JPH0436295A - 6,7-methylene steroid derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R is H, halogen; X is 0, a group of formula II or III; R<1> is 2-4C alkanoyl, benzoyl capable of having a substituent (halogen, 1-4C alkyl, 1-4C alkoxy); the dotted line at the 4 or 5-position of the steroid skeleton exhibits a double bond or the 4 or 5-positions are saturated wherein H at the 5-position is bonded by an alpha or beta-configuration; =C(R2) at the 6 and 7-positions of the steroid skeleton is bonded at 6alpha-, 7alpha-or 6beta-, 7 beta- positions] EXAMPLE:6alpha, 7alpha-Methylene-4-androstene-17beta-o1 acetate. USE:A biosynthesis-inhibiting agent of estrogen compounds (aromatase inhibitor). PREPARATION:A compound of formula IV is reduced-with a metal hydride to prepare a compound of formula V among the compounds of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel 6,7-methylene steroid derivatives. The compounds of the present invention have an aromatase inhibitory effect and are useful as estrogen biosynthesis inhibitors.

[Conventional technology]

The biosynthesis of estrogens is carried out by oxidizing and eliminating formic acid from androgens, which are then aromatized by an enzyme called aromatase. Therefore, if the action of aromatase could be effectively inhibited, it would be effective in treating diseases caused by excess estrogen, and in line with this, some aromatase inhibitors have already been used to treat breast cancer and prostate cancer. It has been found to be effective in treating hypertrophy.

In addition, aromatase antagonists may be used to treat other estrogens/I
It is also useful in the treatment of diseases caused by excessive N, such as uterine cancer, ovarian cancer, endometriosis, male gynecomastia, and male infertility related to oligospermia.

Compounds known as steroidal 70 matase inhibitors include, for example, testolactone (Merck Index, 10th edition, 8999), 4-hydroxy-4-androstene-3,17-dione and its esters (U.S. Pat. 4, 235, 893), 1O-(2-propynyl)-4-nistrene-3°17-dione (JP-A-57-38797'), 10-hydroxymethyl-
3-methylene-4-nystrene-17-one
0-252494), 1O-(2-propynyl)-4
-Nistrene-17one (JP-A-62-212398) and the like are known.

Further, the present inventor has proposed that the 3-position is unsubstituted and the 10-position is a hydroxymethyl group, a difluoromethyl group, a formyl group, or a C
It was discovered that a 4-nystrene compound substituted with a 2-4furcatuyloxymethyl group has an excellent aromatase inhibitory effect, and was previously proposed (Japanese Patent Application Laid-Open No. 2-108696).
(see publication).

[Disclosure of the invention]

In the present invention, R represents a hydrogen atom or a halogen atom; where R1 is substituted with a C2-4 alkanoyl group, a halogen N atom, a Cr-a alkyl group or a Cr-a alkoxy group. the dashed lines at the 4- and 5-positions of the steroid skeleton indicate the presence of a double bond there, or the 4- and 5-positions are saturated and the 5-position The hydrogen atom is bonded to α- or β-; the group substituted at the 6- and 7-positions of the steroid skeleton =C
(R)2 relates to a 6,7-methylene steroid derivative represented by: 6α-7α- or 6β-27β-binding.

In the above formula (I), examples of the ``rc2-a alkanoyl group'' include acetyl, propionyl, or butyryl groups, and examples of the ``rc+-a alkyl group'' include methyl, ethyl, n-propyl, and impropyl groups. Or n-butyl group etc. can be mentioned.

The term "rCr-a alkoxy group" includes an alkyloxy group in which the alkyl moiety is as described above, while the halogen atom includes a fluorine, chlorine, or bromine atom.

Therefore, examples of "benzoyl group optionally substituted with a halogen atom, a C-4 alkyl group, or a Cr-a alkoxy group" include benzoyl, 4-chlorobenzoyl, 4-chlorobenzoyl,
-fluorobenzoyl, 2. 4 dichlorobenzoyl,
4-methylbenzoyl, 2-methoxybenzoyl, 4-
Examples include isopropoquine benzoyl group.

Among the compounds of formula (I) provided by the present invention, a preferred group of compounds is the compound of formula (1) when X represents an oxo group.
It is a compound of Another group of compounds which are also suitable are compounds of the formula (I
) is a compound.

