Novel hexafluoroisopropanol derivatives

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and esters. The disclosed compounds have LXR-alpha and/or LXR-beta agonist properties. In formula (I) R1 is hydrogen, halogen; R2 is lower alkyl, flouro-lower alkyl; R3 is hydrogen, phenyl; R4 is hydrogen, hydroxy; R5 is hydrogen; phenyl; R6 is phenyl, a 5-6-member heteroaryl with one or two heteroatoms selected from nitrogen and sulphur, a 9-member bicyclic heteroaryl with a sulphur atom as a heteroatom, which can be optionally substituted with a halogen, or R6 is , R7 is a lower alkyl; R8 is phenyl which is optionally substituted with one substitute selected from a group consisting of halogen, fluoro-lower alkyl, R9-O-C(O)-, R10R11NC(O)-, phenyl-lower alkoxy; R9, R10, R11 independently represent hydrogen or lower alkyl; L is a single bond, lower alkylene or lower alkenylene; m assumes values from 0 to 3; n is equal to 0 or 1.

EFFECT: obtaining a new compound and a pharmaceutical composition which contains the disclosed compound as an active ingredient for therapeutic and/or preventive treatment of diseases.

23 cl, 47 ex

 

The present invention relates to new derivatives of formula (I):

where R1represents hydrogen, halogen, or lower alkyl;

R2represents lower alkyl, fluoro-lower alkyl, cycloalkyl-lower alkyl, or heterocyclyl-lower alkyl;

R3represents hydrogen, lower alkyl, cycloalkyl, aryl or heterocyclyl;

R4represents hydrogen, hydroxy, lower alkoxy, aryl-lower alkoxy or heterocyclyl-lower alkoxy;

R5represents hydrogen, lower alkyl, aryl or heterocyclyl;

R6represents aryl, heterocyclyl or

;

R7represents a lower alkyl or fluoro-lower alkyl;

R8represents phenyl which is optionally substituted 1-3

substituents selected from the group consisting of hydroxy, amino, halogen, lower alkyl, fluoro-lower-alkyl, hydroxy-lower alkyl, R9-O-C(O)-, R10R11NC(O)-, R12-O-C(O)-lower alkyl, R13-O-C(O)-hydroxy-lower alkyl,

R14R15NC(O)-lower alkyl, R16R17NC(O)-hydroxy-lower alkyl, lower alkoxy, aryl-lower alkoxy, R18-O-C(O)-lower alkoxy and R19R20NC(O)-lower alkyloxy;

R9, R10, R11, R12, R13, R4 , R15, R16, R17, R18, R19and R20independently from each other represent hydrogen or lower alkyl;

L represents a simple bond, a lower alkylene or lower albaniles;

m has a value from 0 to 3;

n is 0 or 1;

and their pharmaceutically acceptable salts and esters.

In addition, the present invention relates to a method for producing the above compounds, pharmaceutical preparations which contain such compounds and to the use of these compounds for the manufacture of pharmaceutical products.

X-receptors of the liver (LXR) are members of the subfamily of the nuclear receptor hormone. LXR is activated by endogenous oxysterols and regulate the transcription of genes controlling various metabolic processes. Described two subtypes - LXR alpha and LXR-beta (articles Willy and others, Genes Dev. 1995, 9, cc.1033-45; Song and others, Proc Natl Acad Sci USA, 1994, 91, cc.10809-13). LXR-beta is expressed ubiquitously, whereas LXR-alpha is expressed mainly in tissues in which cholesterol is metabolized, such as the liver, adipose tissue, intestine and .LXR modulate many physiological responses, including the regulation of cholesterol absorption, splitting cholesterol (the synthesis of bile acids) and the transport of cholesterol from peripheral tissues via LDL plasmas is in the liver. LXR also included in the glucose metabolism, cholesterol metabolism in the brain, cell differentiation and inflammation.

Currently, approximately half of all patients with coronary artery disease have a low concentration of cholesterol in high density lipoprotein in plasma (HDL-C). Terazosina HDL function was first demonstrated almost 25 years ago and has stimulated the study of genetic and environmental factors that affect the levels of HDL-C (article Miller NE., Lipids, 1978, 13, cc.914-9). The protective function of HDL derives from its role in a process called reverse transport of cholesterol. HDL Mediaset remove cholesterol from cells of peripheral tissues, including macrophilia foam cells in atherosclerotic lesions of arterial walls. HDL transports cholesterol to the liver and the Sterol-metabolizing organs for conversion into bile acids and excretion in the feces. Studies have shown that the levels of HDL-C determine the risk of coronary artery disease regardless of cholesterol levels of low density lipoprotein (LDL-C) (article Gordon and others, Am J Med., 1977, 62, cc.707-14).

Currently, it is assumed that the age-standardized prevalence among Americans aged 20 and older who have HDL-C less than 35 mg/DL, is 16% (men) and 5.7% (women). Substantially improve the giving HDL-C currently achieved by treatment with Niacin in a variety of compositions. However, significant unwanted side effects limit therapeutic potential of this approach.

It was found that about 90% of the 14 million patients diagnosed with type 2 diabetes in the United States are overweight or obese, and the majority of patients diagnosed with type 2 diabetes have abnormal concentrations of lipoproteins. Studies have shown that the prevalence of total cholesterol > 240 mg/DL was present in 37% of men diagnosed with diabetes and 44% women. Speed LDL-C > 160 mg/DL are 31% and 44%, and the speed of HDL-C <35 mg/DL are 28% and 11% of men diagnosed with diabetes and women, respectively. Diabetes is a disease in which the patient's ability to control glucose levels in the blood is reduced due to partial disturbance response to the action of insulin. Diabetes type II (T2D) is also called non-insulin-dependent diabetes mellitus (NIDDM), and it was shown that it affects 80-90% of all patients with diabetes in developed countries. When T2D pancreatic islets of Langerhans continue to produce insulin. However, the target organs for insulin action, mostly muscle, liver and adipose tissue exhibit a strong resistance to stimulation of insulin. The body continues to compensate for the manufacture of non-physiological high levels of insulin, which significantly reduced by the settlement of the front stages of the disease, it begins depletion and damage to pancreatic ability to produce insulin. Thus, T2D is a cardiovascular metabolic syndrome associated with multiple comorbid conditions, including insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and inflammatory atherosclerosis.

The first line of treatment of dyslipidemia and diabetes currently typically includes low-fat and low-carb diet, exercise and weight loss. However, success can be medium, and if the disease progresses, it becomes necessary treatment of various metabolic disorders, lipid-modulating agents, such as statins and fibrates for dyslipidemia, and gipoglikemicheskie drugs, such as sulfonylureas, Metformin or activators of the insulin-class thiazolidinedione (TZD) PPARγ-agonists for insulin resistance. Recent studies have proven that the LXR modulators can lead to the formation of compounds with high therapeutic potential, and as such, the LXR modulators should improve the lipid profile in plasma and increase the levels of HDL-C (art Lund and others, Arterioscler. Thromb. Vasc. Biol., 2003, 23, cc.1169-77). It is also known that LXR control the exit of cholesterol from macrofouling foamy cells atherosclero the practical plaques and it was shown that LXR agonists have terazosine properties (Joseph and Tontonoz, Curr. Opin. Pharmacol., 2003, 3, cc.192-7). Thus, the LXR modulators may be effective for the treatment of atherosclerotic disease, which is caused by cardiovascular disease and stroke and heart disease. Recent research has also shown that there is an independent LXR mediated the effect of activation of insulin in addition to its role in terazosina action (article Cao and others, J Biol Chem., 2003, 278, cc.1131-6). Thus, the LXR modulators can also show excellent therapeutic efficacy in increasing HDL and terazosine functions, with additional effects in diabetes compared to currently used drugs.

It was found that the new compounds of the present invention are associated and selectively activate LXR alpha and LXR-beta or deaktiveret LXR alpha and LXR-beta. Therefore, reduced absorption of insulin, increases HDL cholesterol and decreases inflammatory atherosclerosis. Because multiple aspects of combined dyslipidemia and cholesterol homeostasis caused by LXR modulators, the new compounds of the present invention have a high therapeutic potential compared to the compounds already known from the prior art. Therefore, they can use the be useful for the treatment and prevention of diseases, modulated by agonists of LXR-alpha and/or LXR-beta. Such diseases include elevated levels of lipids and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis and inflammatory diseases such as colitis, pancreatitis, cholestasis/fibrosis of the liver, psoriasis and other inflammatory skin diseases, and diseases that have an inflammatory component, such as Alzheimer's disease or weakening of improving cognitive function. Furthermore, the new compounds of the present invention can be used for the treatment and prevention of age and hereditary (e.g., illness, Stargardt) forms of macular degeneration.

Other compounds that bind and activate LXR alpha and LXR-beta, have been previously described (for example, WO 03/099769). However, there is still a need for new compounds with improved properties. The present invention relates to new compounds of formula I that bind to LXR-alpha and/or LX-beta. Compounds of the present invention unexpectedly showed improved pharmacological properties compared to the compounds known from the prior art in relation to, for example, metabolic camera is lnasty, bioavailability and activity.

Unless otherwise stated, the following definitions are provided further to illustrate and define the meaning and scope of various terms used to describe the invention.

In the description, the term "lower" is used to refer to groups that contain from one to seven, preferably from one to four carbon atoms.

The term "halogen" denotes fluorine, chlorine, bromine and iodine, where fluorine, chlorine and bromine, which are preferred,

The term "alkyl", alone or in combination with other groups, denotes a branched or linear monovalent saturated aliphatic hydrocarbon radical containing from one to twenty carbon atoms, preferably from one to sixteen carbon atoms, more preferably one to ten carbon atoms. The lower alkyl groups described below are also preferred alkyl groups.

The term "lower alkyl", alone or in combination with other groups, denotes a branched or linear monovalent alkyl radical containing from one to seven carbon atoms, preferably from one to four carbon atoms. This term is hereinafter represented by such examples of radicals, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like. The lower alkyl group is s optionally can be substituted, for example hydroxy. Such substituted lower alkyl groups are referred to as "hydroxy-lower alkyl". Other possible optional substituents are, for example, halogen. Unsubstituted lower alkyl groups are preferred.

The term "fluoro-lower alkyl" refers to lower alkyl groups which are mono - or several times substituted by fluorine. Examples of fluoro-lower alkyl groups are, for example, CFH2, CF2H, CF3, CF3CH2, CF3(CH2)2, (CF3)2CH and CF2H-CF2.

The term "cycloalkyl" refers to a monovalent carbocyclic radical containing from 3 to 10 carbon atoms, preferably from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "alkoxy" denotes a group R'-O-, where R' represents alkyl. The term "lower alkoxy" denotes a group R'-O-, where R' is a lower alkyl.

The term "dialkoxy" refers to the group R'-S-, where R' represents alkyl. The term "thio-lower alkoxy" denotes a group R'-S-, where R' is a lower alkyl.

The term "fluoro-lower alkoxy" denotes a group R ' -O-, where R is a fluoro-lower alkyl. Examples of fluoro-lower alkoxygroup are, for example, CFH2-O, CF2H-O, CF3-Oh, CF3CH2-O, CF3(CH )2-O (CF3)2SN-O and CF2H-CF2-O.

The term "alkenyl", alone or in combination with other groups, denotes a linear or branched hydrocarbon residue containing olefinic bond and from 2 to 20, preferably from 2 to 16 carbon atoms, more preferably from 2 to 10 carbon atoms. Lower alkeneamine group, described later, are also preferred alkenylamine groups. The term "lower alkenyl" denotes a linear or branched hydrocarbon residue containing olefinic bond and from 2 to 7, preferably from 2 to 4 carbon atoms, such as, for example, 2-propenyl.

The term "quinil", alone or in combination with other groups, denotes a linear or branched hydrocarbon residue containing a triple bond and up to 20, preferably up to 16 carbon atoms.

The term "lower quinil" denotes a linear or branched hydrocarbon residue containing a triple bond and from 2 to 7, preferably from 2 to 4 carbon atoms, such as, for example, 2-PROPYNYL. Lower alkyline groups can be substituted, for example hydroxy.

