NO140305B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF NEW D-HOMOSTEROIDS WITH ALDOSTERONE ANTAGONISTIC EFFECT - Google Patents

Description

The present invention relates to new D-homostroids of the formula

where the stripped bond in the 16,17 position is optional, and R 7 is alkanoylthio with up to 7 C atoms or alkylthio with up to 6 C atoms.

Examples of C^_^-alkanoyl residues are residues of carboxylic acids such as formic, acetic, pivalinic, propionic, butyric, caproic and

oenantic acid. Examples of C1_g-alkyl groups are methyl, ethyl, propyl and butyl.

Of particular interest is the 7α-acetyl-thio-3-oxo-D-homo-21,24-dinor-17aa-chola-4,16-diene-23,17α-lactone.

The D homosteroids of formula I are obtained according to the invention by reacting a D homosteroid of the formula

with a compound R " I -H, where R has the aforementioned meaning.

The introduction of the substituent R 7 in a D-homosteroid of the formula V can take place in a manner known per se by treating the steroid with a thiocarboxylic acid. The reaction can be carried out in an inert solvent such as an ether, e.g. dioxane or tetrahydrofuran, or an alcohol, such as methanol or ethanol, or in a chlorohydrocarbon, such as chloroform. The thiocarboxylic acid is suitably used in excess and can then serve as a solvent.

The compounds of formula V are new. They can be produced by known methods or analogously to the subsequently described methods. D-homosteroids of formula I exhibit pharmacological effects, and of particular interest is their effect on the mineral household in the body. Thus, they can i.a. find use for flushing out oedemas, such as e.g. is caused by heart failure.

Pharmacological trial A

Test for aldosterone antagonists

7α-acetylthio-3-oxo-21, 24-dinor-17ct-chol-4-ene-23,17α-lactone (= 7α-acetylthio-17α-(2-carboxyethyl)-173-hydroxy-A4 -androstene-3 -on-lactone, Spironolactone) A;

7a-acetylthio-3-oxo-D-homo-21,24-dinor-17aa-chol-4-ene-23,17a-lactone B

and

7α-acetylthio - 3-oxo-D-homo-21,24-dinor-17aa-chola-4,16-diene-23,17α-lactone C

The experiment was performed with bilaterally adrenalectomized female rats. The test substances were given orally in a 0.3% NaCl/0.5% tragnate suspension. Immediately afterwards, 5 ug per kg injected subcutaneously.

The animals' urine was collected over a period of 3 hours. The calculated Na<+>/K<+->ratio from the total secretion forms a benchmark for aldosterone antagonism. The following results were obtained:

Pharmacological trial B

Progestative effect of 7α-acetylthio - 3-oxo-21,24-dinor-17α-chol-4-ene-23,17α-lactone A

and

7α-acetylthio - 3-oxo-D-homo-21,24-dinor-17aa-chola-4,16-diene-23,17α-lactone C

Progestative effect is shown in the Clauberg experiment in stimulation of proliferation of the endometrium in the rabbit uterus. The preparations are assessed in group average (n = 4) according to the ..McPliail index (0 = no effect; 4 = maximum effect).

The test results are reproduced in the following table:

Pharmacological trial C

Anti-androgenic effect of 7α-acetylthio-3-oxo-21,24-dinor-17α-chol-4-ene-23,17α-lactone A

and

7a-acetylthio-3-oxo-D-homo-21,24-dinor-17aa-chol-4-ene-23,17a-lactone B

Anti-androgen action manifests itself as inhibition of testosterone propionate-induced growth in androgen-dependent organs.

21-day-old male rats were used as experimental animals.

The treatment took place once a day from the 1st to the 6th day, autopsy on the 8th day. The daily dose was injected in 0.4

ml of a solution of 5 g of sodium carboxymethylcellulose,

4 ml Tween 80, 9 ml benzyl alcohol and physiological saline solution ad 1,000 ml. Six animals were used per group. The control group received only the carrier solution, the standard group 0.2 mg per animals per day testosterone propionate s.c., the experimental group the test substance and at the same time testosterone propionate (0.2 mg per

animals per day s.c.)

