JPH0216760B2 - - Google Patents

Description

1 [In the formula, R ¹ is

[Formula] (R〓 and R〓 represent hydrogen or an alkyl group having 1 to 4 carbon atoms) and an acid addition salt, OR〓 (R〓 represents a methyl group, ethyl group or propyl group), R ² represents a hydrogen atom, a methyl group, or an ethyl group, and R ³ represents -(CH ₂ ) _o -CH ₂ -O(S)H (n=0 to
4), -CH=CH-(CH ₂ ) _o -OR ^V (n=1 to 4,
R ^V represents a hydrogen atom or an alkanoyl group each having 1 to 4 carbon atoms), -C≡C-X
(X represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), -(CH ₂ ) _o -CH ₂ CN (n=0
~3) or

[Formula], R ⁴ is a hydroxy group or each carbon atom 1 to
R ⁵ 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-13α-methyl-
4,9-gonadien-3-one and 11β-(4-dimethylaminophenyl)-17β-
ethynyl-17α-hydroxy-13α-methyl-4,
The compound according to claim 1, which is 9-gonadien-3-one. 3 11β-(4-dimethylaminophenyl)-17β
-Hydroxy-13α-methyl-17α-propynyl-4,9-gonadien-3-one and 11β-(4-dimethylaminophenyl)-17α-
Hydroxy-13α-methyl-17β-propynyl-
The compound according to claim 1, which is 4,9-gonadien-3-one. 4 11β-(dimethylaminophenyl)-17α-hydroxy-13α-methyl-18,19-dinol-4,
9-Pregnadiene-3,20-dione and 17α-acetoxy-11β-(4-dimethylaminophenyl)-13α-methyl-18,19-dinol-4,
The compound according to claim 1, which is 9-pregnadiene-3,20-dione. 5 11β-(4-diethylaminophenyl)-17α
-(3-hydroxypropyl)-17β-hydroxy-13α-methyl-4,9-gonadien-3-one and 11β-(4-diethylaminophenyl)-17β-
(3-hydroxypropyl)-17α-hydroxy-
The compound according to claim 1, which is 13α-methyl-4,9-gonadien-3-one. 6 11β-(4-dimethylaminophenyl)-17β
-Hydroxy-17α-(3-hydroxypropyl)
-13α-methyl-4,9-gonadien-3-one and 11β-(4-dimethylaminophenyl)-17α-
Hydroxy-17β-(3-hydroxypropyl)-
The compound according to claim 1, which is 13α-methyl-4,9-gonadien-3-one. 7 17β-ethynyl-17α-hydroxy-11β-
(4-methoxyphenyl)-13α-methyl-4,9
The compound according to claim 1, which is -gonadien-3-one. 8 11β-(4-dimethylaminophenyl)-17β
-ethynyl-13α-ethyl-17α-hydroxy-
4,9-gonadien-3-one and 17α-acetoxy-11β-(4-dimethylaminophenyl)-13α-ethyl-18,19-dinol-4,
The compound according to claim 1, which is 9-pregnadiene-3,20-dione. 9 11β-(4-dimethylaminophenyl)-17α
-Hydroxy-17β-(3-hydroxy-1(Z)
2. The compound according to claim 1, which is -13α-methyl-4,9-gonadien-3-one (-propenyl). 10 11β-(4-dimethylaminophenyl)-
The compound according to claim 1, which is 17β-ethynyl-16β-ethyl-17α-hydroxy-13α-methyl-4,9-gonadien-3-one. 11 The compound according to claim 1, which is 17β-cyanmethyl-11β-(4-dimethylaminophenyl)-17α-hydroxy-13α-methyl-4,9-gonadien-3-one. 12 General formula: [In the formula, R ¹ is

[Formula] (R〓 and R〓 represent hydrogen or an alkyl group having 1 to 4 carbon atoms) and an acid addition salt, OR〓 (R〓 represents a methyl group, ethyl group, or propyl group) R ² represents a hydrogen atom, a methyl group, or an ethyl group, and R ³ represents -(CH ₂ ) _o -CH ₂ -O(S)H (n=0 to
4), -CH=CH-(CH ₂ ) _o -OR ^V (n=1 to 4,
R ^V represents a hydrogen atom or an alkanoyl group each having 1 to 4 carbon atoms), -C≡C-X
(X represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) -(CH ₂ ) _o -CH ₂ CN (n = 0 to
3) or

