Novel Anti-Inflammatory Androstane Derivatives

Abstract

There are provided according to the invention pharmaceutical compositions comprising a compound of formula (I) wherein R 1 represents C 1-6 alkyl or C 1-6 haloalkyl; R 2 represents —C(═O)-aryl or —C(═O)-heteroaryl, wherein said heteroaryl is a 5 member heterocyclic aromatic ring containing 1-3 hetero atoms selected from N and S, or a 5 member heterocyclic aromatic ring containing 2-3 hetero atoms selected from N, O and S, or a 6 member heterocyclic aromatic ring containing 1-3 hetero atoms selected from N, O and S; R 3 represents hydrogen, methyl (which may be in either the α or β configuration) or methylene; R 4 and R 5 are the same or different and each represents hydrogen or halogen; and represents a single or a double bond; or a physiologically acceptably salt or solvate thereof; and another therapeutically active agent; in admixture with one or more physiologically acceptable diluents or carriers.

1 . A pharmaceutical composition comprising:
 compound of formula (I)   
       
         
           
           
               
               
           
         
       
       wherein
 R 1  represents C 1-6  alkyl or C 1-6  haloalkyl; 
 R 2  represents —C(═O)-aryl or —C(═O)-heteroaryl, wherein said heteroaryl is a 5 member heterocyclic aromatic ring containing 1-3 hetero atoms selected from N and S, or a 5 member heterocyclic aromatic ring containing 2-3 hetero atoms selected from N, O and S, or a 6 member heterocyclic aromatic ring containing 1-3 hetero atoms selected from N, O and S; 
 R 3  represents hydrogen, methyl (which may be in either the α or β configuration) or methylene; 
 R 4  and R 5  are the same or different and each represents hydrogen or halogen; and 
    represents a single or a double bond; 
 or a salt or a solvate thereof; and 
 another therapeutically active agent; 
 in admixture with one or more physiologically acceptable diluents or carriers. 
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein R 2  represents —C(═O)-aryl. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein R 2  represents —C(═O)-heteroaryl, wherein said heteroaryl is a 5 member heterocyclic aromatic ring containing 1-3 hetero atoms selected from N and S, or a 5 member heterocyclic aromatic ring containing 2-3 hetero atoms selected from the N, O and S, or a 6 member heterocyclic aromatic ring containing 1-3 hetero atoms selected from N, O and S. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula (I) is 6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester or a physiologically acceptable salt or solvate thereof. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein said at least one additional therapeutically active agent includes a β 2 -adrenoreceptor agonist. 
     
     
         6 . The pharmaceutical composition according to  claim 5 , wherein said β 2 -adrenoreceptor agonist is at least one selected from the group consisting of salmeterol, salbutamol, formoterol, salmefamol, fenoterol, terbutaline and salts thereof. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein said at least one additional therapeutically active agent includes a PDE4 inhibitor. 
     
     
         8 . The pharmaceutical composition according to  claim 7 , wherein the PDE4 inhibitor is at least one selected from the group consisting of (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 
       (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 
       3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N2-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone; 
       cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid]; 
       cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; 
       (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; 
       (S)-(−)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; and 
       2-carbomethoxy-4-cyano-4-(3-cyclopropyl methoxy-4-difluoromethoxyphenyl)cyclohexan-1-one. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein said at least one additional therapeutically active agent is an anti-histamine, anti-inflammatory agent or antiinfective agent. 
     
     
         10 . The pharmaceutical composition according to  claim 9 , wherein said anti-histamine is methapyrilene or loratadine. 
     
     
         11 . The pharmaceutical composition according to  claim 9 , wherein, said anti-inflammatory agent is a non-steroidal anti-inflammatory drug (NSAID). 
     
     
         12 . The pharmaceutical composition according to  claim 9 , wherein, and said antiinfective agent is an antibiotic or antiviral. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the composition is an ointment, lotion, gel, foam, preparation for delivery by transdermal patch, powder, spray, aerosol, capsule or cartridge for use in an inhaler or insufflator or drop, solution or suspension for nebulisation, suppositories, pessaries, retention enemas, chewable or suckable tablets or pellets, liposome preparation or microencapsulation preparation. 
     
