New amidino derivatives and their use as thrombin inhibitors

Abstract

There is provided compounds of formula I wherein R 1 , R x , Y, R y , n and B have meanings given in the description which are useful as competitive inhibitors of trypsin-like proteases, such as thrombin, and 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 1  represents H, C 1-4  alkyl (optionally substituted by one or more substituents selected from cyano, halo, OH, C(O)OR 1a  or C(O)N(R 1b )R 1c ) or OR 1d ;  
       R 1d  represents H, C(O)R 11 , SiR 12 R 13 R 14  or C 1-6  alkyl, which latter group is optionally substituted or terminated by one or more substitutent selected from OR 15  or (CH 2 ) q R 16 ;  
       R 12 , R 13  and R 14  independently represent H, phenyl or C 1-6  alkyl;  
       R 16  represents C 1-4  alkyl, phenyl, OH, C(O)OR 17  or C(O)N(H)R 18 ;  
       R 18  represents H, C 1-4  alkyl or CH 2 C(O)OR 19 ;  
       R 15  and R 17  independently represent H, C 1-6  alkyl or C 1-3  alkylphenyl;  
       R 1a , R 1b , R 1c , R 11  and R 19  independently represent H or C 1-4  alkyl; and  
       q represents 0, 1 or 2;  
       R x  represents a structural fragment of formula IIa, IIb or IIc,  
       
         
           
           
               
               
           
         
       
       wherein  
       the dotted lines independently represent optional bonds;  
       A and E independently represent O or S, CH or CH 2  (as appropriate), or N or N(R 21 ) (as appropriate);  
       D represents —CH 2 —, O, S, N(R 22 ), —(CH 2 ) 2 —, —CH═CH—, —CH 2 N(R 22 )—,  
       —N(R 22 )CH 2 —, —CH═N—, —N═CH—, —CH 2 O—, —OCH 2 —, —CH 2 S— or —SCH 2 —;  
       X 1  represents C 2-4  alkylene; C 2-3  alkylene interrupted by Z; —C(O)-Z-A 1 -;  
       -Z-C(O)-A 1 -; —CH 2 —C(O)-A 1 -; -Z-C(O)-Z-A 2 -; —CH 2 -Z-C(O)-A 2 -;  
       -Z-CH 2 —C(O)-A 2 -; -Z-CH 2 —S(O) m -A 2 -; —C(O)-A 3 ; -Z-A 3 -; or -A 3 -Z-;  
       X 2  represents C 2-3  alkylene, —C(O)-A 4 - or -A 4 -C(O)—;  
       X 3  represents CH or N;  
       X 4  represents a single bond, O, S, C(O), N(R 23 ), —CH(R 23 )—,  
       —CH(R 23 )—CH(R 24 )— or —C(R 23 )═C(R 24 )—;  
       A 1  represents a single bond or C 1-2  alkylene;  
       A 2  represents a single bond or —CH 2 —;  
       A 3  represents C 1-3  alkylene;  
       A 4  represents C(O) or C 1-2  alkylene;  
       Z represents, at each occurrence, O, S(O) m  or N(R 25 );  
       R 2  and R 4  independently represent one or more optional substituents selected from C 1-4  alkyl, C 1-4  alkoxy (which latter two groups are optionally substituted by one or more halo substituent), methylenedioxy, halo, hydroxy, cyano, nitro, S(O) 2 NH 2 , C(O)OR 26 , SR 26 , S(O)R 26a , S(O) 2 R 26a  or N(R 27 )R 28 ;  
       R 3  represents one or more optional substituents selected from OH, C 1-4  alkoxy, C 1-6  alkyl (optionally substituted by one or more halo group), or N(R 29a )R 29b ;  
       R 25 , R 29a  and R 29b  independently represent H, C 1-4  alkyl or C(O)R 30 ;  
       R 26  represents H or C 1-4  alkyl;  
       R 26a  represents C 1-4  alkyl;  
       R 27  and R 23  independently represent H, C 1-4  alkyl or C(O)R 30 , or together represent C 3-6  alkylene, thus forming a 4- to 7-membered ring, which ring is optionally substituted, on a carbon atom that is α to the nitrogen atom, with an ═O group;  
       R 21 , R 22 , R 23 , R 24  and R 30  independently represent, at each occurrence, H or C 1-4  alkyl;  
       Y represents CH 2 , (CH 2 ) 2 , CH═CH (which latter group is optionally substituted by C 1-4  alkyl), (CH 2 ) 3 , CH 2 CH═CH or CH═CHCH 2  (which latter three groups are optionally substituted by C 1-4  alkyl, methylene, ═O or hydroxy);  
       R y  represents H or C 1-4  alkyl;  
       n represents 0, 1, 2, 3 or 4; and  
       B represents a structural fragment of formula IIIa, IIIb or IIIc  
       
