NO127192B - - Google Patents

Description

Analogy method for the production of new,

therapeutically active 2a,3a-epoxy-2B-alkyl-5a-androstane derivatives.

The present invention relates to an analogue method for the production of new, therapeutically active ,2oc,3a-epoxy-2(3-alkyl-5oc-androstane derivatives of the general formula I,

in which R represents an alkyl group of up to 3 carbon atoms and X represents oxygen or a group of the general formula II, in which R<1> represents hydrogen or a hydrocarbon group of up to 3 carbon atoms and R<11> represents hydrogen, a hydrocarbon-carbonyl group with up to 11 carbon atoms, or a group of formula III in which Y stands for an alkyl group with up to 5 carbon atoms and n is an integer from 4 to 6, and the peculiarity of the analogous procedure is that a compound with the general formula IV

wherein R and X have the above meaning, is treated with an organic peracid in an inert organic solvent, and if desired the compound obtained, when X is an oxo group, is treated with a metallic reducing agent in a suitable organic solvent, or it can be converted into the corresponding 17a -hydrocarbon substituted derivative by treatment with a hydrocarbon-magnesium bromide or a hydrocarbon-lithium compound or an alkyne of up to 3 carbon atoms, or an optionally present 17(3-hydroxy group is treated with a cylating agent in the presence of a base or it may be preferred to the corresponding 17 (3-(1-Alkoxycycloalkyl ether) by treatment with the corresponding alkylenol or dialkyl ketal of cycloalkanone in the presence of an acid catalyst* or an optionally present 17-acyloxy group is hydrolyzed to a hydroxy group, or an optionally present 17a -

unsaturated hydrocarbon group is reduced by catalytic reduction

The group R can be any straight or branched,

saturated hydrocarbon group with up to 3 carbon atoms, such as e.g. methyl, ethyl, propyl and isopropyl. The group Y can be any straight or branched saturated hydrocarbon group of up to 5 carbon atoms, such as, for example, butyl, isobutyl, t-butyl-1-methylpropyl, pentyl, isopentyl, .1-methylbutyl, 1-ethylpropyl, 2 . vinyl, ethynyl, propenyl, isopropenyl and propynyl, in addition to the above-mentioned alkyl groups with up to 3 carbon atoms. As examples of the cycloalkyl group defined by the number n, cycloopentyl, cyclohexyl and cycloheptyl groups can be mentioned. The hydrocarbon-carbonyl group R<11> can be any straight or branched saturated or unsaturated aliphatic, cycloaliphatic or aromatic hydrocarbon-carboxyl-acyl group with up to 11 carbon atoms, such as e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methylbutyryl, trimethyaacetyl, caproyl, enantoyl, capryloyl, pelargonyl, capryl, undecanoyl, undecenoyl, cyclopentanepropionyl, cyclohexanecarbonyl, benzoyl, 3-phenylpropionyl, etc.

The new compounds produced show strong anti-estrogenic activity, uterotropic activity and delayed implantation effect.

They also show a strong myotropic effect followed by a relatively weak androgenic effect. E.g. 2a,3a-epoxy-5'-androstan-17P-ol shows a weak myotropic effect and the introduction of a methyl group in the 2-position results in an increase in the degree of effectiveness up to .15 times as great as the effect of the starting compound. It should be noted that the introduction of the methyl group at the 3-position in the same starting compound resulted in a significant reduction of the same activity. The present compounds are apparently useful as myotropic or anabolic agents for the treatment of malnutrition, the promotion of. granulas ion formation. or in . the treatment of mastopathy and breast cancer, etc.

As examples of starting compounds with formula IV, the following exemplary 5a_androst-2-ene compounds can be mentioned: 2-methyl-5a-androst-2-en-17-one,

2-methyl-5a-androst-2-en-17(3-ol,

2,17a-dimethyl-5a-androst-2-en-17(3-ol,

2-methyl-1 7α-ethyl-5oc-androst-2-en-1 7β-ol,

2-methyl-17α-vinyl-5α-androst-2-en-17(3-ol,

2-methyl-17a-ethyny].-5a-androst-2-en-17(3-ol, 2-methyl-17a-propyl-5a-androst-2-en-17(3-ol, 2 -methyl-17a-allyl-5a-androst-2-en-17P-ol,

2-methyl-17a-propynyl-5a-androst-2-ene-17P-ol, 2-methyl-17a-isopropyl-5a-androst-2-ene-17P~ol, 2-ethyl-5a-androst-2- en-17-one, 2-ethyl-5a- andr ost-2- en-17(3-ol

