Contraception for animals and method thereof

 

(57) Abstract:

Usage: veterinary medicine, namely contraception animals. The inventive contraceptive for animals contains an effective dose of a progestin pre-micronized 3,17-dihydroxy-6-methylpregna-4,6-Dien-20-one or its esters of the General formula I:

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where R and R' = H or acyl group containing from C1to C6carbon atoms, and R may be equal to R', or it may differ. The tool may further comprise a pre-micronized natural or synthetic estrogen. The proposed method of obtaining contraception allows carrying out acylation using a minimum number Alliluyeva agent, namely: 1.1 to 1.5 mol per 1 mol of steroid; to obtain a product of satisfactory quality in a single stage without additional purification; to exclude from the application of pyridine; to carry out the acylation reaction in the environment of a minimum number of dialkylamino, namely: 3 - 5 volumes in 1 weight. including steroid; used as a catalyst for the acylation of a catalytic amount of tertiary amine, e.g. triethylamine or 2,4,6-Tris-(dimethylaminophenyl selection of the target product. 2 S. and 2 C.p. f-crystals.

The invention relates to the field of veterinary medicine and can be used for contraception animals.

Known use as contraceptives natural yellow body hormone progesterone, the introduction of which causes the development of false pregnancy (30 to 45 days). Then the sexual cycle occurs a week later. However, progesterone has a relatively low gestagenna activity, and therefore it is necessary to use in large doses and parenteral which is undesirable (Mashkovsky M. D. Medicines, M. Medicine, 1987, T. 1, S. 590).

It is also known the use of synthetic analogues 17-oksiprogesterona, leading to a delay in the onset of estrus and hunting, for example, in cats and dogs. But all these drugs are also used in significant quantities in oral introduction (Karpov Century A. Obstetrics and gynecology small Pets, M. Rosagropromizdat, 1990).

Known methods of obtaining contraceptives on the basis of progestin, including the interaction of steroid alcohols with anhydride or boronhydride of the appropriate acid in the presence of organic bases as catalizadores pyridine.

When carrying out the acylation reaction in a mixture of pyridine and mixed with water solvent the selection of the target product are carried out by diluting the reaction mass with plenty of water with the addition (or without additions of hydrochloric acid to bind izbytocnogo amount of pyridine. The filtered precipitate is washed on the filter with plenty of water to remove the catalyst, pyridine or hydrochloride (U.S. patent N 3126399, NCI 260 397.4, 1964, the United Kingdom patent N 1055534, MKI C 07 C 169/36).

The disadvantages of these methods are:

use as a solvent or catalyst pyridine, creating environmental problems in industrial production;

the selection of a technical product, using large amount of water requires large amount of equipment;

the need for purification of the product as a separate stage of the process;

the long duration and complexity of the process;

the use of a considerable excess Alliluyeva agent.

The aim of the invention in the part of the funds is to increase safety, improve endurance, increase efficiency and achieve rapid and more prolonged agnetti the th as the progestin contained in the effective number of pre-micronized 3,17-dihydroxy-6-methylpregna-4,6-Dien-20-one or its esters of the General formula I:

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where R and R' is H or acyl group containing C1 to C6 carbon atoms, and R may be equal to R', or it may differ.

In addition, contraceptive may further comprise pre-micronized natural or synthetic estrogen, as is used, for example, ethinylestradiol, esters of estradiol, diethylstilbestrol, etc.

The aim of the invention in terms of method of obtaining contraception is simplifying the process and improving its environmental security:

the reduction in the number of technological operations and complexity of the process;

a significant reduction of the reaction volume and thereby increasing the load on the equipment without the use of equipment of larger capacity;

the exception of pyridine:

a significant reduction in the amount of water used for separation of the target product and its leaching;

reducing the duration of the process;

use the minimum number of Alliluyeva agent;

improving the quality of the target product, which eliminates additional cleaning.

