Substituted azabicyclic compounds

Abstract

This invention is directed to physiologically active compounds of formula (I) wherein represents a bicyclic ring, system, of 9 ring members, in which the ring is an oxazole, and the ring is a benzene ring; R 1 represents hydrogen or a straight- or branched-chain alkyl group of 1 to about 4 carbon atoms, optionally substituted by hydroxy or one or more halogen atoms, or when Z 1 represents a direct bond R 1 may also represent a lower alkenyl or lower alkynyl group, or a formyl group; R 2 represents hydrogen, alkenyl, alkoxy, alkyl, alkylsulphinyl, alkylsulphonyl, alkylthio, aryl, arylalkyloxy, arylalkylsulphinyl, arylalkylsulphonyl, arylalkylthio, aryloxy, arylsulphinyl, arylsulphonyl, arylthio, cyano, cycloalkenyl, cycloalkenyloxy, cycloalkyl, cycloalkyloxy, hydroxy, —SO 2 NR 4 R 5 , —NR 4 SO 2 R 5 , —NR 4 R 5 , —C(═O)R 5 , —C(═O)C(═O)R 5 , —C(═O)NR 4 R 5 , —C(═O)OR 5 , —O(C═O)NR 4 R 5 , or —NR 4 C(═O)R 5 ; R 3 represents —C(═Z)—N(R 7 )R 6 ; A 1 represents a straight or branched C 1-6 alkylene chain optionally substituted by hydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroaryl; Z 1 represents a direct bond, an oxygen or sulphur atom or NH; n is zero; and mis 1; and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (I) and N-oxides thereof, and their prodrugs. Such compounds inhibit the production or physiological effects of TNF and inhibit cyclic AMP phosphodiesterase. The invention is also directed to pharmaceutical compositions comprising compounds of formula (I), their pharmaceutical use and methods for their preparation.

1 . A compound of the general formula (I):  
       
         
           
           
               
               
           
         
         wherein  
         
           
             
             
                 
                 
             
           
         
          represents a bicyclic ring system, of 9 ring members, in which the ring  
         
           
             
             
                 
                 
             
           
         
          is an oxazole, and the ring  
         
           
             
             
                 
                 
             
           
         
          is a benzene ring; 
 R 1  represents hydrogen or a straight- or branched-chain alkyl group of 1 to about 4 carbon atoms, optionally substituted by hydroxy or one or more halogen atoms, or when Z 1  represents a direct bond R 1  may also represent a lower alkenyl or lower alkynyl group, or a formyl group;  
 R 2  represents hydrogen, alkenyl, alkoxy, alkyl, alkylsulphinyl, alkylsulphonyl, alkylthio, aryl, arylalkyloxy, arylalkylsulphinyl, arylalkylsulphonyl, arylalkylthio, aryloxy, arylsulphinyl, arylsulphonyl, arylthio, cyano, cycloalkenyl, cycloalkenyloxy, cycloalkyl, cycloalkyloxy, hydroxy, —SO 2 NR 4 R 5 , —NR 4 SO 2 R 5 , —NR 4 R 5 , —C(═O)R 5 , —C(═O)C(═O)R 5 , —C(═O)NR 4 R 5 , —C(═O)OR 5 , —O(C═O)NR 4 R 5 , or —NR 4 C(═O)R 5 ;  
 R 3  is: —C(═Z)—N(R 7 )R 6    
 
