NO146061B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DERIVATIVES OF 2-IMINOTHIAZOLIDINES AND 2-IMINOTHIAZOLINES - Google Patents

Description

The present invention relates to an analog method

in the production of therapeutically active derivatives of 2-iminothiazolidines and 2-iminothiazolines which, due to their ability to inhibit indoleamine-N-methyl-transferase, are useful in treating

ling of certain mental abnormalities in humans, such as schizophrenia.

The new method compounds have the general

formula;

and pharmaceutically acceptable salts thereof, wherein

R is lower alkyl, especially alkyl with 1-3 carbon atoms, either straight chain or branched, such as methyl, ethyl or propyl;

R-^ is

(a) lower alkyl, especially alkyl with 1-5 carbon atoms substituted

ert with one or more groups selected from

(i) amino,

(ii) lower alkanoylamino, especially alkanoylamino with 2-4 carbon atoms,

(iii) phenyl,

(iv) carboxy,

(v) lower alkanoyl, especially alkanoyl with 2-4 carbon atoms, or (b) pyridyl,

R<6> is

(a) hydrogen,

(b) lower alkyl, especially alkyl of 1-5 carbon atoms,

(c) phenyl, optionally substituted with one or more lower

Alkoxy groups, especially Alkoxy with 1-3 carbon atoms,

(d) pyridyl;

R is

(a) hydrogen, or

(b) lower alkyl, especially alkyl of 1-3 carbon atoms, and

R<5> is

(a) lower alkyl, especially alkyl with 1-3 carbon atoms,

(b) -COR<7>, where

R<7> is

(i) lower alkyl, especially alkyl of 1-3 carbon atoms, or

(ii) phenyl, or

4 5

R and R, together with the nitrogen atom to which they are attached, can be

N,N-dimethylindolamines such as dimethylserotonin and dimethyltryptamine are psychosomimetic agents and are thought to be produced in excessive amounts in individuals with certain mental disorders, most commonly termed schizophrenia. Indolamine-N-methyl-transferase is an enzyme that catalyzes the methylation step in the biosynthesis of these compounds. Consequently, it is believed by those skilled in the art that inhibitors of this enzyme will be of therapeutic value in treating the body chemistry of patients with mental disorders such as schizophrenia, and thus lead to relief of some of the symptoms of the disease. It is thus an aim of the present invention to provide the above-described imines and their pharmaceutically acceptable salts, for the treatment of mental disorders such as schizophrenia.

In a preferred embodiment of the present method, the new compounds are prepared where R 1 is -COR 3.

In an even more preferred embodiment, the new compounds are prepared where R 1 is -COR°? , and R 3 is pyridyl, lower alkanoylaminomethyl, lower alkanoylamino-(benzyl)-methyl, or 2-(3-methylthiazolidin-2-ylideneaminocarbonyl)-ethyl.

The pharmaceutically acceptable salts produced according to the invention are generally acid addition salts formed from a compound of formula I and with an organic or inorganic acid which is known to give a pharmaceutically acceptable acid addition salt, such as hydrochloric acid, hydrogen bromide, dihydrogen phosphate, sulphate , citrate, pamoate, pyruvate, napsylate, isethionate, maleate, fumarate or the like.

When the new process compound has a free carboxyl group, the pharmaceutically acceptable salt may be in the form of an ammonium, alkaline earth or alkali metal salt of the carboxylate group such as sodium, potassium, calcium or similar salt.

A group of the new amide process compounds are prepared according to the following equation:

where Y is Cl-, or N-, and r^ ■i a

is amino-lower alkyl, lower alkanoyl-amino-lower alkyl, lower alkanoylamino-phenyl-lower alkyl, pyridyl, lower alkanoyl-lower alkyl or carboxamido-lower alkyl. When RQ 3 is amino-lower alkyl, the reaction is carried out with the amino group protected e.g. with t-butoxycarbonyl. When Y is (C^_^ alkyl)-0Cs0-, the acylating agent can be formed in situ by treating the corresponding free carboxyl group with a C^_^ lower alkyl chloroformate. The reaction is carried out in an inert solvent<:>such as a chlorinated hydrocarbon, e.g. methylene chloride or chloroform, or dimethylformamide at -5° C to 10° C for 1 - 72 hours.

