HU210930B - Process for producing novel cyclohexyl-sulfonyl-acrylic acid and derivatives and pharmaceutical preparations containing them - Google Patents

Description

The present invention relates to a novel cyclohexylsulfonylacrylic acid of the formula I and its derivatives wherein

R is hydroxy,

C1-C4 alkoxy, halo-substituted phenyloxy, 4- (C1-C4) alkoxy-carbonyl-1-piperazinyl,

4 - [(C 1 -C 4 alkyl) carbonylphenyl] -1-piperazinyl,

4-piperonyl-1-piperazinyl,

2- (C1-C4-alkoxy) -carbonylethylamino;

ethyl-2-pyrrolidinylmethylamino; or

2-benzyloxycarbonyl-1-pyrrolidinyl from L-proline and pharmaceutically acceptable salts thereof.

The present invention also relates to pharmaceutical compositions containing these novel cyclohexylsulfonyl acrylic acid derivatives of formula (I).

The novel compounds of formula I may have the configuration (E) or (Z) and are not known in the literature.

Compounds of similar structure are disclosed in U.S. Patent No. 203,869. and U.S. Patent No. 203,872. Hungarian patents. In these descriptions, the compounds are attributed to an inhibitory effect on gastric acid secretion and an activity against Campylobacter pylori. Compounds with MIC values of 250-1000 mg / l (minimal inhibitory concentration) against this latter bacterium.

In our studies with the novel compounds of the formula I, they have been found to be biologically active, have significant anti-ulcer properties, such as cytoprotective, and also have significant antibacterial activity. The therapeutic activity of the compounds of formula I was investigated by the following methods:

Examination of acidic alcohol-induced gastric damage (Róbert A., Gastroenterology, 1979,77,761-767)

Female rats 120-150 g fasted for 24 hours were used for the study. The test substance was injected into the stomach of rats in a Tween 80 suspension by gavage. Half an hour later, 0.5 ml / 100 g of acidic alcohol was injected into the animals' stomach by gavage. One hour later, the animals were sacrificed, the stomach was removed, and cut along the great curvature. The red-brown bands (hemorrhagic lesions) were weighed and the average total length per stomach was calculated. The efficacy of the test compound was compared to the control group. The effect of the compound of Example 3 of the present invention was: E _D 50 = 0.6 mg / kg po.

Investigation of efficacy against Heliobacter pylori

The efficacy of the compounds of formula I according to the invention was investigated by agar diffusion and agar dilution methods. The assays were performed with a culture of Heliobacter pylori isolated from different human ulcer patients.

The compound of Example 3 had an MIC (minimum inhibitor concentration) of 7.815.4 mg / L.

As can be seen from the pharmacological results, the compounds of the invention and their pharmacologically acceptable salts have a significant gastro-cytoprotective effect and also have an order of magnitude greater potency against the compounds known hitherto.

According to the invention, the novel cyclohexylsulfonylacrylic acid of formula (I) and derivatives thereof, wherein R is as defined above, can be prepared by:

(i) oxidizing 3-cyclohexylthio-2 (Z) -propenoic acid (Π) in the preparation of compounds of formula (I) wherein R is hydroxy; (ii) in preparing compounds of formula (I), wherein R is other than a hydroxyl group of formula (I) wherein:

R is a hydroxyl compound or an activated derivative thereof

(a) halogen phenol, or

(b) C 1-4 alkanol, or

c) a piperazine derivative of the Formula III wherein:

R ¹ is C 1-4 alkoxycarbonyl or

C 1-4 alkylcarbonylphenyl or 3,4- (methylenedioxy) benzyl - or

d) an amine derivative of the Formula IV: wherein:

R ² is 2- (C 1 -C 4 alkoxy) carbonylethyl or 1-ethyl-2-pyrrolidinylmethyl or

e) L-proline benzyl ester, or

f) reacting with diazomethane.

(iii) for compounds of the formula I in which:

R is 4- (C 1 -C 4 alkyl) carbonylphenyl-1-piperazinyl, 2- (C 1 -C 4 alkoxy) carbonyl ethyl amino or 1-ethyl-2-pyrrolidinylmethylamino. converting said basic compound into an acid addition salt.

