NO126366B - - Google Patents

Description

Addendum to patent no. 124,598

The present invention relates to a method

for the production of steroids which are gona-4,9-dien-3-ones.

In Norwegian patent 124,598, a method for the production of, among other things, a group of 13/3-polycarbonalkylgona-4,9-dien-3-ones and their D-homoanalogues; these compounds have a useful pharmacological effect, or are intermediates for the production of other compounds that have such an effect. It has now been found that certain members of this group as well as other compounds, which are closely related to this group, - all of which are new, surprisingly exhibit much better pharmacological action than the rest of the group.

The method according to the invention consists of

preparation of therapeutically active 17-halo-alkynyl-gona-4,9-dien-3-ones of the general formula (I) where each group R is hydrogen or an alkyl group containing up to 5 carbon atoms, R<*>is a n -alkyl group with from 2 to 4 carbon atoms, R 2 is a haloalk-l-ynyl group containing up to 5 carbon atoms and 0 is a methylene or ethylene group, and the method is characterized by a compound of the general formula (II); where W is a ketal group or a tertiary amino group accompanied by a 3,4-ethylenic bond, is hydrolyzed. ;An alkyl group can be a straight chain group or a branched group. When the group R is an alkyl group, it can e.g. be a methyl or ethyl group. R<*> is preferably an ethyl or

ler n-propyl group. R<2> is a haloalkynyl group with the acetylenic bond at the carbon atom closest to the steroid ring. Examples of haloalkynyl groups are chloroethynyl (C1C5C-), bromethynyl, fluoroethynyl and trifluoromethylethynyl groups.

Particularly valuable are such products where each group R

is hydrogen, or only one group R in the molecule is an alkyl group and this is a methyl group, such where R^ is an ethyl group and

2

such where R is a chloroethynyl group.

When W is a ketal group, it is preferably an alkylene dioxy group, especially an ethylene dioxy group. When W is a tertiary amino group, the 3-substituent is preferably a dialkylamino group, e.g. an N-pyrrolidyl group„ The starting material for this hydrolysis process can be obtained by methods where a 3-keto group in a 4,9-dien-3-one (such a compound is described in French patent 1 450 381) is protected by ketalization or formation of an enamine, using a compound where the desired group R^ has not yet been formed. Standard ketalization processes, such as reaction with ethylene glycol in the presence of toluene-p-sulfonic acid can be used to form the 3-ketal group,

and in a similar way, a standard method can be used for the formation of the enamine group.

Hydrolysis of the group W can be easily carried out by

bring the starting material which is dissolved in a suitable organic solvent into contact with mineral acid, e.g. hydrochloric acid,

and recovering the product when the ketal or enamine group has been hydrolyzed off.

In the product from a total synthesis that does not have

comprised a dissolution step, the compound according to the invention will be obtained as racemates of 13/3- and 13a-enantiomers.

The compounds prepared according to this invention and having the structural formula I are useful as pharmaceutical products possessing progestational, pituitary gonadotropic inhibitory properties, or other valuable steroidal hormone properties, and many are active by oral administration. It has been found that in general the properties of the compounds are far better than or different from the properties of the corresponding compounds, which exhibit a 13-methyl group. The difference in the properties between the compounds produced according to the invention, and the corresponding 13-methyl compounds, is furthermore not only a question of difference in degree, but also of difference in quality.

Furthermore, it has been shown that homologation with an additional carbon atom at the 18-position (giving a 13-ethyl group) generally results in a retention and increase of the valuable properties of the corresponding 13-methyl compounds. Compounds of the invention with n-propyl or n-butyl in the 13-position generally exhibit less potency, but are still valuable, because they exhibit specific activities different from those exhibited by the corresponding 13-methyl compounds.

Progestational activity.

Measurement of progestational activity by the Clauberg method according to Elton and Edgren, Endocrinology, 1959, 63,464, has given the following results: The (-)-13/3-methyl compound is indicated for comparison and is one of the most potent progestational agents to date is known.

Pituitary gonadotropic inhibitory activity'.

In an attempt to measure pituitary blockade acti-

the ovary is removed on one side in adult females

rats and these are treated daily for 14 days with the test compound. At autopsy on the 15th day, the remaining ovary (the left one) is removed and weighed. Hemicastration partially frees the hypothalamic-pituitary system from ovarian secretion,

which is measured on the basis of a compensatory overgrowth (hypertrophy) of the remaining ovary. Active compounds prevent this overgrowth, probably by blocking gonadotrophin secretion.

The following results were obtained in this experiment.

Estrogen-antagonistic activity as measured by the mouse vaginal smear test according to Edgren, Proe. Soc. Exp. Biol. Med., 1960, 105, 252 gave the following results.

The separation of estrogen-antagonistic and progestatio-

nal activities that the compound according to the invention exhibits,

is a valuable feature of their properties.

