JPH0413327B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to the use of novel 2-oxa- or -aza-pregnane compounds as progestin agents, and more particularly to the use of novel 2-oxa- or -aza-pregnane compounds as progestin agents. In the formula, A represents a hydrogen atom or a lower alkanoyl group; Z represents an oxygen atom or

The present invention relates to a progestin agent containing as an active ingredient a compound represented by the following formula: where R represents a hydrogen atom or a lower alkyl group; and X represents a halogen atom. As a 2-oxapregnan compound, for example, 17α-acetoxy-2-oxapregna-4,6-diene-3,20-dione having a methyl group at the 6-position has a progestin effect, according to Japanese Patent Publication No. 41-4590. It is disclosed that it has. This time, in the present invention, the 2-oxa- or -aza-pregnane compound of the formula () is a new compound that has not been described in the conventional literature, and is an extremely powerful progestin agent, which can be used to prevent miscarriage and prevent pregnancy. ,
It was found to be useful as a drug for the treatment of respiratory failure, etc. 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" that can be represented by A in the formula () include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, hexanoyl group, etc.
Among these, acetyl group is preferred. Also, Z

In the case of [Formula], R is preferably a hydrogen atom, but it can also be a lower alkyl group, and examples of the "lower alkyl group" that can be represented by R include a methyl group, an ethyl group, and a n-propyl group. , isopropyl group, n-butyl group, isobutyl group, sec
-butyl group, tert-butyl group, etc., and methyl group is particularly preferred. On the other hand, the "halogen atom" represented by X includes fluorine, chlorine, and bromine atoms, of which chlorine atom is preferred. The compound of formula () above can be produced according to the reaction formula below.

[Table] In each of the above formulas, A, Z, X and R 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 compound of formula () is usually oxidized with ethers such as dioxane and tetrahydrofuran; halogenated hydrocarbons such as dichloromethane and chloroform; alcohols such as t-butanol and amyl alcohol; pyridine and these. In a power medium such as a mixture with water, an oxidizing agent such as ozone; osmium tetroxide; a mixture of osmium tetroxide and an oxidizing agent such as potassium chlorate, lead tetraacetate, potassium periodate, etc. The reaction can be carried out at -80°C to the reflux temperature of the reaction mixture. The resulting compound of formula () can be converted into a compound of formula () by reacting with a reagent of formula R ₁ Y, such as methyl iodide, ethyl iodide, etc., in the presence of a silver salt, for example. 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 halogenated 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 any temperature. The resulting compound of formula () is produced in the presence of ammonia or a primary amine of the formula R- _NH2 (Z=

[Formula]) or in the absence (when Z=O) can be converted into a compound of formula (). 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. Using sodium boronate, t-butoxy lithium aluminum hydride, etc., in the presence of inorganic salts, organic acid salts, etc. as necessary, at approximately -20°C.
It can be carried out at temperatures ranging from room temperature to room temperature. formula()
The amount of ammonia or primary amine represented by the formula R- _NH2 to be used for the compound can generally be about 1 to 20 moles of the compound of the formula R- _NH2 per 1 mole of the compound of the formula (). . Alternatively, the compound of formula () in which Z=O can be produced directly by reducing the compound of formula (). This reduction is also carried out in the same manner as described above, using complex metal hydrides, such as sodium borohydride, hydride, etc., in a solvent such as alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; The reaction can be carried out using potassium boron, sodium cyanoborohydride, lithium aluminum t-butoxyhydride, 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 () is then treated in the absence of a solvent or in a suitable inert solvent, such as organic acids such as acetic acid and propionic acid; alcohols such as ethanol and t-butanol; ethers such as tetrahydrofuran and dioxane; Among halogenated hydrocarbons such as chloroform and carbon tetrachloride, approximately -20
℃ to the reflux temperature of the reaction mixture, usually at room temperature, it can be converted into the compound of formula () by reacting with hydrogen halide (HX). The generated compound of formula () can then be dehydrated to obtain the compound of formula () of the present invention. This dehydration is usually carried out in a solvent such as an organic base such as pyridine; an aromatic hydrocarbon such as benzene or toluene; a halogenated hydrocarbon such as chloroform or carbon tetrachloride; or a solvent such as dimethyl sulfoxide.
