Patent EA-000797-B1 (EA)
Title: Novel farnesyl transferase inhibitors, preparation thereof and pharmaceutical composition
Inventor: COMMERSON ALAIN
IPC: A61P43/00
Filed: 1996-07-08
Abstract: 1. A compound of formula (I):   in which: R represents: a group of formula -(CH2)m-X1-(CH2)n --Z in which  X1 represents a single bond or an oxygen or sulphur atom,  m represents an integer equal to 0 or 1, and  n represents an integer equal to 0, 1 or 2; wherein one or more methylene groups in said R group may be substituted by a carboxyl group, an alkoxycarbonyl group, the alkyl portion of which contains 1 to 4 carbon atoms, a carbamoyl group, an alkylcarbamoyl group, the alkyl portion of which contains 1 to 4 carbon atoms, a dialkylcarbamoyl group, the alkyl portion of which contains 1 to 4 carbon atoms, an amino group, an alkylamino group, or a dialkylamino group, wherein each alkyl portion contains 1 to 4 carbon atoms, and Z represents a carboxyl group; a COOR4 group, in which R4 represents a straight or branched alkyl group containing 1 to 3 carbon atoms, or a CON(R5)(R6) group, in which R5 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms, and R6 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms optionally substituted by an amino group, a dialkylcarbamoyl group, the alkyl portion of which contains 1 to 4 carbon atoms, hydroxyl, alkyloxy containing 1 to 4 carbon atoms, mercapto group, alkylthio group containing 1 to 4 carbon atoms, alkyloxycarbonyl group alkyl portion of which contains 1 to 4 carbon atoms, carboxyl, cyano, phenyl optionally substituted by one or more identical or different atoms, or radicals selected from halogen atoms and alkyl groups containing 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, cyano, and trifluoromethyl groups, a 1- or 2-naphthyl, 2- or 3-furyl, 2- or 3-thienyl, 4- or 5-imidazolyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5- thiazolidinyl, or 2-, 3- or 4-pyridyl; or an indanyl or thiochromanyl group, or else R5 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms, and R6 represents a hydroxyl group, an amino group or an alkyloxy group containing 1 to 6 straight- or branched-chain carbon atoms optionally substituted by a phenyl group, or a PO3(OR7)2 group, in which R7 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms, -NH-CO-T group in which T represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms optionally substituted by one or more amino, carboxyl, alkyloxycarbonyl, alkyl portion of which contains 1 to 4 carbon atoms, hydroxyl, alkyloxy group, containing 1 to 4 carbon atoms, mercapto group, alkylthio group containing 1 to 4 carbon atoms, or a residue of quaternary ammonium of formula     preferably is pyridine radical, R1 and R2, which are identical or different, are a hydrogen atom, a halogen atom, or an alkyl group, containing 1 to 4 carbon atoms, alkyloxy group optionally substituted by a dialkylamino group, each portion contains 1 to 4 carbon atoms or together with the nitrogen atom forms a saturated heterocycle containing 5 or 6 ring carbon atoms, an alkylthio group, containing 1 to 4 carbon atoms, alkyloxycarbonyl group, alkyl portion of which contains 1 to 4 carbon atoms; or else R<1> and R2, situated at the ortho position with respect to one another, form a saturated or unsaturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen, optionally substituted by a halogen atom or by an alkyl group containing 1 to 4 carbon atoms or alkyloxy group, containing 1 to 4 carbon atoms or else R1 is a hydrogen atom, a halogen atom, or an alkyl group, containing 1 to 4 carbon atoms, an alkyloxy group optionally substituted by a dialkylamino group, each alkyl portion contains 1 to 4 carbon atoms, an alkylthio group, containing 1 to 4 carbon atoms, an alkyloxycarbonyl group, alkyl portion of which contains 1 to 4 carbon atoms; and R2 is a thioalkyl group, containing 1 to 4 carbon atoms wherein, in this case, the compound of formula (I) exists in the form of a dimer compound wherein the two parts of the dimer are connected via a disulphide bridge; R3 is a hydrogen atom, a halogen atom, or an alkyl group, containing 1 to 4 carbon atoms, an alkenyl group containing 2 to 4 carbon atoms, an alkyloxy group, containing 1 to 4 carbon atoms or an alkylthio group, containing 1 to 4 carbon atoms; X is an oxygen or sulphur atom, or an -NH-, -CO-, methylene group, ethylene group, alkylidene group such as vinylidene or 1,1-cycloalkyl group containing 3 to 6 carbon atoms; and Y is an oxygen or sulphur atom; in the racemic form as optical isomers of general formula (I). 2. A compound according to claim 1, wherein one of R1 and R2 is a hydrogen atom and the other is an alkyloxy group containing from 1 to 4 carbon atoms, R3 is a hydrogen atom, X is a methylene group, Y is an oxygen atom and R is a group of formula -(CH2)m -X1 -(CH2)n -Z-, in which m is equal to 0 or 1, X1 is s a bond, and n is equal to 0, and Z is a carboxyl group or a -COOR4 group in which R4 is an alkyl group containing 1 to 3 carbon atoms, or a CON(R5)(R6) group in which R5 and R6 are defined according to claim 1. 