Prophylactic or therapeutic agent and pharmaceutical composition comprising heterocyclic compound

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

 

The scope to which the invention relates.

The present invention relates to new heterocyclic compounds and their pharmaceutically acceptable salts.

Compounds of the present invention have the effect of reducing the level of triglycerides in the blood, action, lower cholesterol, low-density lipoprotein (hereinafter referred to as "LDL-X"), as well as the effect of reducing the level of glucose in the blood, the action of reducing the level of insulin in the blood, or action that increases the level of cholesterol in high density lipoprotein (hereinafter referred to as "HDL-X"), and action that reduces atherogenic index, which represents the ratio of non-LDL-X to HDL-X and which is calculated by the formula: (total cholesterol - HDL-X)/ (HDL'S). Therefore, the compounds of the present invention can be used for the prevention and treatment of coronary heart disease, heart attack, brain, hyperlipidemia, arteriosclerosis or diabetes.

Background of invention

The syndrome of insulin resistance, complicated carbohydrate and/or lipid metabolism and hypertension, attracts special attention of experts as a factor is very high risk of coronary heart disease. The syndrome of insulin resistance is found in most patients, Strada who were obese and insulin-dependent diabetes mellitus (NIDDM). It is known that the violation of lipid metabolism leading to increased levels of triglycerides in the blood, which is caused primarily by increased levels of chylomicrons, VLDL and remnant lipoproteins, which are intermediate metabolites, as well as reduced levels of HDL-X (Diabetes, 37, 1595-1607 (1988); Arch. Intern. Med., 149, 1514-1520 (1989); Diabetes Care, 14, 173-194 (1991)).

Although it is often stated that the level of triglyceride is probably an important risk factor for diseases arteriosclerosis, however, an explicit correspondence between them has not been established. On the basis of recently obtained results arteriography (Circulation, 90, 2230-2235 (1994)) reported that the level of triglycerides is an independent risk factor for coronary heart disease.

It is well known that HDL-X is inversely proportional to the incidence of coronary heart disease, as revealed from the results of a series of epidemiological studies (Circulation, 79, 8-15 (1989)). It is assumed that HDL participates in the reverse transport of cholesterol in the liver from extrahepatic tissues, and in experiments on animals used as models, it was demonstrated that he possesses an action directed against arteriosclerosis (J. Clin. Invest., 85, 1234-1241 (1990); Nature, 353, 265-267 (1991)).

In the large-scale tested the deposits for the correction of cholesterol was confirmed, the levels of total blood cholesterol, particularly LDL-X, is positively correlated with the incidence of coronary heart disease, and the incidence can be reduced by reducing the specified level (Lipid Research Clinics Program: JAMA, 251, 351 (1984); Lipid Research Clinics Program: JAMA, 251, 365 (1984)).

Accordingly, compounds that reduce the level of triglycerides and LDL's in the blood, and increase of HDL-X or lower atherogenic index, can be used as a drug for the treatment of arteriosclerosis, especially for the prevention or treatment of coronary heart disease. It is also expected that compounds that improve insulin resistance, reduce the level of blood glucose and insulin levels in the blood and improve pathological conditions in complications such as diabetes, hyperinsulinemia, hypertension and obesity, which may be risk factors for arteriosclerotic diseases, and therefore have an effective preventive or therapeutic activity against arteriosclerosis.

Currently, it is known that 2-aryl-5-alkyloxyalkyl derivatives or 2-aryl-5-alkylthiophene derivatives of General formula (A), which have some similarities with the compounds of the present invention, oblad shall have effect, reducing the level of lipids in the blood, or action that reduces the level of glucose in the blood.

where the ring Ar1 is aryl; V is oxygen or sulfur; Ak1 represents hydrogen, alkyl or halogenated; Ak2 is alkylene; Ak3 is alkylen, albaniles or akinyan, optionally substituted alkoxy, alkoxycarbonyl, atillio, arylamino or aryl; Q represents carboxy, 2,4-oxazolidin-5-yl, 2,4-thiazolidin-5-yl or 1,2,4-oxadiazolidine-3,5-Dion-2-yl; and the ring Ar2 represents a group of the formula [B1] or [B2].

For example, in USP 5532256, WO96/05186, JP H7-188227, A, JP S61-85372, A and USP 5401761, it was reported that compounds of General formula (A), namely 2,4-thiazolidinedione derivatives have the effect of reducing the level of lipids in the blood, or action that reduces the level of glucose in the blood.

In JP H9-124623, A, WO95/18125, JP H7-165735, A, USP 5468762 and JP H8-92228, A indicated that compounds of General formula (A), namely 2,4-oxazolidinedione derivatives have the effect of reducing the level of lipids in the blood, or action that reduces the level of glucose in the blood.

In USP 5510360 and USP 5480896 indicated that compounds of General formula (A), namely, 1,2,4-oxadiazolidine-3,5-dinavia derivatives have the effect of reducing the level of lipids in the blood, or action that reduces the level of glucose in the blood.

IN WO99/462325, WO98/00137, WO97/31907, WO96/38415, JP H9-323982, A, JP H8-325264, A, JP H5-507920, And, USP 5510360 and USP 5480896 indicated that compounds of General formula (A), namely, derivatives of carboxylic acids have the effect of reducing the level of lipids in the blood, or action that reduces the level of glucose in the blood.

Compounds of General formula (A) are different in that they have:

(1) 2-aryl-5-alkyloxybenzoic ring or 2-aryl-5-alkylthiophene ring on one end;

(2) carboxy, 2,4-oxazolidin-5-yl, 2,4-thiazolidin-5-yl or 1,2,4-oxadiazolidine-3,5-Dion-2-yl at the other end; and

(3) an aromatic ring, such as benzene, represented by the ring Ar2 in the molecule.

In addition, IN EP-A-220573 shown that oksazola derivatives of General formula (I) have anti-arthritis activity.

where Ar3 represents a substituted phenyl or thienyl; R23represents hydrogen or alkyl; Ak4 is alkylene having 1-2 carbon atoms; each of R24and R25is alkyl; Q1 represents carboxy, alkoxycarbonyl, carbarnoyl, N-allylcarbamate or N,N-dialkylamino.

Description of the invention

One of the purposes of the present invention to provide an effective prophylactic or therapeutic agent against hyperlipidemia, arteriosclerosis, diabetes, hypertension, obesity, etc. that the possession is tons of action, reducing the level of triglycerides in the blood; an action that reduces the level of LDL's in the blood, as well as action that reduces the level of blood glucose or insulin levels in the blood, any action that increases the level of HDL's in the blood, or action that reduces atherogenic index.

To achieve this goal, the authors of the present invention have conducted intensive studies and found that heterocyclic compounds of the formula [1]below, satisfy the objectives and contribute to the implementation of the present invention.

Thus, the present invention relates to a heterocyclic compound of the following formula [1] or its pharmaceutically acceptable salts and pharmaceutical compositions containing this compound as an active ingredient.

where R1represents aryl, aromatic heterocyclic group, or cycloalkyl where the specified aryl or aromatic heterocyclic group optionally substituted by the same or different one to three groups selected from alkyl, halogenoalkane, trihalomethyl, alkoxy, halogen and nitro;

Het represents a divalent aromatic heterocyclic group, where the specified aromatic heterocyclic group optionally substituted by alkyl with elitigation;

D represents alkylene, albaniles, akinyan or a group of the formula [2]:

where W represents CH or nitrogen, m is an integer of 1-10, and n is an integer of 0-9, provided that m + n is an integer of 1-10; and

E represents a group of the formula [3] or [4]:

where Y represents oxygen or sulfur; R3and R4are the same or different, and each represents hydrogen or alkyl; p is an integer 0-2; Z is carboxy, alkoxycarbonyl, hydroxymethyl, carbarnoyl, N-hydroxycarbamoyl, N-allylcarbamate, N,N-dialkylamino, cyano, 1H-5-tetrazolyl, 1-alkyl-5-tetrazolyl or 2-alkyl-5-tetrazolyl, provided that if D represents a group of formula [2], then E is not a group of the formula [4].

Of the heterocyclic compounds of the formula [1] compounds in which Het represents a group of the formula [5z]:

where R22represents hydrogen, alkyl or trihalomethyl, D represents alkylene having 1-2 carbon atoms, E represents a group of the formula [4], and Y represents oxygen, are known compounds. However, the authors of the present invention, it was discovered that compounds of the formula [1] have the effect of reducing the level of triglycerides in the blood; an action that reduces the level of LDL's in the shelter is, and effect, reducing the level of blood glucose, insulin levels in the blood, any action that increases the level of HDL's in the blood, or action that reduces atherogenic index.

Heterocyclic compounds [1], which differs from the compounds of the formula [1], where Het represents a group of the formula [5z]; D is alkylene having 1-2 carbon atoms, R22represents hydrogen, alkyl or trihalomethyl, E represents a group of the formula [4], and Y represents oxygen, are new compounds, which still have not been described in any work.

Of the compounds [1] of the present invention preferred are compounds where D is alkylene, albaniles or akinyan having 3-10 carbon atoms. Other preferred compounds are compounds where Het represents a divalent aromatic heterocyclic group of the formula [5]:

where X is oxygen, sulfur or NR6, R6represents hydrogen or alkyl, and R2represents hydrogen, alkyl or trihalomethyl.

Of the compounds [1] of the present invention, more preferred are compounds where Het represents a divalent aromatic heterocyclic group of the formula [5]; X represents oxygen, sulfur or NR6, R6represents hydrogen or alkyl, R2 represents hydrogen, alkyl or trihalomethyl, and D represents alkylene, albaniles or akinyan having 3-10 carbon atoms.

Of the compounds [1] of the present invention even more preferred are compounds where R1represents phenyl, optionally substituted by one or two groups selected from alkyl, halogen, trihalomethyl and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A]:

where X is defined above, R15represents alkyl or trihalomethyl, and D represents alkylene or albaniles having 3-7 carbon atoms.

Of the compounds [1] of the present invention even more preferred are, firstly, the compounds where R1represents phenyl, optionally substituted by one or two groups selected from alkyl, halogen, trihalomethyl and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A], X represents oxygen, sulfur or NR6, R6represents hydrogen or alkyl, R15represents alkyl or trihalomethyl, D represents alkylene or albaniles having 3-5 carbon atoms, E represents a group of the formula [3], p is 1, Y is oxygen, R3represents hydrogen or alkyl, and Z represents carboxy or alkoxy bonil; and secondly, compounds where R1represents phenyl, optionally substituted by one or two groups selected from alkyl, halogen and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A], X represents oxygen, sulfur or NR6, R6represents hydrogen or alkyl, R15represents alkyl or trihalomethyl, D represents alkylene, albaniles or akinyan having 5-7 carbon atoms, E represents a group of the formula [4], Y is oxygen, R3and R4are the same or different, and each represents hydrogen or alkyl, and Z represents carboxy or alkoxycarbonyl.

Of the compounds [1] of the present invention particularly preferred are, firstly, the compounds where R1represents phenyl, optionally substituted by one or two groups selected from alkyl and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A], X is oxygen, R15represents alkyl, D represents alkylene having 3-5 carbon atoms, E represents a group of the formula [3], p is 1, Y is oxygen, R3is alkyl, and Z represents carboxy; and secondly, compounds where R1represents phenyl, optionally substituted by one or two groups selected from the of Lila, of halogen and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A], X is oxygen, R15represents alkyl, D represents alkylene, albaniles or akinyan having 5-7 carbon atoms, E represents a group of the formula [4], Y is oxygen, R3and R4are the same, and each represents hydrogen or alkyl, and Z is carboxy.

Specific examples of the preferred compounds [1] of the present invention are the following heterocyclic compounds (1)to(14) or their pharmaceutically acceptable salts:

(1) 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenoate]propionic acid,

(2) CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid,

(3) 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-4-hexyloxy]propionic acid,

(4) 2-isobutyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid,

(5) 2-ethyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid,

(6) 2-methyl-CIS-5-{4-[5-methyl-2-(4-triptoreline)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid,

(7) 2-methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)-(E)-3-butenyl]-1,3-dioxane-r-2-carboxylic acid,

(8) CIS-5-{4-[2-(4-tert-butylphenyl)-5-methoxazole-4-yl]butyl}-2-methyl-1,3-dioxane-r-2-carboxylic acid,

(9) 2-methyl-2-[6(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propanol,

(10) 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionic acid,

(11) 2-methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid,

(12) 2-methyl-CIS-5-{4-[5-methyl-2-(3-fluoro-4-were)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid,

(13) 2-methyl-CIS-5-{4-[5-methyl-2-(m-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid and

(14) 2-methyl-CIS-5-{4-[5-methyl-2-(3,4-dimetilfenil)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid.

Used in the description of the present invention, the term "alkyl" means an alkyl group with straight or branched chain, having 1 to 7 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl and isoheptyl. Preferred are alkyl group with a straight chain having 1-3 carbon atoms, e.g. methyl, ethyl, n-propyl.

Examples of the alkyl side groups "halogenated", "trialogical", "alkoxy", "alkoxycarbonyl", "N-allylcarbamate, N,N-dialkylamino", "1-alkyl-5-tetrazolyl and 2-alkyl-5-tetrazolyl" are alkyl groups defined above.

The term "cycloalkyl" means cycloalkyl group having 4-8 carbon atoms, for example, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preferred are cycloalkyl the groups, having 5-7 carbon atoms.

The term "alkylene" means alkylenes group with a straight or branched chain having 1-10 carbon atoms, for example, methylene, ethylene, 1-methylation, 2-mutilation, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptameron, octamethylene, nonmotile and decamethrin. Preferred are alkylene group having 3-10 carbon atoms, and more preferred are alkylene group having 3-7 carbon atoms.

The term "albaniles" means alkenylamine group with a straight or branched chain having 2-10 carbon atoms, for example, ethenylene, 1-propanole, 2-propanole, 1-butylen, 2-butylen, 3-butylen, 1-penttinen, 2-penttinen, 3-penttinen, 4-penttinen, 4-methyl-3-penttinen, 1-hexarelin, 2-hexarelin, 3-hexarelin, 4-hexarelin, 5-hexarelin, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-hoktanyan, 2-hoktanyan, 3-hoktanyan, 4-hoktanyan, 5-hoktanyan, 6-hoktanyan, 7-hoktanyan, 1-nonpenile, 2-nonpenile, 3-nonpenile, 4-nonpenile, 5-nonpenile, 6-nonpenile, 7-nonpenile, 8-nonpenile, 1-decoiler, 2-decoiler, 3-decoiler, 4-decoiler, 5-decoiler, 6-decoiler, 7-decoiler, 8-decoiler and 9-decoiler. Preferred are alkenylamine group having 3-10 carbon atoms, and more preferred are alkenylamine group, have their 3-7 carbon atoms.

The term "akinyan" means alkynylamino group with a straight or branched chain having 2-10 carbon atoms, such as ethynylene, 1-propylen, 2-propylen, 1-Butylin, 2-Butylin, 3-Butylin, 1-pentikinen, 2-pentikinen, 3-pentikinen, 4-pentikinen, 2-methyl-3-pentikinen, 1-geksanalem, 2-geksanalem, 3-geksanalem, 4-geksanalem, 5-geksanalem, 1-Eptingen, 2-Eptingen, 3-Eptingen, 4-Eptingen, 5-Eptingen, 6-Eptingen, 1-actinin, 2-actinin, 3-actinin, 4-actinin, 5-actinin, 6-actinin, 7-actinin, 1-noninert, 2-noninert, 3-noninert, 4-noninert, 5-noninert, 6-noninert, 7-noninert, 8-noninert, 1-decisoin, 2-decisoin, 3-decisoin, 4-decisoin, 5-decisoin, 6-decisoin, 7-decisoin, 8-decisoin and 9-decisoin. Preferred are alkenylamine group having 3-10 carbon atoms, and more preferred are alkenylamine group having 3-7 carbon atoms.

The term "aryl" means an aryl group having 6-10 carbon atoms, for example, phenyl, 1-naphthyl and 2-naphthyl, however, preferred is phenyl.

The term "aromatic heterocyclic ring" means a 5-6-membered aromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, or a specified aromatic ring condensed with a benzene ring. Examples are 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-and is refilled, 2-furyl, 3-furyl, 3-benzofuranyl, 2-thienyl, 3-thienyl, 3-benzothiazol, 2-oxazolyl, 2-thiazolyl, 2-benzothiazolyl, 2-imidazolyl, 4-imidazolyl, 2-benzimidazolyl, 1H-1,2,4-triazole-1-yl, 1H-tetrazol-5-yl, 2-pyridine, 3-pyridyl, 4-pyridyl, pyridine-1-oxide-2-yl, pyridine-1-oxide-3-yl, pyridine-1-oxide-4-yl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazine-2-yl.

The term "divalent aromatic heterocyclic ring" means a 5-6-membered aromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, or a specified aromatic ring condensed with a benzene ring. Examples are pyrroline, indoline, TuranAlem, benzofuranyl, tienlen, benzothiazole, oxazoline, thiazoline, benzothiazoline, imidazoline, benzimidazolyl, 1H-1,2,4-triazoline, peridinin, pyrimidinyl, personalen and 1,3,5-triazine.

Examples of "halogen" is fluorine, chlorine, bromine and iodine.

Examples of the halogen part of the "halogenoalkane" and "trialogical" is a halogen, as defined above.

Specific examples of trialogical are trifluoromethyl, trichloromethyl, 2,2,2-triptorelin and 2,2,2-trichlorethyl.

Compounds [1] of the present invention can be obtained by methods illustrated below, or in the working examples.

Method And

The compound [1A] the present invention where E is g is the UPP formula [3], and Z represents alkoxycarbonyl can be obtained by the interaction of the compounds [11] and the compound [22].

where R1, Het, D, Y, R and R3are as defined above, and R11represents alkyl.

Typically, this reaction can be carried out in a suitable solvent (for example, in a polar solvent such as acetonitrile or N,N-dimethylformamide (DMF), ether solvent such as tetrahydrofuran (THF) or diethyl ether, a halogenated hydrocarbon solvent such as chloroform or dichloromethane, in the ester solvent such as methyl acetate or ethyl acetate, in a hydrocarbon solvent such as benzene, toluene or n-hexane, or a mixture thereof) in the presence of a Lewis acid (for example, piratage complex of boron TRIFLUORIDE) at a temperature of from -20 up to 150°C. Although the reaction time may vary depending on the species of compound [11] and the compound [22] or the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. Connection [22] preferably used in amounts of 1-5 mol per one mol of compound [11].

Method In

The compound [1b] of the present invention, where E represents a group of the formula [4], and Z is carboxy, may be obtained by the reaction of compound [12] and the compound [1], followed by treatment with acid.

where R1, Het, Y, R3and R4are as defined above, L represents a leaving group such as halogen, methanesulfonate or toluensulfonate, T represents halogen, R13and R14are the same or different, and each represents an alkyl, D1is alkylen, albaniles or akinyan having one carbon atom less than D (D has the values defined above).

Connection [14] can be obtained mainly by treating compound [13] metal reagent, such as utility or magnesium, followed by reaction with the compound [12] in the presence of copper iodide or copper bromide at a temperature of from -80 to 150°in an aprotic solvent (for example, in a polar solvent such as acetonitrile or N,N-dimethylformamide (DMF), ether solvent such as tetrahydrofuran (THF) or diethyl ether, a halogenated hydrocarbon solvent such as chloroform or dichloromethane, in the ester solvent such as methyl acetate or ethyl acetate, in a hydrocarbon solvent such as benzene, toluene or n-hexane, or mixtures thereof). Although the reaction time may vary depending on the type of connection [12], compounds [13] and metal reagent or the reaction temperature, but mainly a suitable reaction time should be from 30 minutes to 24 hours. Metal reagent and the compound [12] is preferably used in the amount of 1-1,2 mol per one mol of compound [13].

The compound [1b] can be mainly obtained by treating compound [14] acid (e.g. hydrochloric acid) in an alcohol solvent (e.g. methanol or ethanol) at temperatures from -80 to 80°during the period of time from 5 minutes to 24 hours.

Way

The compound [1C], where D represents albaniles, which is attached to Het in part C unsaturated bond, may be obtained by Wittig reaction using compounds [15] and the compound [16].

where R1, Het, E and T are as defined above, Ph represents phenyl, D2is albaniles having two carbon atoms less than D (D has the values defined above)or a group of formula [2].

This reaction typically can be performed in the same solvent that was used in the above-described method And, in the presence of a base (e.g. sodium hydroxide) at a temperature of from -20 to 150°C. Although the reaction time may vary depending on the species of compound [15] and the compound [16] or from the reaction temperature, however, in General, a suitable reaction time should the city is from 30 minutes to 24 hours. Connection [16] preferably used in the amount of 1-1,2 mol per one mol of compound [15].

Method D

The compound [1d] the present invention where Het represents a group of the formula [5A]:

where X and R15are as defined above, E represents a group of the formula [3] or [4], and Z represents alkoxycarbonyl can also be obtained by the reaction of compound [17] with phosphorus oxychloride, thionyl chloride, phosphorus pentoxide, methyl Davy reagent (2,4-bis(methylthio)-1,3-dithia-2,4-diphosphate-2,4-disulfide), reagent Lawesson (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide), ammonia or alkylamines. When using phosphorus oxychloride, thionyl chloride or phosphorus pentoxide can be obtained oxazoline derivatives; using methyl Davy reagent or reagent Lawesson can be obtained thiazole derivatives; and the use of ammonia or alkylamine can be obtained imidazole derivatives.

where R1D and R15are as defined above, and E represents a group of the formula [31] or [41]:

where R3, R4, R11, Y and R are as defined above.

Typically, this reaction can be conducted in approaching the eat solvent (for example, in a hydrocarbon solvent such as benzene, toluene or xylene, a halogenated hydrocarbon solvent such as chloroform or dichloromethane, in a polar solvent such as N,N-dimethylformamide (DMF), ether solvent such as tetrahydrofuran (THF) or diethyl ether, acetic acid or mixtures thereof) at temperatures from -10 to 200°C. Although the reaction time depends on the type of reagent (for example, phosphorus oxychloride, reagent Lawesson, alkylamine), connection type [17] or from the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. The phosphorus oxychloride, thionyl chloride, phosphorus pentoxide, methyl reagent Devi, the reagent Lawesson, ammonia or alkylamine are preferably used in quantities of 1-10 mol per one mol of compound [17].

Method E

The compound [1E] the present invention where Het is above a group of the formula [5A], E represents a group of the formula [4], and Z represents alkoxycarbonyl can be obtained by the reaction of compound [18] and the compound [19].

where R1, R3, R4, R11, R15, X, Y, L and D1are as defined above.

This reaction can be carried out usually in the same solvent that was used in the above-described method is A, in the presence of a base (e.g. sodium hydride or sodium carbonate) at a temperature of from -20 to 150°C. Although the reaction time may vary depending on the type of compounds [18] and the compound [19] or the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. Connection [19] preferably used in the amount of 1-1,2 mol per one mol of compound [18].

Method F

The compound [1d] the present invention where Het is above a group of the formula [5A], can be obtained by the reaction of compound [20] and the compound [21].

where R1, R15, D, E1and X are as defined above, and L1represents chlorine or bromine.

This reaction can be carried out, usually, in the absence of solvent or in a solvent that was used in the above-described method And, in the presence of a base (e.g. sodium hydride or sodium carbonate) at a temperature of from -20 to 150°C. Although the reaction time may vary depending on the type of connection [20] and the compound [21] or the reaction temperature, but generally, suitable reaction time is from 30 minutes to 24 hours. The compound [21] is preferably used in the amount of 1-1,2 mol per one mol of compound [20].

Method G

The connection form is s [1h] the present invention, where Z is carboxy, may be obtained by hydrolysis of compounds of formula [1g] the present invention where Z is alkoxycarbonyl.

The compound [1g] the present invention can be obtained by condensation of compound [1h] the present invention with alcohol [73] or interaction with the alkylating agent.

In addition, compound [1i] the present invention where Z is carbarnoyl, N-hydroxycarbamoyl, N-allylcarbamate or N,N-dialkylamino can be obtained by the interaction of the compound [1h] the present invention with the compound [82], i.e., ammonia, hydroxylamine, alkylamino or dialkylamino.

where R1, R11, Het, D and E1defined above; R7represents hydrogen, and R8represents hydrogen, hydroxy or alkyl, or R7is alkyl, and R8is alkyl; E2represents a group of the formula [32] or [42]; E3represents a group of the formula [33] or [43]:

where R3, R4, R7, R8, Y and R are defined above.