p-Toluenesulfonic acid, phosphorus oxychloride, p-
This can be carried out by treating with a dehydrating agent such as toluenesulfonyl chloride, methanesulfonyl chloride, thionyl chloride, etc. at room temperature to the reflux temperature of the reaction mixture. Alternatively, compounds of formula () can also be prepared starting from compounds of formula (). In this alternative method, the oxidation of the compound of formula () can be carried out as described above for the oxidation of the compound of formula (), and the resulting compound of formula () and the reagent of formula R ₁ Y can be The reaction can also be carried out in the same manner as described above for the reaction between the compound of formula () and the reagent represented by formula R ₁ Y. The compound of formula () thus formed can be converted to a compound of formula R in the same manner as described above for the reduction of a compound of formula ().
The desired compound of formula () can be obtained by reduction in the presence or absence of ammonia or a primary amine represented by -NH ₂ In addition, the compound of formula () can be obtained in the presence of formic acid. It can also be converted into the desired compound of formula () by reacting with ammonia or a primary amine represented by the formula R-NH ₂ below. This reaction is usually carried out using a large excess of formic acid in the absence of a solvent.
Generally, it can be carried out at the reflux temperature of the reaction mixture. The dosage of ammonia or primary amine represented by the formula R- _NH2 for the compound of the formula () is generally about 1 to 20 moles of the compound of the formula R- _NH2 per 1 mole of the compound of the formula (). I can do it. Furthermore, the compound of formula () above can be directly converted to a compound of formula () by reduction or reaction with ammonia or a primary amine of formula R- _NH2 in the presence of formic acid. can. This reaction can also be carried out in the same manner as described above for the reduction of a compound of formula () or the reaction of a compound of formula () with a compound of formula R- _NH2 in the presence of formic acid. Incidentally, the intermediate of formula () can be obtained by treating the compound of formula () described above with hydrogen halide and then reducing it, or by reacting it with ammonia or a primary amine represented by formula R- _NH2 in the presence of formic acid. It can also be synthesized by The reaction of a compound of formula () with a hydrogen halide and the reduction of the resulting compound of formula () or the reaction with a compound of formula R- _NH2 in the presence of formic acid respectively The reaction with hydrogen halide and the reduction of the compound of formula () or the reaction of the compound of formula () with the compound of formula R-HN ₂ in the presence of formic acid can be carried out in the same manner as described above. Further, the intermediate of formula () can also be synthesized by dehydrating the compound of formula () above. Dehydration of the compound of formula () can be carried out in the same manner as described above for the dehydration of the compound of formula (). Furthermore, the compound of formula () when A is a hydrogen atom can be converted into the corresponding compound of formula () when A represents a lower alkanoyl group by lower alkanoylation by a method known per se. In addition, the compound of formula () when A represents a lower alkanoyl group can be converted into the corresponding compound of formula () when A is a hydrogen atom by hydrolysis by a method known per se. You can also do it. For example, lower alkanoylation of a compound of formula () when A is a hydrogen atom can be carried out using a reactive derivative of a lower alkanoic acid, such as an acid anhydride, an acid halide, etc., in the absence of a solvent or in an inert solvent, e.g. Ethers such as ethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene and toluene; The reaction can be carried out in the presence of an acid catalyst such as chloric acid at room temperature to the reflux temperature of the reaction mixture. The compound of formula () produced as described above can be prepared by means known per se, such as percolation, recrystallization,
It can be isolated and purified by means such as column chromatography and thin layer chromatography. As mentioned above, the 2-oxa- or -aza-pregnane compound of the formula () provided by the present invention has an excellent progestin effect and is useful, for example, as a drug for preventing miscarriage or contraception. . The excellent progestin effect of the compound of formula () of the present invention is demonstrated by the following experiment. Measurement of progesterone effect Using a group of 5 young female rabbits (680-1270 g), the Clauberg-McPhail method was used.
-Mcphail method (Acta Endocrinol., Vol. 78, p. 574, 1975). i.e., of estradiol benzoate.
Administer 2 μg/mouse subcutaneously once a day for 7 days, and then
The test compound was administered subcutaneously twice a day (once on the first day) and once in the morning on the 6th day (10 times in total). Note that estradiol benzoate was dissolved in sesame oil, and the test compound was suspended in 2% Tween 80 physiological saline. The animals were sacrificed in the afternoon of the 6th day, and the weight of the uterus, the width of the endometrium, and the width of the myometrium were measured.
