The method of obtaining finasteride, 17-[n-tert-butylcarbamoyl]-4 - aza-5-androst-1-en-3-one in polymorphic form i or ii, methods for their production

 

(57) Abstract:

The invention discloses a new method of obtaining finasteride, 17 -[N-tert. butylcarbamoyl] -4-Aza - 5-androst-1-EN-3-one (2), which comprises reaction of ester 1], 17 carbalkoxy-4-Aza - 5-androst-1-EN-3-one with t-butylamino the magnesium halide present in a molar ratio to ether complex of at least 2:1, this product is formed from t-butyl amine and aliphatic/aryl magnesium halide at ambient temperature in an inert organic solvent in the atmosphere of inert gas, followed by heating and the release of product finasteride. Revealed two polymorphic crystalline forms I and II of finasteride and methods for their preparation. Finasteride is an inhibitor of 5 - reductase. The method of synthesis of finasteride safe for the environment and non-toxic.

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6 C. and 29 C.p. f-crystals.

Background of the invention

Finasteride, released under the trade name PROSCAR by Merck & Co., Inc. represents and is an inhibitor of 5 - reductase for use in the treatment of acne, female hirsutism, and especially benign prostatic hyperplasia. Cm. U.S. patent 4760071 (1988), enabled with the-butylamine. Another synthesis of finasteride described in Synthetic Communications, 30 (17), p. 2683-90 (1990), incorporated here by reference, involves the reaction of 17-elimidate 4-Aza-5-androst-I-EN-3-one with t-butylamine.

However, both of these reactions require the use of heterocyclic aromatic amines, which are costly and their use is problematic, given their toxicity and threat to the environment. Both of these intermediate compounds derived from 17 - carboxylic acid.

The reaction Bodroux described F. Bodroux in links, 33, 831 (1905), 35, 519 (1906), 1, 912 (1907), Bull. Soc. Chim. 138, 1427 (1904), 140, 1108 (1905), 142, 401 (1906), reveals the reaction holodnognutyh salts of amines with esters. However, there is neither description nor study the possibility of application of the reaction in the case of sterically blocked amine such as t-butylamine with sterically blocked a complex ether, such as I.

In the art the desired method of synthesis of finasteride, which would be environmentally safe, non-toxic and not used aromatic heterocyclic amine. Preferably the reference compound can be 17-beta ester (I), which will relieve the way from one stage when receiving the above-mentioned heterocyclics the
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where

R - C1-C10linear, branched or cyclic alkyl, unsubstituted or substituted by one or more fenelli, which includes stages:

(1) contacting the complex ester I with t-butylamino the magnesium halide, in which the molar ratio of t-butylamino magnesium halide and a complex ester is at least about 2:1, in an inert organic solvent in the atmosphere of inert gas, (2) keeping the reaction mixture at a temperature of at least 10oC and (3) isolation of the product finasteride II.

There are also intermediate compounds used for the synthesis of finasteride. In addition, it is proposed a method of synthesis comprising the isolation and crystallization of certain poly-form crystalline forms of finasteride, as well as polymorphic forms.

This description of the invention

We found that can react with t-butyl amine with a reagent aliphatic/aryl magnesium-halide, such as ethyl magnesium bromide, where the reagent magnesium halide and t-butyl amine are present in a molar ratio of at least about 2:1 to the complex ether (I) to get finasteride II in good yield. The reaction between aliphatic/aryl magnesium-halide protonation of ester A-ring lactam, dissolving thus the steroid, the second mol required for the amidation reaction, and the third mol can be used for the deprotonation of the newly formed amide. In another case, the ester (I) can be deprotonate Grignard reagent separately, and then subjected to reaction with two moles of t-butylamino magnesium halide to conduct amidation.

