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US 9,845,337 B2Granted
Isoxazolidine derivatives
AssigneeChiesi Farmaceutici S.p.A.
InventorsEleonora Ghidini, Andrea Rizzi
Life of this patent
Estimating the term…
Abstract
Anti-inflammatory and antiallergic compounds of the glucocorticosteroid series, according to formula (I) according to formula (I) defined herein are useful for treating diseases of the respiratory tract characterized by airway obstruction.
Claims12
A method of treating a disease selected from the group consisting of asthma and chronic obstructive pulmonary disease, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):
- wherein
- R1 is —(CH2)n—Z—(CH2)n′—R3 wherein n and n′ are each independently 0, 1 or 2;
- Z is a single bond, —S—, —O—, or —OC(R4R5)—;
- R3 is selected from the group consisting of:
- H, halogen, —CN, —OH, —CONH2, (C1-C6)alkyl, (C2-C4)alkenyl, (C1-C6)haloalkyl, (C2-C4)alkynyl, (C1-C6)alkylsulfonyl;
- and (C1-C6)alkylcarbonyl;
- —NR4R5, wherein R4 and R5 are independently selected from the group consisting of (C1-C6)alkyl and (C1-C6)alkoxy;
- (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted by one or more halogen atoms or oxo groups or —CN groups;
- and
- R2 is:
- a group selected from the group consisting of linear or branched (C1-C6)alkoxy and (C1-C6)haloalkyl, optionally substituted by one or more CN groups or halogen atoms;
- or
- —(CH2)mR6, wherein:
- (1) R6 is selected from the group consisting of (C3-C8)heterocycloalkyl, aryloxy, and arylthio, each of which is optionally substituted by one or more substituents selected from the group consisting of oxo, —OH, halogen, —CN, —NH2, —CONH2, —NO2, —NHC(O)H, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)haloalkyl, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)haloalkoxy, (C1-C6)hydroxyalkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarboxyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfanyl, (C1-C6)alkyloxysulfonyl, (C1-C6)haloalkylsulfonyloxy, aminosulfonyl, (C3-C8)cycloalkyl, (C3-C6)heterocycloalkyl, and heteroaryl, wherein m is 0;
- or
- (2) R6 is aryl substituted by one or more (C1-C6)alkylsulfanyl groups, wherein m is 0;
- or
- (3) R6 is selected from the group consisting of (C3-C8)cycloalkyl, aryl, and heteroaryl, each of which is optionally substituted by one or more substituents selected from the group consisting of oxo, —OH, halogen, —CN, —NH2, —CONH2, —NO2, —NHC(O)H, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)haloalkyl, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)haloalkoxy, (C1-C6)hydroxyalkoxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarboxyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfanyl, (C1-C6)alkyloxysulfonyl, (C1-C6)haloalkylsulfonyloxy, aminosulfonyl, (C3-C8)cycloalkyl, (C3-C6)heterocycloalkyl and heteroaryl, wherein m is 0 and
- X and Y are both fluorine,
- or a pharmaceutically acceptable salt thereof.
17 more elements
A method of treating a disease selected from the group consisting of asthma and chronic obstructive pulmonary disease, comprising administering, to a subject in need thereof, an effective amount of a compound selected from the group consisting of:
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-phenyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-p-tolyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-quinolin-6-yl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-pyridin-3-yl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,100bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-m-tolyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5 S,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-8-(4-fluorophenyl)-5-hydroxy-6b-((S)-2-hydroxy-acetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(3-chlorophenyl)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-(4-trifluoromethylphenyl)-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-8-(3-fluoro-phenyl)-5-hydroxy-6b-((S)-2-hydroxy-acetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-o-tolyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5 S,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-3-methyl-phenyl)-4b,12-di-fluoro-5-hydroxy-6b-((S)-2-hydroxy-acetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-3-trifluoromethyl-phenyl)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(3,4-dichlorophenyl)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-bromophenyl)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- 4-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS)-4b-fluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,6b,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-8-yl]-benzonitrile;
- 4-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,6b,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-8-yl]-benzamide;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,100bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-(4-trifluoromethoxy-phenyl)-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- methanesulfonic acid 4-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-2-oxo-2,4-a,4b,5,6,6a,6b,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-8-yl]-phenyl ester;
- (4aS,4bR,5 S,6aS,6bR,9aS,10 aS,10bS,12S)-8-(4-cyclohexyl-phenyl)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4-a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-(4-thiophen-2-yl-phenyl)-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- 4-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,6b,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-8-yl]-benzoic acid methyl ester;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-8-(4-methanesulfonyl-phenyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- 3-[(4aS,4bR,5 S,6aS,6bR,9aS,10 aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,6b,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-8-yl]-benzonitrile;
