Azole derivatives as lipase and phospholipase inhbitors

FIELD: chemistry.

SUBSTANCE: invention relates to azole derivatives of formula I , where: A denotes S, O; W denotes -(C=O)-; X are identical or different and denote =C(-R)- or =N-; Y denotes -O- or -NR1-; R denotes hydrogen, halogen, (C1-C6)-alkyl, nitro; R1 denotes hydrogen; R2 denotes (C5-C16)-alkyl, (C1-C4)alkyl-phenyl, where phenyl can be optionally mono- or poly-substituted with (C1-C6)-alkyl; R3 denotes hydrogen; or R2 and R3 together with the nitrogen atom bearing them can form a monocyclic saturated 6-member ring system, where separate members of this ring system can be substituted with 1 group selected from the following: -CHR5-, -NR5-; R5 denotes (C1-C6)-alkyl, trifluoromethyl; and physiologically acceptable salts thereof. The invention also pertains to methods of producing said compounds and a medicinal agent based on said compounds.

EFFECT: novel compounds and a medicinal agent based on said compounds are obtained, which can be used as hormone-sensitive lipase (HSL) or endothelial lipase (EL) inhibitors.

12 cl, 11 ex

 

The present invention relates to derivatives of asola General formula I, their pharmaceutically applicable salts and their use as medicinal substances.

In WO 2003/0051842 A2 described compounds for the inhibition gormonchuvstvitelnoy lipase. These compounds include derivatives of benzisoxazole and derivatives benzisothiazole. In WO 2004/058749 described derivatives benzisoxazole for inhibition of kinase-3 glikiencintetaza.

The aim of the present invention is the provision of alternative compounds which have inhibitory effect on gormonchuvstvitelnoy the lipase or endothelial lipase.

The present invention relates to a derivative of asola General formula I,

where

A represents S, O;

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

X are identical or different and represent =C(R)- or =N-;

Y represents-O - or-NR1-;

R represents hydrogen, halogen, (C1-C6)-alkyl, (C1-C3)-alkoxy-(C1-C3-alkylene, hydroxy, (C1-C6)-allylmercaptan, amino, (C1-C6)-alkylamino, di(C2-C12)-alkylamino, mono-(C1-C6-alkylaminocarbonyl, di(C2-C8-alkylaminocarbonyl, COOR4, trifluoromethyl, (C1-C6)-alkylsulfonyl, (C1-C6-alkylsulfonyl, aminosulfonyl, nitro, pentafet sulfanyl, (C6-C10)-aryl, CO-NR2R3, - O-CO-NR2R3,-CO-(C1-C6-alkylene-CO-O-(C1-C6)-alkyl, O-CO-(C1-C6-alkylene-CO-OH,-CO-(C1-C6-alkylene-CO-NR2R3 or unsubstituted or mono - or poly-F-substituted (C1-C6)-alkoxy;

R1 represents hydrogen, (C1-C6)-alkyl, benzyl;

R2 represents a (C5-C16)-alkyl, (C1-C4)-alkyl-(C6-C10)-aryl, where aryl may be optionally monogamist or polygamist halogen, (C1-C6)-alkyl, (C1-C3)-alkoxy, hydroxy, (C1-C6)-allylmercaptan, amino, (C1-C6)-alkylamino, di(C2-C12)-alkylamino, mono-(C1-C6-alkylaminocarbonyl, di(C2-C8-alkylaminocarbonyl, (C1-C6-alkoxycarbonyl, cyano, trifluoromethyl, cryptometrics, (C1-C6-alkylsulfonyl, aminosulfonyl, nitro;

R3 represents hydrogen, (C1-C6)-alkyl; or

R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated or partially unsaturated 4-7 membered ring system or a bicyclic saturated or partially unsaturated 8-14-membered ring system, and individual members of these ring systems may be substituted with 1-3 atoms or atomic groups from the following series: -CHR5-, -CR5R5-, -(C=R5)-, -NR5-, -C(=O)-, -O-, -S-, -SO-, -SO -, provided that 2 units from the series-O-, -S-, -SO-, -SO2- may not be adjacent;

R4 represents hydrogen, (C1-C6)-alkyl, benzyl;

R5 represents a (C1-C6)-alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropyl;

tautomeric forms of these compounds and their physiologically acceptable salts.

Preferred are the compounds of formula I, in which

W is -(C=O)-.

Additionally preferred are the compounds of formula I, in which

W is -(C=O)-;

X are identical or different and represent =C(R)- or =N-;

Y represents-O-, -NR1-;

R represents hydrogen, halogen, (C1-C6)-alkyl, hydroxy, amino, COOR4, trifluoromethyl, (C1-C6)-alkylsulfonyl, nitro, pentafluoroethyl, (C6-C10)-aryl, CO-NR2R3, - O-CO-NR2R3 or-CO- (C1-C6-alkylene-CO-O-(C1-C6)-alkyl;

R1 represents hydrogen, (C1-C6)-alkyl;

R2 represents a (C6-C10)-alkyl, (C1-C3)-alkyl-(C6-C10)-aryl, and aryl optionally may be monogamist or polygamist halogen, (C1-C6)-alkyl, (C1-C3)-alkoxy, hydroxy, amino, (C1-C6)-alkylamino, trifluoromethyl, nitro;

R3 is hydrogen, (C1-C6)-alkyl; or

R2 and R3 together with carrying their atom and the PTA may form a monocyclic saturated 5-6-membered ring system or a bicyclic saturated or partially unsaturated 9-10-membered ring system, and individual members of these ring systems may be substituted with 1-3 atoms or atomic groups from the following series-CHR5-, -CR5R5-, -(C=R5)-, -NR5-, -O-, -S-, provided that 2 units from the series-O-, -S - may not be adjacent;

R4 is hydrogen, (C1-C6)-alkyl, benzyl;

R5 represents a (C1-C6)-alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropyl.

Also preferred are the compounds of formula I, in which

W is -(C=O)-;

X are identical or different and represent =C(R)- or =N-;

Y represents-O-, -NR1-;

R represents hydrogen, halogen, (C1-C6)-alkyl, hydroxy, amino, COOR4, trifluoromethyl, (C1-C6)-alkylsulfonyl, nitro, pentafluoroethyl, (C6-C10)-aryl, CO-NR2R3, - O-CO-NR2R3 or-CO-(C1-C6-alkylene-CO-O-(C1-C6)-alkyl, (C1-C6)-alkoxy;

R1 is hydrogen, (C1-C6)-alkyl;

R2 represents a (C6-C10)-alkyl, (C1-C3)-alkyl-(C6-C10)-aryl, and aryl optionally may be monogamist or polygamist halogen, (C1-C6)-alkyl, (C1-C3)-alkoxy, hydroxy, amino, (C1-C6)-alkylamino, trifluoromethyl, nitro;

R3 is hydrogen, (C1-C6)-alkyl; or

R2 and R3 together with carrying their nitrogen atom can form monocyclic will stifle saturated 5-6-membered ring system or a bicyclic saturated or partially unsaturated 9-10-membered ring system, and individual members of these ring systems may be substituted with 1-3 atoms or atomic groups from the following series-CHR5-, -CR5R5-, -(C=R5)-, -NR5-, -O-, -S-, provided that 2 units from the series-O-, -S - may not be adjacent;

R4 is hydrogen, (C1-C6)-alkyl, benzyl;

R5 represents a (C1-C6)-alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropyl.

Particularly preferred compounds of formula I is the compound in which

W is -(C=O)-;

X are identical or different and represent =C(R)- or =N-;

Y represents-O-;

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

R2 represents a (C6-C10)-alkyl or benzyl, and benzyl optionally may be substituted with halogen, (C1-C6)-alkyl or trifluoromethyl;

R3 is hydrogen, (C1-C6)-alkyl; or

R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated 5-6-membered ring system, and the individual members of this ring system may be substituted with 1-2 atoms or atomic groups from the series-CHR5-, -NR5-; and

R5 represents a (C1-C6)-alkyl or cyclopropyl.

Additional particularly preferred embodiment are the compounds of formula I, in which

W is -(C=O)-;

X are identifying the governmental or different and represent =C(R)- or =N-;

Y is-O-;

R represents hydrogen, halogen, nitro, hydroxy, (C1-C3)-alkoxy or (C1-C6)-alkyl;

R2 represents a (C6-C10)-alkyl or benzyl, and benzyl optionally may be substituted with halogen, (C1-C6)-alkyl or trifluoromethyl;

R3 is hydrogen; or

R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated 5-6-membered ring system, and the individual members of this ring system may be substituted with 1-2 atoms or atomic groups from the series-CHR5-, -NR5-; and

R5 represents a (C1-C6)-alkyl, trifluoromethyl or cyclopropyl.

