KR900006219B1 - Process for preparing 2-oxa or aza-pregmane compounds - Google Patents

Abstract

Pregnane cpds. of formula (I) are obtd. from cpd. (II) by oxidn., then either redn., reacting with HX, dehydration, oxidn., reacting R1Y and reducing/RNH2, RNH2/HCO2H or reducing or sequence of corresp. reactions. In the formulas, A=H or C2-6 lower alkanoyl, pref. acetyl; Z= O or -BR- (R= H or C1-6 alkyl); X= halo (pref. Cl).; R1= lower alkyl; Y= I or Br. (I) have anti-androgenic activity and useful for controlling androgen-dependent diseases, esp. for preventing hypertrophy.

Description

Detailed Name of the Invention

Method for preparing 2-oxa-or-aza-pregnan compound

Detailed description of the invention

The present invention relates to a process for the preparation of the novel 2-oxapregnan or 2-azapregnan compound. More specifically, the present invention relates to a method for preparing a compound represented by the following general formula (I).

(식중 R은 수소원자 또는 저급알킬기를 나타낸다)의 기를 나타내고, X는 할로겐원자를 나타낸다.][Wherein A represents a hydrogen atom or a lower alkanoyl group, Z represents an oxygen atom or a general formula

(Wherein R represents a hydrogen atom or a lower alkyl group) and X represents a halogen atom.]

It is already known that 17α-acetoxy-2-oxapregna-4,6-diene-3,20-dione having a methyl group at the 6-position has premenstrual activity (US Pat. No. 3,080,381). ). It is also known that 2-oxapregnane-3,20-dione having a cyano group in the 5-position has anti-male hormone activity (British patent 1,277,754).

2-azapregnan-type compounds are described in J. Org. Chem., 31 (7), 2109 (1966), although 2-aza-5α-pregnan-3,20-dione is described. There is no mention of action.

According to the present invention, the 2-oxa-or-aza-pregnan compound of the general formula (I) is a novel compound which has not been described in the prior art at all, and because of its very strong anti-male hormone activity, it is enlarged prostate, prostate It can be seen that it is useful as a medicament for the prevention, treatment and treatment of diseases caused by androgen such as cancer, alopecia areata, acne and seborrhea.

In addition, since the compound of the general formula (I) exhibits a similar action to progesterone, it can be used as a drug for preventing lactic acid and contraception.

As used herein and in the claims, the term "lower" means a group or compound having up to 6 carbon atoms.

의 기를 나타내는 경우 R은 바람직하게는 수소원자이지만 저급알킬기일 수 있다.For example, "lower alkanoyl groups" represented by A in general formula (I) include acetyl, propionyl, butyryl, isobutyryl, valeryl and hexanoyl groups. Acetyl groups are preferred. Z is

R preferably represents a hydrogen atom but may be a lower alkyl group.

Examples of "lower alkyl groups" represented by R include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl and t-butyl groups. Methyl groups are preferred. "Halogen atoms" represented by X include fluorine, chlorine and bromine atoms. Chlorine atoms are preferred.

Typical examples of the compound of formula (I) provided by the present invention include the followings. 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3.20-dione, 6-chloro-17α-hydroxy-2-oxapregna-4,6-diene-3,20- Dione, 6-chloro-2-oxa-17α-propionyloxyflugna-4,6-diene-3,20-dione, 17α-butyryloxy-6-chloro-2-oxapregna-4,6- Diene-3,20-dione, 6-chloro-2-oxapregna-4,6-diene-3,20-dione, 6-chloro-2-oxa-17α- valeryloxypregna-4,6- Diene-3,20-dione, 6-chloro-17α-hexanoyloxy-2-oxapregna-4,6-diene-3,20-dione, 17α-acetoxy-6-fluoro-2-oxaf REGNA-4,6-diene-3,20-dione, 6-fluoro-2-oxa-17α-propionyloxypregnna-4,6-diene-3,20-dione, 6-fluoro-17α-hexa Noyloxy-2-oxapregna-4,6-diene-3,20-dione, 17α-acetoxy-6-bromo-2-oxapregna-4,6-diene-3,20-dione, 17α -Acetoxy-2-aza-6-chloropregna-4,6-diene-3,20-dione, 2-aza-6-chloro-17α-hydroxypregna-4,6-diene-3,20 Dion 2 -Aza-6-chloro-17α-propionyloxypregna-4,6-diene-3,20-dione, 2-aza-17α-butyryloxy-6-chloropregna-4,6-diene-3 , 20-dione, 2-aza-6-chloro-17α-valeryloxypregna-4,6-diene-3,20-dione, 2-aza-6-chloro-17α-hexanoyloxypregna-4 , 6-diene-3,20-dione, 17α-acetoxy-2-aza-6-chloro-2-methylpregna-4,6-diene-3,20-dione, 17α-acetoxy-2-aza -6-chloro-2-ethylpregna-4,6-diene-3,20-dione, 17α-acetoxy-2-aza-6-fluoropregna-4,6-diene-3,20-dione, 2-aza-6-fluoro-17α-hexanoyloxypregna-4,6-diene-3,20-dione, 17α-acetoxy-2-aza-6-bromopregnna-4,6-diene- 3,20-dion.

Among these compounds, 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione- and 17α-acetoxy-2-aza-6-chloropregna-4,6- Diene-3,20-dione is particularly suitable in terms of its pharmaceutical properties.

