FI80459C - NYA 3- ELLER 5- (3-PYRIDYL) SUBSTITUTE 1H, 3H-PYRROLO / 1,2-C / THIAZOLE-7-CARBOXYLSYROR, VILKA AER MELLAN PRODUKTOR - Google Patents

Description

1 80459

Novel 3- or 5- (3-pyridyl) substituted 1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxylic acids, which are intermediates in the preparation of therapeutically useful pyrrolothiazole-7-carboxylic acid amides, and a process for their preparation

Separated by division separated from application 840108

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

COOH

I (I) R —-N-L-R-, ^ 15, which are useful in the preparation of new drugs and their salts.

In the general formula (I) 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 hydrolysis of a nitrile of formula

CN

25 S

I (II) R —- N - * - R1 wherein R and R1 are as defined above, by any known method for converting a nitrile to an acid without affecting the rest of the molecule, especially by heating under temporal conditions in a high boiling alcohol such as ethylene glycol at a temperature of 100 Between ° C and the reflux temperature of the reaction mixture.

Compounds of general formula (II) in which R and

Ri has the same meaning as in (b) above, i.e. compounds of formula 2 80459

CN

S Π __Μ UII) 5 I_i- can be prepared by reacting 2-chloroacrylonitrile with the formula 10 C1 CH2 = cf (IV)

XN

15 to react with a compound of general formula

-COOH

(V) R - N-COR1 20 wherein R and R1 have the same meaning as in b) above.

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

Compounds of general formula (V) in which R and R 2 have the same meaning as in b) above can be prepared by condensing a compound of general formula N ----- -CO 2 Q (VI) 30 in which Zq is a halogen atom or forms a radical. With CO - a mixed anhydride, a compound of the general formula li 3 80459

- COOE

I (VII)

5 I-NH

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

Condensation of a compound of general formula (VI) with a compound of general formula (VII) is generally carried out in an inert organic solution such as chloroform in the presence of an acid acceptor such as triethylamine at 0-65 ° C.

When E is an alkyl radical, the hydrolysis is carried out by any method known to those skilled in the art, whereby the ester is converted to the acid without further conversion of the molecule, especially by heating under time in water or a mixture of water and alcohol such as water and ethanol at 20-80 ° C.

Compounds of general formula (VII) 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. Biol. Chem., 225, 607 (1957) or S. Wolff, G. Militello et 25 coll., Tet. Letters, 3913 (1979) or H. Gershon and A. Scala, J. Org. Chem. 26, 2347 (1961) or R. Riemschneider and G.A. 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).

Compounds of general formula (II) in which R is a 3-pyridyl radical and R 1 is a hydrogen atom can be prepared by condensing a compound of formula (IV) with a compound of formula 4 80459

—COO H

N-- (VIII) 5 <_> —1-N-CH °

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

The compound of general formula (VIII) can be selected by formylation of a product of formula

-COOH

»-, IX)

/ 7 \ S__NH

15 V-r = r: _X

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

The compound of formula (IX) 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 general formula (I) are useful as intermediates in the preparation of therapeutically active compounds of general formula

W

i I (x) 30 rJ-N - R2 wherein A. R is a 3-pyridyl radical and is a hydrogen atom and a ^) W is an acetyl radical, or 35 b ^) W is a radical of the general formula 11 5 80459 r3 -CON <^ (XI)

Xr 4 wherein - R 3 is a hydrogen atom and R 4 is a pyridyl radical or an alkyl radical having 1 to 5 carbon atoms substituted by a dialkylamino, or 10 - R 3 and R 4 together form an imidazolyl radical, or B. R is a hydrogen atom and R 1 is 3 -pyridyl radical and W is a radical of general formula

15 O

-C 1-4 (XII) wherein M is a radical of general formula 20 -nhr 6 (XIII) wherein R 9 is an alkyl radical of 1 to 5 carbon atoms substituted by a dialkylamino.

To prepare compounds of general formula (X) as defined in A wherein W is a radical of general formula (XI) wherein R 1 and R 4 together form an imidazolyl ring, N, N'-carbonyl-imidazole is reacted with the general formula with a compound of formula (I) wherein R 1 is a hydrogen atom and R is a 3-pyridyl radical, i.e. with a compound of formula

COOH

f (| 1 aA>

35 _! _ U

6 8C459

The reaction is generally carried out in an inert organic solvent such as tetrahydrofuran or dimethylformamide at a temperature of about 20 ° C.