2-ethyl-17a-methyl-5a-androst-2-en-17P-ol,

2,17α-dietjl-5α-androst-2-en-17(3-ol,

2-e thyl-17 α-vinyl-5α-androst-2-en-17(3-ol,

2-ethyl-17a-ethynyl-5a-androst-2-en-17P~ol,

2-ethyl-17a-propyl-5a-androst-2-en-17(3-ol,

2-propyl-5a-androst-2-en-17-one,

2-propyl-5α-androst-2-en-17(3-ol,

2-propyl-17a-methyl-5a-androst-2-en-17(3-ol, 2- propyl-17a- ethyl- 5a- andr ost- 2-en-17(3-ol,

2-propyl-17a-ethynyl-5a-androst-2-en-17P-ol, 2,17a-dipropyl-5a-androst-2-en-17P-ol,

2-propyl-17a-isopropyl-5a-androst-2-en-17(3-ol, 2-i s opr opyl-5a-androst-2-en-17P-ol,

2-isopropyl-17a-methyl-5a-androst-2-en-17(3-ol, 2-isopropyl-17a-ethynyl-5<*-androst-2-en-17(3-ol,

beer. , and their corresponding 1-alkoxycycloalkyl ethers or hydrocarbon carboxy acylates as mentioned above.

When carrying out the method, the starting material with formula IV is treated for the preparation of the compound with formula I with an organic peracid, such as e.g. permauric acid, peracetic acid, perpropionic acid, persmoric acid, trifluoroperacetic acid, monopersuccinic acid, percamphoric acid, perbenzoic acid, monoperphthalic acid, dipterephthalic acid, p-nitroperbenzoic acid, m-chloroperbenzoic acid, etc. in an inert organic solvent such as e.g. benzene, methylene chloride, chloroform, ether, dioxane, acetone, acetic acid, acetonitrile, etc. The reaction is advantageously carried out at temperatures in the range from about -15° to 100 C over a period of 30 minutes to 100 hours. The reaction products can be isolated from the reaction mixture and purified by usual methods, and if desired, reacted further using the aforementioned treatment methods.

Thus, when the product e.g. is 2(3-substituted 2a,3oc-epoxy-5a-androstan-17-one, it can be reduced to the corresponding 2(3-substituted 2a,3a-epoxy-5<*-androstan-17(3-ol by treatment with a metallic reducing agent such as lithium tri-(t-butyoxy) aluminum hydride in a suitable organic solvent in a conventional manner or it can be converted to the corresponding 17α-hydrocarbon substituted derivative by treatment with hydrocarbon magnesium bromide or a hydrocarbon-lithium compound or an alkyne with up to 3 carbon atoms as mentioned under the definition of R' in the conventional way commonly called the Grignard reaction or the like. When the product is a 2(3-substituted 2a,3a-epoxy-5a- androstane-17.P-0I with or without 17a-hydrocarbon substituent, it can be converted to the corresponding hydrocarbon carboxy-acylate as mentioned above by conventional acylation methods using conventional acylating agents such as an acid anhydride or an acid halide in the presence of a base such as p yridine, or it can be etherified to the corresponding 17(3-(1- alkoxycycloalkyl ether) by the action of the corresponding alkylenol or dialkyl ketal of cycloalkanone:

wherein Y and n have the above meaning, in the presence of an acid catalyst in a conventional manner. When the product is a 2(3-substituted 2a,3a-epoxy-5a-androstan-17P-ol without a 17a-substituent, it can be converted to the corresponding 17-one by conventional oxidation methods using chromium trioxide in a basic medium such as e.g. pyridine. When the product is -a 17-acyl derivative of 2(3-substituted 2a,3a-epoxy-5a-androstan-17(3-ol with or without 17a-substituent), it can be converted into the corresponding free 17P- beer-

compounds by conventional alkaline hydrolysis, e.g. by the action of potassium carbonate or potassium hydroxide in a suitable solvent. When the product is a 17oc-unsaturated hydrocarbon substituted derivative of 2(3-substituted 2a,'3a-epoxy-5a-androstan-17(3-ol) it can be hydrogenated to the corresponding dihydro or tetrahydro derivative such as 17a- alkenyl or alkyl compound by conventional catalytic reduction method.

The manufactured compounds are used in human or veterinary medicine either alone or in combination or in preparations in connection with solid or liquid pharmaceutical carriers. The preparations are produced by known methods, e.g. using pharmaceutically acceptable organic or inorganic carriers suitable for enteral or parenteral administration. Suitable carriers are substances that do not react with the active compounds such as e.g. water, vegetable oils, benzyl alcohol, polyethylene glycols, gelatin, lactose, starch, magnesium stearate, talc, white petrolatum, isopropyl myristate or other known pharmaceutical carriers. Preparations for parenteral administration are usually prepared as solutions, e.g. solutions in oil or water, suspensions, emulsion granules, tablets or suppositories. For enteral administration, they may also contain other therapeutically useful substances. The content of active compounds in these preparations, such as an ampoule, is preferably 100y to 500 mg or 1ppm to 50%, or in a tablet in an amount of 1 mg to 250 mg.

