FI80460B - NYA 3- ELLER 5- (3-PYRIDYL-1H-3H-PYRROLO / 1,2-C / THIAZOL-7-S-ALKYLTHIOCARBOXIMIDATE, VILKA AER MELLANPRODUKT VID FRAMSTAELLNING AV MOTSVARANDE TERAPEUTISKT ANVAENDBARID 7-KARBOXID) - Google Patents

Description

1 80460

Novel 3- or 5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-S-alkylthiocarboximidates which are intermediates in the preparation of the corresponding therapeutically useful 7-carboxamide alkylhydrazone and 7-piperidino-5-carboimidylpyrrole fathers

Separated by division of application 840108

The invention relates to novel orthocondensed pyrrole derivatives having the general formula

^ NH

C

/ \ JC ^ SR- Ϊ I U)

15 1 I

R —- N J-Rx and which, including their salts, are useful as intermediates in the preparation of new drugs.

In the general formula (I), R 2 represents an alkyl radical and a) R is a 3-pyridyl radical and R 1 is a hydrogen atom, or b) R is a hydrogen atom and R 1 is a 3-pyridyl radical.

Compounds of general formula (I) may be prepared by reacting a halide of general formula R2Z (II) wherein R2 is as defined above and Z is a halogen atom, preferably iodine, with a compound of general formula 30 csnh2 Λ [λ (III)

R — 1 N J R

35 wherein R and R 2 are as defined above.

The reaction is generally carried out in an organic solvent such as acetone or a mixture of acetone and dimethylformamide at a temperature of 0 to 50 ° C.

2 80460

Compounds of general formula (III) may be prepared using a compound of general formula as a starting material

ς CN

M

R -N —- J-Rx 10 wherein R and are as defined above by any method known to those skilled in the art for converting a nitrile to a thioamide without otherwise affecting the molecule.

It is particularly preferred to react the nitrile of general formula (IV) with hydrogen sulfide in a solvent such as pyridine in the presence of triethylamine at 0-50 ° C.

Compounds of general formula (IV) in which the symbols have the same meaning as in b), i.e. compounds of the formula 20 l_], _ u_a t (v) 25 can be prepared by reacting 2-chloroacrylonitrile of formula

Cl ch2 = c <^ (VI)

30 ^ CN

react with a compound of general formula

/ \ - COOH

35 '| VI11 R — I-N — COR, where R and R 2 have the same meaning as in b).

3 80460

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

Compounds of general formula (VII) in which R and R 1 have the same meaning as in b) above can be prepared by condensing a compound of general formula R 1 CO 2 q (VIII) in which R 1 has the same meaning as in b) above and Zq is 10. halogen atom or forms a mixed anhydride with the radical R 1 CO-, a compound of the general formula

s \ -COOE

I dx)

R - NH

Wherein R is as defined in b) above and E is a hydrogen atom or an alkyl radical, after which, if E is an alkyl radical, hydrolysis is carried out.

Condensation of a compound of general formula (VIII) with a compound of general formula (IX) 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.

When E is an alkyl radical, the hydrolysis is performed by any method known to those skilled in the art to convert the ester to an acid without affecting the molecule in other respects, especially by heating under time in water or a water-alcoholic solvent such as water and ethanol at 20-80 ° C.

Compounds of general formula (IX) may be prepared using or applying the methods described by H.T. Hagasawa, J.A. Elberling, P.S. Fraser and N.S. Nizuno, J. Med. Chem. 14,501 (1971) or B. Belleau, J. Med. Chem. 2, 553 (1960) or J.C. Wriston et C.G. McKenzie, J.

35 Biol. Chem., 225, 607 (1957) or S. Wolff, G. Militello et al., Tet. Letters, 3913 (1979) or H. Gershon and A. Scala, J. Org. Chem. 26, 2347 (1961) or R. Riemschneider and G.A.

4 80460

Hoyer, Z. Naturforsch. 17 B, 765 (1962) or H. Möhrle and C. Karl, Arch. Pharm. 301, 728 (1968) or R.K. Hill, T.H. Chan and J.A. Joule, Tetrahedron 21, 147 (1965).