For the preparation of compounds of general formula (X) as defined in A and wherein W is a radical of general formula (XI) wherein and R 4 are as in b) except that R 1 and together do not form imidazolyl, an amine is obtained. of the general formula: wherein R 1 and R 11 have the same meanings, react with a compound of the general formula (I) in which R 1 is a hydrogen atom, R 2 is a 3-pyridyl radical , i.e. with a compound of the general formula (1 ^) ·

It is particularly preferred to use an acid of general formula (I.) Ά in activated form, for example: 2 0 <*) in acid chloride form; in this case the reaction is carried out in a halogenated solvent such as chloroform, methylene chloride or dichloro-1,2-ethane or an ether such as dioxane at a temperature between 20 ° C and the boiling point of the reaction mixture or 25/3) in the imidazole form, i.e. using the general formula (X ) wherein W is a radical of general formula (XI) wherein R 1 and R 2 together form an imidazolyl radical; in this case, the reaction is carried out in an organic solvent such as tetrahydrofuran or dimethylformamide or a mixture of these solvents at 20 to 80 ° C.

Compounds of general formula (X) as defined in A above, wherein W is an acetyl radical, are prepared by reacting an ethoxymagnesium derivative of ethyl malonate with an acid halide of general formula (IA) as defined above.

The reaction is usually carried out in an organic solvent.

II

7 80459, such as ether or alcohol, or a mixture of these solvents in the presence of an acid acceptor, such as triethylamine, at a temperature between 100 ° C and the reflux temperature of the reaction mixture.

To prepare compounds of general formula (X) as defined in B, wherein the radical of formula XII is as defined in a2), an amine of general formula 10 Rc / 5 HN <"(XV)

Xr6 wherein R (and R8 are as defined above) to react with a compound of formula (I) having the symbols as defined in b), i.e. with a compound of formula

COOH

| I aB '' - N - \ - /

It is particularly preferred to use an acid of general formula (ID) in activated form, such as as an acid chloride, or to react it with N, N1-carbonylimidazole or an alkyl chloroformate before reacting it with an amine of general formula (XV).

In general, it is preferable to use an acid chloride and carry out the reaction in an organic solvent such as chloroform or methylene chloride at a temperature between 0 ° C and the boiling point of the reaction mixture.

Acids of general formula (Ιβ) can be prepared by hydrolyzing nitriles of general formula (III) as defined above.

The hydrolysis can be performed by any method known to those skilled in the art to convert a nitrile to an acid without otherwise altering the molecule. It is generally preferred to carry out the hydrolysis under basic conditions in a high boiling alcohol, for example with potassium hydroxide in ethylene glycol at a temperature between 100 ° C and the boiling point of the reaction mixture.

Nitriles of general formula (III) can be prepared by reacting a compound of general formula (IV) with a compound of general formula (V) as described above.

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

The novel compounds of general formula (I) and the therapeutically active compounds of general formula (X) 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 mother liquor is concentrated; it is separated by filtration or decantation.

The therapeutically active compounds of general formula (X) 25 as defined in A above have interesting pharmacological properties with very low toxicity. The compounds have been shown to be active at concentrations below 50 mg / l in a test measuring their in vitro anti-platelet aggregation effect against 1-O-octadecyl-2-acetyl-3-ns-glycos-30-phosphorylcholine (P.A.F.-Acether) G.V.R. In J. Physiol, Born et al. 168 178 (1963).

Their toxic dose (expressed as 50% of the tap-35 Pavana dose) in mice was generally 300 to 900 mg / kg orally.

Based on these properties, the compounds can be considered for use in the treatment of allergic and inflammatory conditions and in general in the treatment of conditions in which PAF-Ac 2 ther can be considered to have a physiopathological effect.

The therapeutically active compounds of general formula (X) as defined in B above have interesting pharmacological properties which make them useful in the prophylaxis and treatment of thrombotic conditions. The compounds have been shown to have active concentrations of less than 50 mg / l in a test measuring their in vitro anti-collagen-induced platelet aggregation effect 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 (X) may be used for medical purposes as such or in pharmaceutically acceptable doses, i.e. as non-toxic salts at the doses used.

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, maleates, maleate, maleate, , salicylates, phenolithaleinates, methylene bis-β-oxynaphthoates or substitution derivatives of these compounds.

