FI79325B - FOR EXAMINATION OF THERAPEUTIC CONTAINING THERAPEUTIC ANVAENDBARA 6- (3-PYRIDYL-1,2-DIHYDRO-4H-PYRROLO / 1,2-C / 1,3-THIAZINE-8-CARBOXAMIDDERIVAT). - Google Patents

Description

1 79325

Process for the preparation of new therapeutically useful 6- (3-pyridyl) -1,2-dihydro-4H-pyrrolo [1,2-c] -1,3-thiazine-8-carboxamide derivatives 5 Separated from application 845064

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

10 CO-NHR

15 and their acid addition salts. The compounds of formula (I) and their acid addition salts are useful as medicaments.

In the general formula (I), R is an unsubstituted straight-chain or branched alkyl group or a phenyl group having 1 to 4 carbon atoms.

Compounds (I) may be prepared according to the invention; by reacting an N-substituted propiolamide of the general formula HC = C-CONHR (II) in which R is as defined above with N-Nicotinyl-3,4,5,6-tetrahydro-1,3 (2H ) -thiazine-4-carboxylic acid of formula

^ \ ^ C00H

(III) 2 79325

In general, the reaction is carried out in acetic anhydride by heating at 80 to 130 ° C.

Compounds of general formula (II) may be prepared using and applying the method described by W.D. CROW and N.J. LEONARD, J. Org. Chem.

30, 2660 (1965).

Compounds of formula (III) may be prepared by condensing a compound of the general formula ^ -COX '(IV) wherein X' is a hydrogen atom or forming a mixed anhydride with the radical to which it is attached. the general formula is

f N-COOR

I ° (V)

20 S ^ NH

wherein Rq is a hydrogen atom or an alkyl radical, followed by hydrolysis if Rq is an alkyl radical.

Condensation of a compound of general formula (IV) with a compound of general formula (V) is generally carried out in an inert organic solvent such as chloroform in the presence of an acid acceptor such as triethylamine at a temperature of 0 to 65 ° C.

Compounds of general formula (V) may be prepared using or applying the methods described by J.C. WRISTON and C.G. Mc KENZIE, J. Biol. Chem., 225, 607 (1957) or S. WOLFF, G. MILITELLO et al., Tet. Letters, 3913 (1979) or R.L. JOHNSON, E.E. SMISSMAN and N.P. PLOTNIKOFF, J. Med. Chem., 21, 165 (1978).

The novel compounds of general formula (I) can be purified by conventional methods, for example by crystallization, chromatography or successive extractions in an acidic and basic medium.

The compounds of general formula (I) may be converted into acid addition salts with an acid in an organic solvent such as an alcohol, ketone, ether or chlorinated solvent. The salt formed precipitates, possibly after concentration of the solution; it is separated by filtration or decantation.

The novel compounds of general formula (I) have interesting pharmacological properties which make them useful in the therapeutic and prophylactic treatment of thrombotic diseases. They are effective in mice at doses less than 100 mg / kg orally in the serum thromboxane A2 formation assay R.J. FLOWER et al. as measured by technique (Brit. J. Pharmacol. 74, (4) 791 P (1981)).

In addition, the novel compounds of general formula (I) and their salts have low toxicity. The LD50 of Nii-20 den is generally 300-900 mg / kg orally when administered to mice.

As medicaments, the novel compounds of the general formula (I) can be used as such or in the form of pharmaceutically acceptable salts, i.e. non-toxic dosages. Examples of pharmaceutically acceptable salts include addition salts with inorganic acids such as hydrochlorides, sulphates, nitrates, phosphates or with organic acids such as acetates, propionates, succinates, benzoates, fumarates, malates, fattyates, methanesulphonates, methanesulphonates. , salicylates, phenolphthalates, methylene bis-p * oxynaphthoates and substituted derivatives thereof.

The following examples illustrate the invention: 4,79325

Example 1

A suspension of 27.3 g of N-nicotinyl-3,4,5,6-3 tetrahydro-1,3 (2H) thiazine-4-carboxylic acid in 250 cm of acetic anhydride is heated to about 95 ° C. mode. To the resulting solution is added over 15 minutes a solution of 18 g of N-methylpropiolamide in 190 cin of acetic anhydride and the temperature is maintained at about 95 ° C. Keep at this temperature for another 1 hour. This gives a suspension. This suspension is cooled to about 4 ° C for 1 hour.

The crystals formed are filtered off, washed 3 times with a total of 20 cm of acetic anhydride cooled to about 4 ° C and 3 times with a total of 3 60 cm of diethyl ether, then dried under reduced pressure (20 mm of mercury; 2.7 kPa) at about 20 ° C in the presence of crystalline KOH. This gives 12 g of compound which melts at 245 ° C. This compound is dissolved in 3,200 cm of boiling 1-butanol. 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 twice with a total of 20 cm of 1-butanol cooled to about 4 [deg.] C. and 4 times with a total of 200 cm of diethyl ether, then dried under reduced pressure (20 mm of mercury, 2.7 kPa) for approx. At 20 ° C in the presence of crystalline KOH. 10.5 g of N-methyl-6- (3-pyridyl) -1,2-dihydro-4H-pyrrolo [1,2-d] 1,3-thiazine-8-carboxamide are thus obtained in the form of yellow crystals: melting at 248 ° C N-nicotinyl-3,4,5,6-tetrahydro-1,3 (2H) thiazine-4-carboxylic acid is prepared as described in EP-pa-30 Patent Publication No. 0 118 321.

