CH621783A5 - Process for the preparation of novel thiazolines - Google Patents

Description

The present invention relates to a process for the preparation of new thiazolines of the formula I.

40

(II)

45

50

-C-COOR I

e.g.

-H

(I)

wherein X 'is an acid residue, undergoes an acid excretion reaction with a weak acid excretion agent.

2. Process for the preparation of the compound of formula h

- C - COOH

I.

II

where X, hydrogen or methyl, Yt and Y2 are each hydrogen, halogen, C1.s-alkyl, C, _3-alkoxy or trifluoromethyl, R, 5s hydrogen, methyl or ethyl, R2 C, _3-alkyl or C3_r, -Al- kenyl, R is an ester residue and Z is hydrogen, carboxy or a carboxyester group.

Another object of the present invention is a process for the preparation of new thiazolines of the formula

60

(IV)

II

65

3rd

621783

<Y

"è

Y2

These compounds produced according to the invention and the pharmaceutically acceptable salts produced from them are useful as medicaments with anti-inflammatory, analgesic, antirheumatic and antipyretic properties.

The above term C 1-4 alkyl refers to straight as well as branched residues with 1 to 3 carbon atoms, including for example methyl, ethyl, propyl, i-propyl. Halogen means e.g. Fluorine, chlorine and bromine. The term C 1-4 alkenyl includes, for example, 2-propenyl, 2-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl. The term carboxyester includes commonly used ester groups such as alkyl, aralkyl, aryl, cycloalkyl and similar modified carboxy groups.

For Y and Y2, preference is given to hydrogen and halogen, in particular halogen, and most preferably chlorine and fluorine. For R, hydrogen or methyl, in particular methyl, is preferred. For Ra, methyl or allyl, especially methyl, is preferred. As can be seen from the general formula, the grouping -CR, ZCOOH can be substituted either on the thiazoline ring or on the benzene ring. If this group on the benzene ring is substituted, it will advantageously be substituted in the 3- or 4-position, especially the 4-position.

The compounds of the formula I produced according to the invention, in which Z is a carboxy group or a carboxyester group, can be used as intermediates for the preparation of thiazolines in which Z is hydrogen. The thiazolines of the formula I produced according to the invention can also be used for the preparation of the compounds of the formula IV. The ester residue is the same as that explained under the name carboxyester.

The following compounds can be mentioned as examples of the thiazolines produced according to the invention: 2- [3- (3-methyl-4-thiazolin-2-ylidenamino) phenyl acetic acid, 2- [3- (3,4-dimethyl-4-thiazoline- 2-ylidenamino) phenyl] acetic acid,

2-r4- (3,4-dimethyl-4-thiazolin-2-ylidenamino) phenyl] acetic acid,

2- [3-Ch] or-4- (3-methyl-4-thiazolin-2-ylidenamino) pheny]] acetic acid,

2- [3-fluoro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] acetic acid,

2- [3,5-dichloro-4- (3,4-dimethyl-4-thiazolin-2-ylidenamino) -

phenyl] acetic acid, 2- [2-methoxy-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] acetic acid,

2- [3-trifluoromethyl-4- (3,5-dimethyl-4-thiazolin-2-ylidene-

amino) phenyl] acetic acid, 2-f4-chloro-3- (3-methyI-4-thiazolin-2-yIidenamino) phenyI] propionic acid

2- [4,6-dichloro-3- (3-methyl-4-thiazolin-2-ylidenamino) phenylJ-propionic acid,

2- [6-fluoro-3- (3-methyl-4-thiazolin-2-ylidenamino) pheny 1] propionic acid,

2- [4-methyl-3- (3-ethyl-5-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid, 5 2- [4-chloro-3- (3-propyl-4-thiazolin- 2-ylidenamino) phenyl] propionic acid,

2- [4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid,

2- [4- (3,4-Dimethyl-4-thiazolin-2-ylidenamino) phenylpropion-io acid,

2- [4- (3,5-Dimethyl-4-thiazoIin-2-ylidenamino) phenylpropionic acid,

2- [2-chloro-4- (3,4-dimethyl-4-thiazolin-2-ylidenamino) phenylJ propionic acid,

15 2- [2-chloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid,

2- [3-chloro-4- (3,4-dimethyl-4-thiazolin-2-ylidenamino) phenylJ-propionic acid,

2- [3-chloro-4- (3-methyl-4-thiazoIin-2-ylidenamino) phenyI] -20 propionic acid,

2- [2,3-dichloro-4- (3,4-dimethyl-4-thiazolin-2-ylidenamino) -

phenyl] propionic acid, 2- [3,5-dichloro-4- (3,4-dimethyi-4-thiazolin-2-ylidenamino) phenyl] propionic acid, 25 2- [3,5-dichloro-4- (3rd -methyl-4-thiazolin-2-ylidenamino) phenylJ -propionic acid,

2-L3,5-difluoro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenylJ-propionic acid,

2- [2-ethoxy-4- (3-methyl-4-thiazoIin-2-yIidenamino) phenyIJ-30 propionic acid,

2- [3-ethyI-4- (3,4-dimethyI-4-thiazolin-2-yIidenamino) phenyIJ-propionic acid,

2- [2-FIuor-4- (3,4-dimethyl-4-thiazoIin-2-ylidenamino) phenyIJ-propionic acid,

35 2- [2-fluoro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid,

2- [3-fluoro-4- (3,4-dimethyl-4-thiazolin-2-ylidenamino) phenylJ-propionic acid,

2- [3-fluoro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenylJ-40 propionic acid,

2- [3-methoxy-4- (3-methyl-4-thiazolin-2-ylidenamino) phenylJ-propionic acid,

2- [2-methyl-3-chloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenylpropionic acid, 45 2- [2-methyl-4- (3,4-dimethyl-4-thiazolin- 2-ylidenamino) phe-nylpropionic acid, 2- [2-methyl-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid,

2- [3-methyl-4- (3,4-dimethyl-4-thiazolin-2-ylidenamino) phe-50 nyl] propionic acid, 2- [3-methyl-4- (3-methyl-4-thiazolin-2 -ylidenamino) phenyl] -propionic acid,

2- [3-propoxy-4- (3-methyl-4-thiazolin-2-ylidenamino) phenylJ-propionic acid,

55 2- [3-Propyl-4- (3,5-dimethyl-4-thiazolin-2-vlidenamino) phe-nylpropionic acid, 2- [2-trifluoromethyl-4- (3-methyl-4-thiazolin-2-ylidenamino ) -

phenylpropionic acid, 2- [3-trifluoromethyl-4- (3-methyl-4-thiazolin-2-ylidenamino) -60 phenyl] propionic acid,

2- [4- (3-ethyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid.

