N-substituted 1h-indole-5-propionic acids, pharmaceutical composition containing these compounds and their using (variants)

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

 

The present invention relates to new indole derivative, used as insulin sensitizers, particularly activators of the receptor, activated peroxisome proliferation (RAPP). Primarily, the invention relates to compounds of formula I

in which

R1denotes aryl or heteroaryl;

R2denotes hydrogen, alkyl or cycloalkyl;

R3indicates aryloxy, alkenylacyl-, alkoxy - or alkoxygroup, substituted by one to three halogen atoms;

R4denotes hydrogen, alkyl or cycloalkyl;

where any of the substituents R5and R6means

and the other denotes hydrogen, alkyl or cycloalkyl, and where the relationship between the carbon atoms Withaandbpresents a simple carbon-carbon or a double bond;

R7denotes hydrogen, alkyl or cycloalkyl;

R8denotes hydrogen, alkyl or cycloalkyl;

where any of the substituents a and a1represents nitrogen and the other represents oxygen or sulfur;

n denotes 1, 2 or 3;

and their pharmaceutically acceptable salts and esters.

The compounds of formula I and their pharmaceutically acceptable salts and esters are new and possess valuable pharmacological properties. They are Saintes what bilization insulin, in particular activators of the receptor, activated peroxisome proliferation (RAPP).

Receptors activated peroxisome proliferation (RAPP), are members of the superfamily of nuclear hormone receptors, namely activated by ligands of the transcription factors regulating gene expression. Have been identified and cloned their various subtypes. They include RAPPα, RAPPβ (also known as RAPPδ) and RAPPγ. There are at least two major isoforms RAPPγ. While RAPPγ1 ubiquitously expressed in most tissues, the longer isoform RAPPγ2 found almost exclusively in some adipocytes. In contrast, RAPPα is expressed mainly in the liver, kidney and heart. Receptors activated peroxisome proliferation, modulate the many responses of the body, including glucose and lipid homeostasis, cell differentiation, inflammatory responses and cardiovascular disorders.

Diabetes is a disease in which disturbed the patient's ability to regulate glucose levels in the blood due to the fact that he had partially lost the ability to properly respond to insulin. Diabetes type II (TD), which is often called leisureservices Diab is t (nisd), affecting 80-90% of all diabetes cases in developed countries, the islets of Langerhans of the pancreas still produce insulin. However, target organs, mainly muscle, liver and adipose tissue, are absolute resistance to stimulation by insulin, and the body compensates for this phenomenon is the elaboration of non-physiological high levels of insulin. However, at a late stage of the disease the secretion of insulin is reduced by depletion of the pancreas. In addition TD is a symptom of metabolic disease and cardiovascular disease. Among the comorbidities associated with TD, distinguish, for example, insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and inflammatory atherosclerosis.

Modern treatment of diabetes in the early stages mainly includes a diet low in fat and glucose, as well as physical exercise. However, the consistency (compensation) may be mediocre, and as the disease progresses, it becomes necessary treatment of hypoglycemic drugs, such as derivatives of sulfonylurea or Metformin. Was recently offered a promising new class of drugs that restore sensitivity to patients whom now to their own insulin, (drugs that induce sensitivity to insulin), thereby returning the levels of glucose and triglycerides to normal levels and, thus eliminating or at least reducing the requirement for exogenous insulin. Pioglitazone (ActosTM) and rosiglitazone (AvandiaTM) belong to the class of agonists RAPPγ preparations of thiazolidinediones (TZD) and were the first representatives approved for nisd in different countries. However, these compounds have side effects, including rare but serious toxicity to the liver (which is observed with troglitazone), and they increase the body weight in humans. Therefore, an urgent need for new, improved and more effective drugs for the treatment of nisd. Recent studies have provided evidence that coagonist against RAPPα and RAPPγ leads to compounds of higher therapeutic potential, i.e. with an improved lipid profile, providing the best effect normalization of glucose levels and insulin (Keller and Wahli: Trends Endocrin. Metab., (1993), v.4, cc.291-296, Macdonald and Lane: Current Biology, (1995), V.5, cc.618-621).

The new compounds according to the present invention is superior to the compounds known in the prior art, due to the fact that they bind and activate both RAPPαand RAPPγsimultaneously and very efficiently. Indeed, these compounds combine antigistaminny effect activation RAPPγ and antidyslipidemic effect activation RAPPα. As a consequence, reduced plasma glucose and insulin (which is equivalent to the development of insulin sensitivity), and reduces triglycerides and increases cholesterol high density (which is equivalent to improved lipid profile). In addition, such compounds can also reduce cholesterol low-density, lower blood pressure and counteract inflammatory atherosclerosis. Because many aspects of the syndrome disease CHD associated with the action of coagonists RAPPα and γ, it is expected that the compounds will have an increased therapeutic potential compared to the compounds already known from the prior art.

Accordingly, the compounds of formula I can be used for the prevention and/or treatment of diabetes, in particular ainsliezubaida diabetes, high blood pressure, elevated levels of lipid and cholesterol levels, atherosclerotic diseases or syndrome metabolic disorders.

The objects of this invention are the compounds of formula I and their aforementioned pharmaceutically acceptable salts and esters themselves and their use as therapeutically active substances, a method of making such compounds, intermediates, pharmaceutical companies who stand, medicines containing these compounds, their pharmaceutically acceptable salts and esters, the use of these compounds, esters and salts for the prophylaxis and/or treatment of diseases, in particular for the treatment and/or prevention of diabetes, ainsliezubaida diabetes, high blood pressure, elevated levels of lipid and cholesterol levels, atherosclerotic diseases or syndrome metabolic disorders and, in particular, for the prevention and/or treatment ainsliezubaida diabetes, and the application of the said compounds, salts and esters for the production of pharmaceuticals for the treatment and/or prevention of disease, in particularly, for the treatment and/or prevention of diabetes, ainsliezubaida diabetes, high blood pressure, elevated levels of lipid and cholesterol levels, atherosclerotic diseases or syndrome metabolic disorders.

In this description, the term "alkyl", alone or in combination, signifies an alkyl group with straight or branched chain, containing from 1 to 8 carbon atoms, preferably an alkyl group with straight or branched chain, containing from 1 to 6 carbon atoms, and most preferably an alkyl group with straight or branched chain, containing from 1 to 4 carbon atoms. As a researcher who as examples of C 1-C8alkyl groups are straight or branched chain can be called methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric of Penteli, isomeric sexily, isomeric Gately and the isomeric octile, preferably methyl and ethyl and most preferably methyl.

The term "cycloalkyl", alone or in combination, refers to cycloalkyl ring containing from 3 to 8 carbon atoms and preferably cycloalkyl ring containing from 3 to 6 carbon atoms. As examples With3-C8cycloalkyl groups can be called cyclopropyl, methylcyclopropyl, dimethylcyclopropene,cyclobutyl, methylcyclobutane, cyclopentyl, methylcyclopentene, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl.

The term "alkoxy", alone or in combination, signifies a group of the formula alkyl-O-, in which the term "alkyl" has the previously given values, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, preferably methoxy, ethoxy, and most preferably a methoxy group.

The term "alkenyl", alone or in combination, refers to alkenylphenol group with a straight or branched chain, containing from 2 to 8 carbon atoms and carbon-carbon double bond, preference is sustained fashion alkenylphenol group with a straight or branched chain, containing from 2 to 6 carbon atoms, and most preferably alkenylphenol group with a straight or branched chain, containing from 2 to 4 carbon atoms. As examples With2-C8alkenyl groups with straight or branched chain include ethynyl, propenyl, Isopropenyl, butenyl, Isobutanol, isomeric pentenyl, isomeric hexenyl, isomeric heptenyl and isomeric octenyl.

The term "alkenylacyl", alone or in combination, signifies a group of formula alkenyl-O-, in which the term "alkenyl" has the previously given values. As examples of adenylate, propenyloxy, pentyloxy and preferably butenyloxy.

The term "aryl", alone or in combination, signifies a phenyl or naftalina group, preferably the phenyl group, which optionally has one or more substituents, preferably from one to three substituents, each of which is independently selected, for example, from halogen, amino, alkyl, alkoxygroup, alkylcarboxylic group, cyano, carbamoyl group, alkoxycarbonyl group, methylendioxy, carboxypropyl, alkoxycarbonyl group, aminocarbonyl group, alkylaminocarbonyl group, dialkylaminoalkyl group, a hydroxy-group, nitro, alkyl, substituted by one to three halogen atoms, is, for example, trifluoromethyl; such as phenyl, forfinal, chlorophenyl, methoxyphenyl, isopropoxyphenyl, ethylphenyl, isopropylphenyl, tert-butylphenyl, phenyl substituted by trifluoromethyl, phenyl, substituted two metal groups, phenyl substituted by two methoxypropane, phenyl, substituted by two fluorine atoms, phenyl, substituted by two chlorine atoms, phenyl, substituted stands and fluorine, or phenyl substituted by three methoxypropane.

The term "aryloxy", alone or in combination, refers to an aryl-O - group in which the term aryl is defined values. A preferred example is represented by phenoxypropane.

The term "aralkyl", alone or in combination, signifies an alkyl or cycloalkyl group, as defined previously, in which one or more, preferably one hydrogen atom substituted on the aryl group, as defined previously. The preferred groups are benzyl, benzyl, substituted hydroxy, alkoxygroup or halogen, preferably fluorine. Especially preferred is a benzyl group.

The term "amino", alone or in combination, signifies a primary, secondary or tertiary amino group attached through a nitrogen atom, with the secondary amino group is alkyl or cycloalkyl Deputy, and tertiary amino group has two similar or different alkyl or recloak is selected substituent, or two substituent of the nitrogen together form a ring, such as, for example, -NH2methylamino, ethylamino, dimethylamino, diethylamino, methylethylamine, pyrrolidin-1-yl or piperidino etc., preferably amino, dimethylamino and diethylaminopropyl, and in particular primary amino group.

The term "halogen", alone or in combination, refers to fluorine, chlorine, bromine or iodine and preferably fluorine, chlorine or bromine.

The term "carbonyl", alone or in combination, refers to a group-C(O)-.

The term "cyano", alone or in combination, refers to the group-CN. The term "heteroaryl", alone or in combination, refers to an aromatic 5 - to 10-membered heterocycle that contains one or more, preferably one or two heteroatoms selected from nitrogen, oxygen and sulfur, and sulfur is preferred. If necessary, it can be substituted by one or more carbon atoms by halogen, alkyl, alkoxygroup, cyano, halogenation and/or trifluoromethyl. Preferred heteroaryl cycles are pyridinyl or thiophene-2-yl, optionally substituted by one or more, preferably one or two substituents, independently selected from halogen, alkyl, alkoxy, cyano, halogenoalkane and trifloromethyl. Particularly preferred is thiophene-2-yl.

The term "pharmaceutically acceptable Sol is" refers to those salts, which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. Salts formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and with organic acids such as acetic acid, propionic acid, glycolic acid, peruuta acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, N-acetylcysteine, etc. In addition to this these salts can be prepared by adding inorganic or organic base to the free acid. Salts derived from inorganic bases include, without limitation, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, etc. Salts derived from organic bases include, without limitation, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic is ionoobmennye resin, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, primenenie resin and the like, the Compound of formula I may also be present in the form zwitterions. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are sodium salts.

The compounds of formula I may also be solvated, for example hydrated. Solutionone can be produced during the cooking process or can take place, for example, as a consequence gigroskopichnyh properties anhydrous beginning of soedinenii formula I (hydration). The term pharmaceutically acceptable salts include physiologically acceptable solvate.

The term "pharmaceutically acceptable esters" means that compounds of General formula (I) can be derivationally functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically unstable (labile) derivatives of esters, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additional preferred pharmaceutically acceptable esters are alkyl is s, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono - or dialkylaminoalkyl, morpholinoethyl, pyrrolidinedione, piperidinoethyl, piperazinonyl, alkylpiperazine and arylalkyl esters.

In addition, within the scope of claims of the present invention are any physiologically acceptable equivalents of the compounds of General formula (I), such metabolically labile derivatives of esters, which are capable of obtaining the original parent compounds of General formula (I) in vivo.

The term "lipase inhibitor" refers to compounds that are capable of inhibiting the action of lipase, for example, lipases of the stomach or pancreas. For example, orlistat and lipstatin, as they are described in the patent US 4598089 are potential inhibitors of lipase. Lipstatin is a natural product of microbial origin, and orlistat is a product of hydrogenation of lipstatin. Other lipase inhibitors include the class of compounds, referred to as policyname. Anglicani are analogues of orlistat (Mutoh et al., 1994). The term "lipase inhibitor" refers to inhibitors of lipase associated with the polymer, for example, described in the published international patent application WO 99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized by the fact that they replaced one the th or more groups, which inhibit lipase. The term "lipase inhibitor" also includes pharmaceutically acceptable salts of these compounds. The term "lipase inhibitor" preferably refers to orlistat.

Orlistat is a known compound used for the control or prevention of obesity and hyperlipidemia. Cm. patent US 4598089 from July 1, 1986, which also describes how to get orlistat, and the US patent 6004996, which disclosed the corresponding pharmaceutical compositions.

Other suitable pharmaceutical compositions are disclosed, for example, in the publications of international applications WO 00/09122 and WO 00/09123. Additional processes to get orlistat described in the publications of the European application EP 185359, 189577, 443449 and 524495.

Preferably orlistat administered orally in an amount of from 60 to 720 mg / day single dose two or three times a day. Preferably, when the subject is introduced from 180 to 360 mg/day, most preferably, 360 mg/day of a lipase inhibitor, preferably single doses of two or preferably three times a day. The subject is preferably a human, suffering from obesity or overweight, for example, a person with a body mass index of 25 or higher. In General, preferably a lipase inhibitor in the range of about one or two o'clock in the digestion of food containing fat. In General the m for the introduction of a lipase inhibitor, as defined above, preferably, the treatment was administered to a person with a rich family history of obesity and acquired a body mass index of 25 or higher.

Orlistat is possible to introduce people in a part of the traditional oral compositions, such as tablets, coated tablets, hard and soft gelatine capsules, emulsions and suspensions. Examples of media that can be used for tablets, coated tablets, dragées and hard gelatin capsules are lactose, other sugars and sugar alcohols type of sorbitol, mannitol, maltodextrin, or other fillers; surfactants such as sodium lauryl sulfate, Brij 96 or Tween 80; disintegrant, such as glycolate, sodium starch, corn starch or derivatives thereof; polymers such as povidone, crosspovidone; talc, stearic acid or its salts and other Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like, moreover, the pharmaceutical compositions can include conservatives, soljubilizatory, stabilizers, moisturizers, emulsification, sweeteners, substances that give color and smell, salts for modifying the osmotic pressure, buffers, covering substances and antioxidants. They may also contain other therap whitesky important matter. For convenience, the compounds may be presented in the form of single doses and can be prepared by any method known in the pharmaceutical field. Preferably orlistat is administered according to the composition shown in the examples and in the US 6004996, respectively.

Preferred are the compounds of formula I and their pharmaceutically acceptable salts, in particular the compounds of formula I.

Hereinafter, preferred are the compounds of formula I in which R3denotes alkoxygroup or alkoxygroup, substituted by one to three halogen atoms;

R5refers to a group

where the relationship between carbon atoms Withandandbrepresents a single or double carbon-carbon bond;

R6denotes hydrogen;

R7denotes hydrogen;

R8denotes hydrogen;

And denotes oxygen or sulfur; and

And1denotes nitrogen.

Hereinafter, preferred are the compounds of formula I in which R1denotes thiophenyl or phenyl, each optionally substituted from one to three, preferably one or two substituents, independently selected from halogen, alkoxygroup, alkyl or alkyl substituted by 1-3 halogen atoms. Preferred are the above compounds of formula I, in which tiof the Nile presents thiophene-2-yl.

Especially preferred are such compounds corresponding to the formula I, in which R1is thiophenyl, phenyl or phenyl substituted 1 to 3, preferably one or two substituents, independently selected from fluorine, chlorine, methoxy, ethoxy, propyloxy, isopropoxy, methyl, ethyl, propyl of isopropyl, tert-butyl and trifloromethyl. Preferred are the above compounds of formula I, in which thiophenyl represents thiophene-2-yl.

Another preferred embodiment of the present invention are the compounds of formula I in which R2denotes hydrogen, methyl or ethyl, preferably hydrogen or methyl. Particularly preferred are those compounds of formula I in which R2denotes methyl.

Preferred are the compounds of formula I in which R3denotes methoxy, ethoxy, propyloxy, isopropoxy, phenoxy or butenyloxy.

Also preferred are the compounds of formula I in which R3denotes methoxy or ethoxy. Especially preferred are those compounds in which R3indicates ethoxy.

Further preferred are the compounds of formula I in which R4denotes methyl.

Another preferred object of the present invention are the compounds of formula I, in which the s R 4denotes hydrogen.

Preferred is a compound of formula I, where R6means

and R5denotes hydrogen, alkyl or cycloalkyl and where the relationship between carbon atoms Withaandbdenotes a carbon-carbon double bond, preferably a simple carbon-carbon bond.

Especially preferred is the compound of formula I, in which R5means

and R6denotes hydrogen, alkyl or cycloalkyl and where the relationship between carbon atoms Withaandbdenotes a carbon-carbon double bond, preferably a simple carbon-carbon bond.

Also preferred are compounds corresponding to the formula I, where R6denotes hydrogen.

Further preferred are compounds corresponding to the formula I, where R7denotes hydrogen.

Another preferred object of the present invention are the compounds of formula I in which R7denotes methyl.

Further preferred are the compounds of formula I, where R8denotes hydrogen.

Another preferred object of the present invention are compounds corresponding to the formula I, where R8denotes methyl.

Preferred are compounds is ormula I, in which n denotes 1, 2 or 3. Further preferred are such compounds of formula I in which n denotes 1 or 2. Especially preferred are those compounds in which n denotes 1.

Also preferred are the compounds of formula I in which a represents sulfur. Especially preferred are those compounds of formula I in which a represents oxygen.

Preferred are compounds corresponding to the formula I, where a denotes a nitrogen and a1denotes oxygen. These compounds have the following formula:

where the substituents R1-R8and n are defined as above.

Preferred are compounds corresponding to the formula I, where a denotes a nitrogen and a1denotes sulfur. These compounds have the following formula:

where the substituents R1-R8and n have the meanings given above.

