JPS61204198A - 2-oxa-pregnane compound - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (A is H, lower alkanoyl; X is halogen). EXAMPLE:17alpha-Acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione. USE:Preventive, remedy for diseases depending on androgens such as prostato megaly, prostate cancer, psilosis, acne or seborrhea. PREPARATION:For example, a compound of formula II such as 17alpha-acetoxy-6- chloro-1xsi-hydroxy-2-oxapregna-4,6-diene-3,20-dione is allowed to react with a metal hydride complex such as sodium borohydride in an alcohol-water mixed solvent, when needed, in the presence of an inorganic salt such as sodium bicar bonate or organic salt at about -20 deg.C-room temperature to give a compound formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 2-oxapregnan compound, more specifically, in the general formula, A represents a hydrogen atom or a lower alkanoyl group,
X represents a halodane atom.

The compound of formula (1) above has anti-androgen activity and can be used as a drug for the prevention, treatment, and treatment of androdan-dependent diseases such as benign prostatic hyperplasia, prostate cancer, alopecia, zasu, seborrhea, etc. Useful.

As used herein, the term "lower" means that the group or compound to which this term is attached has 6 or fewer carbon atoms.

Examples of the "lower alkanoyl group" represented by A in the formula (1) include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, hexanoyl group, and the like, with acetyl group being preferred.

Further, the "halodan atom" represented by X includes fluorine, chlorine, and bromine atoms, and among them, chlorine atom is preferred.

Representative examples of the compound of formula (1) provided by the present invention are as follows.

17α-7 setoxy 6-chloro 2-oxapregna-4,6-renine-3,20-dione, 6-chloro-1
7α-hydroxy-2-oxapregna-4,6-dinine-3,20-dione, 6-chloro-2-oxa-17
α-propionyloxypregna-4,6-dinine-3
．． 20-dio/, 17α-butyryloxy-6-chloro-2-oxapregna-4,6-renine-3,20-dione) 6-chloro-2-oxa-17α-valeryloxypregna-4,6-renine -3,20-dione) 6-chloro-17α-hexanoyloxy-2-oxapregna-4,6-dinine-3,20-dione, 17α-acetoxy-6-fluoro-2-oxapregna-4,6-renine- 3,20-dione, 6-fluoro-2-oxa-17α-propionyloxypregna-
4,S-diene-3,20-dione, 6-fluoro-17α-hexanoyloxy-2-oxapregna-4,6-renine-3,20-dione, 17α-acetoxy-6-promo 2-oxapregna-4 , 6-renine-3,20-dione and the like.

The compound of formula (1) can be produced according to the reaction formula below.

In each of the above formulas, A and X have the above-mentioned meanings, R represents a lower alkyl group, and Y represents an iodine atom or a bromine atom.

In the above reaction formula, the oxidation of the compound of formula (1) is usually carried out using ethers such as dioxane and tetrahydrofuran; heronated hydrocarbons such as dichloromethane and chloroform; alcohols such as t-butanol and amyl alcohol; In a solvent such as a mixture of these and water, using an oxidizing agent such as a mixture of osmium tetroxide; osmium tetroxide and an oxidizing agent, such as a mixture of potassium chlorate, potassium periodate, lead tetraacetate, etc. The reaction can be carried out at a temperature of about 0° C. to the reflux temperature of the reaction mixture.

The resulting compound of formula (II) can be reduced to the formula (II)
It can be converted into a compound of 1. This reduction is generally carried out in solvents such as alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane, and mixtures of these with water. The reaction can be carried out using sodium cyanoborohydride, t-butoxylithium aluminum hydride, etc. in the presence of an inorganic salt, an organic acid salt, etc., if necessary, at a temperature of about -20°C to room temperature.

The resulting compound of formula (II/) is then treated in the absence of a solvent or in a suitable inert solvent, for example, organic acids such as acetic acid, pro2one; alcohols such as ethanol, t-butanol; tetrahydrofuran, dioxane, etc. ethers;
By reacting with halo r/hydrogen (EX) in halodanized hydrocarbons such as chloroform and carbon tetrachloride at about -20°C to the reflux temperature of the reaction mixture, usually at room temperature, the compound of formula (V) can be obtained. Can be converted into compounds.

