JPS6041695A - 13 alpha-alkylgonane, manufacture and antigestagenic medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (1): 1 [wherein represents a 7'alkyl group having 1 to 4 members, or RI and RIl represent a saturated 5- or 6-membered ring containing N; In the outer ring, there is another heteroatom in addition to Φ of N, namely 0, N,
) and corresponding tertiary N-oxides and acid addition salts, OR (R'' is a methyl group, ethyl group, propyl group, methoxyphenyl group, allyl group or β-dimethylaminoethyl group) R2 represents a hydrogen atom, methyl group or ethyl group, R3 is -(OHz)n-CH3 (n = 0-4),
(OHz)n-OH+-0(8)R” (n = 0~
4, RIV represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), -an=cH-(Cu2)nOR■ (n = 1 to 4,
R■ represents a hydrogen atom, an alkyl group or an alkanoyl group each having 1 to 4 carbon atoms), -a=c-x (x is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms), -rhoden -(('H2)n-aH2aN(n-Q~6) or 11-0-0H2Y (represents a hydrogen atom or ORV), R4 is a hydroxy group, each having 1 to 4 carbon atoms represents an alkyloxy group or an alkanoyloxy group having
or R3 is present at the β position, 14 is present at the α position, and R5 represents a hydrogen atom or an alkyl group at the α or β position having 1 to 4 carbon atoms. .

The present invention also relates to a method for producing the 16α-alkylgonane. The compound has the general formula II: υb [wherein RL, R2 and R5 represent the above, and 2 represents an ethylene group or a 2,2-dimethylpropylene group] by irradiating the compound with ultraviolet rays. The general formula ■ obtained by irradiation [in the formula R1, 12, R5 and 2
represents the above-mentioned 16-nibisteroid to 17-ketone by a method known per se,
It can be produced by converting it into a compound of general formula (1) by decomposition of the 6-ketal protection and elimination of water from the 4,5-position.

The present invention also relates to a pharmaceutical product containing the 16α-alkylgonane.

The compound of the general formula (■) does not have progestin activity by itself and is known as Gestagen (Gestagen).
It has a strong affinity for the progesterone (progesterone) receptor. The compound is a competitive antagonist of progesterone (anti-rstargun) and is suitable for the occurrence of miscarriage. This is because the compound displaces the progesterone needed to maintain pregnancy from the receptors. Therefore, the compounds are important and advantageous in their use for the regulation of post-coital (p,c) fertility.

Corresponding compounds of the Nistran series have already been used as anti-desterden compounds by Fertility and Steril.
ity) 40 (1982), p. 256.

The previously known structure-action relationship for propsterone antagonists suggests that 11β-
This suggests that a 1,6-biaxial arrangement of the aryl group and the 16β-alkyl group is unavoidably necessary. Therefore,
Compared to the Nistran series, 1 completely different molecular localization (m01θ
The strong selective antagonism of the 16α-alkylgonanes of formula I with 16α-alkylgonanes (topoqraphie) is all the more surprising.

In order to characterize the anti-carcinogenic effect of the compounds according to the invention, the abortion effect was examined at the early stage after egg implantation (experiment I) and at the advanced stage after egg implantation (experiment I).

The experiment was conducted on female rats weighing approximately 200 y. The onset of pregnancy was confirmed by the detection of spermatozoa in the postcoital vaginal fluid. The day of sperm detection is considered to be the first day of pregnancy (= day p, c 1).

p, c 5th to p, 07th (experiment ■) and p, CI 3
After implantation of the blastocysts from day to day p, O15 (experiment ■), the animals were treated with the substances and solvents to be tested in each case. p
-c, 9 days and p, c, 17 days to kill the animal;
The implanted embryo and resorption site in the uterus were examined.

Photographs were produced from all uteruses. Lack of implanted embryos was evaluated as miscarriage.

The following anti-destagnes were tested: A: 11β-(4-dimethylaminophenyl)-17β
-Hydroxy-17α-propynyl-4,9-estradin-6-one (standard).

B: 11β-(4-dimethylaminophenyl)-17β
-Hydroxy-17α-(6-hydroxiderovir)-
16α-Methyl-4°9-gonadien-6-one (described in the invention).

C: 11β-(4-dimethylaminophenyl)-17α
-Hydroxy-17β-(6-hydroxyzol)-
13α-Methyl-4°9-gonadien-6-one (described in the invention).

The test substance was mixed with benzyl benzoate/castor oil mixture (ratio 1
:4) Dissolved in. Excipient volume per unit dose is 0.
The penalty was 2. Treatments were performed subcutaneously (s,c).

Abortion effect in early pregnancy of rats p, c, 5th to p, c 7th day treatment, autopsy p, c, 9
Day.

10.0, - - A 5.0 4/4 (1(1)) 0.1 0/4 (0) 0.60/4 (0) 0.1 0/4 (0) 10.0 474 ( 1 [)) 0.3 0/4 (0) 0.1 . 0/4 (0) As a control, Sol Q at ℃, 2 ml + castor oil (1:4) n = 4 rats/group Experiment H In order to test the miscarriage effect in the advanced stage of pregnancy in rats, p, c, 13 Day ~ p, 0.15 day old rats were treated subcutaneously with anti-dastarn (AG) 3.0Tn9/day. p, c, necropsy at 17 days. The autopsy results are shown in Figure 1.