Further preferred are compounds corresponding to the formula I, where a1denotes the nitrogen and a denotes oxygen. These compounds have the following formula:

where the substituents R1-R8and n have the meanings given above.

Further preferred are compounds corresponding to the formula I, where a1oboznachaet the nitrogen and represents sulfur. These compounds have the following formula:

where the substituents R1-R8and n have the meanings given above.

The compounds of formula I can contain one or more asymmetric centers and can be presented in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomers the racemates or mixtures of diastereomeric racemates. Optically active forms may be obtained, for example, by separation of racemates using asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or suenami).

The term "asymmetric carbon atom" means a carbon atom that has four different substituent. According to the Convention Cahn-Ingold-Prelog, asymmetric carbon atom can be "R" or "S" configuration.

Preferred are chiral compounds of formula (I)in which any of the substituents R5and R6preferably R5means

and the other denotes hydrogen, alkyl or cycloalkyl, and the asymmetric carbon atom Cais in the R configuration.

Especially preferred are chiral compounds of formula(I)in which any of the substituents R5 and R6preferably R5means

and the other denotes hydrogen, alkyl or cycloalkyl, and the asymmetric carbon atom Cais in the S configuration.

Preferred are compounds corresponding to the following formula (Ie)

and their pharmaceutically acceptable salts and esters, in which

R1denotes aryl or heteroaryl;

R2denotes hydrogen, alkyl or cycloalkyl;

R3denotes alkoxygroup or alkoxygroup substituted by 1 to 3 halogen atoms;

R4denotes hydrogen, alkyl or cycloalkyl;

And denotes oxygen or sulfur;

n denotes 1, 2 or 3;

and in which the relationship between carbon atoms Withaandbdenotes a single or double carbon-carbon bond.

Further preferred are such compounds of the formula Ie, in which the relationship between carbon atoms Withaandbdenotes a carbon-carbon double bond.

These compounds have the following formula Ia

where the substituents from R1to R4And n have the meanings given above.

Especially preferred are those compounds of formula Ie, in which the relationship between the carbon atoms Caandbdenotes a simple carbon ug is irodou connection.

These compounds have the following formula Ib

where the substituents R1-R4And n have the meanings given above.

Preferred are chiral compounds of formula (Ic),

in which the substituents R1-R4And n have the meanings given above, and the asymmetric carbon atom Withais in the R configuration.

Especially preferred are chiral compounds of formula (Id),

where R1-R4And n have the meanings given above, and the asymmetric carbon atom Withais in the S configuration.

As examples of preferred compounds of formula (I) include the following:

(rat)-2-Ethoxy-3-[1-(5-methyl-2-phenyloxazol-4-ylmethyl)-1H-indol-5-yl]propionic acid;

(S)-2-Ethoxy-3-[1-(5-methyl-2-phenyloxazol-4-ylmethyl)-1H-indol-5-yl]propionic acid;

(rat)-2-Ethoxy-3-{1-[2-(2-forfinal)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(rat)-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid;

(S)-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid;

(rat)-2-Ethoxy-3-[1-(5-methyl-2-o-tolyloxy-4-ylmethyl)-1H-indol-5-yl]propionic acid;

(rat)-2-Ethoxy-3-{1-[2-(2-methox is phenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(S)-2-Ethoxy-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(rat)-2-Ethoxy-3-{1-[2-(2-isopropoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(rat)-3-{1-[2-(3-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid;

(rat)-2-Ethoxy-3-{1-[2-(4-ethylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(S)-2-Ethoxy-3-{1-[2-(4-ethylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(R)-2-Ethoxy-3-{1-[2-(4-ethylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(rat)-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(rat)-3-{1-[2-(4-tert-Butylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid;

(rat)-2-Ethoxy-3-{1-[2-(4-forfinal)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(rat)-2-Ethoxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(S)-2-Ethoxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(rat)-3-{1-[2-(3, 5dimethylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid;

(rat)-3-{1-[2-(3,5-Acid)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid;

(S)-3-{1-[2-(3,5-Acid)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-this is cypraeovula acid;

(rat)-3-{1-[2-(3,5-Differenl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid;

(rat)-3-{1-[2-(3,5-Dichlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid;

(rat)-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(S)-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(rat)-2-Ethoxy-3-[1-(5-methyl-2-thiophene-2-yl-oxazol-4-ylmethyl)-1H-indol-5-yl]propionic acid;

(rat)-2-Ethoxy-3-{1-[2-(3,4,5-trimethoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(rat)-2-Ethoxy-3-[1-(2-phenyloxazol-4-ylmethyl)-1H-indol-5-yl]propionic acid;

(rat)-2-Ethoxy-3-[1-(2-phenylthiazol-4-ylmethyl)-1H-indol-5-yl]propionic acid;

rat-2-Ethoxy-3-[1-(5-methyl-2-phenylthiazol-4-ylmethyl)-1H-indol-5-yl]propionic acid;

(rat)-3-{1-[2-(4-Chlorophenyl)thiazol-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid;

(Z)-2-Methoxy-3-[1-(5-methyl-2-phenyloxazol-4-ylmethyl)-1H-indol-5-yl]-acrylic acid;

(rat)-2-Methoxy-3-[1-(5-methyl-2-phenyloxazol-4-ylmethyl)-1H-indol-5-yl]propionic acid;

(Z)-2-Methoxy-3-{1-[2-(5-methyl-2-phenyloxazol-4-yl)ethyl]-1H-indol-5-yl} -acrylic acid;

(rat)-2-Methoxy-3-{1-[2-(5-methyl-2-phenyloxazol-4-yl)ethyl]-1H-indol-5-yl}propionic acid;

rat-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-3-m is Teal-1H-indol-5-yl} propionic acid;

rat-2-Ethoxy-3-{3-methyl-1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl}-2-ethoxypropionate acid;

rat-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl}propionic acid;

rat-2-Ethoxy-3-{2-methyl-1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-2-methyl-1H-indol-5-yl}propionic acid;

rat-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-2-methyl-1H-indol-5-yl}propionic acid;

rat-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-2-methyl-1H-indol-5-yl}-2-ethoxypropionate acid;

rat-2-Ethoxy-3-[2-methyl-1-(2-phenylthiazol-4-ylmethyl)-1H-indol-5-yl]propionic acid;

rat-3-{1-[2-(4-tert-Butylphenyl)oxazol-4-ylmethyl]-2-methyl-1H-indol-5-yl} -2-ethoxypropionate acid;

rat-3-[1-(5-Methyl-2-o-tolyloxy-4-ylmethyl)-1H-indol-5-yl]-2-propoxyphenol acid;

rat-3-{1-[2-(2-Methoxyphenyl)-5-methoxazole-4-ylmethyl]-1-indol-5-yl}-2-propoxyphenol acid;

rat-3-{1-[5-Methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}-2-propoxyphenol acid;

rat-3-{1-[5-Methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}-2-phenoxypropionic acid;

rat-3-{1-[2-(4-Of propylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-phenoxypropionic acid;

rat-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-phenoxypropionic acid;

rat-3-{1-[2-(4-Fluoro-3-were)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-phenoxypropionic acid;

rat-2-Isopropoxy-3-[1-(5-methyl-2-o-tolyloxy-4-ylmethyl)-1H-indol-5-yl]propionic acid;

rat-2-Isopropoxy-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-isopropoxypropylamine acid;

rat-2-Isopropoxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-2-but-3-enyloxy-3-[1-(5-methyl-2-o-tolyloxy-4-ylmethyl)-1H-indol-5-yl]propionic acid;

rat-2-but-3-enyloxy-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-2-but-3-enyloxy-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-2-but-3-enyloxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-2-Ethoxy-3-{2-methyl-1-[2-(5-methyl-2-phenyloxazol-4-yl)ethyl]-1H-indol-5-yl}propionic acid;

rat-2-Ethoxy-3-{2-methyl-1-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1H-indol-5-yl}propionic acid;

rat-2-Ethoxy-3-{4-methyl-1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-2-Ethoxy-3-{1-[2-(4-isopro ylphenyl)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl}propionic acid;

rat-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl}propionic acid;

rat-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl}-2-ethoxypropionate acid;

rat-3-{1-[2-(3,5-Acid)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl}-2-ethoxypropionate acid;

rat-2-Ethoxy-3-{1-[4-methyl-2-(4-triptoreline)thiazole-5-ylmethyl]-1H-indol-5-yl}propionic acid;

(Z)-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxyacrylate acid;

rat-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-6-yl}propionic acid;

rat-3-{1-[2-(3,5-Acid)-5-methoxazole-4-ylmethyl]-1H-indol-6-yl}-2-ethoxypropionate acid and

rat-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)thiazole-4-ylmethyl]-1H-indol-6-yl}-propionic acid.

As examples of particularly preferred compounds of formula (I) include the following:

(S)-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid;

(S)-2-Ethoxy-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(S)-2-Ethoxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl} propionic acid;

(S)-3-{1-[2-(3,5-Acid)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid and

(S)-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole--ylmethyl]-1H-indol-5-yl}propionic acid.

As examples of particularly preferred compounds of formula (I) include the following:

(S)-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid;

(S)-2-Ethoxy-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(S)-2-Ethoxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(S)-3-{1-[2-(3,5-Acid)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid;

(S)-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-2-Ethoxy-3-{3-methyl-1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl}-2-ethoxypropionate acid;

rat-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl}propionic acid;

rat-3-{1-[5-Methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}-2-propoxyphenol acid;

rat-2-Isopropoxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-2-but-3-enyloxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid; and

rat-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl}propionic acid.

Before occhialini is the connection (S)-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid and its pharmaceutically acceptable salts and esters. Especially preferred is the compound (S)-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid.

Methods for obtaining compounds of formula I are the object of the present invention.

Deputies and signs used in the subsequent description of the methods have the above meanings, unless otherwise indicated.

Compounds of General formula (I), especially compounds

corresponding to the formula (If) or (Ig), in which the substituents R1-R8And, As1and n are as defined above values can be obtained in accordance with scheme I.

Scheme I

A similar reaction scheme with the same sequence of reactions applicable to a number of isomeric compounds, with the aim of obtaining compounds of General formula (I), in particular, compounds of formula (Ih) or (Ii)

the substituent in the 6 position of the indole.

Aldehydes (1) can be brought into interaction with Wittig salt [as, for example, described in Tetrahedron, (1994), t(25), SS-56], such as (1,2-diethoxy-2-oxoethyl)triphenylphosphine chloride or (1-methoxy-2-benzyloxyethyl)triphenylphosphine chloride in solvents such as isopropanol, dichloromethane or tetrahydrofuran or a mixture thereof, in the presence of a base such as potassium carbonate or tetramethylguanidine, preferably at a temperature between 0°and the boiling temperature of the solvent, obtaining a complex acrylic esters (2) in the form E and/or Z isomers. N-alkylation of indoles (2) heterocycles (3) can be carried out in a solvent such as N,N-dimethylformamide or N-organic in the presence of such bases as sodium hydride or tert-butyl potassium, preferably at temperatures between 0°C and room temperature, followed by hydrolysis of the ester group preferably using LiOH or NaOH in a mixture of solvents such as dioxane/water, tetrahydrofuran or ethanol/water, preferably at temperatures between 0°and room temperature to obtain acrylic acid (If). Alternatively, the formation in situ of acrylic acid (If) can be carried out by treatment of indoles (2) heterocycles (3) in the presence of KOH or DMSO at a temperature between 0°s and 80°C, preferably at 22°C.

Catalytic hydrogenation of the compounds (If) in the presence of palladium on coal in solvents such as methanol, ethanol, dichloromethane or tetrahydrofuran or mixtures thereof leads to indolepropionic acids (Ig).

Alternatively, compounds of General formula (Ig), in which R1-R8And, As1and n have the previously defined meanings, can be obtained in accordance with scheme II:

Scheme II

img src="https://img.russianpatents.com/842/8425839-s.jpg" height="127" width="166" >

A similar reaction scheme with the same sequence of reactions applicable to a number of isomeric compounds, with the aim of obtaining compounds of General formula (I), in particular compounds of the formula (Ii)

bearing

the substituent in the 6 position of the indole.

Another in a compound (Ig) in accordance with scheme II should be applied mainly in the case where the radicals R3, R4, R5, R6, R7and R8are constant, a R1, R2and And And1and n change, and when synthesized homochiral compounds, followed by reaction of the same type, as shown in Scheme I. In addition, the formation in situ of the compounds (Ig) can be done by processing a mixture of indoles (4) and heterocycles (3) an excess of sodium hydride in a solvent such as N,N-dimethylformamide, at temperatures between 0°C and room temperature, which directly leads to acids (Ig). Homochiral acid (Ig) can be obtained by the preparation of optically pure or optically enriched intermediate (e.g., enzymatic decomposition into constituent parts racemic esters (4) using, for example, lipase, followed by esterification decomposed acids after separation) and subsequent TRANS is armacia such optically pure or optically enriched esters (4) in optically pure or optically enriched acid (Ig). Alternatively, racemic or optically enriched acid (Ig) can be separated into their antipodes known in the field methods, such as separation of the antipodes via their diastereomeric salts by crystallization with optically pure amines, such as (R) or (S)-1-phenylethylamine, (R) or (S)-1-naphthalene-1-ylethylamine, brucine, quinine or quinidine or by separation of the antipodes special chromatographic methods using either a chiral adsorbents, or chiral eluents.

Compounds of General formula (I), especially compounds in which R5takes different values can be obtained in accordance with Scheme III:

Scheme III

A similar reaction scheme with the same sequence of reactions applicable to a number of isomeric compounds with the aim of obtaining compounds of General formula (I), in particular compounds of the formula (Ii)

bearing

the substituent in the 6 position of the indole.

Formylindole (5)having a suitable protective functional group on the nitrogen of the indole group, for example, 2-trimethylsilylamodimethicone group (SAM) or benzosulfimide group can react with enolate esters of alkoxy-, alkenylacyl or aryloxyacetic acids(preferably obtained at -78° With in a solvent such as tetrahydrofuran, in the presence of a base, such as diisopropylamide lithium) at low temperature with getting Andolini compounds (6) in the form of a mixture of diastereomeric racemates. Compound (6) can be converted into indolepropionic acid (4) through different routes of synthesis depending on the protective group and the nature of the radical R3. If R3contains a double bond, and the protection of the functional group of the indole is used benzolsulfonat group, then preferably apply the following two-stage methodology: 1) removal of water treatment p-toluensulfonate in a solvent such as benzene, preferably by boiling; 2) reaction with magnesium in methanol at reflux, with the intent of restoring the double bond and removal of the protective group. If R3contains no double bond, and the protection of the functional group of the indole is used 2-trimethylsilylamodimethicone group (SAM), then preferably use the following platitudinous methodology: 1) processing methanesulfonamido in a solvent such as dichloromethane, followed by treatment, for example, 1,8-diazabicyclo[5.4.0.]undec-7-Yong(1,5,5) in a solvent such as tetrahydrofuran, preferably at povyshen the th temperature obtaining unsaturated ester compounds as a mixture of E and/or Z isomers; 2) hydrogenation of the double bond in the presence of, for example, palladium on coal in a solvent such as ethanol; 3) saponification of the ester group using standard conditions; 4) removing the protective group using, for example, Tetra-butylammonium fluoride (in the form of a solution in tetrahydrofuran) in a solvent such as N,N-dimethylformamide, in the presence of Ethylenediamine in a preferred temperature range between 50°s and 80°S; 5) re-esterification using, for example, under the conditions, sodium hydrogen carbonate in N,N-dimethylformamide. Can then be carried out the conversion of compounds (4) in the compounds (Ig) by condensation with carbonyl compounds (3) as shown in Schemes I and II.

5-Formylindole (1)in which R6represents hydrogen, alkyl ricecooker, or the corresponding 6-formyl analogues, in which R5represents hydrogen, alkyl or cycloalkyl used as starting materials in Scheme I are known compounds or can be synthesized by methods known in this field. Some selective synthetic route to obtain 5-formylindole (1), which are also applicable for the synthesis of 6-formylindolo shown in Scheme IV.

Scheme IV

R stands for alkyl;

R' denotes hydrogen or alkyl.

Prevremeni the halogenated indoles (7) in formylindole (1) can be carried out, for example, by treatment of the corresponding bromo - or Odendaal this reagent, as alkylate, for example, n-utility, in a solvent such as tetrahydrofuran, preferably at -78°followed by treatment of N,N-dimethylformamide or carbonyliron halogenated indoles (7) carbon monoxide at a pressure of 30-50 bar in solvents such as toluene or benzene, in the presence of a suitable catalyst (e.g. palladium catalyst at temperatures between room temperature and 200° [compare, for example, Angew Chem., international edition England, (1989), T. 28 (10), s] (stage b). Alternatively, formylindole (1) can be obtained from substituted with halogen indoles (7) or 2-carboxyaldehyde (8) by treatment with copper cyanide (I) in quinoline at temperatures between 200°and 270° (compare Liebigs Ann. Chem., (1975), cc.160-194) with subsequent restoration educated so NITRILES by hypophosphite sodium in the presence of Raney Nickel, preferably in a mixture of water, acetic acid and pyridine at temperatures in the range between room temperature and 60° [compare Helvetica Chimica Acta, (1968), t, s-1628] (stage b or C). Substituted with halogen indoles (7) with R7=N by the choice can be obtained from 2-carboxyaldehyde (8) in a solvent such as quinoline, in the presence of catalysis is the Torah decarboxylation, such as copper dust at temperatures between 200°and 270°With (stage a). Formylindole (1) with R7=H can be converted into a corresponding analogue in which R7=alkyl, using methods shown in Scheme IV: 1) introduction of functional protective group for the nitrogen atom of the indole, for example, benzolsulfonate group (for example, using benzosulfimide, tetrabutylammonium hydrosulfate in toluene / 50% aqueous sodium hydroxide); 2) protection of the aldehyde functional group, for example, in the form of dialkylated (stage g); 3) introduction of the substituent R7the first processing, for example, tributyltin in a solvent such as tetrahydrofuran, at temperatures between -70°C and room temperature, followed by reaction with alkylhalogenide at temperatures between -70°C and room temperature (stage d); 4) removing the protective group of the aldehyde, followed by reduction of the corresponding primary alcohol; 5) removing the protective group of the indole, for example, removing benzolsulfonate group using potassium hydroxide in methanol at elevated temperatures; 6) re-oxidation of the primary alcohol to the aldehyde, for example, using conditions Swarna (oxalicacid/dimethylsulfoxide/triethylamine in dichloromethane, -78°C to room temperature) (stage e).