[Formula], R ⁴ is a hydroxy group or each carbon atom 1 to
^R5 represents a hydrogen atom or an alkyl group at the α- or β-position having 1 to 4 carbon atoms. [In the formula, R ¹ , R ² and R ⁵ represent the above, and Z
represents an ethylene group or a 2,2-dimethylpropylene group] and the general formula obtained by irradiating the compound with ultraviolet rays: [In the formula, R ¹ , R ² , R ⁵ and Z represent the above]
The 13-evisteroid represented by is converted into the compound of the general formula by nucleophilic addition to the 17-ketone, decomposition of the 3-ketal protection, and elimination of water from the 4,5-position by a method known per se. The method for producing the 13α-alkylgonane described above. 13 General formula: [In the formula, R ¹ is

[Formula] (R〓 and R〓 represent hydrogen or an alkyl group having 1 to 4 carbon atoms) and an acid addition salt, OR〓 (R〓 represents a methyl group, ethyl group or propyl group), R ² represents a hydrogen atom, a methyl group, or an ethyl group, and R ³ represents -(CH ₂ ) _o -CH ₂ -O(S)H (n=0 to
4), -CH=CH-(CH ₂ ) _o -OR ^V (n=1 to 4,
R ^V represents a hydrogen atom or an alkanoyl group each having 1 to 4 carbon atoms), -C≡C-X
(X represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) -(CH ₂ ) _o -CH ₂ CN (n = 0 to
3) or

[Formula], R ⁴ is a hydroxy group or each carbon atom 1 to
^R5 represents a hydrogen atom or an α- or β-position alkyl group having 1 to 4 carbon atoms. Formulation products.

[Detailed description of the invention]

Industrial Application Field The present invention relates to the general formula: [In the formula, R ¹ is

[Formula] (R〓 and R〓 represent hydrogen or an alkyl group having 1 to 4 carbon atoms) and an acid addition salt, OR〓 (R〓 represents a methyl group, ethyl group, or propyl group) R ² represents a hydrogen atom, a methyl group, or an ethyl group, and R ³ represents -(CH ₂ ) _o -CH ₂ -O(S)H (n=0 to
4), -CH=CH-(CH ₂ ) _o -OR ^V (n=1 to 4,
R ^V represents a hydrogen atom or an alkanoyl group each having 1 to 4 carbon atoms), -C≡C-X
(X represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) -(CH ₂ ) _o -CH ₂ CN (n = 0 to
3) or

[Formula], R ⁴ is a hydroxyl group or 1 carbon atom each
represents an alkanoyloxy group having ~4 atoms, 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 13α-alkylgonane. The compound has the general formula: [In the formula, R ¹ , R ² and R ⁵ represent the above, and Z
represents an ethylene group or a 2,2-dimethylpropylene group] and the general formula obtained by irradiating the compound with ultraviolet rays: [In the formula, R ¹ , R ² , R ⁵ and Z represent the above]
The 13-episteroid represented by is converted into the compound of the general formula by nucleophilic addition to the 17-ketone, decomposition of the 3-ketal protection, and elimination of water from the 4,5-position by a method known per se. It can be manufactured by The present invention also relates to a pharmaceutical product containing the 13α-alkylgonane. Compounds of the general formula have a strong affinity for gestagen receptors without having progestin activity by themselves. The compound is a competitive antagonist of brogesterone (antigestagen) and is relevant for the occurrence of miscarriage. This is because the compound displaces the progesterone needed to maintain pregnancy from the receptors. The compounds are therefore important and advantageous in their use for the regulation of post-coital (pc) fertility. Corresponding compounds of the etran series have already been used as antigestogenic compounds in Fertility and Sterility.
Sterility) 40 (1982), p. 253. The previously known structure-action relationship for progesterone antagonists suggests that a 1,3-biaxial arrangement of 11β-aryl and 13β-alkyl groups is unavoidably necessary for the development of antigestagen activity. are doing. Therefore, the molecular localization is completely different compared to the etran series.
The strong selective antagonism of 13a-alkylgonane with the formula 13a-topoqraphie is all the more surprising. In order to characterize the antigestagen action of the compounds according to the invention, the abortifacient effect was examined in the early stages after egg implantation (experiments) and in the advanced stages after egg implantation (experiments). The experiment was conducted on female rats weighing approximately 200 g.
The onset of pregnancy was confirmed by the detection of sperm in the postcopulatory vaginal fluid. The day of sperm detection is the first day of pregnancy (=p.c1
day). p.c5th to p.c7th (experiment) and p.c13th to p.c15
After implantation of the blastocysts on day (experiment), the animals were treated with the substances and solvents to be tested in each case. p.
At days c.9 and 17 days pc, the animals were sacrificed and the uterus was examined for implanted embryos and resorption sites. Photographs were produced from all uteruses. Lack of implanted embryos was evaluated as miscarriage. The following antigestagens were tested: A: 11β-(4-dimethylaminophenyl)-17β
-Hydroxy-17α-propynyl-4,9-etradien-3-one (standard material). B: 11β-(4-dimethylaminophenyl)-17β
-Hydroxy-17α-(3-hydroxypropyl)-13α-methyl-4,9-gonadiene-3
-on (as described in the invention). C: 11β-(4-dimethylaminophenyl)-17α
-Hydroxy-17β-(3-hydroxypropyl)-13α-methyl-4,9-gonadiene-3
-on (as described in the invention). The test substance was dissolved in a benzyl benzoate/castor oil mixture (ratio 1:4). The excipient volume per unit dose was 0.2 ml. Treatment was performed subcutaneously (sc). Table 1 (Experiment) Effect of miscarriage in early pregnancy of ratte.Treatment on 5th to 7th pc, autopsy on 9th pc.

