Patent GB-1442102-A (GB)
Title: 7h-indolizino-5,6,7-ij-isoquinoline derivatives
IPC: C07D471/16
Filed: 1974-07-25
Abstract: 1442102 7H - Indolizino[5,6,7-ij]isoquinoline derivatives RHONE-POULENC SA 25 July 1974 [27 July 1973 22 Nov 1973 30 May 1974] 32901/74 Heading C2C The invention comprises 7H - indolizino- [5,6,7-ij]isoquinoline derivatives of Formula (I) wherein R represents a hydrogen or halogen atom, or an alkoxy radical containing 1 to 4 carbon atoms, and R 1  represents a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms substituted by (i) a carboxy radical, (ii) an alkoxycarbonyl radical in which the alkoxy moiety contains 1 to 7 carbon atoms, or (iii) a carbamoyl radical, or R 1  represents a phenylalkyl radical in which the alkyl moiety contains 1 to 4 carbon atoms and is substituted by (i) a carboxy radical, (ii) an alkoxycarbonyl radical in which the alkoxy moiety contains 1 to 4 carbon atoms, or (iii) a carbamoyl radical, or R 1  represents an alkanoyl radical containing 1 to 4 carbon atoms or a benzoyl radical, and salts of those compounds wherein R 1  contains a carboxy radical. Compounds of Formula (I) in which R 1  represents a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms substituted by (i) a carboxy radical, (ii) an alkoxycarbonyl radical in which the alkoxy moiety contains 1 to 7 carbon atoms, or (iii) a carbamoyl radical, or R 1  represents a phenylalkyl radical in which the alkyl moiety contains 1 to 4 carbon atoms and is substituted by (i) a carboxy radical, (ii) an alkoxycarbonyl radical in which the alkoxy moiety contains 1 to 4 carbon atoms, or (iii) a carbamoyl radical, may be prepared by reacting a compound of the general formula or an acid addition salt thereof, with a 7H- indolizino[5,6,7 - ij]isoquinolin - 7 - one of the general formula Compounds of Formula (I) in which R 1  represents an alkanoyl radical containing 1 to 4 carbon atoms or a benxoyl radical may be prepared by reacting an acid of formula R 2 -COOH (where R 2  is H, an alkyl radical containing 1 to 3 carbon atoms or phenyl) or a reactive derivative thereof with a compound of formula Compounds of Formula (I) in which R 1  represents an alkyl radical containing 1 to 4 carbon atoms substituted by (i) a carboxy radical, (ii) an alkoxycarbonyl radical in which the alkoxy moiety contains 1 to 7 carbon atoms, or (iii) a carbamoyl radical, or R 1  represents a phenylalkyl radical in which the alkyl moiety contains 1 to 4 carbon atoms and is substituted by (i) a carboxy radical, (ii) an alkoxycarbonyl radical in which the alkoxy moiety contains 1 to 4 carbon atoms, or (iii) a carbamoyl radical, may be prepared by reacting a compound of the general formula (wherein R 3  represents an alkyl radical containing 1 to 4 carbon atoms substituted by (i) a carboxy radical, (ii) an alkoxycarbonyl radical in which the alkoxy moiety contains 1 to 7 carbon atoms, or (iii) a carbamoyl radical, or R 3  represents a phenylalkyl radical in which the alkyl moiety contains 1 to 4 carbon atoms and is substituted by (i) a carboxy radical, (ii) an alkoxycarbonyl radical in which the alkoxy moiety contains 1 to 4 carbon atoms, or (iii) a carbamoyl radical, and X represents a halogen atom with a quaternary ammonium salt of an oxime of the general Formula V). Compounds of Formula (I) in which R 1  represents an alkyl radical containing 1 to 4 carbon atoms substituted by an alkoxycarbonyl radical in which the alkoxy moiety contains 1 to 7 carbon atoms, or R 1  represents a phenylalkyl radical in which the alkyl moiety contains 1 to 4 carbon atoms and is substituted by an alkoxycarbonyl radical in which the alkoxy moiety contains 1 to 4 carbon atoms, may be prepared by converting by a method known per se the carboxy radical of a compound of formula (wherein R 4  represents an alkyl radical containing 1 to 4 carbon atoms substituted by a carboxy radical, or a phenylalkyl radical in which the alkyl moiety contains 1 to 4 carbon atoms and is substituted by a carboxy radical) to an alkoxycarbonyl radical containing 1 to 7 carbon atoms in the alkoxy moiety when R 4  is an alkyl radical substituted by a carboxy radical, or to an alkoxycarbonyl radical containing 1 to 4 carbon atoms in the alkoxy moiety when R 4  is a phenylalkyl radical in which the alkyl moiety is substituted by a carboxy radical. Compounds of Formula (I) in which R 1  represents an alkyl radical containing 1 to 4 carbon atoms substituted by a carbamoyl radical, or R 1  represents a phenylalkyl radical in which the alkyl moiety contains 1 to 4 carbon atoms and is substituted by a carbamoyl radical, may be prepared by converting by a method known per se the carboxy radical of the compound of Formula VII to a carbamoyl radical. Compounds of Formula (I) in which R 1  represents an alkyl radical containing 1 to 4 carbon atoms substituted by a carboxy radical, or a phenylalkyl radical in which the alkyl moiety contains 1 to 4 carbon atoms and is substituted by a carboxy radical, may be prepared by the saponification of a compound of the general formula wherein R 6  represents an alkyl radical containing 1 to 4 carbon atoms substituted by an alkoxycarbonyl radical in which the alkoxy moiety contains 1 to 7 carbon atoms, or a phenylalkyl radical in which the alkyl moiety contains 1 to 4 carbon atoms and is substituted by an alkoxycarbonyl radical in which the alkoxy moiety contains 1 to 4 carbon atoms, to convert the alkoxycarbonyl radical to a carboxy radical. The compounds of Formula III may be prepared by alkaline hydrolysis of an imine of Formula XI The imines of Formula XI may be prepared by cyclization of an isoquinoline derivative of Formula XII which may itself be prepared from compounds of Formula XIII by stirring in an organic solvent, in the presence of an alkali metal hydride. The compounds of Formula XIII may be prepared by reacting an alkali metal cyanide and toluene-p-sulphonyl chloride with an isoquinoline derivative of Formula XIV which may be prepared by reacting a tetrahydrofuran derivative of formula where R 7  is methyl or ethyl, With an 8-aminoisoquinoline derivative of formula The compounds of Formula I are used in pharmaceutical compositions.