CH636613A5 - Process for preparing thiophene derivatives - Google Patents

Description

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2nd

PATENT CLAIMS 1. Process for the preparation of thiophene derivatives of the formula (I)

fertilize quite lengthy due to numerous stages. “Suprofen” has the following formula ckco2k a - b - ch.

in the

A is the ethylene, propylene, ethenylene or propenylene group and

B represents the carbonyl or a hydroxymethylene group which is esterified with a pharmacologically acceptable carboxylic acid having up to 12 carbon atoms, characterized in that

(a) a compound of the formula (VI)

a - b - ch.

acylated with an acylating derivative of a thienyl carboxylic acid, or

(b) thiophene with an acylating derivative of an acid of the formula (VII)

and is described in the journal "Arzneimittelforschung" 25 (11), 1975, and in GB-PS 1446 239.

A group of non-acidic anti-inflammatory agents has now been found which shows a lower level of susceptibility to causing side effects, such as gastrointestinal irritation, and which can be prepared using significantly shorter synthetic steps.

The present invention relates to the preparation of thiophene derivatives of the general formula (I)

a - b - ch.

(I)

A

B

CH3 (VII)

in which B has the meaning given above, acylated.

2. The method according to claim 1, characterized in that

that a compound is used in which the radical A is the 4s propylene group.

3. The method according to claims 1 or 2, characterized in that one uses a compound in which the radical B is the carbonyl group.

4. The method according to any one of claims 1 to 3, characterized in that thienoyl chloride is used as the acylating derivative of thienyl carboxylic acid in the presence of a Lewis acid.

5. The method according to claim 4, characterized in

that 2-thienoyl chloride is used as the acylating derivative in the presence of aluminum chloride or 3-thienoyl chloride in the presence of antimony pentachloride.

6. A process for the preparation of a compound of the formula I in which A has the meaning given in claim 1 and B is the hydroxymethylene group, characterized in that a compound of the formula I in which B is a cabonyl group is prepared in accordance with claim 1 and this is subsequently reduced.

Acidic anti-inflammatory agents, such as "Suprofen", can have side effects on the gastrointestinal tract. In addition, the manufacture of such connections

in the

30 A is the ethylene, propylene, ethenylene or propenylene group and

B represents the carbonyl or a hydroxymethylene group, which is optionally esterified with a pharmacologically acceptable carboxylic acid having up to 12 carbon atoms.

Suitable hydrocarbon radicals of such carboxylic acids are alkyl, alkenyl, aryl, aralkyl radicals or the like, which are represented by carboxyl, carboxamide, hydroxyl, amino groups or by alkoxy, acyloxy, acylamino, alkylamino or dialkylamino radicals or by salt form Amino groups or the like can be substituted. Such a hydrocarbon radical expediently has up to 8 carbon atoms.

Preferred hydrocarbon radicals of these carboxylic acids are the phenyl group, alkyl radicals having 1 to 4 carbon atoms, which can be substituted by phenyl groups, the preferred hydrocarbon radicals also being hydroxyl, acetoxy, methoxy, acetamido, carboxy, amino groups, amino groups in salt form, Alkyl amino radicals with 1 to 4 carbon atoms or dialkylamino radicals with 1 to 4 carbon atoms can be substituted.

Particularly suitable hydrocarbon radicals of the carboxylic acids are alkyl radicals with 1 to 4 carbon atoms, such as the methyl, ethyl and n-propyl group, and furthermore the phenyl, benzyl, phenylethyl, acetoxymethyl, methoxymethyl, hydroxymethyl, Aminomethyl, 2-acetoxy-phenyl, 4-methoxyphenyl, 3,4-dimethoxy-phenyl or the 3,4,5-trimethoxy-phenyl group.

The radical B is expediently the carbonyl or the hydroxymethylene group, the latter being esterified with a carboxylic acid which has 1 to 4 carbon atoms in the alkyl radical.

The phenyl radical of the thiophene-65 derivatives is most appropriately disubstituted in the 1- and 4-positions, since such compounds can be prepared in a particularly simple manner, as is described below.

Particularly suitable connections of the general

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636613

my formula (I) those of the general formulas (II) and (III) below

a - b - ch.

(ii)

a - b - ch.

(iii)

in which the radicals A and B is the one indicated above and in which the radical A denotes the propylene group.

Have meanings.

Favorable results are obtained with thiophene derivatives of the general formulas (I), (II) and (III), in which the radical B is the carbonyl or the hydroxymethylene group

Accordingly, the further thiophene derivatives of the general formulas (IV) and (V) obtained according to the invention are particularly suitable:

chch3 - ch2 - b - ch3

(iv)

chch3 - ch2 - b - ch3

(v)

in which the radical B has the meanings given for the general formula (I).

In the case of the thiophene derivatives of the general formulas (IV) and (V), the radical B is particularly expediently the hydroxymethylene group, particularly advantageously the carbonyl group.

These aforementioned compounds have a chiral center and can therefore be in the form of the R or S isomers or mixtures thereof, such as the R, S form.

