CS244850B2 - Production method of 4-oxothiazolidin-2 ylidenacetamide - Google Patents

Description

A 61 K 31/425

SATZINGER GERHARD dr. _r DENZLINGEN, * HERRMANN MANFRED dr. ί FRITSCHI EDGAR dr., ST '. PETER, * HARTENSTEIN JOHANNES dr., STEGEN-WITTENTAL, 'BARTOŠZYK GERD, WALDKIRCH / FRG / (72) Author of the invention (73) Patent proprietor GČDECKE AKTIENGESELLSCHAFT, WESTERN BERLIN / West Berlin / (54) Method of production of 4-oxothiazolidines -ylideneacetamide

The invention relates to a process for the preparation of novel 4-oxothiazolidin-2-ylideneacetamide derivatives of the general formula I

-CO-N — X — t

R ³

/ 1 /,

R ² r ⁵ in which

R ¹ is hydrogen, saturated or unsaturated aliphatic hydrocarbon residue having up to 4 carbon atoms in a straight or branched chain, a phenyl or benzyl radical,

R represents a hydrogen atom or an alkyl or dialkylaminoalkyl radical of up to 9 carbon atoms in the straight or branched chain,

X represents a direct bond or an alkylene radical of up to 4 carbon atoms in a straight or branched chain and each of R ³ , R ⁴ and R ³ , which are the same or different, represents a hydrogen atom, an alkyl radical of up to 4 carbon atoms in a straight or branched branched chain, alkoxy or alkylthio of up to 4 carbon atoms in the straight or branched chain or two adjacent radicals optionally together form methylenedioxy or ethylenedioxy, halogen, hydroxyl, nitro, carboxyl or alkoxycarbonyl of up to 5 carbon atoms, and each of R ³ and R ² , which may be identical or different, represent a hydrogen atom or an alkyl radical of up to 4 carbon atoms in the straight or branched chain.

Preferred compounds of the present invention are those compounds of formula (I) wherein R ¹ is hydrogen, saturated or unsaturated C 1 -C 3 alkyl, phenyl or benzyl, R is hydrogen, methyl or ethyl or dialkylaminoalkyl with a total of up to 7 carbon atoms, X represents a direct bond or a branched alkylene group having 1 to 3 carbon atoms and each of R ³ , R ⁴ and R ³ , which may be identical or different, represents a hydrogen atom, a methyl group, an ethyl group , methoxy, ethoxy, methylthio or ethylthio, the two adjacent radicals of which may also be methylenedloxy, fluorine, chlorine, bromine or iodine, hydroxyl, nitro, carboxyl

Or an alkoxycarbonyl radical of up to 5 carbon atoms, and each of R and R 'is hydrogen or methyl or ethyl.

Particularly preferred are those compounds of formula I wherein R ¹ is hydrogen, methyl, ethyl, allyl or benzyl group, R ² represents a hydrogen atom, a methyl group, X represents a bond or an ethylidene group and each of R ^3, R ^4, and R ^3, which are identical or different, represents a hydrogen atom, a methyl group or a chlorine or bromine atom and R ³ and R? represents a hydrogen atom.

The process according to the invention for the preparation of the compounds of the general formula (X) ^:

in which

R ^2, R ^3, R ^4, R ³ and X have the above meanings, is reacted with a thioglycolic acid ester of the formula V

HS - C - COOR

A ⁶ (in).

in which

7

R and R are as defined above and

O

R represents an alkyl group of up to 5 carbon atoms, the resulting compound of formula (VI) wherein:

/ VI /,

R, R <R, R, R, R, ^Z and X are as defined above, is then optionally N-alkylated and the resulting compound of formula I is then isolated.

The compounds of formula I are valuable drugs with an unusually broad spectrum of anticonvulsant activity and excellent tolerability. They are particularly suitable for extensive anti -plleptic treatment.

. The term epilepsy (padoucnioe) is a collective term for a group of chronic diseases of the central nervous system, which is the common occurrence of occasional seizures with abnormal motor (seizures), sensory and psychological phenomena.

The incidence of epilepsy is surprisingly large * approximately 0.5% of the population suffers from it. The frequency of forms of epilepsy necessitates pharmacotherapy, which becomes very complicated by the need for a fiasto changing differentiated treatment by different drugs.