The generated compound of formula (V) is then dehydrated to obtain the compound of formula ([) of the present invention. This dehydration is usually carried out in solvents such as organic bases such as pyridine; aromatic hydrocarbons such as benzene and toluene; and halodanized hydrocarbons such as chloroform and carbon tetrachloride. This can be carried out by treating with a dehydrating agent such as phosphorus oxychloride or p-toluenesulfonyl chloride at room temperature to the reflux temperature of the reaction mixture.

The resulting compound of formula (1) can be isolated and purified by methods known per se, such as filtration, extraction, chromatography, and recrystallization.

Alternatively, compounds of formula (l) can also be prepared starting from compounds of formula (l). In this alternative, compounds of formula (l) can be prepared starting from compounds of formula (l).
The oxidation of the compound of formula (II) can be carried out in the same manner as described above for the oxidation of the compound of formula (II), and the resulting compound of formula (
The compound (2) can be converted into the compound (2) by reacting it with a reagent represented by the formula RY, such as methyl iodide, ethyl iodide, etc., in the presence of a silver salt. This reaction is carried out using an excess of the above reagents in the absence of a solvent, or in a solvent such as a halodanized hydrocarbon such as chloroform or carbon tetrachloride; or an ether such as tetrahydrofuran or dioxane, and is generally carried out by refluxing the reaction mixture. It can be carried out at temperature.

The resulting compound of formula (■) can be reduced in the same manner as described above for the reduction of the compound of formula (melon) to obtain the desired compound of formula (1).

In addition, if the compound of the formula (■) is reduced, the formula (1) can be directly obtained.
can be obtained. This reduction can also be carried out in the same manner as described above for the reduction of the compound of formula (It).

Incidentally, the intermediate of formula (■) can also be synthesized by treating the compound of formula (II) described above with hydrogen halide and then dehydrating it. The reaction of the compound of formula (!II) with hydrogen halide and the dehydration of the resulting compound are the reaction of the compound of formula (II/) with hydrogen halide and the dehydration of the resulting compound of formula (V), respectively. Dehydration of the compound can be carried out in the same manner as described above.

Furthermore, the compound of formula (1) when A is a hydrogen atom can be converted into the corresponding compound of formula (1) when A represents a lower alkanoyl group by lower alkanoylation by a method known per se. In addition, the compound of formula (1) where A represents a lower alkanoyl group can be converted into a compound of formula (1) where A is a hydrogen atom by hydrolysis using a method known per se. can.

The 2-oxapredanane compound of the formula (2) provided by the present invention has excellent anti-androgen activity as described above, and is a therapeutic agent for benign prostatic hyperplasia; a therapeutic agent for prostate cancer; It is useful as a therapeutic agent for senile, circular, seborrheic and aglycemic alopecia; a hair nourishing agent; a therapeutic agent for acne vulgaris, etc.

The excellent anti-androgen activity of the compounds of formula (I) of the present invention is demonstrated by the experiments presented below.

Measurement of anti-androgen effect (subcutaneous administration and oral administration) Young male Wistar rats are castrated and divided into groups of 5 rats. One group is untreated and the other group is testosterone propionate (male hormone) 0.05.
my/day/day, and to another group, the test compound is administered subcutaneously or orally, and 0.05η/day of testosterone propionate is administered subcutaneously. One week later, the prostate was dissected, the prostate was taken out, its weight was measured, and the inhibition rate was calculated from the following formula.

Here, α: Prostate weight of the testosterone propionate alone administration group (■), b: Prostate weight of the testosterone propionate + test compound administration group (■), C: Prostate weight of the untreated group (W!Li).

As a result, 17α-acetoxy-6-chloro-2-oxapregna-4,6-renine-3,20~dione is 6η
Subcutaneous administration at 9 days/day showed an inhibition rate of 6% and 6%, and oral administration at 6 days/kg/day showed an inhibition rate of 65.4%.

Thus, the compound represented by formula (1) of the present invention can be administered orally, parenterally (e.g., intramuscularly, intravenously, It can be administered subcutaneously, rectally, etc.) or locally.

