Heterocyclic derivatives which inhibit factor Xa

Abstract

The invention relates to heterocyclic derivatives, or pharmaceutically-acceptable salts thereof, which possess antithrombotic and anticoagulant properties and are accordingly useful in methods of treatment of humans or animals. The, invention also relates to processes for the preparation of the heterocyclic derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect, formula (I).

1 . A compound of the formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is an optionally substituted 5- or 6-membered monocyclic aromatic ring containing 1, 2 or 3 ring heteroatoms selected from oxygen, nitrogen and sulphur atoms;  
 B 1 , B 2 , B 3  and B 4  are independently CH or a nitrogen atom, wherein the ring formed from B 1 , B 2 , B 3  and B 4  may optionally be substituted; with the proviso that at least one of B 1 , B 2 , B 3  and B 4  is nitrogen;  
 T 1  is CH or N;  
 T 2  is CH or N;  
 with the proviso that at least one of T 1  and T 2  is N;  
 X, is SO, SO 2 , C(R 4 ) 2  or CO when T 1  is CH or N; or in addition X 1  is O or S when T 1  is CH;  
 and wherein each R 4  is independently hydrogen or (1-4C)alkyl:  
 L 1  is (1-4C)alkylene or (1-3C)alkylenecarbonyl:  
 R 2  is hydrogen or (1-4C)alkyl;  
 R 3  is hydrogen or (1-4C)alkyl;  
 or R 2  and R 3  are joined to form a C 1-4 alkylene or —CH 2 CO— group; wherein the ring formed by T 1 , R 2 , R 3 , T 2  and L 1  is optionally substituted;  
 X 2  is S(O) y  wherein y is one or two, C(R 5 ) 2  or CO; and each R 5  is hydrogen or C 1-4 alkyl;  
 Q is phenyl, naphthyl, phenyl(1-4C)alkyl, phenyl(2-4C)alkenyl, phenyl(2-4C)alkynyl or a heterocyclic moiety containing up to 4 ring heteroatoms selected from nitrogen, oxygen and sulphur and Q is optionally substituted;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . A compound of formula I as claimed in  claim 1  wherein Q is eiter unsubstituted or substituted by by one, two or three substituents selected from halo, trifluromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, trifluoromethanesulphonyl, carboxy, carbamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1 -4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkoxycarbonyl,  N -(1-4C)alkylcarbamoyl,  N,N -di-(1-4C)alkylcarbamoyl, (2-4C)alkanoyl, (2-4C)alkanoylamino, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl,  N -(1-4C)alkylcarbamoyl-(1-4C)alkyl,  N,N -di-(1-4C)alkylcarbamoyl-(1-4C)alkyl, phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, benzyl, benzoyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl and heteroarylsulphonyl, and wherein said heteroaryl substituent or the heteroaryl group in a heteroaryl-containing substituent comprises a 5- or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatoms selected from nitrogen, oxygen and sulphur, and wherein said phenyl, heteroaryl, phenoxy, phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl or benzoyl substituent optionally bears 1, 2 or 3 substituents selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkoxycarbonyl,  N -(1-4C)alkylcarbamoyl.  N,N -di-(1-4C)alkylcarbamoyl and (2-4C)alkanoylamino.  
     
     
         3 . A compound of formula I as claimed in either  claim 1  or  2  wherein any ring formed by T 1 , R 2 , R 3 , T 2  is either unsubstituted or substituted by one or two substituents selected from hydroxy, oxo, carboxy, (1-4C)alkoxycarbonyl or one of the following; 
 —(CH 2 ) n —R, —(CH 2 ) n —NRR 1 , —CO—R, —CO—NRR 1 , —(CH 2 ) n —CO—R and —(CH 2 ) n —CO—NRR 1 ;  
 wherein n is 1 or 2;  
 R and R 1  are independently selected from hydrogen, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, hydroxy(1-4C)alkyl, carboxy(1-4C)alkyl and (1-4C)alkoxycarbonyl(1-4C)alkyl or where possible R and R 1  may together form a 5- or 6-membered optionally substituted heterocyclic ring which may include in addition to the nitrogen atom to which R and R 1  are attached 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulphur.  
 
     
     
         4 . A compound of formula I as claimed in any of the preceding claims wherein X 1  is CO.  
     
     
         5 . A compound of formula I as claimed in any of the preceding claims wherein X 2  is SO 2 .  
     
     
         6 . A compound of formula I as claimed in any of the preceding claims for use in medical therapy.  
     
     
         7 . Use of a compound of formula I, as defined in any one of the  claims 1  to  5 , in the production of a medicament for treating a Factor Xa mediated disease or medical condition.  
     
     
         8 . A pharmaceutical composition comprising a compound of formula I, as defined in any one of  claims 1  to  5 .  
     
     
         9 . A method of treating a Factor Xa mediated disease or medical condition which comprises administering to a warm-blooded animal requiring such treatment an effective amount of a compound of formual I, as claimed in any one of  claims 1  to  5 .