Preferably, the process of the present invention may be carried out, for example, by reacting a compound of formula I wherein R is hydroxy with a compound of formula III

It is prepared from 3-cyclohexylthio-2 (Z) -propenoic acid by oxidation, preferably by heating in a solution of glacial acetic acid containing hydrogen peroxide. The reaction was carried out in glacial acetic acid containing 30% hydrogen peroxide (3 hours at 100 ° C) in about 80% yield. The compound of formula (II) may be prepared in a manner known in the art, see B. Weibull, Arkiv. To ask. 3, 225-188 (1951)], by reaction of stoichiometric cyclohexyl mercaptan with propionic acid in aqueous sodium hydroxide solution.

The other starting compounds are known commercially available compounds.

The compounds of formula (I) of the present invention wherein R is C 1 -C 4 alkyl, halo-substituted phenyloxy, the compound of formula (I) wherein R is hydroxy are known in the art.

EN 210 930 Β of the resulting activated derivative thereof by acylating the corresponding C 1-4 alkanol or an optionally substituted phenol.

The activated derivative is preferably an acid halide, preferably acid chloride.

The acid chloride derivative is prepared from the corresponding acid, preferably thionyl chloride, by heating for a few hours, and the acid chloride obtained after evaporation of the excess thionyl chloride can be used directly without purification in the acylation step.

The acylation of the compounds of formula (I) wherein R is hydroxy is conveniently carried out in the presence of a minimal stoichiometric amount of the inhaled base, preferably triethylamine, in an inorganic organic solvent, preferably anhydrous dichloromethane, preferably at about 0 ° C. temperature.

Derivatives activated on the carboxy group of a compound of formula (I) wherein R is hydroxy (e.g., mixed anhydride or dicyclohexylcarbodiimide) may be prepared by methods known in the art, such as M. Bodánszky, Principles of Peptide Synthesis. 9-52 of his monograph. SpringerVerlang, Berlin, Heidelberg, New York, Tokyo, 1984.

Compounds of formula (I) according to the present invention wherein R is

4- (C 1 -C 4 alkoxy) carbonyl-1-piperazinyl,

4- (C 1 -C 4 alkyl) carbonylphenyl-1-piperazinyl,

4-piperonyl-1-piperazinyl,

2- (C1-C4-alkoxy) -carbonylethylamino;

ethyl-2-pyrrolidinylmethylamino or 2-benzyloxycarbonyl-1-pyrrolidinyl derived from L-proline may also be prepared from compounds of formula (I) wherein R is hydroxy.

The above-described carboxyl-activated derivative, preferably acid chloride, is reacted with an appropriate base listed below in an inert organic solvent, preferably anhydrous dichloromethane, under reflux: ethoxycarbonylpiperazine, 4-piperazino,

1-piperonylpiperazine, β-alanine alkyl ester, L-proline benzyl ester, or 1-ethyl-2- (methylamino) pyrrolidine.

In general, it is convenient to carry out the reactions in the presence of an inert base, preferably in a stoichiometric ratio, preferably triethylamine. However, it is also possible to react the acid chloride of the compound of formula I, wherein R is hydroxy, with a base component in a minimum of two stoichiometric ratios.

The compounds of formula I wherein R is methyl may also be prepared by reacting a compound of formula I wherein R is hydroxy with diazomethane in the absence of an activating reagent.

The compounds of the present invention may be formulated in pharmaceutical compositions with non-toxic, inert solid or liquid carriers and / or excipients which are conventional for parenteral or enteral administration. Suitable carriers include, for example, water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil and the like. It can be used. The active ingredient may be in the form of conventional pharmaceutical compositions, such as in particular solid forms such as round or square tablets, dragees, capsules such as gelatin capsules, pills, suppositories and the like. in the form of.

The compositions may optionally contain conventional pharmaceutical excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, and the like. also contain. They may be prepared by conventional techniques, such as sieving, mixing, granulating and pressing the components in the case of solid compositions. The compositions may also be subjected to other conventional pharmaceutical techniques such as sterilization.

The process of the present invention is illustrated by the following examples, without limiting the scope of the invention to these examples.

Example 1

3-cyclohexylsulfonyl-2 (Z) -propenoic

5.55 g (29.9 mmol) of 3- (cyclohexylthio) -2-propenoic acid,

A mixture of 11.9 ml of 30% hydrogen peroxide and 60 ml of glacial acetic acid was stirred for 3 hours at 10 ° C. The reaction mixture was evaporated and the residual oil crystallized with n-hexane. The title product weighed 5.3 g. Melting point: 55-57 ° C.

R _f : 0.27 (pyridine / glacial acetic acid / water / ethyl acetate: 16/5/9/70). Yield: 81%.

