NO127193B - - Google Patents

Description

Method of manufacture of

therapeutically active 13-alkyl-17-

haloalkynyl steroids with 3-ol-

or 3-ester groups.

This invention relates to a method for the production of steroid ketones with 17-haloalkynyl groups, and certain of their derivatives.

The process according to the invention is one for the production of a steroid ketone with the structure: where each group R is hydrogen or an alkyl group containing up to 5 carbon atoms, R<1> is an n-alkyl group with 2 to 4 carbon atoms, R 2 is a haloalk-l- ynyl group containing up to 5 carbon atoms and in trans configuration to r\ OR^ is a hydroxy group, an etherified hydroxy group of up to 5 carbon atoms or an acyloxy group of up to 19 carbon atoms, Q is a methylene or ethylene group, Y is hydrogen or an acyl group containing up to 19 carbon atoms, the substituents on the tertiary carbon atoms in ring C are in trans-anti-trans configuration, and ring A contains a double bond in the 4(5) or 5(10) position. The method is characterized by the fact that a steroid ketone with the general formula

12 3

where R, R, R, OR, Q, the configuration of ring C and the double bond in ring A is as indicated above, is reduced at the carbonyl group to form a steroid of the general formula (i) where Y is hydrogen, and that the the compound obtained is then optionally acylated to form a steroid of the general formula (I) where Y is an acyl group.

An alkyl group can in this context be linear or branched. Preferably, R is a methyl or ethyl group.

R"*" can e.g. be an ethyl, n-propyl or n-butyl group. R 2 is a haloalkynyl group with its acetylene bond at the carbohydrate atom closest to the steroidal ring D. Examples of haloalkynyl groups are chloroethynyl (C1CSC-), bromethynyl, fluoro-

3

ethynyl and trifluoromethylethynyl groups. OR can be hydroxy,

an etherified hydroxy group, e.g. a 2-tetrahydropyranyloxy group, or an acyloxy group, e.g. an acetoxy or n-heptanebyloxy group.

Particularly valuable are those compounds in which each group R is hydrogen, or only one group R in the molecule is

an alkyl group and this is a methyl group; those in which R"'' is an ethyl group; those in which R 2 is a chloroethynyl group; those in which OR 3 is hydroxy and those in which Y is an acetyl group.

The starting materials for the reduction process can be prepared by hydrogenation of a compound with structure (II)

where the 3-oxo group is protected using e.g. formation of the enamine, with double bonds in the 3(4) and 5(10) positions, the enoleter, with double bonds in the 2(3) and 5(10) positions and the ketal, with a double bond in the 5(10) or 5(6) position. If the hydrolysis is carried out under mild, acidic conditions, e.g. with oxalic acid, compounds with structure (II) containing the 5(10) double bond are obtained, while if strongly acidic conditions are used, the product is the 4(5)-one. Compounds with structure (II) with the protected oxo group and where OR 3 is hydroxy, can be prepared by alkylation of the corresponding compound containing a 17-oxo group. The hydrolysis and the alkylation have been made the subject of separate protection.

The reduction possibly a steroid ketone with structure (II) to

a steroidal coliol of structure (I), where Y is hydrogen, can be made by using a reagent suitable for reducing a carbonyl group, e.g. sodium borohydride or lithium aluminum tri-tert.-butoxyhydride. A steroid of formula I where Y is hydrogen can then be acylated at the 3-position to give a compound of structure (I), where Y is an acyl group, e.g. an acetyl group,

by using suitable methods for the esterification of a secondary carbinol group. Favorable conditions for the esterification of compounds containing a tertiary carbinol group should be used to

avoid dehydration of the 17-carbinol group.

In the above structures (I) and (II), the 13U and 13a compounds are not completely separated, as the 1313 and 13a forms in the product after a total synthesis that did not include a suitable separation step will be present in equimolecular amounts or in racemate form. Preferably, the starting material in the method according to the invention is a separated 136-enantiomer. The invention particularly encompasses the production of enantiomers with the 138-alkyl group, in the presence or absence of their 13a-alkylene enantiomers, so that it includes the production of the separated 136-ethyl compounds and the 13B forms in admixture with the corresponding 13a forms, especially racemic forms.

The products produced by the method according to the invention are useful either as pharmaceutical preparations with progestational activity, pituitary gonadotropic inhibitory activity,

or other valuable steroidal hormone properties, or as intermediates for such drugs. It has been found that the properties of the drug preparations are generally superior to or different from the properties of the corresponding compounds with a 13-methyl group. However, the difference in properties between the products produced by the method according to the invention and the corresponding 13-methyl compounds is not only a difference in degree, but also a qualitative difference.

