Indazol derivatives as inhibitors of hormone-sensitive lipases

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

 

The present invention relates to the derivatives of indazole General formulas I or II, their pharmaceutically acceptable salts and their use as pharmaceuticals.

Derivatives indazol to stimulate cannabioids receptors described in the patent WO 03/035005 and derivatives 3-aminoundecanoic acid in the patent DE 2458965. The following phenylcarbamoyl in patent WO 2004/046090

and amide 3-amino-5-phenylindol-1-carboxylic acid in US 2004/0097485, both these documents were published after the filing of the corresponding priority of the patent application.

The subject invention are derivatives of indazole General formulas I or II,

in which:

W represents -(C=O)-, -(S=O)-, -(SO2)-;

X is a =(- R)- or =N-;

Y represents-O - or-N(R1);

R represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C3)-alkyl-O-(C1-C3-alkylen, the hydroxy-group, (C1-C6)-allylmercaptan, amino group, (C1-C6)-alkylamino, di-(C2-C12)-alkylamino, mono-(C1-C6-alkylaminocarbonyl, di-(C2-C8-alkylaminocarbonyl, COOR4, cyano, trifluoromethyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfonyl is, aminosulfonyl, a nitrogroup, pentafluoroethyl, (C6-C10)-aryl, (C5-C12-heteroaryl, CO-NR2R3O-CO-NR2R3O-CO-(C1-C6-alkylene-CO-O-(C1-C6)-alkyl, O-CO-(C1-C6-alkylen-WITH-IT,-CO-(C1-C6-alkylene-CO-NR2R3or unsubstituted or mono - or repeatedly replaced by F (C1-C6)-alkyloxy;

R1represents H, (C1-C6)-alkyl, benzyl;

R2represents H, (C1-C6)-alkyl, (C1-C4-alkylphenyl, (C6-C10)-aryl and phenyl, and aryl, if necessary, can be substituted with halogen, (C1-C6)-alkyl, (C1-C3-alkyloxy, hydroxy-group, (C1-C6-allylmercaptan, amino group, (C1-C6-alkylaminocarbonyl, di-(C2-C12-alkylaminocarbonyl, mono-(C1-C6-alkylaminocarbonyl, di-(C2-C8-alkylaminocarbonyl, (C1-C6-allyloxycarbonyl, cyano, trifluoromethyl, cryptomaterial, (C1-C6-alkylsulfonyl, aminosulfonyl, nitrogroup, or Tetraethylenepentamine;

R3represents H, (C1-C6)-alkyl; or

R2and R3along with carrying their nitrogen atom can obrazovawe the ü monocyclic saturated or partially unsaturated 4 - to 7-membered ring system or a bicyclic saturated or partly unsaturated 8 - to 14-membered ring system, moreover, individual members of the ring system can have from one to three times substituted by atoms or groups of atoms from the series-CHR5-, -CR5R5-, -(C=R5)-, -NR5-, -C(=O)-, -O-, -S-, -SO-, -SO2-with such a restriction that the two structural units of the series-O-, -S-, -SO-, -SO2- may not be adjacent;

R4represents hydrogen, (C1-C6)-alkyl, benzyl;

R5is a (C1-C6)-alkyl, halogen, trifluoromethyl, COOR4cyclopropyl, cyclopropyl;

and their physiologically acceptable salts and tautomeric forms, with this limitation, that in the compounds of formula (I) c W = CO

a) R2and R3together with bearing N-atom form a monocyclic or bicyclic ring system in the case, if Y = N(R1), where R1= H or (C1-C6)-alkyl or

b) Y-R1, R2and R3can't take the following values:

Y-R1= OH, R2= if necessary substituted (C6-C10)-aryl and R3= H.

Preferred compounds of formulas I and II, in which

Y represents-O-

or those in which

W represents -(C=O)-.

Additionally preferred compounds of formulas I and II, in which

NR2R3represents a monocyclic saturated 5 - to 6-membered ring C is a topic 4 position contains an atom or group of atoms from a number-CHR5-, -CR5R5-(C=R5)-, -NR5-, -O-, -S-.

Additionally preferred compounds of formulas I and II, in which

X in positions 4, 5, and 7 is a =C(-R), where R = hydrogen.

Especially preferred compounds of formula I or II, in which

W represents -(C=O)-;

X is a =(- R)- or =N-;

Y represents-O-;

R represents hydrogen, halogen, (C1-C6)-alkyl, hydroxy-group, amino group, COOR4, trifluoromethyl, (C1-C6)-alkylsulfonyl, nitro-group, pentafluoroethyl, (C6-C10)-aryl, CO-NR2R3O-CO-NR2R3or O-CO-(C1-C6-alkylene-CO-O-(C1-C6)-alkyl;

R1represents H, (C1-C6)-alkyl, benzyl;

R2is a (C1-C6)-alkyl, benzyl, (C6-C10)-aryl or tetramethylethylenediamine;

R3represents H, (C1-C6)-alkyl; or

R2and R3along with carrying their nitrogen atom may form a monocyclic saturated 5 - to 6-membered ring system or a bicyclic saturated or partially unsaturated 9 - to 10-membered ring system, with individual members of the ring systems can be from one to two times substituted by the atoms or groups of atoms from the series-CHR 5-, -CR5R5, -(C=R5)-, -NR5-, -O-, -S - c this restriction that the two structural units of the series-O-, -S - may not be adjacent;

R4represents hydrogen, (C1-C6)-alkyl or benzyl;

R5is a (C1-C6)-alkyl, halogen, trifluoromethyl, COOR4cyclopropyl, cyclopropyl.

Additional particularly preferred compounds of formula I, in which

W represents -(C=O)-;

X is a =(- R)- or =N-;

Y represents-O-;

R represents hydrogen, a halogen, a nitro-group, a hydroxy-group or (C1-C6)-alkyl;

R1represents H or (C1-C6)-alkyl;

R2is a (C1-C6)-alkyl, benzyl or (C6-C10)-aryl;

R3is a (C1-C6)-alkyl; or

R2and R3along with carrying their nitrogen atom may form a monocyclic saturated 5 - to 6-membered ring system or a bicyclic saturated or partially unsaturated 9 - to 10-membered ring system, with individual members of the ring systems may be replaced by an atom or group of atoms from a number-CHR5-, -NR5-; and

R5is a (C1-C6)-alkyl or cyclopropyl. Especially preferred are also compounds fo the mules II, in which

W represents -(C=O)-;

X is a =(- R)- or =N-;

Y represents-O-;

R represents hydrogen, halogen, (C1-C6)-alkyl, hydroxy-group, amino group, COOR4, trifluoromethyl, (C1-C6)-alkylsulfonyl, nitro-group, pentafluoroethyl, (C6-C10)-aryl, CO-NR2R3O-CO-NR2R3or O-CO-(C1-C6-alkylene-CO-O-(C1-C6)-alkyl;

R1represents H, (C1-C6)-alkyl or benzyl;

R2is a (C1-C6)-alkyl, (C6-C10)-aryl or tetramethylethylenediamine;

R3represents H, (C1-C6)-alkyl; or

R2and R3along with carrying their nitrogen atom may form a monocyclic saturated 5 - to 6-membered ring system or a bicyclic saturated or partially unsaturated 9 - to 10-membered ring system, with individual members of the ring systems can be from one to two times substituted by atoms or groups of atoms from the series-CHR5-, -CR5R5, -(C=R5)-, -NR5-, -O-, -S-, under this restriction, the two structural units of the series-O-, -S - may not be adjacent;

R4represents hydrogen, (C1-C6)-alkyl, benzyl; and

R5is a (C1-C6 )-alkyl, halogen, trifluoromethyl, COOR4cyclopropyl, cyclopropyl.

Very particularly preferred compounds of formula II, in which

NR2R3 represents piperidine, 4 position contains a group of atoms CHR5.

The invention relates to compounds of formula I or II in the form of their salts, racemates, racemic mixtures and pure enantiomers, their diastereomers and mixtures thereof.

Alkyl residues in the substituents R, R1, R2, R3, R4, R5can be both linear and branched. Halogen represents fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.

Under the aryl understand monocyclic or bicyclic aromatic ring system which contains from 6 to 10 C-atoms in the cycle and which, if necessary, independently of one another can contain one to four substituents, preferably one or two substituent, as described here.

Heteroaryl represents a mono - or bicyclic aromatic ring system with 5 to 12 members of the cycle in which at least one atom in the ring system is a heteroatom from the series N, O and S and the remaining atoms are C-atoms.

For use in medicine, particularly applicable pharmaceutically acceptable salts because of their higher water solubility on the alignment with the source or the underlying connections. These salts must contain a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable additive salts of the proposed compounds with acids are salts of inorganic acids such as hydrochloric acid, Hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as, for example, acetic acid, benzolsulfonat, benzoic, citric, econsultancy, fumaric, gluconic, glycolic, setinova, lactic, lactobionic, maleic, malic, methansulfonate, amber, pair-toluensulfonate and tartaric acid. Suitable pharmaceutically acceptable salts with bases are ammonium salts, alkali metal salts (such as sodium and potassium salts), salts of alkaline-earth metals (such as magnesium and calcium salts), and salts of trometamol (2-amino-2-hydroxymethyl-1,3-propane diol), diethanolamine, lysine or Ethylenediamine.

Salts with a pharmaceutically unacceptable anion, such as, for example, triptorelin, equally within the scope of invention as a necessary intermediate products to obtain or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example in vitro, applications.

Used here, the term "physiologically functional about Sevodnya" means each physiologically acceptable derivative of the proposed compounds of formula I or II, for example, ester, which when administered to a mammal, for example, a person in the state (directly or indirectly) to form a compound of formula I or II or its active metabolite.

To physiologically functional derivatives also include prodrugs of the proposed compounds, such as, for example, described H. Okada and others, Chem. Pharm. Bull. 1994, 42, 57-61. These prodrugs can be metabolized in vivo to the proposed connection. These prodrugs may themselves be effective or not.

The proposed compounds can also exist in different polymorphic forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the proposed compounds belong to the scope of the invention and are a further aspect of the invention.

Then all references to "compound(I) of the formula I or II" refers to the compound(s) of formula(s) I or II, as described above, and their salts, solvate and physiologically functional derivatives as described herein.

Application

The proposed compounds of General formula I or II have a striking inhibitory effect on gormonchuvstvitelnoy lipase, HSL, allosteric enzymes in adipocytes, which ingibirovany insulin and is responsible for the degradation of fats in fat cells and thus for the transfer of fatty com is onenew into the bloodstream. Inhibition of these enzymes thus corresponds insulin action proposed connections, which ultimately leads to the reduction of the level of free fatty acids in the blood and blood sugar. They can also be used for metabolic disorders, such as, for example, when non-insulin-dependent diabetes mellitus, diabetic syndrome and direct damage to the pancreas.

These compounds are particularly suitable for the treatment and/or prevention

1. - metabolic fatty acids and impaired glucose;

- violations, which plays the role of insulin resistance.

2. Diabetes, particularly type 2 diabetes, including the prevention of related complications.

Particular aspects are

- hyperglycemia,

- improvement of insulin resistance,

- improving glucose tolerance,

- protection of β-cells of the pancreas,

- inhibition of macro - and microvascular diseases.

