DE1618662C3 - 6-substituted 16alpha-methyl-4-pregnen- or 4,6-pregnadien-3betaol-20-one compounds, processes for their production and pharmaceutical preparations containing them - Google Patents

Description

(D

wherein R ¹ denotes CH ₃ , F or Cl and in which the dashed line in the 6 (7) position denotes that a double bond may be present here, but in which a methyl group in the 6 position has a ^ -configuration if there is no double bond in the 6th position (7) position is present.

2. 6 / ?, 16a-dimethyl-4-pregnen-3 /? - ol-20-one.

3. 6a-fluoro-16a-methyl-4-pregnen-3 /? - ol-20-one.

4. Process for the preparation of compounds of the general formula I, characterized in that that a functionally modified 20-keto group of a corresponding derivative in usual way, e.g. B. by solvolysis, sets in freedom or that a progesterone derivative of general formula II,

It was found that the 16a-methyl-4-pregnen- or 4,6-pregnadien-3 /? -Ol-20-one compounds which are substituted in the 6-position of the general formula I,

-CH,

in which R ¹ and the dashed line in the 6 (7) position have the meaning given, in which a methyl group in the 6 position, however, has / Ϊ configuration, if there is no double bond in the 6 (7) position, with sodium borohydride in pyridine or in anhydrous isopropanol or that a 3 / ?, 20-DiacyIoxy-17a-hydroxy-4-pregnen of the general formula III,

AcO

OAc

-CH ₃

(III)

R ¹

wherein Ac is alkanoyl with 1 to 6 carbon atoms HO

-CH ₃

in which R ¹ denotes CH ₃ , F or Cl and in which the dashed line in the 6 (7) position denotes that a double bond can also be present here, but in which a methyl group in the 6 position has /? - configuration if no double bond in the 6 (7) position, have good anti-oestrogenic, progestative and ovulation-inhibiting effects that are much stronger than those of the natural hormone progesterone.

The compounds of general formula I can accordingly be used as medicaments or else as Intermediate products can be used to manufacture other drugs.

The invention relates to a process for the preparation of compounds of the general formula I, which is characterized by the fact that one

a) a functionally modified 20-keto group of a corresponding derivative in the usual way, z. B. by solvolysis, sets in freedom, or that one

b) a progesterone derivative of the general formula II,

CH ₃

-CH ₃

(Π)

R ¹

wherein R ¹ and the dashed line in 6 (7) -th-

ment have the meaning given, in which a methyl group in the 6-position but / f-configuration if there is no double bond in the 6 (7) position, with sodium borohydride in pyridine or in anhydrous isopropanol or that one

c) a 3 / f, 20-diacyloxy-17 «-hydroxy-4-pregnen der general formula III

CH - OAc

AcO

10

(IH)

20th

where Ac is alkanoyl with 1 to 6 carbon atoms and R ¹ and the dashed line in the 6 (7) position have the meaning given, where ² ^ has a methyl group in the 6 position but / i-configuration, if no double bond in 6 (7) position is present, treated with zinc and then hydrolyzed the product with a strong base or a strong acid.

Ac preferably means acetyl, but also formyl, propionyl, butyryl, isobutyryl, valeryl or Capronyl.

The compounds I can be obtained by solvolysis, preferably hydrolysis, of the corresponding functional Obtained 20-keto derivatives. Preferred keto derivatives are the semicarbazones and the ethylene ketals. The semicarbazones are in a manner known per se from the progesterone derivatives of the formula II obtainable by first blocking its 3-keto group as enamine, then reacting it with semicarbazide, the 3-keto group is set free again with dilute acid and then, for example, with Sodium borohydride reduced. The ethylene ketals are z. B. by realizing the corresponding 30-hydroxy-5-pregnen-20-oneii as well as subsequent Oppenauer oxidation and reduction in 3-position accessible. Other suitable functional derivatives of the compounds of the formula I are other ketals, ζ. Β. the dimethyl, diethyl, propylene ketals, also thioketals (ethylene, propylene, dimethyl, diethylthioketals), Hemithioketals (ethylene, propylene, dimethyl, diethyl hemithioketals), thioenol ethers, cyanohydrins Oximes, phenylhydrazones and Girard derivatives (e.g. Girard T derivatives).

