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(12) Patent Application Publication (10) Pub. No.: US 2005/0090559 A1 Berger Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2005/0090559 A1 Berger Et Al US 20050090559A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0090559 A1 Berger et al. (43) Pub. Date: Apr. 28, 2005 (54) HETEROCYCLICALLY-SUBSTITUTED (30) Foreign Application Priority Data PENTANOL DERIVATIVES, PROCESS FOR THER PRODUCTION AND THEIR USE AS Jul. 1, 2003 (DE)..................................... 103 30 358.8 ANTI-NFLAMMATORY AGENTS Oct. 6, 2003 (DE)..................................... 103 46939.7 (76) Inventors: Markus Berger, Berlin (DE); Stefan Publication Classification Baeurle, Berlin (DE); Hartmut Rehwinkel, Berlin (DE); Norbert Schmees, Berlin (DE); Heike (51) Int. Cl." ..................... A61K 31/495; A61K 31/135; Schaecke, Berlin (DE); Manfred A61K 31/275 Lehmann, Berlin (DE); Konrad Krolikiewicz, Berlin (DE); Arndt (52) U.S. Cl. ........................... 514/651; 564/357; 514/523 Schottelius, Belvedere (CA); Duy Nguyen, Berlin (DE); Anne Mengel, Berlin (DE); Stefan Jaroch, Berlin (57) ABSTRACT (DE) Correspondence Address: The invention relates to pentanol derivatives of general MILLEN, WHITE, ZELANO & BRANIGAN, formula I P.C. 2200 CLARENDON BILVD. SUTE 1400 (I) ARLINGTON, VA 22201 (US) (21) Appl. No.: 10/882,103 (22) Filed: Jul. 1, 2004 Related U.S. Application Data that are Substituted by quinazoline, quinoxaline, cinnoline, indazole, phthalazine, naphthyridine, benzothiazole, dihy (60) Provisional application No. 60/483,907, filed on Jul. droindolone, dihydroisoindolone, benzimidazole or indole, a 2, 2003. Provisional application No. 60/510,085, filed process for their production and their use as anti-inflamma on Oct. 10, 2003. tory agents. US 2005/0090559 A1 Apr. 28, 2005 HETEROCYCLICALLY-SUBSTITUTED PENTANOL and/or carbon atoms are linked to directly adjacent DERIVATIVES, PROCESS FOR THEIR ring-carbon atoms, or NR'R'', whereby R' and R, PRODUCTION AND THEIR USE AS independently of one another, can be hydrogen, ANTI-INFLAMMATORY AGENTS C-C-alkyl or (CO)-C-C-alkyl, 0001. The invention relates to heterocyclically-substi 0011) R' and R, independently of one another, tuted pentanol derivatives, in particular pentanol derivatives mean a hydrogen atom, a methyl or ethyl group, or that are Substituted by quinazoline, quinoxaline, cinnoline, together with the carbon atom mean the chain of a indazole, phthalazine, naphthyridine, benzothiazole, dihy C-C-cycloalkyl ring, droindolone, dihydroisoindolone, benzimidazole or indole, proceSS for their production and their use as anti-inflamma 0012 R means a C-C-alkyl group that is option tory agents. ally Substituted, independently of one another, by one or more groupS. Selected from halogen, hydroxy 0002 From the prior art of WO 00/32584, DE 100 38639 or C-C-alkoxy, or an optionally partially or com A1 and WO 02/10143, anti-inflammatory agents of the pletely fluorinated C-C-alkyl group, an optionally general formula Substituted group that is Selected from C-C-alk enyl, C-C-alkinyl, C-C-cycloalkyl, C-C7-het erocyclyl, aryl, heteroaryl, (C-C-alkyl)C-C-cy (I) cloalkyl, (C-C-alkyl)aryl, O (C-C- alkyl)heteroaryl, 0013 B means a methylene group or a carbonyl group that is optionally Substituted by a methyl or ethyl group, and 0003) are known, whereby the Ar radical comprises 0014 Q means a quinazolinyl, quinoxalinyl, cinno phthalides, thiophthalides, benzoxazinones or phthalazino linyl, indazolyl, phthalazinyl, naphthyridinyl, ben nes. In the experiment, these compounds Show dissociations Zothiazolyl, dihydroindolonyl, dihydroisoindolonyl, of action between anti-inflammatory and undesirable meta benzimidazole or indolyl group that is linked via any bolic actions and are Superior to the previously described position and that optionally can be Substituted by one nonsteroidal glucocorticoids or exhibit at least just as good or more radicals from the group C1-C5-alkyl, C-Cs an action. alkoxy, C-C-alkylthio, C-C-perfluoroalkyl, halo 0004. In addition, compounds in which Q represents an gen, hydroxy, cyano, nitro, or NR'R'', whereby R' aromatic carbocyclic radical are known from WOO3/ and R, independently of one another, can be hydro 0598.99. gen, C-Cs-alkyl or (CO)-C-C-alkyl, whereby phthalazinones are excluded, 0005 The selectivity of the compounds of the prior art compared to the other Steroid receptorS Still requires 0015 as well as their racemates or separately present improvement, however. Stereoisomers, and optionally their physiologically compat ible salts. 0006. It was therefore the object of this invention to make available compounds whose Selectivity is improved com 0016. In view of the prior art WO 98/54159 and WO pared to the other Steroid receptors. 00/32584, phthalazinones were excluded. They are pro duced by the definition in claim 1 of Q=phthalazine in 0007. This object is achieved by the compounds accord combination with the possible Substituent hydroxy, Since ing to the claims. hydroxyphthalazines are at a tautomeric equilibrium with phthalazinones. 