3. Dyslipidemia and its consequences, such as, for example, atherosclerosis, coronary heart disease, cerebrovascular disease and so on, in particular, such (but not limiting), which are characterized by one or more of the following factors:

(high level of triglycerides in the plasma, a high concentration is s of triglycerides in plasma, emerging after a meal

low concentrations of HDL-cholesterol

low concentrations of Area-lipoprotein

high concentrations of LDL-cholesterol

- particles of LDL-cholesterol, low-density

high concentrations of Ares-lipoprotein.

4. Various other Sistani, which may be associated with metabolic syndrome, such as:

- obesity (obesity), including abdominal obesity

- thrombosis, stage high blood coagulability and a tendency to thrombosis (arteries and veins)

- high blood pressure

heart disease, such as, for example, (but not limiting) condition after myocardial infarction, hypertensive heart disease or cardiomyopathy.

5. Other diseases or conditions in which, for example, play the role of inflammatory reaction or differentiation of cells:

- atherosclerosis, such as, for example (but not limited to) coronary atherosclerosis, including angina pectoris or myocardial infarction, stroke

- restenosis or thrombosis of blood vessels

- chronic inflammatory bowel disease, such as Crohn's disease and ulcerative colitis

- pancreatitis

- other inflammatory condition

- retinopathy

- tumor of fat cells (adipose tumor cells)

- carcinoma of the fat cells, such as, for example, liposarcoma is and

- solid tumors and neoplasms such as, for example (but not limited to) carcinoma of the gastrointestinal tract, liver, biliary tract and pancreas, endocrine tumors, carcinomas of the lungs, kidneys and urinary organs, reproductive tract, carcinoma of the prostate, etc.

- acute and chronic myeloproliferative disorders and lymphomas

- angiogenesis

- neurodegenerative diseases

- Alzheimer's disease

multiple sclerosis

- Parkinson's disease

- erythematous-squamous dermatoses such as, for example, psoriasis (psoriasis)

- common acne

- other skin disorders and dermatological conditions which modulate PPAR

eczema and atopic dermatitis

- dermatitis such as, for example, subarray dermatitis or photodermatitis

- keratitis and keratoses such as, for example, sabranie the keratoses, senile keratoses, actinic keratosis, photoinduced or follicular keratosis keratosis

- keloids and prevention of keloids

- warts, including condylomata or Kondylomata acuminata

- viral infection of human papillomavirus (HPV), such as, for example, sexually transmitted papilloma, viral warts such as, for example, molluscum contagiosum, leukoplakia

- papular dermatoses such as, for example, lichen planus

- skin cancer, such as basal, the Ohm, melanoma or lymphoma cutaneous T-cell

- localized benign tumors of the epidermis, such as, for example, keratoderma, epidermal birthmarks

- frostbitten

- high blood pressure

syndrome X

- polycystic ovaries (PCOS)

- asthma

- osteoarthritis

- lupus erythematosus (LE) or inflammatory rheumatic diseases, such as rheumatoid arthritis

- vasculitis

- depletion (cachexia)

- gout

syndrome, ischemia/reperfusion

- acute respiratory distress syndrome (ARDS) ("shock lung")

- lipo lipodystrophies condition, and also for the treatment of unwanted effects of drugs (such as drugs against HIV or tumors)

Herbal remedies

The number of proposed connection that is required to achieve the desired biological effect depends on a number of factors, for example, selected from specific connections, intended use, method of administration and the clinical condition of the patient. In General, the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg dose, suitable for injection, may be injected in to the number from 10 ng to 100 ng per kilogram per minute. Suitable infusion solution for this purpose may include, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active substance. Thus, ampoules for injection may contain, for example, from 1 mg to 100 mg, orally injected dose composition, such as, for example, tablets or capsules, may contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg For the treatment of the aforementioned conditions the compounds of formula I or II can be used by themselves in the form of compounds, but preferably they are presented in the form of a pharmaceutical composition with an acceptable carrier. The media, of course, must be appropriate in the sense that it is compatible with other components of the composition and harmless to the health of the patient. The carrier may be a solid or a liquid or both and is preferably formed with a connection in the form of a single dose, preferably in the form of a tablet, which may contain from 0.05 to 95 wt.% the active substance. Equally there may be additional pharmaceutically active substances, including additional proposed connection. The proposed pharmaceutical composition can be obtained by known pharmaceutical methods, which mainly consist in the fact that the components of the coefficients is mixed with a carrier and/or auxiliary substances.

The proposed pharmaceutical composition applicable for oral, rectal, local, peroral (for example sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although suitable route of administration in each individual case depends on the type and severity treatable condition and the type of the used compounds of the formula I or II. To the scope of the invention also include index composition and index of the composition of the prolonged action. Preferred compositions, resistant to acids and gastric juice. Suitable coatings resistant to gastric juice are acetated cellulose, polyvinyl acetate phthalate, phthalate of hydroxypropylmethylcellulose and anionic polymers of methacrylic acid and methyl ester of methacrylic acid.

Suitable pharmaceutical compounds for oral administration can be presented in the form of separate units such as, for example, capsules, pills, tablets for sucking or tablets, which contain a certain amount of the compounds of formula I or II; in the form of powders or granules; as solutions or suspensions in aqueous or non-aqueous liquid; or as emulsions (type) oil-in-water or water-in-oil. These compositions, as already mentioned, can be made of any approaching what they pharmaceutical way, which includes the stage at which contact the active substance and the carrier (which may consist of one or more additional components). Typically, the compositions have a thorough and homogeneous mixing of the active substance with a liquid and/or finely powdered solid carrier, after which the product if necessary mold. For example, a tablet may be obtained by compressing or molding a powder or granules of the compound, if necessary with one or more additional components. Molded tablets can be obtained by pelletizing compounds in free flowing form such as powder or granules, if necessary in a mixture with a binder, means imparting lubricity, inert diluent and/or one (several) of surface-active/dispersing means in a suitable machine. Molded tablets can be obtained by molding powder, moistened with an inert liquid diluent compounds in a suitable machine.

Pharmaceutical compositions that are applicable for peroral (sublingual) administration comprise tablets for sucking, which contain the compound of formula I or II with flavoring substance, normally sucrose and gum Arabic or Trianta, and lozenges, which contain the compound in an inert OS is ove, such as gelatin and glycerol or sucrose and gum Arabic.

Suitable pharmaceutical compositions for parenteral administration include, for example, sterile aqueous compositions of the compounds of formula I or II, which are preferably isotonic with the blood of the patient. These compositions are preferably administered intravenously, although can also be implemented subcutaneous, intramuscular or intradermal injection. These compounds preferably can be obtained by mixing the compound with water and turning the resulting solution sterile and isotonic with blood. The proposed compositions for injections usually contain from 0.1 to 5 wt.% active connection.

Suitable pharmaceutical compositions for rectal injection preferably represent a single dose candles. They can be obtained by mixing the compounds of formula I or II with one or more conventional solid carriers, for example cocoa butter, followed by molding the mixture.

Suitable pharmaceutical compositions for topical application to the skin preferably are ointments, creams, lotions, pastes, sprays, aerosols or oils. As carriers can be used vaseline, lanolin, polyethylene glycol, alcohols and combinations of two or more of these substances. The active ingredient usually is present in a concentration of from 0.1 to 15 wt.% composition, for example from 0.5 to 2%.

It is also possible transdermal administration. Suitable pharmaceutical compositions for transdermal application can submit a patch, which is suitable for prolonged close contact with the epidermis of the patient. This patch contains suitable active substance, dissolved, if necessary, in a buffered aqueous solution, dissolved and/or dispersed in an adhesive or dispersed in the polymer. A suitable concentration of the active substance is from about 1% to 35%, preferably from about 3% to 15%. As a special active substance can be released by electrotransport or iontophoresis, as described in Pharmaceutical Research, 2(6): 318 (1986).

Compounds of formulas I and II differ favorable action for violations of metabolism. They have a positive effect on fat and sugar metabolism, in particular, they reduce the level of FFA, glycerol and triglycerides and applicable for the prevention and treatment of type II diabetes and atherosclerosis, as well as their diverse complications.

Combination with other drugs

The proposed compounds may be introduced alone or in combination with one or more additional pharmacologically active substances, for example, have a favorable effect will metabolism or often related diseases. Such drugs are as follows.

1. Medications that reduce level of sugar in the blood, antidiabetics.

2. Active substances for the treatment of dyslipidemia.

3. Antiatherosclerotic drugs.

4. Anti-obesity.

5. Anti-inflammatory active substances.

6. Active substances for the treatment of malignant tumors.

7. Antithrombotic active substances.

8. Active substances for the treatment of high blood pressure.

9. Active substances for the treatment of heart failure.

10. Active substances for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.

They can be combined with the proposed compounds of the formula I or II, in particular, to improve synergies. The introduction of combinations of active substances may be carried out either by separate villas active substances to a patient, either in the form of a combined preparation, in which several active substances are present in the same pharmaceutical composition.

As examples:

Antidiabetics

Applicable anti-diabetic agents are, for example, described in the IUCN Red list 2001, part 12 or in the USP Dictionary of USAN and International Drug Names, US Pharmcopeia, Rockville 2003. Antidiabetics include insulin and derivatives of insulin, such as Lantus®(see ) or Apidra®and other fast-acting insulins (see U.S. patent 6221633), modulators of the GLP-1 receptor, such as described in patent WO 01/04146, or such as described in patent WO 98/08871 Novo Nordisk A/S.

Orally active hypoglycemic active substances include, preferably, sulfonylureas, biguanides, meglitinide, oxazolidinedione, thiazolidinone, glucosidase inhibitors, glucagon antagonists, oral GLP-1 agonists, inhibitors of DPP-IV, raskryvali potassium channels, such as, for example, described in patents WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in stimulating glycogenesis and/or glycogenolysis, modulators of absorption of glucose, compounds that alter fat metabolism, which lead to changes in lipid composition of blood, compounds which reduce food intake and digestion, PPAR and PXR to define against-modulators and active ingredients which act on the ATP-dependent potassium channels butaclamol.

In one form of the invention, the compounds of formula I or II is administered in combination with insulin.

In one form of the invention, the compounds of formula I or II is administered in combination with substances, which turns out to be the have an impact on the hepatic production of glucose, such as, for example, inhibitors of glycogen phosphorylase (see patent WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922, WO 03/104188).

In one form of implementation of the compounds of formula I or II is administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.

In one form of implementation of the compounds of formula I or II is administered in combination with an active substance that acts on the ATP-dependent potassium channels bealeton, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or Repaglinide.

In one form of implementation of the compounds of formula I or II is administered in combination with biguanides, such as, for example, Metformin.

In one form of implementation of the compounds of formula I or II is administered in combination with meglitinides, such as, for example, Repaglinide.

In one form of implementation of the compounds of formula I or II is administered in combination with thiazolidinediones, such as, for example, ciglitazone, pioglitazone, rosiglitazone or the compounds described in the patent WO 97/41097 Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-girasolereale]phenyl]methyl]-2,4-thiazolidinedione.

