CS218360B1 - 4- (3β-Acetoxy-5-methyl-19-nor-5β-androst-9-yl-17β-yl) -2-ethoxycarbonyl-1,3-thiazole - Google Patents

Abstract

The invention relates to 4-(3+acetoxy-5-methyl- -19-nor-5/3-androst-9-en-17j3-yl) -2-ethoxycarbonyl-1,3-thiazole and a method for its preparation. The thiazole according to the invention is produced by partially hydrolyzing the corresponding 3,21-diacetoxy derivative of pregna-20- -one to a 21-hydroxy compound, the OH group of which was converted to bromine via mesylate, and the 21-bromoketone thus formed was condensed with thioxamate to give the compound according to the invention. Similar substances of the type of the aforementioned steroidal thiazole serve as analogues of cardiotonically active steroids with proven efficacy and lower toxicity. The advantage of the compound according to the invention is its easier preparation and the fact that this substance does not exhibit hormonal-type efficacy.

Description

The invention relates to 4- (3 + acetoxy-5-methyl-19-nor-5β-androst-9-en-17β-yl) -2-ethoxycarbonyl-1,3-thiazole and a process for its preparation.

The thiazole of the present invention is produced by partially hydrolyzing the corresponding pregna-20-one 3,21-diacetoxy derivative to a 21-hydroxy compound whose OH group is converted to bromine via the mesylate and the 21-bromoketone thus formed is condensed with thioxamate to the compound of invention. Similar substances of the aforementioned sterile thiazole type serve as analogs of cardiotonically active steroids with proven efficacy and lower toxicity.

The advantage of the compound of the invention is the ease of preparation and the fact that it does not exhibit hormonal type activity.

The present invention relates to 4- (3,3-acetoxy-5-methyl-19-nor-5,3-androst-9-en-17H-yl) -2-ethoxycarbonyl-1,3-thiazole and a process for its preparation.

Similar compounds of said steroid thiazole serve as analogues of cardiotonic active substances with proven efficacy and lower toxicity [Ralls J.W. et al. U.S. Pat. 2,793,207 (1957); Chem. Abstr. 52, 464g (1958) and possibly Takamura K. et al., Chem. Pharm. Bull. (Tokyo) 11, 604 and 613 (1963)], with no 14/3-hydroxy group present commonly present in cardiotonic steroids ( see, for example, Černý V. et al., Chemistry of Steroid Compounds, Publishing House of the Czechoslovak Academy of Sciences, Prague 1960, pp. 909-1110), and may not even have a 3/3-hydroxy group glycosylated systems containing other polar unsaturated substituents are common, require the presence of the cited 14/3-hydroxy group [Thomas R. et al. J. Pharm. Sci. 63, 1649 (1974)], which makes cardiotonic steroids difficult and costly to prepare.

Since these highly potent drugs have so far been isolated for pharmacological purposes from natural material, such as plants such as foxglove (Digitalls) or from skins of toads (Bufo), where they are contained in small quantities, their high cost is proportional difficulty of preparation.

On the other hand, in addition to the ease of preparation and the cited lower toxicity, the compounds of the invention are also notable from the literature to show hormonal-type activity.

The present invention provides a novel compound 4- (3/3-acetoxy-5-methyl-19-nor-5S-androst-9-en-17/3-yl) -2-ethoxycarbonyl-1,3-thiazole of formula (I).

Said compound is prepared by treating a derivative of formula (II),

wherein R ¹ is H or an acyl of one to four carbons and R ² is chlorine, a 1: 1 molar ratio of tributyltin hydride in benzene at 50 to 80 ° C with the addition of azo-bis-2-methylpropionitrile or UV light and after evaporation, the residue dissolved in a mixture of benzene and methanol is treated with a base, preferably potassium bicarbonate, in a small amount of water at a temperature of 20 to 80 ° C for 5 minutes to 5 hours and after purification the intermediate obtained is reacted first with methanesulfonyl chloride in pyridine and then with a hydrobromic acid salt, preferably lithium bromide or tetrabutylammonium bromide, and after purification of the intermediate with the thioamide of formula III,

WITH

C — R ³ , /

HzN (III), wherein R ³ is COOC ² H 5, at 0 to 180 ° C for 1 hour to 5 days.

The following are examples of a process for the preparation of novel compounds including intermediates of the invention.