When R 1 is carboxy-lower alkyl, the compounds are prepared by treating the 2-imino compound with a carboxylic acid anhydride such as succinic anhydride in a chlorinated hydrocarbon such as methylene chloride, at 25° C. to the reflux temperature for 1-6 hours.

When Ra 3 is acetylmethyl, it can also be prepared by treating the 2-imino compound with the diketene at 0-10°C in a lower alkanol such as ethanol and allowing the mixture to warm to room temperature.

Another group of the new process compounds are prepared according to the following equation: where X is Cl, Br or -N(CH3)2

R <4> is hydrogen or lower alkyl, and

R 5 is lower alkyl, or

a 7 7

-COR , where R is lower alkyl or phenyl, or

R 4 and Ra 5 together with the nitrogen atom to which they are attached:

When X is chlorine, the method is carried out by mixing the two starting materials at 0 - 10° C in an inert organic solvent such as a chlorinated hydrocarbon, especially methylene chloride, and by heating wood from room temperature to 50° C for up to approx. 6 hours. When X is dimethylamino, the process is carried out by heating a mixture of the starting materials in an inert organic solvent such as benzene, at from 50° C. to the reflux temperature for 10 - 24 hours.

Another group of the new method compounds where:

4 5 and R and R together with the nitrogen atom to which they are bound are: are produced according to the following equation:

In the above equation, the reagent is indicated as an aldehyde for simplicity, but it is intended to include functional equivalents thereof, such as aldehyde precursors, e.g. paraformaldehyde, aminals or the like. The process is carried out by mixing the starting material with the aldehyde or aldehyde precursors in an inert organic solvent such as benzene, toluene or similar

o

nende, and heating at from 50 C and the reflux temperature while removing the water formed by the condensation reaction such as by adding molecular sieves to the reaction mixture or refluxing in a Dean-Stark apparatus.

Under similar reaction conditions, pyridoxal gives a compound with the formula:

In treatment, the process compounds can be administered orally, rectally, intravenously, intramuscularly or intraperitoneally. Doses of 0.10 to 100 mg/kg per day, and preferably 1-10 mg/kg per day's active ingredient is generally sufficient, and it is preferred to use divided doses given two to four times a day.

It should be noted that the particular unit dose form and dosage level depends on the medical history of the individual being treated, and must therefore be left to the doctor's discretion.

Pharmaceutical preparations containing a process compound as active ingredient can be in any known form suitable for oral use, such as tablets, dragees, pastilles, water or oil suspensions, dispersible powders, or granules, emulsions, hard or soft capsules, syrups or elixirs . For intravenous and intramuscular and intraperitoneal use, the pharmaceutical preparations may be in any conventional form of a sterile injectable preparation such as a sterile aqueous or oleaginous solution or suspension. The amount of active ingredient incorporated in a unit dose of the above-described pharmaceutical preparations can be from 1 mg to 500 mg.

Production of starting materials

Method 1

3, 5-dimethyl-2-iminothiazolidine fumarate

Step A: Preparation of methyl N-(2-hydroxypropyl)-dithiocarbamate 40 g (0.242 mmol) of 1-amino-2-propanol oxalate was suspended in 180 ml of pyridine and 101 g of triethylamine was added. The mixture was mechanically stirred for 1 hour, then cooled to 0° C. and 38 g of carbon disulphide (0.5 mol) was added dropwise. After 2 hours at 0° C., 36 g (0.254 mol) of methyl iodide was added dropwise and almost all of the solid dissolved. The mixture was kept in a refrigerator overnight (0 - 5° C). The mixture was poured into 2.4 1 3N sulfuric acid and extracted three times with ether. The ether extracts were washed with water, 3N sulfuric acid, water, aqueous sodium bicarbonate solution and water, and dried over sodium sulfate and evaporated to 18.79 g (47%) of oily methyl N-(2-hydroxypropyl)-dithiocarbamate.

Step B: Preparation of 5-methyl-2-methylthio-2-thiazoline

17.37 g of dithiocarbamate from step A in 30 ml of dry ether was added to 73 ml of thionyl chloride at 0-5° C. The mixture was stirred at 0° C for 2 hours, and then left in a refrigerator overnight. The thionyl chloride was evaporated at 30°C and the remaining oil (containing elemental sulphur) was taken up in saturated sodium bicarbonate solution and extracted with ether. The ether fraction was extracted with dilute hydrochloric acid. The aqueous fraction was made alkaline with sodium hydroxide solution and extracted with ether. Evaporation of the ether gave 6.65 g of floating residue.

