FI79324B - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA PYRROLO / 1,2-C / TIAZOL-7-CARBOXAMID- ELLER -7-ACETAMIDDERIVAT. - Google Patents

Description

1 79324

Process for the preparation of therapeutically useful pyrrolo [1,2-a] 7-thiazole-7-carboxamide or -7-acetamide derivatives Separated by division 845064

The invention relates to a process for the preparation of novel pyrrolo [1,2-q] -thiazole-7-carboxamide or -7-acetamide derivatives of the general formula (I) 10 (ch2) n-CONH2 f> VR (i) I-N - Het 15 and their acid addition salts. The compounds of formula (I) and their acid addition salts are useful drugs.

In general formula (I) either a) R is methyl, n is 0 and Het is 3-pyridyl; or b) R is hydrogen, n is 0 and Het is 5-thiazolyl; or c) R is hydrogen, n is 1 and Het is 3-pyridyl.

Compounds of general formula (I) may be prepared according to the invention by pyrrolo [1,2-c] thiazole-7-carbonitrile or -7-acetonitrile of general formula (II)

(CH2) n-CN

30 Λ 1 s || rR (II] I-N - Het 35 where R, n and Het have the same meaning as above, are hydrolyzed.

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The hydrolysis can be carried out in any manner known to the person skilled in the art without contacting the molecule in other respects, in particular by heating in an alkaline environment in an organic solvent such as tert-butanol at 30-5 85 ° C or in a strongly acidic medium at 20-100 ° C.

Nitriles of the general formula (II) in which n is zero and the other symbols have the same meaning as above can be prepared by reacting a nitrile of the general formula 10 with (III) R-CH = C (III)

CN

Wherein X is a halogen atom such as chlorine or bromine and R is as defined above, to react with a compound of general formula (IV)

/V.C00H

20 I Y (IV.

-OF

CO-Het where Het means the same as above. The reaction is usually carried out in acetic anhydride by heating at 80-130 ° C.

Compounds of general formula (III) may be obtained by applying and using the methods described by L. LECLERCQ and A. BRUYLANTS, Bull. Soc. Chim. ends, 5j), 5 (1949) or J.C. POMMELET et al., Angew. Chem. , 30 93, 594 (1981) or R. CARRIE et al., Bull. Soc. Chim.

France, 1963 (1976) or H. BRINTZINGER et al., Angew. Chem., 60, 312 (1948).

Compounds of general formula IV can be prepared by condensing a compound of general formula (V) 35 Het-COX '(V) 3 79324 wherein X' is a halogen atom or forming a mixed anhydride with the radical to which it is attached. with the general formula (VI) 5 s / \ _ C00Ro | I (VI)

I_NH

10 wherein RQ is a hydrogen atom or an alkyl radical, and the compound thus obtained is hydrolyzed if RQ is an alkyl radical.

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

When Rq represents an alkyl group, the hydrolysis is carried out by methods known to those skilled in the art to convert the ester 20 to an acid and / or alcohol without affecting the other molecule, especially by heating in an alkaline environment in water or a water-alcohol solvent such as water-ethanol at 20-80 ° C.

Compounds of general formula (VI) may be prepared using or applying the methods described by J.C. WRISTON and C.G. McKENZIE, 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).

Nitriles of the general formula (II) in which n is 1 and the other symbols have the same meaning as above can be prepared by condensing tosylmethyl isocyanide of the formula (VII) with CH3 - </ so2ch2n = c (VII) 4 79324, of the general formula (VIII)

CHO

5 (yVr where the symbols have the same meaning as above.

The condensation is generally carried out in two successive steps: a) by carrying out the reaction in a solvent such as 1,2-dimethoxyethane, dimethyl sulfoxide or hexamethylphosphoramide in the presence of a base such as potassium tert-butyrate at a temperature between -60 ° C and 0 ° C; then b) continuing the reaction between 0 ° C and room temperature after the addition of an alcohol such as methanol.

Compounds of general formula (VIII) can be prepared by reacting a compound of general formula (IX): R-CH = C (IX)

^ CHO

Wherein R is as defined above and X 1 represents a halogen atom such as chlorine or bromine with a compound of general formula (IV) as defined above.

In general, the reaction is carried out in acetic anhydride at a temperature of 80 to 130 ° C.

Compounds of general formula (IX) may be prepared using or applying the methods described by H. SCHULZ and H. WAGNER, Angew. Chem. , 6_2, 10 5 (1950) or H. HIBBERT, E.O. HOUGHTON and K.A. TAYLOR, J. Amer. Chem. Soc., 51, 611 (1929).