In one form of implementation of the compounds of formula I or II is administered in combination with a DPPIV inhibitor, such as, for example, described in patents WO 98/19998, WO 99/61431, WO 99/67278, WO 99/67279, WO 01/72290, WO 02/38541, WO 03/040174, in particular, P 93/01 (chlorite is 1-cyclopentyl-3-methyl-1-oxo-2-pentanone), R-31/98, LAF237 (1-[2-[3-gidroksilamin-1 ylamino)acetyl]pyrrolidin-2-(S)-carbonitrile), TS021 (monopersulfate (2S,4S)-4-fluoro-1-[[(2-hydroxy-1,1-dimethylethyl)amino]acetyl]pyrrolidin-2-carbonitrile).

In one form of the invention, the compounds of formula I or II is administered in combination with an agonist PPAR, such as, for example, rosiglitazone, pioglitazone.

In one form of implementation of the compounds of formula I or II is administered in combination with compounds with inhibitory effect on SGLT-1 and/or 2, such as directly or indirectly described in patent PCT/ER/06841, PCT/ER/13454 and PCT/ER/13455.

In one form of implementation of the compounds of formula I or II is administered in combination with inhibitors of α-glucosidase, such as, for example, miglitol or acarbose.

In one form of implementation of the compounds of formula I or II is administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and Metformin, a sulfonylurea and acarbose, Repaglinide and Metformin, insulin and a sulfonylurea, insulin and Metformin, insulin and troglitazone, insulin and lovastatin, etc.

Lipid modulators

In one form of the invention, the compounds of formula I or II is administered in combination with an inhibitor of HMGCoA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, uvastatin, itavastatin is, atorvastatin, rosuvastatin.

In one form of the invention, the compounds of formula I or II is administered in combination with inhibitors of resorption of bile acids (see, for example, U.S. patents 6245744, USA 6221897, USA 6277831, EP 0683773, EP 0683774).

In one form of the invention, the compounds of formula I or II is administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam.

In one form of the invention, the compounds of formula I or II is administered in combination with inhibitors of resorption of cholesterol, such as, for example, described in patent WO 0250027 or ezetimib, tiqueside, pamaquine.

In one form of the invention, the compounds of formula I or II is administered in combination with an inducer of LDL-receptors (see, for example, U.S. patent 6342512).

In one form of implementation of the compounds of formula I or II is administered in combination with ballast substances, preferably insoluble dietary fiber (see, for example, Carob/Caromax®(Zunft H J; and others, Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 September-Oct.), 18(5), 230-6)); Caromax is a Carob-containing product manufactured by Fa. Nutrinova, Nutrition Specialties &Food Ingredients GmbH, Industriepark Hoechst, 65926 Frankfurt am main). Combination with Caromax®can be done in a single composition or in separate cottage compounds of formula I and Caromax®Prices Caromax ®can be entered in the form of food products such as pastries or cereal.

In one form of the invention, the compounds of formula I or II is administered in combination with an agonist PPAR.

In one form of the invention, the compounds of formula I or II is administered in combination with mixed agonist of PPAR alpha/gamma, such as, for example, AZ 242 (tesaglitazar, (S)-3-(4-[2-(4-methysulfonylmethane)ethoxy]phenyl)-2-ethoxypropionate acid), BMS 298585 (N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine) or described in patents WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169, WO 96/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876.

In one form of the invention, the compounds of formula I or II is administered in combination with vibrator, such as, for example, fenofibrate, gemfibrozil, clofibrate, bezafibrat.

In one form of the invention, the compounds of formula I or II is administered in combination with nicotinic acid or Niacin.

In one form of the invention, the compounds of formula I or II is administered in combination with SER-inhibitor, for example, CF-529,414 (torcetrapib).

In one form of the invention, the compounds of formula I or II is administered in combination with AST-inhibitor.

In one form of the invention, the compounds of formula I or II is administered in combination with MTP-inhibit the rum, such as, for example, implitapide.

In one form of the invention, the compounds of formula I or II is administered in combination with an antioxidant.

In one form of the invention, the compounds of formula I or II is administered in combination with an inhibitor of lipoprotein lipase activity.

In one form of the invention, the compounds of formula I or II is administered in combination with an inhibitor of ATP-citrate lyase.

In one form of the invention, the compounds of formula I or II is administered in combination with inhibitors stvalentines.

In one form of the invention, the compounds of formula I or II is administered in combination with an antagonist of lipoprotein(s).

Anti-obesity

In one form of the invention, the compounds of formula I or II is administered in combination with a lipase inhibitor, such as orlistat.

In one form of implementation of the additional active ingredient is fenfluramine or dexfenfluramin.

In another form of implementation of the additional active ingredient is sibutramine.

In one of the optional forms of implementation of the compounds of formula I or II is administered in combination with CART-modulators (see “Cocaine-amphetamine-regulated transcript infliences energy metabolism, anxiety and gastric emptying in mice” Asakawa, A., and others, M.: Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists, for example, hydrochloride {4-[(4-aminoxy azolin-2-ylamino)methyl]cyclohexylmethyl}amide naphthalene-1-sulfonic acids (CGP 71683A)), MS-agonists (e.g., [2-(3a-benzyl-2-methyl-3-oxo-2,3,3A,4,6,7 there is hexahydropyrazino[4,3-c]pyridine-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]amidon 1-amino-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid; (patent WO 01/91752)), antagonism orexin (for example, the hydrochloride of 1-(2-methylbenzothiazol-6-yl)-3-[1,5]naphthiridine-4-rocephine; (SB-334867-A)), H3 agonists (salt of 3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-yl)propan-1-it with oxalic acid (patent WO 00/63208)); TNF agonists, CRF antagonists (e.g., [2-methyl-9-(2,4,6-trimetilfenil)-N-1,3,9-diazafluoren-4-yl]dipropylamine (patent WO 00/66585)), CRF BP-antagonists (e.g., urocortin), agonists urocortin, β3 agonists (e.g., the hydrochloride of 1-(4-chloro-3-methysulfonylmethane)-2-[2-(2,3-dimethyl-1H-indole-6-yloxy)ethylamino]ethanol; (patent WO 01/83451), agonists, MSH (melanocytestimulating hormone)agonists, CCK-a (e.g., salt of {2-[4-(4-chloro-2,5-acid)-5-(2-cyclohexylethyl)thiazole-2-ylcarbonyl]-5,7-dimethylindole-1-yl}acetic acid with triperoxonane acid (patent WO 99/15525))); inhibitors of serotonin reuptake (e.g., dexfenfluramine), mixed serotonin and noradrenergic compounds (e.g., patent WO 00/71549), NT-agonists, for example, salt of 1-(3-ethylbenzophenone-7-yl)piperazine with oxalic acid (patent WO 01/09111), agonists bombezin, antagonists Galan is on, growth hormone (e.g. human growth hormone), compounds which release growth hormones (tert-butyl ether (6-benzyloxy-1-(2-diisopropylaminoethanol)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (patent WO 01/85695)), TRH agonists (see, for example, patent EP 0462884)that breaks down protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists (bromocriptine, depression), inhibitors of lipase/amylase (for example, patent WO 00/40569), PPAR-modulators (e.g., patent WO 00/78312), RXR-modulators or TR-β-agonists.

In one form of the invention, the additional active agent is a leptin.

In one form of implementation of the additional active substance is a dexamfetamine, amphetamine, mazindol or phentermine.

In one form of implementation of the compounds of formula I or II is administered in combination with drugs that affect system heart circulatory and blood vessels, such as, for example, ACE inhibitors (e.g. ramipril), drugs that affect the renin-angiotensin, calcium antagonists, beta-blockers, etc.

In one form of implementation of the compounds of formula I or II is administered in combination : the AI with anti-inflammatory drugs.

In one form of implementation of the compounds of formula I or II is administered in combination with drugs used for cancer therapy and prevention of cancer.

It is clear that every suitable combination of the proposed compounds with one or more of the above-mentioned compounds and optionally with one or more other pharmacologically active substances are considered as falling within the protection scope of the present invention.

The proposed activity of the compounds of formulas I or II was tested on the following enzyme systems:

Preparation of substrate:

Preparation of substrates NAG (NBD-monoacylglycerides)

6 mg of phosphatidylcholine and 6 mg phosphatidylinositol were each dissolved in 1 ml of chloroform. 10 mg NAG was dissolved in 1 ml of chloroform. Two part solution phosphatidylinositol (for example, 83,5 mm), one part of the solution of phosphatidylcholine (for example, of 41.5 μl) and 100 μl of the NAG solution was pietravalle together in a plastic acquired scintillation vessel (final concentration in the sample: 0,0375 mg phospholipid/ml; 0.05 mg/NAG/ml). Chloroform (total volume of 225 μl) were completely removed by blowing a current of the N2. The dried substrate can be stored for up to 3 days at 4°C. To obtain phospholipidosis micelles with intercalated NAG (on the day of the test) the dried substrate was extracted with 20 ml of buffer solution for testing (25 mm Trs/HCl, pH 7.4; 150 mm NaCl) and twice the processed ultrasound by the ultrasonic syringe (Branson Sonifier Type II, Standartmikrospitze): 1. Processing at setting 2, 2 x 1 min each period of 1 min, on ice; 2. Treatment 4, 2 x 1 min each period of 1 min, on ice. During this procedure, the color of the substrate solution was changed from yellow (maximum extinction 481 nm) to red (maximum extinction 550 nm) by intercalation between NAG vesicles/micelles molecules of phospholipids. For use as a substrate (in the next 2 hours) the solution was incubated on ice for 15 minutes

Indirect test NAG:

The test was performed in 1.5-ml Eppendorf tubes or 96-well tablets for 60 min at 30°C. For finding inhibitors HSL 10 µl of the test substance were made in buffer solution for testing (25 mm ris/HCl, pH to 7.4; 150 mm NaCl) in the presence of 16.6% DMSO. Was added 180 μl of substrate solution (20 μg/ml phosphatidylcholine, 10 µg/ml phosphatidylinositol, 50 μg/ml NAG in the buffer solution for testing). After pre-incubation for 15 min at 30°C 20 µl of enzyme solution in buffer solution for testing (from 1 - to 4-fold dilution by pipetting) was measured extinction at 480 nm in a photometer cuvette (0.5 ml cuvette) or the reading device for micrometrology. After 60 min incubation at 30°C again measured is xtinction. The summation of extinction at 480 nm is the amount of enzyme activity. Under standard conditions of 20 μg partially purified HSL leads to changes in the extinction of 0.4 = 4000 arb. units.

A direct test NAG:

Alternatively, to measure changes in the extinction of the substrate solution, the product HSL-reactions were studied by thin-layer chromatography separation of the phases. To do this, the incubation mixture (200 μl total volume, see indirect test NAG) in 2 ml Eppendorf tubes was mixed with 1.3 ml of a mixture of methanol/chloroform/heptane (10:9:7) and then with 0.4 ml of 0.1 m NaOH. After an intense permisiunea (10) produced the separation of the phases by centrifugation (HD, 20 min, room temperature). From the upper aqueous phase was collected equivalent volumes (for example, 0.4 ml) and photometrically determined the extinction at 481 nm. For thin-layer chromatography of the aqueous phase was dried (high vacuum) and then extracted with 50 μl of tetrahydrofuran, 5-µl sample was applied on a plate of silica gel Si 60 (Merck). Chromatography was performed with a mixture of 78 ml simple diethyl ether/22 ml of petroleum ether/1 ml acetic acid as eluent. The amount of the released fluorescent NBD-fatty acid was determined by obtaining phosphorescent image (Molecular Dynamics Storm 840 and Image Quant Software) at a wavelength of excitation of 460 nm and the wavelength of emission of 540-560 nm.