In another alternative embodiment, it is possible first to prepare in advance in the same or in a separate reactor t-butylamino magnesium halide at ambient temperature and then subjected to interaction with 4-Aza-steroid complex air I in a molar ratio of at least 3:1 halide reagent to complex ether, preferably followed by heating to about 100oC. in Another embodiment, t-butyl magnesium halide can be obtained in the same or in a separate reactor in a molar ratio to ether complex I 2:1 and then subjected to interaction with a complex ester I, who had previously been entered into interaction with the same or a different Grignard reagent in a molar ratio of 1:1 for deprotonation and dissolution of ester.

In one specific embodiment, this invention is a method of obtaining finasteride II includes stage

< / BR>< a magnesium halide in an inert organic solvent in the atmosphere of inert gas at a temperature in the range -20oup to 10oC with stirring of the reaction mixture to obtain t-butyl magnesium halide in situ, at least in a molar ratio to ether complex I 3: 1, without interaction of ester with aliphatic/aryl magnesium-halide, to avoid receiving unwanted products of ketone and alcohol; (2) heating the reaction mass to 15 - 100oC for the reaction of ester with t-butyl amino magnesium halide and (3) the allocation of the specified product finasteride II (where t-Bu denotes a tertiary butyl).

Intermediate Galena magnesium salt of 4-Aza-steroid I has the following formula

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in which

R - C1-C10linear, branched or cyclic alkyl, unsubstituted or substituted by one or more fenelli.

Source ester I and its synthesis are described in U.S. patent 4760071. The connection used to obtain I, is a known steroid ester, which is saturated in the 1, 2 position, which dehydrogenases dehydrogenases agent such as benzamidenafil anhydride in chlorobenzene at boiling point.

Source complex air may be the compound in which R is C1-C10linear, branched or cyclic alkyl, measures, methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, ISO-propyl, cyclohexyl, etc., and benzyl, -CH2CH2-phenyl, -CH2CH2CH2-phenyl, etc. R is alkyl straight chain, which is unsubstituted or monogamist the phenyl and better - stands. You can also use alkyl groups with a longer chain, but this is not required.

t-Butyl amine and aliphatic/aryl magnesium halide each is used in a molar ratio to ether complex (I) at least 3:1, to obtain a molar ratio of 3:1, and preferably of 3.5:1 to 5.5:1 t-butyl amine magnesium halide to the complex ether (I), in order to provide a good and complete metamorphosis (I) (II) and to minimize impurities. Reactions can visually depict how the reaction of three moles of t-butylamino magnesium halide formed by the reaction between aliphatic/aryl magnesium-halide and t-butylamine, with one mol of ester I. In another case, the reaction can be represented as the reaction of two moles of t-butyl magnesium halide with one mole of the magnesium halide salt of ester (I).

Aliphatic/aryl magnesium halide is available and can be selected as follows:

(1) aliphatic/aryl part is a C1-C18the line is hexyl, cyclohexyl, octyl, decyl, dodecyl, tetradecyl, octadecyl, benzyl, allyl, vinyl, ethinyl, etc. and (2) the aryl part is a phenyl, or mono-, di - or tri-substituted phenyl in which the substituents can include C1-C4alkyl, C1-C4alkoxy, for example, methyl, methoxy, fluorescent, etc.

The halide is chloride, bromide, fluoride or iodide, preferably bromide or chloride, more preferably a bromide. The preferred ethyl magnesium bromide. The term "aliphatic/aryl magnesium halide" includes aliphatic magnesium halide and aryl magnesium halide.

Used inert solvent is a common solvent in Grignard and may be C4-C8linear or cyclic ether include diethyl ether, di-n-butyl ether, dimethoxyethane, tetrahydrofuran, dioxane and others. The solvent must be dry under the reaction conditions, which is usually carried out in an atmosphere of inert gas such as dry nitrogen, with stirring.

Initially, the reaction is carried out at a temperature sufficient to achieve product education, and may be, for example, between about -40oand the 40oC, better at low temperature, for example about the education t-butylamino magnesium halide and

(2) reactions between complex ether I and t-butyl amino magnesium halide or a Grignard reagent with the formation of magnesium halide salt of ester I.