The term "alkylene" denotes a linear or branched divalent saturated aliphatic hydrocarbon group containing from 1 to 20 carbon atoms, preferably from 1 to 16 carbon atoms, more preferred the equipment for up to 10 carbon atoms. Lower alkylene group, described below, are also preferred alkionovymi groups. The term "lower alkylene" denotes a linear or branched divalent saturated aliphatic hydrocarbon group containing from 1 to 7, preferably from 1 to 6 or from 3 to 6 carbon atoms. Linear alkylene or lower alkylene group are preferred.

The term "albaniles" denotes a linear or branched divalent hydrocarbon group containing olefinic bond and up to 20 carbon atoms, preferably up to 16 carbon atoms, more preferably up to 10 carbon atoms. Lower alkenylamine group, described below, are also preferred alkenylamine groups. The term "lower albaniles" denotes a linear or branched divalent hydrocarbon group containing olefinic bond and up to 7, preferably up to 5 carbon atoms. Linear alkenylamine or lower alkanolamine group are preferred.

The term "aryl" denotes phenyl or naftalina group, preferably the phenyl group, which optionally may be substituted by from 1 to 5, preferably from 1 to 3 substituents, independently selected from the group consisting of lower alkyl, lower alkenyl, lower quinil, dioxo-down is his alkylene (forming, for example, benzodioxolyl group), halogen, hydroxy, CN, CF3, NH2N(H, lower alkyl), N(lower alkyl)2, aminocarbonyl, carboxy, NO2, lower alkoxy, thio-lower alkoxy, lower alkylsulfonyl, aminosulfonyl, lower alkylsulphonyl, lower alkylcarboxylic, lower alkoxycarbonyl, lower alkylsulphonyl-NH, fluoro-lower-alkyl, fluoro-lower alkoxy, lower alkoxy-carbonyl-lower alkoxy, carboxy-lower alkoxy, carbarnoyl-lower alkoxy, hydroxy-lower alkoxy, NH2-lower alkoxy, N(H, lower alkyl)-lower alkoxy, N(lower alkyl)2-lower alkoxy and benzyloxy-lower alkoxy. Preferred substituents are halogen and fluoro-lower alkyl.

The term "heterocyclyl", separately or in combination, denotes a saturated, partially unsaturated, or aromatic 5-10-membered, mono - or bicyclic a heterocycle that contains one or more heteroatoms selected from nitrogen, oxygen and sulfur. If necessary, it can be substituted on one or more carbon atoms, for example, halogen, alkyl, alkoxy, oxo, etc. and/or on a secondary nitrogen atom (i.e.- NH-) alkyl, cycloalkyl, alcoxycarbenium, alkanoyl, phenyl or phenylalkyl, or on a tertiary nitrogen atom (i.e. =N-) oxide, where halogen, alkyl, cycloalkyl and alkoxy are predpochtitelnye. Examples of such heterocyclyl groups are pyrrolidinyl, pyrrolyl, piperidinyl, piperazinil, morpholinyl, thiomorpholine, pyrazolyl, triazolyl, tetrazolyl, isothiazolin, imidazolyl (for example, imidazol-4-yl and 1-benzyloxycarbonylamino-4-yl), benzimidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, hexahydropyridine, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, indolyl (e.g., 2-indolyl), indazole, chinolin (for example, 2-chinolin, 3-chinolin and 1 oxido-2-chinolin), ethanolic (for example, 1-ethanolic and 3-ethanolic), tetrahydropyranyl (for example, 1,2,3,4-tetrahydro-2-chinolin), 1,2,3,4-tetrahydroisoquinoline (for example, 1,2,3,4-tetrahydro-1-occaisonaly), tetrahydropyranyl, honokalani, oxopyrrolidin and benzo[b]thiophenyl. Preferred are pyridinyl, thiazolyl and benzo[b]thiophenyl. Heterocyclyl group may also have a Deputy, as described above for "aryl". Aromatic heterocyclyl group are preferred.

The term "leaving group" denotes a group which may be substituted by a nucleophile (e.g., a secondary amine). Conventional leaving groups are, for example: Cl, Br, I,-SO2-lower alkyl (where the OH-SO2-CH3=OMs), O-SO2the lowest-foralkyl (where O-SO2- CF3=OTf),-SO2aryl (where O-SO2-ptolyl = OTs), O-(para-nitrophenyl).

The compounds of formula (I) can form pharmaceutically acceptable acid salt additive. Examples of such pharmaceutically acceptable salts are salts of compounds of formula (I) with physiologically acceptable mineral acids such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulfonate acid, p-toluensulfonate acid, acetic acid, lactic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term "pharmaceutically acceptable salt" means a salt such. The compounds of formula (I), in which there is a group COOH, can also form salts with bases. Examples of such salts are salts with alkali metal, alkaline earth metal and ammonium, such as, for example, salts with Na, K, CA and ammonium. The term "pharmaceutically acceptable salt" also refers to such salts. Salts obtained by addition of acid, are preferred.

The term "pharmaceutically acceptable esters" refers to derivatives of the compounds of formula (I), in which carboxypropyl transformed into a complex ester group. Lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkylene is, amino-lower alkyl, mono - or di-lower alkylamino-lower alkyl, morpholino-lower alkyl, pyrrolidino-lower alkyl, piperidino-lower alkyl, piperazine derivatives-lower alkyl, lower alkylpiperazine-lower alkyl and kalkilya esters are examples of suitable esters. Methyl, ethyl, propyl, butyl and benzyl esters are the preferred esters. Methyl and ethyl esters are particularly preferred. The term "pharmaceutically acceptable esters" also includes compounds of formula (I), in which the hydroxy-group converted into the corresponding esters with inorganic or organic acids such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, p-toluensulfonate acid and the like, which are non-toxic to living organisms.

In more detail, the present invention relates to compounds of formula (I):

where R1represents hydrogen, halogen or lower alkyl;

R2represents lower alkyl, fluoro-lower alkyl, cycloalkyl-lower alkyl or heterocyclyl-lower alkyl;

R3represents the t of a hydrogen, lower alkyl, cycloalkyl, aryl or heterocyclyl;

R4represents hydrogen, hydroxy, lower alkoxy, aryl-lower alkoxy or heterocyclyl-lower alkoxy;

R5represents hydrogen, lower alkyl, aryl or heterocyclyl;

R6represents aryl, heterocyclyl or

;

R7represents a lower alkyl or fluoro-lower alkyl;

R8represents phenyl which is optionally substituted 1-3

substituents selected from the group consisting of hydroxy, amino, halogen, lower alkyl, fluoro-lower-alkyl, hydroxy-lower alkyl, R9-O-C(O)-, R10R11NC(O)-, R12-O-C(O)-lower alkyl, R13-O-C(O)-hydroxy-lower hydroxy-lower alkyl, R14R15NC(O)-lower alkyl, R16R17NC(O)-hydroxy-lower alkyl, lower alkoxy, aryl-lower alkoxy, R18-O-C(O)-lower alkoxy and R19R20NC(O)-lower alkyloxy;

R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19and R20independently from each other represent hydrogen or lower alkyl;

L represents a simple bond, a lower alkylene or lower albaniles;

m has a value from 0 to 3;

n is 0 or 1;

and their pharmaceutically acceptable salts and the complex is m esters.

The compounds of formula (I) are particularly preferred, and their physiologically acceptable salts are particularly preferred, and their pharmaceutically acceptable esters are particularly preferred, and the compounds of formula (I) are particularly preferred.

The compounds of formula (I) can have one or more asymmetric C atoms and can therefore exist as enantiomeric mixtures, diastereoisomeric mixture or in the form of optically pure compounds.

Preferred compounds of formula (I)as described above are compounds in which R represents hydrogen or halogen, preferably hydrogen or chlorine. Hydrogen and chlorine separately are the preferred option for implementation. Other preferred compounds of formula (I)as described above are compounds in which R2represents a lower alkyl or fluoro-lower alkyl, especially ethyl or 2,2,2-triptorelin. Ethyl and 2,2,2-triptorelin separately are the preferred option for implementation.

Another preferred implementation of the present invention relates to compounds of formula (I)as described above, where R3represents hydrogen or aryl, especially hydrogen or phenyl, especially hydrogen.

Other preferred compounds of formulas is (I), as described above, are compounds in which R4represents hydrogen or hydroxy. Compounds in which R5represents hydrogen, are also preferred.

Another preferred implementation of the present invention relates to compounds of formula (I)as described above, where R6represents phenyl, pyridinyl, thiazolyl or benzo[b]thiophenyl are not substituted with halogen. Each of these groups optionally can be substituted with halogen, preferably phenyl or benzo[b]thiophenyl. Preferably R6represents phenyl, chlorophenyl, pyridinyl, thiazolyl or chlorobenzo[b]thiophenyl, more preferably phenyl.

Another preferred implementation of the present invention relates to compounds as described above, in which R6represents a group

,

where R7represents lower alkyl; R8represents phenyl which is optionally substituted by a Deputy selected from the group consisting of halogen, fluoro-lower-alkyl, R9-O-C(O)-, R10R11NC(O) -, and aryl-lower alkoxy; R9represents hydrogen or lower alkyl; R10and R11independently from each other represent hydrogen or lower alkyl; L represents Rostow communication, lowest alkylene or lower albaniles. In these compounds R7preferably represents methyl. R8preferably represents phenyl, substituted fluoro-lower alkyl, halogen, carboxy or (lower alkyl)2NC(O)-. More preferably R8is a 3-triptoreline, 3-chlorophenyl, 4-carboxyphenyl or 4-(CH3)2NC(O)phenyl. In addition, L preferably represents a simple link.

In a preferred embodiment of the present invention m has a value from 0 to 2, more preferably m is 0. The compounds of formula (I)as described above, where n denotes 0, are also preferred implementation of the present invention.

In particular, the preferred compounds are the compounds of formula (I)described in the examples as individual compounds, and their pharmaceutically acceptable salts and pharmaceutically acceptable esters.

Preferred compounds of formula (I) are compounds selected from the group consisting of the following compounds:

2-[4-(benzylamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol,

2-{4-[(2-Chlorobenzyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-{4-[(3-Chlorobenzyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-{4-[(4-chlorbenzyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-al,

2-[4-(ethylenediamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol,

2-[4-(benzyldimethylamine)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol,

2-{4-[ethyl-(thiazol-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-{4-[ethyl-(pyridine-2-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-{4-[ethyl-(pyridine-3-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-{4-[ethyl-(pyridine-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-{4-[benzyl-(2,2,2-triptorelin)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-{4-[(5-chlorobenzo[b]thiophene-2-ylmethyl)-(2,2,2-triptorelin)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-{4-[ethyl-(2-hydroxy-2-phenylethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

(R) 2-{4-[ethyl-(2-hydroxy-2-phenylethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

(S) 2-{4-[ethyl-(2-hydroxy-2-phenylethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

(R) 2-(4-{[2-(3-chlorophenyl)-2-hydroxyethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,

2-[4-(benzylideneamino)-3-chlorophenyl]-1,1,1,3,3,3-hexaferrite-2-ol,

2-{3-chloro-4-[ethyl-(thiazol-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-{4-[benzyl-(2,2,2-triptorelin)amino]-3-chlorophenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-{3-chloro-4-[ethyl-(3-phenylpropyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-[3-chloro-4-(ethylenediamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol,

1,1,1,3,3,3-hexamer-2-{4-[[5-methyl-2-(3-triptoreline)oxazol-4-ilma is Il]-(2,2,2-triptorelin)amino]phenyl}-propan-2-ol,

2-{4-[[2-(3-chlorophenyl)-5-methyl-oxazol-4-ylmethyl]-(2,2,2-triptorelin)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-(4-{ethyl-[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl]amino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,

2-(4-{[2-(3-chlorophenyl)-5-methyl-oxazol-4-ylmethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,

2-(3-chloro-4-{ethyl-[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl]amino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,

2-(3-chloro-4-{[2-(3-chlorophenyl)-5-methyl-oxazol-4-ylmethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,

2-(4-{[2-(3-benzyloxyphenyl)-5-methoxazole-4-ylmethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,

2-(4-{[2-(4-benzyloxyphenyl)-5-methoxazole-4-ylmethyl]ethylamino} phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,

methyl ester of 3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid,

methyl ester of 4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino)methyl)-5-methoxazole-2-yl]benzoic acid,

3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid,

4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid,

3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N-methylbenzamide,

3-[4-({ethyl-[4-(2,2,2-Cryptor-1-is hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N,N-dimethylbenzamide,

3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzamide,

4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N-methylbenzamide,

4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N,N-dimethylbenzamide,

4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzamide,

2-{4-[(2-benzyl-5-methoxazole-4-ylmethyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-(4-{ethyl-[5-methyl-2-((E)-styryl)oxazol-4-ylmethyl]amino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol and

2-{4-[ethyl-(5-methyl-2-penetration-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

and their pharmaceutically acceptable salts and esters.

