Diarylcycloalkyl derivatives, method of their obtaining, and application as ppar-activators

FIELD: chemistry.

SUBSTANCE: invention concerns a compound of the formula (I) where A ring is (C3-C8)-cycloalkyl or (C3-C8)-cycloalkenyl where two carbon atoms in the cycloalkyl ring can be substituted by oxygen atoms; R1, R2 are H, F, Cl, Br, OH, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl independently from each other; R3 is H or (C1-C6)-alkyl; R4, R5 are H, (C1-C6)-alkyl independently from each other; X is (C1-C6)-alkyl where one carbon atom in the alkyl group can be substituted by oxygen atom; Y is (C1-C6)-alkyl where one carbon atom in the alkyl group can be substituted by oxygen atom; and its pharmaceutically acceptable salts. The invention also concerns such compounds as (+)-cis-2-(3-(2-(4-fluorphenyl)oxazole-4-ylmethoxy)cyclohexyloxymethyl)-6-methylbenzoic acid of the formula 6b , 2-{3-[2-(3-methoxyphenyl)-5-methyloxazole-4-ylmethoxy]cyclohexyl-oxymethyl}-6-methylbenzoic acid of the formula 53 and 2-methyl-6-[3-(5-methyl-2-n-tolyloxazole-4-ylmethoxy)cyclohexylomethyl]benzoic acid of the formula 70 , or their enantiomers. The invention also concerns pharmaceutical composition exhibiting PPARα agonist effect, including one or more compounds of the formula (I) as an active component together with a pharmaceutically acceptable carrier. The pharmaceutical composition is obtained by mixing of active compound of the formula (I) with a pharmaceutically acceptable carrier and rendering it a form viable for introduction.

EFFECT: obtaining of diarylcycloalkyl derivatives applicable as PPAR-activators.

9 cl, 2 tbl, 67 ex

 

The present invention relates to directselling derivatives and to their physiologically acceptable salts and physiologically functional derivatives.

Compounds of similar structure have already been described in the prior art for the treatment of hyperlipidemia and diabetes (PCT/US/00/11490).

The purpose of the present invention is to develop compounds that can be used in therapy as having a triglyceride-lowering action and providing a favorable effect on lipid and carbohydrate metabolism, in particular, for syndromes dyslipidemia, type II diabetes and metabolic syndrome/syndrome X. In particular, the aim of the invention is to provide compounds having improved activity compared with the compounds described in PCT/US14490. This can be achieved, in particular, by activating receptor PPARα.

In accordance with this invention relates to compounds of formula I

in which

ring a represents a (C3-C8-cycloalkyl or (C3-C8)-cycloalkenyl, and in these cycloalkyl or cycloalkenyl the ring one or more carbon atoms may be replaced by oxygen atoms;

R1, R2, R4, R5, independently of one another represent H, F, Cl, Br, OH, NO2, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6 )-alkyl;

R3 represents H or (C1-C6)-alkyl;

X represents (C1-C6)-alkyl, where the alkyl group one or more carbon atoms may be replaced by oxygen atoms;

Y represents a C1-C6)-alkyl, where the alkyl group one or more carbon atoms may be replaced by oxygen atoms;

and their physiologically acceptable salts.

Preference is given to compounds of the formula I, in which

ring A represents A (C3-C8-cycloalkyl or (C3-C8)-cycloalkenyl where cycloalkyl or cycloalkenyl the ring one or more carbon atoms may be replaced by oxygen atoms;

R1, R2, R4, independently of one another represent H, F, Cl, Br, OH, NO2, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl;

R5 represents a (C1-C6)-alkyl;

R3 represents H or (C1-C6)-alkyl;

X represents a C1-C6)-alkyl, where one or more carbon atoms in the alkyl group is replaced by oxygen atoms;

Y represents a C1-C6)-alkyl, where one or more carbon atoms in the alkyl group may be replaced by oxygen atoms;

and their physiologically acceptable salts.

Special preference is given to compounds of the formula I, in which

the ring And made the employed, (C 3-C8-cycloalkyl or (C3-C8)-cycloalkenyl;

R1, R2 independently of one another represent H, F, Cl, Br, OH, NO2, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl;

R3 represents H or (C1-C6)-alkyl;

X represents a C1-C6)-alkyl, where one or more carbon atoms in the alkyl group is replaced by oxygen atoms;

Y represents a C1-C6)-alkyl, where one or more carbon atoms in the alkyl group is replaced by oxygen atoms;

and their physiologically acceptable salts.

Greatest preference is given to compounds of the formula I, having the structure Ia

where

ring a is cyclohexyl;

R1, R2 independently of one another represent H, F, Cl, Br, OH, NO2, CF3, OCF3,(C1-C6)-alkyl or O-(C1-C6)-alkyl;

R3 represents H or (C1-C6)-alkyl;

X represents a C1-C6)-alkyl, where one or more carbon atoms in the alkyl group is replaced by oxygen atoms;

Y represents a C1-C6)-alkyl, where one or more carbon atoms in the alkyl group is replaced by oxygen atoms;

and their physiologically acceptable salts.

This invention covers compounds of formula I in the form of their racemates, the rat is chemical mixtures and pure enantiomers, and, besides, their diastereomers and mixtures of them.

The alkyl radicals in the substituents R1, R2, R3, R4 and R5 may be straight or branched chain.

Pharmaceutically acceptable salts are particularly suitable for use in medical applications due to its greater solubility in water compared to the original or basic compounds. The above salts must be pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable additive salts of acids of the present invention are salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acid salts, such as, for example, acetic acid, benzolsulfonat, benzoic, citric, econsultancy, fumaric, gluconic, glycolic, 2-hydroxyethanesulfonic, lactic, lactobionic, maleic, malic, methansulfonate, succinic, p-toluensulfonate and tartaric acid. Suitable pharmaceutically acceptable base 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 with a pharmaceutically unacceptable anion, such as, for example, triptorelin, also included in the scope of the present invention, the quality of the solid fuel used intermediates to obtain or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic purposes, for example, in in vitro applications.

Used herein, the term "physiologically functional derivative" refers to any physiologically portable derivative compounds of formula I of this invention, for example, complex ether, which is capable, when administered to a mammal, such as, for example, a person, to form (directly or indirectly) a compound of formula I or its active metabolite.

Physiologically functional derivatives also include prodrugs of the compounds of the invention are described, for example, H. Okada et al., in Chem. Pharm. Bull. 1994, 42, 57-61. The aforementioned prodrugs can be transformed in vivo into compounds of the invention. Themselves above prodrugs can be active or not have it.

In addition, the compounds of the invention can exist in different polymorphic forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention are included in the scope of the invention and are a further aspect of the present invention.

All references hereinafter to "the compound(I) of formula I" refers to the compound(s) of formula I, described above, and their salts, solvate and physiologically functional derivatives presented in this description.

The amount of the compounds of formula I, which is necessary to access the e desired biological effect, depends on a number of factors, for example, from specifically selected connection, intended use, method of administration and the clinical condition of the patient. The daily dose is normally in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and per kg 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, which can accordingly be introduced in the form of infusion of 10 ng to 100 ng per kilogram of body weight per minute. Suitable solutions for infusion for these purposes 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 compound. Thus, ampoules for injection may contain, for example, from 1 mg to 100 mg, and the composition for a single dose, which can be introduced orally, such as, for example, tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of treatment of the aforementioned conditions the compounds of formula I can be used as the connection itself, but preferably they are used in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it must be compatible with other ingredients of the composition and do not adversely impact on the health of the patient. Carrier mo is et to be solid or liquid or both and is preferably formulated with the compound as a single dose, for example, in the form of a tablet, which may contain from 0.05 to 95 wt.% active compounds. In addition, there could be other pharmaceutically active agents, including other compounds of formula I. the Pharmaceutical compositions of the invention can be obtained by one of the known pharmaceutical methods, which essentially consist in mixing the active ingredients with pharmacologically acceptable carriers and/or excipients.

The pharmaceutical compositions of the invention are compositions suitable for oral, rectal, local, peroral (for example sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most appropriate method of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compounds of formula I used in each case. Form, coated and forms a slow-release, coated, also not beyond the scope of this invention. Preferred forms, coated, resistant to the action of acids and enzymes of the gastric juice. Suitable coatings resistant to gastric juice, include acetated cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose and the anion is s polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be in the form of a separate (metered) units, such as capsules, pills, 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 excipient; or in the form of an emulsion oil-in-water" or "water in oil". The above compositions can, as already mentioned, to receive any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which may consist of one or more ingredients) is brought into contact. Songs usually get a uniform and homogeneous mixture of the active compound with liquid and/or powdered solid carrier, after which the obtained product is subjected to molding, if required. For example, the tablet can be obtained by compressing or molding a powder or granules of the compound, where appropriate, together with one or more additional ingredients. Molded tablets can be obtained, TableType connection in freely-current form, such as powder or granules, where appropriate, mixed together with a binder, glidant, inert diluent and/or one or more surface is active(s)/dispersant(their) agent(s) in a suitable machine. Molded tablets can be obtained by molding compounds, which is in powder form and which is humidified inert liquid diluent in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual) administration include lozenges, which contain the compound of formula I with a flavoring, normally sucrose and the Arabian gum or tragakant, and lozenges, which comprise the compound in an inert basis such as gelatin and glycerin or sucrose and Arabian gum.

Pharmaceutical compositions suitable for parenteral administration, preferably include sterile aqueous preparations of the compounds of formula I, which are preferably isotonic to the blood of the intended recipient. The above preparations are preferably administered intravenously, although it is also possible introduction via subcutaneous, intramuscular or intradermal injection. These drugs can preferably be obtained by mixing the compound with water and operations, making the resulting solution sterile and isotonic to the blood. Injectable compositions of the invention usually contain from 0.1 to 5 wt.% active connection.

Pharmaceutical compositions suitable for rectal administration, are predpochtitelno in the form of suppositories with a single dose. Suppositories can be obtained by mixing the compounds of formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.

Pharmaceutical compositions suitable for local application to the skin, are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. Carriers that may be used include vaseline, lanoline, polyethylene glycols, alcohols and combinations of two or more of the above substances. The active compound is typically present at a concentration of from 0.1 to 15 wt.% of the total composition, for example, from 0.5 to 2%.

In addition, it is possible transdermal administration. Pharmaceutical compositions suitable for transdermal use, can be in the form of one-off patches that are suitable for dense contact for a long period of time with the epidermis of the patient. Such appropriate patches contain the active compound in the aqueous solution which is buffered, where appropriate, dissolved and/or dispersed in an adhesive or dispersed in the polymer. A suitable concentration of the active compound is from about 1% to 35%, preferably from about 3% to 15%. A special case is the ability to provide active compound to be released using electrotren the port or iontophoresis, described, for example, in Pharmaceutical Research, 2(6): 318 (1986).

In addition, the invention provides a method for producing compounds of formula I, which includes obtaining compounds of formula I, acting in accordance with the reaction scheme below:

With this purpose, the compounds of formula A, where R1, R2, R4 and X have the meanings given above, is subjected to the interaction with NaI in acetone at boiling under reflux for 12-24 hours, receiving compound of formula B.

The connection formulas are subjected to interaction with the compound of the formula where n and m are equal, each, 0-5, receiving the compound of the formula E where R1, R2, R4, m, n and X have the meanings described above. However, as With deprotonated at room temperature in an inert solvent, such as dimethylformamide or tetrahydrofuran, using sodium hydride, and then put together in about 70°C) halide, or (b) the component is first heated with oxide dibutylamine in toluene by distillation of water for several hours and then, the addition of dimethylformamide, cesium fluoride and iodide In turn in E under stirring at room temperature for several hours.

The compound of formula E, using the compound of formula D, in which Y is, as described above, into a compound F, in which R1, R2, R4, R5, X and Y have the values, described above. For the formation of simple essential communication, E deprotonated, for example, in a mixture of dimethylformamide and tetrahydrofuran, using a strong base such as a hydride Na at room temperature, and then alkylate component D, preferably with the addition of the iodide of Na.

The compound of formula F is transformed into the compounds of formula I by hydrolysis of the ester functional group, for example, by heating with potassium hydroxide in alcohol (ethanol, tert-butanol) and releasing the carboxyl group of the formula I by acidification. This carboxyl group conventional methods can be obtained from derivatives of the formula -(C=O)-OR3, where R3 has the meaning described above. The compounds of formula I act favorably on metabolic disorders. They have a positive effect on the metabolism of lipids and sugars and, in particular, reduce the concentration of triglycerides, and they are suitable for the prevention and treatment of type II diabetes and arteriosclerosis.