Preparation of enzyme:

Preparation of partially purified HSL:

The fat cells of the rat isolated from adipose tissue of the epididymis ovarian raw of male rats (Wistar, 220-250 g)were obtained according to published method (e.g., B.S. Nilsson and others, Anal. Biochem. 158, 1986, 399-407; G. Fredrikson and others, J. Biol. Chem. 256, 1981, 6311-6320; Tornquist, etc., J. Biol. Chem. 251, 1976, 813-819). Fat cells 10 rats three times washed by flotation in 50 ml of buffer solution for homogenization (25mm Tris/HCl, pH of 7.4, 0.25 M sucrose, 1 mm DTA, 1 mm DTT, 10 μg/ml leupeptin, 10 μg/ml antipain, 20 μg/ml of pepstatin) and then transferred into 10 ml of buffer solution for homogenization. The fat cells are homogenized in the homogenizer Teflon-in-glass (Braun-Melsungen) for 10 times at 1500 rpm at 15°C. Homogenized centrifuged (Sorvall SM24-Rohrchen, 5000 rpm, 10 min, 4°C). The intermediate layer lying between the top fatty layer and the pellets were collected and the centrifugation was repeated. Resulting intermediate layer centrifuged (Sorvall SM24 - Rohrchen, 20000 rpm, 45 min, 4°C). The intermediate layer was removed and mixed with 1 g of heparin-sepharose (Pharmacia-Biotech, CL-6B, 5 x wash 25 mm Tris/HCl, pH 7.4, 150 mm NaCl). After incubation for 60 min at 4°C were shaken every 15 min) the mixture was centrifuged (Sorvall SM24-Rohrchen, 3000 rpm, 10 min, 4°C). Brought the pH of the top layer to 5.2 by the addition of acetic acid and incubated for 30 min at 4°C. the Precipitate was collected centrifuge the management (Sorvall SS34, 12000 rpm, 10 min, 4°C) and suspended in 2.5 ml of 20 mm Tris/HCl, pH 7.0, 1 mm EDTA, 65 mm NaCl, 13% sucrose, 1 mm DTT, 10 μg/ml leupeptin/pepstatin/antipain. Suspension deliberately over night at 4°C With 25 mm Tris/HCl, pH 7.4, 50% glycerol, 1mm DTT, 10 μg/ml leupeptin, pepstatin, antipain and then brought to a column of hydroxyapatite (0.1 g in 1 ml of suspension, equilibrated with 10 mm potassium phosphate, pH 7.0, 30% glycerol, 1 mm DTT). The column was washed four volumes of buffer solution for equilibration at a flow rate of 20 to 30 ml/h HSL was suirable one volume of buffer solution to trim, containing 0.5 M potassium phosphate, then deliberately (see above) and concentrated 5 - to 10-fold by ultrafiltration (Amicon Diaflo PM 10 Filter) at 4°C. the Partially purified HSL can be stored for 4 to 6 weeks at -70°C.

Test:

To obtain substrates were mixed 25-50 MX[3H] triological (in toluene), 6.8 mmol of its triological and 0.6 mg of phospholipid (phosphatidylcholine/phosphatidylinositol 3:1 weight/vol.), was dried over N2and then was extracted with 2 ml of 0.1 M KPi (pH 7.0) were irradiated with ultrasound (Branson 250, microsparc, installing, 1-2, 2 x 1 min with 1 min interval). After addition of 1 ml of KPi and repeated exposure to ultrasound (4 x 30 sec) on ice with 30-second intervals) was added 1 ml of 20%BSA (KPi) (final concentration of triological 1.7 mm). For the reaction 10 µl of substrate solution was pietravalle to 100 μl of a solution HSL (prepared as indicated) above, diluted in 20 mm KPi, pH 7.0, 1 mm EDTA, 1 mm DTT, 0.02% of BSA, 20 μg/ml of pepstatin, 10 μg/ml leupeptin) and incubated for 30 min at 37°C. After the addition of 3.25 ml of methanol/chloroform/heptane (10:9:7) and 1.05 ml of 0.1 M2CO3, 0.1 M boric acid (pH of 10.5) were thoroughly mixed and then centrifuged (800 x g, 20 min). After separation of the phases was selected the top phase (1 ml) and radioactivity was determined by measuring scintillation liquid.

Summing up

Compounds are usually tested in four independent samples. Inhibition of the enzymatic activity of HSL test substance was determined by comparison with nestorienne control reaction. The calculation of the IC50produced by braking curve with at least 10 concentrations of test substance. Data analysis used the software package GRAPHIT, Elsevier-BIOSOFT.

In this sample indicated the compounds of examples 1 through 103.

Inhibition in the interval IC501 nm - 1 μm.

Receipt of the proposed compounds of General formulas I or II was carried out by known methods, for example, by acylation of substituted or unsubstituted indazols III carbamylcholine IV (method A), or in two stages by turning indazols III with phosgene or an equivalent (compounds), such as trichlorethylene ether chlorocarbonic acid or detrioration ether carboxylic acid is you, and the further conversion of the resulting acid chloride indazolinone acid with amines or aniline (the way In). In the case of compounds in which R3represents hydrogen, imidazole III may also interact with the corresponding isocyanates R2-N=C=O.

Because these reactions usually released acid, it is recommended to accelerate to add a base, such as pyridine, triethylamine, sodium alkali or carbonate of an alkali metal. The reaction can be carried out in a wide temperature range. Generally, it is preferable to set the temperature from 0°C to the boiling point of the used solvent. For injection as a suitable solvent, such as methylene chloride, THF, DMF, toluene, ethyl acetate, n-heptane, dioxane, simple, diethyl ether or pyridine. If you work in anhydrous conditions, are also suitable strong base, such as lithium hydride, sodium hydride or tert-butyl potassium in aprotic solvents such as THF or DMF.

Entered as starting compounds III indazols or appropriate asutamiseni derivatives are commercially available or can be obtained by known literature methods (e.g., L. Baiocchi, G. Corsi Synthesis (1978), 633-648, I. Sekikawa and other J. Het. Chem. (1973), 931-932).

Connections about what their formulas I or II were isolated and purified well-known ways chromatography.

Subsequent examples serve to explain the invention, but not limit it.

Examples

Example 1:

1H-Indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid

300 mg (2,24 mmol) 1H-indazol-3-ol was dissolved in 25 ml THF and cooled to -20°C. was Added dropwise 1.3 ml (2,46 mmol) of phosgene in toluene (20%). and was stirred for 90 min, and the reaction mixture was warmed up to room temperature. The reaction mixture was evaporated and again evaporated with a few ml of toluene. The residue was dissolved in 15 ml of THF and was added dropwise 265 μl (2.2 mmol) of 4-methylpiperidine, then was stirred for 3 h at room temperature, evaporated and purified preparative HPLC (PR18, a mixture of acetonitrile/water with 0.1% TFA). Output: 347 mg (60%), M+H+: 260,4.

Example 2:

4 Methylpiperidin-1-carbonylchloride

9 g (90,75 mmol) 4-methylpiperidine and 13.9 ml (100 mmol) of triethylamine were dissolved in 100 ml of THF and at -30°C was added 54.9 ml (100 mmol) of phosgene in toluene (20%), then was stirred for 2.5 h, and the reaction mixture was warmed to room temperature. The reaction mixture was evaporated, the residue was mixed with methylene chloride, filtered and the filtrate was evaporated. The crude product (12.7 g) was used further without additional purification.

Example 3:

4-Fluoro-1H-indazol-3-silt ether 4-methylpiperidin-1-carbon is Oh acid

100 mg (0.66 mmol) of 4-fluoro-1H-indazol-3-ol and of 116.8 mg (0,72 mmol) 4-methylpiperidin-1-carbonylchloride (example 2) in 10 ml of pyridine was heated and boiled for 4 hours under reflux and left to stand overnight. After addition of 24 mg of 4-methylpiperidin-1-carbonylchloride again heated and boiled for 2 hours under reflux, pyridine drove in vacuum, the residue was dissolved in water and was extracted with ethyl acetate. The organic phase was evaporated and purified preparative HPLC (PR18, a mixture of acetonitrile/water with 0.1% TFA). Yield: 56 mg (31%), M+H+: 278,1.

Example 4:

1-Methyl-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid

of 80.1 mg (0.31 mmol) of 1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid (example 1), was 38.1 mg (0.34 mmol) of potassium tert-butylate and 48.2 mg (0.34 mmol) of iodomethane within 48 h was stirred at room temperature. The solvent is kept in vacuum, the residue was dissolved in water and was extracted with ethyl acetate. The organic phase was evaporated and purified preparative HPLC (PR18, a mixture of acetonitrile/water with 0.1% TFA). Yield: 7 mg (8%), M+H+: 274,1.

Example 5:

100 mg high (0.56 mmol) of 6-Nitro-1H-indazol-3-ol and 135,3 mg (0.83 mmol) of 4-methylpiperidin-1-carbonylchloride (example 2) in 10 ml of pyridine was heated and boiled for 5 hours under reflux and ostalari to stand overnight. Pyridine drove in vacuum, the residue was dissolved in water and what was xtraceroute with ethyl acetate. The organic phase was evaporated and purified preparative HPLC (PR18, a mixture of acetonitrile/water with 0.1% TFA). Yield: 5 mg (3%) A: (3-hydroxy-6-nitroindazole-1-yl)-(4-methylpiperidin-1-yl)methanone, M+H+: 305,1 and 64 mg (38%): 6-nitro-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid, M+H+: 305,1.

Example 6:5-Nitro-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid

200 mg (1.12 mmol) of 5-Nitro-1H-indazol-3-ol and 180,4 mg (1,67 mmol) 4-methylpiperidin-1-carbonylchloride (example 2) in 20 ml of pyridine was heated and boiled for 5 hours under reflux and left to stand overnight. Pyridine drove in vacuum, the residue was dissolved in water and was extracted with ethyl acetate. The organic phase was evaporated and purified preparative HPLC (PR18, a mixture of acetonitrile/water with 0.1% TFA). Yield: 48 mg (14%) M+H+: 304,99.

Example 7:

6-amino-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid

30 mg (0.1 mmol) of 6-Nitro-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid (example 5B) in 15 ml of ethanol was first made in the presence of 10%palladium/coal under hydrogen pressure of 2 bar for 2.5 h at room temperature. The catalyst was aspirated and the filtrate was evaporated. Yield: 21 mg (76%), M+H+: 275,2.

Example 8:

Example 1 was repeated with 2 g (14.9 mmol) of 1H-indazol-3-ol. Along with A: 1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid separation is there isomeric products:(3-hydroxyindole-1-yl)-(4-methylpiperidin-1-yl)methanon With: 2-(4-methylpiperidin-1-carbonyl)-1,2-dihydropyrazol-3-one.