Those compounds of general formula (IV) in which the symbols are the same as in a) above can be prepared by condensing a compound of formula (VI) with a compound of formula:

-COOH

10 M (X) N \>

// \\ __ N —CHO

\ - /

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

A compound of general formula (X) can be prepared by formylating a compound of formula:

-COOH

// N __NH (XI) 20 \ - = - /

The formylation can preferably be performed with formic acid in acetic anhydride at 10 to 25 ° C.

The compound of formula (XI) can be prepared by the method described by A. Banashek and M.I. Shchukina, J. Gen. Chem. U.S.S.R. 31 1374 (1961); Chem. Abstr. 55 24739 h (1961).

The novel compounds of the general formula (I) are particularly useful as intermediates in the preparation of therapeutically active compounds of the general formula? V] j, xii) rJ - n - R1

5 8 O 4 6 O

wherein A. R is a 3-pyridyl radical, is a hydrogen atom and W is a radical of the general formula 5 nn <; -c ^ (XIII) ^ h2 wherein R 'and R ", which may be the same or different, represent an alkyl radical, or B. R is a hydrogen atom and R1 is a 3-pyridyl radical and W is a radical of the general formula

Q

(XIV) wherein a2) Q is an imino radical and M is a piperidino radical, or fc> 2) Q is a dialkylhydrazone radical and M is an amino radical.

Compounds of general formula XII as defined in A. above, wherein W is a radical of general formula (XIII) as defined above, are prepared by reacting a hydrazine of general formula R * H2NNH <^ (XV) \ vR1, wherein R 'and R ", which may be the same or different, denote an alkyl radical to react with a compound of general formula (I) in which R 1 is a hydrogen atom and R is a 3-pyridyl radical, i.e. a compound of general formula 6 80460

^ NH

>? ύΥ

The reaction is generally carried out in an organic solvent such as ethanol at 20 to 80 ° C.

Compounds of general formula (IA) may be prepared by reacting a compound of general formula (II) as defined above with a compound of general formula (III) having the same symbols as in a) above.

The reaction is generally carried out in an organic solvent such as acetone or a mixture of acetone and dimethylformamide at 0-50 ° C.

Compounds of general formula (XII) as defined in B. above, in which the radical of general formula (XIV) is such that Q is an imino radical and M is the same as in a2> above, are prepared by reacting piperidine of general formula (I) with a compound having the same meaning as in b) above, i.e. with a compound of the general formula »M '"' J — Ul_ ^ 3

The reaction is generally carried out in an organic solvent such as chloroform in the presence of a weak acid such as acetic acid at 20 to 65 ° C.

The compound of general formula (ID) can be prepared

O

by reacting a compound of general formula (II) with a compound of general formula (III) in which the symbols are the same as in b) above.

The reaction is generally carried out in an organic solvent such as acetone or a mixture of acetone and dimethylformamide at 0-50 ° C.

Compounds of general formula (XII) as defined in B. above, in which the radical of general formula (XIV) is the same as in b2> above, are prepared by reacting a di-10-alkylhydrazine of general formula (XV) as defined above with isenβ ).

The reaction is generally carried out in an organic solvent such as ethanol at 20 to 80 ° C.

The novel compounds of the general formula (I) and the therapeutically active compounds of the general formula (XII) can be purified by customary known methods, for example by crystallization, chromatography or successive extraction under acidic and basic conditions.

The novel compounds of general formula (I) as well as the therapeutically active compounds of general formula (XII) can be converted into acid addition salts by reacting them with an acid in an organic solvent such as an alcohol, ketone, ether or chlorinated solvent. The salt may not precipitate until the 25 mother liquors are concentrated; it is separated by filtration or decantation.

The therapeutically active compounds of general formula (XII) as defined in A. have interesting pharmacological properties combined with low toxicity. They have been shown to be active at concentrations below 50 mg / L in a test of the in vitro inhibitory effect of compounds against platelet aggregation induced by 1-O-octadecyl-2-O-acetyl-3-ns-glycerophosphorylcholine (P.A.F.-Acether) by C.V.R. Born et al. J. Physiol., 168, 178 (1963). Their 50-35% lethal dose of DL, -q is 300-900 mg / kg orally in mice. Due to these properties, the compounds are useful in the treatment of allergic conditions and inflammatory conditions β 80460 and in general in the treatment of conditions in which P.A.F.-Acether can be considered to have a physiopathological effect.