Connections can be introduced as such, or in combination with one or more additional pharmacologically active substances, for example, act favorably on metabolic disorders, and choose, for example, antidiabetic agents, anti-obesity, anti-hypertension and active compounds for the treatment and/or prevention is IKI complications due to or associated with diabetes.

Particularly suitable additional pharmacologically active substances are:

all antidiabetics mentioned in Chapter 12 Rote Liste 2001. The above remedies can be combined with compounds of the formula I according to the invention, in particular, to improve therapeutic actions of the past due to the manifestation of a synergistic effect. The introduction of combinations of active compounds can be carried out either by separate introduction of active compounds to patients, either in the form of combination products in which many active compounds are present in a single pharmaceutical preparation. A large part of the active compounds listed below were disclosed in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001. Antidiabetics include insulin and derivatives of insulin, such as Lantus® (see www.lantus.com) or HMR 1964, fast-acting insulins (see U.S. patent 6221633), derivatives of GLP-1, such as, for example, derivatives disclosed in international application WO 98/08871 Novo Nordisk A/S, and orally active hypoglycemic active compounds.

Orally active hypoglycemic compounds include, preferably, sulfonylureas, biguanidines, meglitinides, oxadiazolidine preparations, thiazolidinediones, glucosidase inhibitors, antagonist glucagon, agonists of GLP-1, potassium channel openers, such as, for example, openers, disclosed in international applications WO 97/26265 and WO 99/03861 company Novo Nordisk A/S, insulin sensitizers, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, modulators of absorption of glucose, compounds which alter lipid metabolism, such as protivoepidemicheskie active compounds and antilipidemic active compounds, compounds which reduce food intake, PPAR agonists and PXR to define against and active compounds which act on the ATP-dependent potassium channel of the beta cells.

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

In one embodiment of the invention, the compounds of formula I is administered in combination with inhibitors of cholesterol absorption, such as, for example, ezetimib, tiqueside, pemaquid.

In one embodiment of the invention, the compounds of formula I is administered in combination with an agonist of PPAR-gamma, such as, for example, rosiglitazone, pioglitazone, JTT-501, Gl-262570.

In one embodiment of the invention, the compounds of formula I is administered in combination with an agonist of PPAR-alpha, such as, for example, GW 9578, GW 7647.

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

In one embodiment of the invention, the compounds of formula I is administered in combination with an MTP inhibitor such as, for example, implitapide, BMS-201038, R-103757.

In one embodiment of the invention, the compounds of formula I is administered in combination with inhibitors of absorption of bile acids (see, for example, U.S. patent 6245744 or U.S. patent 6221897), such as, for example, HMR 1741.

In one embodiment of the invention, the compounds of formula I is administered in combination with a CETP inhibitor, such as, for example JTT-705.

In one embodiment of the invention, the compounds of formula I is administered in combination with an adsorbent polymeric bile acids, such as, for example, cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of formula I is administered in combination with the inductor of the LDL receptor (LDL) (see U.S. patent 6342512), such as, for example, HMR1171, HMR1586.

In one embodiment of the invention, the compounds of formula I is administered in combination with an ACAT inhibitor, such as, for example, avasimibe.

In one embodiment of the invention, the compounds of formula I is administered in combination with an inhibitor of lipoprotein lipase activity, such as, for example, NO-1886.

In one embodiment of the invention, the compounds of formula I is administered in combination with an inhibitor of ATP-citrate lyase, such as, for example, SB-204990.

In one embodiment of the invention, the compounds of formula I is administered in combination with an inhibitor of squalene synthetase, such as, for example, BMS-188494.

In one embodiment of the invention, the compounds of formula I is administered in combination with an antagonist of lipoprotein(a), such as, for example, CI-1027 or nicotinic acid.

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

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

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

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

In another embodiment, the compounds of formula I is administered in combination is tion with meglitinides, such as, for example, Repaglinide.

In one embodiment, the compounds of formula I is administered in combination with thiazolidinediones, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in international application 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 an inhibitor α-glucosidase, such as, for example, miglitol or acarbose.

In one embodiment, the compounds of formula I is administered in combination with an active compound that acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or Repaglinide.

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, etc

In another 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 a., M.:Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists (e.g., hydrochloride N-{4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}naphthalene-1-sulfonamida (CGP71683A)), MC4 agonists (for example, N-[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]-1-amino-1,2,3,4-tetrahydronaphthalen-2-carboxamide (WO 01/91752)), antagonists of orexin (for example, hydrochloride, 1-(2-methylbenzothiazol-6-yl)-3-[1,5]naphthiridine-4-rocephine (SB-334867-A)), H3 agonists (e.g., salt of oxalic acid, 3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-yl)propan-1-it (WO 00/63208)); TNF agonists, CRF antagonists (e.g., [2-methyl-9-(2,4,6-trimetilfenil)-9H-1,3,9-diazafluoren-4-yl]dipropylamine (WO 00/66585)), antagonists of CRF BP (for example, urocortin), agonists urocortin, agonists β3 (for example, hydrochloride, 1-(4-chloro-3-methysulfonylmethane)-2-[2-(2,3-dimethyl-1H-indole-6-yloxy)ethylamino]ethanol WO 01/83451)), agonists, MSH (melanocyte-stimulating hormone)agonists, CCK-A (e.g., salt triperoxonane acid {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 reuptake of serotonin (e.g., dexfenfluramin), mixed serotoninergic and noradrenergic compounds (e.g., WO 00/71549), 5HT agonists (e.g., salt of oxalic sour the s 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 6-benzyloxy-1-(2-diisopropylaminoethanol)-3,4-dihydro-1H-isoquinoline-2-carboxylate (WO 01/85695)), TRH agonists (see, for example, European patent 0462884), chip off the modulators of 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), DA agonists (parlodel, depressin), inhibitors of lipase/amylase (for example, WO 00/40569), PPAR modulators (for example, WO 00/78312), RXR modulators or agonists TR β.

In one embodiment of the invention, the other active compound is leptin; see, for example, "Perspectives in therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In one embodiment, the other active compound is dexamfetamine or amphetamine.

In one embodiment, the other active compound is fenfluramine or dexfenfluramin.

In another embodiment, the other active compound is sibutramine.

In one embodiment, the other active compound is orlistat.

In one embodiment, the other active compound present is employed, mazindol or phentermine.

In one embodiment, the compounds of formula I is administered in combination with dietary fibre materials, preferably insoluble dietary fiber materials (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 from Nutrinova, Nutrition Specialties &Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt/Main. Combination with Caromax® possible in a single drug or in a separate introduction of the compounds of formula I and Caromax®. In addition, Caromax® may be introduced in the form of food products such as, for example, in bakery products or concentrates muesli.

It is obvious that any suitable combination of the compounds of the invention with one or more of the above-mentioned compounds and optionally one or more other pharmacologically active substances are considered as falling under the protection provided by the present invention.

In addition, this invention relates to the use of compounds of the formula I and their pharmaceutical compositions as ligands for PPAR. Ligands for receptor proliferator peroxisome according to the invention are suitable for use as agonists or antagonists of the receptor PPAR.

Cocktail recipes. is s, activated proliferation peroxisome (PPAR), can be subdivided into three subtypes of PPARα, PPARδ and PPARγ. The above subtypes are encoded by different genes (Motojima, Cell Structure and Function, 18:267-277, 1993). In addition, there are two isotopes of PPARγ: PPARγ1and γ2. These two proteins differ 30 mi amino acids with the terminal NH2group and represent the alternative use of promoters and differences in mRNA splicing (Vidal-Puig, Jiminez, Linan, Lowell, Hamann, Hu, Spiegelman, Flier, Moller, J. Clin. Invest., 97:2553-2561, 1996).

PPAR-modulating biological processes are processes that are modulated by receptors or combinations of receptors that interact with ligands of the receptor PPAR described in this patent. These processes include, for example, the transport of lipids in the plasma and the catabolism of fatty acids, regulation of insulin sensitivity and glucose levels in the blood, in response to hypoglycemia/hyperinsulinism (caused, for example, functional disorders of the beta cells of the pancreas, insulinsecreting tumors and/or autoimmune hypoglycemia due to autoantibodies against insulin, insulin receptor, or autoantibodies that have a stimulating effect on beta-cells of the pancreas), the differentiation of macrophages, leading to the formation of atherosclerotic plaques, the inflammatory reaction is the s, the carcinogenesis, hyperplasia or differentiation of adipocytes.

Obesity is the excessive accumulation of adipose tissue. Recent research in this area has shown that PPARγ plays a Central role in gene expression and differentiation of adipocytes. The excess adipose tissue is associated with the development of serious disorders, such as, for example, non-insulin dependent diabetes mellitus (NIDDM), hypertension, abnormalities in coronary artery disease, hyperlipidemia, obesity and some malignant syndrome. Adipocytes can, through the formation of tumor necrosis factor α (TNFαand other molecules, also have an impact on glucose homeostasis. Non-insulin dependent diabetes mellitus (NIDDM) or type II diabetes is the more common form of diabetes. About 90-95% of patients with hyperglycemia suffer from this form of the disease. That corresponds to NIDDM, then this certainly is the reduced mass of beta cells of the pancreas, a number of different disorders of insulin secretion or decreased sensitivity to insulin tissue. The symptoms of this form of diabetes include fatigue, frequent urination, thirst, blurred vision, frequent infections and slow healing of wounds, diabetic nerve damage and kidney disease.

Resistant to the metabolic effects of insulin is one of the main prisencolinensinainciusol mellitus (NIDDM). Insulin resistance is characterized by decreasing absorption of glucose and the conversion of glucose-sensitive insulin target organs, such as, for example, adipocytes and skeletal muscle, and reduced inhibition of gluconeogenesis in the liver. Functional insulin deficiency and lack of inhibition of gluconeogenesis by insulin in the liver leads to hyperglycemia in a state of starvation. Pancreatic beta cells compensate for insulin resistance increased secretion of insulin. However, the beta cells are unable to maintain this high level of insulin secretion, resulting in glucose-induced insulin secretion decreases, which leads to the deterioration of glucose homeostasis and, ultimately, to the development of overt diabetes. Hyperinsulinemia is also associated with insulin resistance, hypertriglyceridemia, and elevated concentrations of low-density lipoproteins in blood plasma. Insulin resistance and hyperinsulinemia in combination with the above-mentioned metabolic disorders called "syndrome X", and the syndrome X is closely associated with increased risk for development of hypertension and disorders of the coronary arteries.

Metformin is known to the person skilled in the art as a means to treat diabetes in humans (U.S. patent No. 3174901). The main action of Metformin is aimed at reducing the image of the of glucose in the liver. As you know, Troglitazone® operates primarily by improving the ability of skeletal muscle tissue to interact with insulin and absorb glucose. It is known that combination therapy using Metformin and Troglitazone can be used for treating disorders associated with diabetes. (DDT 3:79-88 [in Russian], 1998). It was found that the activators of PPARγin particular, Troglitazone®transform malignant tissue in liposarcoma (fatty tumors) in normal cells (PNAS 96:3951-3956, 1999). In addition, it has been suggested that PPAR activatorsγ may be useful for treatment of tumors of the breast and bowel cancer (PNAS 95:8806-8811, 1998, Nature Medicine 4:1046-1052, 1998).

In addition, activators of PPARγsuch as, for example, Troglitazone®, were also used for the treatment of polycystic ovarian syndrome (PCO). This syndrome, which occurs in women, is characterized by a chronic cessation of ovulation and giperandrogenii. Women with the above syndrome often also suffer from insulin resistance and are at increased risk of developing non-insulin dependent diabetes mellitus (Dunaif, Scott, Finegood, Quintana, Whitcomb, J. Clin. Endocrinol. Metab., 81:3299, 1996). In addition, it was recently revealed that the activators of PPARγ increase the formation of progesterone and inhibit the steroidogeneza in granular cell cultures and, therefore, mo is ut to be applied for the treatment of menopause (U.S. patent No. 5814647, Urban et al., 29 September 1998; B. Lorke et al., Journal of Endocrinology, 159, 429-39, 1998). Menopause is defined as a syndrome of endocrine, somatic and physiological changes that occur in women in the late reproductive phase.