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 non-toxic excipients, binders, lubricants, disintegrants, preservatives, tonicity agents, stabilizers, dispersants, antioxidants, etc. commonly used in such drugs. It can be formulated using additives such as agents, colorants, flavoring agents, and buffering agents.

Such drugs may be in solid form (e.g., tablets, hard capsules, soft capsules, granules, powders, fine granules, emulsions, lozenges, etc.) or semi-solid forms (e.g., suppositories, ointments, etc.) depending on their use. ) and liquid forms (injections, emulsions, suspensions, lotions, sprays, etc.). Therefore, examples of the above-mentioned non-toxic additives that can be used include starch, gelatin, glucose,
Lactose, fructose, maltose, magnesium carbonate, talc,
Magnesium stearate, methylcellulose, carboxymethylcellulose or its salts, gum arabic, polyethylene glycol, p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol, vaseline, carbowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate, Examples include citric acid. The medicament may also contain other therapeutically useful agents.

The content of the compound of the invention in the medicament varies depending on its dosage form, but generally at a concentration of 1 to 100% by weight for solid and semisolid forms and 0.1% for liquid forms. It is desirable to contain the active compound in a concentration of ~10% by weight.

The dosage of the compound of the present invention can vary widely depending on the type of warm-blooded animal including humans, the route of administration, severity of symptoms, doctor's diagnosis, etc., but in general, It can be about 9 to .01 to 10/.

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 and Production Examples.

Example 1 17α-acetoxy-6-chloro-1ξ-hydroxy-
2-Oxapregna-4,6-dinine-3.20-dione 200W9. Sodium hydrogen carbonate 80n! To a mixture of 20 mg of methanol and IQ mg of water was added 72 μ of sodium borohydride, and the mixture was stirred at room temperature for 30 minutes. About 0.4 g of concentrated hydrochloric acid was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate,
It was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by TLC [developing solvent: chloroform] to give 17α-acetoxy-6-chloro-2-
Oxapregna-4,6-ginine-kame 20-dione 12
I got 0■.

Melting point: 253-255°C (acetone-hexane).

JR (KBr, cm-”): 3390.1?10゜1
605.1245゜'II-NMR (CDC18, δ) 20,? 2 (3H
.

ri, 1.21 (3H, Jl), 2.05 (3H, #
).

ZO9 (3H, 5), 4.11 and 421 (2H9A
Bq, J=11J7z), 6.15 (IH, 8).

6, 30 (IH, broad, -s).

MS (m/z-): 406 (M), 363.
346.321,303゜Example 2 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene-3゜20-dione 70
■, para-toluenesulfonyl chloride 4019.4-dimethylaminopyridine 1■ and pyridine 0.97! The mixture was heated to reflux for 2 hours. Add water to the reaction mixture,
The product was extracted with ethyl acetate. The extract was washed with a 50% aqueous hydrochloric acid solution and then with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by TLC [developing solvent, chloroformnia 7 ton (19:1)] to give 17α-acetoxy-6-chloro-2-oxabrevna-4,6-dinine. 52 ml of 3,20-dione was obtained. IH-N of this compound
The MR spectrum was identical to that of the material prepared in Example 1.

Example 3 Methyl 17α-acetoxy-6-chloro-1°20-
Dioxo-A-True 1,2-Secopregna-3,6-
Renin-2-oate 36cm was added to tetrahydrofuran l-
and cooled on ice. Lithium trit-butoxyaluminohydride 6311ILi was added to this solution while stirring under water cooling, and the mixture was stirred for 15 minutes.

Aqueous 20% hydrochloric acid solution was added to the reaction mixture, and the product was extracted with chloroform. The extract was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by TLC [developing solvent, chloroform:acetone (100:1)] to give 17
α-acetoxy-6-chloro-2-oxapregna-4
, 6-renine-3,20-dione (23) was obtained. The 'H-NMR spectrum of this compound was identical to that of the material prepared in Example 1.

