Pyrimidotriazines, method for their preparing, pharmaceutical composition based on thereof and using

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel pyrimidotriazines of the general formula (I):

wherein each R1 and R2 is chosen from the group comprising hydrogen atom, or R1 and R2 form in common chemical bond, -CH2-Ar and Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono- or disubstituted with (lower)-alkoxy-group and naphthyl mono- or disubstituted with (lower)-alkyl, or their pharmaceutically acceptable salts. Also, invention relates to a method for synthesis of these compounds, pharmaceutical composition based on thereof and to using novel pyrimidotriazines for prophylaxis and/or treatment of diabetes mellitus as these compounds possess the strong expressed inhibitory effect on activity of protein tyrosine phosphatase PTP1B.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 27 ex

 

The invention relates to a derivative of pyrimido[5,4-e][1,2,4]triazine-5,7-diamine, which are used for inhibition of patientinitiated primarily RTRV.

The invention relates primarily to compounds of the formula

where R1and R2each is chosen from the group comprising hydrogen, or

R1and R2together mean a chemical bond, -CH2-, -O-, -NH - or-N-R3,

R3means (ness.)alkyl or-CH2-Ar, and

Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono - or disubstituted by the group (ness.)alkyl, (ness.)alkoxy, aryl, cycloalkyl, (ness.)alkylaryl, (ness.)alkoxyaryl, (ness.)alkylsilane, (ness.)alkoxyalkyl, halogen, cyano or trifluoromethyl; naphthyl, mono - or disubstituted by the group (ness.)alkyl, (ness.)alkoxy, aryl, cycloalkyl, (ness.)alkylaryl, (ness.)alkoxyaryl, (ness.)alkylsilane, (ness.)alkoxylalkyl or halogen, or their pharmaceutically acceptable salts.

Patientinitiated (RTR) are key enzymes in the processes of growth and differentiation of cells. Inhibition of these enzymes may affect the modulation multi-stage signaling pathways, in which the role of phosphorylation/dephosphorylation of tyrosine. RTRV is the specific protein is yosipovitch, which is often used as a prototype of this class of enzymes.

Inhibitors RTRS as potential therapeutic agents for the treatment of diabetes. See, for example, Moeller and others, Current Opinion in Drug Discovery & Development, 3(5), 527-540 (2000) or Zhang, Zhong-Yin, Current Opinion in Chemical Biology, 5, 416-423 (2001).

It is established that the compounds of formula

and their pharmaceutically acceptable salts, where R1and R2have the meanings specified below, inhibit patientinitiated primarily RTRV, and, therefore, can be used to reduce the concentration of glucose in plasma (blood) in mammals.

The term "(ness.)alkyl"used in the description of the application separately or in combination, means a linear or branched alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc. (Ness.)alkyl group unsubstituted or substituted by one or more groups independently selected from the range cycloalkyl, nitro, aryloxy, aryl, hydroxy, halogen, cyano, (ness.)alkoxy, (ness.)alkanoyl, (ness.)alkylthio, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl and substituted amino group. Examples of substituted (ness.)alkyl groups include 2-hydroxyethyl, 3-oxobutyl, cyanomethyl and 2-nitropropyl.

The term "qi is loukil" means unsubstituted or substituted 3-7-membered cyclic hydrocarbon radical. The substituents used in the present invention include hydroxy, halogen, cyano, (ness.)alkoxy, (ness.)alkanoyl, (ness.)alkyl, aroyl, (ness.)alkylthio, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, aryl, heteroaryl and substituted amino group.

The term "(ness.)alkoxy" means alkoxygroup straight or branched chain containing up to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy etc.

The term "(ness.)alkylthio" means (ness.)alkyl group attached through a divalent sulfur atom, such as methylmercapto or isopropylacetate.

The term "aryl" means a mono - or bicyclic aromatic group such as phenyl or naphthyl, unsubstituted or substituted with appropriate substituents. Preferred substituents include (ness.)alkyl, (ness.)alkoxy, hydroxy(ness.)alkyl, hydroxy, hydroxyalkoxy, halogen, (ness.)alkylthio, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, cyano, nitro, perfluoroalkyl, alkanoyl, aroyl, arylalkyl, (ness.)quinil and (ness.)alkanolamine. More preferred substituents are (ness.)alkyl, (ness.)alkoxy, hydroxy, halogen, cyano and PERFLUORO(ness.)alkyl. Examples of aryl groups used in the present invention are phenyl, para-tolyl, para-methoxyphenyl, para-chlorophenyl,meta hydroxyphenyl, meta methylthiophenyl, 2-methyl-5-nitrophenyl, 2,6-dichlorophenyl, 1-naphthyl, etc.

The term "(ness.)alkylaryl" means (ness.)the alkyl group mentioned above, in which one or more hydrogen atoms substituted aryl group above. According to the present invention can use any (ness.)alkylaryl, such as benzyl, etc.

The term "(ness.)alkoxyaryl" means (ness.)alkoxygroup above, in which one or more hydrogen atoms substituted aryl group above. According to the present invention can use any (ness.)alkoxyaryl, such as benzyloxy.

The term "(ness.)alkoxycarbonyl" means (ness.)alkoxygroup attached through a carbonyl group. Examples alkoxycarbonyl groups include etoxycarbonyl etc.

The term "pharmaceutically acceptable salt" means the appropriate acid additive salts or basic additive salts, which possess the biological activity and properties of the compounds of formula (I) can be formed using suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of the acid additive salts include salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, sulfamic sour is a, phosphoric acid and nitric acid, and salts of organic acids such as para-toluensulfonate acid, salicylic acid, methanesulfonate acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. are Examples of basic additive salts include salts of ammonium, potassium, sodium and hydroxide of Quaternary ammonium, such as the hydroxide of Tetramethylammonium. Chemical modification of pharmaceutical compounds (i.e. medicines) with the formation of the salt is a known technique to a person skilled in this field, which allows to obtain compounds with improved physical and chemical stability, hygroscopicity, flowability, and solubility. See, for example, H.Ansel and others, Pharmaceutical Dosage Forms and Drug Delivery Systems, 6thEd., 196 and 1456-1457 (1995).

The present invention relates to compounds of formula I

and their pharmaceutically acceptable salts, where

R1and R2each is chosen from the group comprising hydrogen, or

R1and R2together mean a chemical bond, -CH2-, -O-, -NH - or-N-R3,

R3means (ness.)alkyl or-CH2-Ar, a

Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono - or disubstituted by the group (ness.)alkyl, (ness.)ALCO is si, aryl, cycloalkyl, (ness.)alkylaryl, (ness.)alkoxyaryl, (ness.)alkylsilane, (ness.)alkoxyalkyl, halogen, cyano or trifluoromethyl; naphthyl, mono - or disubstituted by the group (ness.)alkyl, (ness.)alkoxy, aryl, cycloalkyl, (ness.)alkylaryl, (ness.)alkoxyaryl, (ness.)alkylsilane, (ness.)alkoxylalkyl or halogen.

