Patent GB-1449331-A (GB)
Title: Benzazepine derivatives
IPC: B01J31/00
Filed: 1974-01-21
Abstract: 1449331 Octahydropyridoindolobenzazepines ENDO LABORATORIES Inc 21 Jan 1974 [22 Jan 1973 11 May 1973 6 Dec 1973 (2)] 02657/74 Heading C2C Novel octahydropyridoindolobenzazepines of the general formula n is zero or one; X is an anion of a pharmaceutically suitable acid; and R is hydrogen; 3-chloro-2-butenyl; 2-bromoallyl; benzyl; benzyl ring-substituted with methyl, methoxy or chloro; phenethyl; 3-phenylpropyl; 3-phenylpropyl ring substituted with chloro, bromo or methoxy; furfurtyl; 2-thenyl; acetonyl; phenacyl; C 1 -C 5 , alkyl; C 3 -C 5  alkenyl; C 3 -C 5  alkynyl; cinnamyl; cinnamyl ring-substituted with chloro, bromo, or methoxy; 3-phenyl-2- propynyl; cyclopropyl ; C 4 -C 8  cycloalkylmethyl (methylcyclopropyl)methyl; (cis - 2,3 - dimethylcyclopropyl)methyl; C 6 -C 8  cyclo = alkenylmethyl; C 6 -C 8  cycloalkadienylmethyl; (2,3-dimethylcycloprop- 2 - en - 1 - yl)methyl; exo - 7 - norcarylmethyl; (cis - 1,6 - dimethylendo - 3 - norcaren - 7 - yl)methyl; (4 - methylbicyclo[2.2.2]oct - 1 - yl)methyl; (4 - methylbicyclo[2.2.2]oct - 2 - en - 1 - yl) methyl; (bicyclo[2.2.1]hept - 2 - yl)methyl; bicyclo[2.2.1]- hept - 2 - en - 5 - yl)methyl; 1 - adamantylmethyl; or 2 - adamantylmethyl, and the hydrogens in the 4a and 14a positions are in trans relationship to each other, are prepared (a) when R is R<SP>a</SP>, which is benzyl; benzyl ring- substituted with methyl, methoxy or chloro; phenethyl; 3 - phenylpropyl; 3 - phenylpropyl ring-substituted by chloro, bromo or methoxy; furfuryl; 2-thenyl; C 1 -C 5  alkyl; cyclopropyl; C 4 -C 8  cycloalkylmethyl; (methyl-cyclopropyl)- methyl; exo - 7 - norcarylmethyl; (4 - methylbicyclo[2.2.2]oct - 1 - yl)methyl; (bicyclo- [2.2.1]hept- 2 - yl)methyl; 1 - adamantylmethyl; or 2 - adamantylmethyl, by reducing with a boron hydride/tetrahydrofuran complex a hexahydro pyridoindolobenzazepine of the general formula wherein R<SP>2</SP> is as R<SP>a</SP> or methoxymethyl or -COR<SP>7</SP>, in which R<SP>7</SP> is phenyl; chlorophenyl; methylphenyl; methoxyphenyl; benzylphenethyl; phenethyl ring - substituted by chloro, bromo or methoxy; 2-furyl; 2-thienyl; hydrogen; C 1 -C 4  alkyl; C 2 -C 4  alkenyl; styryl; styryl ring - substituted by chloro, bromo or methoxy; C 2 -C 7 , cycloalkyl; methylcyclopropyl; C 5 -C 7  cycloalkenyl; C 5 -C 7  cycloalkadienyl; exo - 7 - norcaryl; 4 - methylbioyclo- [2.2.2]oct - 1 - yl; bicyclo[2.2.1]hept - 2 - yl; 4 - methyl - bicyclo[2.2.2]oct - 2 - en - 1 - yl; bicyclo[2.2.1]hept - 2 - en - 5 - yl; 1 - adamantyl; or 2 - adamantyl; followed by acidification; (b) when R is hydrogen, by reacting the corresponding compound in which R is R<SP>6</SP>, which is methyl; ethyl; benzyl; benzyl ring- substituted by chloro, methyl or methoxy; or cyclopropylmethyl, with a compound of the general formula ClCOOR<SP>3</SP>, wherein R<SP>3</SP> is C 1 -C 4  alkyl; vinyl; benzyl; p-methylbenzyl; p-methoxybenzyl; or phenyl, and subjecting the resulting ester of the general