【table】

[Table] Experiment To test the effect of miscarriage in advanced stages of pregnancy in rats, rats from PC13 to PC15 were subcutaneously treated with 3.0 mg/day of antigestagen (AG).
Autopsy on 17 days PC. The autopsy results are shown in Figure 1. Compounds B and C according to the present invention have sufficient abortion effects (miscarriage rate: 4/4) in the case of latus in early pregnancy at a dose of ≧1.0 mg/day. In contrast, reference substance A exhibits the maximum abortifacient (antigestagen) effect only at doses of ≧3.0 mg/day (Table 1). 3.0 mg/day in advanced stages of pregnancy (pc 15-13 days)
The percentage of complete abortion for subcutaneous (sc) administration is 35.4% for B, 52.3% for C and 3.5% for control substance A (Figure 1). The 13α-alkylgonane of the general formula can be used in the form of pharmaceutical products. The preparation is manufactured by the Gallen method known per se.
This is done by mixing with organic or inorganic inert excipients suitable for transdermal and parenteral applications. The dose of the active substance according to the invention is approximately 10-1000 mg/day for humans. The alkyl radicals of the general formulas R and R are required to have 1 to 4 carbon atoms, with methyl and ethyl being preferred. The alkanoyl radicals contained in R _V each have 1 to 4 carbon atoms, acetyl and propionyl radicals being preferred. During the production of novel 13α-alkylgonanes according to the present invention, 13β-alkyl steroids of the general formula are converted into 13-episteroids (13α-alkyl steroids) of the general formula in good yield by UV irradiation. The good yield of this transformed product is surprising. I see,
It has been known that standard series 17-oxosteroids can be converted to 13-epistoids by UV irradiation [A. Butenandt et al.
Ber. Deutsch. Chem. Ges. 74 , p. 1308 (1941)]. However, a mixture of starting material and epimel compound is always obtained, the irradiation time is several hours, and the yield is very small. The search for alternative chemical approaches to the 13-epi series is therefore also still active, as shown by the recent work of Barton et al.: JCS Perkin, p. 2163 (1977). However, the above-mentioned alternatives are not suitable for the preparation of compounds of formula. However, it has been found that UV irradiation of compounds of the formula under certain conditions takes a significantly more favorable course than that of the 11-unsubstituted 17-oxosteroid series. That is, the average irradiation time is only 10-30 minutes and the yield of 13-episteroids 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 with sufficient light from a Hg high-pressure lamp. The temperature of the reaction solution is approximately
The temperature is adjusted to 25 °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, benzol, toluene and mixtures thereof. Irradiation time is approximately 10-50 minutes. The 13-episteroid thus obtained is converted into the final compound of the general formula by nucleophilic addition to the 17-ketone and subsequent reactions in a conventional manner.
The nucleophilic addition of generally proceeds at C-17 with the formation of two possible isomeric forms. In any case, both isomers are pharmacologically active, although there may be differences in potency. Nucleophilic addition of acetylene (ethyne) or propylene is carried out using agents that give -C≡CH or -C≡C-CH ₃ groups. Such agents are, for example, alkali metal acetylides, such as potassium and lithium acetylides or alkali metal methyl acetylides. Organometallic compounds can also be formed in situ and reacted with the 17-ketone of formula. i.e. for example 17
- Ketones can be treated with acetylene and alkali metals, especially potassium, sodium or lithium, in a suitable solvent in the presence of alcohol or ammonia. Alkali metals can also act, for example in the form of methyl or butyllithium.