The following examples serve to illustrate the procedure.

Example 1.

For a solution of 2-methyl-5α-androst-2-ene-17(3-ol acetate

(HJ. Ringold et al. J. Am. Chem Soc. 81, ^27 (1959)) (1.935 g)

in a mixture of 20 ml of methylene chloride and 20 ml of ether, 15 ml of monoperphthalic acid in ether (109 mg/ml) is added and the mixture is allowed to stand overnight at 0°C. The reaction mixture is washed with anhydrous sodium carbonate solution, filtered over anhydrous sodium sulfate and freed from solvent. The residue is recrystallized from acetone and gives 1,601 g of 2a.,3a-epoxy-2(3-methyl-5a-androstane-17(3-ol acetate,

with melting point 208-210°C. = 10.6°. (c=1.073 in chloroform).

Example 2.

2a,3a-e.poxy-2P-methyl-5a-androstan-17P-ol-acetate (Qoh mg) prepared by the method described in example 1 is dissolved in 50 ml of methanol and 800 mg of potassium carbonate in 6 ml of water is added to the solution. The resulting mixture is refluxed for h hours, diluted with water and extracted with methylene chloride. The extract solution is washed with water, dried and evaporated. The residue is recrystallized from an acetone/hexane mixture and gives 626 mg of 2a,3a-epoxy-2(3-methyl-5a-androstane-17P-°1 with melting point 18<1>+-185°C./a/2 <3>= +21.0° (c = 1.012 in chloroform).

Example 3.

For a solution of 2a,3a-epoxy-2|3-methyl-5a-androstan-17f3-ol

(V32 mg) in 2 ml of pyridine is added propionic anhydride (0.5 ii)

and the resulting mixture is allowed to stand overnight at room temperature. The reaction mixture is diluted with ice-cold water and the crystals formed are collected by filtration. Recrystallization from methanol gives ^98 mg of 2α,3α-epoxy-2(3-methyl-5α-androstan-17β-ol propionate. IR: V max011239 cm"<1>).

In a similar way, 2a,3a-epoxy-2(3-methyl-5a-androstan-17P-ol is converted into the corresponding acylates, such as valerate, isovalerate,

enanthate and caprylate by respective reactions with more than equimolar amounts of valeric anhydride, isovaleric anhydride, enanthic anhydride and caprylic anhydride in the presence of pyridine.

Example h.

To a solution prepared by mixing chromium trioxide (1 g) and pyridine (25 ml) under external ice-cooling, 2a,3a~epoxy-2(3-methyl-5a-androstan-17(3-ol) in pyridine is added (20 mL) at the same temperature. The resulting mixture was stirred for 1 hour and allowed to stand at room temperature overnight. The reaction mixture was diluted with ice water and extracted with chloroform. The extract solution was washed with water, dilute hydrochloric acid, dilute sodium carbonate solution, and water in the aforementioned order and then evaporated. The residue is chromatographed over neutral alumina and the eluate from the petroleum ether/benzene fraction is recrystallized from methanol to give 2a,3a-epoxy-2(3-methyl-5a-androstan-17-one. IR: w J^01 17^2 cm<-1>.

Example 5.

To a solution of 2-methyl-5a-androst-2-en-17(3-ol (1.502 g) in a mixture of 20 ml of methylene chloride and 20 ml of ether, 15 ml of monoperphthalic acid in ether (109 mg/ml) is added and aside overnight at 0° C. The reaction mixture is worked up as in example 1 and yields 1,231 mg of 2a,3a-epoxy-2(3-methyl-5a-androstan-17P-ol (from acetone-hexane mixture).

Example 6.

To a suspension of 2a,3a-epoxy-2(3-methyl-5a-androstane-17P~°1 (560 mg) in t-butanol (5 ml) is added cyclopentanonanol methyl ether (1 ml) and p-toluenesulfonic acid ^yridine salt (10 mg). The resulting mixture is stirred for h hours at room temperature and poured into an aqueous dilute sodium carbonate solution. The mixture is extracted with methylene chloride and the resulting extract is worked up in the usual manner to give crude product (636 mg) which gives 17(3- (1 - methoxy-1-cyclopentyloxy)-2a,3a-epoxy-2(3-methyl-5a-androstane (5^3 mg)) by chromatography on aluminum oxide.

IR: V<m>ax0<1>1335'1101 ' 1053 cm_1-

Example 7.

