Prodrugs of thrombin inhibitors

Abstract

There is provided compounds of formula I, R 1 O(O)C—CH 2 —(R)Cgl-Aze-Pab-R 2   I wherein R 1 and R 2 have meanings given in the description, which are usefull as prodrugs of inhibitors of trypsin-like proteases, such as thrombin, and in particular in the treatment of conditions where inhibition of thrombin is required (eg thrombosis) or as anticoagulants.

1 . A compound of formula I,  
       R 1 O(O)C—CH 2 —(R)Cgl-Aze-Pab-R 2    I  
       wherein 
 R 1  represents —R 3  or —A 1 C(O)N(R 4 )R 5  or —A 1 C(O)OR 4 ;  
 A 1  represents C 1-5  alkylene;  
 R 2  (which replaces one of the hydrogen atoms in the amidino unit of Pab-H) represents OH, OC(O)R 6 , C(O)OR 7  or C(O)OCH(R 8 C(O)R 9 ;  
 R 3  represents H, C 1-10  alkyl, or C 1-3  alkylphenyl (which latter group is optionally substituted by C 1-6  alkyl, C 1-6  alkoxy, nitro or halogen);  
 R 4  and R 5  independently represent H, C 1-6  alkyl, phenyl, 2-naphthyl or, when R 1  represents -A 1 C(O)N(R 4 )R 5 , together with the nitrogen atom to which they are attached represent pyrrolidinyl or piperidinyl;  
 R 6  represents C 1-17  alkyl, phenyl or 2-naphthyl (all of which are optionally substituted by C 1-6  alkyl or halogen);  
 R 7  represents 2-naphthyl, phenyl, C 1-3  alkylphenyl (which latter three groups are optionally substituted by C 1-6  alkyl, C 1-6  alkoxy, nitro or halogen), or C 1-12  alkyl (which latter group is optionally substituted by C 1-6  alkoxy, C 1-6 acyloxy or halogen);  
 R 8  represents H or C 1-4  alkyl; and  
 R 9  represents 2-naphthyl, phenyl, C 1-6  alkoxy or C 1-8  alkyl (which latter group is optionally substituted by halogen, C 1-6  alkoxy or C 1-6  acyloxy);  
 provided that when R 1  represents R 3 , R 3  represents benzyl, methyl, ethyl, n-butyl or n-hexyl and R 2  represents C(O)OR 7 , then R 7  does not represent benzyl;  
 or a pharmaceutically-acceptable salt thereof.  
 
     
     
         2 . A compound of formula I, as defined in  claim 1 , wherein A 1  represents C 1-3  alkylene when R 1  represents -A 1 C(O)N(R 4 )R 5 .  
     
     
         3 . A compound of formula I, as defined in  claim 1  or  claim 2 , wherein R 4  represents H or C 1-6  alkyl when R 1  represents -A 1 C(O)N(R 4 )R 5 .  
     
     
         4 . A compound of formula I, as defined in any one of  claims 1  to  3 , wherein R 5  represents C 1-6  alkyl or C 4-6  cycloalkyl when R 1  represents -A 1 C(O)N(R 4 )R 5 .  
     
     
         5 . A compound of formula I, as defined in any one of  claims 1  to  3 , wherein R 4  and R 5  together represent pyrrolidinyl when R 1  represents -A 1 C(O)N(R 4 )R 5 .  
     
     
         6 . A compound of formula I, as defined in any one of  claims 2  to  5 , wherein A 1  represents C 1-3  alkylene, and R 4  represents H or C 1-3  alkyl and R 5  represents C 2-6  alkyl or C 5-6  cycloalkyl, or R 4  and R 5  together represent pyrrolidinyl.  
     
     
         7 . A compound of formula I, as defined in  claim 1 , wherein A 1  represents C 1-5  alkylene when R 1  represents -A 1 C(O)OR 4 .  
     
     
         8 . A compound of formula I, as defined in  claim 1  or  claim 7 , wherein R 4  represents C 1-6  alkyl when R 1  represents -A 1 C(O)OR 4 .  
     
     
         9 . A compound of formula I, as defined in  claim 7  or  claim 8 , wherein A 1  represents C 1-5  alkylene and R 4  represents C 1-4  alkyl.  
     
     
         10 . A compound of formula I, as defined in  claim 1 , wherein R 3  represents H, C 1-10  alkyl (which latter group may be linear or, when there are a sufficient number of carbon atoms, may be branched and/or be partially cyclic or cyclic), or C 1-3  alkylphenyl (which latter groups is optionally substituted, may be linear or, when there are a sufficient number of carbon atoms, be branched), when R 1  represents R 3 .  
     
