CS262700B2

CS262700B2 - Process for preparing new derivative of 1h,3h-pyrrolo-/1,2-c/thiazole

Info

Publication number: CS262700B2
Application number: CS88215A
Authority: CS
Inventors: Jean Louis Fabre; Claude James; Daniel Lave
Original assignee: Rhone Poulenc Sante
Priority date: 1987-07-02
Filing date: 1988-01-12
Publication date: 1989-03-14
Also published as: CS21588A2

Abstract

Způsob výroby nového derivátu lH,3H-pyrrolo(l,2-c)thiazolu vzorce I, jakož i adičních solí této látky s kyselinami, přijatelnými z farmaceutického hlediska tak, že se uvede do reakce reakční produkt p-toluensulfonylchloridu, triethylaminu a kyseliny vzorce II s reakčním produktem triethylaminu a sloučeniny vzorce III, získaný produkt se izoluje a popřípadě se převede na svou adiční sůl s kyselinou, přijatelnou z farmaceutického hlediska. Derivát je vhodný k léčebným účelům v případech, kdy je třeba vytlačit PAF-acetether z míst jeho vazby.A method for producing a novel 1H, 3H-pyrrolo (1,2-c) thiazole derivative of formula I as well as addition salts salts of this compound with acids acceptable from pharmaceutical aspect, by mentioning it the reaction product of p-toluenesulfonyl chloride into the reaction, triethylamine and the acids of formula II with the reaction product of triethylamine and the compound of formula III, the product obtained is isolated and, optionally, is converted to its addition a salt with a pharmaceutically acceptable acid viewpoint. The derivative is suitable for therapeutic purposes in where it is necessary to displace PAF-acetether from his ties.

Description

282700

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of a novel 1 H, 3 H -pyrrolo [1,2-c] thiazole derivative of formula I, QNH ........ -CG "'*' «« I

Zví (0

According to the process of the invention, it is possible to obtain this by reacting the reaction product of p-toluenesulfonyl chloride, triethylamine and the acid of the formula II i.

with the reaction product of triethylamine and compounds of formula III

C 1 CH 3 CH-CONH

The process is usually carried out in an organic solvent medium such as 1,2-dichloroethane or methylene chloride at a temperature of 20 ° C to the reflux temperature of the reaction mixture.

The compound of formula (III) can be obtained by the application or adaptation of methods known from the literature, in particular by treatment with 2,3-dichloropropionyl chloride to 3-aminobenzophenone, the process being carried out in toluene at a temperature between 20 ° C and the reflux temperature of the reaction mixture .

The acid of formula (II) can be obtained by treatment of formic acid with acetic anhydride to give formula IV acid.

followed by dextrorotation in a conventional manner, for example by recrystallization and / or salt formation with optically active bases, for example α-methylbenzylamine, whereupon the salts are isolated and the corresponding acid is liberated.

The new compound of formula (I) can be converted into its acid addition salts by treatment with an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. Usually, the salt obtained precipitates, usually after concentration of the solvent, and can then be separated by filtration or decantation.

The novel compound of the invention and its addition salts have very interesting pharmacological properties which are currently associated with very low toxicity of these compounds.

The compound of formula (I) is effective at inhibitory concentrations (CI50) already in the amount of 1 to 1000 nM in the [3 H] -l-octadecyl-O-2-acetyl-3-ns-glyceirophosphorylcholine (Tritiated Acetone) Fixation Assay at Reception Sites blood platelets. The experiment is performed as follows: a) Preparation of washed rabbit plates

Male New Zealand rabbits (hybrid 2,000) with an average weight of 2.5 kg are used to try. Blood was collected from the ear using 1.9 mM citric acid, 9 mM sodium citrate, 1.75 mM disodium phosphate and 5.6 mM dextrose. The collected blood is centrifuged at 120 g for 20 minutes at 15 ° C. In this way, blood plasma is obtained, a rich platelet (PRP). This plasma was further centrifuged at 1000 g for 15 minutes at 15 ° C. The platelet deposit obtained in this way was first washed with a modified Tyrode solution containing 0.35% bovine serum albumin (BSA), 2 mM magnesium chloride in 1 liter, 0.2 mM 3,12-bis (carboxymethyl) -6,9 -dioxa-3,12-di-azatetradecandioate (hereinafter EGTA) per liter then Tyrode's solution without EGTA. At the end, the platelets are re-dosed in the assay buffer (buffer A) with the following composition: 140 mM NaCl, 2.7 mM KCl, 0.4 mM NaH 2 PO 2, 2 mM MgCl 2, 12 mM NaHCO 3, 10 mM tris buffer with hydrochloric acid, 6.2 mM dextrose and 0.25 ® / o bovine serum albumin. The final platelet concentration in the suspension is adjusted to 4 x 10 8 platelets / ml using the same buffer. b) Performing the experiment itself

