CS255874B2 - Process for preparing substituted 3-phenyliminothiazolidine derivatives - Google Patents

Abstract

Compounds of the general formula Ib, where R1 and R2 independently of each other are hydrogen or C1-4alkyl, R is halogen, C1-4alkyl, halomethyl, nitro, amino, hydroxy, C1-4alkoxy, carboxy or C1-4alkoxycarbonyl and n is 0, 1 or 2, are prepared by reduction of a compound of the general formula Ia, where R1, R2, Ran are as defined above. The reduction is preferably carried out by catalytic hydrogenation using palladium as a catalyst. The product is optionally converted into pharmaceutically acceptable acid addition salts which have antidepressant, antiparkinsonian, antiepileptic and spasmolytic activity.

Description

The invention relates to a process for the production of novel substituted 3-phenyliminothiazolidine derivatives which have pharmaceutical activity.

Hungarian patent application number 164 0 34 -;> describes 2-imino-1-(o-nitrophenyl)imidazolidines. Hungarian patent application number 164 035 relates to a process for the preparation of 2-imidino-1-;o-aminophenyl)imidazolidine derivatives. 2-Imino-3-(o-substituted phenyl)thiazolidine and its light-protective action have been described by T. Huno et al. /Chem. Pharm. Bull. (Tokyo) 14 (11), pp. 1 201 to 1 209 (1966}/.

The subject of the invention is a process for the production of substituted 3-phenyliminothiazolidine derivatives of the general formula Ib

(Ib) where means

2

R and R independently of each other are a hydrogen atom or an alkyl group with 1 to 4 carbon atoms,

R is a halogen atom, an alkyl group with 1 to 4 carbon atoms, a halomethyl group, a nitro group, a hydroxy group, an alkoxy group with 1 to 4 carbon atoms, a carboxy group, an alkoxycarbonyl group with 1 to 4 carbon atoms in the alkoxy moiety or an amino group and η is 0, 1 or 2, and their pharmaceutically acceptable acid addition salts, which consists in reducing a compound of general formula Ia

2 where R 1 , R 2 , Ran have the above-mentioned meaning, and the obtained compound of general formula Ib is optionally converted into its pharmaceutically acceptable acid addition salt.

Preferred examples of the amino compound of general formula Ib are compounds where the amino group is at the 2-position with respect to the phenyl carbon atom attached to the thiazolidine nucleus.

2

In the general formula Ib, R and R preferably each represent a hydrogen atom or a methyl group, n is zero or the number 1, and R is a chlorine atom, a trifluoromethyl group, a methoxy group or a methyl group.

Particularly preferred iminothiazolidine derivatives of the general formula Ib, prepared by the process according to the invention, are:

3-(2-amino-4-chlorophenyl)-2-iminothiazolidine,

3-(2-amino-4-chlorophenyl)-2-imino-5-methylthiazolidine, and their pharmaceutically acceptable acid addition salts.

Pharmaceutically acceptable acid addition salts of the derivatives of general formula Ib may be addition salts with inorganic or organic acids, such as hydrochloride, hydrobromide, sulfate, nitrate, acetate, lactate, fumarate, maleate, tartrate, methanesulfonate, ethanesulfonate, etc.

The reduction of compound la is preferably carried out by catalytic hydrogenation. The hydrogenation is carried out in a suitable solvent, for example in a lower alkanol, such as methanol or ethanol, in the presence of a noble metal catalyst, preferably in the presence of palladium. A supported catalyst may be used. The hydrogenation reaction is preferably carried out at a pressure of 0.1 to 0.5 MPa at elevated temperature or at room temperature, it is preferred to hydrogenate the compound of general formula la at room temperature and at ambient pressure. The product is separated in a manner known per se. Suitably, the catalyst is removed by filtration, the filtrate is evaporated or an excess of acid is added to obtain the product in the form of an acid addition salt at low temperature, for example at a temperature of about 0 ° C. The product is thus isolated either in the form of the free base or in the form of a crystalline acid addition salt.

The obtained compound of formula 1b can be reacted with inorganic or organic acids as indicated to give the corresponding acid addition salts. Similarly, the free bases can be liberated from the acid addition salts by reacting the acid addition salts with bases. These reactions can be carried out by methods known per se. For example, the compound of formula 1b is reacted in a suitable inert solvent with a stoichiometric amount or a slight excess of acid to give the acid addition compound of formula 1b.

