Imidazole derivatives, pharmaceutical composition and method of prevention and/or treatment based on them

 

(57) Abstract:

The invention relates to new imidazole derivative of the formula (I): where R1represents phenyl or pyridinyl, substituted by substituents selected from the group comprising (1) phenyl, (2) furyl, thienyl, (3) halogen, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted phenyl, (8) lower quinil, optionally substituted phenyl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl or phenyl, (10) lower alkyl, optionally substituted, phenyloxy or (11) amino, optionally substituted protected carboxyla; R2represents lower alkyl; R3represents halogen or lower alkyl; R4represents (1) lower alkenyl, optionally substituted phenyl, (2) phenyl, optionally substituted lower alkyl or lower alkenyl, (3) lower alkyl or (4) thienyl, optionally substituted with halogen; a represents a lower alkylene and L represents a simple bond, a lower albaniles or lower alkylene, optionally substituted phenyl or pyridinyl, or-X-CH2- where X represents O or NR5where R5represents hydrogen and eticheskoi composition and preparation having hypoglycemic activity, on the basis of these compounds. The technical result is to provide new compounds and pharmaceutical preparations on their basis in the prevention and/or treatment of disorders associated with deterioration of glucose tolerance, diabetes, diabetes in pregnancy, diabetes complications, syndrome of insulin resistance, polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases, hyperglycemia, pancreatitis, osteoporosis, hyperuricemia, hypertension, inflammatory bowel disease, skin diseases associated with abnormal differentiation of epidermal cells. 6 C. and 8 C.p. f-crystals, 2 tab.

The present invention relates to new derivatives of imidazole. In particular the present invention relates to new derivatives of imidazole and their salts, possess hypoglycemic activity or PDE-V inhibitor activity. The present invention also relates to methods of producing the above-mentioned imidazole derivatives and their salts. Moreover, the present invention relates to pharmaceutical compositions containing the above-mentioned imidazole derivative or its salt as an active ingredient.

Us the practical preparations, containing the above-mentioned imidazole derivative or its pharmaceutically acceptable salt as an active ingredient, which is used as a tool for the prevention and/or treatment of diseases associated with reduced glucose tolerance, diabetes (e.g. type II diabetes), diabetes, pregnant, diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, and the like), syndrome of insulin resistance (e.g., abnormalities of insulin receptors, syndrome Rabson-Mendenhall, leprechaunism, syndrome Kobberling-Dunnigan syndrome Seip syndrome Lawrence, Cushing's syndrome, acromegaly, and the like), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disease (e.g. angina, heart failure, and the like), hyperglycemia (e.g., those that are characterized by metabolic sugars such as disorders associated with eating), pancreatitis, osteoporosis, hyperuricemia, hypertension, inflammatory diseases is the result of which is based on suppressing the activity of cGMP-PDE (especially PDE-V), the relaxation of smooth muscle, bronchodilation activity, vasodilatation activity, suppressing the activity of smooth muscle cells, the suppression of allergies and the like, are used as tools for the prevention and/or treatment of angina, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy, (e.g., diabetic glomerulosclerosis), tubular intestinal diseases (e.g., renal disease, induced by FK506, cyclosporin and the like), renal failure, atherosclerosis, angiostenosis, (e.g., after percutaneous arterioplasty), peripheral vascular disease, apoplexy, chronic reversible obstructive disorders (for example, bronchitis, asthma including chronic asthma and allergic asthma), autoimmune diseases, allergic rhinitis, urticaria, glaucoma, diseases characterized by the deterioration of gut motility (e.g., irritable bowel syndrome), impotence (e.g., organic impotence, physical impotence, and the like), nephritis, cancer cachexia, restenosis after RTSA, cachexia (e.g., progressive weight loss due to lipolisis, endocrine diseases and AIDS), and the like.

A derivative of imidazole (hereinafter referred to as the target compound (I)), which is a new compound of the present invention, has the formula (I):

where R1represents an aryl or heterocyclic group, substituted Deputy selected from the group comprising (1) aryl, (2) heterocyclic group, (3) halogen, (4) halogen (lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted aryl, (8) lower quinil, optionally substituted aryl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl or aryl, (10) aryloxy and (11) amino, optionally substituted by protected carboxy or lower alkyl;

R2represents lower alkyl;

R3represents hydrogen, halogen, lower alkyl or nitro;

R4represents (1) lower alkenyl, optionally substituted aryl or heterocyclic group, (2) aryl, optionally substituted lower alkenyl, (3) lower alkyl or (4) heterocyclic group optionally substituted with halogen;

And represents the lowest alkylen; and

L represents what Ruppel, or-X-CH2- where X represents-O-, NR5where R5represents hydrogen or lower alkyl, or-S-.

The preferred salt of the target compound (I) are conventional salts, which are non-toxic and acceptable for use as a drug. Examples include salts with alkali metal such as sodium and potassium, salts with alkaline earth metal such as calcium and magnesium, salts with inorganic base, such as ammonium salt, salt with organic amine, such as triethylamine, pyridine, picoline, ethanolamine, and triethanolamine, salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid and phosphoric acid, salts of organic carboxylic acids, such as formic acid, acetic acid, triperoxonane acid, maleic acid and tartaric acid, salts of adding sulfonic acid, such as methanesulfonate acid, benzolsulfonat acid and p-toluensulfonate acid, and salts or salt adding a base, such as basic or acidic amino acid such as arginine, aspartic acid and glutamic acid.

The target compound (I) to present the image the value 1:

where each symbol in the formulas defined above.

Many of the definitions above and below here are explained in detail below.

"Lower" means from 1 to 6 carbon atoms, unless otherwise specified.

"Alkyl" and "alkyl group" are each preferably straight or branched alkyl. Preferable specific examples include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, tert-butyl, sec-butyl, 1-pentyl, isopentyl, sec-pentyl, tert-pentyl, methylbutyl, 1,1-dimethylpropyl, 1-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-1-methylpropyl, 1-heptyl, 1-etylhexyl, 2-etylhexyl, 3-etylhexyl, 4-etylhexyl, 5-methylhexan, 1-ethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 1,1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1-propinball, 1-octyl, 1-methylheptan, 2-methylheptan, 3-methylheptan, 4-methylheptan, 5-methylheptan, 6-methylheptan, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 5-ethylhexyl, 1,1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 5,5-diethylhexyl, 1-propylpentyl, 2-propylpentyl and the like.

Of them, preferred is alkenyl containing from 2 to 6 carbon atoms and more preferably ethynyl.

"Cyclo(lower)alkyl" represents cycloalkyl containing from 3 to 10, preferably from 3 to 7 carbon atoms. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and more preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Examples of preferred "lower alkylene" include methylene, ethylene, propylene, butylene, pentile, hexylen and the like, and more preferably alkylene containing up to 4 carbon atoms. Of them, particularly preferred is methylene.

Examples of preferred "lower quinil" include straight or branched quinil, such as ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-butinyl, 1-hexenyl, 5-hexenyl and the like.

Of them, particularly preferred is the LASS="ptx2">Examples of preferred "lower Alcanena" include straight or branched albaniles, such as ethenylene, 1-propanole, 2-propanole, 1-butylen, 2-butylen, 3-butylen, 1-penttinen, 2-penttinen, 3-penttinen, 4-penttinen, 1-hexarelin, 2-hexarelin, 3-hexarelin, 4-hexarelin, 5-hexarelin, methyladenine, utilitarian, 1-Ventilatoren and the like.

Of them, particularly preferred is albaniles containing up to 4 carbon atoms, more preferably ethenylene.

"Lower alkoxy" represents a straight or branched, alkyloxy containing up to 6 carbon atoms. Preferred examples include methoxy, ethoxy, 1 propyloxy, out-propyloxy, 1 bucalossi, isobutoxy, sec-Butylochka, tert-bucalossi, 1-pentyloxy, isopentylamine, sec-pentyloxy, tert-pentyloxy, 2-methylbutoxy, 1 hexyloxy, isohexyl, tert-hexyloxy, sec-hexyloxy, 2-methylpentane, 3 methylpentane, 1 ethylbutyrate, 2-ethylbutylamine, 1,1-dimethylbutylamino, 2,2-dimethylbutylamino, 3,3-dimethylbutylamino, 1-ethyl-1-methylpropyloxy and the like.

More preferred is an alkoxy containing up to 5 carbon atoms, such as methoxy, ethoxy, 1 propyloxy, isopropoxy, 1 bucalossi, Ysera as a fluorine atom, the chlorine atom, bromine atom and iodine atom.

"Halo(lower)alkyl" represents a straight or branched alkyl containing up to 6 carbon atoms, substituted by a fluorine atom, chlorine atom, bromine atom or iodine atom, and preferably a straight or branched alkyl containing 6 carbon atoms, substituted by a fluorine atom, a chlorine atom or a bromine atom. Examples include fluorine-methyl, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, methyl bromide, dibromomethyl, tribromoethyl, 1-foretel, 1-chloroethyl, 1-bromacil, 2-foretel, 2-chloroethyl, 2-bromacil, 1,2-dottorati, 1,2-dichloroethyl, 1,2-dibromoethyl, 2,2,2-triptorelin, heptapteridae, 1-forproper, 1-chloropropyl, 1-bromopropyl, 2-forprofit, 2-chloropropyl, 2-bromopropyl, 3-forproper, 3-chloropropyl, 3-bromopropyl, 1,2-direcror, 1,2-dichloropropyl, 1,2-dibromopropyl, 2,3-direcror, 2,3-dichloropropyl, 2,3-dibromopropyl, 3,3,3-cryptochromes, 2,2,3,3,3-pentafluoropropyl, 2-terbutyl, 2-chlorobutyl, 2-bromobutyl, 4-terbutyl, 4-chlorobutyl, 4-bromobutyl, 4,4,4-tripcomputer, 2,2,3,3,4,4,4-heptafluorobutyl, performatic, 2-terpencil, 2-chloropentyl, 2-bromopentyl, 5-terpencil, 5-chloropentyl, 5-bromopentyl, performancel, 2-forexer, 2-chlorhex, 2-bromohexyl, 6-forexer, 6-chlorhex, 6-bromohexyl, PE is containing up to 6 carbon atoms, which presents, preferably methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyric, sec-butylthio, tert-butylthio, n-pentylthio, isopentyl, sec-pentylthio, tert-pentylthio, 2-methylbutyl, n-hexylthio, isohexyl, tert-hexylthio, second-hexylthio, 2-methylphenylthio, 3 methylphenylthio, 1 ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-1-methylpropyl and the like.

More preferred is alkylthio containing up to 4 carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyric, sec-butylthio, tert-butylthio and the like.

In the present description "aryl" and "aryl group" refers to each unsubstituted aryl or alkyl-substituted aryl. Examples of preferably unsubstituted aryl include C6-C10aryl, such as phenyl, naphthyl and pentalene. Of them, preferred are phenyl and naphthyl.

"Alkyl-substituted aryl" means aryl substituted by at least one alkyl. The number of alkyl substituents is from 1 to 4.

Aryl group "alkyl-substituted aryl" represents the same above-mentioned unsubstituted aryl, and an alkyl group such that the aqueous alkyl-substituted aryl include tolyl, xylyl, mesityl, ethylphenyl, propylphenyl and the like, and more preferably p-tolyl.

"Heterocyclic group" is a saturated or unsaturated, heterogenities or heteroalicyclic group containing at least one heteroatom such as oxygen atom, sulfur atom, nitrogen atom and a selenium atom. Of these unsaturated heterophilically group is preferred. More preferred are heterocyclic groups are described in the following (1), (7) and (9), which are particularly preferably pyridyl, thienyl and furyl.

Heterophilically group includes the following.

(1) unsaturated 3 to 8-membered (more preferably 5 - or 6-membered) heterophilically group containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridin, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl and 2H-1,2,3-triazolyl), tetrazolyl (for example, lH-tetrazolyl and 2N-tetrazolyl) and the like.

(2) Saturated 3 to 8-membered (more preferably 5 - or 6-membered) heterophilically group containing 1 to 4 nitrogen atoms, such as pyrrolidinyl,part 5 - or 6-membered) heterophilically group, containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,5-oxadiazolyl) and the like.

(4) Saturated 3 to 8-membered (more preferably 5 - or 6-membered) heterophilically group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl, Sidney and the like.

(5) unsaturated 3 to 8-membered (more preferably 5 - or 6-membered) heterophilically group containing 1 or 2 sulfur atom and 1 to 3 nitrogen atoms, such as thiazolyl, isothiazolin, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl and 1,2,5-thiadiazolyl), dihydrothiazine and the like.

(6) Saturated 3 to 8-membered (more preferably 5 - or 6-membered) heterophilically group containing 1 or 2 sulfur atom and 1 to 3 nitrogen atoms, such as diazolidinyl and the like.

(7) unsaturated 3 to 8-membered (more preferably 5 - or 6-membered) heterophilically group containing 1 or 2 sulfur atom, such as thienyl, dehydrodidemnin, dehydratation and the like.

(8) Saturated 3 to 8-membered (more preferably 5 - or 6-membered) heterophilically group, anusasana 3-8-membered (more preferably 5 - or 6-membered) heterophilically group, containing one oxygen atom, such as furyl and the like.

(10) Spiroheterocyclic group containing 1 or 2 oxygen atom, such as dissapionting (for example, 1.5-dioxaspiro[5,5]undecane) and the like.