He did

3 / 3,21-Diacetoxy-6/3-chloro-5-methyl-19-nor-5/3-pregn-9-en-20-one (3.5 g) was refluxed in benzene with tributyltin hydride (2, After evaporation of the reaction mixture, the residue was chromatographed on a silica gel column using petroleum ether-benzene (96: 4) to give 3, [beta], 21-diacetoxy-5-methyl-. 19-nor-5S-pregn-9-en-20-one [2 g mp 92-94 ° C, [α] _D ²⁵ +140 ° C (c 1.7; chloroform)] was dissolved in a mixture of benzene and methanol (1: 5) and treated with potassium bicarbonate solution (3 gj in water (60 mL) for 1 hour at 50 ° C) The reaction mixture was evaporated to 1/5 and the residue was partitioned between water and ether, ether The layer was washed with water and dried over sodium sulfate and evaporated to give 1.7 g of 3/3-acetoxy-21-hydroxy-5-methyl-19-nor-5/3-pregn after evaporation. -9-en-20-one as an oil at (α) _D ²⁵ + 100 ° C (c 1.5, chloroform), which was dissolved in pyridine (40 mL), to the solution was added methanesulfonyl chloride (1 mL) while cooling the reaction mixture in an ice bath. The mixture was left at 0 ° C for 3 hours and then partitioned between ice water and ether. The ether extracts were washed with 5% aqueous hydrochloric acid, saturated sodium bicarbonate solution and water. Filtration with activated carbon and magnesium sulfate and crystallization from benzene-ether gave 1.58 g of 3, N-acetoxy-21-methanesulfonyloxy-5-methyl-19-nor-5/3-pregn 9-en-20 153 DEG -157 DEG C. [.alpha.] D @ ²⁵ +129 (c 2.1, chloroform) which was dissolved in acetone (50 ml) and lithium bromide (3.2 g) was added. The mixture was stirred with heating at 50 ° C for 30 minutes, then filtered through a silica gel column which was washed with benzene. The filtrate containing 3R-acetoxy-21-bromo-5-methyl-19-nor-5β-pregn-9-en-20-one was evaporated and dissolved in acetonitrile (50 mL) and ethylthioxamate (665 mg) was added. ). The mixture was heated to boiling for 18 hours, then partitioned between benzene and water and the aqueous washed with ether. The combined organic extracts were evaporated after drying over magnesium sulfate. The residue was chromatographed on silica gel with 4: 1 benzene ether. 800 mg of 4- (3/3-acetoxy-5-methyl-19-nor-5/3-andr-9-ene-17 / 3-) was obtained. yl) -2-methoxycarbonyl-1,3-thiazole as an oil, [α] D ²⁵ + 10.2 ° C (c 2, chloroform), IC spectrum (chloroform): 1728, 1260, 1028 cm ^-1 (CHCOO) 1605, 1505 cm -1 (thiazole), 1715, 1305,

1095 cm ^-1 (ethoxycarbonylthiazole). Mass spectrum (m / z): 471 (M < + >). For

C27H37O4SN (471.66) calculated: 68.76% C, 7.91% H, 6.80% S.

Example 2

The preparation of the thiazole of formula (I) was carried out according to Example 1, except that at the reflux of the first reaction mixture with tributyltin hydride, azo-bis-2-methylpropionitrile was not added to the mixture but treated with UV light 125W mercury. C until reacting.

The obtained 3,3,3,2-diacetoxy-5-methyl-19-nor-5/3-pregn-9-en-20-one (2 g) was dissolved in a 1: 5 mixture of benzene and methanol and treated with a solution. potassium bicarbonate (3 g) in water (55 mL) for 5 hours at room temperature. Example 1 was followed.

Example 3

The preparation of the thiazole of formula (I) was carried out according to Example 1 except that in the final phase the residue was 3/3-acetoxy-21-bromo-5-methyl-19-nor-5/3-pregn-9-en-20- It was dissolved in dimethylformamide (50 mL) and ethyl thioxamate (670 mg) was added. The mixture was heated to 155 ° C for 110 minutes, then poured onto ice.

After thawing the ice, the precipitate was filtered off and washed with water and dried. Chromatography in benzene ether (4: 1) yielded 794 mg of thiazole of formula I, with the same properties as in Example 1.

Claims (2)

SUBJECT OF THE INVENTION 1. 4- (3/3-Acetoxy-5-methyl-19-nor-5/3-androst-9-en-17/3-yl) -2-ethoxycarbonyl-1,3-thiazole of formula I. CH 2 OO 4 -COO ^ Hy (I) 2. A process for the preparation of a compound of formula (I) according to claim 1, which comprises treating a derivative of formula (II) wherein R @ ^{1 is} H or acyl of one to four carbons and R @ ^{2 is} chlorine. 50-80 ° C with the addition of azo-bls-2-methylpropionitrile or UV light and after evaporation, the residue dissolved in a mixture of benzene and methanol is treated with a base, preferably potassium bicarbonate, in a small amount of water at temperature from 20 to 80 ° C for 5 minutes to 5 hours and after purification, the obtained intermediate is reacted first with methanesulfonyl chloride in pyridine and then with a hydrobromic acid salt, preferably lithium bromide or tetrabutylammonium bromide, and after purification of the intermediate with the thioamide III, WITH V, C — R3 OF H 2 N (III) wherein R ⁵ is COOQ 2 H ⁵ , at 0 ° C to 180 ° C for 1 hour to 5 days.