Particularly suitable solvents are dialkyl ethers, tetrahydrofuran, dioxane, benzol and toluene. The 17-ethynyl-17-hydroxy compound is hydrated in alcoholic solution under mercury salt catalysis to yield the 17-acetyl-17-hydroxy compound (Chem.
Ber. 111 (1978), pp. 3086-3093). Introduction of 3-hydroxypropane or 3-hydroxypropene at position 17 can be achieved by reacting the 17-ketone with a metallated derivative of propargyl alcohol, such as 1-lithium-3-tetrahydropyran-2'-yloxy-propyne 1. to form a 17-(3-hydroxy-1-propynyl)-17-hydroxy compound, which is then hydrogenated to a 17-(3-hydroxypropyl- or 3-hydroxypropenyl)-17-hydroxy compound. It is done by certain things. The hydrogenation must then be carried out under conditions that ensure action on the C--C triple bond without saturating the tetrasubstituted 9(10)-double bond. This is the case, for example, in hydrogenation at room temperature and standard pressure in solvents such as methanol, ethanol, propanol, tetrahydrofuran (THF) or acetic acid esters with addition of noble metal catalysts such as platinum or palladium. Hydrogenation of the triple bond of acetylene using a deactivated noble metal catalyst produces compounds with a Z-configured double bond in the hydroxypropenyl group [J. Fried, JA. Edwards: Organic.・Reaction in Steroid Chemistry (Organic
Reactions in Seroid Chemistry), Juan Nostrand Reinhold Company (Van
Nostrand Reinhold Company) 1972, p. 134 and HO House: Modern Synthetic Reaction.
Reactions), 1972, p. 19]. Suitable deactivating noble metal catalysts are 10% palladium on barium sulfate in the presence of an amine or 5% palladium on calcium carbonate with the addition of lead 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 alkylenes into trans-olefins. For example, reduction with sodium in liquid ammonia (J.Am.Chem.
Soc.63 (1941), 216), reduction with sodium amide in liquid ammonia (J.Chem.Soc.1955,
3558), reduction with lithium in low molecular weight amines (J.Am.Chem.Soc.77 (1955), 3378), reduction with borane (J.Am.Soc.93 (1971), 3395 and 94)
(1971), 6560), reduction with diisobutylaluminum hydride and methyl-lithium (J.Am.
Chem.Soc.89 (1967), 5085), especially reduction with lithium aluminum hydrides/alcoholates (J.
Am.Chem.Soc.89 (1967), 4245) is known. Also, reduction of triple bonds by chromium sulfate () in the presence of water or dimethylformamide in a weakly acidic environment (J.Am.Chem.Soc.86 (1964),
4358) and, in general, reduction by the action of transition metal compounds under alternation of the oxidation steps is also possible. The 17-cyanmethyl side chain can be obtained from the 17-ketone of the general formula in a manner known per se, for example via the 17-spiroepoxide and by decomposition of the spiroepoxide with HCN (Z.Chem. 18 (1978), 259-260). It is formed. Furthermore, the introduction of the 17-hydroxyacetyl side chain can be carried out using methods known per se, such as J.Org.Chem. 47 (1982),
2993-2995. The free hydroxy group at position 17 can be esterified or etherified in a manner known per se. After the nucleophilic addition reaction of the 17-ketone, the compound of formula is treated with an acid or an acidic ion exchanger to form the 4(5)-
Water is eliminated with the formation of a divalent bond, and at the same time the ketal is decomposed and any other acid-removable protecting groups that are present are removed. Treatment with acid is carried out in a manner known per se: 3
- A compound of the formula having a ketal group and a 5α-hydroxy group and optionally a protected 17-(3-hydroxypropyl) group of O is dissolved in a water-miscible solvent, i.e. aqueous methanol, ethanol or acetone and A catalytic amount of a mineral or sulfonic acid, i.e., hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid or p-toluene sulfonic acid, or an organic acid such as acetic acid, is added to the solution to remove water and remove the protecting groups. Let it work until it stops. Also, 0~100℃
The reaction, which proceeds at a temperature of , 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) In 300 ml of anhydrous tetrahydrofuran (THF)
11β-(4-dimethylaminophenyl)-3,3
-(2,2-dimethyl-propane-1,3-dioxy)-5α-hydroxy-9(10)-esteren-17-one (melting point 143-145°C) 2.0 g solution,
Irradiate using a Hg high-pressure lamp (Philips HPK125, Tauchlampe, quartz glass reactor) at 25°C for 16 minutes. The solvent is then distilled off in vacuo and the residue is chromatographed over aluminum oxide (Merk, neutral grade) using hexane/acetic acid ester. 11β−(4
-dimethylaminophenyl)-3,3-(2,2
-dimethyl-propane-1,3-dioxy)-
1.46 g of 5α-hydroxy-13α-methyl-9(10)-gonen-17-one are obtained as a colorless oil. (b) Add acetylene to 30% of anhydrous THF (248ml) at 5°C.
Introduce for 1 minute to saturate. Then n in hexane
- 51 ml of a 15% solution of butyllithium is slowly added dropwise and stirred for a further 15 minutes under ice-water cooling. next,
11β-(4-dimethylaminophenyl)-3,3-(2,2-dimethyl-propane-1,3-dioxy)-5α-hydroxy) in 40 ml of anhydrous THF
A solution of 2.7 g of 13α-methyl-9-gonen-17-one 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 thus obtained (2.85 g) is taken to the next stage without further purification. (c) 2.8 g of the crude product obtained in (b) was dissolved in 70% aqueous acetic acid.
Suspend in 29 ml and stir at 50°C for 3 hours. After cooling, dilute with approximately 100 ml of water and concentrate aqueous _NH3.
Adjust the PH value to 10.5 by adding the solution. After extraction with acetic acid, an oily isomer mixture is obtained, which is resolved by column chromatography on silicic acid gel using hexane/acetic acid ester. The sequence of elution gives the following compounds: 1 11β-(4-dimethylaminophenyl)-
17α-ethynyl-17β-hydroxy-13α-methyl-4,9-gonadien-3-one 530 mg,
Melting point 120-123° (acetic acid ester/diisopropyl ether). 2 11β-(4-dimethylaminophenyl)-
17β-ethynyl-17α-hydroxy-13α-methyl-4,9-gonadien-3-one, melting point
201-204℃ (acetic acid ester). If methylacetylene is used instead of acetylene, the following compound can be obtained in the same manner as in (b) and (c). 1 11β-(4-dimethylaminophenyl)-
17β-Hydroxy-13α-methyl-17α-propynyl-4,9-gonadien-3-one (oil). 2 11β-(4-dimethylaminophenyl)-
17α-Hydroxy-13α-methyl-17β-propyl-4,9-gonadien-3-one (oil). (d) A suspension of 1.02 g of mercury oxide (HgO, red) in 20 ml of water is stirred after addition of 0.87 ml of concentrated sulfuric acid for 30 minutes at 60°C. Add 9 ml of this mercury salt solution to 32 ml of acetic acid.
11β-(4-dimethylaminophenyl)-
Add to a solution of 3.25 g of 17β-ethynyl-17α-hydroxy-13α-methyl-4,9-gonadien-3-one. Next, stir at 60°C for 2 hours. For work-up, pour the cooled reaction solution into ice water, adjust the PH value to 10.5 by adding concentrated aqueous NH ₃ solution, and perform extraction with ethyl acetate. The oily crude product thus obtained is crystallized from methylene chloride/diisopropyl ether. 11β−(4−
2.37 g (melting point
224-225℃) is obtained. (e) 2.3 g of 11β-(4-dimethylaminophenyl)-17α-hydroxy-13α-methyl-18,19-dinol-4,9-pregnadiene-3,20-dione in 58 ml of toluene was mixed with 11.6 g of acetic anhydride. After addition of 5.8 g of 4-dimethylaminopyridine and 5.8 g of 4-dimethylaminopyridine, stir at 25° C. for 20 hours. Then pour into a saturated solution of NaHCO ₃ and perform extraction with ethyl acetate. The crude product is chromatographed on silicic acid gel using hexane/ethyl acetate. After crystallization from hexane/ethyl acetate of the main fraction, 17α
-acetoxy-11β-(4-dimethylaminophenyl)-13α-methyl-18,19-dinol-4,
9-Pregnadiene-3,20-dione (melting point
194-195°C) 1.71g is obtained. Example 2 (a) 11β-(4-diethylaminophenyl)-3,3-(2,2-dimethyl-propane-1,3-dioxy)-5α-hydroxy-9 in 300 ml THF
- A solution of esteren-17-one (melting point 223-226°C) is irradiated for 26 minutes under the conditions of Example 1(a). After chromatography of the crude product, 11β-(4-diethylaminophenyl)-3,3-(2,2-dimethyl-propane-1,3-dioxy)-5α-