Example 9:

1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-methylpiperidin-1-carboxylic acid

a) 1H-Pyrazolo[3,4-b]pyridine-3-ol: 5 g (26,94 mmol) ethyl ester of 2-chloronicotinic acid value of 4.76 g (80,82 mmol) hydrazinehydrate (85%). in 10 ml of ethanol was heated and boiled for 6 hours under reflux. The reaction mixture was evaporated. Yield: 3.5 g (96%), M+H+: 135,9.

b) 300 mg (2.2 mmol) of 1H-Pyrazolo[3,4-b]pyridine-3-ol and 538,2 mg (3.3 mmol) of 4-methylpiperidin-1-carbonylchloride (example 2) in 25 ml of pyridine was heated and boiled for 4 hours under reflux and left to stand overnight. After addition of 24 mg of 4-methylpiperidin-1-carbonylchloride again heated up and within 2 hours was boiled under reflux, pyridine drove in vacuum, the residue was dissolved in water and was extracted with ethyl acetate. The organic phase was evaporated and purified preparative HPLC (PR18, a mixture of acetonitrile/water with 0.1% TFA). Yield: 99 mg (17%), M+H+: 261,28.

Example 10:

500 mg (2,16 mmol) 1H-Indazol-3-ylamine connection with sulfuric acid, 419,3 mg (2,59 mmol) 4-methylpiperidin-1-carbonylchloride (example 2) and 300 μl (4,32 mmol) of triethylamine in 30 ml of pyridine was heated in air for 5 h was heated to reflux and left to stand overnight. After addition of 302 μl of triethylamine and 390 mg of 4-methylpiperidin-1-carbonylchloride again heated for 2.5 h of the Pyridine drove in a vacuum, OST the current was dissolved in water and was extracted with ethyl acetate. The organic phase was evaporated and purified preparative HPLC (PR18, a mixture of acetonitrile/water with 0.1% TFA). Yield: 55 mg (10%): (1H-indazol-3-yl)amide of 4-methylpiperidin-1-carboxylic acid, M+H+: 259,1 and of 36.4 mg (7%): (3-aminoindazole-1-yl)-(4-methylpiperidin-1-yl)methanone, M+H+: 259,1.

Example 11:

4-triftormetilfosfinov-1-carbonylchloride

Detrioration ether carboxylic acid (840 mg, and 2.83 mmol) was dissolved in 30 ml of methylene chloride and slowly in an ice bath was mixed with of 2.06 ml (25,24 mmol) of pyridine. After 30 min the portions were slowly added hydrochloride 4-triftormetilfullerenov (1.45 g, 7,65 mmol). After removing the ice bath was stirred for 90 min, the precipitate was aspirated, washed with n-heptane and the filtrate was evaporated. The resulting product (1.9 g) contain a little salt and was immediately used for further transformation.

Example 12:

6-hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-triftormetilfosfinov-1-carboxylic acid

4-Methyl-1H-pyrazolo[3,4-b]pyridine-3,6-diol (1 g, 6.05 mmol), 4-triftormetilfosfinov-1-carbonylchloride (1,436 g, 6.6 mmol) and triethylamine (1,68 ml, 12,11 mmol) in 25 ml of pyridine was stirred for 1 h at room temperature. After addition of 0.5 ml of triethylamine was stirred for 2 h, evaporated and mixed with ethyl acetate and water. The precipitate was aspirated and dried. Output: 765 mg (37%)

6-hydroxy-4-IU the Il-1H-pyrazolo[3,4-b]pyridine-3-silt ether

4-triftormetilfosfinov-1-carboxylic acid. The organic phase is separated and purified preparative HPLC (PR18, a mixture of acetonitrile/water with 0.1% TFA). Yield: 96 mg (5%) of 6-hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-triftormetilfosfinov-1-carboxylic acid, M+H+: 345,13; 102 mg (3%) 4-methyl-3-(4-triftormetilfosfinov-1 carbonyloxy)-1H-pyrazolo[3,4-b]pyridine-6-silt ether 4-triftormetilfosfinov-1-carboxylic acid, M+H+: 524,20; 106 mg (3%)

6-hydroxy-4-methyl-1-(4-triftormetilfosfinov-1-carbonyl)-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-triftormetilfosfinov-1-carboxylic acid, M+H+: 524,52; 54 mg (1.3 per cent)

4-methyl-3-(4-triftormetilfosfinov-1 carbonyloxy)-1-(4-triftormetilfosfinov-1-carbonyl)-1H-pyrazolo[3,4-b]pyridine-6-silt ether 4-triftormetilfosfinov-1-carboxylic acid, M+H+: 703,36.

Example 13:

4-methyl-3-(4-triftormetilfosfinov-1 carbonyloxy)-1H-pyrazolo[3,4-b]pyridine-6-silt ether 4-methylpiperazin-1-carboxylic acid; compound with triperoxonane acid

6-Hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-triftormetilfosfinov-1-carboxylic acid (300 mg, 0.87 mmol), hydrochloride 4-methylpiperazin-1-carbonylchloride (191 mg, 0.96 mmol) and triethylamine (of 0.48 ml of 3.48 mmol) in 10 ml of pyridine was stirred for 5 h at room temperature. After addition of 0.4 ml of triethylamine and 100 mg of the hydrochloride of 4-methylpiperazin-1-carbon is chloride was stirred for 1 h, was evaporated, mixed with ethyl acetate and water and set pH 8. The organic phase was separated (repeated extraction), evaporated and purified preparative HPLC (PR18, a mixture of acetonitrile/water with 0.1% TFA). Yield: 125 mg (25%) of 4-methyl-3-(4-triftormetilfosfinov-1 carbonyloxy)-1H-pyrazolo[3,4-b]pyridine-6-silt ether 4-methylpiperazin-1-carboxylic acid, compound with triperoxonane acid, M+H+: 471,24; 82 mg (13%) 6-hydroxy-4-methyl-1-(4-methylpiperazin-1-carbonyl)-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-triftormetilfosfinov-1-carboxylic acid, compound with triperoxonane acid, M+H+: 471,27.

Example 14:

6-nitro-1H-indazol-3-ol

Methyl ester 2-fluoro-4-nitrobenzoic acid (5 g, 25,11 mmol) and hydrazinehydrate (of 1.34 ml, 27,62 mmol) was dissolved in 250 ml of ethanol was heated for 11 hours boiled under reflux. Added more of 0.26 ml of hydrazine hydrate is added and was heated and boiled under reflux for 6 hours, evaporated and mixed with ethyl acetate and water. The precipitated residue was pumped out and dried. After purification preparative HPLC (PR18, a mixture of acetonitrile/water with 0.1% TFA) received 1.39 g product, M+H+: 180,05.

Example 15:

6-fluoro-1H-indazol-3-ol:

2-amino-4-fermenting acid (25 g, 161,2 mmol) suspended in 250 ml of water and 39 ml conc. of hydrochloric acid. At 0°C was added dropwise sodium nitrite (11.2 g, 161,2 mmol) in 30 ml of water, maintaining the of IVA temperature below 10°C. After 30 min at room temperature was added sodium sulfite (69 g, 400 mmol) in 250 ml of water. After stirring for 2 h was added 30 ml conc. hydrochloric acid and left to stand overnight. Then heated in the course of 9 h was heated under reflux, cooled and sodium bicarbonate was established pH 5.5. The precipitate was aspirated and dried. Output: 19,8 g (81%), M+H+: 152,94.

Example 16:

3-hydroxy-1H-indazol-6-carboxylic acid

Dimethyl 2-aminoterephthalic acid (5 g, of 23.9 mmol) was dissolved in 40 ml of water and 6 ml conc. of hydrochloric acid. At 0°C was added dropwise sodium nitrite (1.65 g, of 23.9 mmol) in 5 ml of water, keeping the temperature below 10°C. After 30 min at room temperature was added sodium sulfite (11,02 g, 87,42 mmol) in 40 ml of water. After stirring for 1 h was added 10 ml conc. hydrochloric acid and left to stand overnight. Then within 24 h was heated at 80°C, cooled and soda lye was established pH 5.5. The precipitate was aspirated and dried. Output: to 2.29 g (54%), M+H+: 179,04.

Example 17:

3-hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid

5-Amino-2H-pyrazole-3-ol (3.1 g, of 31.6 mmol) suspended in 100 ml of methanol. Then was added sodium methylate (5,1 g, 95 mmol) and ethyl ester of 2,4-dioxopentanoate acid (5 g, of 31.6 mmol), was heated in air for 12 h was heated with reverse Hladilnika. The solvent deletion is whether on a rotary evaporator and the residue was mixed with water, the precipitate was aspirated and the filtrate diluted hydrochloric acid brought to pH 6. The precipitated product (both sediment) was aspirated and dried. Yield: 4.9 g (70%), M+H+: 194,09.

Analogous to the described examples were obtained the following compounds.

