NO744667L - - Google Patents

Description

The present invention relates to a process for the production of new imidazo(2,1-a)isoquinolines of formula I

in which Rq stands for hydrogen, fluorine or chlorine, and either R, R^ and R2 are the same or different and in each case stands for hydrogen, fluorine, chlorine, methyl, methoxy or trifluoromethyl, or R and R^, or R^ and R2 together form a methylenedioxy group, with Rq and R^ or R standing for hydrogen, and R^ standing for hydrogen, fluorine, chlorine or methyl, with the condition that 1) if R or R stands for trifluoromethyl, R1 stands for hydrogen, fluorine or chlorine , and 2) no more than two of the substituents Rq, R, R^ and R^ have a meaning other than hydrogen.

The peculiarity of the method according to the invention

is that compounds of formula II

in which R_ has the above meaning, in the presence of an inert organic solvent in an inert gas atmosphere is reacted with compounds of formula III

in which Rq, R, R^l and R£ have the above meaning and X stands for chlorine, bromine or a group of formula OR^, in which R^

means a straight-chain alkyl group with 1-4 carbon atoms, e.g. methyl, ethyl and n-propyl, and the reaction product is hydrolysed.

For the reaction between the compounds of formula II and the compounds of formula III, hazardous hydrocarbons, such as e.g. hexane or heptane, ethers such as diethyl ether or tetrahydrofuran. The reaction is carried out in an inert gas atmosphere, e.g. in a nitrogen atmosphere, and the reaction temperature is suitably from -30 to +50°C, preferably from -20 to 0°C. The reaction duration is 0.5 to 48 hours.

The subsequent hydrolysis of the reaction product can be carried out in a manner known per se, e.g. using water, a dilute mineral acid or an aqueous ammonium chloride solution.

The obtained compounds of formula I can be isolated and purified in a manner known per se. If desired, the free bases of compounds of formula I can be converted into their acid addition salts in a manner known per se and vice versa.

The dilithium compounds of formula II can be prepared by compounds of formula IV

wherein R 3 has the above meaning, in the presence of an inert organic solvent and in an inert gas atmosphere react with compounds of formula V

R5Ei V

in which Rj- stands for an alkyl group with 1-4 carbon atoms.

The reaction between the compounds of formula IV and the compounds of formula V is suitably carried out under reaction conditions which are similar to the reaction conditions used in the reaction of the compounds of formula II with the compounds <C>' of formula III to the compounds of formula I. However, preferably used here a reaction temperature of 25 to 75°C/especially 30 to 40°C. If desired, they can obtain connections. *with formula II is isolated and purified in a manner known per se. The compounds of formula II are preferably used without isolation for the preparation of the compounds of formula I. The compounds of formula III and IV are either known or can be prepared in a manner known per se from known starting compounds. The compounds with formula I can also appear in it with formula Ia; ; wherein Rq, R, R^t R£ and R^ have the above meaning, rendered tautomeric form. The predominant or particularly occurring form depends in particular on the pH value of the surrounding medium. The structure of formula Ia can, for example, consider, if the compounds are in the form of their acid addition salts. Although in the following reference is only made to the form with formula I or the corresponding chemical designations, it is self-evident that the invention is not limited to the preparation of a specific tautomeric form of the compounds of formula I. The compounds of formula I have favorable pharmacodynamic effects. In particular, the compounds of formula I have a stimulating effect on the central nervous system, and this effect is demonstrated in mice at a dose of 0.7 to 25.6 mg/kg in experiments using the method of Spencer, * P.S.J., "Antagonism of Hypothermia in the Mouse by Anti-depressants", in "Antidepressant Drugs", pages 194-204, edited by S. Garattini and M.N.G. Dukes, in Excerpta Medica Foundation, 1967. Similar to this method, reserpine (5 mg/kg i.p.) is administered to a group of 5 mice. 2.1 and 0 hours before and 1.3 and 5 hours after the reserpine infusion, the rectal temperature is measured.

The compounds of formula I likewise have an appetite-suppressing effect, demonstrated in experiments with rats, which were supplied with 25 mg/kg of the active substance and were then examined using it by Randall et al.'(J;P.E.T., 129,

163, 1960) described method.

The compounds of formula I can of course be used as anti-depressants and appetite suppressants. The daily administered dose is from 2.5 to .75 mg, this amount preferably being administered in smaller doses of 0.6 to 40 mg 2 - 4 times a day or in slow-release form.