Among the compounds of formula I, preferred compounds of formula II

where Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono - or disubstituted by the group (ness.)alkyl, (ness.)alkoxy, aryl, cycloalkyl, (ness.)alkylaryl, (ness.)alkoxyaryl, (ness.)alkylsilane, (ness.)alkoxyalkyl, halogen, cyano or trifluoromethyl; naphthyl, mono - or disubstituted by the group (ness.)alkyl, (ness.)alkoxy, aryl, cycloalkyl, (ness.)alkylaryl, (ness.)alkoxyaryl, (ness.)alkylsilane, (ness.)alkoxylalkyl or halogen.

In one preferred embodiment, compounds of formula II, Ar denotes unsubstituted phenyl or unsubstituted naphthyl.

In another preferred embodiment, compounds of formula II, Ar denotes phenyl, monosubstituted group (ness.)alkyl, (ness.)alkoxy, aryl, cycloalkyl, (ness.)alkylaryl, (ness.)alkoxyaryl, halogen, cyano or trifluoromethyl.

In another preferred embodiment, compounds of formula II, Ar denotes phenyl, mannose is displaced group (ness.)alkyl, (ness.)alkoxy, halogen, cyano or trifluoromethyl.

In another preferred embodiment, compounds of formula II, Ar denotes phenyl, disubstituted group (ness.)alkyl, (ness.)alkoxy, halogen or cyano.

In another preferred embodiment, compounds of formula II, Ar denotes naphthyl, monosubstituted group (ness.)alkyl, (ness.)alkoxy, (ness.)alkylaryl, (ness.)alkoxyaryl or halogen.

In another preferred embodiment, compounds of formula II, Ar denotes naphthyl, monosubstituted group (ness.)alkyl, (ness.)alkoxy or halogen.

In another preferred embodiment, compounds of formula II, Ar denotes naphthyl, disubstituted group (ness.)alkyl, (ness.)alkoxy or halogen.

Compounds according to the invention can exist as stereoisomers, especially enantiomers or diastereomers, each of which is included in the scope of the present invention.

Preferred compounds according to the invention is chosen from the series

1. 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine,

2. 3 diethylaminoethylamine[5,4-e][1,2,4]triazine-5,7-diamine,

3. 3-pyrrolidin-1 iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine,

4. 3-piperidine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine,

5. 3-morpholine-4-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine,

6. 3-(4-methylpiperazin-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

7. 3-(4-benzylpiperazine-1-and is methyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

8. 3-(4-naphthalene-2-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

9. 3-(4-naphthalene-1-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

10. 3-(4-biphenyl-4-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

11. 3-[4-(2-Chlorobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

12. 3-[4-(3-Chlorobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

13. 3-[4-(4-Chlorobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

14. 3-[4-(3-methoxybenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

15. 3-[4-(3-terbisil)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

16. 3-[4-(3-trifloromethyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

17. 3-[4-(4-trifloromethyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

18. 3-[4-(3-bromobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

19. 3-[4-(3-cyanobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

20. 3-[4-(2,4-dimethylbenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

21. 3-[4-(4-ethyl-2-methylnaphthalene-1-ylmethyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine and

22. 3-[4-(4-benzyloxybenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine.

More preferred compounds according to the invention is chosen from the series

3-diethylamino is imperiled[5,4-e][1,2,4]triazine-5,7-diamine,

3-(4-benzylpiperazine-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

3-(4-naphthalene-2-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

3-(4-naphthalene-1-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

3-(4-biphenyl-4-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

3-[4-(2,4-dimethylbenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

3-[4-(4-ethyl-2-methylnaphthalene-1-ylmethyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine and

3-[4-(4-benzyloxybenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine.

In addition, preferred is a method of obtaining compounds of formula I, including the interaction of the compounds of formula 3

with the compound of the formula R4Other5where R4means-CH2CH2R1, a R5means-CH2CH2R2where R1and R2have the values specified above.

In addition, preferred compounds of formula I for use as therapeutically active substances.

In addition, preferred compounds of formula I to obtain drugs for the prevention and/or treatment of diabetes.

Another preferred object of the invention is a pharmaceutical composition comprising a compound of formula I terapevticheskii inert carrier.

In addition, the preferred option of the invention is a compound of formula I, obtained in the manner specified above.

In addition, preferred is a method of treatment and/or prevention of diseases associated with glucose levels in the plasma (blood), and the method includes introducing an effective amount of the compounds of formula I. this method is presented as the application of the compounds of formula I for the manufacture of a medicinal product intended for the treatment or prevention of diabetes.

Compounds of the invention inhibit RTRV in vitro and reduce the level of glucose in plasma (blood) in vivo. Therefore, the compounds according to the invention can be used for the treatment of diabetes.

Compounds according to the invention can be administered orally, rectally or parenterally way, for example, intravenous, intramuscular, subcutaneous, intrathecal or percutaneous manner, or sublingually, or in the form of ophthalmic drugs. Examples of dosage forms include capsules, tablets, suspensions or solutions for oral administration, suppositories, injections, eye drops, ointment or spray solutions.

Preferred routes of administration are intravenous, intramuscular, oral, or inhalation methods.

The dose at which the compounds according to the invention BBO shall be effective amount, depend on the specific nature of the active ingredient, age and needs of the patient and the route of administration. Dose any conventional methods, for example, clinical trials for the determination of the maximum dose. In General, preferred is a dose of from approximately 0.1 to 100 mg/kg of body weight per day, more preferably 1-25 mg/kg of body weight per day.

The invention also includes pharmaceutical compositions that contain a pharmaceutically effective amount of the compounds according to the invention and a pharmaceutically acceptable carrier. Such compositions receive conventional methods. Tablets or granules can contain binders, fillers, carriers, or diluents. Liquid compositions can be obtained, for example, in the form of sterile mixing with the water solution. In addition to the active ingredients of the capsules may contain a filler. In addition, the composition may include flavouring agents, and substances that are usually used as preserving, stabilizing, water binding and emulsifying agents, salts for regulating the osmotic pressure, buffer substances and other additives.

The above-mentioned carriers and diluents can include the corresponding pharmaceutically acceptable organic or inorganic substances, for example water, m is tin, lactose, starch, magnesium stearate, talc, Arabic gum, polyalkylene glycols, etc.

Standard doses for oral administration, such as tablets and capsules, preferably contain from 25 mg to 1000 mg of the compounds according to the invention. Compounds according to the invention receive conventional methods. The specific method shown in schemes 1-3.

Intermediate compound 3, containing chloromethylene group have, as shown in figure 1, from hemisulfate 2,4-diamino-2-mercaptopyridine 1, which is a commercial product. Connection 1 S-was identified in (for example, methyliodide in the presence of sodium hydroxide), and then nitrosylated under standard conditions (for example, sodium nitrate in acetic acid at about 50°C)receive interim arylnitrenes connection 2. When replacing the thiomethyl group in compound 2 with hydrazine in a suitable solvent, such as dimethylformamide, at room temperature, followed by condensation with diethylacetal of chlortetracycline, which is a commercial product, when heated (for example, when 85° (C) in acidic medium (for example, in the presence of HCl) are compound 3, containing chloromethylene group.