- 4-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,6b,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-8-yl]-benzene sulfonamide;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-cyclopropylphenyl)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-tert-butyl-phenyl)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- N-{4-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,6b,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-8-yl]-phenyl}-formamide;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-(3-trifluoromethyl-phenyl)-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-(3-trifluoromethoxy-phenyl)-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(3-bromo-phenyl)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-8-benzothiazol-6-yl-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,-9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-8-(4-hydroxy-phenyltrifluoromethansulfonate)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(3-cyclopropyl-phenyl)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-(4-piperidin-4-ylmethyl-phenyl)-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-phenyl-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,-1,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- (4aS,4bR,5S,6aS,6bR,9aS,10 aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-m-tolyl-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- (4aS,4bR,5 S,6aS,6bR,9aS,10 aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-o-tolyl-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-p-tolyl-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- (4aS,4bR,5S,6aS,6bR,9aS,1 aS,10bS,12S)-8-(3-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- (4aS,4bR,5S,6aS,6bR,9aS,10 aS,10bS,12S)-4b,12-difluoro-8-(4-fluorophenyl)-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-pyridin-3-yl-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-8-(3-fluorophenyl)-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-(4-trifluoromethyl-phenyl)-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-phenyl-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10 aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-m-tolyl-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-o-tolyl-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-p-tolyl-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10 bS,12S)-8-(3-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
- (4aS,4bR,5 S,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-8-(4-fluorophenyl)-5-hydroxy-4-a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S—((S)-fluoromethyl)ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-pyridin-3-yl-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
- (4aS,4bR,5 S,6bR,9aS,10aS,10 bS,12S)-4b,12-difluoro-8-(3-fluoro-phenyl)-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S—((S)-fluoromethyl)ester;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-(4-trifluoromethyl-phenyl)-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-6b-(2-fluoro-acetyl)-5-hydroxy-4a,6a-dimethyl-8-phenyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-6b-(2-fluoroacetyl)-5-hydroxy-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- methanesulfonic acid 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4-a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10 bS,12S)-6b-(2-chloroacetyl)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- 4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-6b-(2-methylsulfanyl-acetyl)-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid chloromethyl thioester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid cyclopropylmethyl ester;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid cyanomethyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10 aS,100bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid carbamoylmethyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10 bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid 2,2,2-trifluoro-ethyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid 2-fluoro-ethyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-cyanomethyl ester;
- (4aS,4bR,5 S,6aS,6bR,9aS,10 aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-(2-fluoro-ethyl)ester;
- 4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-(2,2,2-trifluoro-ethyl)ester;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-carbamoylmethyl ester;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-prop-2-ynyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-cyclobutyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothoic acid S-(2-oxo-propyl)ester;
- 4aS,4bR,5 S,6aS,6bR,9aS,10 aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid methyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid cyanomethyl-methyl-amide;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-methyl ester;
- (4aS,4bR,5 S,6aS,6bR,9aS,1 aS,10S,12S)-6b-acetyl-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid 1,1-dimethyl-prop-2-ynyl ester;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid 1,1-dimethyl-allyl ester;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-8-(4-fluorobenzyl)-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-thiophen-2-ylmethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-8-furan-2-yl-methyl-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxy-acetyl)-4a,6a-dimethyl-8-phenyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-6b-(2-hydroxyacetyl)-4a,6a-dimethyl-4a,4b,5,6,6a,6b,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-2-one;
- (4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-phenyl-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chlorophenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carboxylic acid;
- and
- (4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-phenyl-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthrene-6b-carbothioic acid S-fluoromethyl ester;
- or
- a pharmaceutically acceptable salt of said compound.
88 more elements
A method of treating a disease selected from the group consisting of asthma and chronic obstructive pulmonary disease, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):
- wherein
- R1 is —(CH2)n—Z—(CH2)n′—R3 wherein n and n′ are each independently 0, 1 or 2;
- Z is a single bond, —S—, —O—, or —OC(R4R5)—;
- R3 is selected from the group consisting of:
- H, halogen, —CN, —OH, —CONH2, (C1-C6)alkyl, (C2-C4)alkenyl, (C1-C6)haloalkyl, (C2-C4)alkynyl, and (C1-C6)alkylsulfonyl;
- —NR4R5, wherein R4 and R5 are independently selected from the group consisting of (C1-C6)alkyl and (C1-C6)alkoxy;
- (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted by one or more halogen atoms or oxo groups or —CN groups;
- and
- R2 is substituted aryl;
- and
- X and Y are both fluorine,
- or a pharmaceutically acceptable salt thereof.
9 more elements
A method of treating a disease selected from the group consisting of asthma and chronic obstructive pulmonary disease, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):
- wherein
- R1 is —CH2—OH;
- R2 is substituted aryl;
- and
- X and Y are both fluorine,
- or a pharmaceutically acceptable salt thereof.
3 more elements
Dependencies are inferred from the claim text.