JPS5926640B2 - Method for producing ethisterone derivatives having reproductive suppression activity - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to ethisterone derivatives with postcoital activity for reproductive suppression.

The ethisterone derivatives that are the object of the present invention are 3-oxime and 3-oxime-17β esters of ethisterone, and are represented by the following formula (where n is O or 1, and n=1
In this case, R5 is in the 61st or 7th position and R
4 is hydrogen, R1 is hydrogen or -COR2,
Here, R2 is a lower alkyl group, such as a straight or branched lower alkyl group having 1 to 8 carbon atoms such as methyl, ethyl, butyl, pentyl, heptyl, isopropyl, octyl, etc., phenyl group, cycloalkyl group, etc. Cycloalkyl groups having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups, adamantyl groups, cycloalkyl groups having 1 to 5 carbon atoms such as trichloromethyl, tripromonomethyl, trichlorobutyl, etc. is a haloalkyl group,
R3 is a lower alkynyl group, for example a lower alkynyl group having 2 to 5 carbon atoms such as ethynyl, propynyl, butynyl, a lower alkadienyl group, a lower alkadienyl group having 3 to 5 carbon atoms such as propadienyl or butadienyl, and a cycloalkyl group; For example, a cycloalkyl group having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl or cyclopentyl, and R4 is hydrogen, a lower alkyl group such as a lower alkyl group having 1 to 5 carbon atoms, a lower alkylcarbamoyl group such as methylcarbamoyl, a lower alkylcarbamoyl group having 1 to 5 carbon atoms, such as ethylcarbamoyl, butylcarbamoyl, and a cycloalkyl group, such as a cycloalkyl group having 3 to 5 carbon atoms, such as cyclopropyl, cyclobutyl, and cyclopentyl, and R
5 is lower alkyl having 1 to 5 carbon atoms, provided that n-0
, R4 is not hydrogen when R2 is methyl).

Furthermore, within the scope of the present invention are 3-oximeethisterone derivatives within the following structural formula, where R1, R2, R3, R4 and R5 are as defined above.

The above-mentioned compound of the present invention can be obtained by reacting the corresponding 3-one with a suitable hydroxylamine salt in the presence of a base, and, if necessary, recrystallizing from a suitable solvent or column chromatography to obtain geometric isomers. It can be produced by isolation.

Alternatively, compounds in which R1 is -COR2 can be prepared by reacting the corresponding 3-one with a group 0H at the C-17 position with a suitable hydroxylamine salt in the presence of a base, followed by the reaction of the hydroxyl at the C-17 position. They can also be prepared by esterifying the group and, if necessary, isolating the geometric isomers by recrystallization from a suitable solvent or by column chromatography. In addition, the following formula and (in the formula, R1, R2,
Other analogous compounds represented by (R3 and R5 are as defined above) can also be produced by reacting the corresponding 3-one with a suitable hydroxylamine salt in the presence of a base.

All compounds within the above formula are anti-fertilizers (Anti-fertilizers).
-11teringagent), i.e., as an agent that suppresses reproduction when given after sexual intercourse.

In compounds of formula 1, R3 is ethynyl and R
1 and R4 are hydrogen, or R4 is hydrogen and R1 is -
All are new compounds except for the compound which is COCH3. Although free oxime and oxime-17β-acetate have been reported in the prior art, no pharmaceutical activity is claimed for either compound. [For free oximes, see L. Rw. icka. K. Hofmann and H. F. Helv. by Mendahl. Chim
．． Reported in Actal Volume 2l, page 371 (1938),
Oxime-17β-acetate was reported in Canadian Patent No. 855,203]. No reproductive suppression activity has been reported for either compound. Although ethisterone has been used as an oral progestin-like agent for many years, ethisterone and its oxime have no oral antifertility activity even when administered at dosage levels up to approximately five times higher than the level used for the new oxime. does not indicate.

A major drawback of the many common contraceptive methods currently available is that they must be used before intercourse.

This includes oral anti-ovulatory contraception and anti-implantation (Anti-implantation).
This applies not only to intrauterine devices, but also to condoms, spermicidal foam and jelly contraceptive septa, and the like. Therefore, if it is necessary to use these contraceptive methods, consideration and preparation should be made before intercourse. Furthermore, the noted contraceptive methods mentioned above are either inconvenient, as in the case of septa, intrauterine devices, and the like, or potentially harmful, as in the case of certain oral anti-ovulation compounds. Oral contraceptives currently in use generally contain large amounts of estrogens that can cause adverse side effects such as thrombophlebitis and pulmonary embolism. Intrauterine devices can cause uterine penetration during insertion and are painful to the user not only during insertion but also while being held. The present invention provides a method of reproductive control that does not require prior preparation and does not have the drawbacks of conventional methods.
The aim of the present invention is to provide new steroidal oximes with anti-implantation activity. Another object of the present invention is to provide a method for controlling reproduction by postcoital administration of an oxime derivative of ethisterone. The novel 3-oxime and 3-oxime-17β ethisterone derivatives according to the present invention are represented by the following formula;
1 is hydrogen or -COR2, where R2 is lower alkyl, phenyl, cycloalkyl, adamantyl, and trihaloalkyl, R3 is lower alkyl, a lower alkadiene group having 3 to 5 carbon atoms, and cycloalkyl, and R4 is hydrogen, lower alkyl, lower alkylcarbamoyl and cycloalkyl with the proviso that when R2 is methyl, R4 is not hydrogen and when R1 is hydrogen, R4 is not hydrogen).

Novel steroidal oximes are prepared from the corresponding ketoesters (formula) by reaction with hydroxylamine salts, such as hydroxylamine hydrochloride, in the presence of suitable bases such as pyridine, sodium hydroxide, sodium acetate and the like. manufactured by

Ketoesters, which are intermediates in the production of new oximes, are also new compounds.

The novel ketoesters can be combined with ethisterone of the formula R2COCl in suitable solvents such as benzene, toluene and the like.
or with the formula (R2COO)2
It is produced by reacting with an acid anhydride having 0. R2 and R3 in the above formula are the same as defined above, with the exception that R
When 2 is methyl, R3 is not ethynyl. Alternatively, oximes can be prepared from ethisterone by esterifying the hydroxyl group at carbon position 17.Oxime derivatives within formulas 0 to V can also be prepared from the corresponding ketones.

It is believed that the 3-oxime and 3-oxime-17β monoester of ethisterone, which are the subject of the present invention, prevent pregnancy by preventing the implantation of blastocytes when administered orally. .

Generally, from about 2.5 Tn9 to about 10 Tn9 per kilogram of body weight per day.
Administering an amount of m9 for about 6 days after intercourse is effective in suppressing reproduction. The free oxime of the present invention has two types of geometric isomers, named syn type and anti type.

The two forms are shown as follows: (wherein R2 and R3 are as defined above).

Although both isomers exhibit some activity as reproductive suppressants, the anti-isomer tends to be the more active compound.
Pure isomers can be isolated by recrystallization from a suitable solvent or by column chromatography. Generally, it is difficult to obtain a purity higher than 90% without repeating the isolation procedure. Examples are given below for specific illustration. However, it is to be understood that the invention is not limited to the specific details of the examples. Example 1 17-Cyclopropylcarpoxyethisterone 3-oxime (a) 17α-pregn-4-ene-20-yn-3-one-17β-ol-cyclopropylcarboxylateethisterone 5.007 (16 mmol) and 4.137 (48 mmol) of cyclopropylcarboxylic acid chloride in 500 mj of dry benzene.
Refluxed for 1 day.

Removal of the solvent under reduced pressure yields a yellow oil of 7.47. The oil was chromatographed on silicic acid 3507. Elution of the column with a mixture of ethyl acetate-benzene (5%) yields a 3.05y (50%) crystal mass. Recrystallization from cyclohexane gives a pure product with a melting point of 155-155.5°C. (b) 17α-pregnone-4-
En-20-yn-3-one-17β-ol-cyclopropylcarboxylate-3-oxime hydroxylamine hydrochloride 0.957 (13.6 mmol) and 17
α-pregnone-4-ene-20-yn-3-one-17
β-ol-cyclopropylcarboxylate 1,70
7 (4.47 mmol) is dissolved in 25 ml of dry pyridine and the mixture is heated on a steam bath for 1.5 hours.

The reaction mixture is then stirred at room temperature overnight. The solution is slowly poured into 600 ml of water with stirring. A white precipitate is obtained which is filtered off, washed with water and dried. Dissolve the solid in enough chloroform to make a solution;
Then, the chloroform solution was washed with water and Na2sO
4 and evaporated under reduced pressure to give 1.647
An off-white solid is obtained.

Recrystallization from methanol-water gives two oxime products. First product: 0.847 (60% anti:40% syn) Second product: 0.29y (94%
anti: 6% syn) [64%].

A sample for analysis is prepared using silicic acid and a thin layer chromatography preparation plate, and developed using a 15% ethyl acetate solution. In the above procedure, instead of ethisterone, 5α・1
When 7α-pregnone-20-yn-17β-ol-3-one is used, 5α・
17α-pregnone-20-yne-17β-ol-3-
On, the oxime is obtained.

Following the procedure of Example 1 the following compounds are prepared.

Examples Separation of syn and anti isomers of 17α-pregn-4-ene-20-yn-17β-ol-3-one, acetate, oxime Separation of syn and anti isomers by dry column chromatography on silica gel This is achieved by partial division by .

The final separation is completed by chromatography of the rich fraction on a silica gel preparation plate. 17α-pregnone-14-en-20
-In-17β-ol-3-one, acetate, oxime 1.07 cm of a 50/50 mixture of syn/anti to a 50 inch x 1 inch column of WOelm SilicaGel (using an indicator).
Develop with 0% ethyl acetate-cyclohexane.

Examination with ultraviolet light reveals a broad dark band, which is sliced into 1 inch sections (through nylon support tubes) and each section is examined with thin layer chromatography. Slice and examine starting with the more mobile segment (anti). Categories 1-7 (all anti), Categories 8-18 (syn and anti), Categories 19-25 (mostly thin). Repeat this step for another 5 steps.
Repeat for 1.07 0/50 mixtures. Combining the fractions containing only the anti-isomer, evaporating the solvent, and recrystallizing the residue from methylene chloride hexane gives 3
00η of anti-17α-pregn-4-ene-20-yne 17β-ol-3-one, acetate, oxime is obtained as a white powder.

Melting point 178-180'Cw/d1 anti=97.4% (
TLCSCAN).

Mix the category with a lot of syn isomer (550 w), 14-10
Chromatographed on a 00 micron silica gel preparation plate (
40 watts/sheet) and developed with 40% ethyl acetate-cyclohexane.

mechanically separating the silica gel layer containing the syn isomer;
Extracted with 2% MeOH-CH2Cl2, CH2Cl2/
Recrystallization from hexane yields 225η syn-17α-pregnone-4-en-20-yn-17β-ol-3-
ion, acetate, and oxime as a white powder. Melting point 205-207℃ w/d, thin 93.4% (T
LCSCAN).

Using the procedure above, 17α-pregnone-4en-20
-yn-17β-ol-3-one, when the syn and anti isomers of the oxime are separated, melting point 225-230 °C
Syn-17α-pregne-14-en-120-in-17
β-ol-3-one, oxime and melting point 225-2
Anti-17α-pregnone-4-ene-20-yn-17β-ol-3-one, oxime, is obtained at 30°C.

EXAMPLES Preparation of Starting Materials for Example 1 Example 17 α-pregne-4-ene-20-yne 17 β-ol-3-one, cyclopentylcarboxylate 300 m equipped with reflux condenser and magnetic stirrer
0.73 f7 (6.4 mmol) in a 1 volume round bottom flask
of cyclopentylcarboxylic acid and 5 ml (36 mmol) of trifluoroacetic anhydride in 150 ml of dry benzene is stirred for 5 minutes.

Ethisterone (27, 6.4 mmol) is then added and the solution is warmed to reflux temperature for 10 minutes. After stirring overnight (18 hours) at room temperature, the reaction mixture was heated to 100
Wash with 1 m part of 10% sodium hydroxide and water, N
Dry over a2sO4 and concentrate to give a 3,2y yellow oil. The oil is chromatographed over 1607 silica and the product is eluted with a 5% ethyl acetate mixture. Removal of the solvent and recrystallization of the solid residue from aqueous methanol yields 1
7α-pregnone-4-ene-20-yn-17β-ol-3-one, cyclopentylcarboxylate 0.8
2y is obtained. If benzoic acid, cyclohexylcarboxylic acid and cyclopropylcarboxylic acid are used in place of cyclopentylcarboxylic acid in the above procedure, 17α-pregn-4-ene-20-yn-17β-ol-3-
on, benzoate, 17α-pregnone-4-ene-2
0-yne-17β-ol-3-one, cyclohexylcarboxylate and 17α-pregn-4-ene-20-yne 17β-ol-3-one, cyclopropylcarboxylate are obtained.