Those thiophene derivatives in which the radical A is the propylene group have the S or the R, S conformation at the chiral center in a particularly expedient manner, since the S compounds have more effective anti-inflammatory agents than the corresponding R compounds are.

Of interest are therefore medicinal products that contain thiophene derivatives of the general formula (I) and, if appropriate, pharmacologically acceptable carrier materials, diluents, excipients and / or other active ingredients.

The pharmaceutical preparations are usually suitable for oral administration.

The medicinal preparations can be in customary dosage forms, such as tablets, capsules, sachets of a reconstitutable powder or the like. Most expediently, the medicinal products are in the form of single doses with a content of 20 to 600 mg of a compound according to the invention, for example 50 to 400 mg. Medicinal products of this type can be administered once or several times a day, so that the total daily dose for an adult weighing 70 kg is of the order of 40 to 1200 mg, for example 100 to 600 mg.

The pharmaceutical preparations can be prepared in a conventional manner by mixing, filling, tableting and the like, and they can be conventional excipients such as lubricants, disintegrants, binders, fillers, coloring and

Flavorings and the like. The medicinal products can be formulated in a manner known per se, as has been described for known anti-inflammatory agents such as indomethacin, naproxen, ketoprofen, phenylbutazone or the like.

The present invention relates to processes for the preparation of the thiophene derivatives of the general formula 40 (I), which are characterized by claims 1 and 6.

Aromatic acylation usually takes place under customary Friedel-Crafts conditions, for example using an acid chloride in the presence of a Lewis acid, such as aluminum chloride or antimony chloride, in an inert solvent, such as carbon disulfide or methylene chloride.

Such a reaction is most appropriately applied to a compound of the general formulas (VI) or (VII) in which the radical B is the carbonyl group.

The compounds produced according to the invention, in which B is the carbonyl group, can be further processed by reduction to compounds in which the radical B is the hydroxymethylene group. The reaction can be carried out using sodium borohydride in a solvent such as ethynol or by using lithium aluminum hydride in a solvent such as diethyl ether followed by regeneration of the diaryl ketone using manganese dioxide in an inert solvent such as benzene.

The variant (a) of claim 1 is usually used for the preparation of p-substituted compounds of the general formulas (II) and (III). Variant (b) of claim 2 is usually used to prepare the 65 2-thienyl derivatives of the general formula (I). It is emphasized that these short procedures leading to the connections are very expedient.

The examples illustrate the invention.

636613

4th

example 1

4- [4 '- (2' -Thienoyl) phenyl] pentan-2-one

A mixture of 15 g of 4-phenyl-pentan-2-one and 12.8 g of thienyl-2-carboxylic acid chloride is added dropwise to a stirred mixture of 39 g of aluminum chloride in 150 ml of carbon disulfide at 0 ° C. over the course of 60 minutes. After leaving the dark solution obtained overnight at room temperature, the upper layer is decanted and the lower, more viscous layer is carefully poured into about 500 ml of cold water. The crude product is extracted three times with 150 ml of chloroform. The extracts are combined, washed with 200 ml of dilute sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is distilled at 0.08 torr (bp. 190 ° C.). The oil obtained crystallizes from a mixture of ethyl acetate and petroleum ether, and pure 4- [4 '- (2'-thienoyl) phenyl] pentan-2-one of mp 60-61 ° C is obtained.

Example 2

4- [4 '- (2' -Thienoyl) phenyl] butan-2-one

The procedure of Example 1 is repeated, but with the proviso that benzylacetone is used instead of 4-phenylpentan-2-one. The rather crude product initially produced is recrystallized from a mixture of carbon tetrachloride and hexane, and pure 4- [4 '- (2' -Thienoyl) phenyl] butan-2-one, mp 77-78 ° C, is obtained .

Example 3

4- [4 '- (3' -Thienoyl) phenyl] butan-2-one

To a stirred mixture of 3.0 g of 3-thienoyl chloride and 3.0 g of benzylacetone in 50 ml of methylene chloride, 3.3 ml of antimony pentachloride are added dropwise at 0 ° C. over the course of 30 minutes. Then the reaction mixture is left to stand for a further 30 minutes at 0 ° C. and finally for 3 hours at room temperature, a further 3.3 ml of antimony pentachloride is added and the amber-colored solution is left to stand for another 60 minutes at room temperature before being cold in about 50 to 60 ml poured dilute hydrochloric acid. The aqueous layer is separated and washed twice with 100 ml of chloroform. The combined organic layers are washed successively with about 100 ml of dilute aqueous sodium bicarbonate solution and about 100 ml of water, then dried over anhydrous sodium sulfate and evaporated under reduced pressure. 4.4 g of an oily crude product are obtained, which is chromatographed on silica. A mixture of ether and petroleum ether with a boiling range of 40 to 60 ° C is used as the eluent. A pale yellow oil is eluted, which solidifies on standing to a pale amber-colored solid (1.1 g). This solid is chromatographed again, and 400 mg of a colorless solid is obtained, which is recrystallized from a mixture of ether and pentane and analytically pure 4- [4 '- (3'-thienoyl) phenyl] butan-2-one from Mp. 63 to 64 ° C provides.

