Patent EP-0159254-B1 (EP)
IPC: A61K31/00
Filed: 1985-03-28
Granted: 1987-10-07
Abstract: For for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. Compounds with the formula (I) :  see diagramm : EP0159254,P17,F1  in which R1  represents a hydrogen atom or a  see diagramm : EP0159254,P17,F2  radical, R'1  being an alkyl radical containing from 1 to 5 carbon atoms or an aryl radical possibly substituted by a hydroxy radical, an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing form 1 to 5 carbon atoms, the nitro radical or a halogen atom, n represents a whole number variable from 1 to 5, R2 , represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, an aryl or arylalkyl radical containing from 6 to 15 carbon atoms, possibly substituted by an alkyl radical containing from 1 to 5 carbon atoms, an alkoxyl radical containing from 1 to 5 carbon atoms, a hydroxyl radical, a halogen atom or a trifluoromethyl radical, m represents a whole number variable from 0 to 5, R3  represents : - either a saturated cyclic radical containing from 3 to 12 carbon atoms, which can be fused to a phenyl radical, R3  however not being able to represent a cyclohexyl radical when R2  and R1  represent at the same time a hydrogen atom and n=1 and m=O ; - or a phenyl radical possibly substituted by one or more radicals chosen from the following radicals : alkyl containing 1 to 5 carbon atoms, alkoxy containing from 1 to 5 carbon atoms, hydroxyl, nitro, halogeno, trifluoromethyl and  see diagramm : EP0159254,P17,F3  X and X' representing a hydrogen atom or an alkyl radical containing form 1 to 5 carbon atoms or a phenyl radical to which a saturated cyclic radical containing from 5 to 9 carbon atoms is fused ; or a heterocyclic radical chosen from the following radicals : thiazolyl, 4-5-dihydrothiazolyl, pyridinyl, oxazolyl, isoxazolyl, imidazolyl, pyrimidyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, possibly substituted by an alkyl radical containing from 1 to 5 carbon atoms, or a piperidinyl radical substituted by an aralkyl radical containing from 7 to 15 carbon atoms, provided that when R3 représents a phenyl radical possibly substituted by at least one of the radicals previously quoted or when R3 represents one of the heterocyclic radicals mentioned above, possibly substituted by an alkyl radical containing from 1 to 5 cabon atoms, m cannot represent the value 0 and provided that : a) when n=1 or 2, m=1, 2 or 3 and R1 =R2 =H, R3 is not a phenyl radical possibly substituted by one or two alkyl radicals containing form 1 to 5 carbon atoms, b) when m=n=1 and  see diagramm : EP0159254,P17,F4  and R2 =CH3 R3 is not a phenyl radical, as well as their addition salts with acids. For the Contracting State : AT 1. Process for preparing compounds with the formula (I) :  see diagramm : EP0159254,P18,F1  in which R1  represents a hydrogen atom or a  see diagramm : EP0159254,P18,F2  radical, R'1  being an alkyl radical containing from 1 to 5 carbon atoms or an aryl radical possibly substituted a hydroxyl radical, an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 5 carbon atoms, a nitro radical or a halogen atom, n represents a whole number variable from 1 to 5, R2  represent ts a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, an aryl or arylalkyl radical containing from 6 to 15 carbon atoms, possibly substituted by an alkyl radical containing from 1 to 5 carbom atoms, an alkoxy radical containing from 1 to 5 carbon atoms, a hydroxyl radical, a halogen atom or a trifluoromethyl radical, m represents a whole number variable from 0 to 5, R3  represents : - either a saturated cyclic radical containing from 3 to 12 carbon atoms, which can be fused to a phenyl radical, R3  howerer not being able to represent a cyclohexyl radical when R2  and R1  represent at the same time a hydrogen atom and n=1 and m=0 ; - or a phenyl radical possibly substituted by one or more radicals chosen from the following radicals : alkyl containing 1 to carbon atoms, alkoxy containing from 1 to 5 carbon atoms, hydroxyl, nitro, halogeno, trifluoromethyl and see diagramm : EP0159254,P18,F3  X and X' representing a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms or a phenyl radical to which a saturated cyclic radical containing from 5 to 9 carbon atoms is fused ; or a heterocyclic radical chosen from the following radicals : thiazolyl, 4-5-dihydrothiazolyl, pyridinyl, oxazolyl, isoxazolyl, imidazolyl, pyrimidyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, possibly substituted by an alkyl radical containing from 1 to 5 carbon atoms, or a piperidinyl radical substituted by an aralkyl radical containing from 7 to 15 carbon atoms, provided that when R3 represents a phenyl radical possibly substituted by at least one of the radicals previously quoted or when R3 represents one of the heterocyclic radicals mentioned above, possibly substituted by an alkyl radical containing from 1 to 5 carbon atoms, m cannot represent the value 0 and provided that : a) when n=1 or 2, m=1, 2 or 3 and R1 =R2 =H, R3 is not a phenyl radical possibly substituted by one or two alkyl radicals containing from 1 to 5 carbon atoms, b) when m=n=1 and  see diagramm : EP0159254,P19,F4  and R2 =CH3 R3  is not a phenyl radical, as well as their addition salts with acids, characterized in that - to prepare compounds with the formula (I) in which R1 , R2  and R3 and m have the previously given significance and in which n=1 as well as their addition salts with acids, an acid with the formula (II) : see diagramm : EP0159254,P19,F5  in which R'1  and R2  have the significances already indicated, or a functional derivative of this acid, is submitted to the action of a product with the formula (III) : H2 N-(CH2 )m -R3 in which R3  and m have the significances already indicated, so as to obtain a product with the formula (I), in which R1 =  see diagramm : EP0159254,P19,F6  as well as R2 , R3  and m having the significances already indicated and in which n=1, which products with the formula (I) are saponified, if necessary or desired, so as to obtain a product with the formula (I) in which R1 represents a hydrogen atom and which products with the formula (I) are salified, if necessary or desired, by the action of an acid in order to form the salts, - to prepare the compounds with the formula (I) in which R1 , R2  and R3  and m have the previously given significance and in which n represents a whole number variable from 1 to 3, an acid with the formula (IV) :  see diagramm : EP0159254,P19,F7  in which X is a halogen atom, and in which n and R2 have the significances given above, or a functional derivative of this acid, is submitted to the action of a product with the formula (III) H2 N(CH2 )m R3  as defined previously, so as to obtain a product with the formula (V) :  see diagramm : EP0159254,P19,F8  in which X, n, m, R2 and R3  have the previous significances, which is submitted to the action of the anion of a thioacid with the formula (VI) :  see diagramm : EP0159254,P19,F9  in which R'1  is defined as previously, so as to obtain a product with the formula (I) in which see diagramm : EP0159254,P19,F10  R'1 , R2 , R3  n and m having the significances given above, which product with the formula (I) is saponified, if necessary or desired, so as to obtain a product with the formula (I) in which R1  represents a hydrogen atom and which products with the formula (I) are salified, if necessary or desired, by the action of an acid so as to form the salts.