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

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

Example 1 48 g of 3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-b] thiazole-7-carbonitrile were added to a solution of 41.7 g of 3 potassium hydroxide granules in 300 cm of ethylene glycol. The reaction mixture was heated to about 150 ° C for six hours and 30 minutes. The reaction mixture is then stirred for 16 hours at about 20 [deg.] C., after which the solvent is evaporated off under reduced pressure (5 mmHg; 0.7 kPa) at about 100 [deg.] C.

The residue was dissolved in 380 cm of distilled water. 0.5 g of activated carbon was added to the solution, it was filtered and its pH was adjusted to 4 by adding a concentrated aqueous hydrochloric acid solution, keeping the temperature of the reaction mixture at about 20 ° C. The crystals formed were filtered off, washed three to three times with a total of 600 cm of distilled water 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 49.5 g of crude product, melting at 177 ° C. This product was dissolved in 3,840 cm of boiling ethanol. To the resulting solution was added 0.5 g of activated carbon 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 45 cm of ethanol cooled to about 4 [deg.] C. and then three times with a total of 90 cm of diethyl ether and dried under reduced pressure (20 mmHg; 2.7 kPa) for about At 20 ° C in the presence of potassium hydroxide granules. There was thus obtained 36.6 g of 3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxylic acid as cream crystals, melting at 178 ° C.

3- (3-Pyridyl-1H, 3H-pyrrolo [1,2-c] thiazole-7-carbonitrile can be prepared as follows:

A mixture of 249.4 g of 3-formyl-2- (3-pyridyl) thiazolidine-4-carboxylic acid, 457 g of 2-chloroacrylonitrile and 0.2 g of hydroquinone in 1,760 cm of acetic anhydride , was heated to 110-117 ° C for 70 minutes.

The solvent was then evaporated under reduced pressure (20 mmHg; 2.7 kPa) at 50-80 ° C. The residue was collected

II

n 80459 to 3,400 cm 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 3 cm of methylene chloride. The organic extracts were combined,. The mixture was washed three times with a total of 1 500 cm of distilled water, dried over anhydrous magnesium sulphate, 0.5 g of activated carbon was added, filtered and evaporated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the region of 40 ° C.

..... 3

The residue obtained was dissolved in a mixture of 250 cm 3 of ethyl acetate and 500 cm 3 of a 1.8N aqueous hydrochloric acid solution. The organic phase was separated by decantation and extracted twice with a total of 200 cm of distilled water. The aqueous extracts were combined, washed five times with a total of 500 3 cm of ethyl acetate, 0.5 g of activated charcoal 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 3 and then extracted three times with a total of 650 cm of ethyl acetate. The organic extracts are combined, washed three times with a total of 450 cm of distilled water, dried over anhydrous magnesium sulphate, 0.5 g of activated carbon are added to the solution, filtered and evaporated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at about 40 °. C.

71.2 g of crude product were obtained. This product was dissolved in 3,150 cm of boiling 2-propanol and 0.5 g of activated carbon was added to the resulting solution and filtered while 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 m 2 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) for 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 temperature of the reaction mixture below 25 ° C at all times. 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 3,000 cm3 of ethanol and the mixture is heated to reflux for 5 for one minute and then cooled to about 4 ° C for 10 hours; 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 about 20 [deg.] C. 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.

2- (3-pyridyl) thiazolidine-4-carboxylic acid can be prepared according to the method of A. Banashek and M.I. By the method of Shchukina-20a, J. Gen. Chem. U.S.S.R., 31, 1374 (1961); Chem. Abstr. 55, 24739 h, (1961).

Example 2

A mixture of 18.7 g of 5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-g] thiazole-7-carbonitrile, 16.3 g of potassium hydroxide as tablets 3 and 160 cm of ethylene glycol was heated with stirring. at a temperature of about 155 ° C for two hours. After stirring for 16 hours at a temperature in the region of 20 ° C, the solvent was evaporated off under reduced pressure (2 mmHg; 0.27 kPa) at a temperature in the region of 100 ° C. The residue was dissolved in 100 cm 3 of distilled water, and the resulting solution was adjusted to a pH of about 5 by adding 2N aqueous hydrochloric acid. The crystals formed are filtered off, washed three times with a total of 150 cm of acetone and dried under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the presence of potassium hydroxide in the form of tablets at a temperature in the region of 20 ° C. There was thus obtained 17.7 g of crude product, melting at 264 ° C; in. This compound was similarly combined with the compound prepared in the previous 11,133,4459 times and dissolved in a mixture of 650 cm -1 of butanol and 150 cm of dimethylformamide preheated to about 115 ° C. 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 16 hours. The formed crystals were separated by filtration, washed twice with a total of 50 cm 3 of dimethylformamide, three times with a total of 150 cm 3 of ethanol, three times with a total of 150 cm of isopropyl oxide, then three times with a total of 150 cm of diethyl ether. 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. There was thus obtained 16.1 g of the compound, melting at 266 ° C. This compound was suspended in 15,250 cm of distilled water and the suspension was stirred at about 20 ° C for two hours. The crystals formed were filtered off, washed five times with a total of 150 cm of distilled water, three times with a total of 3 90 cm of ethanol, three times with a total of 90 cm of isopropyl oxide, then three times with a total of 90 cm 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 at about 100 ° C. There was thus obtained 15.5 g of 5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxylic acid as cream crystals, melting at 266 ° C.

