JPH01199993A - Novel 2-oxapregnane compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (X is OH group or oxo group bonding to 11 site, 15 site or 16 site of steroid skeleton). EXAMPLE:17alpha-Acetoxy-6-chloro-11beta-hydroxy-2-oxa-4,6-pregnadiene- 3,20-dione. USE:An agent for preventing and treating androgen-dependent disease such as prostatic hyperplasia, prostatic carcinoma, apopecia, etc. and having excellent antiandrogenic hormone activity. PREPARATION:A compound expressed by formula II (-OR1 is bonded to 11 site, 15 site or 16 site of steroid skeleton; R1 is lower alkanoyl) is hydrolyzed by hydrochloric acid, etc., in THF to afford the compound expressed by formula I (X is OH). The resultant compound expressed by formula I is oxidized by further treating the compound, e.g., by Jones reagent consisting of a mixture of chromic acid, sulfuric acid and water to provide the compound expressed by formula I (X is oxo group).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 2-oxapregnan compound, and more specifically, in the general formula, X is 1! of a steroid skeleton. It refers to a compound represented by the following, which represents a hydroxyl group or an oxo group bonded to the 15th or 16th position.

The present inventors have discovered that a novel 17α-alkanoyloxy-6-balogue/-2-oxa-4゜6-pregnagene-3,20-dione compound has excellent anti-drag properties.
We discovered that the activation of UiT and proposed it earlier (Special Ui+
(Refer to Publication No. 204108).

In the present invention, it has now been discovered that the novel 2-oxapregnan compound represented by the formula (1) has even more excellent anti-androgen activity.

Therefore, the compound of formula (I) of the present invention is useful for treating androdef-dependent diseases such as benign prostatic hyperplasia, prostate cancer, alopecia,
It is expected to be used as a drug in the prevention, treatment, and treatment of Zafu, M[In, etc.

In the formula ([), only one hydroxyl 7J or oxo group represented by X is bonded to any of the 11th, 15th, or 16th positions of the steroid skeleton, and when X represents a hydroxyl group, The hydroxyl group can be at the α-position, among others,
Preferably, X is bonded to the 15-position of the steroid skeleton, and compounds of formula (I) in which X is a hydroxyl group at the β-position bonded to the 15-position are particularly preferred.

According to the present invention, 1 the compound of formula (I) in which X represents a hydroxyl group, i.e., in the formula, the hydroxyl group is the 11th position, the 15th position, or the 1st position of the steroid skeleton;
Hydrolyzing the compound of the formula, in which OR+ is bonded to the 11th, 15th or 16th position of the steroid skeleton, and R+ represents a lower alkanoyl group, is bonded to the 6th position. It can be manufactured by

Hydrolysis of the compound of formula (■) is usually carried out using an acid or alkali such as potassium carbonate, etc. in a 6-medium such as an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran or dioxane; dimethylformamide or a mixture thereof; This can be carried out using sodium carbonate, sodium hydrogen carbonate, hydrochloric acid, or the like. The reaction temperature is generally 0~
50°C, preferably around room temperature, and the amount of acid or alkali used is small per mole of the compound of formula (■).
It is advantageous to use both in a proportion of 1 mol, preferably 1.1 to 1.5 mol.

In this way, the compound of the present invention in which X represents a hydroxyl group in the above formula (1), that is, the compound of the above formula (I-a), is obtained, and this compound is further subjected to an oxidation reaction to form the Ij'l notation. (1) can be changed to a compound of the present invention in which X represents an oxo group.

Oxidation of the compound of formula (1-a) can be carried out, for example, in acetate 7.
Jones (J) consisting of a mixture of chromic acid, sulfuric acid and water.
This can be done by treatment with a reagent (ones). The reaction can generally be carried out at 0°C to room temperature, preferably under water cooling, and the amount of Jones reagent used is determined according to the formula (1-a
) is usually preferably about 1.5 to 2 mol per mol of the compound.

In this way, the compound of the present invention in which X represents an oxo group in the above formula (I) can be obtained.