Then chloromethylene derivative 3 is introduced into reaction with various the YMI known amines in a suitable solvent, such as ethanol, when heated (for example, when approximately 80-100° (C) with the formation of appropriate aminomethylphosphonic 4, as shown in scheme 2. In amines have had the formula, R4NR5in scheme 2, R4means-CH2CH2R1, a R5means-CH2CH2R2where R1and R2have the values specified above.

A derivative of piperazine 5 (for example, compound 4, where R4and R5together form the fragment-CH2CH2NHCH2CH2-) is obtained from chlormethine derived 3 and piperazine, as shown in scheme 2. Alkylation of compound 5 different known alkylhalogenide (for example, R3Br or R3I, where R3matter mentioned above) is conducted in a suitable solvent, such as dimethylformamide, in the presence of a suitable base such as potassium carbonate, at room temperature, you get a derivative dialkylamino piperazine 6, as shown in figure 3.

Examples

Example 1

6-Methylthio-5-nitrosopyrimidine-2,4-diamine

Stage 1

To a solution of 105 g of KOH in 1 l of water under stirring was added hemisulfate 2,4-diamino-6-mercaptopyrimidine 1 (70,0), and then methyl iodide (91 ml) and the resulting mixture was intensively stirred for 4 h TBE is the substance was separated by filtration, washed with water and dried in the air during the night, when it got 54,0 g 6-methylthiopyrimidin-2,4-diamine in the form of a solid, yellowish-brown.

1H NMR (DMSO-d6): of 6.20 (s, 2H), 5,90 (s, 2H), of 5.55 (s, 1H), 2,30 (s, 3H).

Stage 2

To a suspension of 6-methylthiopyrimidin-2,4-diamine (50.0 g, 321 mmol) in water (1000 ml) with stirring was added 500 ml of 2 N. acetic acid, the mixture was heated to 50°was rapidly added a solution of NaNO2(24,0 g, 353 mmole 200 ml of N2O) and the mixture was heated at 50°C for 1 h Then the mixture is dark blue/purple color was cooled to room temperature and filtered. Solid blue/purple color is repeatedly washed with water and then ether, and dried in air, to receive of 51.0 g of 6-methylthio-5-nitrosopyrimidine-2,4-diamine 2 in the form of a solid blue/purple color.

1H NMR (DMSO-d6): to 9.70 (s, 1H), 8,10 (s, 1H), 7,95 (m, 2H), 2,43 (s, 3H).

Example 2

6 Hydrazino-5-nitrosopyrimidine-2,4-diamine

To a suspension (12.0 g, 64,9 mmole) 6-methylthio-5-nitrosopyrimidine-2,4-diamine 2 in DMF at room temperature was rapidly added hydrazinehydrate (55% solution of 14.5 ml). The mixture was stirred overnight, then the mixture is hot pink color was filtered, the solid is repeatedly washed with DMF, then with ether, and dried in the air, while recip is whether at 9.53 g of 6-hydrazino-5-nitrosopyrimidine-2,4-diamine in the form of a solid hot pink color.

1H NMR (DMSO-d6): 8,00 (s, 1H), 7,40 (s, 1H), 7,05 (m, 2H), 5,35 (m, 2H).

Example 3

3 Chloromethylpyridine[5,4-e][1,2,4]triazine-5,7-diamine

To a cooled on an ice bath DMF (350 ml) with stirring was added conc. HCl (14 ml) and 7,14 g 6 hydrazino-5-nitrosopyrimidine-2,4-diamine. After 5 min for approximately 2 min was added diethylacetal of chloroacetaldehyde (15,4 ml). The cooling bath was removed, the mixture was heated to room temperature and maintained for 1 h, then the mixture was heated at 85°C for 1.5 h and cooled to room temperature for approximately 2.5 hours the Mixture was filtered to remove a small amount of insoluble material brown filtrate was podslushivaet conc. a solution of NH4OH and were diluted with equal amount of water. The mixture was stirred for 1 h, the solid orange-brown color was separated by filtration and dried in vacuum over P2O5when this was received 3.50 g of 3-chloromethylpyridine[5,4-e][1,2,4]triazine-5,7-diamine 3.

1H NMR (DMSO-d6): of 8.25 (s, 2H), 7,95 (s, 1H), 7,30 (.s, 1H), 5,02 (s, 2H).

Example 4

3-Piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine

A mixture of 3-chloromethylpyridine[5,4-e][1,2,4]triazine-5,7-diamine 3 (2.00 g, 9.5 mmole) and piperazine (2.50 g, 29 mmol) in absolute ethanol was heated the ri 100° With in a sealed tube for 4 h Then the mixture was cooled to room temperature and was evaporated. The crude product was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 30% of CH3SN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was freeze-dried, it was obtained 1.44 g trifenatate 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 yellow.

1H NMR (DMSO-d6): of 9.55 (s, 1H), 9,40 (s, 1H), 8,80 (s, 2H), to 8.45 (s, 1H), 4,15 (s, 2H), 3,10 (m, 4H), 2,80 (m, 4H).

Example 5

3 Diethylaminoethylamine[5,4-e][1,2,4]triazine-5,7-diamine

A mixture of 3-chloromethylpyridine[5,4-e][1,2,4]triazine-5,7-diamine 3 (200 mg, 0.95 mmole) and diethylamine (2.00 ml) in absolute ethanol (2.0 ml) was heated at 100°in a sealed tube for 5 h Then the mixture was cooled to room temperature and concentrated in vacuum. The crude product was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 30% of CH3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was freeze-dried, when it received 65 mg trifenatate 3 diethylaminoethylamine[5,4-e][1,2,4]triazine-5,7-diamine 4 yellow.

1H NMR (DMSO-d6): 9,10 (.s, 1H), 8,90 (.s, 1H), 8,15 (s, 2H), 4,80 (s, 2H), 3,25 (q, 4H), of 1.30 (t, 6H).

Example 6

3-Pyrrolidin-1 iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine

A mixture of 3-chloromethylpyridine[5,4-e][1,2,4]triazine-5,7-diamine 3 (70 mg, of 0.33 mmole) and 1.0 ml of pyrrolidine was heated at 80°in a sealed tube for 7 hours and Then the mixture was cooled to room temperature and concentrated in vacuum. The crude product was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 30% of CH3CN/H2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was evaporated in vacuo, the residue was liofilizovane, received 50 mg of triptoreline 3-pyrrolidin-1 iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (DMSO-d6): 9,15 (.s, 1H), 8,88 (.s, 1H), 8,20 (.s, 2H), to 3.67 (s, 2H), 3,20 (osirm, 2H), 1.85 to 2,10 (m, 4H).

Example 7

3-piperidine-1-iletilerimde[5,4-e][1,2,4]triazine-5.7-diamine

A mixture of 3-chloromethylpyridine[5,4-e][1,2,4]triazine-5,7-diamine 3 (70 mg, of 0.33 mmole) and 1.0 ml of piperidine in a sealed tube was heated at 80°C for 7 h and Then the mixture was cooled to room temperature and concentrated in vacuum. The crude product was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 30% of CH3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product, thing in common and, CH3CN was removed in vacuo, the residue was liofilizovane, received 111 mg trifenatate 3-piperidine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (DMSO-d6): 9,18 (.s, 1H), 8,95 (.s, 1H), 8.30 to (.s, 2H), 4,80 (s, 2H), 3,50 (osirm, 2H), 3,10 (osirm, 2H), 1,35-1,90 (m, 6N).