According to the present invention, the compound of formula (I) is a compound of formula (a) in which the way of bonding R and X and the group =C(R)2 has the above meaning "3- By deoxylating the positions, R and X
and the way of bonding of the group =C(R)2 has the above meaning, or (c) in the formula, the way of bonding of R and X and the group =C(R)2 is or (b) reducing the double bonds at the 4- and 5-positions of the compound of formula (I-a), where X has the above meaning. The group =C(R)2 is present at the double bond at the 6- and 7-positions of the compound of
(d) Further, if necessary, X is β-acyloxy is hydrolyzed to change X to a β-hydroxy group, and when X is a β-hydroxy group, the compound of formula (1) is acylated or oxidized so that X represents a β-acyloxy group or an oxo group. It can be produced by converting the compound of formula (I) into a compound of formula (I).

In the method (a) of the present invention, deoxylation at the 3-position is carried out by reducing the compound of formula (■) (a-1) to change the oxo group at the 3-position to a hydroxy group, and the resulting 3-hydroxy compound The hydroxyl group at the 3-position is changed to an acyloxy group by acylation, and the 3-acyloxy group described later is reduced, or (a-2) the compound of formula (■) and an alkanedi diol are This can be carried out by reacting to convert the oxo group at the 3-position into a thioketal group, and reducing the resulting 3-thioketal compound.

In the above method (a-1), the reduction of the compound of the formula (II) is carried out using a complex metal hydride, such as monoatomic sodium hydride, in a non-toxic solvent such as methanol, ethanol, tetrahydrofuran, dioxano, etc. It can be carried out by treatment with sodium borohydride-cerium chloride, lithium aluminum t-butquine hydride, etc., and the reaction temperature is generally 0°C to 50°C, preferably water cooling to room temperature.

The amount of the complex metal hydride to be used relative to the compound of formula (II) is usually 0.5 to 10 moles per mole of the compound of formula (II).

As a result, a compound in which the oxo group at the 3-position in the compound of the formula (II) is reduced to a hydroxy group is obtained, but if the group X at the 17-position represents an oxo group, the compound of the formula (II) When a compound is used for reduction, a compound in which the group X (oxo group) at the 17-position as well as the 3-position is reduced to a β-hydroxy group can be obtained. Note that even if a compound of formula (II) in which the group X at the 17-position represents an oxo group is used, only the oxo group at the 17-position must be protected in advance with a N-protecting group such as an ethylenedioxy group. If the protective group is removed by mild acid treatment etc. after the reduction reaction, 1
The 7-position oxo group is not reduced.

The resulting 3-hydroxy group, i.e., in the following formula, the bonding method of R and It can be changed into a compound that is a group.

Acylation can be performed, for example, on a compound of formula (IV) above with formula RI
Reactive derivatives of carboxylic acids (for example, acid anhydrides,
(acid halide, etc.).

The reaction is generally carried out using a base such as pyridine, diisopropylethylamine, triethylamine, etc., or an inert solvent such as chloroform, methylene chloride,
This can be carried out in dioxane or the like in the presence of a base as described above. The reaction temperature is generally 0° C. to the reflux temperature of the reaction mixture, preferably room temperature to the reflux temperature of the reaction mixture. In addition, the amount of the reactive derivative of carboxylic acid to be used for the compound of formula (IV) is generally
1.1 reactive derivatives of carboxylic acids per mole of compound of
It is appropriate to use it in a proportion of 10 to 10 moles.

In addition, in this acylation reaction, if acylation is carried out normally using a compound in which the group X at the 17-position of the compound of formula (IV) represents a β-hydroxy group, the acylation at the 3-position and the 17- If the group X (β-hydroxy group) at position 17β-acyloxy is also acylated and the acylation reaction is carried out mildly, it is also possible to selectively acylate only the hydroxy group at position 3.

Thus, a compound is obtained in which the form of bonding of R, According to
It can be changed to the desired compound of formula (I-a).

This reduction reaction is generally carried out using a metal hydride such as sodium borohydride-nickel chloride in an inert solvent such as diethylene glycol dimethyl ether or triethylene glycol dimethyl ether at a reaction temperature of 0°C to 50°C, preferably around room temperature. It can be carried out.

The amount of complex metal hydrochloride used for the compound of formula (V) is:
Usually 5 to 50% of the fine metal hydride per mole of the compound of formula (V)
Advantageously, a proportion of 100 mol is used.

In this way, the desired compound of formula (I-a) is produced.