(11) unsaturated 3 to 8-membered (more preferably 5 - or 6-membered) heterophilically group containing one oxygen atom and 1 or 2 sulfur atom, such as dihydroxyethyl.

Examples heteroalicyclic groups include the following.

(12) Saturated or unsaturated 7 to 12-membered (more preferably 8-10-membered) heteroalicyclic (more preferably heterocyclics) group containing 1 to 4 nitrogen atom.

Specific examples include benzimidazolyl, indolyl, 2,3-dehydrobenzperidol, pyrazolopyrimidines (for example, pyrazolo[1,5-a]pyrimidinyl), tetrahydropyrimidines (e.g., 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl), imidazopyridines (e.g., 4H-imidazo[1,2-b]pyrazolyl), dihydroimidazole (for example, 2,3-dihydroimidazo[1,2-b]pyrazolyl), imidazopyridine (for example, imidazo[1,5-a] (or [1,2-a] or [3,4-a])pyridyl, 1H. (or 3H)-imidazo[4,5-b] (or [4,5-C])pyridyl), pyrrolopyridine (for example, 1H-pyrrolo[3,2-b]pyridyl), pyrazolopyrimidine (is Enzo[with]pyrazolyl), dehydrobenzperidol, benzotriazolyl (for example, benzo[d][1H-1,2,3]-triazolyl), indolizinyl, isoindolyl (for example, lH-isoindolyl), indazole (e.g., 1H. (or 2H or 3H)-indazole), indolinyl, isoindolyl, purinol, hinolinol (e.g., 4H-hinolinol), ethanolic, INAIL, Paladini, naphtalenes (for example, 1,8-naphtalenes), honokalani, dihydroquinoxaline (for example, 1,2-dihydroquinoxaline), tetrahydroquinoxaline (for example, 1,2,3,4-tetrahydroquinoxaline), hintline, dihydroquinazolines (for example, 1,4 (or 3,4)-dihydroquinazolines), tetrahydroquinazoline (for example, 1,2,3,4-tetrahydro-hintline), cinnoline, pteridine, pyrazinamidase (e.g., pyrazino[2,3-d]pyridazinyl), imidazolidinyl (for example, imidazo[1,2-b][1,2,4]triazinyl), imidazopyridine (for example, 1H-imidazo[4,5-b]pyrazinyl), imidazopyridine (for example, 3H-purine, imidazo[1,5-a] (or [3,4-a] pyrimidine), imidazopyridine (for example, imidazo[2,3-b] (or [3,4-b])pyridazinyl), 1H-1-(or 2)pyrimidinyl and the like.

(13) Saturated or unsaturated 7 to 12-membered (more preferably 8-10-membered) heteroalicyclic (more preferably heterocyclics) group containing from 1 to 3 atoms of oxygen.

Specific examples include benzofur is l, isopropanol, benzocaine (for example, 3-benzoxazine), cyclopentadienyl (for example, the cyclopent[b]pyranyl), touroperador (for example, 2H-furo[3,2-b]pyranyl, and the like.

(14) Saturated or unsaturated 7 to 12-membered (more preferably 8-10-membered) heteroalicyclic (more preferably heterocyclics) group containing 1 to 3 sulfur atoms.

Specific examples include benzothiophene (for example, benzo[b]thiophenyl), dehydrodiconiferyl (e.g., 4H-1,3-dicyanovinyl), dicyanovinyl (for example, 1,4-dicyanovinyl) and the like.

(15) Saturated or unsaturated 7 to 12-membered (more preferably 8-10-membered) heteroalicyclic (more preferably heterocyclics) group containing from 1 to 3 nitrogen atoms and 1 or 2 oxygen atom.

Specific examples include doxologically (e.g., 4H-1,3-dioxolo[4,5-d]imidazolyl, benzoxazolyl (e.g., 4H-3,1-benzoxazine), pyridoxine (e.g., 5H-pyrido[2,3-d]oxazinyl), piezoelectric (e.g., 1H-pyrazolo[4,3-d]oxazolyl), properity and the like.

(16) Saturated or unsaturated 7 to 12-membered (more preferably 8-10-membered) heteroalicyclic (more preferably of heterotic etomidate (for example, thieno[2,3-d]imidazolyl), cyanopyridyl, datadictionary (for example, 2,3-dithia-1,5-vasandani) and the like.

(17) Saturated or unsaturated 7 to 12-membered (more preferably 8-10-membered) heteroalicyclic (more preferably heterocyclics) group containing from 1 to 3 oxygen atoms and 1 or 2 sulfur atom.