Peroxisomes are cellular organelles involved in the control of redox potential and oxidative stress in the cells, participating in the metabolism of a large number of substrates, such as, for example, hydrogen peroxide. A number of disorders associated with oxidative stress. So, for example, inflammatory response to tissue damage, pathogenesis of emphysema associated with ischemia lesion body (cob), doxorubicin-induced heart damage caused by drug-induced hepatotoxicity, atherosclerosis and liver damage caused by hyperoxia; in each case associated with generation of reactive oxygen free radical and changes the regenerative capacity of the cell. In this regard, it has been suggested that PPAR activatorsα regulate, in particular, redox potential and oxidative stress in cells and can be used to treat the above disorders (Poynter et al., J. Biol. Chem. 273, 32833-41, 1998).

In addition, it was found that agonists of PPARα inhibit NFKB-mediated transcription and thus m is delirous various inflammatory reactions, such as, for example, the enzymatic pathway induced synthases nitric oxide (NOS) and cyclooxygenase-2 (COX-2) (Pineda-Torra, I. et al., 1999, Curr. Opinion in Lipidology, 10, 151-9) and, therefore, can be used for therapeutic intervention in a number of different inflammatory diseases and other pathological conditions (Colville-Nash et al., Journal of Immunology, 161, 978-84, 1998; Staels et al., Nature, 393, 790-3, 1998). Proliferatory peroxisome activate PPAR, which, in turn, act as transcription factors and induce differentiation, cell growth and proliferation peroxisome. It is also assumed that the PPAR activators play a role in hyperplasia and cancerogenesis and alter the enzymatic characteristics of animal cells, such as cells of rodents; however, the above-mentioned activators of PPAR, appears to have only minimal adverse effects on human cells (Green, Biochem. Pharm. 43(3):393, 1992). Activation of PPAR leads to a rapid increase in gamma glutamyltranspeptidase and catalase.

PPARα activated next medium chain fatty acids and long-chain fatty acids and is involved in the stimulation of β-oxidation of fatty acids in tissues such as liver tissue, heart, skeletal muscle and brown adipose tissue. (Issemann and Green, ibid.; Beck et al., Proc. R. Soc. Lond. 247:83-87, 1992; Gottlicher et al., Proc. Natl. Acad. Sci. USA 89:4653-4657, 1992). Pharmacological activators of PPARαsuch as, nab is emer, fenofibrate, clofibrate, gemfibrozil and bezafibrat, are also involved in a significant reduction in triglyceride levels in plasma and significantly low levels of cholesterinspiegel low density, and their use, in particular, for the treatment of hypertriglyceridemia, hyperlipidemia and obesity. It is known that PPARα also involved in inflammatory disorders (Schoonjans, K., Current Opinion in Lipidology, 8, 159-66, 1997).

Human nuclear receptor PPARδ was cloned from a cDNA Bank of human osteosarcoma cells and is fully described in A. Schmidt et al., Molecular Endocrinology, 6:1634-1641 (1992). The content of this article is an integral part of the description of the present patent application by reference. You can specify that in the literature PPARδ also referred to as PPARβ and NUC1, however, each of these names refers to the same receptor. So, in A. Schmidt et al., Molecular Endocrinology, 6:1634-1641, 1992, for example, a receptor called NUC1. PPARδ detected in embryonic and adult tissue of the individual. There are reports that this receptor is involved in regulation of expression of some fat-specific genes and, therefore, plays a role in the process of adipogenesis (Amri, E. et al., J. Biol. Chem. 270, 2367-71, 1995).

It is known that atherosclerotic disorders are caused by a number of factors, such as hypertension, diabetes, low concentrations of high density lipoprotein high the Oh density (HDL) and high concentrations of low-density lipoprotein (LDL). In addition to reducing risk by affecting the concentration of plasma lipids and other risk factors, agonists of PPARα have direct terazosine actions (Frick, M.H. et al., 1997, Circulation 96:2137-2143, de Faire et al., 1997, Cardiovasc. Drugs Ther. 11 Suppl. 1:257-63).

Recently it was found that agonists of PPARδ are useful to increase the level of HDL cholesterol (HDL) and, therefore, can be used for the treatment of atherosclerotic disorders (Leibowitz et al., WO/9728149). Atherosclerotic disorders include vascular disorders, coronary heart disease, cerebrovascular disorders and disorders of the peripheral vessels. Coronary heart disease includes death from coronary heart disease, myocardial infarction and coronary revascularization. Cerebrovascular diseases include ischemic and hemorrhagic infarctions and transient disturbances of cerebral circulation.

Subtypes of PPARγ involved in the activation of the differentiation of adipocytes and play no role in the stimulation of peroxisome proliferation in the liver. Activation of PPARγ promotes the differentiation of adipocytes by activating the expression of adipisicing gene (Lehmann, Moore, Smith-Oliver, Wilkison, Willson, Kliewer, J. Biol. Chem., 270:12953-12956, 1995). DNA sequences of subtypes of PPARγ described in Elbrecht et al., BBRC 224; 431-437 (1996). Although proliferatory peroxisome, including the fibrates and fatty acids, the asset shall demonstrate the transcriptional activity of PPAR, only derivatives of prostaglandin J2such as metabolite arachidonic acid 15-deoxy-Delta12, 14-prostaglandin J2(15d-PGJ2), have been identified as natural ligands specific for a subtype of PPARγ, which is also associated with the preparations of thiazolidinediones. This prostaglandin activates PPARγ-dependent adipogenic, but activates PPARα only at high concentrations (Formann, Tontonoz, Chen, Brun, Spiegelman, Evans, Cell, 83:803-812, 1995; Kliewer, Lenhard, Wilson, Patel, Morris, Lehmann, Cell 83:813-819, 1995). This further indicates that subtypes of PPAR family differ in their pharmacological response to ligands.

Based on this, we can conclude that compounds that activate PPARα or both, PPARα and PPARγmust be effective hypotriglyceridemic medicines that can be used to treat atherosclerosis-associated dyslipidemia, non-insulin dependent diabetes mellitus, syndrome X (Staels, B. et al., Curr. Pharm. Des., 3 (1), 1-4 (1997)) and familial combined hyperlipidemia (FCH). X syndrome is a syndrome that is characterized by an initial insulin resistant stage, which causes hyperinsulinemia, dyslipidemia and reduced glucose tolerance, which can progress in non-insulin-dependent diabetes mellitus (type II diabetes), characterized .FCH characterized by hypercholesterolemia and hypertriglyceridemia from the same patient and the same family.

The present invention relates to compounds of formula I, suitable for modulation of PPAR, and for a number of other pharmaceutical applications.

The compounds of formula I are suitable in particular for the treatment of dyslipidemia, insulin resistance, diabetes type I and type II impaired glucose tolerance, syndrome X, obesity, disorders associated with increased food intake, thrombosis, inflammation, cardiomyopathy and to protect beta-cells and protect against oxidation of fatty acids (see, for example, Jean-Charles Fruchart, Bart Staels and Patrick Duriez: PPARS, Metabolic Disease and Atherosclerosis, Pharmacological Research, Vol.44, No. 5, 2001; Sander Kersten, Beatrice Desvergne & Walter Wahli: Roles of PPARs in health and disease, NATURE, VOL 405, 25 MAY 2000; Ines Pineda Torra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and Bart Staels: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12: 2001, 245-254).

The activity of the compounds was tested as follows:

To analyze the effectiveness of the substances that are associated with human PPARαactivating its agonistic way, use stable transtitional cell line HEK (HEK = human embryo kidney), designated here as "pure cell line of PPARα".

The activity of agonists of PPARα define in the test, which lasts for 3 days:

Pure cell line of PPARα cultured until 80% confluence in DMEM medium (modificirovana is by way of Dulbecco Wednesday Needle) (#41965-039, Life Technologies) with the following additives: 10% cs-FCS (fetal calf serum, #SH-30068.03, Hyclone), antibiotics (0.5 mg/ml zeatin [#R250-01, Invitrogen], 0.5 mg/ml G418 [#10131-019, Life Technologies], 1% solution of penicillin, streptomycin [#15140-031, Life Technologies]) and 2 mm L-glutamine (#25030-032, Life Technologies). The cultivation is carried out in standard bottles for cell culture (# 33111, Becton Dickinson) in the incubator for cell cultures at 37°C and 5% CO2. 80% confluent cells washed once with 30 ml SPR (#14190-094, Life Technologies), treated with 2 ml of trypsin solution (#25300-054, Life Technologies) at 37°C for 2 min, absorb in 5 ml of medium, described above, and calculate the cytometer. After dilution to a concentration of 500,000 cells/ml, in each case, 100,000 cells were seeded in each well of 96-well tiralongo microplate having wells with transparent plastic bottom (#3610, Corning Costar). Tablets incubated in the incubator for cells at 37°C and 5% CO2within 24 hours.

Agonists of PPARαto be tested, dissolved in DMSO (DMSO) at a concentration of 10 mm. This original solution is diluted with DMEM medium free of Phenol red (#21063-029, Life Technologies), to which were added 5% cs-FCS (cs-FCS) (#SH-30068.03, Hyclone), 2 mm L-glutamine (#25030-032, Life Technologies) and antibiotics, as described above under "seeding cells" (zeatin, G418, penicillin and streptomycin).

Due to the test substance usually COI is primarily with 11 different concentrations (10 μm; of 3.3 μm; 1 μm; of 0.33 μm; 0.1 ám; 0,033 μm; 0.01 µm; 0,0033 μm; 0,001 microns; 0,00033 μm and 0.0001 μm). More potent compounds tested in concentration ranges from 1 μm to 10 PM, or from 100 nm to 1 PM. From each well by aspiration remove the pure cell line of PPARαplanted at day 1, and simultaneously, to cells add test substances diluted in the environment. Dilution and addition of substances can be carried out using an automatic device (Beckman Biomek 2000). The final volume of the test substances diluted in medium, 100 μl per well 96-well plate. The concentration of DMSO (DMSO) in the sample is always below 0.1%.about. in order to prevent the cytotoxic effects of solvent.

To demonstrate that the analysis works on every single tablet each tablet add standard agonist of PPARαwhich also dissolve up to 11 different concentrations. Test tablets incubated in the incubator at 37°C and 5% CO2within 24 hours.

Cell receptor PPARαtreated with the test substances are removed from the incubator and frozen at -20°C for 1 hour to improve the lysis of cells. After thawing tablets (thawing at room temperature for at least 30 minutes) in each well contribute pipette 50 ál of buffer 1 (Luc-Screen kit #LS1000, PE BiosystemsTropix) and then transferred in a device for measuring luminescence, equipped with a device for depositing a pipette (Luminoscan Ascent, LabSystems). The reaction luciferase in a device for measuring start making pipette 50 ál of buffer 2 (Luc-Screen kit #LS1000, PE Biosystems Tropix) in each well of 96-well plate. The addition of a buffer in the individual wells are carried out through specific and regular intervals, following the manufacturer's instructions (LabSystems). All samples measured accurately after 16 minutes after adding buffer 2. The measurement time is 10 seconds per sample.

Approximate data obtained by the device for measuring luminescence, exported to a Microsoft Excel file. Curves dependency dose of activity and values EC50calculated using the program XL.Fit in accordance with the manufacturer's instructions (IDBS).

The results for compounds of the formula I according to the invention are given in table I below:

Table I
Example No.PPARα EC50[nm]
I1
II0,3
IV0,3
VII4
X0,5
XIX16
XXIV0,9
XXV13
XXVIII4
XXIX32
XXXII0,97
XXXIV0,82
XXXVI0,62
XXXVIII0,57
XLI0,6
XLIII0,58
XLIV0,93
XLV10
XLVI0,56
XLVII1,1

From table I it follows that the compounds of formula I according to the invention activate the receptor PPARα, thereby carrying out, similar to clinically used fibrates, reducing the concentration of triglycerides in the body (see, for example, J.-Ch. Fruchard et al.: PPARS, Metabolic Disease and Atherosclerosis, Pharmacological Research, Vol.44, No. 5, 2001; S. Kersten et al.: Roles of PPARs in health and disease, NATURE, VOL 405, 25 MAY 2000; I. Pineda et al.: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12: 2001, 245-254).

The following examples serve to illustrate the invention, but in no way limit it. The measured melting temperature or decomposition temperature (TPL) are uncorrected and, in General, depend on the heating rate.