The invention is illustrated by the following examples,

where the temperature indications are in °C. Infrared (IR) absorption data refer to maximum values given in cm^, and ultraviolet (UV) absorption data refer to maximum values given in nyu with the number in parentheses indicating molecular extinction coefficients at these wavelengths.

Example 1

(-)-17ev-chloroethynyl-13/3-ethyl-3,3-ethylenedioxygona-5 (10),9-(11)-dien-17/3-ol (2.0) was heated with methanol (75 ml) containing concentrated hydrochloric acid (3.0 ml) and water (1.0 ml) for 30 minutes. The solution was poured into aqueous sodium carbonate, extracted with

ether and the ether solution was washed, dried and evaporated. residual

It was recrystallized from a mixture of ethyl acetate and hexane to give (-)-17a-chloroethynyl-13/3-ethylgona-4,9-dien-17/3-ol-3-one (1.1 g),

m.p. 188-190°C. The starting material was prepared as follows: (-)-13/3-ethyl-3,3-ethylenedioxygona-5(10),9(11)-dien-17/3-ol (5.5 g) was heated for 2, 5 hours in a nitrogen atmosphere under reflux with toluene (250 ml) and cyclohexanone (50 ml) containing aluminum isopropoxide (4.0 g). Water (5.0 mL) was added to the cooled solution and the mixture was shaken for 5 minutes. Then anhydrous sodium sulfate was added, mixed

the mixture was filtered and the filtrate evaporated to give a product which was recrystallized from methanol to give (-)-13/3-ethyl-3,3-ethylenedioxygona-5(10),9(11)-dien-17-one (4.1 g).Cis-dichloroethylene

(3.4 g) was added in the course of one hour to lithium-methyl (31.5 g) i

ether (100 mL), followed by (-)-13/3-ethyl-3,3-ethylenedioxygona-5(10),9(11)-dien-17-one (4.0 g) in ether (75 mL ).The mixture became

stirred for 4 hours, cooled to 0° and cleaved by dropwise addition of aqueous ammonium chloride. The organic layer was separated, washed, dried and evaporated to give an impure product.

Example 2

(-)-17α-chloroethynyl-13/3-ethyl-3-pyrrolidinylgona-3,5(10),9(11)-trien-17-one was heated under reflux with acetic acid (50 mL) and water (50 mL ) containing sodium acetate (25 g) for 3 h» The mixture was diluted with water, extracted with ether and the ether solution was washed, dried and evaporated,

and the residue was recrystallized from ethyl acetate/hexane to give (t)-17a-chloroethynyl-130-ethylgona-4,9-dien-17j8-ol-3-one (1.3g),

sm.p. 188-190°.

The starting material was prepared as follows:

(-)-13/3-ethyl-3-pyrrolidinylgona-3,5(10),9(11)-trien-170-ol (5.5 g) was heated under reflux for 2.5 h with toluene (2 .5 ml) and cyclohexanone (50 ml) containing aluminum isopropoxide (4.0 g) under a nitrogen atmosphere. Water (5.0 ml)

was added to the cooled solution and the mixture was shaken for 5 minutes. Anhydrous sodium sulfate was added and the mixture was filtered and the filtrate was evaporated to give crude (i)-13/3-ethyl-3-pyrrolidinylgona-3,5(10), 9(11)-trien-17-one (5.0 g). Cis-dichloro-ethylene (3.4 g) was added to lithium-methyl (31.5 g) over the course of 1 hour

in ether (100 ml) followed by (+)-13/3-ethyl-3-pyrrolidinylgona-

3,5(10),9(11)-trien-17-one (4.0 g) in ether (75 mL). The mixture was stirred for 4 hours, cooled to 0° and cleaved by dropwise addition of aqueous ammonium chloride. The organic layer was ad-

separated, washed, dried and evaporated.

Example 3

(1)-17a-chloroethynyl-3,3(2,2-dimethylpropylenedioxy)-13- /3-n-propylgona-5(10),9(11)-dien-17/3-ol (3.5 g) in methanol (100 ml) and 6N hydrochloric acid (15 ml) was refluxed for 30 minutes.

The cooled solution was diluted with water and extracted with ether. The ether solution was washed, dried and evaporated and resi-

the duet was chromatographed on silica gel eluting with benzene and benzene-ether mixtures. The product was recrystallized from acetonitrile to give (^)-17a-chloroethynyl-13/3-n-propylgona-4,9-rlien-17-0-ol-3-one, m.p. 174-176°, (1.2 g) .

The starting material was prepared as follows: (-)-13/3-n-propylgona-4, 9-dien-17/3-ol-3-one (5 g) in benzene (100 ml) and 2,2-dimethylpropane- 1,3-diol (10 g) was refluxed with p-toluenesulfonic acid (100 mg) for 16 hours. Aqueous sodium bicarbonate was added

sat, and the organic layer was separated, washed with water, dried and evaporated to give an impure residue of (-)-3,3-(2,2-dimethylpropylenedioxy)-13/3-n-propylgona-5 (10 ) .9 (11)-dien-17/3-ol (5 g) .