Example 2

3- (Cyclohexyl-sulfonyl) -2 (E) -propenoic acid (4-chloro-phenyl) ester

a) 3- (Cyclohexylsulfonyl) -2 (E) -propenoyl chloride 4.37 g (0.02 mol) of 3- (cyclohexylsulfonyl) -2 (Z) -propenoic acid are dissolved in 30 ml of thionyl chloride and the the solution was heated at reflux for 3 hours. After evaporation of the thionyl chloride, the residue was dissolved in 20 ml of anhydrous dichloromethane and used directly in the acylation reaction.

b) 2.57 g (0.02 mol) of 4-chlorophenol are dissolved in 30 ml of anhydrous dichloromethane and 5.6 ml (0.02 mol) of triethylamine are added and the mixture is cooled to 0 ° C. Add the solution prepared according to a). After stirring at room temperature for one day, the reaction mixture was poured into water (300 mL), extracted with dichloromethane, and then the organic layer was extracted with 1 N hydrochloric acid, water, 5% sodium carbonate solution. The organic phase is dried over anhydrous magnesium sulfate and then evaporated. The residual oil was crystallized with ethyl acetate. The title product weighs 3.1 g.

Melting point: 126-128 ° C.

R _f : 0.64 (benzene / methanol: 14/3).

Yield: (47%).

HU 210 930 Β

Example 3 1- [3- (Cyclohexylsulfonyl) -2 (E) -propenoyl] -4-ethoxycarbonyl-piperazine

7.9 g (0.05 mol) of 4-ethoxycarbonylpiperazine are dissolved in 30 ml of anhydrous dichloromethane. The solution was cooled to + 10 'C and the acid chloride solution prepared in Example 2 (a) was added dropwise with stirring over 15 minutes. The reaction mixture was stirred at room temperature for 24 hours and then poured into water (300 mL). The organic layer was extracted with 1 N hydrochloric acid, water, saturated sodium chloride, in the following order. The organic phase is dried over anhydrous magnesium sulfate and evaporated. The residual oily product was purified by column chromatography (Kieselgel 60, particle size 0.0630.2 mm, eluent: ethyl acetate). The purified product crystallizes upon exposure to n-hexane.

Weight of the title product: 2.3 g.

Melting point: 92-94 ° C.

R _f : 0.42 (Benzene / methanol: 14/3)

Yield: 32%.

Example 4 1- [3- (Cyclohexylsulfonyl) -2 (E) -propenoyl] -4- (4-acetylphenyl) -piperazine

4-Piperazinoacetophenone (4.08 g, 0.02 mol) was dissolved in anhydrous dichloromethane (50 mL). To the solution was added triethylamine (2.8 mL, 0.02 mol), cooled to 0 ° C, and a solution of the acid chloride prepared in Example 2 (a) in dichloromethane was added dropwise. The reaction mixture was stirred at room temperature for one day and then poured into 500 ml of water. Extract twice with dichloromethane, then extract the organic layer with water, then with saturated sodium chloride solution. It is dried over anhydrous magnesium sulfate and then evaporated. The residual oily product was purified by column chromatography (Kieselgel 0.063-0.2; eluent: ethyl acetate / n-hexane: 5/1). The pure product was crystallized from a mixture of methanol and n-hexane.

The title product weighed 5.8 g.

156-157 ° C.

_Rf: 0.31 (ethyl acetate / n-hexane 5/1).

Yield: 71.8%.

Example 5 1-Piperonyl-4- [3- (cyclohexylsulfonyl) -2 (E) -propenoyl] -piperazine

1.41-piperonylpiperazine (4.41 g, 0.02 mol) was dissolved in 50 ml of anhydrous dioxane, followed by addition of triethylamine (2.8 ml, 0.02 mol). The solution was cooled to 10 ° C and a solution of the acid chloride prepared in Example 2 (a) in dioxane was added dropwise. The reaction mixture was stirred at room temperature for one day, then poured into water (500 mL) and extracted with dichloromethane. The organic phase is extracted with water, saturated sodium chloride, in the following order. The organic phase is evaporated after plowing. The residual oil was crystallized from a mixture of methanol and diethyl ether to give 4.2 g of the title compound. Melting point: 129-130 ° C.

R _f : 0.56 (benzene / methanol: 14/3).

Yield: 49.9%.