Example V l7α-Pregny-4-ene-20-yn-17β-ol-3-one, O-methyloxime 100 mj round bottom flask Heethisterone 57, Methoxyamine hydrochloride 1
．． 51y and 50ml of pyridine.

The mixture is warmed on a steam bath for 2 hours, cooled and poured into 600 ml of a mixture of ice and water. After stirring for 1 hour, the colorless solid that separates is filtered out, washed thoroughly with water and dried.

Recrystallization from benzene yields 1 with a melting point of 215-217°C.
3.07 of 7α-pregnone-4-ene-20-yne 17β-ol-3-one, O-methyloxime is obtained.
If ethisterone acetate and cyclopentyloxyamine hydrochloride are used in place of ethisterone and methoxyamine hydrochloride in the above procedure, 1
7α-pregn-4-ene 20-yn-17β-ol-3-one, acetate, 0-cyclopentyloxime is obtained.

Example 17 α-pregnone-4-ene-20-yne 17β
-ol-3-one, acetate, 0(N-methylcarbamoyl)oxime A solution of 950 watts of ethisterone acetate oxime in 17 ml of acetone was evaporated magnetically under a stream of nitrogen in a 50 m round bottom flask equipped with reflux condensation. Stir with a stirrer.

Using a syringe, add triethylamine (0.20 mO and methyl isocyanate) through the "air barrier" stopper.
1 (0.022 mO). After 1 hour at room temperature, if the thin layer chromatography plate shows that no reaction has occurred,
The reaction mixture is heated under reflux for 2 hours. After stirring overnight at room temperature, the volatiles are removed under reduced pressure resulting in a foam. The foam is crystallized in ether,
A solid of 760 η is obtained. The crystals are then dissolved in purified acetone, treated with activated charcoal, filtered through a short Celite column, and the acetone removed under a stream of nitrogen. Crystals of 17α-pregn-4-ene-20-yn-17β-ol-3-one, acetate, 0-(N-methylcarbamoyl)oxime with a melting point of 180-183°C are obtained. Antifertility effects of compounds (Antilit)
The terminus effect is measured by the following procedure: Adult female mice are smeared daily and just before the oestrous period (proestrus), they are housed overnight with a fertile male mouse.

The next morning, female mice are examined for the presence of sperm in the vaginal wash. The day sperm is found is the first day of pregnancy (first day).
day). The mice are gavaged with the test compound dissolved in sesame oil from day 1 to day 6 of gestation and killed on day 14. Then, the implantation and resorption site (ResOrpt
iOnsite) to examine the ovaries. The comparison group is
Treat in the same manner except that no compound is administered. The test results for the compounds of interest are shown in the table below.

It may disrupt the implantation process by changing the hormonal balance of

The effect of this agent on gamete transport in rabbits suggests that changes in normal gamete transport through the oviduct may also contribute to the effect of the agent. Embodiments of the present invention and related matters are as follows.

1. formula or (wherein R1 is hydrogen or -COR2, where R
2 is lower alkyl, phenyl, cycloalkyl, adamantyl or trihaloalkyl, R3 is lower alkadienyl or cycloalkyl, R4 is hydrogen,
lower alkyl, lower alkylcarbamoyl or cycloalkyl, and R5 is lower alkyl having 1 to 5 carbon atoms, provided that in the case of compound 1, when R2 is methyl, R4 is not hydrogen, and when R1 is hydrogen R4 is not hydrogen), comprising: (a) reacting the corresponding 3-one with a suitable hydroxylamine salt in the presence of a base; or (b) ethisterone or a substituted 3-one. Reacting ethisterone with a suitable hydroxylamine salt in the presence of a base,
Then, the hydroxyl group at the C-17 position is esterified,
A method characterized in that the geometric isomer is isolated by recrystallization from an appropriate solvent or column chromatography, if necessary.

2. The above for preparing compound 1 in which R1 is -COR2, R2 is pentyl, R3 is ethynyl and R4 is hydrogen, characterized in that the corresponding 3-one is reacted with hydroxylamine hydrochloride. Method 1.

3. R1 is COR2, characterized in that the corresponding 3-one is reacted with hydroxylamine hydrochloride;
R2 is phenyl, R3 is ethynyl, and R
The method of 1 above for producing a compound in which 4 is hydrogen.

4. 1 above for producing compound 1 in which R1 is -COR2, R2 is cyclohexyl, R3 is ethynyl and R4 is hydrogen, characterized by reacting the corresponding 3-one with hydroxylamine hydrochloride. the method of.

5. Compound 1 is prepared in which R1 is monoCOR2, R2 is cyclopropyl, R3 is ethynyl and R4 is hydrogen, characterized by reacting the corresponding 3-one with hydroxylamine hydrochloride. Method 1 above.

6. characterized in that R, is COR2 and R is reacted with the corresponding 3-one and hydroxylamine hydrochloride
The method of 1 above for producing compound 1, wherein 2 is cyclopentyl, R3 is ethynyl and R4 is hydrogen.

7. It is characterized by reacting the corresponding 3-one with hydroxylamine hydrochloride.

The method of 1 above for producing compound 1, wherein R1 is -COR2, R2 is trichloromethyl, R3 is ethynyl and R4 is hydrogen. 8. Syn type and Anti type by column chromatography
Characterized by the separation of the syn-type from a mixture of type isomers, the formula (wherein R1 is hydrogen or -COR2, R2 is lower alkyl, phenyl, cycloalkyl,
adamantyl or trihaloalkyl, and R
3 is lower alkynyl, lower alkadienyl or cycloalkyl).

9. 8. The method of 8 above for producing a compound in which R1 is -COR2, R2 is methyl, and R3 is ethynyl.

10. 8. The method of 8 above for producing a compound in which R1 is hydrogen and R3... is ethynyl.

11. characterized by the separation of the anti form from the isomer mixture by column chromatography, wherein R1 is hydrogen or -COR2, where R2 is lower alkyl, phenyl, cycloalkyl, adamantyl or trihaloalkyl. Yes, and R3 is lower alkynyl,
a lower alkadienyl or cycloalkyl).

12. 11. The method of 11 above for producing a compound in which R1 is -COR2, R2 is methyl, and R3 is ethynyl.

13. 11. The method of 11 above for producing a compound in which R1 is hydrogen and R3 is ethynyl.

14. The method of 1 above for producing a compound in which R, is COR2, R2 is methyl and R3 is ethynyl, characterized by reacting the corresponding 3-one with hydroxylamine hydrochloride.

15. R1 is hydrogen, R1 is hydrogen, R
The method of 1 above for producing a compound in which 3 is propynyl and R, is methyl.

16. R1 is hydrogen, R1 is hydrogen, R
The method of 1 above for producing a compound in which 3 is propynyl and R5 is methyl.

17. R1 is hydrogen, R1 is hydrogen, R
Compound V where 3 is ethynyl and R5 is methyl
The method of 1 above for manufacturing.

18. characterized in that ethisterone is reacted with a suitable acid halide of the formula R2COCl or an acid anhydride of the formula (R2COO)20 in a suitable solvent, wherein R2 is lower alkyl, phenyl, cycloalkyl, adamantyl or trihalo-lower alkyl, and R3 is lower alkynyl, lower alkadienyl or cycloalkyl, provided that when R2 is methyl, R3 is not ethynyl).

19. Formula (wherein R1 is hydrogen or -COR2, where R
2 is lower alkyl, phenyl, cycloalkyl, adamantyl or haloalkyl, R3 is lower alkynyl, lower alkadienyl or cycloalkyl,
and R4 is hydrogen, lower alkyl or lower alkylcarbamoyl).

20. The method of 19 above, wherein R1 is hydrogen, R3 is ethynyl and R4 is hydrogen.

21. R1 is -COR2, R2 is methyl,
19 above, wherein R3 is ethynyl and R4 is hydrogen
the method of.

22. 19 above, wherein R2 is cyclopropyl, R3 is ethynyl and R4 is hydrogen.

23. 19. The method of 19 above, wherein the compound is orally administered.

24. 19. The method of 19 above, wherein the compound is administered continuously every day.