2- | 2-chloro-4- (3-ethyl-4-methyl-4-thiazolin-2-ylidenamino) phenyl | propionic acid. 65 2- | 3,5-dichloro-4- (3-propyl-4-thiazolin-2-ylidenamino) phenyl | propionic acid,

2-12-Fluoro-4- (3-propyl-4-methyl-4-thiazolin-2-ylidenamino) phenyl [propionic acid.

r

C - COOH I

H

(IV)

H

621783

2- {3-chloro-4- [3- (2-propenyl) -4-thiazolin-2-ylidenamino] -

phenylpropionic acid, 2- {3-fluoro-4 ~ [3- (2-methyl-2-propenyl) -4-thiazolin-2-ylidene-

amino] phenyl} propionic acid, 2- {3-chloro-4- [4- (3-methyl-2-butenyl) -4-thiazoIin-2-ylidene-

amino] phenyl} propionic acid, 2- [3- (3-methyl-4-thiazolin-2-yIidenamino) phenylJ butyric acid, 2-f2-chloro-3- (3,4-dimethyl-4-thiazolin-2-yIidenamino) phenylJ-butyric acid,

2- [6-fluoro-3- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] butyric acid,

2- [4- (3,4-dimethyl-4-thiazolin-2-yidenidino) phenyl] butyric acid,

2- [3,5-dichloro-4- (3,4-dimethyl-4-thiazolin-2-ylidenamino) -

phenyl] butyric acid, 2- [2-fluoro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] butyric acid,

2- [2-methoxy-4- (3-methyl-4-thiazoIin-2-ylidenamino) phenyl] butyric acid,

2- [3-trifluoromethyl-4- (3,5-dimethyl-4-thiazolin-2-ylidene-

amino) pheny 1] butyric acid, 2- (2-phenylimino-3-methyl-4-thiazoIin-4-yl) acetic acid, 2- [2- (3,5-dichlorophenylimino) -3,5-dimethyl-4-thiazoline -4-yl] acetic acid,

2-f2- (4-fluorophenylimino) -3-methyl-4-thiazolin-4-yl] acetic acid,

2- [2- (4-methoxyphenyliminq) -3-methyl-4-thiazolin-4-yl] acetic acid,

2- [2- (3-trifluoromethylphenylimino) -3-methyl-4-thiazolin-4-yl] acetic acid,

2- (2-phenylimino-3,4-dimethyl-4-thiazolin-5-yl) acetic acid, 2- [2- (4-chlorophenylimino) -3,4-dimethyl-4-thiazolin-5-yl] acetic acid ,

2- [2- (3,5-dichlorophenylimino) -3-methyl-4-thiazolin-5-yl] acetic acid,

2- f 2- (4-fluorophenylimino) -3,4-dimethyl-4-thiazolin-5-yl] acetic acid,

2- [2- (3-methylphenylimino) -3-methyl-4-thiazolin-5-yl] acetic acid,

2- (2-phenylimino-3-methyl-4-thiazolin-4-yl) propionic acid, 2-f2- (4-chlorophenylimino) -3,5-dimethyl-4-thiazolin-4-yl] propionic acid,

2- [2- (3,5-dimethylphenylimino) -3-diethyl-4-thiazolin-4-yl] propionic acid,

2- [2- (4-ethylpheny limino) -3,5-dimethyl-4-thiazoIin-4-yl] propionic acid,

2-r2- (2-fluorophenylimino) -3,5-dimethyl-4-thiazoIin-4-yl] propionic acid,

2-r2- (4-methoxyphenylimino) -3,5-dimethyl-4-thiazolin-4-yl] propionic acid,

2-f2- (4-methylphenylimino) -3-methyl-4-thiazolin-4-yl] -propionic acid,

2- [2- (4-propoxyphenylimino) -3,5-dimethyl-4-thiazolin-4-yl] propionic acid,

2- [2- (3-trifluoromethylphenylimino) -3-methyl-4-thiazolin-4-

-yl] propionic acid, 2- (2-phenylimino-3-ethyI-4-thiazolin-4-yI) propionic acid, 2- [2- (4-chlorophenylimino) -3-propyl-4-thiazolin-4-yl] propion-5 acid,

2- [2- (2-fluorophenylimino) -3- (2-propenyl) -4-thiazolin-4-yl] propionic acid,

2- [2-phenylimino-3- (2-methyl-2-propenyl) -4-thiazolin-4-yl J-propionic acid,

io 2- [2-phenylimino-3- (3-methyl-2-butenyl) -4-thiazolin-4-yl] propionic acid,

2- (2-phenylimino-3,4-dimethyl-4-thiazolin-5-yl) propionic acid, 2- (2-phenylimino-3-methyl-4-thiazolin-5-yI) propionic acid, 2-f2- (4th -Chlorphenylimino) -3,4-dimethyl-4-thiazolin-5-yl] -15 propionic acid, 2- [2- (3,5-dichlorophenylimino) -3,4-dimethyl-4-thiazolin-5-yl] - propionic acid,