Example 4

5-4- [4 '- (2' -Thienoyl) phenyl] pentan-2-one

A mixture of 9.4 g of S-4-phenylpentan-2-one and 8.02 g is added dropwise at 0 ° C. to a stirred mixture of 24.45 g of aluminum trichloride in 95 ml of carbon disulphide over the course of 60 minutes Thienyl-2-carboxylic acid chloride. After the dark solution obtained has been stirred for 24 hours at room temperature, the upper layer is decanted and the lower viscous layer is carefully poured into about 300 ml of ice-cold, dilute hydrochloric acid. The crude product is extracted three times with 100 ml of chloroform. The combined extracts are washed with 120 ml of dilute sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is distilled at 176 to 178 ° C and 0.08 Torr and 9 g of a dark colored oil is obtained, which is chromatographed on aluminum oxide using hexane with increasing amounts of ether as the eluent. 5.9 g of analytically pure S-4- [4 '- (2'-thienoyl) phenyl] pentan-2-one are obtained with an optical rotation [a] b8.5 = -76.53 ° (in benzene ).

The starting compound S-4-phenyl-pentan-2-one is made from S-3-phenyl-butyric acid ([a] o = -60.05 ° in benzene, by the method of H. Rupe in "Liebigs Annalen der Chemie" 369 (1901), 311) via the acid chloride by the following procedure.

100 ml of a 2 m solution of methyl lithium in ether (0.2 mol) are added dropwise at 0 ° C. under nitrogen to 19 g (0.1 mol) copper (I) iodide in 60 ml anhydrous ether. The solution is stirred at 0 ° C. for 10 minutes, cooled to -65 ° C. and S-3-phenyl-butyric acid chloride, which consists of 4.93 g (0.03 mol) of S-3-phenyl-butyric acid and 10 ml of oxalyl chloride has been prepared in 60 ml of anhydrous ether. After 15 minutes, 33 ml of methanol are added dropwise at -65 ° C. When the resulting mixture has reached a temperature of -30 ° C, dilute hydrochloric acid is added to neutralize the solution. Then the mixture is filtered through diatomaceous earth. The ethereal layer is separated and the aqueous layer extracted again with ether. The combined organic layers are then washed with water and dilute sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated. After distillation, 4.1 g of pure S-4-phenyl-pentan-2-one having a boiling point of 110 ° C./11 torr are obtained.

Md = -74.5 ° (in benzene).

Example 5

R-4- [4 '- (2' -Thienoyl) phenyl] pentan-2-one

The procedure of Example 4 is repeated, but with the proviso that R-4-phenyl-pentan-2-one is used as the starting compound. Pure R-4- [4 '- (2'-thienoyl) phenyl] pentan-2-one is obtained with an optical rotation [alò8.5 = + 72.08 ° (in benzene).

The R-4-phenyl-pentan-2-one used as the starting compound is made from R-3-phenyl-butyric acid ([a] "'3 = 57.12 ° in benzene, according to the method of A. Weidler and G. Bergson in "Acta. Chem. Scand." 18 (1964), p. 1484) on the acid chloride as follows.

A mixture of 1.7 ml of ethanol and 0.34 ml of carbon tetrachloride is added dropwise to 5.33 g of anhydrous magnesium. After the exothermic reaction has subsided, 35 ml of ether are carefully added. Then 35.56 g of diethyl malonate, 35 ml of ether and 17.5 ml of ethanol are added at such a rate that the solution remains under reflux at the boil. Boiling is continued overnight. R-3-phenyl-butyric acid chloride, which has been prepared from 28.29 g of R-3-phenyl-butyric acid and oxalyl chloride, in 100 ml of ether is then added dropwise to the resulting stirred solution, the solution being kept at reflux at the boil and then continue boiling for another 4 hours. After acidification with dilute hydrochloric acid, the aqueous layer is extracted with ether and the organic layers are combined, which are washed with water and then evaporated. The resulting oily crude product is then treated for 5 hours with 45 ml of dimethyl sulfoxide and 7 ml of water at 140 ° C. After working up in the usual way, 24.7 g of pure R-4-phenylpentan-2-one having a boiling point of 110 ° C. at 11 torr, [ajo 0 = + 73.0 ° (in benzene).

pharmacology

The thiophene derivative of Example 1 shows in one verse

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administration of 10 mg / kg body weight has a good anti-inflammatory activity in the carrageenin-induced edema test. At a dose of 10 mg / kg body weight, the thiophene derivative of Example 1 does not cause serious irritation in the stomachs of the test animals. When the thiophene derivative of Example 1 is examined in the phenyl-quinone-induced tail curvature test, it shows an ED 50 value of 4.2 mg / kg body weight, while the compound “Suprofen” has an ED 50 value of 0.78.

5 636 613

The thiophene derivative of Example 4 produces a 47 percent inhibition in the carrageenin test when administered at 125 mg / kg body weight and a 52 percent inhibition when administered at 25 mg / kg body weight. In this test, the thiophene derivative of Example 5 elicits 36 percent inhibition when administered at 125 mg / kg body weight, but only 14 percent inhibition when administered at 25 mg / kg body weight.

B