5- (3-Pyridyl) -1H, 3H-pyrrolo [1,2-d] thiazole-7-carbonitrile can be 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 a temperature in the region of 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 14 80459 and dried. under reduced pressure (20 nuriHg; 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 1,250 cm of distilled water, three times with a total of 3,200,200 cm of ethanol, three times with a total of 900 cm of diethyl ether 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. 159.7 g of 5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-b] 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 g of chloroform is added 534 g of nicotinyl chloride hydrochloride over one hour at a temperature of 30 to 52 ° C. 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> diethyl ether 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. 403 g of N-nicotinylthiazolidine-4-carboxylic acid are thus obtained in the form of white crystals, melting at 190 ° C. Application Example 1 30 A solution containing 10.2 g of 3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxylic acid and 10.1 g of N, N'-3-carbonyldiimidazole 150 cm in anhydrous tetrahydrofuran, stirred for one hour and 20 minutes in a dry nitrogen atmosphere, and then 9.5 g of 2-diethylaminoethylamine dissolved in 50 cm of anhydrous tetrahydrofuran was added over 10 minutes at about 25 ° C. Stirring was continued for one hour at about 20 ° C and evaporated.

II

The solvent was then added under reduced pressure (20 mmHg; 2.7 kPa) at about 40 ° C. The residue obtained is taken up in 700 cm -1 of distilled water and the mixture is extracted five times with a total of 3,750 cm of ethyl acetate. The organic extracts are combined, washed five times with a total of 500 cm @ 3 of distilled water, dried over anhydrous magnesium sulphate, 0.5 g of activated carbon was added, filtered and evaporated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at a temperature in the region of 40 [deg.] C. This gave 12.4 g of crude product. 3 To a batch of 2 g of product and dissolved in 100 cm of a boiling mixture of cyclohexane and ethyl acetate (50 to 50 by volume), 0.5 g of activated carbon was added to the resulting solution and filtered while hot, and the filtrate was cooled to about 4 ° C. The crystals formed are filtered off with a filter rod, washed three times with a total of 45 cm of isopropyl oxide and dried under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the region of 20 ° C with potassium hydroxide. in the presence of ksid granules. There were thus obtained 9.8 g of N- (2-diethylaminoethyl) -3- (3-pyridyl-20-yl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxamide as white crystals, melting at 129 ° C. :in.

3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-g] thiazole-7-carboxylic acid was prepared as in Example 1. Application Example 2 A solution containing 2 g of 3- (3-pyridyl) -1H, 2H-Pyrrolo [1,2-g] thiazole-7-carboxylic acid and 1.45 g of Ν, Ν'-carbonyldiimidazole in 40 cm 3 of anhydrous tetrahydrofuran were stirred at about 20 ° C for four hours. To the resulting solution was added 0.5 g of activated carbon, filtered and evaporated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at about 45 ° C. The residue is taken up in 100 cm3 of distilled water and the suspension obtained is stirred at about 20 [deg.] C. for 30 minutes. The crystals were filtered off, washed three times with a total of 60 cm of distilled hydrogen and dried under reduced pressure (20 mmHg; 2.7 kPa) at about 20 ° C in the presence of potassium hydroxide granules. Thus 3 g of 2 g of crude product were obtained. This product was dissolved in 35 cm of 80459 boiling isopropanol. The resulting solution was cooled to about 4 ° C for one hour. The crystals formed were filtered off, washed twice with a total of 20 cm of isopropanol cooled to about 4 [deg.] C. and twice with a total of 20 cm of isopropyl oxide 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 1.7 g of 7- (1-imidazolylcarbonyl) -3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole as cream crystals, melting at 10117 ° C.

