Substituted benzoazole pde4 inhibitors for treating pulmonary and cardiovascular disorders

Abstract

The invention relates to substituted benzothiazoles, benzoxazoles—and their counterparts having pyridine and pyrimidine rings replacing the benzene ring—that are PDE4 inhibitors useful for treating stroke, myocardial infarct, and cardiovascular inflammatory conditions, to pharmaceutical compositions comprising these compounds, and to methods for the treatment of stroke, myocardial infarct, and cardiovascular inflammatory conditions in a mammal. The compounds have general formula I: in which A and B are carbocycles or heterocycles. A particular embodiment is

1 . A compound of formula Ia, Ib or Ic: 
       
         
           
           
               
               
           
         
         or salt thereof wherein 
         U is selected from the group consisting of —S— and —O—; 
         V is selected from the group consisting of H, CH 3 , NH 2 , and CF 3 ; 
         X is selected from the group consisting of CH, C—F, C—Cl, C—Br, C—I, C—NH 2 , C—OH, C—OCH 3 , 
         N, and N—O; 
         Y is selected from the group consisting of N, CH, CF and C-lower alkyl; 
         R 1  is H or lower alkyl; 
         R 2  is selected from the group consisting of H, alkyl, OH, NH 2 , and OCH 3 ; 
         B is an optionally substituted, mono- or bicyclic aryl or heteroaryl; 
         A is an optionally substituted heterocycle or an optionally substituted carbocycle; and 
         A 1  is chosen from
 (a) a residue chosen from 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein R 40  is chosen from H, halogen, OH, NH 2  and CH 3 ; 
           
           (b) a substituted heterocycle of three or fewer rings or substituted carbocycle of three or fewer rings; and 
           (c) a heterocycle that is itself substituted with a heterocycle carrying a further substituent; 
         
         wherein substituents on the heterocycle or carbocycle are chosen from hydroxy, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonyl, carboxyalkylcarbonylamino, carboxyalkylaminocarbonylamino, guanidino, the residue of an amino acid and the residue of an N-methylated amino acid. 
       
     
     
         2 . A compound or salt according to  claim 1  wherein B is phenyl which has a substituent at the 3-position, the 4-position or at both the 3- and 4-positions. 
     
     
         3 . A compound or salt according to  claim 2  wherein B is selected from 3-chlorophenyl, 3-nitrophenyl, 3-cyanophenyl, 3-bromophenyl, 3-acetylphenyl, 3-trifluoromethylphenyl, and 3-methylthiophenyl. 
     
     
         4 . A compound or salt according to  claim 1  wherein B is benzo[c][1,2,5]oxadiazol-5-yl or benzo[d][1,3]dioxol-5-yl. 
     
     
         5 . A compound or salt according to  claim 1  wherein R 1  is H and R 2  is chosen from H and OH. 
     
     
         6 . A compound of formula Ia, Ib or Ic or salt thereof according to  claim 1  wherein A or A 1  is optionally substituted phenyl. 
     
     
         7 . A compound of formula Ia, Ib or Ic or salt thereof according to  claim 1  wherein A or A 1  is selected from the group consisting of optionally substituted 5- and 6-membered ring nitrogen heterocycles. 
     
     
         8 . A compound or salt according to  claim 7  wherein A or A 1  is selected from the group consisting of optionally substituted pyridinyl, morpholin-4-yl, piperazin-1-yl, piperidiny-1-yl, imidazol-1-yl, pyrazol-1-yl, and pyrazol-5-yl. 
     
     
         9 . A compound or salt according to  claim 1  wherein X is selected from the group consisting of CH, C—F, C—OH and N. 
     
     
         10 . A compound or salt according to  claim 1  wherein
 X is selected from the group consisting of CH, C—F, C—OH, N and N—O; 
 Y is N or CH; 
 U is O; 
 V is selected from H, CH 3  and NH 2 ; 
 B is benzo[c][1,2,5]oxadiazol-5-yl or phenyl which has a substituent at the 3-position, the 4-position or at both the 3- and 4-positions; 
 R 1  is H; 
 R 2  is chosen from H and OH; and 
 A or A 1  is selected from the group consisting of optionally substituted phenyl and optionally substituted 5- and 6-membered ring nitrogen heterocycles. 
 