As a result, the 17α-acetoxy-6chloro-2-oxapregna-4,6-diene-3,20 of the present invention
-Dione is 17α which is more than 100 times that of progesterone.
Acetoxy-2-aza-6-chloropregna
4,6-diene-3,20-dione exhibited a progestin effect approximately 25 times that of progesterone. Toxicity 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-6-chloro-2 of the present invention
-Oxapregna-4,6-diene-3,20-dione caused no deaths even at a dose of 3000 mg/Kg. Thus, the compound represented by the formula () of the present invention can be administered orally, parenterally (e.g., intramuscularly, subcutaneously, (e.g., rectally) or locally. When used as a medicament, the compounds of the invention can be formulated into a variety of forms suitable for oral, 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. agent, colorant,
It can be formulated using additives such as flavoring agents and buffering agents. Such preparations may be in solid form (e.g., tablets, hard capsules, soft capsules, granules, powders, fine granules, pills, pastilles, etc.), depending on their use;
It can be prepared in either semi-solid form (eg, suppositories, ointments, etc.) and liquid forms (injections, emulsions, suspensions, lotions, sprays, etc.). Therefore, the non-toxic additives that can be used include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or its salts, gum arabic, polyethylene glycol. ,
Examples include p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol, petrolatum, carbo wax, glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid and the like. The medicament may also contain other therapeutically useful agents. The content of the compound of the invention in the reagent 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 to 10% for liquid forms. It is desirable to contain the active compound in a concentration of % 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 it is generally 0.0005 to 1 mg per day. /Kg. 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. Production example 1 17α-acetoxy-6-chloro-1ξ-hydroxy-2-oxapregna-4,6-diene-3,
72 mg of sodium borohydride was added to a mixture of 200 mg of 20-dione, 80 mg of sodium bicarbonate, 20 ml of methanol, and 10 ml of water, and the mixture was stirred at room temperature for 30 minutes. Approximately 0.4 ml of concentrated 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 and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by TLC [developing solvent, chloroform] to obtain 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione.
Obtained 120 mg. Melting point: 253-255°C (acetone-hexane). IR (KBr, cm ^-1 ): 3390, 1710, 1605, 1245. ^1H -NMR ( _CDCl3 , δ): 0.72 (3H, s), 1.21
(3H, s), 2.05 (3H, s), 2.09 (3H, s), 4.11
and 4.21 (2H, ABq, J = 11Hz), 6.15 (1H,
s), 6.30 (1H, broad s). MS (m/z): 406 (M ⁺ ), 363, 346, 321, 303. Production example 2 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene-3,20-dione 70 mg, para-toluenesulfonyl chloride 400 mg,
4-dimethylaminopyridine 1 mg and pyridine
0.9ml of the mixture was heated to reflux for 2 hours. Water was added to the reaction mixture and the product was extracted with ethyl acetate.
The extract was washed with a 50% aqueous hydrochloric 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 (19:1)] to obtain 17α-acetoxy-6-
Chloro-2-oxapregna-4,6-diene-
52 mg of 3,20-dione was obtained. ¹ H− of this compound
The NMR spectrum was identical to that of the material prepared in Preparation Example 1. Production example 3 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-pregnene-3,20-dione
After stirring a mixture of 1.76 g, methanesulfonyl chloride 1.11 ml and pyridine 5.2 ml under ice cooling for 1 hour,
Stirred at room temperature for 12 hours. Add ice-cold water to the reaction mixture, collect the precipitated crystals, and collect 17α-acetoxy-
6β-chloro-7α-mesyloxy-2-oxa-
2.01 g of pregnene-3,20-dione was obtained. Melting point: 225.5-226.4° (methanol). IR (KBr, cm ^-1 ): 1735, 1350, 1250, 1175. ^1H -NMR ( _CDCl3 , δ): 0.74 (3H, s), 1.48
(3H, s), 2.06 (3H, s), 2.09 (3H, s), 3.08
(3H, s), 4.11 and 4.28 (2H, ABq, J=10
Hz), 4.78 (1H, d, J=3Hz), 4.92 (1H, m),
6.02 (1H, s). A mixture of 2.35 g of 17α-acetoxy-6β-chloro-7α-mesyloxy-2-oxa-4-pregnene-3,20-dione, 0.83 g of potassium acetate and 0.88 ml of dimethyl sulfoxide was stirred at room temperature for 2 hours. Add ice-cold water to the reaction mixture, collect the precipitated crystals, and give 17α-acetoxy-6-chloro-2-
1.37 g of oxapregna-4,6-diene-3,20-dione was obtained. The ¹ H-NMR spectrum of this compound was identical to that of the material prepared in Preparation Example 1. Production example 4 Methyl 17α-acetoxy-6-chloro-1,
36 mg of 20-dioxo-A-nor-1,2-secopregna-3,6-diene-2-oate was dissolved in 1 ml of tetrahydrofuran and cooled on ice. Add 63mg of lithium tri-t-butoxyaluminohydride to this solution.