Another particularly preferred embodiment are the compounds of formula I, in which

W is -(C=O)-;

X are identical or different and represent =C(R)- or =N-;

Y is-NR1-;

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

R1 is hydrogen, (C1-C6)-alkyl;

R2 represents a (C6-C10)-alkyl or benzyl, the benzyl optionally may be substituted with halogen, (C1-C6)-alkyl or trifluoromethyl;

R3 is hydrogen, (C1-C6)-alkyl; or

R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated 5-6-membered ring system which, and individual members of this ring system may be substituted with 1-2 atoms or atomic groups from the series-CHR5-, -NR5-; and

R5 represents a (C1-C6)-alkyl or cyclopropyl.

Additional particularly preferred embodiment are the compounds of formula I, in which

W is -(C=O)-;

X are identical or different and represent =C(R)- or =N-;

Y represents-NR1-;

R represents hydrogen, halogen, nitro, hydroxy, (C1-C3)-alkoxy or (C1-C6)-alkyl;

R1 is hydrogen, (C1-C6)-alkyl;

R2 represents a (C6-C10)-alkyl or benzyl, the benzyl optionally may be substituted with halogen, (C1-C6)-alkyl or trifluoromethyl;

R3 is hydrogen; or

R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated 5-6-membered ring system, and the individual members of this ring system may be substituted with 1-2 atoms or atomic groups from the series-CHR5-,-NR5-; and

R5 represents a (C1-C6)-alkyl, trifluoromethyl or cyclopropyl.

In one embodiment of the present invention A in the compounds of the formula I is O.

In another embodiment of the present invention A in the compounds of the formula I is S.

In an additional embodiment, the present image is etenia Y in the compounds of the formula I is O.

In an additional embodiment, the present invention Y in the compounds of the formula I is NR1 and R1 may have the above values.

Especially preferred are the compounds of formula I, in which

NR2R3 represents piperidine, 4-th position contains an atomic group CHR5.

Additionally preferred are the compounds of formula I, in which X are identical or different and represent from =C(-R).

Additionally preferred are the compounds of formula I, in which X are identical or different and represent =C(R)- or =N -, provided that one of X necessarily represents =N-.

Also preferred are the compounds of formula I, in which X in position 4, 5 and 6 are identical or different and represent =C(R)in position 7 represents =N-.

Additionally preferred are the compounds of formula I, in which X in position 4, 5 and 7 is =C(-R), and R is hydrogen, and at position 6 R is not hydrogen.

Additionally preferred are the compounds of formula I, in which

X in position 4 and 5 is =C(-R), and R is hydrogen, and at position 6 R is not hydrogen.

The present invention relates to compounds of formula I in the form of their salts, racemates, racemic mixtures and pure Anant is the Windows, and to their diastereomers and their mixtures.

The alkyl radicals in the substituents R, R1, R2, R3, R4, R5 may be straight or branched chain. Halogen represents fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

Under the aryl refers to aromatic carbocyclic mono - or bicyclic ring system containing ring or rings from 6 to 10 atoms.

Heteroaryl is mono - or bicyclic aromatic 5-to 12-membered ring system in which at least one atom in the ring system is a heteroatom from the series N, O and S.

For use in medicine are especially suitable pharmaceutically acceptable salts because of their higher water solubility compared to the parent compounds or basic compounds. These salts must contain a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid additive salts of the compounds of the present invention are salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and organic acid salts, such as, for example, acetic acid, benzolsulfonat acid, benzoic acid, citric, econsultancy, fumaric, gluconic, glycolic, setinova, lactic,lactobionic, maleic, malic, methansulfonate, succinic, p-toluensulfonate acid and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), and salts of alkaline earth metals (such as magnesium salts and calcium), salts of trometamol (2-amino-2-hydroxymethyl-1,3-propandiol), diethanolamine, lysine or Ethylenediamine.

Salts with a pharmaceutically unacceptable anion, such as trifurcation, also included in the scope of the present invention as useful intermediates for obtaining or purification of pharmaceutically acceptable salts, and/or for use in non-therapeutic purposes, for example, for use in vitro.

Used in the present invention the term "physiologically functional derivative" refers to any physiologically acceptable derivative compounds of formula I of the present invention, for example ester, capable, when administered to a mammal, such as man, to form (directly or indirectly) a compound of formula I or its active metabolite.

To physiologically functional derivatives also include prodrugs of the compounds of the present invention, for example, described in the publication of H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can metabolised in vvo in the compounds of the present invention. These prodrugs may themselves be active or inactive.

Compounds of the present invention can also exist in different polymorphic forms, such as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the present invention are included in the scope of the present invention and are a further aspect of the present invention.

Forth elsewhere in this document specified in the description, all references to the above-described connection (connection) of formula I" refers to the compound (compounds) of formula I and its salts, solvate and physiologically functional derivatives.

Application

Compounds of the present invention of General formula I have an extremely strong inhibitory effect on gormonchuvstvitelnoy the lipase HSL (HCL), an allosteric enzyme in adipocytes, which is inhibited by insulin and is responsible for the breakdown of fats in fat cells and thus for the transfer of the fatty components in the blood stream. Inhibition of this enzyme, therefore, equivalent to the insulin-like action of the compounds of the present invention, which, ultimately, leads to a decrease in the content of free fatty acids in the blood, and blood glucose. In this regard, they can be used in metabolic disorders, e.g. the measures such as non-insulin dependent diabetes mellitus, diabetic syndrome, and direct damage to the pancreas.

Compounds of the present invention of General formula I may additionally possess inhibitory activity on endothelial lipase EL (E). The preferred substrate for ELECTRICITY are high density lipoprotein HDL (HDL), which has protivoateroskleroticheskim activity. Reduced levels of HDL cholesterol leads to atherosclerosis and its complications such as metabolic syndrome and coronary heart disease. Thus, inhibition of E should lead to the prevention of atherosclerotic disorders.

Compounds of the present invention of formula I can also exert an inhibitory effect on trigliceridos.

Additionally it was revealed that the inhibitory activity of the compounds of the present invention of General formula I in comparison with other lipases is selective.

Compounds of this type are particularly suitable for the treatment and/or prophylaxis of the following violations.

1. Disorders of fatty acid metabolism and disorders of glucose utilization.

2. Violations insulin sensitivity of myocytes, adipocytes and hepatocytes (insulin-resistant) - metabolic syndrome.

3. Diabetes, in particular type 2 diabetes, including the prevention of his donkey is jnani.

In this regard, specific aspects are:

- hyperglycemia,

- improvement of insulin resistance,

- improved glucose tolerance,

- protection of β-cells of the pancreas,

- prevention of macro - and microvascular violations.

4. Dyslipidemia and their complications, such as, for example, atherosclerosis, coronary heart disease, cerebrovascular disorders etc, in particular, characterized by one or more of the following factors (however, not limited by these factors):

- high plasma concentrations of triglycerides, high plasma concentrations of triglycerides after a meal

low concentrations of HDL cholesterol

low concentrations of ApoA lipoprotein

- high concentration of cholesterol low-density lipoprotein LDL (LDL)

particle cholesterol low-density lipoprotein (LDL)

- high concentrations of ApoB lipoprotein

5. Various other conditions that may be associated with metabolic syndrome, such as:

- obesity (overweight), including Central obesity type

- thrombosis, hypercoagulable stage and protrombina (arterial and venous)

- high blood pressure

heart disease, for example, in state after myocardial infarction, hypertensive heart disease or cardiomyopathy (butnot limited to the above)

6. Other disorders or conditions, for example, which may mediate inflammatory reactions or cell differentiation include:

- atherosclerosis, such as coronary sclerosis including angina pectoris or myocardial infarction, stroke (but not limited to the above)

- vascular restenosis or reocclusion

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

- pancreatitis

- other inflammatory condition

- retinopathy

- tumors of adipocytes

- carcinoma of adipocytes, such as liposarcoma

- solid tumor and neoplasm, for example carcinoma of the gastrointestinal tract, liver, biliary tract and pancreas, endocrine tumors, carcinomas of the lungs, kidneys and urinary organs, genital tract, prostate cancer, and so on (but not limited to the above)

- acute and chronic myeloproliferative disorders and lymphomas

- angiogenesis

- neurodegenerative diseases

- Alzheimer's disease

multiple sclerosis

- Parkinson's disease

- erythematous-squamous dermatoses such as psoriasis

- common acne

- other skin disorders and dermatological conditions which modulate PPAR

- eczema and neurodermatitis

- dermatitis, for example subarray dermatitis Il is photodermatol

keratitis and keratoses such as sabranie the keratoses, senile keratoses, actinic keratosis, photo-induced keratoses or follicular keratosis

