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

Abstract

Compounds of formula Ib wherein means r! and R 2 is independently hydrogen or C 1-4 alkyl, R halo, C 1-4 alkyl, halomethyl, nitro-, amino-, hydroxy-, C 1-6 alkoxy- carboxy or C 1-4 alkoxycarbonyl a n 0, 1 or 2, are produced by reduction of the compound of formula (Ia) wherein R1, R2, Ran have as defined above. The reduction is preferably carried out by catalytic hydrogenation using palladium catalyst. Product is optionally converting it to pharmaceutically acceptable acid addition salts having antidepressant, antiparkinsonian, antiepileptic and spasmolytic action.

Description

The invention relates to a process for the preparation of novel substituted 3-phenyliminothiazolidine derivatives having pharmaceutical activity.

Hungarian Patent No. 164 0 34 describes 2-imino-1- (o-nitrophenyl) imidazolidines. Hungarian Patent Specification No. 164,035 relates to a process for the preparation of 2-iodo-1- (o-aminophenyl) imidazolidine derivatives. 2-Imino-3- (nubstituted phenyl) thiazolidine and its light-protecting action have been described by T. Huno et al. Chem. Pharm. Bull. (Tokyo) 14 (11), pp. 1 201-119 (1966)].

The present invention provides a process for the preparation of substituted 3-phenyliminothiazolidine derivatives of formula Ib

(Ib) where is

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 η 0, 1 or 2 and pharmaceutically acceptable acid addition salts thereof, comprising reducing a compound of formula Ia

Wherein R, R, Ran are as defined above, and optionally the compound of formula (Ib) obtained is converted to its pharmaceutically acceptable acid addition salt.

Preferred examples of the amino compound of formula (Ib) are those wherein the amino group is in the 2-position with respect to the phenyl carbon atom attached to the thiazolidine nucleus.

2

In formula (Ib), preferably R and R are each hydrogen or methyl, n is zero or 1 and R is chlorine, trifluoromethyl, methoxy or methyl.

Particularly preferred iminothiazolidine derivatives of formula Ib prepared by the process of the invention are:

3- (2-Amino-4-chlorophenyl) -2-iminothiazolidine

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

The pharmaceutically acceptable acid addition salts of the compounds of formula (Ib) may be inorganic or organic acid addition salts such as hydrochloride, hydrobromide, sulfate, nitrate, acetate, lactate, fumarate, maleate, tartrate, methanesulfonate, ethanesulfonate, and the like.

The reduction of Ia is preferably carried out by catalytic hydrogenation. It is hydrogenated in a suitable solvent, for example 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 can be used. The hydrogenation reaction is preferably carried out at a pressure of 1 to 50 bar at elevated temperature or at room temperature, it is preferred to hydrogenate the compound of formula Ia 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 excess acid is added to give the product as an acid addition salt at a low temperature, for example at about 0 ° C. Thus, the product is isolated either in the form of the free base or in the form of a crystalline acid addition salt.

The compound of formula (1b) obtained can, as mentioned, be reacted with inorganic or organic acids to obtain 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, a compound of Formula 1b is reacted in a suitable inert solvent with a stoichiometric amount or a slight excess of acid to give an acid addition compound of Formula 1b.

The invention also relates to a process for the preparation of all enantiomers, diastereomers and racemates of the compounds of formula (1b).

The novel compounds of formula (1b) prepared by the process of the invention have valuable antidepressant, antiparkinsonian, antiepileptic and spasmolytic properties associated with mild analgesic activity. The activity of the compounds prepared by the process of the invention is verified by the following tests.

1) Acute toxicity in mice

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

During this time, mice are fed a standard mouse food with water ad libitum. Toxicity values are determined by the Lichtefield-Wilcox method.

2) Antagonism of tetrabenazine ptosis in mice

The tetrabenazine ptosis antagonism was tested in groups of ten mice. Mice are treated orally with various dosages of test compounds by administering to the control group of mice the corresponding vehicle without active ingredient. 30 minutes after drug or vehicle delivery, 50 mg / kg of tetfabenazine, which is 3-isobutyl-9,10-dimethyl-1,2,3,4,6,7-hexahydrobenzo [a] quinolizine-2, is administered intraperitoneally. -on, and mice with ptosis 30, 60, 90 and 120 minutes after tetrabenazine administration are counted. The mean ptosis value is then calculated for each group and the deviation from the mean value found for the control group (inhibition) is given as a percentage. From the values obtained, 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 dosed with the test compound, and the mice of the control group are treated with the vehicle alone. Ptosus mice are counted 60 to 120 minutes after administration of the test compound. Test evaluation is performed as described for Test 2).

4) Toxicity of yohimbine in mice

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

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

5) Inhibition of convulsions caused by nicotine assay is performed in mice by the Ston method. One hour after oral treatment, a dose of 1.4 mg / kg of nicotine is injected intravenously, and both the test group and the control group recorded seizures or deaths.