         R 4  and R 5 , which may be the same or different, each represent a hydrogen atom, or an alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heteroarylalkyl group;  
         R 6  is optionally substituted pyridyl;  
         R 7  is a hydrogen atom or an alkyl or amino group;  
         R 8  and R 9 , which may be the same or different, is each a hydrogen atom or alkyl, —CO 2 R 5 , —C(═Z)NR 26 R 27  (where R 26  and R 27  may be the same or different and each is as described for R 5 ), —CN or —CH 2 CN;  
         R 10  and R 11 , which may be the same or different, is each a group —(CH 2 ) p R 6 ;  
         R 12  is a hydrogen atom or an alkyl group;  
         R 13  is a hydrogen or halogen atom or an —OR 28  group (where R 28  is a hydrogen atom or an alkyl, alkenyl, alkoxyalkyl, acyl, carboxamido or thiocarboxamido group);  
         R 14  is a hydrogen atom or an alkyl group;  
         R 15  is a hydrogen atom or a hydroxyl group;  
         R 16  is a hydrogen atom or an alkyl, amino, aryl, arylalkyl or hydroxy group;  
         R 17  is a hydrogen atom or a C 1-4 alkyl or arylC 1-4 alkyl group;  
         R 18  is an amino, alkylamino, arylamino, alkoxy or aryloxy group;  
         R 19  is an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group;  
         R 20  is R 5 , (CH 2 ) p CO 2 R 5  or (CH 2 ) p COR 5 ;  
         R 21  is a group L 1 —R 29 , or R 21  is an optionally substituted cycloalkyl, cycloalkenyl or heterocycloalkyl group which may optionally be fused to an additional optionally substituted aromatic, heteroaromatic, carbocyclic or heterocycloalkyl ring (where the one or more optional substituents, for either or both rings, may be represented by -L 1 —R 29 );  
         L 1  is a straight or branched C 1 6alkylene chain, a straight or branched C 2-6 alkenylene chain, a straight or branched C 2-6 alkynylene chain or a straight or branched C 1-6 alkylene chain containing an oxygen or sulphur atom, a phenylene, imino (—NH—) or alkylimino linkage, or a sulphinyl or sulphonyl group, in which each of the alkylene, alkenylene and alkynylene chains may be optionally substituted, the substituents chosen from alkoxy, aryl, carboxy, cyano, cycloalkyl, halogen, heteroaryl, hydroxyl or oxo; and R 29  is hydrogen, or arylalkoxycarbonyl, carboxy or an acid bioisostere, cyano, —NY 1 Y 2 ;  
         Y 1  and Y 2  are independently hydrogen, alkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, or the group —NY 1 Y 2  may form a 4-6 membered cyclic amine (which may optionally contain a further heteroatom selected from O, S, or NY 1 , or which may be fused to an additional aromatic or heteroaromatic ring);  
         R 22  is a hydrogen atom, a group -L 1 —R 29 , or an optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl group which may optionally be fused to an additional optionally substituted aromatic, heteroaromatic, carbocyclic or heterocycloalkyl ring (where the one or more optional substituents, for either or both rings, may be represented by -L 1 —R 29 ); or both R 21  and R 22  represent aryl or heteroaryl each optionally substituted by  
         -L 1 —R 29 ; or the group —NR 21 R 22  represents an optionally substituted, saturated or unsaturated 3 to 8 membered cyclic amine ring, which may optionally contain one or more heteroatoms selected from O, S or N, and may also be fused to an additional optionally substituted aromatic, heteroaromatic, carbocyclic or heterocycloalkyl ring (where the one or more optional substituents, for any of the rings, may be represented by -L 1 —R 29 );  
         
           
             
             
                 
                 
             
           
         