In addition, the lower alkanoyl group represented by R+ in the compound of formula (■) may include a furukayl group having 2 to 4 carbon atoms, and an acetyl group is particularly preferred.

Further, the compound of formula (I-a) can also be produced by reducing the compound of formula (1) in which X represents an oxo group.

Reduction can be carried out by treating the compound of formula (I) when X represents an oxo group with a metal hydride, for example by reacting with hydrogenated Lcrt-ptoxyaluminoridium in tetrahydrofuran; Alternatively, it can be carried out by reacting sodium borohydride in methanol. The reaction temperature is generally about 0°C to room temperature.

The compound of the formula thus formed can be isolated and purified by a method for its formation, such as filtration, extraction, chromatography, recrystallization, etc.

Formula (II) used as starting material in the reaction
The compound is a new compound that has not been described in conventional literature, and
Depending on the bonding position, the following reaction formula A (when X is bonded to the 11th position of the steroid skeleton), reaction formula +1 (when X is bonded to the 15th position of the steroid skeleton), or reaction formula C
(When X is a steroid bone (attached to the 16th position of δ))
It can be manufactured according to the method described in any of the above.

Reaction formula A Pot number I13 ↓ Oa ■ In each of the above formulas, 1 and 2 are 11-organic acid residues, such as meta/sul: 1-nyl M,! '-Toluensur51. Nyl-containing (, represents a γ-cetyl group, etc., Ac represents γ-cetyl JJ, and!
C has the meaning of +111.

Reaction formula ■3 ■ pot ■ Rei II3 C113 ■ ↓ II3 ■ Rei In each of the above formulas, r2+ and Ac represent the above-mentioned taste.

Reaction 2 〇II3 In each of the above formulas, RI and Ac create the purity of 111f.

For details of the reaction conditions in Reaction Formula A1, Reaction Formula 11, and Reaction Formula C above, please refer to the Examples below.

As mentioned above, the 2-"xapredanane compound of formula (1) provided by the present invention has excellent anti-androgen activity and is useful for treating benign prostatic hyperplasia; +iif for treating prostate cancer; for young people. It is used as a therapeutic agent for t't, middle age, senile, circular, greasy and pityriasis alopecia; hair restoration; a therapeutic agent for vulgaris alopecia; etc.

The excellent anti-androgen activity of the compounds of formula (I) of the present invention is demonstrated by the experiments shown in section 1.

Measurement of refractory hormones/effects Male Wistar juvenile rafts are castrated and divided into groups of 5 animals. Of these, - group is untreated, and the other group is testosterone propionate (male hormone) 0.05
■/1 day was administered subcutaneously, and another group was administered the test compound orally, and testosterone propionate o
, 05g/day administered subcutaneously. After one week 11a, the prostate was dissected, the prostate was taken out, its weight was measured, and the inhibition rate was calculated from the following formula.

a - Nicode, a: Prostate weight of testosterone propionate a7 alone administration group (4), b: Testosterone propionate + test compound administration E
T: Prostate weight (1), C: Prostate weight r1 (g) of untreated group.

The results are shown in the table below. The anti-androgen effect was expressed as the specific activity when chlormadino-7 acetate (CMA), which is widely used as an anti-androgen agent, was taken as 1.

Thus, the compound represented by formula (1) of the present invention can be administered orally, parenterally (for example, intramuscularly, intravenously, subcutaneously) as an antiandrogenic agent for the treatment and treatment of humans and other two-sided animals. administration, rectal administration, etc.) or topically.

When the compound of the present invention is used as a drug, it can be administered orally,
They can be formulated in a variety of forms suitable for parenteral or topical administration. For example, the compounds of the invention may be added to the non-toxic excipients, binders, lubricants, and
It can be formulated using additives such as disintegrants, preservatives, tonicity agents, stabilizers, dispersants, antioxidants, colorants, flavoring agents, and buffering agents.

