FI78482C - Process for preparing a new therapeutically useful (6- (3-pyridyl) -1,2-dihydro-4H-pyrrolo / 1,2-c / -1,3-thiazine-8-carboxyamide - Google Patents

Description

A process for the preparation of a novel therapeutically useful (6- (3-pyridyl) -1,2-dihydro-4H-pyrrolo [1,2-c] -1,3-thiazine-8-carboxamide i 73482 76578)

The present invention relates to a process for the preparation of a novel (6- (3-pyridyl) -1,2-dihydro-4H-pyrrolo [1,2-c] -1,3-thiazine-8-carboxamide of formula I

10 conh2

is \ = J

The invention also relates to a process for the preparation of acid addition salts of a compound of formula I.

The new compound of general formula I and its salts have interesting pharmacological properties which make them useful in the treatment and prevention of thrombosis.

The compound of formula I is prepared by condensing 2-chloroacrylamide of formula III

Cl O

I II

CH2 = C-CNH2 III

With N-nicotinyl-3,4,5,6-tetrahydro-2H-1,3-thiazine-4-carboxylic acid of formula II

30 ^ χ / COOH

S N n-n II

After which the compound thus obtained is isolated and, if desired, converted into an acid addition salt.

2 78482

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

The novel compound of formula (I) may be purified by conventional known methods, for example by crystallization, chromatography or successive extractions in an acidic and basic environment.

The novel compound of formula (I) may be converted into acid addition salts in an organic solvent such as an alcohol, ketone, ether or chlorinated solvent.

10 The salt formed precipitates, possibly by concentration from solution; it is separated by decantation or filtration.

Examples of pharmaceutically acceptable salts include addition salts with inorganic acids such as hydrochlorides, sulfates, nitrates, phosphates or with organic acids such as acetates, propionates, succinates, benzoates, fumarates, malates, methanesulfonates, isothesulfonates, isothesulfonates, isothesulfonates, phenolphthalates, methylene bis-β-oxynaphthoates or substitution derivatives of these compounds.

The novel compound of formula (I) and its salts can be used as medicaments as such or as pharmaceutically acceptable salts, i.e. in non-toxic dosages.

They have been shown to be effective at concentrations below 50 mg / L when measured for their inhibitory activity in an in vitro collagen-induced platelet aggregation assay by the method described by BORN G.V.R. et al. E. Physiol., 168, 178 (1963) J.

In addition, the novel compound of formula (I) and its salts have low toxicity. Their LD50 is generally 200 to 900 mg / kg orally in mice.

Biological Assays The inhibitory effect of a novel compound in an in vitro collagen-induced platelet aggregation assay was determined by the method described in Born, G.V.R. et al., J. Physiol. 168, 178 (1963). In addition, the toxicity of the compound was determined. The following results were obtained: 3 78482

Toxicity (mouse) Collagen induced

D1, -n (mg / kg p.o.) aggregation (rabbit)

Cl50 (mg / l) 300 - 900 2.2 5__

The following example shows how the invention can be implemented in practice.

Example 10 A suspension of 21.5 g of N-nicotinyl-3,4,5,6-tetrahydro- (2H) -1,3-thiazine-4-carboxylic acid and 32 g of 2-3 chloroacrylamide in 250 cm of acetic anhydride, heated to about 75 ° C for 15 minutes, then to about 95 ° C for one hour. The suspension obtained is cooled to about 4 [deg.] C. for one hour and the crystals are filtered off, washed 3 times with a total of 15 cm <3> of acetic anhydride, then 3 times with a total of 45 cm of diethyl ether and dried under reduced pressure (20 mm Hg; 2 .7 kPa) at a temperature of about 20 ° C in the presence of potassium hydroxide in the form of tablets. 16.1 g of compound are thus obtained. This compound is dissolved in 750 cm of distilled water at a temperature of about 45 ° C, then the pH of the resulting solution is adjusted to about 8 by adding sodium bicarbonate. The suspension obtained is cooled to about 4 [deg.] C. for 70 minutes and the crystals are filtered off, washed 3 times with a total of 3,240 cm of distilled water, 3 times with a total of 10 cm 3 of ethanol and 3 times with a total of 30 cm of diethyl ether. and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20 ° C in the presence of potassium hydroxide-30 as tablets. This gives 12.9 g of compound melting at 220 ° C. This compound, combined with 1.3 g of the compound prepared last time, is dissolved in 800 to 3 cm of boiling ethanol. To the resulting solution is added 0.5 g of activated carbon and filtered hot; the filtrate is cooled to about 4 ° C for 1 hour. The crystals formed are filtered off, washed 3 times with a total of 60 g of ethanol cooled to about 4 [deg.] C., then 3 times with a total of 60 cm @ 4 of 78482 diethyl ether and dried under reduced pressure (20 mm Hg; 2.7 kPa) at about 20 [deg.] C. in the presence of potassium hydroxide in the form of tablets. 12.6 g of 6- (3-pyridyl) -1,2-dihydro-4H-pyrrolo [1,2-q] -1,3-thiazine-8-5 carboxamide are thus obtained in the form of white crystals at 220 ° C.

2-Chloroacrylamide can be prepared by S.S. Ivanov and M.M. According to Koton, J. Gen. Chem. USSR., 28, 139, (1959); Chem. Abstr. 52, 12757 d, (1958).

