New mandelic acid derivatives and their use as thrombin inhibitors

Abstract

There is provided a compound of formula (I) wherein R a , R 1 , R 2 , Y and R 3 have meanings given in the description and pharmaceutically-acceptable derivatives (including prodrugs) thereof, which compounds and derivatives are useful as, or are useful as prodrugs of, competitive inhibitors of trypsin-like proteases, such as thrombin, and thus, in particular, in the treatment of conditions where inhibition of thrombin is required (e.g., thrombosis) or as anticoagulants.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R a  represents —OH or —CH 2 OH; 
 R 1  represents one or more optional halo substituents; 
 R 2  represents one or two C 1-3  alkoxy substituents, the alkyl parts of which substituents are themselves substituted by one or more fluoro substituents; 
 Y represents —CH 2 — or —(CH 2 ) 2 —; and 
 R 3  represents a structural fragment of formula I(i) or I(ii): 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 4  represents H or one or more fluoro substituents; and 
 one or two of X 1 , X 2 , X 3  and X 4  represent —N— and the others represent —CH—, 
 
       or a pharmaceutically-acceptable derivative thereof. 
     
     
         2 . The compound as claimed in  claim 1  wherein R 1  represents a single fluoro, chloro or bromo substituent. 
     
     
         3 . The compound as claimed in  claim 2  wherein R 1  represents chloro. 
     
     
         4 . The compound as claimed in  claim 1  wherein R 2  represents —OCHF 2 , —OCF 3 , —OCH 2 CF 3 , —OCH 2 CHF 2 , —OCH 2 CH 2 F or —OCH(CH 2 F) 2 . 
     
     
         5 . The compound as claimed in  claim 4  wherein R 2  represents —OCHF 2 , —OCH 2 CHF 2  or —OCH 2 CH 2 F. 
     
     
         6 . The compound as claimed in  claim 1  wherein R 3  represents a structural fragment of formula I(i). 
     
     
         7 . The compound as claimed in  claim 6  wherein R 4  represents H. 
     
     
         8 . The compound as claimed in  claim 6  wherein, when R 4  represents one or more fluoro substituents, it represents a single fluoro substituent in the 2- or the 3-position, or two fluoro substituents in either the 2- and 5- positions or the 2- and 6-positions. 
     
     
         9 . The compound as claimed in  claim 8  wherein R 4  represents a single fluoro substituent in the 2-position or two fluoro substituents in the 2- and 6-positions. 
     
     
         10 . The compound as claimed in  claim 1  wherein R a  represents OH. 
     
     
         11 . The compound as claimed in  claim 1  wherein the points of substitution of R 1  and R 2  on the relevant phenyl group of the compound of formula I is one or both of the two meta-positions, relative to the point of attachment of that phenyl group to the rest of the molecule. 
     
     
         12 . A pharmaceutically acceptable derivative of a compound of formula I as defined in  claim 1 , which derivative compound is a compound of formula Ia, 
       
         
           
           
               
               
           
         
       
       wherein R 3a  represents a structural fragment of formula I(iii) or I(iv): 
       
         
           
           
               
               
           
         
       
       wherein R 5  represents OR 6  or C(O)OR 7 ;
 R 6  represents H, C 1-30  alkyl, C 1-3  alkylaryl or C 1-3  alkyloxyaryl (the alkyl parts of which latter two groups are optionally interrupted by one or more oxygen atoms, and the aryl parts of which latter two groups are optionally substituted by one or more substituents selected from halo, phenyl, methyl or methoxy, which latter three groups are also optionally substituted by one or more halo substituents); 
 R 7  represents C 1-10  alkyl (which latter group is optionally interrupted by one or more oxygen atoms), or C 1-3  alkylaryl or C 1-3  alkyloxyaryl (the alkyl parts of which latter two groups are optionally interrupted by one or more oxygen atoms, and the aryl parts of which latter two groups are optionally substituted by one or more substituents selected from halo, phenyl, methyl or methoxy, which latter three groups are also optionally substituted by one or more halo substituents); and 
 R a , R 1 , R 2 , Y, R 4 , X 1 , X 2 , X 3  and X 4  are as defined in  claim 1 , 
 
       or a pharmaceutically-acceptable derivative thereof. 
     
     
         13 . The compound as claimed in  claim 12  wherein R 5  represents OR 6 . 
     
     
         14 . The compound as claimed in  claim 13  wherein R 6  represents H or unsubstituted, linear, branched or cyclic C 1-8  alkyl. 
     
     
         15 . The compound as claimed in  claim 14  wherein R 6  represents H or C 1-6  alkyl. 
     
     
         16 . The compound as claimed in  claim 14  wherein R 6  represents linear C 1-3  alkyl, branched C 3-8  alkyl or cyclic C 4-7  alkyl. 
     
     
         17 . The compound as claimed in  claim 15  or  claim 16  wherein R 6  represents methyl, ethyl, n-propyl, i-propyl or cyclobutyl. 
     