The compound of general formula (I) can be manufactured according to the following reaction scheme.

Scheme

[Wherein A, Z, X and R are as defined above, R ₁ represents a lower alkyl group and Y represents an iodine or bromine atom.]

인 경우) 또는 부재하에 (Z=0인 경우) 환원시킴으로써 일반식(Ⅴ)의 화합물로 전환시킬 수 있다. 이 환원 반응은 일반적으로 알코올(예, 메탄올 또는 에탄올), 에테르(예, 테트라히드로 푸란 또는 디옥산) 또는 이들 유기 용매와 물의 혼합물 같은 용매내에서 임의로 유기산염 또는 무기염의 존재하에 수소화붕소 나트륨, 수소화붕소칼륨, 소듐 시아노보로하이드 라이드 또는 리튬 t-부톡시 알루미노하이드라이드 같은 착체 금속 수소화물을 이용하여 약 -20℃∼반응 실온에서 실시할 수 있다. 일반식 R-NH₂로 나타내지는 암모니아 또는 일차아민의 양은 일반적으로 일반식(Ⅳ)의 화합물 1몰에 대하여 약 1∼20몰이다.In the above schemes, oxidation of compounds of general formula (II) is usually carried out with ethers (e.g. dioxane or tetrahydrofuran), halogenated hydrocarbons (e.g. dichloromethane or chloroform), alcohols (e.g. t-butanol or amyl alcohol ), Pyridine or a solvent such as a mixture of these organic solvents and water, and an oxidizing agent such as a mixture of ozone and tetraoxide auxiliary may be used at about -80 ° C to reflux temperature of the reaction mixture. The resulting compound of formula (III) can be converted into a compound of formula (IV) by reacting with a reagent of formula R1Y such as methyl iodide or ethyl iodide, for example in the presence of silver salts. This reaction is generally carried out without solvent using an excess of said reagent at the reflux temperature of the reaction mixture or in a solvent such as a halogenated hydrocarbon (e.g. chloroform, tetrachlorocarbon) or an ether (e.g. tetrahydrofuran or dioxane). It can be carried out. Compound of the generated general formula (Ⅳ) has the general formula R-NH Z (in the presence of ammonia or amines of ₂ alcha

Can be converted to the compound of formula (V) by the reduction) or in the absence (when Z = 0). This reduction reaction is generally carried out by sodium borohydride, hydrogenation, optionally in the presence of an organic acid or an inorganic salt in a solvent such as alcohol (e.g. methanol or ethanol), ether (e.g. tetrahydrofuran or dioxane) or a mixture of these organic solvents and water. The reaction may be carried out at about -20 ° C to room temperature using a complex metal hydride such as potassium boron, sodium cyanoborohydride or lithium t-butoxy aluminohydride. The amount of ammonia or primary amine represented by the general formula R-NH ₂ is generally about 1 to 20 mol with respect to 1 mol of the compound of formula (IV).

The compound of formula (V) wherein Z = 0 can be produced directly by reducing the compound of formula (III). This reduction reaction can be carried out at about −20 ° C. to room temperature using the complex metal hydride described above in the presence of an inorganic salt or an organic acid salt, optionally in the solvent described above.

The compound of formula (V) obtained is either solventless or organic acid (e.g. acetic acid or propionic acid), alcohol (e.g. ethanol or t-butanol), ether (e.g. tetrahydrofuran or dioxane) or halogenated hydrocarbons (e.g. The compound of formula (V =) may be converted by reaction with hydrogen halide (HX) at about -20 ° C to the reflux temperature of the reaction mixture, typically at room temperature, in a suitable inert solvent such as chloroform or carbon tetrachloride.

Dehydration of the compound of formula (VII) thus obtained can yield the compound of formula (I) according to the invention. This dehydration reaction is carried out at room temperature to the reflux temperature of the reaction mixture in a solvent such as an organic base (eg pyridine), aromatic hydrocarbon (eg benzene or toluene), halogenated hydrocarbon (eg chloroform or carbon tetrachloride). Can be carried out by treatment with a dehydrating agent such as p-toluenesulfonic acid, phosphorus oxychloride, p-toluene sulfonyl chloride, methanesulfonyl chloride or thionyl chloride.

In another method, the compound of formula (I) can be obtained using the compound of formula (VII) as a starting material. In this method, the oxidation reaction of the compound of the formula (VII) can be carried out in the same manner as described above with respect to the oxidation reaction of the compound of the formula (II). Reaction of a reagent of the compound with the general formula R _l Y of formula (Ⅸ) generation can be performed in the same way as described above in relation to the compound and the reaction of the formula R _l Y of the reagent of formula (Ⅲ) have. The compound of formula (III) thus obtained is reduced in the absence or presence of ammonia or primary amine of formula R-NH _{2 in} the same manner as described above in connection with the reduction reaction of the compound of formula (VII). The desired compound of formula (I) can be obtained.

The compound of formula (VII) can be converted to the target compound of formula (I) by reacting with ammonia or primary amine of formula R-NH ₂ in the presence of fric acid. This reaction can usually be carried out at the reflux temperature of the reaction mixture without solvent using an excess of formic acid.

The amount of ammonia or primary amine of the general formula R-NH ₂ is generally about 1 to 20 mol with respect to 1 mol of the compound of general formula (X).