In particular, it has been observed that homologation with an additional carbon atom in the 18-position (so that one obtains a 13-ethyl group) generally results in the valuable properties of the corresponding 13-methyl compounds being retained and increased. Products prepared by the method according to the invention with n-propyl or n-butyl in the 13-position generally show less activity, but are still valuable, because they show special activities which are different from those shown by the corresponding 13-methyl compounds.

PROGESTATIONAL ACTIVITY

Measurement of progestational activity by the Clauberg method according to Elton and Edgren, Endocrinology, 1958, 63_, 464, has given the following results:

The (±)-136-methyl compound listed for comparison is one of the most active progestational agents known to date. The activities of the 13B-ethyl compounds are remarkable, especially since the active (±)-enantiomers will have

corresponding activity.

PITUITARY GONADOTROPIC INHIBITORY ACTIVITY

In an experiment to measure pituitary blockade activity, the ovary is removed on one side of adult female 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 wood

to block gonadotrophin secretion. The following results were obtained in this experiment:

The (+)-13fl-methyl compound is used as a standard for comparison and the stated results show a remarkable

significantly increased activity for the compounds according to the invention,

especially considering that they are racemates.

The invention is illustrated by the following examples,

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

EXAMPLE 1

Sodium borohydride (2g) was added to (+)-17a-chloroethynyl-13l3-ethylgon-4-ene-17if-ol-3-one (5g) in ethanol (250ml)

with stirring, and the reaction mixture was then stirred for 3 hours. After acidification with aqueous acetic acid, water was added and the product isolated with ether to give (+),17α-chloroethynyl-13β-ethylgon-4-ene-3,17B-diol (5 g) as an amorphous powder, which seemed to

be a mixture of the 3a and 3Æ forms. IR: 3340, 220;

EXAMPLE 2

To (1)-17a-chloroethynyl-136-ethylgon-4-ene-176-ol-3-one

(2.2 g) in tetrahydrofuran (100 ml) cooled in an ice bath, lithium aluminum tri-tert-butoxide hydride (2.2 g) was added, the reaction mixture stirred under cooling for two hours and then allowed to stand overnight at room temperature. Water and hydrochloric acid were added and the product isolated using ether. The resulting gum was isolated from ether and from light gasoline to give (±)-17α-chloroethynyl-13B-ethylgon-4-ene-3B, 176-diol (0.8 g), m.p. 120-124°C.

EXAMPLE 3

To (±)-176-acetoxy-17a-chloroethynyl-136-ethyl-gon-4-en-3-one (0.5 g) in tetrahydrofuran (20 ml) was added lithium aluminum tri-tert. .5 g). After standing overnight at room temperature, water (1 ml) was added, and the suspended solids were filtered off. Evaporation of the filtrate gave (-)-176-acetoxy-17a-chloroethynyl-138-ethylgon-4-en-3/3-ol as a gum (0.45 g).

IR: 3390, 2225, 1740.

EXAMPLE 4

(±)-17α-chloroethyny1-13B-ethy1-17B-heptanoyloxygon-4-en-3-one (0.59 g) was dissolved in methanol (25 mL) and one excess of sodium borohydride was added. After stirring at room temperature for two hours, 50% aqueous acetic acid (10 ml) was added, the mixture completely in brine and the product isolated using ether as (±)-17α-chloroethynyl-13B-ethyl-176-heptanoyloxygen-4-ene -3-ol (0.5 g); IR: 3380, 2565, 2530, 2220, 1740, 1260.

EXAMPLE 5

(±)-17α-chloroethynyl-13B-ethylgon-4-ene-3,17B-diol (2 g, the product of Example 1) was kept for 16 hours in pyridine (10

ml) containing acetic anhydride (15 ml). After addition of dilute hydrochloric acid, the product was isolated using ether and recrystallized from aqueous methanol to give (±)-3-acetoxy-17a-chloroethynyl-13B-ethylgon-4-en-176-ol (0.9 g) sm.p. 154-160°C.

IR: 3450, 2205, 1725.

EXAMPLE 6

The procedure according to example 5 was repeated using the 36,178^diol according to example 2 (1.4 g) in pyridine (7 ml) and acetic anhydride (10.5 ml), with acidification with 2N sulfuric acid, and 3B- acetoxy-17B-ol (0.8 g), m.p. 163-165°C.