Hydrolysis of compound [1g] can be usually carried out in a mixed alcohol solvent such as methanol, ethanol, isopropanol or tert-butyl alcohol and water, in the presence of acid (e.g. hydrochloric acid, sulfuric acid or p-is toluolsulfonic acid) or base (for example, sodium hydroxide or potassium hydroxide) at a temperature of from -20 to 150°C. Although the reaction time varies depending on the species of compound [1g] or the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. The acid or base is preferably used in an amount of 1-20 mol per one mol of compound [1g].

Condensation of compound [1h] and alcohol [73] can be usually carried out using alcohol as a solvent in the presence of acid (e.g. hydrochloric acid, sulfuric acid or p-toluensulfonate acid) at a temperature of from -20 to 150°C. Although the reaction time varies depending on the species of compound [1h], type of alcohol, or the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. The acid or base is preferably used in an amount of 0.1 to 1.2 mol per 1 mol of compound [1h].

This condensation reaction can also be carried out in the same solvent that was used in the above-described method And, in the presence of a condensing agent (for example, N,N'-dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole) at a temperature of from -20 to 150°C. Although the reaction time may vary depending on the species of compound [1h], type of alcohol or condensing agent, is whether the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. The condensing agent is preferably used in the amount of 1-1,2 mol per 1 mol of compound [1h].

The reaction between the compound [1h] and alkylating agent (for example, trimethylsilyldiazomethane/methanol, methyliodide) can be carried out in the same solvent that was used in the above-described method And, at (-20)-(150)°C. Although the reaction time may vary depending on the species of compound [1h], type alkylating agent or the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. The alkylating agent is preferably used in quantities of 1-2 mol per 1 mol of compound [1h].

The reaction between the compound [1h] and compound [82] can be carried out in a manner analogous to the method of carrying out specified the condensation reaction of compound [1h] and alcohol [73]. In addition, compound [1i] the present invention can be obtained by the reaction of a reactive derivative of the compound [1h] and the compound [82]carried out in a known manner. Examples of the reactive derivatives reagents are mainly used in the amidation reaction, such as halides (acid chloride or bromohydrin), mixed acid anhydride, activated amide, and p

For example, if the reactive derivative is used gelegenheid, the reaction can be carried out in an aprotic solvent (for example, in a polar solvent such as acetonitrile or N,N-dimethylformamide (DMF), ether solvent such as tetrahydrofuran (THF) or diethyl ether, a halogenated hydrocarbon solvent such as chloroform or dichloromethane, in a hydrocarbon solvent such as benzene, toluene or n-hexane, or a mixture thereof) in the presence of a base (e.g. potassium carbonate, sodium carbonate, sodium hydrogen carbonate, hydrogen carbonate potassium, pyridine, 4-dimethylaminopyridine, triethylamine, sodium hydroxide) at a temperature of from -20 to 100°C. Although the reaction time varies depending on the type of gelegenheid and compounds [82] or the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. Connection [82] preferably used in the amount of 1-1,2 mol per one mol of gelegenheid.

Way N

The compound [1k] the present invention, where D represents albaniles, which is attached to Het in part C unsaturated bond, may also be obtained by dehydration of compound [1j] the present invention, where D represents alkylene.

In addition, compound [1k] the present invention m is can be also obtained by hydrogenation of compound [1m] of the present invention, where D represents akinyan, which is attached to Het in part C unsaturated bond.

The compound [1j] the present invention can also be obtained by hydrogenation of compound [1k] the present invention.

where R1, Het, D2and E1defined above.

The dehydrogenation of compound [1j] can be carried out by reaction of the compounds with N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS) in the same solvent that was used in the above-described method And, at a temperature of from -20 to 150°s, followed by reaction with a base (e.g. sodium hydroxide or potassium hydroxide) in an alcohol solvent such as methanol or ethanol. Although the reaction time may vary depending on the species of compound [1j] or the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. NBS, NCS or base, preferably used in the amount of 1-1,2 mol per 1 mol of compound [1j].

Hydrogenation of compound [1] can be carried out in an alcohol solvent (e.g. methanol or ethanol) in the presence of a palladium catalyst (e.g. palladium on calcium carbonate or palladium on coal) at (-20)-(150)°C. Although the reaction time may vary depending on the type of connection [1m], palladium kata is isatori or from the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. The palladium catalyst is preferably used in amounts of 0.05-0.5 mol per 1 mol of compound [1m].

Hydrogenation of compound [1k] can be carried out in an alcohol solvent (e.g. methanol or ethanol) in the presence of a palladium catalyst (e.g. palladium on coal) at (-20)-(150)°C. Although the reaction time may vary depending on the species of compound [1k], from palladium catalyst or the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. The palladium catalyst is preferably used in quantities of 0.05 to 0.2 mol per 1 mol of compound [1k].

The way I

Connection [1n] the present invention where Z is hydroxymethyl may be obtained by reduction of compound [1g] the present invention where Z is alkoxycarbonyl.

where R1, Het, D and E1defined above, and E4represents a group of the following formula [34] or [44]:

where R3, R4, Y and R are defined above.

This reaction can be carried out in the presence of a reducing agent (e.g. lithium aluminum hydride, sodium borohydride or diisobutylaluminum lithium) with the next solvent (for example, in ethereal solvent such as tetrahydrofuran (THF) or diethyl ether, in a polar solvent such as N,N-dimethylformamide (DMF) or dimethyl sulfoxide, an alcohol solvent such as methanol, ethanol or isopropanol, or mixtures thereof) at (-20)-(100)°C. Although the reaction time varies depending on the species of compound [1g] or the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. The reducing agent preferably used in quantities of 0.5 to 2 mol per one mol of compound [1g].

Method J

Connection [1q], where E represents a group of the formula [3] or [4], and Z is cyano, can be obtained from compound [1P] the present invention where Z is carbarnoyl or N-hydroxycarbamoyl.

where R1, Het and D are defined above, and E5represents a group of the following formula [35] or [45], and E6represents a group of the following formula [36] or [46]:

where R3, R4, Y and R are defined above, and R12represents hydrogen or hydroxy.

If you use the original connection, where Z is carbarnoyl, i.e., R12represents hydrogen, it can be usually treated with dehydrating agent (for example, phosphorus pentoxide, thionyl chloride, triflorus the first anhydride or N,N'-dicyclohexylcarbodiimide) in the absence of solvent or in a solvent, similar to the solvent used in the above-described method A. Although the reaction time varies depending on the species of compound [1P], type dehydrating agent or the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 24 hours. Dehydrating agent is preferably used in amounts of 1-5 mol per 1 mol of compound [1P].

If you use the original connection, where Z is N-hydroxycarbamoyl, i.e., R12represents hydroxy, the reaction can be carried out according to the method described by A. Liguori et al., Synthesis, 168 (1987).

The way To

The compound [1r] the present invention where E represents a group of the formula [3] or [4], and Z is 1H-5-tetrazolyl can be obtained by the reaction of compound [1q] the present invention where Z represents cyano, azide.

where R1, Het, D and E6defined above, and E7represents a group of the formula [37] or [47]:

where R3, R4, Y and R are defined above.

This reaction can be usually carried out in a suitable solvent (e.g. an alcohol solvent such as methanol, ethanol or methoxyethanol, in a hydrocarbon solvent such as benzene or toluene, a halogenated hydrocarbon solvent is, such as chloroform or dichloromethane, in a polar solvent such as N,N-dimethylformamide (DMF) or dimethylsulfoxide, in the ether solvent such as tetrahydrofuran (THF)or mixtures thereof) in the presence of azide (e.g. sodium azide, trimethylsilane or azide anti) at 0-200°C. This reaction can be carried out in the presence of additives such as lithium chloride or ammonium chloride. Although the reaction time depends on the type of connection [1q], type azide or the reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 100 hours.

Method L

The compound [1s] of the present invention, where E represents a group of the formula [3] or [4], and Z is 1-alkyl-5-tetrazolyl or 2-alkyl-5-tetrazolyl can be obtained by the reaction of compound [1r] the present invention where Z is 1H-5-tetrazolyl, with an alkylating agent.

where R1, Het, D, E7and L are defined above, R20represents alkyl, and E8represents a group of the formula [38] or [48]:

where R3, R4, Y, R and R20defined above.

This reaction can be carried out, for example, in the same solvent that was used in the above-described method And, in the presence of an alkylating agent (for example, alkylhalogenide, alkyl is of Eilat or alkylsulfate) and grounds at 0-150° C. Examples used of the base is an organic amine (e.g. pyridine or triethylamine), a metal hydride (e.g. sodium hydride), inorganic base (e.g. potassium carbonate, sodium bicarbonate or sodium hydroxide). Although the reaction time may vary depending on the kind of starting compound or reaction temperature, however, in General, a suitable reaction time should be from 30 minutes to 100 hours. Halogenation agent and the base are preferably used in quantities of 1-10 mol, preferably 1-5 mol, per 1 mol of compound [1r].

Compounds of the present invention may exist as tautomers. The present invention relates to the corresponding tautomers, which are included in its scope.

Compounds of the present invention may exist as geometric isomers due to the presence of a double bond. The present invention relates to a corresponding geometric isomers and their mixtures.

Compounds of the present invention can exist as stereoisomers due to the presence of asymmetric carbon atom. The present invention relates to the corresponding stereoisomers and their mixtures.

This stereoisomer may be obtained from the mixture by column chromatography on silica gel.

Furthermore, the specified stereoisomer may be obtained from the mixtures by liquid chromatography on a column for the separation of optically active substances (for example, CHIRALCEL(OD, CHIRALCEL(OF, DAICEL co., Ltd.).

If the connection of the present invention is carboxypropyl, it can be converted into a pharmaceutically acceptable salt in a known manner. Examples of pharmaceutically acceptable salts are the alkali metal salt (e.g. sodium salt, potassium salt and the like), alkali earth metal salt (e.g. calcium salt, magnesium salt and the like), ammonium salt, the salt formed with an organic amine (e.g. triethylamine, lysine, arginine and the like), etc.

For example, the alkali metal salt of the present invention can be obtained by adding one equivalent of sodium hydroxide or potassium hydroxide to the compound of the present invention, preferably, in an alcohol solvent.

Salt of alkaline earth metal present invention can be obtained by dissolving an alkali metal salt obtained as described above, in water, methanol, ethanol or a mixed solvent, and adding one equivalent of calcium chloride or the like

If the connection of the present invention is basic, it can be converted into a pharmaceutically acceptable salt in a known manner. Examples of such salts are the salts formed with inorganic acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or the like; or the ol, formed organic acid, such as fumaric acid, maleic acid, methanesulfonate acid, p-toluensulfonate acid or tpeak, for example, hydrochloride, a compound of the present invention can be obtained by addition of one equivalent of hydrochloric acid to the compound of the present invention, preferably, in an alcohol solvent.

The compound of the present invention or its salt can be isolated and purified from the reaction mixture the reaction described above by any standard method, such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography, etc.

The compounds used as starting materials for the production of compounds of the present invention, are known compounds or they can be obtained, for example, by the methods illustrated below, or by methods described in reference examples.

Obtaining compounds [11a] and [11b]

Of the compounds of the formula [11], used as starting materials in method A, the compounds where D is CH2-D1and Y represents oxygen (compound [11a]) or sulfur (compound [11b]), can be obtained in accordance with the following methods.

where R1, Het D 1, p, T and L are defined above.

The compound [51] can be obtained by dehydration condensation of compound [50] and acetone in an appropriate solvent (e.g. benzene) in the presence of an acid catalyst (e.g. p-toluensulfonate acid).

The compound [52] can be obtained by adding tri-n-butylphosphine and copper iodide to the compound [51] in an appropriate solvent (e.g. anhydrous tetrahydrofuran (THF) and the reaction with the compound [12] at a temperature of -60°With or below. Instead of tri-n-butylphosphine and copper iodide can be used magnesium.

The compound [11a] can be obtained by treating compound [52] in an appropriate solvent (e.g. ethanol or methanol) in acidic medium (for example, in the presence of p-toluensulfonate pyridinium) at 0-100°C.

Connection [11b] can be obtained by converting compound [11a] the bromide by reaction with brainwashin agent (for example, triphenylphosphine/tetrabromomethane or tribromide phosphorus) in an appropriate solvent (e.g. tetrahydrofuran, benzene, followed by reaction with thiourea at a temperature of from -20 to 100°C.

Getting connection [50A]

Of the compounds of the formula [50], used as starting materials for the production of compound [11a]as described above, the compound [50], where p is 1 can be obtained is in accordance with the following methods.

where D1and T are defined above, and R18represents alkyl.

The compound [55] can be obtained by the reaction of compound [53] and diapir malonic acid [54] in an appropriate solvent (e.g. anhydrous tetrahydrofuran) in the presence of a basic catalyst (e.g. sodium hydride) at a temperature of from -50 to 100°C.

Connection [50] can be obtained by reaction of the compound [55] according to the method described above in Method I.

Getting connection [50b]

Of the compounds of the formula [50], used as starting materials for the production of compound [11a]as described above, the compounds [50b], where p is 0, can be obtained in accordance with the following methods.

where D1and T are defined above.

Connection [50b] can be obtained by the reaction of compound [56] with an oxidizing agent (for example, osmium tetroxide) in an appropriate solvent (e.g. diethyl ether) at a temperature of from -20 to 50°C.

Getting connection [50C]

Of the compounds of the formula [50], used as starting materials for the production of compound [11a]as described above, the compounds [50], where p is 2, can be obtained in accordance with the following methods.

where D1T and R18defined above.

<> Connection [59] can be obtained by the reaction of compound [55] and the compound [58] in an appropriate solvent (e.g. tetrahydrofuran or ethanol) in the presence of a base (e.g. sodium alkoxide, such as ethoxide sodium or sodium hydride) at a temperature of from -20°C to room temperature.

Connection [60] can be obtained by hydrolysis of compound [59] according to the method described above in Method G followed by conducting the reaction of decarboxylation by heating at 50 to 150°in the absence of solvent or in an appropriate solvent (e.g. xylene, toluene, ethyl acetate or mixtures thereof).

Connection [50] can be obtained by reduction of compounds [60] according to the method described above in Method I.

Connection [50] can also be obtained by esterification of compound [60] in the standard way, with the subsequent recovery as described above.

Obtaining compounds [11C] and [11d]

Of the compounds of the formula [11], used as starting materials in method A, the compound where Het represents a group of the formula [5A], D represents the D1-CH2, p is 1 and Y is oxygen (compound [11C]) or sulfur (compound [11d]), can be obtained in accordance with the following methods.

where R1, R15, R18D1, X and L are defined above./p>

Connection [81] can be obtained by the reaction of compound [18] and diallylmalonate acid [54] in an appropriate solvent (e.g. tetrahydrofuran or ethanol) in the presence of a base (e.g. sodium alkoxide, such as ethoxide sodium or sodium hydride) at a temperature between -20°C to room temperature.

The compound [11C] can be obtained by reaction of the compound [81] according to the method described above in Method I.

Connection [11d] can be obtained by reaction of the compound [11c] according to the method similar to the connection [11b] from compound [11a].

The connection is obtained [13]

The compound of the formula [13]used as the starting material in the method, can be obtained in accordance with the following methods.

where R3, R4, R11, R13, R14D1, Y and T are defined above.

Connection [61] can be obtained by the reaction of compound [19] and the compound [53], as described in Method E.

Connection [62] can be obtained by treating compound [61] according to the method of hydrolysis, as described above in Method G.

The compound [13] can be obtained by the reaction of compound [62] and the compound [63] in an appropriate solvent (e.g. toluene) at 90-150°C.

The connection is obtained [16]

Connection [16], is used as ohodnocovanie in the way, can be obtained in accordance with the following methods.

where E, D2, T and Ph are defined above.

The compound [16] can be obtained by the reaction of compound [64] and triphenylphosphine in a solvent similar to the solvent described above in Method A, at a temperature of from -20 to 150°C.

The connection is obtained [17]

The compound of the formula [17], used as a starting compound in method D, can be obtained in accordance with the following methods.

where R1, R11, R15, R18E1E2, D and T are defined above.

Connection [67] can be obtained by the reaction of compound [65] and the compound [66] in a solvent similar to the solvent described above in Method A, in the presence of a base (e.g. triethylamine or dimethylaniline) at a temperature of from -20 to 150°C.

Connection [69] can be obtained from compounds [67] and [68] according to the method described above to obtain compounds [59].

Connection [70] can be obtained from compound [69] according to the method described above to obtain compounds [60].

Connection [72] can be obtained by the reaction of compound [70] and the compound [71] in an appropriate solvent (e.g. pyridine) at 50-110°and then, after adding water, at 30-100°C.

The is a group of [17] can be obtained by reaction of the compound [72], carried out as described above in Method G, a compound [1g] is produced from compound [1h].

Getting connection [68A]

Of the compounds of the formula [68]used as starting materials for the production of compounds [17], connection [68A], where E1represents a group of the formula [31]can be obtained in accordance with the following methods.

where D, T, Y, R, R3and R11defined above.

Connection [68A] can be obtained by the reaction of compound [22] and the compound [74], which can be obtained according to the method for obtaining compounds [50]described above in Method A.

Getting connection [68b]

Of the compounds of the formula [68]used as starting materials for the production of compounds [17], connections [68b], where E1represents a group of the formula [41], can be obtained in accordance with the following methods.

where D, T, Y, R3, R4and R11defined above.

Connection [68b] can be obtained by reaction of the compound [19] and the compound [75], the method for obtaining compounds [61]described above.

The connection is obtained [18]

The compound of the formula [18]used as the starting material in method E, can be obtained in accordance with the following methods.

where R1, R 11, R15, X, D1and L is defined above.

The compound [77] can be obtained from compound [76]obtained as described above in Method D by the procedure described above in Method I.

Connection [18] can be obtained by the reaction of compound [77] and brainwashes agent (for example, triphenylphosphine/tetrabromomethane) or sulphonylchloride (for example, p-toluensulfonate) in a solvent similar to the solvent described above in Method A, at a temperature of from -20 to 150°C.

The connection is obtained [21]

The compound of the formula [21]used as the starting material in method F, can be obtained in accordance with the following methods.

where R15, D, E1and L1defined above.

Connection [79] can be obtained by the reaction of compound [78] with an oxidizing agent (e.g. m-chloroperbenzoic acid) in an appropriate solvent (e.g. dichloromethane) at a temperature in the range from -10°C to room temperature.

The compound [80] can be obtained by the reaction of compound [79] with lithium chloride or lithium bromide in an appropriate solvent (e.g. anhydrous tetrahydrofuran (THF) at room temperature.

Connection [21] can be obtained by the reaction of compound [80] with a reagent Johnson (for example, with concentrated sulfuric what Isletas and chromium oxide(VI)) at room temperature.

The compound of the present invention has the effect of reducing the level of triglycerides in the blood, and action that reduces the level of LDL's in the blood, and therefore it can be used for the prevention and treatment of diseases such as hyperlipidemia caused by the high level of triglycerides or total cholesterol in the blood.

Compounds of the present invention have found different effects on QC-y-mouse model of insulin-independent diabetes (NIDDM), which has led to the development of hypertriglyceridemia, hyperglycemia and hyperinsulinemia, for example, effects such as lowering the level of triglycerides in the blood, lowering cholesterol levels of very low density lipoproteins (hereinafter called "LOP-X"), reduction of LDL-X, as well as reducing the level of blood glucose, lower insulin levels in the blood or increase HDL-X, or a decrease in atherogenic index, and therefore, it is assumed that, in comparison with the known compounds, the compounds of the present invention can serve as an excellent prophylactic or therapeutic agent against arteriosclerosis. In addition, the compounds of the present invention, in its effective dose, have a low toxicity.

Accordingly, the compounds and pharmaceutical compositions of the present invention can be used in the us, not only for the prevention and treatment of arteriosclerosis, caused by hyperlipidemia, but they can also be used for prevention and treatment, for example, myocardial infarction, coronary heart disease, including reocclusion after percutaneous intraluminal coronary angioplasty (CVCA), angina and coronary heart disease caused by coronary heart disease, heart attack brain, including cortical infarction branches and myocardial probcause branches, thrombosis and arteriosclerosis caused by both, etc.

In addition, the compounds and pharmaceutical compositions of the present invention can be used for the prevention and treatment of obesity, hypertension, diabetes, especially insulin-independent diabetes.

If the connection of the present invention is used as a medicine, it can be administered to the mammal, including man, in pure form or in the form of pharmaceutical compositions containing this compound in a pharmaceutically acceptable non-toxic and inert medium at a concentration of, for example, from 0.1% to 99.5%, and preferably from 0.5% to 90%.

Examples of the medium are solid, semi-solid or liquid diluents, fillers and other auxiliary processing AIDS, and at least one of them can be used. Pharmaceutical composition, preference is sustained fashion, administered in a single dosage form. The pharmaceutical composition of the present invention can be administered intravenously, orally, in cloth, topically (e.g., percutaneous) or rectally. Obviously, you must use a unit dosage form suitable for each route of administration. Especially preferred is oral administration.

The dose of the pharmaceutical composition for the prevention and treatment of arteriosclerosis should be preferably adjusted depending on the patient's condition, that is, his age, body weight, route of administration, nature and severity of the disease, but, in General, the daily dose of the compounds of the present invention, used as the active ingredient for administration to an adult individual, may be 0.1-100 mg/person, and preferably, 0.5 to 20 mg/person. Dose in excess of the specified interval is not critical, and, in some cases, may be sufficient dose below the specified interval, while in other cases it may be necessary dose exceeding the specified interval. The daily dose may be introduced in the form of 2-3 parts of the total dose.

When using the pharmaceutical composition for the prevention and treatment of diabetes or other diseases, the dose is connected to the I present invention can be adjusted, as explained above.

The best option is the implementation of the present invention

For a more detailed illustration of the present invention are the following examples, including reference examples, working examples, examples, tests, and examples of pharmaceutical preparations, which do not limit the scope of the invention.

Reference example 1

Diethyl (4-chlorobutyl)malonate

To 458 ml anhydrous tetrahydrofuran (THF) is added to 13.4 g of 60% sodium hydride, and then dropwise, under stirring and under cooling with ice, add 160,6 g of diethylmalonate. After the addition stirring is continued for 15 minutes and add of 57.3 g of 1-bromo-4-chlorobutane. The mixture is stirred for 50 hours at room temperature. The reaction mixture was poured into ice water, neutralized with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to distillation under reduced pressure and get to 26.8 g of target compound as a colourless oil.

TKIP-130°C (5 mm Hg)

In accordance with the method described in reference example 1 given the following connections:

diethyl (3-chlorpropyl)malonate and

diethyl (5-chloropentyl)malonate.

Reference example 2

Diethyl (5-hexenyl)is alonet

To 120 ml of anhydrous tetrahydrofuran (THF) is added 4.9 g of 60% sodium hydride, and then dropwise, under stirring and under cooling with ice, add to 29.5 g of diethylmalonate. After the addition stirring is continued for 15 minutes, add 10 g of 6-bromo-1-hexene and the mixture is refluxed for 21 hours. The reaction solution is cooled, poured into ice water, neutralized with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=20:1)) and obtain 14.5 g of target compound in the form of a yellowish oil.

1H-NMR (CDCl3)δ: of 1.23 to 1.47 (10H, m), 1,84-2,11 (4H, m), 3,28-3,37 (1H, m), 4,14-of 4.25 (4H, m), 4,91-of 5.05 (2H, m), 5,69-5,90 (1H, m).

Reference example 3

6-Chloro-2-hydroxymethyl-1-hexanol

To 214 ml of anhydrous ether is added 8 g of lithium aluminum hydride, and then dropwise, under stirring and under cooling with ice, add 26.7 g diethyl (4-chlorobutyl)malonate/53 ml of anhydrous ether. After stirring for 1 hour at room temperature the mixture is cooled with ice water and gradually add 173 ml of tetrahydrofuran/14.7 ml of water. Then add 14.7 ml of 1N sodium hydroxide solution and 35 ml of water, stirred for those who begins 15 minutes and filtered to remove insoluble substances. The filtrate is concentrated to obtain 18.2 g of the target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,22-to 1.38 (2H, m), 1,42 is 1.58 (2H, m), 1,68-of 1.88 (3H, m), 2,36 is 2.44 (2H, m), 3,55 (2H, t), 3,61-and 3.72 (2H, m), of 3.77-3,88 (2H, m).