Example 4 17α-acetoxy-6-chloro-2-oxapregna-4,6-renine-3,20-dione 116η, about 28
A mixture of 0.5 d of sodium methylate methanol solution, 0.1 m of tetrahydrofuran and 5 m of methanol was heated at 70° C. for 10 minutes. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was washed with a 30% aqueous hydrochloric acid solution and then with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by TLC [developing solvent, chloroform:acetone (19:1)'] to obtain 6-chloro-
70 μ of 17α-hydroxy-2-oxapregna-4,6-renine-3,20-dione were obtained.

Melting point: 218-221°C (acetone-hexane).

JR (KBr, cm-'): 3410.1700
゜1605゜IH-NMR (CDC1, δ): 0.75 (3H.

s), 1.20 (3H, g), 2.24 (3H, 8).

4.08 and 419 (2H, ABq, taHg).

6.11 (IH, 11), 6.34 (IH, b
roads).

MS (m, /z): 364 (& ), 321.3
03° Example 5 A mixture of 6-chloro-17α-hydroxy-2-oxapregna-4,6-renine-3,20-dio770 and anhydrous propion [2-] was heated at 130° C. for 6 hours. Water and pyridine were added to the reaction mixture, and after stirring at room temperature for 1 hour, the product was extracted with ethyl acetate. 30% of the extract
The mixture was washed with an aqueous dihydrochloric acid solution and then with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified using TLCr-developing solvent, chloroform:acetone (19:1)) to obtain 6-chloro-2-oxa-17α-globionyloxypregna-4. , 6-renine-3,20-dione (54 lbs.) was obtained.

Melting point: 199-202°C (acetone-hexane).

JR (KBr, cIL''''): 3380.1700°1 600°1H-NMR (CDC13, δ): 0.73 (3H.

g), 1.17 (3H, t, J=7Hz), 1.22 (
3H, a), 105 (3H, a), 238 (2H, q,
J = '1Hz), 4.11 and 4.22 (2H, AB
q, J=12Hz), 6.17 (IH,S).

6.32 (tH, broad a).

MS (m/z)", 420 (M), 377.346
．． 321,303゜Example 6 6-chloro-1
7α-hexanoyloxy-2-oxapregna-4,
6-renine-3,20-dione was obtained.

1B-NMR (CDCI8.δ): o, ra (3H.

8), 0.91 (3H, t, J'=llllZ), 1.2
2 (3H, 8), 105 (3H, #), 411 and 4.21 (IM, ABq, J=11H2), 6.17
(IH, S), 6.32 (tH, broads).

MS (m/z): 462 (Jf), 321.
303゜Example 7 17α-acetoxy-6α, 7α-epoxy-2-oxa-4-pregnene-3,20-dione 100 μ, potassium hydrogen fluoride 200 μ and dimethyl sulfoxide 1
- The mixture was heated at 140'C for 20 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 magnesium sulfate. The crude product obtained by distilling off the solvent was subjected to TLC (development method s, chloroform:acetone (50%
:1)) to give 17α-acetoxy-6-fluoro-2-oxapregna-4,6-renin-3,20-
I got Geo 720■.

SR-NMR (CDCI, δ): 0.72 (3H.

s), 1.22 (3ff, s), 105 (:17.
S).

109 (3j7.a), 4.17 (2H, m), 5.7
0(1j7,6yoadd,/=14Hz), &96(
IH18).

MS (m/z): 390 (Jf),
347, 330° 305.287° Production Example 1 17α-acetoxy-6-chloropregna-1° 4.6
-) diene-3,20-dione 15. Og, osmium tetroxide 0.51! , sodium periodate 33.61!
A mixture of 300 g of dioxane and 98 g of water was heated under reflux for 3 hours. Add 16 g of periodic acid to the reaction mixture,
The mixture was further refluxed for 30 minutes. The reaction mixture was poured into 5% sodium thiosulfate 41 and the product was extracted with ethyl acetate.

The extract was washed with water, dried over anhydrous magnesium sulfate,
The solvent was distilled off. The obtained crude product was purified by silica glu column chromatography [elution solvent: chloroform] and purified by 17α-acetoxy-6-chloro-1ξ-hydroxy-2-oxapregna-4,6-renin-3,20
-Dione 7.2y was obtained.

Melting point: 276-278°C (acetone-hexane).