Depending on the use, such drugs may be in solid form (for example, tablets, hard capsules, soft capsules, granules, powders, fine granules, gunpowder, troches, etc.), semi-solid forms, etc. ! The preparations can be prepared either in the form of liquids (eg, skewers, ointments, etc.) and liquid forms (injections, emulsions, suspensions, lotions, sprays, etc.). Therefore, the above-mentioned non-toxic additives that can be used include, for example, starch, gelatin, glucose, lactose, fructose, maltose, charcoal magnesium,
Talc, magnesium stearate/acid, methylcellulose, carboxymethylcellulose or its salts, gum arabic, polyethylene glycol, p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol, petrolatum, carbowax, glycerin, sodium chloride, sodium sulfite, phosphorus. acid sodium,
Examples include citric acid. The medicament may also include other patches of therapeutic use.

The content of 4-Ll of the compounds of the invention in M-drugs varies depending on the dosage form, but is generally between 1 and 100% by weight for solid and semi-solid forms and at 0 degrees for liquid forms. It is desirable to contain the active compound in a concentration of 0.1 to 0.0% by weight.

The dosage of the compound of the present invention can vary widely depending on the type of target mixed-breed animal including humans, the route of administration, the severity of the symptoms, the doctor's diagnosis, etc., but in general, the dosage is 0.02 per day. ~2@/kg can be obtained. However, as mentioned above, depending on the severity of the patient's symptoms and the doctor's diagnosis, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range. The above dosage can be administered once a day or in divided doses.

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

Example 1 (a) IIβ, I? a-Diacet beef sea 1,4. O
- Pregnatrief-3,20-dione O, 68 g and m-chloroperbenzoic acid 1.08 g in chloroform 3.4 g
The mixture was stirred at room temperature for 9 hours. The product was extracted with ethyl acetate, and the extract was washed with a 10% aqueous sodium hydroxide solution and then with a 4% aqueous sodium hydroxide eR solution. After washing the growing layer with saturated sodium chloride aqueous solution,
It was dried with anhydrous magnesium sulfate. After distilling off the solvent, 1
1β, 17α-diacetoxy-6α.

7α-epoxy-1,4-pregnagene-3゜20-
0.58 g of dione was obtained.

') I-NMR (CDCl2.δ): 0.84 (3
11,s), 1.33(311,s), 2.02(
3H,s), 2.08 (3H,s), 2.10 (3
11°S), 3.51 (IH, m), 3.73
(IH, d, J=3.5Hz), 5.44(
IH, dd, J=3Hz, 6Hz), 6.28 (
111, dd, J=211Z, 10Hz), 6.4
6 (ill, d, J=1.5112), 8.77
(IILd, J = 1011z) (b) 6.3 g of the epoxide compound obtained in step (a) above
Piriji: / 32m1! The mixture was dissolved in water and ozone was bubbled through it for 150 minutes at -20°C. The reaction mixture was stirred at room temperature for 10 minutes, then three portions of 10% aqueous sodium bisulfite were added and stirred at room temperature for 11117 hours. The product was extracted with ethyl acetate, washed with 10% aqueous sulfuric acid TtI solution, then saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 11β, 17α-diacetoxy-6α,
7α-epoxy-1ξ-hydroxy-2-oxa-4-
Pregnene-3,20-dit: 15.0 g was obtained.

'II-NMR (CDC113, δ): 0.82 (
3)1. s), 1.2f3 (3+1.s), 2
．． 02 (311,s), 2.06 (3H,s>
, 2.11 (3H.

s), 3.49 (IH, d, J"4Hz), 3
．． 59 (IN, d, J=4112), 5.3/l
(1 summer (, s), 5.51 (111, m), 6.18 (
IH, 5) (C) 5.0 g of the lactol compound obtained in step (b) above.

Sodium hydroxide 0.45g, sodium acetate 2.5g
.

1 liter of water; 0.30 g of sodium boronate, 0.0 g of phenol.
84g 1 tetrahydrofuran 25m, methanol 20m
1! and 10.6 - of water was stirred in chamber 4 for 30 minutes. Add 15 g of ice and a hydrochloric acid + 8 mQ to the reaction mixture,
Stirred at room temperature for 25 minutes. Add 500 ml of water to the reaction mixture and filter the formed crystals to obtain 6β-chlororl-I.
Iβ.

