Patent GB-1191237-A (GB)
Title: 0,3-Diazacyclo alkeno[2,1-a]isoindole Derivatives and a process for the mnufacture thereof
IPC: C07D487/04
Filed: 1968-03-28
Abstract: 1,191,237. 1,3 - Diazacycloalkeno[2,1-a]isoindole derivatives. F. HOFFMANN - LA ROCHE & CO. A.G. 28 March, 1968 [30 March, 1967; 18 May, 1967], No. 14967/68. Heading C2C. Novel compounds of the general Formula I: wherein B represents an alkylene chain having 2 to 4 carbon atoms in which one or more of the hydrogen atoms may be replaced by lower alkyl groups having 1 to 6 carbon atoms in a straight or branched chain, R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP> and R<SP>4</SP> individually represent a halogen atom or the trifluoro methyl or hydroxy group or a lower alkyl group having 1 to 6 carbon atoms as above or a lower alkoxy group having 1 to 6 carbon atoms in a straight or branched chain and R<SP>8</SP> represents a hydroxy or lower-alkoxy group and the broken lines denote that the atoms or groups attached thereby are optional, tautomers of these compounds in which R<SP>8</SP> is present and represents the hydroxy group and acid addition salts of the said compounds and tautomers are prepared by: (a) condensing a compound of the general Formula IV: wherein R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP> and the broken lines have the significance given above, with a diamine of the general formula H 2 N-B-NH 2 , wherein B has the significance given above; or (b) cyclizing a compound of the general Formula VI: wherein B, R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP> and the broken lines are as defined above, by treatment with a Lewis acid; or (c) reacting a compound of the general Formula VIII: wherein B, R<SP>1</SP>, R<SP>2</SP> and the broken lines are as defined above, or a dehydro derivative thereof of the general Formula X: wherein B, R<SP>1</SP>, R<SP>2</SP> and the broken lines have the significance given above, with an organometallic phenyl compound of the general Formula XI: wherein Z represents Li, MgBr, MgI, or MgCl, R<SP>31</SP> and R<SP>41</SP> individually represent a halogen atom or the trifluoromethyl group or a lower alkyl or lower alkoxy group as defined above and the broken lines have the significance given above; or (d) treating a compound of the general Formula XIII: wherein B, R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP> and the broken lines have the significance given above, with an oxidizing agent and, if desired, oxidizing any product in which R<SP>8</SP> is absent to a corresponding product in which R<SP>8</SP> is present and represents a hydroxy group, if desired, lower-alkylating a resulting product in which R<SP>8</SP> is present and represents a hydroxy group to a corresponding product in which R<SP>8</SP> is present and represents a lower alkoxy group, if desired, separating a racemic mixture obtained into its optically active antipodes and, also if desired, converting any base obtained into an acid addition salt. Starting materials of the Formula XIII are prepared by, for example, dissolving 2-hydrcxymethyl-benzhydrol in benzene, adding anhydrous MgSO 4  and bubbling HBr through the mixture until saturation. Ethylenediamine was then added. Starting materials of the Formula IV are prepared and claimed in Specification 1,191,238. Starting materials of the Formula I, where R<SP>8</SP> is -O-OH are prepared and claimed in Specification 1,191,239. Starting materials of the Formulae VIII and X are prepared and claimed in Specification 1,191,240. 2 - (2 - Amino - ethyl) - 3 - phenyl - phthalimidine is obtained by shaking, 9b-phenyl-1,2,3,9btetrahydro - 5H-imidazo[2,1-a]isoindolone-(5) in acetic acid containing hydrogen chloride, under one atmosphere of hydrogen using platinum oxide as catalyst. 5 - Phenyl - 2,3 - dihydro - 5H - imidazo[2,1-a]- isoindole is prepared by heating at reflux a solution of o-benzoyl-benzaldehyde in toluene and ethylenediamine. 2 - Phenyl - 2,3 - dihydro - 5H - imidazo[2,1-a]- isoindole is prepared by adding titanium tetrachloride in xylene to a solution of 2-(2-aminoethyl)-3-phenyl-phthalimidine in xylene and heating under reflux. Pharmaceutical compositions having use as psychostimulants and (in the case of compounds I where R<SP>8</SP> is lower alkoxy and compounds II, the tautomer of compound I where R<SP>8</SP> is OH) have analgesic, anti-inflammatory, antioedema, and muscle relaxant activity and are useful as anorexigenic or antifungal agents, and (in the case of compounds III, i.e. compounds I where R<SP>8</SP> is H) are useful as anti-inflammatory and antipyretic agents, and containing compounds of the general Formula I defined above or a pharmaceutically acceptable acid addition salt thereof are administered orally, parenterally or enterally and in the case of compound II when used as an antifungal agent, topically, in association with suitable phramaceutical carriers.