This was chromatographed on a column of silica gel using benzene as eluent, whereby 2.5 g were obtained

(16.2%) oily 5-methyl-2-methyl-thio-2-thiazoline.

Step C: Preparation of 3,5-dimethyl-2-methylthio-2-thiazoline-fluoroborate

588 mg of the S-methyl-thiazoline from step B and 592 mg

trimethyloxonium fluoroborate was stirred together in 40 ml of methylene chloride overnight at room temperature. The fluoroborate dissolved slowly as it reacted. The reaction mixture was evaporated to dryness giving a colorless oil which was used directly in the next step.

Step D: Preparation of 3,5-dimethyl-2-iminothiazoline fumarate

The crude fluoroborate salt from step C was dissolved in 40 ml of alcohol and the solution was saturated with gaseous ammonia. The solution was stirred at room temperature for 3 hours. The solution was evaporated to dryness. The remaining oily residue was taken up in 10 ml of water, then 40 ml of chloroform was added with stirring and 40% sodium hydroxide solution was added to make the aqueous fraction strongly alkaline. The two layers were separated, and the aqueous fraction was extracted once more with chloroform. The combined chloroform extracts were dried and evaporated to dryness to give 630 mg of oil. The compound was transferred to the fumarate and crystallized from isopropanol-ether which gave 720 mg of cream-colored crystals with a melting point of 130 - 138° C (73% total yield). Recrystallization of the fumarate from isopropanol ether gave 470 mg of 3,5-dimethyl-2-iminothiazolidine fumarate, m.p. 133 - 136° C.

Method 2

2- imino- 3- methyl- 4- trifluoromethyl- 4- thiazoline- fluorosulfonate

336 mg of 2-amino-4-trifluoromethylthiazole was dissolved in 15 mg of methylene chloride. The flask was placed in an ice bath and 240 mg

CH 2 SO 4 F in 5 ml of methylene chloride was added. The mixture was then placed in a refrigerator over the weekend. The colorless crystals were collected on a filter which gave 450 mg (80%) of 2-imino-3-methyl-4-trifluoromethyl-4-thiazoline-fluorosulfonate with melting point 177-178°C.

Method 3

2- imino- 3- methyl- 4- thiazoline

A mixture of 1.0 g of 2-aminothiazole and 2 ml of methyl iodide in 10 ml of isopropanol was heated under reflux for 2 hours. The hot solution was treated with decolorizing charcoal, filtered, and the filtrate was cooled in a refrigerator. The precipitate was collected on a filter, washed with isopropanol and dried to give 1.377 g (57%) of 2-imino-3-methyl-4-thiazoline.

Method 4

2-imino-3-methylthiazolidine-HCl. 1/2 H^O

A solution of 44.5 g of the corresponding hydroiodide

in 300 ml of water was added to a suspension of 52.5 g (0.366 mol) of silver chloride in 300 ml of water. The mixture was stirred at 80°C for 3.5 hours, cooled and filtered. The filtrate was evaporated to dryness and the solid was crystallized from isopropanol and a little ether, whereby 23.73 g (85%) of 2-imino-3-methylthiazolidine was obtained. HCl.1/2 E20, with melting point 73 - 76° C.

Evaporation of the mother liquors gave a further yield of 4.17 g of the product.

During the application of the method essentially

as described in method 3, but by replacing the methyl iodide and 2-aminothiazole used there with an equimolar amount of an organic halide of the formula R-Hal and a compound of the formula:

the 3-R-2-iminothiazolidines and thiazolines listed in Table I were prepared there according to equation I.

Equation I

Example l

2- dimethylaminomethylimlno— 3- methylthiazolidine

A mixture of 600 mg of 2-imino-3-methylthiazolidine, 10

mg of its hydrogen iodide salt and 550 mg of bis-(dimethylamino)methane in 10 ml of benzene were refluxed overnight. The mixture was evaporated to dryness and the residue was taken up twice in chloroform and evaporated to dryness, thereby obtaining 200 mg of 2-dimethylaminomethylamino-3-methylthiazolidine with a boiling point of 98 - 102° C at 2.5 mm Hg.