Compounds B and C according to the present invention have a sufficient miscarriage effect (miscarriage rate:
4/4). On the other hand, reference material A is ≧6
．． The maximum miscarriage occurred for the first time at a dose of 0.7 days (Anti-Duster r
(Table 1)

In the advanced stages of pregnancy (P, C, 15-16 days), Omy
For subcutaneous (s, c, ) administration on day 6, the percentage of complete abortion was 65.4% for B and 52.6 for C.
%, and in the case of control substance A it is 6.5% (Fig. 1).

General ceremony! The α-alkylgonane of the formula can be used in the form of a pharmaceutical product. The preparations are prepared by the Gallen method known per se by mixing with organic or inorganic inert excipients suitable for enteral, transdermal and parenteral application.

The dose of the active substance according to the invention for humans is approximately 10 to
10001n9/day.

The alkyl group of R■ and R■ in general formula I has 1 to 4 carbon atoms.
methyl and ethyl groups are preferred. It also represents a 6-membered ring, such as a pyrrolidino ring, a piperidino ring,
Included are piperazino rings, morpholino rings, oxa- and thiasiridino rings, and thiacyasiridino rings.

For example, dimethylamino N-oxide, troridino N
-oxide, piperidi7N-oxide, piperazinoN-
Oxide etc.

The alkyl and alkanoyl groups contained in R and Rv each have 1 to 4 carbon atoms, with preference given to methyl, ethyl and acetyl, propionyl.

During the production of the novel 16α-alkylgonane according to the invention,
The 15β-alkyl steroid of the general formula (■) can be irradiated with ultraviolet rays at °C in good yield.
α-alkyl steroid).

The good yield of transformed products is surprising. About X, standard series 1
It is conventionally known that 7-oxysteroid scales change to l- and 13-oxysteroids upon UV irradiation (A
, Butenandt, etc., Ber,
Deutsch, Ohem, Ges, 74.13
08 Sada (1941)). However, a mixture of starting material and evimolized compound is always obtained, the irradiation time is several hours, and the yield is very small. Therefore, the search for alternative chemical avenues to the 16-shrimp series also encouraged Barton.
), etc.: J, O, S, Perkin l.
, 21-63 Negative (1977) shows that it is still active. However, the above-mentioned alternative methods are not suitable for the preparation of compounds of formula (1).

However, it has been found that UV irradiation of rice grains with compounds of formula (1) takes a significantly more advantageous course under certain conditions than with the 11-unsubstituted 17-oxosteroid series. That is, the average irradiation time is only 10 to 60 minutes, which is 1! The yield of l-evisteroid is 60-80%. The irradiation products can optionally be subsequently reacted without chromatographic purification. The essential prerequisites for obtaining good results are the appropriate selection of the solvent, the correct maintenance of the concentration of the irradiated substrate and the irradiation time. These parameters can be determined for each new substrate.

Irradiation is carried out in a quartz glass apparatus using a full source of HgM pressure lamps. The temperature of the reaction solution is adjusted to about 25 DEG C., and the concentration of the solution is 0.1-1.0% by weight. Tetrahydrofuran and dioxane are preferably used as solvents, but also non-polar neutral solvents such as hexane,
Cyclohexane, penzole, doluol and mixtures thereof are used. Irradiation time is approximately 10-50 minutes.

The 16-nibisteroid (1) thus obtained is converted into the final compound of general formula 10) by nucleation to 17-ketone and subsequent reactions in a conventional manner. Nucleation to In generally proceeds at C-17 with the formation of two possible isomeric forms. In any case, the two isomers have different potencies σ
), but is pharmacologically active.

The nuclear force 11 of acetylene (ethyne) or propyne is -
〇miOH or -〇=:('', carried out using agents which provide the -0H3 group. Such agents are, for example, alkali metal acetylides, such as potassium and lithium acetylides or alkali metal methyl acetylides.

Organometallic compounds are also formed in situ, and 17-
Can be reacted with ketones. Thus, for example, 17-ketone can be treated with acetylene and an alkali metal, in particular potassium, sodium or lithium, in the presence of alcohol or ammonia in a suitable bath. Alkali metals can also act, for example in the form of methyl or butyllithium. Particularly suitable solvents are dialkyl ethers, tetrahydrofuran, dioxane, penzole and doluol.

The 17-ethynyl-1-hydroxy compound is hydrated in an alcohol solution under mercury salt catalyst to form 17-acetyl-
yields a 17-hydroxy compound (ahem, Be
r, 111 (1978), pp. 6086-6093)
.

The introduction of 6-hydroxypropane or lo-hydroxyzolobyl into the 17-position involves reacting the 17-ketone with a metallated derivative of propargyl alcohol, such as 1-lithium-6-tetrahydroran-2'-yloxyderobin 1. 17-(6-hydroxy-1-zolotyl)-1
It is carried out by forming a 7-hydroxy compound which is then hydrogenated to a 17-(3-hydroxyzorobyl- or 6-hydroxyzorobyl)-17-hydroxy compound. Hydrogenation then acts on the a-a triple bond.

Tetrasubstituted 9(10)-must be carried out under conditions that ensure that double bonds are not saturated. Platinum receivers in solvents such as acetic acid esters are effective when hydrogenating with the addition of noble metal catalysts such as palladium.

Hydrogenation of the triple bond of acetylene using deactivated noble metal catalysts produces compounds with a 2-configured double bond in the hydroxypropenyl group [J, Fried (Fr1
8(L)1. T. A. Edwards (Edwarn Day)
Organicpeactlons in steroid chemistry
5tero1a Chemistry), Fa7+
Nostrand Reinhold Kanfuzoni (Va
n No5trand Re1nho1+i Comp
any ) 1972.1, p. 4 and E. O. Hause (
House ) :Modern Synthetic React
ions), 1972. p. 19].