Possible ways si the importance of 2-carboxyaldehyde (8) is shown in Schemes XII and XIII.

The initial compounds of the formula (3), in which a denotes oxygen, and1denotes the nitrogen and n is 1 or 2, can be obtained, for example, according to Scheme V.

Scheme V

Aldehydes (1a) are commercially available or known. They are introduced in the condensation with diatomaceae (2A) in accordance with how it is described in the literature (Goto Y.; Yamazaki, M.; Hamana, M.; Chem. Pharm. Bull., (1971), t, s) in the presence of a strong acid, typically HCl, in a polar solvent such as Asón, to obtain oxazol-N-oxide (3A) (stage a). Subsequent processing using POCl3in dichloromethane at reflux receive appropriate primary chlorides (4A) (Goto Y.; Yamazaki, M.; Hamana, M.; Chem. Pharm. Bull., (1971), t, s, stage b). These intermediate used either as such, turned well-known methods into the corresponding alcohols or activated alcohols, such as mesylates or tozilaty or bromides or iodides, or eventually developed further through SN2-reaction with NaCN, leading through the NITRILES 5A (stage b), the complete hydrolysis (stage d) and recovery (stage d), for example, borane in tetrahydrofuran, to "building blocks" (7a). Finally, alcohols (7a) can be converted into compounds of the formula (3), for example, by treatment with methanesulfonamide in dichloromethane in presets is under such grounds, as triethylamine, preferably in the temperature range between -20°and room temperature or by reaction with carbon tetrachloride or tetrabromide carbon and triphenylphosphine in a solvent such as tetrahydrofuran, preferably in the temperature range between room temperature and the boiling temperature of the solvent, which leads to compounds of the formula (3) in the form of methansulfonate, chlorides or bromides, respectively.

4-Chloromethyl-2-aryl - or 2-heteroepitaxial (4A) with R2equal to hydrogen, preferably obtained from the corresponding aryl or heteroaryl of carboxamido and 1,3-dichloroacetone, as described, for example, in Bioorg. Med.Chem.Lett., (2000), V.10(17), SS-2044.

The initial compounds of the formula (3), in which a denotes oxygen, and1denotes the nitrogen, and n means 3 can be obtained, for example, according to Scheme VI:

Scheme VI

Esters of N-acylpyrin (1b) are either commercially available, known or can be obtained by using the standard operations of N-acylation. Monoethylamine esters (2b) can be easily obtained by double deprotonation (1b) using a strong dinucleophiles base, such as LiHMDS, in an aprotic solvent such as THF, -78°followed the treatment allylbromide obtaining selectively S-alkyl products (2b) (stage a). Standard hydrolysis receive the intermediate acid (3b) (stage b), then, following the well-developed in the literature methodology (J.Med.Chem., (1996), t, s), translated into compounds (4b) (stage b).

Closing the ring getting oxazole using as reagents triperoxonane acid and anhydride triperoxonane acid leads to the key intermediate (5b) (stage g), which is subjected to transformations through hydroboration, for example, using 9-BBN in THF and then the next oxidative processing of N2About2and NaOH (stage d), and eventually get the target alcohols (6b). Finally, alcohols (6b) can be converted into compounds of the formula (3), for example, by treatment with methanesulfonamide in dichloromethane in the presence of such a base as triethylamine, preferably in a temperature range between -20°C and room temperature, or by reaction with carbon tetrachloride or tetrabromide carbon and triphenylphosphine in a solvent such as tetrahydrofuran, preferably in the temperature range between room temperature and the boiling temperature of the solvent; thereby obtaining the compounds of formula (3) in the form of methansulfonate, chlorides or bromides, respectively.

The initial compounds of the formula (3)where And denotes sulfur, and1denotes the nitrogen Fe means 1, can be obtained, for example, according to Scheme VII:

Scheme VII

Thioamides (1C) are known compounds or they can be obtained well-known in the field of methods, for example, by treatment of the corresponding carboxamide by pentasulfide phosphorus or a reagent of Lawesson [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide], in a solvent such as toluene, preferably at a temperature between 60°and the boiling point of the solvent. Thioamides (1C) can be condensed with 1,3-dichloroacetone in a solvent such as acetone or acetonitrile, in the temperature range between room temperature and the boiling temperature of the solvent, followed by treatment in a strong acid, e.g. concentrated sulfuric acid, preferably at ambient temperature, thus leading to chloromethylene compounds (3C) (stage a). Alternatively, thioamides (1C) condense with alpha-bromo - or alpha chloretone (4C) in a solvent such as ethanol, preferably at the boiling point, with getting aryldiazonium (5), bearing a methyl functional group in position 4 (stage b) [EP 207453 A2]. Chloromethylene compounds (6C) is obtained by processing data of aryldiazonium (5C) N-chlorosuccinimide in a solvent such as acetonitrile, before occhialino at boiling point (stage) [compare with the publication of the international application WO 0119805 A1].

The initial compounds of the formula (3)where And denotes sulfur, and1denotes the nitrogen, and n represents 2 or 3, can be obtained, for example, according to Scheme VIII:

Scheme VIII

Condensation thioamides (1d) with a suitable bis-electrophilic compound, for example, methyl 4-bromo or 4-chloro-3-oxoalcohols (2d), preferably in a solvent such as toluene, at elevated temperatures (for example, at the boiling point), leads to triazolam (3d), supporting the functional group of ether acetic acid in position 4 (stage a) [compare with the publication of the international application WO 97/31907 A1]. 4-Bromo-3-exulcerate (2d) are known compounds or can be obtained well-known in the field methods [compare with the publication of the international application WO 01/79202 A1]. Thiazole (3d) can then be recovered, for example, lithium aluminum hydride, to thiazolo (4d) (stage b). The selection can be carried out by lengthening the side chain by standard methods, such as the transformation of the alcohol functional group in tsepliaeva (deleted) group, for example, mesilate, followed by treatment with a cyanide, saponification and restoring receiving thiazolo (5d) with hydroxypropyl functional group attached at position 4 (stage b). Ultimately, alcohols (4d) and (5d) can be activated is about mesylates or tozilaty using known standard methods.

The initial compounds of the formula (3)where And denotes sulfur, and1denotes the nitrogen and n is 1, can be obtained, for example, according to Scheme IX.

Scheme IX

Thioamides (1e) are known compounds or they can be obtained well-known in the field of methods, for example, by treatment of the corresponding carboxamide with pentasulfide phosphorus or a reagent of Lawesson [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide], in a solvent such as toluene, preferably at a temperature between 60°and the boiling point of the solvent. Thioamides (1E) can be introduced into the reaction with alkyl-2-halogenoacetyl (2E) in a solvent such as ethanol, preferably at the boiling point, with the production of esters diazocarbonyl acid (3E) (stage a). The recovery of these esters (3E), preferably using lithium aluminum hydride in a solvent such as a simple ether or tetrahydrofuran, preferably between 0°and room temperature leads to primary alcohols (4E) (stage b), which can be used by themselves or can be converted into the corresponding haloesters compound (5e), for example, by treatment with methanesulfonamide in dichloromethane in the presence of 2,6-lutidine, preferably between -20� C and the boiling point of dichloromethane [compare with the publication of the international application WO 02/28433], by treatment with thionyl chloride in a solvent such as dichloromethane or chloroform, preferably at temperatures between -20°C and +50°or treatment tetrabromomethane, triphenylphosphine in a solvent such as tetrahydrofuran at temperatures between 0°and a boiling point of tetrahydrofuran (stage b).

The initial compounds of the formula (3), in which a denotes oxygen, and1denotes the nitrogen and n is 1, can be obtained, for example, according to Scheme X.

Scheme X

4-Substituted 2-allocator-5-carboxylates (2f) (R2denotes alkyl or cycloalkyl group) can be obtained from N-karamanoglu (1f), as described in J.Chem.Soc., Chem. ComMun., (1995), SS-2336: 1) N-availabililty (1f) is treated with oxalylamino in a solvent such as benzene, dichloromethane or tetrahydrofuran, preferably at room temperature, followed by evaporation with the addition of toluene; 2) thus obtained crude intermediate is treated with triethylamine and alcohol, preferably between 0°C and room temperature (stage a). The restoration of the well known techniques of the ester group in the compound (2f), for example, using diiso is utilityrelated in such a solvent, as tetrahydrofuran, leads to primary alcohols (3f) (stage b). Finally, alcohols (3f) can be converted into compounds of the formula (3), for example, by treatment with methanesulfonamide in dichloromethane in the presence of such a base as triethylamine, preferably in a temperature range between -20°C and room temperature, or by reaction with carbon tetrachloride or tetrabromide carbon and triphenylphosphine in a solvent such as tetrahydrofuran, preferably in the temperature range between room temperature and the boiling temperature of the solvent; thereby obtaining the compounds of formula (3) in the form of methansulfonate, chlorides or bromides, respectively.

The initial compounds of the formula (3)in which n represents 2 or 3, can be obtained from the parent compounds of formula (3), in which n denotes 1 or 2, for example, according to Scheme XI.

Scheme XI

Relaxazone alcohols or aryldiazonium alcohols (1g) with chain length, containing n carbon atoms, can be transformed into their counterparts with chain length, containing n+1 carbon atoms, by means well known in the field of methods (Scheme XI), for example, by transformation group of the primary alcohol into a suitable removable group, for example, halide (stage a), reacts is it with cyanide ion (stage b), the saponification (stage), followed by reduction of the formed acid (compound (4g)) to primary alcohols (5g), for example, using DIBORANE in tetrahydrofuran (stage g). Finally, alcohols (5g) can be converted into compounds of the formula (3), for example, by treatment with methanesulfonamide in dichloromethane in the presence of such a base as triethylamine, preferably in a temperature range between -20°C and room temperature, or by reaction with carbon tetrachloride or tetrabromide carbon and triphenylphosphine in a solvent such as tetrahydrofuran, preferably in the temperature range between room temperature and the boiling temperature of the solvent; thereby obtaining the compounds of formula (3) in the form of methansulfonate, chlorides or bromides, respectively.

The initial compounds of the formula (8) can be obtained, for example, according to Scheme XII or Schema XIII:

Preparation of 2-carboxyaldehyde (8)where R6represents hydrogen, alkyl or cycloalkyl through reactions Fisher for the synthesis of indole shown in Scheme XII; schema describes the synthesis of 5-haloperidolum, but equally applicable to the synthesis of 6-haloperidolum, in which R5represents hydrogen, alkyl or cycloalkyl:

Scheme XII (part a)

Scheme XII (part b)

R stands for alkyl.

Halogenation (1h) can be transformed into diasability of Meldrum (3h) by diazotization of halogenosilanes (1h) using, for example, sodium nitrite in aqueous acid at a temperature of approximately 0°s, followed by reaction with acid Meldrum (2h) in a mixture of solvents, such as ethanol/water, preferably at a pH close to neutral, and in the temperature interval between 0°s and 60°With (compare with Organic Process Research & Development, (1998), Vol.2, SS-220) (stage a). Processing (3h) - alcoholate, preferably sodium ethylate, in the corresponding alcohol, preferably at room temperature leads to the hydrazones (6h) (compare with Organic Process Research & Development, (1998), Vol.2, SS-220) (stage b). Alternatively, halogenation (1h) can be converted into the hydrazine (4h), for example, by treatment with sodium nitrite in hydrochloric acid, preferably at temperatures between -10°C and room temperature, with subsequent stepwise recovery of the formed diazonium salts with, for example, tin(II)chloride, preferably in a similar temperature range (stage b). Hydrazines (4h) can then be processed derivatives pyruvate acid (5h) in a solvent such as dichloromethane or toluene, preferably in the temperature range between room is the temperature and the boiling temperature of the solvent, optional with removal of water formed by using molecular sieves or using traps Dean stark obtaining hydrazones (6h) (stage g). Can then be carried out the formation of indoles by processing hydrazones (6h), for example, a strong acid, such as sulfuric acid or p-toluensulfonate, in a solvent such as toluene or xylene, preferably at an elevated temperature up to the boiling point of the solvent, or polyphosphoric acid as reagent and solvent, preferably at temperatures between 150°200°With (compare with J.Chem.Soc., (1955), cc.3499-3503) (stage d). On the basis of asymmetric halogenosilanes (1h), formed isomers indole 7h and 7'h. These two isomers can be separated by known in the field methods, for example, by chromatography or crystallization. Isomer 7h and isomer 7'h may serve as intermediate compounds to obtain the desired 2-carboxyaldehyde (8), which is obtained by saponification of esters of indole (7h or 7'h), for example, using lithium hydroxide in a mixture of dioxane and water at a temperature range between room temperature and 80°With (stage e).

Preparation of 2-carboxyaldehyde (8), in which R6represents hydrogen, alkyl or cycloalkyl based on derivatives of ortho-nitrobenzaldehyde, is provided in Scheme XIII; this scheme describes the synthesis of 5-haloperidolum, but it is equally applicable to 6-haloperidolum, in which R5represents hydrogen, alkyl or cycloalkyl:

Scheme XIII

R stands for alkyl.

Derivatives of ortho-nitrobenzaldehyde (1i) is injected into the reaction with Wittig salt, such as chloride (1,2-diethoxy-2-oxoethyl)triphenylphosphine in a solvent such as isopropanol, dichloromethane or tetrahydrofuran or a mixture thereof in the presence of such a base as potassium carbonate or tetramethylguanidine, preferably between 0°and the boiling point of the solvent, obtaining esters nitrophenylarsonic acid (2i) in the form E and/or Z isomers (stage a). The recovery of esters nitrophenylarsonic acid (2i), for example, metal powder in a solvent such as acetic acid, preferably between 60°and 100°leads to complex aminopenicillin esters (3i) (stage b). Acetylation under standard conditions difficult aminopenicillanic esters (3i) (for example, acetylchloride, triethylamine in dichloromethane between 0°C and room temperature) (stage b), leads to compounds (4i), which undergo the formation of indole in the processing of a strong acid, such as p-toluensulfonate in a solvent such as toluene, preferably at a temperature of to the singing of the solvent (stage g). Saponification of esters of indole (5i), for example, using lithium hydroxide in a mixture of dioxane and water in the temperature range between room temperature and 80°then leads to 2-carboxyaldehyde (8, R4=H) (stage d).

The transformation of compounds of formula I in a pharmaceutically acceptable salt can be carried out by the processing of such compounds, inorganic acid, for example, hydrohalogenation acid, such as, for example, hydrochloric acid or Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acid, such as, for example, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate acid or p-toluensulfonate. The corresponding salts of carboxylic acids can also be prepared from compounds of formula I by treatment with physiologically compatible bases, such as sodium hydroxide or potassium hydroxide, or tertiary amines, such as triethylamine.

The conversion of compounds of formula I in a pharmaceutically acceptable esters or amides can be carried out, for example, treatment with a suitable amino - or hydroxyl groups present in the molecules of carboxylic acid, such as acetic acid, in the presence of a condensing reagent such as hexaphosphate benzotri the evils-1-yloxytris(dimethylamino)phosphonium (THIEF) or N,N-dicyclohexylcarbodiimide (DCCI) with the formation of ether carboxylic acids or carboxylic acid amide.

Preferably, the conversion of compounds of formula I in a pharmaceutically acceptable esters can be carried out, for example, treatment of compounds of formula I in the presence of a condensing reagent such as hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (THIEF) or N,N-dicyclohexylcarbodiimide (DCCI) and 4-dimethylaminopyridine the corresponding alcohol in a solvent such as, for example, N,N-dimethylformamide, according to methods known in the art.

Preferably, the method of obtaining the compounds corresponding to formula I, includes one of the following reactions:

a) reaction of a compound corresponding to the formula

in the presence of compounds corresponding to the formula

b) reaction of the compound corresponding to the formula

in the presence of compounds corresponding to the formula

b) hydrogenation of the compounds corresponding to the formula

where

R3denotes alkoxygroup or alkoxygroup, substituted by one to three halogen atoms; R3means

moreover, the relationship between carbon atoms Withaandbdenotes a carbon-carbon simple is whether the double bond; R6denotes hydrogen; R7denotes hydrogen; R8represents hydrogen; represents oxygen or sulfur; And1represents nitrogen; X denotes halogen or CH3SO3and R denotes alkyl, aryl or arylalkyl.

Further, preferred is a method for obtaining compounds corresponding to formula I, comprising one of the following reactions:

a) reaction of a compound corresponding to the formula

in the presence of compounds corresponding to the formula

where any one of the radicals R5and R6means

and the other denotes hydrogen, alkyl or cycloalkyl and where the relationship between carbon atoms Withaandbdenotes a carbon-carbon single or double bond; X represents halogen or CH3SO3; R denotes alkyl, aryl or arylalkyl; the radicals R1-R4, R7, R8, A, A1and n have the meanings given above. Preferred is the above reaction in a solvent such as N,N-dimethylformamide or N-organic, in the presence of such a base, such as sodium hydride or tert-butyl potassium, preferably between 0°C and room temperature, followed by hydrolysis of the ester function, preferably is using LiOH or NaOH in a mixture of solvents, as dioxane/water, tetrahydrofuran or ethanol/water, preferably between 0°C and room temperature. More preferred is the above reaction in the presence of KOH in DMSO at a temperature between 0°s and 80°C, preferably at 22°C.

b) hydrogenation of the compounds corresponding to the formula

in which any one of the radicals R5and R6means

and the other denotes hydrogen, alkyl or cycloalkyl; and the relationship between carbon atoms Withaandbdenotes a carbon-carbon double bond; R1-R4,R7, R8And, As1and n have the above specified values.

It is preferable hydrogenation in the presence of palladium on coal in solvents such as methanol, ethanol, dichloromethane or tetrahydrofuran or mixtures thereof.

Preferred intermediate compounds are:

ethyl ester of (Z)-2-ethoxy-3-(1H-indol-5-yl)acrylic acid;

ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid;

(S)-2-ethoxy-3-(1H-indol-5-yl)propionic acid;

methyl ester of (S)-2-ethoxy-3-(1H-indol-5-yl)propionic acid;

ethyl ester of (R)-2-ethoxy-3-(1H-indol-5-yl)propionic acid;

benzyl ether of (Z)-3-(1H-indol-5-yl)-2-ethoxyacrylate acids;

ethyl ester of p is C-2-ethoxy-3-(3-methyl-1H-indol-5-yl)propionic acid;

ethyl ester rat-2-ethoxy-3-(2-methyl-1H-indol-5-yl)propionic acid;

methyl ether rat-3-(1H-indol-5-yl)-2-propoxyphenol acids;

methyl ether rat-3-(1H-indol-5-yl)-2-phenoxypropionic acids;

methyl ether rat-3-(1H-indol-5-yl)-2-isopropoxypropylamine acids;

methyl ether rat-2-but-3-enyloxy-3-(1H-indol-5-yl)propionic acid;

ethyl ester rat-2-ethoxy-3-(4-methyl-1H-indol-5-yl)propionic acid and

ethyl ester rat-2-ethoxy-3-(1H-indol-6-yl)propionic acid.