Buffer A, tritiated with α-cetether (0.5 mmol, specific activity 296.101ϋ mmol / l, and plate obtained at 0.5x10 8 in the above manner) was added to a 5 ml tube and the final volume was 0. 5 ml, then incubated for 1 hour at 282700

20 ° C. After this time, 2 ml of buffer A, cooled to 4 ° C, was added and the assay contents were quickly filtered through a WhatmanGP / C filter (trademark) and the tube was washed three times with 2 ml of buffer A cooled to temperature 4 ° C. The filter is placed in a scintillation flask containing 4.5 ml scintillation fluid [Ready Solv, MP (ND Beckman)] and radioactivity with a universal computer (RACK BETA 1218 LKB). Total binding radioactivity is determined in this way. The specific fixation of the tritiated PAF-acetetheir is determined by distinguishing the total bound radioactivity and the radioactivity remaining on the filter by addition of 10 µ- (3-methoxyphenyl) -2- (3-pyridyl) -1H, 3H -pyrrolo [1,2-c] -7-thiazolecarboxamide. For each study product, this experiment was repeated three times at increasing concentrations ranging from 10-1 ° to 10 -4. By reading the above values, the C 50 for each product of the log probit inhibition curve can be graphically determined.

PAF-acetether is known to play a large role in a large number of diseases and a variety of conditions such as allergic reactions (bronchial asthma and bronchitis), as well as inflammatory reactions of gastric and intestinal mucosa of various origins and especially inflammatory reactions after irradiation and after endotoxin shock, as well as problems associated with disorders in platelet aggregation. This substance, which is released in the course of the aforementioned conditions, is fixed to its specific receptors. The above test for the amount of substance that binds to platelet receptors is a model piece that can be used to study the affinity of various products for fixation to those receptors.

The compound obtained by the method of the invention is able to displace PAF-acetether to remove its bonds. Thus, it comes into contact with said substance and is capable of antagonizing its effects. Therefore, the compound obtained by the method of the invention can be expected to play a role in the treatment of the above disorders and diseases.

The concentration of CI 50 in nM for the compound of the present invention was 0.93 when used in solution in hydrochloric acid. Pyrrolothiazole derivatives having a certain inhibitory capacity as described above have already been described in European Patent Specification No. 0 115 979, but the compound of the invention is fixed to receptors in blood platelets at much lower concentrations and is therefore to use the inhibition of the above-mentioned diseases and diseases without risk.

Furthermore, the compound obtainable by the process of the invention has very low toxicity. Its DL50 is greater than 300 mg / kg by oral administration in mice.

For therapeutic use, a compound of formula (I) may be used as such or in the form of non-toxic pharmaceutically acceptable salts.

Among the pharmaceutically acceptable salts, there may be mentioned inorganic acid addition salts such as hydrochlorides, sulfates, nitrates, phosphates or salts with organic acids, for example acetates, propionates, succinates, benzoates, fumarates, maleate, methanesulfonate, isothioate, thiophyl acetate, salicylate, phenophthalene, methylene bis-1 (3-oxynaftoate, or substitution derivatives thereof). , potassium non-lithium, alkaline earth salts, for example calcium or magnesium, and addition salts with organic bases, for example ethanol-lignin or lysine.

The invention is illustrated by the following example. Example To a suspension of 14.3 g of N-foil-methyl-2- (3-pyridyl) -4- (2R, 4R) -thiazolidinecarboxylic acid in 60 ml of 1,2-dichloroethane at a temperature of 20 to 27 min. 6.7 g of triethylamine are added. The suspension obtained is stirred for 20 minutes at a temperature in the region of 20 DEG C., and the resulting solution is stirred for a further 1 hour at a temperature in the range of 22 DEG-26 DEG C. and then added to the solution of 12.6 g of p-toluenesulfonyl chloride in 70 ml at this temperature. 1,2-dichloroethane. In this way, a fine suspension (suspension A) is collected. A solution of 19.3 g of N- (3-benzoylphenyl) -2,3-dichloropropionamide in 100 ml of 1,2-dichloroethane was added to 20 g of triethylamine over a period of 15 minutes at 20-30 ° C . This gives a suspension (suspension B) which is stirred at about 20 ° C for 16 hours. Then, suspension A, prepared in the previous step, is added to the suspension B over a period of 10 minutes at a temperature between 22 and 40 ° C. A new suspension is obtained which is heated to about 86 ° C for 1 hour. Then the suspension is cooled to about 20 ° C and the reaction mixture is washed three times with a total of 600 billion distilled water.

