11beta-(4-dimethylamino-phenyl)-13alpha-alkylogonane derivatives,process for the preparation thereof and pharmaceutical compositions containing the same

This PDF First Page has been artificially created from the Israelian Abstracts llB-(4-DIMETHYLAMIN0PHENYL)13־a-ALKYLG0NANE DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME

תולדות 11 6-נ4-דימתילאמינופניל)-13^אלקילגונאו, תהליר להכנתו ותכשירי רוקחות המכילים אותו

The invention relates to new 13a-alkyl-17 -(3-acyloxy-propyl)gonanes, a process for their manufacture and pharmaceutical preparations containing these compounds and constitutes a modification of Israel Patent 72085.

In Israel Patent 72085 there are described *and claimed 13 a-alkylgonanes and there 1s presented in said patent a general formula which includes within its broad !scope the compounds of the present invention. However, the novel compounds of the present invention were not prepared at said time and are neither exemplified nor specifically mentioned in said patent.

More particularly the present invention provides:

13^-alkylgonanes of general formula I

<img file="IL77204A_D0001.tif" />

where

R stands for an alkanoyl radical with as many as 10 C-atoms or for a benzoyl radical, and

X for an oxygen atom or the grouping N׳^OH.

.

The present invention also provides a process for the preparation of 13tf-alkylgonanes of general formula I

<img file="IL77204A_D0002.tif" />

where

R and X have the meaning indicated above characterized in that a compound of formula II

<img file="IL77204A_D0003.tif" />

(II) is made to react with acid chloride or acid anhydride of general formula III or IV respectively

II

R-C-Cl (r-c)₂0 (III) (IV) where

R has the meaning indicated above . in the presence of bases at temperatures between 0 and 60 °C and, jf _desired^ subsequently react with hydroxylamine hydrochloride in the presence of tertiary amines at temperatures between 20־ and +40 °C.

30C-alkyl-1 76-(3-hydroxypropyl)-4,9-gonadiene-3-ones are known from: European Patent Application No. 84730062.1.

These compounds have a strong affinity for gestagen receptors, without themselves having any gestagenic activity. They are competitive antagonists of progesterone (antigestagens) and are suitable for inducing abortions since they displace the progesterone necessary for maintenance of pregnancy from .ג.־ the receptor. The compounds are thus valuable and of interest from the point of view of their use for postcoital (p.c.) control of fertility.

It has now been found that their bio-availability can,surprisingly, be considerably enhanced by converting these compounds into the 13«-alkyl-176-(3-acyloxypropyl)-gonanes’ of general formula I. In comparison to the previously known 13&lt;X-alkyl-1 76- (3-hydroxypropyl)-4, 9-gonadiene-3-ones they display a prolonged duration. ־.: of effectiveness with the same or greater effect. The fact that the new compounds possess excellent crystallization properties proved to be another advantage. The preparation of the pure active substance is much less difficult in their case than in the case of 1 30i־־alky 1-1 76-(3-hydroxypropyl)-4,9-gonadiene-3-ones .

Furthermore, they possess excellent chemical stability. They can be stored with no difriculty for along period of time at room temperature without decomposing.

<img file="IL77204A_D0004.tif" />

The acyl radical R of general formula I is supposed to contain as many as 10 C-atoms. Possible acyl radicals are, for example, the formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, glycoloyl, cyclopentylacetyl, mono., di-, trichcloroacetyl, benzoyl, trifluoromethylbenzyl and nicotinoyl radicals; preferred are the acetyl and benzoyl radicals.

X stands for an oxygen atom or the group N~OH, with the hydroxyimino radical being in the syn or anti position.

The compounds of general formula I in accordance with the invention are prepared ih accordance with Claim 5 by the generally known methods. The preferred bases for esterification are tertiary amines such as pyridine. The preferred tertiary amine during conversion for the preparation of oximes is pyridine.