The solvolysis of the 20-keto derivatives mentioned takes place in the customary manner described in the literature. the Ketals are preferably split by treatment with dilute acids. Suitable acids are for example hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, p-toluenesulfonic acid, oxalic acid, acetic acid as well as Lewis acids such as boron trifluoride etherate. usually one uses in addition an inert solvent such as methanol, ethanol, acetone, dioxane, ether, tetrahydrofuran, benzene, Chloroform or methylene chloride or mixtures of these solvents, optionally with addition of water. Acetic acid can serve as both a reagent and a solvent at the same time. The split takes place already at room temperature, but can also be used at temperatures up to the boiling point of the Solvent work. Depending on the conditions used, the implementation is after a few Finished minutes to 24 hours.

Thioketals and thioenol ethers are expedient by treatment with mercury chloride / cadmium carbonate at room temperature or with heating, preferably in aqueous acetone, or through Hydrolysis with dilute hydrochloric acid or sulfuric acid split, hemithioketals by the same Acids, with mercury chloride or with Raney nickel, e.g. B. in acetic acid in the presence of sodium acetate. Semicarbazones, Oximes, Phenylhydrazones and Girard T derivatives can also be used in acid Medium, the cyanohydrins, however, with bases such as methanolic potassium methylate or Pyridine. It is also possible to carry out the cleavage in the presence of a carbonyl compound which in turn reacts with the released reagent to form the corresponding derivative. Be like that the semicarbazones are particularly advantageous by treating with pyruvic acid to form the free keto compounds convicted. One works, for example, in aqueous dioxane or aqueous acetic acid at room temperature or, more expediently, at higher temperatures up to the boiling point of the solvent.

The compounds of the formula I can also be obtained by selective reduction of the progesterone derivatives of formula II with sodium borohydride either in pyridine or in anhydrous isopropanol Room temperature. Under these conditions, the keto group in the 20-position does not become essentially non-existent attacked, the desired compounds are obtained after reaction times between about 4 and 24 hours of formula I.

Another way of preparing the compounds of the formula I consists in treating a 30,20-diacyloxy-17'-hydroxy-4-pregnene of the formula III with zinc and then hydrolyzing the product obtained. The 3 / ?, 2O-diacetoxy compounds are primarily suitable as starting compounds. It is either sublimed in the presence of zinc dust (Serini-Logemann reaction) at temperatures between 150 and 200 ^° C., preferably around 180 ^° C., under reduced pressure, or the starting material is boiled for a few hours with zinc dust in toluene or a similar inert solvent. During the conversion, inversion occurs at C (17). The 3 /? - acyloxy-17-iso-4-pregnen-20-one obtained is then saponified by treatment with a strong base or a strong acid and at the same time isomerized at C (17). It is expedient to use methanolic or ethanolic sodium or potassium hydroxide solution and heat it to the boil for 1 to 4 hours.

The compound I is isolated from the reaction mixtures obtained in the customary manner Extraction, crystallization and / or chromatography.

The progesterone derivatives of the formula II used as starting materials according to the invention are either known, or they can be prepared analogously to known compounds. The manufacture of the Compound II is described in DT-OS 15 93 064. The starting compounds of formula III are obtainable by reducing the corresponding 17a-acet-

oxyprogesterone (ζ. B. with lithium aluminum hydride) to the underlying 3 / f, 17 «-20-triplets and subsequent partial acylation.

Typical starting materials of the formula II are:

6a- and ö / i-fluoro-lou-methylprogesterone,
6a- and 6 / i-chloro-1 oii-methylprogesterone,
6ß, 1 oa-dimethyl-progesterone,
6-fluoro- and 6-chloro-6-dehydro-16 (/ - methyl-

progesterone and
6.1 orc-dimethyl-o-dehydroprogesterone.

Typical starting materials of the formula III are:

3 / i, 20-diacetoxy-6 "- and 6 / y-fluoro-16" -methyl-

4-pregnen-17 «-ol,
3 / i, 20-diacetoxy-6 "- and -6 / f-chloro-16" -methyl-

4-pregnen-17 «-ol,
3 / i, 20-diacetoxy-6 / i, 1 öu-dimethyl-'t-pregnen-

17 «-ol,
3 / f, 20-diacetoxy-6-fluoro- and -6-chloro-

16fi-methyl-4,6-pregnadien-17 «-ol and
3 //, 20-diacetoxy-6,16 "-dimethyl-4,6-pregnadiene-17" -ol.

The products of the process can be mixed with conventional pharmaceutical carriers in the human or Veterinary medicine can be used. The carrier substances used are organic or inorganic Substances in question which are suitable for parenteral, enteral or topical application and which do not react with the new compounds, such as water, vegetable oils, polyethylene glycols, Gelatin, milk sugar, starch, magnesium stearate, talc, petroleum jelly, cholesterol. For parenteral In particular, solutions, preferably oily or aqueous solutions, are used for application Suspensions or emulsions. Tablets or coated tablets are also suitable for enteral application, for topical application ointments or creams, which may be sterilized or with auxiliaries, such as preservatives, stabilizers or wetting agents or salts to influence the osmotic Pressure or with buffer substances.

The process products are generally used in doses of 0.1 to 100 mg, preferably 0.5 up to 5 mg administered.

example 1

0.7 g 6a - chlorine -16a - methyl - 4 - pregnen - 3ß - ol-20-one-20-semicarbazone (obtainable by reaction of 6a-chloro-16a-methyl-progesterone with pyrrolidine in methanol to form 3-enamine, Conversion of the same into its 20-semicarbazone, selective acid hydrolysis to 6a - chlorine -16a - methyl - progesterone - 20 - semicarbazone and reduction with sodium borohydride in methanol) are in a mixture of 12 ml of dioxane, 6 ml of water and 0.5 ml of pyruvic acid 20 Heated to 95 ° C for minutes. The reaction mixture is diluted with water and extracted with methylene chloride. The extracts are washed with water and evaporated to give oa-chloro-loa-methyM-pregnen-3 / S-ol-20-one. M.p. 183 to 185 ° (from acetone).

Example 2

The solution of 0.4 g of oa-fluoro-lou-methyl ^ pregnen-3 / * - ol-20-one-20-ethylene ketal (produced by ketalizing o-fluoro-Iou-methyl-S-pregnen ^ -ol-20-one with ethylene glycol in benzene, oxidation to 4-en-3-one with cyclohexanone / aluminum isopropylate and reduction of the 3-keto group with lithium aluminum hydride or sodium borohydride) and 20 mg of oxalic acid in 30 ml of ethanol are left to stand for 36 hours at room temperature. Then with aqueous Ammonia solution neutralized, concentrated under reduced pressure and diluted with water, ίο The excreted 6a-fluoro-16 «-methyl-4-pregnen-3 / f-ol-20-one is sucked off. F. 172 to 173 ° (from ether; [α]? + 95.5 ° (chloroform).

Example 3

2.3 g

ypg /
3.20-diacetate (obtainable by reducing 6β, 1 6a- dimethyl-17α-acetoxy-progesterone with lithium aluminum hydride and subsequent acetylation) are sublimed with 40 g of zinc dust at 180 ° C./0.3 mm. The sublimate is boiled with 200 ml of ether and filtered. The evaporated filtrate is refluxed for 2 hours in 100 ml of 5% strength methanolic potassium hydroxide solution. The solution is concentrated to a small volume under reduced pressure, and about 100 ml of water are added. The suspension obtained is extracted with methylene chloride, the extracts are concentrated, 6β, 6α-ΌΊ- methyl-4-pregnen-3 _i 8-ol-20-one being obtained. Mp 176-177 ° (from acetone); [α]? + 66.6 ° (dioxane).

Example 4

The solution of 1.1 g of o-chloro-o-dehydro-loa-methyl-progesterone (M.p. 127 to 129 °) in 200 ml of anhydrous isopropanol is mixed with 125 mg of sodium borohydride Left to stand at room temperature for 15 hours. After adding 500 ml of water is repeated several times extracted with methylene chloride. The evaporated extract is placed on a glass plate coated with silica gel (20 χ 100 cm) applied. After developing the plate three times with chloroform / petroleum ether / Acetone 4: 4: 1 becomes the o-chloro-loa-methyM.o-pregnadieft-3 / S-oI-20-one containing zone removed from the plate and extracted with chloroform / methanol 1: 1. The extract is evaporated. Mp 173-175 ° (from acetone); [α]? + 11.2 ° (chloroform).

Analogously, from o-fluoro-ö-dehydro-loa-methyl-progesterone (reaction time 2 hours) 6-fluoro-1 6a- methyl-4,6-pregnadiene- 3β -oil-20-one; 171-173 °; [α] f - 46.4 ° (chloroform).

In the following table 1 the progestative efficacies of some process products are given, namely the total doses with which a full transformation of the endometrium is achieved, compared to progesterone, respectively.

methodology

Clauberg test on rabbits (see Mc. Phail, Journal of Physiology, Vol. 83, pp. 145 ff. [1935]); 6 days priming with 5 μg estradiol / animal / day subcutaneously, on a further 5 days 0.5 μg estradiol / animal / day subcutaneous; the test results were evaluated statistically.

Table 1
Active ingredient

progesterone

o-chloro-loa-methyl-4,6-pregnadien-3 / i-ol-20-one

6-fluoro-16a-methyl-4,6-pregnadien-3ß-ol-20-one

6a- fluoro- 16a-methyl-

4-pregnen-3 / f-ol-20-one

6ß, 1 6a-dimethyl-4-pregnen-

3 / i-ol-20-one

Total dose

(mg / animal)

50

5 5 0.5

Effect relation

1 10

10. 10 100 As the following table 3 shows, the antiestrogenic Effect of o-chloro-löa-methyl ^ o-pregnadien-3 /? -Ol-20-one using the same methodology also with the effect of the literature known 6-chloro-4,6-pregnadien-3 ^ f-ol-20-one (see. USA. Patent 33 52 889) compared (subcutaneous application; effect of progesterone: 1):

Table 3

Active ingredient

Animal dose Minimum We number Inhibitory dose relation

(mg / animal) (mg / animal)

It was shown that the four products of the process are 10 or 100 times more effective progestationally than Progesterone.

In the following Table 2 are the minimum inhibitory doses for the antiestrogenic effectiveness of some Process products and compiled by progesterone (subcutaneous application). You have been identified in the uterus weight test on mice according to the methodology of Dorfman and coworkers, Endocrinology, Vol. 68, p. 43 ff. (1960).

6-chlorine-

16a-methyl-

4,6-pregnadiene

3 /? - ol-20-one 6-chloro-

4,6-pregnadiene

3 / S-ol-20-one

30th

0.1-1.0 0.1

30 0.1-1.0 0.3

25th

3 °

Table 2

Active ingredient

Animal number

dose

Minimal We-

Inhibitory

dose relation 35 table

The effect of the substance of the invention was 3 times higher.

In Table 4 are finally the ovulation-inhibiting effects of some process products with that Compiled by progesterone. They were determined by counting the eggs in the right and Left tube of rats after subcutaneous application based on the Suchowsky method and employees, Arzneimittelforschung, Vol. 15, pp. 437 ff. (1965).

(mg / animal) (mg / animal)

Active ingredient

Progesterone 27

6-chlorine- 30

16a-methyl-4,6-pregnadiene

3 /? - ol-20-on

6-fluoro-30

16a-methyl-

4,6-pregnadiene

3 / S-ol-20-one

6a-FIuor- 30

16a-methyl-

4-pregnen-

3j8-ol-20-one

60,16a-dimethyl-30

4-pregnen-

3/3-ol-20-one

0.1-1.0 0.3 1

0.01-0.1 0.1 3

0.01-0.1 0.1

0.01-0.1 0.01 30

0.01-0.1 0.01 30

40

45

Animal dose animals we number without

Ovular relation

tion

(mg / animal) (%)

55 progesterone

6-fluoro

16a-methyl-

4,6-pregnadiene

3/3-ol-20-on '

6a-fluoro

16a-methyl-

4-pregnen-

3 /? - ol-20-on

6 / S, 16a-dimethyl-

4-pregnen-3 / S-ol-20-one

20 1.0 70

10 1.0 90

1.3

10 1.0 100 1.4

10 1.0 90 1.3

The anti-estrogenic effect of the four process products is thus 3 or 30 times as strong as that of progesterone.

The anti-ovulation effects of the three products of the invention are thus 30 to 40% stronger than that of progesterone.

609 617/51

Claims (1)

Patent claims: 1. Compounds of the general formula I, CH ₃ CO HO -CH ₃ and R ¹ and the dashed line in the (^ position have the meaning given, in which a methyl group in the 6 position, however, has the / 9 configuration if there is no double bond in the 6 (7) position with Treated zinc and then hydrolyzed the product with a strong base or acid. 5. A pharmaceutical preparation containing an effective dose of a compound of the formula I. in addition to the usual carriers and additives.