The therapeutically active compounds of general formula (XII) as defined in B. have interesting pharmacological properties which make them useful in the prophylaxis and treatment of thrombotic conditions. The compounds have been shown to be active at concentrations below 50 mg / l in a test measuring their collagen-induced antiplatelet activity in vitro in G.V.R. According to the technique described by Born and colleagues in J. Physiol., 168 178 (1963). Their 50% lethal dose of DL, -q is 300 to 900 mg / kg orally in mice.

Therapeutically active compounds of general formula (XII) may be used for medical purposes as such or in pharmaceutically acceptable, i.e. non-toxic, doses.

Examples of pharmaceutically acceptable salts include addition salts with inorganic acids such as hydrochlorides, sulfates, nitrates and phosphates, and salts with organic acids such as acetates, propionates, succinates, benzoates, fumarates, maleate, maleate, theophylline acetates, salicylates, phenolphthaleinates, methylene bis-β-oxynaphthoates or substitution derivatives of these compounds.

As the salts to which the compounds of general formula (I) can be converted, mention may be made of the above-mentioned therapeutically acceptable salts of the compounds of general formula (XII).

The products of general formula (XII) as defined in A. above are particularly useful in the treatment of diseases in humans in the treatment of allergic and inflammatory conditions and in general those conditions in which P.A.F.-Acether can be considered to have a physiopathological effect. Doses depend on the desired effect and the duration of treatment; they 9,80460 are generally 25 to 100 mg per day administered orally, intravenously or by inhalation to an adult in one or more doses.

The compounds of general formula (XII) 5 as defined in B. above are particularly useful in the treatment of diseases in humans in the prophylaxis and treatment of thrombotic conditions. Doses depend on the desired effect and the duration of treatment; they are generally 100 to 1,000 mg per day orally in one or more doses per adult and 10 to 100 mg parenterally in one or more doses per adult.

In general, the physician will determine the dosage as appropriate as possible for the age, weight, and other factors of the patient being treated.

The following examples show how the invention can be implemented in practice. Application examples show how the compounds of the invention can be converted in practice to therapeutically active compounds of formula (XII).

20 Example 1

A suspension of 7 g of 3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-g] thiazole-7-carbothioamide and 4.2 g of methyl iodide in 250 cm of acetone was stirred at about 20 ° C: in 16 hours. Then 50 cm 3 of dimethyl-formamide were added to the suspension and stirring was continued for another three days. The crystals are then filtered off, washed three times with a total of 90 cm of acetone and dried under reduced pressure (20 mmHg; 2.7 kPa) at about 20 [deg.] C. in the presence of potassium hydroxide granules. There was thus obtained 9.5 g of 3- (3-pyridyl) -30 1H, 3H-pyrrolo [1,2-c] thiazole-7-S-methylthiocarboximidate hydroiodide as yellow crystals, melting at 193-194 ° C.

3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-b] thiazole-7-carbothioamide was prepared as follows: 8.1 g of 3- (3-pyridyl) -1H, 3H-pyrrolo [1 2-C7-thiazole-7-carboxamide was added to 100 cm @ 3 of pyridine saturated with hydrogen sulfide gas at 20 ° C. To the resulting suspension was added 7.3 g of phosphorus pentasulfide, and it was then heated to boiling for two hours while continuously introducing hydrogen sulfide gas into the reaction vessel. The resulting solution was cooled to about 20 ° C and then poured into 1,200 3 5 cm of distilled water. The resulting suspension was kept at about 4 ° C for 16 hours. The crystals were separated by filtration, washed five times with a total of 500 cm of distilled water. 3 five times with a total of 25 cm of ethanol and five times 3 with a total of 100 cm of diethyl ether and then dried under reduced pressure (20 mmHg; 2.7 kPa) at about 20 ° C in the presence of potassium hydroxide granules. There was thus obtained 7.7 g of crude product, melting at 205 ° C. This product was dissolved in 180 cm of boiling 1-butanol. The resulting solution was cooled to about 4 ° C for one hour. The crystals formed were filtered off, washed three times with a total of 15 cm of 1-butanol cooled to about 4 [deg.] C. and three times with a total of 360 cm of diethyl ether and then dried under reduced pressure (20 mmHg; 2.7 kPa). ) at about 20 ° C in the presence of potassium hydroxide crystals. There were thus obtained 7.1 g of 3- (3-pyridyl-20-yl) -1H, 3H-pyrrolo [1,2-d] thiazole-7-carbothioamide as cream-colored crystals, melting at 205 ° C.