After the reaction mixture was stirred and maintained at a temperature sufficient to break through the amidation reaction. The reaction mixture is usually allowed to reach temperature, for example, about 10oC or about room temperature and subsequently heated to 100oC or the boiling point of the solvent. Typically, the heating time ranges from 2 to 12 hours.

In another case t-butylamino the magnesium halide can be obtained in advance, for example, at ambient temperature and then to carry out the reaction with 4-Aza - ether complex of steroid (I) at room temperature.

For processing crude finasteride used traditional methods, as well as a device therefor. Basically, chromatography on silica gel and/or crystallization from a suitable solvent, such as methylene chloride/ethyl acetate or acetic acid/water, used for cleaning finasteride.

The order of addition of ester, t-butylamine and aliphatic aryl magnesium halide can be modified to be back with the choir is, to pre-form a t-butylamino magnesium halide to interact with complex ether I.

The following examples illustrate the method, as claimed here, and they should not be construed as limiting the scope of the disclosed invention here.

Example 1.

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In a flask equipped upper stirrer, inlet for nitrogen and a reflux condenser were placed 840 ml of dry THF and 20.0 g I - methyl ether (I). The resulting suspension was cooled to -5 - -10oC and added 27.6 ml of t-butylamine. Maintaining the temperature of the reaction mixture below 10oC was added a solution of etimani bromide in THF (122 ml, 2 M). The reaction mixture was heated at the boiling temperature of 12 hours and added to a cold (10oC) a solution of 25% ammonium chloride in water. The mixture was heated to 25oC and left to precipitate. The THF solution was separated, the concentration was carried out by atmospheric distillation to 200 ml and the product was crystallized by adding approximately 600 ml of an aqueous solution of HCl. The obtained solid white color stood out by filtration and dried at 70oC in vacuum to obtain 21.7 g (yield 97%) of finasteride. Product finasteride can be cleaned by conventional methods, for example, measures 2.

In a flask equipped upper stirrer, inlet for nitrogen and a reflux condenser were placed 516 ml of dry THF and 27.6 ml of t-butylamine. The solution was cooled to 10oC and while maintaining the reaction temperature below 30oC was added 244 ml of 1 M bromide of etermine in THF. Was added to the suspension containing 10.0 g I - methyl ester I in 100 ml of dry THF. The reaction mixture was heated at the boiling temperature of 4-6 hours and added to a cold (10oC) a solution of 25% ammonium chloride in water. The mixture was heated to 25oC and left to precipitate. The THF solution was separated and concentrated by atmospheric distillation to 200 ml and the product was crystallized by addition of 200 ml of an aqueous solution of HCl. The obtained solid white color stood out and were dried at 70oC in vacuum to obtain 21.6 g (yield 97%) of finasteride.

Polymorphism can be defined as the ability of the same chemical substance can exist in different crystal structures. They are called polymorphs, polymorphic modifications or form. Finasteride, as determined, there are at least two polymorphic resolutiony forms, form I and form II, each of which can be obtained with careful observation userid in an organic solvent and 0% or more by weight of water, so that the amount of organic solvent and water in the mixture was sufficient to exceed the solubility of resolutional forms of finasteride form I in the mixture and resolutiona form of finasteride was less soluble than any other form of finasteride in the mixture: (2) allocation received a solid phase, and (3) removing the solvent.

Organic solvents used in this way include any solvent that can dissolve finasteride. Some examples of organic solvents include, for example, tetrahydrofuran (THF), organic acids, acetic acid ethyl ester (Et OAc), toluene, ISO-propyl, and others. In addition, an organic solvent may be one that is known in engineering as vodosmeshivayuschego. The term "vadomarius solvents" includes solvents that do not form a two-phase system with water under conditions sufficient for crystallization of these polymorphs. For example, vadomarius solvents include, but are not limited to THF, and organic acids such as formic acid, acetic acid, propionic acid and others. In addition, an organic solvent may be a solvent, the solvents, which form a two-phase system with water under conditions sufficient for crystallization of these polymorphs. For example, odonatologica solvents include, but are not limited to toluene, ethyl acetate, ISO-propyl and other.