Example 6

N- [3- (Cyclohexyl-sulfonyl) -2 (E) -propenoyl] - $ - alanine ethyl ester

The hydrochloride salt of β-alanine ethyl ester (3.08 g, 0.02 mol) in anhydrous dichloromethane (50 mL) was treated with 5.6 mL (0.04 mol) + triethylamine. The solution was cooled to 0 ° C and a solution of the acid chloride prepared in Example 2 (a) in dichloromethane was added dropwise. After stirring for one day at room temperature, the reaction mixture was poured into 500 ml of water and extracted with dichloromethane. The organic phase is extracted with water, 1N hydrochloric acid, water, and finally with saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography (Kieselgel 60, particle size: 0.063-0.2; eluent: benzene / acetone / triethylamine: 14/3 / 0.5). The product thus purified crystallized on n-hexane.

3.9 g of the expected product are obtained.

Melting point: 100-102 ° C.

R _f : 0.50 (benzene / acetone / triethylamine: 14/3 / 0.5). Yield: 61%.

Example 7] - [3- (Cyclohexylsulfonyl) -2 (E) -propenoyl] -2 (S) pyrrolidine-carboxylic acid benzyl ester

4.7 g (0.02 mol) of L-proline benzyl ester hydrochloride are suspended in 50 ml of anhydrous dioxane and 5.6 ml (0.04 mol) of triethylamine are added. The suspension is cooled to 10 ° C and a solution of the acid chloride prepared in Example 2 (a) in dioxane is added dropwise. The reaction mixture was stirred at room temperature for one day, then poured into water (500 mL) and extracted with dichloromethane. The organic layer was extracted with 1N hydrochloric acid, water, brine, dried and evaporated. The residual oil was purified by column chromatography (Kieselgel 60, particle size: 0.063-0.2; eluent: ethyl acetate / n-hexane: 3/1). The resulting oil crystallizes from petroleum ether. The title product weighed 2.3 g.

Melting point: 114-116 ° C. [.alpha.] D @ 20: -76.7 DEG (c = 1, chloroform).

R _f : 0.54 (ethyl acetate / n-hexane: 3/1).

Yield: 28.3%.

Example 8

-Ethyl 2 - {[3- (cyclohexylsulfonyl) -2 (E) -propenyl] aminomethyl} -pyrrolidine hydrochloride

1-Ethyl-2- (aminomethyl) pyrrolidine hydrochloride (2.56 g, 0.02 mol) was dissolved in dichloromethane (50 ml) and triethylamine (5.6 ml, 0.04 mol) was added. The mixture was cooled to 0 ° C and the acid chloride prepared according to Example 2 (a) in dichloromethane was added dropwise. After stirring for two days at room temperature, the reaction mixture was poured into water (500 mL) and extracted with dichloromethane. The extract was washed with saturated sodium chloride solution and dried, and the solvent was evaporated. The residual oil was purified by column chromatography (Kieselgel 60, particle size: 0.063-0.2 mm; eluent: acetone / triethylamine: 9/1).

HU 210 930 B

3.8 g of the expected product are obtained.

Melting point: 139-141 ° C.

R _f : 0.60 (acetone / triethylamine: 9/1).

Yield: 52.0%.

Example 9 1- [3-Cyclohexylsulfonyl-2 (Z) -propenoyl] -4-ethoxycarbonyl-piperazine

3.27 g (0.015 mol) of 3-cyclohexylsulfonyl-2 (Z) -propenoic acid in 70 ml of abs. Triethylamine (2.1 mL, 0.015 mol) was added to a solution of tetrahydrofuran, and the solution was cooled to -15 ° C and 1.43 mL (0.0156 mol) of ethyl chloroformate was added dropwise with stirring at this temperature, followed by 2.37 g (0.015 mol) of 1-ethoxycarbonylpiperazine in 15 ml of abs. tetrahydrofuran. The mixture was stirred at -15 ° C for 1 hour, then at room temperature for 1 hour, then poured into water (400 ml) and extracted with dichloromethane (2 x 50 ml). The organic layers were combined, washed with water (10 mL), 1N hydrochloric acid (10 mL), and concentrated over anhydrous magnesium sulfate. The resulting oil was purified by column chromatography. (Eluent: Acetomnhexane 1: 1) The purified oil is evaporated again to give 1.2 g of the title compound in petroleum ether.

Melting point: 108-110 ° C.

Yield: 22.3%.

