The method of producing dihalogenoalkane and a method of producing dihydroxypyridine

 

(57) Abstract:

The invention describes an efficient and productive way to get dihalogenoalkane having the structural formula I

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In this method, the ester of malonic acid (II) is subjected to reaction with heteroassociation (III) formation of an intermediate salt, which may not necessarily be acidified to form dihydroxypyridine (IV); then salt or dihydroxypyridine halodrol. 2 S. and 26 C.p. f-crystals, 2 PL.

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Dihalogenoalkane useful as intermediates in obtaining a variety of agrochemical and pharmaceutical compounds. In particular, 5,7-diploid-6-aryl - 1,2,4-triazolo[1,5-a] pyrimidines are key intermediate compounds in obtaining fungicidal derivatives of triazolopyrimidine, which are described in EP-A2-550113.

In EP-A2-550113 describes how to obtain 5,7-diploid-6-aryl-1,2,4 - triazolo[1,5-a] pyrimidines of the esters of malonic acid and 3 - amino-1,2,4-triazole. However, this method is not entirely satisfactory, because these compounds are pyrimidine get low output.

G. Fischer (Advances in Heterocyclic Chemistry 1993, 57, 81-138) describes the formation of three is m a fridge in glacial acetic acid is a "standard conditions". Y. Makisumi (Chem. Pharm. Bull., 1961, 9, 801-808) reports that under these conditions no condensation occurs diethylmalonate with 3-amino - 1,2,4-triazole. Makisumi describes that this reaction can be carried out in the presence of ethoxide sodium in ethanol and the product dihydroxytestosterone can turn into a corresponding dichlorofluorescein using a large excess of phosphorus oxychloride. However, the way Makisumi is not completely satisfactory for obtaining dihalogenoalkane, because that requires a large excess of phosphorus oxychloride, and the overall yield of the reactions on the basis of diethylmalonate, is often low.

A brief statement of the substance of the invention

This invention provides an effective and productive way to get dihalogenoalkane having the structural formula I

< / BR>
where X1denotes chlorine or bromine;

R denotes phenyl, optionally substituted by one or more halogen, nitro, cyano, C1-C6-alkyl, C1-C6-halogenoalkane, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C4-alkoxycarbonyl, phenyl, phenoxy or benzyloxy groups, naphthyl, optionally substituted by one the>C6-halogenoalkane, C1-C4- alkoxycarbonyl, phenyl, phenoxy or benzyloxy groups, hydrogen,

C1-C6-alkyl, optionally substituted by one or more substituents: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-haloalkoxy group, or C2-C6alkenyl, optionally substituted by one or more halogen, nitro, cyano, C1-C4-alkilani, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-haloalkoxy groups;

X represents CR1or N;

Y represents CR2or N;

Z represents CR3or N;

R1, R2and R3each independently represents hydrogen or C1-C6-alkyl, optionally substituted by one or more halogen, nitro, cyano, C1-C4-alkilani, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, amino, C1-C4-alkylamino or di-(C1-C4-alkyl)amino group, and when R1and R2taken together with the atoms to which they are attached, they may form a ring in which R1R2protezavimo represents hydrogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-haloalkoxy.

This method involves: (a) reaction (1) ester of malonic acid having the structural formula II

< / BR>
where R8and R9each independently represents a C1-C6is alkyl and R is above this value, (2) heterocyclisation having the structural formula III

< / BR>
where X, Y and Z have the above meanings, at a temperature of at least approximately 100oC with formation of an intermediate salt; (b) an optional intermediate acidification of salt water acid for the formation of dihydroxypyridine having the structural formula IV

< / BR>
where R, X, Y and Z have the meanings described above; and (c) gorodilova intermediate salt or dihydroxypyridine at least about two molar equivalents halogenous agent, for example oxychloride forstora, oxybromide phosphorus, pentachloride phosphorus or pentabromide phosphorus or a suitable mixture at a temperature of at least approximately 100oC.