In accordance with the method described in reference example 3 given the following connections:

5-chloro-2-hydroxymethyl-1-pentanol;

7-chloro-2-hydroxymethyl-1-heptanol and

2-hydroxymethyl-7-octene-1-ol.

Reference example 4

Methyl CIS-5-(4-chlorobutyl)-2-methyl-1,3-dioxane-r-2-carboxylate

To 270 ml of acetonitrile add 18 g of 6-chloro-2-hydroxymethyl-1-hexanol and 44 g of methylpiruvate. To the solution mixture under stirring at room temperature add to 65.2 g epirate of boron TRIFLUORIDE (about 47%) and the mixture is stirred for 14 hours. The reaction mixture was poured into sodium hydrogen carbonate solution into ice water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, n-hexane:ethyl acetate=10:1)) and obtain 14.8 g of target compound in the form of a yellowish oil.

1H-NMR (CDCl3)δ: 0,99-1,11 (2H, m), 1,37-of 1.55 (5H, m), 1,68-to 1.82 (2H, m), 1,95-of 2.09 (1H, m)to 3.41 (2H, t), 3,48-of 3.60 (2H, m), 3,83 (3H, s), 3,92-4,00 (2H, m).

In accordance with the method described in reference example 4 given the following connections:

methyl CIS-5-(3-chlorpropyl)-2-methyl-1,3-dioxane-r-2-carboxylate and

methyl CIS-5-(5-chloropentyl)-2-methyl-1,3-dioxane-r-2-carboxylate.

Reference example 5

Diethyl [4-(tetrahydro-2H-Piran-2-yloxy)-(Z)-2-butenyl]malonate

2-[4-Chloro-(Z)-2-butenyloxy]tetrahydro-2H-Piran (100 g) is dissolved in 2000 ml of anhydrous tetrahydrofuran (THF)/600 ml of anhydrous N,N-dimethylformamide. To the solution add 100 g of diethylmalonate, and then, under stirring and under cooling with ice, add 25 g of 60% sodium hydride and the mixture is stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, n-hexane:ethyl acetate=9:1)) and get 65,5 g of target compound in the form of oil.

1H-NMR (CDCl3)δ: 1,27 (6N, t), 1,50-1,90 (6N, m)to 2.67 (2H, t), 3,39 (1H, t), 3,45-of 3.60 (1H, m), 3,80-of 3.95 (1H, m), 4,05-4,35 (6N, m), br4.61 (1H, DD), the 5.45 of 5.75 (2H, m).

Reference example 6

2-Hydroxymethyl-6-(tetrahydro-2H-Piran-2-yloxy)-(Z)-4-HEXEN-1-ol

Diethyl [4-(tetrahydro-2H-Piran-2-yloxy)-(Z)-2-butenyl]malonate (65,5 g) dissolved in 650 ml of anhydrous tetrahydrofuran and added to 15.1 g of sodium borohydride. Then dropwise gradually add 110 g of methanol/275 ml of tetrahydrofuran, stirring while boiling under reflux. After this type of 13.18 the lithium chloride and 11 g of sodium borohydride and the mixture is refluxed for 1.5 hours. The reaction solution is cooled and poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, chloroform)) with the receipt of 22.8 g of target compound in the form of oil.

1H-NMR (CDCl3)δ: 1,40-1,90 (7H, m), 2,20 (2N, W), of 2.26 (2H, DDD), 3.46 in-3,90 (6N, m), 4,10-4,30 (2H, m), and 4.68 (1H, DD), 5,50-5,80 (2H, m).

Reference example 7

Methyl CIS-5-[4-hydroxy-(Z)-2-butenyl]-2-methyl-1,3-dioxane-r-2-carboxylate

Athirat of boron TRIFLUORIDE (approximately 47%, and 26.8 g) dropwise, while cooling with ice, add to the solution 21,79 g of 2-hydroxymethyl-6-(tetrahydro-2H-Piran-2-yloxy)-(Z)-4-HEXEN-1-ol, 430 ml of acetonitrile and 38,57 g methylpiruvate and the mixture is stirred for 15 hours at room temperature. The reaction solution is poured into a solution of sodium bicarbonate in ice-cold water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=7:1)) and receive are 5.36 g of target compound in the form of oil.

1H-NMR (CDCl3)δ: 1,51 (3H, s), of 1.85 (2H, DD), 1,95-of 2.20 (1H, m), 3.43 points (2H, DD), of 3.84 (3H, s), of 3.95 (2H, DD), 4,14 (2H, DD), 5,44 (1H, DDD), 5,70 (1H, DDD).

Reference when the EP 8

Methyl CIS-5-[4-chloro-(Z)-2-butenyl]-2-methyl-1,3-dioxane-r-2-carboxylate

Methyl CIS-5-[4-hydroxy-(Z)-2-butenyl]-2-methyl-1,3-dioxane-r-2-carboxylate (538 mg) was dissolved in 12 ml of N,N-dimethylformamide and added 1.13 g of 2,4,6-trimethylpyridine and 396 mg of lithium chloride. Then, dropwise and with cooling with ice, add 1.07 g of methanesulfonamide and the mixture is stirred for 9 hours at room temperature. The reaction solution was poured into ice-cold water, add 0,5N hydrochloric acid and the solution extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=9:1)) and receive 561 mg of target compound in the form of oil.

1H-NMR (CDCl3)δ: of 1.52 (3H, s), 1,89 (2H, DD), 2,00-of 2.20 (1H, m), of 3.45 (2H, DD), 3,85 (3H, s), of 3.95 (2H, DD), of 4.00 (2H, DD), of 5.53 (1H, DDD), 5,72 (1H, DDD).

Reference example 9

Methyl CIS-5-[4-iodine-(E)-2-butenyl]-2-methyl-1,3-dioxane-r-2-carboxylate

Methyl CIS-5-[4-chloro-(Z)-2-butenyl]-2-methyl-1,3-dioxane-r-2-carboxylate (300 mg) is dissolved in 5 ml of acetone and add sodium iodide. The mixture is refluxed for 2 hours. The reaction solution is cooled, add the ice water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried on the anhydrous magnesium sulfate and concentrated to obtain 353 mg of target compound in the form of oil.

1H-NMR (CDCl3)δ: 1,51 (3H, s)to 1.79 (2H, DD), 2,00-of 2.20 (1H, m)to 3.41 (2H, DD), 3,81 (2H, DD), of 3.84 (3H, t), 3,93 (2H, DD), 5,48-to 5.93 (2H, m).

Reference example 10

Methyl CIS-5-(4-iodobutyl)-2-methyl-1,3-dioxane-r-2-carboxylate

Methyl CIS-5-(4-chlorobutyl)-2-methyl-1,3-dioxane-r-2-carboxylate (14.8 g) was dissolved in 148 ml of acetone and add a 44.2 g of sodium iodide. The mixture is stirred for 22.5 hours at 40°C. the Reaction solution is concentrated and to the residue water is added and the solution extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain 19.9 g of target compound in the form of oil.

1H-NMR (CDCl3)δ: 0,99-1,10 (2H, m), 1,30-1,45 (2H, m)and 1.51 (3H, s), 1,72 is 1.86 (2H, m), 1,97-of 2.08 (1H, m), and 3.16 (2H, t), 3,40 (2H, t), 3,83 (3H, s), 3,92-4,00 (2H, m).

In accordance with the method described in reference example 10, receive the following connections:

methyl CIS-5-(3-improper)-2-methyl-1,3-dioxane-r-2-carboxylate and

methyl CIS-5-(5-iopentol)-2-methyl-1,3-dioxane-r-2-carboxylate.

Reference example 11

6-Bromo-1-(tetrahydro-2H-Piran-2-yloxy)-2-hexyne

In a stream of argon 13,46 g 3-(tetrahydro-2H-Piran-2-yloxy)-1-propene dissolved in 135 ml of anhydrous tetrahydrofuran, and then added dropwise within 20 minutes, stirring at the temperature of the reaction mixture -10°add 60 ml of solution 1,6N n-utility in hexane. The mixture is displaced is up within 1 hour at the same temperature. After stirring for a further 1 hour at room temperature, the temperature of the reaction mixture is brought to -3°and to the mixture of 16.7 ml triamide hexamethylphosphoric acid (NMRA). Then, when the temperature of the reaction mass -10°With portions add 58,14 g of 1,3-dibromopropane and the mixture is stirred for 12 hours at room temperature. The reaction solution was poured into ice water, extracted with ether, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to distillation under reduced pressure to obtain 12.0 g of the target compound as a colourless oil.

TKIP-126°C (5 mm Hg).

Reference example 12

Methyl 2-(6-Bromhexine)-2-methylpropionate

To 120 ml of anhydrous N,N-dimethylformamide add 4.0 g of 60% sodium hydride. To the mixture under stirring and cooling with ice added dropwise 11,81 g of methyl 2-hydroxyisobutyrate and the mixture is stirred for 10 minutes. After that add 122 g of 1,6-dibromohexane and the mixture is stirred for 15 hours at room temperature. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=20:1)) and obtain 6.25 g of the target connection is in the form of a yellowish oil.

1H-NMR (CDCl3)δ: 1,42-1,65 (N, m), 1,80-of 1.94 (2H, m), 3,32 is-3.45 (4H, m), of 3.73 (3H, s).

In accordance with the method described in reference example 12, receive the following connections:

methyl 2-(5-bromopentane)-2-methylpropionate,

methyl 2-(7-bromatology)-2-methylpropionate,

methyl 2-(8-bromostyrene)-2-methylpropionate,

ethyl 2-methyl-2-[6-(tetrahydro-2H-Piran-2-yloxy)-4-hexyloxy]propionate,

ethyl 2-(6-Bromhexine)-2-methylpropionate and

methyl 2-[6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenoate]-2-methylpropionate.

Reference example 13

Ethyl 2-(6-hydroxy-4-hexyloxy)-2-methylpropionate

Ethyl 2-methyl-2-[6-(tetrahydro-2H-Piran-2-yloxy)-4-hexyloxy]propionate (and 3.72 g) was dissolved in 37 ml of ethanol, add 15,372 mg Amberlyst, and the mixture is stirred for 1 hour at 55-60°C. After cooling, the mixture is filtered and the filtrate concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=9:1-3:1)) and obtain 1.98 g of the target compound as a pale yellow oil.

1H-NMR (CDCl3)δ: of 1.29 (3H, t), 1,42 (6N, s), 1.70 to to 1.83 (2H, m), 2,30-2,39 (2H, m), 3,44-3,50 (2H, m), 4,14-4.26 deaths (4H, m).

Reference example 14

Methyl 2-methyl-2-(8-nonyloxy)propionate

To 500 ml of anhydrous N,N-dimethylformamide add 17 g of 60% sodium hydride, and then with stirring and under ice cooling are added dropwise 48 g of methyl 2-gidroxiizomera the rata and the mixture is stirred for 10 minutes. Then add 100 g of 9-bromo-1-nonene (purity 63.4%) and the mixture is stirred for 15 hours at room temperature. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is subjected to distillation under reduced pressure to get a 29.9 g of target compound in the form of a yellowish oil.

TKIP-127° (8 mm Hg).

In accordance with the method described in reference example 14, receive the following connections:

methyl 2-(6-heptyloxy)-2-methylpropionate,

methyl 2-methyl-2-(7-octenoate)propionate and

methyl 2-(9-desenlace)-2-methylpropionate.

Reference example 15

Methyl 2-(8,9-apocynaceae)-2-methylpropionate

Methyl 2-methyl-2-(8-nonyloxy)propionate (40 g) is dissolved in 320 ml of methylene chloride, and then, under stirring and cooling with ice, add a 40.8 g of 70% 3-chloroperbenzoic acid and the mixture is stirred for 15 hours at room temperature. The reaction solution is filtered to remove insoluble substances and the filtrate concentrated. The residue is dissolved in n-hexane and 4 times washed with aqueous 10% potassium carbonate solution, then washed with water, dried over anhydrous magnesium sulfate and concentrated to obtain to 43.2 g of target compound as a colourless oil.

1N-I Is R (CDCl 3)δ: 1,25-1,70 (N, m), 2,44-2,48 (1H, m), 2,72-2,77 (1H, m), 2,85-of 2.97 (1H, m)to 3.34 (2H, t), of 3.73 (3H, s).

In accordance with the method described in reference example 15, receive the following connections:

methyl 2-(6,7-epoxidations)-2-methylpropionate,

methyl 2-(7,8-epoxyoctane)-2-methylpropionate,

methyl 2-(9,10-epoxidations)-2-methylpropionate and

methyl CIS-5-(5,6-epoxyhexane)-2-methyl-1,3-dioxane-r-2-carboxylate.

Reference example 16

Methyl 2-(9-chloro-8-hydroxyalkyloxy)-2-methylpropionate

Methyl 2-(8,9-apocynaceae)-2-methylpropionate (26 g) was dissolved in 260 ml of anhydrous tetrahydrofuran, and then added 6.8 g of lithium chloride and 7 g of acetic acid and the mixture is stirred for 22 hours at room temperature. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain and 31.7 g of target compound in the form of oil.

In accordance with the method described in reference example 16, receive the following connections:

methyl 2-(7-chloro-6-hydroxyethyloxy)-2-methylpropionate,

methyl 2-(8-chloro-7-hydroxyethyloxy)-2-methylpropionate,

methyl 2-(10-chloro-9-hydroxyethyloxy)-2-methylpropionate and

methyl CIS-5-(6-chloro-5-hydroxyhexyl)-2-methyl-1,3-dioxane-r-2-carboxylate.

Reference ol which measures 17

Methyl 2-(9-chloro-8-okonomiaki)-2-methylpropionate

Methyl 2-(9-chloro-8-hydroxyalkyloxy)-2-methylpropionate (31 g) was dissolved in 465 ml of acetone with stirring and under ice cooling are added dropwise 46 ml of Jones reagent obtained by the addition of 10.2 ml of concentrated sulfuric acid and 12 g of chromium oxide (VI) to 45 ml of water. After 3 hours stirring at room temperature the excess Jones reagent is decomposed by the addition of isopropyl alcohol. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=7,5:1)) and get 18,16 g of target compound in the form of oil.

1H-NMR (CDCl3)δ: 1,24-1,40 (6N, m), 1.41 to (6N, C)of 1.45 and 1.75 (4H, m), 2,58 (2H, t)to 3.34 (2H, t), of 3.73 (3H, s)4,07 (2H, s).

In accordance with the method described in reference example 17, will receive the following connections:

methyl 2-(7-chloro-6-occulations)-2-methylpropionate,

methyl 2-(8-chloro-7-oxooctanoate)-2-methylpropionate,

methyl 2-(10-chloro-9-octadecynoic)-2-methylpropionate and

methyl CIS-5-(6-chloro-5-oxohexyl)-2-methyl-1,3-dioxane-r-2-carboxylate.

Reference example 18

Diethyl-p-toluylenediamine

Hydrochloride diethylaminoacetate (20,5 g) suspended V ml of methylene chloride and add to 29.4 g of triethylamine, cooling with ice water. After stirring for 30 minutes, added dropwise 15 g of p-trouillard and the mixture is stirred for 24 hours at room temperature. The reaction solution is washed with water, dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated. To the residue is added isopropyl ether and the resulting crystals are filtered and dried to obtain of 25.9 g of the target compound as white crystals.

TPL 101-102°C.

In accordance with the method described in reference example 18, receive the following connections:

dietilentriaminom,

diethyl (4-chlorbenzoyl)aminomalonate,

diethyl (4-perbenzoate)malonate,

diethyl (4-trifloromethyl)aminomalonate,

diethyl (4-tert-butylbenzoyl)aminomalonate and

diethyl (4-ethylbenzoyl)aminomalonate.

Reference example 19

Ethyl CIS-5-[5,5-bis(etoxycarbonyl)-5-(p-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate

To 27 ml of anhydrous ethanol is added 6.6 g of 20% solution of ethoxide sodium in ethanol and 5.4 g of diethyl-p-toluylenediamine and stirred for 30 minutes at room temperature. Then added dropwise a solution of 6.3 g of methyl CIS-5-(4-iodobutyl)-2-methyl-1,3-dioxane-r-2-carboxylate/5,4 ml of anhydrous ethanol and stirred for 15 hours at 50-60°C. the Reaction solution is elewaut in ice-cold water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=5:1)) and get 4,34 g of target compound in the form of yellowish crystals. TPL=60-63°C.

In accordance with the method described in reference example 19, receive the following connections:

ethyl CIS-5-(4-benzoylamine 4,4-bis(etoxycarbonyl)butyl)-2-methyl-1,3-dioxane-r-2-carboxylate,

ethyl CIS-5-(5-benzoylamino-5,5-bis(etoxycarbonyl)pentyl)-2-methyl-1,3-dioxane-r-2-carboxylate,

ethyl CIS-5-(6-benzoylamine-6,6-bis(etoxycarbonyl)hexyl)-2-methyl-1,3-dioxane-r-2-carboxylate,

ethyl CIS-5-[5,5-bis(etoxycarbonyl)-5-(4-perbenzoate)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

ethyl CIS-5-[5,5-bis(etoxycarbonyl)-5-(4-triphtalocyaninine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

ethyl CIS-5-[5-(4-tert-butylbenzylamine)-5,5-bis(etoxycarbonyl)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

ethyl CIS-5-[5-benzoylamino-5,5-bis(etoxycarbonyl)-(E)-2-pentenyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

5-(5-benzoylamino-5,5-bis(etoxycarbonyl)pentyl)-2,2-dimethyl-1,3-dioxane,

ethyl CIS-5-[5,5-bis(etoxycarbonyl)-5-(4-chlorobenzylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

ethyl CIS-5-[6,6-bis(etoxycarbonyl)-6-(p-toluylene)hexyl]-2-methyl-1,3-di is Xan-r-2-carboxylate,

ethyl CIS-5-[5,5-bis(etoxycarbonyl)-5-(3-fluoro-4-methylbenzylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate and

ethyl CIS-5-[5,5-bis(etoxycarbonyl)-5-(4-ethylbenzylamine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate.

Reference example 20

Ethyl 2-(7-benzoylamine-7,7-bis(etoxycarbonyl)heptyloxy)-2-methylpropionate

To 5 ml of anhydrous ethanol is added 675 mg of 20% solution of ethoxide sodium in ethanol and 698 mg dietilentriaminom and stirred for 30 minutes at room temperature. Then added dropwise a solution of 914 mg of methyl 6-Bromhexine-2-methylpropionate/4 ml anhydrous ethanol and stirred for 15 hours at 50-60°C. the Reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=5:1)) and receive 642 mg of target compound in the form of a yellowish oil.

1H-NMR (CDCl3)δ: 1,10-1,37 (15 NM, m), 1,38 (6N, (C), 1,42 is 1.60 (2H, m), 2,41-2,49 (2H, m), 3,30 (2H, t), 4,11-4,33 (6N, m), 7,40-of 7.60 (4H, m), 7,81-7,86 (2H, m).

In accordance with the method described in reference example 20, receive the following connections:

ethyl 2-methyl-2-[7-(p-toluylene)-7,7-bis(etoxycarbonyl)heptyloxy]propionate,

ethyl 2-[7-benzoylamine-7,7-bis(etox the carbonyl)-4-heptyloxy]-2-methylpropionate,

ethyl 2-[7-(4-chlorobenzylamino)-7,7-bis(etoxycarbonyl)heptyloxy]-2-methylpropionate,

ethyl 2-[7,7-bis(etoxycarbonyl)-7-(4-perbenzoate)heptyloxy]-2-methylpropionate,

ethyl 2-[7-(4-tert-butylbenzylamine)-7,7-bis(etoxycarbonyl)heptyloxy]-2-methylpropionate,

ethyl 2-[6-benzoylamine-6,6-bis(etoxycarbonyl)hexyloxy]-2-methylpropionate,

ethyl 2-[8-benzoylamine-8,8-bis(etoxycarbonyl)octyloxy]-2-methylpropionate,

ethyl 5-benzoylamino-5,5-bis(etoxycarbonyl)pentanoate,

ethyl 6-benzoylamine-6,6-bis(etoxycarbonyl)hexanoate,

ethyl 5,5-bis(etoxycarbonyl)-5-(p-toluylene)pentanoate and

5-(benzoylamine)-1-bromo-5,5-bis(etoxycarbonyl)-(E)-2-penten.

Reference example 21

CIS-5-[5-Carboxy-5-(p-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid

Ethyl CIS-5-[5,5-bis(etoxycarbonyl)-5-(p-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate (4,2 g) dissolved in 33.6 ml of ethanol and add a solution of 2.0 g of sodium hydroxide and 8.4 ml of water. The mixture is refluxed for 5 hours. The reaction solution concentrate. To the residue water is added and the mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain 3,23 g of a yellowish oil. The oil obtained is stirred during the course the e 30 minutes at 130° With obtaining 3.1 g of the target compound as white crystals. TPL 152-156°C.

In accordance with the method described in reference example 21, receive the following connections:

CIS-5-(4-benzoylamine 4-carboxybutyl)-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-(5-benzoylamine 5-carboxypentyl)-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-(6-benzoylamine 6-carboxyethyl)-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-[5-carboxy-5-(4-perbenzoate)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-[5-carboxy-5-(4-triphtalocyaninine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-[5-(4-tert-butylbenzylamine)-5-carboxypentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-[5-benzoylamino-5-carboxy-(E)-2-pentenyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

5-(5-benzoylamine 5-carboxypentyl)-2,2-dimethyl-1,3-dioxane,

2-(7-benzoylamine 7 carboxymethoxy)-2-methylpropionate acid,

2-[7-carboxy-7-(p-toluylene)heptyloxy]-2-methylpropionate acid,

2-[7-benzoylamine-7-carboxy-4-heptyloxy]-2-methylpropionate acid,

2-[7-carboxy-7-(4-chlorobenzylamino)heptyloxy]-2-methylpropionate acid,

2-[7-carboxy-7-(4-perbenzoate)heptyloxy]-2-methylpropionate acid,

2-[7-(4-tert-butylbenzylamine)-7-carboxymethoxy]-2-methylpropionate acid,

2-[benzoylamino-8 carboxymethoxy]-2-methylpropionate acid,

2-(6-benzoylamine 6 carboxymethoxy)-2-methylpropionate acid,

5-benzoylamine 5-carboxypentyl acid,

6 benzoylamino-6-carboxykinase acid,

CIS-5-[5-carboxy-5-(4-chlorobenzylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-[6-carboxy-6-(p-toluylene)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

5-carboxy-5-(p-toluylene)pentane acid,

CIS-5-[5-carboxy-5-(3-fluoro-4-methylbenzylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid and

CIS-5-[5-carboxy-5-(4-ethylbenzylamine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid.

Reference example 22

CIS-5-[5-Acetyl-5-(p-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid

CIS-5-[5-carboxy-5-(p-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid (3.1 g) was dissolved 15.5 ml of pyridine, add to 10.2 ml of acetic anhydride and stirred for 1 hour at 90°C. and Then added dropwise to 10.2 ml of water and the mixture is stirred for 30 minutes at 90°C. the Reaction solution is cooled, poured into ice water, extracted with ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of chloroform:methanol=100:1)) to obtain 2.2 g of the target compound in the form of a yellowish oil.

H-NMR (CDCl3)δ: 0,99-1,10 (2H, m), 1,15-of 1.45 (4H, m), and 1.54 (3H, s), 1,50-to 1.82 (1H, m), 1,84-of 2.15 (2H, m), and 2.27 (3H, s), is 2.40 (3H, s), 3,47 (2H, DD), 3,89-Android 4.04 (2H, m), 4,82 to 4.92 (1H, m), 7,01 (1H, d), 7,22-7,27 (2N, m), 7.68 per-7,74 (2H, m).