Example 8

3-Morpholine-4-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine

A mixture of 3-chloromethylpyridine[5,4-e][1,2,4]triazine-5,7-diamine 3 (200 mg, 0.95 mmole) and 2.0 ml of the research was heated at 80°in a sealed tube for 7 hours and Then the mixture was cooled to room temperature and concentrated in vacuum. The crude product was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 30% of CH3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, received 261 mg trifenatate 3-morpholine-4-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (DMSO-d6): 9,25 (.s, 1H), 9,00 (.s, 1H), 8.30 to (user. s, 2H), 4,80 (s, 2H), 3,85 (m, 4H), 3,30 (m, 4H).

Example 9

3-(4-Methylpiperazin-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

A mixture of 3-chloromethylpyridine[5,4-e][1,2,4]triazine-5,7-diamine 3 (200 mg, 0.95 mmole) and N-methylpiperazine (2.00 ml) was heated at 80°in a sealed tube for 7 hours the ATEM and the mixture was cooled to room temperature and concentrated in vacuum. The crude product was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 30% of CH3CN/N2O/0.1% of TFU) and fraction bright yellow color, containing the product, after removal of CH3CN in vacuum, was liofilizovane, received 178 mg trifenatate 3-(4-methylpiperazin-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (D2O): of 4.45 (s, 2H), 3,10-of 3.60 (m, 8H), 2,90 (s, 3H).

Example 10

3-(4-Benzylpiperazine-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

A mixture of 3-chloromethylpyridine[5,4-e][1,2,4]triazine-5,7-diamine 3 (48 mg, 0,23 mmole) and N-benzylpiperazine (0,12 ml) in ethanol (0.1 ml) was heated at 90°in a sealed tube for 2 hours Then the mixture was cooled to room temperature and concentrated in vacuum. The crude product was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 50% of CH3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, received 26 mg trifenatate 3-(4-benzylpiperazine-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (DMSO-d6): to 7.50 (m, 5H), 4,34 (s, 2H), 4,25 (s, 2H), 2,90 is 3.40 (m, 8H).

Example 11

3-(4-Naphthalene-2-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

RA is Toru of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (30 mg, 0.05 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added 2-bromethalin (17 mg, of 0.075 mmole), and then potassium carbonate (28 mg, of 0.20 mmole). The mixture was stirred at room temperature for 24 h, then transferred in CH3CN/N2O/0.1% of TFU and reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 30% of CH3CN/H2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, received 19 mg trifenatate 3-(4-naphthalene-2-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (DMSO-d6): 9,37 (.s, 1H), 9,23 (.s, 1H), 8,20 (.s, 1H), 7,98 (m, 5H), EUR 7.57 (m, 3H), 4,45 (.s, 2H), 4,15 (.s, 2H), 2,60-to 3.35 (m, 8H).

Example 12

3-(4-Naphthalene-1-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (70 mg, 0.12 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added 1-chloromethylation (0,023 ml of 0.18 mmole), and then potassium carbonate (65 mg, 0,470 mmole). The mixture was allowed to mix at room temperature for 24 h, then transferred to CH3CN/H2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% on the 30% of CH 3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, received 35 mg trifenatate 3-(4-naphthalene-1-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (DMSO-d6): 9,36 (.s, 1H), 9,23 (.s, 1H), 8,53 (.s, 1H), 8,32 (m, 1H), 8,23 (.s, 1H), 8,00 (m, 2H), 7,60 (m, 4H), 4,68 (.s, 2H), 4,23 (.s, 2H), 2,80 is 3.40 (m, 8H).

Example 13

3-(4-Diphenyl-4-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (30 mg, 0.05 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added 4-chloromethylstyrene (15 mg, 0.08 mmole), and then potassium carbonate (28 mg, of 0.20 mmole). The mixture was stirred at room temperature for 24 h, then transferred in CH3CN/N2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 30% of CH3CN/H2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, received 20 mg of triptoreline 3-(4-diphenyl-4-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (DMSO-d6): a 9.60 (s, 1H), 9,43 (s, 1H), 8,83 (.s, 1H), 8,53 (the .s, 1H), 7,35-of 7.82 (m, 9H), to 4.33 (s, 2H), 4,15 (s, 2H), 2,70 is 3.40 (m, 8H).

Example 14

3-[4-(2-Chlorobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (50 mg, 0.08 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added ortho-chlorobenzylchloride (of 0.015 ml, 0.12 mmole), and then potassium carbonate (55 mg, 0.40 mmole). The mixture was stirred at room temperature for 24 h, then transferred in CH3CN/N2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 50% of CH3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, received 17 mg trifenatate 3-[4-(2-Chlorobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (MeOH-d4): 7,40-of 7.70 (m, 4H), of 4.44 (s, 2H), 4,36 (s, 2H), 2,80 is 3.40 (m, 8H).

Example 15

3-[4-(3-Chlorobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (50 mg, 0.08 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added meta-chlorobenzylchloride (of 0.015 ml, 0.12 mmole), and then carbonate Kali is (55 mg, 0.40 mmole). The mixture was stirred at room temperature for 24 h, then transferred in CH3CN/N2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 50% of CH3CN/H2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, while received 9 mg trifenatate 3-[4-(3-Chlorobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (MeOH-d4): 7,40-7,58 (m, 4H), 4,32 (s, 4H), 2,80 is 3.40 (m, 8H).

Example 16

3-[4-(4-Chlorobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (50 mg, 0.08 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added para-chlorobenzylchloride (29 mg, of 0.18 mmole), and then potassium carbonate (55 mg, 0.40 mmole). The mixture was stirred at room temperature for 24 h, then transferred in CH3CN/N2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 50% of CH3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH2CN was removed in vacuo, the residue was liofilizovane, received 21 mg trifenatate 3-[4-(4-Chlorobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]what reazin-5,7-diamine yellow color.

1H NMR (MeOH-d4): to 8.20 (m, 4H), 4,30 (s, 4H), 2,88 is 3.40 (m, 8H).

Example 17

3-[4-(3-Methoxybenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (50 mg, 0.08 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added meta-methoxybenzylamine (19 mg, 0.12 mmole), and then potassium carbonate (55 mg, 0.40 mmole). The mixture was stirred at room temperature for 24 h, then transferred to CH3CN/H2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 50% of CH3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, received 30 mg of triptoreline 3-[4-(3-methoxybenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (MeOH-d4): 7,40 (m, 1H), 7,06 (m, 3H), 4,30 (s, 2H), 4,23 (s, 2H), 3,81 (s, 3H), 2,80 is 3.40 (m, 8H).

Example 18

3-[4-(3-Terbisil)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (50 mg, 0.08 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added meta-tormentilla (0,143 ml, 0.12 mmole), and then potassium carbonate (55 mg, 0.40 mmole). The mixture was stirred at room temperature for 24 h, then transferred in CH3CN/N2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 50% of CH3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, received 11 mg trifenatate 3-[4-(3-terbisil)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (MeOH-d4): 7,18-of 7.60 (m, 4H), to 4.33 (s, 2H), 4,27 (s, 2H), 2,83-to 3.38 (m, 8H).