3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-b] thiazole-7-carboxylic acid was prepared as in Example 1. Application Example 3

A solution of 16 g of 7- (1-imidazolylcarbonyl) -3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-g] thiazole 3 and 16 g was heated to about 150 ° C for 5 hours and 30 minutes. 10.2 g of 2-aminopyridine in 150 cm of anhydrous dimethylformamide. The solution is then evaporated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the region of 80 ° C and the oily residue is taken up in 500 cm of distilled water. Crystals formed. The suspension was stirred at about 20 ° C for 16 hours. The crystals are then filtered off, washed three times with a total of 300 cm of distilled water and dried under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the presence of potassium hydroxide granules. This gave 14.6 g of crude product, melting at 141 ° C. This product 3 was dissolved in 75 cm of boiling ethanol. To the resulting solution was added 0.5 g of activated carbon and filtered hot. The filtrate was cooled to about 4 ° C for one hour. The formed crystals were separated by filtration, washed twice with a total of 10 m 3 of ethanol cooled to about 4 ° C and three times with a total of 15 cm of diethyl ether and then dried under reduced pressure (20 mmHg; 2.7 kPa) for about 20 g. ° C in the presence of potassium hydroxide granules. There was thus obtained 11.6 g of N- (2-pyridyl) -3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxamide as beige crystals melting at 145 ° C.

tl I, 80459 7- (1-imidazolylcarbonyl) -3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-b] thiazole was prepared as in Application Example 2.

Application Example 4 5 To a solution containing diethyl malonate ethoxy-. 3 magnesium derivatives in 65 cm of a mixture of ether and ethanol (3/1 by volume) prepared using 1.34 g of magnesium and 8.8 g of diethyl malonate, 5.1 g of triethylamine were added; To the resulting suspension was added 15 g of 7-chloroformyl-3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-b] thiazole hydrochloride over 10 minutes at about 25-30 ° C, and the reaction mixture was then diluted with 35 g of anhydrous tetrahydrofuran. and stirred at about 20 ° C for 16 hours. Then, 25 cm of a 2N aqueous solution of chloro-15 hydrochloric acid was added to the reaction mixture, and it was extracted five times with a total of 750 cm of ethyl acetate. The combined organic extracts were washed five times with a total of 250 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 50 ° C. C. There was thus obtained 19 g of product, melting at 110 ° C. This product was dissolved in a mixture of 25 cm of acetic acid, 15 cm of distilled water and 3 cm of concentrated sulfuric acid. The resulting solution is heated to about 100 ° C for nine hours and 30 minutes and then cooled to about 20 ° C and diluted with 150 cm 3 of distilled water, 0.5 g of activated carbon is added and the solution is filtered and adjusted to a pH of about nine. by adding sodium carbonate and extracted three times with a total of 450 cm of ethyl acetate. The organic extracts were combined, washed three 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 35 kPa) at about 45 °. C. This gave 9.5 g of product. This product is purified by chromatography on a column 6 cm in diameter containing 480 g of silica gel (0.04-0.063 mm), eluting with mixtures of cyclohexane and ethyl acetate at a pressure of 0.5 bar (51 kPa) and collecting fractions of 200 cm. The first nine fractions obtained by eluting with a mixture of ethyl acetate and cyclohexane (80/20 by volume) were discarded. The following nine fractions obtained by eluting with a mixture of ethyl acetate and cyclohexane (85/15 by volume) were combined and evaporated to dryness under reduced pressure (20 mmHg; 2.7 kPa) at about 50 ° C. There were thus obtained 7.2 g of product. This product was dissolved in 30 cm of boiling isopropanol. To the resulting solution was added 0.5 g of activated carbon and filtered hot. The filtrate was cooled to about 4 ° C for one hour. The formed crystals were separated by filtration, washed three times with a total of 15 cm of isopropanol cooled to about 4 and dried under reduced pressure at 20 ° C in the presence of potassium hydroxide granules. There were thus obtained 5.7 g of 7-acetyl-3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-b] thiazole as cream-colored crystals melting at 100 ° C.

7-Chloroformyl-3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-20] thiazole hydrochloride was prepared as follows: A suspension containing 9.8 g of 3- (3-pyridyl) -1H, 3H-pyrrolo 1,2-C7-thiazole-7-carboxylic acid, 23.8 g of thionyl 3,3-chloride, 0.1 cm of dimethylformamide and 100 cm of 1,2-dichloroethane were heated to reflux for one hour and 25 minutes. The reaction mixture is then cooled and the solvent is evaporated off under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the region of 50 ° C. The residue obtained is suspended in 100 cm of anhydrous cyclohexane and the crystals are filtered off, washed twice with a total of 10 cm of anhydrous cyclohexane and dried under reduced pressure (20 mmHg; 2.7 kPa) at about 20 ° C. There was thus obtained 12.1 g of 7-chloroformyl-3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-d] thiazole hydrochloride as ocher-colored crystals, melting at 185 ° C.

