5-[4-(6-methoxy-1-methyl-1h-benzimidazole-2-ylethoxy)benzyl]- thiazolidine-2,4-dione hydrochloride having hypoglycemic activity

 

The invention relates to 5-[4-(6-methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl] thiazolidin-2,4-dione hydrochloride. Drug, possess hypoglycemic activity, contains as the active ingredient claimed compound and a conventional additive. The method of prevention or treatment of hyperglycemia, diabetes and impaired glucose tolerance in a mammal by introducing an effective amount of 5-[4-(6-methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl] thiazolidin-2,4-dione hydrochloride. The way to improve conditions with insulin resistance in a mammal by introducing an effective amount of the claimed compounds. The technical result - obtaining new compounds with hypoglycemic activity. 10 S. and 4 C.p. f-crystals, 2 tab., 2 Il.

Technical field This invention relates to cleaners containing hydrochloride salt of condensed heterocyclic compounds, which can improve the condition in some diseases caused by insulin resistance, such as hyperglycemia, a condition of reduced glucose tolerance (BHT), diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataract, coronarienne and so on, and has excellent absorption after oral administration.

In addition, this invention relates to a prophylactic and therapeutic agent for the treatment of diabetes, hyperglycemia, decreased glucose tolerance, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts, coronary artery disease, hyperlipidemia, obesity, hypertension, fatty infiltration of the liver, arteriosclerosis, diseases caused by insulin resistance, diabetes, pregnant, polycystic ovary syndrome, cardiovascular diseases (e.g. coronary heart disease), damage to the cell caused by atherosclerosis or ischemic heart disease (for example, cerebral disorders caused by stroke), gout, inflammatory diseases (e.g., epiphyseal osteomyelitis, pain, feverish conditions, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune diseases, pancreatitis), cancer, osteoporosis, cataract, etc., that contains the specified hydrochloride condensed heterocyclic compounds as the active Ingo connection exhibiting excellent activity, improves insulin tolerance, hypoglycemic activity, anti-inflammatory activity, immunoregulatory activity, inhibitory activity against alsoreported, inhibitory activity against 5-lipoxygenase, inhibitory activity against production perechislennih lipids, activating activity against PPAR, protivoseborainey activity, antagonistic activity against leukotrienes, the promoting activity towards the formation of fat cells, inhibitory activity against proliferation of cancer cells and antagonistic activity against calcium.

The prior art Insulin and connections sulfonylureas, such as tolbutamide, glipizide, and so on , is still used as therapeutic agents for the treatment of diabetes and hyperglycemia. Recently became known as therapeutic agents for the treatment of non-insulin dependent diabetes mellitus such thiazolidinedione derivatives as troglitazone, pioglitazone, rosiglitazone, and so on,

In particular, in the publication of Japanese patent application Hei-9(1997)-295970, EP 0745600 and U.S. patent 5886014 revealed 5-[4-(6-methoxy-the ski data, neither the physical properties of its hydrochloride, which is a compound of the present invention.

Description of the invention In the in-depth studies on the synthesis and pharmacology of compounds able to improve the condition of diseases caused by insulin resistance, such as hyperglycemia, States with reduced glucose tolerance, diabetic complications, hyperlipidemia, gestational diabetes, polycystic ovary syndrome, and so on, it was found that the hydrochloride is known condensed heterocyclic compounds showing high pharmacological activity.

Accordingly, a new hydrochloride condensed heterocyclic compounds was obtained by transformation of the known compounds, 5-[4-(6-methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl]thiazolidin-2,4-dione, in its hydrochloride. This hydrochloride exhibits excellent absorption after oral administration with a significantly improved solubility compared to its free connection (the connection is not in the form of its salts). It can provide high pharmacological activity, because it is an excellent absorption after oral administration will give the desired concentration in serum when b is ylethoxy)benzyl] thiazolidin-2,4-dione (hereinafter referred to as "compound a").