Further suitable tertiary bases are, for example, trimethylamine, triethylamine, N,N־dimethylamino pyridine, 1 , 5-diazabicyclo/4.3.£/nonene-5 (DBN) and 1. 5-diazabicyclo/5.4.0/ undecene-5 (DBU).

The 130(-alkylgonanes of general formula I can be used in the form of pharmaceutical preparations. The preparations are manufactured by the methods generally known in galenics by mixing with organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral application.

For humans the dosage of the active ingredients in accordance with the invention amounts to approximately 10 to 1000 mg per day.

The invention is explained with the help of the following examples which, however, are given without limitation to the scope of the invention.

I

Example 1

A solution of 2.4 g of Ί1 6- (4-dimethylaminophenyl)-1 70(hydroxy-1 30&lt;-methyl-1 76 (3-hydroxypropyl) -4,9-gonadiene-

3-one in 7 ml of pyridine and 14 ml of acetanhydride is stirred for 14 hours at 25 °C. This mixture is then poured into warm water (100 ml) at a temperature of approx. 50 °C, stirred for 15 minutes and the cooled emulsion extracted with methylene chloride. The methylene chloride phase is washed neutral with NaHCO-, solution, dried over Na_S0.

4 2 ג and concentrated. Crystallization of the crude product from ethylacetate/diisopropyl ether yields 2.24 g of 1 76(3-acetoxypropyl)-116-(4-dimethylaminophenyl)-17&lt;X -hydroxy1 3K’-methyl-4,9-gonadiene-3-one with a melting point of 162 - 164 °C.

ל R

[a]_D + 436.5° (CHC1₃, c = 0.515).

Example 2

0.36 ml of benzoyl chloride in 4 ml of methylene chloride are dripped, ice-cooled, into a solution of 700 mg of 116(4-dimethylaminophenyl)-1 70(-hydroxy-1 3°(-methyl-1 76- (3-hydroxypropyl)-4,9-gonadiene-3-one. The mixture is stirred for 60 minutes at +,5 °C, then poured into saturated NaHC0₃solution and extracted with ethyl acetate. Crystallization of the crude product from hexane/diisopropyl ether yields 630 mg of 176-(3-benzoyloxypropyl)-116-(4-dimethylaminophenyl)-17«-hydroxy-13c(-methyl-4,9-gonadiene-3-one with a melting point of 114 - 116 °C.

Example 3

A solution of 630 mg of 17g-(3-acetoxypropyl)-11g-(4-dime thylaminopheny1)-17 a-hydroxy-13 a-me thy1-4,9-gonadi ene3־one in 10 ml of pyridine is stirred for 1.5 hours at 0°C after the addition of 600 mg of hydroxylamine hydrochloride. The mixture is subsequently poured into a mixture of ice water and saturated NH₄C1 solution and extracted with ethyl acetate. After chromatography on silica gel with hexane/ethyl acetate 410 mg of 17g(3-acetoxypropyl)-11g-(4-dimethyl-aminophenyl)-17a-hydroxy13a-methyl-4,9-gonadiene-3-one-anti-oxime are obtained with a melting point of 201 - 204°C.

UV (MeOH): λ = 288 nm (ε = 27400).

ΙΠαΧ

Example 4

COMPOSITION OF A TABLET WITH THE PREFERRED COMPOUND 17g- (3-ACETOXYPROPYL)-llg-((4-N,N-DIMETHYLAMINO) -PHENYL) -17a-HYDROXY13'־a-METHYL-4,9-GONADIENE-3-ONE FOR ORAL APPLICATION י '.............

10.0 mg 17g-(3-acetoxypropyl)-11g-((4-N,N-dimethylamino)phenyl)-17a-hydroxy-13a-methyl-4,9-gonadiene-3-one

140.5 mg lactose

69.5 mg corn starch

2.5 mg polyvinylpyrrolidone 25

2.0 mg aerosil

0.5' mg magnesium stearate

225.0 mg