N-nicotinyl-3,4,5,6-tetrahydro-2H-1,3-thiazine-4-10 carboxylic acid can be prepared as follows: A solution of 37.8 g of ethyl N-nicotinyl-3,4,5 The 6-tetrahydro- (2H) -1,3-thiazine-4-carboxylate in a mixture of 80 cm 3 of 5N aqueous sodium hydroxide solution and 80 cm -1 of ethanol is stirred at a temperature in the region of 20 DEG C. for 16 hours. The solvent is then evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 50 ° C. The residue is dissolved in 100 cm of distilled water and the solution obtained is purified by draining through a 4.5 cm diameter column containing 630 g of DOWEX 50 WX-2 (50-100 mesh) 3. Elute with 4000 cm of distilled water, then 1000 with 3 cm of a mixture of water and methanol (50-50 by volume), then with 2000 cm of methanol, then with 2000 cm of distilled water. All corresponding fractions are discarded. The next 6 fractions, obtained by eluting with 2% aqueous pyridine solution, are combined and concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 50 ° C. The residue is dissolved in 150 cm of ethanol and the solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 50 ° C. This is repeated 1 time. The residue 30 finally obtained is dissolved in a mixture of 350 cm of boiling ethanol and water (60-40 by volume). To the resulting solution is added 0.5 g of activated carbon and filtered hot; the filtrate is cooled to about 4 ° C for 1 hour. The crystals formed are filtered off, washed 3 times with a total of 3 to 60 cm of a mixture of ethanol and water (60 to 40 volumes), then 3 times with a total of 60 cm of ethanol and dried under reduced pressure (20 mm Hg; 2.7 kPa) to about 20 ° C at 5 78482 in the presence of potassium hydroxide tablets. 24.2 g of N-nicotinyl-3,4,5,6-tetrahydro- (2H) -1,3-thiazine-4-carboxylic acid are thus obtained in the form of white crystals melting at 214 ° C.

Ethyl N-nicotinyl 3,4,5,6-tetrahydro- (2H) -1,3-thiazine-4-carboxylate can be prepared as follows:

To a suspension of 37.2 g of ethyl 3,4,5,6-tetrahydro- (2H) -1,3-thiazine-4-carboxylate in 350 cm @ 3 of chloro-10 Form is added over a period of 15 minutes about 20 ° To a temperature of 75 g of a mixture of 75 g of triethylamine and 100 cm of chloroform. To the solution thus obtained, 50.4 g of nicotinyl chloride hydrochloride are added over a period of 10 minutes at a temperature in the region of 20 ° C. The reaction mixture is heated to about 65 ° C at 15 hours for 1 hour 45 minutes, then stirred at about 20 ° C for 16 hours. The reaction mixture is washed 3 times with a total of 600 cm of distilled water, then 3 times with a total of 600 cm of saturated aqueous potassium bicarbonate solution, dried over anhydrous magnesium sulphate 20, 0.5 g of activated carbon are added, filtered and concentrated to dryness under reduced pressure (20 mm). Hg (2.7 kPa) at a temperature of about 50 ° C. This gives 52 g of compound. This compound is chromatographed on a 5.2 cm diameter column containing 520 g of silica gel (0.063-0.2 mm) and 500 cm fractions are collected. The first fraction obtained by eluting with a mixture of cyclohexane and ethyl acetate (50-50 by volume) is discarded. 3 subsequent fractions obtained by elution with a mixture of ethyl acetate and cyclohexane (50-50 volumes by 30), the next two fractions obtained by elution with a mixture of ethyl acetate and cyclohexane (70-30 volumes) and the next fraction obtained by elution with ethyl acetate and cyclohexane 80-20 volumes) are combined and concentrated to dryness under reduced pressure 35 (20 mm Hg; 2.7 kPa) at a temperature of about 50 ° C. 37.8 g of ethyl N-nicotinyl-3,4,5,6-tetrahydro- (2H) -1,3-thiazine-4-carboxylate are thus obtained in the form of a yellow oil. / Rf = 0.33; 6 78482 silica gel thin layer chromatography; solvent: ethyl acetate-thiocyclohexane (80-20 by volume).

Ethyl 3,4,5,6-tetrahydro- (2H) -1,3-thiazine-4-carboxylate can be prepared as follows: Saturate for 4 hours at about 20 ° C at 47.7 g 3 , 4,5,6-tetrahydro- (2H) -1,3-thiazine-4-carboxylic acid in 650 cm of ethanol using a stream of dry hydrochloric acid. The suspension is stirred for 3 days at about 20 ° C, then heated with stirring to about 80 ° C at 10 hours for 3 hours and 20 minutes. After cooling the solution to about 4 ° C, the crystals formed 3 are filtered off, washed 3 times with a total of 30 cm of ethanol cooled to about 4 ° C, then 3 times with a total of 120 cm 2 of diethyl ether and dried. Under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20 ° C in the presence of potassium hydroxide in the form of tablets. 37.2 g of ethyl 3,4,5,6- (2H) -1,3-thiazine-4-carboxylate are thus obtained in the form of white crystals, melting at 185 ° C.

3,4,5,6-Tetrahydro- (2H) -1,3-thiazine-4-carboxylic acid can be prepared by J.J. Wriston, Jr., and C.G. Mackenzie, J. Biol. Chem., 225, 607 (1957).

Claims (1)

A process for the preparation of a novel therapeutically useful (6- (3-pyridyl) -1,2-dihydro-4H-pyrrolo [1,3-thiazine-8-carboxamide of the formula I 7 78482 Claim conh2 10 --- 1 - and / or its acid addition salts, characterized in that 2-chloroacrylamide having the formula III-Cl 2 I II CH 2 = C-CNH 2 III is condensed with N-nicotinyl-3,4,5,6-tetrahydro- With 2H-1,3-20-thiazine-4-carboxylic acid of formula II COOH S N- η N 11 25 ^ CO-A ^ after which the compound thus obtained is isolated and, if desired, converted into an acid addition salt.