In addition, this invention relates to a prophylactic and/or therapeutic agent for the treatment of diabetes, hyperglycemia, decreased glucose tolerance, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts, coronary artery disease, hyperlipidemia, obesity, hypertension, fatty infiltration of the liver, arteriosclerosis, diseases caused by insulin resistance, diabetes, pregnant, polycystic ovary syndrome, cardiovascular diseases (e.g. coronary heart disease), damage to the cell caused by atherosclerosis or ischemic heart disease (for example, cerebral disorders due to impact), gout, inflammatory diseases (e.g., epiphyseal osteomyelitis, pain, feverish conditions, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune diseases, pancreatitis), cancer, osteoporosis, cataract, etc., containing as active ingredient the specified connection A.

More in detail this invention relates to a hypoglycemic tool, agent, ulucshauschei, the inhibitor of 5-lipoxygenase, the suppressor production perechislennih lipids, PPAR activator, the cure osteoporosis, leukotriene antagonist, the promoter of the formation of fat cells, suppressor of proliferation of cancer cells or antagonist of the calcium containing compound a as an active ingredient.

5-[4-(6-Methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl] thiazolidin-2,4-dione (hereinafter referred to as "compound B"), the free form of compound a of this invention represented by structural formula (I)In addition, the specified connection And has various isomers. For example, there are optical isomers, dependent asymmetry of the 5-carbon atom thiazolidinones rings. In this structure (I) all stereoisomers based on the asymmetric carbon atoms, and mixtures of isomers in equal amounts or unequal quantities, represented by a single structure. Thus, all of these isomers and their mixtures are included in this invention.

In addition, solvation specified connection And can occur by providing them with opportunities to precrystallization, and such MES connection And would be covered by this invention.

Connect the who, and then turning it into hydrochloride, as shown in example (2), in the usual way.

The connection And the present invention is suitable as a prophylactic and/or therapeutic agent for treatment of diabetes, hyperglycemia, decreased glucose tolerance, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts, coronary artery disease, hyperlipidemia, obesity, hypertension, fatty infiltration of the liver, arteriosclerosis, diseases caused by insulin resistance, diabetes, pregnant, polycystic ovary syndrome, cardiovascular diseases (e.g. coronary heart disease), damage to the cell caused by atherosclerosis or ischemic heart disease (for example, cerebral disorders due to impact), gout, inflammatory diseases (e.g., epiphyseal osteomyelitis, pain, feverish conditions, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune diseases, pancreatitis), cancer, osteoporosis, cataracts and the like.

Connection And in this invention it is possible to introduce, for example,aralnym by in such a dosage form, as injections, suppositories or eye drops. These dosage forms can be manufactured using well-known methods using conventional additives such as excipient, lubricants, binders, disintegrant, stabilizers, corrigentov, diluents and the like.

As for excipients, their examples are organic eccipienti, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch,-starch, dextrin and carboximetilkrahmal; cellulose derivatives such as crystalline cellulose, low substituted hydroxypropylcellulose, hypromellose, carboxymethylcellulose, calcixerollic and internally stitched sodium carboxymethyl cellulose; Arabian gum; dextran; pullulan, and inorganic excipients such as silicate derivatives such as soft silicic acid anhydride, synthetic aluminum silicate and manualoperations; phosphates such as calcium phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate.

As for lubricants, LLC; colloidal silica; waxes such as beeswax and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium salts of fatty acids; laurilsulfate, such as sodium lauryl sulfate and lauryl sulfate, magnesium; silicic acids such as silicic anhydride and silicic acid hydrate, and these derivatives of starch.

Examples of binders are polyvinylpyrrolidone, macrogol and those listed as examples of excipients.

Examples of disintegrants are those listed as examples for the specified excipient, and chemically modified starches and cellulose, such as nitrocresols, natrocarbonatite and crosslinked polyvinylpyrrolidone.