According to the above method (a-2), first, the compound of the formula (II) and the alkanedithiol of the formula R3-A-3H (VT), where A represents a C2-4 alkylene group, are reacted. It will be done.

The reaction between the compound of formula (II) and the alkanedithiol of formula (Vl) can be carried out in the presence of a condensing agent such as p-)luenesulfonic acid or boron trifluoride in a solvent such as acetic acid, benzene, or dioxa7. can be carried out by reacting a compound of formula (II) with an alkali/dithiol of formula (Vl) at a reaction temperature of about θ<0>C to about 100<0>C.

The amount of the alkanedithiol of formula (Vl) to be used in the compound of formula (II) is usually about 1 to 1.2 mol per 1 mol of the compound of formula (II), and the amount of the condensing agent to be used is It may be about 0.05 to 0.5 mol.

The obtained 3-thioketal compound, i.e., the compound of the following formula, in which the bonding method of Rl −
It can be changed to the compound of a).

Reduction can be carried out, for example, by treatment with liquid ammonia and an alkali metal such as lithium, sodium, potassium, etc. in a solvent such as tetrahydrofuran, ethanol, dioxane, or
Alternatively, it can be carried out by treatment with Raney nickel in the same solvent as above. The reaction temperature is around -78° C. when liquid ammonia and alkali metal scrap are used, and the reflux temperature of the reaction mixture is advantageous when Raney nickel is used.

In addition, in this reduction reaction, if the reduction is carried out using a compound of formula (■) in which the group X at the 17-position represents an oxo group, the oxo group at the 17-position is also partially reduced. I
-a), that is, a compound of formula (1-a) where the group X at the 17-position is an oxo group and a compound where the group X at the 17-position is a β-hydroxy group are produced, but they can be separated by column chromatography. It can be separated and purified by chromatography, thin layer chromatography, etc.

If a compound of formula (■) in which R represents a halogen atom is reduced with liquid ammonia and an alkali metal, a compound of formula (1-a) in which R is replaced with a hydrogen atom can be obtained.

According to the method (b) of the present invention, the double bonds at the 4- and 5-positions of the compound of formula (■a) are reduced.

The reaction can generally be carried out by hydrogenation in an inert solvent such as methanol, ethanol, or ethyl acetate using palladium-carbon, platinum oxide, or the like as a catalyst. As for the reaction conditions, a total room temperature and normal pressure are sufficient, but heating and pressurization may also be used.

As a result, a compound in which the 4- and 5-positions are saturated, that is, the compound of formula (I-b), which is the object of the present invention, is obtained.

According to the method (C) of the present invention, a group =C(R)2 is added to the double bonds at the 6- and 7-positions of the compound of formula (III).

In the addition reaction, when R represents a hydrogen atom, the compound of formula (m) is reacted with methylene iodide, or when R represents a halogen atom, the compound of formula (III) is reacted with the compound of formula: C(R )2 (wherein R has the above-mentioned meaning).

The reaction with methylene iodide is generally performed with diethyl ether,
This can be carried out in an inert solvent such as 1,2-dimethoxyethane in the presence of a zinc-copper couple or the like. The reaction temperature is usually room temperature to the reflux temperature of the reaction mixture, and the appropriate amount of methylene iodide to be used is 1 to 20 moles per mole of the compound of formula (III).

The reaction with halocarbe is generally carried out using a halocarbene-forming reagent such as sodium chlorodifluoroacetate, sodium trichloroacetate, or phenyltribromomethylmercury in an inert solvent such as diethylene glycol dimethyl ether, triethylene/glycol methyl ether, or benzene. This can be done by The reaction temperature is generally determined by the reflux temperature of the reaction mixture, and the amount of the halocarbene-forming reagent used is generally 5 to 5 per mole of the compound of formula (III).
It is appropriate to use 100 moles.

Thus, a compound in which a group C(R)2 is added to the double bond at the 6- and 7-positions, i.e., a compound having the above formula (
Compound 1-c) is obtained.

The compound of the formula (1) of the present invention obtained by the above method may further be prepared by hydrolyzing the compound of formula (I) in which X is a β-7 fluoroxy group. -By changing the compound of formula (I) when it represents a hydroxy group, and the compound of formula (I) when X is a β-hydroxy group, by acylating or oxidizing it, X can be a β-acyloxy group or an oxo group. can be changed to a compound of formula (I) where

Hydrolysis of the compound of formula (I) when X is a β-acyloxy group can be carried out, for example, by treatment with an alkali such as sodium hydroxide, potassium hydroxide, sodium methoxide, etc. in an inert solvent such as methanol, ethanol, tetrahydrofuran, etc. This can be done on the container by doing this.