3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxamide was prepared as follows:

A mixture of 13.6 g of 3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carbonitrile was heated with stirring for 3 h 15 min at about 85 ° C with constant stirring. potassium hydroxide 3 as a powder in 150 cm of tert-butyl alcohol. The solvent was then evaporated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the region of 40 ° C, after which the residue was suspended in 500 cm -1 of distilled water and stirred for 5 minutes at a temperature in the region of 20 ° C; the crystals formed were filtered off, washed five times 3 times with a total of 500 cm of distilled water, three times 3 times with a total of 60 cm of ethanol and a further three times with a total of 60 cm of diethyl ether and dried under reduced pressure (20 mmHg; 2.7 kPa) at about 20 ° C in the presence of potassium hydroxide granules. There was thus obtained 12.1 g of crude feed 80460, melting at 208 ° C. This product was combined with 2.2 g of the product previously prepared in the second operation by the same method and dissolved in 800 cm of boiling ethanol. To the resulting solution was added 0.5 g of activated carbon 5 and filtered hot. The filtrate was cooled to about 4 ° C for one hour; the crystals formed are filtered off, washed three times with a total of 30 g of ethanol cooled to about 4 [deg.] C. and dried under reduced pressure (20 mmHg; 2.7 kPa) at about 20 [deg.] C. in the presence of potassium hydroxide granules. There was thus obtained 10.7 g of 3- (3-pyridyl) -1H, 3H-pyrrolo [2 ', 2-q7 thiazole-7-carboxamide as white crystals, melting at 210 ° C.

3- (3-pyridyl-1H, 3H-pyrrolo [1,2-g] thiazole-7-carbonitrile can be prepared as follows: A mixture containing 249.4 g of 3-formyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid, 457 g of 2-chloroacryloyl nitrile and 0.2 g of hydroquinone in 1760 cm of acetic anhydride were heated to 110-117 ° C for 70 minutes.

The solvent was then evaporated under reduced pressure (20 mm mmHg; 2.7 kPa) at 50-80 ° C. The residue was taken up in 400 cm -1 of distilled water; the pH of the resulting suspension was adjusted to 10 by adding 5N aqueous sodium hydroxide solution, followed by extraction four times with a total of 2,500 cm3 of methylene chloride. The organic extracts are combined, washed three times with a total of 1 500 cm of distilled water, dried over anhydrous magnesium sulphate, 0.5 g of activated carbon are added, filtered and evaporated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at about 40 ° C. The residue obtained 3 was dissolved in a mixture of 250 cm of ethyl 30 acetate and 500 cm of a 1.8N aqueous hydrochloric acid solution. The organic phase was separated by decantation and extracted 3 times 3 times with a total of 200 cm of distilled water. The aqueous extracts were combined, washed five times with a total of 500 g of ethyl acetate, 0.5 g of activated carbon 35 was added to the solution and filtered; the pH of the filtrate was adjusted to 10 by adding 10N aqueous sodium hydroxide solution at about 4 ° C and 3 was then extracted three times with a total of 650 cm of ethyl 12,80460 acetate. The organic extracts were combined, washed three times 3 times with a total of 450 cm of distilled water, dried over anhydrous magnesium sulphate, 0.5 g of activated carbon was added to the solution, filtered and evaporated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at about 40 ° C. :in.

