CS262445B2 - Process for preparing new 1h,3h-pyrrolo/1,2-c/-thiazoles - Google Patents

Abstract

Production method of new 1H, 3H-pyrrolo [1,2- a thiazole derivative of formula I, characterized by by treating with N, N'-carbonyldilimidazole to the acid of formula II, the procedure is as follows carried out in tetrahydrofuran at 20 ° C, after completion of the reaction, the resulting product is isolated and, optionally, is converted to its addition acid salt.

Description

The present invention relates to a process for the preparation of a novel 1H, 3H-pyrrolo [1,2-c] thiazole derivative of the formula I

The compound of formula V can be obtained by formylation of a compound of formula VI

S-y-COOH-1-NH (IV) as well as addition salts thereof. According to the process of the present invention, a compound of formula I can be obtained by treating the acid of formula II with N, Nimid-carbonyldiimidazole.

The process is usually carried out in an inert organic solvent such as tetrahydrofuran or dimethylformamide at 20 ° C.

The compound of formula II can be obtained by hydrolysis of the nitrile of formula III

CN (lil)

The compound of formula III can be obtained by treatment with 2-chloroacrylonitrile of formula IV

CL

OF

CH2 = C

CN (IV) to the compound of formula V.

COOH ^J —N-CHO

The reaction is usually carried out in acetic anhydride by heating to 80-130 ° C.

The formlation can preferably be carried out by treatment with formic acid in acetic anhydride at a temperature of 10 to 25 ° C.

The compound of formula (VI) can be obtained by the method of A. Banashek et al. I. Shchukina, J. Chem. USSR 31, 1374 (1961), Chem. Abstr. 55, 24739 (1961).

The compound of formula (I) may be purified by conventional methods known in the art, for example by crystallization, chromatography or sequential extraction in an acidic and basic medium.

The novel compound of formula (I) may be converted to acid addition salts by treatment with an acid in an organic solvent, for example an alcohol, a ketone, an ether or a chlorinated solvent. The resulting salt precipitates upon optional concentration of the solution and can then be separated by filtration or decantation.

The novel compound obtained by the process of the invention and its acid addition salts have interesting pharmacological properties and at the same time low toxicity. They are effective at concentrations below 50 mg / liter in monitoring the in vitro inhibitory activity against platelet aggregation induced by 1-octadecyl-2-acetyl-3-glycerophosphorylcholine (PAF Acether) as described by GVR Born et al. J. Physiol. 168, 178 (1963).

Toxicity expressed as DL 50 in mice is greater than 900 mg / kg when administered orally.

For therapeutic use, the novel compound of formula I may be used as such or in the form of pharmaceutically acceptable salts, i.e., non-toxic, at the dosages employed.

Among the pharmaceutically acceptable salts, inorganic acid addition salts such as hydrochlorides, sulphates, nitrates and phosphates or salts with organic acids such as acetates, propionates, succinates, benzoates, fumarates, maleates, methanesulfonates, isothionates, theofilinacetates, salicylates , phenolphthaleinates, methylene-bis -? - oxynaphthalates and substitution derivatives thereof.

The invention will be illustrated by the following example:

Example

A solution of 2 g of 3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] -7-thiazolecarboxylic acid and 1.45 g

IV)

232445

N, N'-carbonyldiimidazole in 40 mL of anhydrous tetrahydrofuran was stirred at about 20 ° C for 4 hours. The solution obtained is treated with 0.5 g of activated carbon, filtered and evaporated to dryness under reduced pressure, 2.7 kPa at a temperature of about 45 ° C. The residue is mixed with 100 ml of distilled water and the suspension obtained is stirred at approximately 20 degrees Celsius for a total of 30 minutes. The crystals formed are collected by filtration, washed three times with a total of 60 ml of distilled water and then dried under reduced pressure of 2.7 kPa at a temperature of about 20 ° C in the presence of potassium hydroxide in the form of pellets. 2 g of crude product are obtained. This product was dissolved in boiling isopropanol (35 mL). The solution obtained is cooled to about 4 degrees Celsius for 1 hour. The crystals formed are collected by filtration, washed twice with a total of 20 ml of isopropanol cooled to approximately 4 ° C and then twice with a total of 20 ml of isopropyl oxide and then dried under reduced pressure of 2.7 kPa at a temperature of approximately 10 ° C in the presence potassium hydroxide in the form of pellets. 1.7 g of 7- (1-imidazolylcarbonyl) -3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole are obtained _. in the form of cream colored crystals, m.p. 117 ° C.