In accordance with the method described in reference example 22 to obtain the following compounds:

CIS-5-(4-acetyl-4-benzoylamino)-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-(5-acetyl-5-benzoylamino)-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-(6-acetyl-6-benzoylamino)-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-[5-acetyl-5-(4-perbenzoate)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-[5-acetyl-5-(4-triphtalocyaninine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-[5-acetyl-5-(4-tert-butylbenzylamine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-[5-acetyl-5-benzoylamine(E)-2-pentenyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

5-(5-acetyl-5-benzoylamino)-2,2-dimethyl-1,3-dioxane,

2-(7-acetyl-7-benzylaminopurine)-2-methylpropionate acid,

2-[7-acetyl-7-(p-toluylene)heptyloxy]-2-methylpropionate acid,

2-(7-acetyl-7-benzoylamine 4 heptyloxy)-2-methylpropionate acid,

2-[7-acetyl-7-(4-chlorobenzylamino)heptyloxy]-2-methylpropionate acid,

2-[7-acetyl-7-(4-perbenzoate)heptyloxy]-2-methylpropionate acid,

2-[7-acetyl-7-(4-tert-butylbenzylamine is)heptyloxy]-2-methylpropionate acid,

2-(8-acetyl-8-benzoylmethylene)-2-methylpropionate acid,

2-(6-acetyl-6-benzylaminopurine)-2-methylpropionate acid,

5-acetyl-5-benzylaminopurine acid,

6-acetyl-6-benzylaminopurine acid,

CIS-5-[5-acetyl-5-(4-chlorobenzylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-[6-acetyl-6-(p-toluylene)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

5-acetyl-5-(p-toluylene)pentane acid,

CIS-5-[5-acetyl-5-(3-fluoro-4-methylbenzylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid,

CIS-5-[5-acetyl-5-(4-ethylbenzylamine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid and

7-acetyl-7-(benzoylamine)-(E)-4-geptanona acid.

Reference example 23

Methyl CIS-5-[5-acetyl-5-(p-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate

CIS-5-[5-Acetyl-5-(p-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid (2.1 g) is dissolved in 44 ml of benzene and 4.2 ml of methanol, and then with stirring and under ice cooling are added dropwise to 4.2 ml of a 2.0m solution trimethylsilyldiazomethane/hexane. The mixture is stirred for 1 hour and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=2,5:1)) with the receipt of 0.85 g of target compound in the form of a yellowish oil.

1H-NMR (CDCl3)δ: 0,90-1,08 (2H, m), 1,10-1,40 (4H, m), 1,50 (3 is, C)of 1.55 and 1.80 (1H, m), 1.85 to of 2.16 (2H, m), and 2.27 (3H, s), is 2.40 (3H, s)to 3.36 (2H, DD), 3,82 (3H, s)to 3.92 (2H, DD), 4,80-4,89 (1H, m), 6.89 in (1H, d), 7,25 (2H, d), of 7.70 (2H, d).

In accordance with the method described in reference example 23, to obtain the following compounds:

methyl CIS-5-(4-acetyl-4-benzoylamino)-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-(5-acetyl-5-benzoylamino)-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-(6-acetyl-6-benzoylamino)-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-[5-acetyl-5-(4-perbenzoate)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-[5-acetyl-5-(4-triphtalocyaninine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-[5-acetyl-5-(4-tert-butylbenzylamine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate and

methyl CIS-5-[5-acetyl-5-benzoylamine(E)-2-pentenyl]-2-methyl-1,3-dioxane-r-2-carboxylate.

Reference example 24

Methyl CIS-5-[5-acetyl-5-(p-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate

CIS-5-[5-Acetyl-5-(p-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid (20 g) is dissolved in 140 ml of acetonitrile and added to 14.5 ml under the conditions and 14.1 g of potassium carbonate. The mixture is refluxed for 3 hours. The reaction solution is cooled, poured into ice water, extracted with ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. OST is OK purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=2:1)) to obtain 10.3 g of the target compound in the form of a yellowish oil.

In accordance with the method described in reference example 24, we get the following connections:

methyl CIS-5-(5-acetyl-5-benzoylamino)-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-[5-acetyl-5-(4-chlorobenzylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-[6-acetyl-6-(p-toluylene)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-[5-acetyl-5-(3-fluoro-4-methylbenzylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate and

methyl CIS-5-[5-acetyl-5-(4-ethylbenzylamine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate.

Reference example 25

Methyl 6-acetyl-6-benzylaminopurine

6-Acetyl-6-benzylaminopurine acid (4.35 g) was dissolved in 100 ml of methanol and add 0.5 ml of concentrated sulfuric acid. The mixture is refluxed for 2.5 hours. The reaction solution is cooled, poured into ice water, extracted with ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated, resulting in a gain of 4.4 g of target compound in the form of yellowish crystals. TPL 59-60°C.

In accordance with the method described in reference example 25, receive the following connections:

methyl 2-(7-acetyl-7-benzylaminopurine)-2-methylpropionate,

IU the Il 2-[7-acetyl-7-(p-toluylene)heptyloxy]-2-methylpropionate,

methyl 2-(7-acetyl-7-benzoylamine 4 heptyloxy)-2-methylpropionate,

methyl 2-[7-acetyl-7-(4-chlorobenzylamino)heptyloxy]-2-methylpropionate,

methyl 2-[7-acetyl-7-(4-perbenzoate)heptyloxy]-2-methylpropionate,

methyl 2-[7-acetyl-7-(4-tert-butylbenzylamine)heptyloxy]-2-methylpropionate,

methyl 2-(8-acetyl-8-benzoylmethylene)-2-methylpropionate,

methyl 2-(6-acetyl-6-benzylaminopurine)-2-methylpropionate,

methyl 5-acetyl-5-benzylaminopurine,

methyl 5-acetyl-5-(p-toluylene)pentanoate and

methyl 7-acetyl-7-(benzoylamine)-(E)-4-heptenoic.

Reference example 26

Diethyl (3-bromobenzyl)malonate

Sodium hydride (60%, 1.6 g) is suspended in 20 ml of anhydrous tetrahydrofuran/15 ml of anhydrous N,N-dimethylformamide, and under ice cooling are added dropwise to 7.6 ml of diethylmalonate. The mixture is stirred for 15 minutes. Then add a solution of 5 g 3-bromobenzylamine/10 ml of anhydrous tetrahydrofuran and stirred for 1 hour under ice cooling. To the reaction solution was added ice water and the solution extracted with ether, washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=10:1)) to obtain the 5,41 g of target compound as a colourless oil.

1H-NMR (CDCl )δ: 1,22 (6N, t)3,81 (2H, d), 3,61 (1H, t), 4,17 (4H, HF), 7,10-7,20 (2H, m), 7,29-7,40 (2H, m).

In accordance with the method described in reference example 26, receive the following connection:

diethyl (4-bromobenzyl)malonate.

Reference example 27

Diethyl (4-bromophenyl)malonate

In a stream of argon 10,85 g diethylmalonate dissolved in 60 ml of benzene add to 2.75 g of 60% sodium hydride and refluxed. To the solution over 1 hour added dropwise a solution to 5.58 g of ethyl 4-bromophenylacetate/20 ml of benzene and the mixture refluxed for 1 hour. After cooling, to the reaction solution is slowly added dropwise ice water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=10:1)) to obtain the 6,45 g of target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,26 (6N, t), is 4.21 (4H, HF), 4,56 (1H, s), 7,29 (2H, d), to 7.50 (2H, d).

In accordance with the method described in reference example 27, get the following connection:

diethyl (3-bromophenyl)malonate.

Reference example 28

2-(3-Bromobenzyl)-1,3-propandiol

To 94 ml ice solution 1.0m hydride diisobutylaluminum in toluene are added dropwise 5,41 g of diethyl (3-bromobenzyl)malonate 15°or less current is argon. The mixture is stirred for 30 minutes while cooling with ice, warmed to room temperature and stirred for 2 hours. The reaction solution is cooled with ice and slowly added dropwise 21 ml of methanol, and then added dropwise 41 ml of 2N hydrochloric acid. The mixture is stirred for 20 minutes at room temperature. The reaction solution is filtered to remove insoluble substances, extracted with ethyl acetate, washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of chloroform:methanol=10:1)) to obtain a 1.96 g of the target compound as white crystals. TPL 61-63°C.

In accordance with the method described in reference example 28, to receive the following connections:

2-(4-bromobenzyl)-1,3-propandiol,

2-(4-bromophenyl)-1,3-propandiol and

2-(3-bromophenyl)-1,3-propandiol.

Reference example 29

5-(3-Bromobenzyl)-2,2-dimethyl-1,3-dioxane

2-(3-Bromobenzyl)-1,3-propandiol (1.85 g) was dissolved in a mixture of 8 ml of acetone/18 ml of benzene and added 70 mg of the monohydrate of p-toluensulfonate acid. The solution is subjected to azeotropic dehydration using nozzles Dean-stark for 1 hour. After adding a saturated solution of sodium bicarbonate, the mixture is extracted with ethyl acetate, dried over betwedn the m magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=4:1)) to give 1.47 g of the target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,43 (6N, e), 1,90-2,10 (1H, m)2,60 (2H, d), 3,61 (2H, DD), 3,86 (2H, DD), 7,05-7,20 (2H, m), 7,30-7,40 (2H, m).

In accordance with the method described in reference example 29, receive the following connections:

5-(4-bromobenzyl)-2,2-dimethyl-1,3-dioxane,

5-(4-bromophenyl)-2,2-dimethyl-1,3-dioxane and

5-(3-bromophenyl)-2,2-dimethyl-1,3-dioxane.

Reference example 30

2,2-Dimethyl-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane

In a stream of argon 1.45 g of 5-(3-bromobenzyl)-2,2-dimethyl-1,3-dioxane dissolved in 7 ml of anhydrous tetrahydrofuran and cooled in a bath of dry ice and acetone. To the mixture is added to 0.9 ml of N,N,N',N'-tetramethylethylenediamine, and then added dropwise n-utility (1.6 M solution in hexane) at -60°s or less. After stirring for 10 minutes, add a suspension of 1.03 g of tri-n-butylphosphine and 0.97 g of copper iodide/7 ml of anhydrous tetrahydrofuran and the mixture is stirred for 10 minutes. Then added dropwise a solution of 1.52 g of 4-iodomethyl-5-methyl-2-phenyloxazole/7 ml of anhydrous tetrahydrofuran at a temperature of -60°s or less, after which the mixture is stirred for 15 minutes under the same conditions. Bath removed and the mixture is stirred for 1.5 hours. To the reaction the solution was added a saturated aqueous solution of ammonium chloride. The mixture is diluted with water, extracted with ether, filtered to remove insoluble substances, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=4:1)) to give 0.34 g of the target compound as white crystals. TPL 85-87°C.

In accordance with the method described in reference example 30, receive the following connections:

2,2-dimethyl-5-{4-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane,

2,2-dimethyl-5-{4-[(5-methyl-2-phenyloxazol-4-yl)methyl]phenyl}-1,3-dioxane and

2,2-dimethyl-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]phenyl}-1,3-dioxane.

Reference example 31

5-(5-Methyl-2-phenyloxazol-4-yl)-1-pentanol

To 17 ml of anhydrous ether is added 550 mg of lithium aluminum hydride and added dropwise to 3.3 g of methyl 5-(5-methyl-2-phenyloxazol-4-yl)-1-pentanoate/10 ml anhydrous ether. After stirring for 1 hour at room temperature the mixture is cooled with ice water and gradually added dropwise 12 ml of tetrahydrofuran/0.7 ml of water. Then add 0.7 ml of 1N sodium hydroxide solution and 2.5 ml of water and the mixture is stirred for 15 minutes. The mixture is filtered to remove insoluble substances and the filtrate concentrated to obtain 2.9 g of target compound in the form of yellowish crystals. TPL 40-42°C.

In accordance with the methodology, the op is pulling in reference example 31, receive the following connections:

4-(5-methyl-2-phenyloxazol-4-yl)-1-butanol,

4-[5-methyl-2-(p-tolyl)oxazol-4-yl]-1-butanol,

4-[2-(p-tolyl)-5-cryptomaterial-4-yl]-1-butanol,

6-[5-methyl-2-(p-tolyl)oxazol-4-yl]-1-hexanol and

6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-HEXEN-1-ol.

Reference example 32

4-(5-Bromopentyl)-5-methyl-2-phenyloxazol

4-(5-Methyl-2-phenyloxazol-4-yl)-1-pentanol (2.9 g) was dissolved in 62 ml of anhydrous ether and added to 8.4 g of tetrabromomethane. To the mixture is gradually added 6.6 g of triphenylphosphine under ice cooling. The mixture is then stirred for 2.5 hours at room temperature, filtered to remove insoluble substances and the filtrate concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=10:1)) to obtain the 2,61 g of target compound in the form of a yellowish oil.

In accordance with the method described in reference example 31, will receive the following connections:

4-(4-bromobutyl)-5-methyl-2-phenyloxazol,

ethyl 2-(6-bromo-4-hexyloxy)-2-methylpropionate,

4-(4-bromobutyl)-5-methyl-2-(p-toluene)oxazol,

4-(4-bromobutyl)-2-(p-tolyl)-5-cryptomaterial,

4-(6-bromohexyl)-5-methyl-2-(p-tolyl)oxazol and

4-[6-bromo-(E)-2-hexenyl]-5-methyl-2-phenyloxazol.

Reference example 33

Diethyl [5-(5-methyl-2-phenyloxazol-4-yl)pentyl]malonate

To 35 ml of anhydrous tetrahydrofuran is on dropwise, under stirring and cooling with ice, add 650 mg of 60% sodium hydride and 3.9 ml of diethylmalonate. After stirring for 10 minutes add 4-(4-bromopentyl)-5-methyl-2-phenyloxazol (2.5 g). The mixture is stirred for 10 minutes at room temperature, and then refluxed for 12 hours. The reaction solution was poured into ice water, neutralized with diluted hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=10:1)) and get to 2.75 g of the target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,26 (6N, t), 1,32 was 1.43 (4H, m), 1,55-1,75 (2H, m), 1,82 is 2.00 (2H, m), 2,31 (3H, s), 2,47 (2H, t), and 3.31 (1H, t), 4,19 (4H, HF), 7,37-7,47 (3H, m), 7,95-of 8.00 (2H, m).

In accordance with the method described in reference example 33, receive the following connections:

diethyl [4-(5-methyl-2-phenyloxazol-4-yl)butyl]malonate,

diethyl {4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}malonate,

diethyl {4-[2-(p-tolyl)-5-cryptomaterial-4-yl]butyl}malonate and

diethyl [5-(benzoylamine)-5,5-bis(etoxycarbonyl)-(E)-2-pentenyl]malonate.

Reference example 34

4-[6,6-Bis(hydroxymethyl)hexyl]-5-methyl-2-phenyloxazol

To 15 ml of anhydrous ether until the NML type 637 mg of lithium aluminum hydride and 2.6 g of diethyl [5-(5-methyl-2-phenyloxazol-4-yl)butyl]malonate/10 ml anhydrous ether. After stirring for 2 hours at room temperature the mixture is cooled with ice water and dropwise gradually add 14 ml of tetrahydrofuran/0.8 ml of water. Then to the mixture is added 0.8 ml of an aqueous solution of 1N sodium hydroxide and 2.3 ml of water, stirred for 15 minutes and filtered to remove insoluble substances. The filtrate is concentrated and obtain 2.0 g of the target compound as white crystals. TPL=71-74°C.

In accordance with the method described in reference example 34, receive the following connections:

4-[5,5-bis(hydroxymethyl)pentyl]-5-methyl-2-phenyloxazol,

4-[5,5-bis(hydroxymethyl)pentyl]-5-methyl-2-(p-tolyl)oxazol,

4-[5,5-bis(hydroxymethyl)pentyl]-2-(p-tolyl)-5-cryptomaterial and

4-[5,5-bis(hydroxymethyl)pentyl]-5-ethyl-2-(p-tolyl)oxazol.

Reference example 35

4-{3-[2,2-Bis(hydroxymethyl)ethyl]benzyl}-5-methyl-2-phenyloxazol

A solution of a mixture of 320 mg of 2,2-dimethyl-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane, 21 ml of ethanol and 21 mg of p-toluensulfonate pyridinium (PPTS) is stirred for 2 hours at 55-60°C. the Reaction solution is concentrated and the residue purified column chromatography on silica gel (Wakogel C-200, chloroform)) and obtain 305 mg of the target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,90-to 2.15 (1H, m)to 2.29 (3H, s), 2,35 (2N, W), 2,60 (2H, d), of 3.64 (2H, DD), of 3.78 (2H, DD), 3,85 (2H, s),6.90 to-7,50 (7H, m), the 7.85-with 8.05 (2H, m).

In accordance with the method described in reference example 35, receive the following connections:

4-{4-[2,2-bis(hydroxymethyl)ethyl]benzyl}-5-methyl-2-phenyloxazol,

4-{4-[1,1-bis(hydroxymethyl)methyl]benzyl}-5-methyl-2-phenyloxazol,

4-{3-[1,1-bis(hydroxymethyl)methyl]benzyl}-5-methyl-2-phenyloxazol and

4-[5,5-bis(hydroxymethyl)pentyl]-5-methyl-2-phenyloxazol.

Reference example 36

Methyl 5-(5-methyl-2-phenyloxazol-4-yl)pentanoate

Methyl 6-acetyl-6-benzylaminopurine (4.35 g) was dissolved in 87 ml of toluene and added to 2.9 ml of phosphorus oxychloride and refluxed for 50 minutes. The reaction solution is cooled, poured into ice water, neutralized with an aqueous solution of sodium bicarbonate, extracted with ethyl acetate and washed with a saturated solution of salt. The resulting solution was dried over anhydrous magnesium sulfate and concentrated, resulting in a gain 3,40 g of target compound in the form of a yellowish oil.

In accordance with the method described in reference example 36, receive the following connections:

methyl 4-(5-methyl-2-phenyloxazol-4-yl)butanoate,

methyl 4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butanoate,

ethyl 6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexanoate and

methyl 6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenoate.

Reference example 37

1-Bromo-3-[2,2-bis(etoxycarbonyl)-2-(p-toluylene)ethyl]Benz is l

To 100 ml of anhydrous ethanol add 21,45 g of a solution of 20% ethoxide sodium in ethanol and 17,61 g of diethyl-p-toluylenediamine and stirred at room temperature for 30 minutes in an argon atmosphere. After adding dropwise 15,00 g 3-bromobenzylamine the reaction solution is stirred for 8 hours at 55°and then concentrate. To the residue water is added and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and get 29,82 g of target compound as a yellow oil.

1H-NMR (CDCl3)δ: 1,31 (6N, t)to 2.41 (3H, s), 3,74 (2H, s), 4,30 (4H, HF), 6,90-7,40 (7H, m), 7,60-of 7.70 (2H, m).

Reference example 38

1-Bromo-3-[2-carboxy-2-(p-toluylene)ethyl]benzene

1-Bromo-3-[2,2-bis(etoxycarbonyl)-2-(p-toluylene)ethyl]benzene (28,93 g) dissolved in 200 ml of ethanol and add a solution of 9.6 g of sodium hydroxide/60 ml of water, and then refluxed for 3 hours. The reaction solution concentrate. To the residue water is added and washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated to obtain 24,19 g of target compound as a colorless oil. The oil obtained is dissolved in 50 ml of ethyl acetate and, after addition of 150 ml of xylene is stirred for 15 hours at 130° C. the Solvent is distilled off under reduced pressure and the obtained crystals are washed with diethyl ether to obtain 17,22 g of the target compound as colorless crystals. TPL 196-197°C.

Reference example 39

1-[2-Acetyl-2-(p-toluylene)ethyl]-3-Brabanthal

1-Bromo-3-[2-carboxy-2-(p-toluylene)ethyl]benzene (of 16.84 g) dissolved in 85 ml of pyridine, add 55 ml of acetic anhydride and stirred for 3 hours in an argon atmosphere at 90-95°C. Then gradually added dropwise water (55 ml) so that the maximum temperature does not exceed 100°and the mixture is stirred for 20 minutes at 60-70°C. the Reaction solution is cooled, poured into ice water and extracted with the ethyl acetate. The resulting solution was sequentially washed with 10% hydrochloric acid, water and saturated aqueous sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The obtained crystal was washed with isopropyl ether to obtain 13,31 g of target compound in the form of brownish crystals. TPL 106-107°C.

Reference example 40

1-Bromo-3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzene

1-[2-Acetyl-2-(p-toluylene)ethyl]-3-Brabanthal (13,26 g) dissolved in 260 ml of toluene, added 6.8 ml of phosphorus oxychloride and refluxed for 3 chaison the solution is cooled, poured into ice water and extracted with ethyl acetate. The resulting solution was sequentially washed with saturated aqueous sodium bicarbonate, and then dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=4:1)) to obtain the 10,86 g of target compound in the form of yellowish crystals. TPL 74-75°C.

Reference example 41

3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzaldehyde

N,N-Dimethylformamide (30 ml) are added to 9,48 g of 1-bromo-3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzene, 2.83 g of sodium formate and 0.97 g of the dichloride bis(triphenylphosphine)palladium (II) and the mixture is stirred for 9 hours at 110°, barbotine carbon monoxide. To the reaction solution was added water, extracted with ethyl acetate, filtered to remove insoluble substances, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=4:1)) to give 3.58 g of the target compound as colorless crystals. TPL 98-99°C.

Reference example 42

3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl alcohol

3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzaldehyde (3,54 g) is suspended in 35 ml of methanol, and then with stirring and cooling with ice add 230 mg boron is idrica sodium and stirred for 1.5 hours at room temperature. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled at reduced pressure obtaining of 3.54 g of the target compound as colorless crystals. TPL 97-99°C.

Reference example 43

3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzylbromide

3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl alcohol (3,52 g) is suspended in 60 ml of dichloromethane. After addition of 3.77 g of triphenylphosphine and 5.17 g of tetrabromomethane the mixture is stirred for 30 minutes at room temperature. The reaction solution is concentrated and the residue purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=4:1)) with the receipt of 3.96 g of the target compound as colorless crystals. TPL 101-102°C.

Reference example 44

Diethyl 3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzylmalonate

To 15 ml of anhydrous tetrahydrofuran and 7 ml of anhydrous N,N-dimethylformamide add 0,88 mg of 60% sodium hydride. To the mixture, with stirring and ice cooling, added dropwise and 4.40 g of diethylmalonate. After stirring for 15 minutes, add a solution 3,93 g of 3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzylbromide/5 ml anhydrous tetrahydrofuran and stirred for 1 hour under ice cooling. The reaction solution was poured into ice-cold water, ek is tracerout with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=5:1)) and gain of 3.95 g of the target compound as colorless crystals.

1H-NMR (CDCl3)δ: 1,17 (6N, t in), 2.25 (3H, s), of 2.38 (3H, s)3,18 (2H, d), 3,62 (1H, t)4,07 (2H, s), of 4.12 (4H, HF), 7,00-7,30 (6N, m), 7,80-of 7.90 (2H, m).

Reference example 45

2-[3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-propandiol

To 30 ml of anhydrous tetrahydrofuran add 854 mg of lithium aluminum hydride, and then, under stirring and ice cooling, added dropwise 3.94 g diethyl [3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzylmalonate/10 ml of anhydrous tetrahydrofuran. The mixture is stirred for 1.5 hours at room temperature and cooled in the ice water. To the mixture successively added dropwise to 0.85 ml of water, 0,85 ml of 15% sodium hydroxide solution and 2.5 ml of water and stirred for 15 minutes. The mixture is filtered to remove insoluble substances and the filtrate concentrated. The residue is dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue purified column chromatography on silica gel (Wakogel C-200, a mixture of chloroform:methanol=20:1)) and get 2,32 g of the target compound as colorless crystals. TPL 114-115°is.

Reference example 46

Diethyl (3-fluoro-4-methylbenzoyl)aminomalonate

To a solution of 10.1 g of 3-fluoro-4-methylbenzoic acid and 15.2 g of the hydrochloride of diethylaminoacetate in 200 ml of N,N-dimethylformamide successively added 9.7 g of 1-hydroxybenzotriazole, 23 ml of triethylamine and 13.8 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and stirred for 1 hour at room temperature. After adding water to the reaction solution, the mixture is extracted with ethyl acetate. The extract is successively washed with water, 10% hydrochloric acid, water and saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is crystallized by adding isopropyl ether to obtain 15.1 g of the target compound as colorless crystals. TPL 102-103°C.

Reference example 47

1-(p-Toluensulfonyl)-3-[2-(p-tolyl)-5-cryptomaterial-4-yl]propane

3-[2-(p-Tolyl)-5-cryptomaterial-4-yl]-1-propanol (6,40 g)synthesized according to the method described Kawase et al. (Chem. Pharm. Bull., 46, 749-756 (1998)), dissolved in 35 ml of dichloromethane. To successively added to a solution of 293 mg of 4-(dimethylamino)pyridine, with 4.7 ml of triethylamine and 5,13 g p-toluensulfonate and stirred for 3 hours at room temperature. To the reaction solution was added ethyl the Etat and sequentially washed with water, 10% hydrochloric acid and saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is distilled under reduced pressure to get 10,08 g of target compound in the form of light brown crystals. TPL 57-58°C.