71.2 g of crude product were obtained. This product was dissolved in 150 cm 2 of boiling 2-propanol and 0.5 g of activated carbon was added to the resulting solution and filtered hot; the filtrate was cooled to about 4 ° C for one hour. The crystals formed were filtered off, washed three times with a total of 30 cm of 2-propanol cooled to about 4 ° C, 3 three times with a total of 60 cm of diisopropyloxide and then dried under reduced pressure (20 mmHg; 2.7 kPa) at about 20 ° C in the presence of potassium hydroxide granules. There were thus obtained 44 g of 3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carbonitrile as ocher-colored crystals, melting at 117 ° C.

3-Formyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid was prepared as follows: 250 g of 2- (3-pyridyl) thiazolidine-4-carboxylic acid were added to 1,200 cm of formic acid, keeping the reaction. the temperature of the mixture is constantly below 25 ° C. To the solution thus obtained, 875 g of acetic anhydride was added over one hour, keeping the temperature at 10-18 ° C.

After stirring for 20 hours at about 20 [deg.] C., the solvent is evaporated off under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the region of 60 [deg.] C., the residue is taken up in 1000 cm <1> of ethanol and the mixture is heated to reflux for 5 hours. for one minute and then cooled to about 4 ° C for one hour; The crystals formed are filtered off, washed three times with a total of 600 cm of ethanol and then three times with a total of 300 cm of diethyl ether and dried under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the presence of potassium hydroxide granules. There was thus obtained 234.5 g of 3-formyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid as cream crystals, melting at 214 ° C.

II? 80460 2- (3-pyridyl) thiazolidine-4-carboxylic acid can be prepared according to the method of A. Banashek and M.I. By the method described by Shchukina, J. Gen. Chem. U.S.S.R., 31, 1374 (1961); Chem. Abstr. 55, 24739 h, (1961).

5 Example 2

A suspension of 81.3 g of 5- (3-pyridyl) -1H, 3H-pyrrolo [2}, 2-cyanothiazole-7-carbothioamide and 49 g of methyl 3 iodide in a mixture of 3,110 cm of acetone and 1,550 cm dimethylformamide, stirred at about 20 ° C for three days. The crystals formed are filtered off, washed 3 times with a total of 150 cm of acetone, then 3 twice with a total of 500 cm of diethyl ether and dried under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the presence of potassium hydroxide in the form of tablets. -15 lessa. 113 g of hydroiodide of S-methyl-5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-thiocarboximidate are thus obtained in the form of yellow crystals melting at 262 ° C.

5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-a] thiazole-7-carbothioamide can be prepared as follows: A suspension of 22.7 g of 5- (3-pyridyl) -1H, 3H - 3 pyrrolo [1,2-c] thiazole-7-carbonitrile in a mixture of 14 cm of triethyl-3-amine 3a in 32 cm of pyridine, is saturated for five hours at a temperature of about 20 ° C with a stream of hydrogen sulfide gas. After stirring for three days at about 20 ° C, 32 cm of pyridine are added to the reaction mixture and the suspension is resaturated over eight hours at about 20 ° C with gaseous hydrogen sulfide, then stirring is continued for 16 hours at about 20 ° C. The same is repeated twice. The suspension is saturated for a further three hours at a temperature in the region of 20 [deg.] C. with a stream of hydrogen sulphide gas, then the reaction mixture is poured into 500 cm of distilled water. The crystals formed are filtered off, washed four times with a total of 200 cm of distilled water, then 3 times with a total of 100 cm of ethanol, then twice with a total of 100 cm of isopropyl oxide and dried under reduced pressure (20 mmHg; 2.7 kPa) at a temperature of about 20 ° C in the presence of potassium hydroxide in the form of tablets. 26 g of crude product are obtained, melting at 230 ° C. This compound is dissolved in 250 cm of dimethylformamide at a temperature of about 100 ° C. To the resulting solution is added 1 g of activated carbon and filtered hot; the filtrate is cooled to 4 ° C for two hours. The crystals formed are filtered off, washed twice with a total of 40 cm of dimethylformamide, three times with a total of 150 cm of ethanol, then with a total of 150 cm of isopropyl oxide and dried under reduced pressure (20 mmHg; 2.7 kPa). ) at a temperature of about 20 ° C in the presence of potassium hydroxide as tablets. 21 g of 5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carbothioamide are thus obtained in the form of yellow crystals, melting at 243 ° C.