     
         11 . A compound as claimed in  claim 1  or  claim 10 , wherein R 1  represents H, linear C 1-10  alkyl, branched C 3-10  alkyl, partially cyclic C 4-10  alkyl, C 4-10  cycloalkyl, optionally substituted linear C 1-3  alkylphenyl, optionally substituted branched C 3  alkylphenyl.  
     
     
         12 . A compound as claimed in  claim 11 , wherein R 1  represents linear C 1-6  alkyl, C 6-10  cycloalkyl, or optionally substituted linear C 1-3  alklphenyl.  
     
     
         13 . A compound of formula I, as defined in any one of  claims 1  to  12 , wherein R 2  represents OH.  
     
     
         14 . A compound of formula I, as defined in any one of  claims 1  to  12 , wherein R 6  represents optionally substituted phenyl or C 1-17  alkyl (which latter group may be linear or, when there are a sufficient number of carbon atoms, may be branched, be cyclic or partially cyclic, and/or be saturated or unsaturated) when R 2  represents OC(O)R 6 .  
     
     
         15 . A compound as claimed in  claim 14  wherein R 6  represents optionally substituted phenyl, linear C 1-4  alkyl, branched C 3-4  alkyl or cis-oleyl.  
     
     
         16 . A compound as claimed in  claim 15  wherein R 6  represents linear C 1-3  alkyl or branched C 3  alkyl.  
     
     
         17 . A compound of formula I, as defined in any one of  claims 1  to  12 , wherein R 7  represents optionally substituted phenyl, C 1-12  alkyl (which latter group is optionally substituted, may be linear or, when there are a sufficient number of carbon atoms, may be branched, cyclic or partially cyclic, and/or saturated or unsaturated), or C 1-3  alkylphenyl (which latter group is optionally substituted, may be linear or, when there are a sufficient number of carbon atoms, may be branched) when R 2  represents C(O)OR 7 .  
     
     
         18 . A compound as claimed in  claim 17  wherein R 7  represents optionally substituted and/or optionally unsaturated linear C 1-4  alkyl or optionally substituted and/or optionally unsaturated branched C 3-4  alkyl, optionally substituted phenyl, or optionally substituted linear C 1-3  alkylphenyl or optionally substituted branched C 3  alkylphenyl.  
     
     
         19 . A compound as claimed in  claim 18  wherein R 7  represents optionally substituted linear C 1-4  alkyl or optionally substituted branched C 3-4  alkyl, optionally substituted linear C 1-3  alkylphenyl or branched C 3  alkylphenyl.  
     
     
         20 . A compound of formula I, as defined in any one of  claims 1  to  12 , wherein R 8  represents H or methyl, when R 2  represents C(O)OCH(R 8 )OC(O)R 9 .  
     
     
         21 . A compound of formula I, as defined in any one of  claims 1  to  12  or  claim 20 , wherein R 9  represents phenyl, or C 1-8  alkyl (which latter group is optionally substituted, may be linear or, when there are a sufficient number of carbon atoms, may be branched and/or cyclic or partially cyclic) when R 2  represents C(O)OCH(R 8 OC(O)R 9 .  
     
     
         22 . A compound of formula I, as defined in  claim 20  or  claim 21  wherein R 8  represents H or methyl and R 9  represents phenyl, C 5-7  cycloalkyl, linear C 1-6  alkyl, branched C 3-6  alkyl or partially cyclic C 7-8  alkyl.  
     
     
         23 . A compound as claimed in  claim 22  wherein R 8  represents H and R 9  represents C 5-7  cycloalkyl, linear C 1-6  alkyl or partially cyclic C 7-8  alkyl.  
     
     
         24 . A compound as claimed in any one of the preceeding claims wherein, when R 1  represents R 3  and R 3  represents optionally substituted C 1-3  alkylphenyl, the optional substituent C 1-6  alkyl.  
     
     
         25 . A compound as claimed in  claim 24  wherein the substituent is methyl.  
     
     
         26 . A compound as claimed in any one of the preceeding claims wherein, when R 2  represents C(O)OR 7  and R 7  represents optionally subsituted C 1-12  alkyl, the optional substituent is selected from halogen and C 1-6  alkoxy.  
     
     
         27 . A compound as claimed in  claim 26  wherein the substituent is selected from chloro and methoxy.  
     
     
         28 . A compound as claimed in any one of the preceeding claims wherein, when R 2  represents C(O)OR 7  and R 7  represents optionally subsituted phenyl, the optional substituent is selected from C 1-6  alkyl, C 1-6  alkoxy and halogen.  
     