Suitable deactivating noble metal catalysts are 10-thipalladium on barium sulfate in the presence of an amine or 5-thipalladium on calcium carbonate with the addition of lead(II) acetate. Hydrogenation is stopped after absorption of one equivalent of hydrogen.

Compounds having an E-configured double bond in the hydroxypropenyl group are produced by reduction of the acetylene triple bond in a manner known per se. The literature describes numerous methods for converting 7/l/kylene into trans-olefins. For example, reduction with sodium in liquid ammonia (J.

Am, Ohem, Sac, 63 (1'941
), 216), reduction with sodium amide in liquid ammonia (J, Ohem, Soa, 1955, 558), reduction with lithium in low molecular weight amines (J.
.

Am, Ohem, SOC, 77 (1955), 66
7B), reduction with borane (J, Am, BOQ,
93 (1971), Ro695 and 94 ('1971)
, 6560), reduction with diisobutylaluminum hydride and methyl-lithium (J, Am, Ohem
, soc, R39 (1967), 5085), especially reduction with lithium aluminum hydride/alcolade (J, Am, Ohem, Boa, R39(i
967), 4245) are known. Also, the reduction of the triple bond by chromium (I[) sulfate in the presence of water or dimethylformamide in a weakly acidic environment (, r, Am
, Ohem, Boa, 86 (1964), 43
5B) and in general reduction by the action of transition metal compounds under alternation of the oxidation stages is also possible.

If it is desired that the target product of the general formula I has R'/R', the 17-(3-hydroxypropyl)-17-hydroxy compound is oxidized in a manner known per se. The oxidation conditions depend on the nature of the substituent R1 of formula I. If R1 is, for example, a dialkylamino group, oxidizing chromic acid reagents are unsuitable. This is because the reagents act primarily on the dialkylamino groups. In such cases, mercury carbonate/Celai) (Fetizon reagent: M
, Fetizon and M, -GoMier, O□mpt, ree
267 (1968), 900] or platinum/oxygen [H, Muxfeld et al., Angewandte Ohe.
(1962), 157
] must be used. On the other hand, when R1 is an alkoxy group, Jones (J
Oxidizing agents such as chromate-pyridine, pyridinium dichromate or pyridinium chlorochromate may also be used.

The 17-cyanmethyl side chain can be obtained by decomposition (z, Ohem, 1 B (19 '78), 25
9-260).

The introduction of the 17-hydroxyacetyl side chain can also be carried out using methods known per se, for example, as described in J. Org. Ohem, 47 (
1982), 2996-2995.

The free hydroxy group at position 17 can be esterified or etherified in a manner known per se.

After the nucleation reaction of the 17-ketone, the compound of formula (II) is treated with an acid or an acidic ion exchanger to eliminate water with the formation of a 4(5)-double bond and at the same time decompose the ketal and optionally Other acid-removable film-retaining groups present are removed.

The treatment with acid is carried out in a manner known per se. = A compound of formula (1) having a 6-ketal group and a 5α-hydroxyl group and optionally a protected 17-(3-hydroxypropyl) group of O is mixed with water. A catalytic amount of a mineral acid or sulfonic acid, i.e. hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid or ])-) luolsulfonic acid, or acetic acid, is dissolved in a suitable solvent, namely aqueous methanol, ethanol or acetone. An organic acid such as the like is allowed to act until the water is eliminated and the aqueous group is removed. Further, the reaction which proceeds at a temperature of 0 to 100°C can also be carried out using an acidic ion exchanger. The course of the reaction can be followed using analytical methods, for example by thin layer chromatography of the samples taken.

Example 1 a) Anhydrous tetrahydrofuran (THF) 3001n
11β-(4-dimethylaminophenyl)-3 in l,
3-(2,2-dimethyl-propane-1°3-dioxy)-5α-hydroxy-9(10)-estyrene-17
-on (melting point 143-1459C) 2.0.9 solution was heated at 25℃ for 16 minutes using an Hg high-pressure lamp [Philips (
Ph1lipθ) HPK125, immersion lamp (, Tau
chlampe), quartz glass reactor]. The solvent is then distilled off in vacuo and the residue is chromatographed over aluminum oxide (Mark, neutral, grade 1) using hexane/acetic acid ester. 11β-(4-dimethylaminophenyl)-
5,3-(2,2-dimethyl-propane-1,6-dioxy)-5α-hydroxy-16α-methyl-9(10
)-bonene-1-fuon 1.465 is obtained as a colorless oil.

b) Anhydrous Tuy (248mJ) at 5℃ for 7 hours
was introduced for 60 minutes to achieve saturation. Then n- in hexane
Gradually add dropwise 51 ml of a 15% solution of butyllithium,
Stir for an additional 15 minutes while cooling with ice water. Next, anhydrous TEF
11β-(4-dimethylaminophenyl)-3,3-(2゜2-dimethyl-propane-1,
6-dioxy)-5α-hydroxy-16α-methyl-
A solution of 2.7 g of 9-bonene-1-fuon is added dropwise to the suspension of lithium acetylide within 15 minutes and stirred for a further 2 hours at room temperature. Work up by pouring into ice water and extract using acetic acid ester.

The crude product (2,859) thus obtained is taken to the next step without further purification.

c) 2.8 g of the crude product obtained in b) are suspended in 29IIIl of 70% aqueous acetic acid and stirred at 50° C. for 6 hours.

After cooling, dilute with approximately 1 (] rJ mg of water and add fresh NH3 solution to prepare an i 10.5 - il II. After extraction with acetic acid an oily isomer mixture is obtained, which is diluted with hexane/ Resolution by column chromatography on silicic acid gel using acetic acid ester.The following compounds are obtained in the order of elution: 1.11β-(4-dimethylaminophenyl)-17α
-ethynyl-17β-hydroxy-16α-methyl-4
,9-gonadien-6-one 530IRy, melting point 120
~126° (acetic acid ester/diisopropyl ether)
.

2,11β-(4-dimethylaminophenyl)-17β
-ethynyl-17α-hydroxy-16α-methyl-4
, 9-gonadien-6-one, melting point 201-204°C (
acetic acid ester).

If methylacetylene is used instead of ayukithylene, the following compound can be obtained in the same manner as b) and c).

1,11β-(4-dimethylaminophenyl)-17β
-hirroxy16α-methyl-17α-zologinyl-
4,9-gonadien-6-one (oil).

2.11β-(4-dimethylaminophenyl)-17α
-Hydroxy-13α-methyl-17β-propynyl-
4,9-gonadien-6-one (oil).

d) In 2Qml of water (1m of Q oxidized water!! (HgO% red)
1.02g v) Add 60% of concentrated sulfuric acid 0.871M
Stir after addition for 60 minutes at °C. 9ml of this mercury salt solution
of 11β-(4-dimethylaminophenyl)-17β-ethynyl-17α-hydroxy-1 in 62 ml of acetic acid.
6α-methyl-4,9-gonadien-6-one 5.25
Add to the solution of &. Next, stir at 60°C for 2 hours. For work-up, the cooled reaction solution was poured into ice water to prevent leakage of N.
Both values are adjusted to 10.5 by adding H3 solution and extraction is carried out using ethyl acetate. The oily crude product thus obtained is crystallized from methylene chloride/diisopropyl ether. 11β-(4-dimethylaminophenyl)-1
7α-hydroxy-16α-methyl-18,19-dinor-4,9-pregnagene-6,20-dione 2.3
7y (melting point 224-225°C) is obtained.

e)) 11β-(4-dimethylaminophenyl)-17α-hydroxy-16α-methyl-18,19-dinor-4,9-pregnagene-6 in Luol 581
, 20-dione 2.6y, acetic anhydride 11.6XIIt
and after addition of 5.8 g of 4-dimethylaminopyridine 2
Stir at 5°C for 20 hours. It is then poured into a saturated NaHOO3 solution and extracted with ethyl acetate. The crude product is chromatographed on silicic acid gel using hexane/ethyl acetate. After crystallization of the main fraction from hexane/ethyl acetate, 17α-acetoxy-11β-(4-dimethylaminophenyl)-16α-methyl-18,19-dinor-4,9-pregnagene-6,20-dione ( Melting point 194-195°C) 1.71 # is obtained.

Example 2 a) 11β-(4-diethylaminophenyl)-15-(2,2-dimethyl-
Propane-1,5-dioxy)-5α-hydroxy-9
- A solution of esteren-17-one (melting point 226-226°C) is irradiated for 26 minutes under the conditions of example ia a). After chromatography of the crude product, 11β-(4-diethylaminophenyl)-3,3-(2,2-dimethyl-propane-1,6-dioxy)-5α-hydroxy-16α-
1.58 g of methyl-9-bonene-1-fuone are obtained as a colorless oil.

b) 6-tetrahydrobilane-2'-yloxy-1-propyne in 85 mlj of anhydrous THF and 23.1 ml of a 15% solution of n-butyllithium in hexane3.
An organolithium compound is prepared from 94 g at 0°C.

A solution of 3.55 g of the product described under 2a) in 71 vrl of anhydrous THF is then added and stirred for 4 hours at room temperature.

Next, the Kf51 reaction solution is poured into ice water and extracted using acetic acid ester. Crude product (3,85g) 11/-(4
-diethylaminophenyl)-3,5-C2,2-dimethylpropane-1,3-dioxy)-1roα-methyl-
17α-[6-(tetrahydrobilan-2-yloxy)-1-propynyl]-sorgonene-5α.

17β-diol and 11β-(4-diethylaminophenyl)-6,ro-(2,2′-dimethyl-propane-
1,3-dioxy)-16α-methyl-17β-[6-
(Tetrahydrobilan-2-yloxy)-1-propynyl-9-gonene-5α,17α-diol is used for the hydrogenation without further purification.

Q) 6.85g of the crude product obtained in 21)) was added to 10%
After addition of 400 Da of palladium on carbon, hydrogenation is carried out in 95 ml of ethanol at room temperature and standard pressure.

After absorption of 191 ml of hydrogen, the catalyst is filtered off and processed.

+1) Hydrogenated product obtained in 2C) (5,85,9)
is stirred in 50ml of 70% acetic acid at 60°C for 2 hours. After cooling, work up as described under 1c) and subject the resulting isomer mixture to chromatography. The elution order gives the following compounds: 1, 11β-(4-dimethylaminophenyl)-17α-(6-hydroxypropyl)-17β-hydroxy-16α-methyl-4,9-gonadien-5-one (yellow oil) substance) 41Qmguv (methanol): gza6=19080, ε309=19
110゜2.11β-(4-diethylaminophenyl)-17β
-(3-hydroxypropyl)-17α-human mx-
13α-Methyl-4,9-gonadien-6-one (solid form) 1°9y0 As starting material 11β-(4-dimethylaminophenyl)-3,3-(2,2-dimethyl-propane-1,3-
dioxy)-5α-hydroxy-16α-methyl-9-
When using bonene-1-fuon, the following is obtained analogously to b) to d): 1.11/-(4-dimethylaminophenyl)-17β
-Hydroxy-17α-(6-hydroxypropyl)-
15α-Methyl-4,9-gonadien-5-one (oil).

2,11β-(4-dimethylaminophenyl)-17α
-Hydroxy-17β-(3-hydroxypropyl)-
13α-Methyl-4,9-gonadien-5-one (oil).

Example 6 a) 3.3 in dioxane 29 OIRE. 3-(2”,
2-dimethyl-propane-1,3-dioxy)-5α-
Hydroxy-11β-(4-methoxyphenyl)-? −
In a solution of 1.75y of disteren-17-one, Example 1a)
Irradiate for 19 minutes under the conditions described in . After chromatography, 6.5-(2,2-dimethyl-propane-1,
1.459 of α-methyl-9-bonene-1 phion is obtained as a colorless oil.

b) prepared from a saturated solution of acetylene in 450 w of THF; and 133 m/f of a 15% solution of n-butyllithium in hexane or m/jtii of thium acetylide
/ik, 3.3-(2,
2-dimethyl-propane-1,6-dioxy)-5α-
Hydroxy-11β-(4-methoxyphenyl)-16
A solution of 8.2 g of α-methyl-9-bonene-1-fuon is fed. The mixture is then stirred at room temperature for 6 hours, and then the reaction solution is poured into about 6 liters of ice water and extracted with ethyl acetate. The crude product is chromatographed over aluminum oxide using hexane/ethyl acetate. The following compounds are obtained in the general order: 1, 3.3-(2,2-dimethyl-propane-1,'6-dioxy)-17α-ethynyl-11β-(4-methoxyphenyl)-16α-methyl -9-bonene-5α
, 1.8 g of 1-fβ-diol (colorless oil).

2, 5.3-(2,2-dimethyl-propane-1,6
-dioxy)-17β-ethynyl-11β-(4-methoxyphenyl)-16α-methyl-9-bonene-5α,
1 F-β-diol (solid form) 5. '1.9°C) 70% aqueous vinegar 'H133m# in! 1.3-(2゜2-dimethyl-propane-1,3-dioxy)-17β
-ethynyl-1゛1β-(4-methoxyphenyl)-1
3α-Methyl-9-bonene-5α,1-phα-diol 3
．． Stir the solution of 289 at 60°C for 0 minutes. After cooling, pour into ice water, extract with methylene chloride, wash the M+3012 extract with saturated NaHCO3 solution and concentrate. Crystallization of the crude product from ethyl acetate yielded 17β-ethynyl-17α-hydroxy-11β-(
4-methoxyphenyl)-13α-methyl-4,9-gonadien-3-one (melting point 186-187°G) 2
．． 011 is obtained.

Example 4 11β-(4-dimethylaminophenyl)-3,3-(2,2-dimethyl-propane-
Example 1 a)
By irradiating for 20 minutes under the conditions of 11β-(4-dimethylaminophenyl)-3,3
-(2,2-dimethyl-propane-1,6-dioxy)
-15α-ethyl-5α-hydroxy-9-bonene-1
Huon 1.3. ! l is obtained.

11β-(4-dimethylaminophenyl)-3,3(2
,2-dimethylpropane-1,6-dioxy)-1roα
-Ethyl-5α-hydroxy-9-bonene-1 phoon 6.1y is reacted with lithium acetylide under the conditions of Example 1b) and the crude product thereby obtained is reacted with Example 1 c
) is decomposed with acetic acid under the following conditions. After chromatography and crystallization from ethyl acetate/diisozolobyl ether, 11β-(4-dimethylaminophenyl)-17β-
ethynyl-13α-ethyl-17α-hydroxy-4,
9-gonadien-6-one (melting point 197-198°C)
3.2 g is obtained.

[α]”;, 5+450.4° (0HO13, C=0
．． 505) By mercury salt catalytic hydrogenation as in Example 1 cl) and subsequent acetylation as in Example 1e), 11β
-(4-dimethylaminophenyl)-17β-ethynyl-16α-ethyl-17α-hydroxy-4,9-gonadien-6-one from 1.6I, 17α-acetoxy-11β-(4- dimethylaminophenyl)-16α-ethyl-18,19
-Dinol-4,9-pregnagene-3,20-dione (solid form) 720 μm are obtained.

[α) +290.8° (0H (313, (! -0,
515).

Example 5 a) 11β-(4-dimethylaminophenyl)-5,3-(2,2-dimethyl-propane-1,6-dioxy)-5α-hydroxy-16 under the conditions described in Example 21))
α-Methyl-9-goneno-1-fuon 7.3y and 3-
11β-(4-dimethylaminophenyl)-3 after chromatography of the crude product with aluminum oxide using hexane/ethyl acetate by reacting with tetrahydrobilan-2'-yloxy-1-delvin 10.7.9 ,3-(2,2-dimethyl-propane-1
,6-dioxy)-13α-methyl-17β-[6-(
Tetrahydrobilan-2-yloxy)-1-propynyl-9-gonene-5α,17α-diol 4.83
& is obtained as a yellow form.

b) 67 mg ethanol and 0°56 triethylamine
A solution of 2.2 g of the adduct obtained in a) in m1 is hydrogenated at room temperature and standard pressure after addition of 2101 V of palladium on barium sulphate (10%). After absorption of 85.5 ml of hydrogen, the catalyst is filtered off and concentrated. The hydrogenated crude product thus obtained was mixed with 14 ml of 70% acetic acid under the conditions of Example 1C).
Disassemble using. 11β-(4-dimethylaminophenyl)-17α-hydroxy-17β-(6-hydroxy-1(z)-propenyl)-16α-methyl-4,9 after crystallization from ethyl acetate/diisopropyl ether
-gonadien-6-one (melting point 166-165°C) 1
．． 1 g is obtained.

Example 6 a) 3. 3-(2,2-dimethyl-propane-1,
A suspension of 28.6 g of 6-dioxy)-5(10),9(11)-estradien-17-one and bis-dimethylamino-t-butoxymethane was heated at 160° C. for 60 min under argon. Stir. After cooling, the crude product is triturated with about 50 g of ethyl acetate, filtered and the filter cake is crystallized from ethyl acetate. In this way, 16-dimethylaminomethylene-3,3-(2,2-dimethyl-propane-1,6-dioxy)-5(10),9(11)-estradien-17-one (melting point 208 ~211°C) is obtained.

b) Doror 220m1. 16-dimethylamine in ethylene-3,3-(2,2-dimethyl-propane-1
,6-dioxy)-5(10).

85 m6 of a 5% solution of methyllithium in diethyl ether are added to a solution of 14.4 g of 9(11)-estradien-17-one while cooling with ice water. +5~+ after addition
After stirring for 15 minutes at 10° C., the excess reagent is destroyed by carefully adding about 20 ml of water, then the reaction solution is poured into about 6 ml of ice water and extraction is carried out with methylene chloride.

The crude product is chromatographed over neutral aluminum oxide using hexane/ethyl acetate. After crystallization of the main fraction from ethyl acetate, 3.3-(2,2-dimethyl-propane-1°6-dioxy)-16(1-ethylidene-5(10),9(11)-estradine- 17
-Oy(lit!it point 121~123℃>13.0
,! 9 is obtained.

C) Methylene chloride 43 mA, hexachloroacetone 0.
64 penalty and 6.6-(2
,2-dimethyl-propane-1,6-dioxy)-16
(It)-ethylidene-5 (10).

4.3 ml of 60% hydrogen peroxide was added to a solution of 9.4 y of 9(11)-estradien-17-one while cooling with ice water, and the mixture was stirred at 25° C. for 16 hours.

Approximately 100 mg of methylene chloride was added to the reaction mixture for work-up.
The methylene chloride phase is dried over Na2SO4 and concentrated. The 5,10-epoxide mixture thus obtained was treated with A:L using hexane/ethyl acetate.
203 (neutral, grade ■) for chromatography. 6.3-(2,2-dimethyl-propane-1,6
-dioxy)-5α,10α-epoxy-16(]In
)-ethylidene-9(11)-estyren-17-one 4.7 g are obtained. Melting point 139-141°C (ethyl acetate/diisopropyl ether).

d) 3. in wind ethanol 40011Ll. 3-(2,2
-dimethylated-propane-1,6-dioxy)-5α,1
0α-epoxy-16(1)-ethylidene-9(11)
- A solution of 8.2y of estyrene-17-one is hydrogenated at room temperature and standard pressure after the addition of 960 g of palladium on carbon (10%). After absorption of 5111 J of hydrogen, the catalyst is filtered off and concentrated in vacuo. 6.6-( as a colorless oil
2,2-dimethyl-propane-1,3-dioxy)-5
α, 10α-evokine-16β-ethyl-9 (11)
7.7 g of -estyrene-17-one are obtained.

C) Magnesium 1.1', Methiodide # [], 95
4-bromo-N in ml and anhydrous THF 15 Qml
, an organomagnesium compound is produced from 17.9 g of N-dimethylaniline. aucl 544g only after adding 0
C. for 15 minutes, then a solution of 7.7 g of the product obtained in anhydrous TI (in F 70 shoulder 6, d) is added dropwise. It is then stirred at room temperature for 6.5 hours. For work-up, the reaction solution is poured into a mixture of ice water and NH3 solution and extraction is carried out with ethyl acetate. 11β-(4-dimethylaminophenyl)-3,3-(2,2- dimethyl-propane-1,
3-dioxy)-16β-ethyl-5α-hydroxy-
9(10)-Estyrene-17-one (melting point 180-1
81°C) 6.5 g is obtained.

f) A solution of the product obtained in θ) in 6CJO ml of dioxane is irradiated under the conditions of Example 1a).