The compounds of formula I can be used in their free form

bases or in the form of their pharmaceutically acceptable acid addition salts, the effect of the acid addition salts being within the same order of magnitude as the effect of the free bases. Acids suitable for salt formation are inorganic acids, such as: e.g. hydrochloric acid, and organic acids, such as succinic acid.

For their use, the compounds of formula I can be mixed with pharmaceutically acceptable diluents and carriers and optionally also other additives and supplied in the form of

tablets or capsules.

Preferred compounds of formula I are those in which

R, R^, R£ and R^ stand for hydrogen, fluorine or chlorine. Preferably, RQ stands for hydrogen. Particularly preferred are groups of the compounds of formula I, in which a) two of the substituents R, R 1 and R 2 represent hydrogen and the third represents hydrogen, fluorine or chlorine, and

b) <R>q and R^ means hydrogen.

Particularly preferred among the compounds of formula I are

5-(p-fluorophenyl)-2,3,5,6-tetrahydroimidazo(2,1-a)isoquinolin-5-ol.

EXAMPLE 1: 5-(p-fluorophenyl)-2,3,5,6-tetrahydroimidazo (2,1-a(isoquinolin-5-ol.

■ 6.26 g of 2-(6-tolyl)-2-imidazoline and 100 ml of dry tetrahydrofuran are added to a flask filled with nitrogen, which is equipped with a reflux device, reflux condenser and dropping funnel. The solution is stirred and 84 ml of a 1.6-M n-butyllithium solution in hexane is added and the resulting mixture is kept for approx. 5 hours at 35°C. 20.7 g of ethyl p-fluorobenzoate ± 50 ml of dry tetrahydrofuran are then added to the mixture and then kept for 5 hours at 50°C. The reaction mixture is then cooled in an ice bath and 22.8 ml of a saturated aqueous ammonium chloride solution is added. The tetrahydrofuran layer is separated with a separatory funnel, passed over magnesium sulphate, filtered and then evaporated in vacuo. The residue is dissolved in hot methylene chloride-ethanol (1:1) and then cooled. This gives 5-(p-fluorophenyl)-2,3,5,6-tetrahydro-imidazo(2,1-a)isoquinolin-5-ol with melting point 189-190°C.

EXAMPLE 2;

Using the method described in example 1, but by replacing the 2-(o-tolyl)-2-imidazoline used there with equivalent amounts of

a) 2-(4-chloro-2-tolyl)-2-imidazoline or

b) 2-(2-, 4-Xylene)-2-imidazoline is obtained respectively.

a) 5-(p-fluorophenyl)-8-chloro-2,3,5,6-tetrahydroimidazo(2,1-a}isoquinolin-5-ol or b) 5-(p-fluorophenyl)-8-methyl-2, 3,5,6-tetrahydroimidazo(2,1-a)isoquinolin-5-ol.

Using the method described in example 1, but by replacing ethyl-p-fluorobenzoate with equivalent amounts of resp.

c) methyl p-chlorobenzoate

d) m-fluorobenzoyl chloride

e) ethyl p-trifluoromethylbenzoate

f) ethyl benzoate

g) ethyl p-toluate

h) ethyl p-methoxybenzoate

i) ethyl 3,4-methylenedioxybenzoate

j) ethyl 3,4-dibrobenzoate

k) ethyl-o-chlorobenzoate or

1) ethyl 2,4-dichlorobenzoate

obtained respectively

c) 5-p-chlorophenyl)-2,3,5,6-tetrahydroimidazo(2,1-a) isoquinolin-5-ol with melting point 199-200°C d) 5-(m-fluorophenyl)-2,3,5 ,6-tetrahydroimidazo(2,1-a) isoquinolin-5-ol with melting point 210°C (under decomposition) e) 5-(m-trifluoromethylphenyl)-2,3,5,6-tetrahydroimidazo (2,1-a)isoquinoline-5 -ol with melting point L94-196°C (below

a cleavage)

f) 5-phenyl-2,3,5,6-tetrahydroimidazo(2,1-a)isoquinolin-5-ol with melting point 219-221°C, g) 5-(p-tolyl)-2,3,5,6 -tetrahydroimidazo(2,1-a)isoquinolin-5-ol with melting point 181-183°C h) 5-(p-methoxyphenyl)-2,3,5,6-tetrahydroimidazo(2,1-a)isoquinolin-5-ol with melting point 185°C (during cleavage)