Carbonyl derivatives of the general formula (VIII) can be prepared by formylating a compound of the general formula (X) 5 79324 (ΥΥ * (x) I N-J-Het 5 in which R and Het have the same meaning as above.

The formylation is generally carried out by methods known to those skilled in the art for formylating a pyrrole ring without affecting the other molecule, in particular with phosphoryl chloride and dimethylformamide at a temperature of 0-20 ° C.

Compounds of general formula (X) may be prepared by decarboxylation of an acid of general formula (xi) 15

COOH

^ V SR ~ R

I I I (xi) I — n—— Het 20 in which Het and R have the same meaning as above, by methods known per se for decarboxylating an acid, for example by heating in the presence of copper powder.

Acids of general formula (XI) can be prepared by hydrolysis of nitriles of general formula (II) wherein n is zero and other symbols have the same meaning as above.

The hydrolysis of nitriles of general formula (II) can be carried out by any method known to those skilled in the art for converting a nitrile in an acid without otherwise affecting the molecule. It is generally preferred to carry out the hydrolysis in a basic medium in a high boiling alcohol, for example with potassium hydroxy-35 in ethylene glycol at a temperature between 100 ° C and the reflux temperature of the reaction mixture.

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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 environment.

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. They generally have an LD50 value of 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 are addition salts with inorganic acids such as hydrochlorides, sulphates, nitrates, phosphates or with organic acids such as acetates, propionates, succinates, benzoates, fumarates, malates-tetanylates, methanesulphonates, methanesulphonates, hydrates phenolphthalates, methylene bis - / * - oxynaphthoates and their substituted derivatives.

The following examples illustrate the invention:

Example 1 A suspension of 3.6 g of KOH as a powder and 2.6 g of 6-methyl-5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-7,79324

O

carbonitrile 7 in 5 cm 3 of tert-butyl alcohol, heated at about 81 ° C for 10 hours. The suspension is poured into 500 cm-1 of distilled water and the resulting solution is stirred at a temperature in the region of 4 ° C for 3 hours. The crystals formed are filtered off, washed 5 times with a total of 125 cm of distilled water and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the presence of KOH crystals at a temperature in the region of 20 ° C. 2.3 g of compound are thus obtained, melting at 212 ° C. This compound is dissolved in 150 cm · * of 10 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 crystals formed are filtered off, washed twice with a total of 50 cmJ of ethanol and 3 times with a total of 75 cmJ of diethyl ester and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 20 ° C to give KOH crystals. acid. 1.6 g of 6-methyl-5- (3-pyridyl) 1H, 3H-pyrrolo [1,2-s] thiazole-7-carboxamide are thus obtained in the form of white crystals melting at 222 ° C.

6-Methyl-5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-g] thiazole-7-carbonitrile can be prepared as follows: A suspension of 19 g of N-nicotinylthiazolidine-4-carboxylic acid and 58 g of .4 g of 2-bromo-2-butenenitrile in 120 g of acetic anhydride are heated at about 100 ° C for 1 hour. The solution obtained is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 80 ° C. The residue is suspended in 150 cm · * of distilled water. Aqueous 150 cm- * 10N NaOH is added to the suspension and stirred at about 20 ° C for 30 minutes.

O

30 tin time. 300 cm of methylene chloride are then added; the organic phase is separated by decantation and the aqueous phase is extracted twice with a total of 600 g of methylene chloride. The organic extracts are combined, washed 3 times with a total of 300 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 (20,879324 mm of mercury; 2.7 kPa). At a temperature of 60 ° C. 2.6 g of crude product are thus obtained. This compound is chromatographed on a 4 cm diameter column containing 320 g of silica gel (0.04-0.063 mm). Elute with a mixture of ethyl acetate and cyclo-5 in hexane (70-30 by volume) at 0.5 bar.

O

(51 kPa) and collect 50 cmJ fractions. The first 9 fractions are discarded, the serum-containing 8 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. Thus, 1.1 g of compound are obtained. This compound is combined with 4 g of the compound prepared in the same way as before.

O

and dissolved in 75 cmJ of boiling acetonitrile. The resulting solution is filtered hot. The filtrate is cooled to about 20 ° C. The formed crystals are separated by filtration.

O

15 times, wash twice with a total of 20 cm 2 of acetonitrile

O

and 3 times with a total of 75 cm 3 of diethyl ether and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the presence of crystalline KOH at a temperature in the region of 20 ° C. 2.6 g of 6-methyl-5- (3-pyridyl) -1H, 3H-pyrrolo-20 D-, 2- (2-thiazole-7-carbonitrile) are thus obtained in the form of yellowish crystals melting at 190 ° C.