Compounds of formula (VII) can be converted directly to compounds of formula (I) by reducing or reacting with ammonia or primary amines of formula R-NH ₂ in the presence of formic acid. This reaction can also be carried out in the same manner as described above in connection with the reduction of the compound of formula (IV) or the reaction of the compound of formula (X) in the presence of formic acid with the compound of formula R-NH ₂ . Can be.

Intermediates of formula (III) are obtained by treating a compound of formula (III) with hydrogen halide and then reducing the treated compound or reacting with ammonia or primary amine of formula R-NH ₂ in the presence of formic acid. can do. Reaction of the compound of general formula (III) with hydrogen halide, reduction of the compound of general formula (VI) and compound of general formula (VI) which are carried out in the presence of formic acid, and a compound of general formula R-NH ₂ The reaction of the compound of formula (V) and the compound of formula R-NH _{2 with} the reaction of the compound of formula (V) with a hydrogen halide, the reduction of the compound of formula (IV) and in the presence of formic acid The reaction can be carried out in the same manner as described above.

Intermediates of formula (VII) can also be synthesized by dehydrating the compound of formula (VI). The dehydration reaction of the compound of formula (VI) can be carried out in the same manner as described above in connection with the dehydration reaction of the compound of formula (VII).

The compound of formula (I) in which A is a hydrogen atom can be converted into the corresponding compound of formula (I) in which A is a lower alkanoyl group by lower alkanoylation according to a known method. The compound of general formula (I) in which A is a lower alkanoyl group can be converted into the corresponding compound of general formula (I) in which A is a hydrogen atom by hydrolysis according to a known method.

Lower alkanoylation reactions of compounds of formula (I) wherein A is a hydrogen atom are optionally carried out without solvent or in the presence of an acid catalyst such as, for example, p-toluenesulfonic acid or perchloric acid, without solvents or ethers (e.g. diethyl ether, tetrahydro Reactive derivatives of lower alkanoic acid (e.g. lower alkanoic acid) at room temperature to the reflux temperature of the reaction mixture in an inert solvent such as furan or dioxane), halogenated hydrocarbons (e.g. chloroform or carbon tetrachloride) or aromatic hydrocarbons (e.g. benzene or toluene). Acid, anhydride or acid halide).

The compounds of general formula (I) prepared as described so far can be separated and purified by known methods such as filtration, recrystallization, column chromatography or thin layer chromatography (TLC).

Since the 2-oxa- or -aza-pregnan compound of the general formula (I) provided by the present invention has excellent anti-male hormone activity, for example, the treatment of prostatic hypertrophy: the treatment of prostate cancer: immature, Therapeutic for premature, senile or cold-bored seborrheic or bran-shaped alopecia: useful as a treatment for hair growth or vulgaris.

Compounds of general formula (I) can also be used as agents for the prevention of lactic acid or contraception because they exhibit a similar action to progesterone.

Compounds of formula (I) provided by the present invention are characterized by not having adrenal suppression activity.

The following experiments demonstrate the excellent anti-male hormone activity and premenstrual activity of the compounds of formula (I) according to the invention.

Compounds of the invention used in the examples below are represented by the following abbreviations.

A: 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione

B: 6-Chloro-2-oxa-17α-propionyloxiffpfpna-4,6-diene-3,20-dione

C: 17α-acetoxy-2-aza-6-chloropregna-4,6-diene-3,20-dione

D: 17α-acetoxy-2-aza-6-chloro-2-methylpregna-4,6-diene-3,20-dione

(1) Determination of anti-male hormone activity by subcutaneous administration and oral administration

Young male rats of Wister species are castrated and five are divided into several groups. One group does not deal. Testosterone propionate (androgen) is administered subcutaneously in a dose of 0.05 mg / 1 day to a group over a week. In another group, test compounds are subcutaneously or orally administered and simultaneously testosterone propionate is administered daily in a dose of 0.05 mg / 1 day over a week. The animal is then dissected to remove the prostate and weigh it. The ratio of the effect of the test compound to the effect of chlorromnadinone acetate (hereinafter abbreviated CMA) used as an effective control is determined. The results are shown in the table below.

(2) measurement of premenstrual activity

Five young female rabbits (weight 680-1279 g) in each group were tested according to the Clauberg-Mcphail method (K. Kontula et al., Acta Endocrinol 78,574 (1975)). .

Estradiol benzoate is administered subcutaneously to the animal once a day for 7 days at 2 μg / head dose, followed by the test compound twice daily (once on the first day) for another 5 days and once again on the morning of the 6th day. (10 doses in total). Estradiol benzoate is dissolved in sesame oil and the test compound is suspended in physiological saline containing 2% Tween 80. The animals are dissected on the afternoon of the sixth day. The uterus is weighed and the butterfly on the endometrium and the butterfly on the myometrium are measured under a microscope. As a result, it can be seen that Compound A of the present invention exhibits 100 times stronger menstrual activity than progesterone.

(3) toxicity

Suspensions of test compounds suspended in physiological saline containing 2% Tween 80 are orally administered to Wistar male rats (6 weeks old, each group consisting of 5 rats) and the animals observed for 72 hours. As a result, even when Compound A of the present invention was administered in a dose of 3000 mg / kg, death of the rat was not observed.

The compounds of formula (I) according to the invention can therefore be administered orally, parenterally (eg intramuscular, intravenous, subcutaneous or rectal) or topically as agents for the treatment or treatment of the human body or other mammals. have.