Acylation of the compound of formula (1) when X is a β-hydroxy group can be carried out in the same manner as described for the acylation of formula (IV) above, and the oxidation is carried out using the hydroxy group of the steroid compound. The oxidation can be carried out using methods known per se, such as Jones reagent, Moffat reagent, Saleft reagent, etc.

The compound of formula (1) of the present invention thus produced can be isolated and purified from the reaction mixture by methods such as recrystallization, distillation, column chromatography, and thin layer chromatography.

6,7- represented by the formula (1) of the present invention explained above
Methylene steroid derivatives have excellent aromatase inhibitory effects and are used to treat medical diseases caused by excess estrogen, such as breast cancer, uterine cancer, ovarian cancer, male gynecomastia, benign prostatic hyperplasia, and oligospermia. It is useful in the treatment of male infertility.

The aromatase inhibitory effect of the compound of formula (I) of the present invention is as follows.

(1) Measurement of aromatase inhibitory effect Ryan's method (The Journal on
Biological Chemistry, Volume 234, 268-2
Human placental microsomes (centrifuged at 105,000 x g for 60 min) were prepared according to the method of Biochem. The microsomes used were washed twice with 0.5mM dithiothreitol solution, lyophilized, and stored at -20°C.

Aromatase inhibition! The action is described by Thompson and Geatley (
(The Journal of Biological e-Chemistry, Vol. 249, pp. 5373-5378, 1)
974). That is, the method is
The objective is to quantify 3H20 released by aromatization of (1,23H)androstenedione.

Experiments using enzymes were carried out in 67 mM phosphate buffer at pH 7.5, with a final incubation volume of 0.5 ml. Incubation solution is 180 μM
of NADPH, 2 μM (1,2-38) androstenedione, 150 ttg of lyophilized human placental microsomes, 25 drops of methanol, and various concentrations of the test compound. Incubation in air, 37
℃ for 20 minutes and 3 ml of chloroform! After finishing the reaction, stir for 40 seconds. Then, 700
Centrifuge for 10 minutes at
The production amount of 20 samples was measured.

The results are shown in the table below.

Table Compound By tC (μM) Example 2S Example 3 0.45 Example 7 1.0 Example 10 0.6 Thus, the compound represented by formula (I) of the present invention can be used as an estrogen biosynthesis inhibitor. It can be administered orally or parenterally (for example, intramuscularly, intravenously, rectally, transdermally, etc.) for treatment and treatment of humans and other mammals.

When the compound according to the present invention is used as a drug, it can be prepared in accordance with conventional methods using non-toxic excipients commonly used in pharmaceutical preparations such as
It can be manufactured using binders, lubricants, disintegrants, preservatives, tonicity agents, stabilizers, buffers, etc. The dosage of the compound according to the present invention can vary widely depending on the type of human or other mammal to be administered, the route of administration, the severity of the symptoms, the doctor's diagnosis, etc., but in general, the dosage is 0.000 mg/day.
1-100■/kg, 1-50mg/kg for good shielding
It can be done.

The present invention will be further explained below with reference to Production Examples and Examples.

Example 1 6α,7a-methylene-4-androstene-3β,1
7β-diol diacetate 267w5 diethylene glycol dimethyl ether I1m and nickel chloride 1.
1.0 g of sodium borohydride was added to 7 g of the mixture, and the mixture was stirred at room temperature for 20 minutes. Add water to the reaction mixture,
The product was extracted with dichloromethane. The extract was washed with water and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by TLC (developing solvent: benzene:hexane (1:10)) to obtain 6a,7α-methylene-4=androsten-17β-ol acetate.

'H-NMR (CDC1a, δ): 0.84 (3
H,s), 0.97 (3H,s), 2.03 (3H
, s), 4.62 (IH, m), 5.49 (IH, m
).

MS (m/z): 328 (M”), 313.2
53゜Example 2 6α, 7(Z-methylene-4-androstene-17β
-all acetate 3, methanol ld and 10%
A mixture of 0.2 parts of an aqueous sodium hydroxide solution was left at room temperature overnight. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and 6α,7α-methylene-
4-Androsten-17β-ol was obtained.

Melting point: 157-158℃ (Benzene/) Electron H-NMR
(CD(Jl 3. δ): 0.80 (
3H,s), 0.98 (3H,s), 3.
65 (11-1, m), 5.48 (IH, m) aM
S (m/z): 286 (M”), 271.25
3゜Example 3 6α,7α-methylene-4-androstene-17β-
0.01 ml of Joe's reagent was added dropwise to a mixture of 10 ml of All and 1 ml of acetone under water cooling, and the mixture was stirred for 5 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous Fium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained crude product was purified by TLC (developing solvent, chloroform: hexa/(4:1)) to give 6al 7α-methylene/
4-androsten-17-one 6■ was obtained.

Melting point: 135.5-136℃ (acetone)'H-N
MR (CDCf3.δ): 0.93 (3H,s)
, 1.00 (3H, s), 5.52 (IH, m) MS (m/z): 284 (M"), 269° Example 4 6αl 7α-methylene/-4-androstene-17β
-ol 31 A mixture of 0.5-11% benzoyl chloride and 1 ml of pyridine was stirred at room temperature for 1 hour.

Water was added to the reaction mixture, and after stirring day and night, the product was extracted with ethyl acetate. The extract was washed successively with 5% sulfuric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the resulting crude product was subjected to TLC (developing solvent,
Purified with chloroform:hegyusan (1:3)), 6a,
7α-methylene-4-androsten-17β-ol benzoate was obtained.

'H-NMR (CDCf3.δ): 0.99 (6
H, s), 4.85 (IH, m), 5.50 (IH,
m), 7.26-8.13 (5H, m).

MS (m/z): 390 (M"), 105° Example 5 6βl 7β-methylene/-4-androste/-3β,
17β-diol diacetate 21O■ was treated in the same manner as in Example 1 to obtain 6β,7β-methylene-4-anodrosten-17β-ol acetate 102■.

'H-NMR (CDCj3.δ): 0.81 (3
H, s), 0.90 (3H, s), 2.04 (3H,
s), 4.63 (IH, m), 5.54 (IH, t,
J-4Hz).

MS (m/z): 328 (M+), 313.253
゜Example 6 6β,7β-methylene-4-androste/-17β-
All acetate 45- was treated in the same manner as in Example 2 to give 6β,7β-methyleno-4-a/troste/-17β.
- Obtained all 36 fish.

'H-NMR (CDCj) 3.6): 0.76 (
3H, s), 0.91 (3H, s), 3.68 (I
H, m), 5.54 (IH, t, J=4Hz).

MS (m/z): 286 (M”), 27
1.253゜Example 7 6β,7β-methylene-4-androstene 17β-ol 30 pieces were treated in the same manner as in Example 3 to give 6β,7β.
-Methylene-4-androsten-17-one 16■
I got it.

Melting point: 110-113°C (hex/)') (-NMR
(CDCj)3. δ): 0.89 (3H, s),
0.92 (3H, s), 5.55 (IH, t, J
=4Hz).

MS (m/z): 284 (M”), 213
9° Example 8 6a,7α-difluoromethylene-4-androstene-3β,17β-diol 80 mg of diacetate-1B was treated in the same manner as in Example 1 to obtain 6α.

7a-difluoromethylene-4-androstene-17
β-ol acetate 444 was obtained.

IH-NMR (CDCf3.δ): 0.82 (3
H,s), 0.94 (3H,s), 2.03 (3H
, s), 4.61 (!H, m) < 5.59 (IH
, m).

MS (m/z): 384 (M+), 304.
289゜Example 9 6α,7α-difluoromethylene-4-a/troste/
-17β-olacetate) JOOsg was treated in the same manner as in Example 2 to obtain 6α,7α-difluoromethylene/-4
-androsten-17β-ol 88 µm were obtained.

'H-NMR (CDCIa, δ): 0.78 (3
H,s), 0.95 (3H,s), 3.68 (IH
, m), 5.60 (IH, m).

MS (m/z): 322 (M”), 307.
2896 Example 10 75 g of 6α,7α-difluoromethylene-4-androsten-17β-ol was treated in the same manner as in Example 3 to obtain 6α,7a-difluoromethylene-4-a/drosten-17-one 68. I got g.

Melting point: 140-142°C (hexane)'H-NMR (
CDCIa, δ): 0.90 (3H, s), 0.
97 (3H, s), 5.62 (IH, m).

MS (m/z): 320 (M”), 3
05° Example 11 A mixture of 6αl 7α-difluoromethylene-4-androsten-17β-olacetate) 137m, palladium-carbon 70μ and ethanol IOmH was stirred for 6 hours under a hydrogen stream. The reaction mixture was filtered and the residue was washed with chloroporm. The filtrate was distilled off to obtain 6α,7α-difluoromethylene-5β-ando-stan-17β-ol acetate +24-.

'H-NMR (CDCf3.δ): 0.80 (3
H,s), 0.89 (3H,s), 2.03 (3H
, s), 4.63 (IH, m).

MS (m/z): 36B (M+), 351.3
06.291゜Example 2 6a,7α-difluoromethylene-5β-antrostane-17β-ol 116 g of acetate was treated in the same manner as in Example 2 to obtain 6a,7α-difluoromethylene-5
β-Anthrostane-17βol 102g was obtained.

H-NMR (CDCJa, δ): 0.76 (3H
, -s), 0.90 (3H,s), 3.68 (IH
, m).

MS (m/z): 324 (M+), 309.2
91゜Example 13 6α,7a-difluoromethylene-5β-antrostan-17β-ol 38m wo'A Treated in the same manner as in Example 3 to obtain 6a,7α-difluoromethylene-5β-antrostan-17-ol/ I got 35■.

'H-NMR (CDCj3.δ): 0.88 (3
H,s), 0.02 (3H,s),.

MS (m/z): 322 (M+), 307° Example 14 A mixture of 5α-a/drostar 6-e/-17β-ol benzoate 128■ and diethyl ether was refluxed, and 0.4 methylene iodide was added thereto. 464 g of zinc-boiled turnip was added over a period of 2 hours. The reaction mixture was filtered, and the residue was washed with diethyl ether. The filtrate was washed with water and dried over anhydrous magnesium sulfate. 1B#x was distilled off, and the obtained crude product was purified with MIIIL, Ba, 7a using TLCC developing solvent, chloroform:hex/(1:3)).
-) Tyrenor 5α-antrostan-17β-ol
98% of benzoate was obtained.

'H-NMR (CDCIs, 6): 0.82 (3
H,s), 0.98 (3H,s), 4.88 (IH
, m), 7.30-8.13 (5H, m).

MS (m/z): 392 (M”), 270.
255.105゜Example! 5 6α,7α-methylene-5α-antrostane-17β
A mixture of 85 μm of -olbenzoate and 30 μm of 109A potassium hydroxide methanol solution was left overnight at room temperature.

Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crude product was purified by TLC (developing solvent, chloroform) to obtain 70 g of 6α,7a-methylene-5a-antrostan-17β-ol.

'H-NMR (CD (J'3.6): 0.79 (
6H,s), 3.66 (IH,m>.

MS (m/z): 288 (M”), 273.
255゜Example 16 6α,7α-methylene/-5a-a/drostane-17β
-all 18m, pyridine 1- and anhydrous vinegar @ 0.5
ml! The mixture was left at room temperature overnight. A small amount of water was added to the reaction mixture and stirred. The product was extracted with ethyl acetate,
The extract was washed successively with 5% sulfuric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and 6α,7α-methylene-5
α-Anthrostan-17β-ol acetate 1
8. I got g.

Buy H-NMR (CDCf3. δ): 0.
79 (3H, s), 0.83 (3H,
s), 2.03 (3H, s), 4.62 (IH, m
).

MS (m/z): 330 (M”), 315.2
70.255゜Example 17 6a,7α-methylene-5α-antrostane-17β
-all 35- was treated in the same manner as in Example 3, and 6α,
7α-methylene-5α-antrostan-17-one
I got 30-.

'H-NMR (CDC1a, δ): 0.82 (3
H,s), 0.92 (3H,s)e MS (m/z): 286 (M”), 27f.

Example 18 5α-androst-6-en-1 β-ol (benzony) 323. to) ! J ethylene glycol dimethyl ether 6m [! The mixture was refluxed, and a mixture of 3.8 g of sodium chlorodifluoroacetate and triethylene glycol dimethyl ether (9 components) was soaked therein over 20 minutes, and the mixture was further refluxed for 40 minutes. The reaction mixture was filtered and the residue was washed with triethylene/glycol dimethyl ether. The filtrate was evaporated and the product was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crude product was
C (WIJI solution [, chloroform:hexane (1:3)
) and purified with 6α,7α-difluoromethylene-5α-
Androsta 7-17β-ol benzoate 22
I got 9■.