3.8 g of 17α-diace)oxy-7α-hydroxy-2-oxa-4-pregnene-3,20-dione was obtained.

'II-NMR (CD(,j'3.6): 0.84
(311, s), 1.40 (3-TI, s), 2.0
3 (311,s), 2.05 (3H,s), 2.
11 (311°s), 4.08 (III, bro
ad s), 4.14 and 4.26 (211, A[I
Q.

J=10.5Hz), 4.48 (IH, d, J=3H
z), 5.33 (IH.

m), 5.96 (III, 5) (d) Chlorhydrin compound obtained in step (C) above 3.
8 g was dissolved in 11 tubes of pyridine, 2.5 g of methanesulfonyl chloride was added dropwise at 0° C., and the mixture was stirred in a room for 20 hours. 3% hydrochloric acid was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, then a saturated aqueous sodium chloride solution, and dried over anhydrous I/[acid magnesium]. By distilling off MW, 6β-chloro o-3
3.5 g of 1β, 17α-diacetoxy-7α-methanesulfonyloxy-2-oxa-4-pregnene-3,20-dione were obtained.

(e) Mesylate compound 162 obtained in step (d) above
, potassium acetate 120■ and dimethyl sulfoxide
The mixture of 1.2- was stirred at room temperature for 23 hours. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained crude product was purified by TLC (developing solvent, chloroformnia:/(0:1)) to give 6-chloro-11β, 17α-diacetoxy-2-
Oxa-4゜6-Pregnagen-3,20-Gio78
0. I got it.

'If-NMR (CDC113, δ): 0.84 (
3H, s), 1.31 (3II, s), 2.03
(311,s), 2.08 (311,s), 2
．． 09 (311°S), 4.20 (2 summer 1.s
), 5. 20 (III, m), (
3,17 ('III, s), 0.40 (III, b
roadd, J=2 Summer (z) MS (m/z): 46
4 (M”), 422.421.404.370 (f
) 6-chloro-11β,17α-diacetoxy-2-oxa-4,6-bregnadie 7-3.20-diJno1.
0g, approximately 28% sodium methylate methanol solution 0.24mf! A mixture of 120 g of Tetrahydro 7ran and 50 g of methanol was stirred at room temperature for 2 hours. 3% hydrochloric acid was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was
C (extractor solvent, chloroform:acetone (7:i)
) to give 17α-acetoxy-6-chloro-11
157 .beta.-hydroxy-2-oxa-4,6-pregnagene-3.20-dione was obtained.

'H-NMR (CDCIa, δ): 0.97 (3H
,s), 1.45 (311°s), 2.07 (3H
, s), 2.08 (3H, s), 4.21 and 4.4
9 (2H, ABq, J=1111z), 4.23 (Hl
, m>, 0.13 (III.

s), 6.41 (IH, broad d, J=
211z) MS (m/z): 422 (M”)
, 380.379.362.337.319.301.
271 Example 2 A mixture of 17α-acetoxy-6-chloro-11β-hyFOxy-2-oxer 4,6-pregnagene-3°20-dio 7100, 0.5 ml of Jaws reagent and 40 mu of acetone was added at 0°C. Stir for 7 minutes. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 17α-acetoxy-6-chloroa-
2-oxa-4゜6-pregnagen-3, Il, 2
0-trio 798 ■ was obtained.

'H-NMR (CDCjh, δ): 0.60 (31
1,s), 1.36 (31-1°S), 2.0G (
3H,s), 2.13 (3)-1,s), 3.97
(IH, d, J=1+11z), 5.02 (i
ll, d, J=IIIz), 6.25 (IH,
s), 8.35 (I H, broad d, J =
1.5Hz) MS (m/z): 420 (M”)
, 402.378.335 Example 3 (a) 6-chloro-17α-hydroxy-2-oxychloro-
4,6-pregnagene-3,20-dione 104.8
A mixture of 500 g of phosphorus oxychloride and 1.51 g of pyridine was stirred at room temperature for 14 days. The reaction mixture was added to ice water, and the precipitated crystals were collected and recrystallized from methanol to give 83.0 g of 6-chloro-2-oxa-4,6,1 (3-pregnatriene-3,20-dione). Obtained.