3- (3-Pyridyl) -1H, 3H-pyrrolo [1,2-c] -7-thiazolecarboxylic acid can be obtained as follows:

g (3- (3-pyridyl) -1H, 3H-pyrido [1,2-c) -7-thiazolecarbonitrile was added to a solution of 41.7 g of potassium hydroxide in 400 ml of ethylene glycol. The reaction mixture was heated at about 150 degrees Celsius for 6 hours and 30 minutes. After stirring at about 20 ° C for 16 hours, the solvent was evaporated under reduced pressure (0.7 kPa) at about 100 ° C. The residue is dissolved in 380 ml of distilled water. 0.5 g of activated carbon is added to the obtained solution, the mixture is filtered and the filtrate is adjusted to a pH of about 4 by the addition of aqueous hydrochloric acid, maintaining the temperature at about 20 ° C. Crystals are formed which are evaporated by filtration, washed three times with a total of 600 ml of distilled water and then dried under reduced pressure of 2.7 kPa at a temperature of about 20 ° C in the presence of potassium hydroxide in the form of pellets. 49.5 g of crude product having a melting point of 177 DEG C. are obtained. This product was dissolved in 480 µL of boiling ethanol. 0.5 g of charcoal is added to the obtained solution and the mixture is filtered while hot. The filtrate is cooled to about 4 ° C for one hour. Crystals are formed which are collected by filtration, washed three times with a total of 45 ml of ethanol, cooled to about 4 ° C and then three times with a total of 90 ml of diethyl ether, and then dried under reduced pressure of 2.7 kPa at about 20 ° C in the presence of potassium hydroxide in the form of pellets. 36.6 g of 3- (3-pyridyl) -1H, 3H-pyrroloph 1,2-c-7-thiazolecarboxylic acid are thus obtained as cream crystals, m.p. 178 DEG.

3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] -7-thiazolecarbonitrile can be obtained as follows:

A mixture of 249.4 g of 3-formyl-2- (3-pyridyl-4-thiazolidinecarboxylic acid, 457 g of 2-chloroacrylonitrile and 0.2 g of hydroquinone in 1760 ml of acetic anhydride is heated at 110-117 ° C for 70 minutes. The solvent was evaporated under reduced pressure (2.7 kPa) at 50-80 [deg.] C. to give a residue which was mixed with 400 ml of distilled water and the suspension was adjusted to a pH of about 10 by addition of 5N aqueous sodium hydroxide solution. The organic extracts are combined, washed three times with a total of 1500 ml of distilled water, dried over magnesium sulphate, 0.5 g of activated carbon is added, the mixture is filtered and evaporated to dryness. at about 30 DEG C. The residue obtained is dissolved in a mixture of 250 ml of ethyl acetate and 500 ml of a 1.8N aqueous hydrochloric acid solution. It is separated by decantation and extracted twice with a total of 200 ml of distilled water, the aqueous extracts are combined, washed five times with a total of 500 ml of ethyl acetate, 0.5 g of charcoal is added and the mixture is filtered. The filtrate was adjusted to pH 1010 by the addition of 10 N aqueous sodium hydroxide solution at 44 ° C, then extracted three times with a total of 650 mL of ethyl acetate. The organic extracts are combined, washed three times with a total of 450 ml of distilled water, dried over anhydrous magnesium sulphate, 0.5 g of activated carbon are added, the mixture is filtered and evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of about 40 ° C. . 71.2 g of crude product are obtained. This product was dissolved in boiling 2-propanol (150 ml) and 0.5 g of charcoal was added to the obtained solution, and the mixture was filtered hot. The filtrate is cooled to about 4 ° C for one hour. The crystals formed are collected by filtration, washed three times with a total of 30 ml of 2-propanol cooled to about 4 ° C, then three times with a total of 60 ml of isopropyl oxide and then dried under reduced pressure of 2.7 kPa at a temperature of about 20 ° C. the presence of potassium hydroxide in the form of pellets. 44 g of 3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] -7-thiazolecarbonitrile are obtained in the form of ocher-colored crystals, m.p.