This goal is achieved by the proposed advanced method by which the influence with the anhydride or acid chloride of the appropriate acid in a molar ratio of 1.1 to 1.5 1 to the steroid environment dialkylamino, for example, acetone in the ratio of the volume of solvent to the weight of the steroid 3,0-5,0 1 in the presence of catalytic amounts of tertiary amine, e.g. triethylamine or 2,4,6-Tris-(dimethylaminomethyl)-phenol in a molar ratio of 0.0125, 1,0 1 to the steroid.

The initial compounds of General formula II:

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where R' is H or acyl group containing C1 to C6 carbon atoms.

Obtained by known methods of the most promising and accessible steroid raw materials sterols of plant and animal origin - sitosterol and cholesterol (Korchow centuries Boikova centuries Grinenko, S. Getting 17-acetoxymethyl-4-EN-3 b-ol-20-it and its impact on reproductive function in the experiment, Zhur. Chem.-Pharm. N 7, 1985, S. 817 818; Grinenko, S. Popov, E. C. Andryushina Century A. Tuleev I. I. 3-Ethylenically-17 a-oksiprogesterona as an intermediate for the synthesis of derivatives pregnane and method thereof, ed. mon. N 923125, priority 18.12.80; Grinenko, S. Kadatski, M. Korchow centuries Contraception, application N 4902019/14, 11.01.91, solution 28.10.93. BI N 25, 1995; Grinenko, S. Andryushina Century A. Method of getting a 17-oksiprogesterona, ed. mon. N 1392887, 23.06.86).

The molar ratio of Alliluyeva agent and steroid is minimal and amounts to 1.1:1 to 1.5:1.

The ratio of the volume of alcohol / water mixtures and dialkylamino optimally and is 2:1.

Analysis of the known prior art has shown the absence of any information about technical solutions, all the same essential features with the stated means and method thereof, which allows to make a conclusion on the conformity of the proposed technical solutions to the condition of patentability "novelty."

Nor were decisions that have signs consistent with the distinguishing characteristics of the proposed technical solutions that allows to make a conclusion on compliance with the conditions of patentability "inventive step".

The proposed tool and method thereof correspond to the condition of patentability "industrial applicability", as can be used in industry and agriculture, namely in veterinary medicine.

Example 1. The experiment was performed in 13 cats and cats. The preparation was given inside animals sexually Mature cats and to whom otam 2 tablets per day during the same period.

Dose the introduction of the active substance of 0.001 to 0.1 mg per 1 kg of weight of animal. In the case of the earlier manifestations of the inhibitory effect of the drug is ceased.

The results of the experiments showed that the drug causes inhibition of sexual arousal in all animals, like cats, and cats. Further observation of the animals that received the drug showed that during the whole observation period (in month), no cats, no cats has not been repeated sexual arousal.

Example 2. The experiments were conducted on 120 adult rats females weighing 180

200 g with a normal estrous cycle. Animals were kept in standard cages. For feeding used fodder, vegetables and cheese. The vivarium lighting regime. The temperature of the vivarium 20oC.

The drug was administered orally in oil form within 14 days at a dose of 0.8 mg/kg in combination with ethinyl estradiol (0.04 mg/kg).

Females were infused rats-males after 3 days from the beginning of the introduction of the test drugs. Day of pregnancy was determined by the presence of spermatozoa in vaginal smears. Contraceptive activity was estimated by the number of non-pregnant rats from among fertilized.

It is established that Chaty can judge the achievement obtained a highly effective drug, the use of which leads to a rapid and prolonged suppression of sexual arousal in animals.

Example 3. Getting 3,17 a-diacetoxy-6-methylpregna-4,6-Dien-20-she-1A- (R and R' COCH3).

a). To a suspension of 0.5 g of a 17-acetoxy-3 b-hydroxy-6-methylpregna-4,6-Dien-20-it (II, a, R' COCH3) in 2.5 ml of acetone under stirring at room temperature added 0.16 ml of acetic anhydride. The suspension is stirred for 3-5 minutes and add equal portions 4 admission of 0.18 ml of triethylamine for 30 minutes, the Reaction mass is heated to a temperature of 28 to 30oC and stirred at the same temperature. Upon completion of the reaction, to the reaction mass under stirring at room temperature, slowly add 5 ml of a mixture of water and methanol in the ratio of 4:1. The resulting suspension is cooled to a temperature of 5 10oC and maintained at this temperature for 2-3 hours

The precipitate is filtered off, washed on the filter with 2 ml of a mixture of water and methanol in the ratio of 4:1 was cooled to a temperature of 5-10oC.