- keloids and prevention of keloids

- warts, including condylomata or genital warts

infection caused by human papilloma virus (HPV), for example, venereal warts, viral warts such as molluscum contagiosum, leukoplakia

- papular dermatoses such as red flat zoster

- skin cancer such as basal cell carcinomas, melanomas or cutaneous T-cell lymphoma

local benign epidermal tumors, for example, keratoderma, epidermal nevus

- frostbite

- high blood pressure

syndrome X

- polycystic ovary syndrome (PCOS)

- asthma

- osteoarthritis

systemic lupus erythematosus (SLE) or inflammatory rheumatic diseases such as rheumatoid arthritis

- vasculitis

- depletion (cachexia)

- gout

- ischemia/reperfusion syndrome

acute respiratory distress syndrome (ARDS)

Drugs

A number of compounds of the present invention required to achieve the desired biological effect depends on a number of factors, such as specific compounds, intended use, spacebefore and clinical condition of the patient. 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 from 3 to 10 mg/kg/day. An intravenous dose may, for example, be in the range from 0.3 mg to 1.0 mg/kg, which can enter the appropriate way in the form of infusions from 10 ng to 100 ng per kilogram per minute. Suitable for this purpose infusion solutions can contain, 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, and the drug single dose, which can be entered orally, 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 above conditions the compounds of formula I can be used in combination as is, however, preferably they are in the form of a pharmaceutical composition with a suitable carrier. The carrier must be acceptable in terms of compatibility with other ingredients of the composition and the lack of harm to the health of the patient. The carrier may be solid or liquid, or to have these and other properties, and with the connection to be prepared preferably in the form of a preparation of a single dose, for example, in the form of pills, which can with what erati from 0.05% to 95% by weight of the active substance. Also it can contain other pharmaceutically active agents, including other compounds of the present invention. The pharmaceutical compositions of the present invention can be obtained in one of the known pharmaceutical methods, essentially consisting in mixing the ingredients with pharmacologically acceptable carriers and/or excipients.

The pharmaceutical compositions of the present invention is a composition suitable for oral, rectal, local, peroral (for example sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, together with the most suitable route of administration in each individual case depends on the nature and severity of the condition being treated and on the nature of the compounds of formula I used in each case. In the scope of the present invention also includes preparations of coating and drugs with a slow release. Preferred drugs are resistant to acids and gastric juice. Suitable coatings resistant to gastric juice, contain acetated cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical preparations for oral administration could the t to be in the form of separate units, for example, such as capsules, sachets, lozenges or tablets, each of which contains a certain amount of the compounds of formula I; as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an emulsion oil-in-water or water-in-oil. As mentioned above, these compositions can be produced by any suitable pharmaceutical method which includes the stage at which contact the active substance and the carrier (which may consist of one or more additional ingredients). Typically, the compositions are obtained by uniform and homogeneous mixing of the active substance with a liquid and/or powdered solid carrier, after which, if necessary, the product shape. Thus, for example, you can make a tablet by compressing or molding a powder or granules of the compound of the present invention optionally with one or more additional ingredients. Molded tablets can be made by on a suitable tabletting machine granular forms of connection, such as a powder or granules, optionally mixing it with a binder, glidant, inert diluent and/or one or more surface-active/dispersing agent (substance). Molded tablets can be made by molded who I am on a suitable machine, the powdered compound, humidified inert liquid diluent.

Pharmaceutical compositions suitable for peroral (sublingual) administration comprise lozenges containing compound of the formula I with flavoring substance, normally sucrose and gum Arabic or tragakant, and lozenges, which contain the compound in an inert basis such as gelatin and glycerol or sucrose and gum Arabic.

Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of the compounds of formula I, which is preferably isotonic to the blood of the intended recipient. These drugs are administered, preferably intravenously, however, the introduction may be by subcutaneous, intramuscular or intradermal injection. These preparations are preferably can be produced by mixing the compound with water and create a sterile solution that is isotonic to the blood. Compositions for injection of the present invention usually contain from 0.1 to 5% by weight of active compound.

Pharmaceutical compositions suitable for rectal administration, preferably have the form of suppositories with a single dose. They can be produced by mixing the compounds of formula I with one or more conventional solid carriers, for example cocoa butter, and come is the form of the mixture.

Pharmaceutical compositions suitable for topical application to the skin, preferably are in the form of ointment, cream, lotion, paste, spray solution, aerosol or oil. As a carrier you can use vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active substance is present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

Percutaneous introduction is also possible. Pharmaceutical compositions suitable for percutaneous applications, can be in the form of individual patches, suitable for prolonged close contact with the epidermis of the patient. These patches contain, respectively, the active substance in an aqueous solution, optionally buffered, 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%. In particular, the active substance may be released by an electricity transmission or iontophoresis, for example, as described in Pharmaceutical Research, 2 (6): 318 (1986).

The compounds of formula I differ a favorable effect on metabolic disorders. They have a positive effect on the metabolism of lipids and glucose, in particular, reduce triglyceride levels, and are suitable for the prevention and treatment of diabetes II of the IPA and arteriosclerosis, as well as their various complications.

Combination with other drugs

Compounds of the present invention can be introduced as such or in combination with one or more of the following pharmacologically active substances, for example, a favorable effect on metabolic disorders or diseases, often associated with them. Such drugs, for example, are:

1) drugs that reduce the levels of blood glucose, anti-diabetic,

2) the active ingredients for the treatment of dyslipidemia,

3) protivoateroskleroticheskim medicines,

4) anti-obesity

5) anti-inflammatory active ingredients,

6) active ingredients for the treatment of malignant tumors,

7) antithrombotic active ingredients

8) active ingredients for the treatment of high blood pressure,

9) active ingredients for the treatment of heart failure and

10) the active ingredients for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.

These funds can be combined with the compounds of formula I of the present invention, in particular for a synergistic improvement effect. Introduction the combination of active substances can be performed by separate introduction of the Aulnay active ingredients, and in the form of combination products, which in one pharmaceutical drug there are several active ingredients.

We can mention the following examples.

Antidiabetics

Suitable antidiabetics are disclosed, for example, in the Rote Liste 2001, Chapter 12, or in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville, 2003. Antidiabetics include all insulin and derivatives of insulin, such as Lantus® (see www.lantus.com or Apidra®, and other fast-acting insulins (see U.S. patent 6221633), modulators of the GLP-1 receptor, such as described in WO 01/04146, or also, for example, antidiabetics, disclosed in WO 98/08871 (Novo Nordisk A/S). Effective for oral administration of hypoglycemic active ingredients preferably include a sulfonylurea, acting on the ATP-dependent potassium channel of beta cells (for example, disclosed in WO 97/26265 and WO 99/03861), biguanides, meglitinide, glucagon antagonists, oral agonists GLP-1, inhibitors of DPP-IV, insulin sensitizers, for example, modulators of PPAR and PXR to define against, and active ingredients, for example, oxadiazolidine preparations, thiazolidinediones, inhibitors of liver enzymes involved in stimulating gluconeogenesis and/or glycogenolysis, modulators of absorption of glucose, for example, glucosidase inhibitors, compounds affecting lipid metabolism the resulting change in the composition of blood lipids, compounds which reduce food intake or digestion.

In one embodiment of the present invention the compounds of formula I is administered in combination with insulin.

In one embodiment of the present invention the compounds of formula I is administered in combination with substances that affect the glucose production in the liver, for example, inhibitors of glycogen phosphorylase (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922, WO 03/104188).

In one embodiment, the compounds of formula I is administered in combination with an active ingredient acting on the ATP-dependent potassium channel of the beta cells, such as sulfonylureas (e.g. tolbutamide, glibenclamide, glipizide, glimepiride) or glinide (for example, Repaglinide).

In one embodiment, the compounds of formula I is administered in combination with biguanides, such as Metformin.

In one embodiment, the compounds of formula I is administered in combination with an agonist of PPAR-gamma or thiazolidinediones, such as ciglitazone, pioglitazone, rosiglitazone, or with the compounds disclosed in 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 embodiment, the compounds of formula I is administered in combination with a DPPIV inhibitor, as described in WO98/19998, WO99/61431, WO99/67278, WO99/67279, WO01/72290, WO02/38541, WO03/04014, in particular, in combination with 93/01 P (1-cyclopentyl-3-methyl-1-oxo-2-pentamine chloride), P-31/98, LAF237 (1-[2-[3-gidroksilamin-1 ylamino)acetyl]pyrrolidin-2(S)-carbonitrile), TS021 ((2S,4S)-4-fluoro-1-[[(2-hydroxy-1,1-dimethylethyl)amino]acetyl]pyrrolidin-2-carbonitrile monopersulfate).

In one embodiment, the compounds of formula I is administered in combination with compounds having inhibitory effect on SGLT-1 and/or SGLT-2, for example, as disclosed directly or indirectly in WO2004/007517, WO2004/052902, WO2004/052903 and WO2005/121161.

In one embodiment, the compounds of formula I is administered in combination with inhibitors of α-glucosidase, for example miglitol or acarbose.

In one embodiment, the compounds of formula I 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, and so on

Lipid modulators

In one embodiment of the present invention the compounds of formula I is administered in combination with inhibitors of HMG CoA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, uvastatin, pitavastatin, atorvastatin, rosuvastatin.

In one embodiment, nastoyascheevremya the compounds of formula I is administered in combination with inhibitors of absorption of bile acids (see, for example, US patents 6245744, US 6221897, US 6277831, EP 0683 773, EP 0683 774).

In one embodiment of the present invention the compounds of formula I is administered in combination with a polymeric bile acid adsorbent, for example, cholestyramine, colesevelam.

In one embodiment of the present invention the compounds of formula I is administered in combination with inhibitors of resorbtive cholesterol, as, for example, described in WO 02/50027, or ezetimibe, tiqueside, panaxosides.

In one embodiment, the compounds of formula I of the present invention is administered in combination with an inducer of LDL receptors (see, for example, patent US 6342512).

In one embodiment, the compounds of formula I is administered in combination with fillers, preferably insoluble fillers (see, for example, carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6)); Caromax is carob-containing product of the company Nutrinova, Nutrition Specialties &Food Ingredients GmbH, Industriepark Hoechst, 65926 Frankfurt/Main)). Combination with Caromax® possible in a single drug or by separate administration of compounds of the formula I and Caromax®. This Caromax® can be administered in the form of food, such as bakery products or muesli bars.

In one embodiment, the compounds of formula I of the present invention is administered in combination with an agonist of PPAR-alpha

In one embodiment of the present invention the compounds of formula I is administered in combination with a mixture of agonists, PPAR alpha/gamma, such as 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 as described in 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 embodiment of the present invention the compounds of formula I is administered in combination with fibrates, for example, fenofibrate, gemfibrozil, clofibrate, bezafibrat.

In one embodiment of the present invention the compounds of formula I is administered in combination with nicotinic acid or Niacin.

In one embodiment of the present invention the compounds of formula I is administered in combination with a CETP inhibitor, for example with CP-529, 414 (torcetrapib).

In one embodiment of the present invention the compounds of formula I is administered in combination with an ACAT inhibitor.

In one embodiment of the present invention the compounds of formula I is administered in combination with an MTP inhibitor, for example implitapide.

In one embodiment of the present invention the compounds of formula I is administered in combination with an antioxidant.

In one embodiment, to implement the Oia of the present invention the compounds of formula I is administered in combination with an inhibitor of lipoprotein lipase.

In one embodiment of the present invention the compounds of formula I is administered in combination with an inhibitor of ATP-citrate-LiAZ.

In one embodiment of the present invention the compounds of formula I is administered in combination with an inhibitor of squalene synthetase.

In one embodiment of the present invention the compounds of formula I is administered in combination with an antagonist of lipoprotein (a).

Anti-obesity

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

In one embodiment, the additional active ingredient is fenfluramine or dexfenfluramin. In another embodiment, the additional active ingredient is sibutramine.

In an additional embodiment, the compounds of formula I is administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice, Asakawa A, et al., M.: Hormones and Metabolie Research (2001), 33(9), 554-558), NPY antagonists, for example, hydrochloride {4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amide naphthalen-1-sulfonic acid (CGP 71 683A)), MC4 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]amide]-1-amino-1,2,3,4-tetrahydronaphthalen-2-carboxylic what Islami; (WO 01/91752)), antagonists of orexin (for example, 1-(2-methylbenzothiazol-6-yl)-3-[1,5]naphthiridine-4-yl-urea; hydrochloride (SB-334867-A)), H3 agonists (salt of oxalic acid, 3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-yl)propan-1-she (WO 00/63208)); TNF agonist, CRF antagonists (e.g., [2-methyl-9-(2,4,6-trimetilfenil)-9H-1,3,9-diazafluoren-4-yl]dipropylamine (WO 00/66585)antagonists, CRF BP (for example, urocortin)agonists urocortin, β3 agonists (e.g., 1-(4-chloro-3-methysulfonylmethane)-2-[2-(2,3-dimethyl-1H-indole-6-yloxy)ethylamino]ethanol; hydrochloride (WO 01/83451)agonist MSH (melanocyte-stimulating hormone)agonists, CCK-A (for example, triptorelin {2-[4-(4-chloro-2,5-acid)-5-(2-cyclohexylethyl)thiazol-2-ylcarbonyl]-5,7-dimethylindole-1-yl}acetic acid (WO 99/15525)); inhibitors of serotonin reuptake (e.g., dexfenfluramin), with mixed serotoninergicheskie and noradrenaline compounds (for example, WO 00/71549), 5HT agonists, for example, a salt of oxalic acid 1-(3-ethylbenzophenone-7-yl)piperazine (WO 01/09111)agonists bombezin, antagonists Galanina, growth hormone (e.g. human growth hormone), compounds which release growth hormone (tert-butyl ester 6-benzyloxy-1-(2-diisopropylaminoethanol)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (WO 01/85695)), with TRH (see, for example, EP 0462 884)modulator uncoupling protein 2 or 3, 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), c DA agonists (bromocriptin, depressin), with inhibitors of lipase/amylase (for example, WO 00/40569)modulate PPAR (for example, WO 00/78312), RXR-modulators and agonists TR-β.

In one embodiment of the present invention, the additional active ingredient is leptin.

In one embodiment, the additional active ingredient is dexamfetamine, amphetamine, mazindol or phentermine.

In one embodiment, the additional active ingredient is one or more antidiabetics, hypoglycemic active ingredients, inhibitors of HMGCoA-reductase, inhibitors of cholesterol absorption, agonists of PPAR-gamma agonists of PPAR-alpha agonists of PPAR-alpha/gamma, fibrates, MTP inhibitors, inhibitors of absorption of bile acids, CETP inhibitors, polymeric bile acid adsorbents, inductors LDL-receptors, ACAT inhibitors, antioxidants, inhibitors of lipoprotein lipase, inhibitors of ATP-citrate-LiAZ, inhibitors of squalene synthetase, antagonists of lipoprotein(a), lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, preparations of thiazolidinediones, α-glucosidase, active ingredients acting on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, agonists orexin, H3 agonists, TNF agonists, CRF antagonists, antagonists of CRF BP, agonists urocortin, β3-agonists, agonists, MSH (melanocyte-stimulating hormone), CCK agonists, inhibitors of serotonin reuptake, mixed serotoninergicheskih and noradrenalina compounds, 5HT-agonists, agonists of bombezin, antagonists Galanina, growth hormones compounds, releasing growth hormone, TRH agonists, modulators of uncoupling protein 2 or 3, leptin agonists, DA agonists (bromocriptin, depressin), inhibitors of lipase/amylase, modulators of PPAR, RXR modulators or TR-β - agonists or amphetamines.

In one embodiment, the compounds of formula I is administered in combination with drugs acting on the coronary circulation and the vascular system, such as ACE inhibitors (e.g. ramipril), drugs acting on the renin-angiotensin system, calcium antagonists, beta-blockers, and so on

In one embodiment, the compounds of formula I is administered in combination with drugs that have anti-inflammatory effect.

In one embodiment, the compounds of formula I is administered in combination with drugs is mi, used for the treatment of cancer and prevent cancer.

Assume that every suitable combination of the compounds of the present invention with one or more of the above-mentioned compounds and optionally with one or more other pharmacologically effective substances is in the field of protection of the present invention.

