Patent EA-001399-B1 (EA)
Title: Prolylendopeptidase inhibitors
Inventor: KANAI KAROLY
IPC: A61K31/473
Filed: 1996-07-26
Abstract: 1. Compounds of the general formula A-B-C-D-L [I] wherein A is an onefold of manifold substituted or unsubstituted organic cyclic group of the general formula (1)   wherein  R<1>, R<2>, R<3> and R<4> are independently from each other hydrogen atom, halogen atom, hydroxyl group, straight chain or branched chain alkyl or alkenyl- or alkinyl or alkoxy- or alkenyloxy- or alkinyloxy groups containing 1-6 carbon atoms, nitrogroup, amino group, monoalkylamino or monoacylamino group of 1-12 carbon atoms, dialkylamino- or diacylamino group of 2-24 carbon atoms - where the acyl group is an alkyl, aralkyl, cycloalkyl or aryl type -, cyano group, mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group, anilino-, benzoyl, phenoxy-, benzyloxy-, isocyanato group, isothiocyanato-, alkylthio group of 1-6 carbon atoms, sulfamino or sulfamoyl group, thiocyanato or cyanato group; R<5> and R<6> are independently from each other hydrogen atom, hydroxyl group phenyl group or alkyl group of 1- 4 carbon atoms or R<5> and R<6> together mean oxo group; B is  group, wherein m is an integer of 1 to 21; or   if w is zero or 1, then R<9>, R<10>, R<11>, R<12> R<13> and R<14> mean independently from each other hydrogen or alkyl group of 1-6 carbonatoms or a phenyl group, which can be substituted by halogen; or if w is zero, then R<9> and R<11> mean together a chemical bond, R<12> and R<14> mean together 1,3-butadienylene or R<9> and R<11> are hydrogen atoms and R<12> and R<14> are together tetramethylene group; or if w is 1, then R<9> and R<10> are together a chemical bond and R<12> and R<14> are together a prop-1-one-1-yl-3-ilidiene group; C is prolyl group or one of the groups of formula   wherein n is zero, 1 or 2, Hlg is fluorine, chlorine, bromine, or iodine atom, R<5> and R<6> are independently from each other hydrogen atom, hydroxyl group phenyl group or alkyl group of 1-4 cabonatoms or R<5> and R<6> together mean oxo-group; D or L structural unit or one of the group of the formula   where the dotted line is a chemical bond optionally present-, s is 1, 2 or 3, or a group of the formula   wherein R<15> is a hydrogen atom, alkyl group of 1-6 carbon atoms, phenyl or naphthyl group; or a group of the formula   wherein  Z is a NH - group, oxygen atom or sulfur atom; D is a covalent chemical bond or prolyl- or thioprolyl group, or one of groups of formula (37) or (38), (39), (40) or (41); L is pyrrolidino- or 2- cyanopyrrolidino, thiazolidino or 2-cyano-thiazolidino or piperidino group optionally substituted with one halogen atom or geminally with two halogen atoms; or a group of the formula   where R<17> is hydrogen atom or cyano group, n is 0, 1 or 2 ; or a group of the formula   and optical , cis-trans, geometric isomers , epimers, tautomers and salts. 2 Compounds of the general formula (I), wherein A is one of the groups having general formula (1), - wherein R<1> R<2> R<3>and R<4> are independently from each other hydrogen atom, halogen atom, hydroxyl group, straight chain or branched chain alkyl or alkenyl- or alkinyl or alkoxy- or alkenyloxy- or alkinyloxy groups containing 1-6 carbon atoms, nitrogroup, amino group, monoalkylamino or monoacylamino group of 1-12 carbon atoms, dialkylamino- or diacylamino group of 2-24 carbon atoms - where the acyl group is an alkyl, aralkyl, cycloalkyl or aryl type -, cyano group, mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group, anilino-, benzoyl, phenoxy-, benzyloxy-, isocyanato group, isothiocyanato-, alkylthio group of 1-6 carbon atoms, sulfamino or sulfamoyl group, thiocyanato or cyanato group; R<5> and R<6> are independently from each other hydrogen atom, hydroxyl group phenyl group or alkyl group of 1- 4 carbon atoms or R<5> and R<6> together mean oxo group; B is  group, wherein m is an integer 2 or 3; C is a prolyl group or a group of the general formula (38) or (41) - wherein n is 1 or 2; D is a covalent chemical bond; L is a pyrrolidino or thiazolidino group - and optical, cis-trans, geometric isomers, epimers, tautomers and salts. 3. Pharmaceutical composition containing one or more compounds of the general formula (I) - wherein the meanings of A, B, C, D, and L are as given in claim 1 and 2 - and/or optical, cis-trans, geometric isomers, epimers, tautomers and salts together with usual carrier and/or auxiliary materials applied in the pharmaceutical industry or without them. 4. Use of the compounds of the general formula (I) defined in claim 1 for inhibition of prolyl-endopeptidase enzyme in mammals including man. 5. A process for the preparation of compounds of the general formula (I) - where in the meanings of A, B, C, D, and L are as given in claim 1 - and optical, cis-trans, geometric isomers, epimers, tautomers and their salts, characterized in that a racemic or optically active carboxylic acid of the general formula A-B-OH                           [II],` - where the meanings of A and B are as given in claim 1 - are transformed to an acid halide, or an active ester, or to a mixed acid anhydride or to a carbodiimide, and the resulted compound is reacted with a racemic or optically active compound or their salt of the general formula H-CDL                             [III], - where the meanings of C, D and L are as given in claim 1, and the resulted compound of the general formula (I) - where the meanings of A, B, C, D, and L are as given in claim 1 - optionally is separated into their optical, cis-trans, geometric isomers, epimers or tautomers or salts of compounds of general formula (I) is formed, or the compounds of general formula (I) are liberated from their salts. 6. A process according to claim 5 characterized in that, an acid addition salt of compound of general formula (III) is used. 7. A process according to claim 5, characterized in that, a reactive mixed anhydride is formed starting from a compound of the general formula (II) and pivaloylchloride is applied. 8. A process according to claim 5, characterized in that, the reaction is carried out in an organic solvent. 9. A process according to claim 5, characterized in that, the reaction is carried out at a temperature between - 25 degree C and the boiling point of the reaction mixture. 10. A process according to claim 5, characterized in that, the reaction is carried out in the presence of an acid binding agent.