IE42693B1 - Novel esters of oestradiol and branched chain aliphatic or cycloaliphatic carboxylic acids - Google Patents
Novel esters of oestradiol and branched chain aliphatic or cycloaliphatic carboxylic acidsInfo
- Publication number
- IE42693B1 IE42693B1 IE64/80A IE6480A IE42693B1 IE 42693 B1 IE42693 B1 IE 42693B1 IE 64/80 A IE64/80 A IE 64/80A IE 6480 A IE6480 A IE 6480A IE 42693 B1 IE42693 B1 IE 42693B1
- Authority
- IE
- Ireland
- Prior art keywords
- oestradiol
- atoms
- compound according
- methyl
- acid
- Prior art date
Links
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 title claims description 29
- 229930182833 estradiol Natural products 0.000 title claims description 27
- 125000001931 aliphatic group Chemical group 0.000 title claims description 9
- 150000002148 esters Chemical class 0.000 title description 5
- 150000001735 carboxylic acids Chemical class 0.000 title description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 239000005640 Methyl decanoate Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims 8
- 125000002252 acyl group Chemical group 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000001076 estrogenic effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229940073584 methylene chloride Drugs 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- IMHQFVGHBDXALM-UHFFFAOYSA-N 2,2-diethylhexanoic acid Chemical compound CCCCC(CC)(CC)C(O)=O IMHQFVGHBDXALM-UHFFFAOYSA-N 0.000 description 1
- KNRWSAWLDHZTQV-UHFFFAOYSA-N 2-cyclododecylbutanoic acid Chemical compound CCC(C(O)=O)C1CCCCCCCCCCC1 KNRWSAWLDHZTQV-UHFFFAOYSA-N 0.000 description 1
- SFVSLWJGURQFMC-UHFFFAOYSA-N 2-cyclooctylacetic acid Chemical compound OC(=O)CC1CCCCCCC1 SFVSLWJGURQFMC-UHFFFAOYSA-N 0.000 description 1
- AXPAUZGVNGEWJD-UHFFFAOYSA-N 2-methylhexadecanoic acid Chemical compound CCCCCCCCCCCCCCC(C)C(O)=O AXPAUZGVNGEWJD-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- JUADTOTVJUYCRQ-UHFFFAOYSA-N 3-cyclohexylpropanoyl chloride Chemical compound ClC(=O)CCC1CCCCC1 JUADTOTVJUYCRQ-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VZFUCHSFHOYXIS-UHFFFAOYSA-N Cycloheptanecarboxylic acid Chemical compound OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 1
- 208000002197 Ehlers-Danlos syndrome Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 206010067572 Oestrogenic effect Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- -1 boli Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- JWIPDQOXAJMVHL-UHFFFAOYSA-N cyclododecanecarboxylic acid Chemical compound OC(=O)C1CCCCCCCCCCC1 JWIPDQOXAJMVHL-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- VBSHAXJPLHCYTH-UHFFFAOYSA-N cyclooctyl acetate Chemical compound CC(=O)OC1CCCCCCC1 VBSHAXJPLHCYTH-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- TVQGDYNRXLTQAP-UHFFFAOYSA-N ethyl heptanoate Chemical compound CCCCCCC(=O)OCC TVQGDYNRXLTQAP-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229940093932 potassium hydroxide Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL7506407A NL7506407A (en) | 1975-05-30 | 1975-05-30 | PROCESS FOR PREPARING AN ORAL ACTIVE PHARMACEUTICAL PREPARATION. |
| IE1041/76A IE42692B1 (en) | 1975-05-30 | 1976-05-17 | Oestrogenic compositions for oral administration |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE42693L IE42693L (en) | 1976-11-30 |
| IE42693B1 true IE42693B1 (en) | 1980-09-24 |
Family
ID=26319035
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE64/80A IE42693B1 (en) | 1975-05-30 | 1976-05-17 | Novel esters of oestradiol and branched chain aliphatic or cycloaliphatic carboxylic acids |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IE42693B1 (en) |
-
1976
- 1976-05-17 IE IE64/80A patent/IE42693B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE42693L (en) | 1976-11-30 |
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