N-nicotinylthiazolidine-4-carboxylic acid can be prepared as follows:

To a solution of 400 g of thiazolidine-4-carboxylic acid

O

25 acids and 613 g of triethylamine in 4500 cm of chloroform, 543 g of nicotinyl chloride hydrochloride are added over a period of 1 hour at about 30-52 ° C. The resulting solution is heated at about 64 ° C for 4 hours. After stirring for 16 hours at a temperature in the region of 20 [deg.] C., the crystals formed are filtered off, washed 3 times with a total of 1500 sq.

O

roform, then 3 times with a total of 1500 cm of diethyl ether, and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the presence of KOH crystals at a temperature in the region of 20 ° C. 403 g of N-nicotinylthioazolidine-4-35 carboxylic acid are thus obtained in the form of white crystals melting at 190 ° C.

9,79324 2-Bromo-2-butenenitrile can be prepared from L.

According to LECLERCQ and A. BRUYLANTS, Bull. Soc. Chim. ends, 58, 5 (1949).

Example 2 A suspension of 6.5 g of 2- [5- (3-pyridyl) -1H, 3H-

pyrrolo / T.f 2-o7-7-thiazolyl7astonitrile and 8.9 g KOH

O

as a powder in 110 cm 3 of tert-butyl alcohol, is heated to about 80 ° C for 15 minutes. The suspension is poured into 1500 cm3 of distilled water and the mixture is extracted 4 times with a total of 1200 ml of methylene chloride. The organic extracts are combined, washed 3 times with a total of 750 ml 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 a temperature in the region of 60 ° C. This gives 4.9 g of compound melting at 174 ° C. This compound is combined with 0.6 g of the compound prepared in the same way as before, and all are dissolved in 150 cmJ of boiling ethanol. To the resulting solution is added 0.5 g of activated carbon and filtered through Moon. The filtrate is cooled to about 4 ° C for 1 hour. The crystals formed are filtered off, washed 3 times with a total of 75 cm of chilled ethanol at about 4 ° C and 3 times with a total of 75 cm of diethyl ether, then dried under reduced pressure (20 mm of mercury; 2.7 to 25 kPa) at about 20 ° C. in the presence of KOH crystals.

3.4 g of 2- [3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] -β-thiazolyl] acetamide are thus obtained in the form of pale yellow crystals melting at 176 ° C.

2- [3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] -7-thiazolyl] -acetonitrile can be prepared as follows:

To a solution of 8.7 g of tert-potassium butylate in 140 g of 1,2-dimethoxyethane cooled to -30 ° C is added over 20 minutes at about -30 ° C

O

a solution of 7.5 g of tosylmethyl isocyanide in 50 cm of 1,2-dimethoxyethane. The resulting solution is cooled to about -60 ° C, then a solution of 8 g of 5- (3-pyridyl) -1H, 3H-pyrrolo [1] is added over 30 minutes at a temperature of about -60 ° C. 2-O-thiazole-7-carboxaldehyde at 70 cm3C 1,2-dimethoxyethane. The temperature of the resulting solution is raised to about 0 ° C in 1 hour and at this temperature the solution is kept for 5 1 hour 20 minutes. 105 cm3 of methanol are then added over a period of 15 minutes at a temperature of 3-7 ° C. The resulting solution is heated at about 72 ° C for 1 hour 15 minutes, then stirred at about 20 ° C for 16 hours. Evaporate three quarters of the solvent under reduced pressure (20 mm of mercury; 2.7 kPa) to a temperature of about 40 ° C.

O

mode. The residue is dissolved in a mixture of 350 cm

O

water and 250 cmJ of ethyl acetate. The organic phase is separated by decantation and the aqueous phase is extracted 3 times with

O

with 750 cmJ of ethyl acetate. Organic extracts

O

The mixture is washed, washed 3 times with a total of 450 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 a temperature in the region of 50 ° C. This gives 7.6 g of crude product. This compound is chromatographed on a 2.7 cm diameter column containing 75 g of silica gel (0.063-0.2 mm) eluting with a mixture of cyclohexane and ethyl acetate and

O

by collecting 200 cm fractions. The first two fractions obtained by eluting with a mixture of cyclohexane and ethyl acetate (50-50 by volume) are discarded. The next three fractions obtained by elution with a mixture of cyclohexane and ethyl acetate (50-50 by volume) and the next fraction obtained by elution with ethyl acetate alone are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) for about 60 ° C. There are thus obtained 6 g of 2- [B- (3-pyridyl) -1H, 3H-pyrrolo [1,2-g] -7-thiazolyl] acetonitrile as bright yellow crystals melting at 92 ° C.

5- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carb-35-oxaldehyde is prepared as described in EP-A-2. 0 118 321.