3. A compound of formula (I) according to claim 1, which is (3aS, 4R, 9R, 9aS)-4,9-ethano-2-[2-(2-methoxyphenyl)prop-2-en-1-oyl]-9-phenyl-1,2,3,3a,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid, a dextrorotatory enantiomer optionally in the form of an ester containing 1 to 3 carbon atoms. 4. A compound of formula (I) according to claim 1, which is (3aS, 4R, 9R, 9aS)-N-[(S)-t-butylfenylglycinoyl]-4,9-ethano-2-[(2-methoxyphenyl)prop-2-en-1-oyl]-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindol-3a-carboxamide. 5. A compound of formula (I) according to claim 1, which is (3aS, 4R, 9R, 9aS)-N-[(3-pyridyl)methyl]-4,9-ethano-2-[(2-methoxyphenyl)prop-2-en-1-oyl]-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindol-3a-arboxamide. 6. A compound of formula (I) according to claim 1, which is (3aS, 4R, 9R, 9aS)-N-[(2-pyridyl)methyl]-4,9-ethano-2-[(2-methoxyphenyl)prop-2-en-1-oyl]-9-phenyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindol-3a-arboxamide. 7. A process for preparing a compound according to any one of the preceding claim, in which R, R1, R2 and R3 are defined according to claim 1 or 2, Y is an oxygen or sulphur atom, and X is a -CO-, methylene group, ethylene group, alkylidene group or 1,1-cycloalkyl group wherein an acid of formula (II):   in which R1, R2 and X are defined as above and Y is an oxygen or sulphur atom or reacting the methyl ester of said acid or another derivative of said acid such as halogenure or anhydride with a compound of formula (III):   in which R and R3 are defined as above and G1 is a hydrogen atom and then optionally, when R is or contains a --COOR4 group or -PO3(OR7)2, in which R4 and R7 are an alkyl group, saponifying the product obtained from said reaction to obtain said compound of formula (I) in which R is or contains a carboxyl group or converting the product obtained from said reaction by means of a nucleophilic agent to obtain said compound of formula (I) in which R is or contains a -PO3H2 group. 8. A process for preparing a compound according to claim 1 or 2, in which Y is an oxygen or sulphur atom and X is an oxygen atom, characterized in that a haloformate or halothioformate of formula (IV):   in which Y represents an oxygen or sulphur atom, R1 and R2 are defined according to claim 1 or 2 and Hal is a halogen atom reacts with a compound of formula (III), and then optionally, when R is or contains a -COOR4 group or -PO3(OR7)2, in which R4 and R7 are an alkyl group, saponifying the product obtained from said reaction to obtain said compound of formula (I) in which R is or contains a carboxyl group or converting the product obtained from said reaction by means of a nucleophilic agent to obtain said compound of formula (I), in which R is or contains a -PO3H2 group. 9. A process for preparing a compound of according to claim 1 or 2, in which Y is an oxygen or sulphur atom and X is an NH group, characterized in that an isocyanate or an isothiocyanate of formula (V):   in which Y is an oxygen or sulphur atom, and R1 and R2 are defined according to claim 1 or 2, reacts with a compound of formula (III): in which G1 is a hydrogen atom, and then optionally, when R is or contains a -COOR4 group or -PO3(OR7)2, in which R4 and R7 are an alkyl group, saponifying the product obtained from said reaction to obtain said compound of formula (I) in which R is or contains a carboxyl group or converting the product obtained from said reaction by means of a nucleophilic agent to obtain said compound of formula (I), in which R is or contains a -PO3H2 group. 10. A process for preparing a compound of according to claim 1 or 2, in which R1, R2 and R3 are defined according to claim 1 or 2, X is an oxygen or sulphur atom or an -NH-, -CO-, methylene group, ethylene group, alkylidene group or 1,1-cycloalkyl group, Y is an oxygen or sulphur atom, and R is a group of formula -(CH2)m-X1 -(CH2)n-Z, in which X1, m and n are defined according to claim 1 or 2, and Z is a -COOR4 group, in which R4 is a straight or branched alkyl group containing 1 to 3 carbon atoms, characterized in that comprising esterifying a compound of formula (I), in which R1, R2, R3, X, Y, X1, m and n are defined as above and Z represents a carboxyl group. 11. A process for preparing a compound of according to claim 1, in which R1, R2 and R3 are defined according to claim 1, X is an oxygen or sulphur atom or an -NH-, -CO-, methylene group, ethylene group, alkylidene group or 1,1-cycloalkyl group, Y is an oxygen or sulphur atom, and R is a group of formula -(CH2)m-X1-(CH2)n-Z-, in which X1, m and n are defined according to claim 1, and Z is a CON(R5)(R6) group in which R5 and R6 are identical or different are a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms and R6 is a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms option