IE42693B1 - Novel esters of oestradiol and branched chain aliphatic or cycloaliphatic carboxylic acids - Google Patents

Description

The invention relates to novel esters of oestradiol and branched chain aliphatic or cycloaliphatic carboxylic acids, and to methods for their preparation. The invention particularly relates to novel oestradiol 170-esters having the formula: wherein n = 0, 1 or 2, usually 0 or 1 and preferably 0; R, = alkyl (1-10 C), preferably CII^; R2 = II or alkyl (1-10 C), preferably H; R^ = an aliphatic hydrocarbon group having 1-18 C-atoms, preferably 6-12 C-atoms, which group may contain one or more rings having 5-12 C-atoms, preferably 5-7 C-atoms, or Rj and R^ form together with the C-atom to which they are attached a cycloaliphatic hydrocarbon group having 7-12 C-atoms, said cycloaliphatic optionally being Substituted by an aliphatic hydrocarbon group having 1-6 C-atoms, with the proviso that the total number of C-atoms in the ester group is in 2 6,9 3 - 3 the range of 8-20 C-atoms, preferably 9-16 C-atoms and still more preferably 10-14 C-atoms.

The novel esters can be prepared according to methods in use in practice or described in literature, for example by reacting oestradiol with a functional derivative of the branched chain aliphatic or cycloaliphatic monocarboxylic acid such as the acid chloride.

As oestradiol has two hydroxy groups that can be reacted to form an ester, special methods must be used to obtain 17(’-esters with a free 3-hydroxy group.

For example, oestradiol is reacted with the carboxylic acid chloride in a solvent, such as acetone, and in the presence of a base, such as pyridine, to give the 3,178-diester, whereafter use is made of the difference in activity of the 3-ester group and 178-ester group towards saponification to obtain the oestradiol-1713ester, i.e. with a diluted alkaline solution (KOH in an alcohol) the 3-ester group is hydrolyzed.

Specific examples of the branched chain aliphatic and cyclo-aliphatic monocarboxylic acids which can be used for preparing the novel oestradiol 17β-esters are 2'-methyl-octanoic acid, 3'-methyl-octanoic acid, 2'methyl-nonanoic aid, 31-methyl-nonanoic acid, Z'-methyldecanoic acid, 2',2'-dimethyl-decanoic acid, 3'-methyldecanoic acid, 3',3'-dimethyl-nonanoic acid, 2',2'dimethyloctadecanoic acid, 2'methylhexadecanoic acid 3(cycloheptyl)-propionic acid, cyclo-octyl-acetic acid, 2'-methyl-3'-cyclohexyl-propionic acid 3'-cyclohexylbutyric acid, cyclododecyl-butyric acid, cyclododacylcarboxylic acid, 31-propyl-hexanoic acid, 4' ,4'diethyl-hexanoic acid, 21-octyl-dodecanoic acid, 2'ethyl-heptanoic acid, 3'-butyl-heptanoic acid.

As mentioned before, the acid chlorides of these acids can also be used.

The novel oestradiol esters obtained according to - 4 the precess of the invention can be administered in the usual dosage form for enteral administration, such as tablets, powders, capsules, grains, pills, boli, dragees, granulates, microcapsules, solutions, dispersions.

The novel oestradiol esters are particularly useful as oestrogenic substances for oral administration and are particularly effective, when administered orally in the presence of a lipoid substance, preferably a pharmaceutically acceptable non-steroidal lipoid, as disclosed in Patent Specification No. 42692.

The exceptional oestrogenic properties of the preparations according to the invention have been demonstrated using the known Allen-Doisy test (J.A.M.A. (1923) , 81, pages 819-821) in castrated female rats. The oest radio 1-17Γ,-esters were administered orally, dissolved in arachis oil. The results are given in table A.

TABLE A Oestradiol-178-ester Dosage 8 pg 16 pg 32 pg - formate 0/8 0/8 1/8 -pentanoate 0/8 0/8 0/8 -octanoate 0/8 1/8 2/8 -decanoate 2/8 6/8 7/8 -2’-methyl-decanoate 8/8 8/8 8/8 -3'-methyl-decanoate 6/8 8/8 8/8 -undecanoate 2/8 7/8 8/8 -dodecanoate 2/8 6/8 7/8 -tetradecanoate 1/8 6/8 6/8 -hexadecanoate 0/8 0/8 6/8 -octadecanoate 0/8 0/8 2/8 Studies with other lipoid substances, such as sesame oil, soya bean oil, glyceryl· trioleate, oleic acid and undccenoic acid gave similar results. It appears obvious that oestradiol-17 β-esters derived from branched chain carboxylic acids are much more active than the other esters.

Clinical trials in ovarlectomized and in menopausal women, given a daily dosage of 0.1-0.5 mg oestradiol-17β-ester, administered in an oral preparation according to the invention, revealed favourable oestrogenic effects, which suggest the potency of the preparation in EDS-therapy.

During clinical trials in post-menopausal women, given a daily dosage of 1-3 dosage units of an oestrogen and of an oestrogen-gestagen preparation according to the invention for 6 weeks, a distinct decrease in the plasma calcium level was noted, which suggests an antiosteoporotic effect.

The invention is further illustrated by means of the following example.

Example I.

To a solution of 2 g oestradiol in a mixture of 8 ml pyridine and 8 ml acetone, cooled to -10°C, was added dropwise a solution of 4 ml 21-methyl-31 cyclohexylpropionylchloride in 12 ml acetone. The mixture was stirred for 16 hours at 0°C and 6 hours at room temperature. After cooling to -1O°C a solution of 1 ml 2'-methyl-3'-cyclohexyIpropionylchloride in 5 m3 acetone was added and the mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into ice-water (8 g) and stirred for some time to decompose excess acid chloride. The mixture was extracted with methylene chloride. The extract (4 g), containing oestradiol 3,173-diester, was evaporated to dryness and the residue was dissolved in a mixture 42603 - 6 of methanol (19 ml) and tetrahydrofuran (19 ml). The solution was cooled, whereafter a solution of 350 mg potassium-hydroxide in a mixture of 4.8 ml methanol and 2 ml tetrahydrofuran was added. Stirring was effected for 4 hours, while gradually increasing the temperature to 0°C. The reaction mixture was poured into ice-water. Extraction with methylene-chloride, chromatography on silicagel with toluene/ethylacetate 95/5 and crystallization from ether gave 1.5 g oestradiol 17(3-(2'-methyl-31-cyclohexylpropionate), m.p. 154 156°C: /ά7θ°=+39° (in CH2Cl2 ).

In a similar manner the following 17 β-esters of oestradiol were prepared: 2'-methy1-decanoate, 31-methyl-decanoate, 21,2'-dimethyl-decanoate, 3'-cyclohexyl-butyrate, cyclododecanecarboxylate, 31-propyl-hexanoate, 4',41-diethyl-hexanoate, 2'-octyl-dodecanoate, 2',2'-dimethyl-octadecanoate, 2'-ethyl-heptanoate, cycloheptylcarboxylate, cyclo-octyl-acetate, 2',2'-dimethyl-heptanoate, 2' -niethyl-hoxadpcanoate, 2'-ethyl-tetradecanoate, 3'-ethyl-hexanoate, 3'-butyl-heptanoate, 3',3'-dimethyl-nonanoate.

Claims (24)

1. CLAIM S:1. An oestradiol 17B-ester having the formula: wherein 5 n = 0-2; = alkyl (1-10 C) ; R 2 = H or alkyl (1-10 C); R 2 = an aliphatic hydrocarbon group having 1-18 C-atoms, which group may contain one or more rings having 10 5-12 C-atoms; or Rj and Rj form together with the C-atom to which they are attached a cyclo-aliphatic hydrocarbon group having 7-12 C-atoms, said cyclo-aliphatic group optionally being substituted by an aliphatic hydrocarbon group 15 having 1-6 carbon atoms, with the proviso that the total number of carbon atoms in the acyl group is in the range of 8-20 carbon atoms.

2. A compound according to claim 1, wherein n = 0 and R 2 = H. 20

3. A compound according to claim 1, wherein n = 1 and R 2 - II.

4. A compound according to claim 2, wherein )93 - 8 - methyl.

5. A compound according to claim 3, wherein R-^ = methyl.

6. A compound according to claim 2, wherein R.^ and Rg form together with the carbon atom to which they are attached a cyclo-aliphatic group having 7-12 C-atoms.

7. A compound according to claim 3, wherein and Rg form together with the carbon atom to which they are attached a cyclo-aliphatic group having 7-12 C-atoms.

8. A compound according to claims 1-5, wherein Rg - an aliphatic group having 6-12 C-atoms,

9. A compound according to claims 1-8, wherein the total number of carbon atoms in the acyl group is in the range of 9-16 carbon atoms.

10. Oestradiol 17β-(2'methyl-3'-cyclohexylpropionate).

11. Oestradiol 17β-(2'-methyldecanoate).

12. Oestradiol 17β-(3'-methyldecanoate).

13. Oestradiol 17β-(2',2'-dimethyl-decanoate).

14. Oestradiol 17β-(3'-cyclohexyl-butyrate).

15. Oestradiol 17β-(cyclododecane-carboxylate).

16. Oestradiol 17β-(3'-propyl-hexanoate).

17. Oestradiol 17B-(2'-octyl-dodecanoate).

18. Oestradiol 17β-(cyclcheptane-carboxyiate).

19. Oestradiol 17β-(cyclo-octyl-acetate).

20. Oestradiol 17β-(2'-methyl-hexadecanoate). 42633 - 9

21. Oestradiol 173-(2'-ethyl-tetradecanoate).

22. Oestradiol 17B-(3'-ethyl-hexanoate).

23. Oestradiol 17(3-(3'-ethyl-heptanoate).

24. Oestradiol 17 β-(3',3'-dimethylnonanoate).