i) 5-(3,4-methylenedioxyphenyl)-2,3,5,6-tetrahydroimidazo

(2,1-a)isoquinolin-5-ol with melting point 176-178°C

j) 5-(3,4-dichlorophenyl)-2,3,5,6-tetrahydroimidazo(2,1-a)

isoquinolin-5-ol with melting point 212-214°C

k) 5-(2-chlorophenyl)-2,3,5,6-tetrahydroimidazo(2,1-a)

isoquinolin-5-ol with melting point 177-179°C or

1) 5-(2,4-dichlorophenyl)-2,3,5,6-tetrahydroimidazo(2,1-a) isoquinolin-5-ol with melting point 201°C (under decomposition).

EXAMPLE 3: 5-(p-chlorophenyl)-2,3,5,6-tetrahydroimidazo

(2,1-a)isoquinolin-5-ol.

8 g of 2-(o-tolyl)-2(1H)-imidazoline and 200 ml of anhydrous tetrahydrofuran are added to a flask that was equipped with a stirrer, reflux condenser, thermometer and dropping funnel. The reaction mixture is flushed with nitrogen and a solution of 10 5 ml (0.17 thiol n-butyllithium) of a 1.6 molar n-butyllithium solution in benzene is added dropwise at room temperature. The resulting mixture is then stirred and kept for 5 hours at 35°C. The heating is then switched off and the container is immersed in a carbonated ice-acetone bath. The container is disconnected to it

internal temperature has reached approximately -20°c. A solution of 17.5 g of methyl-p-chlorobenzoate in 100 ml of anhydrous tetrahydrofuran is then added dropwise at such a rate that the internal temperature does not rise above -20°C. After the addition is finished, the mixture is kept for 3 hours wet approx. -20°C. The charcoal syréis bath is removed and the reaction mixture is added after reaching a temperature of approx. "0°C dropwise < 30 ml of a saturated aqueous ammonium chloride solution, keeping the temperature below 20°C. The reaction mixture is allowed to stand overnight at room temperature and then the solvent is removed in vacuo. The paste-like residue is added to approx. 200 ml of methylene chloride and then 100 ml of water. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate, filtered off and evaporated under vacuum to a total volume of approx. ) is achieved.

The solid is discharged in the smallest possible amount of hot 95%

ethanol and then evaporated to a volume of approx. 95 ml. On standing at room temperature, 5-(p-chlorophenyl)-2,3,5,6-tetrahydroimidazo(2,1-a)isoquinolin-5-ol is obtained with melting point 198-200°C (under decomposition). Rf 0.30 (CHCl 3 /CH 3 OH 90:10); calculated analysis for C17H15C1N20: C 68.3%, H 5.1%, N 9.4%^Found C 68.2%, H 5.4%, N 9.3%.

Claims (2)

1. Process for the preparation of new imidazo(2,1-a) isoquinolines of formula I in which Rq stands for hydrogen, fluorine or chlorine, and either R, R^ and R2 are the same or different and in the individual case stands for hydrogen, fluorine, chlorine, methyl, methoxy or trifluoromethyl. or R and R^ , or R^ and R 2 together form a methylenedioxy group, RQ' and R 2 or R standing. for hydrogen, and R^ means hydrogen, fluorine, chlorine or methyl, with the proviso that 1) if R or R 2 means trifluoromethyl, R^ stands for hydrogen, fluorine or chlorine, and 2) no more than two of the substituents RQ , R, R1 and R^ have a meaning other than hydrogen, characterized in that compounds with formula II wherein R 1 has the above meaning, in the presence of an inert organic solvent in an inert gas atmosphere is reacted with compounds of formula III in which Rq, R, R^ and R^ have the above meaning and X stands for chlorine, bromine or a group with the formula 0R4, in which R4 means a straight-chain alkyl group with 1-4 carbon atoms, e.g. methyl, ethyl and n-propyl, and the reaction product is hydrolyzed. 2. Process for the preparation of compounds of formula in which R^ means hydrogen, fluorine, chlorine or methyl, characterized in that. connect! watching along formula IV wherein R^ has the above meaning, in the presence of an inert organic solvent and in an inert gas atmosphere is reacted with compounds of formula V in which R,, stands for an alkyl group with 1-4 carbon atoms.