6) Pentatetrazole-induced seizure inhibition assay is performed in mice by the modified Banziger and Han method. Each group, consisting of six mice, is treated orally with test compound and vehicle without active ingredient. One hour after treatment, 125 mg / kg of pentatetrazole was administered intraperitoneally to each animal and the lower eyelid extensor spasm was recorded.

7) Maximum electroshock inhibition

The test is carried out on mice weighing 20-25 g by the Swinyarad method. Corneal electrodes apply electroshocks with the following parameters: 50 Hz, 45 mA and 0.4 seconds. Absolute inhibition of the tonic spasm of the extensor of the lower eyelid is considered to be a criterion for anticonvulsant action. One hour before the electroshock, animals are treated orally with test compounds and a carrier without active ingredient.

8) Antiperistaltic effect on mice

The antiperistaltic activity of the compounds was tested in mice weighing 20-25 g by the method of Stickney et al. Each dose of test compound is administered orally 60 minutes prior to administration of a 10% activated carbon suspension. Simultaneously, control mice are treated in a similar manner using saline or other vehicle. 20 minutes after the administration of the activated carbon suspension, the mice are sacrificed and the total length of the small intestine and the length of the small intestine filled with activated carbon are determined. The inhibition with respect to the control group is calculated in precents. The antiperistaltic effect is considered to be positive if the proportion of small intestine filled with activated carbon suspension does not exceed 50% of the total small intestine length. From these transformed values EDjq ·

9) Analgesic effect on mice (writhing test)

The test is performed on mice using the modified Nebould method. Mice are injected intraperitoneally with 0.75% acetic acid at 20 ml / kg and the characteristic writhing reactions are counted for 5 minutes starting at 5 minutes after initiating the reaction. The number of writhings is observed in both treated and control animals. The inhibition is evaluated as a percentage with respect to the control group.

The tests were carried out with the following compounds of the 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-iminothiazolidine dihydrochloride (ethanesulfonate) = 3- (2-amino-4-chlorophenyl) -2-imino-5-methylthiazolidine ethanesulfonate = 3- (2-amino-4-methylphenyl) -2-iminothiazolidine = 3- (4-aminophenyl) -2- imino-1,3-triazolidine

Test results Table I are are summarized in the following tables. Compound number ^LD 50 mg / kg Antagonism ^ED 50 ^r tetrabenazine ptoses 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? - * iptyline 225 12.0 18.7 T a bulka II Compound number ^LD 50 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 May 50.0 13 1 300 70 18.5 amitriptyline. 225 65 3.5 T a bulka III Compound number ^LD 50 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 a bulka IV Compound number ^LD 50 mg / kg Inhibition of nicotine lethality ED (- i _n 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 No. mg / kg

Inhibition of pentatetrazole spasm ED? G, 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 ^LD 50 mg / kg Inhibition of maximum ED _5q , mg / kg electroshock Tetrapeutický 1 700 70 10.0 3 200 14 14.2 8 f 1000 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

bulka VIII Compound ^LD S0 Analgesic effect (jerk test) number mg / kg ED ₅₀ , 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 bulka IX Compound ^LD 50 mg / kg Potentiation; narcosis number ED _5q , mg / kg Therapeutic index 12 600 41.0 14.0 meprobamate 1 100 ALIGN! 260.0 4.2

Ί

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

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

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

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

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

The invention is illustrated by the following non-limiting examples.

He did

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

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

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

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)

R _f = 0.6.

Example2

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

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 (II) chloride dihydrate in ethanol is heated under an inert gas. to 70 ° C. The reaction takes about 30 minutes, which results in a change in color of the solution. The mixture is poured into approximately 200 ml of water, the ethanol is removed under reduced pressure and the residue is adjusted to pH 9 using 10% aqueous sodium hydroxide solution. The solution was extracted three times with 50 ml of chloroform each. The combined organic phases were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was dissolved in methanol, saturated with hydrogen chloride, and crystal formation was induced by the addition of water.

1.2 g (40% of theory) of 2-imino-3- (2'-araino-4'-chlorophenyl) thiazolidinedihydrochloride are thus obtained in the form of a colorless crystalline powder. Melting point 185 ° C (dec.) (Methanol-ether).

Example

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

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 catalyst. The catalyst, cooled to 0 ° C, was removed by filtration and 3.3 g (2.5 mL, 0.03 mol) of ethanesulfonic acid was added to the filtrate. The resulting mixture was stirred at the above temperature for two hours and then evaporated under reduced pressure. The residue was treated with acetone, filtered, washed with acetone and dried.

2.5 g (63% of theory) of 2-imino-3- (2 ' -amino-6 ' -chlorophenyl) -thiosolidine ethanesulfonate are thus obtained in the form of colorless crystals. Melting point 168-170 ° C (methanol-ether).

Analysis calculated for: 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