3-Formyl-2- (3-pyridyl) -4-thiazolidinecarboxylic acid can be obtained as follows.

250 grams of 2- (3-pyridyl) -4-thiazolidine are added to 1200 ml of formic acid.

202445 carboxylic acid, while maintaining the temperature of the reaction mixture at less than 25 ° C. To the solution thus obtained, 875 g of acetic anhydride are added over 1 hour while maintaining the temperature of the reaction mixture at 10-18 ° C.

After stirring at a temperature in the region of 20 DEG C. for 20 hours, the solvent is evaporated off under reduced pressure (2.7 kPa) at a temperature in the region of 60 DEG C., the residue is treated with 1000 ml of ethanol and heated to boiling for 5 minutes. cool to about 4 ° C for one hour. The crystals formed are separated by filtration, washed three times with a total amount 600 ml of ethanol, then three total 300 ml diethyl ether and then dried under reduced pressure of 2.7 kPa at a temperature of about 20 ° ^C in the presence of potassium hydroxide pellets . 234.5 g of 3-formyl-2- (3-pyridyl) -4-thiazolidinecarboxylic acid are obtained in the form of a cream-colored crystalline substance, m.p. 214 DEG.

2- (3-pyridyl) -4-thiazolidinecarboxylic acid can be obtained as described by A. Banashek et al. I. Shchukina, J. Chem. USSR, 31, 1374 (1961); Chem. Abstr. 55, 24739 (1961).

The compound obtained by the process of the invention can be formulated in free form or in the form of pharmaceutically acceptable addition salts into pharmaceutical compositions containing the compound as such or in admixture with another composition which may also be inert physiologically active. The compositions thus obtained are administered orally, parenterally, rectally or topically.

Solid compositions for oral administration include, in particular, tablets, pills, powders, especially in gelatin capsules or starch wafers, as well as granular products. In these solid compositions, the active ingredient produced by the process of the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica. These compositions may also contain other excipients, for example, glidants, such as magnesium stearate or talc, as well as colorants, as well as coatings, for example dragee lacquers.

Liquid pharmaceutical preparations for oral administration include, in particular, solutions, suspensions, emulsions, syrups and elixirs which also contain inert diluents, for example water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may also contain additional excipients such as diluents, emollients, thickeners, flavoring agents or stabilizing agents.

Sterile compositions for parenteral administration are preferably aqueous or non-aqueous solutions, suspensions or emulsions. As the solvent or medium, water, propylene glycol, vegetable oils, in particular olive oil, organic esters suitable for injection, for example ethyl oleate or other useful organic solvents, can be mentioned.

Compositions of this kind may also contain adjuvants, for example plasticizers, isotonic agents, emulsifiers, dispersants and stabilizing agents. Sterilization of the compositions can be accomplished in several ways, for example, by filtration, incorporation of compositions or agents for sterilization, irradiation, and heating. The compositions may also be prepared as sterile solid compositions which are intended to be reconstituted just prior to use in a sterile injectable medium.

Formulations for rectal administration are in particular suppositories and capsules for use herein containing the active ingredient and other excipients, for example cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Topical formulations are, for example, creams, ointments, emulsions, nasal drops, alcohol solutions and aerosols.

In human medicine, the compound produced by the method of the invention may be used, in particular, for the treatment of allergic and inflammatory diseases and, in general, wherever the physiopathological role of Acetether PAF can be expected.

The doses employed depend on the duration of treatment and are usually in the range of 25 to 100 mg per day when administered orally, intravenously or by inhalation in an adult, the dose may be divided into several individual doses.

In general, the dosage of the active ingredient depends on the age, weight and all other factors which are usually to be considered.

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of a novel 1H, 3H-pyrrolo [1,2-c] thiazole derivative of the formula As well as acid addition salts, characterized in that the acid of formula II is treated with N, N'-carbonyldilmidazole, the process is carried out in tetrahydrofuran at 20 DEG C., after completion of the reaction, the resulting product is isolated and optionally converted to its acid addition salt.