Example I

3-[2-(4-Forfinal)oxazol-4-ylethoxy]cyclohexanol 3

While cooling with ice first, 2.25 g of 80% suspen the AI of sodium hydride and then 5.8 g of 1,3-cyclohexanediol added to a mixture of 50 ml of dimethylformamide and 50 ml of tetrahydrofuran. The mixture was stirred at about 25°C for 3 hours. Then add to 10.5 g of 4-chloromethyl-2-(4-forfinal)oxazole (1), the mixture is heated at 70°C and the progress of the reaction is controlled by thin-layer chromatography. After completion of the reaction the mixture is then poured into a mixture of ice water and extracted with ethyl acetate. The organic phase is separated, dried and concentrated and the residue purified on silica gel flash chromatography (ethyl acetate/n-heptane=1:1). The latter operation results in alcohol 3 in the form of oil. C16H18FNO3(291,33). MS (electrospray ionization, ERIE (ESI)): 292 (M + N+).

Methyl 2-{3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexyloxy)-6-methylbenzoate 5

Under ice cooling 0.3 g suspension (80%) of sodium hydride is introduced into a mixture of 10 ml of dimethylformamide and 20 ml of tetrahydrofuran. Then add 1 g of alcohol 3 in 5 ml of tetrahydrofuran and the mixture is stirred at room temperature for 1 hour. Then add 0.8 g of bromide 4 and the mixture is stirred at room temperature when TLC control within 3-5 hours up until the transformation is essentially complete. The mixture is then poured into a mixture of ice water and neodnokratno extracted with ethyl acetate, the organic phase is washed with a small amount of water, dried over sodium sulfate and concentrated under reduced pressure, and the OST is OK purify by chromatography on silica gel (ethyl acetate:n-heptane=1:2). Get methyl ester 5 in the form of oil.

With26H28FNO5(453,52) MS (ERIE): 454 (M + N+).

2-{3-[2-(4-Forfinal)oxazol-4-ylethoxy]cyclohexyloxy}-6-methylbenzoic acid 6

2 g of ester 5 refluxed in 150 ml of tert-butanol and 24 ml of 50% aqueous solution of potassium hydroxide for 6 hours. 4/5 butanol is removed under reduced pressure and the mixture diluted with water and acidified under cooling with ice. The product is extracted with dichloromethane, dried over sodium sulfate and concentrated under reduced pressure, receiving, filtering of the residue through silica gel (CH2Cl2/MeOH=20:1), acid 6. C25H26FNO5(432,42) MS (ERIE): 433 (M + N+).

Example II

2-(4-Forfinal)-4-iodotyrosine 2

At 120°31 g (123 mmol) of p-fermentated and 33 g (123 mmol) of 1,3-dichloroacetone stirred in the absence of solvent for 2 hours. After cooling to room temperature the product is dissolved in 250 ml of ethyl acetate. The resulting solution was diluted with 400 ml n-heptane and washed 3 times with saturated solution of NaCl. The organic phase is filtered through 250 ml of silica gel and then a layer of residue on the filter was washed with 200 ml of a mixture of n-heptane/ethyl acetate (4:1). The solvent is distilled off, getting 4-CHL is metil-2-(4-forfinal)oxazol 1 in the form of a crude product. The obtained product is dissolved in 650 ml of acetone and then added to 90 g of NaI. The mixture is then refluxed for 16 hours, then a large part of the solvent is removed and the solid residue suspended in 200 ml of a mixture of n-heptane/ethyl acetate (1:1) and filtered through 200 ml of silica gel. The precipitate was washed with 500 ml of a mixture of n-heptane/ethyl acetate (1:1) and the organic phase is concentrated. When the concentration of iodide 2 begins to crystallize in the form of white crystals. TLC (n-heptane/ethyl acetate (6:1) Rf=0,4 to 2 and Rf=0,35 1. C10H7FINO (303,08) MS (ERIE): 304 (M + N+).

10.8 g (br93.1 mmol) of CIS/TRANS-1,3-cyclohexanediol and 15.4 g (61,8 mmol) oxide dibutylamine heated in 800 ml of toluene by distillation of water for 5 hours. 400 ml of toluene is distilled off and then the mixture allow to cool to room temperature and then sequentially add 280 ml of anhydrous DMF, 15 g (x 49.5 mmol) 2 and 12.7 g (80,1 mmol) of dry CsF. The heterogeneous mixture was stirred at room temperature for 20 hours (TLC monitoring of the original substance 2). Add 200 ml of ethyl acetate and the mixture is washed three times with saturated solution of NaCl. The organic phase is filtered through 150 ml of silica gel and concentrated. After adding a mixture of n-heptane/ethyl acetate (6:1) residue crystallizes. Additional recrystallization from a mixture of n-grams is ptan/ethyl acetate gives the product 3A (a mixture of CIS-enantiomers). A mixture of TRANS-enantiomers 3b is obtained from the mother liquor after concentration and chromatography. TLC n-heptane/ethyl acetate (1:1). Rf3a (CIS)=0,2, Rf3b (TRANS)=0,3. C16H18FNO3(291,33) MS (ERIE): 292 (M + N+).

A pair of enantiomers 3A is shared by chiral HPLC. First eluted programalso (+)-enantiomer (+)3A, and then levogyrate (-)-enantiomer (-)3A (Chiralpak AD 250 x 4,6; acetonitrile/methanol (9:1)).

The absolute stereochemistry was established by x-ray diffraction analysis of esters of camphor acid separate diastereomers 3.

Methyl CIS-2-(3-(2-(4-forfinal)oxazol-4-ylethoxy)cyclohexylmethyl)-6-methylbenzoate 5b

1,05 g (3.6 mmol) of (-)3A, 1.3 g (5.4 mmol) of 4 and 130 mg of KI dissolved in 12 ml of anhydrous DMF. Add 140 mg (5.7 mmol) of 95% NaH, and the mixture is then stirred at room temperature for 1 hour. In order to achieve higher output relative to the original substance (-)3A, 2 more times, add the same number 4 and NaH and the mixture, in each case, stirred for 1 hour. Then the mixture was kept over night. The reaction solution was diluted with 150 ml ethyl acetate and poured into 50 ml of water. The mixture was washed 2 more times with NaCl solution and then the organic phase is filtered through silica gel and concentrated, and the residue purified flash chromatography (n-heptane/ethyl acetate, 11). This gives 5b as a colorless amorphous solid. TLC n-heptane-ethyl acetate (1:1). Rf=0,5. C26H28FNO5(453,52) MS (ERIE): 454 (M + N+).

(+)-CIS-2-(3-(2-(4-Forfinal)oxazol-4-ylethoxy)cyclohexylmethyl)-6-methylbenzoic acid 6b

of 4.2 g (9.2 mmol) of 5b was dissolved in 120 ml of tert-BuOH. Add 50 ml of 50% aqueous KOH and the mixture is then boiled at 100°C for 24 hours. For processing of the mixture allow to cool and then diluted with 100 ml of ethyl acetate. The aqueous phase is slightly acidified by addition of 2N aqueous HCl and extracted 2 more times with 100 ml of ethyl acetate. The organic phase is dried over MgSO4, filtered and concentrated and the residue purified flash chromatography (methylene chloride/methanol/concentrated ammonia, 30/5/1). This gives 6b in the form of a white amorphous solid. TLC (methylene chloride/methanol/concentrated ammonia, 30/5/1). Rf=0,3. Recrystallization from toluene. C25H26FNO5(432,42) MS (ERIE): 433 (M + N+).

Example III

(-)-CIS-2-{3-[2-(4-Forfinal)oxazol-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 6A

(+)3A and methyl 2-methyl bromide-6-methylbenzoate 4 give, analogously to example 1, the product 6A molecular weight 432,42 (C25H26FNO5); MS (ERIE): 433 (M + N+).

Example IV

CIS-2-(3-(2-(4-Methoxyphenyl)oxazol-4-ylethoxy)cyclohexylmethyl)-6-methylbenzoic acid 7b

170 mg (0,39 mmol) 6b heated in 4 ml 5,6M solution of NaOMe/MeOH at an oil bath temperature of 120°C for 20 hours. Add ethyl acetate and 2N HCl and the mixture is then subjected to processing similar to the synthesis of 6b. This gives 7b as a colorless amorphous solid. TLC: (methylene chloride/methanol/ concentrated ammonia, 30/5/1). Rf˜ 0,3. C26H29NO6(451,52) MS (ERIE): 452 (M + N+).

Similarly, 6A gives stereoisomeric 7a:

TLC: (methylene chloride/methanol/concentrated ammonia, 30/5/1). Rf˜ 0,3. C26H29NO6(451,52) MS (ERIE): 452 (M + N+).

Example V (11a) and Example VI (11b)

CIS-3-(2-Phenyloxazol-4-ylethoxy)cyclohexanol 12A,b

1,3-Cyclohexanediol and 4-iodomethyl-2-phenyloxazol give the racemate 12 molecular weight 273,33 (C16H19NO3); MS (ERIE): 274 (M + N+).

The enantiomers separated by HPLC on a chiral column. First elute (+)-enantiomer 12A, then (-)-enantiomer 12b (Chiralpak OD 250 x 4,6; n-heptane:ethanol:acetonitrile =110:2:1 + 0,05% triperoxonane acid).

Methyl CIS-2-methyl-6-[3-(2-phenyloxazol-4-ylethoxy)cyclohexylmethyl]benzoate 13A

12A and methyl 2-methyl bromide-6-methylbenzoate give 13A molecular weight 435,52 (C26H29NO5); MS (ERIE): 436 (M + N+).

Methyl CIS-2-methyl-6-[3-(2-phenyloxazol-4-ylethoxy)cyclohexylmethyl]benzoate 13b

12b and methyl 2-methyl bromide-6-methylbenzoate give 13b molecular weight 435,52 (C26H29NO5); MS(ERIE): 436 (M + N+).

CIS-2-Methyl-6-[3-(2-phenyloxazol-4-ylethoxy)cyclohexylmethyl]benzoic acid 11a

Hydrolysis 13A gives 11a molecular weight 421,50 (C25H27NO5); MS (ERIE): 422 (M + N+).

CIS-2-Methyl-6-[3-(2-phenyloxazol-4-ylethoxy)cyclohexylmethyl]benzoic acid 11b

Similarly, 13b 11b gives the molecular weight 421,50 (C25H27NO5); MS(ERIE): 422 (M + N+).

Example VII (14a) and Example VIII (14b)

CIS-3-(2-p-Tolyloxy-4-ylethoxy)cyclohexanol 15A,b

Cyclohexanediol and 4-iodomethyl-2-p-tolyloxy give the racemate 15 molecular weight 287,36 (C17H21NO3); MS(ERIE): 288 (M + N+).

The separation of enantiomers is carried out, using HPLC on a chiral column. First eluted (+)-enantiomer 15A, and then (-)-enantiomer 15b (Chiralpak OD h,6; n-heptane:ethanol:

acetonitrile=110:5:1 + 0,05% triperoxonane acid).

Methyl CIS-2-methyl-6-[3-(2-p-collocato the-4-ylethoxy)cyclohexylmethyl]benzoate 16A

15A and methyl 2-methyl bromide-6-methylbenzoate give 16A molecular weight 449,55 (C27H31NO5); MS(ERIE): 450 (M + N+).

Methyl CIS-2-methyl-6-[3-(2-p-tolyloxy-4-ylethoxy)cyclohexylmethyl]benzoate 16b

15b and methyl 2-methyl bromide-6-methylbenzoate give 16b molecular weight 449,55 (C27H31NO5); MS(ERIE): 450 (M + N+).

CIS-2-Methyl-6-[3-(2-p-tolyloxy-4-ylethoxy)cyclohexylmethyl]benzoic acid 14a

16A gives 14a molecular weight 435,52 (C26H29NO5); MS(ERIE): 436 (M + N+).

CIS-2-Methyl-6-[3-(2-p-tolyloxy-4-ylethoxy)cyclohexylmethyl]benzoic acid 14b

16b gives the desired product molecular weight 435,52 (C26H29NO5); MS(ERIE): 436 (M + N+).

Example IX (17a) and the Example X (17b)

CIS-3-[2-(4-Forfinal)-5-methoxazole-4-ylethoxy]cyclohexanol 18a,b

Cyclohexanediol and 2-(4-forfinal)-4-iodomethyl-5-methoxazole give the racemate 18 molecular weight 305,35 (C17H20FNO3); MS(ERIE): 306 (M + N+). Enantiomers shared by HPLC on a chiral column. First eluted (+)-enantiomer 18a, and then (-)-enantiomer 18b (Chiralpak OD h,6; n-heptane:ethanol:acetonitrile=110:2:1 + 0,05% triperoxonane acid).

Methyl CIS-2-{3-[2-(4-fluoro who enyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic 19a

18a and methyl 2-methyl bromide-6-methylbenzoate give 19a molecular weight 467,54 (C27H30FNO5); MS(ERIE): 468 (M + N+).

Methyl CIS-2-{3-[2-(4-forfinal)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic 19b

18b and methyl 2-methyl bromide-6-methylbenzoate give 19b molecular weight 467,54 (C27H30FNO5); MS(ERIE): 468 (M + N+).

CIS-2-(3-[2-(4-Forfinal)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 17A

Hydrolysis 19a gives 17A molecular weight 453,52 (C26H28FNO5); MS(ERIE): 454 (M + N+).

CIS-2-(3-[2-(4-Forfinal)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 17b

Similarly, 19b 17b gives the molecular weight 453,52 (C26H28FNO5); MS(ERIE): 454 (M + N+).

Example XI (20) and Example XII (21)

Ethyl 5-methyl bromide-2-methylbenzoate 22

ethyl 2-methyl bromide-5-methylbenzoate 23

A solution of 3.5 g of ethyl 2,5-dimethylbenzoic and 3.15 g of N-bromosuccinimide and 100 ml of carbon tetrachloride for 3 hours, refluxed and irradiated with votolimpo 300 watts. The precipitate is filtered off and the filtrate is concentrated chromatographic on silica gel. This gives a mixture of approximately 2:3 (22:3) regioisomeric of benzylbromide 22 and 23 molecular weight 257,13 (C 11H13BrO2); MS(ERI+): 257 (M + N+).

The racemic ethyl CIS-5-{3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexyloxy}-2-methylbenzoate 24 and ethyl racemic CIS-2-{3-[2-(4-forfinal)-oxazol-4-ylethoxy]cyclohexylmethyl}-5-methylbenzoate 25

When 0°With a solution of 150 mg of racemic CIS-3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexanol 3A in 0.5 ml of dimethylformamide is added dropwise to a suspension of 40 mg of sodium hydride (55-65% in paraffin oil) in 1 ml of dimethylformamide. After the evolution of gas added 198 mg of a mixture (2:3) ethyl 5-methyl bromide-2-methylbenzoate 22 and ethyl 2-methyl bromide-5-methylbenzoate 23. After 30 minutes at 0°the mixture is left to react for a further 1 hour at room temperature. The mixture was poured into a solution of ammonium chloride and extracted twice MTBE. The extracts are dried over magnesium sulfate, filtered and concentrated using a rotary evaporator, and the product is then purified by chromatography on silica gel (mobile phase: n-heptane/ethyl acetate 3:1). Chromatography gives more quickly eluruumis product - ethyl racemic CIS-2-{3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexylmethyl}-5-methylbenzoate 25 molecular weight 467,54 (C27H30FNO5); MS(ERI+): 468 (M + N+).

In addition, isolated product, eluruumis later, racemic ethyl CIS-5-{3-2-(4-forfinal)oxazol-4-ylethoxy]cyclohexyloxy}-2-methylbenzoate 24 molecular weight 467,54 (C 27H30FNO5); MS(ERI+): 468 (M + N+).

Racemic CIS-5-{3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexyloxy}-2-methylbenzoic acid 20

A suspension of 47 mg of racemic ethyl CIS-5-{3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexyloxy}-2-methylbenzoate 24, 2 ml of 1,1-dimethylethanol and 50% (wt./wt.) potassium hydroxide is heated at 85°C (oil bath) for 2 hours. the pH was adjusted to 3 using dilute hydrochloric acid, and the mixture is extracted twice MTBE. The extracts are dried over magnesium sulfate, filtered and concentrated on a rotary evaporator and the product is then purified by chromatography. Chromatography gives the product 20 molecular weight 439,49 (C25H26FNO5); MS(ERI+): 440 (M + N+).

Similarly, 20:

Racemic CIS-2-{3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexylmethyl}-5-methylbenzoic acid 21 is obtained from the racemic ethyl CIS-2-{3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexylmethyl}-5-methylbenzoate 25.

Example XIII

Racemic TRANS-2-{3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 26

Racemic TRANS-3b and methyl 2-methyl bromide-6-methylbenzoate give the product 26 molecular weight 439,49 (C25H26FNO5); MS(ERIE): 440 (M + N+).

Example XIV

5-(2-(4-Forfinal)oxazol-4-ileocecal)-1,3-dioxane-5-ylmethanol 28

1.0 g (6.7 mmol) of 5-hydroxymethyl-1,3-dioxane-5-ylmethanol and 0.5 g (16.5 mmol) of compound 2 was dissolved in 20 ml of anhydrous DMF. Add 300 mg of 55% NaH in paraffin oil and the mixture is then stirred at room temperature for 1 hour. Treatment is carried out analogously to the synthesis of compound 5b. This gives 28 in the form of a white amorphous solid. TLC (n-heptane/ethyl acetate 1:2). Rf=0,4. With16H18FNO5(323,33) MS: 324,2 (M + N+).

Methyl 2-{5-[2-(4-forfinal)oxazol-4-ileocecal]-1,3-dioxane-5-ileocecal}-6-methylbenzoic 29

The connection 29 to receive a similar synthesis of compound 5b of 28 and 4.

2-{5-[2-(4-Forfinal)oxazol-4-ileocecal]-1,3-dioxane-5-ileocecal}-6-methylbenzoic acid 27

Connection 27 get similar to the synthesis of 6b 29 by hydrolysis.

Example XV

2-{1-[2-(4-Forfinal)oxazol-4-ileocecal]cyclohex-3-animationtimer}-6-methylbenzoic acid 31

On the basis of (1-hydroxymethylcytosine-3-enyl)methanol, iodide 2 and bromide 4, the procedure described for 27 results of 31 product molecular weight 465,53 (C27H28FNO5); MS(ERIE): 466 (M + N+).

Example XVI

2-{1-[2-(4-Forfinal)oxazol-4-ileocecal]cyclohexylmethoxy}-6-methylbenzoic acid 32

On the basis of (1-hydroxymethylcellulose)methanol, iodide 2 and bromide 4, the procedure described for 27 results of 32 product molecular weight 467,53 (C27H30FNO5); MS(ERIE): 468 (M + N+).

Example XVII

Racemic TRANS-2-{2-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 33

TRANS-1,2-Dihydroxyecdysone, iodide 2 and bromide 4 give, 27 similarly, the desired product molecular weight 439,49 (C25H26FNO5); MS(ERIE): 440 (M + N+).

Example XVIII

2-{4-[2-(4-Forfinal)oxazol-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 34

1,4-Cyclohexanediol, iodide 2 and bromide 4 give 34 molecular weight 439,49 (C25H26FNO5); MS(ERIE): 440 (M + N+).

Example XIX

2-{4-[2-(4-Forfinal)oxazol-4-ylethoxy]cyclopent-2-relaxometer}-6-methylbenzoic acid 35

Cyclopent-2-EN-1,4-diol, iodide 2 and bromide 4 give 35 molecular weight 423,45 (C24H22FNO5); MS(ERIE): 424 (M + N+).

Example XX

2-{5-[2-(4-Forfinal)oxazol-4-yl]methoxy}cyclooctylmethyl}-6-methylbenzoic acid 36/p>

1,5-Cyclooctadiene, iodide 2 and bromide 4 give 36 molecular weight 467,54 (C27H30FNO5); MS(ERIE): 468 (M + N+).

Example XXI

Racemic TRANS-2-{2-[2-(4-forfinal)oxazol-4-ylethoxy]cyclooctylmethyl}-6-methylbenzoic acid 37

TRANS-1,2-Cyclooctanol, iodide 2 and bromide 4 give the desired product molecular weight 467,54 (C27H30FNO5); MS(ERIE): 468 (M + N+).

Example XXII

Racemic CIS-2-{2-[2-(4-forfinal)oxazol-4-ylethoxy]methylcyclohexylamine}-6-methylbenzoic acid 38

CIS-(2-Hydroxymethylcellulose)methanol, iodide 2 and bromide 4 give the product 38 molecular weight 467,54 (C27H30FNO5); MS(ERIE): 468 (M + N+).

Example XXIII

2-{2-[2-(4-Forfinal)oxazol-4-ylethoxy]methylcyclohexylamine}-6-methylbenzoic acid 39

(3-Hydroxymethylcellulose)methanol, iodide 2 and bromide 4 give the product 39 molecular weight 467,54 (C27H30FNO5); MS(ERIE): 468 (M + N+).

Example XXIV

Racemic CIS-2-{3-[2-(4-forfinal)oxazol-4-ileocecal]cyclohexylmethyl}-6-methylbenzoic acid 40

CIS-3-Hydroxymethylcellulose, iodide 2 and bromide 4 give the product 40 molecular weight 453,52 (C26H FNO5); MS(ERIE): 454 (M + N+).

Example XXV

Racemic CIS-2-{3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexylmethoxy}-6-methylbenzoic acid 41

CIS-3-Hydroxymethylcellulose, bromide 4 and iodide 2 (sequence reverse reactions) give the product 41 molecular weight 453,52 (C26H28FNO5); MS(ERIE): 454 (M + N+).

Example XXVI

Racemic CIS-2-{3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexylmethoxy}-6-methylbenzoic acid 42

CIS-3-Hydroxymethylcellulose, iodide 2 and ethyl 2-hydroxy-6-methylbenzoate give the product 42 molecular weight 439,49 (C25H26FNO5); MS(ERIE): 440 (M + N+).

Example XXVII

Racemic TRANS-2-{4-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexylmethoxy}-6-methylbenzoic acid 43

TRANS-4-Hydroxymethylcellulose, iodide 2 and ethyl 2-hydroxy-6-methylbenzoate give the product 43 molecular weight 439,49 (C25H26FNO5); MS(ERIE): 440 (M + N+).

Example XXVIII

Racemic CIS-2-(2-{3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexyl}ethyl)-6-methylbenzoic acid 44

CIS-3-Ethynylcyclohexanol-2-enol, ethyl 2-methyl-6-triftoratsetilatsetonom and iodide give 2 product 44 is the molecular weight is s 437,52 (C 26H28FNO4); MS(ERIE): 438 (M + N+).

Example XXIX

Racemic TRANS-2-(2-{3-[2-(4-forfinal)oxazol-4-ylethoxy]cyclohexyl}ethyl)-6-methylbenzoic acid 45

TRANS-3-Ethynylcyclohexanol-2-enol, ethyl 2-methyl-6-triftoratsetilatsetonom and iodide give 2 product 45 molecular weight 437,52 (C26H28FNO4); MS(ERIE): 438 (M + N+).

Example XXX

Racemic TRANS-2-(2-(3-(2-(4-forfinal)oxazol-4-ylethoxy]cyclohexylmethyl)-6-methylbenzoic acid 46

Racemic TRANS-enantiomeric mixture of 3b (see example I) and methyl 2-methyl bromide-6-methylbenzoate 4 give the desired product molecular weight 439,49 (C25H26FNO5); MS(ERIE): 440 (M + N+).

Example XXXI

Methyl 2-(CIS-3-hydroxycyclohexanone)-6-methylbenzoate 47 and methyl 2-(TRANS-3-hydroxycyclohexanone)-6-methylbenzoate 48

8.7 g of 1,3-cyclohexanediol and 12 g of oxide dibutylamine dissolved in 600 ml of toluene using a water separator, the reaction mixture is heated at boiling point. During the reaction reazioni volume is reduced to half of the original. After 4 hours the reaction mixture is cooled to room temperature and add 300 ml of DMF, 9.0 g of methyl 2-methyl bromide-6-is ethylbenzoic and 9.4 g of cesium fluoride. The mixture is stirred at room temperature for 12 hours. The reaction mixture was diluted by adding ethyl acetate and washed with saturated solution of NaCl. The organic phase is dried over magnesium sulfate, the solvent is removed under reduced pressure and the residue purified flash chromatography on silica gel (n-heptane/ethyl acetate 50:1 → 1:2). This gives about 6 g of alcohol 47 (CIS-racemate) in the form of oil. C16H22O4(278,35), MS(ERIE): 279 (M + N+). Unreacted TRANS-1,3-cyclohexanediol also elute from the chromatographic column. It alkylate analogously to example 1, using sodium hydride and methyl 2-methyl bromide-6-methylbenzoate. After similar processing and chromatography, as described for CIS-racemate, get TRANS-racemate 48 C16H22O4(278,35), MS(ERIE): 279 (M + N+).

