CH503003A - Gonatrienes oestrogenic and antilipaemic agents and - Google Patents

Abstract

Gona-1:3:5(10)-trienes of formula (I). (i) R = H, alkyl (opt. substd.) or acyl, alkoxyalkyl R1 = (2-4C) alkyl Y = CO (opt. ketalised), hydroxymethylene or acyloxymethylene, Z = CO, hydroxymethylene, alkyl hydroxymethylene, or acyloxymethylene Y and Z together may be 17-acyloxy-16:17-epoxy-ethylenic group. The angular H atoms and R1 of ring C are trans-anti-trans. As oestrogenic and antilipaemic agents and inhibitors of pituitary gonadotrophins.

Description

  

  
 



  Process for the production of gonatrienes
This invention relates to a process for the preparation of estradiol-related gonatriene derivatives which have estrogenic, anti-lipemic pituitary gonadotrophin inhibition or other steroid hormone activity and / or which are intermediates for the preparation of other gonatriene derivatives.



   According to the invention, gona-1,3,5 (10) -trienes of the formula I
EMI1.1
 produced, wherein OR is a free, etherified or esterified hydroxyl group, R 'is an alkyl radical of 2 to 4 carbon atoms, R2 is an acyl radical, the hydrogen atoms in positions 8, 9 and 14 with the radical R1 are in trans-anti-trans configuration and the group OR2 is in the cis position to R1.



   The process according to the invention for the preparation of these compounds is characterized in that a compound of formula II is epoxidized, e.g. with a peracid.
EMI1.2
  



   The group R can, for example, be methyl, ethyl, allyl, methoxymethyl, propyl, 2'-tetrahydropyranyl benzyl or 0-chloroethyl or it can be acetyl, propionyl, benzoyl or chloroacetyl. The group R1 is preferably ethyl, but can be n-propyl, n-butyl or isobutyl.



   The starting materials of the formula II can be obtained by enol acylation of compounds of the formula III
EMI2.1
 obtained e.g. with isopropenyl acetate.



   In Structures I through III above are the 13 (3 and 13α-compounds explained in accordance with Horeau-Reichstein
Convention (Fieser & Fieser, Steroide, Reinhold, 1959.



   Page 336), not distinguished separately, and in these
Structures has a solid line that represents an atom or one
Group connecting to the steroid nucleus has no configuration significance but is used solely to indicate the position in the nucleus in which the atom or group is connected. The
The product of an overall synthesis which did not contain a suitable separation step will contain the 13ss and 13a forms in an equimolecular mixture or in racemic form. The starting material is preferably a separated 13ss enantiomenes. The invention particularly includes the enantiomers with the 13ss-alkyl group in the presence or absence of their 13a-alkyl enantiomers.

  It includes the separated 13 (3-alkyl compounds and the 13ss forms in
Mixture with the corresponding 13a forms, in particular racemic mixtures.



   The compounds prepared here in the examples are racemates and are referred to as 13 (3-forms, with the (+) - or (dl) -prefix of the Horeau-Reichstein
Convention was omitted.



   The compounds obtained according to the invention can be incorporated into pharmaceutical preparations. They show different steroid hormone activities. According to standard test methods, 17 (3-acetoxy-16a, 17a-epoxy-13B-ethyl-3-methoxy-gona-1,3.5- (10) -triene shows anti-lipemic activity.



   They can be used as starting materials for the manufacture of other drugs, such as in Switzerland. Patent Nos. 501606 and 501607 are described.



   example 1
3.17 - Diacetoxy - 13ss - äthylgona - 1.3.5 (10), 16-tetraene (1.170 g) was dissolved in sodium dry ether (50 ml) and treated with a solution of monoperphthalic acid in ether (0.28 molar; 25 ml). The mixture was allowed to stand at room temperature for three days and then washed with ice cold sodium carbonate solution and brine, evaporated to give an oil (1.147 g). This product was then combined with one prepared earlier from a small batch (140 mg) and chromatographed over Florisil (100 g) and eluted with benzene and benzene ether.