11 79324

Example 3

A suspension of 6.5 g of KOH powder and 4.6 g of a mixture of (in ratios 20-80) 6-cyano and 7-cyano-5- (5-thiazolyl) -1H, 3H-pyrrolo / T ., 2-o-thiazole in 100 cm3 of 5 tert-butyl alcohol, is kept under reflux for 2 minutes in a bath heated to 100 ° C. Birth-

O

now the suspension is poured into 800 cmJ of distilled water and the crystals obtained are filtered off, washed 6 times with all

O

300 cm of distilled water and 3 times a total of 75

O

10 cmJ of acetone, then dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the presence of crystalline KOH at a temperature in the region of 20 ° C. 1.8 g of compound are obtained, melting at 230 ° C. The previous filtrate is extracted 3 times with a total of 1000 cm 3 of methylene chloride and 3 times with a total of 1000 cm 3 of ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury? 2.7 kPa) at a temperature in the region of 60 ° C. This gives 1 g of compound which melts at 215 ° C. This compound 20 is combined with 1.8 g of the compound obtained above and 1.2 g of the compound prepared in the same manner last time.

O

s. These three batches are dissolved in 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 2 hours. The crystals formed are filtered off, washed twice with a total of 20 g of 1-butanol, twice with a total of 50 cmJ of ethanol and 3 times with a total of

O

75 cmJ of diethyl ether, then dried under reduced pressure (20 mm of mercury? 2.7 kPa) at a temperature in the region of 20 ° C in the presence of KOH crystals. 2.1 g of 5- (5-thiazolyl) -1H, 3H-pyrrolo [1,2-g] thiazole-7-carboxamide are thus obtained in the form of orange crystals, melting at 236 ° C.

A mixture of 6-cyano and 7-cyano-5- (5-thiazolyl) -1H, 3H-pyrrolo [1,2-g] thiazole (20-80) can be prepared as follows: 12,79324

To a solution of 13.1 g of thiazolidine-4-carboxylic acid and 9.8 g of triethyl egg in 360 cm 3 of chloroform is added over 15 minutes at a temperature of about 23-36 ° C.

O

a solution of 14.1 g of 5-chloroformylthiazole in 120 cm 3 of 5 chloroform. The resulting solution is heated at about 64 ° C for 2 hours 15 minutes. After stirring for 16 hours at a temperature in the region of 20 ° C, the solvent is evaporated off under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C.

O

in vacuo and the residue is dissolved in 350 cm 3 of acetone. The suspension obtained is filtered and the filtrate is concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 60 ° C. 26.4 g of compound are thus obtained, which is dissolved

O O

to a mixture of 77 cm 2 of chloroacrylonitrile and 96 cm 2 of acetic anhydride. The resulting solution is heated at about 90 ° C for 2 hours and 45 minutes, then stirred at about 20 ° C for 16 hours. The formed crystals are separated by filtration, washed 2 times in total

O

150 cm 2 of acetic anhydride and 3 times a total of 225 cm of acetone are then dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the presence of KOH crystals at a temperature in the region of 20 ° C. 7.2 g of compound are thus obtained. This

O

the compound is suspended in 150 cm of distilled water. 150 cmJ of 10N aqueous NaOH solution are added to the suspension. The crystals formed are filtered off, washed 4 times with a total of 25,200 cm 3 of distilled water and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the presence of KOH crystals at a temperature in the region of 20 ° C. There is thus obtained 4.6 g of a mixture of 6-cyano and 7-cyano-5- (5-thiazolyl) -1H, 3H-pyrrolo [1] 2-c (thiazole) as chestnut-brown crystals melting at 155 ° C. 30 in 20-80 (based on NMR spectra).

Claims (1)

A process for the preparation of novel therapeutically useful pyrrolo / T-> 2-giaziazole-7-carboxamide or -7-acetamide-5 derivatives of the general formula (I) (CH2) n-CONH2 10 -V I_N- -1- Het wherein a) R is methyl, n is 0 and Het is 3-pyridyl; or b) R is hydrogen, n is 0 and Het is 5-thiazolyl; or c) R is hydrogen, n is 1 and Het is 3-pyridyl, and for the preparation of their acid addition salts, characterized in that the pyrrolo [1,2-g] thiazole-7-carbonitrile or -7-acetonitrile having the general formula (II) 20 <CH2> n-CN Λλ-ι LUI_Het (II> 25 wherein R, n and Het have the same meaning as above, is hydrolysed in a manner known per se to convert the nitrile to the amide, after which the compound thus obtained is isolated, and the obtained compound is, if desired, converted into an acid addition salt.