If you use vadomarius solvents in the above way, the polymorphic form I of finasteride can be obtained using relatively wet mixture of solvents, for example, using glacial acetic acid to obtain form I at an ambient temperature of approximately 25oC, you can use about 83% or more by weight of water.

If you use organic solvents that are considered vodosmeshivayuschego, such as toluene, ethyl acetate, ISO-propyl and other, this method of obtaining form I is carried out in a relatively dry solvent. For example, to get the shape I finasterida of ethyl acetate/water, the amount of water used at most should be about 3.5 mg/ml, and from a mixture of ISO-propyl/water should not be greater than about 1.6 mg/ml, with an ambient temperature of approximately 25oC for both solvents.

Examples of crystallization above are given for methods, provodila receipt of form I in any given mixture of organic solvent, will vary with the temperature as the temperature changes will change the solubility of the substance. For example, if you use ISO-propyl for receipt of form I, at these temperatures the amount of water will be as follows:

Temperature - the amount of water

1,4oC - 0.8 mg/ml or less

6oC - 0.9 mg/ml or less

12oC - 1.0 mg/ml or less

18oC - 1.3 mg/ml or less

Polymorphic form I can also be obtained by heating the polymorphic form II of finasteride at least up to about 25oC in water or an organic solvent for a time sufficient for complete conversion of form II to form I, and the allocation obtained solid phase, for example, by filtering.

Polymorphic form II can be obtained: (1) crystallization from a mixture of finasteride in an organic solvent and water, so that the amount of organic solvent and water in the mixture was sufficient to exceed the solubility of solvated forms of finasteride in the mixture, and solvated form of finasteride was less soluble than any other form of finasteride in the mixture; (2) allocating the obtained solid phase, and (3) removing the solvent.

Organic Rast is iesa solvents. However, upon receipt of the form II of the water-soluble solvent wt.% water used in the solvent mixture will be less than upon receipt of form I from the same vadomarius solvent. For example, to obtain form II of finasteride from a mixture of glacial acetic acid/water, wt.% water in the solvent mixture will be less than 83% at an ambient temperature of approximately 25oC.

In addition, if to obtain form II to use odonatologica solvent, such as ethyl acetate or ISO-propyl, the amount of water in the solvent mixture will be more used in obtaining the form I from the same organic solvent. For example, to obtain form II of finasteride from a mixture of ethyl acetate/water, the amount of water used is more than 3.5 mg/ml, and from a mixture of ISO-propyl/water, this quantity will more than 1.6 mg/ml, in both cases, when the ambient temperature is approximately 25oC. As explained above, the experts it is clear that changes in temperature can affect the amount of water required to obtain form II of any given solvent mixture.

Polymorphic form II can also be obtained by heating the polymorphic form I of finasteride up to temperature is for example about an hour, and allocating the obtained solid phase.

The following examples illustrate methods of obtaining polymorphic forms I and II of finasteride (Proscar,MK 906) and some characteristics. Examples are given to further illustrate the method of obtaining the compounds of the present invention. Examples in no way limit the scope of the present invention and they should not be construed as limiting it.

Example 3.

Form I of finasteride can be obtained by dissolving finasteride in glacial acetic acid (about 100 mg/ml) and addition of water with stirring, until such time as the wt.% water is not greater than or equal to 84%. The obtained solid is collected by filtration and dried in vacuum at a temperature of about 50oC. Obtained form I is characterized by the curve of differential scanning calorimetry (DSC) at a heating rate of 20oC/min in a closed vessel, showing the minimum endotherm with a peak temperature of about 232oC, the temperature at which the extrapolation of about 223oC and heat for about 11 j/g and the maximum melt endotherm with a peak temperature of about 261oC, the temperature at which the extrapolation of approximately 258oC with the corresponding, .31, 3.85, 3.59 and 3.14. FT-IR spectrum (KBr) shows bands at 3431, 3237, 1692, 1666, 1602 and 688 cm-1. Solubility in water and cyclohexane at 25oC is 0.05+ 0.02 and 0.27 + 0.05 mg/g, respectively.