was added under ice-cooling and stirring for 15 minutes. A 20% aqueous 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 obtain 17α-acetoxy-6-chloro-2-
23 mg of oxapregna-4,6-diene-3,20-dione was obtained. The ¹ H-NMR spectrum of this compound was identical to that of the material prepared in Preparation Example 1. Production Example 5 116 mg of 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione,
Approximately 28% sodium methylate methanol solution 0.5
ml, 0.1 ml of tetrahydrofuran and 5 ml 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, 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-17α-hydroxy-2-oxapregna-4,6-diene-
70 mg of 3,20-dione was obtained. Melting point: 218-221°C (acetone-hexane). IR (KBr, cm ^-1 ): 3410, 1700, 1605. ^1H -NMR ( _CDCl3 , δ): 0.75 (3H, s), 1.20
(3H, s), 2.24 (3H, s), 4.08 and 4.19 (2H,
ABq, J=13Hz), 6.11 (1H, s), 6.34 (1H,
broad s). MS (m/z): 364 (M ⁺ ), 321, 303. Production Example 6 A mixture of 70 mg of 6-chloro-17α-hydroxy-2-oxapregna-4,6-diene-3,20-dione and 2 ml of propionic anhydride was heated at 130°C for 6 hours.
heated for an hour. 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. The extract was washed with a 30% aqueous hydrochloric 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 (19:1)] to obtain 6-chloro-2
-Oxa-17α-propionyloxypregna-
54 mg of 4,6-diene-3,20-dione was obtained. Melting point: 199-202°C (acetone-hexane). IR (KBr, cm ^-1 ): 3380, 1700, 1600. ^1H -NMR ( _CDCl3 , δ): 0.73 (3H, s), 1.17
(3H, t, J=7Hz), 1.22 (3H, s), 2.05 (3H,
s), 2.38 (2H, q, J=7Hz), 4.11 and 4.22
(2H, ABq, J=12Hz), 6.17 (1H, s), 6.32
(1H, broad s). MS (m/z): 420 (M ⁺ ), 377, 346, 321, 303. Production Example 7 The same procedure as in Production Example 6 was carried out except that caproic anhydride was used instead of propionic anhydride.
6-chloro-17α-hexanoyloxy-2-oxapregna-4,6-diene-3,20-dione was obtained. ^1H -NMR ( _CDCl3 , δ): 0.73 (3H, s), 0.91
(3H, t, J=6Hz), 1.22 (3H, s), 2.05 (3H,
s), 4.11 and 4.21 (2H, ABq, J = 11Hz),
6.17 (1H, s), 6.32 (1H, broad s). MS (m/z): 462 (M ⁺ ), 321, 303. Production Example 8 A mixture of 100 mg of 17α-acetoxy-6α,7α-epoxy-2-oxa-pregnene 3,20-dione, 200 mg of potassium hydrogen fluoride, and 1 ml of dimethyl sulfoxide 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 purified by TLC [developing solvent, chloroform:acetone (50:1)] to obtain 17α
20 mg of -acetoxy-6-fluoro-2-oxapregna-4,6-diene-3,20-dione was obtained. ^1H -NMR ( _CDCl3 , δ): 0.72 (3H, s), 1.22
(3H, s), 2.05 (3H, s), 2.09 (3H, s), 4.17
(2H, m), 5.70 (1H, broad d, J=14Hz),
5.96 (1H, s). MS (m/z): 390 (M ⁺ ), 347, 330, 305, 287. Production example 9 Methyl 17α-acetoxy-6-chloro-1,
A mixture of 500 mg of 20-dioxo-A-nor-1,2-secopregna-3,6-diene-2-oate, 1.3 g of ammonium acetate, 1.0 g of sodium cyanoborohydride, 5 ml of tetrahydrofuran and 9 ml of methanol was heated at room temperature for 22 hours. Stirred. Approximately 20 ml of 50% aqueous hydrochloric acid solution was added to the reaction mixture, and the
Stirred for an hour and extracted the product with chloroform.