     
     
         11 . A compound or salt according to  claim 1  wherein
 X is selected from the group consisting of CH, C—F, C—OH, N and N—O; 
 Y is N or CH; 
 U is S; 
 V is selected from H, CH 3  and NH 2 ; 
 B is benzo[c][1,2,5]oxadiazol-5-yl or phenyl which has a substituent at the 3-position, the 4-position or at both the 3- and 4-positions; 
 R 1  is H; 
 R 2  is chosen from H and OH; and 
 A or A 1  is selected from the group consisting of optionally substituted phenyl and optionally substituted 5- and 6-membered ring nitrogen heterocycles. 
 
     
     
         12 . A compound or salt according to  claim 6  or  7  wherein B is selected from benzo[d][1,3]dioxol-5-yl, 3-chlorophenyl, 3-nitrophenyl, 3-cyanophenyl, 3-bromophenyl, 3-acetylphenyl, 3-trifluoromethylphenyl, and 3-methylthiophenyl. 
     
     
         13 . A compound or salt according to  claim 12  wherein A or A 1  is selected from the group consisting of optionally substituted pyridinyl, morpholin-4-yl, piperazin-1-yl, piperidiny-1-yl, imidazol-1-yl, pyrazol-1-yl, and pyrazol-5-yl. 
     
     
         14 . A compound or salt according to  claim 1  of formula 
       
         
           
           
               
               
           
         
         wherein 
         A 2  is chosen from phenyl, five-membered heteroaryl, six-membered heteroaryl, 4-7 membered non-aryl heterocycle and fused bicycle; 
         R 7  is H or F; 
         R 8  is chosen from halogen, nitro, acetyl, hydroxyethyl, amino, methylthio, trifluoromethyl, methoxymethyl, methoxycarbonyl, trifluoromethoxy, cyano and 1,3,4-thiadiazol-2-yl, or taken together R 7  and R 8  are methylenedioxy, ═N—O—N═, —NH—CH═N— or difluoromethylenedioxy; 
         R 14  is chosen from H, halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, —NHC(═O)NHalkyl, —NHC(═O)NH-heterocyclyl, -alkyl-NHC(═O)N(alkyl) 2 , heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides and monocyclic heterocycle substituted with any of the foregoing; 
         R 14a  is chosen from hydroxy, carboxy, alkoxycarbonyl, carboxyalkylcarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, carboxyalkylaminocarbonylamino, guanidino, the residue of an amino acid and the residue of an N-methylated amino acid, 5-tetrazolyl and monocyclic heterocycle substituted with any of the foregoing; 
         R 15  is chosen from H, NO 2 , OH, NH 2 , and —NHSO 2 NH 2 ; or 
         R 15  together with R 14  forms methylene dioxy. 
       
     
     
         15 . A compound or salt according to  claim 1  of formula 
       
         
           
           
               
               
           
         
         wherein 
         A 2  is phenyl, five-membered heteroaryl, six-membered heteroaryl, 4-7 membered non-aryl heterocycle or fused bicycle; 
         R 7  is H or F; 
         R 8  is chosen from halogen, nitro, acetyl, hydroxyethyl, amino, methylthio, trifluoromethyl, methoxymethyl, methoxycarbonyl, trifluoromethoxy, cyano and 1,3,4-thiadiazol-2-yl, or taken together R 7  and R 8  are methylenedioxy, ═N—O—N═, —NH—CH═N— or difluoromethylenedioxy; 
         R 14  is chosen from H, —CH 3 , —CH 2 CF 3 , —CF 3 , —CHO, —COOH, —CN, halogen, —OH, —OEt, —C(═O)NH 2 , —C(═O)NHEt, —C(═O)NMe 2 -COOCH 3 , —COOEt, —CH 2 NHC(═O)NH 2 , —CH(CH 3 )NHC(═O)NH 2 , —CH 2 NHC(═O)H, —CH 2 NHC(═O)CH 3 , —CH 2 C(═O)NH 2 , —CH 2 COOH, —CH 2 COOEt, —CH 2 NHC(═O)OEt, —CH 2 NHC(═O)O—C 6 H 5 , —CH 2 NHC(═O)C(═O)NH 2 , —CH 2 NHC(═O)NHEt, —C(CH 3 ) 2 OH, —CH 2 NHC(═O)N(CH 3 ) 2 , —CH 2 NHC(═O)NHCH 3 , —CH 2 NH 2 , —CH(CH 3 )NH 2 , —C(CH 3 ) 2 NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 NHSO 2 CH 3 , —CH 2 C(═O)NHEt, —OCH 3 , —OC(═O)NH 2 , —OCH 2 CH 2 N(CH 3 ) 2 , —OCH 2 CH 2 OCH 3 , —OCH(CH 3 )COOH, —SCH 2 COOH, —NHC(═O)NH 2 , —NHC(═O)NHEt, —NHCH 3 , —NHEt, —NH(tBoc), —NHCH 2 COOH, —N(CH 3 )CH 2 COOH, —NHC(═O)NHCH 2 CH 2 Cl, —NHSO 2 NH 2 , —NHEt, —N(CH 3 ) 2 , —NH 2 , —NH(CH 3 )C(═O)NH 2 , —NHSO 2 CH 3 , —N(SO 2 CH 3 ) 2 , —NHC(═O)OCH 3 , —NHC(═O)OtBu, —NHC(═O)CH 3 , —SO 2 NH 2 , —NHC(═O)CH 2 CH 2 COOH, —NHC(═O)NHCH 2 COOH, —CH 2 NHCHO, —NHC(═O)NHCH 2 COOEt, —NHC(═O)NH(CH 2 ) 3 COOEt, —NHC(═O)NH(CH 2 ) 2 COOEt, —N(CH 3 )CH 2 CH 2 OH, —NHC(═O)OEt, —N(Et)C(═O)OEt, —NHC(═O)NH(CH 2 ) 2 COOH, —NHC(═O)CH 2 N(CH 3 ) 2 , —NHC(═O)NH(CH 2 ) 3 COOH, —NHC(═O)CH 2 NH 2 , —NHC(═O)CH 2 CH 2 NH 2 , —NHC(═O)CH 2 NH(tBoc), 
       