td align="justify"> 351,17
ExampleNameM+H+
181H-indazol-3-silt ether 3-methylpiperidin-1-carboxylic acidof 260.2
19(3,4-Dihydro-2H-quinoline-1-yl)-(3-hydroxyindole-1-yl)methanon294,3
20(3-Hydroxyindole-1-yl)pyrrolidin-1-ylmethanone232,3
21(3-Hydroxyindole-1-yl)thiomorpholine-4-ylmethanol264,4
22(3,4-Dihydro-1H-isoquinoline-2-yl)-(3-hydroxyindole-1-yl)methanon294,5
23Methylphenylene 3-hydroxyindole-1-carboxylic acid268,3
241-Methyln-indazol-3-silt ether 3-methylpiperidin-1-carboxylic acid 274,4
25(3-Methoxyindol-1-yl)-(3-methylpiperidin-1-yl)methanon274,4
26Dibutylated 3-hydroxyindole-1-carboxylic acid290,16
271H-Indazol-3-silt ether diethylcarbamyl acid234,11
281H-Indazol-3-silt ether diisopropylcarbodiimide acid262,13
291H-Indazol-3-silt ether piperidine-1-carboxylic acid246,10
30(1,3-Dihydroindol-2-yl)-(3-hydroxyindole-1-yl)methanon280,12
316-Trifluoromethyl-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid328,16
326-Fluoro-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid278,13
336-Chloro-1H-indaz the l-3-silt ether 4-methylpiperidin-1-carboxylic acid 294,06
346-Methyl-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid274,12
35(6-Chloro-3-hydroxyindole-1-yl)-(4-methylpiperidin-1-yl)methanon294,12
36(3-Hydroxyindole-1-yl)-(octahydrocyclopenta-2-yl)methanon286,16
371H-Indazol-3-silt ether octahydrocyclopenta-2-carboxylic acid286,17
381H-Indazol-3-silt ester of 3,4-dihydro-1H-isoquinoline-2-carboxylic acid294,13
396-Chloro-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-methylpiperidin-1-carboxylic acid309,14
40(3-Hydroxypyrazolo[3,4-b]pyridine-1-yl)-(4-methylpiperidin-1-yl)methanon261,17
414-Methyl-3-(4-methylpiperidin-1 carbonyloxy)-1H-pyrazolo[3,4-b]pyridine-6-silt ether 4-methylpiperidin-1-carbon is acid 416,24
426-Hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-methylpiperidin-1-carboxylic acid291,20
43(6-Fluoro-3-hydroxyindole-1-yl)-(4-methylpiperidin-1-yl)methanon278,18
44(6-Fluoro-3-hydroxyindole-1-yl)-(octahydrocyclopenta-2-yl)methanon304,20
45(3,4-Dihydro-1H-isoquinoline-2-yl)-(6-fluoro-3-hydroxyindole-1-yl)methanon312,17
466-Fluoro-1H-indazol-3-silt ether octahydrocyclopenta-2-carboxylic acid304,21
476-Fluoro-1H-indazol-3-silt ether piperidine-1-carboxylic acid264,17
486-Fluoro-1H-indazol-3-silt ether methylphenylcarbinol acid286,17
496-Fluoro-1H-indazol-3-silt ester of 3,4-dihydro-1H-isoquinoline-2-carboxylic acid12,13
501H-Pyrazolo[4,3-c]pyridine-3-silt ether 4-methylpiperidin-1-carboxylic acid261,15
516-Bromo-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid338,08
52Methyl ester of 3-(4-methylpiperidin-1 carbonyloxy)-1H-indazol-6-carboxylic acid318,17
531H-Indazol-3-silt ether (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamino acidand 364.8
546-Chloro-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-silt ester of 3,4-dihydro-1H-isoquinoline-2-carboxylic acid343,16
556-Trifluoromethyl-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-methylpiperidin-1-carboxylic acid329,19
56(6-Fluoro-3-methoxyindol-1-yl)-(4-methylpiperidin-1-yl)methanon292,20
575,6-Debtor-1H-indazol-3-silt ether 4-methylpiperidin-1-arbonboy acid 296,25
58(3,4-Dihydro-1H-phthalazine-2-yl)-(6-fluoro-3-hydroxyindole-1-yl)methanon313,15
59(6-Chloro-3-hydroxy-4-methylpyrazolo[3,4-b]pyridine-1-yl)-(3,4-dihydro-1H-isoquinoline-2-yl)methanon343,12
601-Benzyl-6-hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-methylpiperidin-1-carboxylic acid381,27
616-Methanesulfonyl-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid338,17
626-Hydroxy-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-methylpiperidin-1-carboxylic acid277,15
63(3,6-Dihydrotetrazolo[3,4-b]pyridine-1-yl)-(4-methylpiperidin-1-yl)methanon277,15
64(6-Chloro-3-hydroxy-4-methylpyrazolo[3,4-b]pyridine-1-yl)-(4-methylpiperidin-1-yl)methanon309,13
654-Methyl-3-(4-meth is piperidin-1 carbonyloxy)-1H-pyrazolo[3,4-b]pyridine-6-silt ether methyl ester of succinic acid 405,26
666-Fluoro-1H-indazol-3-silt ether 4-methylpiperazin-1-carboxylic acid; compound with triperoxonane acid279,15
671H-pyrazolo[3,4-b]pyridine-3-silt ester of 3,4-dihydro-1H-isoquinoline-2-carboxylic acid295,18
686-Fluoro-1H-indazol-3-silt ether 4,4-deformability-1-carboxylic acid300,25
694-Methyl-3-(4-methylpiperidin-1 carbonyloxy)-1H-pyrazolo[3,4-b]pyridine-6-silt ether 4,4-deformability-1-carboxylic acid438,31
706-Fluoro-1H-indazol-3-silt ester of 6,7-dihydro-4H-thieno[3,2-e]pyridine-5-carboxylic acid318,11
711-(6-Fluoro-1H-indazol-3-silt) ether 4-benzyl ester piperidine-1,4-dicarboxylic acid398,26
726-Fluoro-1H-indazol-3-silt ether thiomorpholine-4-carboxylic acid282,13
736-Fluoro-1H-indazol-3-silt ether 4-triftormetilfosfinov-1-carboxylic acid332,16
746-Fluoro-1H-indazol-3-silt ether 2,6-dimethylmorpholine-4-carboxylic acid294,18
766-Fluoro-1H-indazol-3-silt ether morpholine-4-carboxylic acid266,15
776-Fluoro-1H-indazol-3-silt ester of 3,4-dihydro-1H-phthalazine-2-carboxylic acid; compound with triperoxonane acid313,14
786-Hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4,4-deformability-1-carboxylic acid313,17
796-Chloro-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4,4-deformability-1-carboxylic acid331,14
804,6-Debtor-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid296,17
81Mono-(6-fluoro-1H-indazol-3-silt) ether piperidine-1,4-dicarboxylic to the slots 308,20
826-Fluoro-1H-indazol-3-silt ether 4-foreperiod-1-carboxylic acid282,10
836-Fluoro-1H-indazol-3-silt ether 4-cyclopropylmethyl-1-carboxylic acid305,24
846-Fluoro-1H-indazol-3-silt ether piperazine-1,4-dicarboxylic acid399,13
851-(6-Fluoro-1H-indazol-3-silt) ester 4-ethyl ester 4-foreperiod-1,4-dicarboxylic acid354,13
86(4-Cyclopropylmethyl-1-yl)-(6-fluoro-3-hydroxyindole-1-yl)methanon305,35
876-Fluoro-1H-indazol-3-silt ether 4,4-dimethylpiperidin-1-carboxylic acid292,19
886-Fluoro-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid292,13
891H-Indazol-3-silt ester of 4-(3,4-dimetilfenil)piperazine-1-carboxylic acid
906-Chloro-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-triftormetilfosfinov-1-carboxylic acid263,07
915-fluoro-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid278,22
924-Methyl-3-(4-methylpiperidin-1 carbonyloxy)-1H-pyrazolo[3,4-b]pyridine-6-silt ether 4-triftormetilfosfinov-1-carboxylic acid470,18
936-Fluoro-1H-indazol-3-silt ether 4-cyclopropylidene-1-carboxylic acid302,14
946-Hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-cyclopropylmethyl-1-carboxylic acid318,21
951-[4-methyl-3-(4-methylpiperidin-1 carbonyloxy)-1H-pyrazolo[3,4-b]pyridine-6-silt] ether 4-benzyl ester piperidine-1,4-dicarboxylic acid536,40
966-Pentafluoroethyl-1H-indazol-3-silt ether 3-methylpiperidin-1-carboxylic acid 386,32
974-Methyl-3-(4-methylpiperidin-1 carbonyloxy)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid319,17
984-Methyl-6-(4-methylpiperidin-1-carbonyl)-1H-pyrazolo[3,4-b}pyridine-3-silt ether 4-methylpiperidin-1-carboxylic acid400,26
994-Methyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine-3-silt ether 4-methylpiperidin-1-carboxylic acid351,34
1004,6-Debtor-1H-indazol-3-silt ether 4-triftormetilfosfinov-1-carboxylic acid350,11
1016-(4-Methylpiperidin-1-carbonyl)-1H-indazol-3-silt ether 4-methylpiperidin-1-carboxylic acid385,25
102Benzylated 6-chloro-3-hydroxyindole-1-carboxylic acid302,10
103Exiled 6-Chloro-3-hydroxyindole-1-carboxylic acid296,16

Information about the biological activity of the compounds.

Table 1. Inhibi the ith action of the compounds of General formulas I or II on gormonchuvstvitelnoy the lipase.

N
ExampleFormulaXRR1R2/R3IC50 (μm)
12NN4 methyl-piperidine0,36
32FN4 methyl-piperidine0,44
42Nmethyl4 methyl-piperidine0,79
52 NO2N4 methyl-piperidine0,29
62NO2N4 methyl-piperidine1,13
72NH2N4 methyl-piperidine1,04
92NHN4 methyl-piperidine0,245
122NHE, methylN4-CF3-piperidine4,4
132NCCA-(methyl-piperazine), methylN4-CF3-piperidine0,093
191NNthe quinoline12,99
201NNpyrrolidin18,42
211NNthiomorpholine10,88
221NN isoquinoline14,17
292NNpiperidine1,5
301NNthe isoindole13,5
312CF3N4 methyl-piperidine0,03
322FN4 methyl-piperidine0,04
332CL N4 methyl-piperidine0,18
342methylN4 methyl-piperidine0,24
351CLN4 methyl-piperidine>30
361NNoctahydrocyclopenta34,95
372NNOctahydrocyclopenta1,15
382 HN2-tetrahydroquinolin0,44
392NCl, methylN4 methyl-piperidine0,02
401NHN4 methyl-piperidine>30
412NCCA-4 methyl-piperidine, methylN4 methyl-piperidine0,01
422NHE, methylN4 methyl-piperidine0,39
431 FN4 methyl-piperidine0,82
441FNOctahydrocyclopenta17,42
451FNdecahydroquinoline3,01
462FNOctahydrocyclopenta0,47
472FNpiperidine0,33
482 FNmethyl, phenyl8,29
492FNTetrahydroisoquinoline0,17
502NNN4 methyl-piperidine2,04
512VGN4 methyl-piperidine0,17
522Soo-methylN4 methyl-piperidine0,19
532 HN1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalen>30
542NCl, methylNTetrahydroisoquinoline0,27
552NCF3N4 methyl-piperidine0,17
561Fmethyl4 methyl-piperidine>30
572F, FN4 methyl-piperidine 2,24
581FN1,2,3,4-tetrahedrite-Latin>30
591NCl, methylNTetrahedrite-quinoline32,2
602NHE, methylbenzil4 methyl-piperidine0,97
612SO2-methylN4 methyl-piperidine0,16
622NHE4 methyl-piperidine9,65
631NHEN4 methyl-piperidine14,42
641NCl, methylN4 methyl-piperidine33,83
652NEA2H4COO-methyl, methylN4 methyl-piperidineto 4.41
662FN4 methyl-piperazine3,41
67NNHTetrahydroisoquinoline0,42
682FH4-di-F-piperidine0,44
692NCCA-(di-F-piperidine), methylH4 methyl-piperidine0,01
702FH4,5,6,7-tetrahydrothieno[3,2-C]pyridine0,11
712FHp is peridin-4-MEO-benzyl 9,56
722FHthiomorpholine>30
732FHpiperidine-4-CF30,2
742FH3,5-di-methyl-morpholine21,67
762FHmorpholine8,11
772F H1,2,3,4-tetrahydropyrazin>30
782NHE, methylH4-di-F-piperidine12,54
792NCl, methylH4-di-F-piperidine0,9
802F, FH4 methyl-piperidine0,02
822FH4-F-piperidine0,91
832FH4-cyclopropyl-piperidine33,64
842FH4-Zoobenthic-piperazine>30
852FN4F, 4-COOEt-piperidine1,22
861FN4-cyclopropyl-piperidine33,64
872FN4-di-methyl-piperidine0,824
882Fmethyl4 methyl-piperidine0,3
892HN(3,4-di-methyl-phenyl)-4-piperazin3,603
902NCl, methylN4-CF3-piperidine0,034
912FN4 methyl-piperidine0,67
922NOCO-(4CF3-piperidine), methyl N4 methyl-piperidine0,013
932FN4-cyclepro drinking-DIN-piperidine0,078
942NHE, methylN4-cyclopropyl-piperazine>30
952NCCA-(4-MEO-benzyl)-piperidine, methylN4 methyl-piperidine0,01
962SF5N4 methyl-piperidine0,056
102 1ClNN, benzil>30
1031ClNN, hexyl>30

1. Derivatives indazole General formulas I or II,

where W represents -(C=O)-,
X is a =C(R)- or one of X is a =N, a
the rest are =C(-R);
Y represents-O-;
R represents hydrogen, halogen, (C1-C6)-alkyl, hydroxy-group, amino group, COOR4, trifluoromethyl, (C1-C6)-alkylsulfonyl, nitro-group, pentafluoroethyl, phenyl, CO-NR2R3, - O-CO-NR2R3, - O-CO-(C1-C6-alkylene-CO-O-(C1-C6)-alkyl,
R1 represents H, (C1-C6)-alkyl, benzyl;
R2 represents a (C1-C6)-alkyl, benzyl, phenyl or Tetraethylenepentamine;
R3 represents H, (C1-C6)-alkyl; or
R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated the th from 5 - to 6-membered ring system or a bicyclic saturated or partially unsaturated 9 - to 10-membered ring system, moreover, individual members of the ring systems can be from one to two times substituted by atoms or groups of atoms from the series-CHR5-, -CR5R5-, -(C=R5)-, -NH, -NR5-, -O-, -S-, with the restriction that the two structural units of the series-O-, -S-, cannot be adjacent;
R4 represents hydrogen, (C1-C6)-alkyl, benzyl;
R5 represents a (C1-C6)-alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropyl;
and their physiologically acceptable salts, with this limitation, that in the compounds of formula (I) YR1, R2 and R3 cannot simultaneously have the following values:
YR1=OH, R2=phenyl and R3=H.