The invention also relates to a process for the preparation of all enantiomers, diastereomers and racemates of compounds of general formula lb.

The novel compounds of general formula Ib, prepared by the method according to the invention, have valuable antidepressant, antiparkinsonian, antiepileptic and spasmolytic properties, combined with a mild analgesic effect. The efficacy of the compounds prepared by the method according to the invention is verified by the following tests.

1) Acute toxicity in mice

Acute toxicity is determined using mice of both sexes (CFLP strain, body weight 18 to 22 g). Six mice are used for each dose. The test compound is administered orally in a volume of 20 ml/kg body weight. After administration, the mice are observed for seven days.

During this time, the mice are fed a standard mouse diet and have access to water ad libitum. Toxicity values are determined by the Lichtefield-Wilcox method.

2) Antagonism of tetrabenazine ptosis in mice

The antagonism of tetrabenazine ptosis is tested in groups of ten mice. The mice are treated orally with various doses of the test compounds, while the control group of mice is given the corresponding vehicle without the active substance. Thirty minutes after the introduction of the active substance or vehicle alone, 50 mg/kg of tetfabenazine, which is 3-isobutyl-9,10-dimethyl-1,2,3,4,6,7-hexahydrobenzo /a/ quinolizin-2-one, is administered intraperitoneally, and the mice with ptosis 30, 60, 90 and 120 minutes after the administration of tetrabenazine are counted. The mean value of ptosis is then calculated for each group and the deviation from the mean value found for the control group (inhibition) is reported as a percentage. From the values obtained, the Εϋ^θ is calculated.

3) Antagonism of reserpine ptosis in mice

Each group of 10 mice is treated subcutaneously with 6 mg/kg reserpine. After 60 minutes, the mice are administered the test compound, while the control group is treated with vehicle alone without the active substance. Mice with ptosis 60 to 120 minutes after administration of the test compound are counted. The tests are evaluated in the same way as in test 2).

4) Yohimbine toxicity in mice

The test is performed by the Quinton method. Each group, consisting of 10 mice, is treated with the test compound and the vehicle without active substance.

After one hour, the test group is administered a sublethal dose of yohimbine intraperitoneally in an amount of 20 ml/kg body weight. The number of dead mice is determined 1 hour and 24 hours after the administration of yohimbine.

5) Inhibition of convulsions caused by nicotine: The test is performed on mice using the Stone method. One hour after oral treatment, a dose of 1.4 mg/kg nicotine is injected intravenously and the resulting convulsion or death is recorded in both the test and control groups.

6) Inhibition of pentatetrazole-induced spasm: The test is performed on mice by a modified method of Banziger and Han. Each group of six mice is treated orally with the test compound and a vehicle without active substance. One hour after treatment, each animal is given 125 mg/kg of pentatetrazole intraperitoneally and the spasm of the lower eyelid extensor is recorded.

7) Maximum electroshock inhibition

The test is performed on mice weighing 20 to 25 g using the Swinyarad method. Electroshocks with the following parameters are applied through corneal electrodes: 50 Hz, 45 mA and 0.4 seconds. The criterion for anticonvulsant (anti-twitch) action is considered to be complete inhibition of tonic spasm of the lower eyelid extensor. One hour before the electroshock, the animals are treated orally with the test compounds and a vehicle without the active substance.

8) Antiperistaltic effect on mice

The antiperistaltic effect of the compounds is tested on mice weighing 20 to 25 g using the method of Stickney and co-workers. Each dose of the test compound is administered orally 60 minutes before administration of a 10% suspension of activated charcoal. At the same time, control mice are treated in a similar manner using saline or another vehicle. 20 minutes after administration of the activated charcoal suspension, the mice are killed and the total length of the small intestine and the length of the small intestine filled with activated charcoal are determined. The inhibition is calculated in percent with respect to the control group. The antiperistaltic effect is considered positive if the proportion of the small intestine filled with the activated charcoal suspension does not exceed 50% of the total small intestine length. EDjq values are calculated from the values thus transformed.

9) Analgesic effect on mice (wriggle test)

The test is performed on mice using a modified Nebould method. Mice are given 0.75% acetic acid intraperitoneally in a dose of 20 ml/kg and the characteristic writhing responses are counted for 5 minutes, starting from the fifth minute after the reaction is induced. The number of writhings in both treated and control animals is observed. Inhibition is evaluated as a percentage with respect to the control group.