Especially preferred compounds of formula (I) are compounds selected from the group consisting of the following compounds:

2-[4-(benzylideneamino)-3-chlorophenyl]-1,1,1,3,3,3-hexaferrite-2-ol,

2-{4-[benzyl-(2,2,2-triptorelin)amino]-3-chlorophenyl}-1,1,1,3,3,3-hexaferrite-2-ol,

2-(4-{ethyl-[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl] amino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,

2-(4-{[2-(3-chlorophenyl)-5-methoxazole-4-ylmethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,

4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoin the I acid and

4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N,N-dimethylbenzamide,

and their pharmaceutically acceptable salts and esters.

It is clear that from compounds of General formula (I) of the present invention can be obtained derivative functional groups to obtain derivatives that are capable of transforming back to the original compound in vivo.

The present invention also relates to a method for producing compounds of formula (I)as described above, which includes

a) reaction of compounds of formula (II):

with a compound LG-CHR3-(CH2)m-(CR4R5)n-R6or

b) reaction of compounds of formula (III):

with a compound LG-R2,

where R1, R2, R3, R4, R5, R6, m, and n are as defined above and LG represents a leaving group.

The reaction of the compound of formula (II) with a compound LG-CHR3-(CH2)m-(CR4R5)n-R6or the compounds of formula (III) with a compound LG-R2can be carried out under reaction conditions known to the person skilled in the art. Such reaction can usually be carried out in a solvent such as, for example, DMF, THF, acetonitrile or acetone, optional is the presence of a base, such as DIPEA or2CO3when the temperature is suitable, for example, in the range of 20-200°C. Suitable leaving groups are well known to the person skilled in the technical field, for example, halogen (I, Br, Cl), triflate (OTf), mesilate (OMs), tosylate (OTs) or para-nitrophenolate.

The present invention also relates to compounds of formula (I)as described above, obtained by the method as described above.

Obtaining compounds of formula (I)as described above, is illustrated in figure 1:

Scheme 1

Treatment of aniline 1a/b (PG=optional protective group) LG-R2(where LG is a leaving group such as, for example, Cl, Br, I, MsO, TsO, or TfO) or allermuir agent (carboxylic acid anhydride or carboxylic acid chloride, such as, for example, anhydride triperoxonane acid or benzoyl chloride) and subsequent recovery in the intermediate amide compounds (e.g., NR3) results in compounds 2A/b (stage a). Alternative education intermediate amide compounds can also be carried out by treating compound 1a/b carboxylic acid in the presence of, for example, EDCI and NOWT or other conventional reagents used for obtaining the amides of the carboxylic acids."(CHR3)(CH2)m(CR4R5)nR6"a group injected article on the Hai b reaction of compounds 2A/b with connection "LG-(CHR 3)(CH2)m(CR4R5)nR6". The alternate connection 2A/b then you can handle allermuir agent such as ClOC(CH2)m(CR4R5)nR6in the presence of a base or carboxylic acid HOOC(CH2)m(CR4R5)nR6in the presence of, for example, EDCI and NOWT or other conventional reagents used for obtaining the amides of the carboxylic acid. The obtained intermediate amide compound restored (for example, using NR3) to obtain the derivatives with R3=N. If the connection 2A/b is treated with oxirane 5, optionally in the presence of a Lewis acid such as, for example, lithium perchlorate or ZnCl2(for example, analogously to the method described in the articles: Chini, etc., J. Org. Chem., 1991, 56(20), cc. 5939-5942; Duran Pachon and others, Tet. Lett., 2003, 44(32), cc. 6025-6027), can be obtained derivatives with m=0, n=1 and R5=HE. The methods used for the introduction (CHR3)(CH2)m(CR4R5)nR6groups can also be used for compounds 1a/b (stage C). Deputy R2introduced later in connection 4A/b in accordance with the methods described above (stage d). If the stage d is incompatible with the functional groups present in the compound 4A/b, they can be appropriately protected prior to the introduction of R2and then they could the t to be removed protective group. O-protected derivative 1b can be obtained from compound 1A in accordance with the standard described in the prior art techniques used to protect alcohols (for example, by treating compound 1A silylium agent such as TESCl, in the presence of a suitable base, such as DBU). Conditions for the introduction of some O-protective groups (for example, O-benzylidene benzylbromide in the presence

To2CO3) may require preliminary protection of the amino group (for example, the introduction of Vos2O), which then remove the protective group after protection of the hydroxyl group. Remove the O - and N-protective groups, if desired or necessary, is carried out in accordance with the relevant standard techniques commonly known to a person skilled in the art (for example, removal of the N-Boc protection in the presence of TFWC or N-disilylgermane using TBAF). The usual conditions for the introduction and removal of protective groups, for example, can be taken from the books "Protective Groups in Organic Synthesis", T.W.Greene and P.G.M.Wuts, 2nd ed., 1991, Wiley N.Y.

Derivatives with R4= hydroxy can be converted into derivatives with R4= alkoxy, aryl-lower alkoxy and heterocyclyl-lower alkoxy processing reagent LG-RIIwhere RII= lower alkyl, aryl-lower alkyl or heterocyclyl-lower alkyl in the presence of a base, such as, for example, K 2CO3. Derivatives with R4= hydroxy and R5=N can be oxidized (i.e. CR4R5make C=O) and processed ORGANOMETALLIC reagent, such as, for example, Li-R5or BrMg-R5where R5represents lower alkyl, aryl or heterocyclyl, obtaining derivatives with R4= hydroxyl and R5= lower alkyl, aryl or heterocyclyl. If necessary, a functional group (for example, present in R6inconsistent with the terms used for these transformations R4and R5can be appropriately protected and then they can be removed protective group (in accordance with the methods described, for example, in the book "Protective Groups in Organic Synthesis", T.W.Greene and P.G.M.Wuts, 2nd ed., 1991, Wiley N.Y.).

Derivatives 1a/b - 4a/b with R1=N can be transformed into derivatives with R1= halogen treatment halogenation agent, such as NCS, NBS, NIS, or N-Forbes(trifloromethyl)amine. Derivatives 1a/b - 4a/b with R1= lower alkyl can be obtained from the derivatives with R1=N one-stage alkylation Friedel-Craftsa or in two stages by acylation Friedel-Craftsa and subsequent reduction of the carbonyl group (for example, recoveries of type wolf-Kishner or Clemmensen). Alternative derivatives with R1=Cl, Br, or I can put what I and exchange reactions of halogen to metal by using, for example, BuLi or EtMgBr, and then treated with alkylating agent such as, for example, alkylated. Instead of the alkylating agent can be used aldehyde Snorkel leading to the compounds with R1=1-hydroxyalkyl, which can be desoxyribose, for example, by hydrogenolysis in the presence of a catalyst such as Pd/C, or the processing of regenerating agent such as, for example, BH3·Me2S or Et3Si-H, optionally in the presence of an acid or Lewis acid, such as, for example, TFUK or BF3·OEt2(for example, analogously to the procedure described in articles Pearlstein and others, Bioorg. and Med. Chem. Lett., 2003, 13, cc.1829-1835; Mewshaw, etc., Bioorg. and Med. Chem. Lett., 2002, 12, cc.307-310; Sakagani and others, Synlett., 1996, cc.163-164). If necessary, sensitive functional groups present in compounds 1a/b-4a/b, can be appropriately protected to obtain derivatives with R1= halogen or lower alkyl and may be withdrawn protective group at a later stage (for example, in accordance with the methods described, for example, in the book "Protective Groups in Organic Synthesis", T.W.Greene and P.G.M.Wuts, 2nd ed., 1991, Wiley N.Y.).

A large number of connections LG-(CHR3)(CH2)m(CR4R5)nR6in which R1-R6, L, m, n, and LG stated above, are commercially available. If they are not commercially available, Animagus to be obtained from the appropriate commercially available starting materials, such as, for example, the alcohol BUT-(CHR3)-(CH2)m(CR4R5)nR6the alkyl ether EP-(CH2)m-(CR4R5)nR6or carboxylic acid HOOC-(CH2)m-(CR4R5)nR6according to standard literature methods known to the person skilled in the art. If they are not commercially available, the halides of the structure of halogen-(CHR3)-(CH2)m(CR4R5)nR6where the halogen = Cl or Br and R3= aryl or heterocyclyl or both m and n=0, can be obtained, for example,

of H2CR3-(CH2)m(CR4R5)nR6processing NCS or NBS, respectively (for example, article Togo and others, Syn. Lett, 2003, cc.702-704). Oxirane, such as compound 5 can be obtained by treating 1-bifunctionalized of Atanov C(HR3)=C(R5R6) is usually used epoxidised agent such as msra (for example, articles Durley, etc., J. Med. Chem., 2002, 45, 18, cc. 3891-3904; Tian and others, Org. Lett., 3, 12, 2001, cc.1929-1932). Most of the compounds of the LG(CHR3)(CH2)m(CR4R5)nR6where R3, R4, R5=H, and R6= heterocyclyl can be obtained in accordance with literature methods (for example, patents Binggeli and other WO 200292084 and WO 97019311, Bouillot and other WO 2004006922; Morita and others, JP 9095482; articles Cynkowski other, J. Chem. Soc. Chem. Commun., 1995, cc. 2335-2336; Kodama and others, US 6472386; Faul and others, Heterocycles, 2001, 55 (4), cc.689-704).

After receiving the connection 3A/b in accordance with the above descriptions of the synthesis, functional groups present in R, not necessarily can be obtained derivatives. Examples of conventional transformations such functional groups are presented next.

Benzyloxy usually converted into hydroxy; hydroxy - lower alkoxy, Ra-O-C(O)-lower alkoxy, and RaRb-NC(O)-lower alkoxy; Ra-O-C(O) - hydroxymethyl and-C(O); BUT-S(O) RaRbNC(O); hydroxymethyl - formyl where these functional groups may be present separately or to form part of a larger functional group, and where Raand Rbindependently from each other represent hydrogen or lower alkyl. Methods for these transformations are widely described in the prior art and are known to the person skilled in the technical field.

Formyl can usually be converted into a 1-hydroxyalkyl the addition of halide alkaline or alkylate. On the formyl group can be obtained derivatives with 2-(lower alkyl-O-C(O))-1-hydroxyethylene group, for example Zn(O)-mediated addition of ether α-bromoxynil acid (reaction reformed). If 2-(lower alkyl-O-C(O))-1-hydroxyethyl obtained from the formyl group, direct the o attached to the aryl or heterocyclyl, the transformation in alkoxycarbonylmethyl group can be carried out by deoksigenirovanii, for example, by hydrogenolysis in the presence of a catalyst such as Pd/C, or the processing of regenerating agent such as, for example, BH3·Me2S or Et3Si-H, optionally in the presence of an acid or Lewis acid, such as, for example, TFUK or BF3·OEt2. An alternative transformation in alkoxycarbonylmethyl group may be 1,2-elimination (e.g., caused by the processing of Tf2O in the presence of a base, such as DIPEA) and subsequent hydrogenation of the intermediate alkene. Such an intermediate connection alkene can also be obtained directly from formyl derivative by obtaining olefins Wittig, Wittig-Horner, Wadsworth-Emmons or Peterson. Methods for getting olefins can be found in numerous sources and are widely known to a person skilled in the technical field.

To obtain the derivatives of functional groups in R6sensitive functional groups in the compound 3A/b can be appropriately protected (e.g., sellerbuyer hydroxy-group) and they can be removed protective group, if desired or necessary (as described, for example, in the book "Protective Groups in Organic Synthesis", T.W.Greene and P.GM.Wuts, 2nd ed., 1991, Wiley N.Y.).