formula to hydrolysis or, when R<SP>3</SP> is benzyl or substituted benzyl, to hydrolysis or hydrogenolysis; (c) when R is R<SP>c</SP>, which is as R with the exception of hydrogen, cyclopropyl and (cis-2,3-dimethylcyclopropyl)methyl, by alkylating the corresponding compound in which R is hydrogen with a compound of the general formula (i) R<SP>c</SP>Z, wherein Z is Cl, Br, I or -OS(O) 2  R<SP>8</SP>, in which R<SP>8</SP> is CH 3 , phenyl or p-tolyl, or (ii) wherein R<SP>9</SP> is C 1 -C 4  alkyl, in the presence of an acid acceptor; (d) when R is R<SP>d</SP>, which is as R with the exception of hydrogen, acetonyl, phenacyl, cyclopropyl, cinnamyl, substituted cinnamyl, 3-phenyl-2-propynyl and (cis-2,3- dimethylcyclopropyl)methyl, by acylating the corresponding compound wherein R is hydrogen with a compound of the general formula QCOR<SP>4</SP>, wherein R<SP>4</SP> is 2-chloro-1-propenyl; 1- bromovinyl; phenyl; chlorophenyl; methylphenyl; methoxyphenyl; benzyl; phenethyl; phenethyl ring-substituted with chloro, bromo, or methoxy; 2-furyl; 2-thienyl; hydrogen; C 1 -C 4 -alkyl; C 2 -C 4  alkenyl; C 2 -C 4  alkynyl; styryl; styryl ring substituted with chloro, bromo, or methoxy; phenylethynyl; C 3 -C 7  cycloalkyl; methylcyclopropyl; C 5 -C 7  cycloalkenyl; C 5 -C 7  cycloalkadienyl; 2,3-dimethylcycloprop - 2 - en - 1 - yl; exo - 7 - norcaryl; cis - 1,6 - dimethyl - endo - 3 - norcaren - 7 - yl; 4 - methyl - bicyclo[2.2.2]oct - 1 - yl; bicyclo- [2.2.1]hept - 2 - yl; 4 - methylbicyclo[2.2.2]- oct - 2 - en - 1 - yl; bicyclo - [2.2.1]hept - 2 - en- 5 - yl; 1 - adamantyl; or 2 - adamantyl; Q is -Cl, -Br, C 1 -C 4  alkoxy; or R<SP>5</SP> is different from R<SP>4</SP> and is C 1 -C 4  alkyl, provided that when R<SP>4</SP> is hydrogen, R<SP>5</SP> is methyl; and R<SP>6</SP> is C 1 -C 4  alkyl; and reducing the resulting ketone of the general formula with a metal hydride; and (e) when R is (cis- 2,3-dimethylcyclopropyl)methyl, by catalytically hydrogenating the corresponding compound in which R is (2,3-dimethylcycloprop-2-en-1-yl)- methyl; followed optionally by salification of a resulting free base. Hexahydropyridoindolobenzazepines of the second general formula above are prepared (a) when R<SP>2</SP> is methoxymethyl, by reacting the corresponding compound in which R<SP>2</SP> is hydrogen with chloromethyl methyl ether; (b) when R<SP>2</SP> is hydrogen, benzyl or -COR<SP>7</SP>, by condensing 5 - amino - 10,11 - dihydro - 5H - dibenz- [b,f]azepine with 4-piperidone, optionally 1- substituted by benzyl or -COR<SP>7</SP>, in the presence of an acid; (c) when R<SP>2</SP> is -CH 2 R<SP>7</SP>, by reducing the corresponding compound in which R<SP>2</SP> is -COR<SP>7</SP>; and (d) when R<SP>2</SP> is -COR<SP>7</SP>, by acylating the corresponding compound in which R<SP>2</SP> is hydrogen. Pharmaceutical compositions having analgesic and sedative-tranquillizer activity comprise, as active ingredient, at least one pyridoindolobenzazepine of the first general formula above, together with a pharmaceutically suitable vehicle.