2- [2- (2-fluorophenylimino) -3,4-dimethyl-4-thiazolin-5-yl] propionic acid,

20 2- [2- (4-methoxyphenylimino) -3,4-dimethyl-4-thiazolin-5-yI] propionic acid,

2- [2- (2-methylphenylimino) -3,4-dimethyl-4-thiazolin-5-yI] propionic acid,

2- [2- (3-trifluoromethylphenylimino) -3-methyl-4-thiazolin-5-25 -yl] propionic acid,

2- (2-phenylimino-3-ethyl-4-methyl-4-thiazolin-5-yl) propionic acid,

2- [2- (3,5-dimethylphenylimino) -3-ethyl-4-thiazolin-5-yl] propionic acid,

30 2- (2-phenylimino-3-propyl-4-thiazolin-5-yl) propionic acid, 2- [2- (4-chloropheny] imino) -3-propyl-4-methyl-4-thiazolin-5-

-yl] propionic acid, 2- [2-phenylimino-3- (2-propenyl) -4-thiazolin-5 -yl] propionic acid,

35 2- [2-Phenylimino-3- (2-methyl-2-propenyl) -4-methyl-4-thiazo-lin-5-yl] propionic acid, 2- (2-phenylimino-3-methyl-4-thiazoline -4-yI) butyric acid, 2-f 2- (4-chlorophenylimino) -3,5-dimethyl-4-thiazolin-4-yl] butyric acid,

40 2-r2- (3,5-dichlorophenylimino) -3-methyl-4-thiazolin-4-yI] butyric acid,

2- [2- (2-fluorophenyimino) -3,5-dimethyl-4-thiazolin-4-yl] butyric acid,

2- [2- (4-trifluoromethylphenylimino) -3-methyl-4-thiazoline-4-45-yl] butyric acid,

2- (2-phenylimino-3-methyl-4-thiazolin-5-yl) butyric acid, 2- [2- (3,5-dichlorophenylimino) -3,4-dimethyl-4-thiazoIin-5-yl] butyric acid ,

2- f 2- (4-fluorophenylimino) -3,4-dimethyl-4-thiazolin-5-yl] -so butyric acid and its esters and pharmaceutically acceptable salts.

The process starting from the corresponding thiazole derivative can be demonstrated using the following reaction scheme:

R

3rd

-C-COOR I

Z.

Quaternization (i)

-II

(III)

r2 ^ Ys

- mi

Ri

-è-

COOK

-H

(II)

5

621783

(II)

Acid eau B schoiclung s roaction

(ii)

with weak elimination agent

Î1

T-COOR

I.

e.g.

-H

(I)

Hydrolysis and (I) decarboxylation h

"C-COOH I

H

-H

(IV)

wherein XI; Y1: Y2, R15 R, and Z each has the above meaning, R is an ester residue, X ~ is an acid radical.

The starting compound III, in which Z is hydrogen, is a known compound which was disclosed in German Offenlegungsschrift No. P 2450617.0 of April 30, 1975. The preparation of the starting compound in which Z is carboxy or a carboxyester group is also described in the aforementioned publication. The compounds can be prepared by modifying the a-carbon of the acetic acid residue with dialkyl carbonate such as diethyl carbonate.

As can be seen from the above reaction scheme, the starting compound III is quaternized. The quaternization can be carried out using a quaternizing agent, for example using an appropriate alkyl halide, e.g. Iodide, bromide or chloride, of alkyl such as methyl, ethyl, propyl or isopropyl, or by means of appropriate alkenyl halide, e.g. Al-kenyl iodide, bromide or chloride, such as 2-propenyl, 2-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl; by means of an appropriate aromatic sulfonic acid alkyl ester, such as alkyl benzenesulfonic acid ester, p-toluenesulfonic acid alkyl ester, or by means of corresponding di-alkyl sulfates, e.g. Dimethyl sulfate, diethyl sulfate, etc. Although a reaction solvent is not necessary, an inactive neutral solvent, such as e.g. an alcohol, e.g. Methanol or ethanol, a hydrocarbon e.g. Benzene, toluene or xylene, an ether, e.g. Ether or tetrahydrofuran, dimethylformamide or a mixture thereof. The reaction can be carried out at a temperature from room temperature to 150 ° C for one to 180 hours, although the reaction temperature and the reaction time can be appropriately changed in accordance with other reaction conditions. The reaction can be accelerated using pressure.

The resulting quaternary ammonium salt of Formula II is subjected to an acid excretion reaction, denoted by ii in the above reaction chart. A hydrohalic acid or an aromatic sulfonic acid can be eliminated from the compound II. The reaction takes place with the aid of acid excretion agents, e.g. with an alkali metal carbonate, e.g. Sodium carbonate or potassium carbonate, an alkali metal bicarbonate, e.g. Sodium bicarbonate or potassium bicarbonate or with ammonia.

The reaction is advantageously carried out in a solvent, e.g. in water, a halogenated hydrocarbon, e.g. Chloroform or methylene chloride, a hydrocarbon, e.g. Benzene, toluene or xylene or an ether, e.g. Ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, ethylene glycol-30 col-dialkyl ether or diglyme. The reaction can be carried out with stirring of the above-mentioned compound II with the acid eliminating agents mentioned above, with or without a solvent.

The resulting product can be hydrolyzed if necessary. The hydrolysis is usually carried out in the usual manner used for the carboxylic acid esters. The product can be mixed with an acid, e.g. Hydrochloric acid, sulfuric acid, hydrobromic acid or acetic acid, or a base, e.g. Sodium hydroxide, potassium hydroxide, sodium 40 carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, can be hydrolyzed in water or a suitable organic solvent containing water.

The compound II in which Z is a carboxyl or a carboxy ester group can be further subjected to decarboxylation 45. This decarboxylation is usually carried out in a conventional manner, such as heating compound II.

The compounds I and IV thus obtained can be converted into pharmaceutically acceptable non-toxic salts in accordance with the requirements for separation, purification, formulation and the like. Such salts include, for example, alkali metal salts, e.g. Sodium salt, potassium salt, lithium salt, alkaline earth metal salts such as calcium salt, magnesium salt, barium salt, and aluminum salt.