The transformation of compounds of formula (I) into a pharmaceutically acceptable salt can be carried out by treatment of such compounds, inorganic acid, for example halogen acid, such as, for example, hydrochloric acid or Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acid, such as, for example, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate acid or p-toluensulfonate acid. The corresponding carboxylate salt can also be obtained from compounds of formula (I) by treatment with physiologically acceptable bases.

The conversion of compounds of formula (I) into pharmaceutically acceptable esters can be carried out, for example, treatment with a suitable amino - or hydroxy groups present in the molecules of carboxylic acid, such as acetic acid, an appropriate reagent, such as benzotriazol-1-yloxytris(dimethylamino)phosphodiesterase (THIEF) or N,N-dicyclohexylcarbodiimide (DCCI) to obtain the ester of carboxylic acid or carboxylic acid amide.

Even if the connections are not described in the examples, the compounds of formula (I), as well as intermediate products can be obtained in accordance with the same str is Obama or in accordance with the methods, described above. The source reagents are commercially available or are known in the prior art.

As described above, it was found that the new compounds of the present invention are associated and selectively activate LXR alpha and LXR-beta or deaktiveret LXR-alpha and LX-beta. Consequently, reduces the absorption of cholesterol, increases HDL cholesterol and decreases inflammatory atherosclerosis. Therefore, they can be used for treatment and prophylaxis of diseases which are modulated LXR-alpha and/or LXR beta agonists. Such diseases include elevated levels of lipids and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis and inflammatory diseases such as colitis, pancreatitis, cholestasis/fibrosis of the liver, psoriasis and other inflammatory skin diseases, and diseases that have an inflammatory component, such as Alzheimer's disease or weakening of improving cognitive function. Furthermore, the new compounds of the present invention can be used for the treatment and prevention of age and hereditary (e.g., illness, Stargardt) forms of macular degeneration.

Therefore, toadie the invention also relates to pharmaceutical compositions, containing compound as described above and a pharmaceutically acceptable carrier and/or adjuvant.

The present invention also includes compounds as described above for use as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prevention of diseases which are modulated LXR-alpha and/or LXR beta agonists, particularly as therapeutically active substances for the treatment and/or prevention of increased lipid levels, increased cholesterol levels, low HDL cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, macular degeneration and/or Alzheimer's disease.

In another preferred embodiment, the present invention relates to a method of therapeutic and/or prophylactic treatment of diseases which are modulated LXR-alpha and/or LXR beta agonists, particularly for therapeutic and/or prophylactic treatment of increased lipid levels, increased cholesterol levels, low HDL cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, insurancesave is imago diabetes, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, macular degeneration and/or Alzheimer's disease, which includes the introduction of the connection, as described above, a person or an animal.

The present invention also includes the use of compounds as described above for therapeutic and/or prophylactic treatment of diseases which are modulated LXR-alpha and/or LXR beta agonists, particularly for therapeutic and/or prophylactic treatment of increased lipid levels, increased cholesterol levels, low HDL cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, macular degeneration and/or Alzheimer's disease.

The present invention also relates to the use of compounds as described above for the manufacture of drugs for therapeutic and/or prophylactic treatment of diseases which are modulated LXR-alpha and/or LXR beta agonists, particularly for therapeutic and/or prophylactic treatment of increased lipid levels, increased levels of the her cholesterol, low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, macular degeneration and/or Alzheimer's disease. Such medicines include connection, as described above.

Prevention and/or treatment of elevated lipid levels, increased cholesterol levels, atherosclerotic diseases, dyslipidemia, or diabetes, are the preferred indications for the use, especially the prevention and/or treatment of elevated lipid levels, increased cholesterol levels, atherosclerotic diseases or dyslipidemia, especially the prevention and/or treatment of atherosclerotic disease or dyslipidemia.

The following tests were carried out to determine the activity of compounds of the present invention. Basic information for analysis can be found in the article: Nichols JS, and others, "Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain". Anal Biochem., 1998, 257, cc.112-119.

The expression vectors of the mammal designed to Express the full-LXR alpha and LXR-beta man. Bacterial expression vectors designed for the Ali to get glutathione-s-transferase (GST), merged with the ligand-binding domain (LBD) LXR-alpha man (AA 164-447) and LXR-beta human (AA 155-460). For this part of the sequences encoding the LBD, amplified from full-length clones by PCR and then subcloned into plasmid vectors. The final clones were verified by analysis of the DNA sequence (articles Willy and others, Genes Dev., 1995, 9, cc. 1033-45; Song and others, Proc Nati Acad Sci USA, 1994, 91, cc. 10809-13).

The induction, expression and purification of GST-LBD fused proteins was performed in a strain of cells of E. coli BL21(pLysS) by standard methods (Reference: Current Protocols in Molecular Biology, Wiley Press, edited by Ausubel, etc).

Analysis of radioligand binding

Binding to LXR alpha and LXR-beta receptor was analyzed in buffer containing 50 mm HEPES, pH 7.4, 10 mm NaCl, 5 mm MgCl2. In each of the 96 wells were binding reaction 500 ng fused protein GST-LXRα-LBD or 700 ng GST-LXRea-LBD with 80 µg or 40 µg SPA granules (Amersham Pharmacia), respectively, in a final volume of 50 ál with shaking. The obtained turbid suspension were incubated for 1 h at RT and centrifuged for 2 min at 1300 X g. The supernatant containing unbound protein was removed and the dry residue containing coated with receptor pellets re-suspended in 50 µl of buffer. Added radioligand (for example, 100,000 dpm (N-(2,2,'2-trifluoromethyl)-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]benzosulfimide)), and the reaction mixture was incu is Aravali at RT for 1 h in the presence of test compounds and then spent counting scintillation proximity. All analyses on binding was carried out in 96-well tablets and the number of bound ligands were measured on the instrument Packard TopCount with assist OptiPlate (Packard). Curves of the dose was built in range

concentrations from 10-10M10-4M

Analysis of transcriptional reporter gene luciferase

The kidney cells baby hamster (VNC ADS CCL10) were grown in DMEM containing 10% FBS, at 37°C in an atmosphere of 95% O2:5%CO2. Cells were cultivated in 6-hole tablets with a density of 10 cells/well and then parties were transferrable either in full LXRα or full-LXRβ plasmids for expression, plus a reporter plasmid expressing the luciferase under the control of LXR response. The transfection was carried out with reagent Fugene 6 (Roche Molecular Biochemicals) according to the proposed Protocol. Six hours after transfection the cells were collected by trypsinization and were cultivated in 96-well tablets with a density of 104cells/well. After 24 h binding cells the medium was removed and replaced with 100 μl of medium containing no phenol red, containing test compounds or reference ligand (final concentration of DMSO is 0.1%). After incubation of cells for 24 h with substances 50 μl of supernatant were removed and then added 50 μl of Luciferase reagent Constant-Light (Roche Molecular Biochemicals) for lysis of cells and initiate Rea is of luciferase. Luminescence as a measure luciferase activity was determined using the device Packard TopCount.

Transcriptional activity in the presence of the test substance were expressed as the ratio of changes in luminescence compared to the luminescence of cells incubated without substance. The values of EC50was calculated using the software XLfit (ID Business Solutions Ltd. UK).

The compounds of formula (I) have activity in at least one of the above tests (EU50or IC50from 1 nm to 100 μm, preferably from 1 nm to 10 μm, more preferably from 1 nm to 1 μm.

For example, the following compounds showed the following values IC50in the analysis of the binding:

ExampleThe binding of LXR-alpha IC50[µmol/l]The binding of LXR-beta IC50[µmol/l]
10,0460,031
180,0170,0034
300,00270,0057

These results were obtained using the above analysis.

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

Obtaining pharmaceutical drugs can be performed in a manner known to a person skilled in the art by introducing described compounds of formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a form for herbal injection together with suitable, non-toxic, inert, therapeutically acceptable solid or liquid materials of the carrier and, if desired, usual pharmaceutical adjuvants.

Suitable materials carriers are not only inorganic materials carriers, but also organic materials carriers. So, for example, as materials carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used lactose, corn to Ajmal or its derivatives, talc, stearic acid or its salts. Suitable materials carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient carriers may not be used, however, will be necessary in the case of soft gelatin capsules). Suitable materials carriers to obtain solutions and syrups are, for example, water, polyols, saccharose, invert sugar and the like. Suitable materials carriers for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable materials carriers for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable materials carriers for local products are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

Conventional stabilizers, preservatives, moisturizing and emulsifying agents that improve the consistency agents, odorants, salts for regulating the osmotic pressure, buffer substances, soljubilizatory, dyes and masking agents and antioxidants can be used as headlamp is aceticacid adjuvants.

The dosage of the compounds of formula I can vary within wide limits depending on the controlled disease, age and individual condition of the patient and the route of administration, and will, of course, be installed in accordance with the individual requirements in each particular case. For adult patients acceptable a daily dosage is from about 1 to 1000 mg, especially from about 1 to 300 mg, depending on the severity of the disease and specific pharmacokinetic profile of the compound may be injected in one or more of the daily dosage units, for example at 1 to 3 dosage units.

The pharmaceutical preparations normally contain 1-500 mg, preferably 1-100 mg of the compounds of formula I.

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

Examples

Abbreviations:

AU2About = acetic anhydride, CH2Cl2= dichloromethane,tBuOH = tert-butanol, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DIPEA=N-ethyldiethanolamine, DMF = dimethylformamide, EDCI=N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, EtOAc = ethyl acetate; EtOH = ethanol, Et2O = diethyl ether, equiv. = equivalent, HCl = hydrochloric acid, NOUT=1-hydroxybenzotriazole, Meon = methanol, NH4Cl = the of lore ammonium, NaOH = sodium hydroxide, NaOMe = sodium methoxide, NCS=N-chlorosuccinimide, CT = room temperature, TBAF = fluoride of tertbutylamine, TFAA=anhydride triperoxonane acid, TESC1 = chlorotriethylsilane, THF = tetrahydrofuran.

General remarks

All reactions were carried out in argon atmosphere.

Example 1

2-[4-(Benzylamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol 1,1.

A solution of 5 g (or 19.3 mmole) of 2-(4-AMINOPHENYL)-1,1,1,3,3,3-hexaferrite-2-ol in 25 ml of pyridine was treated with 2.2 ml (23,3 mmole) AU2O. the Mixture was stirred at 60°C for 2 h and the solvent was partially evaporated. The residue was divided between dilute aqueous HCl solution and Et2O. the combined organic phases were dried Na2SO4and was evaporated to obtain 5.7 g of crude N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]ndimethylacetamide, which was dissolved in 100 ml of DMF, was treated with 3.4 ml (22,7 mmole) of DBU and then dropwise at 0°C and 3.8 ml (22,7 mmole) TESCl. The resulting mixture was stirred at RT for 10 h and then poured into a saturated aqueous solution of NH4Cl and Et2O. the Phases were separated and the aqueous phase was extracted with Et2O. the combined organic phases were dried Na2SO4and evaporated obtaining of 8.3 g of crude N-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]ndimethylacetamide, which was dissolved in 100 ml of THF and was treated with 3.4 ml of 1M solution NR3·THF in THF. The mixture is ipatio under reflux for 4 h and the solvent was partially evaporated. After adding a saturated aqueous solution of NH4Cl and Et2O, the phases were separated and the aqueous phase was extracted with Et2O. the combined organic phases were dried Na2SO4and was evaporated. Column chromatography on silica gel using a mixture of n-heptane/EtOAc 9:1 resulted in obtaining 7.5 g (96%) of ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amine, light yellow oil, MS: 402 (MN+).

1,2

To a solution of 0.5 g (1,24 mmole) of ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amine in 2 ml of DMF was added 0.3 ml (2.5 mmole) of benzylbromide and the mixture was stirred over night at 80°C. After the separation between 2M aqueous solution of NaOH and Et2O, drying the combined organic phases Na2SO4and evaporation of the resulting crude substance was dissolved in 5 ml Meon, were treated with 1 ml of 2M solution of NaOMe in Meon and was stirred for 30 minutes Evaporation of the solvent and column chromatography on silica gel using a mixture of n-heptane/EtOAc 95: 5 yielded 0.33 g (70%) of 2-[4-(benzylamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol, light yellow semi-solid substance, MS: 378 (MN+).