Example 19

3-[4-(3-Trifloromethyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (50 mg, 0.08 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added meta-triftormetilfosfinov (0,021 ml of 0.14 mmole), and then potassium carbonate (55 mg, 0.40 mmole). The mixture was stirred at room temperature for 24 h, then transferred in CH3CN/N2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 50% of CH3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, received 3 mg of triptoreline 3-[4-(3-trifloromethyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (MeOH-d4): 7,63-a 7.92 (m, 4H), to 4.38 (s, 2H), 4,32 (s, 2H), 2,85-to 3.38 (m, 8H).

Example 20

3-[4-(4-Trifloromethyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (50 mg, 0.08 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added para-triftormetilfosfinov (0,021 ml of 0.14 mmole), and then potassium carbonate (55 mg, 0.40 mmole). The mixture was stirred at room temperature for 24 h, then transferred in CH3CN/N2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 50% of CH3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, received 22 mg trifenatate 3-[4-(4-trifloromethyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (MeOH-d4): to 7.77 (m, 4H), 4,37 (s, 2H), 4,33 (s, 2H), 2,90-to 3.38 (m, 8H).

Example 21

3-[4-(3-Bromobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5-7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (50 mg, 0.08 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added meta-br is benzylbromide (34 mg, of 0.14 mmole), and then potassium carbonate (55 mg, 0.40 mmole). The mixture was stirred at room temperature for 24 h, then transferred in CH3CN/N2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18,eluent: gradient from 0% to 50% of CH3CN/H2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, received 15 mg of triptoreline 3-[4-(3-bromobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (MeOH-d4): 7,38-7,80 (m, 4H), 4,30 (s, 4H), 2,85-to 3.38 (m, 8H).

Example 22

3-[4-(3-Cyanobenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (50 mg, 0.08 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added meta-cyanobenzeneboronic (23 mg, of 0.18 mmole), and then potassium carbonate (55 mg, 0.40 mmole). The mixture was stirred at room temperature for 24 h, then transferred to CH3CN/H2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 50% of CH3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, received 12 mg trifenatate 3-[4-(3-zienab nil)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (MeOH-d4): 7,60-a 7.92 (m, 4H), 4,37 (s, 2H), 4,27 (s, 2H), 2.95 and-to 3.35 (m, 8H).

Example 23

3-[4-(2,4-Dimethylbenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (50 mg, 0.08 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added 2,4-dimethylbenzylamine (0,020 ml of 0.13 mmole), and then potassium carbonate (55 mg, 0.40 mmole). The mixture was stirred at room temperature for 24 h, then transferred in CH3CN/N2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 50% of CH3CN/H2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, while received 10 mg of triptoreline 3-[4-(2,4-dimethylbenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (DMSO-d6): 9,40 (user. s, 1H), 8,17 (users, 2H), 7,00-7,40 (m, 3H), 4,28 (.s, 2H), 4,10 (.s, 2H), 2.95 and-to 3.35 (m, 8H), was 2.34 (s, 3H), of 2.28 (s, 3H).

Example 24

3-[4-(4-Ethyl-2-methylnaphthalene-1-ylmethyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (50 mg, 0.08 mmole) (obtained as described in example 4) in the ear DMF (1.0 ml) under stirring was added 1-chloromethyl-2-methylnaphthalene (34 mg, of 0.18 mmole), and then potassium carbonate (55 mg, 0.40 mmole). The mixture was stirred at room temperature for 24 h, then transferred in CH3CN/N2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 50% of CH3CN/N2O/0.1% of TFU) and fraction bright yellow color, containing the product, after removal of CH3CN in vacuum, was liofilizovane, got 23 mg trifenatate 3-[4-(4-ethyl-2-methylnaphthalene-1-ylmethyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (MeOH-d4): 8,07 (m, 1H), 7,92 (m, 2H), 7,40-to 7.50 (m, 3H), of 4.90 (s, 2H), 4,37 (s, 2H), 2,70 (s, 3H), 2,80 is-3.45 (m, 8H).

Example 25

3-[4-(4-Benzyloxybenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine

To a solution of triptoreline 3-piperazine-1-iletilerimde[5,4-e][1,2,4]triazine-5,7-diamine 5 (50 mg, 0.08 mmole) (obtained as described in example 4) in dry DMF (1.0 ml) under stirring was added 1-chloromethyl-2-methylnaphthalene (27 ml, 0.12 mmole), and then potassium carbonate (58 mg, at 0.42 mmole). The mixture was stirred at room temperature for 24 h, then transferred in CH3CN/N2O/0.1% of TFU and was purified by reversed-phase GHUR (Rainin C18, eluent: gradient from 0% to 50% of CH3CN/N2O/0.1% of TFU), fraction of a bright yellow color, containing the product were combined, CH3CN was removed in vacuo, the residue was liofilizovane, the ri was received 23 mg trifenatate 3-[4-(4-benzyloxybenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine yellow color.

1H NMR (DMSO-d6): 9,63 (s, 1H), 9,50 (s, 1H), 8,91 (.s, 1H), 8,77 (.s, 1H), 7,40 (m, 7H), 7,05 (m, 2H), 5,12 (s, 2H), 4,25 (s, 2H), 4,17 (s, 2H), 2,60 is 3.40 (m, 8H).

Example 26

Inhibition RTRV in vitro

RTRW (1-321) of the person cloned from cDNA library of human using conventional techniques of molecular biology. The cDNA sequence was identical to the published sequence RTRV person (registration number M). Protein expressed in E.coli and purified as described Barford D. and others, J. Mol. Biol., 239, 726-730 (1994).

Determination of inhibition Strasnoy activity

Measurement Strasnoy activity conducted by one of two methods.

In the first method of determining inhibitory activity against RTRV as the substrate used peptide containing phosphotyrosine, amino acid sequence which corresponds to section 1146 (TRDI(pY) (E) of the insulin receptor containing autophosphorylating tyrosine. The reaction was carried out under the following conditions:

RTRW (0.5 to 2 nm) were incubated with compound for 15 min in a buffer solution containing 37.5 mm MES, pH of 6.2, 140 mm NaCl, 0.05% BSA and 300 nm DTT. The reaction was initiated by adding 50 μm of the substrate. After incubation at room temperature (22-25° (C) within 20 min the reaction was stopped by addition of KOH and measured the amount of free phosphate using malachite green as described in the literature (see Harder and others, Biochem. J., 298, 395 (1994).

In the second method determined the total inhibitory activity against RTRS using set RTRS. The substrate (6,8-debtor-4-methylumbelliferone, DiFMUP, the company Molecular Probes) was used at a concentration, which was used in the measurement of Kmfor each enzyme. The composition of the buffer solution was identical to the above in the analysis using the malachite green, except that instead of the MES used 37.5 mm diacylglycerol, pH of 6.2. The reaction was stopped by addition of KOH. In this case, the measured fluorescence dephosphorylating product (λvasb360 nm, λCOI460 nm).