2. Derivatives indazole formulas I and II according to claim 1, where NR2R3 represents a monocyclic saturated 5 - to 6-membered ring system, which is in the 4 position contains an atom or group of atoms from a number-CHR5-, -CR5R5, -(C=R5)-, -NR5-, -O-, -S-.

3. Derivatives indazole formula I and II according to claim 1, where X in positions 4, 5, and 7 is a =C(-R), where R= hydrogen.

4. Derivatives indazole formula I or II according to claim 1, where W represents -(C=O)-;
X is a =C(R)- or one of X is a =N-, the rest are =C(-R);
Y represents-O-;
R represents hydrogen, halogen, (C1-C6)-alkyl, hydroxy-group, amino group, COOR4, trifluoromethyl, (C1-C6)-alkylsulfonyl, nitro-group, pentafluoroethyl, phenyl,CO-NR2R3, O-CO-NR2R3 or-O-CO-(C1-C6-alkylene-CO-O-(C1-C6)-alkyl;
R1 represents H, (C1-C6)-alkyl, benzyl;
R2 represents a (C1-C6)-alkyl, benzyl, phenyl or tetramethylethylenediamine;
R3 represents H, (C1-C6)-alkyl; or R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated 5 - to 6-membered ring system or a bicyclic saturated or partially unsaturated 9 - to 10-membered ring system, with individual members of the ring systems can be from one to two times substituted by atoms or groups of atoms from the series-CHR5-, -CR5R5-, -(C=R5)-, -NR5-, -O-, -S-, with the restriction that the two structural units from a number of -O-, -S-, cannot be adjacent;
R4 represents hydrogen, (C1-C6)alkyl or benzyl;
R5 represents a (C1-C6)-alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropyl.

5. Derivatives indazole formula I according to claim 1, where W represents -(C=O)-;
X represents-C(R)- or one of X is a =N-, the rest are =C(-R);
Y represents-O-;
R represents hydrogen, a halogen, a nitro-group, a hydroxy-group or (C1-C6)-alkyl;
R1 represents H or (C1-C6)-alkyl;
R2 represents a (C1-C6)-alkyl benzyl or phenyl;
R3 represents a (C1-C6)-alkyl; or
R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated 5 - to 6-membered ring system or a bicyclic saturated or partially unsaturated 9 - to 10-membered ring system, with individual members of the ring systems can be from one to two times substituted by atoms or groups of atoms from the series-CHR5-, -NR5-;
R5 represents a (C1-C6)-alkyl or cyclopropyl.

6. Derivatives indazole formula II according to claim 1, where W represents -(C=O)-;
X is a =C(R)- or one of X is a =N-, the rest are a =(- R);
Y represents-O-;
R represents hydrogen, halogen, (C1-C6)-alkyl, hydroxy-group, amino group, COOR4, trifluoromethyl, (C1-C6)-alkylsulfonyl, nitro-group, pentafluoroethyl, phenyl, CO-NR2R3, - O-CO-NR2R3 or-O-CO-(C1-C6-alkylene-CO-O-(C1-C6)-alkyl;
R1 represents H, (C1-C6)-alkyl or benzyl;
R2 represents a (C1-C6)-alkyl, phenyl or tetramethylethylenediamine;
R3 represents H, (C1-C6)-alkyl; or
R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated 5 - to 6-membered ring system or a bicyclic saturated or partially easymenu from 9 - to 10-membered ring system, moreover, individual members of the ring systems can be from one to two times substituted by atoms or groups of atoms from the series-CHR5-, -CR5R5-, -(C=R5)-, -NR5-, -O-, -S-, with the restriction that the two structural units of the series-O-, -S-, cannot be adjacent;
R4 represents hydrogen, (C1-C6)-alkyl, benzyl; and R5 represents a (C1-C6)-alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropyl.

7. Derivatives indazole formula II according to claim 1, where NR2R3 represents piperidine, 4 position contains a group of atoms CHR5.

8. Drug, possess inhibitory effect on gormonchuvstvitelnoy lipase containing one or more derivatives of indazole formula I or II according to one or more of claims 1 to 7.

9. The use of derivatives indazole formula I or II according to one or more of claims 1 to 7 for the treatment and/or prevention of metabolic fatty acids and impaired uptake of glucose.

10. The use of derivatives indazole formula I or II according to claim 9 for the treatment and/or prevention of disorders, in which plays the role of insulin resistance.

11. The use of derivatives indazole formula I or II according to claim 9 for the treatment and/or prevention of diabetes and related complications.

12. The use of derivatives indazole formula I or II according to claim 9 for the treatment and/or prevention of dyslipidemia and its complications

13. A method of obtaining a medicinal product containing one or more derivatives of indazole formula I or II according to one or more of claims 1 to 7, characterized in that the active substance is mixed with pharmaceutically suitable carrier and this mixture is processed in a form suitable for injection.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention relates to the method for production of the compound of the formula (1a), being an inhibitor of thrombocyte aggregation (1a), where X is halogen atom. The method includes interaction of compounds of the formula (II), (II), where X has above mentioned value and Y and Z independently from each other are leaving groups, with optically active alkamine with formation of diastereoisomers admixture.

EFFECT: development of the new advantageous method for production of the bioactive compound.

48 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the method for preparation of hexachloroantimonates of 2,3-dihydro[1,3]thiazolium of general formula wherein R1 is alkyl or phenyl, R2 is alkyl, phenyl or hydrogen, R1+R2 is cycloalkyl by the interreaction of 4,6-dimethyl-2-pyrimidinsulfenyl chloride with corresponding olefine in presence of antimony pentachloride in equimolar ratio in the media of methylene chloride.

EFFECT: claimed compounds can be used in production of pharmaceutical preparations and biologically active substances.

2 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

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21 cl, 228 ex

Thienopyrazoles // 2358978

FIELD: chemistry.

SUBSTANCE: description is given of thienopyrazol of formula I its pharmaceutically acceptable salts or esters, in which X represents N or C-R7; X1 represents N or C-R1; R1, R2, R3, R4, R5 and R6 are independently chosen from a group which contains hydrogen, possibly substituted acyl, alkyl, alkoxy group, acylaminogroup, alkoxyalkyl, (Y1)(Y2)NC(=O)-, alkoxycarbonyl, aryl, halogen, carboxy group; or R5 and R6 together with two carbon atoms with a double bond, with they are bonded, form a benzene ring; R7 is a hydrogen atom, halogen or alkyl; and Y1 and Y2 are independently a hydrogen atom, alkyl, aryl or heteroaryl, or Y1 and Y2 together with a nitrogen atom, with which they are bonded, form a heteroaryl group or heterocycloalkyl group. The invention also relates to pharmaceutical compositions, containing these compounds. Thienopyrazoles can be used for treating diseases, which can be affected by protein kinase inhibition, particularly, interleukin-2-induced tyrosine kinase.

EFFECT: wider field of application of the compounds.

14 cl, 1 tbl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention refers to Clopidogrel process by optical separation of its racemic form with using optically active amine of formula V to make optically active form of compound of formula III or its acid-additive salt followed with methylation of compound III or its salts. The intermediate product of formula resulted from reaction of racemic form of Clopidogrel and amine V.

EFFECT: possibility to make a high-yield end product.

22 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new spirocyclic cyclohexane derivatives of general formula I , where: R1-R3, R5-R10, W, X are disclosed in the claim 1 of formula.

EFFECT: compounds exhibit analgesic activity to be applied for making a medical product for pain therapy.

20 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention concerns development of method of obtaining furylhetarylmethane derivatives of the general formula I applicable as semiproducts for obtainment of new polycyclic derivatives of thieno[2,3-b]pyridine. Method of obtaining furylhetarylmethanes with thieno[2,3-b]pyridine fragment of the general formula I involves forming furylhetarylmethane structure by alkylation of furane ring catalysed by acids; reaction is performed by boiling alcohols of 3-amino[2,3-b]pyridine and 2-methylfurane range in dioxane in the presence of 0.2-0.4 ml of acid catalyst, which is a mix of 70% perchloric acid, acetic anhydride and glacial acetic acid at the ratio of HClO4:(CH3CO2)O:CH3COOH=0.056:0.033:0.052 mol for 1.5-8 hours. It allows forming new heterocyclic system of furylhetarylmethanes with thieno[2,3-b]pyridine fragment by alkylation of 2-methylfurane by 2-hydroxy(phenyl)methyl-4,6-disubstituted-3-substituted carboxamidothieno[2,3-b]pyridines.

EFFECT: obtaining compounds applicable as semiproducts for obtainment of new polycyclic derivatives.

2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,11b-cys-dihydrotetrabenazene of general formula (1) or to its antipode . Invention also relates to composition, to pharmaceutical composition, to application of 3,11b-cys-dihydrotetrabenazene, to method of obtaining 3,11b-cys-dihydrotetrabenazene by i. 1, to compounds of formula (II), (III), as well as to ester of Mosher's acid and 3,11b-cys-dihydrotetrabenazene.

EFFECT: obtaining novel biologically active compounds possessing activity as inhibitor of vesicular carrier of monoamines VMAT2.

23 cl, 12 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula IId and their pharmacologically acceptable salts. In formula IId M represents -CH- or -N-; R2c bonded with carbon atom of 5-member ring and is selected from hydrogen and methyl; R2d is bonded with carbon atom from 6-member ring and selected from hydrogen and fluorine; one of R2a and R2b represents methoxy, and other is Q1X1, where X1 represents -O-, and values of other radicals are given in formula IId, to pharmaceutical composition, inhibiting antiogenesis and/or reducing vessel permeability, which contains as active component compound of formula IId, to application of invention compounds for preparation of medication and to compounds of 7-benzyloxy-4(4-fluorine-2-methylindol-5-iloxy)-6-methoxyquinazoline and 4-(4-fluorine-2- methylindol -5-yloxy)-7-hydroxy-6-methoxyquinazo-line.

EFFECT: development of effective method of obtaining quinazoline compounds.

12 cl, 54 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to application of derivatives of 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine of formula [I] as active ingredient for preparation of medication possessing anti-tumor activity, as well as to novel compounds of formula [I'], their pharmaceutically acceptable salts, hydrates and solvates. In formula[I] or [I'] values X1 and X2 are respectively selected from nitrogen atom and carbon atom, group is respectively selected from or . Other radical values are given in invention formula.

EFFECT: compounds can be applied for treatment and prevention of diseases induced by undesirable cell proliferation, such as cancer, rheumatism, etc.

