Composition for inhibition of cathepsin k

Abstract

The present invention relates to the a method of inhibiting bone resorption in a mammal in need thereof with an oral pharmaceutical composition comprising a cathepsin K inhibitor, or a pharmaceutically acceptable salt thereof, or a mixture thereof, according to a continuous schedule having a dosage interval of once weekly, biweekly, twice monthly or once monthly.

1 . A method of inhibiting bone resorption in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a cathepsin K inhibitor, or a pharmaceutically acceptable salt thereof, or a mixture thereof, characterized by a single-dose AUC 0-168  of about 2.00-80.0 μM/hr and a C min  of about 10 nM to about 200 nM, as an oral unit dose according to a once weekly, biweekly, twice monthly or once monthly dosing regimen. 
     
     
         2 . A method of inhibiting bone resorption in a mammal in need thereof comprising administering to the mammal about 2.5 mg to about 200 mg of a cathepsin K inhibitor according to Formula I: 
       
         
           
           
               
               
           
         
         wherein R 1  is C 1-3  alkyl which is substituted with two to seven halo; 
         R 2  is hydrogen or halo; 
         X is N or CH; 
         D is aryl or heteroaryl, wherein each said aryl or heteroaryl group, which may be monocyclic or bicyclic, is optionally substituted on either the carbon or the heteroatom with one to four substituents independently selected from methyl, C 1-6  haloalkyl, halo or —SO 2 R 4 ; 
         R 3  is hydrogen, C 1-6  alkyl, C 2-6  alkynyl, halo, cyano, aryl, heteroaryl, C 3-8  cycloalkyl, heterocyclyl, —OR 4 , —C(O)N(R 5 )(R 6 ), —C(R 5 )(R 6 )OH, —C(R 5 )(R 6 )N(R 4 ) 2 , —SO m R 4 , —SO 2 N(R 4 )(R 5 ), or —SO 2 N(R 5 )C(O)(R 7 ); wherein said alkyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted on either the carbon or the heteroatom with one to five substituents independently selected from C 1-6  alkyl or halo; 
         R 4  is hydrogen, C 1-6  alkyl, aryl, aryl(C 1-4 )alkyl, heteroaryl, heteroaryl(C 1-4 )alkyl, C 3-8  cycloalkyl, C 3-8  cycloalkyl(C 1-4 )alkyl, or heterocyclyl(C 1-4 )alkyl; which are optionally substituted with one, two, or three substituents independently selected from halo, alkoxy or —SO 2 R 7 ; 
         R 5  is hydrogen, C 1-6  alkyl, or C 1-6  haloalkyl; 
         R 6  is hydrogen, C 1-6  alkyl, or C 1-6  haloalkyl; 
         Or R 5  and R 6  can be taken together with the carbon or nitrogen atom between them to form a 3 to 6 membered ring; 
         R 7  is hydrogen or C 1-6  alkyl which is optionally substituted with one, two, or three substituents independently selected from halo or cyano; 
         m is an integer from zero to two; 
         or a salt, stereoisomer, N-oxide derivative, or a mixture thereof, as an oral unit dose according to a once weekly, biweekly, twice monthly or once monthly dosing regimen. 
       
     
     
         3 . The method according to  claim 2  wherein the cathepsin K inhibitor is
 N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide; 
 N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[2′-methyl-4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide; 
 N 2 -{(1S)-1-[4′-(aminosulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-N 1 -(1-cyanocyclopropyl)-4-fluoro-L-leucinamide; 
 N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -[(1S)-2,2,2-trifluoro-1-(4′-fluorobiphenyl-4-yl)ethyl]-L-leucinamide; 
 N 2 -((1S)-1-{4′-[1-(aminocarbonyl)cyclopropyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-N 1 -(1-cyanocyclopropyl)-4-fluoro-L-leucinamide; 
 N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -((1S)-2,2,2-trifluoro-1-{4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]phenyl}ethyl)-L-leucinamide; 
 N 2 -((1S)-1-{4′-[1-(aminocarbonyl)cyclopropyl]-2′-fluorobiphenyl-4-yl}-2,2,2-trifluoroethyl)-N 1 -(1-cyanocyclopropyl)-4-fluoro-L-leucinamide; 
 N 1 -(1-cyanocyclopropyl)-N 2 -((1S)-1-{4′-[(1R)-2,2-difluoro-1-hydroxyethyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-4-fluoro-L-leucinamide; 
 N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -((1S)-2,2,2-trifluoro-1-{4-[5-methyl-6-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)-L-leucinamide; 
 N 1 -(1-cyanocyclopropyl)-N 2 -{(1S)-1-[4′-(1-cyanocyclopropyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-4-fluoro-L-leucinamide; 
 N 2 -[(1S)-1-(4-{5-[1-(aminocarbonyl)cyclopropyl]-3-chloropyridin-2-yl}phenyl)-2,2,2-trifluoroethyl]-N 1 -(1-cyanocyclopropyl)-4-fluoro-L-leucinamide; 
 N 2 -[(1S)-1-(5-{4-[1-(aminocarbonyl)cyclopropyl]phenyl}pyridin-2-yl)-2,2,2-trifluoroethyl]-N-1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide; 
 N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -((1S)-2,2,2-trifluoro-1-{5-[4-(methylsulfonyl)phenyl]pyridin-2-yl}ethyl)-L-leucinamide; 
 N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfinyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide; 
 N 1 -(1-cyanocyclopropyl)-N 2 -{(1S)-2,2-difluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-4-fluoro-L-leucinamide; 
 or a salt thereof. 
 