         
           
           
               
               
           
         
       
       wherein  
       X 5 , X 6 , X 7  and X 8  independently represent CH, N or N—O;  
       X 9  and X 10  independently represent a single bond or CH 2 ;  
       R 31  represents an optional substituent selected from halo, C 1-4  alkyl (which group is optionally substituted by one or more halo group), N(R 32 )R 33 , OR 34  or SR 35 ;  
       R 32  and R 33  independently represent H, C 1-4  alkyl or C(O)R 36 ;  
       R 34 , R 35  and R 36  independently represent H or C 1-4  alkyl; and one of D 1  and D 2  represents H, and the other represents H, OR a , NHR a , C(═X 11 )X 12 R b , or D 1  and D 2  together represent a structural fragment of formula IVa:— 
       
         
           
           
               
               
           
         
       
       R a  represents H or -A 5 [X 14 ] n [C(O)] r R e ;  
       R b  represents -A 5 [X 14 ] n [C(O)] r R e ;  
       A 5  represents, at each occurrence, a single bond or C 1-12  alkylene (which alkylene group is optionally interrupted by one or more O, S(O) m  and/or N(R f ) group, and is optionally substituted by one or more of halo, OH, N(H)C(O)R g , C(O)N(R g )R h , C 3-7 -cycloalkyl (which cycloalkyl group is optionally interrupted by one or more O, S(O) m  and/or N(R f ) group and/or is optionally substituted by one or more substituents selected from C 1-6  alkyl, C 1-6  alkoxy, halo, ═O or ═S), Het and C 6-10  aryl (which aryl and Het groups are themselves optionally substituted by one or more substituents selected from C 1-6  alkyl (optionally substituted by one or more halo substituent), C 1-6  alkoxy, halo, cyano, C(O)OR 9 , C(O)N(R 9 )R h  and N(R f )R g ));  
       R c  and R d  both represent H; or one of R c  and R d  represents H or C 1-7  alkoxy and the other represents C 1-7  alkyl (which alkyl group is optionally interrupted by one or more O atoms); or R c  and R d  together represent C 3-8  cycloalkyl, which cycloalkyl group is interrupted by one or more O, S(O) m  and/or N(R f ) group;  
       R e  represents, at each occurrence, H, C 1-12  alkyl (which alkyl group is optionally interrupted by one or more O, S(O) m  and/or N(R f ) group, and/or is optionally substituted by one or more substituents selected from halo, OH, N(H)C(O)R g  and C(O)N(R g )R h ), A 7 -C 3-7 -cycloalkyl (which cycloalkyl group is optionally interrupted by one or more O, S(O) m  and/or N(R f ) group and/or is substituted by one or more substituents selected from C 1-6  alkyl, C 1-6  alkoxy, halo, ═O and ═S), A 7 -C 6-10  aryl or A 7 -Het (which aryl and Het groups are optionally substituted by one or more substituents selected from C 1-6  alkyl (optionally substituted by one or more halo substituent), C 1-6  alkoxy, halo, cyano, C(O)OR 9 , C(O)N(R 9 )R h  and N(R f )R g );  
       A 7  represents a single bond or C 1-7  alkylene (which alkylene group is optionally interrupted by one or more O, S(O) m  and/or N(R f ) group, and/or are optionally substituted by one or more of halo, OH, N(H)COR 9  and CON(R g )R h );  
       Het represents, at each occurrence, a five- to ten-membered heteroaryl group, which may be aromatic in character, containing one or more nitrogen, oxygen or sulphur atoms in the ring system;  
       n and r independently represent 0 or 1;  
       X 11 , X 12  and X 14  independently represent O or S;  