'II-NMR (CDCl13.δ): 0.97 (3
1-L S>, 1.23 (3H.

s), 2.28 (3H, s), 4.06 and 4.2
4 (21-1, ABq, J=11Hz), 6.19
(IH,s) ,6.36 (11-1,d, J=2
Hz), 6, 72 (IH, dd, J=2Hz, 3
11z)' MS (m/z): 34B (M"),
3311303.175 (b) 500 tg of the dehydro compound obtained in step (a) above and dimethylformamide! 3
+nQ mixture with 90μ of sodium hydride, tert.
-Butanol 7.5 saliva and dimethylformamide +3+
d mixture under oxygen pressure (40 kg/cJ
) at -28°C for 4 hours. The reaction mixture is
% aqueous acetic acid solution, and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was subjected to TLC [developing solvent, chloroform:acetate 7 (0:
1)] to produce 6-chloro-j7α-hydroxy-
2-Oxa-4,6,15-pregnatriene-3,2
0-Dione 85 was obtained.

'H-NMR (CDC1'3.δ): 0.86 (3
H,s), 1.23 (311°s), 2.27 (3
11,s), 4.08 and 4.24 (2+1.AI
IQ, J=111(z), 6.11 (IH, dd
, J=3Hz, 611z), 6.21 (11
1, s), 6.35 (IH, broad d,
J=6Hz), 6.48 (III, d.

J=1.5Hz) MS (m/z): 3B2 (M”), 310.30
1. Furthermore, by acetylating the 17α-hydroxy compound obtained above in a conventional manner using acetic anhydride-pyridine,
17α-acetoxy-6-chloro-2-oxa-4,6
, 15-pregnatriene-3°20-dione was obtained.

Low II-NMR (CDCl2.δ): 0.87 (31
1,s), 1.24 (31Ls), 2.04 (3H
, s), 2.18 (311, s), 4.09 and 4.
25 (211, AIIQ, J=11l-1z), 8
．． 22 (III, s), 8.32 (III.

broad d, J ”6+Iz), 6.43 (
I) I, dd, J=2.5Hz, EiHz), 6
．． 47 (11-1, broad s) MS (m/z
): 404 (M”), 361.310.301 (
C) 11a-hydroxy compound 8 obtained in step (b) above
A mixture of 5.4 g of lithium acetate, 54 ml of N-bromoacetamide 380R% acetic acid, and 18 ml of ethyl acetate was stirred in chamber 4 for 35 minutes. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent was purified by TLC (eluent, benzene:ethyl acetate (4:1)) to give I5β-acetoxy-16α-bromo6-chloro-
270 ml of 17α-hydroxy-2-oxa-4,6-bregnadier 7-3°20-dione was obtained.

'H-NMR (CDCf3, δ): 0.9B (31
1,s), 1.23 (3tl.

s), 2.14 (31-summer, s), 2.24 (31
1,s), 4.09 and 4.23(2H, Al3q,
J=11Hz), 5.10 (IH,d, J=2.5
LIz), 5.45 (IH,m), 6.14 (I
II, broads), 6.21 (11-1,
5) (d) Bromo compound 270w obtained in step (C) above
g1 tributyltin 2ml! A mixture of 25 g of 2.2'-azobisisobutyronitrile and 15 mQ of tetrahydrofurano was heated under reflux for 2 hours. The reaction mixture was evaporated under reduced pressure, and the resulting substance was purified by TLC (developing solvent, chloroform:acetone (19:1)) to obtain I5β-acetoxy-6-chloro-17α-hydroxy-2-oxa- 4,6-pregnagen-3,20
-Zion 109. I got it.