5- (3-Pyridyl) -1H, 3H-pyrrolo [f] 2-thiazole-7-carbon-15-nitritrile is prepared as follows:

A suspension of 403 g of N-nicotinylthiazolidine-3,4-carboxylic acid in a mixture of 1,350 cm 2 of chloro-3-acrylonitrile and 1,750 cm of acetic anhydride is heated at 90 ° C for two hours and 40 minutes. During this time, it is observed how the mixture becomes uniformly clear after 30 minutes, after which precipitation occurs after 10 minutes. After cooling to about 4 ° C for 16 hours, the crystals formed are filtered off, washed twice with a total of 200 cm of acetic anhydride, three times with a total of 300 cm of acetone and dried under reduced pressure (20 mmHg; 2.7 kPa) at a temperature of about 20 ° C in the presence of potassium hydroxide 3 as tablets. The compound thus obtained is suspended in 2,400 cm 2 of 2N aqueous sodium hydroxide solution. After stirring for 1 hour and 30 minutes at a temperature in the region of 20 [deg.] C., the crystals formed are filtered off, washed five times with a total of 3 1,250 cm of distilled water, three times with a total of 1,200 3 3 cm of ethanol, three times with a total of 900 cm of diethyl ether and dried under reduced pressure (20 mmHg; 2.7 35 kPa) at a temperature in the presence of potassium hydroxide in the form of tablets at about 20 ° C. 159.7 g of 5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carbonitrile are thus obtained in the form of cream-colored crystals, melting at 170 ° C.

N-nicotinylthiazolidine-4-carboxylic acid can be prepared as follows: To a solution of 400 g of 4-thiazolidinecarboxylic acid and 613 g of triethylamine in 4,500 cin of chloroform are added over a period of 30-52 ° C, 534 g of nicotinyl chloride hydrochloride. The resulting solution is heated at about 64 ° C for four hours. After stirring for 16 hours at a temperature in the region of 20 DEG C., the crystals formed are filtered off, washed three times with a total of 1,500 cm3 of chloroform, then three times with a total of 1,500 cm @ 3 of diethyl ether and dried under reduced pressure. at a pressure (20 mmHg; 2.7 kPa) at a temperature of about 20 ° C in the presence of potassium hydroxide in the form of tablets. 403 g of N-nicotinylthiazolidine-4-carboxylic acid are thus obtained in the form of white crystals, melting at 190 ° C. Application example 1

Suspension of 9.5 g of 3- (3-pyridyl) -1H, 3H-20 pyrrolo [1,2-q] thiazole-7-S-methylthiocarboximidate hydrochloride and 1.6 g of N, N- dimethylhydrazine in 125 cm ethanol, was heated to about 78 ° C for four hours and 30 minutes. The resulting solution was evaporated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at about 60 ° C. The residue obtained was dissolved in 250 cm3 of distilled water, and the solution thus obtained was extracted three times with a total of 300 cm of ethyl acetate, 0.5 g of activated carbon was added thereto, filtered, the filtrate was adjusted to about 10 with 10N aqueous sodium hydroxide solution, and extracted three times. ker-30 with a total of 300 cm of ethyl acetate. The organic extracts were combined, washed three times with a total of 300 cm of distilled water, dried over anhydrous magnesium sulphate, 0.5 g of activated carbon were added, filtered and evaporated to dryness under reduced pressure (20 mmHg; 2.7 35 kpa) at about 50 ° C. C. There was thus obtained 4.8 g of crude product, which was purified by chromatography on a 4 cm diameter column containing 320 g of silica gel (0.04-0.063 mm).