     
         18 . The compound as claimed in  claim 1 , wherein the 
       
         
           
           
               
               
           
         
       
       fragment is in the S-configuration. 
     
     
         19 . The compound as claimed in  claim 1 , wherein the fragment 
       
         
           
           
               
               
           
         
       
       is in the R-configuration when R a  represents —OH or is in the S-configuration when R a  represents —CH 2 OH. 
     
     
         20 . The compound as claimed in  claim 1  which is:
 Ph(3-Cl)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab;   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab;   Ph(3-Cl)(5-OCHF 2 )—(S)CH(CH 2 OH)C(O)-Aze-Pab;   Ph(3-Cl)(5-OCF 3 )—(S)CH(CH 2 OH)C(O)-Aze-Pab;   Ph(3-OCHF 2 )—(R)CH(OH)—CO-Aze-Pab;   Ph(3-OCF 3 )—(R)CH(OH)—CO-Aze-Pab;   Ph(3-Cl)(5-OCH 2 CF 3 )—(R)CH(OH)C(O)-Aze-Pab;   Ph(3-Cl)(5-OCH 2 CHF 2 )—(R)CH(OH)C(O)-Aze-Pab;   Ph(3-Cl)(5-OCH 2 F)—(R)CH(OH)C(O)-Aze-Pab;   Ph(3-Cl)(5-OCH 2 CH 2 F)—(R)CH(OH)C(O)-Aze-Pab;   Ph(3-Cl)(5-OCH(CH 2 F) 2 )—(R)CH(OH)C(O)-Aze-Pab;   Ph(3-F)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab;   Ph(3-Br)(5-OCH 2 F)—(R)CH(OH)C(O)-Aze-Pab;   Ph(3-Br)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab;   Ph(3-Cl, 5-OCHF 2 )—(R)CH(OH)C(O)-Pro-Pab;   Ph(3-Cl, 5-OCHF 2 )—(R)CH(OH)C(O)-Aze-NH—CH 2 -((2-amidino)-5-pyridinyl);   Ph(3-Cl, 5-OCHF 2 )—(R)CH(OH)C(O)-Aze-NH—CH 2 -((5-amidino)-2-pyrimidinyl);   Ph(3-Cl, 5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(3-F);   Ph(3-Cl, 5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(2,6-diF);   Ph(3-Cl, 5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(2,5-diF).   Ph(3-Cl)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(OMe);   Ph(3-Cl)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(OEt);   Ph(3-Cl)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(OnPr);   Ph(3-Cl)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(OiPr);   Ph(3-Cl)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(OcBu);   Ph(3-Cl)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(OH);   Ph(3-Cl)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(COOcPentyl);   Ph(3-Cl)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(Z);   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OMe);   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OCH 2 -3-(5-Me-isoxazole));   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OCH 2 -3-pyridine);   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OiBu);   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OEt);   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OBn);   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OcHexyl);   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OcBu);   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OCH 2 CH 2 OPh(3-CF 3 ));   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OBn(4-Cl));   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OBn(3-MeO));   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OBn(2-Br));   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(OBn(4-Me));   Ph(3-Cl)(5-OCF 3 )—(R)CH(OH)C(O)-Aze-Pab(O-4-heptyl);   Ph(3-Cl)(5-OCF 3 )—(S)CH(CH 2 OH)C(O)-Aze-Pab(OMe);   Ph(3-Cl)(5-OCF 2 CF 3 )—(R)CH(OH)C(O)-Aze-Pab(OMe);   Ph(3-Cl)(5-OCF 2 CHF 2 )—(R)CH(OH)C(O)-Aze-Pab(OMe);   Ph(3-Cl)(5-OCF 2 F)—(R)CH(OH)C(O)-Aze-Pab(OMe);   Ph(3-Cl)(5-OCF 2 CH 2 F)—(R)CH(OH)C(O)-Aze-Pab(OMe);   Ph(3-Cl)(5-OCF(CH 2 F) 2 )—(R)CH(OH)C(O)-Aze-Pab(OMe);   Ph(3-F)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(OMe);   Ph(3-Br)(5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(OMe);   Ph(3-Cl, 5-OCH 2 CHF 2 )—(R)CH(OH)C(O)-Aze-Pab(OH);   Ph(3-Cl, 5-OCF 2 CH 2 F)—(R)CH(OH)C(O)-Aze-Pab(OH);   Ph(3-Cl, 5-OCHF 2 )—(R)CH(OH)C(O)-Pro-Pab(OMe);   Ph(3-Cl, 5-OCHF 2 )—(R)CH(OH)C(O)-Aze-NH—CH 2 -((2-methoxy-amidino)-5-pyridinyl);   Ph(3-Cl, 5-OCHF 2 )—(R)CH(OH)C(O)-Aze-NH—CH 2 -((5-methoxy-amidino)-2-pyrimidinyl);   Ph(3-Cl, 5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(2,6-diF)(OMe); or   Ph(3-Cl, 5-OCHF 2 )—(R)CH(OH)C(O)-Aze-Pab(2,5-diF)(OMe).   
     
