithKline Beecham compound SB-210661 protein has an indirect role. Nevertheless, antagonists of 5-lipoxygenase activating protein are used to inhibit leukot 55 riene synthesis in the cell and as such they are also used in combination with the compounds of the formula I and thus form embodiments according to the invention. Compounds which bind to 5-lipoxygenase activating pro tein and thus block utilisation of the endogenous pool of 60 arachidonic acid which is present have been synthesised from indole and quinoline structures; see Ford-Hutchinson et al., ibid., Rouzer et al. “WK-886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-chal 65 lenged leukocytes', J. 5 Biol. Chem. 265, 1436–42, 1990, Two further different, related classes of 5-lipoxygenase and Gorenne et al., “{(R)-2-quinolin-2-yl-methoxy)phenyl)- inhibitors comprise various pyridinyl-Substituted 2-cyanon 2-cyclopenty1 acetic acid} (BAY x1005), a potent leukot US 7,129,241 B2 33 34 riene synthesis inhibitor: effects on anti-IgE challenge in of these LTB antagonists is CGS-25019c, which is shown human airways”. J. Pharmacol. Exp. Ther. 268, 868–72. below: 1994. MK-591, with the name quiflipon sodium, conforms to the formula 5 O n NH2.

O 1n 11n O N -( 10 CGS-25O19C S 2 O OntaZolast, a member of a class of benzoxaolamines N N which are LTB antagonists, is described in EP 535 521 15 (Anderskewitz et al.): N

COONa

C MK-591

25 The above-mentioned indole and quinoline classes of compounds, including the specific compounds MK-591, Ontozolast MK-886 and BAY x 1005, or any of the above-described derivatives of any of the above-mentioned classes, are 30 The same working group also discovered a class of combined with the compounds of the formula I and thus benzenecarboximideamides which are LTB antagonists, form embodiments according to the invention. which are described in WO97/21670 (Anderskewitz et al.) and WO 98/11 119 (Anderskewitz et al.) and of which BIIL Combinations with Receptor Antagonists for the Leukot 284/260 is a typical representative: rienes LTB, LTC LTD and LTE 35 A compound of the formula I or a plurality of compounds of the formula I is or are used in combination with receptor antagonists for the leukotrienes LTB, LTC, LTD and HO O -O- LTE. The most significant of these leukotrienes in terms of 40 mediating an inflammatory response are LTB and LTD. NH. Classes of antagonists for the receptors of these leukotrienes are described in the paragraphs which follow. 4-Bromo-2,7-dimethoxy-3H-phenothiazin-3-ones, BIIL 284,260 including L-651,392, are effective LTB antagonists which 45 are described in U.S. Pat. No. 4,939,145 (Guindon et al.) and U.S. Pat. No. 4,845,083 (Lau et al.) Zafirlukast is an LTC LTD and LTE receptor antago nist which is commercially available under the name Acco late R. It belongs to a class of heterocyclic amide derivatives 50 which is described in U.S. Pat. No. 4,859,692 (Bernstein et Br 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. 5,482.963: U.S. Pat. No. 5,583,152 (Bernstein et al.) and U.S. Pat. No. 5,612,367 (Timko et al.): 55 S O. -O L-651,392 60 O

A class of amidino compounds, which includes CGS 25019c, is described in U.S. Pat. No. 5,451,700 (Morrissey 65 Zafirlukast and Suh): U.S. Pat. No. 5.488,160 (Morrissey), and U.S. Pat. No. 5,639,768 (Morrissey and Suh). A typical representative US 7,129,241 B2 35 36 Ablukast is an LTD receptor antagonist which carries the rine, phenylpropanolamine, pseudoephedrine, naphazo designation Ro 23-3544/001: line hydrochloride, oxymetazoline hydrochloride, tet rahydrozoline hydrochloride, Xylometazoline hydrochloride and ethylnorepinephrine hydrochloride; O 5 (h) C- and C2-adrenoreceptor agonists in combination with H inhibitors of 5-lipoxygenase (5-LO); On 11-10 O OH. (i) anticholinergic agents, including ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine and telenZepine; O OH O 10 () - to B-adrenoreceptor agonists, including metaproter enol, isoproterenol, isoprenaline, albuterol, Salbutamol, Ablukast formoterol, Salmeterol, terbutaline, orciprenaline, bitolterol mesylate and pirbuterol: (k) theophylline and aminophylline; Montelukast is an LTD receptor antagonist which is 15 (1) Sodium cromoglycate; commercially available under the name Singulair R and is (m) muscarinic receptor (M1, M2 and M3) antagonists; described in U.S. Pat. No. 5,565,473: (n) COX-1 inhibitors (NSAIDs); COX-2 selective inhibi tors, including rofecoxib, and nitric oxide NSAIDs:

(o) insulin-like growth factor type I (IGF-1) mimetics; (p) ciclesonide; 1xcoon. (q) inhalation glucocorticoids with reduced systemic side

effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticaSone propionate and mometasone 25 furoate: Montekulast (r) tryptase inhibitors; (s) platelet activating factor (PAF) antagonists; (t) monoclonal antibodies against endogenous inflammatory Other LTD receptor antagonists include pranlukast, Ver entities; lukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 30 (u) IPL 576; 45715A) and BAY x 7.195. (v) antitumour necrosis factor (TNFC) agents, including The above-mentioned phenothiazin-3-one class of com etanercept, infliximab and D2E7: pounds, including L-651,392, the class of the amidino (w) DMARDs, including leflunomide: compounds, including CGS-25019c, the class of the ben (x) TCR peptides; ZOxazolamines, which includes ontazolast, the class of the 35 (y) interleukin converting enzyme (ICE) inhibitors; benzenecarboximideamides, which is typified by BIIL 284/ (z) IMPDH inhibitors; 260, the heterocyclic amide derivatives, including (aa) adhesion molecule inhibitors, including VLA-4 antago Zafirlukast, ablukast and montelukast, and the classes of nists; compounds to which they belong, or any of the above (bb) cathepsins: described derivatives of any of the above-mentioned classes, 40 (cc) MAP kinase inhibitors; are combined with the compounds of the formula I and thus (dd) glucose 6-phosphate dehydrogenase inhibitors; form embodiments according to the invention. (ee) kinin B and B receptor antagonists; Combinations with Other Therapeutic Agents (f) gold in the form of an aurothio group together with One or more compounds of the formula I are used various hydrophilic groups; together with other therapeutic agents as well as non 45 (gg) immunosuppressive agents, for example cyclosporine, therapeutic agents and combinations are thus formed which azathioprine and methotrexate; are further embodiments according to the invention and (hh) anti-gout agents, for example colchicine; which are suitable for the treatment of a whole series of (ii) Xanthine oxidase inhibitors, for example allopurinol; different diseases, pathological disorders and conditions (i) uricoSuric agents, for example probenecide, Sulfinpyra described herein. These embodiments include one or more 50 Zone and benzbromarone; compounds of the formula I together with one or more of the (kk) antineoplastic agents, especially antimitotic medica following Substances: ments, including the Vinca alkaloids, Such as vinblastine (a) PDE IV inhibitors: and Vincristine; (b) 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase acti (l) agents for promoting growth hormone secretion; 55 (mm) inhibitors of matrix metalloproteases (MMPs), i.e. the Vating protein (FLAP) antagonists; stromelysins, collagenases and gelatinases, as well as (c) dual inhibitors of 5-lipoxygenase (5-LO) and antagonists aggrecanase, especially collagenase-1 (MMP-1), collage of platelet activating factor (PAF); nase-2 (MMP-8), collagenase-3 (MMP-13), stromel (d) leukotriene antagonists (LTRAS), including LTB, LTC ysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromel LTD and LTE antagonists; 60 ysin-3 (MMP-11): (e) antihistamine H receptor antagonists, including cetiriz (nn) transforming growth factor (TGFB); ine, loratadine, desloratadine, fexofenadine, astemizole, (oo) platelet-derived growth factor (PDGF); aZelastine and chlorpheniramine; (pp) fibroblast growth factor, for example basic fibroblast (f) gastroprotective H2 receptor antagonists; growth factor (bFGF); (g) C- and C2-adrenoreceptor agonist vasoconstrictor sym 65 (qq) granulocyte macrophage colony stimulating factor pathomimetic agents administered orally or topically for (GM-CSF); decongestant use, including propylhexedrine, phenyleph (rr) capsaicin; US 7,129,241 B2 37 38 (SS) tachykinin NK and NK receptor antagonists selected the particular salt form thereof which is being used. Fur from the group consisting of NKP-608C; SB233412 (tal thermore, it is clear to the person skilled in the art that an netant) and D-4418; aqueous Solution of the active ingredient provides the fastest (tt) elastase inhibitors selected from the group consisting of absorption of the active ingredient into the body of a patient UT-77 and ZD-0892, and 5 being treated, while lipid solutions and Suspensions, as well (uu) adenosine A2a receptor agonists. as Solid dosage forms, result in less rapid absorption of the Pharmaceutical Compositions and Fromulations active ingredient. Oral ingestion of an active ingredient of The description which follows relates to the manner in the formula I is the most preferred method of administration which the compounds of the formula I, if desired together for reasons of safety, convenience and economy, but absorp with other therapeutic agents or non-therapeutic agents, are 10 tion of an oral dosage form of this type may be adversely combined with predominantly conventional pharmaceuti affected by physical properties, such as polarity, Vomiting cally acceptable excipients to form dosage forms which are caused by irritation of the gastrointestinal mucous mem suitable for the different methods of administration which brane, degradation by digestive enzymes and low pH, are utilised for any given patient, and appropriate to the 15 irregular absorption or propulsion in the presence of food or disease, pathological disorder or condition for which a given other medicaments, and metabolism by enzymes of the patient is being treated. mucous membrane, the intestinal flora, or the liver. Formu The pharmaceutical compositions according to the inven lation of the active ingredient as different pharmaceutically tion comprise any one or more of the above-described acceptable salt forms may be effective in overcoming or inhibitor compounds according to the invention or a phar alleviating one or more of the above-mentioned problems in maceutically acceptable salt thereof as also described above, connection with the absorption of oral dosage forms. together with a pharmaceutically acceptable excipient in The preferred pharmaceutical salts mentioned above accordance with the properties and expected behaviour of include, but are not limited to, acetate, besylate, citrate, such excipients which are well known to the person skilled fumarate, gluconate, hemisuccinate, hippurate, hydrochlo in the art. 25 ride, hydrobromide, isethionate, mandelate, meglumine, The amount of active ingredient that can be combined nitrate, oleate, phosphonate, pivalate, sodium phosphate, with the excipient