In addition, the compounds of the formulas I and IV produced according to the invention can form pharmaceutically acceptable salts with a variety of inorganic or organic acids. Such salts are, for example, the hydro-60 chloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, thiocyanate, carbonate, acetate, oxalate, succinate, maleate, tartrate, citrate, benzoate, salicylate and phthalate.

The thiazolines of the formulas I and IV produced according to the invention are optically active compounds and can be separated into 65 D and L isomers. Optical resolution can be done in a conventional manner, and both isomers can be used alone or as a mixture, depending on the therapeutic requirements.

621783

6

The compounds produced according to the invention and their pharmaceutically non-toxic salts have anti-inflammatory, antirheumatic, analgesic and antipyretic activities. These pharmacological activities were examined using the following methods and the results are recorded in Table I.

Test method

1. Acetic acid curvature method

Male DS mice from 20 to 23 g in weight were treated by intraperitoneal injection of 0.1 ml / 10 g in weight of 0.6% acetic acid 60 minutes after administration of a test compound. The time course of the curling or writhing (with pain) during 10 minutes is counted. ED3I is calculated using the Bliss method.

2. Effect on a foot inflamed by yeast

A test compound is administered orally to female Wistar rats of 180 to 200 g body weight, shortly before subcutaneous injection of 0.1 ml of a 20% yeast suspension into the sole tissue of the foot. Two hours later the pain threshold is determined by pressing the foot with a piston and calculated using the method of Litchfield and Wilcoxon [J. Pharmacol. Exp. Ther. 96, 99-113 (1949)].

3. Effect as an additional aid for arthritis

For this test, female Wistar rats weighing from 140 to 160 g are selected which show typical arthritis in the foot on the 21st day after intradermal injection of dead tuberculosis bacilli. There will be a test compound on these arthritic rats twice a day during

Results

determination

1. Acetic acid curvature test

2. Foot inflamed by yeast

3. Arthritis

4. Antioedem effect

5. Antipyretic effect - 0.5 ° C

",, .... mouse

6. Acute toxicity j ^ atte

Note: Connection 1 Connection 2 Connection 3 Connection 4 A

administered orally for five consecutive days. 5 hours after the last medication, the change in the swelling volume of the arthric foot is measured. ED30 is calculated using the Bliss method.

5

4. Antioedema effectiveness

As a logistic agent 0.05 ml of an aqueous solution of 1% Icelandic moss is used. After 30 minutes, female Wistar rats weighing 180 to 200 g of test compound were orally administered, the phlogistic agent being injected subcutaneously into the sole of the rat's foot. The swelling volume is measured three hours after the injection of the Icelandic moss, and the antioedem activity is determined by determining the ratio of the oedematous volume of the foot treated to that of the untreated foot. ED50 is calculated using the Bliss method.

20 5. Antipyretic effect

A test compound is administered orally to female Wistar rats weighing 180-200 g, 16 hours after the injection of 2 ml of a 15% suspension of yeast into the subcutaneous tissue of the hip 25 of these rats. The temperature in the rectum is then measured every hour for 5 hours. The effective dose is calculated using the Bliss method.

6. Acute toxicity 30 For a dose level, a group of 10 male DS mice weighing 20 to 23 g or ten female Wistar rats weighing 180 to 200 g are used for the above purpose. LDri0 is determined after 72 hours of oral administration of a test compound. This 35 LD5 is calculated using the Bliss method.

As can be seen from Table I, the thiazoline derivatives produced according to the invention have anti-inflammatory, 65 analgesic, antirheumatic and antipyretic activities which are stronger than the commercially available compounds, such as indomethacin, mefenamic acid and phenylbutazone. The ED; i "value of the anti-edema effect of

TABLE 1

Active ingredient mg / kg ED (%)

Indomethacin

Mefenic acid

Phenylbutazone

Verb. 1

Verb. 2

Verb. 3

Verb. 4

50

6.5

203

430

6.8

11

18th

21st

100

23

110

120

14

5.4

7.2

7.8

30th

1

37

9

23

9

41

25th

30th

4.5

15

48

4.1

0.25

1.6

3.2

0.9

1.2

4th

3rd

1.3

0.6

1.6

17 51

2103 2750

1414 874

750 (A) 750 (A)

750 (A) 500 (A)

1250 (A)> 1000 (A)

750 (A) 750 (A)

2- [3-chloro-4- (3-methyl-4-thiazolin-2-yIidenamino) phenyl] propionic acid

2- [3-fluoro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid

2- [3,5-dichloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid

2- [3,5-dichloro-4- (3,4-dimethyl-4-thiazolin-2-yIidenamino) phenyl] propionic acid

adoption

7

621 783

Calcium 2- [2-fluorine-4- (3,4-dimethyl-4-thiazolin-2-ylidene-amino) phenyl propionate and calcium 2- (3-methyl-2-phenyl-imino-4-thiazoline -4-yl) propionate is 7.1 mg / kg or 16.4 mg / kg. The other compounds produced according to the invention have the same pharmacological effects.

From the above it can be seen that the said compounds of formula I and their pharmaceutically acceptable salts are useful in the treatment of various inflammations, pains and rheumatic ailments in human beings and animals.

The compounds mentioned can be administered orally, percutaneously or by injection alone or in combination with a pharmaceutically acceptable carrier. The compounds are advantageously used in combination with one or more carriers adapted to the particular route of administration. The carriers to be used are predetermined by their solubility and chemical property of the compound and the route of administration. The following may be mentioned as solid carriers for internal or external use: lactose, sucrose, starch, dextrin, sodium bicarbonate, liquorice powder, talc, kaolin, bentonite, calcium carbonate, paraffin and gelatin, water, ethanol can be mentioned as a gel or liquid carrier , i-Propa-nol, chloroform, glycerin and the like. «Freon» can also be used for aerosols.