Example 2

3- methyl- 2- succinimidomethyliminothiazolidine

53.9 g of bromomethylsuccinimide was added portionwise to a mixture of 32.7 g of 2-imino-3-methylthiazolidine and 42 ml of triethylamine and 150 ml of methylene chloride. The reaction occurred spontaneously. The mixture was evaporated to dryness and the residue taken up in chloroform and sodium hydroxide solution. The aqueous phase was separated and extracted three times with chloroform. The combined chloroform extracts were dried and evaporated to dryness. The residue was crystallized twice from benzene to give 13.5 g of 3-methyl-2-succinimidomethyliminothiazolidine, m.p. 142 - 144° C.

Example 3

2- benzamidomethylimino- 3- methylthiazolidine- maleate

A solution of 676 mg of N-chloromethylbenzamide in 15 ml of methylene chloride was slowly added to an ice-cold mixture of 2.0 ml of triethylamine, 488 mg of 2-imino-3-methylthiazolidine and 25 ml of methylene chloride. After stirring for 2 hours at room temperature, the mixture was evaporated to dryness. The residue was dissolved in methylene chloride, washed with water and dilute hydrochloric acid. The combined aqueous phases were made alkaline with sodium bicarbonate and extracted with methylene chloride. The methylene chloride was washed with water, dried and evaporated to dryness. The residue was triturated with ether and the product as free base (250 mg) was collected on a filter.

The maleate salt was prepared from 11.0 g of the free base and 5.12 g of maleic acid in 100 ml of methanol and isolated by adding ether to initial bleaching, grafting and cooling, whereby 10.42 g of 2-benzamidomethylimino-3-methylthiazolidine- maleate with sml.p. 120 - 121° C.

Another yield of 4.28 g was isolated from the mother liquors and had a melting point of 119 - 120°C.

Example 4

Bis-[3-methylthiazolidin-2-ylideneamino]-methane

A mixture of 25 g of 2-imino-3-methylthiazolidine, 6.5 g of paraformaldehyde, 75 g of molecular sieves, and 250 ml of benzene was refluxed for 5 hours. 30 g of molecular sieves and 6.5 g of paraformaldehyde were added and reflux was continued overnight. The molecular sieves were collected on a filter and washed well with benzene. The combined filtrate and washings were evaporated to dryness yielding 21 g of crystalline bis-[3-methylthiazolidin-2-ylideneamino]-methane of m.p. 57 - 59° C.

A hydrochloride salt was prepared by dissolving 350 mg

in 2 ml of water and 2 ml of 6N hydrochloric acid and evaporate to an oily residue. Evaporation of acetone, isopropanol and benzene from the residue followed by trituration gave crystalline hydrochloride salt.

Using the method essentially as described in example 4, but by replacing the paraformaldehyde used there with an equimolar amount of acetaldehyde, benzaldehyde (or aminal), 3,4-dimethoxybenzaldehyde, 4-pyridinecarboxaldehyde and pyridoxal, respectively: 1 ,1-bis-(3-methylthiazolidin-2-ylideneamino)-ethane dihydrochloride, m.p. 292°C

α,α-bis-(3-methylthiazolidin-2-ylideneamino)-toluene, m.p. 167 - 169° C

α,α-bis-(3-methylthiazolidin-2-ylideneamino)-3,4-dimethoxytoluene, m.p. 144 - 145 C

α,α-bis-(3-methylthiazolidin-2-ylideneamino)-Y-picoline, m.p.

110 - 113° C

Example 5

N,N'-bis-(3-methylthiazolidin-2-ylidene)-succinamide

Step A: Preparation of bis-(4-nitrophenyl)-succinate

A mixture of 2.36 g (20 mmol) succinic acid, 6.516 g (44 mmol) 4-nitrophenol and 8.24 g (40 mmol) N,N<1->dicyclohexylcarbodiimide was stirred at room temperature in 225 ml of ethyl acetate in 2 days. The mixture was filtered and the filtrate was evaporated to dryness. The residue was triturated with 40 ml of chloroform and the solids were collected on a filter and air dried to give 1.38 g of bis-(4-nitrophenyl) succinate, m.p. 176 - 178° C.

