DK145906B - METHOD OF ANALOGUE FOR THE PREPARATION OF N, N-DIMETHYL-TRANS-2- (M-HALOGENPHENYL) BICYCLO (2,2,2) OCT-3-YL METHYLAMINE AND ACID ADDITION SALTS THEREOF - Google Patents

Description

in ir \ (19) DENMARK {Wj

^ (12) PUBLICATION WRITING (11) 145906B

DIRECTORATE OF

THE PATENT AND TRADEMARKET SYSTEM

(21) Application No 5557/76 (51> | ntCL3 g 07 C 87/457 (22) Filing date 25 Jul 1976 (24) Running day 25 Jul 1976 (41) Aim available 25 Jan Jan 1977 ( 44) Submitted 11 Apr 19 ^ 5 (86) International application no.

(86) International filing day (85) Continuation day - (62) Master application no. -

(30) Priority Jul 24 1975 * 51064/75, GB

(71) Applicant LILLY INDUSTRIES LIMITED, London W1R OPA, GB.

(72) Inventor Eric Wildsmith, GB.

(74) Clerk Th. Ostenfeld Patenfrbureau A / S.

(54) Analogous procedure for the preparation of N, N-dimethyl-trans-2- (m-ha = logenphenyl) bicyclo (2,2,2) oct-3-yl-methylamine and its acid addition salts.

The present invention relates to an analogous process for the preparation of novel meta-halophenylbicyclo [2,2,2] octane derivatives which are highly active on the central nervous system.

In Belgian Patent Specification No. 806,808, a class of phenylbicyclo [2,2,2] octanes of the same general type as the compounds prepared by the process of the present invention is disclosed, which compounds are described as having activity on the central nervous system.

^ It has now surprisingly been found that a small novel class of compounds within the scope of the aforementioned Belgian patent has effective and unexpectedly better effect on the central nervous system, the compounds having notably improved anti-depressant and anti-psychotic activity, in comparison with the known bicyclo [2,2,2] octanes of the same type mentioned in this patent. The compounds prepared according to the present invention also possess good therapeutic indices.

The compounds of the present invention are trans-compounds of the general formula (II ch 2 n (ch 3) 2 (I)

kJ

wherein X is halogen, or acid addition salts thereof.

By the term "halogen" is meant fluorine, bromine, chlorine or iodine.

The groups -CH 2 N (CH 2 and m-halo-phenyl) are trans-relative to each other.

Those skilled in the art will appreciate that the compounds of general formula (I) may exist in two enantiomeric forms, and the invention comprises the preparation of the (+) and (-) forms separately and non-racemic mixtures thereof as well as the racemic form. mixing the enantiomeric forms.

As examples of acid addition salts may be mentioned the pharmaceutically acceptable non-toxic addition salts with suitable acids such as the salts with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, or with organic acids such as organic carboxylic acids, e.g. glycolic acid, maleic acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid, salicylic acid, o-acetoxybenzoic acid, nicotinic acid or isonicotinic acid, or organic sulfonic acids, e.g. methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, toluene-β-sulfonic acid or naphthalene-2-sulfonic acid;

The process of the invention is characterized in that the amino group is methylated in a trans compound having the general formula (II) rTYCH 2 <RTI ID = 0.0> (X) </RTI> wherein X is halogen and R is hydrogen or methyl, and if desired decomposes a prepared racemic compound into the individual enantiomers or, if desired, converts a prepared compound into an acid addition salt thereof.

A particularly preferred compound prepared according to the invention is N, N-dimethyl-trans-2- (m-chlorophenyl) bicyclo [2,2,2] oct-3-yl-methylamine, e.g. in the form of the hydrochloride of the compound.

The surprisingly enhanced effect of the novel compounds of formula (I) and their acid addition salts can be demonstrated by well-known test experiments, such as antagonism of reserpine hypothermia and reserpine catalepsy in mice and rats.

To detect antagonism of reserpine-induced hypothermia in rats, groups of 4 female Wister rats were used. The animals were injected subcutaneously with 5 mg / kg reserpine and after 17 hours the rectal temperature was measured. Immediately thereafter, the test compounds were administered orally and additional temperature determinations were made after 30 minutes and every hour thereafter for up to 6 1/2 hours. In order to simplify the determination of the reversal of reserpine-induced hypothermia, the so-called "temperature index" method was used. Assuming the average pre-dose ice temperature for each group, the average temperature changes from this number were summed at 0.5, 1.5, 2.5, 3.5, 4.5, 5.5 and 6, 5 hours and ϊ · '- 4 145906 was called "temperature index" (TI). The test compounds were considered active if the TI value was more than 5 units hyperthermic from the control results. In the following table, 0 shows no effect (TI less than 5), + indicates a TI in the range of 5-10, ++ indicates a TI in the range of 10-15, and +++ indicates a TI of more than 15. This procedure is a good test for testing compounds that are believed to be valuable as antidepressants.