       
         
           
           
               
               
           
         
       
       and monocyclic heterocycle substituted with any of the foregoing;
 R 14a  is chosen from —COOH, —OH, —COOCH 3 , —COOEt, —CH 2 COOH, —CH 2 COOEt, —OCH(CH 3 )COOH, —SCH 2 COOH, —CH 2 NHC(═O)OEt, —CH 2 NHC(═O)C(═O)NH 2 , —NHCH 2 COOH, —N(CH 3 )CH 2 COOH, —NHSO 2 NH 2 , —NHC(═O)CH 2 CH 2 COOH, —NHC(═O)NHCH 2 COOH, —NHC(═O)NHCH 2 COOEt, —NHC(═O)NH(CH 2 ) 3 COOEt, —NHC(═O)NH(CH 2 ) 2 COOEt, —NHC(═O)NH(CH 2 ) 2 COOH, —NHC(═O)NH(CH 2 ) 3 COOH, 5-tetrazolyl and monocyclic heterocycle substituted with any of the foregoing; 
 R 15  is chosen from H, NO 2 , OH, NH 2 , and —NHSO 2 NH 2 ; or 
 R 15  together with R 14  forms methylene dioxy. 
 
     
     
         16 . A compound or salt according to  claim 1 , wherein Y is N. 
     
     
         17 . A compound or salt according to  claim 1 , wherein Y is CH. 
     
     
         18 . A compound or salt according to  claim 1 , wherein U is S. 
     
     
         19 . A compound or salt according to  claim 1 , wherein U is O. 
     
     
         20 . A compound or salt according to  claim 1 , wherein V is selected from H, CH 3  and NH 2 . 
     
     
         21 . A salt of a compound of  claim 1  wherein the salt is a pharmaceutically acceptable salt. 
     
     
         22 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt according to  claim 1 . 
     
     
         23 . A pharmaceutical composition comprising
 (a) a pharmaceutically acceptable carrier;   (b) a compound or pharmaceutically acceptable salt according to  claim 1 ; and   (c) a second agent chosen from cholinesterase inhibitors, NMDA antagonists, calpain inhibitors and antioxidants.   
     
     
         24 . A pharmaceutical composition according to  claim 23  wherein said second agent is chosen from tacrine, huperzine, donepezil, lanicemine, remacemide, neramexane, memantine, vitamin E and coenzyme Q10. 
     
     
         25 . A method for the treatment or prophylaxis of a disease or condition mediated by peripheral phosphodiesterase-4 comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         26 . A method according to  claim 25  wherein said disease or condition is chosen from stroke, myocardial infarct, and cardiovascular inflammatory conditions. 
     
     
         27 . A method according to  claim 25  wherein said disease or condition is cancer. 
     
     
         28 . A method according to  claim 25  wherein said disease or condition is chosen from asthma and COPD. 
     
     
         29 . A method for treating or preventing bone loss comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         30 . A method for treating bladder inflammation, bladder overactivity and pain arising from bladder inflammation comprising administering to a mammal a therapeutically effective amount of a compound according to  claim 1 .