As described above, the compounds of formula (I) of the present invention can be used as medicines for the treatment and/or prevention of diseases which are modulated by agonists RAPPα and/or RAPPγ. Examples of such diseases are diabetes, particularly leisureservices diabetes, high blood pressure, elevated lipid levels and cholesterol, atherosclerosis, syndrome disorders of metabolism, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic defeat ovarian cancer, inflammatory diseases (such as, for example, inflammation of the crown, inflammatory bowel disease, colitis, pancreatitis, cholestasis/fibrosis of the liver, and diseases that have an inflammatory component, such as, for example, Alzheimer's disease or defeat/pedause is by improving cognitive function and proliferative diseases (cancers, such as, for example, liposarcoma cancer, colon cancer, prostate cancer, pancreatic cancer and lung cancer). Use as a medicinal product for the treatment and/or prevention ainsliezubaida diabetes is preferred.

The compounds of formula I, described above for use as therapeutically active substances, is the next object of the present invention. Preferred is the use as therapeutically active substances for the prevention and/or treatment of diabetes, ainsliezubaida diabetes, high blood pressure, elevated levels of lipid and cholesterol, atherosclerosis, syndrome metabolic disorders, and particularly preferred is leisureservices diabetes.

Also, the object of the invention is the above-described compounds for the preparation of drugs for the treatment and/or prevention of diseases which are modulated by agonists RAPPα and/or RAPPγpreferably for the manufacture of medicines for the treatment and/or prevention of diabetes, ainsliezubaida diabetes, high blood pressure, elevated levels of lipid and cholesterol, atherosclerosis, syndrome metabolic disorders, and particularly preferred is reinsel nesavisimy diabetes.

Similarly, the object of the present invention are pharmaceutical compositions containing a compound of the formula I described above and a therapeutically inert carrier. Another object of the present invention is the above pharmaceutical composition, optionally containing a therapeutically effective amount of a lipase inhibitor, particularly, when the lipase inhibitor is represented by orlistat.

The object of the invention is also the use of the above compounds for the preparation of drugs, in particular for the treatment and/or prevention of diseases which are modulated by agonists RAPPα and/or RAPPγ, preferably of diabetes, ainsliezubaida diabetes, high blood pressure, elevated levels of lipid and cholesterol, atherosclerosis, syndrome metabolic disorders, and particularly preferred is leisureservices diabetes.

The next object of the present invention is the use of compounds of formula I in the manufacture of medicinal products for the treatment and/or prevention of diseases which are modulated by agonists RAPPαand/or RAPPγ, in a patient who receives treatment with the lipase inhibitor. Preferred is the above-mentioned application, wherein the lipase inhibitor is represented orlist the volume. Especially preferred is the above application for the treatment and/or prevention of diseases in which the disease presents with diabetes, leisureservices diabetes, high blood pressure, elevated lipid levels and cholesterol, atherosclerosis, syndrome metabolic disorders, and particularly preferred is leisureservices diabetes.

The following object of the present invention includes compounds that are produced in accordance with one of the above methods.

Another object of the invention is a method of treatment and/or prevention of diseases which are modulated by agonists RAPPα and/or RAPPγ preferably diabetes, ainsliezubaida diabetes, high blood pressure, elevated levels of lipid and cholesterol, atherosclerosis, syndrome metabolic disorders, and particularly preferably ainsliezubaida diabetes, which is administered an effective amount of compounds of formula I. Another object of the present invention is the above method, which additionally includes an introduction to the human a therapeutically effective amount of a lipase inhibitor, particularly, when the lipase inhibitor is represented by orlistat. The above method for simultaneous, separate or is using serial injection is also an object of the present invention.

Methods of analysis

To determine the activity of compounds of the formula I can be applied the following tests.

Background information on current methods of analysis can be found at: Nichols JS, et al., "Development of a scintillation proximity assay for peroxisome proliferator - activated receptor gamma lig and binding domain", (1998), Anal. Biochem., t, s-119.

The cDNA clones of the full length human RAPPαand a mouse RAPPγ were obtained by polymerase chain reaction (PCR) at room temperature (K.T.) from adipose person and liver cDNA mouse, respectively, cloned into a plasmid vector and verified by DNA sequencing. Constructed of bacterial and human expression vectors to produce glutathione-s-transferase (GT), and proteins of the DNA binding domain of Gal4 fused with the ligand binding domain (LSD) RAPPγ (amino acids (AA) 174 to 476) and RAPPα (aa 167 to 469). To do this, part of the cloned sequences encoding these LSD, amplified from the full length clones by PCR and then subcloning in plasmid vectors. The final clones confirmed by analysis of DNA sequences.

The induction, expression and purification of the fused protein GT-LSD is carried out in cells of E. coli strain BL21(pLysS) by standard methods (reference: Current Protocols in Molecular Biology, Wiley Press, the publishing house Ausubel et al.).

Analysis of the binding of radioligand

Linking the recipe is RA RAPPα analyze buffer TCE (10 mm Tr denotes - HCl, pH 8, 50 mm KCl, 2 mm EDTA, 0.1 mg/ml bovine serum albumin (BSA), free fatty acids, and 10 mm DTT). In each of the 96 wells incubated at 2.4 μg equivalent fused protein GT-RAPPα-LSD and radioligand, for example, 40000 number of decays/min 2(S)-(2-benzoylamino)-3-{4-[1,1-detriti-2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid in a volume of 100 μl with K.T. within 2 hours Associated ligand is removed from unbound ligand by solid-phase separation using layer MultiScreen (Millipore), filled with 80 μl SG25, in accordance with the manufacturer's recommendations.

Receptor binding RAPPγ analyze in TCE (50 mm Tr denotes-HCl, pH 8, 50 mm KCl, 2 mm EDTA, 0.1 mg/ml BSA, free fatty acids, and 10 mm DTT). In each of the 96 reactions in the wells 140 ng equivalent fused protein GT-RAPPγ-LSD is associated with a 10 µg grains of sodium polyacrylate (SPA) (PharmaciaAmersham) in a final volume of 50 ál with shaking.

The obtained suspension is incubated for 1 h at K.T. and centrifuged for 2 min at 1300 g. The supernatant containing unbound protein was removed and the semi-rounded granules containing coated with receptor grain, dissolved in 50 µl of buffer, DE. To associate with radioligands add, for example, 10000 number of decays/min 2(S)-(2-benzoylamino)-3-{4-[1,1-detriti-2-(5-methyl-2-FeNi is oxazol-4-yl)ethoxy]phenyl}propionic acid in 50 ál, the reaction is incubated at K.T. within 1 h and shall count scintillation coincidence. All analyses linking is carried out in a 96-well tablets and the amount of bound ligand is measured on the instrument Packard TopCount using optical plates (OptiPlates (Packard company). The nonspecific binding determined in the presence of 10 M disjoint connections. Curves dose-response build on the results of three repetitions in the concentration range from 10-10M to 10-4M

Analyses of transcriptional reporter gene luciferase kidney Cells baby hamster (VNC ADS CCL10) grown in medium Needle, modified, Dulbecco (DMEM)containing 10% FBS at 37°C in an atmosphere of 95%O2:5%CO2. Cells were seeded in 6-well plate at a density of 10 cells/well and then randomly parties transferout expression plasmids or pFA-RAPPγ-LSD, or pFA-RAPPα-LSD plus a reporter plasmid pFR-luc and expression of the plasmid that encodes secreterial the form of alkaline phosphatase (SEAP) as a normalization control. Transfection is performed with the use of reagent Fugene 6 (Roche Molecular Biochemicals) according to the recommended methodology. After 6 h after transfection, the cells are harvested by trypsinization and seeded in 96-well plates at a density of 10 cells/well. Wednesday will be removed after 24 h, in order to let the b cells to attach, and replaced with 100 μl of medium free of phenol red, containing the test substance or reference ligand (final concentration of 0.1% DMSO). After incubation of cells for 24 h with substances that emit 50 μl of the supernatant and analyzed in relation to the activity of SEAP (Roche Molecular Biochemicals). The remaining discard supernatant, add 50 ál of PBS into the hole and then one lung volume of the reagent constant luciferase (Roche Molecular Biochemicals) for lizirovania cells and initiation of the luciferase reaction. Measure the luminescence of SEAP and luciferase in the instrument Packard TopCount. The normalize luciferase activity using control SEAP, and transcriptional activity in the presence of the test substance is expressed as the excess activity compared with cells incubated in the absence of the substance. The value IS calculated using XLfit (ID Business Solutions Ltd. UK).

Compounds of the present invention demonstrate the value of the IC50from 0.1 nm to 50 μm, preferably from 1 nm to 10 μm, in particular, 1-3500 nm, more preferably from 20 to 1000 nm, for RAPPα and RAPPγ. Further, the compounds exhibit values EU50from 0.1 nm to 50 μm, preferably from 1 nm to 10 μm, more preferably 1-3500 nm, in particular from 20 to 1000 nm, for RAPPα and RAPPγ.

The following table presents the measured values for some selected with the of dinani of the present invention and compounds, known from the prior art (e.g. Rosiglitazone, Drugs, 1999, t(6), SS-930).

RAPPα IC50(µm)RAPPγ IC50(µm)RAPPα EC50(µm)RAPPγ EU50(µm)
Example 50,240,361,520,17
Example 80,280,400,190,56
Example 180,030,180,080,13
Example 210,030,0050,030,07
Example 250,120,050,060,05
Example 390,060,110,470,02
Example 441,641,415,242,70
Rosiglitazoneinactive1,1inactive0,41

The compounds of formula I and their pharmaceutically acceptable salts and esters can be used as medicines, for example, in the form of pharmaceutical preparations for enteral, parenteral or local administration. the x can be entered, for example, orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, for example in the form of suppositories, parenterally, for example, in the form of injectable solutions or solutions for injection, or topically, for example in the form of ointments, creams or oils.

Obtaining pharmaceutical preparations can be carried out by methods known to anyone skilled in this field specialist, by transferring the described compounds of formula I and their pharmaceutically acceptable salts and esters in herbal dosage forms for administration in combination with suitable non-toxic, inert, therapeutically compatible solid or liquid carriers and, if necessary, with conventional pharmaceutical adjuvants.

Suitable materials for media presents not only inorganic materials, but also organic materials carriers. So, for example, as materials carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used lactose, corn starch or derivatives thereof, talc, stearic acid and its salts. Suitable materials media for soft gelatine capsules are, for example, vegetable oils, waxes, fats and palaverde and liquid floor is Ola (depending on the nature of the active ingredient in the case of soft gelatin capsules may not be needed any media). Suitable materials media for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and the like). Suitable materials carrier injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable materials media for suppositories are, for example, natural and zaterjannye oils, waxes, fats and policie or liquid polyols. Suitable materials media for local products are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

Conventional stabilizers, preservatives, moisturizers, emulsification, substances that improve consistency, substances that improve the smell, salts for modifying the osmotic pressure, buffer substances, soljubilizatory, colorants and masking agents, and antioxidants can be considered as pharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limits depending on the disease, which needs to be controlled, the age and individual characteristics of the patient and mode of administration, and can be, of course, chosen in each case depending on the individual who's needs. For adult patients a daily dose of approximately 0.1 mg to approximately 1000 mg, in particular, should be considered a dose of from 0.1 mg to approximately 100 mg Next preferred dose for adults is from about 1 mg to about 1000 mg, in particular, should be considered a dose of from 1 mg to about 100 mg, depending on the dosage is convenient to introduce the daily dose in the form of a multiple unit dosage forms.

Conveniently, when the pharmaceutical preparations contain about 0.05-500 mg, preferably 0.05 to 100 mg of the compounds of formula I. Preferred pharmaceutical preparations contain approximately 0.5 to 500 mg, preferably 0.5 to 100 mg of the compounds of formula I.

The following examples serve to further illustrate the present invention. However, they are in no way intended to limit the scope of the claims.

Examples

a) Preparation of intermediate compounds:

The drug 1

Ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid

a) Ethyl ester of (Z)-2-ethoxy-3-(1H-indol-5-yl)acrylic acid

To a solution of 25,73 g (1.2 diethoxy-2-oxoethyl)triphenylphosphine chloride in 200 ml of dichloromethane was added when 0°With 8.0 ml tetramethylguanidine and the mixture is heated to 22°C. the Mixture is treated of 5.81 g of 5-formylindole and continue stirring the ri 40° C for 16 hours the Mixture is again treated 25,73 g Wittig salt and 8.0 ml tetramethylguanidine and continue stirring at 40°C for 24 h, after which the transformation is complete. The mixture is evaporated and the residue distributed between ethyl acetate and water. The organic layer is dried, evaporated and the residue is subjected to chromatography on silica gel (n-hexane/ethyl acetate, 2:1) to give 9.80 g of the compound indicated in the title, in the form of oil, which solidified while keeping at 22°s, becoming pale yellow solid.

MS:(M)+259,2.

b) Ethyl ester of rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid.

A suspension of ethyl ether 9.7 g (Z)-2-ethoxy-3-(1H-indol-5-yl)acrylic acid in 100 ml of EtOH and 1.0 g of Pd/C (10%) hydronaut with 22°C for 2 h, after which the absorption of hydrogen ceases. The suspension is filtered, the filtrate evaporated and the residue is subjected to chromatography on silica gel (n-hexane/ethyl acetate, 2:1) to obtain 8.7 g of the compound indicated in the title, in the form of a white solid.

MS:(M)+262,2.

The product 2

Ethyl ester of (R)-2-ethoxy-3-(1H-indol-5-yl)propionic acid and methyl ester of (S)-2-ethoxy-3-(1H-indol-5-yl)propionic acid

A solution of 5.00 g of ethyl ether rat-2-ethoxy-3-(1H-indol-5-yl)-propionic acid in 170 ml of tert-butyl methyl ether emulsification by mixing with 675 ml,1 M sodium chloride, 3 mm of sodium phosphate at pH 7.0. Add 200 mg hirashima L-6 (included in the sale by the company Roche Diagnostics) and support through a controlled pH 7.0 added under vigorous stirring with 0.1 n sodium hydroxide solution (pH-stat). After consumption of 81.6 ml (43% conversion; 5,7 h), the reaction mixture was extracted with (2×500 ml dichloromethane) and receive (R)-enriched ethyl ester. The aqueous phase is acidified to pH 2.5 and extracted with (3×500 ml dichloromethane) to give 1.64 g (S)-2-ethoxy-3-(1H-indol-5-yl)propionic acid in the form of a yellowish foam, 94% (Chiralcel-OJ, 25 cm × 4.6 mm; 80% heptane / 20% (EtOH+1,5% TFU).

MS: (M)+233,1. [α]D=-30,0° (1.1% in EtOH).

To mix the solution 0,70 g (S)-acid in 6 ml of methanol and 0.6 ml of water, add 0.6 M solution diazomethane in ethyl ether until the gas evolution stops (15 ml). The mixture is evaporated and the residue is subjected to chromatography on RP-18 (CH3CN/N2Oh, 1:1) obtaining of 0.37 g of methyl ester of (S)-2-ethoxy-3-(1H-indol-5-yl)propionic acid as a brown oil.

MS:(M+N)+248,2.

(R)-enriched ester (2.91 in g, 81%) is subjected to a second similar enzymatic hydrolysis (100 ml tert-butyl methyl ether, 400 ml of the buffer 30 mg hirashima L-6). After absorption of 12.4 ml taraudage substances (45 h), the reaction mixture was extracted (3×500 ml dichloromethane) with the receipt of 2.45 g of ethyl ester of (R)-2-ethoxy-3-(1 ሺ-indol-5-yl)propionic acid as a brown oil, 96% (conditions see above).

MS:(M+N)+262,1, (M+NH4)+279,1. [α]D=+10,5° (1.1% in EtOH).

Drug 3

Benzyl ether of (Z)-3-(1H-indol-5-yl)-2-ethoxyacrylate acid

To a solution 3,70 g (1-methoxy-2-benzyloxyethyl)triphenylphosphine chloride in 60 ml of dichloromethane was added when 0°With 1.07 ml tetramethylguanidine and the mixture is heated to 22°C. the Mixture is treated with 2.25 g of 5-formylindole and continue stirring at 40°C for 16 hours the Mixture is again treated 3,70 g Wittig salt and 1.07 ml tetramethylguanidine and continue stirring at 40°C for 24 h, after which the transformation is complete. The mixture is evaporated and the residue distributed between ethyl acetate and water. The organic layer is dried, evaporated and the residue is subjected to chromatography on silica gel (n-hexane/ethyl acetate, 4:1) to obtain the rate of 1.67 g of compound indicated in the title, in the form of a pale yellow oil.

MS:(M+N)+308,2.

The product 4

Ethyl ester rat-2-ethoxy-3-(3-methyl-1H-indol-5-yl)propionic acid

Similarly to the procedure described for preparations 1A) and 1B), 3-methyl-1H-indole-5-carbaldehyde [Helv.Chim. Acta, (1968), t(7), SS-28] is subjected to interaction with (1,2-diethoxy-2-oxoethyl)triphenylphosphine chloride in dichloromethane in the presence of tetramethylguanidine with obtaining the ethyl ester of (Z)-2-ethoxy-3-(3-methyl-1H-indol-5-yl)acrylic acid, which latter is therefore hydronaut with obtaining the substance, specified in the header, in the form of a colorless oil.

MS:(M+N)+276,3.

The drug 5

Ethyl ester rat-2-ethoxy-3-(2-methyl-1H-indol-5-yl)propionic acid

a) 2-Methyl-1H-indole-5-carbaldehyde

A mixture of 3.9 g of 2-methyl-1H-indol-5-carbonitrile [Journal of Organic Chemistry, (1994), v.9(21), SS-7], 7,22 g monohydrate hypophosphite sodium and 2,60 g Ni-Raney in a mixture of 110 ml of acetic acid (50%) / pyridine, 1:1, stirred at 45°C for 75 min After cooling to room temperature, the reaction mixture is filtered (dicalite), then the filtrate is poured into a mixture of ice water and extracted 3 times with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate and evaporated. The residue is crystallized from n-heptane to obtain 3,19 g 2-methyl-1H-indole-5-carbaldehyde as a pale red solid.