The racemates 47 and 48 separated by chromatography on chiral phase (Chiralpak AD/2 CH,6); n-heptane:ethanol:methanol = 25:1:0,5 + 0,1% triperoxonane acid, Rf(47A)=8,9 min; retention time enantiomer: Rf(47b)=9,9 min (absolute retention times vary depending on the accuracy of compliance chromatography).

The reactions described below, can be carried out with pure stereoisomers and mixtures of stereoisomers.

Methyl 2-{3-[2-(4-bromophenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic 49

At room temperature, 50 mg of 60% suspension of sodium hydride and then 408 mg of 2-(4-bromophenyl)-4-iodomethyl-5-methoxazole added to a solution of 200 mg of methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate in 5 ml of dimethylformamide. After 1 hour add methyl tert-butyl ether and the mixture is extracted with water. The organic phase is dried over magnesium sulfate, the solvents removed under reduced pressure and the residue purified RP-HPLC (RP-HPLC). This gives 49 as a pale yellow oil. C27H30BrNO5(528,45), MS(ERIE): 528,2 530,2 (M + N+).

2-{3-[2-(4-Bromophenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 50

117 mg 49 stirred in a mixture of 10 ml of tert-butanol and 1 ml of 10N aqueous solution of potassium hydroxide at 90°C. two days Later, the mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvents removed under reduced pressure and the residue purified RP-HPLC. This gives 50 in the form of amorphous solids. C26H28BrNO5(514,52), MS(ERIE): 514,29, 516,29 (M + N+).

Example XXXII

2-{3-[2-(3-Bromophenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 51

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(bromophenyl)-4-iodomethyl-5-methoxazole give, analogously to example 50, the product 51 molecular weight 514,42 (C26H28BrNO5), MS(ERIE): 514,30, 516,30 (M + N+).

Example XXXIII

2-{3-[2-(3-Forfinal)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 52

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(3-forfinal)-4-iodomethyl-5-methoxazole give, analogously to example 50, the product 52 molecular weight 453,52 (C26H28FNO5), MS(ERIE): 454,35 (M + N+).

Example XXXIV

2-{3-[2-(3-Methoxyphenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 53

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(3-methoxyphenyl)-4-iodomethyl-5-methoxazole give, analogously to example 50, 53 product molecular weight 465,55 (C27H31NO6), MS(ERIE): 466,37 (M + N+).

Example XXXV

2-{3-[2-(3-Triptoreline)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 54

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(3-triptoreline)-4-iodomethyl-5-methoxazole give, analogously to example 50, 54 product molecular weight 503,52 (C27H28F3NO5), MS(ERIE): 504,37 (M + N+).

Example XXXVI

2-{3-[2-(3-Chlorophenyl)-5-METI oxazol-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 57

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(3-chlorophenyl)-4-iodomethyl-5-methoxazole give, analogously to example 50, 57 product molecular weight 469,97 (C26H28ClNO5), MS(ERIE): 470,43 (M + N+).

Example XXXVII

2-{3-[2-(4-Chlorophenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 58

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(4-chlorophenyl)-4-iodomethyl-5-methoxazole give, analogously to example 50, the product 58 molecular weight 469,97 (C26H28ClNO5), MS(ERIE): 470,40 (M + N+).

Example XXXVIII

2-{3-[2-(3-Were)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 59

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(3-were)-4-iodomethyl-5-methoxazole give, analogously to example 50, 59 product molecular weight 449,55 (C27H31NO5), MS(ERIE): 450,53 (M + N+).

Example XXXIX

2-{3-[2-(3,4-Dimetilfenil)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 61

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(3,4-dimetilfenil)-4-iodomethyl-5-methoxazole give, analogously to example 50, 61 product molecular weight 463,58 (C28H33NO5), MS(ERIE): 464,22 (M + N+).

Example XL

2-{3-[2-(2,4-Dimetilfenil)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 62

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(2,4-dimetilfenil)-4-iodomethyl-5-methoxazole give, analogously to example 50, 62 product molecular weight 463,58 (C28H33NO5), MS(ERIE): 464,22 (M + N+).

Example XLI

2-{3-[2-(2-Were)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 63

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(2-were)-4-iodomethyl-5-methoxazole give, analogously to example 50, 63 product molecular weight 449,55 (C27H31NO5), MS(ERIE): 450,20 (M + N+).

Example XLII

2-{3-[2-(3-Trifloromethyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 64

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(3-trifloromethyl)-4-iodomethyl-5-methoxazole give, analogously to example 50, 64 product molecular weight 519,52 (C27H28F3NO6), MS(ERIE): 520,20 (M + N+).

Example XLIII

2-{3-[2-(3,4-Acid)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 67

Methyl 2-(3-hydroxycyclohexyl simetal)-6-methylbenzoate and 2-(3,4-acid)-4-iodomethyl-5-methoxazole give, analogously to example 50, 67 product molecular weight 495,58 (C28H33NO7), MS(ERIE): 496,20 (M + N+).

Example XLIV

2-{3-[2-(3-Cyanophenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 68

13 mg of 2-{3-[2-(3-bromophenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid and 25 mg of cyanide of zinc dissolved in 5 ml of dimethylformamide. The reaction mixture Tegaserod and saturated with argon, and add 20 mg tetranitroaniline. The mixture was stirred at 100°C for 12 hours. After cooling to room temperature, water is added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvents removed under reduced pressure and the residue purified RP-HPLC. This gives 68 in the form of an amorphous light yellow solid. C27H28N2O5(460,53), MS(ERIE): 461,20 (M + N+).

Example XLV

2-Methyl-6-[3-(5-methyl-2-phenyloxazol-4-ylethoxy)cyclohexylmethyl]benzoic acid 69

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-phenyl-4-iodomethyl-5-methoxazole give, analogously to example 50, 69 product molecular weight 435,52 (C26H29NO5), MS(ERIE): 43632 (M + N +).

Example XLVI

2-Methyl-6-[3-(5-methyl-2-p-tolyloxy-4-ylethoxy)cyclohexylmethyl]benzoic acid 70

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(4-were)-4-iodomethyl-5-methoxazole give, analogously to example 50, 70 product molecular weight 449,55 (C27H31NO5), MS(ERIE): 450,36 (M + N+).

Example XLVII

2-{3-[2-(4-Methoxyphenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid 71

Methyl 2-(3-hydroxycyclohexyl)-6-methylbenzoate and 2-(4-methoxyphenyl)-4-iodomethyl-5-methoxazole give, analogously to example 50, 71 product molecular weight 465,55 (C27H31NO6), MS(ERIE): 466,37 (M+N+).

Tableted pharmaceutical composition of the following composition

Ingredient (per 1 tablet)Mass mg
Connection in accordance with the invention1
Maize starch27
Microcrystalline cellulose (MCC)58
Polyvinylpyrrolidone (povidone)5
Sodium-crosscarmelose8
Magnesium stearate1

g is tovat, as noted below. Use the amount of water required degree of purification, sufficient to dissolve the compound. When this water is alkalinized to pH 10...12 or acidified using 1M solutions of hydroxide natira or hydrochloric acid, depending on the nature of the connection in accordance with the invention. The connection is stirred until dissolution. Add the remaining volume of water in accordance with the instruction manual mixer in which the mixing maize starch, part of the sodium-crosscarmelose, part of the microcrystalline cellulose and povidone. The mixture granularit in the apparatus with fluidized bed (perhaps the use of high shear granulator). The wet granules are dried in an air dryer at a temperature of inlet air less than or equal to 60°With in a period of time sufficient to achieve a moisture content, specified by the instruction manual of the granulator. The granules pass through a sieve of suitable gauge (1.2 mm) and mixed with the remaining part of sodium crosscarmelose, MCC and shearaton magnesium in a suitable mixer. Finally the mixture tabletirujut on a suitable press.

EXAMPLE XLVIII

Methyl-2-{1R,3S-3-[2-(3-forfinal)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoate (72)

At room temperature, 50 mg of 60% suspension of sodium hydride and C is the of 1.08 mmol of 2-(3-forfinal)-4-iodomethyl-5-methoxazole added to a solution of 200 mg of methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate (47A) in 5 ml of dimethylformamide. After completion of the reaction, the speed of which was controlled by TLC (approximately one hour), add methyl tert-butyl ether (˜30 ml) and the mixture is extracted with water. The organic phase is dried over magnesium sulfate, the solvents removed under reduced pressure and the residue purified RP-HPLC. This gives 72 in the form of a light yellow oil. C27H30FNO5(467,54), MS(ERIE): 468 (M + N+).

2-{1R,3S-3-[2-(3-Forfinal)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (73)

100 mg 72 stirred in a mixture of 10 ml of tert-butanol and 1 ml of 10N aqueous solution of potassium hydroxide at 90°C. After completion of the reaction according to TLC (up to two days) and the mixture acidified with hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvents removed under reduced pressure and the residue purified RP-HPLC. This gives an amorphous solid, the product is 73, with a molecular mass of 453,52 (C26H28FNO5), MS(ERIE): 454,35 (M + N+).

EXAMPLE XLIX

2-{1R,3S-3-[2-(3-Methoxyphenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (74)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(3-methoxyphenyl)-4-iodomethyl-5-methoxazole give in similar conditions, opican the x for 72 and 73, product 74 molecular weight 465,55 (C27H31NO6), MS(ERIE): 466,37 (M + N+).

EXAMPLE L

2-{1R,3S-3-[2-(3-Triptoreline)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (75)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(3-triptoreline)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, product 75 molecular weight 503,52 (C27H28F3NO5), MS(ERIE): 504,37 (M + N+).

EXAMPLE LI

2-{1R,3S-3-[2-(3-Chlorophenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (76)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(3-chlorophenyl)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, the product 76 molecular weight 469,97 (C26H28ClNO5), MS(ERIE): 470,43 (M + N+).

EXAMPLE LII

2-{1R,3S-3-[2-(4-Chlorophenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (77)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(4-chlorophenyl)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, 77 product molecular weight 469,97 (C26H28ClNO5), MS(ERIE): 470,40 (M + N+).

EXAMPLE LIII

2-{1R,3S-3-[2-(3-Were)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (78)Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(3-were)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, the product 78 molecular weight 449,55 (C27H31NO5), MS(ERIE): 450,53 (M + N+).

EXAMPLE LIV

2-{1R,3S-3-[2-(3,4-Dimetilfenil)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (79)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(3,4-dimetilfenil)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, 79 product molecular weight 463,58 (C28H33NO5), MS(ERIE): 464,22 (M + N+).

EXAMPLE LV

2-{1R,3S-3-[2-(2,4-Dimetilfenil)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (80)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(2,4-dimetilfenil)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, the product 80 molecular weight 463,58 (C28H33NO5), MS(ERIE): 464,22 (M + N+).

Example LVI

2-{1R,3S-3-[2-(2-Were)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (81)

Methyl 2-(1R,3S3-hydroxycyclohexanone)-6-methylbenzoate and 2-(2-were)-4-iodomethyl-5-methoxazole give under similar conditions, described for 72 and 73, 81 product molecular weight 449,55 (C27H31NO5), MS(ERIE): 450,20 (M + N+).

EXAMPLE LVII

2-{1R,3S-3-[2-(3-Trifloromethyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (82)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(3-trifloromethyl)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, 82 product molecular weight 519,52 (C27H28F3NO6), MS(ERIE): 520,20 (M + N+).

EXAMPLE LVIII

2-{1R,3S-3-[2-(3,4-Acid)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (83)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(3,4-acid)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, 83 product molecular weight 495,58 (C28H33NO7), MS(ERIE): 496,20 (M + N+).

EXAMPLE LIX

2-Methyl-6-[1R,3S-3-(5-methyl-2-phenyloxazol-4-ylethoxy)cyclohexylmethyl}benzoic acid (84)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-phenyl-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, 84 product molecular weight 435,52 (C26H29NO5), MS(ERIE): 436,32 (M + N+).

EXAMPLE LX

2-Methyl-6-[1S,3R-3-(5-methyl-2-phenyloxazol-4-ylethoxy]cyclohexylmethyl}benzoic acid (85)

Methyl 2-(1S,3R-3-hydroxycyclohexanone)-6-methylbenzoate (47b) and 2-phenyl-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, 85 product molecular weight 435,52 (C26H29NO5), MS(ERIE): 436,32 (M + N+).

