4,9-ethano-benzo(F)isoindole derivatives as farnesyl transferase inhibitors

A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, in which R.sub.1, R.sub.2 and R.sub.3 are defined according to claim 1, X represents an oxygen or sulphur atom or an --NH--, --GO--, methylene, ethylene, alkylidene or 1,1-cycloalkyl group containing 3 to 6 carbon atoms, Y represents an oxygen or sulphur atom, and R represents a group of formula --(CH.sub.2).sub.m --X.sub.1 --(CH.sub.2).sub.n --Z in which X.sub.1, m and n are defined according to claim 16, and Z represents a CON(R.sub.5)(R.sub.6) group in which R.sub.5 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms and R.sub.6 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms optionally substituted by an amino, alkylamino, dialkylamino, alkyloxy, alkylthio, alkyloxycarbonyl, carboxyl, cyano, phenyl optionally substituted by one or more identical or different groups selected from alkyloxy and trifluoromethyl groups, 1- or 2-naphthyl, 2- or 3-furyl, 2- or 3-thienyl, 4- or 5-imidazolyl, 4- or 5-thiazolyl, 2-, 3- or 4-pyridyl, indanyl, and thiochromanyl groups, wherein the alkyl portions and groups in the definition of R.sub.6 contain 1 to 4 carbon atoms, or R.sub.5 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms and R.sub.6 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, said process comprising reacting a compound of formula HN(R.sub.5)(R.sub.6), in which R.sub.5 and R.sub.6 are defined as above, with a compound of formula (I) in which R.sub.1, R.sub.2, R.sub.3, X, Y, X.sub.1, m and n are defined as above and Z represents a carboxyl group, under conditions sufficient to obtain said compound of formula (I) or a salt thereof.

A compound of formula (I):

• ##STR32## in which:
• R represents:
• a group of formula --(CH.sub.2).sub.m --X.sub.1 --(CH.sub.2).sub.n --Z in which
• X.sub.1 represents a single bond or a 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 at least one alkoxycarbonyl group containing 1 to 4 carbon atoms;
• and
• Z represents
• a carboxyl group, or
• a COOR.sub.4 group, in which R.sub.4 represents a straight or branched alkyl group containing 1 to 2 carbon atoms, or
• a CON(R.sub.5)(R.sub.6) group, in which R.sub.5 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms, and R.sub.6 represents a hydrogen atom, an indanyl or thiochromanyl group, or a straight or branched alkyl group containing 1 to 6 carbon atoms optionally substituted by one or more amino, alkylamino, dialkylamino, hydroxyl, alkyloxy, mercapto, alkylthio, aralkylthio, alkyloxycarbonyl, carboxyl, cyano, phenyl optionally substituted by one or more identical or different groups selected from halogen atoms and alkyl, alkyloxy, and trifluoromethyl groups, or a 1- or 2-naphthyl, 2- or 3-furyl, 2- or 3-thienyl, 4- or 5-imidazolyl, 2-, 4- or 5-thiazolyl, 2-, 3- or 4-pyridyl group, wherein each of the alkyl portions provided in the definition of R.sub.6 that is not of a specifically defined carbon length contains 1 to 4 carbon atoms;
• or R.sub.5 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms, and R.sub.6 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 PO(OR.sub.7).sub.2 group, in which R.sub.7 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 2 carbon atoms, or
• an aromatic heterocycle,
• or R represents an --NH--CO--T group in which T represents a hydrogen atom or a straight or branched alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more amino, carboxyl, alkyloxycarbonyl, or alkylthio groups, wherein each of the alkyl portions provided in the definition of T that is not of a specifically defined carbon length contains 1 to 4 carbon atoms;
• R.sub.1 and R.sub.2, which are identical or different, are selected from a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, a straight or branched chain alkyloxy or aralkyloxy group, optionally substituted by a dialkylamino group wherein the two alkyl portions of said dialkylamino group may form, together with the nitrogen atom to which they are attached, a saturated heterocycle containing 5 or 6 ring carbon atoms, an alkylthio group, and an alkyloxycarbonyl group;
• or R.sub.1 and R.sub.2, situated at the ortho position with respect to one another, together with the ring carbon atoms to which they are attached form a saturated or unsaturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen, optionally substituted by a halogen atom;
• or R.sub.1 represents a hydrogen atom, a halogen atom, an alkyl group, an alkyloxy group optionally substituted by a dialkylamino group, an alkylthio group, or an alkyloxycarbonyl group, and R.sub.2 represents a thioalkyl group, 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 formed from the two thioalkyl R.sub.2 groups, and further wherein each of the alkyl portions and groups provided in the definition of R.sub.1 and R.sub.2 contains 1 to 4 carbon atoms;
• R.sub.3 represents a hydrogen atom, a halogen atom, an acyl group, an alkenyl group containing 2 to 4 carbon atoms, or an alkyloxy group, wherein each of the alkyl portions provided in the definition of R.sub.3 that is not of a specifically defined carbon length contains 1 to 4 carbon atoms;
• X represents an oxygen, or an --NH--, --CO--, an optionally substituted methylene, ethylene, alkylidene, or 1,1-cycloalkyl group containing 3 to 6 carbon atoms;
• and
• Y represents an oxygen or sulphur atom;
• or a pharmaceutically acceptable salt thereof.