25. Formula (wherein R1 is hydrogen or -
COR2, where R2 is lower alkyl, phenyl, cycloalkyl, adamantyl or trihaloalkyl, R3 is lower alkynyl, lower alkadienyl or cycloalkyl, and R4 is hydrogen, lower alkyl, lower alkylcarbamoyl, or cycloalkyl and R5 is lower alkyl having 1 to 5 carbon atoms, provided that in the case of compound I, when R2 is methyl, it is not hydrogen, and when R1 is hydrogen, R4 is not hydrogen.

26. The compound of 25 above, prepared by the method of Embodiment 2 above or a method chemically equivalent thereto, wherein R1 is -COR2, R2 is pentyl, R3 is ethynyl and R4 is hydrogen.

27. The compound of 25 above, prepared by the method of Embodiment 3 above or a method chemically equivalent thereto, wherein R1 is -COR2, R2 is phenyl, R3 is ethynyl and R4 is hydrogen.

28. prepared by the method of embodiment 4 above or a method chemically equivalent thereto, R1 is -COR2, R2 is cyclohexyl, R3 is ethynyl, and R4
25 above, wherein is hydrogen.

29. produced by the method of Aspect 5 above or a method chemically equivalent thereto, R1 is -COR2, and R2
is cyclopropyl, R3 is ethynyl, and R4 is hydrogen.

30, produced by the method of Embodiment 6 above or a method chemically equivalent thereto, in which R1 is -COR2 and R2
is cyclopentyl, R3 is ethynyl, and R4 is hydrogen.

31. R1 is -COR2, and R2 is produced by the method of Embodiment 7 or a method chemically equivalent thereto;
is trichloromethyl, R3 is ethyl, and R4 is hydrogen.

32. Formula (wherein R1 is hydrogen or -
COR2, where R2 is lower alkyl, phenyl, cycloalkyl, adamantyl or trihaloalkyl, and R3 is lower alkynyl, lower alkadienyl or cycloalkyl).

33. produced by the method of Embodiment 9 above or a method chemically equivalent thereto, R1 is -COR2, and R2
is methyl and R3 is ethynyl.

34.

The compound of 32 above, wherein R1 is hydrogen and R3 is ethynyl, prepared by the method of Embodiment 10 above or a method chemically equivalent thereto. 35. produced by the method of embodiment 11 above or a method chemically equivalent thereto, wherein R1 is hydrogen or -COR2, where R2 is lower alkyl, phenyl, cycloalkyl,
adamantyl or trihaloalkyl, and R
3 is lower alkynyl, lower alkadienyl or cycloalkyl).

36. produced by the method of Embodiment 12 above or a method chemically equivalent thereto, R1 is -COR2, and R
3 above, where 2 is methyl and R3 is ethynyl
5 compounds.

37. prepared by the method of embodiment 13 above or a method chemically equivalent thereto, wherein R1 is hydrogen and R3
The compound of 35 above, wherein is ethynyl.

38. produced by the method of the above aspect 14 or a method chemically equivalent thereto, R1 is -COR2, and R
25 above, where 2 is methyl and R3 is ethynyl
compound.

39. A compound of Embodiment 1 above, prepared by the process of Embodiment 15 above, or a process chemically equivalent thereto, wherein R1 is hydrogen, R3 is propynyl and R5 is methyl.

40. A compound of Embodiment 1 above, prepared by the process of Embodiment 16 above, or a process chemically equivalent thereto, wherein R1 is hydrogen, R3 is propynyl and R5 is methyl.

41. Compound VO42. of Embodiment 1 above, prepared by the process of Embodiment 17 above, or a process chemically equivalent thereto, wherein R1 is hydrogen, R3 is ethynyl and R5 is methyl. prepared by the method of Embodiment 18 above or a method chemically equivalent thereto, of the formula or cycloalkyl, provided that when R2 is methyl, R3 is not ethynyl).

43. Formula (wherein R1 is hydrogen or -COR2, where R
2 is lower alkyl, phenyl, cycloalkyl, adamantyl or trihaloalkyl, R3 is lower alkynyl, lower alkadienyl or cycloalkyl, R4 is hydrogen, lower alkyl, lower alkylcarbamoyl or cycloalkyl, and R5 is carbon Lower alkyl of numbers 1 to 5, provided that in the case of compounds R2
is methyl, R4 is not hydrogen, and when R1 is hydrogen, then R4 is not hydrogen).