          where:  
         R 30  is hydrogen atom or an alkyl, hydroxyalkyl or alkoxyalkl group;  
         R 31  is a hydrogen atom or an alkyl, carboxy, CONHOR 14 , N-alkylaminoalkyl, N,N-dialkylaminoalkyl or alkoxyalkyl group; or R 30  and R 31  together represent a —CH 2 —O—CH 2 —O—CH 2 — group;  
         R 32  is a hydrogen atom, or amino, alkyl, aminoalkyl, hydroxyalkyl, hydroxy, acyl, alkoxycarbonyl, methoxycarbonylalkyl, —(CH 2 ) p CONY 3 Y 4 ;  
         Y 3  and Y 4  are each independently hydrogen or alkyl;  
         —(CH 2 ) p SO 2 NY 3 Y 4 , —(CH 2 ) p PO 3 H 2 , —(CH 2 ) p SO 2 NHCOalkyl, or —(CH 2 ) p SO 2 NHCOR 6 ;  
         R 33  is C 1-4 alkyl, CH 2 NHCOCONH 2 , CH═—C(R 43 )R 44 , cyclopropyl (optionally substituted by R 43 ), CN, CH 2 OR 44  or CH 2 NR 44 R 45 ;  
         R 43  is R 44  or fluorine and R 44  is hydrogen or C 1-4 alkyl optionally substituted by 1 to 3 fluorine atoms;  
         R 45  is hydrogen, OR 44 , or C 1-4 alkyl optionally substituted by 1 to 3 fluorine atoms;  
         NR 44 R 45  represents a 5 to 7 membered cyclic amine optionally containing one or more additional heteroatoms selected from O, N, and S;  
         R 34  is methyl or ethyl optionally substituted by 1 or more halogen atoms;  
         R 35  is R 14 , —OR 14 , —C 2 R 14 , —COR 14 , —CN, —CONY 3 Y 4  or —NY 3 Y 4 ;  
         R 36  is —C(═Z)R 14 , —CO 2 R 14 , —CONY 3 Y 4  or —CN;  
         R 37  and R 39 , which may be the same or different, is each a hydrogen atom, alkyl, acyl, arylalkyl, —(CH 2 ) p CO 2 R 5 , —CONHR 5 , heteroarylalkyl, aryl, or heteroaryl;  
         R 38  is acyl, aroyl, —C(═O)cycloalkyl, alkoxycarbonyl, cycloalkoxycarbonyl, carboxy, alkoxyalkyl, —NO 2 , —CH 2 H, —CN, —NR 14 COR 5 , —NR 14 CONY 5 Y 6 , —NR 14 SO 2 R 46 , —SO 2 R 46  or —CONY 5 Y 6 ;  
         R 46  is alkyl, cycloalkyl, trifluoromethyl, aryl, arylalkyl or —NY 5 Y 6 ;  
         Y 5  and Y 6  are independently selected from hydrogen, alkyl, cycloalkyl, aryl or arylalkyl, or Y 5  and Y 6  together form a 4- to 7-membered heterocyclic or carbocyclic ring;  
         R 40  is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, acyl, aroyl, —C(═O)cycloalkyl, —CH 2 OH, alkoxyalkyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, —CN, —NO 2 , or —SO 2 R 46 ;  
         R 41  is —CN, —C(Z)R 47  (where R 47  is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, C 1-6 alkoxy, arylalkoxy, aryloxy or —NY 5 Y 6 ) or SO 2 R 46 ; R 42  is hydrogen, alkyl, cycloalkyl, acyl, aroyl, —C(═O)cycloalkyl, alkoxycarbonyl, cycloalkoxycarbonyl, carboxy, —CN, —SO 2 R 46  or —CONY 5 Y 6 ;  
         W is (CH 2 ) r  or NR 39 ;  
         Z 3  is an oxygen atom, NR 14  or NOR 14 ;  
         s is zero or an integer 1 to 4;  
         r is 1 to 4; and  
         Y is an oxygen atom, C(═O), CH(OH) or C(OR 14 )(CH 2 ) p R 6 ;  
         R 24  is R 5  or CONHR 25 ;  
         R 25  is hydrogen, C 1-3 alkyl or (CH 2 ) q R 6 ;  
         p is zero or an integer from 1 to 5;  
         q is zero or 1;  
         X 1  and X 2 , which may be the same or different, is each a hydrogen or fluorine atom;  
         X 3  is a chlorine or fluorine atom, alkoxy, aryloxy, heteroaryloxy, arylalkyloxy or heteroarylalkyl;  
         X 4  is a halogen atom or hydroxy;  
         Z represents an oxygen or sulphur atom; 
 A 1  is a straight or branched C 1-6 alkylene chain optionally substituted by hydroxyl, alkoxy, oxo, cycloalkyl, aryl or heteroaryl;  
 Z 1  represents a direct bond, an oxygen or sulphur atom or NH;  
 n is zero; and  
 m is 1;  
 and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (I) and N-oxides thereof, and their prodrugs.  
 
       
     
     
         2 . A compound according to  claim 1  in which R 1  represents C 1-4 alkyl optionally substituted by one or more halogen atoms.  
     
     
         3 . A compound according to  claim 1  in which Z 1 represents a direct bond or an oxygen atom.  
     
     
         4 . A compound according to  claim 1  in which A 1  represents a direct bond or a straight- or branched-chain alkylene linkage containing from 1 to 6 carbon atoms and optionally substituted by alkoxy.  
     