When the compound according to the present invention is used as a medicament, it may be prepared in various forms suitable for oral, parenteral or topical administration. Compounds of the present invention using conventional, pharmaceutically acceptable non-toxic auxiliaries such as, for example, excipients, binders, lubricants, disintegrants, preservatives, isotonic agents, stabilizers, dispersants, antioxidants, colorants, perfumes or buffer solutions. Can be formulated.

These agents can be used in solid form (eg tablets, hard capsules, soft capsules, granules, powders, crushed crystals, pills or troches), semisolid formulations (eg suppositories and ointments) and liquid preparations (injectable preparations, Emulsions, suspensions, lotions or sprays). Examples of pharmaceutically acceptable nontoxic adjuvants include starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or its salts, gum arabic, polyethylene glycol , Alkyl p-hydroxybenzoate, syrup, ethanol, propylene glycol, waseline, carbowax, glycerol, sodium chloride, sodium sulfite, sodium phosphate, citric acid and the like. The medicament may also include other therapeutically acceptable medicaments.

The content of the compound of the present invention in the medicament is determined according to the form of the medicament. Generally from 1 to 100% by weight is preferred in solid and semisolid formulations and from 0.1 to 10% by weight in liquid formulations.

Dosage of the compound of the present invention is very wide depending on whether the subject is human or other mammal, the route of administration, the severity of the disease, the diagnosis of a doctor, and the like. Generally it is about 0.01-10 mg / kg / day. Of course, doses of the present compounds outside of this range may be administered according to the severity of the disease or the diagnosis of the physician. A daily dose of the compound may be administered at one time or in divided portions. The invention is explained in more detail in the following examples and preparations.

Example 1

To a mixture of 200 mg l7α-acetoxy-6-chloro-1ε-hydroxy-2-oxapregna-4,6-diene-3,20-dione, 80 mg sodium hydrogen carbonate, 20 ml ethanol and 10 ml water Sodium borohydride (72 mg) is added and the mixture is stirred at room temperature for 30 minutes. Concentrated hydrochloric acid (about 0.4 ml) is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The crude product is purified by TLC (developing solvent: chloroform) to yield 120 mg of 17α-acetoxy-6-chloro-2-oxapregna-4,6-di-3,20-dione.

Melting Point: 253 ~ 255 ℃

IR (KBr, cm ^−l ): 3390,1710,1605,1245.

): 0.72(3H,s),1.2l(3H,s),2.05(3H,s),2.09(3H,s), 4.11&4.21(2H,ABq,J=1lHz), 6 .15(lH,s), 6.30(lH,br s). · ^l H-NMR (CDC1 _3,

): 0.72 (3H, s), 1.2l (3H, s), 2.05 (3H, s), 2.09 (3H, s), 4.11 & 4.21 (2H, ABq, J = 1lHz), 6 .15 (lH , s), 6.30 (lH, br s). ·

MS (m / z): 406 (M ⁺ ), 363, 346, 321, 303.

Example 2

70 mg of 17α-acetoxy-6β-chloro-17α-hydroxy-2-oxa-4-pregene-3,20-dione, 400 mg of P-toluenesulfonylchloride, lm1 4-dimethylaminopyridine and 0.9m1 The mixture of pyridine of is heated under reflux for 2 hours.

Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed successively with 50% hydrochloric acid and saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was evaporated and the crude product was purified by TLC (developing solvent: chloroform / acetone (19/1)) to give 52 mg of 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20 -Dione is obtained. The ¹ H-NMR spectrum of this compound is the same as that of the compound obtained in Example 1.

Example 3

A mixture of 1.76 g of 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregene-3,20-dione, 1.1lm1 methanesulfonylchloride and 5.2m1 pyridine was subjected to ice cooling 1 For hours, stir for 12 hours at room temperature. Ice-cold water is added to the reaction mixture, and the precipitated crystals are collected by filtration to obtain 2.0 lg of 17α-acetoxy-6β-chloro-7α-mesyloxy-2-oxa-4-pregnene-3,20-dione. .

Melting Point: 225.5 ~ 226.4 ℃

IR (KBr, cm ⁻¹ ): 1735,1350,1250,1175.

) : 0.74(3H,s), 1.48(3H,s), 2.06(3H,s), 2.09(3H,s), 3.08(3H,s), 4.1l & 4.28(2H,ABq,J=10Hz), 4.78(lH,d,J=3Hz), 4.92(lH,m), 6.02(lH,s). ^l H-NMR (CDC1 _3,

): 0.74 (3H, s), 1.48 (3H, s), 2.06 (3H, s), 2.09 (3H, s), 3.08 (3H, s), 4.1l & 4.28 (2H, ABq, J = 10Hz) , 4.78 (lH, d, J = 3 Hz), 4.92 (lH, m), 6.02 (lH, s).

A mixture of 2.35 g of 17α-acetoxy-6β-chloro-7α-mesyloxy-2-oxa-4-pregene-3,20-dione, 0.83 g potassium acetate and 0.88 ml dimethylsulfoxide was added at room temperature. Stir for hours. Ice-cold water is poured into the reaction mixture, and the precipitated crystals are collected by filtration to obtain 1.37 g of 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione. The ^l H-NMR spectrum of this compound is the same as that in Example 1.