       X 13  represents O or N(R f );  
       R f  represents, at each occurrence, H, C 1-4  alkyl or C(O)R g ;  
       R g  and R h  independently represent, at each occurrence, H or C 1-4  alkyl; and  
       m represents, at each occurrence, 0, 1 or 2;  
       or a pharmaceutically acceptable salt thereof;  
       provided that:  
       (a) A and E do not both represent O or S;  
       (b) E and D do not both represent O or S;  
       (c) when R 1  represents OR 1d  and X 1  represents —C(O)-Z-A 1 ,  
       -Z-CH 2 —S(O) m -A 2 - or -Z-C(O)-Z-A 2 , then A 1  or A 2  (as appropriate) do not represent a single bond;  
       (f) when X 4  represents —CH(R 23 )—, R 1  does not represent OH;  
       (g) when A 5  represents a single bond, then n and r both represent 0;  
       (f) when A 5  represents C 1-12  alkylene, then n represents 1;  
       (g) when A 5  represents —CH 2 —, n is 1 and r is 0, then R e  does not represent H; and  
       (h) the compound is not:— 
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Pro-Pab;  
       (R)- or (S)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Pro-Pab;  
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab×HOAc;  
       (R)- or (S)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab;  
       1-hydroxy-5-methoxytetralin-1-yl-C(O)-Aze-Pab×HOAc;  
       1-hydroxy-5,7-dimethyltetralin-1-yl-C(O)-Aze-Pab×HOAc;  
       1-hydroxy-7-aminotetralin-1-yl-C(O)-Aze-Pab×HOAc;  
       1-hydroxytetralin-1-yl-C(O)-Aze-Pab×HOAc;  
       7-methoxytetralin-1-yl-C(O)-Aze-Pab×HOAc;  
       (R)- or (S)-7-methoxy-1-methyltetralin-1-yl-C(O)-Aze-Pab;  
       4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab×OAc;  
       (S)- or (R)-1-hydroxy-4-methoxyindan-1-yl-C(O)-Aze-Pab;  
       1-hydroxy-5-methoxytetralin-1-yl-C(O)-Aze-Pab(OH);  
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(OH);  
       4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab(OH);  
       4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab(OMe);  
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab-(C(O)OCH 2 CC1 3 );  
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab-(C(O)OCH 2 CH 3 );  
       7-methoxy-1-allyltetralin-1-yl-C(O)-Aze-Pab×HOAc;  
       (S)- or (R)-1-hydroxy-7-chlorotetralin-1-yl-C(O)-Pro-Pab;  
       1-n-propyl-7-methoxytetralin-1-yl-C(O)-Aze-Pab×HOAc;  
       6-chloro-4-hydroxychroman-4-yl-C(O)-Aze-Pab×HOAc;  
       4-hydroxychroman-4-yl-C(O)-Aze-Pab×HOAc;  
       6,8-dichloro-4-hydroxychroman-4-yl-C(O)-Aze-Pab×HOAc;  
       6-fluoro-4-hydroxychroman-4-yl-C(O)-Aze-Pab×HOAc;  
       4-hydroxy-6-methylchroman-4-yl-C(O)-Aze-Pab×HOAc;  
       8-chloro-4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab×HOAc;  
       6-chloro-4-hydroxy-8-methylchroman-4-yl-C(O)-Aze-Pab×HOAc;  
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O—C(O)-i-Pr);  
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O—C(O-Et);  
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O—C(O)—Ch);  
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O-allyl);  
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O-Bzl);  
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab-(CO—O-methallyl);  
       1-hydroxy-7-aminotetralin-1-yl-C(O)-Aze-Pab(OH);  
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O-Val);  
       (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-(Me)Pab; or  
       9-hydroxyfluoren-9-yl-C(O)-Aze-Pab×HOAc.  
     