Tests were performed with the following compounds of general formula Ib:

= 3-(2-amino-4-chlorophenyl)-2-iminothiazolidine hydrochloride = 3-(2-amino-5-chlorophenyl)-2-iminothiazolidine hydrochloride = 3-(2-amino-4-chlorophenyl)-2-imino-4-methylthiazolidine dihydrochloride = 3-(2-amino-4-trifluoromethylphenyl)-2-iminothiazolidine hydrochloride = 3-(2-amino-4-methoxyphenyl)-2-iminothiazolidine dihydrochloride = 3-(2-amino-4-chlorophenyl)-2-iminothiazolidinedi(ethanesulfonate) = 3-(2-amino-4-chlorophenyl)-2-imino-5-methylthiazolidineethanesulfonate = 3-(2-amino-4-methylphenyl)-2-iminothiazolidine = 3-(4-Aminophenyl)-2-imino-1,3-triazolidine

Test Results Table I are summarized in the following tables. Compound number ^LD50 mg/kg Antagonism ^ED 50 ^ř tetrabenazine ptos Therapeutic index 1 700 18.0 39.0 2 800 25.0 32.0 3 200 3.0 67.0 4 1 300 40.0 32.5 7 1 200 16.0 75.0 8 1 000 1.5 667.0 12 600 7.2 83.0 arai t?-*iptylin 225 12.0 18.7 T and bulk II Compound number ^LD50 mg/kg Antagonism ed ₅₀ , mg/kg reserpine ptoses Therapeutic index 1 700 50 14.0 3 200 3 67.0 4 1 300 34 38.0 8 1 000 20 50.0 13 1 300 70 18.5 amitriptyline. 225 65 3.5 T and bulk III Compound number ^LD50 mg/kg Potentiation of yohimbine toxicity ED^q, mg/kg Therapeutic index 2 800 50.0 16.0 8 1 000 22.0 45.5 12 60 45.0 13.3 13 1 300 52.0 25.0 14 400 20.0 20.0 amitriptyline 225 12.5 18.0 T and bulk IV Compound number ^LD50 mg/kg Inhibition of lethality by nicotine ED(- _n i mg/kg Therapeutic index 1 700 25.0 5.6 3 200 6.4 31.3 8 1 000 12.0 83.3 12 600 6.0 100.0 13 1 300 10.0 130.0 trihexylphenidyl 365 40.0 9.1

Table V

Compound number mg/kg

Inhibition of pentatetrazole spasm EDjjg, mg/kg Therapeutic index

1 700 22.0 31.8 2 800 78.0 10.2 3 200 7.8 25.6 4 1,300 160.0 8U 8 1,000 14.0 71.4 12 600 15.0 40.0 trimethadione 2,050 490.0 4.3

Table VI

Compound number ^LD50 mg/kg Inhibition of maximal ED _5q , mg/kg electroshock Therapeutic 1 700 70 10.0 3 200 14 14.2 8 f 1,000 80 12.5 12 600 12 30.0 trimethadione 2,050 400 5.3

index

Table VII

Compound number

LDj-θ Inhibition of intestinal peristalsis mg/kg ^ED 50' Tetrapeutic index

4 1 300 66 19.70 4 (diethanesulfonate) 1 300 25 52.00 7 (diethanesulfonate) 2 000 200 10.00 8 1 000 95 10.50 14 400 50 4.40 papaverine 380 185 2.01

bulk VIII Compound ^LD S0 Analgesic action (twitch test) number mg/kg _ED5Q , mg/kg Therapeutic index 2 800 43 18.6 4 130 (diethanesulfonate) 1 300 160 8.1 8 1 000 170 5.9 12 600 34 17.7 13 1 3 0.0 160 8.1 paracetamol 510 180 2.9 bulk IX Compound ^LD50 mg/kg Potentiation ; anesthesia number _ED5q , mg/kg Therapeutic index 12 600 41.0 14.0 meprobamate 1 100 260.0 4.2

I

Pharmaceutical compositions containing as active ingredient a compound of the general formula Ib or a pharmaceutically acceptable acid addition salt thereof can be prepared by methods known per se for the preparation of pharmaceutical compositions.

These pharmaceutical compositions are preferably in the form of orally administrable compositions, such as tablets, capsules, coated tablets, solutions, suspensions and the like, or parenterally administrable compositions, such as sterile solutions or suspensions.