Example 4

It is dissolved in 1 ml of methyl tetrahydrofuran and the solution is ice-cooled. 63 mg of lithium tri-t-butoxyaluminohydride is added while stirring under ice-cooling, and the mixture is stirred for 15 minutes. 20% aqueous hydrogen chloride solution is added to the reaction mixture, and the mixture is extracted with chloroform. The extract is washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. 23 mg of 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20 by evaporating the solvent and purifying the crude product with TLC [developing solvent: chloroform / acetone (100/1)]. -Dione is obtained. ^L H-NMR spectrum of this compound is the same as that of the compound obtained in Example 1.

Example 5

116 mg of 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione, about 28% ethanol solution of 0.5m1 sodium methylate, 0.1 ml tetrahydrofuran and The mixture of 5 ml of methanol is heated at 70 ° C. for 10 minutes. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract was washed successively with 30% aqueous hydrogen chloride solution and saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. 70 mg of 6-chloro-17α-hydroxy-2-oxapregna-4,6-diene-3 by evaporation of the solvent and purification of the crude product by TLC [developing solvent: coloform / acetone (19/1)]. To obtain 20-dione.

Melting Point: 218 ~ 221 ℃

IR (KBr, cm ^-1 ): 3410,1700,1605.

) : 0.75(3H,s), 1.20(3H,s), 2.24(3H,s), 4.08 & 4.19(2H,ABq,J=13Hz), 6.11(lH,s), 6.34(lH,br s). ^l H-NMR (CDC1 _3,

): 0.75 (3H, s), 1.20 (3H, s), 2.24 (3H, s), 4.08 & 4.19 (2H, ABq, J = 13Hz), 6.11 (lH, s), 6.34 (lH, br s) .

MS (m / z): 364 (M ⁺ ), 321, 303.

Example 6

A mixture of 70 mg of 6-chloro-17α-hydroxy-2-oxapregna-4,6-diene-3,20-dione and 2 ml propionic acid anhydride is heated at 130 ° C. for 6 hours. Water and pyridine are added to the reaction mixture, and the mixture is stirred at room temperature for 1 hour and then extracted with ethyl acetate. The extract was washed successively with 30% aqueous hydrogen chloride solution and saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the crude product was purified by TLC [developing solvent: chloroform / acetone (19/1)] to give 54 mg of 6-chloro-2-oxa-17α-propionyloxypregna-4,6-diene-3, 20-dione is obtained.

Melting Point: 199 ~ 202 ℃

IR (KBr, cm ^-1 ): 3380,1700,1600.

) : 0.73(3H,s), l.17(3H,t,J=7Hz), 1.22(3H,s), 2.05(3H,s), 2.38(2H,q,J= 7Hz), 4.11 & 4.22(2H,ABq,J=12Hz), 6.17(lH,s), 6.32(lH,br s). ^l H-NMR (CDCl _3,

): 0.73 (3H, s), l.17 (3H, t, J = 7Hz), 1.22 (3H, s), 2.05 (3H, s), 2.38 (2H, q, J = 7Hz), 4.11 & 4.22 (2H, ABq, J = 12 Hz), 6.17 (lH, s), 6.32 (lH, br s).

MS (m / z): 420 (M ⁺ ), 377,346,321,303.

Example 7

Example 6 was repeated but 6-chloro-17α-hexanoyloxy-2-oxapregna-4,6-diene-3,20-dione was obtained using caproic anhydride instead of propionic anhydride.

) : 0.73(3H,s), 0.91(3H,t,J=6Hz), 1.22(3H,s), 2.05(3H,s), 4.1l & 4.21 (2H,ABq,J=1lHz), 6.17(1H, s), 6.32(lH,br s). ^l H-NMR (CDC1 _3,

): 0.73 (3H, s), 0.91 (3H, t, J = 6Hz), 1.22 (3H, s), 2.05 (3H, s), 4.1l & 4.21 (2H, ABq, J = 1lHz), 6.17 ( 1 H, s), 6.32 (l H, br s).

MS (m / z): 462 (M ⁺ ), 321,303.

Example 8

A mixture of 100 mg 17α-acetoxy-6α, 7α-epoxy-2-oxy-4-pregnene-3,20-dione, 200 mg potassium hydrogen fluoride and 1 ml dimethylsulfoxide is heated at 140 ° C. for 20 minutes. Water is added to the reaction mixture and the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the crude product was purified by TLC [developing solvent: chloroform / acetone (50 / l)] to give 20 mg of 17α-acetoxy-6-fluoro-2-oxapregna-4,6-diene-3, 20-dione is obtained.

) : 0.72(3H,s), 1.22(3H,s), 2.05(3H,s), 2.09(3H,s), 4.17(2H,m), 5.70(lH, brd,J=14Hz), 5.96(lH,s). ^l H-NMR (CDCl _3,

): 0.72 (3H, s), 1.22 (3H, s), 2.05 (3H, s), 2.09 (3H, s), 4.17 (2H, m), 5.70 (lH, brd, J = 14Hz), 5.96 ( lH, s).

MS (m / z): 390 (M ⁺ ), 347,330,305,287.

Example 9

500 mg of methyl 17α-acetoxy-6-chloro-1,20-dioxo-A-nor-1,2-secopregna-3,6-diene-2-oate, 1.3 g ammonium acetate, 1.09 A mixture of sodium cyanobohydride, 5 ml of tetrahydrofuran and 9 ml of ethanol is stirred at room temperature for 22 hours. To the reaction mixture is added about 20 ml of a 50% aqueous hydrogen chloride solution, the mixture is stirred at room temperature for 1 hour and extracted with chloroform. The extract is washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the crude product was purified by TLC [developing solvent: chloroform / methanol (19/1)] to give 17α-acetoxy-2-aza-6-chloropregna-4,6-diene- as a colorless crystalline powder. 295 mg of 3,20-dione is obtained.

Melting Point: 286.6 ~ 287.6 ℃

IR (KBr, cm ^-1 ): 3400, 1725, 1660.

) : 0.71(3H,s), 1.17(3H,s), 2.06(3H,s), 2.10(3H,s), 3.27(2H,m), 6.l4(lH, brs), 6.23(lH,br s), 6.77(lH,br s). ^l H-NMR (CDCl _3,

): 0.71 (3H, s), 1.17 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 3.27 (2H, m), 6.l4 (lH, brs), 6.23 (lH, br s), 6.77 (lH, br s).

MS (m / z): 405 (M ⁺ ), 320,302.

Example 10

Repeat Example 9 with 17α-acetoxy-2-aza-6-chloro-2-methylpregna-4,6-diene using methylamine hydrochloride and 30% ethanol solution of methylamine in place of ammonium acetate. -3,20-dione is obtained.

Melting Point: 292.6 ~ 293.6 ℃

IR (KBr, cm ^-1 ): 3400,1725,1650

) : 0.71(3H,s), 1.12(3H,s), 2.06(3H,s), 2.09(3H,s), 3.02(3H,s), 3.12 & 3.33(2H,ABq,J=13Hz), 6.13(lH,s), 6.14(lH,s).H-NMR (CDC1 ₃ ,

): 0.71 (3H, s), 1.12 (3H, s), 2.06 (3H, s), 2.09 (3H, s), 3.02 (3H, s), 3.12 & 3.33 (2H, ABq, J = 13Hz), 6.13 (lH, s), 6.14 (lH, s).

MS (m / z): 419 (M ⁺ ), 359,334,316.

Example 11

Reflux a mixture of 300 mg 17α-acetoxy-6-chloro-1-hydroxy-2-oxapregna-4,6-diene-3,20-dione, 3.5 g ammonium formate and 4 ml of 99% formic acid Under heating for 28 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydroxide solution, 30% aqueous hydrogen chloride solution and saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the crude product was purified by TLC [developing solvent: chloroform: acetone (6/1)] to 50 mg of 17α-acetoxy-2-aza-6-chloropregna-4,6-diene-3,20 -Dione (Rf = 0.5) is obtained. The ¹ H-NMR spectrum of this compound is the same as that of the compound obtained in Example 9. Furthermore, 30 mg of 2-aza-6-chloro-17α-hydroxypregna-4,6-diene-3,20-dione having an Rf value of about 0.3 is obtained.

) : 0.75(3H,s), 1.13(3H,s), 2.25(3H,s), 3.24(2H,m), 6.09(lH,brs), 6.21 (lH,br s), 6.77(1H,br s). ¹ H-NMR (CDC1 ₃ ,

): 0.75 (3H, s), 1.13 (3H, s), 2.25 (3H, s), 3.24 (2H, m), 6.09 (lH, brs), 6.21 (lH, br s), 6.77 (1H, br s).

MS (m / z): 363 (M ⁺ ), 320.

Example 12

80 mg of 17α-acetoxy-2-aza-6-chloro-2-methylpregna-4,6-diene-3,20-dione, 0.5m1 sodium methylate 30% methane solution, 3m1 tetrahydro The mixture of furan and 1 ml of methanol is heated at 60 ° C. for 30 minutes. Water is added to the reaction mixture and the mixture is extracted with chloroform. The extract is washed with water and dried over anhydrous magnesium sulfate. The crude product was purified by TLC [developing solvent: chloroform / acetone (9/1)] to give 55 mg of 2-aza-6-chloro-17α-hydroxy-2-methylpregna-4,6-diene-3,20. -Dione is obtained.

) : 0.77(3H,s), 1.12(3H,s), 2.27(3H,s), 3.01(3H,s), 1.17 & 3.33(2H, ABq,J=12Hz), 6.12(lH,s), 6.15(lH,br s). ¹ H-NMR (CDC1 ₃ ,

): 0.77 (3H, s), 1.12 (3H, s), 2.27 (3H, s), 3.01 (3H, s), 1.17 & 3.33 (2H, ABq, J = 12Hz), 6.12 (lH, s), 6.15 (lH, br s).

MS (m / z): 377 (M ⁺ ), 359,334.

Example 13

A mixture of 15 mg 2-aza-6-chloro-17α-hydroxy-2-methylpregna-4,6-diene-3,20-dione and 0.5 ml of propionic anhydride is heated at 130 ° C. for 6 hours. The reaction mixture is cooled to room temperature and about 0.5 ml of pyridine and about 0.5 ml of water are added. The mixture is left at room temperature for 15 hours and then extracted with ethyl acetate. The extract was washed successively with 50% aqueous hydrogen chloride solution and saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the crude product was purified by TLC [developing solvent: chloroform / acetone (9/1)] to give 14 mg of 2-aza-6-chloro-2-medyl-17α-propionyloxypregna-4,6-. Obtain diene-3,20-dione.