Examples of the stabilizer are esters of p-oksibenzoynoy acid, such as methylparaben and propylparaben; derivatives of alcohols, such as chlorobutanol, benzyl alcohol and phenethyl alcohol; phenol derivatives such as phenol and cresol; thimerosal; dehydroacetic acid and sorbic acid.

Examples corrigentov are those sweeteners, the substance that gives the sour taste, aromatizatorom the invention for adults varies depending on symptoms, age, route of administration and the like. In the case of oral route of administration, the daily dosage is, for example, from 0.01 mg/kg (preferably 0.1 mg/kg) as the lower limit up to 2000 mg/kg (preferably 500 mg/kg, more preferably 100 mg/kg) as the upper limit in a single dose or divided into several doses in accordance with the symptoms. In the case of intravenous administration, the daily dosage of the compounds And for an adult varies from 0.001 mg/kg (preferably 0.01 mg/kg) as the lower limit to 500 mg/kg (preferably 50 mg/kg) as an upper limit, which is preferably administered in a single dose or in several divided doses according to the symptoms.

The best way of carrying out the invention Examples 5-[4-(6-Methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl] thiazolidin-2,4-dione hydrochloride(1) 5-[4-(6-Methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl]thiazolidin-2,4-dione (compound) a Mixture of 21.8 g of 5-methoxy-N-methyl-1,2-phenylenediamine (see reference example 9, the publication of Japanese patent application Hei-9 (1997)-295970)), 63,4 g 5-(4-methoxycarbonylbenzyl)thiazolidin-2,4-dione (see comparative example 21, the publication of Japanese patent application Hei-9 (1997)-295970), 250 ml of 1,4-dioxane and 750 ml ConCentra was filtered. The residue was mixed with 800 ml of 5% aqueous sodium hydrogen carbonate solution and stirred at room temperature for 2 hours. Undissolved material was filtered, dissolved in a mixture of 1000 ml of N,N-dimethylformamide and 200 ml of methanol and treated with activated charcoal. The activated carbon was filtered and the filtrate was concentrated to about 50 ml by evaporation of solvents. To the residue was added 750 ml of diethyl ether and the mixture was left to stand at room temperature for 2 days. The precipitate was filtered with the receipt of 20.1 g of the desired compound having a melting point 267-271oC and Rf= 0,68 (thin layer chromatography on silica gel; solution of 5% ethanol in methylene chloride).

(2) 5-[4-(6-Methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl]thiazolidin-2,4-dione hydrochloride (compound A)
A mixture of 10.6 g of 5-[4-(6-methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl] thiazolidin-2,4-dione (compound) obtained in (1), and 100 ml of 4 N. hydrochloric acid - 1,4-dioxane was stirred at room temperature for 1 hour. The reaction mixture was concentrated and stirred with ethyl acetate. The precipitated product was filtered and washed with ethyl acetate to obtain of 11.0 g of the compound named in the reception which Mr. dimethyl sulfoxide using TMS (tetramethylsilane) as internal standard(M. D.): 3,11 (1H, DD, J=14 Hz and 9 Hz), to 3.34 (1H, DD, J=14 Hz and 4 Hz), the 3.89 (3H, s), 3,98 (3H, s), 4,91 (1H, DD, J=9 Hz and 4 Hz), 5,64 (2H, s), 7,14 (2H, d, J=9 Hz), to 7.15 (1H, d, J=9 Hz), 7,25 (2H, d, J=9 Hz), to 7.50 (1H, s), of 7.70 (1H, d, 9 Hz), 12,04 (1H, s, disappeared inside adding D2O).

Experiment biological tests
Used male rats (ZDF/Gmi-fa/fa) with spontaneous diabetes who were aged 8-10 weeks.