Practical examples of suitable pharmaceutical preparations of the compound of formula I produced according to the invention are tablets, capsules, pills, ointments, granules, powders, supositories, aerosols and injectable solutions.

Therapeutic compositions comprise 1 to 500 mg of one or more compounds of the formula I produced according to the invention with or without a pharmaceutically acceptable carrier. Said compound I is generally administered to humans and animals in the order of a 30th part of the practical dose of mefenamic acid, i.e. 20 to 1000 mg of the compound I can be administered orally to humans either in single or divided dose amounts within a period of 24 hours. The connection is made all at once, even in acute conditions.

The process according to the invention described above is explained in more detail with the following examples.

example 1

(1) A mixture of 6.3 g of ethyl 2- [4- (N-thiazol-2-yl-amino) phenyl] propionate, 30 ml of methyl iodide and 30 ml of ethanol is at 50 to 55 ° C for 20 hours heated under nitrogen. After evaporation of ethanol and methyl iodide, the resulting residue is washed with ether and then with ethyl acetate, and 8.0 g of 3-methyl-2- [4- (l-ethoxycarbonylethyl) anilino] thiazolium iodide are obtained in an 84% yield .

(2) The product thus obtained is dissolved in methylene chloride. The solution is washed with 10% aqueous potassium carbonate solution and evaporated to remove methylene chloride. The resulting residue is dissolved in ether, the solution is dried over potassium carbonate and the ether is removed by evaporation. 5.5 g of ethyl 2- [4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl propionate are obtained in an 83% yield.

IR v S cm-1 1735, 1615, 1590.

NMR £ DC | 32.9 (4H, aromatic), 3.5 (d, 1H), 4.2 (d, 1H), 5.9 (q, 2H), 6.3 (q, 2H), 6 , 6 (s, 3H), 8.5 (d, 1H), 8.8 (t, 3H).

(3) 5.5 g of the product thus obtained are dissolved in a mixture of 28 ml of a 20% aqueous potassium hydroxide solution and 28 ml of ethanol, and the solution is kept at room temperature for one hour. To

Evaporation of the methanol, the solution is neutralized with hydrochloric acid, brought to pH 5 with acetic acid, salted out with sodium chloride and then extracted with ether. The ether solution is dried over magnesium sulfate and evaporated. The resulting residue is recrystallized from ethyl acetate and 4.3 g of 2- [4- (3-methyl-4-thiazolin-2-ylidenamino) phenylpropionic acid with F from 130 to 132 ° C. and with a 73% strength are obtained Yield. IR v mä ^ cnr1 1710, 1595.

io Analysis for: C13H1402N., S

calculated: C 59.52 H 5.36 N 10.64 S 12.18 found: C 59.79 H 5.36 N 10.41 S 12.18

15

The corresponding hydrochloride recrystallized from ethanol has an F of 154 to 155 ° C.

IRv m "JxoIcm- '1708, 2470 (wide).

Example 2

(1) A solution of 14 g of ethyl 2- [3,5-dichloro-4- (N-20-thiazol-2-ylamino) phenyl] propionate in 70 ml of methyl iodide is placed on an oil bath at 50 to 55 ° C under Treated stirring at reflux. After removing the methyl iodide, the resulting residue is dissolved in methylene chloride. The solution is then washed three times with 20% aqueous potassium carbonate solution, dried over potassium carbonate and evaporated to remove methylene chloride. The resulting oily residue is then subjected to column chromatography using silica gel. 30 to 7.2 g of ethyl 2- [3,5-dichloro-4- (3-methyl-4-thiazolin-2-ylideneamino) phenyl] propionate are obtained from benzene and 2% benzene eluents.

IR v S cm- '1738, 1735, 1620.

(2) A solution of 6.0 g of the above product in a mixture of 30 ml of ethanol and 30 ml of 20% aqueous potassium hydroxide solution is kept at room temperature for one hour. After evaporation of ethanol, the resulting solution is neutralized with hydrochloric acid and brought to pH 5 with acetic acid.

40, whereupon a precipitate of 2- [3,5-dichloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionic acid resulted. This precipitate is filtered off, washed with water and dried, and 5 g of crystals with F of 161 to 165 ° C. are obtained. After recrystallization from methyl acetate, the crystals showed an F of 165 to 167 ° C. The yield was 84%.

IR v S1 cm-1 3125,3075, 1710, 1600.

Analysis for: C ^ Hj-OaNaSCL

calc .: C 47.13 ~ H 3.65_ N 8.46 S 9.68 Cl 21.40 50 found: C 47.37 H 3.69 N 8.67 S 9.56 Cl 21.17

2.4 g of the product are dissolved in 33 ml of an aqueous solution of 0.3 g of sodium hydroxide. The solution is washed with ether and 2 ml of an aqueous solution 55 of 533 mg calcium chloride dihydrate are added to the solution. The crystals which have separated out are filtered off and 2.5 g of the calcium salt having an F of from 265 to 270 ° C. (dec.) Are obtained.

Example 3

60 (1) A mixture of 3.8 g of ethyl 2- | 3-chloro-4- (N-thiazol - 2-ylamino) phenyl] propionate, 11.4 ml of methyl iodide and 11.4 ml of ethanol is added Heated at 100 ° C. for 6 hours in a sealed tube. The ethanol and the methyl iodide are then evaporated off. The residue is washed with benzene 65 and dissolved in methylene chloride. The solution is then washed with 20% aqueous potassium carbonate solution and to remove the methylene chloride , The residue is then reduced to that in Bei

621783

8th

treated game 1 described and there are 2.45 g, that is in 62% yield, of ethyl 2- [3-chloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] propionate.

IR v S cm-1 1735, 1615, 1585.

(2) The product thus obtained is hydrolyzed in the manner described in Example 1 (3) and recrystallized from ether / hexane, and 2.08 g of 2- [3-chloro-4- (3-methyl-4 -thiazolin-2-yIidenamino) phenyl] propionic acid with F from 132 to 133 ° C.