Epilepsy drugs belong to different chemical groups. These groups include barbiturates, pyrlmidones, hydantoins, oxazolidinediones, succinimides, benzodiazepines, iminostilbenes and valproates. Depending on their effects in laboratory models, representatives of these groups are more or less suited for the treatment of partial (focal), generalized, temporal or myoclonal seizures and absences. Accordingly, an ideal anti-epileptic would be a substance that is capable of suppressing all kinds of seizures and absences and that does not cause any unwanted, side effects. _t

A disadvantage of known anti-epileptic drugs is that they often fail to control seizures and can cause central nervous system disorders and other side effects to aplastic anemia (Goodman, Gilman, The Pharmacological Basis of Therapeutics - 6th ed. 1980, p. 451). and more/.

Although known anticonvulsants are used in the appropriate selection and combination, seizures can only be controlled in 50% of the patients given these agents. And even in successful cases, it is usually necessary to accept unpleasant side effects.

The compounds of the formula I exhibit not only an extremely broad spectrum of activity, but also high activity and extremely good tolerability. Although these findings have so far been supported only by animal experiments, it is expected that the compounds produced by the method of the invention will represent a significant advance in the treatment of epilepsy in its numerous forms.

The compounds of formula I may exist in the Z and E configuration due to the carbon-carbon double bond on the thiazolidine ring. The invention includes both of these forms.

Compounds of formula IV may be prepared from cyanoacetic esters - such as ethyl cyanoacetate - by reaction with the appropriate aniline derivatives of formula VII

®2 ^N— γΤγ / VII /,

R® in which

R ³ , R ⁴ and R ⁵ are as defined above, according to generally known methods, for example by heating the reactants while distilling off the liberated ester alcohol.

The compounds of formula I prepared in this manner can be administered in liquid or solid form enterally or parenterally. In particular, aqueous phases are used as injectables which contain conventional additives such as stabilizers and solubilizers.

Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly disperse silicic acid, higher molecular weight fatty acids such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular polymers. such as polyethylene glycols / oral compositions may optionally contain flavorants and / or sweeteners.

The dosage of the compounds prepared by the method of the invention depends on the type and severity of the disease in the individual case. The oral single dose is about 10 to 200 mg.

The invention is illustrated by the following example.

Example (Z) - (4-Oxothiazolidin-1-ylidene) -N- (2,6-dimethylphenyl) acetamide

4.2 g (35 mmol) of ethyl thioglylic acid are mixed with 6.6 g (35 mmol) of 2,6-dimethylanilides of cyanoacetic acid and 0.13 g (1 mmol) of potassium carbonate.

15 ml of ethanol are then added and the mixture is heated to reflux for 3.5 hours with stirring. After addition of an additional 15 ml of ethanol, the mixture was cooled to 40 ° C. The precipitate formed is filtered off with suction, the crude product is recrystallized from 50% aqueous acetic acid, washed neutral with water and dried under reduced pressure.

(Z) - (4-Oxothiazolidin-2-ylidene) -N- (2,6-dimethylphenyl) acetamide, m.p. 250 DEG C. (dec.).

The 2,6-dimethylanilide used as starting material is prepared as follows:

Ethyl cyanoacetate (11.3 g, 0.1 mol) was mixed with 2,6-dimethylaniline (15.7 g, 0.13 mol) and heated to 170 ° C with stirring. The ethanol which is released is continuously distilled off. The temperature ee is gradually increased up to 195 ° C. After 6 hours the reaction is complete.

After cooling, the contents of the beaker were recrystallized from 350 ml of ethanol. The cyanacetic acid 2,6-dimethylanilide obtained is obtained in the form of colorless crystals, m.p. 204 DEG-206 DEG.

The following compounds were prepared in a similar manner:

b) (Z) - (3-Methyl-4-oxothiazolidin-2-ylidene) -N- (2-chlorophenyl) acetamide, m.p. 193 DEG-194 DEG C. (dec.) (from methanol) (c) (Z) - (3-Methyl-4-oxothiazolidin-2-ylldene) -N- (3-chlorophenyl) acetamide, m.p.