EXAMPLE LXI

2-Methyl-6-[1R,3S-3-(5-methyl-2-p-tolyloxy-4-ylethoxy]cyclohexylmethyl}benzoic acid (86)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(4-were)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, 86 product molecular weight 449,55 (C27H31NO5), MS(ERIE): 450,36 (M + N+).

EXAMPLE LXII

2-Methyl-6-[1S,3R-3-(5-methyl-2-p-tolyloxy-4-ylethoxy]cyclohexylmethyl}benzoic acid (87)

Methyl 2-(1S,3R-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(4-were)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, 87 product molecular weight 449,55 (C27H31NO5), MS(ERIE): 450,36 (M + N+).

EXAMPLE LXIII

2-{1R,3S-3-[2-(4-Methoxyphenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (88)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(4-methoxyphenyl)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, 88 product molecular weight 465,55 (C27H31NO6), MS(ERIE): 466,37 (M + N+).

EXAMPLE LXIV

2-{1S,3R-3-[2-(4-Methoxyphenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (89)

Methyl 2-(1S,3R-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(4-methoxyphenyl)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, 89 product molecular weight 465,55 (C27H31NO6), MS(ERIE): 466,37 (M + N+).

EXAMPLE LXVI

2-{1R,3S-3-[2-(3-Bromophenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (90)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(3-bromophenyl)-4-iodomethyl-5-methoxazole give under similar conditions as described for 72 and 73, the product 90 molecular weight 514,42 (C26H28BrNO5), MS(ERIE): 514,30, 516,30 (M + N+).

EXAMPLE LXVI

2-{1R,3S-3-[2-(4-Bromophenyl)-5-methoxazole-4-ylethoxy]cyclohexylmethyl}-6-methylbenzoic acid (91)

Methyl 2-(1R,3S-3-hydroxycyclohexanone)-6-methylbenzoate and 2-(4-bromophenyl)-4-iodomethyl-5-methoxazole give during the same period the s conditions, described for 72 and 73, 91 product molecular weight 514,42 (C26H28BrNO5), MS(ERIE): 514,29, 516,29 (M + N+).

EXAMPLE LXVII

Method:

Methyl-[2-(1S,4R-4-tert-butyldimethylsilyloxy-2-relaxometer)-6-methyl]benzoate

8,2 g 1S,4R-4-tert-Butyldimethylsilyloxy-2-enol in 20 ml of anhydrous dimethylformamide (DMF) is added dropwise in an argon atmosphere at 0°to a suspension of 1.6 g of 60% NaH in 12 ml of anhydrous DMF. Then add at 0°With 20 ml of 60% (2-methyl bromide-6-methyl)methylbenzoate. When you are finished adding bath with ice is removed and the mixture is stirred at room temperature for 6 hours. Then add 200 ml of methyl tert-butyl ether (MTBE) and the organic phase is washed with 200 ml of water and 200 ml saturated NaCl solution. The organic layer is dried over MgSO4and the solvents removed. The remaining residue purified by chromatography (SiO2, n-heptane/MTBE 8:1=>3:1)to give the product, methyl-[2-(1S,4R-4-tert-butyldimethylsilyloxy-2-relaxometer)-6-methyl]benzoate in the form of a yellow oil. C21H32O4Si (376,57), GHMC (ERIE): 377 (MN+).

Methyl-[2-(1S,4R-4-hydroxycyclopent-2-relaxometer)-6-methyl]benzoate

To a solution of 2.3 g of methyl-[2-(1S,4R-4-tert-butyldimethylsilyloxy-2-relaxometer)-6-methyl]benzoate in 20 ml of THF, add 10 ml of 1M solution tetrabutyl is onitored in THF and the mixture is stirred for 20 min at room temperature. The mixture is diluted with 100 ml of MTBE and washed with 3 times 100 ml of water, then 50 ml of a saturated solution of NaCl. The organic layer is dried over MgSO4and the solvent is removed. The remaining residue purified by chromatography (SiO2, n-heptane/MTBE 1:1)to give the product, methyl-[2-(1S,4R-4-hydroxycyclopent-2-relaxometer)-6-methyl]benzoate in the form of a yellowish oil. C15H18O4(262,31). IHMS (ERIE): 263 (MN+).

Methyl-{2-methyl-6-[1S,4R-4-(5-methyl-2-phenyloxazol-4-ylethoxy)cyclopent-2-relaxometer]}benzoate

300 mg of methyl-[2-(1S,4R-4-hydroxycyclopent-2-relaxometer)-6-methyl]benzoate in 2 ml of anhydrous DMF is added dropwise in an argon atmosphere to a suspension of 55 mg of 60% NaH in 3 ml of anhydrous DMF. After stirring for 20 min at room temperature add a solution of 320 mg of 5-methyl-2-phenyloxazol-4-iletileri in 1 ml of DMF. The mixture is stirred for 90 min at room temperature, then add 0.5 ml of isopropanol followed by the addition of 20 ml of MTBE. The solution is washed with 3 times 20 ml of water, then 20 ml of saturated NaCl solution, the organic layer is dried over MgSO4and the solvents removed. The remaining residue purified by chromatography (SiO2, n-heptane/MTBE 5:1). Selected fractions containing the product, and after removal of the solvents again subjected to chromatography (SiO2, n-heptane/ethyl acetate 10:1)to give the product, methyl-{2-methyl-6-[1S,4R-4-(5-IU the Il-2-phenyloxazol-4-ylethoxy)cyclopent-2-relaxometer]}benzoate, in the form of a yellowish oil. C25H25NO5(419,48). IHMS (ERIE): 420 (MH+).

2-Methyl-6-[1S,4R-4-(5-methyl-2-phenyloxazol-4-ylethoxy)cyclopent-2-relaxometer]benzoic acid

60 mg of Methyl-{2-methyl-6-[1S,4R-4-(5-methyl-2-phenyloxazol-4-ylethoxy)cyclopent-2-relaxometer]}benzoate in 1 ml of 10M aqueous KOH and 1 ml of tert-butanol is stirred for 4 days at 100°C. the Mixture is diluted with 10 ml of water and extracted 3 times with 10 ml of ethyl acetate. The combined organic layers dried over MgSO4and the solvents removed. Purification of the remaining residue with the help of HPLC gives 2-methyl-6-[1S,4R-4-(5-methyl-2-phenyloxazol-4-ylethoxy)cyclopent-2-relaxometer]benzoic acid as a colourless oil. C24H23NO5(405,45). IHMS (ERIE): 406 (MN+).

td align="center"> LIX
TABLE 1A
Example No.PPARα; EC50[nm]
XLVIII0,25
XLIX0,52
L0,19
LI0,31
LII0,10
LIII0,40
LIV0,08
LV0,09
LVI0,54
LVII0,13
LVIII0,46
0,20
LX10
LXI0,08
LXII0,56
LXIII0,13
LXIV1,1
LXV0,48

1. The compound of the formula

in which ring a represents a (C3-C8-cycloalkyl or (C3-C8)-cycloalkenyl where cycloalkene the two ring carbon atoms may be replaced by oxygen atoms;

R1, R2 independently of one another represent H, F, Cl, Br, HE, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl;

R3 represents H or (C1-C6)-alkyl;

R4, R5, independently of one another, represent H, (C1-C6)-alkyl;

X represents (C1-C6)-alkyl, where one carbon atom in the alkyl group may be replaced by oxygen atom;

Y represents a (C1-C6)-alkyl, where one carbon atom in the alkyl group may be replaced by oxygen atom;

and its physiologically acceptable salt.

2. The compound of formula I according to claim 1,

where ring a represents a (C3-C8-cycloalkyl or (C3-C8)-cycloalkenyl where cycloalkene the two ring carbon atoms may be Amenti atoms of oxygen;

R1, R2 independently of one another represent H, F, Cl, Br, HE, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl;

R3 represents H or (C1-C6)-alkyl;

R4 represents H, (C1-C6)-alkyl;

R5 represents a (C1-C6)-alkyl;

X represents (C1-C6)-alkyl, where one carbon atom in the alkyl group is replaced by oxygen atom;

Y represents a (C1-C6)-alkyl, where one carbon atom in the alkyl group is replaced by oxygen atom;

and its physiologically acceptable salt.

3. The compound of formula I according to claim 1 or 2, where

ring a represents a (C3-C8-cycloalkyl or (C3-C8)-cycloalkenyl;

R1, R2 independently of one another represent H, F, Cl, Br, HE, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl;

R3 represents H or (C1-C6)-alkyl;

X represents (C1-C6)-alkyl, where one carbon atom in the alkyl group is replaced by oxygen atom;

Y represents a (C1-C6)-alkyl, where one carbon atom in the alkyl group is replaced by oxygen atom;

and its physiologically acceptable salt.

4. The compound of formula I according to claim 1 or 2, having the structure Ia

ring a represents cyclohexa-1,3-diyl;

R1, R2 independently of one another represent H, F, Cl, Br, HE, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl;

R3 represents H or (C1-C6)-alkyl;

X represents (C1-C6)-alkyl, where one carbon atom in the alkyl group is replaced by oxygen atom;

Y represents a (C1-C6)-alkyl, where one carbon atom in the alkyl group is replaced by oxygen atom;

and its physiologically acceptable salt.

5. The pharmaceutical composition active agonist of PPARαcomprising one or more compounds of one or more of claims 1 to 4 as an active ingredient together with a pharmaceutically acceptable carrier.

6. A method of obtaining a pharmaceutical composition active agonist of PPARα and comprising one or more compounds of one or more of claims 1 to 4 as an active ingredient together with a pharmaceutically acceptable carrier, which comprises mixing the active compounds with pharmaceutically acceptable carrier and making the mixture forms suitable for injection.

7. (+)-CIS-2-(3-(2-(4-Forfinal)oxazol-4-ylethoxy)cyclohexyloxy-methyl)-6-methylbenzoic acid 6b

8. 2-{3-[2-(3-Methoxyphenyl)-5-methoxazole-4-ylethoxy]cyclohexyloxy-methyl}-6-methylbenzoic acid of formula 53

or its enantiomer of the formula

9. 2-Methyl-6-[3-(5-methyl-2-p-tolyloxy-4-ylethoxy)cyclohexyloxy-methyl]benzoic acid of formula 70

or its enantiomer of the formula



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyridine and new pyrimidine derivative, their pharmaceutically accepted salt or hydrate of the general formula (I): . The invention also relates to the pharmaceutical composition, which possesses the inhibiting activity with respect to the receptor of the growth factor of hepatocytes; to the inhibitor of the receptor of the growth factor of hepatocytes, the inhibitor of angiogenesis, the antitumor drug, the inhibitor of cancerous metastatic spreading, that contains the pharmacologically effective dose of the said compounds, its pharmaceutically acceptable salt or hydrate.

EFFECT: inhibitory activity.

27 cl, 45 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula (I) where: X is O; Y represents a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHC(O)R33), CH(NHS(O)2R34), CH2O or CH2S; Z is C(O), or if Y is a bond, then Z can also be S(O)2; R1 could be substituted with phenyl; R4 is hydrogen, C1-6-alkyl (substituted possibly by C3-6-pilkoalkyl) or C3-6-cycloalkyl; R2, R3, R5, R6, R7 and R8 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; type independently indicate 0 or 1; R9 could possibly be substituted with an aryl or heterocycle; R10, R32 and R35 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; R33 and R34 are C1-6-alkyl or C3-6-cycloalkyl; where the aforesaid aryl and heterocyclic groups, when possible, can be substitute with: halogen cyanogens, nitro, hydroxyl, oxo, S(O)Kr12, OC(O)NR13R14, NR15R16, NR17C(O)R18, NR19C(O)NR20R21, S(O)2NR22R23, NR24S(O)2R25, C(O)NR26R27, C(O)R28, CO2R29, NR30CO2R31, by C1-6-alkyl (which itself can be monosubstituted with NHC(O)phenyl), C1-6-halogenalkyl, C1-6-alkoxy(C1-6)alkyl, C1-6-alkoxy, C1-6-halogenaloxy, C1-6-alkoxy(C1-6)-alkoxy, C1-6-alkylthio, C2-6-alkenyl, C2-6-alkinil, C3-10-cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkyl, morpholinyl, heteroaryl, heteroaryl(C1-4)alkyl, heteroarylhydroxy of heteroaryl(C1-4)alkoxy, where any of the said phenyl and heteroaryl groups can be substituted by halogen, hydroxyl, nitro, S(O)r(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-.4-alkyl)2, cyanogens, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), CO2H, CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3; k and r independently mean 0, 1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 independently represent hydrogen, C1-6-alkyl (probably replaced by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), C3-6-cycloalkyl, phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), NH(C1-4-alkyl)2, S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, S(O)2)(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H5 CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3); alternatively, NR13R14, NR15R16, NR20R21, NR22R23, NR26R27 can independently form 4-7-member heterocyclic ring, selected from the group, which includes: azetidine (which can be substituted by hydroxyl or C1-4-alkyl), pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter is probably substituted by C1-4-alkyl on the peripheral nitrogen; R12, R25, R28 and R31 are independently C1-6-alkyl (possibly substituted by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4- alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connec to form a ring as described hereabove for R13 and R14), cyanogen, C1-4- alkyl, C1-4- alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), NHC(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3); or its N-oxide; or its pharmaceutically acceptable salt, solvate or solvate of its salt, which are modulators of activity of chemokines (especially CCR3); also described is the pharmaceutical composition on their basis and the method of treating the chemokines mediated painful condition.

