NO143503B - ANALOGY PROCEDURE FOR THE PREPARATION OF 13-ALKYL-D-HOMO-GONA DIES WITH HORMONE EFFECT - Google Patents

Description

The present invention relates to an analogous method by

position of 13-alkyl-D-homo-gonadienes with endocrine action with formula

3 13

where R is (H,H) or (a-H,0-0-C_-acyl), R lower-alkyl,

„17aØ „ ^llaa .. , , n i

R H, R ethynyl, lower-alkyl.

The D-homostroids of formula I can be obtained according to the invention

by converting a D homosteroid with formula

13 3

where R , R and the dotted line in the A ring have the

given meaning

1V 3. CL

with an organometallic compound that emits a residue R , and that, if desired, an esterified D-homosteroid with the formula

<_> , n<17aØ> is H.

I where R is H.

The term C^_^-acyl shall particularly denote organic acid residues, e.g. residues of alkane carboxylic acids such as acetic acid, propionic acid, caproic acid, valerian acid, or oxalic acid, succinic acid, citric acid or residues of aromatic carboxylic acids such as benzoic acid.

Lower alkyl residues can contain up to 7 C atoms and be straight-chain or branched. Examples of this are methyl, ethyl, propyl, isopropyl, butyl and isomers. Preferred residues R"*"3 are methyl and ethyl. A preferred group of compounds within formula I are those compounds where R^~^ is methyl or ethyl and the double bond in ring A is in the 4,5-position. Furthermore, such compounds of formula I are preferred in which R"<*>"^<act> is hydrogen, ethynyl, chloroethynyl or butadiinyl and R is hydrogen.

Examples of compounds with formula I are: 17aØ-hydroxy-13-methyl-D-homo-qona-4,16-diene,

17aa-ethynyl-17aØ-hydroxy-13-methyl-D-homo-gona-4,16-diene, 17aa-ethynyl-13-ethyl-17aØ-hydroxy-D-homo-gona-4,16-diene, 17aØ- acetoxy-17aa-ethynyl-13-ethyl-D-homo-gona-4,16-diene, 30,17aØ-diacetoxy-13-methyl-D-homo-gona-4,6-diene, 30,17aØ-diacetoxy- 17aa-ethynyl-13-methyl-D-homo-gona-4,6-diene, 30,17aØ-diacetoxy-17aa-ethynyl-13-ethyl-D-homo-gona-4,6-diene.

The reaction of the 17a-keto group in a compound of formula III with an organometallic compound can be carried out in a manner known per se. The organometallic compound may be a Grignard compound (eg ethynyl magnesium bromide, propynyl magnesium bromide, vinyl magnesium bromide) or an alkali metal organic compound such as Na, K or Li acetylide, or vinyl lithium. For the preparation of 17aa-unsubstituted compounds with formulas I, complex metal hydrides can be used as organometallic compounds, e.g. di-(lower alkyl)aluminum hydrides such as diisobutylaluminum hydride; tri-lower oxyaluminum such as triisopropoxyaluminum; lithium aluminum hydride;'• sodium aluminum (or boron) hydride; or trimethoxy or trimethoxy lithium aluminum hydride. Suitable solvents for this are hydrocarbons, e.g. cyclohexane, benzene, toluene; and ethers, e.g. diethyl ether or tetrahydrofuran. The D-homosteroids of formulas III which are used as starting materials can be prepared as described in the examples or analogously to these.

The compounds of formula I all have endocrine action. Thus, they are e.g. strongly progestagen. They can e.g. find use as cycle regulators. For these purposes, dosages of 0.01 to 0.1 mg/kg come into consideration. Furthermore, an androgenic effect was observed, especially with the compounds with R<17act>= h.

The process products can be used in the form of pharmaceutical preparations which contain them in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral application, such as e.g. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. and can be in solid form, e.g. as tablets, dragees, suppositories, capsules; or in liquid form, e.g. as solutions, suspensions or emulsions.

EXAMPLE 1

To a solution of 2.6 g of 13-ethyl-D-homogona-4,16~dien-17a-one in 50 ml of absolute tetrahydrofuran was added 1.66 g of lithium acetylide-ethylenediamine complex and the mixture was stirred while constantly blowing through acetylene 90 minutes at room temperature. For work-up, the mixture was carefully poured into 250 ml of water and extracted 3 times with ether. The ether extracts were washed with water, dried with Na 2 SO 4 and evaporated in vacuo. The residue was chromatographed on 100 g of silica gel. 1.8 g of pure 17α-ethynyl-13-ethyl-17α-hydroxy-D-homo-gona-4,16-diene were eluted with hexane-acetone (95:5). Temp. 95-97° (ether-hexane), [α]D25° = - 193°

(C = 1.0 in dioxane).

The starting material can be prepared as follows:

A solution of 3.14 g of 13-ethyl-3-methoxy-D-homogona-2,5(10),16-trien-17af}-ol in 150 ml of methanol was mixed with 10 ml of 1 N and 3 ml of conc. aqueous hydrochloric acid and stirred for 12 hours at 25°C. The methanol was evaporated on a rotary evaporator and the aqueous residue was extracted 3 times with dichloromethane. The organic phases gave, after washing with bicarbonate solution, drying over sodium sulphate and evaporation on a rotary evaporator, 2.9 g of 13-ethyl-17a(3-hydroxy-D-homogona-4,16-dien-3-one, m.p. 191-192°C.

4.0 g of 17aØ-hydroxy-13-ethyl-D-homo-gona-4,16-dien-3-one was reacted with ethanedithiol in methanol and boron trifluoride etherate as a catalyst to 3,3-ethylenedithio-13- ethyl-17α[3-hydroxy-D-homo-gona-4,16-diene with m.p. 156-158°C. This was dissolved in tetrahydrofuran, added to a mixture of 150 ml of liquid ammonia and 30 ml of tetrahydrofuran at -50°C and then reduced by the addition of 300 mg of lithium in 50 ml of liquid ammonia to the amorphous 13-ethyl-17a@- hydroxy-D-homo-qona-4,16-diene. 1.90 q of this substance was dissolved in 65 ml of acetone, cooled to 0°C and mixed with 2.0 ml of Jones reagent (CrO-j in 8 N t^SO^) over 5 minutes. The crude product gave, after recrystallization, 1.3 g of pure 13-ethyl-D-homo-gona-4,16-dien-17a-one. Temp. 78-79°C (methanol), [α]D25° = - 10.1° (c - 1.0 in dioxane), 62?5 = 7870.

EXAMPLE 2

In an analogous manner to example 1, 3|3-acetoxy-13-ethyl-17α3-hydroxy-17α-methyl-D-homo-gona-4,16-diene, m.p. 119-121°C, [α]D25=-103°C (c = 1.0 in dioxane) is prepared.

Claims (1)

Analogous method for the production of 13-alkyl-D-homo-gonadienes with endocrine action with formula where R<3> means (H,H) or (a-H, 3-O-C^-acyl) , R<13> lower-alkyl, R"'"73'3 H, R^<7aa> ethynyl, lower-alkyl , characterized by converting a D-homo-steroid with formula 13 3 where R , R and the dotted line in the A-ring have the meaning stated above, with an organometallic compound that gives off the residue R^<7aa>, and that, if desired, an obtained D-homosteroid of formula I is esterified where R<17a0> is H.