(-)-3,3-(2,2-dimethylpropylenedioxy-13/3-n-propylgona-5(10),9(11)-dien-17/3-ol (4.5 g) in toluene (200 ml) and 2-butanone (80 ml)

was refluxed with aluminum isopropoxide (4.5 g) for 4 ti-

more. The cooled solution was stirred with water (5 mL) for 20 min.

ter and dried by adding anhydrous sodium sulfate. Blendin-

gen was filtered, and the filtrate was evaporated to give (-)-3,3-(2,2-dimethylpropylenedioxy)-13/3-n-propylgona-5(10),9(11)-diene-17-

on (4.2 g).

(-)-3,3-(2,2-dimethylpropylenedioxy)-13/3-n-propylgona-5(10),9(11)-dien-17-one (4 g) was added with stirring to lithium chloroacetylide [ prepared from lithium methyl (3.5 g) and cis-1,2-dichloro-

ethylene (16 g)] in ether (75 mL) under nitrogen and the mixture was re-

stirred for 43 hours at room temperature. The mixture was poured into water and extracted with ether. The ether solution was washed, dried and

evaporated to give (-)-17a-chloroethynyl-3,3-(2^-dimethylpropylenedioxy-1S/S-n-propylgona-S (10),9(11)-dien-17/3-ol (4 g).

Example 4

(-)-17aa-chloroethynyl-3,3-propylenedioxy-13/3-ethyl-D-homo-gona-5(10),9(11)-dien-17ao;-ol (4 g) in methanol (100 ml) and 6N salt-

acid (15 mL) was refluxed for 30 min. The mixture was diluted with water and extracted with ether. The ether solution was washed, dried and evaporated, and the residue was crystallized from ethyl acetate to give (-)-17αo;-chloroethynyl-13/3-ethyl-D-homogona-4,9-dien-17a/3-ol-3- on, mp. 208-209° (1.8 g) .

The starting material was prepared as follows:

(-)-13/?-ethyl-D-homogona-4,9-dien-17aa-ol-3-one (5 g) in

benzene (100 ml) and propylene glycol (15 ml) were refluxed with p-toluenesulfonic acid (100 mg) for 16 hours. The cooled dissolver

ming was diluted with aqueous sodium bicarbonate, the organic layer was separated, washed and dried. The solvent was removed to give (-)-3,3-propylenedioxy-13/3-ethyl-D-homogona-5(10),9(11)-diene-

17α/3-ol (5 g) .

(-)-3,3-propylenedioxy-13/3-ethyl-D-homogona-5 (10),9(11)-

dien-17aj9-ol (5 g) in toluene (200 ml), 2-butanone (80 ml) and aluminum

nium isopropoxide was refluxed for 5 hours. The cool-

te solution was stirred with water (5 ml) for 20 minutes and dried by adding anhydrous sodium sulfate. The desiccant was

filtered, and the filtrate was evaporated under reduced pressure to give (-)-3,3-propylenedioxy-13/3-ethyl-D-homogona-5(10),9(11)-dien-17a-one (5, 1 g).

(-)-3,3-propylenedioxy-13/3-ethyl-D-homogona-5 (10) ,9 (11) -

dien-17a-one (5 g) was added with stirring to lithium chloroacetylide (prepared from lithium methyl 3.5 g, and cis-1,2-dichloroethyl (16 g))

in ether (75 mL) under nitrogen and the mixture was stirred for 48 h at room temperature. The mixture was poured into water and extracted with ether. The ether solution was washed, dried and evaporated to give

(-)-17aff-chloroethynyl-"3,3-propylenedioxy-13/3-ethyl-D-homogona-5 (10) ,

9(11)-dien-17α/3-ol (4.8 g).

Claims (3)

1. Process according to patent no. 124 598 for the production of therapeutically active 17-halogenalkynyl-gona-4,9-dien-3-ones of the general formula (I) where each group R is hydrogen or an alkyl group containing up to 5 carbon atoms, R^" is an n-alkyl group with from 2 to 4 carbon atoms, R 2 is a haloalk-l-ynyl group containing up to 5 carbon atoms and Q is a methylene or ethylene group, characterized in that a compound of the general formula (II) where W is a ketal group or a tertiary amino group accompanied by a 3,4-ethylenic bond, is hydrolyzed. 2"Procedure as stated in claim 1, characterized by using a starting material of the formula (II) where W is an ethylenedioxy or N-pyrrolidyl group. 3. Method as set forth in claim 1 or 2, characterized in that a starting material of the formula (II) is used where R" is an ethyl group.