CZ139893A3 - 17-hydroxy-b-homo-androst-4-ene-3,7a-diones and process of their preparation - Google Patents

Description

The present invention relates to 17-hydroxy-β-homo-androst-4-ene-3,7α-dione, compounds with potential antiandrogenic activity, and a process for their preparation.

BACKGROUND OF THE INVENTION

Currently, only cyproterone acetate is used in the treatment of diseases of androgen-dependent tissues [Gráf

K. J., Brotherton J., and Neumann F .: Clinical Uses of Antiandrogens in Androgens II and Antiandrogens, Η. E. Vose and G. Oertel (eds.), 485, Springer Verlag, Berlin 1974.], flutamide [Neri, R., Florance, K., Koziol, P., and Van Cleave, S .: Endocrinology 91, 427 (1972). .] and its hydroxy derivative [Tucker H., Crook JW and Chesterton GJ: J. Med. Chem. 3, 954 (1988).] And anandron [Raynaud J P., Bonne C., Bouton et al. M., Lagacé L. and Labrie F .: J. Steroid Biochem. 11, 93 (1979)]. Since these compounds are also devoid of side effects, the search for further antiandrogens to replace these substances continues. One possibility is compounds with modified skeleton [Stark L., Hampl R., Kasal A .: Antihormone Action of Steroids with Modified Ring Structure in Receptor Mediated Antisteroid Action, Μ. K. Agarwal (ed.), P. 17, Walter de Gruyter, Berlin 1987.). The present invention provides a process for the preparation of 7α-keto-β-homo-testosterone and 7α-keto-β-homo-epitestosterone, compounds having potential antiandrogenic activity.

SUMMARY OF THE INVENTION

Starting compound for the preparation of 17-hydroxy-β-homo-androst-4-ene-3,7α-dione of formula I

wherein R is a protecting group which can be selectively removed in addition to the 17B-benzoyloxy group such as HCO, CH ₃ CO or CH ₃ CH ₂ CO and the like. Reaction of this with diazomethane in the presence of aluminum chloride yields a mixture from which it can be isolated, for example, silica gel column chromatography, 3B-acyloxy-17B-benzoyloxy-B-homo-5-androst-5-en-7a-one, i.e. a compound of formula III

wherein R is as above. Selective deprotection at the 3-position, for example by saponification in an acidic medium, preferably hydrochloric acid in methanol, affords the 3B-hydroxy derivative of the general formula III in which R is hydrogen. This derivative by oxidation, such as Jones oxidation in acetone at about 0 ° C or Oppenaur oxidation, provides a conjugated ketone. Subsequent removal of the benzoyl group from the 17-position by alkaline hydrolysis, for example by treatment with an alkali metal hydroxide, preferably sodium or potassium hydroxide in methanol, affords the desired 17-hydroxy-β-homo-an3 drost-4-ene-3,7a-diones of formula I .

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 3B-acetoxy-17B-benzoyloxy-B-homo-androst-5-en-7a-one (compound of formula III wherein R is CH3CO and the wavy line represents the β configuration)

3B-Acetoxy-17B-benzoyloxy-androst-5-en-7-one (compound of formula II wherein R is CH ₃ CO and the wavy line is β configuration; 450 mg, 1.0 mmol) is dissolved in absolute ether . To this solution was added a solution of diazomethane (420 mg, 10.0 mmol) in ether (16.2 mL). To this solution was added 25 mg of aluminum chloride, after two minutes an additional 25 mg of aluminum chloride and after another five minutes of 50 mg of aluminum chloride. During the reaction, the yellow color of the solution disappears rapidly and a white cloudy solution is formed. After an additional 10 minutes at room temperature, the reaction mixture was poured into water and the product was worked up by ether extraction in the usual manner. Distilling off the solvent yielded 490 mg of a residue which did not contain the starting compound but contained, among other products, a slightly higher Rf (petroleum ether-acetone 6: 1 ratio) than the starting compound. This residue was chromatographed on a silica gel column (200 g, eluting with petroleum ether / acetone 12: 1). Treatment of the fractions containing the compound with Rf almost identical to the starting compound gave a 172 (37%) residue which crystallized from ethanol to give 95 mg (20.5%) of the title compound, mp 153-154 ° C (methanol), NMR spectrum: 0.96 s, 3 H (3 x H-18), 1.09 s, 3 H (3 x H-19), 2.03 s, 3 H (3B-acetate), 4.61 m, 1 Η (H-3a), 4.83 dd, 1 Η (H-17a, J = 9 Hz, J '= 7.5 Hz), 5.16 m, 1 H (W _1/2 = 5 Hz, H-6), 7.36 to 7.64 m, 2 H and 7.97 to 8.09 m, 3 H (5 x phenyl proton benzoate). IR: 1,733, 1,245 (acetate), 1,718 (seven-membered ketone), 1,718, 1,274 (benzoate), 1,642 (double bond). Mass spectrum: m / z 464 (M ^& lt ^{; +} & gt ^; ), 404 (M-CH3COOH), 282 (M-CH3COOH4)

-CgHg (COOH). For C 7 HH, gOg (464.6) calculated: 74.97% C, 7.81% H, found: 75.06% C, 7.83% H.