Step B: Preparation of N,N'-bis-(3-methylthiazolidin-2-ylidene)-succinamide

A mixture of 80 mg of 2-imino-3-methylthiazolidine, 118 mg of bis-(4-nitrophenyl)-succinate and 8 ml of chloroform was refluxed for 5.5 hours. The mixture was diluted with chloroform, washed twice with sodium carbonate solution, dried over sodium sulfate and evaporated to dryness. The residue was crystallized from 2 ml of methanol giving 68 mg of N,N<1->bis-(3-methylthiazolidin-2-yl idene)-succinamide, m.p. 181 - 183° C.

Example 6

N-(3-methylthiazolidin-2-ylidene)-aminoacetamide dihydrochloride Step A: Preparation of N-(3-methylthiazolidin-2-ylidene)-t-butoxycarbonylaminoacetamide

0.25 ml of ethyl chloroformate at -5° C was added to a solution of 350 mg of t-butoxycarbonylaminoacetic acid and 0.4 ml of triethylamine in 10 ml of methylene chloride at -5° C. After stirring for 5 minutes at -5° C, there was added a solution of 610 mg of 2-imino-3-methylthiazolidine hydrogen iodide and 1.0 ml of triethylamine in

10 ml of methylene chloride also at -5° C. Stirring was continued at -5° C for 15 minutes and 1 hour at room temperature. The reaction mixture was washed with 200 g/l citric acid solution, sodium bicarbonate solution, and water, dried and evaporated to dryness. The residue was triturated with ether, petroleum ether and ether and finally collected, whereby pure N-(3-methylthiazolidin-2-ylidene)-t-butoxycarbonylaminoacetamide was obtained.

Step B: Preparation of N-(3-methylthiazolidin-2-ylidene)-aminoacetamide dihydrochloride

2.0 g of the product from step A was dissolved in 100 ml of chloroform and the solution was saturated with hydrogen chloride gas by bubbling through the solution for 20 minutes. After 2 hours at room temperature, excess hydrogen chloride was removed by bubbling in nitrogen. The precipitated product was collected and air-dried under nitrogen to give 1.66 g of N-(3-methylthiazolidin-2-ylidene)-aminoacetamide dihydrochloride with m.p. 190 - 194° C.

By using the procedure essentially as described in Example 6, step A, but by replacing the t-butoxycarbonylaminoacetic acid used therein with an equimolar amount of 2-acetyl-amino-2-benzylacetic acid, riicotinic acid, acetoacetic acid and 3-methyl-2-succinyliminothiazolidine (see example 7 ), respectively: N-(3-methylthiazolidin-2-ylidene)-2-acetylamino-2-benzylacetamide, m.p. 142 - 149° C

N-(3-methylthiazolidin-2-ylidene)-nicotinamide., m.p. 108 - 109° C N-(3-methylthiazolidin-2-ylidene)-acetoacetamide, m.p. 43 - 45° C and

N,N'-bis-(3-methylthiazolidin-2-ylidene)-succinamide, m.p. 183 - 184° C.

Example 7

N-(3-methylthiazolidin-2-ylidene)-acetylaminoacetamide

1.19 g of 4-nitrophenyl-acetylaminoacetate was added portionwise to a solution of 580 mg of 2-imino-3-methylthiazolidine in 60 ml of chloroform. After stirring for 2 hours at room temperature, the solution was evaporated to dryness. The residue was triturated with ether and collected on a filter. The crude product was dissolved in chloroform, washed with sodium bicarbonate solution, dried and evaporated to dryness. 1 Trituration with ether gave 600 mg of N-(3-methylthiazolidin-2-ylidene)-acetylaminoacetamide, m.p. 138 - 139° C.

Example 8

3- methyl- 2- succinyliminothiazolidine

2.0 g of succinic anhydride was added to a solution of 2-imino-3-methylthiazolidine in 70 ml of methylene chloride. After refluxing for 3 hours, the mixture was filtered and the filtrate was evaporated to dryness. The residue was triturated with ether and collected on a filter whereby 3.63 g of 3-methyl-2-succinyliminothiazolidine with m.p. 90 105° C.

The product of Example 8 was converted to the sodium salt by dissolving 864 mg of it in 25 ml of water and adding 336 mg

sodium bicarbonate. The mixture was evaporated to dryness and the residue was triturated with isopropanol. The solids were collected on a filter giving 730 mg of 3-methyl-2-succinyliminothiazolidine sodium salt of m.p. 205 - 210° C.