This invention also provides an effective and efficient way of obtaining Digi the product IV was produced using the procedure described above, according to which the intermediate salt is acidified; then the product IV can be selected, if needed.

Thus, the purpose of this invention is the provision of an effective new way to get dihalogenoalkane.

Another purpose of this invention is the provision of a new method of obtaining dihydroxypyridine.

Other objectives and advantages of this invention will be obvious to specialists in this field from the following further description and the attached claims.

Detailed description of the invention

According to one preferred variants of the present invention, the ester of malonic acid of the formula (II) is subjected to reaction with at least one molar equivalent of heterocyclisation represented by formula III, preferably in the range of temperatures of approximately 120oC - 200oC, more preferably approximately 150oC - 180oC, and optionally in the presence of a base and/or solvent to form an intermediate salt. Intermediate salt halodrol at least two molar equivalents of phosphorus oxychloride, oxybromide phosphorus, pentachloride phosphorus or pentabromide FOS.

As advantages, it was found that dihalogenoalkane can be obtained with high yield and good purity efficient and productive method of the present invention. In contrast, dihalogenoalkane get with a relatively low output when receiving them famous in this area ways.

Another advantage of this invention is that the method of the invention can be carried out in one tank, when the intermediate salt is acidified. Holding the chain reactions in a single tank is vysokogermetichnym, because it avoids the isolation of intermediate compounds and significantly reduces the amount of waste chemicals.

According to another preferred variant of the present invention the intermediate salt get in the presence of added base. The base is preferably present in a quantity of at least one molar equivalent relative to the ester of malonic acid. Bases suitable for use in the method of this invention include tertiary amines, such as three(C2-C6-alkyl) amines, pyridine, substituted pyridine, quinoline, substituted lachnosterna metals, such as calcium hydroxide and magnesium hydroxide; C1-C6-alkoxides of alkali metals, such as ethoxide sodium tert-piperonyl potassium; C1-C6-alkoxides of alkaline earth metals such as ataxic magnesium; carbonates of alkali metals such as sodium carbonate and potassium carbonate; and carbonates of alkaline earth metals such as calcium carbonate. Preferred bases include three (C2-C6-alkyl) amines, such as triethylamine and tributylamine, pyridine, 4-(N, N-dimethylamino) pyridine, quinoline,N, N,N',N'-tetramethylrhodamine, and triethylamine and tributylamine are more preferred.

The intermediate salt of this invention are represented by structural formula V upon receipt in the absence of added base and the structural formula VI upon receipt in the presence of added base:

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where R, X, Y and Z have the above values and "base" represents the added base.

According to another preferred variant of the present invention is the solvent. Solvents suitable for use in the method of the present invention have a boiling point of at least approximately 80oC and include IU the mono - and dehalogenase and mixtures thereof; polycyclic aromatic hydrocarbons such as naphthalene, alkylnaphthalene and mixtures thereof; alcohols, such as butanol; and mixtures thereof. The solvent of the present invention preferably has a boiling point in the range of approximately 80oC - 220oC, more preferably approximately 120oC - 180oC. Mesitylene is one of the main tion of the solvents of this invention.

The reaction between the ester of malonic acid and heterocyclisation preferably performed at a pressure of about 1 ATM or higher. If the response includes a solvent having a boiling point (defined at normal atmospheric pressure) below the reaction temperature, the pressure of the reaction should be increased so that the boiling point of the solvent increased, at least up to the reaction temperature.