Gain of 0.54 g of compound Ia with a yield of 97.5% in the form of a crystalline white powder with a melting point 197-198oC.

b). To a suspension of 0.5 g of a 17-acetoxy-3 b-hydroxy-6-the 4,6-Tris-dimethylaminomethyl)-phenol in 0.5 ml of acetone. The suspension is heated to a temperature of 28-30oC and stirred until dissolution. Upon completion of the reaction, to the reaction solution was added at room temperature, 5 ml of a mixture of water and ethanol in the ratio of 4:1. The resulting suspension is cooled to a temperature of 5 to 10oC and kept at this temperature for 2-3 hours

The precipitate is filtered off, washed on the filter with 2 ml of a mixture of water and ETANA in the ratio of 4:1 was cooled to a temperature of 5-10oC.

Obtain 0.52 g of compound Ia with the release of 93.9 per cent in the form of a crystalline white powder with a melting point 196-198oC.

Example 4. Getting 17-acetoxy-3 b-butoxy-6-methylpregna-4,6-Dien-20-she-Ib-[R COCH3, R' CO(CH2)2CH3]

To a suspension 133 g of compound IIa and 0,266 g of 4-(dimethylamino)-pyridine in 500 ml of acetone under stirring at room temperature add to 79.2 ml of butyric acid anhydride. The suspension is stirred for 3-5 min and added dropwise slowly over 30 min 6 ml of dry triethylamine. The reaction mass was incubated for 2 h at a temperature of 34-36oC. Upon termination of the reaction the reaction mass is then cooled to room temperature and added dropwise with stirring slowly for 20-30 min 1 l is t at this temperature for 2-3 hours

The precipitate is filtered off, washed on the filter with 100 ml of a mixture of methanol and water in the ratio 1:1 was cooled to a temperature of 5-10oC.

Get 146,12 g of compound Ib with the release of 93% in the form of a crystalline white powder with a melting point 128-130oC.

With the aim of increasing contraceptive received steroid drugs are subjected to micronization.

The proposed method is environmentally friendly, less time consuming in comparison with known methods and allows to obtain a high quality product with the release of 90-98%

1. Contraception for animals on the basis of progestagen, characterized in that it contains an effective amount as a progestogen-pre-micronized 3,17-dihydroxy-6-methylpregna-4,6-Dien-20-one or its esters of the General formula I

< / BR>
where R and R' is H or allgraph containing from C1to C6carbon atoms, and R may be equal to R', or it may differ.

2. Means under item 1, characterized in that it further comprises a pre-micronized natural or synthetic estrogen in an effective amount.

3. The method of obtaining contraceptives dlclose in the presence of a catalyst and isolation of the target product, characterized in that the interaction of steroid alcohol with the anhydride or acid chloride of the appropriate acid is carried out in a molar ratio of 1.1 to 1.5 1 to the steroid environment dialkylamino in the volume ratio of solvent to the weight of the steroid, is 3.0 to 5.0:1, as a catalyst used tertiary amine in a molar ratio of 0.0125 1,0 1 to the steroid, and the selection of the target product are carried out by diluting the reaction mass twice the amount of the mixture of water and aliphatic alcohol in the ratio of 1:1 to 4:1 by volume dialkylamino.

4. The method according to p. 3, characterized in that as dialkylamino use acetone, tertiary amine, the triethylamine or 2,4,6-Tris-(dimethylaminomethyl)-phenol or 4-(dimethylamino)-pyridine, or a combination of them.

 

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