     
         5 . A compound according to  claim 1  in which R 3  represents —C(═O)NHR 6 .  
     
     
         6 . A compound according to  claim 5  in which R 6  is substituted on both positions adjacent to the position of attachment of R 6  to the rest of the molecule.  
     
     
         7 . A compound according to  claim 5  in which R 6  is substituted by two methyl or halogen moieties on both positions adjacent to the position of attachment of R 6  to the rest of the molecule.  
     
     
         8 . A compound according to  claim 5  in which R 6  is 3,5-dimethylpyrid-4-yl, 3,5-dihalopyrid-4-yl or an N-oxide of such groups.  
     
     
         9 . A compound of formula (Ia)  
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , A 1  and Z 1  are as defined in  claim 1 , Q 1  is CH, CX 5  (where X 5  is halogen), a nitrogen atom or N + —O −  and  
         
           
             
             
                 
                 
             
           
         
          (where R 5  represents a hydrogen atom or a methyl group), and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (I) and N-oxides thereof and their prodrugs.  
       
     
     
         10 . A compound according to  claim 9  in which R 1  represents C 1-4 alkyl optionally substituted by one or more halogen atoms.  
     
     
         11 . A compound according to  claim 9  in which R 1  represents methyl or difluoromethyl.  
     
     
         12 . A compound according to  claim 9  in which R 2  represents a straight- or branched-chain C 1-4 alkyl group, or cycloalkyl, alkoxy, aryl, or aryloxy.  
     
     
         13 . A compound according to  claim 9  in which R 3  represents —C(═O)—NHR 6 .  
     
     
         14 . A compound according to  claim 13  in which R 6  is substituted on both positions adjacent to the position of attachment of R 6  to the rest of the molecule.  
     
     
         15 . A compound according to  claim 13  in which R 6  is substituted by two methyl or halogen moieties on both positions adjacent to the position of attachment of R 6  to the rest of the molecule.  
     
     
         16 . A compound according to  claim 13  in which R 6  is 3,5-dimethylpyrid-4-yl, 3,5-dihalopyrid-4-yl or an N-oxide of such groups.  
     
     
         17 . A compound according to  claim 9  in which A 1  represents a straight- or branched-chain alkylene linkage containing 1 to 6 carbon atoms optionally substituted by alkoxy.  
     
     
         18 . A compound according to  claim 9  in which  
       
         
           
           
               
               
           
         
         represents  
         
           
             
             
                 
                 
             
           
         
          and where R 5  is a hydrogen atom.  
       
     
     
         19 . A compound according to  claim 9  in which Q 1  is a CH linkage.  
     
     
         20 . A compound according  claim 9  in which Z 1  is an oxygen atom.  
     
     
         21 . A compound according to  claim 9  in which R 1  is methyl or difluoromethyl, R 2  is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, aryl, or aryloxy, R 3  is —C(═O)—NIR 6 , A 1  is a methylene linkage;  
       
         
           
           
               
               
           
         
         Q 1  is a CH linkage and Z 1  is an oxygen atom, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (Ia) herein and N-oxides thereof, and their prodrugs.  
       
     
     
         22 . A compound of formula (Ib)  
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , A 1  and Z 1  are as defined in  claim 1 , and Q represents a CH linkage or a nitrogen atom, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (Ib) and N-oxides thereof, and their prodrugs.  
       
     
     
         23 . A compound according to  claim 22  in which R 1  is hydrogen or methyl, R 2  is C 4-9 alkyl, C 3-7 cycloalkyl, or aryl, R 3  is —C(═O)—NHR 6 , A 1  is a methylene linkage, Z 1  is a direct bond, and Q is a CH linkage or a nitrogen atom, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (Ib) herein and N-oxides thereof, and their prodrugs.  
     
     
         24 . A compound of formula (Ic)  
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , A 1  and Z 1  are as defined in  claim 1 , Q 1  is CH, CX 5  (where X 5  is halogen), a nitrogen atom or N + —O −  and Z is an oxygen or sulphur atom, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (Ic) and N-oxides thereof, and their prodrugs.  
       