Example 70

3-cyclohexylsulfonyl-2 (Z) -propenoic acid methyl ester

To a solution of 3-cyclohexylsulfonyl-2 (Z) -propenoic acid (6.47 g, 30 mmol) in dichloromethane (50 mL) was added a solution of diazomethane (33 mmol) in dichloromethane slowly with stirring. The reaction mixture was evaporated in vacuo and purified by column chromatography. (Eluent: ethyl acetate: hexane 3/1) 3.1 g of the title crystalline product are obtained.

Melting point: 69-70 ° C.

Yield: 44.5%.

Example 77

3-Cyclohexyl-szulfcmil-2 (Z) -propenoic acid methyl ester

To a solution of 3-cyclohexylsulfonyl-2 (Z) -propenoic acid (6.47 g, 30 mmol) in dichloromethane (50 mL), methanol (1.2 mL, 30 mmol), dicyclohexylcarbodiimide (6.2 g, 30 mmol) and a catalytic amount of 4 dimethylaminopyridine is added. The reaction mixture was stirred for 8 hours at 20 ° C. The organic phase is then extracted with water, 5% sodium bicarbonate solution, water again, 1N hydrochloric acid, and finally water. The resulting material was dried over anhydrous magnesium sulfate, then concentrated and crystallized. Weight: 3.1 g.

Melting point: 69-70 ° C.

Yield: 46%.

Claims (4)

A process for the preparation of a novel cyclohexylsulfonylacrylic acid of formula (I) and derivatives thereof wherein R is hydroxy; C 1-4 alkoxy, halo-substituted phenyloxy, 4- (C 1 -C 4) alkoxycarbonyl-1-piperazinyl, 4 - [(C 1 -C 4 alkyl) carbonylphenyl] -1-piperazinyl, 4-piperonyl-1-piperazinyl, 2- (C1-C4-alkoxy) -carbonylethylamino; 1-ethyl-2-pyrrolidinylmethylamino; or For the preparation of 2-benzyloxycarbonyl-1-pyrrolidinyl group derived from L-proline and their pharmaceutically acceptable salts, (i) in the preparation of compounds of formula (I) wherein R is hydroxy, the compounds of formula (H) Oxidation of 3-cyclohexylthio-2 (Z) -propenoic acid, ii) in the preparation of compounds of formula I wherein R is other than hydroxy - a compound of formula (I): wherein R is a hydroxyl compound or an activated derivative thereof (a) halogen phenol, or (b) C 1-4 alkanol, or c) with a piperazine derivative of the formula: wherein: R ¹ is C 1 -C 4 alkoxycarbonyl or C 1 -C 4 alkylcarbonylphenyl or 3,4-methylenedioxy-benzyl - or d) an amine derivative of the Formula IV: wherein: R ² is 2- (C 1 -C 4 alkoxy) carbonyl ethyl or 1-ethyl-2-pyrrolidinylmethyl - or e) L-proline benzyl ester, or f) reacting with diazomethane and optionally iii) for compounds of formula I wherein R is 4- (C 1-4 alkyl) carbonylphenyl-1-piperazinyl, 2- (C 1-4 alkoxy) carbonyl; ethylamino or 1-ethyl-2-pyrrolidinylmethylamino converting the resulting basic compound into a pharmaceutically acceptable acid addition salt. Process for the preparation of a pharmaceutical composition, characterized in that the novel cyclohexylsulfonylacrylic acid or a derivative thereof represented by the process according to claim 1, in which R represents a hydroxy group, C1-C4 alkoxy substituted with halo phenyloxy, 4- (C 1 -C 4 alkoxy) carbonyl-2-piperazinyl, 4 - [(C 1 -C 1 alkyl) carbonylphenyl] -1-piperazinyl, 4-piperonyl-1-piperazinyl group, 2- (C1-C4-alkoxy) -carbonylethylamino; 1-ethyl-2-pyrrolidinylaminomethyl; or The 2-benzyloxycarbonyl-1-pyrrolidinyl group derived from L-proline, or a pharmaceutically acceptable salt thereof, is admixed with pharmaceutically acceptable carriers and / or excipients. HU 210 930 Β Int.Cl. ⁶ : C07C317 / 24 II sII c = c-c I H S-C = C-COOH I I Η H (II) ΓΆ n1 HN ^ / N-Rl (III) H ₂ NR ² Published by the National Office for Inventions, Budapest Responsible: Gyurcsekné Philipp Clarisse Head of Unit ARCANUM Databases - BUDAPEST (IV)