In some embodiments of the method of the invention using aqueous acid for acidification of the intermediate salt. Aqueous acids, are suitable for use in the method are aqueous mineral acids such as hydrochloric acid, Hydrobromic acid and sulfuric acid, and aqueous organic acid, such as triperoxonane acid, and hydrochloric acid, bmore to enable the reaction intermediate salt or dihydroxypyridine with a suitable palodiruyut agent under conditions contributing to the formation of the desired dihalogenoalkane. You can use any gaodirelwe agent and conditions known in this field of knowledge. Preferably gaodirelwe agent and conditions are described herein for the preferred variants of the present invention. Favorably perform the reaction of haloiding at atmospheric pressure or at a pressure greater than atmospheric pressure. The term "them suitable mixture" in relation to this application and the claims against Ganoderma agents described herein, is defined as a mixture of phosphorus oxychloride and pentachloride phosphorus or a mixture of oxybromide phosphorus and pentabromide phosphorus.

The method of the present invention is particularly useful for obtaining dihalogenoalkane, in which

X1denotes chlorine;

R denotes phenyl, optionally substituted by one or more substituents: halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl, phenoxy or benzyloxy groups, or

naphthyl;

X represents CR1or N;

Y represents CR2;

Z represents N and

R1and R2cardy, they may form a ring in which R1R2represented by the structure:

-CH=CH-CH=CH-.

As an advantage of this invention is particularly useful to obtain 5,7-diploid-6-aryl-1,2,4-triazolo[1,5-a]pyrimidines of formula I, where X1denotes chlorine;

R denotes phenyl, optionally substituted by one or more radicals: halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-haloalkoxy groups;

X and Z represent N and

Y denotes CH.

The method of the present invention can provide a surprisingly high outputs dihydroxypyridine and dihalogenoalkane. One of the key factors is the temperature of the reaction between an ester of malonic acid and heterocyclisation. The use of the base and/or solvent may also increase yields in some embodiments. Specialists in this field will be able without undue experimentation to select the preferred combination of temperature and optional base and/or solvent for a particular option in the scope of the present invention upon consideration of the preceding description of the preferred options and the following nitrative examples. The invention is not limited to the particular described or illustrated variant embodiment and covers the full scope of the appended claims.

Example 1

Obtain 3-amino-1,2,4-triazole salt of 5,7-dihydroxy-6-(2-chloro - 6-forfinal)-1,2,4-triazolo[1,5-a]pyrimidine

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A mixture of diethyl-(2-chloro-6-forfinal)-malonate (29 g, 0.1 mol), 3-amino-1,2,4-triazole (of 8.4 g, 0.1 mol) and solvent mesitylene (10 ml) is heated at 160oC for 7 hours and filtered, obtaining a solid substance. The solid is washed with diisopropyl ether and dried, getting listed in title product as a solid (18 g, 50% yield, so pl. 260-266oC).

Following basically the same procedure, but using a suitable solvent and/or base, get a salt of 5,7-dihydroxy-6-(2-chloro-6-forfinal)-1,2,4-triazolo[1,5-a] pyrimidine presented in Table I.

Example 2

Getting 5,7-dichloro-6-(2-chloro-6-forfinal)-1,2,4-triazolo [1,5-a]pyrimidine

< / BR>
A mixture of 3-amino-1,2,4-triazolone salt of 5,7-dihydroxy-6-(2 - chloro-6-forfinal)-1,2,4-triazolo[1,5-a] pyrimidine (34.8 g, 0,095 mol) and phosphorus oxychloride (100 ml) is heated in an autoclave at 140oC (2.8 bar) for 4 hours, and the excess oxychloride tastaturi and poured into a mixture of water and dichloromethane (300 ml, 1:1) while maintaining the temperature of the mixture below 30oC. the Organic phase is separated, dried over anhydrous sodium sulfate and concentrated in vacuo, yielding an oil, which crystallized during the night, giving the desired product as a solid (22,4 g, 74% yield, so pl. 118-120oC).