MS:(M)+159,1.

b) Ethyl ester of rat-2-ethoxy-3-(2-methyl-1H-indol-5-yl)propionic acid

Similarly to the procedure described for preparations 1A) and 1B), 2-methyl-1H-indole-5-carbaldehyde is subjected to interaction with (1,2-diethoxy-2-oxoethyl)triphenylphosphine chloride in dichloromethane in the presence of tetramethylguanidine with obtaining the ethyl ester of (Z)-2-ethoxy-3-(2-methyl-1H-indol-5-yl)acrylic acid, which consistently hydronaut obtaining substances specified in the header, in the form of a colorless oil.

MS:(M+N)+ 276,3.

The drug 6

Methyl ether rat-3-(1H-indol-5-yl)-2-propoxyphenol acid

a) 1-(2-trimethylsilylethynyl)-1H-indole-5-carbaldehyde

To a stirred suspension of 5.45 g of sodium hydride (55% in mineral oil) in 100 ml of N,N-dimethylformamide added at 0-5°With a solution of 16.8 g of indole-5-carboxaldehyde in 100 ml of N,N-dimethylformamide and then 24,46 ml of 2-(trimethylsilyl)ethoxymethylene. The reaction mixture was then heated to ambient temperature and continue stirring for 16 hours. Then it was poured into ice, neutralized to pH 4 with 1 N. HCl and extracted three times with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate and evaporated to obtain a brown oil, which was purified by chromatography (silica gel, eluent: gradient of n-heptane / EtOAc) to obtain the 25,52 g of 1-(2-trimethylsilylethynyl)-1 H-indole-5-carbaldehyde as a pale yellow oil.

MS:(M)+275,2.

b) Ethyl ester of 3-hydroxy-2-propoxy-3-[1-(2-trimethylsilyl-ethoxymethyl)-1H-indol-5-yl]propionic acid (mixture of diastereomers)

To a solution of 30 mmol of diisopropylamide lithium in 50 ml of tetrahydrofuran added at -78°4,39 g ethyl ester propoxyethanol acid [Journal of the American Chemical Society, (1996), t(41), SS-9907], dissolved in 25 ml of tetrahydrofuran; after 30 min stirring at -78&x000B0; To add a solution of 3.31 g of 1-(2-trimethylsilylethynyl)-1H-indole-5-carbaldehyde in 30 ml of tetrahydrofuran and after another 30 min the reaction mixture was quenched by adding 25 ml of N2On and allowed to warm to ambient temperature. Then it is extracted with ethyl acetate and the combined organic phases are washed with water, dried over magnesium sulfate and evaporated to obtain a pale brown oil, which was purified by chromatography (silica gel, gradient of n-heptane / EtOAc) to give the ethyl ester with 4.65 g of 3-hydroxy-2-propoxy-3-[1-(2-trimethylsilylethynyl)-1H-indol-5-yl]propionic acid (mixture of diastereoisomers) as a yellow oil.

MS:(M+NH4)+439,4.

b) Ethyl ester of 2-propoxy-3-[1-(2-trimethylsilylethynyl)-1H-indol-5-yl]-(Z,E)-acrylic acid

to 3.67 g of ethyl ester of 3-hydroxy-2-propoxy-3-[1-(2-trimethylsilylethynyl)-1H-indol-5-yl]propionic acid (mixture of diastereomers) was dissolved in 100 ml dichloromethane and cooled to 0°; then spend processing of 1.40 ml of triethylamine, and then add to 0.67 ml methanesulfonanilide. After two hours stirring at 0°C, the reaction mixture was poured into a cold solution of sodium bicarbonate in water and extracted with ethyl acetate to give, after drying over magnesium sulfate and evaporation, the 3.65 g of the crude ethyl ester of 3-chloro-2-propoxy-3[1-(2-trimethylsilylethynyl)-1H-indol-5-yl]propionic acid (mixture of diastereomers). This crude intermediate product is dissolved in 100 ml of tetrahydrofuran and treated 3,82 g of 1,8-diazabicyclo[5.4.0.]undec-7-ene(1,5,5). The reaction mixture was then stirred for 8 hours at 50°C, then poured into ice, neutralized to pH 4 with 1 N. HCl and extracted three times with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate and evaporated to obtain a light brown oil, which was purified by chromatography (silica gel, gradient of n-heptane / EtOAc) to give 1.84 g of ethyl ester of 2-propoxy-3-[1-(2-trimethylsilylethynyl)-1H-indol-5-yl]-(Z,E)-acrylic acid as a pale yellow oil.

MS:(M+N)+404,5.

d) Ethyl ester rat-2-propoxy-3-[1-(2-trimethylsilylethynyl)-1H-indol-5-yl]propionic acid

of 1.81 g of ethyl ester of 2-propoxy-3-[1-(2-trimethylsilylethynyl)-1H-indol-5-yl]-(Z,E)-acrylic acid hydronaut over 0.45 g of Pd-C 10% in 75 ml ethanol; after 90 min the reaction mixture was filtered and evaporated to obtain a rate of 1.67 g of the crude product, which was purified by chromatography (silica gel, gradient of n-heptane / EtOAc) to give the ethyl ester of 1.43 g rat-2-propoxy-3-[1-(2-trimethylsilylethynyl)-1H-indol-5-yl]-propionic acid as light yellow oil.

MS:(M+N)+to 406.4.

d) rat-2-propoxy-3-[1-(2-trimethylsilylethynyl)-1H-indol-5-yl]-propionate the acid

Dissolve to 1.23 g of ethyl ether rat-2-propoxy-3-[1-(2-trimethylsilylethynyl)-1H-indol-5-yl]propionic acid in 40 ml of dioxane and then treated with 7.6 ml of a solution of lithium hydroxide (1 molar solution in water) and stirred for 16 hours at ambient temperature. Extraction of the reaction mixture of N2O/HCl and dichloromethane, followed by drying the organic phase with sodium sulfate and evaporation leads to 1.27 g of crude product which is purified by chromatography (silica gel, gradient of n-heptane / EtOAc) to obtain the 0,98 g rat-2-propoxy-3-[1-(2 - trimethylsilylethynyl)-1H-indol-5-yl]-propionic acid as light yellow oil.

MS:(M-N)-376.3 on.

(e) rat-3-(1H-indol-5-yl)-2-propoxyphenol acid

Dissolving 0.96 g rat-2-propoxy-3-[1-(2-trimethylsilylethynyl)-1H-indol-5-yl]propionic acid in 40 ml of N,N-dimethylformamide. Add to 0.94 ml of Ethylenediamine, and then add 7,63 ml of a solution of tetrabutylammonium fluoride (1 molar solution in tetrahydrofuran); then to the reaction mixture was added a small amount of molecular sieves and the mixture is heated to 80°C. After 6 hours the mixture is cooled to K.T., filtered, the filtrate poured into ice water and extracted three times with dichloromethane.

The organic phase is washed with water, dried over MgSO4again filtered and evaporated. Cheese the rat-3-(1H-indol-5-yl)-2-propoxy-propionic acid used in the next stage without purification.

f) Methyl ether rat-3-(1H-indol-5-yl)-2-propoxyphenol acid

Raw rat-3-(1H-indol-5-yl)-2-propoxyphenyl acid dissolved in 5 ml of N,N-dimethylformamide, then add of 0.54 g of sodium bicarbonate and 0.32 ml under the conditions. Stir the mixture at K.T. for 7 hours, then poured into ice water and extracted three times with ethyl acetate; after drying over MgSO4and evaporation, get the crude product, which was purified by chromatography (silica gel, gradient of n-heptane / EtOAc) to give to 0.47 g of methyl ester rat-3-(1H-indol-5-yl)-2-propoxyphenol acid as a pale yellow oil.

MC:(M)+261,1

Preparation 7

Methyl ether rat-3-(1H-indol-5-yl)-2-phenoxypropionic acid

Similarly to the procedure described for preparations 1B and 1G)specified in the title compound is obtained from 1-(2-trimethylsilylethynyl)-1H-indole-5-carbaldehyde [drug 6A)] and ethyl ether phenoxyalkanoic acid as a colourless oil.

MS:(M+N)+296,2.

Preparation 8

Methyl ether rat-3-(1H-indol-5-yl)-2-isopropoxypropylamine acid

Similarly to the procedure described for preparations 1B and 1G)specified in the title compound is obtained from 1-(2-trimethylsilylethynyl)-1H-indole-5-carbaldehyde [drug 6A)] and ethyl ether isopropoxyethanol acid [Tetrahedron (1982), v.38(17), SS-9] VI is e light yellow solid.

MS:(M+N)+262,1.

Preparation 9

Methyl ether rat-2-but-3-enyloxy-3-(1H-indol-5-yl)propionic acid

a) 1-benzazolyl-1H-indole-5-carbaldehyde

Dissolve to 15.8 g of indole-5-carbaldehyde in 300 ml of tetrahydrofuran and cooled to 0°C. Then added in small portions 5,12 g of sodium hydride (55% in mineral oil) followed by slow addition of 15.2 ml of benzosulfimide, drop by drop. After the reaction mixture was allowed to warm to ambient temperature and continue stirring for 16 hours. Then it was poured into ice, neutralized with 1 N. HCl to pH 4 and extracted three times with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate and evaporated to obtain crude product, which was purified by chromatography (silica gel, gradient of n-heptane / EtOAc) to obtain 4.09 g 1-benzazolyl-1H-indole-5-carbaldehyde in the form of a pink solid.

MC:(M)+285,1.

b) Ethyl ester of 3-(1-benzazolyl-1H-indol-5-yl)-2-but-3-enyloxy-3-hydroxypropionic acid (mixture of diastereomers)

To a solution of 17.7 ml diisopropylamide lithium (2 molar solution in tetrahydrofuran) in 40 ml of tetrahydrofuran, add a solution 5,61 g of ethyl ether but-3-relaxicon acid [Tetrahedron, (1982), v.38(17), cc.2733-9] in 30 ml of tetrahydrofuran at -78°S. After s is remesiana for 30 min was added a solution of 4.05 g of 1-benzazolyl-1H-indole-5-carbaldehyde in 30 ml of tetrahydrofuran and stirring at -78° To continue for a further 30 minutes and Then the reaction quenched by adding 50 ml of saturated solution of ammonium chloride in water and allow it to warm to ambient temperature. Then extracted with ethyl acetate and the combined organic phases are washed with water, dried over magnesium sulfate and evaporated to obtain crude product, which was purified by chromatography (silica gel, gradient of n-heptane / EtOAc) to obtain the 4,37 g of ethyl ester of 3-(1-benzazolyl-1H-indol-5-yl)-2-but-3-enyloxy-3-hydroxypropionic acid (mixture of diastereomers) as a colorless oil.

MS:(M)+443,2.

b) Ethyl ester of 3-(1-benzazolyl-1H-indol-5-yl)-2-but-3-enyloxy-(Z,E)-acrylic acid

Dissolve a 3.87 g of ethyl ester of 3-(1-benzazolyl-1H-indol-5-yl)-2-but-3-enyloxy-3-hydroxypropionic acid (mixture of diastereomers) in 200 ml of benzene and added 0.16 g of p-toluenesulfonic acid; the mixture is then stirred for 16 hours at 80°C. After evaporation of the solvent the residue is purified by chromatography (silica gel, gradient of n-heptane / dichloromethane) to give 3.28 g of ethyl ester of 3-(1-benzazolyl-1H-indol-5-yl)-2-but-3-enyloxy-(Z,E)-acrylic acid as a pale yellow oil.

MS:(M+N)+426,1.

d) Methyl ether rat-2-but-3-enyloxy-3-(1H-indol-5-yl)propionic acid

Dissolve 2,97 g of ethyl ester of 3-(1-baselslt the Il-1H-indol-5-yl)-2-but-3-enyloxy-(Z,E)-acrylic acid in 100 ml of methanol. Then added 1.70 g of magnesium (0) and the reaction mixture heated to 60°C. After 15 minutes, it is cooled to ambient temperature and stirring is continued for 4 hours. Then solvent evaporated, and the residue is poured into ice, neutralized with 1 N. HCl to pH 4 and extracted three times with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate and evaporated to obtain crude product, which was purified by chromatography (silica gel, gradient of n-heptane / EtOAc) to give 1.60 g of the methyl ester rat-2-but-3-enyloxy-3-(1H-indol-5-yl)-propionic acid as light yellow oil.

MS: (M+H)+274,2.

The drug 10

Ethyl ester rat-2-ethoxy-3-(4-methyl-1H-indol-5-yl)propionic acid

a) Ethyl ester of 3-(3-bromo-2-methyl-6-nitrophenyl)-2-ethoxy-(Z,E)-acrylic acid

Similarly to the procedure described for the preparation 1A), 3-bromo-2-methyl-6-nitrobenzaldehyde [European patent application (1982), EP 54180 A2] enter into reaction with (1,2-diethoxy-2-oxoethyl)triphenylphosphine chloride in dichloromethane in the presence of tetramethylguanidine and get ethyl ester 3-(3-bromo-2-methyl-6-nitrophenyl)-2-(Z,E)-ethoxyacrylate acid as a pale yellow oil.

MS:(M+H)+358,0; 360,0.

b) Ethyl ester of 3-(6-amino-3-bromo-2-were)-2-ethoxy-(Z,E)-acrylic acid

Dissolve of 14.25 g (39.8 mmole) of ethyl EPE is 3-(3-bromo-2-methyl-6-nitrophenyl)-2(Z,E)-ethoxyacrylate acid in 150 ml of acetic acid. Add small portions to 6.67 g (119,4 mmole) of iron powder and then the reaction mixture is stirred for 16 hours. To complete the reaction, it is heated at 80°C for another 2 hours, then cooled to room temperature and poured into a sodium hydrogen carbonate solution in N2O. Add 150 ml of ethyl acetate and the mixture is intensively stirred for 30 minutes, then filtered (dicalite) and extracted twice with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate and evaporated to obtain crude product, which was purified by chromatography (silica gel, gradient of n-heptane / EtOAc) to obtain 7,11 g of ethyl ester of 3-(6-amino-3-bromo-2-were)-2-ethoxy-(Z,E)-acrylic acid as an orange solid.

MS:(M+H)+328,1; 330,1.

b) Ethyl ester of 3-(6-acetylamino-3-bromo-2-were)-2-ethoxy-(Z,E)-acrylic acid

Dissolve 6.7 g (20.4 mmole) ethyl ester of 3-(6-amino-3-bromo-2-were)-2-ethoxy-(Z,E)-acrylic acid in 100 ml of dichloromethane; then added with stirring 7,11 ml (51,0 mmol) of triethylamine. After that, the mixture is cooled to 5°and added dropwise to 1.61 ml (22.5 mmole) of acetylchloride. Then the mixture was allowed to warm to ambient temperature. After stirring for 90 minutes the reaction mixture is poured into ice water and extracted three times dichloro what ETANA. The combined organic phases are washed with water, dried over magnesium sulfate and evaporated to obtain crude product, which was purified by chromatography (silica gel, gradient of n-heptane / EtOAc) to obtain the 7,76 g of ethyl ester of 3-(6-acetylamino-3-bromo-2-were)-2-ethoxy-(Z,E)-acrylic acid as a pale yellow oil.

MS: (M-C2H5)+340,0; 342,0.

d) Ethyl ester 5-bromo-4-methyl-1H-indole-2-carboxylic acid

Dissolve 7,63 g (20,6 mole) of ethyl ester of 3-(6-acetylamino-3-bromo-2-were)-2-ethoxy-(Z,E)-acrylic acid in 300 ml of toluene; then added 0.36 g (of 2.06 mmole) of p-toluenesulfonic acid and the reaction mixture is refluxed with stirring for 18 hours. After evaporation of the solvent the residue is dissolved in dichloromethane, add water and bring the pH value to pH 8-9. The mixture is then extracted three times with dichloromethane. The combined organic phases are washed with water, dried over magnesium sulfate and evaporated to obtain 5,43 g of crude ethyl ester 5-bromo-4-methyl-1H-indole-2-carboxylic acid as a pale yellow solid.

MC:(M)+281,0; 283,0.

d) 5-Bromo-4-methyl-1H-indole-2-carboxylic acid

Dissolve lower than the 5.37 g (19,0 moles) ethyl ester 5-bromo-4-methyl-1H-indole-2-carboxylic acid in 150 ml of dioxane; then add 38,1 ml (38,1 mmole) solution of lithium hydroxide (1 m is a regular solution in water) and the reaction mixture is stirred for 60 hours at room temperature. After evaporation of the solvent the residue is dissolved in dichloromethane; add water and bring the pH value to pH 2-3; the mixture is then extracted three times with dichloromethane. The combined organic phases are washed with water, dried over magnesium sulfate and evaporated to obtain 4,82 g of crude 5-bromo-4-methyl-1H-indole-2-carboxylic acid as off-white solid.

MS:(M-N)-252,0; 254,0.

e) 4-Methyl-1H-indol-5-carbonitril

Dissolve 4.71 g (18.5 mmol) of 5-bromo-4-methyl-1H-indole-2-carboxylic acid and of 5.03 g (56,2 mmole) of copper cyanide in 35 ml of quinoline and the solution heated at 230°C for 90 minutes. Then the reaction mixture was cooled to ambient temperature and poured into crushed ice. Bring the pH value of the mixture to pH 2-3 and the mixture was sequentially extracted three times simple ether. The combined organic phases are washed with water, dried over magnesium sulfate and evaporated to obtain crude product, which was purified by chromatography (silica gel, gradient of n-heptane / EtOAc) to obtain a 2.36 g of 4-methyl-1H-indol-5-carbonitrile in the form of a light brown solid.

MS:(M+H)+157,2.

g) 4-Methyl-1H-indole-5-carbaldehyde

Similarly to the procedure described for the preparation 1A), 4-methyl-1H-indol-5-carbonitril enter into reaction with monohydrate hypophosphite sodium in the presence of Ni-Raney in a mixture of acetic acid/PIR is Dean and receive a 4-methyl-1H-indole-5-carbaldehyde as a pale yellow solid.

MS:(M+H)+160,2.