     
         14 . The pharmaceutical composition according to  claim 13 , wherein the composition is a dry powder. 
     
     
         15 . The pharmaceutical composition according to  claim 13 , wherein the composition is a spray. 
     
     
         16 . The pharmaceutical composition according to  claim 15 , wherein said composition is a pressurized metered dose inhaler formulation comprising a fluorocarbon or hydrogen-containing chlorofluoro carbon as propellant 
     
     
         17 . The pharmaceutical composition formulation according to 16, further comprising a surfactant and/or a cosolvent. 
     
     
         18 . The pharmaceutical composition of  claim 2 , wherein said at least one additional therapeutically active agent includes a β 2 -adrenoreceptor agonist. 
     
     
         19 . The pharmaceutical composition according to  claim 18 , wherein said β 2 -adrenoreceptor agonist is at least one selected from the group consisting of salmeterol, salbutamol, formoterol, salmefamol, fenoterol, terbutaline and salts thereof. 
     
     
         20 . The pharmaceutical composition according to  claim 2 , wherein said at least one additional therapeutically active agent includes a PDE4 inhibitor. 
     
     
         21 . The pharmaceutical composition according to  claim 20 , wherein the PDE4 inhibitor is at least one selected from the group consisting of (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 
       (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 
       3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N2-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone; 
       cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid]; 
       cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; 
       (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; 
       (S)-(−)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; and 
       2-carbomethoxy-4-cyano-4-(3-cyclopropyl methoxy-4-difluoromethoxyphenyl)cyclohexan-1-one. 
     
     
         22 . The pharmaceutical composition according to  claim 2 , wherein said at least one additional therapeutically active agent is an anti-histamine, anti-inflammatory agent or antiinfective agent. 
     
     
         23 . The pharmaceutical composition according to  claim 22 , wherein said anti-histamine is methapyrilene or loratadine. 
     
     
         24 . The pharmaceutical composition according to  claim 22 , wherein, said anti-inflammatory agent is a non-steroidal anti-inflammatory drug (NSAID). 
     
     
         25 . The pharmaceutical composition according to  claim 22 , wherein, and said antiinfective agent is an antibiotic or antiviral. 
     
     
         26 . The pharmaceutical composition of  claim 2 , wherein the composition is an ointment, lotion, gel, foam, preparation for delivery by transdermal patch, powder, spray, aerosol, capsule or cartridge for use in an inhaler or insufflator or drop, solution or suspension for nebulisation, suppositories, pessaries, retention enemas, chewable or suckable tablets or pellets, liposome preparation or microencapsulation preparation. 
     
     
         27 . The pharmaceutical composition according to  claim 26 , wherein the composition is a dry powder. 
     
     
         28 . The pharmaceutical composition according to  claim 26 , wherein the composition is a spray. 
     
     
         29 . The pharmaceutical composition according to  claim 28 , wherein said composition is a pressurized metered dose inhaler formulation comprising a fluorocarbon or hydrogen-containing chlorofluoro carbon as propellant. 
     
     
         30 . The pharmaceutical composition formulation according to 29, further comprising a surfactant and/or a cosolvent. 
     
     
         31 . The pharmaceutical composition of  claim 3 , wherein said at least one additional therapeutically active agent includes a β 2 -adrenoreceptor agonist. 
     
     
         32 . The pharmaceutical composition according to  claim 31 , wherein said β 2 -adrenoreceptor agonist is at least one selected from the group consisting of salmeterol, salbutamol, formoterol, salmefamol, fenoterol, terbutaline and salts thereof. 
     
     
         33 . The pharmaceutical composition according to  claim 3 , wherein said at least one additional therapeutically active agent includes a PDE4 inhibitor. 
     
     
         34 . The pharmaceutical composition according to  claim 33 , wherein the PDE4 inhibitor is at least one selected from the group consisting of (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 
       (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 
       3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N2-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone; 
       cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid]; 
       cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; 
       (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; 
       (S)-(−)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; and 
       2-carbomethoxy-4-cyano-4-(3-cyclopropyl methoxy-4-difluoromethoxyphenyl)cyclohexan-1-one. 
     