The effectiveness of the compounds of formula I of the present invention were tested in the following enzyme systems analysis:

1. The study of inhibition HCL

1.1. Preparation of partially purified HCL.

Isolated fat cells of rats were obtained from the adipose tissue of the epididymis testis of male rats (Wistar breed, 220-250 g), not treated, by treatment with collagenase according to published methods (e.g., Nilsson S et al., Anal. Biochem. 158, 1986, 399-407; G. Fredrikson et al., J. Biol. Chem. 256, 1981, 6311-6320; H. Tornquist et al., J. Biol. Chem. 251, 1976, 813-819). Fat cells from 10 rats were washed three times by flotation, each time with 50 ml of homogenization buffer (25 ml Tris/HCl, pH of 7.4, 0.25 M sucrose, 1 mm ethylenediaminetetraacetic acid EDTA, 1 mm dithiothreitol (DTT), 10 μg/ml leupeptin, 10 μg/ml of anesthetic, 20 μg/ml of pepstatin) and eventually was placed in 10 ml of homogenization buffer. The fat cells are homogenized in the homogenizer Teflon-in-glass (Braun-Melsungen) in 10 receptions at 1500 rpm. in min and 15°C. Homogenized centrifuged (probe the Kah Sorvall SM24, at 5000 rpm. in minutes, for 10 minutes at 4°C). Remove supernatant between the layer of fat on top and the sediment, and repeated centrifugation. Then the resulting supernatant centrifuged (in test tubes Sorvall SM24, with about 20000. in minutes, for 45 minutes at 4°C). The supernatant was removed and added to 1 g of heparin-sepharose (Pharmacia-Biotech, CL-6B, washed 5 times with 25 mm Tris/HCl, pH 7,4, 150 mm NaCl). After incubation at 4°C for 60 minutes with shaking at intervals of 15 minutes), the mixture was centrifuged (in test tubes Sorvall SM24, at 3000 rpm. in minutes, for 10 minutes at 4°C). the pH of the supernatant was brought to 5.2 by adding glacial acetic acid and incubated for 30 minutes at 4°C. Precipitates were collected by centrifugation (Sorvall SS34, at 12000 rpm. in minutes, for 10 minutes at 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/analgesic substances. The suspension is dialyzed over night at 4°C against 25 mm Tris/HCl, pH of 7.4, 50% glycerol, 1 mm DTT, 10 μg/ml leupeptin, pepstatin, analgesic substances and then loaded in hydroxyappatite column (0.1 g in 1 ml of suspension, balanced potassium phosphate, 10 mm, pH 7.0, 30% glycerol, 1 mm DTT). The column was washed with 4 volumes of equilibrating buffer at a flow rate of 20 to 30 ml/h HCL was suirable one volume equilibrating buffer containing the th 0.5 M potassium phosphate, then dialyzed (see above) and through the ultrafiltration was carried out by 5-10-fold concentration (filter Amicon Diaflo PM 10) at 4°C. the Partially purified HCL you can save 4 to 6 weeks at a temperature of -70°C.

1.2. Research activity HCL.

To obtain the substrate was mixed 25-50 MX [3H]triological (in toluene), 6.8 mmol of its triological and 0.6 mg of phospholipids (phosphatidylcholine/phosphatidylinositol in the ratio of weight to volume (V/o) 3:1), dried with N2and then placed in 2 ml of 0.1 M KPi (pH 7.0) by ultrasonic treatment (Branson 250, microtip, installing, 1-2, 2 times × 1 minute, with 1 minute interval). After adding 1 ml of KPi and re ultrasonic treatment (4 times for 30 seconds on ice for 30 seconds) was added 1 ml of 20% bovine serum albumin BSA (KPi) (final concentration of triological 1.7 mm). For the reaction of 100 μl of substrate solution was Ngapali in 100 μl of solution HCL (HCL prepared as described above was diluted in 20 mm Kpi, pH 7.0, 1 mm EDTA, 1 m DTT, 0.02% of bovine serum albumin BSA, 20 μg/ml of pepstatin, 10 μg/ml leupeptin) and incubated for 30 minutes at 37°C. After the addition of 3.25 ml of methanol/chloroform/heptane (10:9:7) and 1.05 ml of 0.1 M K2CO3, 0.1 M boric acid (pH of 10.5) carried out a thorough mixing and the final centrifugation (800 × g, for 20 minutes). After divided the phase I deleted one equivalent of the upper phase (1 ml) and radioactivity was determined by measuring the scintillation fluid.

1.3. Evaluation of inhibitory effect of HCL.

Usually the substances tested in 4 independent mixtures. Inhibition of enzyme activity HCL the test substance was determined by comparison with a control reaction without inhibition. The values of the 50% inhibitory concentration (IC50thought along the curve of inhibition, with at least 10 concentrations of test substance. Data analysis used the software package GRAPHIT, Elsevier-BIOSOFT.

2. The study of inhibition E.

2.1. Obtaining E.

Recombinant cell lines (CHO, HEK293) cell culture medium (conditioned medium) free E as a secretory protein at high concentration. After concentration it is used as the enzyme solution.

2.2. Research activity E.

Phospholipase-specific substrate 1,2-bis(4,4-debtor-5,7-dimethyl-4-Bora-3a,4a-diaza-s-indocin-3-undecanoyl)-sn-glycero-3-phosphocholine (manufactured by Molecular Probes) is used to characterize the enzymatic activity of endothelial lipase and actions of inhibitors. Hydrolysis of A1-ester bonds of phospholipids by the enzyme releases the fluorescent dye Bodipy, which can be detected after separation by thin-layer chromatography HPTLC plate (silica gel 60, Merck) or directly by changing the value of fluorescence in the reaction vessel.

Prepare the substrate solution, taking 100 mcg of 1,2-bis(4,4-debtor-5,7-dimethyl-4-Bora-3a,4a-diaza-s-indocin-3-undecanoyl)-sn-glycero-3-phosphocholine (manufactured by Molecular Probes), 2.4 mg tripalmitin (Sigma) and 7.9 mg DOP-choline (1,2-dioleoyl-sn-glycero-3-phosphocholine) 393 μl of chloroform, and the subsequent transfer 157 μl in a clean reaction vessel. After evaporation of the solvent liquid mixture is dissolved in 4 ml of 200 mm TRIS-HCl, 150 mm sodium chloride, pH 7,4, by double treatment with ultrasound. Subsequent enzymatic reaction occurs within 60 minutes at 37°C. For this purpose, 45 μl of the substrate solution is incubated with 1 μl of inhibitor suitable concentration (dissolved in DMSO, to control use pure DMSO solution) and 5 μl of enzyme solution (conditioned medium). Then 3 μl of the tested mixture is placed on a HPTLC plate (silica gel 60, Merck) and the released fluorescent dye allocate to determine using elution solvent (diethyl ether: petroleum ether: acetic acid [78:22:1]). After evaporation of the eluent, the plate is read in the scanner for fluorescence detection. Increased release of fluorescent dye in the reaction of inhibition should be considered a measure of the enzymatic activity.

2.3. Evaluation of inhibitory effect of EL.

Depending on the concentration of the inhibitor is reduced fermentati the activity, when this IC50denotes the concentration of inhibitor at which there is half of the maximum enzyme activity.

In these studies, the compounds of the above examples showed the following values IC50:

ExampleIC50[µm] HCLIC50[μm] E
10,12
20,12
30,1
40,1
50,1
714,6
814,6
100,67
110,26

Ways to get

Obtaining compounds of General formula I of the present is subramania carried out, essentially, by known methods, for example, by acylation of substituted or unsubstituted azoles II carbamylcholine III (method A), or by 2-stage interaction Isola II with phosgene or equivalents, such as trichloromethyl chlorocarbonate, dichloromethyl carbonate or 4-nitrophenyl chloroformate and additional reactions derived analkarneval acid with amines IV (method B). For compounds in which R3 is hydrogen (formula Ia), azoles II can also react with the appropriate isocyanates V R2-N=C=O (method C).

Because these reactions are typically exempt acid, it is recommended to add a base, such as pyridine, triethylamine, sodium hydroxide or carbonates of alkali metals. The reaction can be carried out in a wide temperature ranges. It is shown that it is generally preferable to operate at the temperature of the used solvent in the range from 0°C to the boiling point. Examples of the used solvents are methylene chloride, tetrahydrofuran THF, dimethylphthalate DMF, toluene, ethyl acetate, n-heptane, dioxane, diethyl ether or pyridine. When applying anhydrous conditions also proved the suitability of strong bases, such as lithium hydride, sodium hydride or a tertiary piperonyl potassium, in suitable solvents such as THF or E Is F.

The azoles used as starting compounds II or the corresponding Aza-substituted derivatives are commercially available or possible to manufacture by known literature methods (for example, K., Bowden, G. Crank, W, J. Roos, J.Chem.Soc. 1968, 172-185; T. Chiyoda, K. Iida, K. Takatori, M. Kajiwara, Synlett 2000, 10, 1427-1428; M.A. Khan, F.K. Rafla, J.Chem.Soc. 1975, 693-694).