Example 3

Getting 5,7-dichloro-6-(2-chloro-6-forfinal)-1,2,4-triazolo [1,5-a]pyrimidine

< / BR>
A mixture of 3-amino-1,2,4-triazole (12,6 g, 0.15 mol), diethyl- (2-chloro-6-forfinal) malonate (47,6 g, 0.15 mol) and tributylamine (27.8 g, 0.15 mol) is heated at 170oC, giving the opportunity to Athanasia formed during the reaction of ethanol. After 2 hours the remaining ethanol is removed by a slow stream of nitrogen for 30 minutes. Then the reaction mixture is cooled to 130oC and added dropwise phosphorus oxychloride (69 g, 0.45 mol) dropwise over 20 minutes. The obtained transparent brown solution is heated under reflux for 6 hours, cooled to room temperature and added slowly to a mixture of toluene/water (5:6) (1100 ml) under stirring. The organic phase is separated, washed successively with diluted hydrochloric acid and water, dried over anhydrous sodium sulfate and concentrated in vacuo, obtaining a brown viscous, maroczy-6-(2-chloro-6-forfinal)-1,2,4-triazolo [1,5-a] pyrimidine

< / BR>
A mixture of diethyl-(2-chloro-6-forfinal)-malonate (7,3 g 0,025 mol), 3-amino-1,2,4-triazole (2.1 g, 0,025 mol), mesitylene (20 ml) and pyridine (5 ml) is heated under reflux for 7 hours at 170oC, cooled to room temperature and decanted, getting solid. A solution of the solid in water (50 ml), acidified with concentrated hydrochloric acid (5 ml) and the resulting precipitate is collected, washed with water and dried, getting listed in title product as a solid (5 g, 71% yield, so pl. 220oC).

Following basically the same procedure, but using a suitable solvent and/or base, get 5,7-dihydroxy-6- (2-chloro-6-forfinal)-1,2,4-triazolo[1,5-a]pyrimidine with the outputs specified in Table II.

Comparative example

Getting 5,7-dihydroxy-6-(2-chloro-6-forfinal)-1,2,4-triazolo [1,5-a] pyrimidine

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Diethyl-(2-chloro-6-forfinal)malonate (108 g, and 0.37 mol) and 3-amino-1,2,4-triazole (31,2 g and 0.37 mol) are added to a solution of ethoxide sodium (prepared previously by dissolving sodium (8.5 g, and 0.37 mol) in ethanol (250 ml)). The reaction mixture is heated under reflux for 50 hours, cooled to room temperature and filtered, obtaining tlaut of concentrated hydrochloric acid and the precipitate is collected, washed with water and dried, getting listed in title product as a solid (15.7 g, 14.5 percent output, so pl. 215oC).

Example 5

Getting 2-aminobenzimidazole salt of 5,7-dihydroxy-6- (2-chloro-6-forfinal)benzamidopiperidine

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A mixture of diethyl-(2-chloro-6-forfinal)-malonate (5.8 g, 0.02 mol) and mesitylene heated under reflux handle portions 2-aminobenzimidazole (2.7 g, 0.02 mol) for 2 hours, heated under reflux for 4 hours, cooled to room temperature and diluted with acetone. The resulting mixture was filtered, getting listed in title product as white crystals (5.1 g, 55% yield, so pl. 313-325oC.

1. The method of producing dihalogenoalkane General formula I

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in which X1represents chlorine or bromine;

R represents phenyl, optionally substituted by one or more halogen, nitro, cyano, C1- C6alkyl, C1- C6haloalkyl, C1- C6alkoxy, C1- C6haloalkoxy, C1- C4alkoxycarbonyl, phenyl, phenoxy or benzyloxypropionic; naphthyl, optionally substituted by one or more halogen, nitro, cyano, C1- C6alkyl, C1- C1- C6alkyl, optionally substituted by one or more halogen, nitro, cyano, C1- C4alkyl, C1- C4haloalkyl, C1- C4alkoxy or C1- C4haloalkoxy; C3- C8cycloalkyl, optionally substituted by one or more halogen, nitro, cyano, C1- C4alkyl, C1- C4haloalkyl, C1- C4alkoxy or C1- C4haloalkoxy; C2- C6alkenyl, optionally substituted by one or more halogen; nitro, cyano, C1- C4alkyl, C1- C4haloalkyl, C1- C4alkoxy or C1- C4haloalkoxy;