In addition, form I of finasteride can be obtained by recrystallization from dry (H2O < 1 mg/ml) ethyl acetate and isopropylacetate at ambient temperature (25oC). The selected solid is dried in vacuum at 50oC and has the same physical characteristics as specified above.

In addition, form I was obtained by mixing form II during the night in dry toluene at room temperature and isolation of the obtained solid phase. Form I was obtained by mixing form II during the night in dry acetonitrile at ambient temperature and the allocation obtained solid phase.

Example 4.

Form II of finasteride can be obtained by dissolving finasteride in glacial acetic acid (about 100 mg/ml) and addition of water with stirring until until wt.% water will not be equal to 75%, but will not exceed 80%. The obtained solid is collected by filtration and dried in vacuum to about 100oC. the resulting form II is characterized by a DSC curve when soon is atural about 261oC, the temperature at which the extrapolation of approximately 258oC with the appropriate heat for about 89 j/g X-ray diffraction pattern of the powder is characterized by a d-spacing 14,09; 10,36; 7,92; 7,18; 6,40; 5,93; 5,66; 5,31; 4,68; 3,90; 3,60 3.25. FT-IR spectrum (KBr) shows bands at 3441, 3215, 1678, 1654, 1597, 1476 and 752 cm-1. Solubility in water and cyclohexane at 25oC amounted to 0.16+of 0.02 and 0.42+0.05 mg/g, respectively.

In addition, the form II of finasteride can be obtained by recrystallization from ethyl acetate containing from 3.5 to 30 mg/ml of water, or from isopropylacetate containing from about 1.6 to 15 mg/ml of water at ambient temperature (25oC). Selected solids are dried in vacuum at about 80oC and have the same physical characteristics as described above.

Form II can also be obtained by heating form I up to 150oC, holding for one hour and cooled again to room temperature. This form II has the same physical characteristics as presented above.

1. Way get finasteride formula II

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characterized in that it comprises (1) contacting a complex ester of the formula I

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where R represents a linear, branched (C1-C10) EA is at least about 2:1, in an inert organic solvent in the atmosphere of inert gas; 2) keeping the reaction mixture at a temperature of at least 10oC and 3) isolation of the product finasteride formula II.

2. The method according to p. 1, characterized in that it further includes a step of interaction of t-butylamine and aliphatic or aryl magnesium halide in an inert organic solvent with the formation of t-butylaminoethyl halide before the interaction with a complex ester I.

3. The method according to p. 2, characterized in that it further includes a step of interaction of ester I with aliphatic or allanigue in the temperature range 10 - 30oC in an inert organic solvent to form gelemanovo salt of ester before I interact with t-butylamino the magnesium halide.

4. The method according to p. 1, characterized in that the halide is selected from bromide and chloride.

5. The method according to p. 2, characterized in that the aliphatic/ aryl magnesium halide contains C1-C18linear, branched or cyclic alkyl, benzyl, allyl, vinyl or ethinyl radical, and aryl radical is phenyl or phenyl substituted from 1 to 3 C1-C4-alkilani, C1-C4-alkoxygroup alkyl magnesium bromide or cycloalkyl magnesium bromide.

7. The method according to p. 1, characterized in that the inert solvent is a C4-C8linear or cyclic ether.

8. The method according to p. 7, wherein the inert organic solvent selected from diethyl ether, di-n-butyl ether, dimethoxyethane, tetrahydrofuran and dioxane.

9. The method according to p. 1, wherein R is chosen from methyl, ethyl, propyl and butyl.

10. The method according to p. 9, wherein R represents methyl.

11. The method according to p. 1, characterized in that the molar ratio of t-butylaminoethyl halide and a complex ester 1 is about 3.5:1 to 5.5:1.

