CS262444B2 - Process for preparing new 1h,3h-pyrrolo/1,2-c/-thiazoles - Google Patents

Abstract

Method of production of new lH, 3H-pyrrolo [1,2] - a thiazole derivative of formula (I), by treating with 2-chloroacrylonitrile to a compound of formula III in an anhydride medium acetic acid by heating to v between 80 and 130 ° C, whereupon it is obtained the resulting product is isolated and optionally added converted to its acid addition salt. CN ! ..... N (AND) S 'X'r-CURRENT ..- i ---- N-CHO (lil)

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

as well as addition salts thereof. The process of the present invention provides a compound of formula I by treatment with 2-chloroacrylonitrile of formula II

Cl /

CH2 = C \

CN (II) to the compound of formula III

after optionally concentrating the solution and then separating it 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 less than 50 mg / liter in monitoring the inhibitory activity of in vitro platelet aggregation induced by 1-octadecyl-2-acetyl-3-glycerophosphorylcholine (PAF Acether) according to the method of 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- (3-oxynaphthoates) and substitution derivatives thereof.

The invention will be illustrated by the following example:

Example

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

The compound of formula III can be obtained by formylation of a compound of formula IV

(Vl)

The formulations 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 IV can be obtained as described in A-BANASHEK and Μ. I. SHCHUKINA, J. Chem. U.S.S.R. 31, 1973 (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 can 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 salt formed precipitates

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. 40 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. the phases are 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 is adjusted to a pH of about 10 by adding an aqueous solution of 10N sodium hydroxide at about 4 ° 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 activated carbon 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-thiazolldinecarboxylic acid are added to 1200 ml of formic acid, maintaining the reaction temperature below 25 DEG C. To the solution thus obtained is added 875 g of anhydrides over 1 hour. acetic acid 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 boiled for 5 minutes. cool to about 4 ° C for one hour. Crystals are formed which are collected by filtration, washed three times with a total of 600 ml of ethanol, then three more times with a total of 300 ml of diethyl ether, and then dried under reduced pressure of 2.7 kPa at about 20 degrees Celsius in the presence of potassium pellet. . 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. Benashek and I. I. Shchukina, J. Gen. Chem. USSR, 31, 1374 (1961); Chem. , 24739 h (1961).

The compound obtained by the process of the invention may be formulated in the free form of pharmaceutically acceptable addition salts into pharmaceutical compositions containing the compound as such or in admixture with another composition which may be inert also 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 adjuvants, for example, lubricants, such as magnesium stearate or talc, as well as colorants, as well as coatings, for example, dragées.

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, polyethylene 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.

Formulations for topical administration are, for example, creams, ointments, emulsions, nose 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, where physiopathological roles are expected

Claims (1)

Acetether PAF. The doses employed depend on the duration of the treatment and are usually in the range of 25 to 100 mg per day when administered orally, intravenously or 282444 by inhalation in an adult, the dose may be divided into several unit doses. In general, the dosage of the active ingredient depends on the age, weight and all other factors which are usually to be considered. I will invent the object A process for the preparation of a novel 1H, 3H-pyrrolo [1,2-c] thiazole derivative of the formula I with 4 -COOH -N-CHO'N Jj (III) (I) and its acid addition salts, characterized in that 2-chloro, arylacrylonitrile is treated with a compound of formula II in an acetic anhydride medium by heating to a temperature in the range of 80 to 130 ° C, the resulting product is isolated and optionally converted to its acid addition salt. Severography, n. Race 7, Most Price 2,40 KCs