X represents CR1or N;

Y represents CR2or N;

Z represents CR3or N;

R1, R2and R3are each independently hydrogen or C1- C6alkyl, optionally substituted by one or more halogen, nitro, cyano, C1- C4alkyl, C1- C4haloalkyl, C1- C4alkoxy, C1- C4haloalkoxy, amino, C1- C4alkylamino or di(C1- C4alkyl)amino groups; and, the where R1R2presents structure-CR4=CR5-CR6=CR7-, where R4, R5,

R6and R7are each independently hydrogen, nitro, cyano, C1- C4alkyl, C1- C4haloalkyl, C1- C4alkoxy or C1- C4haloalkoxy;

which involves the reaction of an ester of malonic acid of General formula II

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in which R8and R9represent each independently C1- C6alkyl;

R have the above values,

with heteroassociation General formula III

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in which X, Y and Z have the above values,

and gorodilova, characterized in that the interaction of the compounds II and III is carried out at a temperature of not less than 100oWith, if necessary, in the presence of a base to obtain an intermediate salt dihydroxypyrimidine and source heteroassociative II or used grounds and galoidirovaniya subjected directly or intermediate salt, or dihydroxypyridine obtained by acidification of the intermediate salt water acid using haloiding at least two equivalent halogenous agent.

2. The method according to p. 1, otlychayuschehosya phosphorus, pentabromide phosphorus and a suitable mixture, and the stage of haloiding carried out at a temperature not less than 100oC.

3. The method according to p. 1, characterized in that the ester of malonic acid is subjected to reaction with heteroassociation at 120 - 200oC.

4. The method according to p. 1, characterized in that the ester of malonic acid is subjected to reaction with heteroassociation in the presence of a base.

5. The method according to p. 4, characterized in that the substrate is used in a quantity of at least one molar equivalent relative to the ester of malonic acid.

6. The method according to p. 4, characterized in that the substrate is selected from the group consisting of tertiary amine, a hydroxide of an alkali metal, hydroxide of alkaline earth metal, C1- C6-alkoxide of an alkali metal, C1- C6-alkoxide of the alkali earth metal, a carbonate of an alkali metal and a carbonate of alkaline earth metal.

7. The method according to p. 6, characterized in that the tertiary amine selected from the group consisting of three(C2- C6-alkyl)amine, pyridine, substituted pyridine, quinoline, substituted quinoline,N, N,N',N'-tetramethylrhodamine.

8. The method according to p. 1, characterized in that the ester of malonic Kelisa fact, the solvent has a boiling point of 80 to 220oC.

10. The method according to p. 8, wherein the solvent is selected from the group consisting of aromatic hydrocarbons, chlorinated aromatic hydrocarbons, polynuclear aromatic hydrocarbons, alcohol and mixtures thereof, and the boiling point of the solvent is equal to at least 80oC.

11. The method according to p. 10, characterized in that the aromatic hydrocarbon selected from the group consisting of mesitylene, toluene, xylene and mixtures thereof, polynuclear aromatic hydrocarbon selected from the group consisting of naphthalene, alkylnaphthalene and mixtures thereof, and the alcohol is a butanol.

12. The method according to p. 1, characterized in that heteroassociation used in a quantity of at least one molar equivalent relative to the ester of malonic acid.

13. The method according to p. 1, wherein the aqueous acid is a mineral acid selected from the group consisting of hydrochloric acid, Hydrobromic acid and sulfuric acid.

