CH629490A5 - Processes for preparing the novel N,N'-bis-(3-methylthiazolidin-2-ylidene)succinamide. - Google Patents

Description

The invention relates to processes for the preparation of the new N, N 'bis (3-methylthiazolidin-2-ylidene) succinamide which, because of its ability to inhibit indoleamine N-methyl transferase, for the treatment of various mental disorders (such as Schizophrenia) can be used in human medicine.

N, N-dimethylindoleamines, such as dimethylserotonin or dimethyltryptamine, are psychotomimetics that are thought to be produced in excessive amounts by people suffering from certain mental disorders (which usually fall under the term “schizophrenia”). Indoleamine-N-methyl-transferase is an enzyme that catalyzes the methylation steps in the biosynthesis of these compounds. Therefore, inhibitors of this enzyme are believed to have therapeutic value in controlling the body's chemical balance in patients with mental disorders (such as schizophrenia) and therefore alleviate some symptoms of the disease. It was therefore the object of the invention to provide a process for the preparation of such an inhibitor and its pharmacologically tolerable salts.

The new compound which can be prepared according to the invention has the following formula

20th

25th

30th

-O-C

.NH

"N (Ci-4-alkyl) 2-,

-O-C

CH:

0 (Ci-4-alkyl)

or -0- (Ci-4-alkyl), brings to implementation.

In the second process according to the invention, the compound of formula II described further above with a compound of formula

9 0

H II

Y - C - CH2 - CH2 - c ~ Y

in which Y is described above, brought to reaction and in the third process according to the invention said compound of formula II is used with the compound of formula 45

O ii

• n-cch2ce2c

V

\ n.

O

for hoocch2ch2c-n = ^

I.

ch.

(I)

The first process according to the invention for the preparation of the new compound of the formula I is characterized in that the compound of the formula rNH

(ii)

50 'ÎÎ

I.

ch3

in the presence of ethyl chloroformate.

The compound of the formula I obtained according to the invention can be converted into corresponding salts.

The pharmacologically acceptable salts which can be prepared according to the invention are acid addition salts which can be formed from a compound of the formula I and a known pharmacologically acceptable organic or inorganic acid which provides acid addition salts; Examples of such salts are the hydrochlorides, hydrobromides, dihydrogen phosphates, sulfates, citrates, pamoates (embonates), pyruvates, napsilicates (2-naphthalene sulfonates), 65 isethionates, maleinates and fumarates.

O

II

If Y in starting materials (Ci-4-aikyl) is OCO-,

629490

4th

the acylating agent can be prepared in situ by reacting the free carboxyl group with a chloroformic acid Ci-4-alkyl ester. This reaction is preferably carried out for 1 to 72 hours at -5 to 10 ° C in the presence of an inert organic solvent, e.g. a chlorinated hydrocarbon, such as methylene dichloride or chloroform, or dimethylformamide. Medicaments containing the aforementioned active ingredient can be administered orally, rectally, intravenously, intramuscularly or intraperitoneally. Active substance doses of 0.1 to 100 mg / kg / day (preferably from 1 to 10 mg / kg / day) are generally sufficient. Administration is preferably carried out 2 to 4 times a day using partial doses.

It is emphasized that the choice of the exact single dosage form and dose depends on the patient's medical history and is therefore left to the discretion of the therapist.

The pharmaceuticals mentioned can be in any conventional form suitable for oral use, for example as tablets, trochisci, lozenges, aqueous or oily suspensions, dispersible powders, granules, emulsions, hard or soft capsules, syrups or elixirs. For intravenous, intramuscular and intraperitoneal purposes, the drugs can be in any conventional form, e.g. as sterile injectables (such as sterile aqueous or oily solutions or suspensions). The proportion of active substance contained in a single dosage form of the medicinal product can amount to 1 to 500 mg.