Example 9

2- acetoacetylimino- 3- methylthiazolidine

A solution of 13 g of the diketene in 100 ml of ethanol was added dropwise to an ice-cold solution of 18 g of 2-imino-3-methylthiazolidine in 100 ml of ethanol. The mixture was allowed to warm spontaneously to room temperature and was then evaporated to dryness. The residue was triturated with ether, collected on a filter and dried in a desiccator to give 2-acetoacetylimino-3-methylthiazolidine of m.p. 4 3 - 4 5°C.

In the process description above, the following condensation is indicated to obtain N,N<1->bis-(3-methyl-thiazolidin-2-ylidene)-succinamide: where Rfl is 3-ercarboxamido-lower alkyl, which

0

in;

(C1-4-alkyl)OCO- or . In this reaction, Y can also be

-OCH 2 CN

or -O (C 1 -alkyl).

In a similar way, the product N,N<1->bis-(3-methyl-thia-zolidin-2-ylidene)-succinamide can be prepared as follows:

where Y is as stated above. These condensation reactions are carried out in an anhydrous inert organic solvent such as chloroform, tetrahydrofuran, toluene or the like, from -10° C. to the reflux temperature for 1 to approx. 72 hours.

Another procedure for the synthesis of N,N'-bis-(3-methyl-thiazolidin-2-ylidene)-succinamide is illustrated as follows:

where Z is hydroxy, bromine, chlorine or other leaving groups such as tosyloxy, mesyloxy or the like. The cyclization proceeds under aqueous acidic conditions, as the strength of the acid and the reaction time depend on the nature of Z. When Z is hydroxy, reinforced hydrochloric acid, or mineral acids of similar strength are required for periods of 10 - 48 hours, and when Z is e.g. halogen or tosyloxy, is a trace

of the acid formed by cyclization sufficient to catalyze the cyclization so that much shorter times such as a few minutes, and less strongly acidic conditions are required.

Example 10

To a mixture of 21.6 g of 3-methyl-2-succinyliminothiazolidine from example 12 and 10.2 g of triethylamine in 80 ml of anhydrous chloroform, 13.7 g of isobutyl chloroformate is added dropwise at -5° to 0° C. After 30 minutes of stirring, add 10.2 g of 2-imino-3-methylthiazolidine in 50 ml of chloroform, the temperature being kept at 0° C by external cooling. After 1 hour of aging at room temperature, the precipitated triethylamine hydrochloride is filtered off. The chloroform filtrate is washed with sodium bicarbonate solution, dried over sodium sulphate and the solvent is removed in vacuo. The residue is recrystallized from methanol to obtain N,N'-bis-(3-methyl-thiazolidin-2-ylidene)-succinamide, m.p. 183 - 184°C.

Example 11

A mixture of 3.1 g succinic acid, 7.4 g triethylamine and 10.1 g chloroacetonitrile in 50 ml ethyl acetate is refluxed for 3 hours. The precipitated triethylamine hydrochloride is filtered off and the filtrate is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.

The crude di-cyanomethylsuccinate (3.9 g) is dissolved in 80 ml of tetrahydrofuran. 3.88 g of 2-imino-3-methylthiazolidine and 0.8 ml of acetic acid are added and the reaction mixture is left at room temperature

temperature for 48 hours.

The mixture is poured into 300 - 350 g of ice water and extracted with ethyl acetate. The combined extracts are washed with sodium bicarbonate solution, and then with water. The ethyl acetate phase is dried over sodium sulphate, filtered and evaporated in vacuo. The residue is recrystallized from methanol to obtain N,N'-bis-(3-methylthiazolidin-2-ylidene)-succinamide, m.p. 183 - 184°C.

Example 12

A mixture of 15.5 g of succinyl chloride and 20.5 g of 2-imino-3-methylthiazolidine in 150 ml of dry toluene is refluxed until two equivalents of hydrogen chloride are formed. The solution is cooled to room temperature and washed with saturated sodium bicarbonate solution. After removal of the solvent in vacuo, the residue is recrystallized from methanol which gives N,N'-bis-(3-methyl-thiazolidin-2-ylidene)-succinamide, m.p. 183 - 184°C.