Below detailed examples serve to illustrate the present invention without restricting its scope.

EXAMPLES

Example 1:

6 chlorobenzo[d]isoxazol-3-yl 4-methylpiperidin-1-carboxylate

200 mg (1.18 mmol) of 6-chlorobenzo[d]isoxazol-3-ol, to 228.7 mg (1,41 mmol) 4-methylpiperidin-1-carbonylchloride and 164 μl (2.36 mmol) of triethylamine were dissolved in 10 ml of pyridine and stirred at room temperature for 24 hours. The reaction mixture was concentrated, the residue was dissolved in water and was extracted with ethyl acetate. The organic fraction was concentrated and was purified preparative HPLC (PR18, acetonitrile/water, 0.1% of triperoxonane acid (TFA). The output was: 147 mg (42%), M+H+: 295,2.

Example 2:

Isoxazole[5,4-b]pyridine-3-yl 4-methylpiperidin-1-carboxylate

125 mg (0,918 mmol) isoxazole[5,4-b]pyridine-3-ol, 178 mg (1.1 mmol) 4-methylpiperidin-1-carbonylchloride and 255 ál (of 1.84 mmol) of triethylamine were dissolved in 10 ml of pyridine and stirred for 4 hours at room temperature Additionally dobavlaet 89 mg (0.55 mmol) of 4-methylpiperidin-1-carbonylchloride and 128 μl (to 0.92 mmol) of triethylamine and continued stirring for 6 hours at room temperature. The reaction mixture was given concerts, the residue was dissolved in water and was extracted with ethyl acetate. The organic fraction was given concerts and was purified preparative HPLC (PR18, acetonitrile/water with 0.1% TFA). The output was: 101 mg (42%), M+H+: 262,1.

Example 3:

6 chlorobenzo[d]isoxazol-3-yl 4-triftormetilfosfinov-1-carboxylate

Spent a reaction analogous to example 1, 200 mg (1.18 mmol) of 6-chlorobenzo[d]isoxazol-3-ol was subjected to interaction with 305 mg (1,41 mmol) 4-triftormetilfosfinov-1-carbonylchloride. Output: 229 mg (56%), M+H+: 349,05.

Example 4:

Isothiazol[5,4-b]pyridine-3-yl 4-methylpiperidin-1-carboxylate

Spent a reaction analogous to example 1, in which 60 mg (0.4 mmol) isothiazol[5,4-b]pyridine-3-she was subjected to interaction with 76 mg (0.47 mmol) of 4-methylpiperidin-1-carbonylchloride. Yield: 29 mg (27%), M+H+: 278,13.

Example 5:

Benzo[d]isothiazol-3 - yl 4-methylpiperidin-1-carboxylate

Spent a reaction analogous to example 1, in which 45 mg (0.3 mmol) benzo[d]isothiazol-3-one was subjected to interaction with 58 mg (0.36 mmol) of 4-methylpiperidin-1-carbonylchloride. Yield: 26 mg (32%), M+H +: 277,14.

Example 6:

1-hexyl-3-(5-nitrobenzo[d]isothiazol-3-yl)urea

100 mg (0,513 mmol) 5-nitrobenzo[d]isothiazol-3-ylamine suspended in 5 ml of THF. After addition of 78.1 mg (0.61 mmol) of 1-isocyanates the mixture was stirred at room temperature (RT) during the course is 2 hours and at 70°C for 2 hours. Then added addition of 0.3 mmol of a solution of 1-isocyanates and stirring was continued for 6 hours at 70°C. the Reaction mixture was given concerts, the residue was dissolved in water and was extracted with ethyl acetate. The organic fraction was given concerts and was purified preparative HPLC (PR18, acetonitrile/water with 0.1% TFA). Yield: 18 mg (11%), M+H+: 323,15.

Example 7:

1-(2-methylbenzyl)-3-(5-nitrobenzo[d]isothiazol-3-yl)urea

Spent a reaction similar to example 6, in which 100 mg (0.51 mmol) of 5-nitrobenzo[d]isothiazol-3-ylamine were subjected to interaction from 90.4 mg (0.61 mmol) of 1-isocyanatomethyl-2-methylbenzoate. Yield: 11 mg (6%), M+H+: 343,16.

Example 8:

1-benzo[d]isoxazol-3-yl-3-sexymachine

Spent a reaction similar to example 6, in which 100 mg (0.75 mmol) benzo[d]isoxazol-3-ylamine were subjected to interaction with 114 mg (0.89 mmol) of 1-isocyanates. Yield: 27 mg (14%), M+H+: 262,15.

Example 9:

Isothiazole[5,4-b]pyridine-3-yl 4-triftormetilfosfinov-1-carboxylate

Spent a reaction analogous to example 1, in which 2,99 g (9,82 mmol) isothiazole[5,4-b]pyridine-3-ol was subjected to interaction with 2,33 g (10,81 mmol) 4-triftormetilfosfinov-1-carbonylchloride. Yield: 1.3 g (40%), M+H+: 332,09.

Example 10:

6-chlorzoxazone[5,4-b]pyridine-3-yl 4-methylpiperidin-1-carboxylate

Spent a reaction analogous to example 1, in which 55 mg (0.32 mmol) of 6-chloris xazole[5,4-b]pyridine-3-ol was subjected to interaction with 62.7 mg (0,39 mmol) 4-methylpiperidin-1-carbonylchloride. Yield: 22 mg (24%), M+H+: 296,04.

Example 11:

6-methylisoxazole[5,4-b]pyridine-3-yl 4-methylpiperidin-1-carboxylate

Spent a reaction analogous to example 1, in which 140 mg (0,93 mmol) 6-methylisoxazole[5,4-b]pyridine-3-ol was subjected to interaction with 181 mg (1.12 mmol) of 4-methylpiperidin-1-carbonylchloride. Yield: 135 mg (53%), M+H+: 276,10.

1. The compound of the formula I

in which a represents S, O;
W is -(C=O)-;
X are identical or different and represent =C(R)- or =N-;
Y represents-O - or-NR1-;
R represents hydrogen, halogen, (C1-C6)-alkyl, nitro;
R1 represents hydrogen;
R2 represents a (C5-C16)-alkyl, (C1-C4)-alkyl-phenyl, where phenyl may be optionally mono - or polygamist (C1-C6)-alkyl;
R3 represents hydrogen; or
R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated 6-membered ring system, with individual members of this ring system may be substituted with 1 group from the following range: -CHR5-, -NR5-;
R5 represents a (C1-C6)-alkyl, trifluoromethyl;
and its physiologically acceptable salt.

2. The compound of formula I according to claim 1, where
W is -(C=O)-;
X are identical or different and represent =C(R)- or =N-;
Y represents-O-, -NR1-;
R represents hydrogen, halo is Yong, (C1-C6)-alkyl, nitro;
R1 represents hydrogen;
R2 represents a (C6-C10)-alkyl, (C1-C3)-alkyl-phenyl, and phenyl optionally may be mono - or polygamist (C1-C6)-alkyl;
R3 is hydrogen; or
R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated 6-membered ring system, with individual members of this ring system may be substituted with 1 group from the following range: -CHR5-, -NR5-;
R5 represents a (C1-C6)-alkyl, trifluoromethyl.

3. The compound of formula I according to claim 1 or 2, where
W is -(C=O)-;
X are identical or different and represent =C(R)- or-N-;
Y represents-O-;
R represents hydrogen, halogen, nitro or (C1-C6)-alkyl;
R2 represents a (C6-C10)-alkyl or benzyl, and benzyl optionally may be substituted (C1-C6)-alkyl;
R3 is hydrogen; or
R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated 6-membered ring system, and the individual members of this ring system may be substituted with 1 group of series-CHR5-, -NR5-; and
R5 represents a (C1-C6)-alkyl or trifluoromethyl.

4. The compound of formula I according to claim 1 or 2, where
W is -(C=O)-;
X are identical or different and represent =C(R)- and-N-;
Y is-NR1-;
R represents hydrogen, halogen, nitro or (C1-C6)-alkyl;
R1 is hydrogen;
R2 represents a (C6-C10)-alkyl or benzyl, the benzyl optionally may be substituted (C1-C6)-alkyl;
R3 is hydrogen; or
R2 and R3 together with carrying their nitrogen atom may form a monocyclic saturated 6-membered ring system, and the individual members of this ring system may be substituted with 1 group of series-CHR5-, -NR5-; and
R5 represents a (C1-C6)-alkyl or trifluoromethyl.

5. The compound of formula I according to claim 1 or 2, where
NR2R3 is a piperidine, 4-th position contains an atomic group CHR5.