To a solution of 2,17a-dimethyl-5a-androst-2-en-17P~ol (2,010 g)

16 ml of monoperphthalic acid in ether (109 mg/ml) is added to a mixture of 20 ml of dichloromethane and 20 ml of ether and allowed to stand overnight at 0°C. The reaction mixture is washed with aqueous sodium carbonate, dried over sodium sulphate and freed of solvent. The residue is recrystallized from acetone and gives 1,557 g of 2a,3a-epoxy-2(3-17a-dimethyl-5a-androstan-17P_ol.

Example 8.

For a solution of 2-methyl-17a-ethynyl-5"-androst-2-en-17(3-ol

(1.00 g) in a mixture of 8 ml of dichloromethane and 8 ml of ether, add 8 ml of monoperphthalic acid in ether (105 mg/ml) and leave overnight at 0°C. The reaction mixture is washed with aqueous sodium carbonate solution, dried over anhydrous sodium sulfate and freed from solvent. The residue is recrystallized from acetone and gives 0.965 g of 2α,3α-epoxy-2β-methyl-17α-ethynyl-5α-androstan-17(3:-ol.

IR: V<max01>3390' 3256' 209°' 1059 cm~<1>•

Example 9.

Dry acetylene gas is introduced into a 30 ml tetrahydrofuran-ether (2:1) mixture for 1 hour. A solution of 1.5 g of potassium metal in anhydrous amyl alcohol (10 ml) is added to the solution. While stirring, 2a,3a-epoxy-2(3-methyl-5<x-androstan-17-one (1.350 g) in tetrahydrofuran/ether mixture (1:1, 20 ml) is added dropwise to the above mixture over 30 minutes during which acetylene gas is introduced therein. After stirring and introduction of acetylene gas for 3 hours, aqueous ammonium chloride solution is added. The resulting mixture is extracted with ether and the extract is washed with water, aqueous sodium carbonate solution and water in the aforementioned order, filtered over anhydrous sodium sulfate and evaporated. The residue is recrystallized from methylene chloride/methanol mixture and gives 1.280 g of 2a,3a-epoxy-28-methyl-17a-ethynyl-5'-androstan-17P-ol.

Example 10.

To a suspension of Lindler catalyst (kOO mg) in 10 ml of ethyl acetate is added a solution of 2a,3a-epoxy-2(3-methyl-17a-ethynyl-5a-androstan-17|3-ol (^09 mg) in a mixture of ether (5 ml)

and ethyl acetate (10 mL) and the resulting mixture is hydrogenated.

After 15 minutes, the reaction mixture is filtered to remove the catalyst and the filtrate is evaporated. The residue is recrystallized from methylene chloride/methanol mixture and gives 356 mg of 2a,3a-epoxy-2(3-methyl-17a-vinyl-5a-androstan-17|3:-ol. IR: w ^ol 3^08, 3087 , 1632, 912 cm".

Example 11.

300 mg of 10$ palladium-containing calcium carbonate catalyst is hydrogenated in 10 ml of ethyl acetate. To the mixture is added a suspension of 2a,3a-epoxy-2p-methyl-17-a-ethynyl-5a-androstan-17(3-ol. (136 mg) in ethyl acetate (25 ml) and the resulting mixture is hydrogenated by room temperature 1 15 minutes. The reaction mixture is worked up as in example 10 and' yields 98 mg of 2a,3a-epoxy-2(3-methyl-17a-ethyl-5a-androstane-17P~ol. IR: y JJax01 '920cm_1 •

Claims (1)

Analogous process for the production of new, therapeutically active 2a,3a-epoxy-2(3-alkyl-5a-androstane derivatives of the general formula I, in which R stands for - an alkyl group with up to 3 carbon atoms and X stands for oxygen or a group with the general formula II, in which R' stands for hydrogen or a hydrocarbon group with up to 3 carbon atoms and R' <1> stands for hydrogen, a hydrocarbon-carbonyl group with up to 11 carbon atoms, or a group of formula III in which Y stands for an alkyl group with up to 5 carbon atoms and n is an integer from h to 6, characterized in that a compound with the general formula IV wherein R and X have the above meaning, is treated with an organic peracid in an inert organic solvent, and if desired the compound obtained, when X is an oxo group with a metallic reducing agent, is treated in a suitable organic solvent, or it can be converted into the corresponding 17-oc-hydrocarbon-substituted derivative by treatment with a hydrocarbon-magnesium bromide or a hydrocarbon lithium compound or an alkyne with up to 3 carbon atoms, or an optionally present 17(3 - hydroxy group is treated with an acylating agent in the presence of a base or it can is etherified to the corresponding 17(3 -(1-Alkoxycycloalkyl ether) by treatment with the corresponding alkylenol or dialkyl ketal of cycloalkanone in the presence of an acid catalyst, or an optionally present 17-acyloxy group is hydrolyzed to a hydroxy group, or a any 17a unsaturated hydrocarbon group present is reduced by catalytic reduction.