The organic phase is separated, dried over anhydrous magnesium sulphate, 0.5 g of decolorizing charcoal is added, the mixture is filtered and the filtrate is evaporated to dryness under reduced pressure of 2.7 kPa at a temperature of about 60 ° C. 29.3 g of product are obtained, which product is dissolved in 500 ml of ethyl acetate. The solution obtained is treated with 0.5 g of decolorizing active charcoal and 30 g of silica with an average particle diameter of 0.020 to 0.045 mm, filtered and the filtrate is evaporated to dryness under reduced pressure (2.7 kPa).

Claims

2S2700 temperature about 60 ° C. 25.5 g of crude product are obtained in this way, which is dissolved in 130 ml of boiling ethanol / 85: 15 water. 0.5 g of decolorizing active carbon is added and the mixture is filtered while hot. The filtrate was cooled to about 20 ° C for 16 hours. Crystals are formed, separated by filtration, washed twice with a total of 60 ml of ethanol / water 85:15 and then three times with 150 ml of diethyl ether and dried under reduced pressure at 2.7 kPa. at about 20 ° C, the presence of potassium hydroxide in the form of a pellet. 13.75 g of (+) - N- (3-benzoylphenyl) -3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] -7-thiazolecarboxamide are obtained in the form of a hydrate. a cream-colored crystalline substance with a melting point of 110 ° C. Optical Rotation [.alpha.] D @ 20 = + 88.2 DEG + 1 DEG (c = 1.02, dimethylformamide). N-Formyl-2- (3-pyridyl) -4- (2R, 4R) -thiazolidinecarbonylic acid can be obtained as follows: To 420 ml of formic acid at a temperature of about 10 ° C over a period of 25 minutes. to 340 g of acetic anhydride. The resulting solution was stirred at about 10 ° C for 30 minutes and then, at 50 ° C, a total of 233 g of 2- (3-pyridyl) -4- (2R, 4R) acid was added over about 50 minutes. thiazolidinecarboxylate. The solution was stirred at about 10 ° C for 30 minutes and stirred for 16 hours at about 20 ° C. Then the solvent is evaporated off from a reduced pressure of 2.7 kPa at a temperature of about 60 ° C. The residue obtained is suspended in 2,600 ml of boiling ethanol. The resulting suspension is cooled to about 4 ° C for 2 hours. Crystals are formed, separated by filtration, washed twice with a total of 530 ml of ethanol, cooled to about 4 DEG C. and then dried in the air. 245 g of product with a melting point of 230 DEG C. are obtained. 60 g of this product are dissolved in 540 ml of 50% aqueous ethanol at boiling point. The resulting solution is cooled to about 10 ° C for 2 hours. Crystals are formed which are separated by filtration, washed three times with a total of 300 ml of ethanol and then three times more with 450 ml of diethyl ether, and then dried under reduced pressure (2.7 kPa) at approximately 20 DEG C. in the presence of potassium hydroxide in the form of potassium hydroxide. pellets. 48.2 g of N-formyl-2- (3-pyridyl) -4- (2R, 4R) -thiazolidinecarboxylic acid are thus obtained in the form of a white crystalline substance with a melting point of 250 ° C. Optical Rotation [α] D 20 - +100 0 + 1 ° (c = 1.37, 1N sodium hydroxide). N- (3-benzoylphenyl) -2,3-dichloropropionamide can be obtained as follows: A solution of 29.6 g of 3-aminobenzophenone in 40 ml of toluene is added over a period of 20 minutes to a temperature of 60 to 105 ° C. a solution of 24.2 g of 2,3-dichloropropionyl chloride in 80 ml of toluene. The resulting solution was heated to about 110 ° C for three hours, then stirred at about 20 ° C for 16 hours. The solvent was then evaporated under reduced pressure (2.7 kPa) at a temperature of about 60 ° C. The residue obtained is dissolved in 250 ml of boiling isopropyl oxide. The resulting solution was cooled to approximately 20 ° C for 16 hours. Crystals are formed which are separated by filtration, washed three times with a total of 300 ml of isopropyl oxide and dried under reduced pressure (2.7 kPa) to approximately 20 DEG C. in the presence of potassium hydroxide pellets. 38.9 g of N- (3-benzoylphenyl) -1,3-dichloropropionamide are thus obtained in the form of creme-colored crystals with a melting point of 92 ° C. 3-aminobenzophenone can be obtained as described by R. Geigy and W. Koenigs, Ber., 18, 2400 (1885). DETAILED DESCRIPTION OF THE INVENTION The process for the preparation of the novel 1H, 3H-pyrrolo [1,2-c] thiazole derivative of the formula I is CQNH M- j.

with the reaction product of triethylamine and the compounds of formula III (1) -CH-CO 2 11 -CO-C & with a pharmaceutically acceptable acidic reaction product comprising reacting the reaction product of p-toluenesulfonyl chloride, triethylamine and the acid of formula II with the product obtained is isolated and optionally converted to its addition salt with pharmaceutically acceptable. Severografia, n. P. Plant 7, Most Price 2,40 Kcs