When determining the kinetic parameters of the reaction to use the specified buffer solutions except that the reaction was initiated by addition of enzyme and stopped after 10 minutes

According to the results of the above analysis of the in vitro value IC50in relation RTRV the compounds of the present invention is less than 500 microns, preferably less than 100 microns.

According to the results of in vitro assays all compounds described in the examples 4-25 when inhibition RTRV characterized by the value of the IC50less than 30 microns.

Example 27

The effect of compounds on the level of glucose in plasma (blood) when tested in mice

To measure the anti-diabetic action is conducted the test compounds in vivo in well-known model of type 2 diabetes and obesity in rodents.

Obese mice (ob/ob

For evaluating the effect of compounds on the reduction of glucose levels while reducing the level of triglycerides used male and female mice ob/ob (line C57BL6/J) weighing 40-50 g (see Diabetologia, 14, 141-148 (1978)) (Jackson Labs). Animals pre-distributed into groups of 10-12 individuals depending on the glucose level and body weight. Animals received normal feed and had free access to water. Analyzed the connection (suspended in 1% Na-CMC) was administered daily through a stomach tube for five days. Just before the introduction in animals grafted part of the tail, the blood was collected from the tail vein and determined the concentration of glucose in plasma (blood) on the first day of the experiment. On the fifth day after 2 h after injection in a similar way the blood was collected and determined the concentration of glucose. Then the animals were anestesiology and were killed by exsanguination. Blood and tissues were collected for analysis. Compounds were considered active if they caused a statistically significant (p≤0.05) reduction in blood glucose compared with glucose levels of mice treated with media.

Obesity in mice C57BL6/J (DIO mice)induced by diet

In mice caused type 2 diabetes when the content of a diet high in fat for 4-6 months (Diabetes, 37, 1163-1167 (Sept., 1988)). Male line C57BL6/J (age 4 weeks) was kept on a diet with a high fat diet for 4-6 weeks. During this time, the animals developed hyperglycemia and hyperinsulinemia, and body weight was 40-50, DIO Mice (n=6) were weighed and were deprived of food for 2 h before oral administration of the analyzed compounds. Immediately prior to the introduction of substances through the gastric tube the blood was collected from the tail vein and were determined by the glucose concentration (time 0), as described above. The analyzed compound was administered to the animals 1 time a day for five days, the control animals (receiving device) of the analyzed compounds were not introduced. On the fifth day were measured glucose level before injection (time 0) and after 2 and 4 h after injection. After 4 h after injection was measured insulin levels and triglycerides. Compounds were considered active if experimental animals they caused a statistically significant (p≤0.05) reduced levels of glucose, insulin and triglycerides in the blood compared to animals treated with the media.

Test compounds described in examples 5, 10 and 13, in mice in vivo was performed according to the procedure described in example 27. These compounds reduced the level of blood glucose by at least 15%.

1. Perimetritis General formula

where R1and R2each means hydrogen or

R1and R2together form a chemical bond, -CH2-, -O-, -NH - or-N-R3 ;

R3means nissalke or the group-CH2-Ar, where

Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl; phenyl, mono - or disubstituted nissolia, halogen, cyano, trifluoromethyl, phenyl, benzyloxy or nissalke; naphthyl, mono - or disubstituted nissolia;

or their pharmaceutically acceptable salts.

2. Compounds according to claim 1 of the formula

where Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl; phenyl, mono - or disubstituted nissolia, halogen, cyano, trifluoromethyl, phenyl, benzyloxy or nissalke; naphthyl, mono - or disubstituted nissolia,

or pharmaceutically acceptable salts of compounds of formula II.

3. Compounds according to claim 1, where Ar denotes unsubstituted phenyl or unsubstituted naphthyl.

4. Compounds according to claim 1 or 2, where Ar denotes phenyl, monosubstituted nissolia, halogen, cyano, trifluoromethyl, phenyl, benzyloxy or nissalke.

5. Compounds according to claim 1, where Ar denotes phenyl, monosubstituted nissolia, nissalke, halogen, cyano or trifluoromethyl.

6. Compounds according to claim 1, where Ar denotes phenyl, disubstituted nissolia, nissalke, halogen or cyano.

7. Compounds according to claim 1, where Ar denotes naphthyl, monosubstituted nissolia.

8. Connections P1, where Ar denotes naphthyl, disubstituted nissolia.

9. Compounds according to claim 1, selected from the range

3 diethylaminoethylamine[5,4-e][1,2,4]triazine-5,7-diamine,

3-(4-benzylpiperazine-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

3-(4-naphthalene-2-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

3-(4-naphthalene-1-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

3-(4-biphenyl-4-iletileri-1-ylmethyl)pyrimido[5,4-e][1,2,4]triazine-5,7-diamine,

3-[4-(2,4-dimethylbenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine.

3-[4-(4-ethyl-2-methylnaphthalene-1-ylmethyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine and

3-[4-(4-benzyloxybenzyl)piperazine-1-ylmethyl]pyrimido[5,4-e][1,2,4]triazine-5,7-diamine.

10. A method of obtaining a compound according to any one of claims 1 to 10, including the interaction of the compounds of formula 3

c compound of formula R4Other5where R4means-CH2CH2R1, a R5means-CH2CH2R2where R1and R2have the meanings indicated in claim 1.

11. Compounds according to any one of claims 1 to 9 for use as therapeutically active substances.

12. Compounds according to any one of claims 1 to 9 to obtain drugs for the prevention and/or is ecene diabetes.

13. Pharmaceutical composition having inhibitory activity against patientinitiated RTRV and containing a compound according to any one of claims 1 to 9 and a therapeutically inert carrier.

14. Compounds according to any one of claims 1 to 9, obtained by the method according to claim 10.

15. The use of compounds according to any one of claims 1 to 9 for the manufacture of a medicinal product intended for the prevention and/or treatment of diabetes.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: chemical industry; method of production of the fluorine-containing compounds.

SUBSTANCE: the invention is pertaining to the chemical industry, in particular, to the improved method of production of fluorine-containing compounds from the halogen-containing, compounds, preferably, from chlorine-containing compounds due to an exchange of halogen for fluorine at presence of the HF-additional compound of the mono- or bicyclic amine with at least two atoms of nitrogen. At that at least one atom of nitrogen is built in the cyclic system as the fluorating agent; or at presence of anhydrous hydrogen fluoride - as the fluorating agent and the indicated HF-additional compound of the mono- or bicyclic amine as the catalyst. At usage of the applicable solvents the reaction mixtures can be divided into two phases and thus to simplify the reprocessing of the products. The invention also is pertaining to the HF-additional compounds of 1.5-diazabicyclo[4.3.0]non-5-en and N,N-dialkylaminopiridin, where alkyl represents C1-C4alkyl and where the molar ratio of HF to amine makes 1:1, and to HF- additional compounds 1.8- diazabicyclo[5.4.0]undecyl-7-ene, where the molar ratio of HF to amine compounds more than 1:1.

EFFECT: the invention ensures at usage of the applicable solvents to divide the reaction mixture into two phases and thus to simplify reprocessing of the products.