+ 1-1-N~IR (CDCf3.δ): 0.02
(311,S), 1.25 (31Ls), 2.10
(3H,s), 2.30 (311,s), 4.00
and s: 23 (211, ADq, J=11Hz),
5.39 (II-1, m), 6.21 (III.

s) , 0.28 (2) (, d, J=2Hz) (0
) +5a-acetoxy compound 15 obtained in step (d) above
g, acetic anhydride 0.25nffl, dioxane 1ml! and 60% persalt 1:acid 1d was stirred at room temperature for 20 minutes.

Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was diluted with saturated charcoal and an aqueous solution of sodium hydroxide, dried over anhydrous sodium sulfate, and the solvent was distilled off. )) to give 6-chloro-+5a,
17α-Diacetox-2-oxa-4,6-preg-
''-diene-3,20-diono I4 was obtained.

'II-NMR(CDCI/3.δCo,ri1 (31
1, s>, 1.20 (311°5), 2.00 (3
11,s), 2.08 (311,s), 2.0
0 (311,s), 4,! O and 4.25 (2+1
．． Al34. J=11!1z), 5.34 (III,
m), 0.22 (III, s), 0.27 (I
Ratio d, J=211z)8+S (m/z): 4
G4 (M+), 404, 379, 362, 34
4.310.301 (r)6-rirru 15β, +7a-diacetoxy-2-oxa-4,6-bregnadie 7-3.20-
Ziono I+oQ, potassium carbonate 40■, methanol 1
A mixture of 0 ml and 5 g of water was stirred in room d for 100 minutes. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was dried over anhydrous sodium chloride and the solvent was distilled off. The obtained ill product was subjected to TLC [developing solvent,
benzene:ethyl acetate (5:1)), 17
α-acetoxy-6-chloro-15β-hydroxy-2
-Oxa-4,6-prephnadiene-3,20-diono 15■ was obtained.

'I-l-1-N (CD(J'a, δ): 0.99
(311,s>, 1.24 (311°s), 2.
08 (011,s> , 4.10 and 4.25 (2
11, A11q, J=11l-1z), 4.49
(III, m), 6.20 (ltl, s),
8.50 (II-1°d, J=2Hz) MS (m/z): 422 (M”), 370.
362.344.337.310.301 Furthermore, 6-chloro-15β, 17α-dihydroxy-
2-oxa-4,6-pregnagene-3°20-dione IOg and 15β-acetoxy-6-chloro-17α
-Hydroxy-2-oxa-4,6-pregnagene-
3,20-dione 35. I got it.

Example 4 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnagene-3°20-dio/1 female, Jeannes reagent 5d and acetone 0.5-
The mixture was stirred at 0°C for 5 minutes. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was purified with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium. The solvent was distilled off to give 17α-acetoquine-6-chloro0-2-oxa-4゜[;-pregnagen-3,15,20-)
Zeon l■ was obtained.

'11-NMR (CDCI3.6): 0.81
(3H,s), 1.22 (311°s), 2.1
3 (3) [, s) , 2.17 (311, s) ,
4.08 and 4.25 (211, A[]Q, J=11
Hz), 6.22 (IH,s), 7.16 (III
.

MS (m/z): 420 (M”), 3
60,335.317.299 Example 5 17α-acet 1. Sea 6-ri a low 2-oxa-4,
6-Bregnadie y-3,15,2CP-)dione I
A mixture of n, 4 g of hydrogenated trit-butoxyaluminolithium and 0,4 m of tetrahydrofuran (!) was stirred at room temperature for 35 minutes. 3% hydrochloric acid was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was It was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.The crude product obtained by distilling off the solvent was analyzed by TLC (developing solvent, chloroform:acetate):/(9:1). )) and purified with 17α
-acetoxy-6-chloro-+5α-hydroxy-2-
Oxa-4,6-bregnazier 7-3,20-dione 0
．． I got 1 penny.