C) Ethyl ester rat-2-ethoxy-3-(4-methyl-1H-indol-5-yl)propionic acid

Similarly to the procedure described for preparations 1A) and 1B), 4-methyl-1H-indole-5-carbaldehyde enter into reaction with (1,2-diethoxy-2-oxoethyl)triphenyl of phosphonium chloride in dichloromethane in the presence of tetramethylguanidine and receive the ethyl ester of (Z,E)-2-ethoxy-3-(4-methyl-1H-indol-5-yl)acrylic acid, which consistently hydronaut with getting the connection specified in the header, in the form of a light brown solid.

MS:(M+NH4)+293,2.

Preparation 11

Ethyl ester rat-2-ethoxy-3-(1H-indol-6-yl)propionic acid

Similarly to the procedure described for preparations 1A) and 1B), 1H-indole-6-carbaldehyde enter into reaction with (1,2-diethoxy-2-oxoethyl)triphenylphosphine chloride in dichloromethane in the presence of tetramethylguanidine and receive the ethyl ester of (Z,E)-2-ethoxy-3-(1H-indol-6-yl)acrylic acid, which consistently hydronaut with getting the connection specified in the header, in the form of a colorless solid.

MS:(M+H)+262,2.

b) Receiving end connections

General description alkylation of indoles with subsequent in situ hydrolysis (Examples 1-32, 34)

To a solution of 1 mmole of indole in 7 ml of DMSO was added when 22°4 mmole powdered KOH, continue stirring for 15 minutes, then we use the t solution of 1.7 mol of chloride or nelfinavir in 1 ml DMSO and continue stirring until completion of the reaction (during the night). The dark reaction mixture is acidified to pH=3 with formic acid and then distributed between ethyl acetate and saturated aqueous NH4Cl. The aqueous layer was extracted several times with ethyl acetate, and the organic layer washed several times with water. The combined organic layers dried, evaporated, and the residue is subjected to chromatography on silica gel and RP-18 using a mixture of ethyl acetate/n-hexane or CH3CN/H2O, respectively, in different ratios, and receive connections described in the following examples.

Example 1

rat-2-Ethoxy-3-[1-(5-methyl-2-phenyloxazol-4-ylmethyl)-1H-indol-5-yl]-propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-phenyl-5-methoxazole, the connection specified in the header, get with the release of 64% in the form of a pale yellow solid.

MS:(M-N)-403,3.

Example 2

(S)-2-Ethoxy-3-[1-(5-methyl-2-phenyloxazol-4-ylmethyl)-1H-indol-5-yl]-propionic acid

Based on the methyl ester of (S)-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-phenyl-5-methoxazole, the connection specified in the header, get with the release of 64% in the form of a colorless oil.

MS:(M-N)-403,3.

Example 3

rat-2-Ethoxy-3-{1-[2-(2-forfinal)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid

On the basis of e is silt ether rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(2-forfinal)-5-methoxazole, the connection specified in the header, get with the release of 47% in the form of a yellow solid.

MS:(M+N)+423,3.

Example 4

rat-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(2-chlorophenyl)-5-methoxazole, the connection specified in the header, get with the release of 31% in the form of a yellow solid.

MS:(M+H)+RUR 439,3.

Example 5

(S)-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid

Based on the methyl ester of (S)-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(2-chlorophenyl)-5-methoxazole, the connection specified in the header, get with the release of 56% in the form of a pale brown amorphous solid.

MS:(M-N)-437,2.

Example 6

rat-2-Ethoxy-3-[1-(5-methyl-2-o-tolyloxy-4-ylmethyl)-1H-indol-5-yl]-propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-5-methyl-2-o-tolylacetate, the connection specified in the header, get with the release of 43% in the form of a pale brown solid.

MS:(M+H)+419,3.

Example 7

rat-2-Ethoxy-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl-1H-indol-5-yl}-propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propional the th acid and 4-chloromethyl-2-(2-methoxyphenyl)-5-methoxazole, the connection specified in the header, get with the release of 56% in the form of a pale yellow solid.

MS:(M+N)+435,3.

Example 8

(S)-2-Ethoxy-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-propionic acid

Based on the methyl ester of (S)-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(2-methoxyphenyl)-5-methoxazole, the connection specified in the header, get off exit 66% in the form of a pale yellow solid.

MS:(M-N)-433,2.

Example 9

rat-2-Ethoxy-3-{1-[2-(2-isopropoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(2-isopropoxyphenyl)-5-methoxazole, the connection specified in the header, get with the release of 60% in the form of a brown oil.

MS:(M+H)+463,3.

Example 10

rat-3-{1-[2-(3-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxy-propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(3-chlorophenyl)-5-methoxazole, the connection specified in the header of the receive exit 21% in the form of a yellow solid.

MS:(M+N)+RUR 439,3.

Example 11

rat-2-Ethoxy-3-{1-[2-(4-ethylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)about the Ionova acid and 4-chloromethyl-2-(4-ethylphenyl)-5-methoxazole, the connection specified in the header, get with the release of 41% in the form of a yellow solid.

MS:(M+H)+433,4.

Example 12

(S)-2-Ethoxy-3-{1-[2-(4-ethylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-propionic acid

Based on the methyl ester of (S)-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(4-ethylphenyl)-5-methoxazole, the connection specified in the header, get with the release of 47% in the form of a colorless solid.

MS:(M-N)-that amount to 431,3.

Example 13

(R)-2-Ethoxy-3-{1-[2-(4-ethylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-propionic acid

On the basis of the ethyl ester of (R)-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(4-ethylphenyl)-5-methoxazole, the connection specified in the header, get with the release of 60% in the form of a pale yellow solid.

MS:(M-N)-431,2.

Example 14

rat-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(4-isopropylphenyl)-5-methoxazole, the connection specified in the header, get with the release of 48% in the form of a yellow solid.

MS: (M+N)+447,4.

Example 15

rat-3-{1-[2-(4-tert-Butylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)prop is about acid and 4-chloromethyl-2-(4-tert-butylphenyl)-5-methoxazole, the connection specified in the header, get with the release of 50% in the form of a brown oil.

MS:(M+H)+461,3.

Example 16

rat-2-Ethoxy-3-{1-[2-(4-forfinal)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(4-forfinal)-5-methoxazole, the connection specified in the header, get with the release of 39% in the form of a colorless solid.

MS:(M+N)+423,3.

Example 17

rat-2-Ethoxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-5-methyl-2-(4-triptoreline)oxazole, the connection specified in the header, get with the release of 27% in the form of a yellow solid.

MS:(M+H)+473,2.

Example 18

(S)-2-Ethoxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid

Based on the methyl ester of (S)-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-5-methyl-2-(4-triptoreline)oxazole, the connection specified in the header, get with the release of 50% in the form of a pale yellow solid.

MS:(M-N)-471,1.

Example 19

rat-3-{1-[2-(3.5-Dimetilfenil)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-shall ndol-5-yl)propionic acid and 4-chloromethyl-2-(3, 5dimethylphenyl)-5-methoxazole, the connection specified in the header, get with the release of 45% in the form of a pale yellow solid.

MS:(M+H)+433,4.

Example 20

rat-3-{1-[2-(3,5-Acid)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(3,5-acid)-5-methoxazole, the connection specified in the header, get with the release of 50% in the form of a colorless solid.

MS:(M-N)-463,2.

Example 21

(S)-3-{1-[2-(3.5-Acid)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid

Based on the methyl ester of (S)-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(3,5-acid)-5-methoxazole, the connection specified in the header, get with the release of 43% in the form of a pale pink solid.

MS:(M-N)-463,2.

Example 22

rat-3-{1-[2-(3,5-Differenl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(3,5-differenl)-5-methoxazole, the connection specified in the header, is obtained in yield of 20% in the form of a brown oil.

MS:(M+H)+441,3.

Example 23

rat-3-{1-[2-(3,5-Dichlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid

On the basis of the ethyl ester rat-2-ethoxy-3(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(3,5-dichlorophenyl)-5-methoxazole, the connection specified in the header, get with 4% in the form of a pale yellow solid.

MS:(M+N)+473,1 and 475,2.

Example 24

rat-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(4-fluoro-3-were)-5-methoxazole, the connection specified in the header, get with the release of 48% in the form of a colorless solid.

MS:(M+H)+437,3.

Example 25

(S)-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid

Based on the methyl ester of (S)-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-(4-fluoro-3-were)-5-methoxazole, the connection specified in the header, get with the release of 58% in the form of a pale yellow solid.

MS:(M-N)-435,2.

Example 26

rat-2-Ethoxy-3-[1-(5-methyl-2-thiophene-2-yl-oxazol-4-ylmethyl)-1H-indol-5-yl]-propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-5-methyl-2-thiophene-2-yl-oxazole, the connection specified in the header, get with the release of 31% in the form of a yellow solid.

MS:(M+H)+411,2.

Example 27

rat-2-Ethoxy-3-{1-[2-(3,4 .5-trimethoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl)propionic acid

On the basis of the ethyl ester of the AC-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-5-methyl-2-(3,4,5-trimethoxyphenyl)oxazole, the connection specified in the header, get with the release of 3% in the form of a white solid.

MS:(M+H)+495,2.

Example 28

rat-2-Ethoxy-3-[1-(2-phenyloxazol-4-ylmethyl)-1H-indol-5-yl]propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-phenyloxazole, the connection specified in the header, is obtained in yields of 80% in the form of a brown oil.

MS:(M+H)+to € 391.1.

Example 29

rat-2-Ethoxy-3-[1-(2-phenylthiazol-4-ylmethyl)-1H-indol-5-yl]propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-chloromethyl-2-phenylthiazole, the connection specified in the header, get with the release of 64% in the form of a brown oil.

MS:(M+N)+407,3.

Example 30

rat-2-Ethoxy-3-[1-(5-methyl-2-phenylthiazol-4-ylmethyl)-1H-indol-5-yl]propionic acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-methyl bromide-5-methyl-2-phenylthiazole, the connection specified in the header of the receive exit 1% in the form of a yellow oil.

MS:(M+H)+UAH 421,2.

Example 31

rat-3-{1-[2-(4-Chlorophenyl)thiazol-4-ylmethyl]- 1H-indol-5-yl}-2-ethoxypropionate acid

On the basis of the ethyl ester rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid and 4-(chloromethyl)-2-(p-chlorophenyl)thiazole, the connection specified in the header, get with the release of 23% in the form of a brown oil.

MC:M+H) +441,3.

Example 32

(Z)-2-Methoxy-3-[1-(5-methyl-2-phenyloxazol-4-ylmethyl)-1H-indol-5-yl]-acrylic acid

Based on benzyl ester (Z)-3-(1H-indol-5-yl)-2-ethoxyacrylate acid and 4-chloromethyl-2-phenyl-5-methoxazole, the connection specified in the header, is obtained in 75% yield as off-white solid.

MS:(M+N)+389,2.

Example 33

rat-2-Methoxy-3-[1-(5-methyl-2-phenyloxazol-4-ylmethyl)-1H-indol-5-yl]-propionic acid

A suspension of 80 mg of (Z)-2-methoxy-3-[1-(5-methyl-2-phenyloxazol-4-ylmethyl)-1H-indol-5-yl]acrylic acid in 5 ml of methanol and 2 ml of dichloromethane and 30 mg of Pd/C (10%) is subjected to hydrogenation at 22°and 1 bar until the cessation of hydrogen absorption (3 h). The mixture is filtered, the filtrate evaporated and the residue is subjected to preparative chromatography high pressure (ghvd) (RP-18, CH3CN/H2O, gradient) to give 49 mg of the compound indicated in the title, in the form of a yellow oil.

MS:(M-N)-389,1.

Example 34

(Z)-2-Methoxy-3-{1-[2-(5-methyl-2-phenyloxazol-4-yl)ethyl]-1H-indol-5-yl}-acrylic acid

Based on benzyl ester (Z)-3-(1H-indol-5-yl)-2-ethoxyacrylate acid and 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester methanesulfonic acid, the connection specified in the header, get with the release of 5% in the form of a colorless solid.

MS:(M+N)+403,4.

Example 35

rat-2-Methoxy-3-{1-[2-(5-methyl-2-Fe is isoxazol-4-yl)ethyl]-1H-indol-5-yl}-propionic acid

A suspension of 9 mg of (Z)-2-Methoxy-3-{1-[2-(5-methyl-2-phenyloxazol-4-yl)-ethyl]-1H-indol-5-yl}acrylic acid in 2 ml of methanol and 1 ml of dichloromethane and 6 mg of Pd/C (10%) is subjected to hydrogenation at 22°and 1 bar until the cessation of hydrogen absorption (2 hours). The mixture is filtered, the filtrate evaporated and the residue is subjected to ghvd (RP-18, CH3SN/N2Oh, gradient) to obtain 7 mg of the compound indicated in the title, in the form of a colorless oil.

MS:(M-N)-403,3.

Example 36

rat-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl}propionic acid

a) Ethyl ester of rat-2-ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methyl-oxazol-4-ylmethyl]-3-methyl-1H-indol-5-yl}propionic acid

0.28 g (1.0 mmol) of ethyl ether rat-2-ethoxy-3-(3-methyl-1H-indol-5-yl)propionic acid (preparation 4) and 0.30 g (1.2 mmole) of 4-chloromethyl-2-(4-isopropylphenyl)-5-methoxazole dissolved under argon in 5.0 ml of N,N-dimethylformamide; add 0,048 g (1.1 mole) of sodium hydride (55% in mineral oil) and then stirred the reaction mixture for 48 hours at ambient temperature. Then it is diluted with water and extracted with simple ether. The combined organic phases are dried over MgSO4and evaporated. The resulting residue is purified Express chromatography (silica gel; eluent: a gradient of hexane in ethyl acetate) and obtain 0.32 g (67%) of ethyl ether rat-2-ethoxy--{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl}propionic acid as colorless oil.

MS:(M+H)+489,5.

b) rat-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl} propionic acid

Dissolve ethyl ester rat-2-ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl }propionic acid (310 mg, to 0.63 mmole) in 5 ml of dioxane, and then slowly added to 0.95 ml of LiOH solution (1 n solution in water) at room temperature. The resulting mixture is stirred for 48 hours and then poured into ice, neutralized to pH 4 with 1 N. HCl and extracted three times with dichloromethane. The combined organic phases are washed with water, dried over magnesium sulfate and evaporated; the crude product is purified by chromatography (silica gel, eluent: gradient dichloromethane / methanol) to obtain 210 mg (72%) rat-2-ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl}propionic acid as colorless solid.

MS:(M-N)-459,4.

Example 37

rat-2-Ethoxy-3-{3-methyl-1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid

By analogy with the methods described in the Examples 36A) and (36B), ethyl ester of rat-2-ethoxy-3-(3-methyl-1H-indol-5-yl)propionic acid (preparation 4) is injected into the reaction with 4-chloromethyl-5-methyl-2-(4-triptoreline)oxazolam with obtaining the ethyl ester of rat-2-ethoxy-3-{3-methyl-1-[5-methyl-2-(4-triptoreline)oxazol-4-and the methyl]-1H-indol-5-yl}propionic acid, which consistently omelet with getting the connection specified in the header, in the form of a colorless oil.

MS:(M-N)-485,4.

Example 38

rat-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl}-2-ethoxypropionate acid

By analogy with the methods described in the Examples 36A) and (36B), ethyl ester of rat-2-ethoxy-3-(3-methyl-1H-indol-5-yl)propionic acid (preparation 4) is injected into the reaction with 4-chloromethyl-2-(2-chlorophenyl)-5-methoxazole with obtaining the ethyl ester rat-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl}-2-ethoxypropionate acid, which consistently omelet with getting the connection specified in the header, in the form of a colorless solid.

MS:(M-N)-451,2.

Example 39

rat-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl} propionic acid

By analogy with the methods described in the Examples 36A) and (36B), ethyl ester of rat-2-ethoxy-3-(3-methyl-1H-indol-5-yl)propionic acid (preparation 4) is injected into the reaction with 4-chloromethyl-2-(4-fluoro-3-were)-5-methoxazole with obtaining the ethyl ester of rat-2-ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl}propionic acid, which consistently omelet with getting the connection specified in the header, in the form of a colorless solid.

MS:(M-N)-449,3.

Example 40

rat-2-Ethoxy-3-{2-methyl-1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid

By analogy with the methods described in the Examples 36A) and (36B), ethyl ester of rat-2-ethoxy-3-(2-methyl-1H-indol-5-yl)propionic acid (preparation 5) was injected to react with 4-chloromethyl-5-methyl-2-(4-triptoreline)oxazolam with obtaining the ethyl ester of rat-2-ethoxy-3-{2-methyl-1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid, which consistently omelet with getting the connection specified in the header, in the form of a colorless oil.

MS:(M-N)-485,4.

Example 41

rat-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-2-methyl-1H-indol-5-yl}propionic acid

By analogy with the methods described in the Examples 36A) and (36B), ethyl ester of rat-2-ethoxy-3-(2-methyl-1H-indol-5-yl)propionic acid (preparation 5) was injected to react with 4-chloromethyl-2-(4-isopropylphenyl)-5-methoxazole with obtaining the ethyl ester of rat-2-ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-1H-indol-5-yl}propionic acid, which consistently omelet with getting the connection specified in the header, in the form of a colorless oil.

MS:(M-N)-459,4.

Example 42

rat-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-2-methyl-1H-indol-5-yl}propionic acid

By analogy with meth what digami, described in the Examples 36A) and (36B), ethyl ester of rat-2-ethoxy-3-(2-methyl-1H-indol-5-yl)propionic acid (preparation 5) was injected to react with 4-chloromethyl-2-(4-fluoro-3-were)-5-methoxazole with obtaining the ethyl ester of rat-2-ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-2-methyl-1H-indol-5-yl}propionic acid, which consistently omelet with getting the connection specified in the header, in the form of a colorless oil.

MS:(M+H)+451,3

Example 43

rat-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl-2-methyl-1H-indol-5-yl}-2-ethoxypropionate acid

By analogy with the methods described in the Examples 36A) and (36B), ethyl ester of rat-2-ethoxy-3-(2-methyl-1H-indol-5-yl)propionic acid (preparation 5) was injected to react with 4-chloromethyl-2-(2-chlorophenyl)-5-methoxazole with obtaining the ethyl ester rat-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-2-methyl-1H-indol-5-yl}-2-ethoxypropionate acid, which consistently omelet with getting the connection specified in the header, in the form of a colorless solid.