32 cl, 11 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I): , where: R1 represents hydrogen atom, (C1-C4)-alkyl, group -(CH2)mOH, group -(CH2)mCN, group -(CH2)mNR9R10; R2 represents hydrogen atom or (C1-C4)-alkyl; R3 represents phenyl, substituted with radicals R6, R7, R8; R4 represents: group ; heterocyclic radical selected from radicals: ; ; ; R5 represents hydrogen atom or (C1-C4)-alkyl; R6, R7 and R8 represent independently on each other hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, cyanogroup, group -(CH2)nNR9R10, group -O-(CH2)mNR9R10; R9 and R10 represent independently on each other hydrogen atom or (C1-C4)-alkyl; or R9 and R10 together with nitrogen atom, to which they are bonded, form heterocyclic radical, selected from pyrrolidin-1-yl, pyperidin-1-yl, morpholin-4-yl or pyperasin-1-yl, substituted or non-substituted in position 4 with (C1-C4)-alkyl; R11 represents hydrogen atom or (C1-C4)-alkyl; R12 represents hydrogen atom, (C1-C4)-alkyl, group -(CH2)m-CO-R16; R13 represents hydrogen atom, (C1-C4)-alkyl, phenyl, group NR17R18, group ; R14 represents hydrogen atom, (C1-C4)-alkyl, group -NR17R18; R15 represents hydrogen atom, (C1-C4)-alkyl, group -NR19R20, -COO(C1-C4)-alkyl; R16 represents hydroxyl, (C1-C4)-alkoxy, group -NR9R10; R17 and R18 represent independently on each other hydrogen atom or (C1-C4)-alkyl; R18 can also represent group -COR21, group -SO2R22; R19 and R20 represent independently on each other hydrogen atom or (C1-C4)-alkyl; R20 can also represent (C3-C6)-cycloalkyl, (C3-C6)-cycloalkylmethyl, group -(CH2)mNR9R10; R21 represents (C1-C4)-alkyl, (C3-C6)-Cycloalkyl, group -(CH2)mNR9R10; R22 represents (C1-C4)-alkyl; m equals 1, 2 or 3; n equals 1, 2 or 3. As well as to medication and pharmaceutical composition, to method of obtaining it and its application in therapy.

EFFECT: obtained and described are novel compounds which can be useful in medicine.

14 cl, 67 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , in which A is selected from one or several X and/or Y groups; X represents methylene group; Y represents C2-alkinylene group; n represent integer number from 1 to 5; R1 represents group R2, optionally substituted with one or several R3 and/or R4 groups; R2 represents group selected from pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphtyl, chinolinyl, isochinolinyl, dihydroisochinolinyl, 2-oxo-3,4-dihydrochinolinyl, indolyl, benzimidazolyl, pyrrolopyridinyl; R3 represents group selected from halogen atoms, groups C1-6-alkyl, C3-7-Cycloalkyl, C1-6-alkoxy, NR5R6 and phenyl; R4 represents group selected from groups: phenyl, naphtyl, pyridinyl; R4 group or groups can be substituted with one or several R3 groups, similar or different from each other; R5 and R6 independently on each other represent C1-6-alkyl group; R7 represents hydrogen atom or C1-6-alkyl group; R8 represents hydrogen atom or group C1-6-alkyl, C3-7-cycloalkyl, C3-7-Cycloalkyl- C1-3-alkylene; in form of base, acid-additive salt, hydrate or solvate. Invention also relates to methods of obtaining formula (I) compound by any of ii. 1-3, to compounds, determined by general formula (IV), (VII), to pharmaceutical composition, as well as to application of formula (I) compounds by any of ii. 1-3.

EFFECT: obtaining novel biologically active compounds possessing activity of enzyme FAAH inhibitors.

10 cl, 5 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) to its salts, in which X is bivalent radical NR2, O; R1 is cyanogroup; n equals 1; R2 is: i) C1-10alkyl, substituted with aryl, where said aryl is substituted with radical -COOR4; or R2 is ii) C1-10alkyl, substituted with radical selected from -O-NR5a-C(=NR5b)-NR5cR5d, -NR7R8, radical

in which each Q1 independently is simple bond, -CH2-; each Q2 independently is O; each R4 independently is hydrogen; each R5a, R5b, R5c, R5d independently is hydrogen; R7 is C1-4alkyl; R8 is arylC1-4alkyl; R11 is aryl, C1-4alkylcarbonyl, C1-4alkyloxycarbonyl, hydroxyC1-4alkyl, "Гет"2; each R12 independently is hydroxy, C1-4alkyl; R13a is C1-4alkyl; each R13b is C1-4alkyl; or R2 is iii) radical of formula:

-CpH2p-CH(OR14)-CqH2qR15 (b-3);

CH2-CH2-(O-CH2-CH2)m-OR14 (b-4);

CH2-CH2-(O-CH2-CH2)m-NRI7eR17b (b-5); where in radical (b-3) one of hydrogen atoms in -CpH2p- and one of hydrogen atoms in - CH(OR14)-CqH2q-, which are not part of R14, can be substituted with simple bond or C1-4alkandiyl group; p equals 1, 2 or 3; q equals 0, 1, 2 or 3; each m independently equals 1-10; each R independently is hydrogen, C1-4alkyl, C1-4alkylcarbonyl; R15 is substituent selected from group consisting of NR16aR16, pyrrolidine, pyperidinyl, homopyperidinyl, piperazinyl, , 4-(C1-4alkyl)-piperazinyl, 4-(C1-4alkylcarbonyl)-piperazinyl, 4-(C1-4alkyloxycarbonyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl; R16a and R16b, independently on each other, are hydrogen, C1-6alkyl or C1-6alkyl, substituted with aryl; R17a and R17b, independently on each other, are hydrogen, C1-4alkyl; or R17a and R17b, together with nitrogen atom, to which they are bonded, form pyrrolidine, morpholinyl; each R18 independently is arylC1-4alkyl; R19 is hydrogen; R3 is nitrogroup; aryl is phenyl; "Гет"2 is piridyl. Invention also relates to pharmaceutical composition, to method of obtaining compound on any of ii 1-4, as well as to compounds of formula (IV-a), (IV-b),(V).

EFFECT: obtaining novel biologically active compounds possessing ability to inhibit HIV.

11 cl, 18 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining 5-bromo-7-azaindole obtaining, which includes: stage 1: reduction of 7-azaindole, receiving 7-azaindoline; stage 2: bromination of 7-azaindoline, receiving 5-bromo-7-azaindoline; stage 3: oxidation of 5-bromo-7-azaindoline receiving 5-bromo-7-azaindole.

EFFECT: elaboration of method of obtaining 5-bromo-7-azaindole.

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining 5-methoxy-7-azaindol, which includes mixing of 5-bromo-7-azaindole solution, copper (I) bromide and sodium methylate in mixture of "degassed" DMFA (dimethyl formamide) and methanol; mixing of obtained mixture at temperature of surrounding environment in nitrogen atmosphere; and then heating of mixture with reverse refrigerator.

EFFECT: elaboration of method of obtaining 5-methoxy-7-azaindole.

1 cl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) or pharmaceutically acceptable salts thereof, where R1 is chosen from a group containing optionally substituted C1-C6alkyl, lower alkoxy group, (lower)alkoxy(lower)alkyl, cycloalkyoxy(lower)alkyl, lower thioalkyl, (lower)alkylthio(lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R2 is chosen from a group containing optionally substituted (lower)alkyl, cycloalkyl, cycloalkyl(lower)alkyl; R3 is chosen from a group containing halogen, cyano group, optionally substituted (lower alkyl, lower thioalkyl, aryl, aryl(lower)alkyl, lower alkenyl, lower alkynyl); R4 is chosen from a group containing hydrogen, halogen, cyano group, hydroxyl group, optionally substituted (lower alkyl, lower alkoxy group, aryl, pyridyl, aryl(lower)alkyl, heteroaryl, which is an aromatic mono- or bicyclic hydrocarbon, containing from 5 to 9 ring atoms, from which one or more is a heteroatom, chosen from O, N or S, and an amino group) and a group, with formula R8-Z-(CH2)n-; where Z is a single bond or chosen from a group consisting of O, NH, CH2, CO, SO, SO2 or S; where R8 is chosen from a group containing optionally substituted (aryl, pyridyl); and where n=0, 1 or 2; R5 represents hydrogen; R6 is chosen from a group containing halogen, optionally substituted lower alkoxy group; R7 is one or more substitutes, independently chosen from a group containing hydrogen, optionally substituted lower alkoxy group; where the optional substitute or substitutes when R1-R8 are independently chosen from a group containing halogen, hydroxyl group, lower alkyl, mono- or di(lower)alkylamino group, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono- or di(lower)alkylaminocarbonyl, amino group, carboxyl group, lower alkoxy group, C3-C12cycloalkyl, (lower)alkylcarbonyl, (lower)alkoxycarbonyl, nitrile, aryl; all of which, except halogen, are independently optionally substituted with one or more substitutes, chosen from a group containing halogen, hydroxyl group, lower alkyl, sulfinyl, sulfonyl, sulfanyl, amino group, carboxyl group, lower alkoxy group, carbamoyl. Invention also relates to formula (I'), to a pharmaceutical composition, as well as use of formula (I) compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds, for preventing or treating bone diseases, associated with very low or resorption of calcium.

6 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to compounds of formula I , which are inhibitors of p38 kinase and may be used in medicine, where A represents N or N+O-; R1 represents phenyl or heterocyclyl; R2 represents heterocyclyl; R3 represents H, carbocyclic radical, aryl or heterocyclyl; R4 represents H, Ra, halogen, -ORa', -CN, -CONRa'Ra', -NRa'Ra', -NRa'CORa' or -NRa'CO2Ra; R5 may be connected to any of nitrogens of pyrazole ring of compound in formula I and represents H, alkyl, alkenyl, carbocyclic radical, aryl or heterocyclyl; Ra independently represents alkyl, carbocyclic radical, aryl or heterocyclyl; each Ra' independently represents H or Ra.

EFFECT: preparation of new biologically active compounds.

41 cl, 299 ex, 15 tbl

FIELD: chemistry.

SUBSTANCE: compounds of the invention can be used for treating or preventing diseases and conditions, mediated by peroxisome proliferator activated gamma receptor (PPARγ). In formula (I) W represents a COOH group or -COOC-C1-C4alkyl; Y represents NH; Z represents S or O; X represents O; R1-R6 each independently represents a hydrogen atom or substitute, chosen from a group consisting of: C1-C4-alkyl, thienyl or phenyl, where phenyl is optionally substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, a halogen atom; -NO2 and -CN; A represents C1-C4-alkyl, -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, aryl, chosen from a group consisting of phenyl, naphthyl, or heteroaryl, chosen from a group consisting of oxazolyl, isoxazolyl, thienyl, pyridyl, thiazolyl, thiadiazolyl, benzo[b]thienyl, imidazolyl, indolyl and carbazolyl, where aryl and heteroaryl are substituted or not substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, phenyl and a halogen atom; and n is an integer from 0 to 4. The invention also relates to a pharmaceutical composition, containing the invented compound as an active component, use of the compounds to make a medicinal agent, and method of treatment.

EFFECT: obtaining new biologically active compounds.

22 cl, 6 ex

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