14. The method according to p. 1, characterized in that gorodilova performed at a pressure of more than one atmosphere.

15. The method according to p. 1, characterized in that X1Ohm, C1- C4-alkyl, C1- C4-haloalkyl, C1- C4-alkoxy, C1- C4-haloalkoxy, phenyl, phenoxy or benzyloxy groups, or naphthyl; X represents CR1or N; Y represents CR2; Z represents N; and R1and R2, each independently, represent hydrogen, and when R1and R2taken together with the atoms to which they are attached, they may form a ring in which R1R2represented by the structure-CH=CH-CH=CH-.

16. The method of producing dihydroxypyridine General formula IV

< / BR>
in which R represents phenyl, optionally substituted by one or more halogen, nitro, cyano, C1- C6alkyl, C1- C6haloalkyl, C1- C6alkoxy, C1- C6haloalkoxy, C1- C4alkoxycarbonyl, phenyl, phenoxy or benzyloxypropionic; naphthyl, optionally substituted by one or more halogen, nitro, cyano, C1- C6alkyl, C1- C6haloalkyl, C1- C6alkoxy, C1- C6haloalkoxy, C1- C4alkoxycarbonyl, phenyl, phenoxy or benzyloxypropionic; hydrogen; C1- C6alkyl, optionally Zam 1 - C4alkoxy or C1- C4haloalkoxy; C3- C8cycloalkyl, optionally substituted by one or more halogen, halogen, nitro, cyano, C1- C4alkyl, C1- C4haloalkyl, C1- C4alkoxy or C1- C4haloalkoxy; C2- C6alkenyl, optionally substituted by one or more halogen, nitro, cyano, C1- C4alkyl, C1- C4haloalkyl, C1- C4alkoxy or C1- C4haloalkoxy; X represents CR1or N; Y represents CR2or N; Z represents CR3or N; R1, R2and R3represent, each independently, hydrogen or C1- C6alkyl, optionally substituted by one or more halogen, nitro, cyano, C1- C4alkyl, C1- C4haloalkyl, C1- C4alkoxy, C1- C4haloalkoxy, amino, C1- C4alkylamino or di(C1- C4alkyl)amino groups, or when R1and R2taken together with the atoms to which they are attached, they may form a ring in which R1R2presents structure-CR4= CR5-CR6= CR7-, where R4, R5- C4haloalkyl, C1- C4alkoxy or C1- C4haloalkoxy,

which involves the reaction of an ester of malonic acid of General formula II

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in which R8and R9represent each independently C1- C6alkyl;

R have the above values,

with heteroassociation General formula III

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in which X, Y and Z have the above values,

characterized in that the interaction of the compounds II and III is carried out at a temperature of not less than 100oWith, if necessary, in the presence of a base to obtain an intermediate salt dihydroxypyrimidine and source heteroassociative II or used by the Foundation, which is acidified with aqueous acid.

17. The method according to p. 16, wherein the temperature is between 120 - 200oC.

18. The method according to p. 16, characterized in that the ester of malonic acid is subjected to reaction with heteroassociation in the presence of a base.

19. The method according to p. 18, wherein the base is present in a quantity of at least one molar equivalent relative to the ester of malonic acid.

20. The method according to p. 18, characterized in that the substrate is selected from the group consisting of critic is an alkali metal, C1- C6-alkoxide of the alkali earth metal, a carbonate of an alkali metal and a carbonate of alkaline earth metal.

21. The method according to p. 20, characterized in that the tertiary amine selected from the group consisting of three(C2- C6-alkyl)amine, pyridine, substituted pyridine, quinoline, substituted quinoline,N, N,N',N'-tetramethylrhodamine.

22. The method according to p. 16, characterized in that the ester of malonic acid is subjected to reaction with heteroassociation in the presence of a solvent.

23. The method according to p. 25, characterized in that the boiling point of the specified solvent is 80 - 220oC.

24. The method according to p. 22, wherein the solvent is selected from the group consisting of aromatic hydrocarbons, chlorinated aromatic hydrocarbons, polynuclear aromatic hydrocarbons, alcohol and mixtures thereof and the boiling point of the solvent is equal to at least 80oC.