MS:(M-N)-451,2

Example 44

rat-2-Ethoxy-3-[2-methyl-1-(2-phenylthiazol-4-ylmethyl)-1H-indol-5-yl]-propionic acid

0.28 g (1.0 mmol) of ethyl ether rat-2-ethoxy-3-(2-methyl-1H-indol-5-yl)propionic acid (preparation 5) is injected into the reaction from 0.23 g (1.1 mmole) of 4-chloromethyl-2-phenylthiazole in 5 ml of N,N-dimethylformamide in the presence 009 g (2.0 mmole) of sodium hydride (55% in mineral oil) at K.T. for 16 hours. Then the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic phases are dried over MgSO4and evaporated. The resulting residue is purified Express chromatography (silica gel; eluent: gradient of n-heptane and ethyl acetate) and gain of 0.38 g (90%) rat-2-ethoxy-3-[2-methyl-1-(2-phenylthiazol-4-ylmethyl)-1H-indol-5-yl]-propionic acid as light brown solid.

MS:(M-N)-419,2.

Example 45

rat-3-{1-[2-(4-tert-Butylphenyl)oxazol-4-ylmethyl]-2-methyl-1H-indol-5-yl}-2-ethoxypropionate acid

By analogy with the method described in Example 44, ethyl ester rat-2-ethoxy-3-(2-methyl-1H-indol-5-yl)propionic acid (preparation 5) is injected into the reaction with 2-(4-tert-butylphenyl)-4-chlorothioxanthone with getting rat-3-{1-[2-(4-tert-butylphenyl)oxazol-4-ylmethyl]-2-methyl-1H-indol-5-yl}-2-ethoxy-propionic acid as a light brown solid.

MS:(M-N)-459,4.

Example 46

rat-3-[1-(5-Methyl-2-o-tolyloxy-4-ylmethyl)-1H-indol-5-yl]-2-propoxyphenol acid

By analogy with the method described in Example 44, methyl ester rat-3-(1H-indol-5-yl)-2-propoxyphenol acid (preparation 6) is injected into the reaction with 4-chloromethyl-5-methyl-2-o-collocation with getting rat-3-[1-(5-methyl-2-o-tolyloxy-4-ylmethyl)-1H-indol-5-yl]-2-propoxyphenol acid in the form of a light brown, the CSOs oil.

MS:(M-N)-that amount to 431,3.

Example 47

rat-3-{1-[2-(2-Methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-propoxyphenol acid

By analogy with the method described in Example 44, methyl ester rat-3-(1H-indol-5-yl)-2-propoxyphenol acid (preparation 6) is injected into the reaction with 4-chloromethyl-2-(2-methoxyphenyl)-5-methoxazole with getting rat-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-propoxy-propionic acid as pale yellow solid.

MS:(M-N)-447,3.

Example 48

rat-3 - {1-[5-Methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}-2-propoxyphenol acid

By analogy with the method described in Example 44, methyl ester rat-3-(1H-indol-5-yl)-2-propoxyphenol acid (preparation 6) is injected into the reaction with 4-chloromethyl-5-methyl-2-(4-triptoreline)oxazolam with getting rat-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}-2-propoxyphenol acid in the form of a pale yellow solid.

MS:(M-N)-485,4.

Example 49

rat-3-{1-[5-Methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}-2-phenoxypropionic acid

By analogy with the method described in Example 44, methyl ester rat-3-(1H-indol-5-yl)-2-phenoxypropionic acid (product 7) enter into reaction with 4-chloromethyl-5-methyl-2-(4-triptoreline)oxazolam with getting rat-3-{1-[5-methyl--(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}-2-phenoxypropionic acid as colorless solid.

MS:(M-N)-519,4.

Example 50

rat-3-{1-[2-(4-Isopropylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-phenoxypropionic acid

By analogy with the method described in Example 44, methyl ester rat-3-(1H-indol-5-yl)-2-phenoxypropionic acid (product 7) enter into reaction with 4-chloromethyl-2-(4-isopropylphenyl)-5-methoxazole with getting rat-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-phenoxypropionic acid as off-white solids.

MS: (M-N)-493,3

Example 51

rat-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-phenoxypropionic acid

By analogy with the method described in Example 44, methyl ester rat-3-(1H-indol-5-yl)-2-phenoxypropionic acid (product 7) enter into reaction with 4-chloromethyl-2-(2-chlorophenyl)-5-methoxazole with getting rat-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-phenoxypropionic acid as off-white solids.

MS:(M-N)-485,3.

Example 52

rat-3-{1-[2-(4-Fluoro-3-were)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-phenoxypropionic acid

By analogy with the method described in Example 44, methyl ester rat-3-(1H-indol-5-yl)-2-phenoxypropionic acid (product 7) enter into reaction with 4-chloromethyl-2-(4-fluoro-3-were)-5-methoxazole with getting rat-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ILM is Teal]-1H-indol-5-yl}-2-phenoxypropionic acid as off-white solid.

MS:(M-N)-483,3.

Example 53

rat-2-Isopropoxy-3-[1-(5-methyl-2-o-tolyloxy-4-ylmethyl)-1H-indol-5-yl]-propionic acid

By analogy with the method described in Example 44, methyl ester rat-3-(1H-indol-5-yl)-2-isopropoxypropylamine acid (preparation 8) is injected into the reaction with 4-chloromethyl-5-methyl-2-o-collocation with getting rat-2-isopropoxy-3-[1-(5-methyl-2-o-tolyloxy-4-ylmethyl)-1H-indol-5-yl]-propionic acid as off-white solid.

MS:(M-N)-that amount to 431,3.

Example 54

rat-2-Isopropoxy-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid

By analogy with the method described in Example 44, methyl ester rat-3-(1H-indol-5-yl)-2-isopropoxypropylamine acid (preparation 8) is injected into the reaction with 4-chloromethyl-2-(2-methoxyphenyl)-5-methoxazole with getting rat-2-isopropoxy-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid as colorless solid.

MS:(M-N)-447,3.

Example 55

rat-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-isopropoxypropylamine acid

By analogy with the method described in Example 44, methyl ester rat-3-(1H-indol-5-yl)-2-isopropoxypropylamine acid (preparation 8) is injected into the reaction with 4-chloromethyl-2-(2-chlorophenyl)-5-methoxazole with getting rat-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-1H and the Dol-5-yl}-2-isopropoxypropylamine acid as a light brown solid.

MS:(M-N)-451,2.

Example 56

rat-2-Isopropoxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid

By analogy with the method described in Example 44, methyl ester rat-3-(1H-indol-5-yl)-2-isopropoxypropylamine acid (preparation 8) is injected into the reaction with 4-chloromethyl-5-methyl-2-(4-triptoreline)oxazolam with getting rat-2-isopropoxy-3-{1-[5-methyl-2-(4-triptoreline)-oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid as colorless solid.

MS:(M-N)-485,4.

Example 57

rat-2-but-3-enyloxy-3-[1-(5-methyl-2-o-tolyloxy-4-ylmethyl)-1H-indol-5-yl]propionic acid

By analogy with the method described in Example 44, methyl ester rat-2-but-3-enyloxy-3-(1H-indol-5-yl)propionic acid (preparation 9) is injected into the reaction with 4-chloromethyl-5-methyl-2-o-collocation with getting rat-2-but-3-enyloxy-3-[1-(5-methyl-2-o-tolyloxy-4-ylmethyl)-1H-indol-5-yl]-propionic acid in the form of a light brown solid.

MS:(M-N)-443,3.

Example 58

rat-2-but-3-enyloxy-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid

By analogy with the method described in Example 44, methyl ester rat-2-but-3-enyloxy-3-(1H-indol-5-yl)propionic acid (preparation 9) is injected into the reaction with 4-chloromethyl-2-(2-methoxyphenyl)-5-methoxazole with getting rat-2-but-3-EN is Loxy-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid as light brown oil.

MS:(M-N)-459,3.

Example 59

rat-2-but-3-enyloxy-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid

By analogy with the method described in Example 44, methyl ester rat-2-but-3-enyloxy-3-(1H-indol-5-yl)propionic acid (preparation 9) is injected into the reaction with 4-chloromethyl-2-(2-chlorophenyl)-5-methoxazole with getting rat-2-but-3-enyloxy-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid as light yellow solid.

MS:(M-N)-463,2.

Example 60

rat-2-but-3-enyloxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid

By analogy with the method described in Example 44, methyl ester rat-2-but-3-enyloxy-3-(1H-indol-5-yl)propionic acid (preparation 9) is injected into the reaction with 4-chloromethyl-5-methyl-2-(4-triptoreline)oxazolam with getting rat-2-but-3-enyloxy-3-{1-[5-methyl-2-(4-triptoreline)-oxazol-4-ylmethyl]-1H-indole-5-yl}propionic acid as light yellow solid.

MS:(M-N)-497,3.

Example 61

rat-2-Ethoxy-3-{2-methyl-1-[2-(5-methyl-2-phenyloxazol-4-yl)ethyl]-1H-indol-5-yl}propionic acid

By analogy with the method described in Example 44, ethyl ester rat-2-ethoxy-3-(2-methyl-1H-indol-5-yl)propionic acid (preparation 5) is injected into the reaction with 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester of methanesulfonic is with getting rat-2-ethoxy-3-{2-methyl-1-[2-(5-methyl-2-phenyloxazol-4-yl)ethyl]-1H-indol-5-yl}propionic acid as light yellow viscous oil.

MS:(M+H)+433,3.

Example 62

rat-2-Ethoxy-3-{2-methyl-1-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1H-indol-5-yl}propionic acid

By analogy with the method described in Example 44, ethyl ester rat-2-ethoxy-3-(2-methyl-1H-indol-5-yl)propionic acid (preparation 5) is injected into the reaction with 3-(5-methyl-2-phenyloxazol-4-yl)propyl ether of methansulfonate with getting rat-2-ethoxy-3-{2-methyl-1-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1H-indole-5-yl}propionic acid as an orange viscous oil.

MS:(M-N)-445,3.

Example 63

rat-2-Ethoxy-3-{4-methyl-1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid

By analogy with the method described in Example 44, ethyl ester rat-2-ethoxy-3-(4-methyl-1H-indol-5-yl)propionic acid (preparation s) is injected into the reaction with 4-chloromethyl-5-methyl-2-(4-triptoreline)oxazolam with getting rat-2-ethoxy-3-{4-methyl-1-[5-methyl-2-(4-triptoreline)-oxazol-4-ylmethyl]-1H-indole-5-yl}propionic acid as a yellow solid.

MS:(M-N)-485,3.

Example 64

rat-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl}propionic acid

By analogy with the method described in Example 44, ethyl ester rat-2-ethoxy-3-(4-methyl-1H-indol-5-yl)propionic acid (preparation s) is injected into the reaction with 4-chloromethyl-2-(4-isopropylphenyl)-5-methoxazole with p what lay in rat-2-ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl}propionic acid as light yellow solid.

MS:(M-N)-459,3.

Example 65

rat-2-Ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl} propionic acid

By analogy with the method described in Example 44, ethyl ester rat-2-ethoxy-3-(4-methyl-1H-indol-5-yl)propionic acid (preparation s) is injected into the reaction with 4-chloromethyl-2-(4-fluoro-3-were)-5-methoxazole with getting rat-2-ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl} propionic acid as a yellow solid.

MS:(M-N)-449,3.

Example 66

rat-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl}-2-ethoxypropionate acid

By analogy with the method described in Example 44, ethyl ester rat-2-ethoxy-3-(4-methyl-1H-indol-5-yl)propionic acid (preparation s) is injected into the reaction with 4-chloromethyl-2-(2-chlorophenyl)-5-methoxazole with getting rat-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl}-2-ethoxypropionate acid as a yellow solid.

MS:(M-N)-451,2.

Example 67

rat-3-{1-[2-(3,5-Acid)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl}-2-ethoxypropionate acid

By analogy with the method described in Example 44, ethyl ester rat-2-ethoxy-3-(4-methyl-1H-indol-5-yl)propionic acid (preparation s) is injected into the reaction with 4-chloromethyl-2-(3,5-acid)-5-methoxazole with getting rat-3-1-[2-(3,5-acid)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl}-2-ethoxypropionate acid the form of a yellow solid.

MS:(M-N)-477,2.

Example 68

rat-2-Ethoxy-3-{1-[4-methyl-2-(4-triptoreline)thiazole-5-ylmethyl]-1H-indol-5-yl}propionic acid

By analogy with the methods described in the Examples 36A) and (36B), ethyl ester of rat-2-ethoxy-3-(1H-indol-5-yl)propionic acid (preparation 1) is injected into the reaction with 5-chloromethyl-4-methyl-2-(4-triptoreline)thiazole [international application PCT (2001), WO 01/00603 A1] to obtain ethyl ester rat-2-ethoxy-3-{1-[4-methyl-2-(4-triptoreline)thiazole-5-ylmethyl]-1H-indol-5-yl}propionic acid, which consistently omelet with getting the connection specified in the header, in the form of a yellow solid.

MS:(M-N)-487,3.

Example 69

(Z)-3-{1-[2-(2-Chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxyacrylate acid

By analogy with the methods described in the Examples 36A) and (36B), ethyl ester of (Z)-2-ethoxy-3-(1H-indol-5-yl)acrylic acid (preparation 1A) is injected into the reaction with 4-chloromethyl-2-(2-chlorophenyl)-5-methoxazole with obtaining the ethyl ester of (Z)-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxyacrylate acid, which consistently omelet with getting the connection specified in the header, in the form of a colorless solid.

MS:(M+N)+437,2; (M+Na)+459,2

Example 70

rat-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-6-yl}propionic acid

what about the analogy with the method, described in Example 44, ethyl ester rat-2-ethoxy-3-(1H-indol-6-yl)propionic acid (preparation 11) is injected into the reaction with 4-chloromethyl-2-(4-isopropylphenyl)-5-methoxazole with getting rat-2-ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-6-yl}-propionic acid as light yellow viscous oil.

MS:(M-N)-445,4.

Example 71

rat-3-{1-[2-(3,5-Acid)-5-methoxazole-4-ylmethyl]-1H-indol-6-yl}-2-ethoxypropionate acid

By analogy with the method described in Example 44, ethyl ester rat-2-ethoxy-3-(1H-indol-6-yl)propionic acid (preparation 11) is injected into the reaction with 4-chloromethyl-2-(3,5-acid)-5-methoxazole with getting rat-3-{1-[2-(3,5-acid)-5-methoxazole-4-ylmethyl]-1H-indol-6-yl}-2-ethoxypropionate acid as a yellow solid.

MS:(M-N)-463,3.

Example 72

rat-2-Ethoxy-3-{1-[2-(4-isopropylphenyl)thiazole-4-ylmethyl]-1H-indol-6-yl}-propionic acid

By analogy with the method described in Example 44, ethyl ester rat-2-ethoxy-3-(1H-indol-6-yl)propionic acid (preparation 11) is injected into the reaction with 4-chloromethyl-2-(4-isopropylphenyl)thiazole with getting rat-2-ethoxy-3-{1-[2-(4-isopropylphenyl)thiazole-4-ylmethyl]-1H-indol-6-yl}propionic acid as a yellow viscous oil.

MS: (M-N)-447,2.

Example

Tablets comprising the following components, can be manufactured tra the investment method:

ComponentsPills
The compound of the formula Iof 10.0-100.0 mg
Lactose125,0 mg
Corn starch75,0 mg
Talc4.0 mg
Magnesium stearate1.0 mg

Example B

Capsules comprising the following components, can be manufactured in the traditional way:

ComponentsOn capsule
The compound of the formula I25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg

The example In

Solutions for injection, comprising the following components, can be manufactured in the traditional way:

The compound of the formula I3.0 mg
Gelatin150,0 mg
Sodium carbonateto get
the final pH 7
Phenol4,7 mg
Water for injectable solutionsto 1.0 ml

1. Compounds of formulas is

where R1denotes thiophenyl or phenyl, optionally substituted from one to three substituents, independently selected from halogen, C1-8alkoxy, C1-8the alkyl and C1-8of alkyl, substituted by one to three halogen atoms;

R2denotes hydrogen or C1-8alkyl;

R3indicates phenoxy,2-8alkenylacyl or1-8alkoxy;

R4denotes hydrogen or C1-8alkyl;

and one of the substituents R5and R6means

and the other denotes hydrogen, and where the relationship between carbon atoms Withaandbdenotes a carbon-carbon single or double bond;

R7denotes hydrogen or C1-8of alkyl;

R8denotes hydrogen or C1-8of alkyl;

moreover, any of a and a1represents nitrogen and the other represents oxygen or sulfur;

n denotes 1, 2 or 3,

and their pharmaceutically acceptable salts and esters.

2. Compounds according to claim 1, in which

R3stands With1-8alkoxy;

R5means

where the relationship between carbon atoms Withaandbdenotes a carbon-carbon simple is whether the double bond;

R6denotes hydrogen;

R7denotes hydrogen;

R8denotes hydrogen;

And denotes oxygen or sulfur

and1denotes nitrogen.

3. Compounds according to claim 1, in which R1denotes thiophenyl, phenyl or phenyl containing from one to three substituents independently selected from fluorine, chlorine, methoxy, ethoxy, propyloxy, isopropoxy, methyl, ethyl, propyl, isopropyl, tert-butyl and trifloromethyl.

4. Compounds according to claim 1, in which R2denotes hydrogen, methyl or ethyl.

5. Compounds according to claim 4, in which R2denotes methyl.

6. Compounds according to claim 1, in which R3denotes methoxy, ethoxy, propyloxy, isopropoxy, phenoxy or butenyloxy.

7. Compounds according to claim 1, in which R3denotes methoxy or ethoxy.

8. Compounds according to claim 1, in which R4denotes hydrogen.

9. Compounds according to claim 1, in which R4denotes methyl.

10. Compounds according to claim 1, in which the relationship between carbon atoms Withaandbdenotes a simple carbon-carbon bond.

11. Compounds according to claim 1, in which R6denotes hydrogen.

12. Compounds according to claim 1, in which R7denotes hydrogen.

13. Compounds according to claim 1, in which R7denotes methyl.

14. Compounds according to claim 1, in which R8denotes hydrogen.

15. Connect the deposits according to claim 1, in which R8denotes methyl.

16. Compounds according to claim 1, in which a denotes oxygen or sulfur, And indicates nitrogen.

17. Compounds according to clause 16, in which a denotes oxygen.

18. Compounds according to claim 1, in which n denotes 1.

19. Compounds according to claim 1, selected from

(S)-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acids;

(S)-2-ethoxy-3-{1-[2-(2-methoxyphenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(S)-2-ethoxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid;

(S)-3-{1-[2-(3,5-acid)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acids;

(S)-2-ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-2-ethoxy-3-{3-methyl-1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid;

rat-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl}-2-ethoxypropionate acids;

rat-2-ethoxy-3-{1-[2-(4-fluoro-3-were)-5-methoxazole-4-ylmethyl]-3-methyl-1H-indol-5-yl}propionic acid;

rat-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}-2-propoxyphenol acids;

rat-2-isopropoxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid

rat-2-but-3-enyloxy-3-{1-[5-methyl-2-(4-triptoreline)oxazol-4-ylmethyl]-1H-indol-5-yl}propionic acid and

rat-2-ethoxy-3-{1-[2-(4-isopropylphenyl)-5-methoxazole-4-ylmethyl]-4-methyl-1H-indol-5-yl}propionic acid.