materials to form a single dosage form Stearate, Sulfate, Sulfosalicylate, tartrate, thiomalate, tosylate varies depending upon the patient being treated and the and tromethamine. particular method of administration. However, it is clear that a certain dosage and treatment regime for a particular patient 30 If a compound of the formula I contains more than one depends on a wide variety of factors, including the efficacy group which is capable of forming pharmaceutically accept of the particular compound used, the age, body weight, able salts of this type, the invention also covers multiple salts. Typical multiple salt forms include, but are not limited general state of health, sex, the diet, the time of adminis to, bitartrate, diacetate, difumarate, dimeglumine, diphos tration, the excretion rate, medicament combination, and the phate, disodium and trihydrochloride. judgment of the treating physician and the severity of the 35 particular disease being treated. The amount of active ingre The pharmaceutical compositions according to the inven dient may also depend on the therapeutic or prophylactic tion comprise one or more of the above-described inhibitor agent, if any, with which the active ingredient is jointly compounds or a pharmaceutically acceptable salt thereof as administered. also described above, together with a pharmaceutically The compounds of the formula I can be used in the form 40 acceptable excipient in accordance with the properties and of acids, esters, or other chemical classes of compounds to expected behaviour of such excipients which are well known which the compounds described belong. It is also within the to the person skilled in the art. Scope of the present invention to use these compounds in the The term “excipient in the present connection includes form of pharmaceutically acceptable salts derived from acceptable diluents, carriers, adjuvants, constituents, solu various organic and inorganic acids and bases. An active 45 bilisers, viscosity modifiers, preservatives and other agents ingredient comprising a preferred compound is often used in which are well known to the person skilled in the art for the form of one of its salts, in particular if this salt form providing the final pharmaceutical composition with favour provides the active ingredient with improved pharmacoki able properties. In order to illustrate these excipients, there netic properties compared with the free form of the active follows a brief review of pharmaceutically acceptable ingredient or another salt form of the active ingredient used 50 excipients which can be used in the pharmaceutical compo previously. It may also be the case that only the pharma sitions according to the invention, and thereafter a more ceutically acceptable salt form of the active ingredient detailed description of the various types of constituents. provides this active ingredient with a desired pharmacoki Typical excipients include, but are by no means limited to, netic property which it did not previously possess, and may the following: ion exchange compositions, alumina, alu even have a positive effect on the pharmacodynamics of this 55 minium Stearate, lecithin, serum proteins, for example active ingredient with respect to its therapeutic activity in human serum albumin, phosphates, glycine, Sorbic acid, the body. potassium Sorbate, partial glyceride mixtures of Saturated The pharmacokinetic properties of the active ingredient vegetable fatty acids, hydrogenated palm oils, water, salts or which may be favourably affected include, for example, the electrolytes, for example prolamine Sulfate, disodium hydro manner in which this active ingredient is transported through 60 genphosphate, potassium hydrogenphosphate, Sodium chlo cell membranes, which in turn can have a direct and positive ride and Zinc salts, colloidal silica, magnesium trisilicate, effect on the absorption, distribution, biotransformation and polyvinylpyrrolidone, cellulose-based Substances, for excretion of this active ingredient. Although the method of example Sodium carboxymethylcellulose, polyethylene gly administration of the pharmaceutical composition is impor col, polyacrylates, waxes, polyethylene-polyoxypropylene tant, and various anatomical, physiological and pathological 65 block polymers and wool fat. aspects can crucially affect bioavailability, the solubility of In particular, the excipients used in the pharmaceutical the active ingredient is usually dependent on the nature of compositions according to the invention includes various US 7,129,241 B2 39 40 classes and types of additives which are selected indepen effectively remove harmful compounds and metals. These dently from the groups essentially mentioned in the follow include, for example, dipotassium edetate, disodium edetate ing paragraphs. and EDTA. Acidifying and alkalising agents are added to obtain a Dermatological active ingredients are added to the phar desired or predetermined pH; they comprise acidifying maceutical compositions according to the invention where they are to be applied topically; they include, for example, agents, for example acetic acid, glacial acetic acid, malic wound healing agents. Such as peptide derivatives, yeast, acid and propionic acid. Stronger acids, such as hydrochloric panthenol, hexylresorcinol, phenol, tetracycline hydrochlo acid, nitric acid and Sulfuric acid, can be used, but are less preferred. Alkalising agents include, for example, edetol, ride, lamin and kinetin; retinoids for the treatment of skin 10 cancer, for example retinol, tretinoin, isotretinoin, etretinate, potassium carbonate, potassium hydroxide, Sodium borate, acitretin and arotinoid, mild antibacterial agents for the Sodium carbonate and Sodium hydroxide. Alkalising agents treatment of skin infections, for example resorcinol, Salicylic which contain active amino groups, such as diethanolamine acid, benzoyl peroxide, erythromycin-benzoyl peroxide, and trolamine, can also be used. erythromycin and clindamycin; antifungal agents for the Aerosol propellants are required if the pharmaceutical 15 treatment of tinea corporis, tinea pedis, candidiasis and tinea composition is to be delivered as an aerosol under consid versicolor, for example griseofulvin, azoles, such as micona erable pressure. Such propellants include, for example, Zole, econazole, itraconazole, fluconazole and ketoconazole, acceptable chlorofluorocarbons, such as dichlorodifluo and allylamines, such as naftifine and terfinafine; antiviral romethane, dichlorotetrafluoroethane and trichloromonof agents for the treatment of herpes simplex of the skin, luoromethane, nitrogen, a volatile hydrocarbon, such as shingles and chickenpox, for example acyclovir, famciclovir butane, propane or isobutane, or mixtures thereof. and Valacyclovir, antihistamines for the treatment of pruritis, Antimicrobial agents, including antibacterial, antifungal atopic and contact dermatitis, for example diphenhy and antiprotozoal agents, are added if the pharmaceutical dramine, terfenadine, asternizole, loratadine, cetirizine, composition is applied topically to areas of the skin which acrivastine and temelastine, topical anaesthetics for reliev are likely to have been exposed to a harmful environment or 25 ing pain, irritation and itching, for example benzocaine, Sustained abrasions or cuts which makes the skin Susceptible lidocaine, dibucaine and pramoxine hydrochloride, topical to infection by bacteria, fungi or protozoa. Antimicrobial analgesics for relieving pain and inflammation, for example agents include compounds, Such as benzyl alcohol, chlo methyl salicylate, camphor, menthol and resorcinol, topical robutanol, phenylethyl alcohol, phenylmercuric acetate, antiseptics for the prevention of infection, for example potassium Sorbate and Sorbic acid. Antifungal agents include 30 benzalkonium chloride and povidone-iodine, and vitamins compounds, such as benzoic acid, butylparaben, ethylpara and derivatives thereof. Such as tocopherol, tocopherol ben, methylparaben, propylparaben and sodium benzoate. acetate, retinoic acid and retinol. Antimicrobial preservatives are added to the pharmaceu Dispersing and Suspending agents are employed as adju tical compositions according to the invention in order to vants in the preparation of stable formulations and include, protect them against the growth of potentially harmful 35 for example, poligeenan, povidone and silicon dioxide. microorganisms, which usually invade the aqueous phase, Emollients are preferably non-oily, water-soluble sub but in Some cases can also grow in the oil phase of a stances which soften and soothe the skin, especially skin that composition. Thus, preservatives with both aqueous and has become dry due to excessive loss of water. Such lipid solubility are desired. Suitable antimicrobial preserva Substances are used with pharmaceutical compositions tives include, for example, alkyl p-hydroxybenzoates, pro 40 according to the invention which are intended for topical pionate salts, phenoxyethanol, methylparabensodium, pro application; they include, for example, hydrocarbon oils and pylparaben-sodium, Sodium dehydroacetate, benzalkonium waxes, triglyceride esters, acetylated monoglycerides, chloride, benzethonium chloride, benzyl alcohol, hydantoin methyl and other alkyl esters of Co-Co-fatty acids, derivatives, quaternary ammonium compounds and cationic Co-Co-fatty acids, Co-Co-fatty alcohols, lanolin and polymers, imidazolidinylurea, diazolidinylurea and triso 45 derivatives, polyhydric alcohol esters, such as polyethylene glycol (200–600), polyoxyethylene sorbitan fatty acid dium ethylenediamine tetraacetate (EDTA). Preservatives esters, wax esters, phospholipids and sterols; emulsifiers for are preferably employed in amounts of from about 0.01% by the preparation of oil-in-water emulsions; excipients, for weight to about 2.0% by weight of the total composition. example laurocapram and polyethylene glycol monomethyl Antioxidants are added to protect all the constituents of 50 ether, humectants, for example sorbitol, glycerol and hyalu the pharmaceutical composition from damage or degrada ronic acid, ointment bases, for example Vaseline, polyeth tion by oxidants present in the composition itself or in the ylene glycol, lanolin and poloxamer, penetration enhancers, environment in which they are used, for example anoXomer, for example dimethyl isosorbide, diethyl glycol monoethyl ascorbyl palmitate, butylhydroxyanisole, butylhydroxytolu ether, 1-dodecylazacycloheptan-2-one and dimethyl sulfox ene, hypophosphorous acid, potassium metabisulfite, propyl. 