   3.17B-diacetoxy-l 6cr-17a-epoxy-13 (3-ethyl-gona-l, 3.5 (10) -triene (575.4 mg) was obtained as an oil from the benzene ether fractions obtained in addition A mixture of the above epoxide and subsequent ketol (52.2 mg) was obtained as a white solid from the later benzene-ether fractions 3-Acetoxy13ss-ethyl-gona-1,3,5 (10) -tnen-16a-ol-17-one (544.9 mg) was obtained.

  The first eluate was crystallized from ethanol to give the epoxide (344.2 mg); M.p. 170 to 171.50 C; this was recrystallized from ethanol to give a product with a melting point of 172 bis
173.50 C. (Found: 71.95 O / o C, 7.24 0 / o H; the gross formula C3H8O5 requires 71.85 lo C, 7.34% H).



   The raw material was produced as follows:
3.31 g of 3-acetoxy-130-ethyl-gona-1,3,5 (10) -trien-17-one were dissolved in 50 ml of isopropenyl acetate, treated with 500 mg of p-toluenesulfonic acid and kept on the boiling water bath overnight. The solvent was partially distilled off, the mixture was diluted with ether, washed, dried and evaporated to give 3.54 g of brown oil. The product was chromatographed on 200 g of Florisil and eluted with benzene. The first fractions gave 1.44 g of 3,17-diacetoxy-13ss-ethyl-gona-1,3, 5 (10), 16-tetraene as a slowly crystallizing oil. Recrystallization from ethanol at -5 C gives this diacetate in the form of platelets; M.p. 89-89.50 C.

  Found: 75.25 0 / o C; 7.34 / o H. (The gross formula Co,., H2sO,) requires 74.97 <) / o C; 7.66 e / o H.)
Example 2
17 - Acetoxy-13 (3-ethyl - 3 - methoxygona-1,3,5 (10), 16tetraene (9.28 g) in dry ether (400 ml) was treated with a 1N solution of monoperphthalic acid (100 ml) in ether treated, and the mixture left to stand for 5 days at room temperature.

  The solution was then washed, dried, evaporated and gave a yellow resin which was column treated with benzene (400ml) through Florisil (80 g), crude 17, -acetoxy-16a, 17a-epoxy-13 (3-ethyl- Gave 3-methoxy-gona-1,3,5 (10) -triene (6.5 g).



   The starting material was prepared as follows: 13ss - ethyl - 3 - methoxy-gona - 1,3,5 (10) - trien-17-one (16.8 g) in isopropenyl acetate (200 ml) and p-toluenesulfonic acid (3 g) was heated to 100 "C for 18 hours and then the solvent was gradually distilled down to approximately 75 ml over a period of 6 hours. The mixture was then cooled, diluted with ether (2: 1) and washed with saturated potassium bicarbonate solution and brine, the organic Layer dried and evaporated.

  The resulting brown solid was crystallized from ethanol (200 ml) to give the 1 7-acetoxy-1 3 (3-ethyl-3-methoxy-gona-1,3,5- (10), 16-tetraene (9, 8 g); m.p. 128 to 1300 C and, recrystallized from ethanol, had a melting point of 133.5 to 134.50 C. (Found: 77.65 O / o C; 8.45 o / o H; the gross formula C22H2sO requires 77.61 i0 / o C; 8.29 o / o H.)

 

Claims (1)

PATENT CLAIM Process for the production of a gona-1,3,5 (10) -triene of the formula I. EMI3.1 wherein OR is a free, etherified or esterified hydroxyl group, R1 is an alkyl radical of 2 to 4 carbon atoms, R2 is an acyl radical, the hydrogen atoms in positions 8, 9 and 14 with the radical R1 are in the trans-anti-trans configuration and the Group OR2 is in the cis position to Rt, characterized in that a compound of the formula II EMI3.2 epoxidized. SUBCLAIMS 1. The method according to claim, characterized in that the epoxidation is carried out with a peracid. 2. The method according to claim, characterized in that Rl is the (3-ethyl radical.