Example 2

2-{4-[(2-Chlorobenzyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 1,2, from ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl] amine and 1-chloro-2-chloromethylbenzene received the 2-{4-[(2-Chlorobenzyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, light yellow oil, MS: 412 (MN+), 1Cl).

Example 3

2-{4-[(3-Chlorobenzyl)ethylamino]phenyl}-1.1.1.3.3.3-hexaferrite-2-ol

Analogously to example 1,2, from ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amine and 1-chloro-3-chloromethylbenzene was obtained 2-{4-[(3-Chlorobenzyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, light yellow oil, MS: 412 (MN+, 1Cl).

Example 4

2-{4-[(4-Chlorbenzyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 1,2, from ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amine and l-chloro-4-chloromethylbenzene was obtained 2-{4-[(4-chlorbenzyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, light yellow oil, MS: 412 (MN+, 1Cl).

Example 5

2-[4-(Ethylenediamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 1,2, from ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amine and 2-phenylethylamine received 2-[4-(ethylenediamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol, light yellow oil, MS: 392 (MN+).

Example 6

2-[4-(Benzyldimethylamine)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 1,2, from ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl] amine and bromodiphenylmethane received 2-[4-(benzyldimethylamine)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol, rose oil, MS: 454 (MH+).

Example 7

2-{4-[Ethyl-(thiazol-4-ylmethyl)amino]f the Nile}-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 1,2, from ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amine and 4-chloromethylthiazole was obtained 2-{4-[ethyl-(thiazol-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, light brown oil, MS: 385 (MN+).

Example 8

2-{4-[Ethyl-(pyridine-2-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 1,2, from ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl] amine and hydrobromide 2-pommerellen was obtained 2-{4-[ethyl-(pyridine-2-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, white solid, MS: 379 (MH+).

Example 9

2-{4-[Ethyl-(pyridine-3-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 1,2, from ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amine hydrochloride and 3-pommerellen was obtained 2-{4-[ethyl-(pyridine-3-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, light brown oil, MS: 379 (MH+).

Example 10

2-{4-[Ethyl-(pyridine-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 1,2, from ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amine hydrochloride and 4-pommerellen was obtained 2- {4-[ethyl-(pyridine-4-ylmethyl)amino]phenyl} -1,1,1,3,3,3-hexaferrite-2-ol, light brown oil, MS: 379 (MH+).

Example 11

2-{4-[benzyl-(2.2.2-triptorelin)amino]phenyl}-1,1,1,3,3,3-g is Xaltocan-2-ol

11,1

A solution of 3.0 g (of 11.6 mmole) of 2-(4-AMINOPHENYL)-1,1,1,3,3,3-hexaferrite-2-ol in 40 ml of CH2Cl2was treated with 3.0 ml of a (17.4 mmole) and DIPEA is added dropwise at 0°C. 1.8 ml (12.9 mmole) TFAA. After stirring for 1 h at RT the mixture was divided between saturated aqueous NH4Cl and Et2O. the combined organic phases were dried Na2SO4and evaporated obtaining of 4.2 g (quantitative) of crude 2,2,2-Cryptor-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]acetamide", she is a light brown oil, MS: 356 (MN+).

11.2

A solution of 4.2 g (11.8 mmole) of 2,2,2-Cryptor-N-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]ndimethylacetamide in 30 ml of THF was treated and 24.2 ml of 1M solution of complex NR3THF in THF. The mixture was stirred for 72 h at RT and then boiled under reflux for 2 hours After cooling down to CT and the mixture was divided between saturated aqueous NH4Cl and Et2O. the combined organic phases were dried Na2SO4and was evaporated. Column chromatography on silica gel using a mixture of n-heptane/EtOAc 4:1 resulted in the receipt of 3.0 g (74%) of 1,1,1,3,3,3-hexamer-2-[4-(2,2,2-triptoreline)phenyl]propan-2-ol, light brown oil, MS:342 (MN+).

11.3

A solution of 100 mg (0,29 mmole) 1,1,1,3,3,3-hexamer-2-[4-(2,2,2-triptoreline)phenyl]propan-2-ol in 0.5 mltBuOH was treated with 0.1 ml (from 0.84 mmole) of benzylbromide lane and Merivale at 100°C for 10 h in a sealed tube. Evaporation of solvent and column chromatography on silica gel using a mixture of n-heptane/EtOAc 8:1 resulted in the receipt of 10 mg (8%) 2-{4-[benzyl-(2,2,2-triptorelin)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, blue oil, MS: 432 (MN+).

Example 12

2-{4-[(5-Chlorobenzo[b]thiophene-2-ylmethyl)-(2,2,2-triptorelin)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

A solution of 100 mg (0,29 mmole) 1,1,1,3,3,3-hexamer-2-[4-(2,2,2-triptoreline)phenyl] propan-2-ol (example 11,2) in 0.5 ml+BuOH was treated with 115 mg (of 0.44 mmole) of 5-chloro-2-chlorodibenzo[b]thiophene and stirred at 120°C for 10 h in a sealed tube. Evaporation of solvent and column chromatography on silica gel using a mixture of n-heptane/EtOAc 8:1 resulted in the receipt of 30 mg (19%) 2-{4-[(5-chlorobenzo[b]thiophene-2-ylmethyl)-(2,2,2-triptorelin)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, light yellow oil, MS: 520 ((M-N)-, 1Cl).

Example 13

2-{4-[Ethyl-(2-hydroxy-2-phenylethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

13,1

A solution of 4 g (10 mmol) of ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amine (example 1,1) in 12 ml of acetonitrile was treated with 2.3 ml (20 mmol) of racemic phenyloxirane and 2.12 g (20 mmol) of lithium perchlorate. The resulting mixture was stirred over night at 80°C in a sealed tube. The crude substance was divided between saturated aqueous NH4Cl and Et2O and Obyedinennaya phase was dried Na 2SO4and was evaporated. Column chromatography on silica gel using a mixture of n-heptane/EtOAc 9:1 yielded 3.5 g (66%) of 2-{ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amino} -2-phenylethanol, light yellow oil, MS: 522 (MN+) and value (0.475) g (9%) 2-{ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amino}-1-phenylethanol, light yellow oil, MS: 522 (MN+).

13,2

A solution of 300 mg (of 0.58 mmole) of 2-{ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amino}-1-phenylethanol in 7.5 ml of THF was treated with 1.5 ml of 1M solution of TBAF in THF and stirred at RT for 1 h Evaporation of the solvent and column chromatography on silica gel using a mixture of n-heptane/EtOAc 9:1 resulted in the receipt of 153 mg (65%) of 2-{4-[ethyl-(2-hydroxy-2-phenylethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, white solid, MS: 408 (MN+).

Example 14

(R) 2- {4-[Ethyl-(2-hydroxy-2-phenylethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 13, from ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl] amine and (S) of phenyloxirane received (R) 2-{4-[ethyl-(2-hydroxy-2-phenylethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, light yellow oil, MS: 408 (MN+).

Example 15

(S) 2-{4-[Ethyl-(2-hydroxy-2-phenylethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 13, from ethyl-[4-(2,2,2-Cryptor-1 treatise is Biloxi-1-trifloromethyl)phenyl]amine and (R) of phenyloxirane received (S) 2-{4-[ethyl-(2-hydroxy-2-phenylethyl)amino]phenyl} -1,1,1,3,3,3-hexaferrite-2-ol, light yellow oil, MS: 408 (MN+).

Example 16

(R) 2-(4-{[2-(3-Chlorophenyl)-2-hydroxyethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 13, from ethyl-[4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]amine and (S) (3-chlorophenyl)oxirane received (R) 2-(4- {[2-(3-chlorophenyl)-2-hydroxyethyl]ethylamino} phenyl)-1,1,1,3,3,3-hexaferrite-2-ol, yellow oil, MS: 440 (M-N)-, 1Cl).

Example 17

2-[4-(Benzylideneamino)-3-chlorophenyl]-1,1,1,3,3,3-hexaferrite-2-ol

A solution of 20 mg (0.05 mmole) 2-[4-(benzylamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol (example 1,2) in 0.5 ml of 2-propanol was treated with 7 mg (0.05 mmole) NCS. The resulting mixture was stirred at 80°C for 10 h and the solvent was evaporated. Column chromatography on silica gel using a mixture of n-heptane/EtOAc 9:1 yielded 17 mg (82%) of 2-[4-(benzylideneamino)-3-chlorophenyl]-1,1,1,3,3,3-hexaferrite-2-ol, colorless oil, MS: 412 (MN+, 1Cl).

Example 18

2-{3-Chloro-4-[ethyl-(thiazol-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 17 from 2-{4-[ethyl-(thiazol-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol (example 7) was obtained 2-{3-chloro-4-[ethyl-(thiazol-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, light brown solid, MS: 419 (MH+, 1Cl).

Example 19

2-{4-[Benzyl-(2,2,2-triptorelin)amino]-3-chlorophenyl}-1,1,1,3,3,3-hexaferrite-2-ol

Similar what about the example 17, 2-{4-[benzyl-(2,2,2-triptorelin)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol (example 11,3) was obtained 2-{4-[benzyl-(2,2,2-triptorelin)amino]-3-chlorophenyl}-1,1,1,3,3,3-hexaferrite-2-ol, light yellow oil, MS: 466 (MN+, 1Cl).

Example 20

2-{3-Chloro-4-[ethyl-(3-phenylpropyl)AMINOPHENYL}-1,1,1,3,3,3-hexaferrite-2-ol

20,1

Analogously to example 17 from 2-(4-AMINOPHENYL)-1,1,1,3,3,3-hexaferrite-2-ol was obtained 2-(4-amino-3-chlorophenyl)-1,1,1,3,3,3-hexaferrite-2-ol, light brown solid, MS: 292 (M-N)-, 1Cl).

20.2

A solution of 1 g (3.4 mmole) of 2-(4-amino-3-chlorophenyl)-1,1,1,3,3,3-hexaferrite-2-ol in 5 ml of pyridine was treated at 0.42 ml (4.4 mmole) AU2Oh and stirred at 70°C for 10 h, the Solvent was evaporated, the residue was dissolved in THF, was treated with 2M aqueous NaOH solution and was stirred for 1 h at RT. After acidification of the mixture to pH about 7 with an aqueous solution of HCl was added Et2O and H2Oh, the phases were separated and the aqueous phase was extracted with Et2O. the combined organic phases were dried Na2SO4and was evaporated to obtain 1.1 g (about 94%) of crude N-[2-chloro-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]ndimethylacetamide, which was dissolved in 20 ml of DMF and treated with 0.65 ml (4,37 mmole) of DBU and then at 0°C dropwise to 0.73 ml (4,37 mmole) TESCl. The mixture was stirred overnight and poured into a mixture of saturated aqueous solution of NH4 Cl and Et2O. the Phases were separated and the aqueous phase was extracted with Et2O. the combined organic phases were dried Na2SO4and evaporated obtaining of 1.53 g (93%) of crude N-[2-chloro-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]ndimethylacetamide, yellow oil, MS: 450 (MN+, 1Cl).

20,3

A solution of 1.54 g (3,42 mmole) of crude N-[2-chloro-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]ndimethylacetamide in 20 ml of THF was treated 6.85 ml 1M solution of complex NR3·THF in THF. The mixture was boiled under reflux for 3 h and the solvent was evaporated. The residue was divided between saturated aqueous NH4Cl and Et2O. the combined organic phases were dried Na2SO4and the solvent was evaporated. Column chromatography on silica gel using a mixture of n-heptane/EtOAc 95:5 resulted in the receipt of 0,922 g (61%) of [2-chloro-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]-N-ethylamine, colorless liquid, MS: 436 (MN+, 1Cl).