55 ide (DMSO); preservatives, for example benzalkonium octyl and dodecyl gallate, sodium metabisulfite, Sulfur diox chloride, benzethonium chloride, alkyl p-hydroxybenzoates, ide and tocopherols. hydantoin derivatives, cetylpyridinium chloride, propylpa Buffer substances are used to maintain a desired pH of a raben, quarternary ammonium compounds, such as potas composition, once established, from the effects of external sium benzoate and thimerosal; sequestering agents, includ influences and equilibrium shifts of constituents of the 60 ing cyclodextrins, solvents, for example acetone, alcohol, compositions. The buffer substance can be selected from amylene hydrate, butyl alcohol, corn oil, cottonseed oil, those known to the person skilled in the art of the prepara ethyl acetate, glycerol, hexylene glycol, isopropyl alcohol, tion of pharmaceutical compositions, for example calcium isostearyl alcohol, methyl alcohol, methylene chloride, min acetate, potassium metaphosphate, potassium dihydrogen eral oil, peanut oil, phosphoric acid, polyethylene glycol, phosphate and tartaric acid. 65 polyoxypropylene 15 Stearyl ether, propylene glycol, pro Chelating agents serve to maintain the ionic strength of pylene glycol diacetate, Sesame oil and purified water, the pharmaceutical composition; they bind to and thereby stabilisers, for example calcium saccharate and thymol. US 7,129,241 B2 41 42 Surfactants, for example lapyrium chloride, laureth 4, i.e. Sequestering agents are used to improve the stability of C-dodecyl-(1)-hydroxy-poly(oxy-12-ethanediyl) or polyeth the pharmaceutical composition according to the invention; ylene glycol monododecyl ether. they include, for example, the cyclodextrins, which are a Emulsifiers, including emulsifying and thickening agents family of natural cyclic oligosaccharides which are capable and emulsion aids, are used for the preparation of oil-in of forming inclusion complexes with a variety of Substances water emulsions if these form the basis of the pharmaceu and are of varying ring size, those having 6, 7 and 8 glucose tical compositions according to the invention. These emul radicals per ring usually being referred to as C-cyclodex sifiers include, for example, non-ionic emulsifiers, such as trins, B-cyclodextrins and Y-cyclodextrins, respectively. Co-Co fatty alcohols and the products of the condensation Suitable cyclodextrins include, for example, C-cyclodextrin, of these fatty alcohols with from 2 to 20 mol of ethylene 10 B-cyclodextrin, Y-cyclodextrin, 6-cyclodextrin and cation oxide or propylene oxide, the product of the condensation of ised cyclodextrins. (C-C)alkylphenols with from 2 to 20 mol of ethylene Solvents which can be used in the preparation of the oxide, mono- and di-Co-Co fatty acid esters of ethylene pharmaceutical compositions according to the invention glycol, Co-Co fatty acid monoglyceride, diethylene glycol, include, for example, acetone, alcohol, amylene hydrate, polyethylene glycols having an MW of 200–6000, polypro 15 butyl alcohol, corn oil, cottonseed oil, ethyl acetate, glyc pylene glycols having an MW of 200–3000 and in particular erol, hexylene glycol, isopropyl alcohol, isbStearyl alcohol, sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethyl methyl alcohol, methylene chloride, mineral oil, peanut oil, ene Sorbitan, hydrophilic wax esters, cetostearyl alcohol, phosphoric acid, polyethylene glycol, polyoxypropylene 15 oleyl alcohol, lanolin alcohols, cholesterol, mono- and dig Stearyl ether, propylene glycol, propylene glycol diacetate, lycerides, glyceryl monostearate, polyethylene glycol sesame oil and purified water. monostearate, mixed mono- and distearic esters of ethylene Stabilisers which are suitable for use include, for glycol and polyoxyethylene glycol, propylene glycol example, calcium saccharate and thymol. monostearate and hydroxypropylcellulose. Emulsifiers Thickening agents are typically used in formulations for which contain active amino groups can also be used; these topical application in order to provide these with the desired typically include anionic emulsifiers, such as fatty acid 25 Viscosity and the desired handling properties; they include, Soaps, for example Sodium, potassium and triethanolamine for example, cetyl ester wax, myristyl alcohol, paraffin, soaps of Co-Co fatty acids, alkali metal, ammonium or synthetic paraffin, emulsifying wax, microcrystalline wax, Substituted ammonium salts of (Co-Co.)alkylsulfate, bleached wax and yellow wax. (Co-Co.)alkylsulfonates and (Co-Cso)alkyl ethoxyether Sugars are frequently used to provide the pharmaceutical sulfonates. Other suitable emulsifiers include castor oil and 30 compositions according to the invention with various hydrogenated castor oil, lecithin; and polymers of 2-prope desired properties and to improve the results achieved; they noic acid together with polymers of acrylic acid, both include, for example, monosaccharides, disaccharides and crosslinked with allyl ethers of sucrose and/or pentaeryth polysaccharides, such as glucose, Xylose, fructose, reose, ritol, having varying viscosities and identified by product ribose, pentose, arabinose, allose, tallose, altrose, mannose, names carbomer 910, 934, 934P 940, 941 and 1342. Cat 35 galactose, lactose. Sucrose, erythrose, glyceraldehyde, or ionic emulsifiers which contain active amino groups may any combinations thereof. also be used, including those based on quaternary ammo Surfactants are used to provide multi-component pharma nium, morpholinium and pyridinium compounds. Similarly, ceutical compositions according to the invention with sta amphoteric emulsifiers which contain active amino groups, bility, to enhance existing properties of these compositions, Such as cocobetaines, lauryldimethylamine oxide and 40 and to provide the compositions with new desired proper cocoylimidazoline, can be used. Emulsifiers and thickening ties. Surfactants are used as wetting agents, antifoams, for agents that can be used also include cetyl alcohol and reducing the Surface tension of water, and as emulsifiers, Sodium Stearate, and emulsion aids, such as oleic acid, dispersants and penetration enhancers; they include, for Stearic acid and Stearyl alcohol. example, lapyrium chloride; laureth 4, i.e. C-dodecyl-(r)- 45 hydroxypoly(oxy-12-ethanediyl) or polyethylene glycol Excipients include, for example, laurocapram and poly monododecyl ether, laureth 9, i.e. a mixture of polyethylene. ethylene glycol monomethyl ether. glycol monododecyl ethers having an average of 9 ethylene If the pharmaceutical composition according to the inven oxide groups per molecule, monoethanolamine, nonoxynol tion is to be applied topically, penetration enhancers can be 4, 9 and 10, i.e. polyethylene glycol mono(p-nonylphenyl) used, including, for example, dimethyl isosorbide, diethyl 50 ether, nonoxynol 15, i.e. C-(p-nonylphenyl)-p-hydroxypen glycol monoethyl ether, 1-dodecylazacycloheptan-2-one and tadecatoxyethylene), nonoxynol 30, i.e. C-(p-nonyl-phe dimethyl sulfoxide (DMSO). Such compositions typically nyl)-()-hydroxytriacontaCoxyethylene), poloxalene, i.e. non also comprise ointment bases, for example Vaseline, poly ionic polymer of the polyethylenepolypropylene glycol type, ethylene glycol, lanolin and poloxamer, which is a polyoxy MW-approx. 3000, poloxamer, referred to above in the ethylene-polyoxypropylene block copolymer, which may 55 discussion of ointment bases, polyoxyl (8), (40) and (50) also serve as Surfactant or emulsifier. Stearate, i.e. poly(oxy-12-ethanediyl), C.-hydro-()-hydroxy Preservatives are used to protect pharmaceutical compo octadecanoate, polyoxyl 10 oleyl ether, i.e. poly(oxy-1,2- sitions according to the invention against degradation by ethane-diyl), C.-(Z)-9-octadecenyl-(o-hydroxy-, polysorbate ambient microorganisms, and include, for example, benza 20, i.e. Sorbitan, monododecanoate, poly(oxy-1,2- lkonium chloride, benzethonium chloride, alkyl p-hydroxy 60 ethanediyl), polysorbate 40, i.e. Sorbitan, monohexade benzoates, hydantoin derivatives, cetylpyridinium chloride, canoate, poly(oxy-12-ethanediyl), polysorbate 60, i.e. Sor monothioglycerol, phenol, phenoxyethanol, methylparaben, bitan, monooctadecanoate, poly(oxy-12-ethanediyl). imidazolidinylurea, Sodium dehydroacetate, propylparaben, polysorbate 65, i.e. Sorbitan, trioctadecanoate, poly(oxy-1, quaternary ammonium compounds, especially polymers, 2-ethanediyl), polysorbate 80, i.e. sorbitan, mono-9-octade Such as polixetonium chloride, potassium benzoate, sodium 65 cenoate, poly(oxy-12-ethanediyl), polysorbate 85, i.e. Sor formaldehyde Sulfoxylate, sodium propionate and thimero bitan, tri-9-octadecenoate, poly(oxy-12-ethanediyl). sal. Sodium lauryl Sulfate, Sorbitan monolaurate, Sorbitan US 7,129,241 B2 43 44 monooleate, Sorbitan monopalmitate, Sorbitan monostearate, excipients which are frequently used include lactose and Sorbitan sesquioleate, Sorbitan trioleate and Sorbitan tristear corn Starch. Lubricants. Such as magnesium Stearate, are also ate. typically added. In the case of oral administration in capsule The pharmaceutical compositions according to the inven form, useful diluents include lactose and dried corn starch. tion are prepared in an extremely simple manner as is well If aqueous solutions are to be used orally, the active ingre known to the average person skilled in the art. If the dient is combined with emulsifiers and Suspension media. If pharmaceutical compositions according to the invention are desired, certain Sweeteners, flavours or dyes can also be simple aqueous solutions or solutions in other solvents, the added. However, the pharmaceutical compositions accord various constituents of the overall composition are com ing to the invention can also be administered in the form of bined in any desired practical sequence, which is determined 10 Suppositories for rectal administration. Such Suppositories principally by considerations of convenience. The constitu can be produced by mixing the agent with a Suitable non ents that have lower solubility in water, but adequate solu irritating excipient which is solid at room temperature, but bility in the same auxiliary solvent with water, can all be liquid at the rectal temperature and therefore melts in the dissolved in this auxiliary solvent, after which the auxiliary rectum and thus releases the medicament. These substances solution is added to the water content of the excipient, 15 include cocoa butter, beeswax and polyethylene glycols. causing the Substances dissolved therein to dissolve in the The pharmaceutical compositions according to the inven water. To support this dispersion process or dissolution tion can also be administered topically, in particular if areas process, a Surfactant can be employed. or organs that are readily accessible by topical application If the pharmaceutical compositions according to the form the target of treatment, including eye diseases, skin invention are to be in the form of emulsions, the constituents diseases, or diseases of the lower digestive tract. Suitable of the pharmaceutical composition are combined in accor topical formulations can easily be prepared for these areas or dance with the following general procedures. The continu Organs ous water phase is firstly heated to a temperature in the range Topical application for the lower intestinal tract can be from about 60° C. to about 95°C., preferably from about 70° effected as a rectal Suppository formulation, as described C. to about 95°C., with the choice