   
   
       2 . A compound as claimed in  claim 1  wherein R 1  represents OH or C 1-4  alkyl (which latter group is optionally substituted by cyano or OH).  
   
   
       3 . A compound as claimed in  claim 1  wherein R x  represents a structural fragment of formula IIa or IIb.  
   
   
       4 . A compound as claimed in  claim 1  wherein, when R x  represents a structural fragment of formula IIa, then the dotted lines represent bonds, A and E both represent CH and D represents —CH═CH—;  
   
   
       5 . A compound as claimed in  claim 1  wherein, when R x  represents a structural fragment of formula IIa, X, represents optionally unsaturated C 2 - or C 3 -alkylene, or -Z-A 3  (in which Z represents O, S(O) m  or N(R 25 ) (in which R 25  is as defined in  claim 1  or represents C 1-4  alkyl or C(O)R 30  and m and R 30  are as defined in  claim 1)  and A 3  represents C 1 - or C 2 -alkylene (which latter group is optionally unsaturated)).  
   
   
       6 . A compound as claimed in  claim 1  wherein Y represents CH 2 , (CH 2 ) 2  or (CH 2 ) 3 .  
   
   
       7 . A compound as claimed in  claim 1  wherein B represents a structural fragment of formula IIIa in which X 5 , X 6 , X 7  and X 8  all represent CH.  
   
   
       8 . A compound as claimed in  claim 1  wherein, when D 1  and D 2  together represent a structural fragment of formula IVa, in which X 13  is O, then one of R c  and R d  represents H or C 1-7  alkoxy and the other represents C 1-7  alkyl.  
   
   
       9 . A compound as claimed in  claim 1 , wherein, when D 1  or D 2  represents OR a  and R a  represents -A 5 [X 14 ] n [C(O)] r R e , and 
 (i) A 5  is a single bond, then R e  is:—
 (1) A 7 -aryl, optionally substituted by one or more halo, C 1-6  alkoxy, C 1-6  alkyl or halo-C 1-6 -alkyl substituents; or  
 (2) H or linear, branched, optionally unsaturated, and/or cyclic, C 1-12  alkyl, which cyclic alkyl group is optionally interrupted by an O atom and, optionally, a further atom or S(O) m  group; or when  
   (ii) A 5  is linear or branched C 1-12  alkylene, X 14  is O and r is 0, then R e  is C 1-3  alkyl or A 7 -aryl, in which A 7  is a single bond.    
   
   
       10 . A compound as claimed in  claim 1 , wherein, when D 1  or D 2  represents OR a , then R a  is H or C 1-4  alkyl.  
   
   
       11 . A compound as claimed in  claim 1 , wherein, when D 1  or D 2  represents —C(═X 11 )X 12 R b , in which X 11  represents O and X 12  represents O or S, and, in which R b  group, A 5  represents a single bond then R e  represents optionally unsaturated C 1-6  alkyl, A 7 -C 6-10 -aryl (in which A 7  represents a single bond or C 1-2  alkylene, and which A 7 -C 6-10 -aryl group is optionally substituted by one or more halo, C 1-4  alkyl and/or C 1-4  alkoxy groups), or A 7 -C 3-7 -cycloalkyl, in which A 7  represents a single bond or linear or branched C 1-7  alkylene, and which cycloalkyl group is optionally substituted by C 1-3  alkyl.  
   
   
       12 . A compound of formula I, as defined in  claim 1 , wherein the fragment  
     
       
         
         
             
             
         
       
       is in the S-configuration.  
     
   
   
       13 . A pharmaceutical formulation including a compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.  
   
   
       14 . A compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.  
   
   
       15 . A compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition where inhibition of thrombin is required.  
   
   
       16 . A compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment of thrombosis.  
   
   
       17 . A compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for use as an anticoagulant.  
   
   
       18 . The use of a compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, as active ingredient in the manufacture of a medicament for the treatment of a condition where inhibition of thrombin is required.  
   
   
       19 . The use as claim in  claim 18 , wherein the condition is thrombosis.  
   
   
       20 . The use of a compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, as active ingredient in the manufacture of an anticoagulant.  
   
   
       21 . A method of treatment of a condition where inhibition of thrombin is required which method comprises administration of a therapeutically effective amount of a compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, to a person suffering from, or susceptible to, such a condition.  
   
   
       22 . A method as claimed in  claim 21 , wherein the condition is thrombosis.  
   
   
       23 . A method as claimed in  claim 21 , wherein the condition is hypercoagulability in blood tissues.  
   