JR (KBr, cx), 3510.1?25゜1
618.1258° IH-NMR (CDCI, δ): o, 72 (aH.

J), 1.20 (3B, #), 2.06 (3H, a
).

zt2 (aH, s), 5.5t (t#, a), a, 21
(1#, #), a3 s (t#, b de oa
ds).

MS (m/z): 422 (M), 380.37
6.362,337,319゜Production Example 2 17α-acetoxy-6-chloro-1ξ-hydroxy-
2-Oxapregna-4,6-dinine-3.20-dione 4.6 g, silver oxide 2311 and methyl iodide 50-
The mixture was heated to reflux for 3 hours.

Insoluble matter was removed by filtration, liquid F was distilled off, and methyl 17α
-acetoxy-6-chloro-1,20-dioquine-A-
4.19y of colorless crystalline powder of true 1,2-secopregna-16-renin-2-oate was obtained.

IH-NMR (CDC1, δ): 0.71 (3H9#
), 1.48 (aH, a), zo2 (3H, 8).

2-08 (3H, 8), &68 (3B, 8), 6.
32 (IH, 6roαd s), 6.48 (tH+
a) +9.57 (IH, 8).

Production Example 3 17α-acetoxy-6α,7α-epoxy pregnath
1,4-diene-3,20-dione 200 cape to dichloromethane 15I117! and dissolved in pyridine 15m,
Ozone was bubbled through for 10 minutes at -78°C.

The reaction mixture was stirred at room temperature for 10 minutes, and 3 d of 10% sodium bisulfite was added thereto, followed by stirring at room temperature for 1 hour.

The product was extracted with chloroform, and the extract was washed with an aqueous 10-thiosulfuric acid solution, then with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by TLC [developing solvent, chloroform:acetone (9:1)] to obtain 17α-acetoxy-
146 µ of 6α,7α-epoxy-1ξ-hydroxy-2-oxa-4-pregnene-3,20-dione was obtained.

IH-NMR (CDCl, -D, 0, δ): 0.70
(38,j), 1.18 (3H, &), 2.05 (
3H, 8),? -12 (3H, 5), 3.47 (tH
.

d, J=4Hz), a, 54(tH, d, J=4Hz)
, 5.43 (IH, J), 6.17 (lE, s).

Production Example 4 17α-acetoxy-6α, α-epoxy-1ξ-hydroxy-2-oxa-4-pregnene-3,20~dione 185~, sodium hydrogen carbonate 68m9, sodium borohydride 7111! f, tetrahydrofuran 4.
4 m, methanol 10 me and water 8.9 F, /! The mixture was stirred at room temperature for 30 minutes. A 10-thiosulfuric acid aqueous solution was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure to give 17α-acetoxy-6α,7
α-Epoxy-2-oxa-4-pregnene-3,20
-Dione 140Wli was obtained.

IH-NMR (CDCls, δ): 0.7G (3J7
゜J) + Lls (aH, s), zQs (3H, s
).

2. 11 (3B, a), 3.48 (lH, d, J=
4Hz), 3.52 (IH, d, J=4Hz), 4
．． 11 (2H, m), 6.10 (tH, a).

Production Example 5 Concentrated hydrochloric acid α1- was added to a tetrahydro7/4-solution of 17α-acetoxy-6α,7α-epoxy-2-oxa-4-pregnene-3,20-dione 97~, and 1-
Stirred for 0 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 magnesium sulfate. The solvent was distilled off under reduced pressure,
17α-acetoxy-6β-chloro-7α to hydroxy-2-oxa-4-7″ lugnene-3,20-dione 1
0211q was obtained.

1E-NMR (CDCl2.δ): o, 72 (sH.

' ) + 1-46 (3H, a ) + Z Q
6 (3H+s)+zs 1 (311,s), s
97 (tff, m), 4.11 and 4.28 (2
H, ABq, / = 11//g).

4.46 (IH, d, J=3Hz), 5.5t (IH
.

8).