After crystallization of the irradiated crude product from diisozolobyl ether, 11β-(4-dimethylaminophenyl)-3,3
-(2,2-dimethyl-propane-1,ro-dioxy)
-16β-ethyl-5α-hydroxy-16α-methyl-9(10)-bonene-1-fuone (melting point 192-19
4° C.) 1.74 g is obtained.

g) Example 1 Under the conditions of b), the product obtained in f) 1.
4 g is reacted with lithium acetylide. Ethyl acetate/
After crystallization of the crude product from diisozolobyl ether,
11β-(4-dimethylaminophenyl)-3,5-C
2,2-dimethyl-propane-1,6-dioxy)-1
7β-ethynyl-16β-ethyl-16α-meglu-9(10)-bonene-5α,1-phα-diol (melting point 1
62-164°C) 960~ is obtained.

h) Example i The product 76 obtained in g) under the conditions of c)
0 m9 is reacted with 70 thiacetic acid 8a. Crystallization of the crude product from hexane/diethyl ether resulted in 11β
-(4-dimethylaminophenyl)-17β-ethynyl-16β-ethyl-17α-hydroxy-16α-methyl-4,9-gonadien-6-one (melting point 195-19
7℃) 460~ is also good.

Preparation of Example 7 11β-(4
-dimethylaminophenyl)-5,5-C2゜2-dimethyl-propane-1,6-dioxy)-5α-hydroxy-16α-methyl-9(10)-bonene-1 huone 5.0 g and trimethyrusulfonium Iodide 4.
2.66 g of potassium t-butyrate is added dropwise to the #74.9 suspension while cooling with ice water. Stir at 25°C for 4 hours,
Next, pour into ice water and perform extraction using ethyl acetate.

After removal of the solvent, the initially oily crude product was crystallized from ethyl acetate/diimpropyl ether to give 11β.
-(4-dimethylaminophenyl)-3,5-C2,2
-dimethyl-propane-1,6-dioxy)-5α-hydroxy-13α-methyl-9(10)-bonene-1α-spiro-1′,2′-oxirane (melting point 264~
266°C) 4.211 is obtained.

b) Dissolve 2.0 g of the spiro-oxirane obtained in a) in 84 g of ethanol and, after addition of 4.6 g of potassium cyanide, heat under reflux for 4 hours. Cooling bath g with saturated NaHO
Inject into O3 solution and perform extraction with ethyl acetate.

The crude product obtained after evaporative concentration was purified at 70% without further purification.
% acetic acid and stirred for 60 minutes at 60°C.

After cooling, it was poured into ice water and diluted with NH3 solution.
Prepare 0°5... and extract t# using methylene chloride.
conduct. After chromatography of the crude product on silicic acid gel with hexane/acetone and crystallization of the royal fraction from ethanol, 1.4 g of 17β-cyanmethyl-4,9-gonadien-6-one (melting point 165-167°C) were obtained. can get.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the abortifacient effect of the compound according to the present invention in the advanced stages of pregnancy in rats. Figure 1 Tomei, A Soe no Ju 52.3% B C Continued on page 61 Priority claim [Phase] 198 Group April 4 [Phase] West Germany (
DE) [Stock] P 13036.5 Multiple occurrences Akira Rudolf Buich Berlielt, Federal Republic of Germany SE8
Marker Schibile Beier Marker: Walter Elgar Marker: Berliner Berlibeer, Federal Republic of Germany Marker: Debuted Hengouer: Marker: Ralf Loop Berlirase, Federal Republic of Germany Marker: 31st Uhlandstrasse 12 Schollermer Allee 12 N28 Jahnstrasse 9 N45

Claims (1)