275.3 ° C (dec.) (From dimethylsulfoxide (d) (Z) - (3-methyl-4-oxothiazolidin-2-ylidene) -N- (4-chlorophenyl) acetamide, m.p. 295.5 ° C) (dec) (dimethyl sulfoxide / methanol) (e) (Z) - (3-methyl-4-oxothiazolidin-2-ylidene) -N- (2,3-dimethylphenyl) acetamide, m.p. 205-207 ° C; (dec) (from ethanol) (f) - (-) - (3-Methyl-4-oxothiazolidin-2-ylidene) -N- (1-phenylethyl) acetarald, m.p. -propanol with petroleum ether (g) - [- (Z) - (3-methyl-4-oxothiazolidin-2-ylidene) -N- (1-phenylethyl) acetamide, m.p. 55 DEG-60 DEG C. (from di-chloromethane) (+) - (Z) - (3-Methyl-4-oxothiazolidin-2-ylidene) -R- (1-phenylethyl) acetamide, m.p. 65-70 ° C (from dichloromethane) (i) (Z) -) 244 DEG-245 DEG C. (from 3-methyl-4-oxothiazolidin-2-ylidene) -N- (2-chloro-6-methylphenyl) acetamide; 224 DEG-226 DEG C. (from toluene) to (Z) - (3-methyl-4-oxoth) oxothiazolidin-2-ylidene (-N-) -2,6-dichlorophenyl acetamide; Aiazolidin-2-ylidene (-N-) (2,4,6-trimethylphenyl) acetamide, m.p. 249.8 ° C (dec.) (from ethanol)

1) (Z) - (3-Methyl-4-oxothiazolidin-2-ylidene) -N- (4-bromo-2,6-dimethylphenyl) acetamide, m.p. 263 DEG C. (from methanol) (m) (Z) - (3-Methyl-4-oxothiazolidin-2-ylidene) -N-methyl-N- (2-methylphenyl) acetamide, m.p. 114-115 ° C, from diisopropyl ether (n) (Z) - (3-methyl-4); oxothiazolidin-2-ylidene (-N-methyl-N- (3-methylphenyl) azetamide, m.p. 117-118 ° C) from diiosopropyl ether (o) (Z) - (3-methyl-4-oxothiazolidin-2-ylidene) (N-methyl-N- (2,6-dimethylphenyl) acetamide, m.p. 153-154 ° C) from diisopropyl ether (p) (Z) - (3-ethyl-4-oxothiazolidin-2-ylidene) -N- (2,6-dimethylphenyl) acetamide, m.p.

282.3 ° C (dec.) (From 2-propanol) (q) (Z) - (3-allyl-4-oxothiazolidin-2-ylidene) -N- (2,6-dimethylphenyl) acetamide, m.p. 5 DEG C. (dec.) From a mixture of 2-propanol with water (R) (Z) - (3-Benzyl-4-oxothiazolidin-2-ylidene) -N- (2,6-dimethylphenyl) acetamide, m.p. m.p. 167-168 ° C (from toluene) with ethyl 3-methyl-2- (3-methyl-4-oxothiazolidin-2-ylidene) acetylamino] benzoic acid, m.p. 167-168 ° C (from tetrahydrofuran / petroleum ether). t) (Z) -N- (2-Methoxy-6-methylphenyl) - (3-methyl-4-oxothiazolidin-2-ylidene) acetamide, m.p. 158-160 ° C (from isopropanol). N- (2-methylthiophenyl) - (3-methyl-4-oxothiazolidin-2-ylidene) acetamide, m.p. 177-178 ° C (from toluene) (v) (Z) - (3-methyl-4-oxothiazolidin-2) -ylidene (-N-) (3,4,5-trimethoxyphenyl) acetamide, m.p. 224 DEG-225 DEG C. (from isopropanol) (w) (Z) -N- (2-methyl-6-nitrophenyl) - (3-methyl) -4-oxothiazolidin-2-ylidene (acetamide, m.p. 218-219 ° C) from toluene / acetone em (x) (Z) -N- (2-Diethylaminoethyl) -N- (2,6-xylyl) - (3-methyl-4-oxothiazolidin-2-ylldene) acetamide hydrobromide, m.p. 261.5 ° C (from ethanol) (Z) - (3-methyl-4-oxothiazolidin-2-ylidene) acetanilide, m.p. 212-215 ° C. ethanol (z) (Z) -N- (4-chloro-2-nitrophenyl) - (3-methyl-4-oxothiazolidin-2-ylidene) acetamide, m.p. 264 DEG-265 DEG C. (from dimethylformamide / water) (aaa) (2-hydroxy-4- [β-methyl-4-oxothiazolidin-2-ylidene] acetylamino] benzoic acid ethyl ester, m.p. 236-237 ° C) from dimethylformamide / water (bb) (Z) -N- (3) -diethylaminopropyl [-N- (2,6-xylyl) - [3-methyl-4-oxothiazolidin-2-ylidene] acetamide hydrochloride, m.p. 222 DEG-223 DEG C. (from isopropanol) (cc) (Z) -N- (2-Dimethylaminoethyl) -N- (2,6-xylyl) - (3-methyl-4-oxothiazolidin-2-ylidene) acetamide hydrochloride, m.p. 268.8 ° C (from ethanol) (dd) (Z) - N- (3-dimethylaminopropyl) -N- (2,6-xylyl) - [3-methyl-4-oxothiazolidin-2-ylidene] acetamide hydrobromide, m.p. 253.6 ° C (from ethanol (ee) acid) From (3-methyl-2 - [(3-methyl-4-oxothiazolidin-2-ylidene)] acetylamino) benzo, m.p. 186.9 ° C (from dichloromethane) (f) (Z) - (4-oxo-3). -phenylthiazolidin-2-ylidene / -N- (2,6-xylyl) acetamide, m.p. C (from ethanol)