of temperature used 25 above, or in the form of a suitable enema formulation. depending on the physical and chemical properties of the Topically active transdermal patches can likewise be used. constituents which form the oil-in-water emulsion. As soon For topical application, the pharmaceutical compositions as the continuous water phase has reached the selected can be formulated as a Suitable ointment comprising the temperature, the constituents of the final composition which active constituent Suspended or dissolved in one or more are to be added at this stage are mixed with the water with 30 excipients. Excipients for topical administration of the com vigorous stirring and dispersed therein. Next, the tempera pounds according to the invention include, but are not ture of the water is restored approximately to the initial limited to, mineral oil, paraffin oil, white Vaseline, propylene level, after which the constituents of the composition which glycol, polyoxyethylene-polyoxypropylene compound, form the next step are added to the composition mixture with emulsifying wax and water. However, the pharmaceutical moderate stirring, and mixing is continued for from about 5 35 compositions can also be formulated as a suitable lotion or to about 60 minutes, preferably from about 10 to about 30 cream comprising the active constituents Suspended or dis minutes, depending on the constituents of the first two steps. Solved in one or more pharmaceutically acceptable excipi The composition mixture is then passively or actively cooled ents. Suitable excipients include, but are not limited to, to from about 20° C. to about 55° C. in order that further mineral oil, Sorbitan monostearate, polysorbate, cetyl ester components can be added in the remaining steps, after which 40 wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and sufficient water is added that the originally determined Water. concentration in the overall composition is reached. Pharmaceutical compositions to which the present com In accordance with the present invention, the pharmaceu pound extends also include those in which the therapeuti tical compositions can be in the form of a sterile injection cally effective amount of an active ingredient comprising a preparation, for example a sterile aqueous or oil-based 45 compound of the formula I which is required for the treat Suspension for injection. This suspension can be formulated ment or prevention of diseases, pathological disorders and in accordance with techniques known in the art using conditions which are mediated by or associated with modu Suitable dispersants, wetting agents and Suspension media. lation of PDE IV activity as described herein is provided in The sterile injection preparation can also be a sterile solution a dosage form which is Suitable for systemic administration. or Suspension for injection in a non-toxic parenterally 50 A pharmaceutical composition of this type comprises the acceptable diluent or solvent, for example in the form of a active ingredient in a suitable liquid form for delivery by: (1) Solution in 1,3-butanediol. Acceptable constituents and Sol injection or infusion, be it intraarterially, intra- or transder vents which can be used include water, Ringer's solution and mally, Subcutaneously, intramuscularly, intraspinally, isotonic saline Solution. In addition, sterile stabilised oils are intrathecally or intravenously, where the active ingredient usually used as solvent or Suspension medium. For this 55 (a) is in the form of a dissolved substance in solution, (b) is purpose, any mild stabilised oil, including synthetic mono present in the discontinuous phase of an emulsion or in the or diglycerides, can be used. Fatty acids, such as oleic acid discontinuous phase of an emulsion with phase reversal, in and its glyceride derivatives, are suitable for the preparation which the phase inverts on injection or infusion, where of injectables, as are natural pharmaceutically acceptable emulsions of this type comprise Suitable emulsifiers, or (c) oils, such as olive oil or castor oil, in particular in the form 60 is present as a suspended Solid in colloidal or microparticu of their polyethoxylates. These oil solutions or Suspensions late form in a Suspension, where this Suspension comprises can also contain a long-chain alcohol. Such as RH, HCIX or Suitable Suspension media, (2) injection or infusion into a similar alcohol, as diluent or dispersant. suitable body tissues or cavities as a depot, where the The pharmaceutical compositions according to the inven composition stores the active ingredient and Subsequently tion can be administered orally in any orally acceptable 65 releases it for systemic distribution in the form of a delayed dosage form, including, but not limited to, capsules, tablets, release, Sustained release or controlled release, (3) instilla aqueous Suspensions or solutions. In the case of oral tablets, tion, inhalation or insufllation of the pharmaceutical com US 7,129,241 B2 45 46 position in a suitable solid form into suitable body tissues or delayed release, Sustained release or controlled release, cavities, where the active ingredient (a) is present in a Solid where the composition also comprises constituents which implant of the composition which ensures release of the ensure that the active ingredient primarily acts locally and active ingredient in the form of delayed release, Sustained causes little systemic carryover, or where the pharmaceutical release or controlled release, (b) is present in a particulate composition comprises the active ingredient in a Suitable composition which is inhaled into the lungs, or (c) is present solid form for delivery of the inhibitor by the following in a particulate composition which is blown into Suitable method: (3) instillation, inhalation or insufflation at this body tissues or cavities, where the composition is, if desired, local site, where the active ingredient is present in: (a) a solid ready for the release of the active ingredient in the form of implant of the composition which is implanted at this local delayed release, Sustained release or controlled release, or 10 site, where the composition releases the active ingredient to (4) ingestion of the pharmaceutical composition in a suitable the said local site optionally in the form of delayed release, solid or liquid form for peroral delivery of the active Sustained release or controlled release, (b) in a particulate ingredient, where the active ingredient is present in a Solid composition which is inhaled into a local site, also including dosage form, or (b) is present in a liquid dosage form. the lungs, or (c) in a particulate composition which is blown Individual dosage forms of the above-described pharma 15 into a local site, where the composition comprises constitu ceutical compositions include (1) Suppositories as a special ents which ensure that the active ingredient primarily acts type of implant, comprising bases which are solid at room locally, with insignificant systemic carryover, and optionally temperature, but melt at body temperature and thus slowly releases the active ingredient locally in the form of delayed release the active ingredient they contain into the Surround release, Sustained release or controlled release. For oph ing body tissue, where the active ingredient is absorbed and thalmic use, the pharmaceutical compositions can be for transported to effect systemic administration, (2) Solid per mulated as micronised Suspension in isotonic, pH adjusted oral dosage forms selected from the group consisting of (a) sterile Saline solution, or, preferably, as solutions in isotonic, delayed-release oral tablets, capsules, caplets, lozenges, pH adjusted sterile saline solution, with or without preser troches and multiparticulates, (b) enteric-coated tablets and vatives, such as benzylalkonium chloride. Alternatively, for capsules which prevent release and absorption in the stom 25 ophthalmic use, the pharmaceutical compositions can be ach and thus enable delivery distal to the stomach of the formulated in an ointment, Such as Vaseline. patient being treated, (c) Sustained-release oral tablets, cap The pharmaceutical compositions according to the inven Sules and microparticulates which provide systemic release tion can also be administered by nasal aerosol or inhalation of the active ingredient in a controlled manner over a period using a nebuliser, dry powder inhaler or dispensing inhaler. of up to 24 hours, (d) fast-disintegrating tablets, (e) encap 30 Such compositions are prepared by techniques which are Sulated Solutions, (f) oral pastes, (g) granules incorporated well known in pharmaceutical formulation and can be into the food of a patient being treated, and (h) liquid peroral prepared in the form of solutions in saline solution with dosage forms selected from the group consisting of solu benzyl alcohol or other suitable preservatives, absorption tions, Suspensions, emulsions, inverse emulsions, elixirs, promoters for improving bioavailability, fluorohydrocarbons extracts, tinctures and concentrates. 35 and/or other conventional solubilising agents or dispersants. Pharmaceutical compositions to which the present com As already mentioned, the compounds of the formula I pound extends also include those in which the therapeuti according to the invention can be administered systemically cally effective amount of an active ingredient comprising a to a patient to be treated in the form of a pharmaceutical compound according to the invention which is required for composition in a suitable liquid form by injection or infu the treatment or prevention of diseases, pathological disor 40 Sion. There are various sites and organ systems in the body ders and conditions which are mediated by or associated of the patient which will allow the correctly formulated with modulation of PDE IV activity as described herein is pharmaceutical composition, as soon as it has been injected provided in a dosage form which is suitable for local or infused, to permeate the entire body and all organ systems administration to a patient being treated, where a pharma of the patient being treated. An injection is a single dose of ceutical composition of this type comprises the active ingre 45 the pharmaceutical composition forced, usually by means of dient in a suitable liquid form for delivery of the active a syringe, into the relevant tissue. The most frequent types ingredient by (1) local injection or infusion, be it intraarte of injection are intramuscular, intravenous and Subcutane rially, intraarticularly, intrachondrially, intracostally, intrac ous. By contrast, an infusion is the gradual introduction of ySticly, intra- or transdermally, intrafascicularly, intraliga the pharmaceutical composition into the relevant tissue. The mentously, intramedullarly, intramuscularly, intranasally, 50 most frequent type of infusion is intravenous. Other types of intraneurally, intraocularly, i.e. ophthalmic administration, injection or infusion include intraarterial, intra- or