IR v

Nujol cnr1 2500 (wide), 1950 (wide), 1720, 1580.

Analysis for: C13H1302N2SC1 calc .: C 52.61 H 4.42 found: C 52.83 H 4.61

N 9.44 S 10.80 Cl 11.95 N 9.40 S 10.90 Cl 11.84

Example 4

(1) A solution of 9.0 g of ethyl 2- [2-chloro-4- (N-4-methyl-thiazol-2-ylamino) phenyl] propionate in 50 ml of methyl iodide is placed on an oil bath at 50 ° C treated under reflux with stirring for 20 hours to give a precipitate. The methyl iodide is then evaporated off. The residue is washed with ethyl acetate and recrystallized from ethanol / ethyl acetate and then from aqueous ether, and 7.7 g of 3,4-dimethyl-2- [2-chloro-4- (l-ethoxycarbonylethyl) anilino] thiazoium iodide with F are obtained from 199 to 202 ° C. The yield is 60%.

IR v

Nuiol cnr1 3075, 1730, 1608.

Analysis for: CU; H2n02N., SCI I

calc .: C 41.17 H 4.32 N 6.00 S 6.87 Cl 7.60 I 27.19 found: C 40.96 H 4.32 N 6.01 S 6.79 Cl 7.61 I 27.17

(2) 7.7 g of the product thus obtained are dissolved in methylene chloride. The solution is washed three times with 20% aqueous potassium carbonate solution, then dried over potassium carbonate and evaporated. The residue is subjected to column chromatography using alumina. 5.6 g of ethyl 2- [2-chloro-4- (3,4-dimethyl-4-thiazolin-2-ylideneamino) phenyl] propionate are obtained as an oily residue from a benzene eluent.

holds 5.9 g of 2- [3-fluoro-4- (3-methyl-4-thiazoIin-2-ylidenamino) phenyl] propionic acid. After recrystallization from ethyl acetate and then from 10% acetone / ethyl acetate, crystals with an F of 151 to 152 ° C. are obtained. The yield was 75%.

5 IR v Säiol2500 (broad), 1900 (broad), 1710, 1580.

Analysis for: C1:, HK102N2SF

calc .: C 55.70 H 4.64 N 9.99 S 11.44 F 6.78 found: C 55.60 H 4.93 N 9.93 S 11.57 F 6.84

Example 6

(1) A mixture of 6.5 g of 2- [3-chloro-4- (l-diethoxycar-bonylethyl) ani! Ino] thiazole, 40 ml of methyl iodide and 40 ml of ethanol are heated at 50 ° C for 24 hours. The procedure similar to that in Example 1 (1) leads to 5.2 g

15 3-Methyl-2- [3-chloro-4- (l-diethoxycarbonylethyl) anilino] thiazolium iodide. After recrystallization from ethanol, crystals with F at 192 to 193 ° C. are obtained.

IR v m "* 'cm" 1 1743, 1720.

Analysis for: C18H2204N2SC1I

20 calc .: C 41.19 H 4.23 N 5.34 S 6.11 Cl 6.76 I 24.18 found: C 41.20 H 4.15 N 5.29 S 5.99 CI 6, 56 I 24.11

(2) A suspension of 8.8 g of the product obtained in methylene chloride is washed with 20% aqueous potassium carbonate solution. The solution is then washed with water, dried over potassium carbonate and evaporated to remove the methylene chloride. The residue is then subjected to alumina column chromatography and eluted with benzene. After evaporation of the solution

This gives 6.3 g of diethyl 2-methyl-2- [2-chloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] malonate with a 94.5% yield.

25th

IR v ccu cm-1 1733, 1615.

(3) To 5.6 g of the above product, 30 ml of ethanol and 30 ml of 20% aqueous potassium hydroxide solution are added. This solution is then kept at room temperature for one hour and evaporated. The residue is neutralized and adjusted to pH 5 with hydrochloric acid and extracted with ether. The extract is washed with water, dried over magnesium sulfate and evaporated. 5.0 g of the resulting residue are crystallized from acetone / hexane and 4.4 g of crystals are obtained, which is in 86% yield, with F from 132 to 133 ° C.

IR v Säx'cm_1 2450, 1900 (broad), 1718, 1608.

Analysis for: C ^ H ^ OoNoSCl calc .: C 54.10 H 4.86 N 9.01 S 10.32 Cl 11.41 found: C 54.38 H 4.84 N 8.95 S 10.38 Cl 11.40

Example 5

(1) A mixture of 11.1 g of ethyl 2- [3-fluoro-4- (N-thiazol-2-yIamino) phenyl] propionate, 44.5 ml of methyl iodide and 44.5 ml of ethanol is added at 50 to 55 ° C heated for 48 hours. The resulting mixture is treated in the manner described in Examples 1 and 2 and 6.8 g of ethyl 2- [3-fluoro-4- (3-methyl-4-thiazolin-2-ylideneamino) phenyl are obtained ] propionate. The yield was 58.5%.

IR v ™ x 1730> 1620 '1600-

(2) 6.8 g of the product thus obtained are hydrolyzed in the manner described in Example 1 (3) and he (3) 6.3 g of the product obtained are in a mixture of 33 ml of ethanol, 33 ml of a 20th % aqueous potassium hydroxide solution. The solution is then kept at room temperature for 16 hours, the ethanol is then evaporated and the resulting solution is adjusted to pH 6 with hydrochloric acid and evaporated to dryness under reduced pressure. 40 The residue thus obtained is extracted with hot acetone and after evaporation of the acetone, a residue of 2-methyl-2- [2-chloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] is obtained. malonic acid, which decomposes at 90 ° C. This residue is then heated on a water bath for 45 minutes and a dilute aqueous sodium bicarbonate solution is added to the residue. The solution is then washed with chloroform and then with ether, treated with activated carbon, brought to pH 6 with hydrochloric acid and evaporated to dryness. The resulting residue is then extracted with hot acetone and this is then evaporated. The residue is recrystallized from 10% ethanol / acetone and 3.4 g of 2- [2-chloro-4- (3-methyl-4-thiazolin-2-ylideneamino) phenyl] propionic acid with F at 215 are finally obtained up to 220 ° C (dec.). 55 IR v £ äo1 cm l 2775, 2450, 2000-1900 (wide), 1730, 1715, 1610.