Reference example 48

4-[2-(p-Tolyl)-5-cryptomaterial-4-yl]Botanical

To 40 ml of dimethyl sulfoxide add 10,08 g of 1-(p-toluensulfonyl)-3-[2-(p-tolyl)-5-cryptomaterial-4-yl]propane and of 1.16 g of sodium cyanide and the mixture is stirred for 2 hours at 90°C. To the reaction solution was added water and the mixture extracted with diethyl ether, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and get 6,35 g of target compound in the form of light brown crystals. TPL 41-42,5°C.

Reference example 49

Methyl 4-[2-(p-tolyl)-5-cryptomaterial-4-yl]butanoate

4-[2-(p-Tolyl)-5-cryptomaterial-4-yl]butanetriol (5,28 g) dissolved in 40 ml of methanol and stirred for 10 minutes under ice cooling and the bubbling gaseous hydrogen chloride. After the termination of ozonation the mixture is heated to room temperature and stirred for 30 minutes. To the reaction solution add 5 ml of water and the mixture is stirred for 30 minutes and then incubated overnight at room the Oh temperature. After adding water, the reaction solution is extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=3:1)) to obtain the 5,63 g of the target compound as colorless crystals.

TPL of 44.5-45°C.

Reference example 50

Methyl 4-(permitil)benzoate

Anhydrous acetonitrile (150 ml) are added to a 25.00 g of methyl (4-(methyl bromide)benzoate, 19,02 g of potassium fluoride and of 9.51 g of calcium fluoride and the mixture is refluxed for 3 days. The reaction solution concentrate. After adding 200 ml of acetonitrile any insoluble matter is filtered off and the filtrate is again concentrated. The residue is purified column chromatography on silica gel (YMC·GEL(SIL-60-230/70, a mixture of n-hexane:ethyl acetate=10:1-4:1), and then distilled under reduced pressure to get it accounted for 14.45 g of target compound as a colorless oil. TKIP,5-119°C/18 mmHg

1H-NMR (CDCl3)δ: 3,93 (3H, s), 5,44 (2H, d), 7,40-7,46 (2H, m), 8,03-of 8.09 (2H, m).

Reference example 51

4-(Permitil)benzoic acid

In 200 ml of methanol is dissolved 8,68 g of methyl 4-(permitil)benzoate and under stirring and ice cooling are added dropwise 77 ml of an aqueous solution of 1N sodium hydroxide. Then MES stirred for 3.5 hours at room temperature. After acidification of the mixture of 1N hydrochloric acid, the precipitated crystals are filtered off and the filtrate concentrated. Precipitated crystals combined with the residue obtained from concentration of the filtrate, and add water. The mixture is extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent is distilled under reduced pressure to get 7.47 g of the target compound as colorless crystals. TPL 192-194°C.

Reference example 52

4-(Permitil)benzoyl chloride

4-(Permitil)benzoic acid (6.20 g) was dissolved in 30 ml of benzene, add 0.3 ml of N,N-dimethylformamide, and then added dropwise to 4.4 ml of thionyl chloride. The mixture is stirred for 1 hour at 40°and then refluxed for a further 1 hour. The solvent is distilled under reduced pressure to get 6,70 g of target compound as a pale yellow oil.

Reference example 53

Ethyl 6-chloro-2-etoxycarbonyl-2-(p-toluylene)hexanoate

Sodium (6.42 per g) dissolved in 390 ml of ethanol at room temperature. To the solution add 78.0 g diethyl-p-toluylenediamine and boiling with reflux condenser are added dropwise 47.9 g of 1-bromo-4-chlorobutane. The mixture is refluxed for 20 hours. The reaction solution concentrate. To the residue water is added and the mixture washed with ethyl acetate. PEFC is sequential washing with 10% hydrochloric acid and water, the solution is dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=9:1)) to give 55.7 g of the target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,26 (6N, t), 1,26-of 1.42 (2H, m), 1,72 is 1.86 (2H, m), is 2.41 (3H, s), 2,44-2,52 (2H, m), 3,51 (2H, t), 4,28 (4H, HF), 7,24-7,28 (2H, m), of 7.48 (1H, s), 7,71 to 7.75 (2H, m).

Reference example 54

6-Chloro-2-(p-toluylene)hexanoic acid

Ethyl 6-chloro-2-etoxycarbonyl-2-(p-toluylene)hexanoate (103,2 g) dissolved in 412 ml of ethanol, add a solution of 24.5 g of sodium hydroxide/98 ml of water and refluxed for 16 hours. The reaction solution concentrate. To the residue is added ethyl acetate. The mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated to obtain 80,0 g of a colorless resin. To the resulting resin add 75 ml of acetic acid and refluxed for 10 hours. After stirring and cooling the mixture precipitated crystals are washed with ethyl acetate and recrystallized from acetic acid to obtain 26,0 g of the target compound as colorless crystals. TPL 177-181°C.

Reference example 55

8-Chloro-4-(p-toluylene)-3-octanone

6-Chloro-2-(p-toluylene)hexanoic acid (10.0 g) is dissolved in 15 ml of anhydrous pyridine, add 15 ylpropionic anhydride and stirred for 2.5 hours at 90° C. To the mixture slowly add 15 ml of water so that the maximum temperature does not exceed 85°C, and stirred for 20 minutes at 80°C. the Reaction solution is cooled, poured into ice water and extracted with diethyl ether. The extract is successively washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=8:1-4:1)) to obtain 6.0 g of the target compound as colorless crystals. TPL 85-86°C.

Reference example 56

4-(4-Chlorobutyl)-5-ethyl-2-(p-tolyl)oxazol

In 150 ml of toluene is dissolved 6.5 g of 8-chloro-4-(p-toluylene)-3-octanone add to 4.1 ml of phosphorus oxychloride and refluxed for 1.5 hours. The reaction solution is cooled, poured into ice water and extracted with ethyl acetate. The extract was sequentially washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=8:1)) to obtain 5.5 g of the target compound in the form of yellowish crystals.

1H-NMR (CDCl3)δ: of 1.27 (3H, t), 1,78-to 1.87(4H, m)of 2.38 (3H, s), 2,52 (2H, t)to 2.67 (2H, q), of 3.57 (2H, t), of 7.23 (2H, d), 7,84-7,89 (2H, m).

Reference example 57

Diethyl 4-[5-ethyl-2-(p-tolyl)oxazol-4-yl]butylmalonate

It is 32.8 ml 21% ethoxide sodium in ethanol add, boiling under reflux, and 16.7 ml of diethylmalonate. Then added dropwise 5.0 g of 4-(4-chlorobutyl)-5-ethyl-2-(p-tolyl)oxazol/5 ml ethanol and the mixture refluxed for 7 hours in an argon atmosphere. The reaction solution was poured into ice water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=10:1)) and obtain 2.65 g of the target compound as a yellow oil.

1H-NMR (CDCl3)δ: 1,25 (6N, t)of 1.29 (3H, t), 1,35 of 1.46 (2H, m), 1,65-of 1.73 (2H, m), 1,88 of 1.99 (2H, m), 2,39 (3H, s), 2,48 (2H, t), of 2.66 (2H, q), of 3.32 (1H, t), 4,13-4.26 deaths (4H, m), 7,22 (2H, d), 7,87 (2H, d).

Reference example 58

In accordance with the procedure described in the example below 6, you receive the following connections:

2,2-dimethyl-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane,

methyl 4-(5-methyl-2-phenyloxazol-4-yl)butyrate and

methyl 3-(5-methyl-2-phenyloxazol-4-yl)propionate.

Reference example 59

1-(o-Toluylene)-2-propanol

To 100 ml of a solution of 5.83 g of 1-amino-2-propanol in toluene added to 18.0 ml of triethylamine, and then, under stirring and cooled and ice, dropwise added slowly to 10 ml of a solution of 10.00 g of o-trouillard in toluene. After stirring for 30 minutes the ice bath removed and the mixture is stirred for further 1 hour at room temperature. To the reaction solution was added water and the mixture extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid, ice water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is crystallized by adding diethyl ether obtaining of 7.25 g of the target compound as colorless crystals. TPL 78-81°C.

In accordance with the method described in reference example 59, receive the following connections:

1-(4-pharmacyventolin)-2-propanol,

1-(m-toluylene)-2-propanol and

1-(cyclohexylcarbonyl)-2-propanol.

Reference example 60

1-(o-Toluylene)-2-propanone

Chlorproma pyridinium (15,91 g) is added, stirring, to 143 ml suspension 7,13 g of 1-(o-toluylene)-2-propanol and 15,91 g celite in dichloromethane. The mixture is stirred for 4 hours at room temperature. The reaction solution was purified column chromatography on silica gel (Wakogel C-200, chloroform)), and the solvent is distilled off under reduced pressure. The eluate is again purified column chromatography on silica gel (Wakogel C-200, a mixture of n-GE is San:ethyl acetate=1:2)) to give 5.73 g of the target compound as colorless crystals. TPL 65-66°C.

In accordance with the method described in reference example 60, you receive the following connections:

1-(2,4-dimethylbenzylamine)-2-propanone,

1-(4-pharmacyventolin)-2-propanone,

1-(m-toluylene)-2-propanone,

1-(3,4-dimethylbenzylamine)-2-propanone,

1-(4-methoxybenzylamine)-2-propanone and

1-(cyclohexylcarbonyl)-2-propanone.

Reference example 61

Methyl CIS-5-[5-acetyl-5-(o-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate

In the atmosphere of argon, 40 ml of a suspension of 1.18 g of 60% sodium hydride in N,N-dimethylformamide is cooled to -25°in a bath of dry ice and acetone, and then added dropwise slowly add 15 ml 5,65 g of 1-(o-toluylene)-2-propanone in N,N-dimethylformamide. After stirring for 1 hour dropwise slowly add 5 ml of a solution of 10.09 g of methyl CIS-5-(4-iodobutyl)-2-methyl-1,3-dioxane-r-2-carboxylate in N,N-dimethylformamide and the mixture is stirred for a further 1 hour. To the reaction solution was added 1 ml of 1N hydrochloric acid and then water and the mixture extracted with diethyl ether. The extract was washed with an aqueous solution of 0.5% aqueous sodium hydroxide, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=1:1)), with 6,38 g target connect the deposits in the form of a colorless oil.

1H-NMR (CDCl3)δ: 1,01-1,08 (2H, m), 1,22-of 1.39 (4H, m)and 1.51 (3H, s), 1,62-1,71 (2H, m), 1,97-of 2.09 (1H, m), of 2.28 (3H, s), is 2.44 (3H, s), 3,39 (2H, t), 3,83 (3H, s), of 3.94 (2H, DD), 4,84 (1H, HF), of 6.49 (1H, d), 7,22-7,42 (4H, m).

In accordance with the method described in reference example 61, receive the following connections:

methyl CIS-5-[5-acetyl-5-(2,4-dimethylbenzylamine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-[5-acetyl-5-(4-pharmacyventolin)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-[5-acetyl-5-(m-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-[5-acetyl-5-(3,4-dimethylbenzylamine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-[5-acetyl-5-(4-methoxybenzylamine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-[5-acetyl-5-(2-anolamine)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate and

methyl CIS-5-[5-acetyl-5-(cyclohexylcarbonyl)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate.

Reference example 62

1-(3,4-Dimethylbenzylamine)-2-propanol

To 30 ml of a solution of 5.00 g of 3,4-dimethylbenzoic acid and 2.75 g of 1-amino-2-propanol in N,N-dimethylformamide successively added of 4.95 g of 1-hydroxybenzotriazole, of 6.96 ml of triethylamine and 7,02 g of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and the mixture is stirred for 15 minutes at room temperature. After adding water, the reaction solution is extracted with ethyl acetate, succession is entrusted washed with 10% hydrochloric acid, ice water and saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and get 6,28 g of the target compound as colorless crystals. TPL 77-78°C.

In accordance with the method described in reference example 62, you receive the following connections:

1-(2,4-dimethylbenzylamine)-2-propanol and

1-(4-methoxybenzylamine)-2-propanol.

Reference example 63

Methyl 2-(2-anolamine)acetate

To 250 ml of suspension 12,56 g of the hydrochloride of methyl 2-aminoacetate in dichloromethane add 20,24 g of triethylamine and stirred at room temperature for 30 minutes. After cooling with ice dropwise slowly add 20 ml 14,66 g of 2-trailhead in dichloromethane. The ice bath removed and the mixture is stirred for 14 hours at room temperature. The precipitated crystals are filtered and washed with dichloromethane. The solvent is distilled off from the filtrate under reduced pressure. To the residue to precipitate add tert-butyl methyl ether. Both products combine and get 17,20 g of target compound in the form of brownish crystals.

1H-NMR (CDCl3)δ: of 3.80 (3H, s)to 4.23 (2H, d), 6,62 (1H, W), to 7.09 (1H, DD), to 7.50 (1H, DD), EUR 7.57 (1H, DD).

Reference example 64

2-(2-Anolamine)sodium acetate

To 200 ml 16,70 g of methyl 2-(2-anolamine)acetate is in methanol are added 20 ml of an aqueous solution was 4.02 g of sodium hydroxide and refluxed for 30 minutes. The solvent is distilled off under reduced pressure. The residue is crystallized by addition of isopropanol to obtain 18,03 g of target compound in the form of light yellow crystals.

Reference example 65

1-(2-Anolamine)-2-propanone

To 44,0 ml suspension 16,70 g 2-(2-anolamine)of sodium acetate in β-picoline add 42,7 ml acetic anhydride and stirred for 3 hours at room temperature. After cooling with ice sequentially and slowly added dropwise to 26.3 ml of ethanol, 129,7 ml of water and 45,2 ml of concentrated hydrochloric acid and then the mixture is stirred for 15 minutes at the same temperature. After removing the ice bath, the mixture is stirred for a further 15 minutes at room temperature. Then add water (250 ml) and the precipitated crystals are separated and washed with water. The crystals add 37,0 ml of water and the mixture is refluxed for 1 hour. After addition of 14.0 g of sodium chloride, the mixture is refluxed for another 1 hour. The reaction solution is extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After the addition of activated carbon (Kyoryoku-sirasagi(MOIWY433) the mixture is stirred for 30 minutes at room temperature. The solvent is distilled off under reduced pressure. The residue is crystallized by adding tert-butyl methyl ether to obtain 7,15 g target is connected to the I in the form of light brown crystals.

1H-NMR (CDCl3)δ: of 2.27 (3H, s), 4,34 (2H, d), to 6.80 (1H, W), to 7.09 (1H, DD), to 7.50 (1H, DD), EUR 7.57 (1H, DD).

Reference example 66

4-[5,5-Bis(methyl bromide)pentyl]-5-methyl-2-(p-tolyl)oxazol

To 15 ml of a solution of 2.25 g of 4-[5,5-bis(hydroxymethyl)pentyl]-5-methyl-2-(p-tolyl)oxazole in N,N-dimethylformamide successively added to 3.92 ml γ-Kalinina, to 2.57 g of lithium bromide and 2.3 ml of methanesulfonanilide and stirred under heating for 2.5 hours at 80°C. To the reaction solution was added water and the mixture extracted with ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=9:1)) to give 1.45 g of the target compound as a brown oil.

1H-NMR (CDCl3)δ: 1,30-of 1.55 (2H, m), 1.60-to of 1.85 (4H, m), 1,95-2,15 (1H, m), 2,31 (3H, s), of 2.38 (3H, s), 2.49 USD (2H, t), 2,82 was 3.05 (4H, m), 7,38 was 7.45 (2H, m), 7,94 shed 8.01 (2H, m).

Reference example 67

4-[5,5-Bis(acetyltributyl)pentyl]-5-methyl-2-(p-tolyl)oxazol

To 4 ml 923 mg of 4-[5,5-bis(methyl bromide)pentyl]-5-methyl-2-(p-tolyl)oxazole in polyethylene glycol 200 added 1.18 g of thioacetate potassium and stirred for 1.5 hours under heating at 80°C. To the reaction solution was added water and the mixture extracted with ethyl acetate, washed with saturated salt solution, sushi is t over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=9:1)) to obtain 830 mg of the target compound as a brown oil.

1H-NMR (CDCl3)δ: 1,35 of 1.50 (4H, m), 1,55-1,70 (2H, m), 1,75-of 1.95 (1H, m), 2,32 (3H, s), 2,33 (6N, (C), of 2.38 (3H, s), 2,47 (2H, t), 2,82 was 3.05 (4H, m), 7,20-of 7.25 (2H, m), 7,84-7,89 (2H, m).

In accordance with the method described in reference example 67, receive the following connection:

5-methyl-4-(6-acetyldigoxin)-2-(p-tolyl)oxazol.

Reference example 68

4-[5,5-Bis(mercaptomethyl)pentyl]-5-methyl-2-(p-tolyl)oxazol

To 8 ml of a solution of 830 mg of 4-[5,5-bis(acetyltributyl)pentyl]-5-methyl-2-(p-tolyl)oxazole in methanol added 8 mg of aqueous 1N solution of sodium hydroxide and refluxed for 1 hour. The reaction solution is acidified with 1N hydrochloric acid, extracted with dichloromethane and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and get 675 mg of the target compound as a pale yellow oil.

1H-NMR (CDCl3)δ: 1,25-1,95 (N, m), 2,31 (3H, s), of 2.38 (3H, s), 2,48 (2H, t), 2,55-to 2.85 (4H, m), 7,16-7,24 (2H, m), 7,81-7,89 (2H, DD).

Reference example 69

Ethyl 6-iodixanol

To 112 ml 13,38 g of ethyl 6-bromhexina in acetone add 26,97 g of sodium iodide and the mixture is refluxed for 18 hours. The reaction solution is cooled, filterwords remove insoluble substances and washed with acetone. The filtrate is concentrated and, after addition of water, extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain 16,21 g of target compound in the form of a red-yellow oil.

1H-NMR (CDCl3)δ: of 1.26 (3H, t), 1,39-is 1.51 (2H, m), 1,58-of 1.73 (2H, m), 1,78-of 1.92 (2H, m), 2,31 (2H, t), 3,19 (2H, t), of 4.13 (2H, HF).

Reference example 70

Ethyl 7-acetyl-7-(p-toluylene)heptanoate

The suspension (100 ml), 60% sodium hydride (2.64 g) in N,N-dimethylformamide is cooled to -18°in a bath with ice and sodium chloride dropwise and slowly added 31 ml br12.62 g of 1-(p-toluylene)-2-propanone in N,N-dimethylformamide. After stirring for 1 hour dropwise slowly added 31 ml 16,21 g of ethyl 6-iodixanol in N,N-dimethylformamide. The ice bath removed and the mixture is stirred for 18 hours at room temperature. After adding ice water, the reaction solution is extracted with ethyl acetate, sequentially washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=3:1)) to obtain 13,13 g of target compound as a yellow oil.

1H-NMR (CDCl3)δ: 1,201,45 (4H, m)of 1.24 (3H, t), and 1.54-1.77 in (3H, m), 2,01-of 2.08 (1H, m), 2.23 to-2,31 (2H, t), is 2.40 (3H, s), 2,78 (3H, s), 4,11 (2H, HF), 4,18-of 4.90 (1H, m), 6.90 to (1H, d), 7,25 (2H, d), 7,71 (2H, d).

Reference example 71

Ethyl 2-(6-idexists)-2-methylpropionate

To 76 ml 12,16 g of ethyl 2-(6-Bromhexine)-2-methylpropionate in acetone add holds 18.52 g of sodium iodide and the mixture is refluxed for 18 hours. The reaction solution is cooled, filtered to remove insoluble substances and washed with acetone. The filtrate is concentrated and, after addition of water, extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain of 14.46 g of target compound in the form of a red-yellow oil.

1H-NMR (CDCl3)δ: of 1.29 (3H, t), 1,37-of 1.40 (4H, m), 1.41 to (6N, (C), 1,55-of 1.62 (2H, m), 1,80-to 1.87 (2H, m), 3,19 (2H, t), of 3.56 (2H, t), of 4.12 (2H, HF).

Reference example 72

Ethyl 2-[7-acetyl-7-(p-toluylene)heptyloxy]-2-methylpropionate

Suspension (70 ml) of 1.81 g of 60% sodium hydride in N,N-dimethylformamide is cooled to -18°in a bath with ice and sodium chloride dropwise and slowly add 21 ml 8,67 g of 1-(p-toluylene)-2-propanone in N,N-dimethylformamide. After stirring for 1 hour dropwise slowly add 21 ml 14,10 g of ethyl 2-(6-idexists)-2-methylpropionate in N,N-dimethylformamide. Bath is removed and the MCA is ü stirred for further 18 hours at room temperature. After adding ice water, the reaction solution is extracted with ethyl acetate, sequentially washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=3:1)) to obtain 12,20 g of target compound as yellow crystals.

1H-NMR (CDCl3)δ: 1,23-1,41 (6N, m)of 1.27 (3H, t), 1,39 (6N,) and 1.51-of 1.57 (2H, m), 1,71-of 1.74 (1H, m), 2,01-of 2.08 (1H, m), and 2.27 (3H, s), is 2.40 (3H, s), of 3.32 (2H, t)to 4.17 (2H, q), 4.80 to the 4.90 (1H, m), 6.89 in (1H, d), of 7.25 (2H, d), 7,71 (2H, d).

Reference example 73

7-(Benzoylamine)-7-carboxy-(E)-4-geptanona acid

To 170 ml of a solution of 8.50 g of diethyl [5-(benzoylamine)-5,5-bis(etoxycarbonyl)-(E)-2-pentenyl]malonate in ethanol add 34 ml of an aqueous solution of sodium hydroxide (5.53 g) and refluxed for 20 hours. The reaction solution is concentrated and, after addition of water, the residue was washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated to obtain a return of 6.58 g of light yellow oil. The oil obtained is dissolved in 90 ml of ethyl acetate. To the solution was added 90 ml of xylene and stirred for 15 hours at 130°C. the Solvent is distilled off under reduced pressure and obtained the crystals washed with isopropyl ether, giving to 4.52 g of the target compound as colorless crystals. TPL 138°C.

Example 1

Methyl 2-methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate

4-[5,5-Bis(hydroxymethyl)pentyl]-5-methyl-2-phenyloxazol (36 g) was dissolved in 432 ml of acetonitrile and add 25.4 g of methylpiruvate. To the mixture, stirring at room temperature, add to 35.3 g epirate of boron TRIFLUORIDE (about 47%) and refluxed for 2 hours. The reaction solution is cooled, poured into ice water solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, n-hexane:ethyl acetate=7,5:1)) and erwerbende earlier fractions concentrated to obtain 16.5 g of the target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,00-1,12 (2H, m), 1,22-of 1.40 (2H, m), 1,55-1,70 (5H, m), 1,90-of 2.20 (1H, m), is 2.30 (3H, s), a 2.45 (2H, t), 3,39 (2H, t), 3,82 (3H, s), of 3.95 (2H, DD), 7,37-7,47 (3H, m), 7,92-8,03 (2H, m).

Example 2

Methyl 2-methyl-TRANS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate

The last fraction of example 1 collect and concentrate to obtain 11 g of residue, which is again purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:etelaat is=to 7.5:1)) to obtain the 0,83 g of target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,33-1,44 (3H, m)and 1.51 (3H, s), 1,63-of 1.78 (4H, m), of 2.33 (3H, s), of 2.51 (2H, t), 3,75-3,81 (2H, m), 3,83 (3H, s), 3,91-3,99 (2H, m), 7,38 was 7.45 (3H, m), of 7.96 shed 8.01 (2H, m).

In accordance with the methods described in examples 1 and 2, receive the following connections:

methyl CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

methyl TRANS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

methyl 2-ethyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

methyl 2-isobutyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

methyl 2,5-dimethyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

methyl 2,5-dimethyl-TRANS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

methyl 5-ethyl-2-methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

methyl 5-ethyl-2-methyl-TRANS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-TRANS-5-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[(5-methyl-2-phenyloxazol-4-yl)methyl]phenyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]phenyl}-,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[2-(p-tolyl)-5-cryptomaterial-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[5-ethyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate and

ethyl 2-ethyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate.