transder intraosteally, intrapelvicly, intrapericardially, intraspinally, mal (including Subcutaneous), or intraspinal, in particular intrasternally, intrasynovially, intratarsally or intrathecally, intrathecal. In these liquid pharmaceutical compositions, the also including constituents which ensure delayed release, active ingredient may be in the form of a dissolved Substance controlled release or Sustained release of the active ingre 55 in solution. This is the commonest and most preferred type dient into this local site; where the active ingredient (a) is in of Such a composition, but requires an active ingredient in a the form of a dissolved substance in solution, (b) is present salt form that has reasonably good solubility in water. Water in the discontinuous phase of an emulsion or in the discon (or saline solution) is by far the most preferred solvent for tinuous phase of an emulsion with phase reversal, in which Such compositions. Occasionally Supersaturated solutions the phase inverts on injection or infusion, where emulsions 60 can be used, but these present stability problems and are of this type comprise Suitable emulsifiers, or (c) is present as therefore impractical for everyday use. a Suspended solid in colloidal or microparticulate form in a If it is not possible to obtain a preferred compound in a Suspension, where this suspension comprises suitable Sus form which has the requisite solubility in water, as is pension media, or (2) is in the form of an injection or Sometimes the case, it is within the skill of the average infusion as a depot for release of the active ingredient at the 65 person skilled in the art to prepare an emulsion, which is a local site, where the composition stores the active ingredient dispersion of Small droplets of a liquid, the discontinuous or and subsequently releases it to the local site in the form of internal phase, in a second liquid, the continuous or external US 7,129,241 B2 47 48 phase, with which it is immiscible. The two liquids are kept sition comprising the active ingredient. For example, the in the emulsified State by pharmaceutically acceptable emul active ingredient in powder form may be inhaled into the sifiers. If the active ingredient is a water-insoluble oil, it can lungs using conventional devices for aerosol formation of therefore be administered in an emulsion in which it forms particulate formulations. The active ingredient as a particu the discontinuous phase. If the active ingredient is water late formulation can also be administered by insufflation, i.e. insoluble, but can be dissolved in a water-immiscible sol blown or otherwise dispersed into suitable body tissues or vent, an emulsion can likewise be used. Although the active cavities by simple dusting or using conventional devices for ingredient would most frequently be used as the discontinu aerosol formation of particulate formulations. These particu ous or internal phase of a so-called oil-in-water emulsion, it late compositions can likewise be formulated in accordance could also be used as the discontinuous or internal phase of 10 with well-known principles and with known materials to an emulsion with phase reversal, which is usually referred to give an active ingredient with delayed release, Sustained as a water-in-oil emulsion. Here, the active ingredient is release or controlled release. soluble in water and could be administered as a simple aqueous solution. However, emulsions of this type with Other means of systemic administration, in which the phase reversal reverse on injection or infusion into an 15 active ingredients according to the invention are used either aqueous medium, Such as the blood, and offer the advantage in liquid or solid form, include the transdermal, intranasal of faster and more efficient dispersion of the active ingre and ophthalmic methods of administration. In particular, dient into this aqueous medium than on use of an aqueous transdermal patches can be produced by techniques known Solution. Emulsions with phase reversal are prepared using in medicament delivery and applied to the skin of the patient Suitable pharmaceutically acceptable emulsifiers that are to be treated, after which the active ingredient, owing to its known in the art. formulated solubility properties, migrates through the epi If the active ingredient has limited water solubility, it can dermis and into the dermal layers of the patient’s skin, where also be administered as a suspended solid in colloidal or it is taken up as part of the general circulation of the patient finely divided form in a suspension prepared using Suitable and finally and ultimately results in systemic distribution of pharmaceutically acceptable Suspension media. The Sus 25 the active ingredient over a desired, extended period of time. pended solids comprising the active ingredient may also be These also include implants which are placed beneath the formulated as delayed release, Sustained release or con epidermal layer of the skin, i.e. between the epidermis and trolled release compositions. the dermis of the skin of the patient being treated. Such an Although systemic administration is most frequently car implant is formulated in accordance with well-known prin ried out by injection or infusion of a liquid, there are many 30 ciples and materials which are frequently used in this situations in which it is advantageous or even necessary to delivery technique, and can be produced in Such a way that deliver the active ingredient as a solid. Systemic adminis the active ingredient is delivered into the systemic circula tration of solids is carried out by instillation, inhalation or tion of the patient in accordance with the principle of insufflation of a pharmaceutical composition in a suitable controlled release, Sustained release or delayed release. Solid form comprising the active ingredient. Instillation of 35 Subepidermal (subcuticular) implants of this type can be the active ingredient may entail inserting a solid implant of used just as easily as transdermal patches and offer the same the composition into suitable body tissues or cavities. The effective delivery, but without being subjected to the deg implant may comprise a matrix of biocompatible and bio radation, damage or accidental removal as a consequence of degradable Substances in which particles of a solid active the patch being exposed on the outermost layer of the ingredient are dispersed, or in which droplets or isolated 40 patient’s skin. cells of a liquid active ingredient may possibly be included. In the above description of pharmaceutical compositions The matrix should wherever possible be broken down and comprising a preferred compound, the equivalent expres completely absorbed by the body. The composition of the sions “administration”, “administration of, “administering matrix is also preferably selected so as to provide controlled and “administer a have been used with respect to these release, Sustained release or delayed release of the active 45 pharmaceutical compositions. In the present connection, ingredient over extended periods of time, even several these expressions are intended to mean that a patient in need months. of treatment is provided with a pharmaceutical composition The term “implant usually refers to a solid pharmaceu according to the invention by any of the methods of admin tical composition comprising the active ingredient, while the istration described here, where the active ingredient is a term “depot usually denotes a liquid pharmaceutical com 50 preferred compound or a prodrug, a derivative or a metabo position comprising the active ingredient, which is deposited lite thereof which is suitable for the treatment of a disease, in any Suitable body tissue or any Suitable body cavity and pathological disorder or condition which is mediated by or thus forms a reservoir or pool which slowly migrates into the associated with modulation of PDE IV activity in this Surrounding tissue and organs and finally and eventually is patient. The present invention therefore extends to any other systemically distributed. However, these distinctions are not 55 compound which, on administration to a patient, is capable always handled strictly in the art, and it is therefore intended of directly or indirectly making a preferred compound that the scope of the present invention also extends to liquid available. Such compounds are known as prodrugs, and a implants and Solid depots, and even solid and liquid mixed large number of established procedures exist for the prepa forms in each case. Suppositories can be regarded as a type ration of Such prodrug forms of the preferred compounds. of implant, since they comprise bases which are solid at 60 The dose or dosage of the for the treatment or prevention room temperature, but melt at a patient's body temperature of a disease, pathological disorder or condition which is and thus slowly release the active ingredient with which they mediated by or associated with modulation of PDE IV are provided into the Surrounding tissue of the patients activity depends on a variety of factors, such as the nature body, where the active ingredient is absorbed and trans of the inhibitor, the size of the patient, the aim of the ported away and is thus administered systemically. 65 treatment, the nature of the pathology to be treated, the Systemic administration can also be carried out by inha pharmaceutical composition used in each case and the lation or insufllation of a powder, i.e. a particulate compo observations and conclusions of the treating physician. US 7,129,241 B2 49 50 In the case of an oral dosage form, for example a tablet or The invention also relates to a set (kit) consisting of capsule, Suitable doses of the compounds of the formula I separate packs of are between about 0.1 g of active ingredient/kg and about (a) an effective amount of a compound of the formula I 50.0 mg of active ingredient/kg of body weight per day, and/or pharmaceutically usable derivatives, Solvates and preferably between about 5.0 g of active ingredient/kg and 5 stereoisomers thereof, and mixtures thereof in all ratios, about 5.0 mg of active ingredient/kg of body weight per day, and more preferably between about 10.0 ug of active ingredient/ (b) an effective amount of a further medicament active kg and about 1.0 mg of active ingredient/kg of body weight ingredient. per day, most preferably between about 20.0 ug of active ingredient/kg and about 0.5 mg of active ingredient/kg of 10 The set comprises suitable containers, such as boxes, body weight per day. individual bottles, bags or ampoules. The set may, for example, comprise individual ampoules each containing an If the dosage form is administered topically to the bron effective amount of a compound of the formula I and/or chia and lungs, for example by means of a powder inhaler pharmaceutically usable derivatives, Solvates and stereoiso or nebuliser, suitable doses of the compounds are between 15 mers thereof, including mixtures thereof in all ratios, and an about 0.001 