     
     
         25 . A compound according to  claim 24  in which R 1  is methyl or difluoromethyl, R 2  is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, aryl, or aryloxy, R 3  is —C(═O—NHR 6 , or 
 A 1  is a methylene linkage, Q 1  is a CH linkage, and Z and Z 1  are both oxygen atoms, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (Ic) herein and N-oxides thereof, and their prodrugs.  
 
     
     
         26 . A compound of formula (Id)  
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , A 1  and Z 1  are as defined in  claim 1 , Q 1  is CH, CX 5  (where X 5  is halogen), a nitrogen atom or N + —O −  and Z is an oxygen or sulphur atom, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (Id) and N-oxides thereof, and their prodrugs.  
       
     
     
         27 . A compound according to  claim 26  in which R 1  is methyl or difluoromethyl, R 2  is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, aryl, or aryloxy, R 3  is —C(═O)—NHR 6 , A 1  is a methylene linkage, Q 1  is a CH linkage, and Z and Z 1  are both oxygen atoms, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (Id) herein and N-oxides thereof, and their prodrugs.  
     
     
         28 . A compound of formula (Ie)  
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , A 1  and Z 1  are as defined in  claim 1 , and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (Ie) and N-oxides thereof, and their prodrugs.  
       
     
     
         29 . A compound according to  claim 28  in which R 1  is hydrogen or methyl, R 2  is C 4-9 alkyl, C 3-7 cycloalkyl, or aryl, R 3  is —C(═O)—NHR 6 , A 1  is a methylene linkage and Z 1  is a direct bond, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (Ie) herein and N-oxides thereof, and their prodrugs.  
     
     
         30 .  
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , A 1  and Z 1  are as defined in  claim 1 , and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (If) and N-oxides thereof, and their prodrugs.  
       
     
     
         31 . A compound according to  claim 30  in which R 1  is hydrogen or methyl, R 2  is C 1-4 alkyl, C 3-7 cycloalkyl, or aryl, R 3  is —C(═O)—NHR 6 , A 1  is a methylene linkage and Z 1  is an oxygen atom, and N-oxides thereof, and their prodrugs, and pharmaceutically acceptable salts and solvates of the compounds of formula (If) herein and N-oxides thereof, and their prodrugs.  
     
     
         32 . A compound according to  claim 1  selected from the group consisting of: 
 N-(3,5-dichloro-4-pyridyl)-4-methoxy-2-methoxymethyl-benzoxazole-7-carboxamide;  
 N-(3,5-dichloro-4-pyridyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;  
 N-(3,5-dichloro-4-pyridyl)-2,7-dimethoxy-3H-benzimidazole-4-carboxamide;  
 2-cyclopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;  
 2-isopropyl-N-(3,5-dichloro-4-pyridyl)-7-methoxy-3H-benzimidazole-4-carboxamide;  
 2-cyclopropyl-N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-3H-benzimidazole-4-carboxamide;  
 N-(3,5-dimethyl-4-isoxazolyl)-7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxamide;  
 2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazole;  
 4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-2-methoxymethyl-3H-benzimidazole;  
 and the corresponding pyridine N-oxides, and their prodrugs, and pharmaceutically acceptable salts and solvates thereof.  
 
     
     
         33 . A compound according to  claim 1  which is selected from 2-cyclopropyl-4-(3,5-dimethyl-4-pyridylmethoxy)-7-methoxy-3H-benzimidazole; and its corresponding pyridine N-oxide, and its prodrugs, and pharmaceutically acceptable salts and solvates thereof.  
     
     
         34 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1  or a prodrug thereof, and pharmaceutically acceptable salts and solvates thereof in association with a pharmaceutically acceptable carrier or excipient.  
     
     
         35 . A method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of TNF, comprising administering to said patient a compound of formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof as claimed in  claim 1 .  
     
     
         36 . A method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of type IV cyclic AMP phosphodiesterase, comprising administering to said patient a compound of formula (I)or a prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof as claimed in  claim 1 .  
     
     
         37 . A method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of type IV cyclic AMP phosphodiesterase or of TNF, comprising administering to said patient an effective amount of a compound of formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof as claimed in  claim 1.