'H-NMR (CDCIs, δ): 0.7Fj (3
H,s), 0.95 (3H,s), 4.87 (IH
, m), 7.27-8.15 (5H, m).

MS (m/z): 428 (M”), 413.
408.306.1o56 Example 19 6a,7α-difluoromethylene/=5α-a/drostane-17β-ol benzoate 220-, 25 ml of methanol and 10% 10% potassium hydroxide methanol solution
The mQ mixture was left at room temperature overnight.

Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.

The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and 6α,7α-difluoro[]methyleneno-
140 units of 5a-a/drostane-17β-ol were obtained.

'H-NMR<CDCl3.6): 0.76 (6
N, s), 3.67 (IH, m) a MS (m/z): 324 (M”), 309.
291° Example 20 6αl 7α-difluoromethylene/-5α-antrostan-17β-ol 30. g was treated in the same manner as in Example 16 to obtain 6α,7α-difluoromethane/-5a-a/drostane-! 32 ml of 7β-ol acetate was obtained.

'H-NMR (CDCIs, δ): 0.77 (3
H, s), 0.81 (3H, s), 2.03 (3H,
s), 4.63 (IH, m).

MS (m/z): 366 (M”), 351.3
06.291゜Example 21 6α,7α-difluoromethylene-5α-antrostan-17β-ol 50 μl was treated in the same manner as in Example 3 to obtain 6α,7α-difluoromethylene/-5α-androsta/- 49 pieces of 17-ono were obtained.

Melting point: 162-166°C (hexano)'H-NMR (
CDCf3. δ): 0.80 (3H, s), 0.
89 (3H, s).

MS (m/z): 322 (M"), 307° Example 22 6α,7a-difluoromethylene-3,3 ethylenedithio-4-androsten-17-one 415 ml was dissolved in dry tetrahydrofuran, metallic sodium 810
mg liquid ammonia solution 60ml! and stirred for 30 minutes. After removing most of the ammonia by stirring, a saturated ammonium chloride solution was added, followed by 5% hydrochloric acid to make the mixture acidic, and the mixture was extracted with ethyl acetate. 5% organic layer
It was washed with an aqueous sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography (solvent: hexane/ethyl acetate) and recrystallization to give 6α,7α-methyl/-4-androste/-17one 69. and 6
α,7α-methylene-4-androste/-17β-ol 42K was obtained.

Production Example 1 17β-acetoxy-6α,7α-methylene 4-androsten-3-one 200■ and cerium chloride 24+)
g was dissolved in 1.7 ml of methanol, 30 ml of sodium borohydride was added, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 6α,7α-methylene/-4-androstene-3β.

17β-diol 17β-acetate 183 was obtained.

'H-NMR (CDCfa, δ): 0.84 (3
H,s), 1.02. (3H,s), 2.03 (3H
,s), 4.16 (IH,m), 4.62(1](,
m), 5.49 (IH, broids).

MS (m/z): 344 (M+), 326° Production Example 2 6a, 7α-methylene-4-a/troste/3β, 17
β-diol 17β-acetate 54Il1g1 A mixture of viridi/2ml and anhydrous acid *i- was left overnight at room temperature, and a small amount of water was added to the zero repulsion mixture and stirred. The product was extracted with ethyl acetate, and the extract was washed successively with 5% sulfuric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. Distill the solvent, 6
a, 7α methyl/-4-androstene-3β, 17β
Diol diacetate 60μ was obtained.

H-NMR (CDCl2.6): 0.84 (3H
,s), 1.03 (3H,s), 2.03 (3H,
s), 2.05 (3H, s), 4.61 (IH, m)
, 5.25 (IH, m), 5.42 (IH, bro
ad s).

MS (m/z): 386 (M”), 344.
326゜Production Example 3 200 units of 17β-acetoxy-6β,7β-methylene 4-androsten-3-one were treated in the same manner as in Production Example 1 to produce 6β,7β-methylea-4-androsten-3β,
17β-diol 7β-acetate 192 volumes were obtained.

H-NMR (CDCf3.δ): 0.80 (3H
,s), 0.96 (3H,s), 2.04 (3H,
s), 4.16 (IH, m), 4.63 (IH, m)
, 5.54 (IH, broad s).