Hydroxy-13α-methyl-9-gonene-17-
1.58 g of ion are obtained as a colorless oil. (b) 3.94 ml of 3-tetrahydropyran-2'-yloxy-1-propyl in 85 ml of anhydrous THF and 23.1 ml of a 15% solution of n-butyllithium in hexane.
An organolithium compound is prepared from g at 0°C. A solution of 3.53 g of the product described under 2(a) in 71 ml of anhydrous THF is then added and stirred for 4 hours at room temperature. Next, the reaction solution is poured into ice water and extracted using acetic acid ester. Crude product (3.85g)
11β-(4-diethylaminophenyl)-3,3
-(2,2-dimethylpropane-1,3-dioxy-13α-methyl-17α-[3-(tetrahydropyran-2-yloxy)-1-propynyl]
-9-gonene-5α, 17β-diol and 11β-
(4-diethylaminophenyl)-3,3-(2,
2'-dimethyl-propane-1,3-dioxy)
-13α-methyl-17β-[3-(tetrahydropyran-2-yloxy)-1-propynyl]-9
The -gonene-5α,17α-diol is used for the hydrogenation without further purification. (c) 3.85 g of the crude product obtained in 2(b) are hydrogenated in 95 ml of ethanol at room temperature and standard pressure after addition of 400 mg of 10% palladium on carbon. After absorption of 191 ml of hydrogen, the catalyst is filtered off and concentrated. (d) The hydrogenated product (3.85 g) obtained in 2(c) was
Stir in 30 ml of 70% acetic acid at 60°C for 2 hours. After cooling, work up as described under 1(c) and chromatography of the resulting isomer mixture. The elution order gives the following compounds: 1 11β-(4-dimethylaminophenyl)-
410 mg of 17α-(3-hydroxypropyl)-17β-hydroxy-13α-methyl-4,9-gonadien-3-one (yellow oil). UV (methanol): ε ₂₆₆ = 19080, ε ₃₀₉ = 19110. 2 11β-(4-diethylaminophenyl)-
1.39 g of 17β-(3-hydroxypropyl)-17α-hydroxy-13α-methyl-4,9-gonadien-3-one (solid form). As starting material 11β-(4-dimethylaminophenyl)-3,3-(2,2-dimethyl-propane-1,3-dioxy)-5α-hydroxy-
When using 13α-methyl-9-gonen-17-one, the following can be obtained in the same manner as in (b) to (d): 1 11β-(4-dimethylaminophenyl)-
17β-hydroxy-17α-(3-hydroxypropyl)-13α-methyl-4,9-gonadien-3-one (oil). 2 11β-(4-dimethylaminophenyl)-
17α-hydroxy-17β-(3-hydroxypropyl)-13α-methyl-4,9-gonadien-3-one (oil). Example 3 (a) 3,3-(2,2-dimethyl-propane-1,3-dioxy)-5α-hydroxy-11β-(4-methoxyphenyl)-9 in 290 ml of dioxane.
- In a solution of 1.75 g of esteren-17-one, Example 1
Irradiate for 19 minutes under the conditions described in (a). After chromatography, 3,3-(2,2-dimethyl-propane-1,3-dioxy)-5α-hydroxy-11β-(4-methoxyphenyl)-13α-
1.45 g of methyl-9-gonen-17-one are obtained as a colorless oil. (b) To a suspension of lithium acetylide prepared from a saturated solution of acetylene in 450 ml of THF and 130 ml of a 15% solution of n-butyllithium in hexane, 3,3-(2,2-dimethyl-propane- 1,3-dioxy)-5α-hydroxy-11β-(4-methoxyphenyl)-13α
A solution of 8.2 g of methyl-9-gonel-17-one is added dropwise. The mixture is then stirred at room temperature for 3 hours, and then the reaction solution is poured into about 3 liters of ice water and extracted with ethyl acetate. The crude product is chromatographed over aluminum oxide using hexane/ethyl acetate. The elution order gives the following compounds: 1 3,3-(2,2-dimethyl-propane-
1,3-dioxy)-17α-ethynyl-11β-
(4-methoxyphenyl)-13α-methyl-9
-gonene-5α,17β-diol (colorless oil) 1.8g. 2 3,3-(2,2-dimethyl-propane-
1,3-dioxy)-17β-ethynyl-11β-
(4-methoxyphenyl)-13α-methyl-9
-gonene-5α,17β-diol (solid form) 5.1 g. (c) 3,3-(2,2-dimethyl-propane-1,3-dioxy)-17β in 33 ml of 70% aqueous acetic acid.
-ethynyl-11β-(4-methoxyphenyl)-
A solution of 3.28 g of 13α-methyl-9-gonene-5α,17α-diol is stirred at 60° C. for 30 minutes. After cooling, pour into ice water, perform extraction with methylene chloride, wash MeCl ₂ extract with saturated NaHCO ₃ solution and concentrate. Crystallization of the crude product from ethyl acetate yielded 17β-ethynyl-
17α-hydroxy-11β-(4-methoxyphenyl)-13α-methyl-4,9-gonadiene-3
2.0 g of -one (melting point 186-187°C) are obtained. Example 4 11β-(4-dimethylaminophenyl)-3,3-(2,2-dimethyl-propane-