g of active ingredient/kg and about 10.0 mg of effective amount of a further medicament active ingredient active ingredient/kg of body weight per day, preferably in dissolved or lyophilised form. between about 0.5g of active ingredient/kg and about 0.5 mg of active ingredient/kg of body weight per day, more All temperatures above and below are given in C. In the preferably between 1.0 g of active ingredient/kg and about examples which follow, “conventional work-up” means: 0.1 mg of active ingredient/kg of body weight per day, most water is added if necessary, the pH is adjusted, if necessary, preferably between about 2.0 g of active ingredient/kg and to between 2 and 10, depending on the constitution of the about 0.05 mg of active ingredient/kg of body weight per end product, the mixture is extracted with ethyl acetate or day. dichloromethane, the phases are separated, the organic phase In order to explain the range of the daily oral dose that 25 is dried over sodium sulfate and evaporated, and the product could be used as described above and with the aid of a is purified by chromatography on silica gel and/or by typical body weight of 10 kg and 100 kg, suitable doses of crystallisation. the compounds of the formula I are between about 1.0–10.0 ug and 500.0–5000.0 mg of the active ingredient comprising 30 a preferred compound per day, preferably between about Mass spectrometry (MS) (electron impact ionisation) M' 50.0 and 500.0 ug and 50.0–500.0 mg of the active ingre FAB (fast atom bombardment) (M + H)" dient comprising a preferred compound per day, more pref erably between about 100,0–1000.0 ug and 10.0-100.0 mg of an active ingredient comprising a preferred compound per day, most preferably between about 2000–20,000 ug and 35 EXAMPLE 1. about 5.0–500 mg of the active ingredient comprising a preferred compound per day. These dosage. ranges represent 1.1 5.0 g of Z-Tyr(tBu)-OSu (2) are added to a solution of total doses of the active ingredient per day for a particular 2.5 g of (1) in 25 ml of pyridine at room temperature, and patient. The number of times per day that a dose is admin the mixture is stirred for a further 16 hours. The mixture is istered depends on pharmacological and pharmacokinetic 40 poured into 500 ml of ice-water and subjected to conven factors, such as the half-life of the active ingredient, which tional work-up, giving, after chromatography on silica gel reflects its rate of catabolism and clearance, as well as the (ethyl acetate/petroleum ether 2:1), 6.27 g of the compound minimum and optimum blood plasma level or other body I-A-1 (see Table 1). fluid levels of the active ingredient in a patient that are necessary for therapeutic efficacy. 45 1.2 Conventional ether cleavage and work-up gives I-A-2. When determining the number of doses per day and the 1.3 Reaction of I-A-2 with chloroethanol in DMF with amount of active ingredient per dose that will be adminis addition of potassium carbonate with stirring for 4 hours and tered, numerous other factors must also be considered. conventional work-up gives the compound I-A-3. Another Such factor is not least the particular response of the 1.493 mg of I-A-3 is hydrogenated under conventional patient being treated. Thus, for example, if the active ingre 50 conditions in 30 ml of methanol and 93 mg of Pd/C catalyst. dient is used for the treatment or prevention of asthma on After the catalyst has been separated off, removal of the topical administration via aerosol inhalation into the lungs, solvent gives 59 mg of I-A-4. from one to four doses consisting of actuations of a dis pensing device, i.e. "puffs' of an inhaler, are administered Compounds of the Formula I-A per day, each dose comprising from about 50.0 ug to about 55 10.0 mg of active ingredient. I-A The invention furthermore also relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically usable derivatives, Solvates and stereoiso mers thereof, mixtures thereof in all ratios, and, if desired, excipients and/or adjuvants. The invention furthermore also relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically usable derivatives, Solvates and stereoiso 65 mers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient. US 7,129,241 B2 51 52 evaporated in a Genevac(R), evaporated, and the residue is TABLE 1. purified via HTP, giving 0.053 g of I-A-11. The compounds of the formula I-A have the 3.5 Analogously to 3.4, reaction of I-A-10 with pyridine S configuration, unless stated otherwise. 4-carbaldehyde gives the compound I-A-12. No. Ra Rb Notes EXAMPLE 4 -A-1 Benzyloxycarbonyl tert-Butyl -A-2 Benzyloxycarbonyl H -A-3 Benzyloxycarbonyl CHCH-OH 4.1 3.3 g of DAPECI N-(3-dimethylaminopropyl)-N- -A-4 H CHCH-OH 10 ethylcarbodiimide and 1.7 g of NMM (N-methylmorpho -A-5 Benzyloxycarbonyl CHCH-NMe, -A-6 CHCHNMe, CHCHNMe, line) are added to a solution of 5.0 g of BOC-D-TyrMe)-OH -A-7 H CHCH-NMe, (4) and 2.6 g of HOBt in 10 ml of DMF. The mixture is -A-8 Fmoc tert-Butyl -A-9 H tert-Butyl stirred at room temperature for 4 hours, 3.9 g of (1) are -A-10 H H 15 introduced, and the mixture is stirred for a further 16 hours. -A-11 Benzyl H A further equivalent of DAPECI is added, and the mixture -A-12 Pyridine-4-methyl H -A-13 BOC CH R configuration is stirred at room temperature for a further 16 hours. -A-14 BOC CH Conventional work-up gives 8.1 g of I-A-13. -A-15 CH-CO— tert-Butyl 4.23.3 g of DAPECI and 1.7 g of NMM are added to a -A-16 CH-CO— H solution of 5.0 g of BOC-Tyr(Me)-OH (5) and 2.6 g of HOBt in 10 ml of DMF. The mixture is stirred at room temperature for 4 hours, 3.9 g of (1) are introduced, and the mixture is EXAMPLE 2 stirred for a further 16 hours. A further equivalent of 25 DAPECI is added, and the mixture is stirred at room 2.1 A solution of 1.06 g of I-A-2, 290 mg of 1-chloro-2- temperature for a further 16 hours. Conventional work-up (N,N-dimethylamine)ethane hydrochloride and 2 g of potas gives 7.0 g of I-A-14. sium carbonate in 5 ml of DMF is stirred at room tempera ture for 50 hours and stirred at 100° for 16 hours. The 4.3 0.36 ml of POCl is added with stirring and ice mixture is subjected to conventional work-up, and the resi cooling to a solution of 0.8 g of (1) and 1.0 g of Ac-Tyr due is purified via HTP (high throughput purifier; flash 30 (tPu)-OH (6) in 10 ml of pyridine. The mixture is stirred at chromatography), giving 287 mg of I-A-5 and 21 mg of room temperature for a further 16 hours. The pyridine is I-A-6 (Table 1). removed under reduced pressure, the mixture is poured into 2.2 287 mg of I-A-5 is hydrogenated under conventional ice-water and Subjected to conventional work-up, and the conditions in 5g of THF and 400 mg of Pd/C catalyst. After 35 residue is purified over silica gel (ethyl acetate/petroleum the catalyst has been separated off, removal of the solvent ether 1:1), giving 0.3 g of I-A-15. gives 159 mg of I-A-7. 4.4A solution of 1.0 g of I-A-15 and 5 ml of TFA in 20 ml of dichloromethane is stirred at room temperature for 1 EXAMPLE 3 hour. The TFA and the DCM are removed, and the residue 40 is Subjected to conventional work-up, giving 0.8g of I-A-16. 3.11.1 ml of POCl are added with stirring and ice cooling to a solution of 2.6 g of (1) and 5.0 g of Fmoc-Tyr EXAMPLE 5 (tBu)-OH (3) in 30 ml of pyridine. The mixture is stirred at room temperature for a further 16 hours. The pyridine is 45 5.1 0.38 ml of POCl is added with stirring and ice removed under reduced pressure, the mixture is poured into cooling to a solution of 0.9 g of (1) and 1.0 g of BOC-B- ice-water and Subjected to conventional work-up, and the (3-pyridyl)-D-Ala-OH (7) in 10 ml of pyridine. The mixture residue is purified over silica gel (ethyl acetate/petroleum is stirred at room temperature for a further 16 hours. The ether 1:1), giving 2.3 g of I-A-8. pyridine is removed under reduced pressure, the mixture is 3.2 Removal of the Fmooc protecting group from I-A-8 is 50 poured into ice-water and Subjected to conventional work carried out under conventional conditions with modified up, and the residue is purified by means of flash chroma polystyrene resin (piperazinomethyl-PS). 2.3 g of starting tography (ethyl acetate/methanol gradient 0-20%), giving material give 1.4 g of I-A-9. 0.4 g of I-B-1 (see Table 2). 3.31 ml of trifluoroacetic acid is added to a solution of 55 Compounds of the Formula I-B 454 mg of I-A-9 in 3 ml of dichloromethane, and the mixture is stirred at room temperature for 16 hours. The acid and solvent are removed, the residue is dissolved in DCM. 1 g of polymer-bound bicarbonate is added, and the mixture is stirred for 16 hours. 60 After the polymer has been separated off, removal of the solvent gives 303 mg of I-A-10. 3.4 100 mg of polymer-bound cyanoborohydride are added to a solution of 80 mg of I-A-10, 0.021 ml of benzaldehyde and 0.3 ml of acetic acid in 3 ml of dichlo 65 romethane, and the mixture is stirred at room temperature for 16 hours. The polymer is removed, the mixture is US 7,129,241 B2 53 54 flat-base microtitre plates. The cultures are prepared in TABLE 2 triplicate, including a control group. Solutions of the com pounds of the formula I in DMSO are prepared in a The compounds of the formula I-B have the R configuration, unless stated otherwise. concentration of 10 M and diluted with culture medium. The control cultures are treated with DMSO concentrations No. Ra Rb Notes corresponding to the inhibitor concentrations. I-B-1 BOC 3-Pyridyl The culture Supernatants from three independent experi I-B-2 H 3-Pyridyl ments are pooled, and the cytokine activity in the Superna I-B-3 BOC 4-Pyridyl I-B-4 H 4-Pyridyl 10 tant is measured using commercially available ELISA test kits. The data are calculated as percentage inhibition/stimula 5.2 A solution of 0.4 g of I-B-1 and 1 ml of TFA in 4 ml tion of the control without the compound, and the ICso value of dichloromethane is stirred at room temperature for 16 or ECso value during the stimulation is determined there hours. The TFA and the DCM are removed, and the residue 15 from. is Subjected to conventional work-up, giving 164 mg of I-B-2. The example below relate to pharmaceutical preparations: 5.3 0.8g of DAPECI and 0.43 ml of NMM are added to EXAMPLEA a solution of 1.0 g of BOC-D-4-pyridylalanine (8) and 0.6 g. of HOBt in 5 ml of DMF. The mixture is stirred at room Injection Vials temperature for 4 hours, 0.9 g of (1) is introduced, and the mixture is stirred for a further 16 hours. Conventional A solution of 100 g of an active ingredient of the formula work-up gives 0.4 g of I-B-3. I and 5 g of disodium hydrogenphosphate in 31 of bidistilled 5.4 A solution of 0.35 g of I-B-3 and 1 ml of TFA in 10 25 water is adjusted to pH 6.5 using 2N hydrochloric acid, ml of dichloromethane is stirred at room temperature for 1 sterile filtered, transferred into injection vials, lyophilised hour. The TFA and the DCM are removed, and the residue under Sterile conditions and sealed under sterile conditions. is subjected to conventional work-up, giving 0.19 g of I-B-4. Each injection vial contains 5 mg of active ingredient.