The extract was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained crude product was purified by TLC [developing solvent, chloroform:methanol (19:1)],
295 mg of 17α-acetoxy-2-aza-6-chloropregna-4,6-diene-3,20-dione was obtained as a colorless crystalline powder. Melting point: 286.6-287.6℃ (methanol). IR (KBr, cm ^-1 ): 3400, 1725, 1660. ^1H -NMR ( _CDCl3 , δ): 0.71 (3H, s), 1.17
(3H, s), 2.06 (3H, s), 2.10 (3H, s), 3.27
(2H, m), 6.14 (1H, broad s), 6.23 (1H,
broad s), 6.77 (1H, broad s). MS (m/z): 405 (M ⁺ ), 320, 302. Production Example 10 In Production Example 9, 17α-
Acetoxy-2-aza-6-chloro-2-methylpregna-4,6-diene-3,20-dione was obtained. Melting point: 292.6-293.6℃ (acetone). IR (KBr, cm ^-1 ): 3400, 1725, 1650. ^1H -NMR ( _CDCl3 , δ): 0.71 (3H, s), 1.12
(3H, s), 2.06 (3H, s), 2.09 (3H, s), 3.02
(3H, s), 3.12 and 3.33 (2H, ABq, J=13
Hz), 6.13 (1H, s), 6.14 (1H, s). MS (m/z): 419 (M ⁺ ), 359, 334, 316. Production example 11 17α-acetoxy-6-chloro-1ξ-hydroxy-2-oxapregna-4,6-diene-3,
300 mg of 20-dione, 3.5 g of ammonium formate and
A mixture of 4 ml of 99% formic acid was heated to reflux for 28 hours. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was washed successively with an aqueous sodium hydroxide solution, a 30% aqueous hydrochloric acid solution, and a saturated aqueous sodium bicarbonate solution, and then dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by TLC [developing solution, chloroform:acetone (6:1)] to obtain 17α-acetoxy-2 from an R value of about 0.5.
-aza-6-chloropregna-4,6-diene-
50 mg of 3,20-dione was obtained. ¹ H− of this compound
The NMR spectrum was identical to that of the material prepared in Preparation Example 9. Furthermore, 30 mg of 2-aza-6-chloro-17α-hydroxypregna-4,6-diene-3,20-dione was obtained from an R value of about 0.3. ^1H -NMR ( _CDCl3 , δ): 0.75 (3H, s), 1.13
(3H, s), 2.25 (3H, s), 3.24 (2H, m), 6.09
(1H, broad s), 6.21 (1H, broad s), 6.67
(1H, broad s). Ms (m/z): 363 (M ⁺ ), 320. Production example 12 17α-acetoxy-2-aza-6-chloro-2
A mixture of 80 mg of -methyl pregna-4,6-diene-3,20-dione, 0.5 ml of 30% sodium methylate methanol solution, 3 ml of tetrahydrofuran and 1 ml of methanol was heated at 60°C for 30 minutes. Water was added to the reaction mixture, and the product was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate. The obtained crude product was purified by TLC [developing solvent: chloroform:acetone (9:1)] to give 2-aza-6-chloro-17α-hydroxy-2-methylpregna-4,6-diene-3,
55 mg of 20-dione was obtained. ^1H -NMR ( _CDCl3 , δ): 0.77 (3H, s), 1.12
(3H, s), 2.27 (3H, s), 3.01 (3H, s), 1.17