     
     
         4 . The method according to  claim 3  wherein the cathepsin K inhibitor is N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide. 
     
     
         5 . The method according to  claim 4  further comprising an agent selected from the group consisting of an organic bisphosphonate; an estrogen receptor modulator; an androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; an integrin receptor antagonist; an osteoblast anabolic agent; calcium; Vitamin D; a synthetic Vitamin D analogue; a Nonsteroidal anti-inflammatory drug; a selective cyclooxygenase-2 inhibitor; an inhibitor of interleukin-1 beta; a LOX/COX inhibitor; a RANKL inhibitor; and the pharmaceutically acceptable salts and mixtures thereof. 
     
     
         6 . The method according to  claim 5  wherein the agent is Vitamin D. 
     
     
         7 . The method according to  claim 6  wherein the amount of Vitamin D is 2,400 IU, 5,600 IU, 7,000 IU, 8,400 IU, 11,200 IU, 14,000 IU, 15,400 IU, 16,800 IU or 19,600 IU. 
     
     
         8 . The method according to  claim 2  where the oral unit dose is a tablet. 
     
     
         9 . The method according to  claim 2  where the oral unit dose is a capsule. 
     
     
         10 . The method according to  claim 2  where the oral unit dose is a liquid. 
     
     
         11 . The method according to  claim 4  where the mammal is identified as suffering from or susceptible to upper gastrointestinal disorders. 
     
     
         12 . The method according to  claim 11  wherein the upper gastrointestinal disorder is gastrointestinal reflux disease, esophagitis, dyspepsia or ulcers. 
     
     
         13 . The method according to  claim 2  for treating osteoporosis. 
     
     
         14 . A pharmaceutical composition comprising about 2.5 mg to about 200 mg of a cathepsin K inhibitor selected from
 N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide;   N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[2′-methyl-4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide;   N 2 -{(1S)-1-[4′-(aminosulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-N 1 -(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;   N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -[(1S)-2,2,2-trifluoro-1-(4′-fluorobiphenyl-4-yl)ethyl]-L-leucinamide;   N 2 -((1S)-1-{4′-[1-(aminocarbonyl)cyclopropyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-N 1 -(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;   N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -((1S)-2,2,2-trifluoro-1-{4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]phenyl}ethyl)-L-leucinamide;   N 2 -((1S)-1-{4′-[1-(aminocarbonyl)cyclopropyl]-2′-fluorobiphenyl-4-yl}-2,2,2-trifluoroethyl)-N 1 -(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;   N 1 -(1-cyanocyclopropyl)-N 2 -((1S)-1-{4′-[(1R)-2,2-difluoro-1-hydroxyethyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-4-fluoro-L-leucinamide;   N 1 -(1-cyanocyclopropyl)-N 2 -((1S)-1-{4′-[(1S)-2,2-difluoro-1-hydroxyethyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-4-fluoro-L-leucinamide;   N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -((1S)-2,2,2-trifluoro-1-{4-[5-methyl-6-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)-L-leucinamide;   N 1 -(1-cyanocyclopropyl)-N 2 -{(1S)-1-[4′-(1-cyanocyclopropyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-4-fluoro-L-leucinamide;   N 2 -[(1S)-1-(4-{5-[1-(aminocarbonyl)cyclopropyl]-3-chloropyridin-2-yl}phenyl)-2,2,2-trifluoroethyl]-N 1 -(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;   N 2 -[(1S)-1-(5-{4-[1-(aminocarbonyl)cyclopropyl]phenyl}pyridin-2-yl)-2,2,2-trifluoroethyl]-N-1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;   N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -((1S)-2,2,2-trifluoro-1-{5-[4-(methylsulfonyl)phenyl]pyridin-2-yl}ethyl)-L-leucinamide;   N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfinyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide;   N 1 -(1-cyanocyclopropyl)-N 2 -{(1S)-2,2-difluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-4-fluoro-L-leucinamide;   (1R,2R)—N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1H-pyrazol-3-yl]cyclohexanecarboxamide;   (1R,2R)—N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1-methyl-1 H-pyrazol-3-yl]cyclohexanecarboxamide;   (1R,2R)—N-(1-cyanocyclopropyl)-5,5-dichloro-2-[4-[4-(methylsulfonyl)phenyl]-1-methyl-1 H-pyrazol-3-yl]cyclohexanecarboxamide;   (1R,2R)—N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxamide;   (1R,2R)—N-(1-cyanocyclopropyl)-5,5-dichloro-2-[4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxamide;   or a salt thereof.   
     
     
         15 . The pharmaceutical composition according to  claim 14  wherein the cathepsin K inhibitor is N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide or a salt thereof. 
     
     
         16 . The composition according to  claim 15  which is oral. 
     
     
         17 . The composition according to  claim 16  which is a unit dose. 
     
     
         18 . The composition according to  claim 17  which is a weekly dose. 
     
     
         19 . The composition according to  claim 18  wherein the cathepsin-K inhibitor is N 1 -(1-cyanocyclopropyl)-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucinamide. 
     
     
         20 . The composition according to  claim 19  which is a tablet. 
     
     
         21 . The composition according to  claim 19  which is a capsule. 
     
     
         22 . The composition according to  claim 19  which is a powder. 
     
     
         23 . The composition according to  claim 19  which is a liquid. 
     
     
         24 - 42 . (canceled)