99) (Z) - (1- (2-Chloro-6-methylphenyl) - (4-oxo-3-phenylthiazolidin-2-ylidene) acetamide, m.p. 213-214 ° C) from ethanol (hh) (Z) - (3,5-Dimethyl-4-oxothiazolidin-3-ylidene) -N- (2,6-xylyl) acetamide, m.p. 220-222 ° C (from ethanol)

Pharmacological comparative experiments

Methodology

General

In the varicose tests, 0.8% methocel jelly was used as vehicle for all substances. The premedication time is 30 minutes, unless otherwise stated, and the application is performed intragastrically in 20 ml.kg ^-1 body weight.

The test animals are male (NMRI) mice weighing 18 to 24 g, which were kept in conditioned conditions. 24 hours (unless otherwise stated) before the start of the experiment, the feeding is stopped, but the water is kept until the start of the experiment.

For audiogenically induced convulsions, male DBA / 2J mice weighing 5-10 g were used, which were delivered 1 day prior to the experiment and were not fasted.

10 animals were tested for each dose.

Phenytoin, valproate, GABA and baclofen are used as positive standards.

Test models

1 / Isoniazid-induced seizure

Isonicotinic hydrazide (isoniazide) at a dose of 250 mg.kg ^-1 , administered subcutaneously, was used as a seizure agent, with an observation period of 90 minutes.

2 / Convulsion induced by administration of strychnine

Crystalline strychnine nitrate, administered subcutaneously, at a dose of 1.1 mg.kg ^-1 was used as a spasmodic agent, with an observation period of 20 minutes pa

3 / electric shock

For electric shock, instruments (HSE type 207) are used to elicit irritating reactions. To transmit shock, the electrodes in the form of clips are mounted on the mouse ears. The shock duration is 0.3 seconds, the current density is 35 mA (self-regulating voltage). Phenytoin sodium (EPANUTIN) is administered intragastrally or subcutaneously as a positive standard at a dose of 50 mg / kg. The observation period of the animals is 5 minutes.

4 / Pentetrazole-induced seizure

Pentetrazole at a dose of 140 mg.kg ^-1 administered subcutaneously was used as a seizure agent. The observation time of the animals is 20 minutes.

5 / Picrotoxin-induced convulsion

Picrotoxin is administered subcutaneously at a dose of 15 mg.kg ¹ . Observe the animals for 20 minutes.

6 / bicucullin-induced seizure

Bicucullin purum at a dose of 3.0 mg / kg is administered subcutaneously as a seizure agent. The observation time of the animals is 20 minutes.

7 / Semicarbacid-induced seizure

Semicarbacid hydrochloride was administered subcutaneously as a seizure agent at a dose of 1000 mg.kg ^-1 . The time of observation of the animals is always 90 minutes pa

8/3 ** mercaptopropionic acid spasm

Dilute 3-mercaptopropionic acid with saline; pH of the solution is adjusted to 7 by adding sodium hydroxide at a concentration of 6 M ^-1 and adding a solution of sodium chloride to a final volume adjusted to 10 ml.kg ^-1.

The observation time of the animals is 30 minutes.

9 / Audiogenically induced convulsions

Animals are exposed to a tone of 10.9 kHz at 110 dBA for 30 seconds. The observation time of the animals is 1 minute.