The inhibition of testosterone propionate-dependent growth and androgen-dependent organs, seminal vesicle, ventral prostate and musculus levator ani was calculated according to the following formula and listed in Table 1:

The results are reproduced in the following table:

As is known from J. Clin. Endocrinol. Metab. 41 (1975)

777 have spironolactone side effects. It has now been found that the compounds of formula I with comparable aldosterone-antagonistic action (See experiment A) do not have these side effects.

As can be seen from trial B, the progestative side effects of the known spironolactone A could be confirmed in the Clauberg trial. In the parallel experiments carried out with compound C according to the present invention, however, no progestative effect was found. Experiment C shows that the known compound A has an anti-androgen side effect

ning which the compound B according to the present invention, on the other hand, does not have. An anti-androgen effect can e.g. lead to potency disorders To the assessment of the percentages in trial C, it must be added that values below 20% must be considered not relevant and that the mean value of the 3 organs must be taken into account.

EXAMPLE 1

A solution of 1.0 g of 3-oxo-D-homo-2},24-dinor-17act-chola-4,6-dien-23,17a-lactone in 6 ml of thioacetic acid was kept for 3 hours at room temperature. The reaction mixture was poured onto ice water and extracted with ether. The ether extract was washed with dilute NaOH and water, dried with Na 2 SO 4 and evaporated in vacuo. The residue was chromatographed over silica gel. The ether/hexane-(1:1) eluates gave pure 7oc-acetylthio-3-oxo-D-homo-21,24-dinor-17aa-chol-4-ene-23,17a-lactone, m.p. 193-195° (methanol), = 1900, [a]^<5> =

-26 (c = 0.1 in dioxane).

The starting material was prepared as follows: 36 - acetoxy-17a - ene in new 1 -17-hydroxy-D-homo-andro st - 5-ene was transferred with butyllithium in the lithium salt, which reacted with CO2 to 33 ,17a8-dihydroxy-D -homo-pregn-5-ene-20-yn-21-carboxylic acid, m.p. 194-196°, [oc]D - -123°. This acid was hydrogenated catalytically in alkaline solution and after anacidification gave 38-. hydroxy-D-homo-21,24-dinor-17aa-chola-5,20-diene-23,17a-lac-tone, m.p. 205-207°, [oc]D = -43°. Catalytic hydrogenation with Pd/C in ethanol finally afforded 3B-hydroxy-D-homo-21,24-di-nor-17aa-chol-5-ene-23,17a-lactone, m.p. 24o-243°, [oc]D = -99°

(c = 0.1 in dioxane).

From a mixture of 12.50 g of 3|3-hydroxy-D-homo-21, 24-dinor-17aa-chol-5-ene-23,17a-lactone, 160 ml of cyclohexanone and 400 ml of toluene were first stirred and argon gassing 80 ml solvent distilled from. 15.0 g of aluminum tert-butylate was then added and heated for 2 hours under reflux cooling at a water separator. For the preparation, the reaction mixture was evaporated to a volume of approx. 200 ml, then poured onto ice water/diluted hydrochloric acid and extracted with methylene chloride. The organic extract was washed with water, dried with Na 2 SO 4 and evaporated in vacuo. The residue was freed in high vacuum at 140° from the solvent and low-molecular condensation products and finally chromatographed on silica gel. With methylene chloride/acetone (95:5) 10.3 g of pure 3-oxo-D-homo-21,24-dinor-17aoc-chol-4-ene-23,17a-lactone were isolated. S. p. 220-221° (acetone/isopropyl ether); <£> 166o°» [a]^<5> = +72°. A solution of 4.0 g of 3-oxo-D-homo-21,24-dinor-17a<x-chol-4-ene-23,17a-lactone in 200 ml of dioxane, containing 6.5% HCl, was over the course of 3 minutes added a solution of 3.1 g of 2,3-dibr-5,6-dicyano-benzoquinone in 50 ml of dioxane, containing 6.5% HCl. The mixture was then stirred for 7 minutes at room temperature, 50 g of NaHCO 3 added, stirred for a further 30 minutes at room temperature and finally heated for 30 minutes under reflux. The mixture was cooled, the precipitate filtered off and the filtrate filtered through 100 g of "Alox II", finally being further eluted with ethyl acetate. The combined filtrates were evaporated in vacuo. The residue was chromatographed on 200 g of silica gel. With methylene chloride/acetone (97:3) pure 3-6kso-D-homo-21,24-dinor-17aa-chola-4,6-diene-23,17a-lactone was isolated, s.p. 242-244°.

