DK142951B - ANALOGY PROCEDURE FOR THE PREPARATION OF SPIROLACTONES - Google Patents

Description

(11) PUBLICATION MANUAL 142951 DENMARK <«'> int ci' o o? j 21/00 '(21) Application No 4542/78 (22) Filed on 12 Oct. 1978 (24) Live day 1 6th nov. 1977 (44) The application made on the basis of the subpoena publication published on 2 pm. 1981

DIRECTORATE OF

THE PATENT AND TRADE MARKET (3 °) P "®" ** ^ den

Nov 16 1976, 2652761, J) E

(71> SCHERING AKTIENGESELLS CHAPT, Berlin and Bergkamen, Muellers trass a 170-T78, 1 Berlin 65 * DE.

(72) inventor: Rudolf Wieehert, Petzow ers tr as se 8A, 1000 Berlin 59 * DE: Die = ter Bittier, Boellcauer Pfad 11, 1000 Berlin 27 * DE: Ulrich Kerb, Prinz = regent's race 7 * 1000 Berlin 51 * DE: Jorge Uasals-Stenzel * Wicherrt = strasse 20, 1000 Berlin 53 * DE: Wolfgang Losert * Niedstrasse 12, 1000 Berlin 4l, BE. ~ (74) Plenipotentiary in the proceedings:

The company Chas. Hude.

(64) Analogous process for the preparation of spirolactones.

The invention relates to an analogous process for the preparation of novel spirolactones of formula I: rf0 CH2 142951 2 wherein the 15, 16-methylene group can. be a- or 3 ~ positioned.

The compounds of the invention possess valuable pharmacological properties. They are, among other things, diuretics of the type α = dosterone antagonists, ie. they reverse the effect of desoxycortico = sterone on sodium and potassium excretion. The compounds of the invention are shown in the test model of Hollmann (G. Hollmann et al., Tubular Wirkungen und renal Elimination of the Spiro lactone, Naunyn-Schmiedebergs Arch. Exp. Path. Pharmak. , Renale Wirkungen des d-Aldosterons und seines Antagonist Spironolactons, Diss. Med. Fak. FU Berlin 1966) surprising in their effect to be superior in comparison to the known spironolactone.

The following table sets forth data for the diuretic effect of compounds prepared in accordance with the invention and for the compound known from DK patent 123,353 63 '73-methylene-20-spirox-4-ene-3,21-dione in comparison with the effect. of spironolactone.

Table.

Substance Relative activity 7α-Acetylthio-3-oxo-4-androsten- [17 (3 ~ 1 *) -spiro-5 '] perhydrofuran-2'-one (Spironolactone) 63,73-methylene-20-spirox-4 en-3,21-dione 1 (0.9 - 1.3) (DK Patent 123,353) 15a, 16a, 63,73-dimethylene-3-oxo-4-androstene [17 (3 "1") - spiro -5 '] perhydrofuran-2'-one 2 (1,7-2,4) 63,73,153,16 3-dimethylene-3-oxo-4-androstentyl? (3-1 ') - spiro-5'] perhydrofuran-2'-one 5 (4,1-6,3)

The process of the invention for the preparation of the above-mentioned spirolactones of formula I is characterized in that methylene Δ 'unsaturated spirolactones of formula II are methylenerated in a manner known per se: 142951 3 , the 7-position.

The methylation of the compounds of formula II takes place according to methods known per se, e.g. by reaction with dimethylsulfoxonium = methylide in an aprotic solvent, such as dimethylsulfoxide, di-methylformamide, dioxane or a mixture of dimethylsulfoxide and tetrahydrofuran, where appropriate working at 20-40 ° C under protective gas such as nitrogen.

The preparation of dimethyl sul foxonium methyl suitably utilizes trimethylsulphoxinoimide iodide or chloride with a base such as sodium pyhydride, sodium hydroxide, potassium tertiary butylate or sodium methylate.

The starting material 15a, 16a-methylene-3-oxo-4,6-androstadien- [17 (0-1 ') - spiro-5'] -perhydrofuran-2'-one can be prepared as follows: 15 g of 30-hydroxy 15a, 15a-methylene-5-androsten-17-one (prepared, for example, according to DOS 2 109,555 is treated in 150 ml of absolute tetrahydrofuran under ice-cooling with 3.6 g of lithium and then 30 ml of drip is added over 30 minutes -bromo-3-dimethoxypropane, After 2 1/2 hours of stirring at ice bath temperature, separate from unreacted lithium and stir the filtrate into ice water.

The precipitated precipitate is filtered off, washed with water and taken up in methylene chloride. After drying and evaporation, the residue is chromatographed on silica gel. Dpr is obtained 16.8 g of 17a- (3'-dimethoxypropyl) -15a, 16a-methylene-5-androsten-30,170-diol. A diisopropyl ether / acetope recrystallized sample melts at 153-159 ° C.