12. The method according to p. 11, characterized in that the molar ratio of t-butylaminoethyl halide and ether complex I, is about 4:1 to 5:1.

13. 17-[N-tert-butylcarbamoyl]-4-Aza-5-androst-1-EN-3-one formula

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which exists in polymorphic form I having characteristic absorption bands obtained from x-ray powder diffraction with the spectral d-intervals in 6,44; 5,69; 5,36; 4,89; 4,55; 4,31; 3,85; 3,59 3.14, the curve of differential scanning calorimetry with a heating rate of 20oC/min, which shows the minimum endotherm with a peak temperature is which shows the maximum melt endotherm with a peak temperature of about 261oC and the temperature at which the extrapolation of approximately 258oC with the appropriate heat for about 89 j/g FT-IR spectrum (Commission), with bands at 3431, 3237, 1692, 1666, 1602 and 688 cm-1and solubility in water and cyclohexane at 25oC 0,05+0,02 0,27+0.05 mg/g, respectively.

14. Connection on p. 13 obtained: 1) crystallization from a mixture of finasteride in an organic solvent and 0% or more by weight of water so that the amount of organic solvent and water in the mixture is sufficient to exceed the solubility of resolutional form of finasteride in the mixture, and resolutiona form fin-steride was less soluble than any other form of finasteride in the mixture; 2) the allocation obtained solid phase, and 3) removing the solvent.

15. Connection on p. 14, characterized in that the organic solvent used in the method is glacial acetic acid, and the weight percentage of water in the solvent mixture is at least about 83%.

16. Connection on p. 14, characterized in that the organic solvent used in the method is ethyl acetate and the amount of water in the solvent mixture is not more than about 3.5 mg/ml

17. Connection on p. 14, characterized in that the solvent is not more than about 1.6 mg/ml

18. Connection on p. 13 formula

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which exists in polymorphic form I obtained by heating form II of finasteride in an organic solvent or in water to a temperature of at least about 25oC and highlighting the obtained solid phase.

19. Connection on p. 18, characterized in that the solvent used in the method are selected from water, toluene and acetonitrile.

20. 17-[N-tert-butylcarbamoyl]-4-Aza-5-androst-1-EN-3-one formula

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which exists in polymorphic form II, having the characteristics of the absorption bands obtained from x-ray powder diffraction with the spectral d-intervals in 14,09; 10,36, 7,92; 7,18; 6,40; 5,93; 5,66; 5,31; 4,68; 3,90; 3,60 3.25, the curve of differential scanning calorimetry with a heating rate of 20oC/min, which demonstrates one of the melt endotherm with a peak temperature of about 261oC and the temperature at which the extrapolation of approximately 258oC with the appropriate heat for about 89 j/g, FT-IR spectra (in KBr) bands on 3441, 3215, 1678, 1654, 1597, 1476 and 752 cm-1and solubility in water and cyclohexane at 25oC 0,16+of 0.02 and 0.42+0.05 mg/g, respectively.

21. Connection on p. 20 formula

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which exists in polymorphic form II obtained esto organic solvent and water in the mixture is sufficient to have exceeded the limit of solubility of the solvated form of finasteride in the mixture, and solvated form of finasteride was less soluble than any other form of finasteride in the mixture; 2) isolation of the obtained solid phase; 3) removing the solvent.

22. Connection on p. 21, characterized in that the organic solvent used in the method is glacial acetic acid, the weight percentage of water in the solvent mixture is less than 83%.

23. Connection on p. 21, characterized in that the organic solvent used in the method is ethyl acetate and the amount of water in the mixture of solvents is more than 3.5 mg/ml

24. Connection on p. 21, characterized in that the organic solvent used in the method is isopropylacetate and the amount of water in the solvent mixture over 1.6 mg/g

25. Connection on p. 20 formula

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which exists in polymorphic form II obtained by heating form I of finasteride up to a temperature of at least about 150oC.

