CS216823B2 - Method of makijg the dea-steroid - Google Patents

Description

The invention relates to a process for the preparation of the novel deA-steroids of the formula I

in which

R ¹ represents hydrogen or an acylthio group having 1 to 15 carbon atoms,

R ² represents hydrogen or alkyl having 1 to 8 carbon atoms,

Y is hydrogen,

A is hydroxy, or

Y and A together represent an O-C bond, n is a number of 0 or 1 and the dotted ring-bound bonds are optional, wherein R ¹ is hydrogen when A is hydroxy or when the double bond at position 11 (12) is also present, as well as salts of such compounds in which A is hydroxy.

The term "acyl" refers to a residue of a saturated or unsaturated aliphatic carboxylic acid, a cycloaliphatic, araliphatic or aromatic carboxylic acid, preferably having up to 15 carbon atoms. Examples of such acids are formic acid, acetic acid, pivalic acid, propioic acid, butyric acid, caproic acid, enanthic acid, undecylene acid, oleic acid, cyclohexylpropionic acid, cyclopentylpropionic acid, phenylacetic acid and benzoic acid. Particularly preferred acyl groups are C 1 -C 7 allkanoyl groups, in particular acetyl.

The term "alkyl" includes straight or branched aliphatic or cycloaliphatic hydrocarbon radicals, preferably with up to 8 carbon atoms. Examples of such radicals include methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl. Lower alkyl groups preferably contain up to 5 carbon atoms.

Suitable salts are, in particular, alkali metal salts, for example sodium and potassium salts as well as ammonium salts, and also alkaline earth metal salts such as calcium salts. Potassium salts are preferred.

The deA-steroids of the formula I can be obtained according to the invention by dehydrogenating the compound of the formula II

in which

R ^2, at the dotted line have the above meanings, then optionally the reaction product opens a lactone ring or -on the reaction product with a compound of formula ^{R 1} SH, wherein R ¹ has the abovementioned meaning, and the compound obtained is optionally converted to salt.

The introduction of the substituents R ¹ may be effected in known manner by treatment with a thiocarboxylic acid such as thioacetic acid. This reaction may be carried out in an inert solvent such as an ether such as dioxane or tetrahydrofuran, or an alcohol such as methanol or ethanol, or a chlorinated hydrocarbon such as chloroform. The reagent, i.e. the thiocarboxylic acid, is conveniently used in excess and can serve as a solvent.

The cleavage of the lactone ring is carried out in a manner known per se, for example by treatment with a base such as sodium hydroxide or potassium hydroxide in a solvent such as an optionally aqueous alcohol such as (aqueous) methanol, ethanol or isopropyl alcohol at a temperature between about 0 ° C to refluxing the reaction mixture, preferably at about 50 ^° C. The salts thus obtained, which correspond to the base used, can be converted to the free acids by acidification, for example with hydrochloric acid. The acids obtained can be converted into salts by reaction with suitable bases.

The double bond at position 11 (12) can be introduced in a manner known per se into the corresponding starting materials saturated at position 11 (12) of formula II with a saturated ring C by treatment with dehydrogenating agents such as chloranil.

The compounds of formula I and their salts can be used as medicaments. These compounds are, inter alia, effective diuretically and are useful in blocking the effect of aldosterone or desoxycarticosterone acetate and can be used, for example, as potassium-sparing diuretics or for the removal of edema.

The effect of the antagonist effect of aldosterone is determined by the following test:

Female specimens of Holtzman rats (150-180 g) are bilaterally adrenal glands 70 to 74 hours prior to the experiment. After this operation, animals receive 0.9% sodium chloride solution as drinking water and commercial dry food; 16 to 17 hours before the experiment, feed intake is stopped while the salt solution remains available ad libitum. Sodium and potassium in urine are determined by a flame photometer. Test substances are dissolved in 0.3% sodium chloride solution and applied at 30 ml / kg by gastric tube. Each experiment was performed concurrently with a control group treated in the same way but receiving the same volume of pure sodium chloride solution instead of test substances; after 30 min, aldosterone is administered by subcutaneous injection; 120 minutes after administration of the test substances, the bladders of the animals are emptied by light suprapubic compression. The animals are then housed in metabolic cages without water or feed. Urine is collected three times per hour and the bladders of the animals are finally emptied by compression. Urine collected spontaneously with the rest of the urine is collected. The test results are given in the table below (urine volume V, Na ⁺ and K ⁺ in% of control group):

substance dose V Na ⁺ K ⁺ (mg / kg)

H 0.1 135 213 76

H = 5-oxo---tetranor-17α-pregna-9,11-diene-21,17-carbolactone

AND

The compounds of the formula I and their salts can be used as medicaments, for example in the form of pharmaceutical preparations containing these compounds or their salts in admixture with an organic or inorganic inert carrier suitable for enteral or parenteral administration, such as water, gelatin, acacia , lactose, starches, stearic acid magnesium salt, talc, vegetable oils, polyalkylene glycols, petrolatum, etc. The pharmaceutical preparations may be in solid form, such as tablets, dragees, suppositories, capsules, or in liquid form, such as solutions, suspensions or emulsion. These preparations are optionally sterilized or optionally contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for influencing the osmotic pressure or buffers. These preparations may contain still other therapeutically valuable substances.

The manufacture of medicaments is carried out in a manner known per se by mixing the compound of formula I or a salt thereof with a non-toxic, inert, in such formulations, a customary solid and / or liquid carrier suitable for therapeutic application, such as those mentioned above, and optionally converted to the desired form. As a dosage unit for administration to adult patients, about 16 to about 10 mg / kg per day is contemplated.