) : 0.71(3H,s), 1.12(3H,s), 1.17(3H,t,J=7Hz), 2.05(3H,s), 3.38(2H,q, J=7Hz), 3.03(3H,s), 3.12 & 3.33(2H,ABq,J=13Hz), 6.13(lH,s), 6.14(lH,s). ¹ H-NMR (CDC1 ₃ ,

): 0.71 (3H, s), 1.12 (3H, s), 1.17 (3H, t, J = 7Hz), 2.05 (3H, s), 3.38 (2H, q, J = 7Hz), 3.03 (3H, s ), 3.12 & 3.33 (2H, ABq, J = 13 Hz), 6.13 (lH, s), 6.14 (lH, s).

Example 14

-히드록시-2-옥사프레그나-4,6-디엔-3,20-디온을 수득한다.15.0 g l7α-acetoxy-6-chloropregna-1,4,6-triene-3,20-dione, 0.5 g osmium tetraoxide, 33.6 g sodium iodide, 300 m1 dioxane and 98 m1 The mixture of water is heated under reflux for 3 hours. Periodic acid (16 g) is added to the reaction mixture and the mixture is refluxed for another 30 minutes. The reaction mixture is added to 4 l of 5% sodium hyposulfite and extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate. 7.2 g of 17α-acetoxy-6-chloro-1 by evaporation of the solvent and purification of the crude product by silica gel column chromatography (eluent: chloroform).

-Hydroxy-2-oxapregna-4,6-diene-3,20-dione is obtained.

Melting Point: 276∼278 ℃

IR (KBr, cm ⁻¹ ): 3510,1725,16l6,1258.

) : 0.72(3H,s), 1.20(3H,s), 2.06(3H,s), 2.12(3H,s), 5.51(lH,s,), 6.21 (lH, s), 6.35(lH, br s). ¹ H-NMR (CDC1 ₃ ,

): 0.72 (3H, s), 1.20 (3H, s), 2.06 (3H, s), 2.12 (3H, s), 5.51 (lH, s,), 6.21 (lH, s), 6.35 (lH, br s).

MS (m / z): 4.22 (M ^< ^{+ &} gt ^; ), 380,376,362,337,319.

Example 15

46 g of 17α-acetoxy-6-chloro-1ε-hydroxy-2-oxapregna-4,6-diene-3.20-dione, a mixture of 239 silver oxide and 50 ml of methyl iodide under reflux for 3 hours Heat. The insoluble material was filtered off and the filtrate was distilled to give ethyl 17α-acetoxy-6-chloro-1,20-dioxo-A-nor-1,2-secopregna-3,6-diene- as a colorless crystalline powder. 4.19 g of 2-oate are obtained.

) : 0.71(3H,s), 1.48(3H,s), 2.02(3H,s), 2.08(3H,s), 368(3H,s), 6.32(lH, brs), 6.48(lH,s), 9.57(lH,s) ¹ H-NMR (CDC1 ₃ ,

): 0.71 (3H, s), 1.48 (3H, s), 2.02 (3H, s), 2.08 (3H, s), 368 (3H, s), 6.32 (lH, brs), 6.48 (lH, s) , 9.57 (lH, s)

Example 16

200 mg of 17α-acetoxy-6α, 7α-epoxypregna-1,4-diene-3,20-dione are dissolved in 15 ml of dichloromethane and 5 ml of pyridine and passed through ozone at −78 ° C. for 10 minutes. The reaction mixture is stirred at room temperature for 10 minutes and 3 ml of 10% sodium hydrogen sulfite is added. The mixture is stirred at rt for 1 h and extracted with chloroform. The extract was washed successively with 10% sulfuric acid and saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. 146 mg of 17α-acetoxy-6α, 7α-epoxy-1ξ 一 hydroxy-2-oxa-4-pregnene by evaporating the solvent and purifying the crude product with TLC [developing solvent: chloroform / acetone (9/1)]. -3,20-dione is obtained.

) : 0.70(3H,s), 1.18(3H,s), 2.05(3H,s), 2. 12(3H,s), 3.47(lH,d,J=4Hz), 3.54(lH,d,J=4Hz), 5.43(lH,s), 6.17(1H,s). ¹ NMR (CDCI ₃ -D ₂ O,

): 0.70 (3H, s), 1.18 (3H, s), 2.05 (3H, s), 2. 12 (3H, s), 3.47 (lH, d, J = 4Hz), 3.54 (lH, d, J = 4 Hz), 5.43 (lH, s), 6.17 (1H, s).

Example 17

185 mg of 17α-acetoxy-6α, 7α-epoxy-1ξ-hydroxy-2-oxa-4-pregnene-3,20-dione, 68 mg sodium bicarbonate, 71 mg sodium borohydride, 4.4m1 tetra A mixture of hydrofuran, 10 ml of methanol and 8.9 ml of water is stirred at room temperature for 30 minutes. 10% sulfuric acid is added to the reaction mixture, which is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure affords 140 mg of 17α-acetoxy-6α, 7α-epoxy-2-oxa-4-pregene-3,20-dione.

) : 0.70(3H,s), 1.18(3H,s), 2.05(3H,s), 2.11(3H,s), 3.48(lH,d,J=4Hz), 3.52(lH,d,J=4Hz), 4.11(2H,m), 6.10(1H,s). ¹ H-NMR (CDC1 ₃ ,

): 0.70 (3H, s), 1.18 (3H, s), 2.05 (3H, s), 2.11 (3H, s), 3.48 (lH, d, J = 4Hz), 3.52 (lH, d, J = 4Hz ), 4.11 (2H, m), 6.10 (1H, s).