and 3.33 (2H, ABq, J = 12Hz), 6.12 (1H,
s), 6.15 (1H, broad s). MS (m/z): 377 (M ⁺ ), 359, 334. Production example 13 2-aza-6-chloro-17α-hydroxy-2
A mixture of 15 mg of -methylpregna-4,6-diene-3,20-dione and 0.5 ml of propionic anhydride was heated at 130°C for 6 hours. The reaction mixture was cooled to room temperature, about 0.5 ml of pyridine and about 0.5 ml of water were added and left at room temperature for 15 hours, and 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, chloroform:acetone (9:1)] to obtain 2-aza-6-chloro-2-methyl-17α-propionyloxapregna. 14 mg of -4,6-diene-3,20-dione was obtained. ^1H -NMR ( _CDCl3 , δ): 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 and 3.33 (2H, ABq, J=13Hz), 6.13
(1H, s), 6.14 (1H, s). Production example 14 17α-acetoxy-6-chloropregna-1,
4,6-triene-3,20-dione 15.0g, osmium tetroxide 0.5g, sodium periodate 33.6
3 g, a mixture of 300 ml of dioxane and 98 ml of water
The mixture was heated to reflux for an hour. 16g periodic acid to the reaction mixture
was added and refluxed for an additional 30 minutes. 5% reaction mixture
The product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography [elution solvent: chloroform],
17α-acetoxy-6-chloro-1ξ-hydroxy-2-oxapregna-4,6-diene-3,20
- 7.2 g of dione were obtained. Melting point: 276-278°C (acetone-hexane). IR (KBr, cm ^-1 ): 3510, 1725, 1616, 1258. ^1H -NMR ( _CDCl3 , δ): 0.72 (3H, s), 1.20
(3H, s), 2.06 (3H, s), 2.12 (3H, s), 5.51
(1H, s), 6.21 (1H, s), 6.35 (1H, broad
s). MS (m/z): 422 (M ⁺ ), 380, 376, 362, 337,
319. Production example 15 17α-acetoxy-6-chloro-1ξ-hydroxy-2-oxapregna-4,6-diene-3,
A mixture of 4.6 g of 20-dione, 23 g of silver oxide and 50 ml of methyl iodide was heated under reflux for 3 hours. Insoluble matter was removed by filtration, and the liquid was distilled off to give methyl 17α-acetoxy-6-chloro-1,20-dioxo-A-
nor-1,2-secopregna-3,6-diene-
4.19 g of colorless crystalline powder of 2-oate was obtained. ^1H -NMR ( _CDCl3 , δ): 0.71 (3H, s), 1.48
(3H, s), 2.02 (3H, s), 2.08 (3H, s), 3.68
(3H, s), 6.32 (1H, broad s), 6.48 (1H,
s), 9.57 (1H, s). Production example 16 200 mg of 17α-acetoxy-6α,7α-epoxy pregna-1,4-diene-3,20-dione was dissolved in 15 ml of dichloromethane and 15 ml of pyridine, and -
Ozone was passed through for 10 minutes at 78°C. The reaction mixture was stirred at room temperature for 10 minutes, 3 ml of 10% sodium bisulfite was added thereto, and the mixture was stirred at room temperature for 1 hour. The product was extracted with chloroform, and the extract was washed with a 10% aqueous sulfuric 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)].