6. The compound of formula I according to claim 1 or 2, where
X are identical or different and represent =C(R)- or =N -, provided that one X is =N-.

7. The compound of formula I according to claim 1 or 2, where
X are identical or different and represent in position 4, 5 and 6 =C(R)in position 7 represents =N-.

8. The compound of formula I according to claim 1 or 2, where
X are identical or different and represent =C(-R).

9. The compound of formula I according to claim 1 or 2, where
X in position 4 and 5 is =C(-R)-where R is hydrogen, and at position 6 R is not hydrogen.

10. Drug, inhibiting gormonchuvstvitelnoy lipase (GCL) or endothelial what ipsu (E), containing one or more compounds of the formula I according to claims 1-9.

11. The method of obtaining compounds of General formula I according to claims 1 to 9, which includes:
a) acylation of azoles of the formula II carbamylcholine formula III;
or
b) interaction of azoles of the formula II in two stages, first with phosgene or equivalents, such as trichloromethylcarbonate, detrioration or 4-nitrophenylphosphate, and in the second stage - with amines of the formula IV, in which the substituents have the above values.

12. The method of obtaining compounds of General formula I, where R3 is hydrogen (formula Ia), according to claims 1 to 9, including the interaction of azoles of the formula II with an isocyanate of the formula V:O=C=N-R2.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel sulphonamidethiazole pyrimidine derivatives of formula (I)

, which are glucokinase activators or to their enantiomers, mixture of enantiomers or pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on the novel compounds, use of the compounds to prepare a medicinal agent and to a method of activating glucokinase. In formula (I) R1 denotes (C1-C10)alkoxy, R2 denotes (C3-C6)cycloalkyl, R3 denotes hydrogen, and values of substitutes R4 and R5 are given in the formula of invention.

EFFECT: more effective use of the compounds.

33 cl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to derivatives of 5,7-disubstituted [1,3]thiazolo[4,5-d]pyrimidine-2(3H)-one of formula (I) where R1 represents CH3 or CH3CH2; R2 represents H, 3-CN, 2-CF3, 2-F, 3-F, 3-CF3, 3-CONH2 or SO2CH3; R3 represents H; R4 represents H or CH3; and R5 represents H; or, when R4 represents CH3, R5 represents H or F; and to its pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition exhibiting properties of CX3CR1 receptor antagonist containing compound (I) of formula or its pharmaceutically acceptable salt mixed with a pharmaceutically acceptable diluent or carrier.

EFFECT: enabled administration of the derivatives of 5,7-disubstituted [1,3]thiazolo[4,5-d]pyrimidine-2(3H)-one as selective CX3CR1 receptor antagonists.

13 cl, 1 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-cyclohexylaminomethylthiazole[3,2-a]benzimidazole dihydrochloride of formula I: , having immunotropic and anti-aggregation activity.

EFFECT: novel compounds have useful biological properties.

2 cl, 8 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds which possess inhibiting properties with respect to PI3-kinase of general formula (1), where R1 is selected from group, including -NHRC, -NHC(O)Rc, -NHC(O)ORc, -NHC(O)NRcRc and -NHC(O)SRc, R2 stands for residue, optionally substituted with one or two substituents R4, selected from group, including C1-C6alkyl, C3-C8cycloalkyl, 5-6-member heterocycloalkyl with one heteroatom, selected from nitrogen and sulphur, phenyl, benzyl and 5-6-member heteroaryl, including 1-2 nitrogen atoms, R3 stands for optionally substituted with one or several substituents Re and/or Rf residue, selected from group, including phenyl and 5-6-member heteroaryl with 1-3 heteroatoms, selected from nitrogen and oxygen, R4 represents residue, selected from group, including Ra, Rb, and substituted with one or several identical or different substituents Rc and/or Rb , Ra in each case is independently selected from group, including C1-C6alkyl, phenyl, 4-7-member heterocycloalkyl with 1-2 heteroatoms, selected from nitrogen and oxygen, and 9-member heteroaryl with one atom of nitrogen as heteroatom, Rb in each case is independently selected from group, including =O, -ORc, -NRCRC, halogen, -CF3, -CN, -S(O)Rc, -C(O)Rc, -C(O)ORc, -C(O)NRcRc, -C(O)N(Rg)NRcRc, -N(Rg)C(O)Rc, -N(Rg)S(O)2Rc, -N(Rg)S(O)2NRcRc, -N(Rg)C(O)ORc and -N(Rg)C(O)NRcRc, RC in each case independently represents hydrogen or optionally substituted with one or two identical or different substituents R and/or Re residue, selected from group, including C1-C6alkyl, C3-C8cycloalkyl, C6-C9aryl, 4-7-member heterocycloalkyl with 1-2 heteroatoms, selected from nitrogen and oxygen, and 5-6-member heteroaryl with 1-2 heteroatoms, selected from nitrogen, oxygen and sulphur, Rd in each case independently represents hydrogen or optionally substituted with one or two identical or different substituents Re and/or Rf residue, selected from group, including C1-C6alkyl, C3-C8cycloalkyl, phenyl, 4-7-member heterocycloalkyl with 1-2 heteroatoms, selected from nitrogen and oxygen, and 5-10-member heteroaryl with one atom of nitrogen, Re in each case is independently selected from group, including =O, -ORf, -SRf, -NRfRf, -CN, -S(O)2Rf, -C(O)Rf, -C(O)ORf, -C(O)NRfRf and -OC(O)Rf, Rf in each case independently represents hydrogen or optionally substituted with one or two identical or different substituents Rg residue, selected from group, including C1-C6alkyl, C3-C8cycloalkyl, phenyl, 4-7-member heterocycloalkyl with 1-2 heteroatoms, selected from nitrogen and oxygen and 5-6-member heteroaryl with one heteroatom, selected from nitrogen and sulphur, Rg in each case independently represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl and 4-7-member heterocycloalkyl with one nitrogen as heteroatom, as well as to their pharmaceutically harmless acid-additive salts. Invention also relates to compounds, used as intermediate products of synthesis of formula (I) compounds, pharmaceutical composition and application of compounds for preparation of medication, possessing properties of PI3-kinase inhibitor.

EFFECT: elaborated are novel compounds, which possess properties of PI3-kinase inhibitor.

11 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) and formula (II), their tautomers and pharmaceutically acceptable salts. In formula (I) and in formula (II), X - S; R1 - H; R2 - NR5R6; R3 - 5-6-member heteroaryl with 1 heteroatom, selected from N and S, or phenyl, optionally substituted with one or two substituents, selected from halogen, amino, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-halogenalkyl and C1-C6-halogenalkoxy; R4 - H, C1-C6 alkyl, C1-C6 alkoxy or XR3, where X and R3 are determined above; R5 - H; R6 - H; L - N or CR7, where R7 - H; M - S. Invention also relates to pharmaceutical composition, containing as active component invention compound, to method of inhibiting activity of caseinkinase lε and to method of obtaining compounds of formula (I) or formula (II).

EFFECT: compounds of claimed invention possess properties of casein kinase lε inhibitors.

13 cl, 5 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel acylsulfonamide peri-substituted condensed bicyclic compounds of general formula (I), values of radicals are given in invention formula. Also described is pharmaceutical composition based on formula (I) compound.

EFFECT: compounds can be used for inhibition of prostaglandin E2 binding with receptor EP3.

30 cl, 371 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat diseases mediated by the nicotinic acetylcholine receptor, such as derangement of memory. In general formulae , and A is an indazolyl, benzothiazolyl or isobenzothiazolyl group which corresponds to structural formulae a) to c) respectively or X is O; R1 is H, F, Cl, Br, I, cycloalkyl containing 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; ; R2 is H; R3 is H; R4 is H, F, Cl, Br, I, cycloalkyl which contains 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; R5 is H; Ar is an aryl group containing 6 carbon atoms which is unsubstituted or substituted once or several times with halogen; and Het is a 5- or 6-member heteroaromatic group containing a heteroatom in the ring which is selected from N, O and S, or a 6-member saturated heterocyclic group which contains a heteroatom in the ring which is selected from N and O; and their pharmaceutically acceptable salts, where, if the said compound has formula I, the indazolyl group of group A is bonded through its 3rd, 4th or 7th position, the benzothiazole group of group A is bonded through the 4th or 7th position, the isobenzothiazole group of group A is bonded through the 3rd, 4th or 7th position.

EFFECT: obtaining compounds with properties of nicotinic acetylcholine receptor (nAChR) ligands, and pharmaceutical compositions based on the said compounds.