26. The method of obtaining polymorphic form I-17-[N-tert-butylcarbamoyl]-4-Aza-5-androst-1-EN-3-one under item 13, including: 1) crystallization from a mixture of finasteride in organicism is enough, that limit was exceeded solubility resolutional form of finasteride in the mixture, and resolutiona form of finasteride was less soluble than any other form of finasteride in the mixture; 2) isolation of the obtained solid phase, and 3) removing the solvent.

27. The method according to p. 26, wherein the organic solvent is glacial acetic acid and the weight percentage of water in the solvent mixture is at least about 83%.

28. The method according to p. 26, wherein the organic solvent is ethyl acetate and the amount of water in the solvent mixture is not more than about 3.5 mg/ml

29. The method according to p. 26, wherein the organic solvent is ISO-propyl and the amount of water in the solvent mixture is not more than about 1.6 mg/ml

30. The method of obtaining polymorphic form I-17-[N-tert-butylcarbamoyl]-4-Aza-5-androst-1-EN-it, including the heating of form II of finasteride in water or an organic solvent to a temperature of at least about 25oC and the allocation of the resulting solid phase.

31. The method of obtaining polymorphic form II 17-[N-tert-butylcarbamoyl]-4-Aza-5-androst-1-EN-3-p. 20, including: 1) chlorites and water in the mixture is sufficient to have exceeded the limit of solubility of the solvated form of finasteride in the mixture, and solvated form of finasteride was less soluble than any other form of finasteride in the mixture; 2) isolation of the obtained solid phase, and 3) removing the solvent.

32. The method according to p. 31, wherein the organic solvent is glacial acetic acid and the weight percentage of water in the solvent mixture is less than about 83%.

33. The method according to p. 31, wherein the organic solvent is ethyl acetate and the amount of water in the solvent mixture more than about 3.5 mg/ml

34. The method according to p. 31, wherein the organic solvent is ISO-propyl and the amount of water in the solvent mixture is more than about 1.6 mg/ml

35. The method of obtaining polymorphic form II 17-[N-tert-butylcarbamoyl]-4-Aza-5-androst-1-EN-3-one, comprising heating form I of finasteride up to a temperature of at least about 150oC.

Priority points:

19.11.92 - PP.1-12;

29.01.93 - PP.13, 14, 19, 20, 24-27, 31, 32;

05.11.93 - PP. 15-18, 21-23, 28-30, 33-35.

 

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FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention describes novel halogen- and pseudohalogen-substituted 17-methylene-4-azasteroids of the general formula (I) wherein each R20 and R20a means independently fluorine, chlorine, bromine atom, (C1-C4)-alkyl, hydrogen atom (H), cyano-group; R4 and R10 mean hydrogen atom or methyl group; both R1 and R2 represent hydrogen atom and form an additional bond. Compounds are inhibitors of 5α-reductase and can be used in treatment of diseases caused by the enhanced blood and tissue testosterone and dihydrotestosterone level.

EFFECT: valuable medicinal and biochemical properties of compounds.

9 cl, 5 dwg, 1 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I) or its pharmaceutically acceptable salt, or an enantiomer wherein n = 0 or 1; a - b means -CF=CH or -CHFCH2; R1 represents (C1-C3)-alkyl wherein alkyl is unsubstituted; R2 represents hydrogen atom; R3 is chosen from (C1-C4)-alkyl, (CH2)n-cycloheteroalkyl and (CH2)n-aryl; or R2 and R3 form in common 6-membered saturated ring condensed with 5-membered aromatic ring system comprising 2 heteroatoms chosen from nitrogen atom (N), and pharmaceutical compositions. Compounds of the formula (I) represent modulators of androgen receptors (AR) possessing tissue-selective effect. Proposed compounds are useful as androgen receptors agonists in osseous and/or muscle tissue in antagonizing AR in male patient prostate or in female patient uterus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