'H-NMR (CDCl2.δ): 0.74 (3H,
S), 1.22 (311°s), 2.04 (311
, s) , 2.14 (3H, s) , 4.00 and 4
．． 23(2)1. ABcl, J”l IHz),
4.31 (11-1, m), 8.21 (111
゜s), 13.07 (IH, d, J=2tlz
) MS (m/z): 422 (M”), 370.3
62.344.337, furthermore, 17α-7cetoxy-rerolow 15β-hydroxy-2-oxa-4,6
-Pregnagen-3,20-dione 0.8μ was obtained.

Example 6 (a) 6-rioo-2-oxa-4,6,10-pregnathrie:/-3,20-dione 3. A mixture of 4.6 g of Og, m-chloroperbenzoic acid and 40 g of dichloromethane was stirred at room temperature for 24 hours. The reaction mixture was extracted with ethyl acetate, and the extract was diluted with 5% aqueous sodium thiosulfate solution, 5%
It was washed successively with an aqueous sodium carbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 6-ri' rj -IGa, +1a -
xboxy-2-t-4-f-4゜6-pregnagene-
3.4 g of 3,20-dione was obtained.

'II-NMR (CDCJ3.δ): 1.11 (3
11,s), 1.20 (311゜s), 2.03
(311,s), 3.76 (III,s), 4.0
5 and 4,22 (211, Al3q, j=t 1ll
z), 6.17 (Ill, s), 6.24 (1
1-1°d, J=211z) MS (m/z): 362 (M”), 340.302.2
67(b) Epoxide compound 17 obtained in step (a) above
A mixture of 4 drops, 0.35 drops of concentrated sulfuric acid, and 7 drops of glacial acetic acid was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution,
It was dried with anhydrous magnesium sulfate. The product 11 obtained by distilling off the solvent was purified by TLC [developing solvent, chloroform:acetone (0:1)] to give 16β-acetoxy-6-lyrolow 17α-hydroxy-2-oxa-4. , 756 reports on 6-pregnagene-3,20-geo were obtained.

'II-NMRCCDCl3. δ): 1.03 (3
ratio S), 1.22 (311°s), 2.08 (3H,
s), 2.24 (311,s), 4.06 and 4.2
3 (2+1.Aoq, J=11Hz), 4.85
(III, dd, J=611z, 8Hz) ,0
．． 19 (III, s), 6.30 (111,
d, j=211z) MS (m/z): 42
2 (M+), 370.362.334.301(
C) acetate compound 7G41 obtained in step (b) above,
Acetic anhydride 12 saliva, dioxane 24111! and 60%A
Pi-acid 009ml! The mixture was stirred at room temperature for 5 minutes. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the +8 medium was subjected to TLC (developing solvent, benzene/:ethyl acetate (7:3).
)) to give 6-chloro-16β,17α-diacetoxy-2-oxa-4°6-bregnadie y-3,
518 ml of 20-dione was obtained.

'II-NMR (CDCJ3.δ): 1.10 (3
H,s), 1.22 (311゜s), 2.09 (
3H,s), 2.12 (311,s), 2.
19 (3H, s), 4.07 and 4.24 (2H,
Al3c1. J=1111z), 5.25 (III,
dd, J=5+1z, 811z), 6.10
(IH, s), 6.28 (III, d.

J = 2 Hz) MS (m/z): 464 (M”), 422.
404.379.362.320.301 (d) 6-chloro-16β, +7α-diacetoxy-
2-Oxa-4,6-pregnagene-3,20-dio 7273. gs potassium carbonate 44■, tetrahydro 7 run 20ml! ,methanol! A mixture of 0 saliva and 3.7 water was stirred in chamber 4 for 25 minutes. 3% hydrochloric acid was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The crude product obtained by evaporation of the solvent was purified with TLCC solvent, chloroformnia (9:1) to give 17α-acetoxy-6-chloro-16β-hydroxy-2-oxa-4.゜6-Bregnasier 7-3.20-Geo/75■
I got it.