     
         29 . A compound as claimed in  claim 28  wherein the substituent is selected from methyl, methoxy and chloro.  
     
     
         30 . A compound as claimed in any one of the preceeding claims wherein when R 2  represents C(O)OR 7  and R 7  represents optionally subsituted C 1-3  alkylphenyl, the optional substituent is nitro.  
     
     
         31 . A compound as claimed in  claim 1  which is 
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 CH═CH 2 ;  
 nPrOOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 CH═CH 2 ;  
 tBuOOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 CH═CH 2 ;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COOEt;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COO-nBu;  
 PrlC(O)CH 2 CH 2 CH 2 OOCCH 2 —(R)Cgl-Aze-Pab-Z;  
 ChNHC(O)CH 2 OOCCH 2 —(R)Cgl-Aze-P-Z;  
 (nPr) 2 NC(O)CH 2 OOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 OOCC(CH 3 ) 3 ;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 OOCC(CH 3 ) 3 ;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COOCH(CH 3 )OOCCH 3 ;  
 MeOOCCH 2 —(R)Cgl-Aze-Pab-OOCPh;  
 MeOOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 BnOOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 nPrOOCCH 2 —(R)Cgl-Aze-Pab-Z;  
 nPrOOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 iPrOOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 tBuOOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 (nPr) 2 NCOCH 2 OOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 ChNHCOCH 2 OOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-OAc;  
 HOOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 HOOCCH 2 —(R)Cgl-Aze-Pab-O-cis-Oleyl;  
 Cyclooctyl-OOCCH 2 —(R)Cgl-Aze-Pab-Z;  
 tBuCH 2 OOCCH 2 -(R)Cgl-Aze-Pab-Z;  
 (2-Me)BnOOCCH 2 -(R)Cgl-Aze-Pab-Z;  
 ChCH 2 OOCCH 2 —(R)Cgl-Aze-Pab-Z;  
 ChOOCCH 2 —(R)Cgl-Aze-Pab-Z;  
 PhC(Me) 2 OOCCH 2 —(R)Cgl-Aze-Pab-Z;  
 (Me) 2 CHC(Me) 2 OOCCH 2 —(R)Cgl-Aze-Pab-Z;  
 BnOOCCH 2 —(R)Cgl-Aze-Pab-COOPh(4-OMe);  
 ChCH 2 OOCCH 2 —(R)Cgl-Aze-Pab-COOPh(4-OMe);  
 (2-Me)BnOOCCH 2 —(R)Cgl-Aze-PabOOPh(4-OMe);  
 EtOOCCH 2 -(R)Cgl-Aze-Pab-COOPh(4-Me);  
 BnOOCCH 2 —(R)Cgl-Aze-Pab-COOPh(4-Me);  
 BnOOCCH 2 —(R)Cgl-Aze-Pab-COO-nBu;  
 iPrOOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 CH═CH 2 ;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COO-iBu;  
 BnOOCCH 2 —(R)Cgl-Aze-Pab-COO-nPr;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 OOCCh;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 OCCH 2 Ch;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COOCH(Me)OOCPh;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 OOCPh;  
 BnOOCCH 2 —(R)Cgl-Aze-Pab-COOCH(Me)OAc;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 OAc;  
 tBuOOCCH 2 -(R)Cgl-Aze-Pab-COOCH 2 OAc;  
 MeOOC—C(═CHEt)CH 2 —OOCCH 2 —(R)Cgl-Aze-Pab-Z;  
 Men-OOCCH 2 —(R)Cgl-Aze-Pab-COOPh(4-OMe); and  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 CCl 3 .  
 
     
     
         32 . A compound as claimed in  claim 1  which is 
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 CCl 3 ;  
 BnOOCCH 2 —(R)Cgl-Aze-Pab-COOnBu;  
 nPrOOCCH 2 —(R)Cgl-Aze-Pab-Z;  
 Cyclooctyl-OOCCH 2 —(R)Cgl-Aze-Pab-Z;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-COOCH 2 OOCCh;  
 MeOOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 nPrOOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 iPrOOCCH 2 —(R)Cgl-Aze-Pab-OH;  
 BnOOCCH 2 —(R)Cgl-Aze-Pab-OH; and  
 EtOOCCH 2 —(R)Cgl-Aze-Pab-OAc.  
 
     
     
         33 . A compound of formula I, as defined in  claim 1 , with the additional proviso that R 1  does not represent -A 1 C(O)OR 4 .  
     
     
         34 . A compound of formula I, as defined in  claim 1 , with the additional proviso that R 4  and R 5  do not independently represent H.  
     