Analysis for: C13H1I302N2SC1

calc .: C 52.61 H 4.42 N 9.44 S 10.80 Cl 11.95 found: C 52.83 H 4.48 N 9.28 S 10.84 Cl 12.08

60

Example 7

(1) A mixture of 8.9 g of 2- [3-chloro-4- (N-thiazol-2-yl-amino) phenyl] acetate, 44 ml of methyl iodide and 44 ml of ethanol is kept at 50 to 55 ° C for 42 Heated 65 hours with stirring. The ethanol and methyl iodide are evaporated off and the residue is washed with ether and a precipitate is formed on standing at room temperature. The precipitate is mixed with ethyl acetate and

9

621783

afterwards washed with cold acetone and recrystallized from acetone and 6.6 g of 3-methyl-2- [2-chloro-4 - (ethoxycarbonylmethyl) anilino] thiazolium iodide with F at 147 to 148 ° C. are obtained.

(2) A solution of 6.6 g of the product obtained above in methylene chloride is washed three times with 10% aqueous potassium carbonate solution and then dried over potassium carbonate. Evaporation of the solvent gave 4.62 g of ethyl 2- [3-chloro-4- (3-methyl-4-thiazolin-2-ylidenamino) phenyl] acetate and in a 100% yield.

IR v S cnrI 1740> 1620> 1595-

(3) 4.62 g of the above product is hydrolyzed in the manner described in Example 1 (3) and crystals with F at 155 to 158 ° C. are obtained. Recrystallization from ethyl acetate and then from acetone gives 3.48 g of pure desired compound with F at 158 to 159 ° C. The yield was 83.5%.

IRv ^ Jxo12500 (broad), 1700, 1570.

Analysis for: C12HnÒ2N2SCl calc .: C 50.98 ~ H 3.92 N 9.91 S 11.34 Cl 12.54

Found: C 50.98 H 3.97 N 9.71 S 11.31 Cl 12.66

Example 8

(1) A mixture of 12 g of ethyl 2- [3-chloro-4- (N-thiazol-2-yl-amino) phenyl] propionate, 6.1 g of allyl bromide and 25 ml of ethanol is stirred at 70 for 8 days heated to 75 ° C. The ethanol is then evaporated and the residue washed with ether and then dissolved in methylene chloride. The solution obtained is washed with aqueous potassium carbonate solution and dried over potassium carbonate. The methylene chloride is then evaporated off and 12.3 g of an oily residue are obtained. The residue is then acetylated with 48 ml of anhydrous acetic acid with heating at 120 to 125 ° C for three hours. The resulting mixture is dissolved in benzene and extracted with 10% hydrochloric acid. The extract is washed with benzene, alkalized with sodium bicarbonate and then extracted with ether. The residue obtained after evaporating the ether is subjected to column chromatography using silica gel. 3.3 g of ethyl 2- [3-chloro-4- (3-allyl-4-thiazolin-2-ylidenamino) phenyl] propionate are obtained from an eluent of 50% hexane / benzene and hexane / benzene 1: 2 with a yield of 24.5%.

IR v max cm "1 1735, 1610, 1590.

(2) 3.3 g of the above product are hydrolyzed in the manner described in Example 1 (3) to obtain 3.0 g of the desired compound. Recrystallization from ether / hexane gives 2.78 g of pure product with F at 114 to 115 ° C. The yield is 92.5%.

IR v mäx'cnr1 2500 (wide), 1950 (wide), 1720, 1600, 1570, 1550.

Analysis for: Clr, H150oN2SCl calc .: C 55.81 H 4.68 N 8.68 S 9.93 Cl 10.98 found: C 55.94 H 4.69 N 8.72 S 9.90 Cl 11 , 02

Example 9

(1) A mixture of 6.15 g of ethyl 2- (2-anilinothiazol-4-yl) propionate, 17 ml of methyl iodide and 17 ml of ethanol is heated at 100 ° C for 11.5 hours in a sealed tube. The resulting mixture is treated with potassium carbonate in the manner described in Example 1 (2) and, after recrystallization from ether / hexane, 1.6 g of ethyl 2- (2-phenylimino-3-methyl-4-thiazoline) 4-yl) propionate with F from 80 to 81 ° C.

IRv S cm-1 1740.1610.1580.690.

Analysis for: C15HlsO., NS

calc .: C 62.04 ~ H 6.25 N 9.65 S 11.04 found: C 62.20 H 6.24 N 9.70 S 11.03 (2) 1.6 g of the product obtained dissolved in a mixture of 8 ml of 95% ethanol and 8 ml of 20% aqueous potassium hydroxide solution. The solution is kept at room temperature for one hour. After evaporation of ethanol, the residue is dissolved in water, the solution is neutralized with hydrochloric acid and then washed with ether. After adding 405 mg calcium chloride dihydrate, a precipitate is formed. The precipitate is filtered off and washed with water, and 1.56 g of calcium 2- (2-phenylimino-3-methyl-4-thiazolin-4-yl) propionate with F at 152 to 153 ° C. (dec.) Are obtained. .

IR v Sì0'cm- '3300 (wide), 1550 (wide).

Analysis for: (C13HI30., N., S) .2Ca. 3H., 0

calc .: C 50.63 H 5.23 N 9 ^ 08 Ca 6.50 found: C 50.62 H 5.21 N 8.95 Ca 6.54

Note: Carbon dioxide was split off from the carboxy group during elemental analysis.