(Found : 70.8% C, 7.9% H, 9.0% Cl.

C23H36°3Cl requires: 70'8% c'7/75%H»9.1% Cl).

EXAMPLE 7

To (t)-17B-acetoxy-17a-chloroethynyl-136-ethylgon-4-ene-

3B-ol (0.45 g) in dry pyridine (20 ml) was added to acetic anhydride (1 ml) and the solution was allowed to stand overnight at room temperature. The mixture was poured into water, acidified with dilute hydrochloric acid and the product recovered using ether and recrystallized from ether as (±)-17α-chloroethynyl-36,17B-diacetoxy-13B-ethylgon-4-ene (0.2 g) , sm.p. 144-145°C. IR: 2210, 1745, 1730.

(Found : 69.6% C, 7.6% H, 8.2% Cl,

<C>25<H>33°4Cl requires: 69/5% C, 7.5% H, 8.2% Cl.

EXAMPLE 8

To (±)-17a-chloroethynyl-13B-ethyl-17B-heptanoyl-oxygon-4-en-3-ol (0.5 g) in pyridine (5 ml) was added acetyl chloride (0.12 g) in benzene ( 4 ml) and the mixture stirred for 20 hours. Product

tet was then cooled in ice while adding water, and the mixture completely in brine and the product isolated by means of benzene as (±)-3-acetoxy-17a-chloroethyny1-13B-ethy1-17B-heptanoyloxygon-

gen (0.2 g), a gum. IR: 2210, 1740, 1670.

EXAMPLE 9

To a clear solution of (-)-17α-chloroethynyl-136-ethylgon-4-ene-3B,17B-diol (0.8 g) in pyridine (25 ml) was added succinic anhydride (1.0 g) and the mixture stirred for 3 days and then poured into water (100 ml). After standing for 5 minutes, the solution was acidified with dilute hydrochloric acid and the product isolated using ether and crystallized from a mixture of acetone and hexane as

Claims (2)

17α-chloroethynyl-13B-ethylgon-4-ene-38,176-diol-3B-hemisuccinate (0.5 g), m.p. 155-157°C, with one molecule of hexane of crystallization. IR: 3370, 2200, 1740, 1710. On treatment in acetone with sodium bicarbonate it was converted to sodium hemisuccinate, which was recrystallized from a mixture of ether and alcohol, m.p. 160-170°C (splitting). EXAMPLE 10 (±)-17α-chloroethynyl-13B-ethylgon-4-ene-3B,176-diol (1.0 g) was added to pyridine (1 ml) and n-heptanoic anhydride (1.1 ml) and the mixture was allowed to stand for 24 hours and then poured into water and stirred for two hours, acidified with dilute sulfuric acid and again stirred for two hours. Isolation of the product using ether, and crystallization from methanol gave (±)-17a-chloroethynyl-13B-ethyl-36-heptanoyloxygon-4-en-176-ol (0.65 g), m.p. 142-144°C. 1. Process for the production of therapeutically active 13-alkyl-17-halogenalkynyl steroids with 3-ol- or 3-ester- groups and of the general formula where each group R is hydrogen or an alkyl group containing up to 5 carbon atoms, R <*> is an n-alkyl group of 2 to 4 carbon atoms, R o is a haloalk-l-ynyl group containing up to 5 carbon atoms and is in trans configuration to R 1 , OR 3 is one hydroxy group, an etherified hydroxy group with up to 5 carbon atoms or an acyloxy group of up to 19 carbon atoms, Q is a methylene or ethylene group, Y is hydrogen or an acyl group containing up to 19 carbon atoms, the substituents on the tertiary carbon atoms in ring C are in trans-anti-trans configuration, and ring A contains a double bond in 4(5)- or 5( 10) position, characterized by that a steroid ketone with the general formula 12 3 where R, R, R, OR, Q, the configuration of ring C and the double bond in ring A is as indicated above, is reduced at the carbonyl group to form a steroid of the general formula (I) where Y is hydrogen, and that the the compound obtained is then optionally acylated to form a steroid of the general formula (I) where Y is an acyl group. 2. Procedure as stated in claim 1, characterized in that a compound of formula (II) 12 3 where each R is hydrogen, R is ethyl/ R is chloroethynyl, OR is hydroxy and Q is a methylene group, is reduced by the carbonyl group.