16.5 g of 17a (3'-dimethoxypropyl) -15a, 16a-methylene-5-andrpene-30,170-diol are stirred in 410 ml of 70% acetic acid for 18 hours at room temperature.

It is stirred in ice water, the precipitated precipitate is filtered off, taken up in chloroform and washed with sodium bicarbonate solution and water.

142951 4

After drying and evaporation, the residue is chromatographed on silica gel.

11.5 g of 33-hydroxy-15a, 16a-methylene-5-androsten- [17 (β-1 ') -spiro-51] -perhydrofuran-2'ξ-οΐ are obtained. A diisopropyl ether / acetone recrystallized sample melts at 194-202 ° C.

10.5 g of 3B-hydroxy-15a, 16a-methylene-5-androsten- [17 (β-1 ') - spiro-5'] - perhydrofuran-21ξ-οΐ are treated in 210 ml of absolute toluene with 21 ml of cv = clohexanone and 2 , 1 g of aluminum isopropylate in 20 ml of absolute toluene and heated for 45 minutes under slow distillation. Then diluted with methylene chloride, washed with 2N sulfuric acid and water, dried and evaporated. 11.5 g of crude 15a, 16a-methylene-3-oxo-4-androsten- [17 (B-1 ') -spiro-51] -perhydrofuran-2'-ol are obtained as an oil. A sample purified by thin-layer preparative chromatography and recrystallization from diisopropyl ether / acetone melts at 259-268 ° C.

UV: ε241 = 1G500.

10.5 g of 15a, 16a-methylene-3-oxo-4-androsten- [17 (β-1 ') - spiro-5'] - perhydrofuran-2 'ξ-οΐ are treated in 100 ml of acetone under ice-cooling with 10 ml of chromic sulfuric acid ( prepared from 267 g of CrO4, 400 ml of water and 230 ml of concentrated sulfuric acid, then with water filled to 1 liter) and stirred for 1 hour. Then stir in ice water, wash with water and take up in methylene chloride. After drying and evaporation, the residue is chromatographed on silica gel. 8.2 g of 15a, 16a-methylene-3-oxo-4-androsten- [17 (β-1 ') - spiro-5'] -perhydrofuran-21-one are obtained. A diisopropyl ether / acetone recrystallized sample melts at 180-181 ° C.

UV: ε240 = 16600 · 7.2 g of 15a, 16a-methyl-3-oxo-4-androsten- [17 (β-1 ') - spiro-5'] - perhydro-furan-2'-one are treated in 72 absolute ml of dioxane and 7.2 ml of ortho formic acid = triethyl ester with a solution of 7.2 ml of absolute dioxane and 0.26 ml of concentrated sulfuric acid and stir for 30 minutes at room temperature. Then 2 ml of pyridine is added, diluted with ether, washed with water and dried. After evaporation, 8.5 g of crude 3-ethoxy-15a, 16a-methylene-3,5-androstadien- [17 (3-1 ') -spiro-5'] -perhydrofuran-2'-one are obtained.

UV: ε241 = 15700.

8.5 g of 3-ethoxy-15a, 16a-methylene-3,5-androstadien- [17 (β-1 ') - spiro-5'] - perhydrofuran-2'-one are dissolved in 192 ml of acetone, cooled in an ice bath, treated With 1.32 ml of pyridine, 6.08 g of sodium acetate and 60.8 ml of water, 4.51 g of N-bromosuccinimide was then added and 6.08 ml of acetic acid was added over 10 minutes. Then stir for 1 hour at ice-bath temperature, dilute with ether, wash with water and dry. After evaporation, 9.6 g of crude 63-bromo-3-oxo-4-androsten- [17 (β-1 ') - spiro-5'} - perhydrofuran-21-one are obtained.

9.6 g of 6β-bromo-3-oxo-4-androsten- [17 (β-1 ') -spiro-5'] -perhydrofuran-2 '-one are stirred in 96 ml of dimethylformamide with 3.75 g of lithium carbonate and 4.4 g of lithium bromide for 18 hours at 100 ° C. Then stir in ice water and the precipitated precipitate is sucked off, taken up in methylene chloride, washed with 2N sulfuric acid and water and dried. After evaporation, the residue is chromatographed on silica gel. There are obtained 6.5 g of 15α, 16α-methylene-3-oxo-4,6-andro = stien- [17- (β-1) -spiro-5 '] -perhydrofuran-2'-one. A sample from diisopropyl ether recrystallized melts at 180.5-182.5 ° C.

UV; ε283 ~ 26300.