0008. This invention therefore relates to compounds of general formula I 0017 Compounds of general formula I in which 0018. A stands for an aryl group, a benzyl group or (I) a phenethyl group, whereby the aryl, benzyl or phenethyl group optionally can be Substituted by one or more radicals from the group of C-C-alkyl, C-C-alkoxy, C-C-alkylthio, C-C-perfluoro alkyl, halogen, hydroxy, cyano, nitro, O-(CH), O-, O-(CH), CH, -O-CH=CH-, or -(CH), , whereby n=1 0009 in which or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon 0010) A stands for an aryl, a benzyl or a phenethyl atoms, or NR'R'', whereby R' and R, independently group, whereby the aryl, benzyl or phenethyl group of one another, can be hydrogen, C-C-alkyl or optionally can be Substituted by one or more radicals (CO)-C-C-alkyl, from the group C1-C5-alkyl, C-C-alkoxy, C-C- alkylthio, C-C-perfluoroalkyl, halogen, hydroxy, 0.019 R' and R, independently of one another, cyano, nitro, -O-(CH), O--O-(CH), mean a hydrogen atom, a methyl or ethyl group, or CH-, O-CH=CH-, or (CH2)2-, together with the carbon atom of the chain mean a whereby n=1 or 2, and the terminal oxygen atoms C-C-cycloalkyl ring, US 2005/0090559 A1 Apr. 28, 2005 0020) R' means a C-C-alkyl group or an option optionally partially or completely fluorinated C-C-alkyl ally partially or completely fluorinated C-C-alkyl group are a Subject of the invention. grOup, 0032) Compounds of general formula I in which R is a 0021 B means a methylene group or a carbonyl C-C-alkyl group or an optionally partially or completely group that is optionally Substituted by a methyl or fluorinated C-C-alkyl group are a special Subject of the ethyl group, and invention. Preferred are the CF group and the CFs group. 0022 Q means a quinazolinyl, quinoxalinyl, cinno 0033. The C-C- or C-C-alkyl groups can be straight linyl, indazolyl, phthalazinyl, naphthyridinyl or ben chain or branched and can Stand for a methyl, ethyl, n-pro Zothiazolyl group that is linked via any position and pyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, or n-pentyl, that optionally can be Substituted by one or more 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group. radicals from the group of C1-C5-alkyl, C-C- A methyl or ethyl group is preferred. alkoxy, C-C-alkylthio, C-C-perfluoroalkyl, halo gen, hydroxy, cyano, nitro or NR'R'', whereby R' 0034) For a partially or completely fluorinated C-C- and R, independently of one another, can be hydro alkyl group, for example, the following partially or com gen, C-C-alkyl or (CO)-C-C-alkyl, whereby pletely fluorinated Straight-chain or branched groups are phthalazinones are excluded, considered: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trif 0023 as well as their racemates or separately present luoroethyl, tetrafluoroethyl, and pentafluoroethyl. Of the Stereoisomers, and optionally their physiologically compat latter, the trifluoromethyl group or the pentafluoroethyl ible Salts are one aspect of the invention. group is preferred. 0024 Compounds of general formula I in which 0035 A C-C-perfluoroalkyl group is defined as a com 0025. A stands for an aryl group, a benzyl group or pletely fluorinated Straight-chain or branched alkyl group, a phenethyl group, whereby the aryl, benzyl or Such as, e.g., CF, C2Fs, C-F7, C. Fo, or CSF11. phenethyl group optionally can be Substituted by one or more radicals from the group of C-C-alkyl, 0036) Alkyl radicals R and R together with the carbon C-C-alkoxy, C-C-alkylthio, C-C-perfluoro atom of the chain can form a 3- to 6-membered ring. The alkyl, halogen, hydroxy, cyano, nitro, methyl group or the ethyl group is preferred for R' and R. -O-(CH), O-, -O-(CH), CH, 0037 AS alkyl radicals R and R, C-C-alkyl is pre -O-CH=CH-, -(CH), , whereby n=1 or ferred, whereby the C-C-alkyl group can be Straight-chain 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon or branched. atoms, or NR'R'', whereby R' and R, independently 0038. The C-C-alkoxy groups in A and Q can be of one another, can be hydrogen, C-C-alkyl or Straight-chain or branched and Stand for, for example, a (CO)-C-C-alkyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso 0026 R' and R, independently of one another, butoxy, tert.-butoxy or n-pentoxy, 2,2-dimethylpropoxy, mean a hydrogen atom, a methyl or ethyl group, or 2-methylbutoxy or 3-methylbutoxy group. A methoxy or together with the carbon atom of the chain mean a ethoxy group is preferred. C-C-cycloalkyl ring, 0039 The C-C-alkylthio groups in A and Q can be 0027) R' means a C-C-alkyl group or an option Straight-chain or branched and Stand for a methylthio, eth ally partially or completely fluorinated C-C-alkyl ylthio, n-propylthio, iso-propylthio, n-butylthio, iso-bu tylthio, tert.-butylthio or n-pentylthio, 2,2-dimethylpropy grOup, lthio, 2-methylbutylthio or 3-methylbutylthio group.
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