MS (m/z): 344 (M+), 329
．． 326゜Production Example 4 6β,7β-methylene/-4-a/drosten = 3β,1
7β-diol 17β-acetate 192 K was treated in the same manner as in Production Example 2 to obtain 6β,7β methylene-4-androstene-3β,17β diol diacetate 2
I got 11■.

'H-NMR (CDCl2.δ): 0.80 (3
H,s), 0.97 (3H,s), 2.04 (3H
, s), 2.05 (3H, s), 4.62 (IH, m
), 5.27 (IH, m), 5.4Ei (IH, b
road s).

MS (m/z): 386 (M”), 344.
326゜Production Example 5 17β-acetoxy-6a,7α-difluoro7tylene-4-androsten-3-ono+37ylene was treated in the same manner as in Production Example 1 to produce 6α,7α-difluoromethylene-4
-Androsteno 3β.

127 mg of 17β-diol 17β-acetate was obtained.

'H-NMR(CDCj)a, δ): 0.82
(3H,s), 0.99 (3H,s), 2.03 (
3H, s), 4.25 (IH, m), 4.63 (IH
, m), 5.60 (IH, broad s).

MS (m/z): 380 (M”), 362° Production Example 6 6α,7α-difluoromethylene-4-androste/
-3β, 17β-diol 17β-acetate 63
0■ was treated in the same manner as in Production Example 2 to obtain 669IIg of 6α,7α-difluoromethylene-4-androstene-3β,17β-diol diacetate.

'H-NMR (CDCfh, δ): 0.82 (3
H, s), 1.01 (3H, s), 2.03 (3H,
s), 2.05 (3H, s), 4.63 (IH, m)
, 5.29 (IH, m), 5.54 (IH, bro
ad s).

MS (m/z): 422 (M”), 380.3
62.320° Production Example 7 4.6-Androstadiene-3,17-dione 2.
Reflux a mixture of 35 g of diethylene glycol dimethyl ether and 40 g of diethylene glycol dimethyl ether, and add 31 g of sodium chlorodifluoroacetate and 55 g of diethylene glycol dimethyl ether.
Add the liquid mixture dropwise for 20 minutes under light protection, and then add the mixture for another 5 minutes.
Refluxed for an hour. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained crude product was purified by silica gel column chromatography (solvent: hexane/ethyl acetate) and recrystallization (solvent: methanol) to obtain 6a.

7α-difluoromethylene-4-androstene-3,
1.57 g of 17-dione was obtained.

Melting point: 192.5-193.5°C Direct H-NMR (CDCJa, δ): 0.
94 (3H, s), 1.16 (3H, g)
, 5.99 (IH,s).

MS (m/z): 334 (M+).

Production Example 8 f3a,7a-difluoromethylene-4-a/do ClX
7:/-3,17-city 500++ gwo vinegar fi9r
A 10.5 mC solution of ethanedithiol 145+@ and p-)luenesulfonic acid 140- in acetic acid was added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 200ml of water and extracted with ethyl acetate. The organic layer was washed with 5LA aqueous sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography (solvent: hexa7/ethyl acetate) and recrystallization (solvent: acetate//water).
1 7α-Difluoromethylene-3,3-ethylenedithio-4-androsten-17-one 472 ■ was obtained.

Melting point: 164-165°C 'H-NMR (CDCj3.δ): 0.90 (3
H, s), 1.00 (3H, s), 3.33 (4H,
broad s), 5.83 (IH, s).

Claims (1)

[Claims] 1. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R represents a hydrogen atom or a halogen atom; , chemical formula, table, etc. ▼, where R^1 is a C_2_-_4 alkanoyl group or a halogen atom, a C_1_-_4 alkyl group or a C_
1_-_4 Represents a benzoyl group optionally substituted with an alkoxy group; broken lines at the 4- and 5-positions of the steroid skeleton represent the presence of a double bond there, or the 4- and 5-positions It is saturated and the hydrogen atom at the 5-position is bonded to the α- or β-position; the group =C(R)_2 substituted at the 6- and 7-positions of the steroid skeleton is 6α -, 7α- or 6β-
, 7β-. 2. The steroid derivative according to claim 1, wherein X represents an oxo group. 3. The steroid derivative according to claim 1, wherein double bonds are present at the 4- and 5-positions of the steroid skeleton.