The starting material 153,16B-methylene-3-oxo-4,6-androstadien- [17 (3-1 ') -spiro-51] -perhydrofuran-21-one can be prepared as follows: 15 g of 3 | 3-hydroxy- 158.16 | 3-Methylene-5-androsten-17-one (prepared, for example, according to German Patent No. 1,593,500) is reacted in 150 ml of absolute tetrahydrofuran with 3.27 g of lithium and 29 ml of l-bromo-3 -dimethoxypropane for 2 hours at ice bath temperature and 4 hours at room temperature. Unreacted lithium is filtered off, the filtrate is stirred in ice water, the precipitate is filtered off and taken up in methylene chloride. After drying and evaporation, the residue is chromatographed on silica gel. 17.4 g of 17α (3'-dimethoxypropyl) -150,163-methylene-5-androsten-30,173-diol are obtained.

17.0 g of 17a- (31-dimethoxypropyl) -15 | 3.16 | 3-methylene-5-androsten-3,3,17 | 3-diol is stirred in 340 ml of 70% acetic acid for 18 hours at room temperature. Then stir in ice water and the precipitated precipitate is filtered off and taken up in methylene chloride. The methylene chloride phase is washed with sodium hydrogen carbonate solution and water, dried and evaporated. 13.8 g of 3β-hydroxy-153,163-methylene-5-androsten- [17 (β-1 ') -spiro-5'] -perhydrofuran-2'-ol are obtained as crude product.

8.8 g of 33-hydroxy-158.16 (3-methylene-5-androsten- [17 (8-1 ') - spiro-5'] - per = hydrofuran-2'ξ-οΐ are treated in 176 ml of absolute toluene and 17.6 ml of cyclo = 6 142951 hexanone with 1.76 g of aluminum isopropylate in 50 ml of absolute toluene and heated for 3 hours under slow distillation, then diluted with ether, washed with 2N sulfuric acid and water, dried and evaporated. 4.3 g of 15β, 16β-methylene-3-oxo-4-androsten- [17 (β-lr) -spiro-5 '] -perhydrofuran-2'-one are obtained. sample melts at 178.5-179.5 ° C.

UV: ε241 * 16500.

4.2 g of 15β, 16β-methylene-3-oxo-4-androsten- [17 (β-1 ') - spiro-5'] - perhydride = furan-2'-one are heated in 84 ml of tertiary butanol with 4, 2 g of chloranil for 18 hours at reflux. The solvent is distilled off in vacuo and the residue is chromatographed on silica gel. For further purification, preparative layer chromatography is used. 1.1 g of 150.16p-methylene-3-oxo-4,6-androstadien- [17 (β-1 ') - spiro-5'] -perhydrofuran-2'-one is obtained as an oil.

UV: ε284 = 25700.

Upon completion of the reaction, the reaction mixture is worked up in the usual manner such as precipitation, extraction, recrystallization and / or chromatography.

The pharmacologically active compounds prepared according to the invention of the general formula I can be used according to per se known galenic methods for drugs, especially for oral application.

The dosage of the compounds of the invention is in humans at 20-500 mg per day. day.

The following examples serve to illustrate the invention.

Example 1 2.75 g of trimethylsulfoxonium iodide is stirred in 57 ml of dimethylsulfoxide with 341 ml of 80% sodium hydride oil suspension for 2 hours at room temperature. To the nearly clear solution is added 2.0 g of 15a, 16a-methylene-3-oxo-4,6-androstadien- [17 (β-1 ') -spiro-51] -perhydrofuran-21-one, and there stir for 24 hours at room temperature.

It is then stirred in ice water and the precipitate is filtered off, washed with water and taken up in methylene chloride. After drying and evaporation

Claims (1)

The residue is purified by several times preparative layer chromatography. 520 mg of 60,70,15a, 16a-dimethylene-3-oxo-4-androsten- [17 (0-1-1) -spiro-5 '] -perhydrofuran-2'-one are obtained. UV: ε266 = 18000 Example 2 1.4 g of trimethylsulfoxonium iodide is stirred in 25 ml of dimethylsulfoxide with 170 mg of 80% sodium hydride oil suspension for 1 1/2 hours under nitrogen. To the nearly clear solution is added 1.0 150,160-methylene-3-oxo-4,6-androstadien- [17 (0-1 ') -spiro-51] -perhydrofuran-2'-one dissolved in 10 ml of dimethyl sulfoxide. After stirring for 24 hours at room temperature, stir in ice water, filter the precipitated precipitate, take up ether, wash with water and dry. The residue obtained after evaporation is purified by several times preparative layer chromatography. 170 mg of 60.70, 150,160-dimethylene-3-oxo-4-androsten- [17 (0-1 ') -spiro-51] -perhydrofuran-2'-one are obtained as an oil. UV; ε266 = 18400. Patent claims. Analogous Process for Preparation of Spirol Lactones of Formula I O [- Formula II: