DE1643054B2 - 1ALPHA, 2ALPHA-METHYLENE-4-CHLORINE-DELTA HOCH 4 -BW. DELTA HOCH 4,6-7-METHYL COMPOUNDS OF THE PREGNAN SERIES, THE PROCESS FOR THEIR PRODUCTION AND THE MEDICINAL PRODUCTS CONTAINED - Google Patents

Description

CH,

C = O

O = ¹

where R is hydrogen or the acyl radical of one of the in _J0 where R is hydrogen or the acyl radical of one of the carboxylic acids customary in steroid chemistry and steroid chemistry and

C ₇

./
Q,

mean a saturated or unsaturated carbon-carbon bond and the 7-methyl group ^ is constant if

C ₇

represents a saturated carbon-carbon bond.

2. Medicaments based on compounds according to claim 1.

3. Process for the preparation of compounds according to claim 1, characterized in that one to a compound of the general formula II

; OR

45

(II)

where R is hydrogen or the acyl radical of one of the carboxylic acids customary in steroid chemistry, a hydrohalic acid HX with X meaning chlorine, bromine or iodine to act from of the 70-halomethyl compound obtained, the halogen reductively removed and, if desired, then saponified or an esterified hydroxyl group esterifies a free hydroxyl group and, if desired, introduces a double bond in the 6,7-position.

55

60 C ₇

a saturated or unsaturated carbon-carbon bond mean and the 7-methyl group is ^ - position, if

C ₇

represents a saturated carbon-carbon bond.

Possible acid residues are residues that are derived from acids that are commonly used in steroid chemistry can be used for esterifications. Preferred acids are organic carboxylic acids with up to 15 Carbon atoms, especially lower and medium aliphatic carboxylic acids. Furthermore, the Acids also unsaturated, branched, polybasic or in the usual way, e.g. B. by hydroxyl, amino groups or halogen atoms. Cycloaliphatic, aromatic, mixed aromatic-aliphatic are also suitable or heterocyclic acids, which can also be substituted in the usual way. as preferred acids are for example:

Acetic acid, propionic acid, caproic acid, oenanthic acid,
Undecylic acid, oleic acid, trimethyl acetic acid,
Dichloroacetic acid, cyclopentylpropionic acid,
Phenylpropionic acid, phenylacetic acid,
Phenoxyacetic acid, dialkylaminoacetic acid,
Piperidinoacetic acid, succinic acid, benzoic acid and others

The 7-methyl steroids of the general formula 1 have valuable therapeutic properties in their own right or are therapeutic intermediates for their manufacture effective substances.

The surprisingly strong gestagenic effectiveness of the new pregnane derivatives is also particularly interesting, outperform progestogens known for their effectiveness. The following table shows the superiority of the compounds according to the invention using the example of 4-chloro.17-acetoxy-7j8-methyl-1 <x, 2 "-methylene-4-pregnen-3,20-dione (1) and of 4-chloro-17-acetoxy-7-methyll «, 2« -methylene-4,6-pregnadiene-3,20-dione (H) in comparison with the known gestagens IH to V,

The test results were in the well-known Clauberg test determined after oral application to infantile rabbits. In the table the for To achieve a positive effect, the minimum amount (threshold dose) required is indicated. s

Tabel

Serial
No.

substance

Threshold dose (y) to

15th

20th

I 4-chloro-t7-acetoxy-7 / J-methyl-3
1 a, 2a-methylene-4-pregnen-3,20-dione

II 4-ChloΓ-17-acetoxy-7-methyl-3
1 Ä, 2ix-methylene-4,6-pregnadiene-3,20-dione

III U-acetoxy-ea-methyl-100
4-pregnen-3,20-dione

IV e-chlorine - ^ - acetoxy- 30
4,6-pregnadiene-3,20-dione

V Wß-Hydroxy ^ a-ethinyl-130
4-oestrien-3-one

The active ingredients according to the invention are used for practical use, for example for gestagen therapy processed with the usual carriers in galenic pharmacy and in the usual application forms, z. B. tablets, coated tablets, capsules, injection solutions, etc., transferred. The dosage takes place according to the severity of the illness. In general, between 1 and 100 mg of active ingredient will be used Administer daily.

The invention also relates to a process for the preparation of the above-mentioned compounds of general formula I, characterized in that compounds of general formula II

(H) «s

so

wherein R is hydrogen or the acyl radical in one of the Steroid chemistry usual carboxylic acid means a hydrohalic acid HX with X meaning Chlorine, bromine or preferably iodine have an effect of the 7/3 halomethyl compound obtained is halogen reductively removed and, if desired, then saponified an esterified hydroxyl group or a free one Esterified hydroxyl group and, if desired, introduces a double bond in the 6,7 position

The action of the hydrohalic acid HX on the 1 ", 2"; 6p, 7 /? - dimethylene steroid takes place in itself known way, for example by adding the acid HX to the dissolved steroid as a solvent those which are inert towards the steroid and the hydrohalic acid come into question. Inert Solvents are e.g. B. ethers such as tetrahydrofuran and dioxane, hydrocarbons such as hexane and benzene, chlorinated hydrocarbons such as methylene chloride and chloroform and carboxylic acids such as acetic acid and Formic acid. The hydrohalic acid can also during the reaction from its alkali salt with eiper lower carboxylic acid, e.g. B. formic acid are released.

The reaction proceeds at temperatures of about 0 to 50 ⁰ C, preferably at 20 to 3O ⁰ C, with an optimal yield. Side effects are to be expected at higher temperatures. It is surprising that only the 6 / J, 7 /} - methylene group is split and not also the! «^« - methylene group, because from German patent specification 11 22 944 it is known that the cyclopropane ring in the l «, 2a Methylene-4-en-3-ketosystam is converted into the corresponding la-halomethyl grouping under the same reaction conditions. It is also known from German Patent 11 58 966 that when the 6a, 7'-epoxide is opened with hydrochloric acid, the 1,2-position cyclopropane ring is simultaneously split up by the addition of HCl. The course of the reaction according to the invention could therefore not be foreseen.

In addition to the selective ring opening, the stereospecificity of the reaction is also surprising. While on the introduction of the 7-methyl group into the 4,6-diene-3-keto system with methyl magnesium halide each an isomer mixture of 7% - and 70-methyl compounds arises, the action of hydrohalic acid on the 6jS?, 7/3-methylene verbi ^ - Only the 70-halomethyl component was obtained.

The halogen is removed reductively from the 7β-halomethyl steroids obtained primarily. The reduction will carried out in a manner known per se. To achieve a simultaneous reduction of the I «, 2 <x methylene ring and To avoid the ^ -unsaturated 3-keto system, however, it is advisable to use conditions that are as gentle as possible apply. The reduction is therefore preferably carried out with Raney nickel as a catalyst Temperatures of about 10 to 80 ° C carried out.

A free hydroxyl group or ester group in the 17-position can according to the known regulations be esterified or saponified.

The subsequent introduction of the, d ⁶ double bond, if desired, is carried out by methods known per se. Suitable dehydrating agents are, for example, chloranil or 2,3-dichloro-5,6-dicyanobenzoquinone. The A ⁶ double bond can, however, also be introduced under milder conditions by first brominating the 7j} -methyl-4-a-3-ketone in the allyl position with N-bromosuccinimide and from the isolated 6-bromine compound with lithium halide and Splitting off alkali carbonate in dimethylformamide hydrogen bromide.

The starting material 4-chloro-17-acetoxyiA ^ «, - 6j3,7 /} - diniethylen-4 pregnen-3,20-dione can be produced as follows:

6 g of 4-chloro-17-acetoxy-l, 4,6-pregnatrien-3,20-dione are mixed with an essential diazomethane solution (made from 60 g nitrosomethylurea, 440 ml Ether and 320 ml of 40% potassium hydroxide solution) and 7 days in a closed vessel at room temperature ditched. The excess solvent is then stripped off in vacuo. The as residue remaining bis-pyrazoline compound is dissolved in 240 ml of acetone and added dropwise with stirring mixed with 12 ml of 70% perchloric acid. After the evolution of gas, ten times the amount of ice water is added

stirred in, the deposited precipitate filtered off, taken up in methylene chloride, washed with water and dried over sodium sulfate. After evaporation to dryness, the residue is chromatographed on silica gel. After recrystallization from Essigester obtained 1.2 g of 4-chloro-17-acetoxy-la, 2a; 6 / J, 70-dimethylene-4-pregnene-3,20-dione of melting point 278-279 ⁰ C.

example 1

3.0 g of 4-chloro-17-acetoxy-ta, 2a; 6jJ, 70-dimethylene-4-pregnen-3,20-dione (prepared according to a) are dissolved in 75 ml of formic acid with 15 g of potassium iodide for 7 hours at 30 ^° C stirred. After ice-water precipitation, the precipitate is filtered off with suction, taken up in methylene chloride and the methylene chloride phase is washed with sodium thiosulfate solution and water. After drying over sodium sulfate and evaporation to dryness, the crude 4-chloro-17-acetoxy-7 /? - iodomethyl-1 a, 2 "-methylene-4-pregnen-3,20-dione (a purified sample melts at 211 - 212 ⁰ C, UVIS _255-12600) Raney nickel catalyst g in 180 ml of methanol at 10 for 4 hours at room temperature. The Raney nickel is then filtered off and the filtrate is evaporated to dryness in vacuo. The residue obtained in this way is taken up in methylene chloride, washed with water, dried over sodium sulfate and evaporated to dryness. After chromatography on silica gel, 2.3 g of 4-chloro-17-acetoxy-70-methyl-1 <x are recrystallized from isopropyl ether. 2 <x-methylene-4-pregnen-3,20-dione with a melting point of 236-237 ° C.

UV = E ₂₅₆ = 11100.

Example 2

713 mg of 4-chloro-17-acetoxy-7 | i-methyl-la, 2a-methylene-4-pregnen-3,20-dione are in 33 ml of absolute carbon tetrachloride with 325 mg of N-bromosuccinimide and 50 mg of dibenzoylperoxod refluxed for 70 minutes. It is then made with methylene chloride diluted, washed with water and dried over sodium sulfate. After evaporation to dryness is the crude bromine compound in 15 ml of dimethylformamide with 385 mg lithium carbonate and 450 mg lithium bromide Heated to 115 ° C. for 5 hours with stirring and a stream of nitrogen. After that, with ether diluted, washed with dilute sulfuric acid and with water, dried over sodium sulfate and im Evaporated to dryness in vacuo. The residue is chromatographed on silica gel, and recrystallized from isopropyl ether, 510 mg 4-chloro-17-

yyp
dione with a melting point of 213-214.5 ° C.
307 = 18,500.

Example 3

200 mg of 4-chloro-17-acetoxy-7-methyl-1 «£« -methylene-4,6-pregnadiene-3,20-dione are dissolved in 30 ml of methanol with 3.2 ml of 1N sodium hydroxide solution for 17 hours at room temperature touched. It is then neutralized with acetic acid and largely concentrated in vacuo. After ice-water precipitation, the precipitate is filtered off with suction, washed neutral and dried. Recrystallized from isopropyl ether, 110 mg of 4-chloro-17-hydroxy-7-methyl-1,2a-methylene-4,6-pregnadiene-3,20-dione with a melting point of 224.5-226.5 ° C. are obtained.
UV: E ₃ Og = 19,100.

Example 4

100 mg of 4-chloro-17-hydroxy-7-methyl-liX, 2'-methylene-4,6-pregnadiene-3,20-dione are in 3 ml of caproic anhydride with 50 mg of p-toluenesulfonic acid for 3 days Left to stand at room temperature. The reaction mixture is mixed with a little pyridine and then distilled in a stream of steam. The aqueous phase is then extracted with ether, the ether phase over

ίο Sodium sulfate dried and in a vacuum to dryness evaporated. After purification by preparative thin layer chromatography, 85 mg of 4-chloro-17-he-

xanoyloxy ^ -methyl-la ^ Ä-methylen ^ .e-pregnadien-3,20-dione obtained as an oil.

UV: 6307-17,900.

Example 5

700 mg of 4-chloro-17-acetoxy-7jS-methyl-l <%, 2 <x -methylene-4-pregnen-3,20-dione are dissolved in 70 ml of methanol with 11.2 ml of 1N sodium hydroxide solution for 16 hours stirred in a stream of nitrogen at room temperature. It is then, as described in Example 3, worked up. After recrystallization from isopropyl ether / methylene chloride, 405 mg of 4-chloro-17-hydroxy-7 /? - methy) -l <x, 2 "-methylene-4-pregnen-3,20-dione with a melting point of 219-221.5 ° C received.
UV: 625 "- 11300.

Example 6

100 mg 4-chloro-17-hydroxy-7 /} - methyl-1 <x, 2a-methylene-4-pregnen-3,20-dione are, as described in Example 4, with caproic anhydride and p-toluenesulfonic acid implemented and worked up After purification via preparative thin-layer chromatography

graphie 60 mg ^ -Chlor - ^ - hexanoyloxy-Zji-methyll «, 2« -methylene-4-pregnen-3,20-dione obtained as an oil.
UV: e _2se - 10,800.

Example 7
Gelatin capsules, each containing 1 mg of active ingredient

Composition for 1 capsule:
1 mg 4-chloro-17-acetoxy-7 / i-methyl-

lft, 2a-methylene-4-pregnen-3,20-dione
(Particle size 2 - 8 μ, occasionally up to 16 μ)
66.5 mg milk sugar (DAB 6)
67.5 mg

The substances can be mixed homogeneously and filled into hard gelatine capsules as usual.

Example 8
Tablets containing 5 mg of active ingredient each.

Composition for one tablet:
5,000 mg 4-chloro-17-acetoxy-7-methyl-

l «£« -methylene-4,6-pregnadiene-3,20-dione
(Particle size: 2 - 8 μ, occasionally up to 16 μ)

24,000 mg milk sugar (DAB 6)
to 45.065 mg corn starch (USP 16)
4,000 mg talc (DAB 6)
1,400 mg gelatin, white (DAB 6)
0.500 mg sodium lauryl sulfate (USP16)
0.024 mg methyl p-oxybenzoate
(DAB 6.3. Addendum)

0.011 mg propyl p-oxybenzoate

(DAB 6.3. Addendum)

80,000 mg

Milk sugar, corn starch, talc, gelatin and sodium lauryl sulfate serve as fillers, p-oxybenzoic acid methyl ester and propyl p-oxybenzoate as preservatives.

The tablets are produced in the usual way on a tablet press. (Diameter: 6 mm with Score line; Height: 2.6 - 2.7 mm, hardness: approx. 4 kg [Stokes hardness tester]; Disintegration in water at 20 "C: approx. 30 Seconds)

Example 9

Aqueous solutions for oral application,
ImI = 1 mg active ingredient

Composition for 100 ml:

100 mg 4-chloro-17-acetoxy-7-methyl-

1 «^« - methylene-4,6-pregnadiene-3,20-dione

20 ml of ethyl alcohol

25 ml propylene glycol / ad 100 ml redist. Water.

Example 10

Ampoules with oily solutions for intramuscular
Injection, 1 ml = 2 mg of active ingredient.

200 mg of 4-chloro-17-acetoxy-70-methyll «£« -methylene-4-pregnen-3,20-dione are dissolved in sesame oil / ben-

Cyl alcohol (50: 1) ad 100 ml, filled into 1 ml ampoules and sterilized in a manner known per se.

Example 11

2.1 g of 17-acetoxy-4-ch! Or-la, 2 "; 6 | J, 7 / i-dimethylene-4-pregnen-3,20-dione are added to 60 ml of formic acid with 12 g of potassium bromide for g hours Stirred at 30 ° C. After ice-water precipitation, the precipitate is filtered off with suction, taken up in methylene chloride and the methylene chloride phase is washed with sodium thiosulfate solution and water. After drying over sodium sulfate, it is evaporated to dryness in vacuo. The crude 17-acetoxy-4-chloro-7 / I-bromo-methyl-1,2 "-methylene-4-pregnen-3,20-dione is mixed with 10 g of Raney nickel in 150 ml of methanol for 6 hours at room temperature -Catalyst stirred. The Raney nickel is then filtered off and the filtrate is evaporated in vacuo. The crude product is chromatographed on silica gel with acetone-hexane. 1.3 g of 17-acetoxy-4-chloro-7 / f-niethyl.1 <x £ a-methylene-4-pregnen-3,20-dione with a melting point of 234-236 ° C. are obtained. UV: ε ₂₅₆ - 11-000.

609528/463

Claims (1)

Patent claims: 1. Compounds of the general formula I
CH ₃ C = O
OR (D The invention relates to 1 ", 2" -Methylene-4-chloro- <d ⁴ - or 4 ⁴⁶ -7-methy | -compounds of the pregnane series of the general formula I.