Example 3

Methyl 2-methyl-CIS-5-[4-(2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate

In 5 ml of acetonitrile was dissolved 1.25 g of 4-[5,5-bis(hydroxymethyl)pentyl]-2-phenyloxazole and add 927 mg methylpiruvate. To this mixture, stirring at room temperature, add 1.3 g epirate of boron TRIFLUORIDE (about 47%) and refluxed for 3 hours at room temperature. The reaction solution is cooled, poured into ice water solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, n-hexane:isopropyl ether=1:1)) and erwerbende earlier fractions concentrated to obtain 450 mg of the target compound as white crystals. TPL 71-74°C.

1H-NMR (CDCl3)δ: 1,01-1,12 (2H, m), 1,27 was 1.43 (2H, m)and 1.51 (3H, s), 1,59-of 1.74 (2H, m), 1,90-of 2.20 (1H, m), of 2.56 (2H, t), 3,39 (2H, t), 3,83 (3H, s), of 3.96 (2H, DD), 7,41-7,47 (4H, m), 7,99-with 8.05 (2H, m).

Example 4

Methyl 2-methyl-TRANS-5-[4-(2-phenyloxazol-yl)butyl]-1,3-dioxane-r-2-carboxylate

The last fractions of example 3 collect and concentrate. The residue is again purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:isopropyl ether=1:1)) and obtain 110 mg of the target compound as a colourless oil.

1H-NMR (CDCl3)δ: of 1.25 to 1.48 (2H, m)and 1.51 (3H, s), 1,63 and 1.80 (5H, m), 2,62 (2H, t), 3,76-3,86 (5H, m), 3,92-4,00 (2H, m), 7,41-7,47 (4H, m), 8,00-with 8.05 (2H, m).

Example 5

Methyl 2-methyl-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane-2-carboxylate

To 5 ml of acetonitrile added 297 mg of 4-{3-[2,2-bis(hydroxymethyl)ethyl]benzyl}-5-methyl-2-phenyloxazole and 369 mg of methylpiruvate. To this mixture, stirring at room temperature, add 544 mg epirate of boron TRIFLUORIDE (about 47%) and the mixture is stirred for 14 hours at room temperature. The reaction solution is cooled, poured into ice water solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, n-hexane:ethyl acetate=3:1)) to give 185 mg of the mixture (CIS:TRANS=2,5:1, based on the total values NMR) as a colourless oil.

Example 6

Methyl 2-methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate

Methyl CIS-5-[5-acetyl-5-(p-toluylene)is entyl]-2-methyl-1,3-dioxane-r-2-carboxylate (0.85 grams) is dissolved in 17 ml of toluene. After adding 644 mg of phosphorus oxychloride, the mixture is refluxed for 2.5 hours. The reaction solution is cooled, poured into ice water, neutralized with an aqueous solution of sodium bicarbonate, extracted with ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, chloroform:methanol=100:1)) to obtain the 0,42 g of target compound as white crystals. TPL 92-94°C.

Elemental analysis for C22H29NO5:

calculated (%): C, 68,20; N, rate of 7.54; N, 3,61

found (percent): C, 68,07; N, The 7.43; N, 3,65.

In accordance with the procedure described in example 6, receive the following connections:

methyl 2-methyl-CIS-5-[3-(5-methyl-2-phenyloxazol-4-yl]propyl]-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl]butyl]-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-[5-(5-methyl-2-phenyloxazol-4-yl]pentyl]-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-{4-[2-(4-forfinal)-5-methoxazole-4-yl]butyl}-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl CIS-5-{4-[2-(4-tert-butylphenyl)-5-methoxazole-4-yl]butyl}-2-methyl-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[5-methyl-2-(4-triptoreline)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)-(E)-2-butenyl]-1,3-dioxan-2-carboxylate,

methyl 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propionate,

methyl 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionate,

methyl 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-4-hexyloxy]propionate,

methyl 2-{6-[2-(4-chlorophenyl)-5-methoxazole-4-yl]hexyloxy}-2-methylpropionate,

methyl 2-{6-[2-(4-forfinal)-5-methoxazole-4-yl]hexyloxy}-2-methylpropionate,

methyl 2-{6-[2-(4-tert-butylphenyl)-5-methoxazole-4-yl]hexyloxy}-2-methylpropionate,

methyl 2-methyl-2-[7-(5-methyl-2-phenyloxazol-4-yl)heptyloxy]propionate,

methyl 2-methyl-2-[5-(5-methyl-2-phenyloxazol-4-yl)pentyloxy]propionate,

methyl 2-[6-(5-ethyl-2-phenyloxazol-4-yl)hexyloxy]-2-methylpropionate,

methyl 2-methyl-2-{6-[5-methyl-2-(4-pyridyl)oxazol-4-yl]hexyloxy}propionate,

methyl 2-methyl-2-{6-[5-methyl-2-(3-pyridyl)oxazol-4-yl]hexyloxy}propionate,

methyl 2-methyl-CIS-5-{4-[5-methyl-2-(4-chlorophenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{5-[5-methyl-2-(p-tolyl)oxazol-4-yl]pentyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[5-methyl-2-(3-fluoro-4-were)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[5-methyl-2-(4-ethylphenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[5-methyl-2-(2,4-dimetilfenil)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[2-(4-formationl)-5-methoxazole-4-libutil}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[5-methyl-2-(m-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[5-methyl-2-(o-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[5-methyl-2-(3,4-dimetilfenil)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[5-methyl-2-(4-methoxyphenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[5-methyl-2-(2-thienyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

methyl 2-methyl-CIS-5-{4-[2-cyclohexyl-5-methoxazole-4-yl]butyl}-1,3-dioxane-r-2-carboxylate and

ethyl 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionate.

Example 7

Methyl 2-methyl-2-[6-(2-phenyloxazol-4-yl)hexyloxy]propionate

The mixture 956 mg benzamide and 1.1 g of methyl 2-(8-chloro-7-oxooctanoate)-2-methylpropionate stirred for 2 hours at 120°C. the Reaction solution is cooled, dissolved in ethyl acetate, washed by adding sodium bicarbonate, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=9:1)) to give 658 mg of target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,36 of 1.50 (10H, m), 1.55V and 1.80 (4H, m), of 2.54 2.63 in (2H, m)to 3.35 (2H, t), of 3.73 (3H, s), 7,41-7,47 (4H, m), 7,99-with 8.05 (2H, m).

In accordance with the procedure described in example 7, receive following the e connection:

methyl 2-methyl-2-[7-(2-phenyloxazol-4-yl)heptyloxy]propionate,

methyl 2-{7-[2-(4-chlorophenyl)oxazol-4-yl]heptyloxy}-2-methylpropionate,

methyl 2-{7-[2-(4-forfinal)oxazol-4-yl]heptyloxy}-2-methylpropionate,

methyl 2-{6-[2-(4-forfinal)oxazol-4-yl]hexyloxy}-2-methylpropionate and

methyl 2-methyl-2-[8-(2-phenyloxazol-4-yl)octyloxy]propionate.

Example 8

Methyl 2-methyl-2-[7-(2-phenylthiazol-4-yl)heptyloxy]propionate

The mixture 783 mg thiobenzamide and 1.0 g of methyl 2-(9-chloro-8-okonomiaki)-2-methylpropionate stirred for 2 hours at 120°C. the Reaction solution is cooled and dissolved in ethyl acetate, washed by adding sodium bicarbonate, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=9:1)) to obtain 963 mg of target compound as pale yellow oil.

1H-NMR (CDCl3)δ: 1,36-1,39 (6N, m), 1,42 (6N, (C), and 1.54-of 1.61 (2H, m), 1,72 and 1.80 (2H, m), 2,78-of 2.86 (2H, m), 3,31-to 3.38 (2H, m), of 3.73 (3H, s), 6.87 in (1H, s), 7,39-7,46 (3H, m), to $ 7.91-of 7.96 (2H, m).

In accordance with the procedure described in example 8, get the following connection:

methyl 2-methyl-2-[8-(2-phenylthiazol-4-yl)octyloxy]propionate.

Example 9

2-Methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid

Methyl 2-methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane--2-carboxylate (15,76 g) dissolved in 215 ml of methanol, add a solution of 2.53 g of sodium hydroxide/28 ml of water, the mixture is refluxed for 4 hours. The reaction solution is cooled, poured into ice water, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is dissolved under heating in a mixture of toluene/n-hexane and leave to cool. The precipitate is filtered off and get 13,52 g of target compound.

1H-NMR (CDCl3)δ: 1,00-of 1.15 (2H, m), 1,25-1,45 (2H, m), 1,50-1,70 (5H, m), 1,90-of 2.20 (1H, m), 2,32 (3H, s), 2,52 (2H, t), 3,49 (2H, DD), 3,99 (2H, DD), 7,40-to 7.50 (3H, m), of 7.90-with 8.05 (2H, m)to 9.70 (1H, Shir.).

Elemental analysis for C20H25NO5:

calculated (%): C, 66,84; N, 7,01; N, 3,90

found (percent): C, 66,76; N, To 7.09; N, 3,82.

Example 10

2-Methyl-CIS-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane-r-2-carboxylic acid

Methyl 2-methyl-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane-r-2-carboxylate (mixture of CIS:TRANS=3:1) (185 mg) was dissolved in 5 ml of methanol, add a solution of 0.5 ml of 2N sodium hydroxide and refluxed for 1 hour. The reaction solution is cooled, poured into ice water, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated solution Sol is, dried over anhydrous magnesium sulfate and concentrated. To the residue is added ether. The precipitated crystals are filtered off, recrystallized from acetonitrile and dried to obtain 109 mg of the target compound as white crystals. TPL 147-149°C.

Elemental analysis for C24H25NO5:

calculated (%): C, 70,75; N, 6,18; N, 3,44

found (percent): C, 70,85; N, Of 6.26; N, 3,33.

Example 11

2-Methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

Methyl 2-methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate (250 mg) is dissolved in 2.5 ml of methanol, add a solution of 51 mg of sodium hydroxide/0.6 ml water and the mixture is refluxed for 4 hours. The reaction solution is cooled, poured into ice water, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. To the residue is added ether. The precipitate is filtered off, dissolved by heating in acetonitrile and leave to cool. The precipitate is filtered off and dried, resulting in a gain of 196 mg of the target compound.

Elemental analysis for C21H27NO5:

calculated (%): C, 67,54; N, 7,29; N, 3,75

found (percent): C, 67,57; N, Of 7.25; N, 3,76.

Connection examples 12-52 get in the accordance with the methodology described in example 11.

Example 12

2-Methyl-TRANS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid

TPL 135-140°C.

1H-NMR (CDCl3)δ: 1,38 of 1.50 (3H, m), and 1.56 (3H, s), 1,60-1,80 (4H, m), of 2.33 (3H, s)to 2.54 (2H, t), with 3.79 (2H, DD), a 4.03 (2H, DD), 7,20 (1H, W), 7,40 is 7.50 (3H, m), of 7.90-8,10 (2H, m).

Elemental analysis for C20H25NO5:

calculated (%): C, 66,84; N, 7,01; N, 3,90

found (percent): C, 67,35; N, 7,00; N, of 3.77.

Example 13

2-Methyl-CIS-5-[5-(5-methyl-2-phenyloxazol-4-yl)pentyl]-1,3-dioxane-r-2-carboxylic acid

TPL 135-137°C.

Elemental analysis for C21H27NO5:

calculated (%): C, 67,54; N, 7,29; N, 3,75

found (percent): C, 67,44; N, 7,34; N, of 3.77.

Example 14

2-Methyl-CIS-5-[4-(2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid

Elemental analysis for C19H23NO5:

calculated (%): C, 66,07; N, Of 6.71; N, 4,06

found (percent): C, 66,09; N, Of 6.75; N, is 4.03.

Example 15

CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid

TPL 119-121°C.

Elemental analysis for C19H23NO5:

calculated (%): C, 66,07; N, Of 6.71; N, 4,06

found (percent): C, 66,02; N, 6,87; N, 4,18.

Example 16

TRANS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid

TPL 103-105°C.

Elemental analysis for C19H23NO5:

calculated (%): C, 66,07; N, Of 6.71; N, 4,06

found (percent): C, 66,07; N, Of 6.99; N, Android 4.04.

the example 17

2-Methyl-TRANS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

TPL 120-122°C.

Elemental analysis for C21H27NO5:

calculated (%): C, 67,54; N, 7,29; N, 3,75

found (percent): C, 67,61; N, To 7.35; N, 3,74.

Example 18

CIS-5-{4-[2-(4-tert-butylphenyl)-5-methoxazole-4-yl]butyl}-2-methyl-1,3-dioxane-r-2-carboxylic acid

Elemental analysis for C24H33NO5:

calculated (%): C, 69,37; N, 8,00; N, 3,37

found (percent): C, 69,26; N, Of 7.96; N, 3.43 points.

Example 19

CIS-5-{4-[2-(4-forfinal)-5-methoxazole-4-yl]butyl}-2-methyl-1,3-dioxane-r-2-carboxylic acid

TPL 138-139,5°C.

Elemental analysis for C20H24FNO5:

calculated (%): C, 63,65; N, 6,41; N, 3,71

found (percent): C, 63,62; N, To 6.58; N, 3,69.

Example 20

2-Methyl-CIS-5-{4-[5-methyl-2-(4-triptoreline)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

Elemental analysis for C21H24F3NO5:

calculated (%): C, 59,01; N, To 5.66; N, 3,28

found (percent): C, 59,14; N, Of 5.83; N, 3,29.

Example 21

2-Ethyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid

Elemental analysis for C21H27NO5:

calculated (%): C, 67,54; N, 7,29; N, 3,75

found (percent): C, 67,05; N, 7,24; N, 3,60.

Example 22

2-Isobutyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid

TPL 126-130°C.

Elemental analysis for C23the 31NO5:

calculated (%): C, 68,80; N, 7,78; N, 3,49

found (percent): C, 68,72; N, 7,88; N, 3.45 points.

Example 23

2,5-Dimethyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid

TPL 147-150°C.

Elemental analysis for C21H27NO5:

calculated (%): C, 67,54; N, 7,29; N, 3,75

found (percent): C, 68,17; N, 7,76; N, 3.46 in.

Example 24

2,5-Dimethyl-TRANS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid

TPL 142-144°C.

Elemental analysis for C21H27NO5:

calculated (%): C, 67,54; N, 7,29; N, 3,75

found (percent): C, 67,35; N, 7,37; N, 3,44.

Example 25

5-Ethyl-2-methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid

TPL 155-158°C.

Elemental analysis for C22H29NO5:

calculated (%): C, 68,20; N, rate of 7.54; N, 3,61

found (percent): C, 68,18; N, To 7.59; N, 3,49.

Example 26

5-Ethyl-2-methyl-TRANS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid

TPL 126-130°C.

Elemental analysis for C22H29NO5:

calculated (%): C, 68,20; N, rate of 7.54; N, 3,61

found (percent): C, 67,77; N, EUR 7.57; N, 3,47.

Example 27

2-Methyl-CIS-5-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1,3-dioxane-r-2-carboxylic acid

TPL 131-134°C.

Elemental analysis for C19H23NO5:

calculated (%): C, 66,07; N, Of 6.71; N, 4,06

found (percent): C, 65,59; N, 6,69; N, 3,92.

Example 28

2-Methyl-what Rance-5-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1,3-dioxane-r-2-carboxylic acid

TPL 164-166°C.

Elemental analysis for C19H23NO5:

calculated (%): C, 66,07; N, Of 6.71; N, 4,06

found (percent): C, 65,64; N, 6,70; N, 3,91.

Example 29

2-Methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)-(E)-2-butenyl]-1,3-dioxane-r-2-carboxylic acid

TPL 148-150°C.

Elemental analysis for C20H23NO5:

calculated (%): C, 67,21; N, Of 6.49; N, 3,92

found (percent): C, 67,26; N, 6,36; N, 3,82.

Example 30

2-Methyl-5-{4-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane-2-carboxylic acid

There was obtained a mixture of (CIS:TRANS=4:1, based on the integral values NMR)

Elemental analysis for C24H25NO5:

calculated (%): C, 70,75; N, 6,18; N, 3,44

found (percent): C, 70,69; N, 6,23; N, 3.45 points.

Example 31

2-Methyl-CIS-5-{4-[(5-methyl-2-phenyloxazol-4-yl)methyl]phenyl}-1,3-dioxane-r-2-carboxylic acid

TPL 215-216°C.

Elemental analysis for C23H23NO5:

calculated (%): C, 70,21; N, Of 5.89; N, 3,56

found (percent): C, 70,02; N, 5,88; N, 3,35.

Example 32

2-Methyl-CIS-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]phenyl}-1,3-dioxane-r-2-carboxylic acid

TPL 122-124°C.

Elemental analysis for C23H23NO5:

calculated (%): C, 70,21; N, Of 5.89; N, 3,56

found (percent): C, 70,05; N, Between 6.08; N, 3,51.

Example 33

2-Methyl-CIS-5-{4-[5-methyl-2-(3-pyridyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

TPL 126-129°C.

Elemental analysis on the I 19H24N2O5:

calculated (%): C, 63,32; N, Of 6.71; N, to 7.77

found (percent): C, 63,16; N, 6.73 X; N, EUR 7.57.

Example 34

2-Methyl-2-[5-(5-methyl-2-phenyloxazol-4-yl)pentyloxy]propionic acid

TPL 66-68°C.

Elemental analysis for C19H25NO4·H2O

calculated (%): C, 65,31; N, 7,79; N, 4,01

found (percent): C, 65,20; N, To 7.84; N, is 4.03.

Example 35

2-Methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propionic acid

Elemental analysis for C20H27NO4

calculated (%): C, 69,54; N, 7,88; N, 4,05

found (percent): C, 69,12; N, 7,86; N, 4,11.

Example 36

2-Methyl-2-[7-(5-methyl-2-phenyloxazol-4-yl)heptyloxy]propionic acid

TPL 70-71°C.

Elemental analysis for C21H29NO4

calculated (%): C, 70,17; N, 8,13; N, 3,90

found (percent): C, 70,03; N, 8,15; N, 3,90.

Example 37

2-Methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl)hexyloxy]propionic acid

Elemental analysis for C21H29NO4

calculated (%): C, 70,17; N, 8,13; N, 3,90

found (percent): C, 70,07; N, 8,07; N, 3,92.

Example 38

2-Methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-4-hexyloxy]propionic acid

Elemental analysis for C20H23NO4

calculated (%): C, 70,36; N, 6,79; N, 4,10

found (percent): C, 70,24; N, 6,51; N, 3,90.

Example 39

2-{6-[2-(4-Chlorophenyl)-5-methoxazole-4-yl]hexyloxy}-2-methylpropionate acid

Elemental analysis for C20the 26ClNO4

calculated (%): C, 63,24; N, Of 6.90; N, 3,69

found (percent): C, 63,17; N, PC 6.82; N, 3,82.

Example 40

2-{6-[2-(4-Forfinal)-5-methoxazole-4-yl]hexyloxy}-2-methylpropionate acid

TPL 64-67°C.

Elemental analysis for C20H26FNO4

calculated (%): C, 66,10; N, 7,21; N, 3,85

found (percent): C, 66,18; N, 7,30; N, 4,06.

Example 41

2-{6-[2-(4-tert-Butylphenyl)-5-methoxazole-4-yl]hexyloxy}-2-methylpropionate acid

TPL 89-91°C.

Elemental analysis for C24H35NO4

calculated (%): C, 71,79; N, 8,79; N, 3,49

found (percent): C, 71,79; N, 8,81; N, 3,52.

Example 42

2-[6-(5-Ethyl-2-phenyloxazol-4-yl)hexyloxy]-2-methylpropionate acid

TPL at 88.5-89°C.

Elemental analysis for C21H29NO4

calculated (%): C, 70,17; N, 8,13; N, 3,90

found (percent): C, 70,36; N, 8,07; N, 3,90.

Example 43

2-Methyl-2-[6-(2-phenyloxazol-4-yl)hexyloxy]propionic acid

TPL 75-77°C.

Elemental analysis for C19H25NO4

calculated (%): C, 68,86; N, 7,60; N, 4,23

found (percent): C, 68,89; N, A 7.62; N, 4,27.

Example 44

2-Methyl-2-[7-(2-phenyloxazol-4-yl)heptyloxy]propionic acid

TPL 72-75°C.

Elemental analysis for C20H27NO4

calculated (%): C, 69,54; N, 7,88; N, 4,05

found (percent): C, 69,67; N, 7,89; N, 4,06.

Example 45

2-Methyl-2-[8-(2-phenyloxazol-4-yl)octyloxy]propionic acid

TPL 59-61°C.

E. emanny analysis for C 21H29NO4

calculated (%): C, 70,17; N, 8,13; N, 3,90

found (percent): C, 70,02; N, 8,30; N, 3,91.

Example 46

2-{7-[2-(4-Chlorophenyl)oxazol-4-yl]heptyloxy}-2-methylpropionate acid

TPL 91-93°C.

Elemental analysis for C20H26ClNO4

calculated (%): C, 63,24; N, Of 6.90; N, 3,69

found (percent): C, 63,39; N, 6,98; N, 3.72 points.

Example 47

2-{7-[2-(4-Forfinal)oxazol-4-yl]heptyloxy}-2-methylpropionate acid

TPL 67-74°C.

Elemental analysis for C20H26FNO4

calculated (%): C, 66,10; N, 7,21; N, 3,85

found (percent): C, 65,90; N, 7,06; N, 3,84.

Example 48

2-{6-[2-(4-Forfinal)oxazol-4-yl]hexyloxy}-2-methylpropionate acid

TPL 80-83°C.

Elemental analysis for C19H24FNO4

calculated (%): C, 65,31; N, 6,92; N, 4,01

found (percent): C, 65,15; N, 6,77; N, 3,91.

Example 49

2-Methyl-2-[7-(2-phenylthiazol-4-yl)heptyloxy]propionic acid

TPL 71-72°C.

Elemental analysis for C20H27NO3S

calculated (%): C, 66,45; N, 7,53; N, a 3.87

found (percent): C, 66,46; N, EUR 7.57; N, 3,98.

Example 50

2-Methyl-2-[8-(2-phenylthiazol-4-yl)octyloxy]propionic acid

TPL 64-70°C.

Elemental analysis for C21H29NO3S·H2O

calculated (%): C, 64,09; N, 7,94; N, 3,56

found (percent): C, 64,67; N, 7,89; N, 3,83.

Example 51

2-Methyl-2-{6-[5-methyl-2-(4-pyridyl)oxazol-4-yl]hexyloxy}propionic acid

TPL 91-93#x000B0; C.

Elemental analysis for C19H26N2O4

calculated (%): C, 65,88; N, 7,56; N, 8,09

found (percent): C, 65,79; N, 7,52; N, 8,03.

Example 52

2-Methyl-2-{6-[5-methyl-2-(3-pyridyl)oxazol-4-yl]hexyloxy}propionic acid

1H-NMR (CDCl3)δ: 1,25-1,50 (10H, m), 1,55-1,75 (4H, m), of 2.34 (3H, s)of 2.50 (2H, t), of 3.45 (2H, t), 7,35-7,42 (1H, m), compared to 8.26-8.30 to (1H, m), 8,62-8,66 (1H, m), of 9.21-which 9.22 (1H, m).

Example 53

2-Methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)-(E)-3-butenyl]-1,3-dioxane-r-2-carboxylic acid

Methyl 2-methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)-3-butenyl]-1,3-dioxane-r-2-carboxylate (7.5 g) was dissolved in 30 ml of N,N-dimethylformamide and, under stirring and ice cooling, is added dropwise slowly add a solution of 3.57 g of N-bromosuccinimide (NBS)/20 ml of N,N-dimethylformamide. After stirring for 30 minutes the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=7:1)) to give 215 mg of oil. The oil obtained is dissolved in 3 ml of methanol. To the solution was added 70 mg of sodium hydroxide and 0.8 ml of water and the mixture is refluxed for 2.5 hours and concentrated. After adding ice, the residue acidified with 1N hydrochloric acid, extra is irout with ethyl acetate, washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, ethyl acetate)to obtain 30 mg of the target compound.

1H-NMR (CDCl3)δ: 1,22 (2H, DDD), of 1.65 (3H, s), 2,00-2,30 (3H, m), of 2.38 (3H, s), 3,51 (2H, DD), was 4.02 (2H, DD), 4,20 (1H, W), x 6.15-6.40 (2H, m), 7,40-of 7.60 (3H, m), of 7.90-8.20 (2H, m).