20.4

A solution of 100 mg (0,23 mmole) of [2-chloro-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]-N-ethylamine in CH2Cl2processed 0,08 ml (0,46 mmole) DIPEA and 0.07 ml (0,46 mmole) 3-phenylpropionylamino. The mixture was stirred at RT for 10 h and was treated with 0.4 ml of 1 M solution of TBAF in THF. Evaporation of solvent and column chromatography on silica gel using with whom thou n-heptane/EtOAc 4:1 resulted in the receipt of 70 mg (67%) of N-[2-chloro-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]-N-ethyl-3-phenylpropionamide, light yellow oil, MS: 454 (MN+, 1Cl).

20,5

A solution of 70 mg (0.15 mmole) of N-[2-chloro-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]-N-ethyl-3-phenylpropionamide in 3 ml of THF was treated with 1 ml of 1M complex NR3·THF in THF and was stirred for 10 h at 80°C in a sealed tube. Evaporation of solvent and column chromatography on silica gel using a mixture of CH2Cl2/n-heptane 1:1 resulted in 60 mg (91%) of 2-{3-chloro-4-[ethyl-(3-phenylpropyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, colorless oil, MS: 440 (MN+, 1Cl).

Example 21

2-[3-Chloro-4-(ethylenediamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol

21,1

Analogously to example 20,4, from [2-chloro-4-(2,2,2-Cryptor-1 triethylsilyl-1-trifloromethyl)phenyl]-N-ethylamine and phenylacetylide was obtained N-[2-chloro-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]-N-ethyl-2-phenylacetamide, yellow resinous substance, MS: 440 (MH+, 1Cl).

21,2

Analogously to example 20,5, from N-[2-chloro-4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]-N-ethyl-2-phenylacetamide was obtained 2-[3-chloro-4-(ethylenediamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol, colorless oil, MS: 426 (MN+, 1Cl).

Example 22

1,1,1,3,3,3-Hexamer-2-{4-[[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl]-(2,2,2-triptorelin)amino]phenyl}-propan-2-ol

22,1

4-Chloromethyl-5-methyl-2-(3-triptoreline)oxazole was obtained from 3-triptoreline is zaldehyde similar methodology, described Binggeli and other (WO 02/092084).

22,2

A mixture of 100 mg (0,29 mmole) 1,1,1,3,3,3-hexamer-2-[4-(2,2,2-triptoreline)phenyl]propan-2-ol (example 11,2), 81 mg (0,29 mmole) of 4-chloromethyl-5-methyl-2-(3-triptoreline)oxazole and about 10 mg of NaI in DMF was stirred for 1 week at 125°C and then was divided between saturated aqueous NH4Cl and Et2O. Drying the combined organic phases Na2SO4and column chromatography on silica gel using a gradient of n-heptane/EtOAc resulted in the receipt of 2 mg (about 1%) of 1,1,1,3,3,3-hexamer-2-{4-[[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl]-(2,2,2-triptorelin)amino]phenyl}propan-2-ol, yellow solid, MS: 581

(MN+).

Example 23

2-{4-[[2-(3-Chlorophenyl)-5-methoxazole-4-ylmethyl]-(2,2,2-triptorelin)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

23,1

4-Chloromethyl-2-(3-chlorophenyl)-5-methoxazole was obtained from 3-chlorobenzaldehyde similarly to the method described Binggeli and other (WO 02/092084).

23,2

Analogously to example 22,2, from 1,1,1,3,3,3-hexamer-2-[4-(2,2,2-triptoreline)phenyl]propan-2-ol and 4-chloromethyl-5-methyl-2-(3-chlorophenyl)oxazole was obtained 2-{4-[[2-(3-chlorophenyl)-5-methoxazole-4-ylmethyl]-(2,2,2-triptorelin)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, yellow solid, MS: 547 (MN+, 1Cl).

Example 24

2-(4-{Ethyl-[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl]amino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol

24,

A solution of 1 g (3,86 mmole) of 2-(4-AMINOPHENYL)-1,1,1,3,3,3-hexaferrite-2-ol in 2 ml of THF and 5 ml of pyridine was treated of 0.44 ml (4,63 mmole) AU2About and was stirred for 2 h at 60°C. the Solvent was evaporated and the crude substance was divided between dilute aqueous HCl solution and Et2O. the combined organic phases were dried Na2SO4and the solvent was evaporated. The residue was dissolved in 5 ml of THF, was treated with 7.7 ml of a 1M solution NR3·THF in THF and boiled under reflux for 2 hours the Solvent was evaporated and the residue was divided between dilute aqueous NaOH solution and Et2O. the Aqueous phase is then acidified by addition of an aqueous solution model HC1 up to pH values of about 7 and was extracted with Et2O. the combined organic phases were dried Na2SO4and the solvent was evaporated to obtain 1.07 g (96%) of crude 2-(4-ethylaminomethyl)-1,1,1,3,3,3-hexaferrite-2-ol, light yellow solid, MS: 288 (MN+).

24,2

A solution of 100 mg (0.35 mmole) of 2-(4-ethylaminomethyl)-1,1,1,3,3,3-hexaferrite-2-ol and 96 mg (0.35 mmole) of 4-chloromethyl-5-methyl-2-(3-triptoreline)oxazole (example 22,1) in 0.5 ml DMF was stirred overnight at 80°Spoke separation of the crude mixture between saturated aqueous NH4Cl and Et2O the combined organic phases were dried Na2SO4and the solvent was evaporated. Speaker chromatogra the Oia on silica gel using a mixture of toluene/EtOAc resulted in the receipt of 91 mg (53%) of 2-(4-{ethyl-[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl]amino} phenyl)-1,1,1,3,3,3-hexaferrite-2-ol, yellow solid, MS: 527 (MN+).

Example 25

2-(4-{[2-(3-Chlorophenyl)-5-methoxazole-4-ylmethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 24,2, from 2-(4-ethylaminomethyl)-1,1,1,3,3,3-hexaferrite-2-ol and 4-chloromethyl-5-methyl-2-(3-chlorophenyl)oxazole (example 23,1) was obtained 2-(4-{[2-(3-chlorophenyl)-5-methoxazole-4-ylmethyl]ethylamino} phenyl)-1,1,1,3,3,3-hexaferrite-2-ol, orange solid, MS: 493 (MN+, 1Cl).

Example 26

2-(3-Chloro-4-{ethyl-[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl]amino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 17 from 2-(4-{ethyl-[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl] amino} phenyl)-1,1,1,3,3,3-hexaferrite-2-ol (example 24) was obtained 2-(3-chloro-4-{ethyl-[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl]amino} phenyl)-1,1,1,3,3,3-hexaferrite-2-ol, yellow resinous substance, MS: 561 (MN+, 1Cl).

Example 27

2-(3-Chloro-4-{[2-(3-chlorophenyl)-5-methoxazole-4-ylmethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol

Analogously to example 17 from the obtained 2-(4-{[2-(3-chlorophenyl)-5-methoxazole-4-ylmethyl]ethylamino} phenyl)-1,1,1,3,3,3-hexaferrite-2-ol (example 25) was obtained 2-(3-chloro-4-{[2-(3-chlorophenyl)-5-methoxazole-4-ylmethyl]ethylamino} phenyl)-1,1,1,3,3,3-hexaferrite-2-ol, yellow waxy solid, MS: 527 (MN+, 2Cl).

Example 28

2-(4-{[2-(3-Benzyloxyphenyl)-5-methoxazole-4-ylmethyl]these are the amino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol

28,1

2-(3-Benzyloxyphenyl)-4-chloromethyl-5-methoxazole was obtained from 3-benzyloxy-benzaldehyde analogous to the procedure described Binggeli and other (WO 02/092084).

28,2

Analogously to example 24,2, from 2-(4-ethylaminomethyl)-1,1,1,3,3,3-hexaferrite-2-ol and 2-(3-benzyloxyphenyl)-4-chloromethyl-5-methoxazole received 2-(4-{[2-(3-benzyloxyphenyl)-5-methoxazole-4-ylmethyl] ethylamino} phenyl)-1,1,1,3,3,3-hexaferrite-2-ol, white solid, MS: 563 (M-N)-.

Example 29

2-(4-{[2-(4-Benzyloxyphenyl)-5-methoxazole-4-ylmethyl]ethylamino} phenyl)-1,1,1,3,3,3-hexaferrite-2-ol

29,1

2-(4-Benzyloxyphenyl)-4-chloromethyl-5-methoxazole was obtained from 4-benzyloxy-benzaldehyde analogous to the procedure described Binggeli and other (WO 02/092084).

29,2

Analogously to example 24,2, from 2-(4-ethylaminomethyl)-1,1,1,3,3,3-hexaferrite-2-ol and 2-(4-benzyloxyphenyl)-4-chloromethyl-5-methoxazole received 2-(4-{[2-(4-benzyloxyphenyl)-5-methoxazole-4-ylmethyl] ethylamino} phenyl)-1,1,1,3,3,3-hexaferrite-2-ol, light yellow solid, MS: 563 (M-N)-.

Example 30

Methyl ester of 3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid

30.1

Methyl ester of 3-(4-chloromethyl-5-methoxazole-2-yl)benzoic acid was obtained from methyl ester 3-formylbenzoate acid analogously to the method described Binggeli and other (WO 02/092084).

30.2

Ana is ogino example 24,2, from 2-(4-ethylaminomethyl)-1,1,1,3,3,3-hexaferrite-2-ol and methyl ester of 3-(4-chloromethyl-5-methoxazole-2-yl)benzoic acid was obtained methyl ester 3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid, light yellow foam, MS: 515 (M-N)-.

Example 31

Methyl ester of 4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid

31.1

Methyl ester of 4-(4-chloromethyl-5-methoxazole-2-yl)benzoic acid was obtained from methyl ester 4-formylbenzoate acid analogously to the method described Binggeli and other (WO 02/092084).

31.2

Analogously to example 24,2, from 2-(4-ethylaminomethyl)-1,1,1,3,3,3-hexaferrite-2-ol and methyl ester of 4-(4-chloromethyl-5-methoxazole-2-yl)benzoic acid was obtained methyl ester 4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid, light yellow foam, MS: 515 (M-N)-.

Example 32

3-[4-({Ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid

A solution of 92 mg (of 0.18 mmole) of methyl ester of 3-[4-({ethyl-[4-(2,2,2-Cryptor-

1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid (example 30,2) in 1 ml THF was treated with 1 ml of a 1M aqueous solution of LiOH and stirred at RT for 1 is. The resulting mixture was acidified to pH 4-5 with aqueous solution of HCl and was divided between Et2O and H2O. the combined organic phases were dried Na2SO4and was evaporated to obtain 79 mg (88%) of 3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl] amino} methyl)-5-methoxazole-2-yl] benzoic acid, light yellow solid, MS: 503 (MN+).

Example 33

4-[4-({Ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-ilantin acid

Analogously to example 32, from methyl ester 4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid (example 31,2) was obtained 4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid, light yellow solid, MS: 503 (MN+).

Example 34

3-[4-({Ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N-methylbenzamide

A solution of 22 mg (0.04 mmole) of 3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid (example 32) in 1 ml DMF was treated with 9 mg (0,13 mmole) of methylamine hydrochloride and 0.03 ml (0,26 mmole) 4-methylmorpholine and cooled to 0°C. After addition of 12 mg (0.06 mmole) and EDCI 1 mg (0.001 mmole), the mixture NOT they were heated to CT, was stirred for 6 h and were divided settled between Et 2O and saturated aqueous NH4Cl. The combined organic phases were dried Na2SO4and was evaporated. Column chromatography on silica gel using EtOAc resulted in the receipt of 17 mg (75%) of 3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N-methylbenzamide, colorless resinous substance, MS: 516

(MN+).

Example 35

3-[4-({Ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N,N-dimethylbenzamide

Analogously to example 34 from 3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid and dimethylamine hydrochloride was obtained 3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N,N-dimethylbenzamide, colorless resinous substance, MS: 530, (MN+).

Example 36

3-[4-({Ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzamide

Analogously to example 34 from 3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid and ammonium chloride was obtained 3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzamide, colorless resinous substance, MS: 502 (MN+).

Example 37

4-[4-({Ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-triptime retil)phenyl]amino}methyl)-5-methoxazole-2-yl]-N-methylbenzamide

Analogously to example 34, from 4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid (example 33) and methylamine hydrochloride was obtained 4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N-methylbenzamide, white solid, MS: 516 (MN+).