     
         35 . A compound of formula I, as defined in  claim 1 , with the additional proviso R 6  does not represent C 1-17  alkyl, when R 2  represents OC(O)R 6 .  
     
     
         36 . A compound of formula I, as defined in  claim 1 , wherein R 1  represents -A 1 C(O)OR 4 .  
     
     
         37 . A compound of formula I, as defined in  claim 1 , wherein R 4  and R 5  independently represent H.  
     
     
         38 . A compound of formula I, as defined in  claim 1 , wherein R 6  represents C 1-17  alkyl, when R 2  represents OC(O)R 6 .  
     
     
         39 . A pharmaceutical formulation including a compound of formula I as defined in any one of  claims 1  to  38 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.  
     
     
         40 . A compound of formula I, as defined in any one of  claims 1  to  38 , or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.  
     
     
         41 . A compound of formula I as defined in any one of  claims 1  to  38 , or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition where inhibition of thrombin is required.  
     
     
         42 . A compound of formula I as defined in any one of  claims 1  to  38 , or a pharmaceutically acceptable salt thereof, for use in the treatment of thrombosis.  
     
     
         43 . A compound of formula I as defined in any one of  claims 1  to  38 , or a pharmaceutically acceptable salt thereof, for use as an anticoagulant.  
     
     
         44 . The use of a compound of formula I as defined in any one of  claims 1  to  38 , 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.  
     
     
         45 . The use as claimed in  claim 44 , wherein the condition is thrombosis.  
     
     
         46 . The use of a compound of formula I as defined in any one of  claims 1  to  38 , or a pharmaceutically acceptable salt thereof, as active ingredient in the manufacture of an anticoagulant.  
     
     
         47 . 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 of formula I as defined in any one of  claims 1  to  38 , or a pharmaceutically acceptable salt thereof, to a person suffering from, or susceptible to, such a condition.  
     
     
         48 . A method as claimed in  claim 47 , wherein the condition is thrombosis.  
     
     
         49 . A method as claimed in  claim 47 , wherein the condition is hypercoagulability in blood and tissues.  
     
     
         50 . The use of a compound of formula I, as defined in  claim 1  but without the provisos, as a prodrug.  
     
     
         51 . A process for the preparation of compounds of formula I which comprises: 
 (a) for compounds of formula I in which R 2  represents OH, reaction of a corresponding compound of formula I, wherein R 2  represents OC(O)R 6  and R 6  is as defined in  claim 1  with an alkoxide base;    (b) for compounds of formula I in which R 2  represents OH, reaction of a corresponding compound of formula I wherein R 2  represents C(O)OR 7  and R 7  is as defined in  claim 1  with hydroxylamine, or an acid addition salt thereof;    (c) reaction of a corresponding compound of formula II,    H—(R)Cgl-Aze-Pab-R 2    II     wherein R 2  is as defined in  claim 1  with a compound of formula III,    R 1 O(O)C—CH 2 -L 1    III     wherein L 1  represents a leaving group and R 1  is as defined in  claim 1;     (d) for compounds of formula I in which R 1  represents H and R 2  represents OH or C(O)OR 7 , reaction of a corresponding compound of formula I wherein R 1  represents C 1-10  alkyl or C 1-3  alkylphenyl, and R 2  represents OH or C(O)OR 7 , with a base;    (e) for compounds of formula I wherein R 2  represents OC(O)R 6  and R 6  is as defined in  claim 1 , reaction of a corresponding compound of formula I wherein R 2  represents OH, with a compound of formula IV,    R 6 C(O)—O—C(O)R 6    IV     or a compound of formula V,    R 6 C(O)Hal   V     wherein Hal represents Cl or Br and, in both cases, R 6  is as defined in  claim 1;     (f) for compounds of formula I in which R 1  represents H and R 2  represents OC(O)R 6 , and R 6  is as defined in  claim 1 , reaction of a corresponding compound of formula VI,    P 1 O(O)C—CH 2 —(R)Cgl-Aze-Pab-R 2    VI     wherein P 1  represents an acid labile ester protecting group and R 2  represents OC(O)R 6 , wherein R 6  is as defined in  claim 1 , with an acid;    (g) for compounds of formula I in which R 1  represents R 3 , R 3  represents C 1-10  alkyl or C 1-3  alkylphenyl, and R 2  represents OH or C(O)OR 7 , and R 7  is as defined in  claim 1  by a transesterification of a corresponding compound of formula VII,    R 1a O(O)C—CH 2 —(R)Cgl-Aze-Pab-R 2    VII     wherein R 1a  represents a C 1-10  alkyl or C 1-3  alkylphenyl group other than that being formed, or an alternative labile alkyl substituent and R 2  is as defined in  claim 1.