Production Example 6 17α-acetoxy-6α,7α-epoxy-1ξ-hydroxy-2-oxa-4-pregnene-3,20-dione 201R? and 16% hydrogen chloride-ethyl acetate solution 3- was stirred at room temperature for 10 minutes. A saturated aqueous solution of hydrogen carbonate was added to the reaction mixture, and the product was extracted with ethyl acetate.

The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and 17α-acetoxy-6β-chloro-1ξ, 7α-
Dihydroxy-2-oxa-4-pregnene-3,20
- Obtained Zeon 21■.

IH-NMR (CDC!, δ): 0.72 (3H.

8), 1.43 (3H, s), zos (3H, s)
.

112 (3j7.s), 193 (IH, m), 454 (
IH, d, J=4Hz), 5.43 (IH.

broada), a05 (1//, a).

Production Example 7 17α-acetoxy-6β-chloro-1ξ, 7α-dihydroxy-2-oxa-4-pregnene-3,20-dione 17GWi, sodium hydrogen carbonate 62μ, tetrahydrofuran 4ml, methanol 9.2- and water 8, 2
64 μ of sodium borohydride was added to the mixture of - under stirring at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and 50% aqueous hydrochloric acid solution 4- was added. The product was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by TLC [developing solvent, chloroform:acetone (9:1)] to give 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4.
154 mq of -pregnene-3,20-dione was obtained. The IH-NMR spectrum of this compound was identical to that of the material prepared in Preparation Example 5.

An example of manufacturing a drug containing the compound of the present invention is as follows.

Formulation example A Tablet formulation: 5 tablets 20-dione 5.0 starch
11.7 Lactose
79.3 Carboxymethyl cellulose calcium z5 Talc
1.0 Magnesium Stearate
0.5100, O Misaki 17α-acetoxy-6-chloro-2-oxapregna-4,6-dinine-3,20-dione crystals are ground to a particle size of 70 microns or less, and starch, milk powder and carboxymethyl cellulose calcium are added to the powder. Add and mix well. Add 10 pieces of starch to the above mixed powder and mix with stirring to produce granules. After drying, the particles are sized to a particle size of around 1000 microns, mixed with talc and magnesium stearate, and tableted.

Formulation Example B Capsule formulation: 10η capsules 20-dione starch 50.0 Lactose 47.011α
01q Thoroughly crush the crystals of 17α-acetoxy-6-chloro-2-oxapregna-4,6-renine-3,20-dione, mix starch, lactose, and magnesium stearate, and mix well. Fill into No. capsule.

Procedural amendment (voluntary) February 24, 1985 Michibe Uga, Commissioner of the Patent Office Name of the invention 2 - Oxapregnan compound 3 Relationship with the case of the person making the amendment Patent applicant address Akasaka 2, Minato-ku, Tokyo Chome 5-1-4, Deputy
Person 〒107 (】) In the fourth line from the bottom of the second page of the specification, there is "Productivity".
Corrected to "bonds".

(2) On page 8, line 10 of the same page, the words "pion, etc." are corrected to "pionic acid, etc."

(3) On page 9, line 8 of the same page, the text "temperature, de" is corrected to "temperature de".

(4) Add the following sentence between the 4th and 6th lines from the bottom of page 16.

A test compound was suspended in 2% Tween 80 physiological saline and orally administered to a group of 5 male Wistar rats (6 weeks old) and observed for 72 hours.As a result, 17α-acetoxy-φ -Chloro 2-Oxapregna $-4゜6
-Soen-6.20-No deaths were observed even at a dose of 3000 kg/yu. ” (5) In the second line of page 17, correct the phrase “with sodium” to read “with sodium aqueous solution.”

(6) On page 21, line 4 of the same page, r13Hzj is written as rJ=
Corrected to 15H2J.

(7) On page 26, line 8 of the same page, replace “1H” with “2H”.
” he corrected.

(8) On page 27, line 16 of the same page, the phrase "washed with ram" is corrected to "washed with rum aqueous solution."

that's all

Claims (1)

[Claims] 1. A compound represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) In the formula, A represents a hydrogen atom or a lower alkanoyl group, and X represents a halogen atom. 2. The compound according to claim 1, wherein A is an acetyl group. 3. Claim 1 or 2 in which X is a chlorine atom
Compounds described in Section.