The examples below are intended to explain the invention in more detail; the preparation describes the manufacturing ring of starting products.

example 1

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

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

A mixture of 2.36 g (20 mmol) of succinic acid, 6.516 g (44 mmol) of 4-nitrophenol and 8.24 g (40 mmol) of N, N'-dicyclohexylcarbodiimide is in for 2 days at room temperature

225 ml of ethyl acetate stirred. The mixture is then filtered and the filtrate evaporated to dryness. The residue is rubbed with 40 ml of chloroform. The solids are filtered off and air dried. 5 1.38 g of bis (4-nitrophenyl) succinate, mp. 176 to 178 ° C., are obtained.

Step B: Preparation of N, N'-bis (3-methylthiazolidin-2-ylidene) succinamide io A mixture of 80 mg of 2-imino-3-methylthiazolidine, 118 mg of bis (4-nitrophenyl) succinate and 8 ml of chloroform is refluxed for 5 hours. The mixture is then diluted with chloroform, washed twice with sodium carbonate solution, dried over sodium sulfate 15 and evaporated to dryness. When the residue is recrystallized from 2 ml of methanol, 68 mg of N, N'-bis (3-methylthiazolidin-2-ylidene) succinamide of mp 181 ° to 183 ° C. are obtained.

Preparation 1 3-methyl-2-succinyliminothiazolidine 2 g of succinic anhydride are dissolved in a solution of

2-Imino-3-methylthiazolidine entered in 70 ml of methylene dichloride. The mixture is boiled under reflux for 3 hours and filtered. The filtrate is evaporated to dryness, the residue is rubbed with ether and filtered. 3.63 g are obtained

3-methyl-2-succinyliminothiazolidine, mp 90-105 ° C. The product from Example 12 is converted into the sodium salt

transferred by dissolving 864 mg of product in 25 ml of water and adding 336 mg of sodium bicarbonate. The mixture is evaporated to dryness and the residue is rubbed with isopropanol. The solids are filtered off; This gives 730 mg of the sodium salt of 3-methyl-2-succinylimino-nothiazolidine, mp. 205 to 210 ° C.

Analogously to preparation 1, but instead of 2-imino-3-methylthiazolidine, the equivalent amount of a corresponding 2-imino-3-R-thiazoline is used, the 3-R-2-succinyliminothiazoline also shown in Table VIII is obtained according to reaction equation VIII .

25th

30th

35

Reaction equation VIII

, 2 n i

r h

*

. XN ^ N-C-CH0CH0COOH l II 2 2

r o

R

Thiazoline CH3-

Table VIII

RJ

H

2-Acetoacetylimino-3-methylthiazolidine In explaining the processes, the following condensation resulting in N, N'-bis (3-methylthiazo-lidin-2-ylidene) succinamide is disclosed in the above description:

5

629490

where R4 is the group of formulas:

f

-ch2ch2c

° / s— ^ s -och: '

ck

H2CN,

h oh

3 10

o ph means and Y e.g. a chlorine atom,

nh

/ = V - ° -Cx -O-C

/ ~~ 0 N (Ci-4-alkyl) 2, 0 (Ci-4-alkyl)

20 or-0 (Ci-4-alkyl).

The product, namely N, N'-bis (3-methylthiazolidin-2- (Ci-4-alkyl) OCO- or -N3. Ylidene) succinamide, can be used according to the invention as well

With this implementation, Y can also make a remainder of the following:

O O

11 »

H + Y-C-CH2CH2-C-Y

in.

0-! U2-

ch.

-1 2

where Y has the meaning given above. These condensations are usually carried out in the presence of an anhydrous, inert organic solvent such as chloroform, tetrahydrofuran or toluene for 1 to about 72 hours at temperatures from -10 ° C to the reflux temperature.

The following examples illustrate the synthesis of N, N'-bis (3-methylthiazolidin-2-ylidene) succi-namide by the methods described above.