[Scope of Claims] 1° [represents an alkyl group having 1 to 4 atoms in the formula, or RI and R2 represent a saturated 5- or 6-membered ring containing NY, in which case there is a Also 51 different atoms 0. If N and S are included (may be included), suitable tertiary N-oxides and acid addition salts, for OR (Rm is a methyl group, ethyl group, propyl group, methoxyphenyl group, allyl group or β -dimethylaminoethyl group j), R2 represents a hydrogen atom, methyl group or ethyl group, R3 represents -(CH2)nOH3 (n = O~4),
(OHs+)n OH20(8)R■(n = O~4
, RIV represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
R■ represents a hydrogen atom, an alkyl group or an alkanoyl group each having 1 to 4 carbon atoms), 10==O-X (X represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or) (OH2)HCH20N (n, = Q to 6) or 1-O-OH2Y (Y represents a hydrogen atom or ORV, R-' is a hydroxy group, each having 1 to 4 carbon atoms) represents an alkyloxy group or an alkanoyloxy group having an
or R3 is present at the β position, R4 is present at the α position, and R5 represents a hydrogen atom or an alkyl group at the α or β position having 1 to 4 carbon atoms. . 2,11β-(4-dimethylaminophenyl)-17α
-ethynyl-17β-hydroxy-16α-methyl-4
,9-gonadien-6-one and 11β-(4-dimethylaminophenyl)-17β-ethynyl-17α-hydroxy-13α-methyl-4,9
The compound 0 according to claim 1 which is -gonadien-6i 6,11β-(4-dimethylaminephenyl)-17β
-Hydroxy-16α-methyl-17α-propynyl-
4,9-gonadien-6-one and 11β-(4-dimethylaminophenyl)-17α-hydroxy-16α-methyl-17β-propynyl-4,
Claim 1 which is q--rnathien-6-one
Compounds described in Section. 4, 11β-(dimethylaminophenyl)-17α-hydroxy-16α-methyl-18゜19-dinol-4,
9-Pregnagen-6220-dione and 17α-acetoxy-11β-(4-dimethylaminophenyl)-13α-methyl-18,19-dinol-4,
The compound according to claim 1, which is 9-pregnagene-3,20-dione. 5,11β-(4-diethylaminophenyl)-17α
-(6-hydroxypropyl)-17β-hydroxy-
13α-methyl-4,9-gonadien-6-one and 11β-(4-diethylaminophenyl)-17β-(
6-hydroxypropyl)-17α-hydroxy-1'
The compound according to claim 1, which is 5α-methyl-4,9-gonadien-6-one. 6,11β-(4-dimethylaminophenyl)-17β
-Hydroxy-17α-(6-hydroxypropyl)-
15α-methyl-4,9-gonadien-6-one and 11β-(4-dimethylaminophenyl)-17α-hydroxy-17β-(6-hydroxypropyl)-13
The compound according to claim 1, which is α-methyl-4,9-gonadien-6-one. 7.17β-ethynyl-17α-hydroxy-11β-
(4-methoxyphenyl)-16α-methyl-4,9-
The compound according to claim 1, which is gonadien-6-one. 8,11β-(4-dimethylaminophenyl)-17β
-ethynyl-16α-ethyl-17α-hydroxy-4
,9-gonadien-6-one and 17α-acetoxy-11β-(4-dimethylaminophenyl)-13α-ethyl-18,19-dinol-4,
The compound according to claim 1, which is 9-pregnajey1.20-dione. 911β-(4-dimethylaminophenyl)-17α-
Hydroxy-17β-(6-hydroxy-1(z)-propenyl)-16α-methyl-4,9-gonadiene-6
The compound according to claim 1, which is -one. 10.11β-(4-dimethylaminophenyl)-17
β-ethynyl-16β-ethyl-17α-human tetraxy-
The compound according to claim 1, which is 16α-methyl-4,9-gonadien-3-one. 11. The compound according to claim 1, which is 17β-cyanmethyl-11β-(4-dimethylaminophenyl)-17α-hydroxy-16α-methyl-4,9-gonadien-6-one. 12. General formula l: [Represents an alkyl group having 1 to 4 cores, or RI and R11 represent a saturated 5- or 6-membered ring containing N, in which case, in addition to N, there is another one in the ring. 0. ) and corresponding tertiary N-oxides and acid addition salts, 0RIII (R111 is a methyl group, ethyl group, propyl group, methoxyphenyl group, allyl group or β-dimethylamineethyl group) R2 represents a hydrogen atom, a methyl group or an ethyl group, and R3 represents -(OHz)n-Ous (n = O~4)
, (OHs+)n 012-0(S)R■(n = D
~4, RIV represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), 1-OH=OB (OH2)n OR" (n = 1
~4, R■ represents a hydrogen atom, an alkyl group or an alkanoyl group each having 1 to 4 carbon atoms), -amia-X (X represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or (represents a halogen) (O)12)n-OH2ON (n -Q~6) or 110-0)12Y (Y represents a hydrogen atom or ORV), R4 is a hydroxy group, and each carbon represents an alkyloxy group or an alkanoyloxy group having 1 to 4 atoms, or in this case R3 is in the ℃α position with respect to the steroid skeleton and R4 is in the β position
or R3 is present at the β position, R4 is present at the α position, and R5 represents a hydrogen atom or an alkyl group at the α or β position having 1 to 4 carbon atoms. In manufacturing, a compound represented by the general formula ■: OH [in the formula, R1, R2 and R5 represent the above, and 2 represents an ethylene group or a 2,2-dimethylpuronlene group] is irradiated with ultraviolet rays. And the general formula (■) obtained by ultraviolet irradiation: OH [In the formula, R1, R2, R6 and 2 represent the above]
The 16-nibisteroid represented by is converted into a compound of general formula (1) by nucleation to 17-ketone, decomposition of 6-ketal retention, and elimination of water from the 4.5-position by a method known per se. The method for producing the 16α-alkylgonane as a percentage. 16. General formula I: [Represents an alkyl group having 1 to 4 cores, or RI and R represent a saturated 5- or 6-membered ring containing N, in which case, in addition to N, there is another group in the ring. one heteroatom, i.e. O, N, S) and corresponding tertiary N-oxides and acid addition salts, OR■' (R1 is a methyl group, an ethyl group, a progyl group, methoxyphenyl group, allyl group or β-dimethylaminoethyl group); R2 represents a hydrogen atom, methyl group or ethyl group; R3 is -(OI(2)n OH3 (n = 0-4)
, (OH2)n-OH20(S)RIV (n = 0~
4, RIV represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), -(!H=OH-(Chi2)n-ORV (n' =
1-41. v represents a hydrogen atom, an alkyl group or an alkanoyl group each having 1 to 4 carbon atoms), -Q=Q −X (x represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or ).rodene -(OH2)n-OH2ON (n = U~3) or 1 -O-0H2Y (Y does not represent a hydrogen atom or ORV), R4 is a hydroxy group, each having 1 to 4 carbon atoms represents an alkyloxy group or an alkanoyloxy group, or this yR3 is at the 1α position with respect to the steroid skeleton, and R4 is at the β position
14, General formula 111 : [Alkyl group having 1 to 4 formula cores or R1 and R■ are N
saturated 5- or 6-membered ring containing N (in addition to N, the ring may also contain one more heteroatom, i.e. 0, N, S) and the corresponding tertiary N-oxide and Acid addition salt, 0RII (R1l+ represents a methyl group, ethyl group, propyl group, methoxyphenyl group, allyl group or β-dimethylaminoethyl group), R2 represents a hydrogen atom, methyl group or ethyl group, R5 represents a hydrogen atom or an α- or β-position alkyl group having 1 to 4 carbon atoms, and 2 represents an ethylene group or a 2,2-dimethylpropylene group.
6-Nibisteroids.