The test results and compounds tested are shown in the following table: /p^.cVNtclV2 S /; 'Year

Pore Link Ar Reversion of Reserpine-1 Hypothermia (Dose) 1 · 3-Chlorophenyl +++ (25) 2. Phenyl (unsubstituted) 0 (40) 3. 2-Chlorophenyl ++ (20) 4. 4-Chlorophenyl 0 (20) + (40) 5. 4-Fluorophenyl + (40) 6. 4-Bromophenyl ++ (40) 7. 3,4-Dichlorophenyl + (20) + (40), _____ [___

Compound 1. is a compound prepared by the process of the invention and is found to be substantially more active than the corresponding unsubstituted, 2- and 4-halo, as well as 3,4-dihalo-substituted compounds, cf. Belgian Patent No. 806,808.

145906 5

The method according to the invention is further elucidated with reference to the following example.

Example trans-m-chlorocinnamonitrile.

m-Chlorobenzaldehyde (210.75 g, 1.5 m) cyanoacetic acid (127.5 g, 1.5 m) and pyridine (150 ml) were heated at reflux for 2 days. The solution was evaporated to give an oil which was distilled to form a mixture of isomers (72% trans / 23% cis, 5% aldehyde). Yield (129 g, 53%), bp 70-85 ° C at 0.8 mm. The substance was dissolved in isopropanol and allowed to fractional crystallization at 0 ° C. The solid was filtered off and lyophilized. Yield of pure trans isomer was 15 g (6.1%), bp 104-106 ° C at 1 mm, mp 26-28 ° C.

trans-6- (m-chlorophenyl) bicyclo [2,2,2] oct-2-ene-5-carbonitrile trans-m-chlorocinnamonitrile prepared as above (9.2 g, 0.056 m) and 1,3-cyclohexadiene (8.03 ml, 0.084 m) was added to a sealed tube with a trace of hydroquinone and 1,2-dichlorobenzene and heated at 150-160 ° C for 2 weeks. The solution was evaporated to give a golden oil (12 g) which was washed several times with cold 40-60 ° C gasoline and then repeatedly with 60-80 ° C gasoline. These last leach fractions were collected and reduced to a viscous oil (10.2 g, 75%).

trans-2- (m-chlorophenyl) bicyclo [2,2,2] octane-3-carbonitrile.

trans-6- (m-chlorophenyl) bicyclo [2,2,2] oct-2-ene-5-carbonitrile prepared as above (9.4 g, 0.038 m) was hydrogenated in ethanol at atmospheric pressure in the presence of 5 % Palladium-on-charcoal (1.0 g). After taking up the theoretical amount of hydrogen, the catalyst was filtered off and the solution reduced to an oil (9.1 g, 97%). This was crystallized by dissolving in ethanol, mp 112-113 ° C.

Analysis: Calculated: C, 73.32; H, 6.56; N, 5.7; Cl, 14.43; Found: C, 73.43; H, 6.41; N, 5.82; Cl 14.38.

Trans-2- (m-chlorophenyl) bicyclo [2,2,2] oct-3-yl-methylamine, hydrochloricol __ trans-2- (m-chlorophenyl) bicyclo [2,2,2] octane-3-carbonitrile prepared as above (8.0 g, 0.032 m) in dry tetrahydrofuran (20 ml) was added dropwise to a cooled and stirred solution of lithium aluminum hydride (1.61 g, 0.042 m) in dry tetrahydrofuran (20 ml). After the addition, the solution was allowed to warm to room temperature and stirred overnight. 5N sodium hydroxide (1.6 ml) and then water (7 ml) were carefully added to form a fine white precipitate which was filtered off. The filtrate was dried over magnesium sulfate and evaporated after filtration to an oil which, by dissolving in ethanolic hydrochloric acid and slow ether addition, gave the hydrochloride salt (6.8 g, 74%), mp 220-222 ° C.

N, N-dimethyl-trans-2- (m-chlorophenyl) bicyclo [2,2,2] oct-3-yl-methylamine, hydrochloride.

To the trans-2- (m-chlorophenyl) bicyclo [2,2,21oct-3-yl-methylamine, hydrochloride prepared above (3.0 g, 0.011 m) was added sodium bicarbonate (0.92 g, 0.011 m) and dimethylformamide (30 ml). The flask was cooled to 0 ° C and a mixture of formic acid 90% (2.29 ml, 0.055 m) and formaldehyde 37-40% (3.78 ml, 0.055 m) was added slowly. After addition, the solution was slowly heated to reflux. After 5 hours, the solution was cooled, added to water (80 ml), made alkaline with solid potassium hydroxide (pH = 8) and extracted with ethyl acetate (3 x 30 ml). The combined organic phase was washed with water (2 x 30 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo to give an oil (2.10 g, 61%). The hydrochloride salt formed using ethanol hydrochloric acid and the title compound was recrystallized from ethanol ether (2.1 g) mp 217-219 ° C.

Analysis: Calculated: C, 64.96; H, 8.01; N, 4.45; Cl 22.56 Found: C 64.67; H, 7.82; N, 4.44; Cl, 22.64.