The invention is illustrated in more detail by the following examples.

Example 1

2.6 g of 5-oxo-A-tetranor-17α-pregn-9-ene-21,17-carbolactone are dissolved in 39 ml of tert-butanol and the solution is boiled together with 2.6 g of chloranil for 5 hours under an atmosphere argon under reflux. The cooled reaction product was poured into ice water and extracted with ether. The organic phases are washed twice with 0.1 N sodium hydroxide solution and then with sodium chloride solution until neutral. The crude product thus obtained is chromatographed on a 100-fold amount of silica gel using hexane / ethyl acetate (2: 1) as the eluent. The crude product crystallized from a mixture of acetone and isopropyl ether. There was thus obtained 5-oxo-A-tetranor-17α-pregna-9,11-diene-21,17-carbolactone, m.p. 122-123 ° C, [α] _D ²⁵ = -211 ° (dioxane, c = 0) , 2),

UV spectrum λ = 289 nm, λ = 26200.

In an analogous manner, 5-oxo-1,2,3,4,19-pentanone-17α-pregn-9-ene-21,17-carbolactone is obtained from 5-oxo-1,2,3,4,19-pentano- 17α-pregna-9,11-diene-21,17-carbolactone. 153 DEG-154 DEG C. (from methylene chloride / ether),

UV spectrum λ _max = 180 nm, ε = 2700, [α] _D = -234 ° (dioxane, 0.5%).

Example 2 g of 5-oxo-A-tetranor-17α-pregna-9,11-diene-21,17-carholactone is dissolved in 40 ml of isopropyl alcohol and 3.42 ml of potassium hydroxide solution (2 Nj) is added and the reaction mixture is stirred The solution is then concentrated by adding several times isopropanol (to azeotropically remove the water), and with vigorous stirring a 6-vol. filtered and immediately dried under high vacuum at 80 ° C to give 1.83 g of potassium 17-hydroxy-5-oxo-17-β-tetranor-17α-pregna-9,11-diene-21-carboxylate, which burns at 169 ° C (then foam), [a] _D = -113.4 (ethanol, 0.5),

UV spectrum λ = 292 nm, ε = 24,950.

Sodium-17-hydr, oxy-5-oxo-N-tetranor-17a-pregna-9, llidene-21-carboxylate, [α] _D = -118 ^c (ethyl alcohol 0.5 θ / ο) was prepared in an analogous manner,

UV spectrum λ = 293 nm, ε = 22,600.

Example 1 a d 3

433 mg of S-oxo-N-tefranor-1α-pregha-S, N-diene-21,17-carbolactoin are dissolved in 8.7 ml of isopropyl alcohol and 8.7 ml of water. 56.4 mg of calcium hydroxide was added to the solution. The mixture was stirred under argon for 2 hours at 50 ° C and then the reaction solution was concentrated by adding isopropanol several times. After addition of ethyl acetate, the crude product is filtered off and dried. 386 mg of calcium 17-hydroxy-5-oxo-N-tetranoir-17α-pregna-9,11-diene-21-carboxylate, m.p. 201-204 ° C (from a mixture of isopiropropyl alcohol and ethyl acetate), are obtained.

Example 4

610 mg of 5-oxo---tetranor-17α-pregna-9,11-dieine-21,17-carbolactone was boiled in 5 ml of thioacetic acid for 5 hours under reflux and under an argon atmosphere. For work-up, the reaction solution was poured onto ice-water and extracted with ether. The organic phases are washed first with 1 N potassium hydroxide solution, then with water until neutral. After drying over magnesium sulphate and evaporation, the crude product is chromatographed on 150 g of silica gel using toluene / ethyl acetate as eluent. The first eluted fraction consists of unreacted starting material. 36 mg of pure 12 / 3- (acetylthio) -5-oxo-mg-tetranor-17α-pregn-9-ene-21,17-carbolactone, m.p. ° C, [α] _D = -45 ° (dioxane).

Example A

An oral tablet may have the following composition:

active substance, for example 5-oxo-A-tetranor-17α-pregna-

-9,11-diene-21,17-carbolactone 25 mg cornstarch 100 mg lactose 50 mg polyvinylpyrrolidone 15 mg magnesium stearic acid salt 2 mg

Example B

An oral capsule may have the following composition:

an active ingredient, for example

5-oxo---tetranor-17α-pregna-9,11-diene-21,17-carbolactone 25 mg corn starch 125 mg lactose 125 mg

Claims (2)

A process for the preparation of deA-steorides of the formula I by dehydrogenating a compound of the formula II (CH 2 COA) In which R ¹ represents hydrogen or an acylthio group having 1 to 15 carbon atoms, R ² represents hydrogen or alkyl having 1 to 8 carbon atoms, Y is hydrogen, A is hydroxy, or Y and A together represent an O-C bond, n is 0 or 1, and the dotted marked bonds in the ring are optional, wherein R ¹ is hydrogen when A is hydroxy or when a double bond is present at position 11 (12) as well as and salts of such compounds wherein A is hydroxy, wherein: R ^2, at the dotted line have the above meanings, then optionally opens in the reaction product, the lactone ring or the reaction product with a compound of formula R ^X SH, wherein R ¹ has the abovementioned meaning, and the compound obtained is optionally converted into a salt . 2. A process according to claim 1 for the preparation of 5-oxo-A-tetranor-17a-pregna-9,11-diene-21,17-carbolactone, characterized in that 5-oxo-A-tetranor-iya-pregn- g-en-Z1-γ-carbolactone dehydrogenates.