3- (3-Pyridyl) -1H, 3H-pyrrolo [1,2-b] thiazole-7-carboxylic acid was prepared as in Example 1.

Ethoxymagnesium diethyl malonate was prepared as described in C.A. Reynolds & C.R. Hauser, Org. Synth. Coll.

Il 19 80459

Butter. 4, 708 (1963).

Application example 5

To a suspension of 12 g of 7-chloroformyl-5- (3-

O

pyridyl) -1H, 3H-pyrrolo [2 / b] thiazole in 200 cm of methylene chloride, a solution of 13.9 g of 2-diethylaminoethylamine in 50 cm at 50 ° C is added over a period of 20 minutes at about 20 ° C. in methylene chloride. The resulting solution is stirred for 16 hours at about 20 ° C. The compound precipitates.

3 3

Then 250 cm of methylene chloride and 100 cm 2N are added

10 aqueous sodium hydroxide solution; the organic phase is separated by decantation, washed with 100 g of 2N aqueous sodium hydroxide solution, then three times with a total of 600 cm of distilled water, dried over anhydrous potassium carbonate, 0.5 g of activated carbon are added, filtered and concentrated to dryness under reduced pressure (20 mmHg; 2.7; kPa) at a temperature of about 60 ° C. This gives 12 g of crude product. This compound is dissolved in 60 cm of boiling acetonitrile. To the resulting solution is added 0.5 g of activated carbon and filtered hot; the filtrate is cooled to about 4 ° C for two hours. The crystals formed are filtered off, washed twice with a total of 20 cm of acetonitrile cooled to about 4 [deg.] C., then three times with a total of 150 cm of isopropyl oxide and dried under reduced pressure (20 mmHg; 2.7 kPa) at about 20 [deg.] C. in the presence of potassium hydroxide in the form of tablets. 6.4 g of N- (2-diethylaminoethyl) -5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxamide are thus obtained in the form of light light brown crystals melting at 106 ° C.

7-Chloroformyl-5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole hydrochloride is prepared as follows: A suspension of 8.8 g of 5- (3-pyridyl) -1H, 3H-pyrrolo [1 The 2-o-thiazole-7-carboxylic acid in a mixture of 3 to 6.25 cm of thionyl chloride, 0.05 cm of dimethylformamide 3 and 100 cm of 1,2-dichloroethane is heated to reflux under reflux for 2 hours and 30 minutes. The reaction mixture is cooled to a temperature in the region of 20 ° C and concentrated under reduced pressure (20 mmHg; 20 80459 2.7 kPa) at a temperature in the region of 60 ° C. The residue obtained is suspended in 150 cm of cyclohexane and the solvent is evaporated off under reduced pressure (20 mmHg; 2.7 kPa) at a temperature in the region of 60 ° C. The same is repeated twice. 10 g of 5-chloroformyl-5- (3-pyridyl) -pyrrolo [1,2-c] thiazole hydrochloride are thus obtained in the form of cream-colored crystals melting at 220 ° C.

5- (3-Pyridyl) -1H, 3H-pyrrolo [1,2-b] thiazole-7-carboxylic acid can be prepared as in Example 2.

Il

Claims (2)

1. New 3- or 5- (3-pyridyl) substituted 1H, 3H-pyrrolo / 1,2-othiazole-7-carboxylic acids, their acid addition salts included, which are intermediates in the preparation of corresponding, therapeutically useful pyrrolothiazole -7- carboxylic acid amides, characterized in that they have the general formula (I) pOOH s 0 (I) rJ - N-1 - r wherein a) R is a 3-pyridyl radical and R hydrogen atom, or b) R is a hydrogen atom and R 3 is a 3-pyridyl radical. Process for the preparation of compounds according to claim 1, characterized in that a nitrile of the general formula 20 ηΛ RΛN-1-Rri wherein R and R an alkaline medium in ethylene glycol at a temperature between 100 ° C and the reflux temperature of the reaction mixture, after which the thus obtained compound is isolated and, if desired, converted into an addition salt with an acid. Il