Example 10

(1) A mixture of 7.0 g of ethyl 2- [2- (4-chlorophenylamino) -4-methylthiazol-5-yl] acetate and 35 ml of methyl iodide is on an oil bath at 40 ° C for Treated for 24 hours with stirring at reflux. After evaporating off methyl iodide, the residue is dissolved in ether / ethyl acetate, a precipitate being formed. The precipitate is filtered off and crystallized from ethanol / ethyl acetate and 2- (4-chlorophenylamino) -3,4-dimethyl-5-ethoxycarbonylmethylthiazolium iodide with F at 163 to 164 ° C. is obtained in 72.5% yield.

Analysis for: Cir, H, s02N2SClI

calc .: C 39.79 H 4.01 N 6.18 S 7.08 Cl 7.83 I 28.03 found: C 39.86 H 4.00 N 6.21 S 6.80 Cl 7.58 I 27.89

(2) 7.4 g of the product obtained is suspended in 50 ml of methylene chloride. The suspension is then treated three times with 20% aqueous potassium carbonate solution and dried over potassium carbonate to give a residue. The residue is subjected to column chromatography using alumina and eluted with benzene. 5.2 g of ethyl 2- [2- (4 - chlorophenylimino) -3,4-dimethvl-4-thiazolin-5-yl] acetate are obtained from the eluent in 98% yield.

IRv S cm-1 1738> 1640 '1600-

(3) To 3.0 g of the above product, 15 ml of a 20% aqueous potassium hydroxide solution and 15 ml of ethanol are added. The solution is kept at room temperature for one hour. After evaporation of ethanol, the solution is adjusted to pH 7 with hydrochloric acid and there are 0.68 g of calcium chloride. dihydrate fed to the solution. After evaporation of the solvent, the residue is extracted with hot ethanol / acetone. Insoluble substances are filtered off and the extract is concentrated to remove ethanol and acetone. The residue is recrystallized from hexane and crystals with F of 186 to 192 ° C. are obtained. The crystals are washed with ether and recrystallized from ether and 1.20 g of calcium 2- [2- (4-chlorophenylimino-3,4-dimethyl-4-thiazolin-5-yl] acetate are obtained in the form of Crystals and with a 38.5% yield.

Analysis for: (ClrH12OaN, SCl) .Ca. 2nd 5H20

calc .: C 46.14 H 4.32 N 8.28 Cl 10.48 Ca 5.92 found: C 46.42 H 4.42 N 8.28 Cl 10.51 Ca 5.53

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

621783

10th

Examples 11 to 25 The following. Compounds are prepared in a manner similar to that described in Examples 1-8.

CH

\ Jt / ^ CHC

HCOOH

Example No.

Xi

Yi

Y2

F (° C)

11

H

4-C1

H

3rd

146-147

12th

H

3-CFa

H

4th

129-132

13

H

2-CH3

3-C1

4th

168-171 (Z)

14

H

2-CF,

H

4th

128-131

15

H

3-OCH3

H

4th

148-151

16

H

2-CH3

H

4th

217-219

17th

H

3-CHs

H

4th

HCl 198-201

18th

H

2-F

H

4th

155-157

19th

4-CH3

H

H

4th

150-156 (Z)

20th

4-CH3

3-C1

H

4th

126-130 (Z)

21st

4-CH3

3-F

H

4th

135-136

22

4-CH3

2-F

H

4th

Approx. 2H, 0 202-204

23

4-CH, 3

3-CHa

H

4th

123-126

24th

4-CH3

3-C1

5-C1

4th

198-201

25th

4-CH3

2-CH3

H

4th

147-149

*: The position of the benzene ring, substituted by the 4-thiazolin-2-ylidenamino group.

Z: decompose.

Ca: calcium salt.

H2O: hydrate.

HCl: hydrochloride.

Examples 26 to 29 The following compounds are prepared using procedures similar to those described in Examples 9 and 10.

55

60

65

PS

CHCOOH

Example No.

Y!

F (° C)

26

2-F

Ca.4H.O 175-178

27th

4-C1

Approx. 2H20 163-166

28

H

Approx. H20 131-135

29

3-CH3

Approx. H, 0 165-168

Ca: calcium salt. H2O: hydrate.

v

Claims (5)

621783 2nd PATENT CLAIMS 1. Process for the preparation of new thiazoline derivatives of the formula F1 -C-COOR i Z -H characterized in that according to the method of claim 1, the compound of formula - C - COOR I Z ' (I) 10 (I) - H wherein X1 is hydrogen or methyl, Y1 and Y2 any hydrogen, halogen, Ci_3-alkyl, C1.3-alkoxy or trifluoromethyl, Rj hydrogen, methyl or ethyl, R2 C. ^ .- alkyl or C., _ 5-AlkenyI, R. Ester residue and Z is hydrogen, carboxy or a carboxyester residue, and their pharmaceutically acceptable salts, characterized in that a compound of the formula *1 -C-COOR -H 15 produces in which Z 'is a carboxy or carboxyester residue, and then hydrolyzed and decarboxylated. 3. A process for the preparation of a compound of formula IV, characterized in that after the 20 drive of claim 1 a connection of. Formula I, in which Z is hydrogen and R is an ester radical, and then hydrolyses them. 4. The method according to claim 1, characterized in that the quaternization with a C ^ -Al- 25 alkyl or C3.0 alkenyl halide, a corresponding aromatic sulfonic acid alkyl ester or a corresponding dialkyl sulfate. 5. The method according to claim 1, characterized in that the quaternization at a temperature (III) 30 from room temperature to 150 ° C. 6. The method according to claim 1, characterized in that the weak acid eliminating agent is an alkali metal carbonate, an alkali metal bicarbonate or ammonia. 35 wherein X ,, Y ,, Y2, R ,, R and Z have the above meaning, quaternized accordingly and then the ammonium salt of the formula thus obtained -C-COOR I. e.g. -H