'II-NMR (CDC1a, δ): 1.00 (3
11,s>, 1.23 (311°s), 2.07
(311,s) ,2.14 (311,s) ,4.
08 and 4.25 (2H, ABq, J=1111z)
, 4.31 (IH, dd, J=511z, 8l-
1z), 8.21 (III, s), 6.31
(11-1, d, J=211z) MS (m/z): 4
22(M”), 380.362.337.301 Example 7 (a) 6-chloro-2-oxa-4,8,1 [i-pregnatriene-3,20-dione 300., ace):
To a mixture of /IOmQ and 0.1 mQ of glacial acetic acid was added a mixture of 144 μm of potassium permanganate, 6 times of acetone, and 0.1 mQ of water, and the mixture was stirred at 0° C. for 3 minutes. 1 in the reaction mixture
1.2ml of 0% sulfite rtII satrium aqueous solution! was added and the precipitate was filtered. The liquid was distilled off, and the 8 residues were extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate/'-aqueous solution, then with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent was analyzed by TLC (bit opening 1 opening 8 soot 7 tons of loloformnia (4:1)) to determine whether Lf, 6-chloro-16α, +7α-dihydroxy-2-oxa -4
, 6~Pregnazier 7-3.20-geo/82■ was obtained.

'II-NMR (CDCI3.6): 0.74 (31
1,s), 1.20 (3H.

s), 2.24 (3H, s), 4.07 and 4.2
3 (2H, Al3q, J=1st 1z), 5.08
(11-1, dd, J=31-1z, 811z)
, 6.18 (III, s), E3.28 (
11-1, broad 5) (b) Diol compound 75n1 obtained in step (a) above, 1.2 ml of acetic anhydride! A mixture of 2.4% dioxane and 60% persalt dry acid was stirred at room temperature for 10 minutes. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution, then with a saturated aqueous sodium chloride solution 7B, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was subjected to TLCC extrusion solvent, chloroform:
acetoy(9:I)) to give 6-chloro-16α
, 30 μl of 1ph α-diacetyl 2-oxa-4°6-bregnadie/-3,20-dione were obtained.

'II-NMR (CDC13, δ): 0.77 (31
1,s), 1.21 (311°5), 1y05 (3
11,s), 2.09 (3tl,s), 2.16
(3H,s), 4.09 and 4.25 (21■, Al
3Q, J=11Hz), 6.21 (III.

s), 8.25 (III, broad s),
6.30 (III, m)MS (m/z): 4
64 (M10), 422,404.379.362
．． 320.301 (c) 6-ri or no 1 (iα, +7α-diacetoxy-2-oxa-4,6-preg-J.diene-3
,20-dione 100n to 0. It was dissolved in methanol + 8 solutions of IN hydrochloric acid and left to stand at 100 ml. The reaction mixture was added to water and the product was extracted with ethyl acetate. The extract was drained with water and dried over anhydrous magnesium sulfate. The 1[product obtained by distilling off the solvent was purified by TLC (development + 8 soot, roloform, acetone (0:1)) to obtain 17α-acetoxy-6-[10-I6α-hydroxy- 2-oxa-4,6-pregnagene-3,20-dio/ was obtained.

+11-NMrSe(CI)CI3. 6):0.81
(311,s), 1.21 (311゜s), 2.0
4 (311,s), 2.14 (311,s), 4
．． lO and 4.25 (2+1.A11c1.J=111
1z), 5.35 ([1,m), 0.21 (III
.

s), 0.31 (III, d, J”2121-1z)
(m/z): 422 (M”), 380.362.3
37.301 Patent Applicant Teikoku Organ Seisaku Mulberry Powdering Company Procedures Amendment Old (Voluntary) February 29, 1985 Director General of the Patent Office Kunio Ogawa 1, Indication of Case 1988 Patent Application No. 22755 2, Invention Name of tRKl 2-oxapregnan compound 3, Relationship with the tenant making the amendment Full text of the patent applicant's specification 6, Contents of the amendment Preservation of the specification (no change in content)

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) In the formula, X represents a hydroxyl group or oxo group bonded to the 11th, 15th, or 16th position of the steroid skeleton. A compound represented by , . 2. The compound according to claim 1, wherein X is bonded to the 15th position of the steroid skeleton. 3,17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadiene-3,20
The compound according to claim 1, which is a -dione.