Example 2

Preparation of 3B-hydroxy-17e-benzoyloxy-β-homo-androst-5-en-7a-one (compound of formula III wherein R is hydrogen and the wavy line is β configuration)

To a solution of 3B-acetoxy-17B-benzoyloxy-B-homo-androst-5-en-7a-one (compound of formula III wherein R is CH-JCO) (131 mg, 0.28 mmol) in methanol ( 25 ml) was added 37% hydrochloric acid (0.7 ml). The reaction mixture was allowed to stand for 4 h at room temperature. Then the mixture is evaporated to dryness in vacuo, 100 ml of benzene and 100 ml of ethanol are added and the mixture is evaporated to dryness in vacuo. The residue was purified on two plates of silica gel, eluting with chloroform / ether (1: 1). This afforded 172 mg (60.5%) of a residue which crystallized from ethanol to give 25 mg (21%) of the title compound, mp 245-246 ° C (subl. 220 ° C), NMR spectrum: 1.00 and 1, 03 two s, 2 x 3 H (together: 3 x H-18 and 3 x H-19), 2.45 to 2.68 m, 2 Η (H-4), 3.54 m, 1 H (H -3a, W _1/2 = 22 Hz), 3.66 d, 1 Η (H-7, J = 11 Hz), 4.94 m, 1 H (H-17 <Z, W _1/2 = 15 Hz), 5.44 d, 1 Η (H-6, J = 9 Hz), 7.64 to 7.39 m, 3 H and 7.99 to 8.13 m, 2 H (5 x phenyl protons) . IR: 3,622 (hydroxyl), 1,718, 1,274 (benzoate). For ^C 27 ^h 34 ° 4 (422.6) calculated: 76.74% C, 8.11% H, found:

% C, 76.30;% H, 8.19.

Example 3

Preparation of 17B-Benzoyloxy-β-homo-androst-4-ene-3,7a-dione

From a solution of 3B-hydroxy-17B-benzoyloxy-B-homo-androst-5-en-7a-one (compound of formula III wherein R is hydrogen) (130 mg, 0.31 mmol) in toluene (15 mL) 3 ml of solvent was distilled off, then cyclohexanone (2 ml) was added and a further 2.5 ml of solvent was distilled off. Iso5 aluminum propoxide (140 mg, 0.70 mmol) was added to the solution. Boil the mixture to distill about 6 ml of the mixture over 45 minutes. The reaction mixture was then cooled, poured into water and treated with ether extraction in the usual manner. The residue was applied to a silica gel column (100 g), eluting sequentially with a 9: 1.5: 1.2: 1 mixture of petroleum ether and ether and a 10: 10: 1 mixture of chloroform and ether and methanol to give 155 mg of an oil. Purification on four silica gel plates (2: 3 petroleum ether / ether). Yield: 121 mg (78.5%). 214-216 ° C (aqueous ethanol), NMR spectrum: 0.98 s, 3 H (3 x H-18), 1.26 s, 3 H (3 x H-19), 4.91 dd, 1 H (H-17a, J = 9.0 Hz, J '= 7.5 Hz), 5.76 s, 1 Η (H-4), 7.35-7.65 m, 3 H and 7.98-7 8.10 m, 2H (5 x phenyl proton). IR (KBr): 1716, 1275 (benzoate), 1713 inflex (C = O 7-membered ring), 1674, 1610 (C = C-C = O). For C27H32O4 (420.5) calculated: 77.11% C, 7.67% H, found: 76.91% C, 7.52% H.

Example 4

Preparation of 17B-hydroxy-B-homo-androst-4-ene-3,7a-dione (compound of formula I wherein the wavy line represents configuration B)

17 H -Benzoyloxy-β-homo-androst-4-ene-3,7α-dione (compound prepared according to the preceding example 3) (110 mg, 0.26 mmol) was dissolved in methanol (35 mL). To this solution was added potassium hydroxide (300 mg, 5.4 mmol). The mixture was allowed to stand for 5 hours at room temperature. It is then poured into water and the product is worked up by extraction into chloroform. The residue obtained (91 mg) was purified on four silica gel plates (1: 1 chloroform / ether). Thus, 36 mg (43%) of the non-crystalline title product were obtained. 1 H NMR spectrum: 0.79 s, 3 H (3 x H-18), 1.25 s, 3 H (3 x H-19), 3 , 57 to 3.78 m,

Δ (H-17a), 5.72 s, 1 H (H-4). IR: 3,628 (hydroxyl), 3,018 (double bond), 1,711 (seven-membered ketone), 1,676, 1,620, 1,558 (C = C-C = O). For C2qH2qO3 (316.4) calculated: 75.92% C, 8.92% H, found: 75.59% C, 8.71% H.