By irradiating 1.84 g of 1,3-dioxy)-5α-hydroxy-18-methyl-9-ester-17-one for 20 minutes under the conditions of Example 1(a), 11β-(4- dimethylaminophenyl)-3,
3-(2,2-dimethyl-propane-1,3-dioxy)-13α-ethyl-5α-hydroxy-9-
1.36 g of gonen-17-one are obtained. 11β-(4-dimethylaminophenyl)-3,3
6.1 g of -(2,2-dimethylpropane-1,3-dioxy)-13α-ethyl-5α-hydroxy-9-gonen-17-one are reacted with lithium acetylide under the conditions of Example 1(b), The crude product thus obtained is decomposed with acetic acid under the conditions of Example 1(c).
After chromatography and crystallization from ethyl acetate/diisopropyl ether, 11β-(4-dimethylaminophenyl)-17β-ethynyl-13α-ethyl-17α-hydroxy-4,9-gonadiene-
3.2 g of 3-one (melting point 197-198 DEG C.) are obtained. [α] ²⁵ _D +450.4° (CHCl ₃ , c=0.505) By mercury salt catalytic hydrogenation as in Example 1(d) and subsequent acetylation as in Example 1(e), 11β-( 4-
dimethylaminophenyl)-17β-ethynyl-13α
-Ethyl-17α-hydroxy-4,9-gonadien-3-one from 1.3 g, after chromatographic purification, 17α-acetoxy-11β-(4-dimethylaminophenyl)-13α-ethyl-18,19
720 mg of -dinol-4,9-pregnadiene-3,20-dione (solid form) are obtained. [α] ²⁵ _D +290.8° (CHCl ₃ , c=0.515). Example 5 (a) 11β-(4-dimethylaminophenyl)-3,3-(2,2-dimethyl-propane-1,3-dioxy)-5α-hydroxy under the conditions described in Example 2(b) -13α-methyl-9-gonen-17-one
11β-(4-dimethyl aminophenyl)
-3,3-(2,2-dimethyl-propane-1,
3-dioxy)-13α-methyl-17β-[3-(tetrahydropyran-2-yloxy)-1-propynyl]-9-gonene-5α,17α-diol
4.83 g are obtained as a yellow foam. (b) 67ml ethanol and 0.56ml triethylamine
A solution of 2.2 g of the adduct obtained in (a) is hydrogenated at room temperature and standard pressure after addition of 210 mg of palladium on barium sulfate (10%). Hydrogen 83.5
After absorption of ml, filter off the catalyst and concentrate. The hydrogenated crude product thus obtained was subjected to the conditions of Example 1(c).
Digest using 14 ml of 70% acetic acid. Ethyl acetate/
11β after crystallization from diisopropyl ether
-(4-dimethylaminophenyl)-17α-hydroxy-17β-(3-hydroxy-1(Z)-propenyl)-13α-methyl-4,9-gonadien-3-one (melting point 133-135°C) 1.1 g is obtained. Example 6 11β-(4-dimethylaminophenyl)-17α-
Ethynyl-16β-ethyl-17α-hydroxy-
Production of 13α-methyl-4,9-gonadien-3-one. (a) 3,3-(2,2-dimethyl-propane-1,
A suspension of 3-dioxy)-5(10), 9(11)-estradien-17-one and 28.6 g of bis-dimethylamino-t-butoxymethane is stirred at 160° C. for 60 min under argon. . After cooling, the crude product is triturated with about 50 ml of ethyl acetate, filtered and the filter cake is crystallized from ethyl acetate. In this way, 16-dimethylaminomethylene-3,3
-(2,2-dimethyl-propane-1,3-dioxy)-5(10),9(11)-estradiene-17-
(melting point 208-211°C). (b) 16-dimethylaminoethylene-3,3-(2,2-dimethyl-propane-1,3-dioxy)-5(10),9(11)-estradien-17-one in 220 ml of toluene 14.4 85 ml of a 5% solution of methyllylithium in diethyl ether are added dropwise to the solution of g under ice-water cooling. +5~+10 after addition
C. for 15 minutes, the excess reagent is destroyed by carefully adding about 20 ml of water, then the reaction solution is poured into about 3 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. 3,3-(2,2-dimethyl-propane-1,3-dioxy)-16(E)-ethylidene-5(10),9(11)-estradiene after crystallization of the main fraction from ethyl acetate. 13.0 g of -17-one (melting point 121-123°C) are obtained. (c) 43ml of methylene chloride, hexachloroacetone
3,3-(2,
2-dimethyl-propane-1,3-dioxy)
-16(E)-Ethylidene-5(10),9(11)-estradien-17-one in a solution of 9.4 g under ice water cooling.
Add 4.3 ml of 30% hydrogen peroxide dropwise and then cool at 25 °C for 16
Stir for an hour. For work-up, the reaction mixture is diluted with approximately 100 ml of methylene chloride, washed successively with 5% Na ₂ S ₂ O ₃ solution and water, the methylene chloride phase is dried over Na ₂ SO ₄ and concentrated. do. The 5,10-epoxide mixture thus obtained is chromatographed over Al ₂ O ₃ (neutral, grade) using hexane/ethyl acetate. 3,3-(2,2-dimethyl-propane-