     
         35 . The pharmaceutical composition according to  claim 3 , wherein said at least one additional therapeutically active agent is an anti-histamine, anti-inflammatory agent or antiinfective agent. 
     
     
         36 . The pharmaceutical composition according to  claim 35 , wherein said anti-histamine is methapyrilene or loratadine. 
     
     
         37 . The pharmaceutical composition according to  claim 35 , wherein, said anti-inflammatory agent is a non-steroidal anti-inflammatory drug (NSAID). 
     
     
         38 . The pharmaceutical composition according to  claim 35 , wherein, and said antiinfective agent is an antibiotic or antiviral. 
     
     
         39 . The pharmaceutical composition of  claim 3 , wherein the composition is an ointment, lotion, gel, foam, preparation for delivery by transdermal patch, powder, spray, aerosol, capsule or cartridge for use in an inhaler or insufflator or drop, solution or suspension for nebulisation, suppositories, pessaries, retention enemas, chewable or suckable tablets or pellets, liposome preparation or microencapsulation preparation. 
     
     
         40 . The pharmaceutical composition according to  claim 39 , wherein the composition is a dry powder. 
     
     
         41 . The pharmaceutical composition according to  claim 39 , wherein the composition is a spray. 
     
     
         42 . The pharmaceutical composition according to  claim 41 , wherein said composition is a pressurized metered dose inhaler formulation comprising a fluorocarbon or hydrogen-containing chlorofluoro carbon as propellant. 
     
     
         43 . The pharmaceutical composition formulation according to 42, further comprising a surfactant and/or a cosolvent. 
     
     
         44 . The pharmaceutical composition of  claim 4 , wherein said at least one additional therapeutically active agent includes a β 2 -adrenoreceptor agonist. 
     
     
         45 . The pharmaceutical composition according to  claim 44 , wherein said β 2 -adrenoreceptor agonist is at least one selected from the group consisting of salmeterol, salbutamol, formoterol, salmefamol, fenoterol, terbutaline and salts thereof. 
     
     
         46 . The pharmaceutical composition according to  claim 4 , wherein said at least one additional therapeutically active agent includes a PDE4 inhibitor. 
     
     
         47 . The pharmaceutical composition according to  claim 46 , wherein the PDE4 inhibitor is at least one selected from the group consisting of (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 
       (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone; 
       3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N2-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone; 
       cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid]; 
       cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]; 
       (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; 
       (S)-(−)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate; and 
       2-carbomethoxy-4-cyano-4-(3-cyclopropyl methoxy-4-difluoromethoxyphenyl)cyclohexan-1-one. 
     
     
         48 . The pharmaceutical composition according to  claim 4 , wherein said at least one additional therapeutically active agent is an anti-histamine, anti-inflammatory agent or antiinfective agent. 
     
     
         49 . The pharmaceutical composition according to  claim 48 , wherein said anti-histamine is methapyrilene or loratadine. 
     
     
         50 . The pharmaceutical composition according to  claim 48 , wherein, said anti-inflammatory agent is a non-steroidal anti-inflammatory drug (NSAID). 
     
     
         51 . The pharmaceutical composition according to  claim 48 , wherein, and said antiinfective agent is an antibiotic or antiviral. 
     
     
         52 . The pharmaceutical composition of  claim 4 , wherein the composition is an ointment, lotion, gel, foam, preparation for delivery by transdermal patch, powder, spray, aerosol, capsule or cartridge for use in an inhaler or insufflator or drop, solution or suspension for nebulisation, suppositories, pessaries, retention enemas, chewable or suckable tablets or pellets, liposome preparation or microencapsulation preparation. 
     
     
         53 . The pharmaceutical composition according to  claim 52 , wherein the composition is a dry powder. 
     
     
         54 . The pharmaceutical composition according to  claim 52 , wherein the composition is a spray. 
     
     
         55 . The pharmaceutical composition according to  claim 53 , wherein said composition is a pressurized metered dose inhaler formulation comprising a fluorocarbon or hydrogen-containing chlorofluoro carbon as propellant. 
     
     
         56 . The pharmaceutical composition formulation according to 55, further comprising a surfactant and/or a cosolvent.