Example 18

To a solution of 97 mg of 17α-acetoxy-6α, 7α-epoxy-2-oxa-4-pregene-3,20-dione dissolved in 4 ml of tetrahydrofuran was added concentrated hydrochloric acid (0.lml) and the solution was added. Stir at room temperature for 10 minutes. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure yields 102 mg of 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene-3,20-dione.

) : 0.72(3H,s), 1.46(3H,s), 2.06(3H,s), 2.11(3H,s), 3.97(1H,m), 4.11 & 4.28(2H,ABq,J=1lHz), 4.46(lH,d,J=3Hz), 5.97(lH,s). ¹ H-NMR (CDC1 ₃ ,

): 0.72 (3H, s), 1.46 (3H, s), 2.06 (3H, s), 2.11 (3H, s), 3.97 (1H, m), 4.11 & 4.28 (2H, ABq, J = 1lHz), 4.46 (lH, d, J = 3 Hz), 5.97 (lH, s).

Example 19

A mixture of 20 mg of 17α-acetoxy-6α, 7α-epoxy-1ξ-hydroxy-2-oxa-4-pregene-3,20-dione and 3 ml of 16% hydrochloric acid / ethylacetate solution was stirred at room temperature for 10 minutes. do. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and the solvent is evaporated to afford 21 mg of 17α-acetoxy-6β-chloro-1ξ, 7α-dihydroxy-2-oxa-4-pregene-3,20-dione.

): 0.72(3H,s), 1.43(3H,s), 2.05(3H,s), 2.12(3H,s), 3.93(lH,m), 4.54(lH, d,J=4Hz), 5.43(lH,br s), 6.05(lH,s). ¹ H-NMR (CDC1 ₃ ,

): 0.72 (3H, s), 1.43 (3H, s), 2.05 (3H, s), 2.12 (3H, s), 3.93 (lH, m), 4.54 (lH, d, J = 4 Hz), 5.43 ( l H, br s), 6.05 (l H, s).

Example 20

170 mg of 17α-acetoxy-6β-chloro-1ξ, 7α-dihydroxy-2-oxa-4-pregene-3,20-dione, 62 mg sodium hydrogencarbonate, 4 ml tetrahydrofuran, 9.2 ml methanol And sodium borohydride (64 mg) to a mixture of 8.2 ml of water. The reaction mixture is stirred for 30 minutes at room temperature and 4 ml of 50% hydrochloric acid is added. The mixture is extracted with ethyl acetate, and the extract is washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the crude product was purified by TLC [developing solvent: chloroform / acetone (9/1)] to give 154 mg of 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene- 3,20-dione is obtained. The ^l H-NMR spectrum of this compound is the same as that of the compound obtained in Example 18.

The following preparations illustrate the preparation of a medicament containing a compound of the invention.

Production Example A

Manufacture of tablets

Prescription: 5mg tablet

17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione 5.0

Starch 11.7

Lactose 79.3

Carboxymethyl Cellulose Calcium 2.5

Talc 1,0

Magnesium Stearate 0.5

100.0mg

17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione was pulverized to a particle size of 70 microns or less, and starch, lactose and carboxymethyl cellulose calcium were added thereto. Mix well. 10% starch is added to the mixed powder, stirred and mixed to form granules. After drying, the particle size of the granules is adjusted to about 1000 microns and the activity and magnesium stearate are added. Mix and tablet.

[Manufacture example B]

Manufacture of capsules

Prescription: 10mg capsule

17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione 10.0

Starch 50.0

Lactose 47.0

Magnesium Stearate 3.0

110.0mg

The crystals of 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione are crushed well and mixed with starch, lactose and magnesium stearate. After complete mixing, the mixture is filled into No. 5 capsules.

Claims (5)

A process for producing a compound of formula (I) below, wherein the compound of formula (iii) is dehydrated.

[Wherein, A represents a hydrogen atom or a lower alkanoyl group, and Z represents an oxygen atom or a general formula

(R represents a hydrogen atom or a lower alkyl group), and X represents a halogen atom.] A method for producing a compound of formula (I), wherein the compound of formula (VII) is reduced.

[Wherein, A represents a hydrogen atom or a lower alkanoyl group, and Z represents an oxygen atom or a general formula

(R represents a hydrogen atom or a lower alkyl group), and X represents a halogen atom.] A method for producing a compound of formula (I), wherein the compound of formula (VII) is reacted with a compound of formula R-NH ₂ in the presence of formic acid.

[Wherein, A represents a hydrogen atom or a lower alkanoyl group, and Z represents an oxygen atom or a general formula

And R represents a hydrogen atom or a lower alkyl group, and X represents a halogen atom.] Order characterized by the general formula (Ⅹ) compound to Sikkim general formula R-NH to reduction under or without the presence of a compound of _2, or the general formula R-NH ₂ compound in the presence of formic acid and reaction of the formula ( Process for the preparation of the compound of I).

[Wherein, A represents a hydrogen atom or a lower alkanoyl group, and Z represents an oxygen atom or a general formula

And R represents a hydrogen atom or a lower alkyl group, X represents a halogen atom and R ₁ represents a lower alkyl group.] A process for preparing general formula (I) below, wherein A is lower alkanoyl, characterized by lower alkanoylation of a compound of formula (I) wherein A is a hydrogen atom.

[Wherein, A represents a hydrogen atom or a lower alkanoyl group, and Z represents an oxygen atom or a general formula

(R represents a hydrogen atom or a lower alkyl group), and X represents a halogen atom.]