20. The connection according to claim 19, which represents (S)-3-{1-[2-(2-chlorophenyl)-5-methoxazole-4-ylmethyl]-1H-indol-5-yl}-2-ethoxypropionate acid.

21. Compounds according to any one of claims 1 to 20, having agonistic activity against peroxisome of proliferation RAPPα and/or RAPPγ.

22. Compounds according to any one of claims 1 to 20, used for preparation of medicines for the prevention and/or treatment of diseases which are modulated by agonists RAPPα and/or RAPPγ.

23. Pharmaceutical composition having agonistic activity against peroxisome of proliferation RAPPα and/or RAPPγcontaining compound according to any one of claims 1 to 20 and a therapeutically inert carrier.

24. The pharmaceutical composition according to item 23, further containing a therapeutically effective amount of a lipase inhibitor.

25. The pharmaceutical composition according to paragraph 24, in which the lipase inhibitor is represented by orlistat.

26. The use of compounds according to any one of claims 1 to 20 for the preparation of drugs for the treatment and/or prevention of diseases which are modulated agonist is mi RAPPα and/or RAPPγ.

27. The use of compounds according to any one of claims 1 to 20 for the preparation of drugs for the treatment and/or prevention of diseases which are modulated by agonists RAPPα and/or RAGOTγ, in a patient who is also receiving treatment with the lipase inhibitor.

28. The application of item 27, in which the lipase inhibitor is a orlistat.

29. The use according to any one of PP-28, where the disease presents with diabetes, leisureservices diabetes, high blood pressure, elevated lipid levels and cholesterol, atherosclerosis, syndrome metabolic

30. The application of clause 29, where the disease presents leisureservices diabetes.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I):

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound of the formula (I): or its pharmaceutically acceptable salt wherein X is chosen from the group consisting of carbon (C), oxygen (O), nitrogen (N) and sulfur (S) atoms; Z represents nitrogen atom (N); Y is chosen from the group consisting of =O, =S or their tautomers; SPU means a spacer element providing distance d between Z and N atom wherein -SPU- represents bi-radical -(CR6R7)n- wherein n means 1, 2, 3, 4 or 5; N atom in common with R1 and R2 forms heterocyclic ring wherein indicated heterocyclic ring is chosen from the group consisting of piperidine and 8-azabicyclo[3.2.1]octane and wherein heterocyclic ring is substituted with one or more substitutes R4 chosen from the group consisting of hydrogen atom, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkylidene, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkyloxyimino-group each of them is substituted optionally with a substitute R5 and wherein at least with one of indicated substitutes R4 is represented by R4' chosen from the group consisting of (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkylidene wherein each of them is substituted optionally with a substitute R5 wherein R5 is chosen from the group consisting of hydrogen, halogen atom, hydroxy-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, (C2-C8)-alkenyl and (C2-C8)-alkynyl; RX can absent or can be chosen from the group consisting of hydrogen atom and optionally substituted (C1-C8)-alkyl; R3 can be represented in 0-4-fold range and chosen from the group consisting of halogen atom, optionally substituted (C1-C8)-alkyl and (C1-C8)-alkoxy-group; each R6 and R7 is chosen optionally and independently among the group consisting of hydrogen atom, hydroxy-group and optionally substituted (C-C8)-alkyl. Also, invention relates to a pharmaceutical composition possessing the selective activity with respect to M and/or M4-subtypes of muscarinic receptors and antagonism with respect to D2-dopamine receptors and comprising compound of the formula (I) by claim 1 in common with pharmaceutically acceptable carriers or excipients. Also, invention relates to a method for enhancing activity of cholinergic receptor comprising interaction of cholinergic receptor and system comprising cholinergic receptor with the effective amount of at least one compound of the formula (I) by claim 1. Also, invention relates to using the compound according to any claim among 1-11 or its pharmaceutically acceptable salt, or pharmaceutical composition containing any base for preparing a medicinal preparation used in prophylaxis aim or treatment of psychosis or for attenuation of symptoms associated with psychosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, chemical technology, pesticides.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (I): wherein Q means nitrogen atom (N); Y means nitro-group (-NO2); Z means -NR3; R1 and R2 mean in common alkylene bridge that comprises two or three carbon atoms and, optionally, a heteroatom chosen from the group comprising -NR5 and oxygen atom (O); R3 means unsubstituted (C1-C12)-alkyl; R5 means hydrogen atom (H) or (C1-C12)-alkyl. Method involves the following steps: (a) interaction of compound of the formula (II): wherein X means a leaving group with a halogenated agent to yield compound of the formula (III): wherein W means halogen atom and wherein treatment of compound of the formula (III) involves extraction of compound of the formula (III) with hydrochloric acid taken in the concentration 10-50 wt.-%, and (b) interaction of the synthesized compound of the formula (III) with compound of the formula (IV): wherein R1, R2, Y, Z and Q have above given values. In the process for synthesis of compound of the formula (III) the stage (a) involves purification stage wherein formed crude product is treated with water at acid range of pH values.

EFFECT: improved method of synthesis.

3 cl, 6 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): in free form or as a salt wherein Ar1 means phenyl substituted with one or some halogen atoms; Ar2 means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C1-C8)-alkyl, (C1-C8)-halogenalkyl, (C1-C8)-alkoxy-group or (C1-C8)-alkoxycarbonyl; R1 means hydrogen atom or (C1-C8)-alkyl optionally substituted with hydroxy-,(C1-C8)-alkoxy-, acyloxy-group, -N(R2)R3, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl, -CON(R4)R5 or monovalence cyclic organic group; each among R2 and R3 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R2 means hydrogen atom and R3 means acyl or -SO2R6, or R and R3 in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R4 and R5 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R4 and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R6 means (C1-C8)-alkyl, (C1-C8)-halogenalkyl or phenyl optionally substituted with (C1-C8)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar1 means para-chlorophenyl and R1 means hydrogen atom then Ar2 doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

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

7 cl, 47 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

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

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to a new biologically active compound of 4-oxoquinoline that is useful as an anti-HIV agent and to its pharmaceutically acceptable salt. Invention describes an anti-HIV agent comprising compound of 4-oxoquinoline represented by the following formula [I] or its pharmaceutically acceptable salt as an active component wherein ring Cy represents phenyl group, naphthyl group or pyridyl group and each this group is substituted optionally with 1-5 substituted chosen from the following group A wherein A represents the group consisting of cyano-group, phenyl group, nitro-group, halogen atom, (C1-C4)-alkyl group, halogen-(C1-C4)-alkyl group, halogen-(C1-C4)-alkoxy-group, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3 and -COORa1 wherein Ra1 and Ra2 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or benzyl group, and Ra3 represents (C1-C4)-alkyl group; R1 represent a substitute chosen from the following group B, or (C1-C10)-alkyl group optionally substituted with 1-3 substitutes chosen from halogen atom and the following group B wherein the group B represents the group consisting of phenyl group optionally substituted with phenyl group or 1-5 halogen atoms; (C3-C6)-cycloalkyl group, imidazolyl group, benzothiophenyl group, thiazolyl group optionally substituted with 1-3 (C1-C6)-alkyl groups, morpholinyl group, pyridyl group, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4 and -NRa5COORa6 wherein Ra4 and Ra5 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or phenyl group; Ra6 represents (C1-C4)-alkyl group; R2 represents hydrogen atom or (C1-C4)-alkyl group; R31 represents hydrogen atom, cyano-group, hydroxy-group, halogen atom or (C1-C4)-alkoxy-group; X represents -C-R32, and Y represents -C-R33 or nitrogen atom wherein R32 and R33 are similar or different and each represents hydrogen atom, cyano-group, halogen atom, pyrrolidinyl group, (C1-C10)-alkyl group optionally substituted with 1-3 halogen atoms, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10 or -N=CH-NRa10Ra11 wherein Ra7 and Ra8 are similar or different and each represents hydrogen atom, phenyl group or (C1-C10)-alkyl group optionally substituted with (C3-C6)-cycloalkyl group or hydroxy-group; Ra9 represents (C1-C4)-alkyl group and Ra10 and Ra11 are similar or different and each represents hydrogen atom or (C1-C4)-alkyl group. Also, invention describes compound of the formula (III) given in the invention description, integrase inhibitor, antiviral agent, ant-HIV composition, anti-HIV agent, using compound of 4-oxoqionoline, method for inhibition of integrase activity, method for prophylaxis or treatment of viral infectious disease, pharmaceutical composition used for inhibition of integrase activity, antiviral composition and commercial package (variants). Invention provides the development of a pharmaceutical agent possessing inhibitory effect on activity of integrase.

EFFECT: valuable medicinal properties of compound, agent and composition.

40 cl, 7 tbl, 250 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

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

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, chemical technology, insecticides.

SUBSTANCE: invention relates to derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide represented by the general formula (I): wherein R represents (C1-C6)-alkyl group that can be substituted with one or some halogen atoms; R1 represents hydrogen atom, (C1-C6)-alkyl group that can be substituted with one or some substituted chosen from group of substitutes A, (C2-C6)-alkenyl group or acyl group; X represents group of the formula -C-R2 or nitrogen atom; each among R2 and R3 represents independently hydrogen atom, halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from group of substitutes A, (C3-C7)-cycloalkyl group, (C2-C6)-alkenyl group, (C3-C7)-cycloalkenyl group, formyl group, group of the formula: -CH=NOR4 (wherein R4 represents hydrogen atom or (C1-C6)-alkyl group, cyano-group, phenyl group that can be substituted with one or some substitutes chosen from group of substitutes B, 5- or 6-membered heterocyclic group (heterocycle comprising 1-2 heteroatoms that are similar and chosen from nitrogen atom), (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or phenoxy-group. The group of substitutes A represents group consisting of halogen atom, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group, cyano-group and phenyl group. The group of substitutes B represents group consisting of halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from above given group of substitutes A, (C1-C6)-alkoxy-group that can be substituted with one or some substitutes chosen from above given group of substitutes A, or its salt. Also, invention relates to insecticide comprising a derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide or its salt as an active component and a carrier optionally. Also, invention relates to a method for synthesis of derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide. Invention provides synthesis of derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide possessing the high insecticide activity.

EFFECT: improved method of synthesis, valuable properties of derivatives.

18 cl, 3 tbl, 91 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (1): wherein Y means -O-, -S- or -N(R2)- wherein R2 means hydrogen atom, (C1-C10)-alkyl or aralkyl; Z means 2,5-furanyl, 2,5-thiophenyl, 4,4'-stilbenyl or 1,2-ethyleneyl residue; R1 means hydrogen or halogen atom, (C1-C10)-alkyl, (C1-C10)-alkoxy-group, cyano-group, -COOM or -SO3M wherein M means hydrogen atom or alkaline or alkaline-earth metal atom. Method for synthesis involves carrying out the reaction of compound of the formula (2): with dicarboxylic acid of the formula: HOOC-Z-COOH (3) or with it ester wherein Y, Z and R1 have values given above in N-methylpyrrolidone or N,N-dimethylacetamide medium in the presence of an acid catalyst and optionally in the presence of an accessory solvent able to remove water from the reaction mixture.

EFFECT: improved method of synthesis.

11 cl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of sulfonamide of the general formula (I): wherein A means a substitute chosen from 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) optionally substituted with 1 or 2 halogen atoms, (C1-C4)-alkyl or phenyl radical, or 5- or 6-membered heteroaryl radical comprising 1 or 2 atoms of O, N or S; bicyclic heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from O, N or S and optionally substituted with 1 or 2 halogen atoms or (C1-C4)-alkyl; R1 means hydrogen atom (H), (C1-C4)-alkyl, benzyl; n means 0, 1, 2, 3 or 4; R2 means -NRR5 or the group of the formula: wherein a dotted line means optional chemical bond; R, R4 and R5 mean independently H or (C1-C4)-alkyl; or one of its physiologically acceptable salts. Compounds of the formula (1) possess antagonistic activity with respect to serotonin HT6-receptors that allows their using in pharmaceutical composition and for preparing a medicament.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, anti-microbial preparations.

SUBSTANCE: invention relates to compounds useful as anti-microbial agents. Claimed compounds are effective against to certain human and animal pathogens, including Gram-positive aerobic bacteria such as multi-resistant staphylococcus, streptococcus and enterococcus, as well as anaerobic organisms such as species Bacterioides spp. and Clostridia spp., and acid resistant organisms such as Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium spp.

EFFECT: new anti-microbial agents.

2 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel class of 5-membered heterocyclic compounds of the general formula (I): or cosmetically acceptable salts. Invention describes a compound represented by the formula (I) and its pharmaceutically or cosmetically acceptable salt wherein R1 is chosen from linear or branched (C1-C12)-alkyl, (C3-C7)-cycloalkyl, phenyl, naphthyl, C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatoms when they present are chosen independently from oxygen (O), nitrogen (N) or sulfur (S) atom and substituted optionally wherein substitutes are chosen from the first group comprising halogen atom, hydroxy0, nitro-, cyano-, amino- oxo-group and oxime, or from the second group comprising linear or branched (C1-C8)-alkyl wherein a substitute from indicated second group is optionally substituted with R10, or wherein heteroaryl is substituted with -CH2-C(O)-2-thienyl; Y is absent or chosen from the group consisting of (C1-C12)-alkyl-Z or (C2-C8)-alkyl wherein Z is chosen from sulfur, oxygen or nitrogen atom; A and B are chosen independently from nitrogen atom (N), -NH, -NR6, sulfur, oxygen atom to form heteroaromatic ring system; R2, R3 and R4 are chosen independently from the first group comprising hydrogen, halogen atom, or R3 and R4 form phenyl ring in adjacent positions; R5 is absent or chosen from the group comprising -CH2-phenyl, -CH2(CO)R7, -CH2(CO)NHR8 and -CH2(CO)NR8R9 that are substituted optionally with R10; R6, R7, R8 and R are chosen independently from the group comprising linear or branched (C1-C8)-alkyl, (C3-C7)-cycloalkyl, C5-heterocycloalkyl, benzylpiperidinyl, phenyl, naphthyl, heteroaryl, alkylheteroaryl, adamantyl, or R8 and R9 form piperidine ring, and R means 3,4-ethylenedioxyphenyl wherein substitutes in indicated group are substituted optionally with R10, and heteroaryl means C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatom when they present are chosen independently from O, N or S; R10 is chosen from halogen atom, hydroxy-, nitro-, cyano-, amino-, oxo-group, perhalogenalkyl-(C1-C6) or oxime; X means halide ion under condition that when groups/substitutes present at the same or at adjacent carbon or nitrogen atoms then can form optionally 5-, 6- or 7-membered ring optionally containing one o some double bonds and containing optionally one or some heteroatoms chosen from O, N or S. Also, invention describes a method for synthesis of these compounds, their therapeutic and cosmetic using, in particular, in regulation of age and diabetic vascular complications. Proposed compounds show effect based on the triple effect as agent destroying AGE (terminal products of enhanced glycosylation), inhibitors of AGE and scavengers of free radicals that do their suitable in different therapeutic and cosmetic using. Also, invention relates to pharmaceutical and cosmetic compositions comprising these compounds and to methods for treatment of diseases caused by accumulation of AGE and/or free radicals in body cells. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

73 cl, 4 tbl, 63 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of N-triazolylmethylpiperazine of the general formula (I): , wherein R1 means hydrogen atom or (lower)-alkyl; R2 means (lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, cycloalkyl with 5-6 carbon atoms in cycle, pyridinyl-(lower)-alkyl, possibly bi-substituted phenyl-(lower)-alkyl, phenyloxy-(lower)-alkyl substituted with halogen atom in phenyl ring; R3 means (lower)-alkyl, (lower)-alkyloxycarbonyl-(lower)-alkyl or (C5-C6)-cycloalkyl, or both R2 and R3 in common with nitrogen atom to which they are bound form substituted pyrrolidine ring or cyclic group of the formula (a): , wherein A means nitrogen, oxygen atom, methylene or methylidene group wherein its double bond is formed in common with adjacent carbon atom at position 3 of the group (a), and if A means nitrogen atom then this nitrogen atom has substitute R4', and in this case n means 2 or 3, and R4' means (lower)-alkyl, possibly substituted phenyl-(lower)-alkyl, possibly substituted pyridyl, pyridyl-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, pyrimidyl-(C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(lower)-alkyl or morpholinyl-(lower)-alkyl; R4 and R5 mean hydrogen atom and in all cases n means a whole number from 1 to 2; R4 means hydrogen atom, (lower)-alkyl, (lower)-alkoxy-(lower)-alkyl, (lower)-alkoxycarbonyl, (lower)-alkoxycarbonyl-(lower)-alkyl, di-(lower)-alkylamino-(lower)-alkyl, phenyl, pyrrolidinyl, pyrrolidinyl-(lower)-alkyl, pyridyl or piperidinyl, cyclohexyl, cyclohexyl-(lower)-alkyl, phenyl-(lower)-alkyl, pyridyl monosubstituted with (lower)-alkyl, phenyl-(lower)-alkyl monosubstituted with (lower)-alkyl, pyrimidyl, pyridyl-(lower)-alkyl, morpholinyl-(lower)-alkyl; R5 means hydrogen atom, (lower)-alkyl or (lower)-alkoxy-(lower)-alkyl, or R4 and R5 taken in common mean spiroethylenedioxy-group bound with carbon atom of the group (a), (C3-C4)-alkylene bound with two adjacent atoms of the group (a) or phenyl anellated by two adjacent carbon atoms of the group (a), and their physiologically acceptable acid-additive salts also. Also, invention relates to methods for synthesis of these compounds, a medicinal agent based on thereof and intermediate compound in synthesis of novel compounds. Novel compounds are antagonists of neurokinin receptors and display effect in peripheral region preferably and can be used in treatment of functional and inflammatory disorders of digestive tract.

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

10 cl, 4 tbl, 4 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I):

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

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