Tabulkal

Comparison of anticonvulsant effect in seizure models 1 / to 9 /

EDjj ₀ /mg.kg ¹ intragastral, male mice /

Substance from example no. elektro- by shock convulsion induced pentetra- zolem semicarbabic picrotoxin cidem stryohnine 1 a / 13.6 19.85 14.06 11.30 14.88 1 i / 6.47 1.90 1.59 2.34 5.09 1 j / Comparing 4.03 substances 1.80 3.41 1.52 5.68 phenytoin 50 / ED 100 / 12,5 /i.v./ 50 / ED 100 / 50 / ED 90 / 200 inactive valprost 200 / ED 40 / ca.250 100 ALIGN! inactive inactive GABA inactive 500 60 inactive inactive baclofen ^{+ //} 20 May 100 ALIGN! 4 30 8.5

+/- side effects in all seizures models

continuation of Table

acid isoni- bicucul- audio · 3-mercapto- propionic azide linem genně 8.7 5.32 2.68 2.9 1.29 1.24 0.9 3.0 1.73 5.0 0.8 2,0 38 12.5 2.3

154 135 __, - - __ __ 20 May 2,0 20 May 5

Acute toxicity and therapeutic index

Acute toxicity determinations were performed on male (NMRI) mice weighing 18-23 g. All experimental animals were fasted for 20 hours prior to the start of the experiment. Water is available ad libitum. There are 4 experimental animals per dose group.

Dose escalation is logarithmic. Test substances are administered intragastrally as a suspension in 0.88% methocel. Application volume was 20 ml.kg ¹ body weight. The animals are observed for a total of 7 days.

Table II

Compound from the example C. -1 “ ⁵⁰ /mg.kg ¹ intragastral / / male mice / therapeutic index ^LD 50 / ^ED 50 ^{+ /} 1 a / 1 980 99.8 - 738.8 1 i / > 1,600 > 243.3 - 1777.8 1 j / 1 600 281.6 - 2000 valprost 2 000 fi - 14.8 GABA > 5,000 > 10-80 phenytoin 490 2,5 - 213 baclofen 200 2 - 100 ⁺ / calculated always for the highest and lowest ED ₅₀

Tables I and II clearly show, on the one hand, the broader spectrum of activity of the compounds of the formula I (Table 1) and, on the other hand, the extremely favorable relative safety of these compounds on the basis of therapeutic indexes (Table II).

AND

AND

Claims (2)

24485C SCOPE OF THE INVENTION A process for the preparation of 4-oxothlazolidin-2-ylldeneacetamide derivatives of the general formula I (1), in which: R ³ is hydrogen, saturated or unsaturated aliphatic hydrocarbon residue having up to 4 carbon atoms in a straight or branched chain, a phenyl or benzyl radical, R represents a hydrogen atom or an alkyl or dialkylaminoalkyl radical of up to 9 carbon atoms in a straight or branched chain, x. is a direct bond or an alkylene radical having up to 4 carbon atoms in straight or branched chain and Λ C, each of R ^J, R and R, which are identical or different, represents a hydrogen atom, an alkyl radical having up to 4 carbon atoms in a straight or branched a chain, alkoxy or alkylthio of up to 4 carbon atoms, in a straight or branched chain, or two adjacent residues optionally together form methylenedioxy or ethylenedioxy, halogen, hydroxyl, nitro, carboxyl or alkoxycarbonyl of up to 5 carbon atoms and each of R ⁶ and R ⁷ , which may be identical or different, represent a hydrogen atom or an alkyl radical of up to 4 carbon atoms in the straight or branched chain, characterized in that the compound of the formula IV in R ³ _r 4 NC - CH 1 - I - X - ^R kterém in which 2 3 4 5 R, R, R, R and x are as defined above, reacted with a thioglycolic acid ester of formula V R ⁷ I 8 HS - C - COOR (IV), lions in which: R® and R ⁷ have the meaning indicated and výěe O R represents an alkyl group of up to 5 carbon atoms, the resulting compound of formula (VI) in which: R ³ , R ³ , R 6, R ⁷ , R ⁷ , R ⁷ and X are as defined above, are subsequently optionally N-alkylated, and the compound of formula I thus obtained is then isolated. 244650 2. The process of item 1 for producing compounds of formula I wherein: R ¹ is hydrogen, saturated or unsaturated aliphatic hydrocarbon residue having up to 4 carbon atoms in straight or branched chains, phenyl or benzyl,