1,3-dioxy)-5α,10α-epoxy-16
(E)-ethylidene-9(11)-esteren-17-one
4.7g is obtained. Melting point 139-141°C (ethyl acetate/diisopropyl ether). (d) 3,3-(2,2-dimethyl-propane-1,3-dioxy)-5α in 400 ml of ethanol,
A solution of 8.2 g of 10α-epoxy-16(E)-ethylidene-9(11)-esteren-17-one is hydrogenated at room temperature and standard pressure after addition of 930 mg of palladium on carbon (10%). After absorption of 510 ml of hydrogen, the catalyst is filtered and concentrated in vacuo. 3,3-(2,2-dimethyl-propane-1,3-dioxy)-5a,10a-epoxy- as a colorless oil
16β-ethyl-9(11)-esteren-17-one 7.7
g is obtained. (c) An organomagnesium compound is prepared from 1.4 g of magnesium, 0.05 ml of methyl iodide and 17.9 g of 4-bromo-N,N-dimethylaniline in 150 anhydrous THF. After addition of 44 g of CuCl 3 , it is stirred for 15 minutes at 0° C. and then a solution of 7.7 g of the product obtained in (d) in 70 ml of anhydrous THF is added dropwise. Then stir at room temperature for 3.5 hours. For work-up, the reaction solution is poured into a mixture of ice water and NH ₃ 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)-esteren-17-one (melting point
180-181°C) 6.5g is obtained. (f) A solution of the product obtained in (e) in 600 ml of dioxane is irradiated under the conditions of Example 1(a). After crystallization of the irradiated crude product from diisopropyl ether, 11β-(4-dimethylaminophenyl)-
3,3-(2,2-dimethyl-propane-1,
1.74 g of 3-dioxy)-16β-ethyl-5α-hydroxy-13α-methyl-9(10)-gonen-17-one (melting point 192-194°C) are obtained. (g) Product 1.4 obtained in (f) under the conditions of Example 1(b)
g is reacted with lithium acetylide. After crystallization of the crude product from ethyl acetate/diisopropyl ether, 11β-(4-dimethylaminophenyl)-3,3-(2,2-dimethyl-propane-1,3-dioxy)-17β-ethynyl- 16β
-ethyl-13α-methyl-9(10)-gonene-5α,
960 mg of 17α-diol (melting point 132-134°C) are obtained. (h) Under the conditions of Example 1(c), the product obtained in g 760
react with 8 ml of 70% acetic acid. Crystallization of the crude product from hexane/diethyl ether resulted in 11β-(4-dimethylaminophenyl)-
17β-ethynyl-16β-ethyl-17α-hydroxy-13α-methyl-4,9-gonadiene-3-
(melting point 195-197°C) is obtained. Example 7 Preparation of 17β-cyanmethyl-11β-(4-dimethylaminophenyl)-17α-hydroxy-13α-methyl-4,9-gonadien-3-one 11β-(4-dimethylaminophenyl) in 60 ml of dimethylformamide. enyl)-3,3-(2,2-dimethyl-propane-1,3-dioxy)-5α-hydroxy-13α-methyl-9(10)-gonen-17-one
5.0g and trimethylsulfonium iodide 4.74
2.63 g of potassium t-butyrate is added dropwise to the suspension of 10 g 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 crude product, initially oily, was crystallized from ethyl acetate/diisopropyl ether to give 11β-(4-dimethylaminophenyl)-
3,3-(2,2-dimethyl-propane-1,3
-dioxy)-5α-hydroxy-13α-methyl-
4.2 g of 9(10)-gonene-17α-spiro-1',2'-oxirane (melting point 234-236°C) are obtained. (b) 2.0 g of the spiro-oxirane obtained in (a) was dissolved in 84 ml of ethanol, and 4.6 g of potassium cyanide was added.
After addition of g, the mixture is heated to reflux for 4 hours. Pour the cooled solution into saturated _NaHCO3 solution and perform extraction with ethyl acetate. The crude product obtained after evaporative concentration is taken up in 26 ml of 70% acetic acid without further purification and stirred at 60° C. for 60 min. After cooling, pour into ice water, adjust the pH to 10.5 by adding NH ₃ solution and perform extraction with methylene chloride. 17β-cyanmethyl-4,9- after chromatography of the crude product on silicic acid gel using hexane/acetone and crystallization of the main fraction from ethanol.
Gonadien-3-one (melting point 135-137℃) 1.4
g is obtained.

[Brief explanation of drawings]

FIG. 1 is a graph showing the abortifacient effect of the compound according to the present invention in the advanced stage of pregnancy in latte.

Claims (1)

[Claims]