Orally administrable pharmaceutical compositions contain conventional carriers such as gelatin, sorbitol, lactose, sugar, starch, calcium phosphate, polyvinylpyrrolidone, magnesium stearate, talc, polyethylene glycol, silicon dioxide, sodium lauryl sulfate, and the like.

Compositions for parenteral administration contain conventional carriers for such types of compositions, such as sorbitol, sugar solutions, glycerin, propylene glycol, ethanol, and the like.

The daily dose of the compound of general formula Xb is generally 0/1 to 1000 mg/kg and preferably 1 to 100 mg/kg.

The method according to the invention is further explained by the following practical examples, which, however, do not limit the invention in any way.

Example

Preparation of 2-imino-3-(4'-aminophenyl)thioazolidine

1.1 g (0.005 mol) of 2-imino-3-(4'-nitrophenyl)thiazolidine is hydrogenated in 30 ml of anhydrous dioxane in the presence of 0.8 g of 10% palladium on carbon as catalyst. The catalyst is then removed by filtration, the filtrate is evaporated in vacuo, the crystalline residue is treated with ether, filtered and dried.

This gives 0.68 g (70% of theory) of 2-imino-3-(4'-aminophenyl)thiazolidine in the form of colorless crystals. The melting point is 148 DEG C. (isopropanol-petroleum ether).

Analysis for C^H^N^S (molecular weight 193.3) calculated: C 55.93% H 5.74% N 21.74% found: C 56.13% H 5.83% N 21.62%

Thin layer chromatography (ethanol - dioxane - concentrated aqueous ammonia 3:6:1)

_Rf = 0.6.

Example2

Preparation of 2-imino-3-(2'-amino-4'-chlorophenyl)thiazolidine dihydrochloride

A mixture of 2.6 g (0.01 mol) of 2-imino-3-(4'-chloro-2'-nitrophenyl)thiazolidine and 11.3 g (0.05 mol) of tin chloride dihydrate in ethanol is heated under inert gas to a temperature of 70 °C. The reaction takes place in approximately 30 minutes, which is indicated by a change in the color of the solution. The mixture is poured into approximately 200 ml of water, the ethanol is removed under reduced pressure and the pH of the residue is adjusted to 9 using 10% aqueous sodium hydroxide solution. The solution is extracted three times with 50 ml of chloroform each time. The combined organic phases are washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is dissolved in methanol, saturated with hydrogen chloride and the formation of crystals is induced by the addition of water.

1.2 g (40% of theory) of 2-imino-3-(2'-amino-4'-chlorophenyl)thiazolidinedihydrochloride are thus obtained in the form of a colorless crystalline powder. The melting point is 185°C (with decomposition) (methanol - ether).

Example

Preparation of 2-imino-3(2'-amino-6-chlorophenyl)thiazilidineethanesulfonate

2.96 g {0.011 7 mol} of 2-chloro-6-nitro-N(2-thiocyanatoethyl)aniline are hydrogenated in a mixture of 50 ml of methanol and 50 ml of dichloromethane in the presence of 0.3 g of palladium on carbon as a catalyst. The mixture, cooled to 0 °C, is filtered to remove the catalyst and 3.3 g (2.5 ml, 0.03 mol) of ethanesulfonic acid are added to the filtrate. The mixture obtained is stirred at the above temperature for two hours and then evaporated under reduced pressure. The residue is treated with acetone, filtered, washed with acetone and dried.

This gives 2.5 g (63% of theory) of 2-imino-3-(2”-amino-6”-chlorophenyl)thiozolidineethanesulfonate in the form of colorless crystals. The melting point is 168 to 170 °C (methanol - ether).

Analysis for calculated: Cl 10.47% N 12.39% S 18.88% found: Cl 10.12% N 12.40% S 19.11%

Claims (1)

SUBJECT OF THE INVENTION CLAIMS 1. A process for the preparation of substituted 3-phenyliminothiazolidine derivatives of the general formula (1b) EMI3.0 [0000] wherein is 1 2 R and R independently of one another are hydrogen or alkyl of 1 to 4 carbon atoms, R is halogen, C1-C4alkyl, halomethyl, nitro, hydroxy, C1-C4alkoxy, carboxy, C1-C4alkoxycarbonyl or amino, and is 0,1 or 2, and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula (Ia) is reduced