53 cl, 95 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: described is a bromohydrate of 4-methoxy-7,7-dimethyl-9-(5'-carboxyamyl)amino-6H-7,8-dihydropyrimido-(4,5-b)-1,4-benzthiazine (hereinafter methiazine) and a method for synthesis of the said compound. Methiazine has anti-tumour and anti-reductase activity, which has cytostatic and cytotoxic effect which inhibits synthesis of nucleic acids and can be used in medicine. Bromohydrate of 4-methoxy-7,7-dimethyl-9-(5'-carboxyamyl)amino-6H-7,8-dihydropyrimido-(4,5-b)-1,4-benzthiazine of formula I , is obtained by reacting dimedone with ω-amino caproic acid in a medium of boiling isopropanol to obtain enamine-ketone which is subjected to bromation with bromosuccinimide with further treatment with 4-methoxy-5-amino-6-mercaptopyrimidine in a medium of boiling isopropanol.

EFFECT: improved method.

2 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of tetrahydrobenzoxazines

in which substitute R1 denotes a hydrocarbyl residue having 1-3000 carbon atoms, and substitutes R2, R3, R4 and R5 independently denote hydrogen atoms, hydroxyl groups or hydrocarbyl residues, having 1-3000 carbon atoms, respectively, and in which substitutes R3 and R4 or R4 and R5 with a partial structure -O-CH2-NR7-CH2-, bonded to the benzene ring, can also form a second tetrahydrooxazine ring, where R7 denotes hydrocarbyl residues having 1-3000 carbon atoms, provided that at least one of substitutes R1, R2, R3, R4, R5 or R7 are polyisobutenyl, having 3000 carbon atoms and the rest of the substitutes from the group R1, R2, R3, R4, R5 or R7, if they denote hydrocarbyl residues, have 1-20 carbon atoms, respectively, as anti-oxidants for stabilising mineral oil and fuel products against the effect of light, oxygen and heat. The invention also describes jet fuel and jet fuel additive concentrate containing tetrahydrobenzoxazine of formula (I).

EFFECT: preparation of stabilisers having improved stabilisation of nonliving organic material, particularly jet fuel against the effect of light, oxygen and heat.

9 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of compounds of formula (A), where R1 denotes halogen, C1-C6halogenalkyl, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2 denotes halogen, C1-C4alkyl or C1-C4alkoxy; R3 and R4 independently denote a branched C3-C6alkyl; and R5 denotes C3-C12cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanoylamino(C1-C6)alkyl, HO(O)C-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)-(C1-C6)alkyl, or their pharmaceutically acceptable salts which have renin inhibiting activity, as well as to basic intermediate compounds obtained during steps for synthesis of the desired compounds and to methods for synthesis of said intermediate compounds.

EFFECT: alternative synthesis method.

43 cl, 8 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula pharmaceutically acceptable salts thereof, where ---- independently denotes a single or double bond; ring Q is imidazole, triazole (for example 1,2,3-triazole or 1,3,4-triazole), tetrazole or oxadiazole; B denotes C(R7)(R8) or C(R7), where if the bond between B and Y is a single bond, B denotes C(R7)(R8), and when the bond between B and Y is a double bond, B denotes C(R7); Y denotes C(R7), C(R7)(R8) or O, where if the bond between B and Y is a single bond, Y denotes C(R7)(R8) or O, and when the bond between B and Y is a double bond, B denotes C(R7); Z1 denotes -CH2-, -(CH2)2-, -CH2CH-CH3-, where Z1 is bonded on the left side to a nitrogen atom or -(CH2)3-; X denotes C(R1) or N; A denotes quinolyl, quinazolinyl or benzofuranyl, any of which is optionally substituted with 1-4 substitutes, which can be identical or different and are selected from a group comprising halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C(O)N(R3)(R4), 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; when R is present, each independently denotes halogen, C1-6-alkyl; each R1 denotes hydrogen or methyl; each R2 denotes cyano, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -C(NOR5)R6, -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6, 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; R3 and R4 independently denote hydrogen; C1-6-alkyl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3 and R4 are bonded to the same nitrogen atom, they, together with the nitrogen atom, they form a 4-, 5- or 6-member ring which optionally contains one extra O atom in the ring; R5 denotes C1-4-alkyl; R6 denotes C3-7-cycloalkyl or C1-6-alkyl; R7 and R8 independently denote hydrogen or C1-6-alkyl; p equals 0, 1 or 2; r equals 0, 1, 2 or 3; s equals 0, 1, 2 or 3. The invention also relates to 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide, 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}imidazo-[1,5-a]quinoline-3-carboxamide, dihydrochloride 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide, 7-methyl-6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide, to use of the compound in any of claims 1-16, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, having 5-HT1 receptor mediated activity.

23 cl, 195 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of a compound of formula , where R1 is an alkyl or aryl group, or a pharmaceutically acceptable salt or solvate thereof, including hydrate, involving reaction of a compound of formula with a Grignard reagent of formula , where X is a halogen selected from Cl, Br and I, and R1 is an alkyl or aryl group; and optional conversion of the obtained free base compound of formula (I) to a pharmaceutically acceptable salt. The invention also relates to a compound of formula II; a compound of formula , where X is a halogen selected from O, Br and I and to use of formula II and IIIA compounds in synthesis of delmopinol and a derivative of the formula I compound.

EFFECT: novel method for synthesis of a compound of formula I using novel intermediate compounds of formulae II and IIIA.

18 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are derivatives of 5H-pyrazolo[1,5-c][1,3]benzoxasin-5-yl)phenylmethanon of formula , possessing ability to inhibit HIV replication, where values of R1, R2, R3 substitutes are given in invention formula. Also describes is pharmaceutical preparation and application of compound for obtaining medication applied for treatment of conditions associated with HIV infection.

EFFECT: claimed compounds are applicable for prevention or treatment of HIV-produced infection and for AIDS treatment.

15 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I with anti-HIV activity , where R1 represents C1-6(Ar1)alkyl or C1-6(Ar1)oxyalkyl; R2 represents hydrogen or OR14; R3 represents hydrogen, halogen, hydroxyl, cyano, C1-6alkyl, C5-7cycloalkenyl, C1-6halogenalkyl, C1-6alkoxy, C1-6alkylthio, N(R8)(R9), NHAr2, N(R6)COR7, OCON(R8)(R9), OCH2CON(R9)(R9), CO2R6, CON(R8)(R9), SOR7, S(=N)R7, SO2R7, SO2N(R6)(R6), PO(OR6)2, C2-4(R12)alkynyl, R13, Ar2 or Ar3; R4 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R5 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R6 represents hydrogen or C1-6alkyl; R7 represents C1-7alkyl; R8 represents hydrogen or C1-6alkyl; R9 represents hydrogen, C1-6alkyl, C1-6hydroxyalkyl or C1-6(C1-6dialkylamino)alkyl; or N(R8)(R9) taken together represent azetidinyl, pyrrolydinyl, (R10)-piperidinyl, N-(R11)-piperazinyl, morpholinyl or dioxothiazinyl; R10 represents hydrogen; R11 represents hydrogen, C1-6alkyl, COR6 or CO2R6 ; R12 represents hydrogen, hydroxyl, N(R6)(R6), OSO2R7 or dioxothiazinyl; R13 represents dioxothiazinyl; R4 represents hydrogen or C1-6alkyl; Ar1 represents ,,,,,,,,; or Ar2 represents tetrazolyl, triazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, furanyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl or indolyl, and is substituted with 0-2 substitutes selected from a group consisting of halogen, benzyl, C1-6alkyl, C1-6alkoxy, N((R8)(R9), CON(R8)(R9) and CO2R8; Ar3 represents phenyl substituted with 0-2 substitutes selected from a group consisting of halogen, cyano, hydroxy, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)methyl, C1-6halogenalkoxy, N(R8)(R9), CON(R6)(R6) and CH2N(R8)(R9), or represents dioxolanylphenyl; and X-Y-Z represents C(R14)2OC(R14)2C(R14)2, C(R14)2OC(R14)2C(R14)2C(R14)2; or pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition.

EFFECT: bicyclic heterocycles are disclosed, as well as their use HIV integrase inhibitors.

21 cl, 38 dwg, 8 tbl, 282 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrolidine derivatives of general formula (1) or its pharmaceutically acceptable salts where R101 and R102 values are described by the patent claim. The compounds inhibit serotonin and/or norepinephrine and/or dopamine reabsorption thereby allowing to be used for treating depression and anxiety disorder. A method for preparing thereof is described.

EFFECT: preparation of new pyrrolidine derivatives.

10 cl, 162 tbl, 7 ex

Up!