44. A compound according to embodiment 1 above, wherein R1 is -COR2, R2 is pentyl, R3 is ethynyl and R4 is hydrogen.

45. The compound of embodiment 1 above, wherein R1 is -COR2, R2 is phenyl, R3 is ethynyl and R4 is hydrogen.

46. A compound according to embodiment 1 above, wherein R1 is -COR2, R2 is cyclohexyl, R3 is ethynyl and R4 is hydrogen.

47. A compound according to embodiment 1 above, wherein R1 is -COR2, R2 is cyclopropyl, R3 is ethynyl and R4 is hydrogen.

48. The compound of embodiment 1 above, wherein R1 is -COR2, R2 is cyclopentyl, R3 is ethynyl and R4 is hydrogen.

49. A compound according to embodiment 1 above, wherein R1 is -COR2, R2 is trichloromethyl, R3 is ethynyl and R4 is hydrogen.

50. Formula (wherein R1 is hydrogen or -COR2, where R
2 is lower alkyl, phenyl, cycloalkyl, adamantyl or trihaloalkyl and R3 is lower alkynyl, lower alkadienyl or cycloalkyl).

51. R1 is -COR2, R2 is methyl,
and the compound of 50 above, wherein R3 is ethynyl.

52. The compound of 50 above, wherein R1 is hydrogen and R3 is ethynyl.

53. Formula (wherein R1 is hydrogen or -COR2, where R
2 is lower alkyl, phenyl, cycloalkyl, adamantyl or trihaloalkyl and R3 is lower alkynyl, lower alkadienyl or cycloalkyl).

54. The compound of 53 above, wherein R1 is -COR2, R2 is methyl and R3 is ethynyl.

55. 5 above, where R1 is hydrogen and R3 is ethynyl
3 compounds.

56. The compound of 43 above, wherein R1 is -COR2, R2 is methyl and R3 is ethynyl.

57. The compound of 43 above, wherein R1 is hydrogen, R3 is propynyl, and R5 is methyl.

58, The compound of 43 above, wherein R1 is hydrogen, R3 is propynyl, and R5 is methyl.

59. The compound VO6O. of 43 above, wherein R1 is hydrogen, R3 is ethynyl and R5 is methyl. Formula (wherein R2 is lower alkyl, phenyl, cycloalkyl,
adamantyl or trihalo-lower alkyl, and R3 is lower alkynyl, lower alkadienyl or cycloalkyl, with the proviso that when R2 is methyl, R
3 is not ethynyl).

61. Formula 1, substantially as described herein and in the Examples
, , or a method for producing a compound having v.

62. Formula 11, produced by the method of 61 above,
or a compound having V.

63. The active ingredient has the formula, or A postcoital mammalian reproductive inhibitor.

Claims (1)

[Claims] 1 Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I, IV, V) (In the formula, n is 0 or 1, and when n=1, R_5 is 6- or 7-position and R_4 is hydrogen or -COR_2, where R_2 is lower alkyl, phenyl, cycloalkyl, adamantyl or trihaloalkyl, and R_3
is lower alkynyl, lower alkadienyl or cycloalkyl, R_4 is hydrogen, lower alkyl, lower alkylcarbamoyl or cycloalkyl, and R_5 is lower alkyl having 1 to 5 carbon atoms, where n
= 0, when R_2 is methyl and R_4 is not hydrogen), the method comprises reacting the corresponding 3-one with a suitable hydroxylamine salt in the presence of a base, and A method characterized in that geometric isomers are isolated, if necessary, by recrystallization from a suitable solvent or column chromatography. 2 Formulas▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I, IV, V) (In the formula, n is 0 or 1, and if n=1, R_5 is at the 6- or 7-position. and R_4 is hydrogen and R_1 is -COR_2, where R_2
is lower alkyl, phenyl, cycloalkyl, adamantyl or trihaloalkyl, R_3 is lower alkynyl, lower alkadienyl or cycloalkyl, R_4 is hydrogen, lower alkyl, lower alkylcarbamoyl or cycloalkyl, and R_5 is the number of carbon atoms 1 to 5 lower alkyl, provided that when n=0, when R_2 is methyl, R_4 is not hydrogen), the method comprising: adding hydroxyl at the C-17 position in the presence of a base; by reacting the corresponding 3-one with a suitable hydroxylamine salt, then esterifying the hydroxyl group at the C-17 position, and optionally by recrystallization from a suitable solvent or column chromatography. A method characterized in that geometric isomers are isolated.