80460 BC

Eluted at a pressure of 0.5 bar (51 kPa) with mixtures of methylene chloride and methanol, collecting 100 cm-4 fractions. The first 13 fractions obtained by eluting with a mixture of methylene chloride and methanol (90/10 by volume) were discarded. The next four fractions obtained by eluting with a mixture of methylene chloride and methanol (90/10 by volume), the following nine fractions obtained by eluting with a mixture of methylene chloride and methanol (80/20 by volume) and the next 10 fractions obtained by eluting with a mixture of methylene chloride and methanol (80/20 by volume) and a mixture of methanol (50/50 by volume), combined and evaporated to dryness under reduced pressure at about 60 ° C. This gave 3.1 ή of product which was dissolved in 20 cm of ethanol. The resulting cloudy 3 solution was filtered and 8.1 cm 3 of a 5.35N ethanol solution of hydrogen chloride-1 gas was added; the resulting hydroclone was precipitated from 3 of its solution by adding 2 cm of diethyl ether. The ether solution was cooled to about 4 ° C for 16 hours, after which the crystals were filtered off, washed five times with a total of 75 cm of a mixture of diethyl ether and ethanol (volume ratio 50/50) and five times with a total of 75 cm diethyl ether and then dried under reduced pressure (20 mmHg; 2.7 kPa) at about 20 ° C in the presence of potassium hydroxide granules. There were thus obtained 2.7 g of 3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-g] thiazole-7-carboxamide dimethylhydrazone dihydrochloride as cream crystals, melting at 195 ° C.

The hydroiodide of 3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-b] thiazole-7-S-methylthiocarboximidate can be prepared as in Example 1.

^ Application example 2

A suspension of 20.2 g of S-methyl-5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-d] thiazole-7-thiocarboximidate and 3.4 g of N, N-dimethylhydrazine per 100 cm in ethanol, heated to reflux for five hours and 30 minutes, then filtered while hot. After cooling to about 20 DEG C., 350 cm of diethyl ether are added to the filtrate. The resulting suspension is stirred at about 20 ° C for 30-180460 minutes. The crystals formed are filtered off, washed twice with a total of 100 cm of a mixture of ethanol and diethyl ether (50 to 50 by volume) and dried under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the region of 20 ° C. 5 sa in the presence of potassium hydroxide tablets. The compound obtained is suspended in a mixture of 300 cm of water and 3,300 cm of ethyl acetate. To this suspension is added 100 cm of 10N aqueous sodium hydroxide solution. The organic phase is separated by decantation and the aqueous phase is extracted twice with a total of 300 cm of ethyl acetate. The organic extracts are combined, washed three times with a total of 300 cm of distilled water, dried over anhydrous magnesium sulphate on ice, 0.5 g of activated carbon are added, filtered and concentrated under reduced pressure (20 mmHg; 2.7 kPa). This compound is dissolved in 10 parts 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 one hour.

The formed crystals are separated by filtration, washed three. 3 times with a total of 30 cm of ethanol cooled to about 4 ° C and three times with a total of 60 cin of isopropyl oxide and dried under reduced pressure (20 mmHg; 2.7 kPa) at about 20 ° C as tablets in the presence of potassium hydroxide. 4.95 g of 5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-q] thiazole-7-carboxamidide-25-hydrazamide are obtained in the form of cream-colored crystals melting at 170 ° C.

Hydroiodide of S-methyl 5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-thiocarboximidate can be prepared as in Example 2.

30 Application example 3

Stir at 20 ° C for 3 hours a suspension of 20.2 g of S-methyl-5- (3-pyridyl) -1H, 3H-pyrrolo-1,2,2-thiazole-7-thiocarboximidate hydroiodide, 8.6 g piperidine and 10.5 g of acetic acid in 500 g of chloroform.