The reaction described above can also be carried out in the presence of equivalent amounts of a tertiary base such as triethylamine or dimethylaniline or the like at room temperature.

Example 13

To a solution of 20 g of succinyl diisothiocyanate,

(J. Chem. Soc. 67_, 565) in 50 ml of acetone, 7.51 g of f}-methylaminoethanol in 20 ml of acetone are added. The reaction mixture is heated under reflux for 30 minutes, and: after cooling to room temperature, it is poured into 350 - 400 ml of ice-cold water. The precipitated N-succinyl-N<1->methyl-N'-2-hydroxyethyl-thiourea is filtered off and purified by crystallization from ethanol.

The substituted urea is dissolved in 100 ml of 75% sulfuric acid and allowed to stand at room temperature for 24 hours. On pouring the mixture into 5 - 6 times its volume of ice water, N,N'-bis-(3-methylthiazolidin-2-ylidene)-succinamide precipitates. Recrystallization from methanol gives pure N,N'-bis-(3-methyl-thiazolidin-2-ylidene)-succinamide, m.p. 183 - 184°C.

Claims (1)

Analogous method for the preparation of new therapeutically active compounds with the structural formula: or pharmaceutically acceptable salts thereof, wherein R is lower alkyl, R<1> is (a) lower alkyl, which may be substituted with one or more of the groups (i) araino, (ii) lower alkanoylamino, (iii) phenyl, (iv) carboxy, (v) lower alkanoyl, or ( b) pyridyl, R<6> is (a) hydrogen, (b) lower alkyl, (c) phenyl, either unsubstituted or substituted with one or more lower alkoxy groups, (d) pyridyl; 4 is R is (a) hydrogen, or (b) lower alkyl, and R<5> is (a) lower, alkyl, or (b) -COR7,'where<7> is R is (i) lower alkyl, or (ii) phenyl; or 4 5 R and R are together with the nitrogen to which they are attached characterized in that: i a) a compound with the structural formula: or a pharmaceutically acceptable salt thereof, wherein R is as defined above, and 4 R is as defined above, and R 5 is (a) lower alkyl, or a 7 (b) -COR , wherein R 7 is as indicated above, or R<4> and R^ together with the nitrogen to which they are attached, is produced by reacting a compound with the structural formula: where R is as above, with a compound of the formula: where X is chlorine, bromine or -NCCH^)^/ and R^ is as indicated above, b) a compound with the structural formula: or a pharmaceutically acceptable salt thereof, where R is as stated above and R is hydrogen, lower alkyl or phenyl optionally substituted with one or more alkoxy groups, is produced by reacting a compound with the structural formula III with a compound of the formula R 2 -CHO or a functional equivalent thereof, where R is as indicated above, c) a compound with the structural formula: or a pharmaceutically acceptable salt thereof, where R is as indicated above, is prepared by reacting a compound of the structural formula III with pyridoxal, d) a compound of the structural formula: or a pharmaceutically acceptable salt thereof, wherein R is as defined above, and RQ is (a) lower alkyl substituted with (1) lower alkanoylamino and phenyl, (2) lower alkanoyl, or (b) pyridyl; is prepared by reacting a compound with the structural formula III with a compound with the structural formula: 0 where Y is chlorine, p-nitroenoxy, -N3, or (C-^-alkyl) -OC0-, and R is as indicated above, e) a compound with the formula: is prepared by treating a compound of the formula: with a compound of the formula: "in the presence of ethyl chloroformate, or with a compound of the formula: where Y is as indicated above, f) a compound with the formula: or a pharmaceutically acceptable salt thereof, wherein R is as above, and R g is lower alkylene; is prepared by reacting a compound of formula III with a compound of formula: where R Q is as stated above, g) a compound with the structural formula: or a pharmaceutically acceptable salt thereof, where R is as indicated above, is prepared by reacting a compound of structural formula III with the diketene, h) a compound of formula: is prepared by treating a compound of formula VIII with a compound of formula: where Z is chlorine, p-nitrophenoxy, -N^, or -O-(C 4 -alkyl), or i) a compound of formula: is produced by cyclizing a compound with structural formula: where A is a leaving group selected from -OH, -Br, -Cl, -O-tosyl or -O-mesyl, and that a compound obtained is optionally transferred to a pharmaceutically acceptable salt thereof.