Example 38

4-[4-({Ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N,N-dimethylbenzamide

Analogously to example 34, from 4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid (example 33) and dimethylamine hydrochloride was obtained 4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N,N-dimethylbenzamide, white solid, MS:530 (MH+).

Example 39

4-[4-({Ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzamide

Analogously to example 34 from 3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid (example 33) and ammonium chloride was obtained 4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzamide, white solid MS: 502 (MN+).

Example 40

2-{4-[(2-Benzyl-5-methoxazole-4-ylmethyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-on the Sabbath.

40,1

2-Benzyl-4-chloromethyl-5-methoxazole received from phenylacetaldehyde similarly to the method described Binggeli and other (WO 02/092084).

40,2

Analogously to example 24,2, from 2-(4-ethylaminomethyl)-1,1,1,3,3,3-hexaferrite-2-ol and 2-benzyl-4-chloromethyl-5-methoxazole and 2-benzyl-4-chloromethyl-5-methoxazole was obtained 2-{4-[(2-benzyl-5-methoxazole-4-ylmethyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, dark brown oil, MS: 473 (MN+).

Example 41

2-{4-[Ethyl-(5-methyl-2-((E)-styryl)oxazol-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

41,1

4-Chloromethyl-5-methyl-2-((E)-styryl)oxazol was obtained from (E)-3-phenylpropenal similarly to the method described Binggeli and other (WO 02/092084).

41,2

Analogously to example 24,2, from 2-(4-ethylaminomethyl)-1,1,1,3,3,3-hexaferrite-2-ol and 4-chloromethyl-5-methyl-2-((E)-storelocate and 4-chloromethyl-5-methyl-2-storelocate was obtained 2-{4-[ethyl-(5-methyl-2-((E)-styryl)oxazol-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, light yellow solid, MS: 485 (MH+).

Example 42

2-{4-[Ethyl-(5-methyl-2-penetration-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol

A solution of 40 mg (0.08 mmole) of 2-{4-[(2-benzyl-5-methoxazole-4-ylmethyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol in 1 ml Meon was treated with 20 mg of Pd/C (10%) and was first made at atmospheric pressure for 20 hours Filtration and evaporation resulted in the receipt of 25 mg (62%) of 2-{4-[the Teal-(5-methyl-2-penetration-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol, light yellow oil, MS: 487 (MN+).

Example

Film-coated tablets containing the following ingredients can be obtained in the usual way:

IngredientsPills
Engine:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Anhydrous lactose60,0 mg70.0 mg
Povidone K3012.5 mg15,0 mg
Nitroglicerine starch12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(Kernel weight)120,0 mg350,0 mg
Film coating:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg

Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredient was sieved and mixed with microcrystalline cellulose and the mixture was granulated with a solution of polyvinylpyrrolidone in water. The granulate was mixed with Nitroglycerinum starch and magnesium stearate and compressed to obtain cores weighing 120 or 350 mg, respectively. The core was coated with an aqueous solution / suspension of the above film coating.

Example B

Capsules containing the following ingredients can be obtained in the usual way:

IngredientsOn capsule
Soy is inania formula (I) 25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg

Components are sieved and mixed and filled into capsules of size 2.

The example In

Injectable solutions may have the following composition:

The compound of formula (I)3.0 mg
The polyethylene glycol 400150,0 mg
Acetic acidto pH 5.0
Water for injection solutionsto 1.0 ml

The active ingredient was dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH value was brought to 5.0 with acetic acid. The volume was made up to 1.0 ml by adding the remaining amount of water. The solution was filtered, filled into vessels using the right equipment and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can be obtained in the usual way:

The contents of the capsules
The compound of formula (I)5.0 mg
Yellow wax8.0 mg
Gidrirovannoe soybean oil8.0 mg
Partially hydrogenated vegetable oil34,0 mg
Soybean oil110,0 mg
The weight of the contents of the capsules165,0 mg
Gelatin capsule
Gelatin75,0 mg
Glycerol 85%32,0 mg
The Karion 838.0 mg (dry matter)
Titanium dioxide0.4 mg
Iron oxide yellow1.1 mg

The active ingredient was dissolved in the hot melt the other ingredients and the mixture was filled in soft gelatin capsules of suitable size. Filled soft gelatin capsules were treated in accordance with ordinary the mi methods.

Example D

The sachet containing the following ingredients can be obtained in the usual way:

The compound of formula (I)50.0 mg
Lactose, fine powder1015,0 mg
Microcrystalline cellulose (AVICEL PH 102)1400,0 mg
The sodium carboxymethyl cellulose14,0 mg
Polyvinylpyrrolidone K 3010.0 mg
Magnesium stearate10.0 mg
Odorants1.0 mg

The active ingredient was mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules were mixed with magnesium stearate and fragrances and filled into sachets.

1. The compounds of formula (I):

where R1represents hydrogen, halogen;
R2represents lower alkyl, fluoro-lower alkyl;
R3represents hydrogen, phenyl;
R4represents hydrogen, hydroxy;
R5 represents hydrogen, phenyl;
R6represents phenyl, 5-6 membered heteroaryl containing one or two heteroatoms, selected from nitrogen and sulfur, 9-membered bicyclic heteroaryl containing a sulfur atom as a heteroatom, which may be optionally substituted with halogen,
or R6represents a
;
R7represents lower alkyl;
R8represents phenyl which is optionally substituted by 1 Deputy selected from the group consisting of halogen, fluoro-lower-alkyl, R9-O-C(O)-,
R10R11NC(O)-, phenyl-lower alkoxy;
R9, R10, R11independently from each other represent hydrogen or lower alkyl;
L represents a simple bond, a lower alkylene or lower albaniles;
m has a value from 0 to 3;
n is 0 or 1;
and their pharmaceutically acceptable salts and esters.

2. Compounds according to claim 1, where R1represents a hydrogen or chlorine.

3. Compounds according to claim 1, where R2represents ethyl or 2,2,2-triptorelin.

4. Compounds according to claim 1, where R3represents hydrogen.

5. Compounds according to claim 1, where R5represents hydrogen.

6. Compounds according to claim 1, where R6represents phenyl, pyridinyl, thiazolyl or benzo[b]thiophenyl, which is not necessarily Emesene halogen.

7. Compounds according to claim 1, where R6represents phenyl, chlorophenyl, pyridinyl, thiazolyl or chlorobenzo[b]thiophenyl.

8. Compounds according to claim 1, where R6represents phenyl.

9. Compounds according to claim 1, where R6represents a

where R7represents lower alkyl;
R8represents phenyl which is optionally substituted by a Deputy selected from the group consisting of halogen, fluoro-lower-alkyl, R9-O-C(O)-,
R10R11NC(O) -, and phenyl-lower alkoxy;
R9represents hydrogen or lower alkyl;
R10and R11independently from each other represent hydrogen or lower alkyl;
L represents a simple bond, a lower alkylene or lower albaniles.

10. Compounds according to claim 9, where R7represents methyl.

11. Compounds according to claim 9, where R8represents phenyl, substituted fluoro-lower alkyl, halogen, carboxy or (lower alkyl)2NC(O)-.

12. Compounds according to claim 9, where R8is a 3-triptoreline, 3-chlorophenyl, 4-carboxyphenyl or 4-(CH3)2NC(O)phenyl.

13. Compounds according to claim 9, where L is a simple link.

14. Compounds according to claim 1, where m has a value from 0 to 2.

15. Compounds according to claim 1, where m denotes 0.

16. Compounds according to claim 1, where n denotes 0.

17. Link is but to claim 1, selected from the group consisting of the following compounds:
2-[4-(benzylamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol,
2-{4-[(2-Chlorobenzyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{4-[(3-Chlorobenzyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{4-[(4-chlorbenzyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-[4-(ethylenediamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol,
2-[4-(benzyldimethylamine)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol,
2-{4-[ethyl-(thiazol-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{4-[ethyl-(pyridine-2-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{4-[ethyl-(pyridine-3-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{4-[ethyl-(pyridine-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{4-[benzyl-(2,2,2-triptorelin)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{4-[(5-chlorobenzo[b]thiophene-2-ylmethyl)-(2,2,2-triptorelin)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{4-[ethyl-(2-hydroxy-2-phenylethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
(R) 2-{4-[ethyl-(2-hydroxy-2-phenylethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
(S) 2-{4-[ethyl-(2-hydroxy-2-phenylethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
(R) 2-(4-{[2-(3-chlorophenyl)-2-hydroxyethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
2-[4-(benzylideneamino)-3-chlorophenyl]-1,1,1,3,3,3-hexaferrite-2-ol,
2-{3-chloro-4-[ethyl-(thiazol-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{4-[benzyl-(2,2,2-triptorelin)amino]-3-chlorophenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-{3-chloro-4-[ethyl-(3-phenylpropyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-[3-chloro-4-(ethylenediamino)phenyl]-1,1,1,3,3,3-hexaferrite-2-ol,
1,1,1,3,3,3-hexamer-2-{4-[[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl]-(2,2,2-triptorelin)amino]phenyl}propan-2-ol,
2-{4-[[2-(3-chlorophenyl)-5-methoxazole-4-ylmethyl]-(2,2,2-triptorelin)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-(4-{ethyl-[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl]amino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
2-(4-{[2-(3-chlorophenyl)-5-methoxazole-4-ylmethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
2-(3-chloro-4-{ethyl-[5-methyl-2-(3-triptoreline)oxazol-4-ylmethyl]amino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
2-(3-chloro-4-{[2-(3-chlorophenyl)-5-methoxazole-4-ylmethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
2-(4-{[2-(3-benzyloxyphenyl)-5-methoxazole-4-ylmethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
2-(4-{[2-(4-benzyloxyphenyl)-5-methoxazole-4-ylmethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
methyl ester of 3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid
methyl ester of 4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid
3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)FeNi is]amino}methyl)-5-methoxazole-2-yl]benzoic acid,
4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid,
3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N-methylbenzamide,
3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N,N-dimethylbenzamide,
3-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzamide,
4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N-methylbenzamide,
4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N,N-dimethylbenzamide,
4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzamide,
2-{4-[(2-benzyl-5-methoxazole-4-ylmethyl)ethylamino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-(4-{ethyl-[5-methyl-2-((E)-styryl)oxazol-4-ylmethyl]amino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol and
2-{4-[ethyl-(5-methyl-2-penetration-4-ylmethyl)amino]phenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
and their pharmaceutically acceptable salts and esters.

18. Compounds according to claim 1, selected from the group consisting of the following compounds:
2-[4-(benzylideneamino)-3-chlorophenyl]-1,1,1,3,3,3-hexaferrite-2-ol,
2-{4-[benzyl-(2,2,2-triptorelin)amino]-3-chlorophenyl}-1,1,1,3,3,3-hexaferrite-2-ol,
2-(4-{ethyl-[5-methyl-2-(3-Tr is formationl)oxazol-4-ylmethyl]amino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
2-(4-{[2-(3-chlorophenyl)-5-methoxazole-4-ylmethyl]ethylamino}phenyl)-1,1,1,3,3,3-hexaferrite-2-ol,
4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]benzoic acid, and
4-[4-({ethyl-[4-(2,2,2-Cryptor-1-hydroxy-1-trifloromethyl)phenyl]amino}methyl)-5-methoxazole-2-yl]-N,N-dimethylbenzamide,
and their pharmaceutically acceptable salts and esters.

19. Pharmaceutical compositions having the properties of an agonist of LXR-alpha and/or LXR-beta, containing as active ingredient a compound according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier and/or adjuvant.

20. Compounds according to any one of claims 1 to 18, having the properties of an agonist of LXR-alpha and/or LXR-beta.

21. Compounds according to any one of claims 1 to 18 as an active substance for obtaining a medicinal product having the properties of an agonist of LXR-alpha and/or LXR-beta.

22. The use of compounds according to any one of claims 1 to 18 for the manufacture of drugs for therapeutic and/or prophylactic treatment of diseases which are modulated LXR-alpha and/or LXR beta agonists.