36 cl, 2 tbl, 72 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes an improved method for synthesis of 17β-substituted 4-azaandrost-1-en-3-one of the general formula (I): wherein R means -OH, (C1-C4)-alkyl, (C1-C4)-alkenyl, phenyl, benzyl and others, or their pharmaceutically acceptable salts. Method involves insertion protective groups into 3-keto-4-aza (lactam) form of compound of the general formula (II): wherein R has indicated values to form compound of the general formula (III): wherein R3 means trialkylsilyl, or in common with R4 residue -C(O)-C(O)- or -C(O)-Y-C(O)- wherein R4 means tert.-butyloxycarbonyl preferably; Y means -(CH2)n wherein n = 1-4, or ortho-phenylene. Then a synthesized compound is converted in the presence of a dehydrogenation catalyst of in the presence of benzoquinone, allylmethylcarbonate, allylethylcarbonate and/or allylpropylcarbonate, and ▵1-double bond is introduced in 1,2-position followed by removal of protective groups and, if necessary, (when R means -OH) conversion to salts. Method provides the high yield and purity degree of synthesized compounds.

EFFECT: improved method of synthesis.

21 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: description is given of thiomorpholine derivatives of steroids with general formula I . These steroids are characterised by presence of a thiomorpholine fragment, bonded to a C17 steroid skeleton through an alkylene spacer, where R4 and R4' are hydrogen and methyl, under the condition that, both R4 and R4' represent hydrogen at the same time.

EFFECT: invention can be successfully used for stimulating meiosis of human oocyte.

12 cl, 2 ex, 5 tbl, 6 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to production of new tritiated analogues of physiologically active compounds - triterpene glycosides of holothurians Cucumaria of formula: .

EFFECT: there are produced new tritiated analogues of physiologically active compounds.

2 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to racemic 3,17β-dihydroxy-7α,18-dimethyl-6-oxaextra-1,3,5(10),8(9)-tetraene diacetate of formula .

EFFECT: production of the substance exhibiting osteoprotective, hypocholesteremic and antioxidant action with lowered uterotropic activity.

1 cl, 2 ex, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-oxa- and 4-aza-16α, 17α-cyclohexanopregnanes (4-oxa- and 4-aza-pregna-D'-pentaranes), which can be used n medicine to treat malignant tumours, having general formula I , where X=0 or NR, R=R1=R2=R4=H where R1+R3 form a bond. Said compounds are obtained by oxidising ring A 16α, 17α-cyclohexano-progesterone with potassium permanganate and sodium periodate in the presence of sodium carbonate in 5-oxo-A-nor-3,5-secoacid followed by closure of ring A in 4-oxa-16α, 17α-cyclohexanopregn-5-en-20-one while treating with a sodium acetate dehydrating agent in Ac2O and in 4-aza-16α, 17α-cyclohexanopregn-5-en-20-one using ammonium acetate in acetic acid.

EFFECT: compounds are effective inhibitors of oestrogen-stimulated cell proliferation HeLa.

2 cl, 2 ex, 1 tbl

FIELD: biochemistry.

SUBSTANCE: disclosed is a composition for stimulating natural protection and inducing resistance to diseases caused by Candidatus Liberibacter asiaticus in citrus plants (Huanglongbing) containing natural brassinosteroid or analogue of brassinosteroid. Described is a method for preventing or treating Huanglongbing (HLB) disease in citrus, characterised by periodic application of brassinosteroid on plants. Described is use of brassinosteroid for making composition for stimulating natural protection and inducing resistance to diseases caused by Candidatus Liberibacter asiaticus in citrus plants (Huanglongbing), where said composition is periodically applied.

EFFECT: described is a method for stimulating natural protection and inducing resistance to diseases caused by Candidatus Liberibacter asiaticus in citrus plants (Huanglongbing), characterised by application of brassinosteroid compound on plant.

11 cl, 7 dwg, 3 tbl, 8 ex

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