The test compound suspended in 0.5% CMC solution and a dose of 0.33 mg/mlkg orally was administered force continuously for 2 weeks. The sugar level in the blood was measured in the usual way. So, the end of the rat tail cut off (about 1 mm) and blood was collected using hematocrite tube, treated with heparin on coagulation and centrifuged. The resulting plasma was estimated using Glucoloader F (A&T).

Table 1 presents the test results on the activity to reduce blood sugar compound A (this invention), the compounds In the group not treated with drugs. In addition, all values in table 1 represent the average value of the results of trials using 6 of male rats with spontaneous diabetes (ZDF/Gmi-fa/fa).

From the results in table 1 it is evident that the compound a of this invention showed more high is the Achar blood group, not receiving drugs increased over time.

Experiment on solubility
To 200 ml 1 fluid of the Japanese Pharmacopoeia (1000 ml of a solution made by mixing 2.0 g of sodium chloride with 7.0 ml of hydrochloric acid and water) was added 40 mg of compound a or compound b and the mixture was stirred using a stirrer at 37oWith 300 ml conical beaker. After one hour, 10 ml of sample was filtered through Acrodisk LC13 (PVDF produced by the German Science Co.). The first 3 ml was discarded, and the next 7 ml was collected in a test tube for testing. From this sample of 5 ml was carefully collected with a pipette and added to 2 ml of methanol, in advance accurately measured in the test tube.

The number was determined by HPLC and the solubility was determined by a calibration curve obtained by the following method.

A calibration curve was obtained by making a methanol standard solution connection And with a concentration of 400, 100 and 20 μg/ml by mixing 2 ml of each standard solution with 5 ml 1 fluid of the Japanese Pharmacopoeia, and determination by HPLC.

The HPLC conditions
Analytical column: L-column ODS (3D 4.6 mm x 15 cm, manufactured Chemical Evaluation and Research Institute, Japan).

Mobile phase: a mixture of 0.01 mol/l buffer the RA column: 40oC.

Detector: a device for measuring absorption in the ultraviolet region (measurement at a wavelength of 290 nm).

From the results of table 2 it is evident that the compound As obtained by transformation of a compound Into its hydrochloride, demonstrates significantly better solubility than the connection Century.

Example dosage forms
Dosage forms containing the compound a of this invention as the active ingredient can be manufactured, for example, in accordance with the following methods.

Dosage form 1. Powder.

The powder obtained by grinding a mixture of 4 g of compound a of this invention, 10 g polyvinylpyrrolidone, and 0.5 g of hydroxypropylmethylcellulose (brand name: TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd) in a vibration mill for 30 minutes.

Dosage form 2. The capsule.

In a mixture of 100 g of acetone and 100 g of ethanol was dissolved 20 g of compound a and 20 g of polyvinylpyrrolidone and the solution is sprayed over 200 g nitrocresols using a granulator with a fluidized bed to obtain granules. Pellets (10 g) is mixed with 0.1 g of hydroxypropylmethylcellulose (brand name: TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd) and 1.9 g of lactose. Then 0.24 g of the mixture loaded into gelatinosa the/p> 1 g of compound a and 1 g of polyvinylpyrrolidone dissolved in a mixture of 5 g of acetone and 5 g of ethanol, and the solution was concentrated in vacuo using a rotary evaporator to remove the organic solvents. The thus obtained solid substance is pulverized to obtain fine granules. To 1 g of finely ground granules add 0.25 g of crystalline cellulose, 0.25 g hydroxypropylcellulose with a low level of substitution, 0.05 g of hydroxypropylmethylcellulose (brand name: TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd), 0.18 g of lactose and 0.2 g of magnesium stearate and the mixture tabletirujut using tablet press machine to obtain tablets.

Industrial application
This compound, 5-[4-(6-methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl]thiazolidin-2,4-dione hydrochloride, shows excellent activity for improving tolerance to insulin, hypoglycemic activity, anti-inflammatory activity, immunoregulatory activity, inhibitory activity against alsoreported, inhibitory activity against 5-lipoxygenase, inhibitory activity against production perechislennih lipids, activating activity against PPAR, protivoseborainey activity, antagonistic, inhibitory activity against proliferation of cancer cells and antagonistic activity against calcium.