A compound of formula (I):

• ##STR33## in which:
• R represents:
• a group of formula --(CH.sub.2).sub.m --X.sub.1 --(CH.sub.2).sub.n --Z in which
• X.sub.1 represents a single bond,
• m represents an integer equal to 0, and
• n represents an integer equal to 0;
• and
• Z represents
• a carboxyl group, or
• a COOR.sub.4 group, in which R.sub.4 represents an alkyl group containing 1 carbon atom, or
• a CON(R.sub.5)(R.sub.6) group, in which R.sub.5 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms, and R.sub.6 represents a hydrogen atom, an indanyl group, or a straight or branched alkyl group containing 1 to 6 carbon optionally substituted by one or more alkyloxy, mercapto, alkylthio, aralkylthio, carboxyl, cyano, phenyl optionally substituted by one or more identical or different groups selected from alkyl, alkyloxy, and trifluoromethyl groups, or a 2- or 3-furyl, 2- or 3-thienyl, 4- or 5-imidazolyl, 2-, 4- or 5-thiazolyl, or a 2-, 3- or 4-pyridyl group, wherein each of the alkyl portions provided in the definition of R.sub.6 that is not of a specifically defined carbon length contains 1 to 4 carbon atoms;
• or R.sub.5 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms, and R.sub.6 represents an alkyloxy group containing I to 6 straight- or branched-chain carbon atoms optionally substituted by a phenyl group;
• R.sub.1 and R.sub.2, which are identical or different, are selected from a hydrogen atom, a straight or branched chain alkyloxy or aralkyloxy group optionally substituted by a dialkylamino group wherein the two alkyl portions of said dialkylamino group may form, together with the nitrogen atom to which they are attached, a saturated heterocycle containing 5 or 6 ring carbon atoms, and an alkylthio group, and further wherein each of the alkyl portions and groups provided in the definition of R.sub.1 and R.sub.2 contains 1 to 4 carbon atoms;
• R.sub.3 represents a hydrogen atom, or a halogen atom, or an aralkyloxy group, wherein each of the alkyl portions and groups provided in the definition of R.sub.3 contains 1 to 4 carbon atoms;
• X represents an optionally substituted methylene or vinylidene group;
• and
• Y represents an oxygen or sulphur atom;
• or a pharmaceutically acceptable salt thereof.

A compound of formula (I):

• ##STR34## in which:
• R represents:
• a group of formula --(CH.sub.2).sub.m --X.sub.1 --(CH.sub.2).sub.n --Z in which
• X.sub.1 represents a single bond,
• m represents an integer equal to 0, and
• n represents an integer equal to 0;
• and
• Z represents
• a carboxyl group, or
• a COOR.sub.4 group, in which R.sub.4 represents a straight or branched alkyl group containing 1 carbon atom, or
• a CON(R.sub.5)(R.sub.6) group, in which R.sub.5 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms, and R.sub.6 represents a hydrogen atom, an indanyl group, or a straight or branched alkyl group containing 1 to 6 carbon atoms optionally substituted by one or more, alkyloxy, aralkylthio, alkyloxycarbonyl, carboxyl, cyano, phenyl optionally substituted by one or more identical or different groups selected from alkyl, and alkyloxy groups, or a 2- or 3-furyl, 2- or 3-thienyl, 4- or 5-imidazolyl, 2-, 4- or 5-thiazolyl, or 2-, 3- or 4-pyridyl group,
• wherein each of the alkyl portions provided in the definition of R.sub.6 that is not of a specifically defined carbon length contains 1 to 4 carbon atoms;
• or R.sub.6 represents a hydrogen atom or a straight or branched alkyl group containing 1 to 6 carbon atoms, and R.sub.6 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;
• R.sub.1 and R.sub.2, which are identical or different, are selected from a hydrogen atom, and a straight or branched chain alkyloxy group optionally substituted by a dialkylamino group wherein the two alkyl portions of said dialkylamino group may form, together with the nitrogen atom to which they are attached, a saturated heterocycle containing 5 or 6 ring carbon atoms, wherein each of the alkyl portions provided in the definition of R.sub.1 and R.sub.2 contains 1 to 4 carbon atoms;
• R.sub.3 represents a hydrogen atom;
• X represents an optionally substituted methylene or vinylidene;
• and
• Y represents an oxygen or sulphur atom;
• or a pharmaceutically acceptable salt thereof.