Example 2

A mixture of 21.6 g of 3-methyl-2-succinyliminothiazo-lidin from preparation 1 and 10.2 g of triethylamine in 80 ml of anhydrous chloroform is treated dropwise at -5 to 0 ° C. with 13.7 g of isobutyl chloroformate. After stirring for 30 minutes, 10.2 g of 2-imino-3-methylthiazolidine in 50 ml of chloroform are added, the temperature being kept at 0 ° C. by external cooling. After aging for 1 hour at room temperature, the precipitated triethylamine hydrochloride is filtered off. The chloroform filtrate is washed with sodium bicarbonate solution, dried over sodium sulfate and freed from the solvent in vacuo. The residue is recrystallized from methanol. This gives N, N'-bis (3-methylthiazolidin-2-ylidene) succinamide.

Example 3

A mixture of 3.1 g of succinic acid, 7.4 g of triethylamine and 10.1 g of chloroacetonitrile in 50 ml of ethyl acetate is boiled under reflux for 3 hours. The precipitated triethylamine hydrochloride is then filtered off. The filtrate is sown with

Washed 35 tiger sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.

The crude dicyanomethyl succinate (3.9 g) is dissolved in 18 ml of tetrahydrofuran. 3.88 g of 2-imino-3-methyl-thiazolidine and 0.8 ml of acetic acid are added and the reaction mixture is left to stand for 48 hours at room temperature.

The mixture is then quenched by pouring onto 300 to 350 g of ice water and then extracted with ethyl acetate. The combined extracts are washed with sodium bicarbonate solution and then water. The 45 ethyl acetate phase is dried over sodium sulfate, filtered and evaporated in vacuo. Recrystallization of the residue from methanol gives N, N'-bis (3-meth-ylthiazolidin-2-ylidene) succinamide.

Example 4

A mixture of 15.5 g of succinyl chloride and 20.5 g of 2-imino-3-methylthiazolidine in 150 ml of anhydrous toluene is boiled under reflux until two equivalents of hydrogen chloride have formed. The solution is then cooled to room temperature and washed with saturated sodium bicarbonate solution. The residue remaining after evaporation of the solvent in vacuo is recrystallized from methanol: N, N'-bis (3-methyl-60 thiazolidin-2-ylidene) succinamide is obtained.

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

B

Claims (7)

629490 PATENT CLAIMS 1. Process for the preparation of the new compound of formula \ \ V.A N ' n-c-ck2ch2 \ N ' I. CH. i-c-ch2ch2-c CH. | () 10 and their pharmacologically acceptable acid addition CH, salts, characterized in that the compound of Formula and their pharmacologically acceptable acid addition salts, characterized in that the compound of formula 15 (II) with a connection of the formulas 0 = j- XM / l CH where Y is chlorine, KO O II (Ci-i-alkyl) OCO-, FWF F F qA- ° - O ch, ch0c-y 2 \ _, O-, -OCH2CN, H OH \ ^ r = \ —O-P-N-ï-,} I \ J / OPh -o-c. NH N (Ci-4-alkyl) 2 CH: -O-C \ (II) 25th with a compound of formula O O Y-C-CH2CH2-C-Y wherein Y is chlorine NO; 30th // * O-, -N. O II (Ci-4-Alk ', l) OCO-, -OCH 35 »IJgL OPh w 2CN '"0, H NH -O-C -O-C. / CH2 N (Ci-4-alkyl) 2, \ 0 (Ci-4-alkyl) 50 or is -0- (Ci-4-alkyl), brings to the reaction, and a compound obtained is optionally converted into the corresponding salts. 3. Process for the preparation of the new compound of formula 55 n-c-ch2ch2 0 (Ci-4-alkyl) N. I I do CH, or-0- (Ci-4-alkyl), brings to the reaction, and a J J compound obtained if necessary into the corresponding 65th Salts transferred. and their pharmacologically acceptable acid addition 2. Process for the preparation of the new compound of the salts, characterized in that the compound of the formula formula 3rd 629490 rsv ï CÎ3 with the compound of the formula O II J hoocch2ch2c-n = ^ with a connection of the formulas (ii) 0 fi N-C-CH2CH2C-ï SD ch., in the presence of ethyl chloroformate and if necessary, a compound obtained is converted into the corresponding salts. 15