Example 5

Preparation of 3B-acetoxy-17α-benzoyloxy-β-homo-androst-5-en-7a-one (compound of formula II wherein R is CH 3 CO and the wavy line represents the configuration a) c

3B-Acetoxy-17α-benzoyloxy-androst-5-en-7-one (compound of formula II wherein R is as described above and the wavy line is in the α configuration; 450 mg, 1.0 irimole) is dissolved in absolute ether (100 mg). ml). To this solution was added a solution of diazomethane (420 mg, 10.0 mmol) in ether (16.2 mL). Then, aluminum chloride (50 mg) was added to the solution, after two minutes an additional 25 mg of aluminum chloride and after another five minutes 50 mg of aluminum chloride. During the reaction, the yellow color of the solution disappears rapidly and a white cloudy solution is formed. After an additional 10 minutes at room temperature, the reaction mixture was poured into water and the product was worked up by ether extraction in the usual manner. The residue was chromatographed on a silica gel column (200 g), eluting with a 9: 1 to 7: 1 mixture of petroleum ether and ether. Treatment of fractions containing a compound with slightly higher Rf than the starting compound of the formula gave 207 mg (45%). NMR spectrum: 0.91 s, 3 H (3 x H-18), 1.03 s, 3 H (3 x H-19), 2.03 s, 3 H (3B-acetate) ), 4.58 m, 1 H (H-3a, W1 / 2 = 21 Hz), 5.11 d, 1 H (J = 6 Hz, 17B-H), 5.46 dd, 1 H (J = 10 Hz, J '= 1.5 Hz, H-6J, 7.38-7.65 m, 2 H and 7.96-8.10 m, 3 H (5 x phenyl proton benzoate) Mass spectrum: m / z 404 (M-CH 3 COOH), 282 (404-C ₆ H ₅ COOH). For C 9 H _{36 2} O ₅ (464.6) calculated: 74.97% C 7.81% H found: 75 % C, 7.99% H.

Example 6

Preparation of 3B-hydroxy-17α-benzoyloxy-β-homo-androst-5-en-7a-one (compound of formula III wherein R is hydrogen and the wavy line is a)

To a solution of 3B-acetoxy-17o: -benzoyloxy-B-homo-androst-5-en7

-7a-one (compound of formula III wherein R is CH 3 CO and the wavy line is &lt;2; 464 mg, 1.0 mmol) in methanol (40 mL) is added 37% hydrochloric acid (2.0 mL). The reaction mixture was allowed to stand for 4 h at room temperature. Then the mixture is evaporated to dryness, poured into water and the product is worked up by ether extraction in the usual manner. The residue was purified by silica gel chromatography (50 g, eluting with 1: 1 petroleum ether / ether). To give 318 mg (75%) of residue which by crystallization from ethanol gave 161 mg (38%) of title product, mp 130-132 ° C ^{Χ Η} NMR spectrum: 0.91 s, 3H (3 x H-18 ), 1.01 s, 3 H (3 x H-19), 3.57 m, 1 Η (H-3a, W _1/2 = 22 Hz), 3.71 d, 1 Η (H-7, J = 11 Hz), 5.11 d, 1H (H-17 ', J = 6 Hz), 5.44 d, 1 H (H-6, J = 9 Hz), 7.38 to 7.57 m, 3 H and 7.97 to 8.09 m, 2H (5 x phenyl protons). IR: 3,619 (hydroxyl), 1,717, 1,274 (benzoate) 1,701sh (seven-membered ketone), 1,637 (C = C). For C ₂₇ H ₃₄ O ₄ (422.6) calculated: 76.74% C, 8.11% H, found: 76.52% C, 8.00% H.