^248 = 27200' ta]D = +25° (c = 0.1 in dioxane).

With methylene chloride/acetone (9:1) 3-oxo-D-homo-21,24-dinor-17aoc-chola^1,4,6-trien-23,17a-lactone with melting point 179-180° was then eluted .

£222 = 11600, <É>255 = 9300, €298 = 12500, [oc]£<5><=><+1>5° (c = 0.1 in dioxane).

EXAMPLE 2

In a manner analogous to Example 1, the 7oc-acetylthio-3-oxo-21,24-dinor-17aa-chola-4,16-diene-23,17a-lactone was obtained from 3-oxo-D-homo-21,24 -dinor-17aa-chola-4,6,16-triene-23,17a-lactone. S. p. 143-145° (from acetone-isopropyl ether) -, [oc]D =

-28° (dioxane).

The starting material was prepared as follows: 3B-acetoxy-D-homo-androst-5-en-17a-one was brominated with CuBr2 and by subsequent treatment with calcium carbonate converted to dimethylacetamide and acetylation with acetarihydride-pyridine to 3B-acetoxy-D-homo -androsta-5,16-dien-17a-one. This compound was converted into 3B-acetoxy- 17aa-(31,31-ethylenedioxa-propyl)-17a-hydroxy-D-homo-androst-5-ene. Acid saponification of this ethylene ketal, oxidation according to Jones, saponification of the 30-acetoxy group with K 2 CO 3 and subsequent treatment with acid led to 33-hydroxy-D-homo-21,24-dinor-17aa-chola-5,16-diene- 23,17α-lactone. The latter was oxidized using B^/LiB^/LiCOg in dimethylformamide at 80°C to 3-oxo-D-homo-21,24-dinor-17aa-chola-4,6,16-trien-23,17a- the lactone s.p. 214-214.50.

EXAMPLE 3

2.4 g of 3-oxo-D-homo-17aa-pregna-4,6,16-trien-21,17a-carbo-lactone is suspended in a mixture of 9.2 ml of methanol and 2.4

ml of water. 1.920 g of n-thio-valeric acid is added to this suspension and stirred overnight at room temperature. The thio-valerianate is cooled by dilution with water, filtered off and washed neutrally with water. The dried residue is crystallized from methanol-water. 2.4 g of 7a-(valerylthio)-3-oxo-D-homo-17aa-pregna-4,16-diene-21,17a-carbolactone are thus obtained. UVA.max = 238 nm £= 18700.

EXAMPLE 4

5.6 g of 3-oxo-D-homo-17aa-pregna-4,6,16-trien-21,17a-carbo-lactone are boiled in 16.5 ml of ethyl mercaptan and 1.7 ml of piperidine for 3 days at reflux. The solvent is then distilled off in a vacuum and the residue is crystallized from methanol. 3.1 g of 7a-(ethylthio)-3-oxo-D-homo-17aa-pregna-4,16-diene-21,17a-carbolactone is thus obtained.

UV = A. max = 240 nm = 16000.

Claims (2)

1. Analogous method for the production of D-homosteroids with aldosterone-antagonistic action with the formula where the dotted bond in the 16,17 position is facultative, and R 7 is alkanoylthio with up to 7 C atoms or alkylthio with up to 6 C atoms, characterized by reacting a D homosteroid with the formula where R 7 has the aforementioned meaning with a compound R<7->H. 2. Method according to claim 1 for the production of 7a-acetylthio-3-oxo-21,24-dinor-17aa-chola-4,16--dien-23,17a-lac-tone characterized by reacting the corresponding D- homosteroid of formula V with thioacetic acid.