25. The method according to p. 24, characterized in that the aromatic hydrocarbon selected from the group consisting of mesitylene, toluene, xylene and mixtures thereof, polynuclear aromatic hydrocarbon selected from the group consisting of naphthalene and alkylnaphthalene and mixtures thereof, and the alcohol is sobunsha least one molar equivalent relative to the ester of malonic acid.

27. The method according to p. 16, wherein the aqueous acid is a mineral acid selected from the group consisting of hydrochloric acid, Hydrobromic acid and sulfuric acid.

28. The method according to p. 16, characterized in that R represents a phenyl, optionally substituted by one or more substituents: halogen, C1- C4-alkyl, C1- C4-haloalkyl, C1- C4-alkoxy, C1- C4-haloalkoxy, phenyl, phenoxy or benzyloxy groups, or naphthyl; X represents CR1or N; Y represents CR2; Z represents N; and R1and R2each independently represents hydrogen or R1and R2taken together with the atoms to which they are attached, may form a ring in which R1R2represented by the structure-CH=CH-CH=CH-.

 

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20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to improved synthesis method of pyrlindone hydrochloride having formula (I) 1. Method features intramolecular cyclization of 6-methyl-1-(2-chloroethyl-imino)-1,2,3,4-tetrahydrocarbazole hydrochloride of formula IV 2 at 80°-140°C with alkali agent in presence of phase transfer catalyst to provide 1,2,5,6-tetrahydro-8-methyl-pyrazine[3,2,1-j,k]-4H-carbazole of formula VI 3 followed by reduction at 80°-120°C. Method of present invention makes in possible to produce compound of formula I with yield nearly 70 % and purity more than 99 %.

EFFECT: method of high yield with reduced amount of alkali agent and phase transfer catalyst.

7 cl, 2 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: compounds satisfying the formula I 1 are disclosed, wherein each R1 and R2 independently to one another are H, OH, OA or Hal; or R1 and R2 together are -O-CH2-O- or -O-CH2-CH2-O-; R3 and R4 are A-group; X - group monosubstituted with R8, R5 or R7; R5 is linear or branched C1-C10-alkylene, wherein one or two CH2-groups may be substituted with oxygen atom; R7 is phenyl or phenylmethyl; R8 is COOH, COOA, CONH2, CONHA, CON(A)2 or CN; F is C1-C6-alkyl; and Hal is F, Cl, Br, or I, as well as physiologically acceptable salts or solvates thereof. Methods for production of claimed compounds (I) and pharmaceutical composition containing the same also are disclosed. Said compounds and pharmaceutical composition have activity as phosphodiesterase V inhibitors and are useful in treatment of cardiovascular diseases and potency disorders.

EFFECT: pharmaceutically applicable compounds and compositions.

7 cl, 16 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pyrrolopyridazine derivative of the following formula: wherein R1 represents (C3-C7)-cycloalkyl-(C1-C6)-alkyl group that can be substituted optionally with (C1-C6)-alkyl group; R2 represents (C1-C6)-alkyl group; R3 represents hydroxymethyl group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbonyloxymethyl group, (C1-C6)-alkoxycarbonyloxymethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxycarbonyl group; R4 represents (C6-C10)-aryl group that can be substituted optionally with substitutes taken among the group consisting of (C1-C6)-alkyl groups, halogen-(C1-C6)-alkyl groups, (C1-C6)-alkoxy-groups, halogen-(C1-C6)-alkoxy-groups and halogen atoms; A represents imino-group, oxygen or sulfur atom, or its pharmaceutically acceptable salt. Pyrrolopyridazine derivatives elicit inhibitory activity with respect to gastric juice secretion and protective activity with respect to stomach mucosa and can be useful as a curative agent for prophylaxis or treatment of ulcer disease. Except for, invention relates to a pharmaceutical composition based on compounds of the invention and to a method for prophylaxis and treatment of ulcer disease.

EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

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