EXAMPLE I 30 EXAMPLEB Effect of the Compounds of the Formula I on the Suppositories Proliferation of T-cells

35 A mixture of 20 g of an active ingredient of the formula Peripheral blood monocytes (PBMCs) are isolated from I is melted with 100 g of soya lecithin and 1400 g of cocoa the blood of healthy donors by the Lymphoprep gradient butter, poured into moulds and allowed to cool. Each Sup method. In each well, 200,000 PBMCs are cultivated in pository contains 20 mg of active ingredient. RPMI1640 culture medium with 5% of heat-deactivated human serum (AB pool) for 5 days at 37° C. and 10% CO EXAMPLE C in 96-well flat-base microtitre plates. The T-cells of the 40 PBMC sample are stimulated selectively against CD3 with Solution a monoclonal antibody. The cultures are prepared in tripli cate, including a control group without treatment. A solution is prepared from 1 g of an active ingredient of The compounds of the formula I are dissolved in DMSO 45 the formula I, 9.38 g of NaH2PO2 HO, 28.48 g of in a concentration of 10 M and diluted with culture NaHPO.12 HO and 0.1 g of benzalkonium chloride in medium. The control cultures are treated with DMSO cor 940 ml of bidistilled water. The pH is adjusted to 6.8, and the responding to the inhibitor concentration. H-thymidine is solution is made up to 1 1 and sterilised by irradiation. This added to the cultures 18 hours before the end of the assay. Solution can be used in the form of eye drops. The uptake of the radioactivity into the cells is then mea 50 Sured using a beta counter. The values of at least three EXAMPLED independent experiments are calculated as percentage inhi bition of the control (mean SFN) without inhibitor. The Ointment ICso value is determined from these values. 55 500 mg of an active ingredient of the formula I are mixed EXAMPLE II with 99.5 g of Vaseline under aseptic conditions. Effect of the Compounds of the Formula I on EXAMPLE E Cytokine Production in Human Peripheral Blood 60 Monocytes Tablets Peripheral blood monocytes (PBMCs) are isolated from A mixture of 1 kg of active ingredient of the formula I, 4 the blood of healthy donors by the Lymphoprep gradient kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 method. In each well, 200,000 PBMCs are cultivated in 65 kg of magnesium Stearate is pressed in a conventional RPMI1640 culture medium with 5% of heat-deactivated manner to give tablets in Such a way that each tablet contains human serum (AB pool) at 37° C. and 10% CO in 96-well 10 mg of active ingredient. US 7,129,241 B2 55 56 EXAMPLE F

Coated Tablets

Tablets are pressed analogously to Example E and Sub 5 sequently coated in a conventional manner with a coating of -N Y, NE s Sucrose, potato starch, talc, tragacanth and dye. Y \ EXAMPLE G O N N N 10 Capsules / R / V V NF NF 2 kg of active ingredient of the formula I are introduced in a conventional manner into hard gelatine capsules in Such its O O W \ a way that each capsule contains 20 mg of the active 15 2 NS 2N, ingredient. N EXAMPLE H R is A, cycloalkyl having 3–7 carbon atoms or alkyle Ampoules necycloalkyl having 4-8 carbon atoms, R is H, COOH, COOA, CONH, CONHA, CONAA', A solution of 1 kg of active ingredient of the formula I in NH, NHA, NAA', NCOA, NCOOA, OH, OA, (CH)- 60 l of bidistilled water is sterile filtered, transferred into aryl or (CH), Het, ampoules, lyophilised under Sterile conditions and sealed R" is alkyl having 1-10 carbon atoms, cycloalkyl having 3-7 carbon atoms, alkylenecycloalkyl having 4-8 car under sterile conditions. Each ampoule contains 10 mg of 25 active ingredient. bon atoms or alkenyl having 2-8 carbon atoms, in which one, two or three CH groups may be replaced The invention claimed is: by O, S, SO, SO, NH, NMe, NEt and/or by 1. A compound of formula I —CH=CH groups, 1–7 H atoms may be replaced by F and/or Cl, 30 and/or 1 H atom may be replaced by R. RI R'' is H, A, COOA"R, CONH CONHA"R, CON 7 \ R3 (A"R)(A"R), NH, NHA"R, N(A"R)(A"R), M V NCOA"R, NCOOA"R, OH or OA"R, R21 \= N-N N-R 35 R" is H, A, COOA"R, CONH CONHA"R or CON (A"R)(A"R), Y is alkylene having 1-10 carbon atoms or alkenylene having 2-8 carbon atoms, in which one, two or three SO CH groups may be replaced by O, S, SO, SO. NH or 40 NR'' and/or in which R" and Rare each, independently of one another, H, OH, 1–7 H atoms may be replaced by F and/or Cl, OR, SR, SOR, SOR or Hal, A and A' are each, independently of one another, alkyl R" and R together are alternatively —OCHO or having 1-10 carbon atoms or alkenyl having 2-8 –OCHCHO , carbon atoms, R is H, A"R, COA"R, COOA"R, CONH, 45 in which one, two or three CH groups may be replaced CONHA"R, CONCA"R)(A"R), NH, NHA"R, by O, S, SO, SO, NH or NR'' and/or N(A"R)(A"R), NCOA"R or NCOOA"R, 1–7 H atoms may be replaced by F and/or C1, or R is H, A"R, COA"R, COOA"R, CONH, aryl or Het, A and A' together are alternatively an alkylene chain CONHA"R or CONCA"R)(A"R), 50 B is an aromatic isocyclic or heterocyclic radical, which having 2–7 carbon atoms, in which one, two or three may be unsubstituted or monosubstituted, disubstituted CH groups may be replaced by O, S, SO, SO, NH, or trisubstituted by R. Rand/or R', NR, NCOR' or NCOOR, X is alkylene having 1-10 carbon atoms or alkenylene A" and A" are each, independently of one another, absent, having 2-8 carbon atoms, in which one, two or three 55 alkylene having 1-10 carbon atoms, alkenylene having CH groups may be replaced by O, S, SO, SO. NH or 2-8 carbon atoms or cycloalkylene having 3–7 carbon NA"R9, atoms, 1–7 H atoms may be replaced by F and/or Cl, in which one, two or three CH groups may be replaced and/or 1 or 2 H atoms may be replaced by R'' and/or by O, S, SO, SO, NH or NR'' and/or 12 60 1–7 H atoms may be replaced by F and/or Cl, A" and A" together are alternatively an alkylene chain and R7 are each, independently of one another, H. A"R. having 2–7 carbon atoms, in which one, two or three OH, OA"R, NH, NHA"R, N(A"R)(A"R), CH groups may be replaced by O, S, SO, SO, NH, NHCOA"R, NHCOOA"R, NHCONH, NR, NCOR' or NCOOR, NHCONHA"R, NHCON(A"R)(A"R), Hal, COOH, 65 aryl is phenyl, naphthyl, fluorenyl or biphenyl, each of COOA"R, CONH CONHA"R, CONCA"R) which is unsubstituted or monosubstituted, disubsti (A"R), tuted or trisubstituted by Hal, R'', OR, N(R'), US 7,129,241 B2 57 58 NO, CN, COOR, CONCR), NRCOR', 10. A compound according to claim 1, in which NR'CON(R'), NRSOA, COR', SON(R'), or R" and R are each, independently of one another, H. S(O).R'', methoxy, ethoxy, benzyloxy, propoxy, isopropoxy, dif R" is H or alkyl having 1–6 carbon atoms, luoromethoxy, F, Cl, cyclopentyloxy, cyclohexyloxy or R" is alkyl having 1–6 carbon atoms, 5 cycloheptyloxy, Het is a monocyclic or bicyclic Saturated, unsaturated or R" and R together are alternatively —OCHO or aromatic heterocyclic ring having 1 or 2 N, O and/or S —OCHCH O , atoms, which may be unsubstituted or monosubstituted R is H, A"R, COA"R, COOA"R, CONH, or disubstituted by oxo, Hal, R', OR, N(R'), NO, CONHA"R, CONCA"R)(A"R), NH, NHA"R, CN, COOR, CONCR), NRCOR, NRICON 10 N(A"R)(A"R), NCOA"R or NCOOA"R, (R'), NRSOR, COR', SONR' and/or S(O), R is H, R14, X is methylene, ethylene, propylene or butylene, Hal is F, Cl, Br or I, A" and A" are each, independently of one another, absent m is 0, 1 or 2, and or alkylene having 1, 2, 3 or 4 carbon atoms, and 15 R is H. (CH)-aryl or (CH), Het, n is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt, or a stereoisomer or a pharmaceutically acceptable salt, or a stereoisomer thereof. thereof. 