EFFECT: obtaining new compounds possessing useful biological properties.

13 cl, 238 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) or their pharmaceutically acceptable salts, where R1 and R2 are H or Me; R3 is H, hydroxy or (1-4C)alkoxi; R4 is H, OH, (1-4C)alkoxi; R5 is OH, (1-4C)alkoxi or R7; provided the R4 is H, then R5 differs from OH or (1-4C)alkoxi; R6 is (2-5C)heteroaryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, bromine or chlorine; (6C)aryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, (1-4)C-alkoxi, bromine, chlorine, phenyl or (1-4C) (di)alkylamino; (3-8C)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)-alkyl; R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroaryl-carbonylokxi, R8-(2-4C)alkoxi, R9-methylamino or R9-methoxi; R8 is amino, (1-4C)alkoxi, (di)(1-4C)-alkylamino, (2-6C)-heterocycloalkyl, (2-6C)heterocycloalkylcarbonylamino or (1-4C)-alkoxicarbonylamino; and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. The invention also relates to the pharmaceutical composition which contains the said derivatives, and to the application of the derivatives in fertility modulating.

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

15 cl, 51 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) , or their pharmaceutically acceptable salts, where R1 and R2 are H, Me; R3 is (2-6C)-hetercycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl, (6C)aryl(1-4C)-alkyl, (2-6C)hetercycloalkylcarbonylamino(2-4C)alkyl, R5-(2-4C)alkyl or R5-carbonyl(1-4C)alkyl; R4 is (2-5C)heteroaryl (6C)aryl, not necessarily substituted with one or more substitutes selected from bromine, chlorine, nitro, phenyl, (1-4C)alkyl, trufluoromethyl, (1-4C)alkoxi or (1-4C)alkylamino; or (2-6C)hetercycloalkyl; R5 is (di (1-4C)alkylamino, (1-4C)alkoxi, amio, hydroxy, (6C)arylamino, (di)(3-4C)alkenylamino, (2-5C)heteroaryl(1-4C)alkylamino, (6C)aryl(1-4C)alkylamino, (di)[(1-4C)alkoxi(2-4C)alkyl]amino, (di)[(1-4C)alkylamino2-4C)alkyl]amino, (di)[amino(2-4C)alkyl]amino or (di)[hydroxy(2-4C)alkyl]amino. The invention also relates to the pharmaceutical composition based on the compound with formula (I) and to the application of the compound with the formula (I).

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

10 cl, 44 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 1-sulphonyl-4-aminoalcoxyindole of formula (I) are described, or pharmaceutically acceptable salts thereof, where n is 2 or 3; each of R1 and R2 independently of each other stands for hydrogen, or lower alkyl, or R1 and R2 together with corresponding nitrogen atom may be a part of heterocyclic group, which is selected from morpholino, pyrrolidinyl; R3 stands for hydrogen, or R3 and R1 together with R3 nitrogen atom may be a part of four- or five-membered ring, where R1 and R3 together form an alkylene group; R4 stands for hydrogen; R5 stands for hydrogen; R6 stands for naphthyl, phenyl, not necessarily substituted with one or two substituents, each of which may be a lower alkyl, haloid, lower alcoxy, cyano group, lower alkylsulphonyl, acyl, trifluoromethyl, acetamide, or quinolinyle, thienyl, not necessarily halogen-substituted. The said compounds are selective 5-НТ6 antagonists.

EFFECT: pharmaceutical composition is a receptor modulator.

17 cl, 1 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes cyclic-substituted diphenylazethidinones of the formula (I): wherein each radical among R1, R2, R3, R4, R5 and R6 means independently of one another (C1-C30)-alkylene-(LAG)n wherein n = 1-2; one or two carbon atoms in alkylene residue are replaced with phenyl or piperazinyl residues or (C3-C10)-cycloalkyl residue; one or some carbon atoms in alkylene residue can be replaced with -S(O)n wherein n = 2; -O-, -(C=O)- or -NH-; hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J), O-(C1-C6)-alkyl; (LAG)n means mono- or tricyclic trialkyl ammoniumalkyl residue, -(CH2)0-SO3H, -(CH2)0-COOH, -(CH2)0-C(=NH)(NH2), and pharmaceutically acceptable salts also. Proposed compounds decrease the serum cholesterol content. Also, invention describes using these compounds for preparing a medicinal agent used in treatment of lipid metabolism disorders.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 1 tbl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new displaced heterocyclic derivatives that can be used in treatment of diabetes and to reduce the content of cholesterol. In formula m is 1; n is 1; Q is C; A is -(CH2)x2-0-(CH2)x3-, where x2 varies from 1 to 3 and x3 is 0; B is a bond or it is (CH2)x4, where x4 varies from 1 to 2; X represents CH or N; X2, X3, X4, X5, X6 represent C, N, O; provided that one from X2 X3 X4 X5 and X6 represents N; and at least one of X2, X3, X4, X5, and X6 represents C; R1 represents H or C1-C6alkyl; R2 is H; R2a, R2b and R2c can be equal or different and selected from H, C1-C6alkyl, C1-C6alkoxy, halogen or thyano; R3 is selected from phenyloxycarbonile, C1-C6alkyloxycarbonile, phenylcarbinol, phenyl, alkoxy; Y represents CO2R4 (where R4 represents H or C1-C6alkyl); (CH2)m can be not necessarily displaced by 1 substitute.

EFFECT: produced are pharmaceutical composition for treatment of diabetes and to reduce the content of cholesterol.

13 cl, 2 tbl, 22 dwg, 88 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts. Proposed compounds possess properties of agonists of receptors activated by peroxisome proliferators (PPAR agonists) and can be used in treatment of such diseases as diabetes mellitus, hypertension, atherosclerotic diseases and others. In the general formula (I) R1 means lower alkyl, monocyclic (C3-C6)-cycloalkyl; R2 means hydrogen atom, halogen atom, lower alkyl, lower alkoxy-group wherein at least one of three radicals R3, R4, R5 or R6 is not hydrogen atom; or R3 and R4 are bound together to form a ring with carbon atoms to which they are bound, and R3 and R4 mean in common -CH=CH-S-, -S-CH=CH-, -CH=CH-CH=CH-, and R5 and R6 are given above; R7 means lower alkyl, lower alkenyl; R8 means hydrogen atom or lower alkyl; n = 1, 2 or 3. Also, invention relates to a pharmaceutical composition based on the invention compounds and to using compounds of the invention in preparing medicinal agents used in treatment and/or prophylaxis of diseases mediated by agonists PPARα and/or PPARγ.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 13 sch, 71 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters. Proposed compounds possess properties of agonists of receptors activated by peroxisome proliferators (PPAR agonists) and can be used in treatment of such diseases as diabetes mellitus, hypertension, atherosclerotic diseases and others. In the general formula (I) R1 represents phenyl, optionally mono-, di- or tri-substituted with halogen atom, lower alkyl, fluorine-lower alkyl, lower alkoxy-group; R2 represents hydrogen atom or lower alkyl; R3 and R4 represents independently of one another hydrogen atom, hydroxy-group, halogen atom, lower alkyl, fluorine-(lower alkyl), lower alkoxy-group wherein at least one of radicals R3 and R4 doesn't represent hydrogen atom; R5 represents lower alkoxy-group; R6 represents hydrogen atom or lower alkyl; n = 1. Also, invention relates to a pharmaceutical composition based on compounds of the invention.

EFFECT: valuable medicinal properties of compounds.

19 cl, 1 tbl, 7 sch, 56 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds of the general formula (I): wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents hydrogen atom, -CO-R3 wherein R3 represents (C2-C6)-alkyl substituted optionally with halogen atom, -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom or (C1-C4)-alkyl; R5 represents (C1-C8)-alkyl, (C2-C8)-alkenyl and others; Y represents compound of the formula: wherein R7 represents hydrogen atom or (C1-C4)-alkyl; R8 represents (C5-C8)-alkyl, (C4-C8)-cycloalkyl and others; X represents oxygen atom or sulfur atom and others. Also, invention relates to pharmaceutically acceptable salts of these compounds. Compounds of the formula (I) possess hypoglycemic and/or hypolipidemic activity and can be used in medicine in treatment of diabetes mellitus, hyperlipidemia, hyperglycemia, diseases caused by resistance to insulin and other diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 3 tbl, 131 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of oxazole that are useful as insulin sensitizing agents being especially as activators of PPAR. Invention relates to compounds of the formula (I): and its pharmaceutically acceptable salts and esters wherein R1 represents phenyl; R2 represents (C1-C8)-alkyl; R represents (C1-C8)-alkyl, aralkyl, phenyl, (C1-C8)-alkylcarbonyl, phenylcarbonyl, (C1-C8)-alkyl-S(O)2- or phenyl-S(O)2-; R4 represents aralkyl; R5, R6, R7 and R8 represent hydrogen atom; n = 1, 2, 3, 4 or 5. Invention provides preparing medicinal agents used in prophylaxis and/or treatment of diseases mediated by agonists of PPARα and/or PPARγ.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 5 sch, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents azido, -OR4, -NHR4 wherein R4 represents hydrogen atom or unsubstituted groups chosen from acyl, thioacyl, (C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkoxythiocarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy, -C(C=S)-S-(C1-C6)-alkyl, -(C=S)-NH2, -(C=S)-NH-(C1-C6)-alkyl, -C(=S)-N-((C1-C6)-alkyl)2, -C(=S)-NH-(C2-C6)-alkenyl, -C(C=S)-(C=O)-(C1-C6)-alkoxy, thiomorpholinylthiocarbonyl; R2 and R3 can be similar or different and represent independently hydrogen atom, halogen atom, (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl; heterocyclic moiety represents 5-membered heterocycle wherein Z represents sulfur (S), oxygen (O) atom or -NRb wherein Rb represents hydrogen atom or unsubstituted (C1-C6)-alkyl, (C3-C6)-cycloalkyl, aryl or aryl-(C1-C6)-alkyl; Y1 represents group =O or =S ; Y2 and Y3 represent independently hydrogen atom, and if Y2 and Y3 present in common on adjacent carbon atoms then they form 6-membered aromatic cyclic structure substituted if necessary with (C1-C6)-alkyl, or to its pharmaceutically acceptable salt. Also invention relates to a pharmaceutical composition possessing antibacterial activity and containing as an active compound the compound of the formula (I) taken in the effective dose and a pharmaceutically acceptable carrier, diluting agent, excipient. Also, invention relates to method for synthesis of compound of the formula (I). Method for synthesis of compound of the formula (I) wherein R1 represents group -NHR4 wherein R4 means acyl, (C1-C6)-alkoxycarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy and -(C=S)-S-(C1-C6)-alkyl involves acetylation of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 represents hydrogen atom and all symbols are given above and using halide. Method for synthesis of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 means thioacyl, (C3-C6)-cycloalkoxythiocarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl involves the following steps: (i) conversion of compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents hydrogen atom, and all symbols are given above to compound of the formula (I) wherein R1 represents isothiocyanate group by reaction with thiophosgene, and (ii) conversion of compound of the formula (I) wherein R1 represents isothiocyanate group to compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents -C(=S)-OR4d wherein R4d represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, and all symbols are given above, in reaction with alcohol. Compounds of the formula (I) are used in treatment of bacterial infection that involves administration of compound of the formula (I) in a patient needing in this treatment. Invention provides synthesis of oxazolidinone compounds possessing antibacterial activity.

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

7 cl, 1 tbl, 144 ex

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