Example 54

2-Methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenoate]propionate potassium

To 20 ml of a solution of 920 mg of methyl 2-[6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenoate]-2-methylpropionate in methanol are added 20 ml of an aqueous solution of 206 mg of sodium hydroxide and the mixture refluxed for 20 hours. The reaction solution concentrate. After adding ice water, the residue acidified with 10% hydrochloric acid. The mixture is extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is purified column chromatography on silica gel (Wakogel C-200, chloroform)to obtain 670 mg of 2-[6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenoate]-2-methylpropionic acid in the form of a colorless oil. A portion (100 mg) obtained oil is transformed into potassium salt using potassium hydroxide. After addition of isopropyl ether, the precipitate is filtered off and obtain 88 mg of the target compound.

20H24NO4It·1/2 H2O:

calculated (%): C, 61,51; N, Of 6.45; N, 3,59

found (percent): C, 61,56; N, 6,24; N, 3,53.

Example 55

2-Methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propanol

To 214 ml of anhydrous ether is added 1.35 g of lithium aluminum hydride and, under stirring and ice cooling, is added dropwise slowly add a solution of 10.7 g of methyl 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propionate/40 ml of anhydrous ether and the mixture is stirred for 1 hour. To this mixture dropwise slowly add 43 ml of tetrahydrofuran/1.7 ml of water, and then 6.3 ml of water and 1.7 ml of 1N sodium hydroxide, after which the mixture is stirred for 15 minutes and filtered to remove insoluble substances. The filtrate is concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=3:1)) to obtain 8.44 grams of target compound.

Elemental analysis for C20H29NO3·1/2 H2O:

calculated (%): C, 70,55; N, 8,88; N, 4,11

found (percent): C, 70,95; N, 8,67; N, 4,21.

Connection examples 56-58 receive in accordance with the procedure described in example 55.

Example 56

2-{6-[2-(4-tert-Butylphenyl)-5-methoxazole-4-yl]hexyloxy}-2-methylpropanol

1H-NMR (CDCl3)δ: 1,14 (6N, (C), 1,34 was 1.43 (11N, m), 1,45-1,75 (6N, m), 1,95-2,10 (1H, m), 2,31 (3H, s), 2,47 (2H, t), 3,30-to 3.41 (4H, m), 7,41 was 7.45 (2H, m), 7,88-a 7.92 (2H, m).

Elemental analysis for C24H37 NO3·H2O:

calculated (%): C, 71,07; N, RS 9.69; N, 3,45

found (percent): C, 70,89; N, To 9.32; N, 2,20.

Example 57

2-Methyl-2-{6-[5-methyl-2-(3-pyridyl)oxazol-4-yl]hexyloxy}propanol

1H-NMR (CDCl3)δ: 1,15 (6N, (C), 1,34-of 1.40 (4H, m), 1,45-of 1.85 (4H, m), 1,95-2,10 (1H, m), of 2.34 (3H, s), a 2.45 (2H, t), 3,31 is 3.40 (4H, m), 7,27 and 7.36 (1H, m), by 8.22-of 8.28 (1H, m), 8,61-8,64 (1H, m), 9,20-of 9.21 (1H, m).

Elemental analysis for C19H28N2O3·H2O:

calculated (%): C, 65,12; N, 8,63; N, 7,99

found (percent): C, 65,24; N, Of 8.40; N, 7,73.

Example 58

r-2-Hydroxymethyl-2-methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane

TPL 58-59°C.

Elemental analysis for C21H29NO4:

calculated (%): C, 70,17; N, 8,13; N, 3,90

found (percent): C, 69,97; N, With 8.05; N, 3,88.

Example 59

2-Methyl-2-{6-[5-methyl-2-(4-pyridyl)oxazol-4-yl]hexyloxy}propenolatomethyl salt

Methyl 2-methyl-2-{6-[5-methyl-2-(4-pyridyl)oxazol-4-yl]hexyloxy}propionate (210 mg) was dissolved in 20 ml of anhydrous ether, is added 44 mg of lithium aluminum hydride and the mixture is stirred for 30 minutes under ice cooling. Then added dropwise 5 ml of tetrahydrofuran/0.33 ml of water, stirred for 15 minutes, filtered to remove insoluble substances and the filtrate concentrated. The residue is dissolved in ether. To the solution was added 59 mg methanesulfonic acid/1 ml of ether and filtered off the precipitated crystals, which are about the see ether and dried to obtain 195 mg of the target compound as pale yellow crystals. TPL 128-130°C.

Elemental analysis for C19H28N2O3·CH4O3S·H2O:

calculated (%): C, 53,79; N, To 7.67; N, 6,27

found (percent): C, 53,87; N, 7,28; N, 6,17.

Example 60

2-Methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carbohidrazona acid

2-Methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid (350 mg) was dissolved in 7.5 ml of tetrahydrofuran and added 174 mg of 1,1'-carbonyldiimidazole and the mixture is stirred for 24 hours at room temperature. The reaction solution concentrate and add 3 ml of methanol to dissolve the residue, and then added dropwise a solution of 190 mg of chloride of hydroxylamine/6 ml methanol and 336 mg of triethylamine, after which the mixture is stirred for 4 hours at room temperature. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of chloroform:methanol=100:1)) to obtain a 53.8 mg of target compound as white crystals. TPL 115-116°C.

Elemental analysis for C20H26N2O5·1/4 H2O:

calculated (%): C, 63,39; N, 7,05; N, 7,39

found (percent): C, 63,35; N, 6,85; N, 7,37.

Connection examples 61-77 receive in accordance with the procedure described in example 11.

Example 61

2-Methyl-CIS-5-{4-[5-methyl-2-(4-chlorophenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

TPL 145-146°

Elemental analysis for C20H24ClNO5:

calculated (%): C, 60,99; N, 6,14; N, 3,56

found (percent): C, 60,75; N, Of 6.25; N, 3,36.

Example 62

2-Methyl-CIS-5-{5-[5-methyl-2-(p-tolyl)oxazol-4-yl]pentyl}-1,3-dioxane-r-2-carboxylic acid

TPL 118-119°

Elemental analysis for C22H29NO5:

calculated (%): C, 68,20; N, rate of 7.54; N, 3,61

found (percent): C, 68,20; N, 7,53; N, 3,60.

Example 63

2-Ethyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

TPL 123-126°

Elemental analysis for C22H29NO5:

calculated (%): C, 68,20; N, rate of 7.54; N, 3,61

found (percent): C, 69,22; N, 7,53; N, 3,21.

Example 64

2-Methyl-CIS-5-{4-[5-methyl-2-(3-fluoro-4-were)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

Elemental analysis for C21H26FNO5:

calculated (%): C, 64,44; N, 6,69; N, to 3.58

found (percent): C, 64,49; N, Of 6.68; N, 3,90.

Example 65

2-Methyl-CIS-5-{4-[5-methyl-2-(4-ethylphenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

TPL 147°

Elemental analysis for C22H29NO5:

calculated (%): C, 68,20; N, rate of 7.54; N, 3,61

found (percent): C, 67,99; N, 7,50; N, 3,76.

Example 66

2-Methyl-CIS-5-{4-[2-(the-tolyl)-5-cryptomaterial-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

TPL 130-131°

Elemental analysis for C21H24F3NO5:

calculated (%): C, 59,01; N, To 5.66; N, 3,28

found (percent): C, 59,11; N, 5,67; N, 3,16.

Example 67

2-Methyl-CIS-5-{4-[5-methyl-2-(2,4-dimetilfenil)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

TPL 130-131°

Elemental analysis for C22H29NO5:

calculated (%): C, 68,20; N, rate of 7.54; N, 3,61

found (percent): C, 68,25; N, 7,53; N, 3,65.

Example 68

2-Methyl-CIS-5-{4-[2-(4-formationl)-5-methoxazole-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

TPL 144-145°

Elemental analysis for C21H26FNO5:

calculated (%): C, 64,44; N, 6,69; N, to 3.58

found (percent): C, 64,35; N, 6,69; N, 3,52.

Example 69

2-Methyl-CIS-5-{4-[5-ethyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

TPL 160-161°

Elemental analysis for C22H29NO5:

calculated (%): C, 68,20; N, rate of 7.54; N, 3,61

found (percent): C, 68,15; N, 7,52; N, 3,56.

Example 70

2-Methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)thiazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

Elemental analysis for C21H27NO4S:

calculated (%): C, 64,76; N, Of 6.99; N, 3,60

found (percent): C, 64,68; N, 6,97; N, 3,64.

Example 71

2-Methyl-CIS-5-{4-[5-methyl-2-(m-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

Elemental analysis for C21H27NO5:

calculated (%): C, 67,54; N, 7,29; N, 3,75

found (percent): C, 67,57; N, 7,22 N, 3,80.

Example 72

2-Methyl-CIS-5-{4-[5-methyl-2-(o-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

TPL 121-122°

Elemental analysis for C21H27NO5:

calculated (%): C, 67,54; N, 7,29; N, 3,75

found (percent): C, 67,47; N, 7,29; N, 3,71.

Example 73

2-Methyl-CIS-5-{4-[5-methyl-2-(3,4-dimetilfenil)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

Elemental analysis for C22H29NO5:

calculated (%): C, 68,20; N, rate of 7.54; N, 3,61

found (percent): C, 68,31; N, 7,53; N, 3,65.

Example 74

2-Methyl-CIS-5-{4-[5-methyl-2-(4-methoxyphenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

Elemental analysis for C21H27NO6:

calculated (%): C, 64,77; N, Of 6.99; N, 3,60

found (percent): C, 64,80; N, 7,13; N, 3,57.

Example 75

2-Methyl-CIS-5-{4-[5-methyl-2-(2-thienyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

Elemental analysis for C18H23NO5S:

calculated (%): C, 59,16; N, 6,34; N, 3,83

found (percent): C, 59,45; N, 6,32; N, 3,76.

Example 76

2-Methyl-CIS-5-{4-[2-cyclohexyl-5-methoxazole-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

TPL 118-121°

Elemental analysis for C20H31NO5:

calculated (%): C, 65,73; N, 8,55; N, 3,83

found (percent): C, 65,75; N, To 8.57; N, 3,80.

Example 77

2-Methyl-CIS-5-{4-[1,5-dimethyl-2-(p-tolyl)imidazole-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid

TPL 192-194°C (decomposition).

Elementy the analysis for C 22H30N2O4·1H2O

calculated (%): C, 65,32; N, Of 7.97; N, 6,93

found (percent): C, 65,36; N, 7,58; N, 6.75 in.

Example 78

Methyl 2-methyl-CIS-5-[3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-dioxane-r-2-carboxylate

2-[3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-propandiol (to 2.29 g) was dissolved in 38 ml of acetonitrile and added 2.65 g of methylpiruvate. To this mixture, stirring at room temperature, type of 3.69 g epirate of boron TRIFLUORIDE (about 47%) and stirred for 18 hours at room temperature. The reaction solution was poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=4:1)) and previously erwerbende fraction concentrate with getting 752 mg of target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,49 (3H, s), of 2.20 to 2.35 (3H, m), of 2.25 (3H, s), of 2.38 (3H, s), of 3.48 (2H, t), 3,80-of 3.95 (4H, m), 3,83 (3H, s), 6,92-7,24 (6N, m), 7,80-of 7.90 (2H, m).

Example 79

Methyl 2-methyl-TRANS-5-[3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-dioxane-r-2-carboxylate

The last fractions of the compounds of example 78 collect and concentrate to obtain 294 mg of the target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,57 3H, C)of 2.20 to 2.35 (1H, m), of 2.25 (3H, s), of 2.38 (3H, s), 2,98 (2H, d), 3,70-3,88 (4H, m), 3,82 (3H, s), 3,93 (2H, DD), 7,00-7,30 (6N, m), 7,87 (2H, d).

Example 80

2-Methyl-CIS-5-[3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-dioxane-r-2-carboxylic acid

In 20 ml of methanol is dissolved 968 mg of methyl 2-methyl-CIS-5-[3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-dioxane-r-2-carboxylate. After the addition of 3.3 ml of a 1N aqueous solution of sodium hydroxide, the mixture is refluxed for 1.5 hours. The reaction solution concentrate. After adding water, the residue was washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid, extracted with diethyl ether, dried over anhydrous magnesium sulfate and concentrated. The residue is crystallized by adding diethyl ether and washed with isopropyl ether to obtain 733 mg of the target compound as colorless crystals.

TPL 151-152°C.

Elemental analysis for C25H27NO5:

calculated (%): C, 71,24; N, 6,46; N, 3,32

found (percent): C, 71,50; H, 6.42 Per; N, 3,48.

Example 81

2-Methyl-TRANS-5-[3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-dioxane-r-2-carboxylic acid

The target connection receive in accordance with the procedure described in example 80.

Elemental analysis for C25H27NO5:

calculated (%): C, 71,24; N, 6,46; N, 3,32

found (percent): C, 70,18; N, 6,34; N, 3,31.

Example 82

2-IU the Il-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dition-r-2-carboxylic acid

To 2 ml of a solution of 124 mg of methyl 2-methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dition-r-2-carboxylate in methanol was added 1 ml of aqueous 1N sodium hydroxide and the mixture refluxed for 1.5 hours. The reaction solution concentrate. After adding water, the residue was washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue is crystallized by addition of isopropyl ether and washed with n-hexane to obtain 88 mg of the target compound as colorless crystals. TPL 157-159°C.

Elemental analysis for C21H27NO3S2:

calculated (%): C, 62,19; N, Of 6.71; N, 3,45

found (percent): C, 61,93; N, 6,70; N, 3.40 in.

Example 83

2-Methyl-TRANS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dition-r-2-carboxylic acid

The target connection receive in accordance with the procedure described in example 82.

TPL 162-164°C.

Elemental analysis for C21H27NO3S2:

calculated (%): C, 62,19; N, Of 6.71; N, 3,45

found (percent): C, 61,75; N, Of 6.66; N, 3,42.

Example 84

2-Methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexylthio}propionic acid

In an argon atmosphere for 24 mg of pulverized sodium hydroxide is added to 2 ml of a solution of 100 mg 4-(6-acetyldigoxin)-5-methyl-2-(p-tolyl)oxazole in ACE the Ohe and stirred for 2 hours at room temperature. To the resulting solution was added 20 μl of water followed by the addition of 113 mg of 1,1,1-trichloro-2-methyl-2-propanol·0.5 hydride (chloretone), and then three portions at intervals of 30 minutes type of 96.5 mg of pulverized sodium hydroxide. The mixture is stirred for a further 18 hours at room temperature. The reaction solution concentrate. After adding water, the residue is extracted with diethyl ether. The organic layers are combined, washed with water and washing with acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layers are combined sequentially washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of chloroform:methanol=100:1)) and the resulting crystals are washed with n-hexane to obtain 28,0 mg of target compound in the form of light yellow crystals.

TPL 111°C.

Elemental analysis for C21H29NO3S2:

calculated (%): C, 67,17; N, 7,78; N, of 3.73

found (percent): C, 67,33; N, A 7.85; N, 3,67.

Example 85

2-Methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionitrile

Tribromide phosphorus (6,77 g) are added to 94 ml of a solution of 4.90 g of 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionohydroxamic acid in benzene and boiled with reverse holo is rinicom for 4 hours. The reaction solution is cooled and poured into ice water. After adding an aqueous solution of saturated sodium bicarbonate, the mixture is extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=9:1)) with the receipt of 3.32 g of the target compound as colorless crystals. TPL 36°C.

Elemental analysis for C21H28N2O2·1/5 H2O:

calculated (%): C, 73,31; N, 8,32; N, 8,14

found (percent): C, 73,21; N, Of 8.27; N, 7,88.

Example 86

5-[1-Methyl-1-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}ethyl]tetrazol

Sodium azide (4.12 g) and of 2.97 g of ammonium chloride is added to 27 ml of a solution of 2.70 g of 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionitrile in N,N-dimethylformamide and the mixture is stirred for 1.5 hours at 120°C. To the reaction solution was added ice water, extracted with ethyl acetate, sequentially washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of chloroform:methanol=100:1-50:1)and recrystallized from isopropyl ether to obtain 1,69 g of target compound in the form of bescot what's crystals. TPL 87°C.

Elemental analysis for C21H29N5O2:

calculated (%): C, 65,77; N, A 7.62; N, 18,26

found (percent): C, 65,67; N, The 7.65; N, 17,97.

Example 87

2-Methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxamide

In an argon atmosphere 45 ml of a solution of 3.00 g of 2-methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid in tetrahydrofuran is cooled with ice and add to 1.12 ml of triethylamine, and then added dropwise 5 ml of a solution 959 mg ethylchloride in tetrahydrofuran. After stirring for 45 minutes, added dropwise 45 ml of a mixture of ammonia and saturated tetrahydrofuran and then stirred for further 1 hour. To the reaction solution was added water, extracted with ethyl acetate, sequentially washed with saturated sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the obtained crystals are washed with diethyl ether obtaining of 2.81 g of the target compound as colorless crystals. TPL 146-147°C.

Elemental analysis for C21H28N2O4:

calculated (%): C, 67,72; N, 7,58; N, 7,52

found (percent): C, 67,26; N, rate of 7.54; N, 7,39.

Example 88

2-Methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carbonitril

In an argon atmosphere 2,04 ml of triethylamine are added dropwise to 34 ml of a solution of 2.2 g of 2-methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxamide in tetrahydrofuran. After stirring for 10 minutes under ice cooling, is added dropwise slowly add 5 ml of a solution of 1.53 g triperoxonane anhydride in tetrahydrofuran and stirred for further 1 hour. To the reaction solution was added water, extracted with diethyl ether, washed sequentially with saturated sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=4:1)) to obtain the 2,07 g of the target compound as colorless crystals. TPL 79-80°C.

Elemental analysis for C21H26N2O3:

calculated (%): C, 71,16; N, 7,39; N, of 7.90

found (percent): C, 71,01; N, 7,42; N, of 7.90.

Example 89

Methyl 2-methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dition-r-2-carboxylate

To 20 ml of a solution of 635 mg of 4-[5,5-bis(mercaptomethyl)pentyl]-5-methyl-2-(p-tolyl)oxazole in acetonitrile add 0,344 ml methylpiruvate and of 0.48 ml epirate of boron TRIFLUORIDE (about 47%) and refluxed for 2 hours. The reaction solution is cooled, poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-exan:ethyl acetate=9:1)) and erwerbende earlier fractions concentrated to obtain 124 mg of the target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,25-of 1.55 (4H, m), 1.69 in (3H, s), 1,70-1,90 (3H, m), 2,31 (3H, s), of 2.38 (3H, s), 2,40-2,60 (4H, m), of 3.54 (2H, m), of 3.77 (3H, s), 7,22 (2H, s), 7,86 (2H, s).

Example 90

Methyl 2-methyl-TRANS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dition-r-2-carboxylate

The last fractions of the compounds of example 89 collect and concentrate to obtain 124 mg of the target compound as a colourless oil.

1H-NMR (CDCl3)δ: 1,30-1,50 (4H, m), 1,55-1,90 (7H, m), 2,31 (3H, s), of 2.38 (3H, s), 2,47 (2H, t), 2,58 (2H, DD), of 3.07 (2H, DD), 3,11 (2H, s), 7.23 percent (2H, d), 7,87 (2H, d).

Example 91

2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionohydroxamic acid

To 20 ml 4,84 g of ethyl 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionate in methanol add 3,47 g hydroxylaminopurine, and then, under stirring and ice cooling, slowly added dropwise 12.5 ml of a 5M solution of potassium hydroxide in methanol. The ice bath removed and the mixture is stirred for 36 hours at room temperature. The reaction solution concentrate. The residue is acidified with 50% aqueous solution of acetic acid, add water and extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. After addition of toluene, the residue is concentrated and again concentrated after addition of ethanol resulting in a gain of 4.90 g of the target compound as a pale yellow oil.

1H-NMR (CDCl3)δ: 1,36-of 1.41 (4H, m), 1,38 (6N, (C), 1,53 is 1.70 (4H, m), 2,31 (3H, s), of 2.38 (3H, s), 2,48 (2H, t), 3,37 (2H, t), of 7.23 (2H, d), 7,87 (2H, d).

Example 92

Methyl 2-methyl-CIS-5-{4-[1,5-dimethyl-2-(p-tolyl)imidazole-4-yl]butyl}-1,3-dioxane-r-2-carboxylate

To 20 ml of a solution of 0.80 g of methyl CIS-5-[5-acetyl-5-(p-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate in xylene add 1.5 ml of a 2M solution of methylamine in tetrahydrofuran and 0.84 ml of acetic acid. The mixture is subjected to azeotropic dehydration for 2 hours using a nozzle Dean-stark. The reaction solution is cooled, poured into aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of chloroform:methanol=100:1)) to give 634 mg of the target compound as a pale yellow oil.

1H-NMR (CDCl3)δ: 0,97-1,10 (2H, m), 1,20-1,40 (2H, m), 1,50 (3H, s), 1,54 is 1.70 (2H, m), 1,90-to 2.15 (1H, m)to 2.18 (3H, s), of 2.38 (3H, s), of 2.51 (2H, t), to 3.38 (2H, t), 3,53 (3H, s), 3,83 (3H, s), of 3.95 (2H, DD), 7.23 percent (2H, DD), was 7.45 (2H, DD).

Example 93

Methyl 2-methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)thiazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate

In 10 ml of tetrahydrofuran is dissolved 1.01 g of methyl CIS-5-[5-acetyl-5-(p-toluylene)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate. After you have added 1.42 g of 2,4-bis(methylthio)-1,3-dithia-2,4-diphosphate-2,4-disulfide (methyl of real the NT Devi) the mixture is stirred for 3 hours at 50-55° With, and then another 3 hours at 70-75°C. To the reaction solution was added ethyl acetate, sequentially washed with 10% hydrochloric acid, water and 10% sodium hydroxide, dried over magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (Wakogel C-200, a mixture of n-hexane:ethyl acetate=5:1)) to give 384 mg of the target compound as a pale yellow oil.

1H-NMR (CDCl3)δ: 1,00-of 1.15 (2H, m), 1,23-of 1.40 (2H, m)and 1.51 (3H, s), 1.60-to or 1.77 (2H, m), 1,92 with 2.14 (1H, m), 2,37 (6N, C)to 2.66 (2H, t), 3,39 (2H, t), 3,83 (3H, s), of 3.95 (2H, DD), 7,20 (2H, d), of 7.75 (2H, d).

Experimental example 1

Effect on carbohydrate and lipid metabolism in KK-Ay-mouse

The experiment was performed using compounds described in the Examples as the test compounds, and troglitazone (5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylethoxy)benzyl]-2,4-thiazolidinedione) as the control connection.

Each test compound at a certain dose within 4 days of oral introduced QC-ythe mice (10-week-old males), used as a model of NIDDM. The next day after the last injection in mice not subjected to starvation, from the blood vessels of the tail took blood to get heparinised plasma. Then, when anesthesia pentobarbital took blood from the large abdominal veins to get sivaram is I. The level of glucose (UG), triglycerides (UT) and insulin levels (IM) in plasma was determined using test glucose CII-test Wako (Wako Pure Chemical Industries, Ltd.), CLINTECH TG-S (IATORON LABORATORIES, INC.) or test triglyceride E-test WAKO (Wako Pure Chemical Industries, Ltd.), and set to measure the level of insulin in rats (Morinaga Biochemistry Research Institute) or T-test to determine the level of mouse insulin REBIS (Mouse Insulin ELISA (TMB) KIT, Shibayagi Co., Ltd), respectively. In addition, the amount of levels RNP-X and levels of LDL-X serum (hereinafter referred to "(O)LDL-X"), total cholesterol (TC) and HDL-X was measured using high performance liquid chromatography to measure cholesterol lipoprotein (TOSON CORPORATION). Since the levels of ANP'S and LDL's can't be measured separately, then measure the level Of LDL-H. Atherogenic index (AI) was calculated according to the following formula:

AI=[(level B)-(HDL-X)]/(HDL-X)

The results are presented in table 1.

td align="center"> -29
Table 1

Effect on carbohydrate and lipid metabolism in KK-Ay-mouse
The percentage change of each parameter compared to control group (%)
Test connectionDose (mg/kg)OH UGIM(A)LDL-XHDL-XAI
Example 391-56-14-20-5336-73
Example 141-29-22-67-3819-45
Example 91-46-12-36-2936-49
Example 541-72-24-14-7724-83
Example 381-50-21-39-3838-65
Example 213-52-18-26-265-38
Example 201-31-15-44-3330-44
Example 533-51-46-37-493-62
Example 183-43-12-1-2076-5
Example 5510-45-222-4462-72
Example 373-51-5-27-5433-70
Example 113-83-36-16-8911-91
Example 811-62-8-21-7632-83
Example 641-53-12-20-6321-72
Example 703-37-155-3341-53
Example 713-89-51-61-901-90
Example 733-92-53-68-90-8-85
Example 743-46-18-33-5855-72
Example 753-47-23-5037-61
Troglitazone300-11-9-22-26-8-7

Compounds of the present invention have an excellent effect of reducing the level of triglycerides in the blood, and the effect of reducing the level Of LDL-X. in Addition, the compounds of the present invention have the effect of reducing the level of glucose in the blood, the action of reducing the level of insulin in the blood, or action that increases the level of HDL-X, or action that reduces atherogenic indexofmin that the compounds of the present invention can be used as a preventive or therapeutic agent for the treatment of arteriosclerosis, etc.