   
       24 . A process for the preparation of compounds of formula I which comprises: 
 (i) the coupling of a compound of formula IV,                          wherein R 1  and R x  are as defined in  claim 1  with a compound of formula V,                          wherein R y , Y, n and B are as defined in  claim 1;     (ii) the coupling of a compound of formula VI,                          wherein R 1 , R x  and Y are as defined in  claim 1  with a compound of formula VII,      H(R y )N—(CH 2 ) n —B  VII    wherein R y , n and B are as defined in  claim 1;     (iii) for compounds of formula I in which D 1  or D 2  represents OR a  or NHR a , reaction of a compound of formula VIII,                          wherein B 1  represents a structural fragment of formula IIId, IIIe or IIIf                          and R 1 , R x , Y, R y , n, R 31 , X 5 , X 6 , X 7 , X 8 , X 9  and X 10  are as defined in  claim 1  with a compound of formula IX,      H 2 NX a R a   IX    wherein X a  represents O or NH and R a  is as defined in  claim 1;     (iv) for compounds of formula I in which D 1  or D 2  represents OR a  or NHR a , reaction of a compound of formula I in which D 1  or D 2  (as appropriate) represents C(O)OR b1 , in which R b1  represents a protecting group with a compound of formula IX as defined above;    (v) for compounds of formula I in which D 1  or D 2  represents OR a  or NHR a , R a  represents -A 5  [X 14 ] n [C(O)] r R e , in which A 5  does not represent a single bond, and n represent 1, reaction of a compound of formula I in which D 1  or D 2  (as appropriate) represents OH or NH 2 , with a compound of formula X,      L 1 A 5a [X 14 ][C(O)] r R e   X    wherein L 1  represents a suitable leaving group, A 5a  represents A 5 , as defined in  claim 1  except that it does not represent a single bond, and X 14 , r and R e  are as defined in  claim 1;     (vi) for compounds of formula I in which D 1  or D 2  represents OR a  or NHR a , R a  represents -A 5 [X 14 ] n [C(O)] r R e , in which A 5  represents C 2-12  alkylene, which alkylene group is branched at the carbon atom that is α to the O or N atom of OR a  or NHR a  (as appropriate, and which group is optionally branched at the carbon atom that is β to that atom, n represents 1, r represents 0 and R e  is as defined in  claim 1 , reaction of a compound of formula I in which D 1  or D 2  (as appropriate) represents OH or NH 2 , with a compound of formula XI,                          or a geometrical isomer thereof, or a mixture of such geometrical isomers, in which R b1  and R b3  each represent H or an alkyl group, provided that the total number of carbon atoms provided by R b1  and R b3  does not exceed 10, and wherein X 14  and R e  are as defined in  claim 1;     (vii) for compounds of formula I in which D 1  or D 2  represents OR a  or NHR a , R a  represents -A 5  [X 14 ] n [C(O)] r R e , in which A 5  represents a single bond, and R e  represents A 7 -C 3-6 -cycloalkyl, in which A 7  represents a single bond, and the cycloalkyl group is interrupted by at least one O or S atom, which atom is between the carbon atom at the point of attachment to the O or NH group of OR a  or NHR a , and a carbon atom that is α to that point of attachment, and which cycloalkyl group is optionally interrupted by one or more O or S(O) m  group and/or optionally substituted by one or more ═O group, reaction of a compound of formula I, in which D 1  or D 2  (as appropriate) represents OH or NH 2 , with a compound of formula XII,                          wherein X 15  represents O or S and X 16  represents C 1-4  alkylene (which alkylene groups is optionally interrupted by one or more O or S(O) m  group and/or optionally substituted by one or more ═O group);    (viii) for compounds of formula I in which D 1  or D 2  represents C(X 11 )X 12 R b , reaction of a compound of formula I in which D 1  and D 2  both represent H with a compound of formula XIII,      L 2 -C(X 11 )X 12 R b   XIII    wherein L 2  represents a suitable leaving group, and X 11 , X 12  and R b  are as defined in  claim 1;     (ix) for compounds of formula I in which D 1  and D 2  together represent a structural fragment of formula IVa, reaction of a corresponding compound of formula I in which D 1  or D 2  represents OH or NHR f  (in which R f  is as defined in  claim 1) , with a compound of formula XV,      (R c )(R d )C(R c1 )(R c2 )  XV    wherein R c1  and R c2  both represent —OR c3 , in which R c3  represents C 1-3  alkyl, or together represent ═O, and R c  and R d  are as defined in  claim 1;     (x) for compounds of formula I in which one or more of X 5 , X 1 , X 7  and X 8  represent N—O, oxidation of a corresponding compound of formula I in which X 5 , X 6 , X 7  and/or X 8  (as appropriate) represent(s) N; or    (xi) for compounds of formula I in which any one of Z, X 1 , R 2 , R 4 , A 5 , A 7 , R c , R d  and/or R e  comprises or includes a S(O) or a S(O) 2  group, oxidation of a corresponding compound of formula I (or a compound corresponding to a compound of formula I) wherein Z, X 1 , R 2 , R 4 , A 5 , A 7 , R c , R d  and/or R e  (as appropriate comprise(s) or include(s) a S group;    (xii) for compounds of formula I in which D 1  and D 2  both represent H, removal of a OR a , NHR a  or C(═X 11 )X 12 R b  group (in which R a , R b , X 11  and X 12  are as defined in  claim 1) , or removal of a structural fragment of formula IVa as defined in  claim 1 , from a corresponding compound of formula I; or    (xiii) introduction and/or interconversion of a substituent on an aromatic and/or non-aromatic, carbocyclic and/or heterocyclic ring in a corresponding of compound of formula I.