17 cl, 13 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel derivative of 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole, namely its hydrobromide, eliciting properties of antagonist of serotonin 5-HT3-receptors that can be used in therapy of cytotoxic nausea and vomiting. New salt is low toxic and exceeds bemesetron by anti-serotonin activity that is a selective 5-HT3- antagonist.

EFFECT: improved and valuable medicinal properties of derivative.

2 cl, 2 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anellated carbamoylazaheterocycles of the general formula (1) that possess inhibitory property of kinase activity and eliciting, for example, an anticancer activity. Also, compounds can be used as agonists, antagonists, receptor modulating agents, antiparasitic and antibacterial agents. Also, invention relates to a method for synthesis of compounds of the formula (1), a pharmaceutical composition based on thereof and a focused library for assay of leader-compounds. In compounds of the general formula (1) W represents 6-oxopiperazine, [1,4]-thiazepane, [1,4]-oxazepane or [1,4]-diazepane cycle anellated with at least one optionally substituted and optionally condensed heterocycle or carbocycle Q; Q represents optionally substituted thiophene, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted thiazole, optionally substituted pyrrolidine, optionally substituted indole, optionally substituted benzofuran, optionally substituted pyridine, optionally substituted quinoline, optionally substituted benzene or optionally substituted naphthalene cycle; R1, R2 and R represent independently of each another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl.

EFFECT: improved preparing method, valuable biological and medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to new compounds of the formula (I) wherein R1 and R2 can be similar or different and represent independently (C1-C6)-alkyl that are selective inhibitors of enzyme phosphodiesterase, and to their pharmaceutically acceptable salts or stereoisomers. Also, invention involves a method for preparing the preferable compound, i. e. 5-[[2-ethoxy-5-(cis-2,6-dimethylpiperazin-4-ylsulfonyl)phenyl]]-1-methyl-3-n-propyl-7,6-dihydro-1H-pyrazolo[4,3-d]pyrimidine-7-one. Also, invention proposes new intermediate compounds used in method for synthesis of this compound. Compounds of the formula (I) show very high effectiveness in treatment of diseases associated with impotence, such as the male erectile sterility but they exhibit such features as prolonged therapeutic effectiveness and lower toxicity. Also, invention relates to a pharmaceutical composition used in treatment of impotence and using compound of the formula (I) in preparing the medicinal preparation designated for treatment of diseases associated with impotence.

EFFECT: valuable medicinal properties of compound.

8 cl, 7 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound and to all its enantiomeric and diastereomeric forms and pharmaceutically acceptable salts that are able to prevent extracellular release of inflammatory cytokines. Proposed compounds have the formula (I): wherein R represents: (a) -OR3 or (b) -NR4aR4b; R3 represents unsubstituted or substituted phenyl wherein substitutes are: (i) halogen atom; (ii) (C1-C6)-alkyl; (iii) trifluoromethyl; (iv) trichloromethyl; (v) tribromomethyl; (vi) cyano-group, and (vii) (C1-C6)-alkoxy-group; each R4a and Rb represents independently: (a) hydrogen atom or (b) -[C(R5aR5b)]xR6 wherein index x = 0-5; each R5a and R5b represents independently hydrogen atom, linear or branched (C1-C4)-alkyl, (C3-C7)-cyclic alkyl; R6 represents -OR7 or (C1-C4)-alkyl; R7 represents hydrogen atom or (C1-C4)-alkyl; R1 represents halogen-substituted phenyl; each among links R2a and R2b is chosen independently from the groups consisting of: (a) hydrogen atom; (b) -O(CH2)jR8; (c) -(CH2)jCO2R10; (d) -(CH2)jCON(R10)2; (e) a double bond when R2a and one R2b are chosen with formation of a double bond; (f) a ring when one R2a and one R2b are chosen with formation a ring and indicated ring is chosen from the group consisting of: (i) benzene and (ii) dioxalane; each R8 and R10 represents independently hydrogen atom or (C1-C4)-alkyl; j represents index from 0 to 5; m represents index from 1 to 3; n represents index from 1 to 3, and m + n = 4. Also, invention relates to a pharmaceutical composition based on abovementioned compounds that inhibits extracellular release of inflammatory cytokines, and a method for regulation of extracellular release of inflammatory cytokines.

EFFECT: valuable medicinal properties of compounds.

10 cl, 9 tbl, 11 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to bicyclic heterocyclic substituted phenyloxazolidinones that represent compounds of the formula (I): wherein R is taken from the group consisting of -OH, O-heteroaryl, -N3, -OSO2R'', -NR'''R'''', or the formula: wherein: (ii) R'' represents direct or branched alkyl comprising up to 5 carbon atoms; (iii) R''' and R'''' are taken independently from the group consisting of hydrogen atom (H), -CO2-R1, -CO-R1, -CS-R1 and -SO2-R4 wherein R1 is taken among the group consisting of cycloalkyl comprising from 3 to 6 carbon atoms and direct or branched alkyl comprising up to 6 carbon atoms; R4 is taken from direct or branched alkyl comprising up to 4 carbon atoms; and R4a represents -CN or -NO2; R4b represents -SR4c, amino-group, -NHR4c or -NR4cR4d wherein R4c and R4d are taken independently from hydrogen atom (H) or alkyl; X represents from 0 to 4 members taken independently from the group consisting of halogen atom; and Y represents radical of the formula (II): or (III): wherein R5, R6, R7 and R8 represent independently hydrogen atom (H), or R and R6 and/or R7 and R8 form in common oxo-group; R9 and R10 represent independently hydrogen atom (H); A, B, C and D are taken from carbon atom (C) and nitrogen atom (N) to form phenyl ring or 5-6-membered heteroaromatic ring wherein the indicated heteroaromatic ring comprises from 1 to 4 members taken from the group consisting of nitrogen atom (N); Z is taken from alkyl, heteroaryl comprising nitrogen atom (N); and m represents 0 or 1. These compounds are useful as antibacterial agents and can be used for treatment of patient with the state caused the bacterial infection or with the bacterial infection caused by S. aureus and E. faecium.

EFFECT: valuable medicinal properties of compounds.

45 cl, 1 tbl, 50 ex

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

SUBSTANCE: invention relates to new compounds of the formula (1): and its salts wherein X means unsubstituted monocyclic (5-6-membered) ring system comprising nitrogen atom (N); or X means condensed bicyclic (9-12-membered) ring system comprising N-atom that can be substituted with substitute -SO2-phenyl; Z represents hydrogen atom (H) or means a condensed bicyclic (9-12-membered) unsubstituted or substituted ring system comprising at least one heteroatom, N-atom; Ar represents unsubstituted phenyl ring; each among L1, L2 and L3 represents independently a bond, -CO, -SO2 or -CH2 wherein at least one among L2 and L3 must involve -CO or -SO2; L2 and L3 can represent can represent independently -CONH or -CONHCH2 also; n = 0, 1 or 2; each R1 and R2 represents independently hydrogen atom (H) or a direct (C1-C6)-alkyl chain; Y comprises at least one substituted or unsubstituted phenyl ring or 5-6-membered heteroaromatic ring comprising at least one N-atom as a heteroatom; wherein optional substituted are chosen among the group consisting of halogen atom, alkyl, -COOH, -OH or -NH2; or Y represents 6,7-dihydropyrrolo[3,4-b]pyridine-5-one; wherein ring nitrogen atom can be oxidized optionally. Also, invention relates to a pharmaceutical composition used in treatment states regulated by chemokine CXCR4 or CCR5 receptors based on these compounds. Invention provides preparing new compounds and medicinal agents based on thereof for aims in treatment of HIV- and FIV-infected patients.