Accordingly, the compound of the present invention is suitable as a prophylactic and/or therapeutic agent for treatment of diabetes, hyperglycemia, decreased glucose tolerance, diabetic complications (e.g. retinopathy, nephropathy, neurosis, cataracts, coronary artery disease, hyperlipidemia, obesity, hypertension, fatty infiltration of the liver, arteriosclerosis, diseases caused by insulin resistance, diabetes, pregnant, polycystic ovary syndrome, cardiovascular diseases (e.g. coronary heart disease), damage to the cell caused by atherosclerosis or ischemic heart disease (for example, cerebral disorders due to impact), gout, inflammatory diseases (e.g., epiphyseal osteomyelitis, pain, feverish conditions, rheumatoid arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia, autoimmune diseases, pancreatitis), cancer, osteoporosis, cataracts and the like.

Data ISA (compound of the present invention) with reduced glucose tolerance.

Male rats Zucker Fatty (fa/fa), which showed symptoms of reduced glucose tolerance, was acquired at the age of 6 weeks at the firm Charles River Japan, Inc. They were sustained for 3 weeks before the start of the experiment. Feed F2 (Funabashi Farm Co., Ltd) and water was given libitum.

9-week-old rats Zucker Fatty entered the compound And within 1 week the dose of 1 mg/kg Control group is injected with a solution of 0.5% sodium carboxymethyl cellulose as a filler. After a specified exposure they were starving during the night. Oral injected with a glucose solution [50%(wt./about.)]. Blood was taken from the tail vein immediately before the administration of glucose (0 min) and after 30, 60, 90 and 150 minutes after administration of the glucose solution. To determine the level of glucose in plasma using Glucoloader GXT (A&T Corp. ), in which glucose is oxidized by glucose oxidase contained in the column, and the resulting oxidation products determined using an electrode. On the attached Fig. 1 shows the results of the tests. As can be seen from these results, the dynamics of change of glucose levels in the control group gives the curve of glucose tolerance, which are clearly visible symptoms reduced glucose tolerance. On the contrary, the group treated with sedimentogenesis And useful in the treatment reduced glucose tolerance.

Test data is the treatment of hyperglycemia.

In the comparative test were used four connections. Connection And represents cleaners containing hydrochloride salt of the compounds of formula (I), the compound In the corresponding free form. Thus, the connection And represents cleaners containing hydrochloride salt, as claimed in the present invention. The connection is With cleaners containing hydrochloride salt of the compounds of formula (II), the compound D - corresponding free form. Compounds C and D represent examples 4 and 3 respectively of the EP 0745600. These compounds were selected for comparison because the connection is only cleaners containing hydrochloride of the compound obtained in the mentioned patent. In addition, compounds C and D is very structurally similar compounds a and B. the Difference occurs only in the pattern of substitution on the benzimidazole fragment.

Hypoglycemic effect
A blood sample was taken from the tail vein of mice QC (aged 4-5 months) with established diabetes and after centrifugation was measured by the glucose level in the plasma. Then the mice were divided into groups (4 mice per group). Within three days the mice were injected powdered food (F-2, Funabashi Farm), which contained the test compound at concentrations of 0.0001% (connecting the ZMA group, which was introduced compounds in a free form, would be almost the same. Groups of mice that were injected compound, were named "group entered medicine", and the group of mice that were injected powdered food without test connection "control". After three days from the tail vein of each mouse took a blood sample and measured the concentration of plasma glucose using a glucose analyzer ("Glucoloader-GXN", A&T Inc.). The speed of decrease of glucose in plasma was calculated by the equation:
The speed of decrease of glucose in plasma (%) = (average level of glucose in the plasma of control - the average level of glucose in the plasma group entered the medicinal product) x 100/glucose levels in plasma of control.

