GB1225411A - - Google Patents

Abstract

1,225,411. 5H - Imidazo [2,1-a] isoindole derivatives. SANDOZ Ltd. 22 March, 1968 [23 March, 1967], No. 13968/68. Heading C2C. Novel 5H-imidazo [2,1-a] isoindole derivatives of the general Formula I where R, R 1 and R 2 , which may be the same or different, each signifies a hydrogen, chlorine, or fluorine atom, or a trifluoromethyl radical, a straight-chain alkyl radical of 1 to 4 carbon atoms or a straight-chain alkoxy radical of 1 to 4 carbon atoms, provided that (1) R, R 1 and R 2 are such that there is never a trifluoromethyl radical on each of two adjacent carbon atoms, and (2) when R or R 2 is a trifluoromethyl radical, R 1 is a hydrogen, chlorine or fluorine atom, R 3 signifies a hydrogen, chlorine or fluorine atom, R 4 and R 5 , which may be the same or different, each signifies a hydrogen, chlorine orfluorineatom, ora trifluoromethylradical, a straight-chain alkyl radical of 1 to 4 carbon atoms or a straight chain alkoxy radical of 1 to 4 carbon atoms, provided that when one of R 4 or R 5 is a trifluoromethyl radical, the other is a hydrogen, chlorine or fluorine atom, or R 4 and R 5 taken together signify -O-CH 2 -O-, and R 6 signifies a hydrogen or fluorine atom with the further provisos that (i) not more than two of R 3 , R 4 , R 5 and R 6 are other than hydrogen, and (ii) not more than three of R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are other than hydrogen, and that when R, R 3 , R 4 , R 5 and R 6 all signify a hydrogen atom, (iii) R 1 and R 2 do not both represent chlorine atoms, (iv) R 1 does not represent a chlorine atom when R 2 represents a hydrogen atom, (v) R 2 does not represent a fluorine atom when R 1 is a hydrogen atom, and their acid addition salts are prepared in a process which comprises treating a compound of Formula II in which R to R 6 are as defined above, with lithium aluminium hydride in an inert ether solvent in an inert atmosphere at a temperature not exceeding 45‹ C. and contacting the reaction product in solution, after decomposition of any remaining lithium aluminium hydride, with air or oxygen, and when an acid addition salt is desired, salifying the resulting compound of Formula I. Compounds I also exist in other forms. 2 - Iodo - 5 - chlorotoluene is prepared by treating 2-methyl-4-chloroaniline in acetic acid with a sodium nitrite and sulphuric acid solution and treating the resultant mixture with a potassium iodide solution in water. 2 - Methyl - 4 - chlorobenzhydrol is prepared by treating 2-iodo-5-chlorotoluene in ether with magnesium shavings in ether and treating the resultant Grignard reagent with benzaldehyde in diethyl ether. The mixture is cooled and then treated with a saturated ammonium chloride solution and then with anhydrous sodium sulphate. 2 - Benzoyl - (halogen) - benzoic acids where halogen is (i) 4,5-dichloro and (ii) 5-chloro are prepared by (i) treating 2-methyl-4,5-dichlorobenzophenone with sodium hydroxide and potassium permanganate; (ii) treating 2- methyl-4-chlorobenzhydrol with the same reagents. 2 - Methyl - 4,5 - dichlorobenzophenone is prepared by treating 3,4-dichlorotoluene with benzoyl chloride and aluminium trichloride. 2 - (3<SP>1</SP> - Trifluoromethyl - benzoyl) - benzoic acid is prepared by treating a Grignard reagent, prepared from magnesium turnings in tetrahydrofuran and m-bromobenzotrifluoride, with phthalic anhydride, toluene and hydrochloric acid. 2,6 - Dichloro - 3 - trifluoromethyl - benzoic acid is prepared by pouring a mixture of n-butyllithium and 2,4-dichlorobenzotrifluoride in ether onto solid carbon dioxide. 2,6 - Dichloro - 3 - trifluoromethyl - benzophenone is prepared by treating 2,6-dichloro-3- trifluoromethylbenzoic acid with thionyl chloride and aluminium trichloride in benzene and pouring the mixture on to an ice and concentrated hydrochloric acid mixture. 2 - Chloro - 3 - trifluoromethyl - 6 - cyano - benzophenone is prepared by treating 2,6-dichloro-3- trifluoromethylbenzophenone with potassium cyanide, cuprous chloride and anhydrous dimethyl formamide and then pouring the cooled solution into ice water. 2 - Benzoyl - 3 - chloro - 4 - trifluoromethylbenzoic acid is prepared by treating 2-chloro-3- trifluoromethyl-6-cyanobenzophenone with potassium hydroxide and then with concentrated hydrochloric acid. 9b(Ar) - 1,2,3,9b - tetrahydro - 5H - imidazo- [2,1-a]isoindol-5-ones where Ar is 31-trifluoromethylphenyl, or 3<SP>1</SP>,5<SP>1</SP>-dichlorophenyl are prepared from the corresponding 2-(halogenbenzoyl) benzoic acid, ethylene diamine, toluene and #-toluene-sulphonic acid. 9b - Phenyl - 7,8 - dichloro - 1,2,3,9b - tetrahydro - 5H - imidazo[2,1-a]isoindol - 5 - one, 9b- (4<SP>1</SP> - chlorophenyl) - 7,8 - dichloro - 1,2,3,9btetrahydro - 5H - imidazo[2,1-a]isoindol - 5 - one, 9b - phenyl - 7 (or 8) - chloro - 1,2,3,9b - tetrahydro - 5H - imidazo[2,1-a]isoindol- 5 - one, 9b - phenyl - (8 or 6) - fluoro - 1,2,3,9b - tetrahydro - 5H - imidazo[2,1-a]ivoindol - 5 - one, 9bphenyl - 9 - chloro - 8 - trifluoromethyl - 1,2,3,9btetrahydro - 5H - imidazo[2,1-a]isoindol- 5 - one, 9b - phenyl - 7,8 - methylenedioxy - 1,2,3,9btetrahydro - 5H - imidazo[2,1-a]isoindol- 5 - one and 9b - phenyl - 7,8 - dimethyl - 1,2,3,9b - tetrahydro - 5H - imidazo[2,1-a]isoindol- 5 - one are prepared similarly. Pharmaceutical compositions having appetite depressant activity and also central nervous system stimulant activity and containing compounds of the general Formula I defined above, are administered orally or parenterally in association with conventional pharmaceutical carriers and/or other adjuvants. The provisos (iii), (iv) and (v) above exclude compounds described and claimed in copending Specifications 1,225,412 and 1,225,413..