23. The use of compounds according to any one of claims 1 to 18 for the manufacture of medicinal products intended for therapeutic and/or prophylactic treatment of increased lipid levels, increased cholesterol levels, low HDL cholesterol, high LDL-choles the Wendy Erin, atherosclerotic diseases, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, sepsis, inflammatory diseases, skin diseases, colitis, pancreatitis, cholestasis of the liver, liver fibrosis, macular degeneration and/or Alzheimer's disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I

where A, B and D each denotes N or CR5, where one of A, B and D denotes N, R1 denotes OR6, R2 denotes halogen, C1-C4alkyl, halogen(C1-C4)alkyl or OR7, R3 denotes a heteroarylalkyl group in which the heteroaryl fragment contains 5-6 atoms in the ring, at least one of which is an N atom, and the alkyl fragment with a branched or straight chain contains 1-5 carbon atoms, R4 denotes C3-C10cyclalkyl, C6-C14aryl, unsubstituted or substituted with one or more substitutes selected from a group comprising halogen, alkoxy, terazol-5-yl, 2-(heterocyclyl)tetrazol-5-yl or a carboxy group; heteroaryl containing 5-6 atoms in the ring; heterocyclic group saturated or partially saturated, containing 5-6 atoms in the ring, at least one of which is an N atom, unsubstituted or substituted with one or more substitutes selected from a group comprising alkoxy, alkoxyalkoxy, oxo, alkoxycarbonyl, alkylsulfanyl, alkylsufonyl or phenylsulfonyl; R5 denotes H; R6 denotes H or C1-C4alkyl with a branched or straight chain, unsubstituted or substituted with one or more halogens, R7 denotes H or C1-C12alkyl with a branched or straight chain, unsubstituted or substituted with one or more substitutes selected from a group which includes halogen; C3-C10cyclalkyl; saturated heterocyclic group containing 5-6 atoms in the ring, at least one of which is an O atom, or a heterocylcylalkyl group in which the heterocyclic fragment is saturated, partially saturated or unsaturated and contains 5-10 atoms in the ring, at least one of which is an O atom; or to a pharmaceutically acceptable salt thereof, as well as to a pharmaceutical composition for inhibiting PDE4 enzyme activity and to use of the said compound to prepare a medicinal agent.

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

65 cl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a thiazole compound with formula

by reacting a compound with formula with ammonia and formaldehyde, obtaining a hexahydrotriazine compound with formula , with subsequent hydrolysis of compound with formula (2), as well as compounds with general formula (2) and a method of producing said compounds. In general formulae (1), (2) and (3) X1 is a hydrogen atom or a halogen atom, X2 is a halogen atom.

EFFECT: method is described for producing thiazole through aminomethylation.

13 cl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 5-amidino-2-hydroxybenzenesulfonamide of the general formula (I): wherein R2 means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (A): wherein (A) means -COORA, -CONRBRC, 3-7-membered monocyclic heterocycloalkyl group comprising one or two heteroatom in ring chosen from atoms N, O, S that can comprise oxo-group and 5-6-membered monocyclic aromatic heterocyclic group comprising one-three heteroatoms in ring chosen from atoms N, O, S that can comprise oxo-group or lower alkyl wherein RA means hydrogen atom (H), 3-7-membered monocyclic aliphatic alkyl group, lower alkyl that can comprises a substitute chosen from the group (i) wherein (i) means -COORA1 wherein RA1 means hydrogen atom (H), -OCORA2 wherein RA2 means lower alkyl group, -OCOORA3 wherein RA3 means lower alkyl, -ORA4 wherein RA4 means hydrogen atom (H), lower alkyl -CONRA5RA6 wherein RA5 and RA6 mean independently hydrogen atom (H), lower alkyl, or -NRA5RA6 forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; wherein RB and RC mean independently hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (ii), or -NRBRC forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; (ii) means -COORB1 wherein RB1 means hydrogen atom (H), lower alkyl; T means oxygen atom (O), sulfonyl group; or TR1 means -SO2NRB3RC3 wherein RB3 and RC3 means independently hydrogen atom (H), lower alkyl; R2 means lower alkyl, phenyl that can comprise one-three substitutes chosen from the group (B) wherein (B) means halogen atom, -COORE, sulfamoyl, lower alkylsulfonyl wherein RE means lower alkyl; Q means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (D) wherein (D) means 5-6-membered monocyclic aromatic heterocyclic group that can comprise one-three heteroatom chosen from atoms N, O, S that can comprise a substitute chosen from the group (iv) wherein (iv) means oxo-group, lower alkyl; Z means hydrogen atom (H), hydroxyl group (OH), -COORN wherein RN means lower alkyl that can comprise a substitute chosen from the group (viii) wherein (viii) means -OCOR5 wherein RN5 means lower alkyl that can comprise -OCORN51 wherein RN51 means lower alkyl; or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit activated factor X in blood coagulation system that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and compositions.

12 cl, 5 tbl

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new compound, i. e. to 4-[2-(aminomethyl)-1,3-thiazole-4-yl]-2,6-di-(tert.-butyl)phenol and a pharmaceutical composition used for inhibition of lipid peroxidation and/or as a modulating agent of sodium channels and a medicinal agent comprising this compound. Invention provides the enhanced effectiveness of inhibition of lipid peroxidation and modulation of sodium channels activity.

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

22 cl, 349 ex

The invention relates to new and nitrate salts of heterocyclic compounds of formulas (a) and (b), where R is hydrogen, alkoxyl, R1- alkyl, alkoxyl, R2is hydrogen, alkyl, R3- alkyl, alkoxyl, X denotes N-R11or oxygen, R11means the free valence, Y represents N-R16, sulfur or alkyl, R16means hydrogen; other values radicals presented in the description of the invention

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol-substituted ether derivatives of formula (I) to their pharmaceutically acceptable salts and to esters which are capable of bonding with LXR-alpha and/or LXR-beta, as well as to pharmaceutical compositions based on said compounds. In formula (I) R1 is hydrogen, lower alkyl or halogen, one of groups R2 and R3 is hydrogen, lower alkyl or halogen, and the second of groups R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6. Values of R4, R5, R6 m and n are given in the formula of invention.

EFFECT: novel compounds have useful biological properties.

22 cl, 4 dwg, 102 ex

FIELD: chemistry.

SUBSTANCE: invention relates to versions of the method of producing chiral non-racemic compound of formula I where R1 represents . Values of the rest of the radicals are given in the formula of invention. Formula I compound is obtained in several steps. The starting material used is cis-1,3-cyclohexanediol. One of the key steps is enzymatic formation of ester or enzymatic splitting of ester.

EFFECT: method is described for production of enantiomeric forms of derivatives of 1,3-cyclohexanedio in cis orientation.

8 cl, 80 ex

FIELD: chemistry.

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

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

10 cl, 5 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula and their pharmaceutically acceptable salts used as inhibiting agent in the relation of fermentative beta-secretase and it also relates to pharmaceutical compositions based on the formula. In general formula one of RN and RN' represents hydrogen, and another represents - C(=O)-(CRR')0-6R100, or where R4 is chosen from the group including H; NH2; -NR50CO2R51; -(C1-C4)-alkyl-NR50CO2R51; where n7 is equal to 0, 1, 2 or 3; R50 represents H or C1-C6alkyl; R51 is chosen from the group including phenyl-(C1-C4)-alkyl and (C1-C6)-alkyl; X is chosen from the group including -(C1-C6)-alkylidenyl optionally substituted with 1, 2 or 3 metal groups; Z is chosen from the group including bond, SO2, SO and S; Y stands for (C1-C10)-alkyl; R1 represents -(C1-C6)-alkylphenyl where phenyl ring is optionally substituted by 1, 2, 3 or 4 halogen atoms; R and R' independently represent hydrogen or (C1-C6)-alkyl; R2 represents hydrogen; R3 represents hydrogen; Rc represents - (CR245R250)0-4-aryl; where aryl is optionally substituted by 1, 2 or 3 R200; R200 is chosen from the group including (C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups R205; halogen; C=N; R205 stands for halogen; R245 and R250 in each case stands for H; either R245 or R250 are taken together with carbon atom whereto attached to form carbocycle from 3, 4, 5, 6 or 7 carbon atoms; R100 represents 5-6-merous heteroaryl with 1-2 heteroatoms chosen from nitrogen and sulphur, -phenyl-W-heteroaryl where heteroaryl is 5-6-merous ring containing 1-2 heteroatoms, chosen from nitrogen and oxygen and where cyclic parts of each group are optionally substituted by 1, 2 or 3 groups independently chosen among C1-C6alkyl, -(CH2)0-4-CO2-NR105R'105, -(CH2)0-4-SO2-NR105R'105, -(CH2)0-4-N(R150)-CO-R105, -(CH2)0-4-N(R150)-SO2-R105; W represents -(CH2)0-4; R105 and R'105 independently represent (C1-C6)-alkyl optionally substituted with -NH2 or halogen; R150 represents hydrogen.

EFFECT: compounds can be applied to prevent and treat diseases mediated by excess activity of beta-secretase such as Alzheimer's disease.

11 cl, 12 tbl, 3 dwg, 1729 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula (I): where R1 and R2 each independently represents a hydrogen atom, C1-8 alkyl or a halogen atom; R3 represents C1-8 alkyl, which can be substituted with 1-3 halogen atom(s) or phenyl; R4 represents a hydrogen atom or C1-8 alkyl; R5 and R6 each independently represents a hydrogen atom; X represents a sulphur atom or oxygen atom; ring A is 4-(trifluoromethyl)piperidin-1-yl, 2,2-difluoro-1,3- benzodioxol-5-yl or 3,4-dihydro-1H-isoquinolin-2-yl. The invention also relates to salts or solvates of this derivative, as well as medicinal preparation, pharmaceutical composition, method of preventing and/or treating diseases, caused by PPAR, and use of this derivative.

EFFECT: obtaining new biologically active compounds, which can be used for preventing and/or treating diseases caused by PPARδ.

8 cl, 39 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula , in which R represents H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl. In the alkyl, one or more CH2-groups can be substituted with -O-. The invention also relates to the method of obtaining these compounds. The method involves reacting dimethylbenzoic acid ester with formula where R assumes values given above, with a chlorinating agent in an inert solvent or without a solvent at temperature above 40°C, and then cleaning, if necessary. Formula (I) compounds are essential intermediate products during synthesis of PPAR agonists with formula , in which R represents H, (C1-C12)-alkyl or (C1-C4)-alkyl-(C6-C12)-aryl. In the alkyl, one or more CH2-groups can be substituted with -O-; Y represents -(CH2)3-, 1,3-phenylene, 1,3-cyclohexanediyl; R' represents H, F, Br, CF3, (C1-C6)-alkyl, O-(C1-C6)-alkyl, phenyl; CF3; obtained from reaction of compounds with formula with formula (I) compounds in toluene, N-methylpyrrolidone or other aprotic solvents, in the presence of a suitable base, at temperature lying in the -78°C - +50°C interval, with subsequent extractive processing and, if necessary, crystallisation of the end product.

EFFECT: obtaining new compounds.

8 cl, 5 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

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

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

9 cl, 2 tbl, 67 ex

FIELD: chemistry; oxa-and thiazole derivatives.

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

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

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of [18F]fluororganic compounds ensured by reaction of [18F]fluoride and relevant halogenide or sulphonate with alcoholic vehicle of formula 1 where R1, R2 and R3 represent hydrogen atom or C1-C18 alkyl.

EFFECT: possibility for mild process with low reaction time and high yield.

21 cl, 2 tbl, 27 ex

FIELD: chemistry.

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

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

13 cl, 2 tbl, 22 dwg, 88 ex

FIELD: chemistry of organophosphorus compounds, chemical technology.

SUBSTANCE: invention describes a method for synthesis of monohydroperfluoroalkanes, bis-(perfluoroalkyl)phosphinates and perfluoroalkylphosphonates. Method involves treatment of at least one perfluoroalkylphosphorane with at least one base wherein base(s) are chosen from group consisting of alkali-earth metal hydroxides, metalloorganic compound in useful solvent or at least one organic base and an acid in useful reaction medium. Also, invention describes novel perfluoroalkylphosphonates and bis-(perfluoroalkyl)phosphinates, using novel perfluoroalkylphosphonates and bis-(perfluoroalyl)phosphinates as ionic liquids, catalysts of phase transfer or surfactants.

EFFECT: improved method of synthesis.

18 cl, 19 ex

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