To the suspension are then added 360 cm -1 of 2.8N aqueous sodium hydroxide solution 3 and 200 cm of chloroform. The organic phase is separated by decantation and the aqueous phase is extracted twice with a total of 100 cm of chloroform. The organic extracts are combined, washed three times with a total of 750 g of distilled water, dried over anhydrous magnesium sulphate, 0.5 g of activated carbon are added and concentrated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the region of 60 ° C. 15 g of compound are thus obtained, which is dissolved in 200 cm @ 2 of boiling ethyl acetate. After cooling to about 20 ° C, the crystals formed are filtered off and the filtrate is concentrated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the region of 60 ° C. 14.1 g of compound are thus obtained. This compound is dissolved in 130 cm 3 of an ethanol solution of 19.3 cm 4 of 4N ethanolic hydrochloric acid is added to the resulting solution of ethanol 3a, then it is cooled to a temperature of about 4 ° C for one hour. The crystals formed are filtered off, washed three times with a total of 75 cm 3 of ethanol 3a three times with a total of 150 cm of diethyl ether and dried under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the form of tablets of about 20 ° C. in the presence of potassium hydroxide. 13.7 g of crude product are thus obtained in the form of di-20 hydrochloride, melting at 264 ° C. This compound is combined with 2.4 g of the compound obtained previously and 3 is dissolved in 200 cm of ethyl acetate. The organic phase is separated by decantation and the aqueous phase is extracted twice with a total of 200 cm of ethyl acetate. The organic extracts are combined, dried over anhydrous potassium carbonate, 0.5 g of activated carbon are added, filtered and concentrated under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the region of 60 ° C. This gives 13 g of compound. This compound is chromatographed on a 2.4 cm diameter column containing 65 g of silica gel (0.063-0.2 mm) eluting with a mixture of acetonitrile and ammonia (d = 0.92) and 100 cm-4 fractions are collected. The first two fractions obtained by elution with a mixture of acetonitrile and ammonia (95-5 by volume) are discarded. The third fraction obtained by eluting with a mixture of acetonitrile and ammonia (95-5 by volume) and the following nine fractions obtained by eluting with a mixture of acetonitrile and ammonia 19 80460 (90-10 by volume) are combined and concentrated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at a temperature of about 40 ° C. 11.3 g of compound are thus obtained. This compound is rechromatographed on 6 columns 6 cm in diameter containing 480 g of silica gel (0.04-0.063 mm). Elute with a mixture of methylene chloride, methanol and 20% ammonia (12 to 6-1 by volume) at a pressure of 0,5 bar (51 kPa) and collect the 100 cm fractions. The first seven fractions are discarded, the next 14 fractions are combined and concentrated under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the region of 40 ° C. This gives 9.6 g of compound. This compound is dissolved in 350 cm 3 of boiling ethyl acetate and the resulting suspension is filtered hot; then the filtrate is cooled to about 20 ° C and concentrated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at about 60 ° C. This gives 9.1 g of compound. This compound is dissolved in 100 cm of ethanol. To the resulting solution is added 12.4 g of an ethanolic solution of 4.7N hydrochloric acid and cooled to about 4 ° C for two 20 hours. The crystals formed are filtered off, washed twice with a total of 50 g of ethanol cooled to about 4 [deg.] C., then three times with a total of 150 cm of diethyl ether and dried under reduced pressure (20 mmHg; 2.7 kPa) in the presence of potassium hydroxide tablets.

This gives 9.7 g of compound. This compound is dissolved in a boiling mixture of 175 cm of ethanol and 10 cm of distilled water. To the resulting solution is added 0.5 g of activated carbon and filtered hot; the filtrate is cooled to about 4 ° C for three hours. The crystals formed are filtered off, washed three times with a total of 30 cm 3 of ethanol and three times with a total of 75 cm of diethyl ether and dried under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the form of tablets of about 20 ° C. in the presence of potassium hydroxide. 4.5 g of 7-piperidino-80460-carboimidyl-5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-q] thiazole dihydrochloride are thus obtained in the form of pale yellow crystals melting at 284 ° C.

Hydroiodide of S-methyl-5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-b] thiazole-7-thiocarboxylate is prepared as in Example 2.

Il

Claims (4)

21 80460 Novel 3- or 5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-S-alkylthiocarboxyimidates, including their acid addition salts, which are therapeutically useful in the preparation of intermediates. -carboxyamidealkylhydrazone and 7-piperidino-carboimidylpyrrolothiazole derivatives, characterized in that their general formula is (I) 10 c (i) 1 R 1 -N-R 15 wherein R 6 is an alkyl radical and a) R is a 3-pyridyl radical and R 1 is a hydrogen atom, or b) R is a hydrogen atom and R 1 is a 3-pyridyl radical. Process for the preparation of 3- or 5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-S-alkylthiocarboximidates of the general formula (I) and their acid addition salts, characterized in that a halide of general formula (II) R2Z (II) wherein R2 is the same as in claim 1 and Z is a halogen atom is reacted with a compound of general formula (III) 30 CSNH2