     
         21 - 38 . (canceled) 
     
     
         39 . A process for the preparation of a compound of formula I as defined in  claim 1 , which comprises:
 (i) the coupling of a compound of formula II,   
       
         
           
           
               
               
           
         
       
       wherein R a , R 1  and R 2  are as defined in  claim 1  with a compound of formula III, 
       
         
           
           
               
               
           
         
       
       wherein Y and R 3  are as defined in  claim 1 ;
 (ii) the coupling of a compound of formula IV, 
 
       
         
           
           
               
               
           
         
       
       wherein R a , R 1 , R 2  and Y are as defined in  claim 1  with a compound of formula V,
   R 3 CH 2 NH 2   V 
 
       wherein R 3  is as defined in  claim 1 ;
 (iii) for compounds of formula I in which R 1  does not represent one or more halo groups, reduction of a corresponding compound of formula Ia, as defined in  claim 12 , in which R 5  represents OR 6 , wherein R 5  and R 6  are as defined in  claim 12 ; 
 (iv) reaction of a corresponding compound of formula XVIA or XVIB, as defined in  claim 47 , with a source of ammonia; 
 (v) reaction of a compound of formula XIVA, 
 
       
         
           
           
               
               
           
         
       
       wherein R a , R 1 , R 3  and Y are as defined in  claim 1  with:
 (a) a corresponding fluorinated haloalkane; or 
 (b) for compounds of formula I in which R 2  represents —OCH 2 CF 3 , —OCH 2 CHF 2 , —OCH 2 CH 2 F or —OCH(CH 2 F) 2 , a compound of formula XIVJ,
   R x S(O) 2 OR y   XIVJ 
 
 
       wherein R x  represents C 1-4  alkyl, C 1-4  perfluoroalkyl or phenyl (optionally substituted by methyl, nitro or halo) and R y  represents —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F or —CH(CH 2 F) 2 ;
 (vi) for compounds of formula I in which R 1  does not represent one or more halo groups, hydrogenation of a corresponding compound of formula I in which R 1  represents one or more halo groups; or 
 (vii) deprotection of a protected derivative of a compound as claimed in  claim 1 . 
 
     
     
         40 - 46 . (canceled) 
     
     
         47 . A process for the preparation of a compound of formula Ia as defined in  claim 12 , which comprises:
 (a) reaction of a corresponding compound of formula II as defined in  claim 39  with a compound of formula XV,   
       
         
           
           
               
               
           
         
       
       wherein Y is as defined  claim 1  and R 3a  is as defined in  claim 12 ;
 (b) reaction of a corresponding compound of formula IV as defined in  claim 39  with a compound of formula XVI,
   R 3a CH 2 NH 2   XVI 
 
 
       wherein R 3a  is as defined in  claim 12 ;
 (c) for compounds of formula Ia in which R 5  represents OH, reaction of a corresponding compound of formula XVIA or XVIB, 
 
       
         
           
           
               
               
           
         
       
       wherein R a , R 1 , R 2 , R 4 , Y, X 1 , X 2 , X 3  and X 4  are as defined in  claim 1 , with hydroxylamine;
 (d) for compounds of formula Ia in which R 5  represents OR 6 , reaction of a compound of formula XVII, 
 
       
         
           
           
               
               
           
         
         wherein R 3b  represents a structural fragment of formula I(v) or I(vi): 
       
       
         
           
           
               
               
           
         
       
       wherein R b  represents —CH 2 CH 2 —Si(CH 3 ) 3  or benzyl, or a tautomer thereof, and R a , R 1 , R 2 , Y, R 4 , X 1 , X 2 , X 3  and X 4  are as defined in  claim 1  with a compound of formula XVIII,
   R 6 ONH 2   XVIII 
 
       wherein R 6  is as defined in  claim 12 , or an acid addition salt thereof, followed by removal of the —C(O)OR b  group;
 (e) for compounds of formula Ia in which R 5  represents OH, reaction of a compound of formula XVII, as defined above, in which R b  represents benzyl with hydroxylamine, or an acid addition salt thereof; 
 (f) for compounds of formula Ia in which R 5  represents COOR 7 , reaction of a corresponding compound of formula I as defined in  claim 1  with a compound of formula XIX,
   L 1 COOR 7   XIX 
 
 
       wherein L 1  represents a leaving group and R 7  is as defined in  claim 12 ; or
 (g) for compounds of formula Ia in which R 5  represents OCH 3  or OCH 2 CH 3 , reaction of a corresponding compound of formula Ia in which R 5  represents OH with dimethylsulfate or diethylsulfate, respectively. 
 
     
     
         48 - 49 . (canceled)