11. A compound according to claim 1, in which 2. A compound according to claim 1, in which R" and R are each, independently of one another, H. R" and R are each, independently of one another, H. methoxy, ethoxy, benzyloxy, propoxy, isopropoxy, dif methoxy, ethoxy, benzyloxy, propoxy, isopropoxy, dif luoromethoxy, F, Cl, cyclopentyloxy, cyclohexyloxy or luoromethoxy, F, Cl, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, cycloheptyloxy, R" and R together are alternatively —OCHO or or a pharmaceutically acceptable salt, or a stereoisomer —OCHCH O , thereof. 25 R is H, A"R, COA"R, COOA"R, CONH, 3. A compound according to claim 1, in which CONHA"R, CONCA"R)(A"R), NH, NHA"R, R" and Rare each, independently of one another, meth N(A"R)(A"R), NCOA"R or NCOOA"R, oxy, ethoxy, propoxy, isopropoxy, cyclopentyloxy or F. R is H, or a pharmaceutically acceptable salt, or a stereoisomer X is methylene, ethylene, propylene or butylene, thereof. 30 A" and A" are each, independently of one another, absent 4. A compound according to claim 1, in which or alkylene having 1, 2, 3 or 4 carbon atoms, R" is 4-methoxy, and R’ is H. (CH)-aryl or (CH), Het, R’ is 3-ethoxy, aryl is phenyl, naphthyl, fluorenyl or biphenyl, each of or a pharmaceutically acceptable salt, or a stereoisomer which is ursubstituted or monosubstituted by OR', 35 R" is H or alkyl having 1–6 carbon atoms, thereof. Het is pyridyl, pyridyl N-oxide, thienyl, furyl, pyrrolyl, 5. A compound according to claim 1, in which pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isox R is H, aZolinyl, oxazolinyl, thiazolinyl, pyrazolinyl, imida or a pharmaceutically acceptable salt, or a stereoisomer Zolinyl, naphthyl, quinolinyl, isoquinolinyl, cinnolinyl, thereof. 40 phthalazinyl, quinazolinyl or quinoxalinyl, and 6. A compound according to claim 1, in which B is phenyl which is unsubstituted or monosubstituted by R is H, COO(CH,)-aryl, COA"H, COOA"H, A"NAA', OR', N(R'), O-alkylene-N(R'), or O-alkylene-OH, A"-aryl or A"Het, or unsubstituted pyridyl, or a pharmaceutically acceptable salt, or a stereoisomer or a pharmaceutically acceptable salt, or a stereoisomer thereof. 45 thereof. 7. A compound according to claim 1, in which 12. A compound according to claim 1, in which X is methylene, ethylene, propylene or butylene, R" and R are each, independently of one another, meth or a pharmaceutically acceptable salt, or a stereoisomer oxy, ethoxy, propoxy or isopropoxy, thereof. R is H. fluorenylmethyloxycarbonyl, acetyl, tert-buty 8. A compound according to claim 1, in which 50 loxycarbonyl, benzyloxycarbonyl, N,N-dimethylami B is phenyl, pyridyl, pyridyl N-oxide, thienyl, furyl, noethyl, benzyl or pyridylmethyl, pyrrolyl pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, R is H, isoxazolinyl, oxazolinyl, thiazolinyl, pyrazolinyl, imi X is methylene, ethylene, propylene or butylene, dazolinyl, naphthyl, quinolinyl, isoquinolinyl, cinnoli R" is H or alkyl having 1–6 carbon atoms, 55 Het is pyridyl, and nyl, phthalazinyl, quinazolinyl or quinoxalinyl, each of B is phenyl which is unsubstituted or monosubstituted by which is unsubstituted or may be monosubstituted, OR', N(R'), O-alkylene-N(R') or O-alkylene-OH, disubstituted or trisubstituted by OH, OA, NH, NAA', or unsubstituted pyridyl: O-alkylene-NAA' or O-alkylene-OH, or a pharmaceutically acceptable salt, or a stereoisomer or a pharmaceutically acceptable salt, or a stereoisomer 60 thereof. thereof. 13. A compound according to claim 1, which is 9. A compound according to claim 1, in which a) benzyl {1-(1S)-(4-tert-butoxybenzyl)-2-3-(3-ethoxy B is phenyl which is unsubstituted or monosubstituted by 4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl)-2- OR', N(R'), O-alkylene-N(R') or O-alkylene-OH, oxoethylcarbamate, or unsubstituted pyridyl, 65 b) benzyl 2-3-(3-ethoxy-4-methoxyphenyl)-5,6-dihy or a pharmaceutically acceptable salt, or a stereoisomer dro-4H-pyridazin-1-yl)-1-(1S)-(4-hydroxybenzyl)-2- thereof. oxoethylcarbamate,

US 7,129,241 B2 61 62 NHCOA"R, NHCOOA"R, NHCONH, in which one, two or three CH groups may be replaced NHCONHA"R, NHCON(A"R)(A"R), Hal, COOH, by O, S, SO, SO, NH or NR and/or COOA"R, CONH CONHA"R, CONCA"R) 1–7 H atoms may be replaced by F and/or C1, or (A"R), aryl or Het, A and A' together are alternatively an alkylene chain N having 2–7 carbon atoms, in which one, two or three t / CH groups may be replaced by O, S, SO, SO, NH, /N Y NRO, NCOR0 or NCOOR, -N Y, N s 10 A" and A" are each, independently of one another, absent, alkylene having 1-10 carbon atoms, alkenylene having 2-8 carbon atoms or cycloalkylene having 3–7 carbon atoms, in which one, two or three CH groups may be replaced 15 by O, S, SO, SO, NH or NR'' and/or 1–7 H atoms may be replaced by F and/or Cl, A" and A" together are alternatively an alkylene chain having 2–7 carbon atoms, in which one, two or three CH groups may be replaced by O, S, SO, SO, NH, NR, NCOR' or NCOOR, R is A, cycloalkyl having 3–7 carbon atoms or alkyle aryl is phenyl, naphthyl, fluorenyl or biphenyl, each of necycloalkyl having 4-8 carbon atoms, which is unsubstituted or monosubstituted, disubsti R is H, COOH, COOA, CONH CONHA, CONAA', 25 tuted or trisubstituted by Hal, R'', OR, N(R'), NH, NHA, NAA', NCOA, NCOOA, OH, OA, (CH)- NO, CN, COOR, CONCR), NRCOR', aryl or (CH), Het, NR'CON(R'), NRSOA, COR', SON(R'), or R" is alkyl having 1-10 carbon atoms, cycloalkyl having S(O).R'', 3-7 carbon atoms, alkylenecycloalkyl having 4-8 car R" is H or alkyl having 1–6 carbon atoms, bon atoms or alkenyl having 2-8 carbon atoms, 30 in which one, two or three CH groups may be replaced R'' is alkyl having 1–6 carbon atoms, by O, S, SO, SO, NH, NMe, NEt and/or by Het is a monocyclic or bicyclic Saturated, unsaturated or —CH=CH groups, aromatic heterocyclic ring having 1 or 2 N, O and/or S 1–7 H atoms may be replaced by F and/or Cl, atoms, which may be unsubstituted or monosubstituted and/or 1 H atom may be replaced by R. or disubstituted by oxo, Hal, R', OR, N(R'), NO, R is H, A, COOA"R, CONH CONHA"R, CON 35 CN, COOR, CONCR), NRCOR, NRICON (A"R)(A"R), NH, NHA"R, N( "R)(A"R), (R'), NRSOR, COR', SONR' and/or S(O), NCOA"R, NCOOA"R, OH or OA"R, R14, R° is H, A, COOA"R, CONH CONHA"R or CON Hal is F, Cl, Br or I, (A"R)(A"R), 40 m is 0, 1 or 2, and Y is alkylene having 1–10 carbon atoms or alkenylene n is 0, 1, 2, 3 or 4, having 2-8 carbon atoms, in which one, two or three CH groups may be replaced by O, S, SO, SO. NH or or a pharmaceutically acceptable salt, prodrug, Solvate or NR'' and/or a stereoisomer thereof. 1–7 H atoms may be replaced by F and/or Cl, 45 17. A compound according to claim 16, which is in the A and A' are each, independently of one another, alkyl form of a solvate. having 1-10 carbon atoms or alkenyl having 2-8 carbon atoms, UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 7,129,241 B2 Page 1 of 1 APPLICATIONNO. : 10/516876 DATED : October 31, 2006 INVENTOR(S) : Hans-Michael Eggenweiler It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Column 56, line 39, reads “CH groups should read -- CH2 groups -- Column 56, line 45, reads “CH groups should read -- CH2 groups -- Column 58, line 9, reads “CON(AR)(AR”), should read -- CONCAR)(AR”), -- Column 58, line 36, reads “ursubstituted should read -- unsubstituted -- Column 60, line 32, reads “A compund should read -- A compound -- Column 61, line 43, reads “CH groups should read -- CH2 groups -- Column 62, line 1, reads “CH groups should read -- CH2 groups -- Column 62, line 35, reads “by oxo, should read -- by oxo group. --

Signed and Sealed this Tenth Day of July, 2007 WDJ

JON. W. DUDAS Director of the United States Patent and Trademark Office