Example 7

Preparation of 17α-Benzoyloxy-β-homo-androst-4-ene-3,7α-dione

From a solution of 3B-hydroxy-17 (2-benzoyloxy-B-homo-androst-5-en-7a-one) (a compound of formula III wherein R is hydrogen and the wavy line is <2; 400 mg, 0.95 9 ml of solvent was distilled off, then cyclohexanone (6 ml) was added and an additional 7.5 ml of solvent was distilled off and aluminum isopropoxide (400 mg, 1.99 mmol) was added. The reaction mixture was cooled, poured into water and treated with ether extraction as usual, and the residue was applied to a silica gel column (400 g), eluting sequentially with a mixture of petroleum ether and ether. ratio 9: 1.5: 1.2: 1: 1 to give 292 mg (73%) of an oil which recrystallized from carbon tetrachloride to give 201 mg (51%) of the title product, mp 221-223 ° C (sublimates from 205 ° C) ° C), 1 H NMR spectrum: 0.88 s, 3 H (3 x H-18), 1.25 s, 3 H (3 x H-19), 5.10 d, 1 Η (H-17B) ,

J = 6 Hz), 5.75 s, 1 H (H-4), 7.39 to 7.67 m, 3 H and 7.99 to 8.14 m, 2 H (5 x phenyl proton). IR (KBr): 1716, 1274 (benzoate), 1716 (C = O 7-membered ring), 1681, 1612 (C = CC = O). For C 27 ^H 32 ° 4 (420.5) calculated: 77.11% C, 7.67% H, found: 76.83% C, 7.43% H.

Example 8

Preparation of 17? -Hydroxy-β-homo-androst-4-ene-3,7a-dione (uebelen compound of formula I wherein -R 'is hydrogen' -a-wavy line represents configuration a)

17α-Benzoyloxy-β-homo-androst-4-ene-3,7α-dione (compound prepared according to the preceding example 7) (105 mg, 0.25) was dissolved in methanol (10 mL). To this solution was added potassium hydroxide (100 mg, 1.8 mmol). The mixture was allowed to stand for 18 hours at room temperature. It is then poured into water and the product is worked up by extraction into chloroform in the usual manner. The obtained residue (100 mg) was purified on four silica gel plates (eluting with chloroform / ether 2: 1: 0.2).

This afforded 32 mg (41%) of a residue which crystallized from carbon tetrachloride to give 14 mg (18%) of the title product, m.p. 136-139 ° C (after crystal change at 60-70 ° C), NMR spectrum: 0.72 s, 3 H (3 x H-18), 1.21 s, 3 H (3 x H-19) 2.76 d, 1H (J = 5.5 Hz, Η-17β), 5.75 s, 1H (H-4). IR: 3

627, 3,620, 1,066 (hydroxyl), 3,026 (double bond), 1,711 (seven-membered ketone), 1,678, 1,664, 1,611 (C = CC = O). Mass spek- 4 trum (FAB): m / z 317 (M +), 299 (317-H ₂ O), 284 (299-CH _3). For ^C 2O ^H 28 O3 (316.42) calculated: 75.92% C 8.92% H Found:?

% C, 76.03;% H, 8.91.

Claims (8)

17-Hydroxy-β-homo-androst-4-ene-3,7a-diones of formula (I) OH (I) / wherein a wavy line denotes the configuration and / or β. A process for the preparation of 17-hydroxy-B-homo-androst-4-ene-3,7a-dione according to claim 1, characterized in that the compound of formula II From s-c-g g / gc. (II) / wherein R represents a hydroxyl protecting group which can be selectively removed in addition to a 17B-benzoyloxy group such as HCO, CH ₃ CO or CH ₃ CH ₂ CO, is converted by reaction with diazomethane under aluminum chloride catalysis to a compound of formula III (III) / wherein R as described above in the obtained compound is deprotected at the 3-position, the free hydroxy-hydroxyl group at the 3-position is oxidized, followed by removal of the benzo10yl group at the 17-position. 17-hydroxy-β-homo-androst-4-ene-3,7α-dione of formula I Process according to Claim 2, characterized in that an acetyl protecting group is used as the hydroxyl protecting group in the 3-position. 17-hydroxy-β-homo-androst-4-ene-3,7α-dione of formula I 4. A process according to claim 2, wherein the 3-protecting group is removed by acid hydrolysis. 17-hydroxy-β-homo-androst-4-ene-3,7α-dione of formula I Process according to claim 2, characterized in that the oxidation is carried out by Oppenauer oxidation. 17-hydroxy-β-homo-androst-4-ene-3,7α-dione of formula I 6. The process of claim 2 wherein the deprotection at position 17 is carried out by hydrolysis with an alkali metal hydroxide in an organic solvent. 17-hydroxy-β-homo-androst-4-ene-3,7α-dione of formula I A process according to claim 2a, wherein the alkali metal hydroxide is potassium or sodium hydroxide. 17-hydroxy-β-homo-androst-4-ene-3,7α-ions of formula I 8. A process according to claim 2a wherein the organic solvent is methanol.