N-methylpropiolamide is prepared by W.D. CROW and N.J. According to LEONARD, J. Org. Chem. 30, 2660 (1965). Example 2

To a solution of 16.2 g of N-nicotinyl-3,4,5,6-3,35 tetrahydro-1,3 (2H) thiazine-4-carboxylic acid in 160 cm of 5 79325 acetic anhydride is added over a period of 2 minutes about 85 ° At C, a solution of 14 g of N-phenylpropol-3-amide in 60 cm of acetic anhydride. The solution obtained is heated at a temperature in the region of 85 ° C for 1 hour, then the solvent is evaporated off under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 70 ° C. The residual oil 3 is suspended in 310 cm of a mixture of 0.4N aqueous NaOH solution 3a. The mixture obtained is extracted 3 times with a total of 750 cm of ethyl acetate. The organic extracts are combined, washed twice with 3 × 4 cm of distilled water, dried over anhydrous magnesium sulphate, 0.5 g of activated carbon are added, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at about 50 ° C: n temperature. 23.5 g of compound are thus obtained, which is chromatographed on a 6 cm diameter column containing 480 g of silica gel (0.04-0.063 mm). Elute with a mixture of ethyl acetate and cyclohexane (80-20 by volume) at a pressure of 0.5 bar 3 and collect 200 cm fractions. The first 8 fractions are discarded. The next 6 fractions of compound-20 are concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. This gives 5.8 g of compound. The next 7 fractions are combined, concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. This gives 4.2 g of the compound 25, which is rechromatographed on a 6 cm diameter column containing 480 g of silica gel (0.04-0.063 mm). Elute with a mixture of ethyl acetate and cyclohexane (80-20 by volume) at a pressure of 0.5 bar and collect 200 cm fractions. The first 8 fractions are discarded, the next 4 fractions are combined, concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 50 ° C. 1.8 g of compound are thus obtained, which is added to 5.8 g of the compound obtained above and 0.5 g of the compound prepared in the same manner as before; this whole batch is dissolved in 100 cm of 6 79325 boiling isopropanol. To the resulting solution is added 0.5 g of activated carbon and filtered hot. The filtrate is cooled to about 4 ° C for 30 minutes. The crystals formed 3 are filtered off, washed twice with a total of 20 cm of isopropanol cooled to about 4 [deg.] C. and 3 times with a total of 60 cm of isopropyl oxide, then dried under reduced pressure (20 mm of mercury; 2.7 kPa) for about 20 minutes. ° C in the presence of KOH crystals. 4.6 g of N-phenyl-6- (3-pyridyl) -1,2-dihydro-4H-pyrrolo [1,2-c] 1,3-thiazine-8-carboxamide are obtained in the form of orange crystals, melting at 160 ° C. :in.

N-nicotinyl-3,4,5,6-tetrahydro-1,3 (2H) thiazine-4-carboxylic acid is prepared as described in EP 0 118 321.

N-phenylpropiolamide can be prepared as follows:

To a solution of 28 g of propargyl acid in 170 cm of anhydrous tetrahydrofuran is added over 20 minutes at a temperature of about 4 ° C a solution of 82.4 g of dicyclohexylcarbodiimide in 170 cm of anhydrous tetrahydrofuran and the resulting the suspension is stirred for 30 minutes at a temperature of about 4 ° C. A solution of 37.9 g of aniline in anhydrous tetrahydrofuran is then added over 25 minutes and maintained at the same temperature, and the suspension is stirred at about 4 ° C for 1 hour, then at about 20 ° C for 16 hours. The crystals are filtered off, washed 3 times with a total of 90 cm of tetrahydrofuran and discarded. The filtrate is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. The remaining oil is dissolved in 350 cm of methylene chloride. The solution obtained is washed 5 times with a total of 400 g of 1N aqueous hydrochloric acid, 3 times with a total of 300 cm of distilled water, 5 times with a total of 400 cm of 1N aqueous NaOH solution and 5 times with a total of 300 cm of 500 cm distilled water, dried over anhydrous 7 79325 magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 63 g of compound are thus obtained, which is chromatographed on a column 5.3 cm in diameter containing 600 g of silica gel (0.063-0.2 mm), eluting with methylene chloride and collecting 1 liter fractions. The first 2 fractions are discarded. The next 8 fractions are combined, concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 40 ° C. 24.5 g of compound are thus obtained, which is dissolved in 3 75 cm of boiling carbon tetraclond. The resulting solution is cooled to about 4 ° C for 1 hour. The crystals formed are filtered off, washed 3 times with a total of 25 cm of carbon tetrachloride cooled to about 4 [deg.] C. and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature of about 20 [deg.] C. in the presence of KOH crystals. 20 g of N-phenylpropiolamide are thus obtained in the form of yellowish crystals which melt at 86 ° C.

Claims (1)

A process for the preparation of new therapeutically useful 6- (3-pyridyl) -1,2-dihydro-4H-pyrrolo [2,2-c7-1,3-thiazine-5-n-8-carboxamide derivatives of the general formula ( I) CONHR 0-10 λ 'wherein R is an unsubstituted, straight-chain or branched alkyl group or phenyl group having 1 to 4 carbon atoms, and for the preparation of their acid addition salts, characterized in that the N-substituted propiolamide of general formula (II) H-C = C-CONHR (II) 2 O in which R is as defined above is reacted with N-nicotinyl-3,4,5,6-tetrahydro-1,3 (2H) -thiazine-4-carboxylic acid, of the formula (III) wherein the compound thus obtained is isolated and, if desired, converted into an acid addition salt.