Comparative test results
On the attached Fig. 2 shows comparative data for biological studies.

The connection according to EP 0745600 shows almost two times stronger activity than its free form, compound D, in the speed reduction of plasma glucose. According to the test method of the present invention, the connection shows almost three times stronger activity than its free form, the connection D. the person skilled in the art will wait like 20 times stronger than the activity of the free form of compounds In this comparative test. This effect is much more pronounced than expected by the person skilled in the art based on the data disclosed in EP 0745600.


Claims

1. 5-[4-(6-Methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl]thiazolidin-2,4-dione hydrochloride.

2. Drug, possess hypoglycemic action, containing the active ingredient and conventional additives, characterized in that as the active ingredient contains a connection on p. 1.

3. Preventive or therapeutic agent for hyperglycemia containing compound under item 1 as an active ingredient.

4. Prophylactic or therapeutic agent against reducing the tolerance to glucose-containing compound under item 1 as an active ingredient.

5. Prophylactic or therapeutic agent against diabetic complications, containing the compound under item 1 as an active ingredient.

6. Prophylactic or therapeutic agent against diseases caused by insulin tolerance containing compound under item 1 as an active ingredient.

7. The connection p is ulanovoy resistance.

8. Connection on p. 1, used as the active ingredient of the medicinal product for the prevention or treatment of hyperglycemia.

9. Connection on p. 1, used as the active ingredient of the medicinal product for the prevention or treatment of diabetic complications.

10. Connection on p. 1, used as the active ingredient of the medicinal product for the prevention or treatment reduced glucose tolerance.

11. The way of improvement in insulin resistance in a mammal, comprising an introduction to the specified mammal an effective amount for improving the condition with insulin resistance, and specified improves with insulin resistance means is a connection on p. 1.

12. A method of preventing or treating hyperglycemia in a mammal, comprising an introduction to the specified mammal an effective amount of antihyperglycemics means in a specified antihyperglycemics means is a connection p. 1.

13. The method of prevention or treatment of complications of diabetes in a mammal, comprising an introduction to the specified mammal an effective amount, a under item 1.

14. The method of prevention or treatment reduced glucose tolerance in a mammal, comprising an introduction to the specified mammal an effective amount, effective for the prevention or treatment reduced glucose tolerance, with the specified tool is a connection on p. 1.

 

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< / BR>
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< / BR>
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The invention relates to new derivatives oksiminoalkil acid of the formula (I), where R1is oxazolyl, optionally substituted with 1-2 substituents selected from lower alkyl, phenyl, teinila, furil; thiazolyl, optionally substituted with 1-2 substituents selected from lower alkyl, phenyl; unsubstituted chinoline and so on; X represents a bond or the group-NR6- where R6represents hydrogen or C1-4alkyl; n represents an integer from 1 to 3; Y represents an oxygen atom or the group-NR7- where R7is hydrogen; ring a represents a benzene ring, optionally substituted by one or two1-4alkoxy; p is an integer from 1 to 3; R2represents phenyl, optionally substituted lower alkyl, halogen, and so on; unsubstituted furyl; unsubstituted pyridyl; pyridinyl-1-oxide; q is an integer from 0 to 6; m represents 0 or 1; R3represents a hydroxy-group, lower alkoxy or-NR9R10where R9and R10represent identical or different groups selected from hydrogen, lower alkyl and lower alkylsulfonyl; R4and R5represent identical or different groups selected from hydrogen or

The invention relates to new derivatives of benzothiazole General formula (I) or its salt, where p denotes 1; X1and X2together form =O; R1denotes hydrogen, halogen, alkyl, alkoxy; R2denotes hydrogen; R3denotes a-Z4-R6, -Z13-NR7R8; Z4denotes a-Z11-C(O)-Z12-, -Z11-C(O)-O-Z12-; Z11and Z12represent a simple bond or alkylene; Z13denotes a-Z11-C(O)-Z12-; R4denotes hydrogen; R5denotes phenyl, substituted groups Z1, Z2selected from alkyl, halogen, nitro, -HE, hydroxyalkyl, -C(O)Z6, -C(O)OZ6-Z4-NZ7Z8where Z4represents a simple bond; biphenyl, substituted alkyl; naphthalenyl, which optionally can be substituted-HE; chinoline, substituted alkyl; heterocyclics; Z6denotes alkyl which may be optionally substituted by a group-Z4-NZ7Z8, morpholinium; Z7, Z8each independently represents alkyl; R6denotes alkyl optionally substituted by cyano, methoxy, phenyl, -Z4-NZ7Z8and so on; R7denotes hydrogen, alkyl; R8denotes alkyl, the long is Z4-NZ7Z8; and t

The invention relates to new derivatives of aminothiazole formula I and their pharmaceutically acceptable salts, where R1and R2independently of one another denote hydrogen, fluorine or lower alkyl; R3denotes heteroaryl selected from oxazolyl, which is substituted by one or more substituents selected from lower alkyl, halogen, carbamoyl, allyloxycarbonyl, alkylcarboxylic; or benzoxazole; R4denotes hydrogen;-alkyl which can be optionally substituted with halogen, alkoxy, hydroxy, allyloxycarbonyl, alkylcarboxylic, amino, carbamoyl; CO-cycloalkyl; CO-aryl, where aryl represents phenyl which may be optionally substituted with halogen, lower alkyl, alkoxy, amino, cyano or naphthyl, and so on; or COO-alkyl; COO-cycloalkyl; soo-phenyl; COO-alkyl-phenyl; SO2-alkyl; SO2-phenyl, C(NCN)NH-phenyl, where phenyl may be optionally substituted with halogen; R5denotes hydrogen; m is an integer from 0 to 2; n is 0
The invention relates to a method of producing dibenzothiazoledisulphide oxidation alkaline solution of 2-mercaptobenzthiazole oxygen in the presence of a catalyst - derived phthalocyanine cobalt at the 50oWith, the process is carried out at 3-10-fold excess of 2-mercaptobenzthiazole solubility in a weak alkaline medium, where the concentration of the alkali metal hydroxide is 0.35 to 1.0 wt.%, in the presence of desulfosarcina cobalt as a catalyst in number (3-5)X10-4mol 1 mol 2-mercaptobenzthiazole

The invention relates to new pyrimidine derivative of General formula (I) or their pharmaceutically acceptable salts, with high antisecretory activity with the properties of reversible proton pump inhibitor that can be used to obtain valuable medicines
The invention relates to the technology of organic synthesis, namely industrial method for producing N,N'-DICYCLOHEXYL-2-benzothiazolesulfenamide used as accelerator of sulfur vulcanization of rubber mixtures

The invention relates to a method of obtaining modified in the 16,17-position epothilones, according to which the protected position of 3.7 or unprotected epothilone a or b a) hydronaut double bond in position 16,17 or) double bond in position 16,17 spend epoxidation and, if necessary, the obtained epoxide reduced to the alcohol in position 16, to a method for epothilone-N-oxides, in which the protected position of 3.7 or unprotected epothilone And or transferred to N-oxide, the N-oxide optionally subjecting the reaction of Qatar; the method of obtaining modified in the C-19 position epothilones by metallizirovanaya in position C-19 secured or unsecured epothilone a or b, as well as to modified epothilones General formula I

)-cis-3-(2'-benzimidazolyl)-1,2,2 - trimethylcyclopentanone acid exhibiting hypoglycemic and antidiabetes action" target="_blank">

The invention relates to medicine, specifically to a new biologically active compound () -CIS-3-(2'-benzimidazolyl)-1,2,2-trimethylcyclopentanone acid exhibiting hypoglycemic and antidiabetes action
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