An example of a pharmaceutical composition 1

The pill (oral administration)

Composition one tablet (200 mg)

The compound of example 7120 mg
Corn starch88 mg
Crystalline cellulose80 mg
Calcium salt of carboxymethylcellulose10 mg
Light silicic acid anhydride1 mg
Magnesium stearate1 the g

The mixture containing the ingredients in the above ratio, pressed and get a tablet for oral administration.

An example of a pharmaceutical composition 2

The pill (oral administration)

Composition one tablet (120 mg)

The compound of example 111 mg
Lactose60 mg
Corn starch30 mg
Crystalline cellulose20 mg
Hydroxypropylcellulose7 mg
Magnesium stearate2 mg

The mixture containing the ingredients in the above ratio, pressed and get a tablet for oral administration.

Example pharmaceutical compositions 3

The pill (oral administration)

Composition one tablet (180 mg)

1 mg
The compound of example 73100 mg
Lactose45 mg
Corn starch20 mg
Nizkozameshhennoj hydroxypropylcellulose9 mg
Polyvinyl alcohol (partially saponified)5 mg
Magnesium stearate

The mixture containing the ingredients in the above ratio, pressed and get a tablet for oral administration.

Industrial applicability

Compounds of the present invention have an excellent effect of reducing the level of triglycerides in the blood; the effect of reducing the level Of LDL's in the blood, as well as the effect of reducing the level of glucose in the blood, the action of reducing the level of insulin in the blood, any action that increases the level of HDL's in the blood, or action that reduces atherogenic index, and therefore they can be used for the prevention or treatment of coronary heart disease, cerebral infarction, hyperlipidemia, arteriosclerosis, diabetes, hypertension, obesity, etc.

1. Prophylactic or therapeutic agent against hyperlipidemia, containing as active ingredient a heterocyclic compound of the formula [1]

where R1represents aryl, optionally substituted by the same or different one to three groups selected from alkyl, halogenoalkane, trihalomethyl, alkoxy, halogen;

Het represents a divalent aromatic heterocyclic group of the formula [5]

where X represents oxygen, sulfur and is and NR 6;

R6represents hydrogen or alkyl;

R2represents hydrogen, alkyl, trihalomethyl;

D represents alkylene, albaniles;

E represents a group of the formula [3] or [4]

where Y represents oxygen or sulfur;

R3and R4are the same or different and each represents hydrogen or alkyl;

p is 1;

Z represents carboxy, alkoxycarbonyl, cyano, 1H-5-tetrazolyl;

or its pharmaceutically acceptable salt.

2. Prophylactic or therapeutic agent against hyperlipidemia according to claim 1, where D is alkylene, albaniles.

3. Prophylactic or therapeutic agent against hyperlipidemia according to claim 1 where Het represents a divalent aromatic heterocyclic group of the formula [5]

where X is oxygen, sulfur or NR6, R6represents hydrogen or alkyl, and R2represents hydrogen, alkyl or trihalomethyl.

4. Prophylactic or therapeutic agent against hyperlipidemia according to claim 1 where Het represents a divalent aromatic heterocyclic group of the formula [5]

where X is oxygen, sulfur or NR 6, R6represents hydrogen or alkyl, R2represents hydrogen, alkyl or trihalomethyl, and D represents alkylene, albaniles.

5. Prophylactic or therapeutic agent against hyperlipidemia according to claim 4, where R1represents phenyl, optionally substituted by one or two groups selected from alkyl, halogen, trihalomethyl and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A]

where X is oxygen, sulfur or NR6, R6represents hydrogen or alkyl, R15represents alkyl or trihalomethyl, and D represents alkylene or albaniles having 3-7 carbon atoms.

6. Prophylactic or therapeutic agent against hyperlipidemia according to claim 5, where R1represents phenyl, optionally substituted by one or two groups selected from alkyl, halogen, trihalomethyl and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A], where X is oxygen, sulfur or NR6, R6represents hydrogen or alkyl, R15represents alkyl or trihalomethyl; D represents alkylene or albaniles having 3-5 carbon atoms; E represents a group of the formula [3], where p is 1, Y is oxygen, R3is in Gorod or alkyl, a Z is carboxy or alkoxycarbonyl.

7. Prophylactic or therapeutic agent against hyperlipidemia according to claim 5, where R1represents phenyl, optionally substituted by one or two groups selected from alkyl, halogen and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A], where X is oxygen, sulfur or NR6, R6represents hydrogen or alkyl, R15represents alkyl or trihalomethyl; D represents alkylene, albaniles having 5-7 carbon atoms; E represents a group of the formula [4], where Y is oxygen, R3and R4are the same or different and each represents hydrogen or alkyl, and Z represents carboxy or alkoxycarbonyl.

8. Prophylactic or therapeutic agent against hyperlipidemia according to claim 6, where R1represents phenyl, optionally substituted by one or two groups selected from alkyl and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A], where X is oxygen, R15is alkyl; D represents alkylene having 3-5 carbon atoms; E represents a group of the formula [3], where p is 1, Y is oxygen, R3is alkyl, and Z is carboxy.

9. Prophylactic or therapeutic agent is Rotel hyperlipidemia according to claim 7, where R1represents phenyl, optionally substituted by one or two groups selected from alkyl, halogen and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A], where X is oxygen, R15is alkyl; D represents alkylene, albaniles having 5-7 carbon atoms; E represents a group of the formula [4], where Y is oxygen, R3and R4are the same, and each represents hydrogen or alkyl, Z represents a carboxy.

10. Prophylactic or therapeutic agent against hyperlipidemia according to claim 1, selected from the group consisting of the following compounds (1)to(14), such as

(1) 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenoate]propionic acid,

(2) CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid,

(3) 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-4-hexyloxy]propionic acid,

(4) 2-isobutyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid,

(5) 2-ethyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid,

(6) 2-methyl-CIS-5-{4-[5-methyl-2-(4-triptoreline)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid,

(7) 2-methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)-(E)-3-butenyl]-1,3-dioxane-r-2-carboxylic acid,

p num="1398"> (8) CIS-5-{4-[2-(4-tert-butylphenyl)-5-methoxazole-4-yl]butyl}-2-methyl-1,3-dioxane-r-2-carboxylic acid,

(9) 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propanol,

(10) 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionic acid,

(11) 2-methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid,

(12) 2-methyl-CIS-5-{4-[5-methyl-2-(3-fluoro-4-were)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid,

(13) 2-methyl-CIS-5-{4-[5-methyl-2-(m-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid and

(14) 2-methyl-CIS-5-{4-[5-methyl-2-(3,4-dimetilfenil)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid.

11. Pharmaceutical composition having the effect of reducing the level of triglycerides and cholesterol low-density lipoprotein (LPN-X), containing the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient composition comprises a heterocyclic compound of the formula [1]

where R1represents aryl, optionally substituted by the same or different one to three groups selected from alkyl, halogenoalkane, trihalomethyl, alkoxy, halogen;

Het represents a divalent aromatic heterocyclic group of the formula [5]

where X is oxygen, sulfur or NR6;

R6represents hydrogen or alkyl;

R2represents hydrogen, alkyl, trihalomethyl;

D represents alkylene, albaniles;

E represents a group of the formula [3] or [4]

where Y represents oxygen or sulfur;

R3and R4are the same or different and each represents hydrogen or alkyl;

p is 1;

Z represents carboxy, alkoxycarbonyl, cyano, 1H-5-tetrazolyl;

or its pharmaceutically acceptable salt.

12. Prophylactic or therapeutic agent against arteriosclerosis, containing as active ingredient a heterocyclic compound of the formula [1]

where R1represents aryl, optionally substituted by the same or different one to three groups selected from alkyl, halogenoalkane, trihalomethyl, alkoxy, halogen;

Het represents a divalent aromatic heterocyclic group of the formula [5]

where X is oxygen, sulfur or NR6;

R6represents hydrogen or alkyl;

R2the stand is made of hydrogen, alkyl, trihalomethyl;

D represents alkylene, albaniles;

E represents a group of the formula [3] or [4]

where Y represents oxygen or sulfur;

R3and R4are the same or different and each represents hydrogen or alkyl;

p is 1;

Z represents carboxy, alkoxycarbonyl, cyano, 1H-5-tetrazolyl;

or its pharmaceutically acceptable salt.

13. Prophylactic or therapeutic agent against ischemic heart disease containing as an active ingredient a heterocyclic compound of the formula [1]

where R1represents aryl, optionally substituted by the same or different one to three groups selected from alkyl, halogenoalkane, trihalomethyl, alkoxy, halogen;

Het represents a divalent aromatic heterocyclic group of the formula [5]

where X is oxygen, sulfur or NR6;

R6represents hydrogen or alkyl;

R2represents hydrogen, alkyl, trihalomethyl;

D represents alkylene, albaniles;

E represents a group of the formula [3] or [4]

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where Y represents oxygen or sulfur;

R3and R4are the same or different and each represents hydrogen or alkyl;

p is 1;

Z represents carboxy, alkoxycarbonyl, cyano, 1H-5-tetrazolyl;

or its pharmaceutically acceptable salt.

14. Prophylactic or therapeutic agent against heart attack brain, containing as active ingredient a heterocyclic compound of the formula [1]

where R1represents aryl, optionally substituted by the same or different one to three groups selected from alkyl, halogenoalkane, trihalomethyl, alkoxy, halogen;

Het represents a divalent aromatic heterocyclic group of the formula [5]

where X is oxygen, sulfur or NR6;

R6represents hydrogen or alkyl;

R2represents hydrogen, alkyl, trihalomethyl;

D represents alkylene, albaniles;

E represents a group of the formula [3] or [4]

where Y represents oxygen or sulfur;

R3and R4are the same or different and each represents hydrogen or alkyl;

p num="1466"> p is 1;

Z represents carboxy, alkoxycarbonyl, cyano, 1H-5-tetrazolyl;

or its pharmaceutically acceptable salt.

15. Prophylactic or therapeutic agent against reocclusion after CVCA containing as active ingredient a heterocyclic compound of the formula [1]

where R1represents aryl, optionally substituted by the same or different one to three groups selected from alkyl, halogenoalkane, trihalomethyl, alkoxy, halogen;

Het represents a divalent aromatic heterocyclic group of the formula [5]

where X is oxygen, sulfur or NR6;

R6represents hydrogen or alkyl;

R2represents hydrogen, alkyl, trihalomethyl;

D represents alkylene, albaniles;

E represents a group of the formula [3] or [4]

where Y represents oxygen or sulfur;

R3and R4are the same or different and each represents hydrogen or alkyl;

p is 1;

Z represents carboxy, alkoxycarbonyl, cyano, 1H-5-tetrazolyl;

or its pharmaceutically acceptable salt.

16. And preventive and therapeutic agent against diabetes, containing as active ingredient a heterocyclic compound of the formula [1]

where R1represents aryl, optionally substituted by the same or different one to three groups selected from alkyl, halogenoalkane, trihalomethyl, alkoxy, halogen;

Het represents a divalent aromatic heterocyclic group of the formula [5]

where X is oxygen, sulfur or NR6;

R6represents hydrogen or alkyl;

R2represents hydrogen, alkyl, trihalomethyl;

D represents alkylene, albaniles;

E represents a group of the formula [3] or [4]

where Y represents oxygen or sulfur;

R3and R4are the same or different and each represents hydrogen or alkyl;

p is 1;

Z represents carboxy, alkoxycarbonyl, cyano, 1H-5-tetrazolyl;

or its pharmaceutically acceptable salt.

17. Heterocyclic compound of the formula [1]

where R1represents aryl, optionally substituted by the same or different one to three groups selected from alkyl, halogenoalkane, Tr is halogenoalkane, alkoxy, halogen;

Het represents a divalent aromatic heterocyclic group of the formula [5]

where X is oxygen, sulfur or NR6;

R6represents hydrogen or alkyl;

R2represents hydrogen, alkyl, trihalomethyl;

D represents alkylene, albaniles;

E represents a group of the formula [3] or [4]

where Y represents oxygen or sulfur;

R3and R4are the same or different and each represents hydrogen or alkyl;

p is 1;

Z represents carboxy, alkoxycarbonyl, cyano, 1H-5-tetrazolyl;

or its pharmaceutically acceptable salt, provided that the excluded compound of the formula [1], where D represents alkylene having 1-6 carbon atoms, and E represents a group of the formula [4], where Y is oxygen.

18. Heterocyclic compound according to 17, where D represents alkylene, albaniles having 3-10 carbon atoms, or its pharmaceutically acceptable salt.

19. Heterocyclic compound according to 17, where Het represents a divalent aromatic heterocyclic group of the formula [5]

where X is oxygen, sulfur or NR6, R6represents hydrogen or alkyl, and R2represents hydrogen, alkyl or trihalomethyl; or its pharmaceutically acceptable salt.

20. Heterocyclic compound according to 17, where Het represents a divalent aromatic heterocyclic group of the formula [5]

where X is oxygen, sulfur or NR6, R6represents hydrogen or alkyl, R2represents hydrogen, alkyl or trihalomethyl, D represents alkylene, albaniles having 3-10 carbon atoms; or its pharmaceutically acceptable salt.

21. Heterocyclic compound according to claim 20, where Het represents a divalent aromatic heterocyclic group of the formula [5A]

where X is oxygen, sulfur or NR6, R6represents hydrogen or alkyl, D represents alkylene or albaniles having 3-7 carbon atoms;

R15represents alkyl or trihalomethyl; or its pharmaceutically acceptable salt.

22. Heterocyclic compound according to claim 20, where R1represents phenyl, optionally substituted by one or two groups selected from alkyl, halogen, trihalomethyl and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A], where X represents oxygen, with the ru or NR 6, R6represents hydrogen or alkyl, R15represents alkyl or trihalomethyl; D represents alkylene or albaniles having 3-5 carbon atoms; E represents a group of the formula [3], where p is 1, Y is oxygen, R3represents hydrogen or alkyl, Z represents a carboxy or alkoxycarbonyl; or its pharmaceutically acceptable salt.

23. Heterocyclic compound according to item 21, where R1represents phenyl, optionally substituted by one or two groups selected from alkyl, halogen and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A], where X is oxygen, sulfur or NR6, R6represents hydrogen or alkyl, R15represents alkyl or trihalomethyl; D represents alkylene, albaniles having 7 carbon atoms; E represents a group of the formula [4], where Y is oxygen, R3and R4are the same or different and each represents hydrogen or alkyl, Z represents a carboxy or alkoxycarbonyl, or its pharmaceutically acceptable salt.

24. Heterocyclic compound according to item 22, where R1represents phenyl, optionally substituted by one or two groups selected from alkyl and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A], where X is present is employed, oxygen, R15is alkyl; D represents alkylene having 3-5 carbon atoms; E represents a group of the formula [3], where p is 1, Y is oxygen, R3is alkyl, and Z represents carboxy; or its pharmaceutically acceptable salt.

25. Heterocyclic connection on p. 23, where R1represents phenyl, optionally substituted by one or two groups selected from alkyl, halogen and alkoxy; Het represents a divalent aromatic heterocyclic group of the formula [5A], where X is oxygen, R15is alkyl; D represents alkylene, albaniles having 7 carbon atoms; E represents a group of the formula [4], where Y is oxygen, R3and R4are identical and each represents alkyl, Z represents a carboxy; or its pharmaceutically acceptable salt.

26. Heterocyclic connection 17, selected from the group consisting of the following compounds (1)to(10), such as:

(1) CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid,

(2) 2-isobutyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid,

(3) 2-ethyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid,

(4) 2-methyl-CIS-5-{4-[5-methyl-2-(4-triptoreline)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic to the slot,

(5) 2-methyl-CIS-5-[4-(5-methyl-2-phenyloxazol-4-yl)-(E)-3-butenyl]-1,3-dioxane-r-2-carboxylic acid,

(6) CIS-5-{4-[2-(4-tert-butylphenyl)-5-methoxazole-4-yl]butyl}-2-methyl-1,3-dioxane-r-2-carboxylic acid,

(7) 2-methyl-CIS-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid,

(8) 2-methyl-CIS-5-{4-[5-methyl-2-(3-fluoro-4-were)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid,

(9) 2-methyl-CIS-5-{4-[5-methyl-2-(m-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid and

(10) 2-methyl-CIS-5-{4-[5-methyl-2-(3,4-dimetilfenil)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylic acid or its pharmaceutically acceptable salt.

27. Heterocyclic compound selected from the group consisting of the following compounds (1)to(11), such as:

(1) 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propionic acid,

(2) methyl 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propionate,

(3) 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionic acid,

(4) methyl 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionate,

(5) 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-4-hexyloxy]propionic acid,

(6) methyl 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-4-hexyloxy]propionate,

(7) 2-{6-[2-(4-chlorophenyl)-5-methoxazole-4-yl]hexyloxy}-2-meth is proponowa acid,

(8) methyl 2-{6-[2-(4-chlorophenyl)-5-methoxazole-4-yl]hexyloxy}-2-methylpropionate,

(9) 2-methyl-2-{6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenoate}propionic acid,

(10) methyl 2-{6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenoate}-2-methylpropionate and

(11) 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propanol or their pharmaceutically acceptable salt.

28. Heterocyclic compound according to p. 27, selected from the group consisting of the following compounds (1)to(6), such as

(1) 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propionic acid,

(2) 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl] hexyloxy}propionic acid,

(3) 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-4-hexyloxy]propionic acid,

(4) 2-{6-[2-(4-chlorophenyl)-5-methoxazole-4-yl]hexyloxy}-2-methylpropionate acid,

(5) 2-methyl-2-{6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenoate}propionic acid and

(6) 2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propanol or their pharmaceutically acceptable salt.

29. Prophylactic or therapeutic agent against obesity, containing as active ingredient a heterocyclic compound of the formula [1]

where R1represents aryl, optionally substituted by the same or the hypoxia one to three groups selected from alkyl, halogenoalkane, trihalomethyl, alkoxy, halogen;

Het represents a divalent aromatic heterocyclic group of the formula [5]

where X is oxygen, sulfur or NR6;

R6represents hydrogen or alkyl;

R2represents hydrogen, alkyl, trihalomethyl;

D represents alkylene, albaniles;

E represents a group of the formula [3] or [4]

where Y represents oxygen or sulfur;

R3and R4are the same or different and each represents hydrogen or alkyl;

p is 1;

Z represents carboxy, alkoxycarbonyl, cyano, 1H-5-tetrazolyl;

or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing compound of the formula: . Method involves interaction of compound of the formula: with compound of the formula: wherein Q means chlorine or bromine atom in the presence of solvent or diluting agent, an interphase catalyst and a base wherein solvent or diluting agent represent carbonic acid esters, an interphase catalyst represents ammonium quaternary salt, and a base represents carbonate. Method provides inhibition of process in formation of undesirable isomers.

EFFECT: improved preparing method.

1 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of azetidine formula

in which R denotes an element of the formula

R1denotes a methyl radical or ethyl, R2denotes a naphthyl radical, hinely, phenyl, possibly substituted by one or more halogen atoms, alkyl radicals, alkoxyl, hydroxyl, etc.,, R3and R4identical or different, represent a phenyl radical, possibly substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, trifluoromethyl, etc.,, R5denotes an alkyl radical or phenyl, substituted by one or more halogen atoms, R6and R7identical or different, denote a hydrogen atom or an alkyl radical, or R6and R7together with the nitrogen atom to which they are connected, form piperidinyl or pieperazinove cycle, substituted alkyl, R’6and R’7identical or different, denote a hydrogen atom or an alkyl radical, or R’6and R’7together with the nitrogen atom to which they are connected, form a pyrolidine or pieperazinove cycle, possibly substituted by one alkyl radical, cycloalkyl, -ALK-O-ALK, hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are connected, form a loop imidazole, piperazinone, thiomorpholine, etc., R8denotes alkyl, R9denotes a hydrogen atom, an alkyl radical or an alkyl, substituted dialkylamino, phenyl, etc.,, R10and R11identical or different, denote a hydrogen atom or alkyl, R12and R13together with the nitrogen atom to which they are connected, form a loop of the research, a R16and R17together with the nitrogen atom to which they are connected, form a loop of piperidine, R’ denotes a hydrogen atom or the radical-CO-ALK, ALK denotes an alkyl or alkylene, and alkyl or alkylene radicals or their parts and CNS radicals or their parts are straight or branched chain, containing from 1 to 6 carbon atoms, and their optical isomers and their salts with mineral or organic acid

The invention relates to new derivatives epothilone formula I, where the bond indicated by a wavy line indicates that the bond “a” is either CIS-or TRANS-form; (I) R2absent or represents oxygen; “a” denotes a single or double bond; “b” is absent or represents a simple bond; and “C” is absent or represents a simple bond, provided that when R2denotes oxygen, then “b” and “C” both represent a simple bond and a represents a simple bond; if R2no, the “b” and “C” both are absent and “a” represents a double bond; and if “a” represents a double bond, R2“b” and “C” are absent; R3denotes a radical selected from the group comprising hydrogen; (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; -CH2-OH; R4and R5independently of one another denote hydrogen; R1denotes a radical of the structure (a-d); (II) if R3means (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; CH2-HE; and other symbols except for the R1have the values listed above in their characters except for the R1have the above values, R1can also represent a fragment of formula (j); or a salt of the compounds of formula I, if there is a salt-forming group

The invention relates to 1-(3-heteroaromatic or prop-2-enyl)-4-benzylpiperidine formula (1), where X Is O, NR1, S, or CH2; Y is CH; Z is CH; Y and Z together may denote C= S; R1, R2and R3is hydrogen, R4- fluorine

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

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

8 cl, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

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

9 cl, 47 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to an efficient and economical methods of producing intermediates for the synthesis of HIV protease inhibitors, related nelfinavir-mesilate and including nelfinavir-mesilate

The invention relates to a tool that activates the germination of wheat seeds, which means using 4-(5-R-2-furyl)methylidene-2-phenyl-5(4H)-oxazolone formula 1, in which 1.1 R=-C6H5; 1.2 R=p-CH3-C6H4; 1.3 R= p-Br-C6H4

The invention relates to new piperidine derivative of formula (I)

< / BR>
where X represents the group< / BR>
Ar represents phenyl, one-deputizing or disubstituted by a halogen atom or (C1-C3)alkyl, R1represents a chlorine atom, a bromine atom, (C1-C3)alkyl or trifluoromethyl, R2represents a group-CR3R4СОNR5R6, R3and R4represent identical radicals selected from methyl, ethyl, n-propyl or n-butyl, or R3and R4together with the carbon atom form a (C3-C6)cycloalkyl, R5and R6represent hydrogen, (C1-C3)alkyl or together with the nitrogen atom form a 4-morpholinyl, or their salts, solvate or hydrate

The invention relates to new derivatives of phenyl - and aminobenzenesulfonamide formula

< / BR>
where a denotes (R1SO2NR2-), (R3R60NSO2NR2-); X represents-NH-, -CH2- or-OCH2-; Y represents 2-imidazoline, 2-oxazoline or 4-imidazole; R1means (NISS

The invention relates to 1-(3-heteroaromatic or prop-2-enyl)-4-benzylpiperidine formula (1), where X Is O, NR1, S, or CH2; Y is CH; Z is CH; Y and Z together may denote C= S; R1, R2and R3is hydrogen, R4- fluorine

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

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