17α-acetoxy-6α,7α-epoxy-1ξ-hydroxy-2-oxa-4-pregnene-3,20-
146 mg of dione was obtained. ^1H -NMR ( _CDCl3 - _D2O , δ): 0.70 (3H, s),
1.18 (3H, s), 2.05 (3H, s), 2.12 (3H, s),
3.47 (1H, d, J = 4Hz), 3.54 (1H, d, J = 4
Hz), 5.43 (1H, s), 6.17 (1H, s). Production example 17 17α-acetoxy-6α,7α-epoxy-1ξ-hydroxy-2-oxa-4-pregnene-3,20
-Dione 185mg, sodium bicarbonate 68mg, sodium borohydride 71mg, tetrahydrofuran
A mixture of 4.4 ml, methanol 10 ml and water 8.9 ml was stirred at room temperature for 30 minutes. A 10% aqueous sulfuric acid solution 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 to obtain 17α-acetoxy-6α,7α-epoxy-
2-oxa-4-pregnene-3,20-dione
Obtained 140 mg. ^1H -NMR ( _CDCl3 , δ): 0.70 (3H, s), 1.18
(3H, s), 2.05 (3H, s), 2.11 (3H, s), 3.48
(1H, d, J=4Hz), 3.52 (1H, d, J=4
Hz), 4.11 (2H, m), 6.10 (1H, s). Production Example 18 To a solution of 97 mg of 17α-acetoxy-6α,7α-epoxy-2-oxa-pregnene-3,20-dione in 4 ml of tetrahydrofuran was added 0.1 ml of concentrated hydrochloric acid, and the mixture 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 bicarbonate solution and dried over anhydrous magnesium sulfate. Distill the solvent under reduced pressure to obtain 17α
-acetoxy-6β-chloro-7α-hydroxy-
2-oxa-pregnene-3,20-dione 102mg
I got it. ^1H -NMR ( _CDCl3 , δ): 0.72 (3H, s), 1.46
(3H, s), 2.06 (3H, s), 2.11 (3H, s), 3.97
(1H, m), 4.11 and 4.28 (2H, ABq, J=11
Hz), 4.46 (1H, d, J = 3Hz), 5.97 (1H, s). Production example 19 17α-acetoxy-6α,7α-epoxy-1ξ-hydroxy-2-oxa-4-pregnene-3,20
A mixture of 20 mg of -dione and 3 ml of a 16% hydrogen chloride-ethyl acetate solution was stirred at room temperature for 10 minutes. Saturated aqueous sodium hydrogen carbonate solution 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-
21 mg of acetoxy-6β-chloro-1ξ,7α-dihydroxy-2-oxa-4-pregnene-3,20-dione was obtained. ^1H -NMR ( _CDCl3 , δ): 0.72 (3H, s), 1.43
(3H, s), 2.05 (3H, s), 2.12 (3H, s), 3.93
(1H, m), 4.54 (1H, d, J=4Hz), 5.43 (1H,
broad s), 6.05 (1H, s). Production example 20 17α-acetoxy-6β-chloro-1ξ,7α-dihydroxy-2-oxa-4-pregnene-3,20
- 170 mg of dione, 62 mg of sodium bicarbonate, 4 ml of tetrahydrofuran, 9.2 ml of methanol and water
64 mg of sodium borohydride was added to the 8.2 ml mixture at room temperature with stirring. Reaction mixture at room temperature
After stirring for 30 minutes, 4 ml of 50% aqueous hydrochloric acid solution 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 obtain 17α-acetoxy-6β-
154 mg of chloro-7α-hydroxy-2-oxa-pregnene-3,20-dione was obtained. The ¹ H-NMR spectrum of this compound was identical to that of the material prepared in Preparation Example 18. Examples of drugs containing the compound of the present invention are as follows. Example 1 5mg tablet 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20 5.0 Starch 11.7 Lactose 79.3 Carboxymethyl cellulose calcium 2.5 Talc 1.0 Magnesium stearate 0.5 100.0mg 0.03mg tablet 17α-acetoxy -6-Chloro-2-oxapregna-4,6-diene-3,20-dione 0.03 Starch 8.0 Lactose 67.97 Calcium carboxymethylcellulose 2.5 Talc 1.0 Magnesium stearate 0.5 80.0mg 17α-acetoxy-6-chloro-2-oxapregna -Crystals of 4,6-diene-3,20-dione are ground to a particle size of 70 microns or less, and starch and
Add lactose and carboxymethylcellulose calcium and mix well. Add 10% starch paste 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.

Claims (1)

[Claims] 1 formula In the formula, A represents a hydrogen atom or a lower alkanoyl group; Z represents an oxygen atom or [Formula], where R represents a hydrogen atom or a lower alkyl group; X is a halogen atom. A progestin agent whose active ingredient is the compound shown in 2. A progestin agent containing as an active ingredient the compound according to claim 1, wherein A is an acetyl group. 3. A progestin agent containing as an active ingredient the compound according to claim 1, wherein Z represents an oxygen atom or [Formula]. 4. A progesterone agent containing as an active ingredient the compound according to claim 1, wherein X is a chlorine atom. 5 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione or
A progestin agent containing as an active ingredient the compound according to claim 1, which is 17α-acetoxy-2-aza-6-chloropregna-4,6-diene-3,20-dione. 6. The progestin agent according to claim 1, which is used to prevent miscarriage. 7. The progestin agent according to claim 1, which is used for contraception. 8. The progestin agent according to claim 1, which is in an oral dosage form.