EFFECT: valuable medicinal properties of compounds and composition.

15 cl, 57 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

11 cl, 2 tbl, 27 ex

FIELD: medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising epidermal growth factor (EGF) used in treatment of wounds on skin and soft tissues of lower limb in diabetic patient. Method of treatment involves topical infiltration of EGF-containing solution into different points and by contours of tissue damaged zone to provide administration of the solution into wound in the total volume 4-20 ml and irrigation of all deep surface of wound base and edges with the indicated composition. Invention provides prevention of diabetic limb amputation, stimulation of cellular proliferation in patients with foot ulcer being especially in geriatrics.

EFFECT: valuable medicinal properties of pharmaceutical composition.

19 cl, 1 tbl, 9 ex

FIELD: pharmaceutical industry, in particular production of stable ginger extract-based preparation.

SUBSTANCE: claimed preparation contains dry ginger extract and polyvinyl pyrrolidone as stabilizing ancillary agent in specific ratio. Method for production of said preparation includes extraction of ground ginger roots to produce liquid extract solution, solution concentration to produce viscous extract, dilution of viscous extract, addition of polyvinyl pyrrolidone solution as stabilizing ancillary agent to natural extract, stripping and drying. Also disclosed is galenia preparation, containing abovementioned stabilized ginger extract-based preparation and additional ancillary agents such as silicium dioxide, maltodextrin, magnesium stearate, cellulose or carboxymethylstarch. Such preparation is useful in treatment of dyspeptic disorders, naupthia sypptoms, as antiemetic agent, antidiabetic agent, etc. Stable ginger extract-based preparation obtained by abovementioned method and galena preparation based on the same are characterized by constant ratio of [6]-gingerol to [6]-shogaol.

EFFECT: stable therapeutic agent based on ginger extract.

13 cl, 2 dwg, 7 tbl, 4 ex

FIELD: medicine, endocrinology, pharmaceutical industry.

SUBSTANCE: invention relates to composition possessing the pathogenetic antidiabetic effect that comprises dry aqueous extracts of forest gymnema, tall elecampane and grape bunches taken in the definite ratio. The composition show effective action on all pathogenetic links of insulin-dependent diabetes mellitus: it normalizes blood carbohydrates level in prediabetic period, normalizes carbohydrate metabolism in diabetes mellitus of II type based on regeneration of β-cells in pancreas islet producing insulin, normalizes autoimmune responses in diabetes mellitus of II type and normalizes metabolism in diabetes mellitus based on antioxidants and trace elements. Invention is used in treatment and prophylaxis of diabetes mellitus.

EFFECT: valuable medicinal properties of composition.

6 cl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzoic acid of the formula (I): , wherein represents 0, 1 or 2; R1 represents halogen atom, (C1-C4)-alkyl group that is possibly substituted with one or more fluorine atoms, (C1-C4)-alkoxyl group that is possibly substituted with one or more fluorine atoms and when n represents 2 then substitutes at R1 can be similar or different; R2 represents direct (C2-C7)-alkyl group; R3 represents hydrogen atom (H) or -OCH3; W represents oxygen (O) or sulfur (S) atom, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition used in treatment of hyperlipidemia, dyslipidemia, diabetes mellitus and obesity and comprising derivative of benzoic acid of the formula (I) in mixture with pharmaceutically acceptable adjuvants, excipients and/or carriers. Also, invention relates to using derivative of benzoic acid of the formula (I) for preparing a medicinal agent used in treatment of resistance to insulin. Also, invention relates to a method for synthesis of derivative of benzoic acid of the formula (I) and used for synthesis of intermediate compound of the formula (II) given in the invention description. Invention provides preparing derivatives of benzoic acid representing selective modulators of PPARα.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 14 ex

Glp-1 analogs // 2288232

FIELD: peptides, medicine, pharmacy.

SUBSTANCE: invention relates to novel peptide analogs of glucagons-like peptide-1 and its pharmaceutically acceptable salts that are used in treatment of mammals.

EFFECT: valuable medicinal properties of analogs.

10 cl, 1 tbl, 411 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel analogs of fatty acids of the general formula (I): R1-[Xi-CH2]n-COOR2 wherein R1 represents (C6-C24)-alkene with one or more double bond, and/or (C6-C24)-alkyne; R2 represents hydrogen atom or (C1-C4)-alkyl; n represents a whole number from 1 to 12; I represents an uneven number and shows position relatively to COOR2; Xi is chosen independently of one another from the group comprising oxygen (O), sulfur (S) and selenium (se) atom and -CH2 under condition that at least one among Xi is not -CH2 and under condition that if R1 represents alkyne then a carbon-carbon triple bond is located between (ω-1)-carbon atom and (ω-2)-carbon atom, or between (ω-2)-carbon atom and (ω-3)-carbon atom, or between (ω-3)-carbon atom and (ω-4)-carbon atom, and to their salts and complexes. The claimed compounds can be used in treatment and/or prophylaxis of X syndrome, obesity, hypertension, hepatic fatty dystrophy, diabetes mellitus, hyperglycemia, hyperinsulinemia and stenosis. Also, invention relates to methods for preparing novel analogs of fatty acids. Also, invention relates to a nutrient composition comprising indicated analogs of fatty acids and to a method for reducing the total body mass or amount of lipid tissue in humans or animals. Invention provides the development of novel fatty acid analogs-base compositions or methods for suppression of stenosis, restenosis or associated disorders as result of proliferation and mobilization of vessel smooth muscle cells after, for example, traumatic damages of vessels during surgery operation in vessels.

EFFECT: improved preparing method, valuable medicinal properties of analogs.

12 cl, 2 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: the present insulin solution for peroral intake should be applied for treating patients with diabetes mellitus. The suggested insulin solution consists of water and insulin, additionally, it contains sodium chloride at the following ratio of components, weight%: insulin 0.005-0.02, sodium chloride 0.5-1.0, water - up to 100.0. The innovation provides decreased glucose level in blood of animals in case of peroral intake of the solution up to 40% at insulin dosages being about 10 U/kg animal body weight.

EFFECT: higher efficiency.

12 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel solid formulation of anti-arrhythmic medicinal agents. Invention describes crystalline formulation of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benznitrile, tert.-butyl-2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-dizabicyclo[3.3.1]non-3-yl}ethylcarbamate, tert.-butyl-2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate or tert.-butyl-2-{7-[(25)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate and their pharmaceutically acceptable salts. Also, invention describes methods for their synthesis, a pharmaceutical preparation based on thereof, a method for prophylaxis or treatment of arrhythmia and their using.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

73 cl, 22 dwg, 22 tbl, 23 ex

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