Specific examples include thienopyrrole (e.g., thieno[2,3-b]furanyl) and the like.

(18) Saturated or unsaturated 7 to 12-membered (more preferably 8-10-membered) heteroalicyclic (more preferably heterocyclics) group containing 1 nitrogen atom and 1 oxygen atom and 1 sulfur atom.

Specific examples include occationaly (e.g., 4H[1,3]-oxathiolan[5,4-b]pyrrolyl) and the like.

(19) Saturated or unsaturated 7 to 12-membered (more preferably 8-10-membered) heteroalicyclic (more preferably heterocyclics) group containing 1 or 2 atoms of selenium.

Preferred examples include benzoilekgonil (for example, benzo[b](or []) selenophene) and the like.

(20) Saturated or unsaturated 7 to 12-membered (more preferably 8-10-membered) heteroalicyclic (more preferably heterotic selenopidae (for example, selenium[3,2-b]pyridyl) and the like.

Preferred "aryl group" "aryloxy" represents the above-mentioned "aryl group", which is more preferably phenyl.

"Protected carboxy" is preferably esterified carboxy.

Examples of preferred ester groups esterified carboxy include: lower alkalemia ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, tert-butyl methyl ether, pentalogy ether and hexyl ether, optionally containing at least one suitable Deputy, which presents a lower alkanoyloxy(lower)alkylbis ether (for example, acetoxymethyl ether, propionylacetate ether, butyrylacetate ether, veterinarinary ether, pivaloyloxymethyl ether, hexaniacinate ester, 1 (or 2)-ecotoxicology ester, 1 (or 2 or 3)-acetoxypropionyl ester, 1 (or 2, 3 or 4)-acetoxyvalerenic ester, 1 (or 2)-propionylacetate ester, 1 (or 2 or 3)-propionoxypiperidine ester, 1 (or 2)-butyrylacetate ester, 1 (or 2)-isobutyrylacetate ester, 1 (or 2)-pivaloyloxy ether, 3,3-dimethylbutylamino ester, 1 (or 2)-pentanedinitrile ether), lower alkanesulfonyl(lower)alkilany ether (for example, 2-mutilative ether), mono-(or di - or tri -) halo(lower)alkilany ether (for example, 2-togetherby ether and 2,2,2-trichlorethylene ether), lower alkoxycarbonyl-(lower)alkilany ether (for example, methoxycarbonylmethyl ether, ethoxycarbonylmethylene ether, 2-methoxycarbonylmethylene ether, 1-ethoxycarbonylmethylene ether and 1-isopropoxycarbonyloxymethyl ether), thalidomide(lower)-alkilany ester and (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkilany ether (for example, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester and (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl) ether; lower alkenilovyh ether (for example, vinyl ester and allyl ester); lower alkinilovymi ether (for example, atinlay ether and propenyloxy ester); aryl(lower)alkilany ester, optionally containing at least one suitable substitute, such as mono(or di - or tri-)phenyl(lower)alkilany ether, optionally containing at least one suitable Deputy, which presents benzyl ether, 4-methoxybenzylidene)methyl ether, 3,4-dimethoxybenzyl ether and 4-hydroxy-3,5-di-tert-butylbenzylamine complex ester; arrowy ester, optionally containing at least one suitable substitute, such as phenyl ether, 4-hlorfenilovy ether, tallowy ether, tert-BUTYLPEROXY ether, Kilroy ether, mesityloxy ether and comenjoy ether; cyclo(lower)alkilany ether (for example, cyclohexyloxy ester); Caligraphy ester and the like.

When the above substituents substituted, the number of substituents is preferably from 1 to 4, unless otherwise noted.

Preferred examples of the target compound (I) is a compound of formula (IA):

where R2represents methyl;

R3represents chlorine;

R4represents (1) lower alkenyl, optionally substituted aryl, (2) aryl, (3) lower alkyl or (4) heterocyclic group optionally substituted with halogen;

R6represents (1) aryl, (2) heterocyclic group, (3) bromine, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, substituted aryl, (8) lower quinil, substituted aryl, (9) lower alkoxy optionally substituted cyclo(n is placed protected carboxy or lower alkyl;

L represents attilan,

and its salt.

Of the above compounds (IA) compound, where R4represents aryl or lower alkenyl, optionally substituted aryl, R6represents bromine, lower alkenyl, substituted aryl, lower quinil, substituted aryl, or lower alkoxy, optionally substituted cyclo(lower)alkyl, and salt are particularly preferred.

Of the above compounds (I) compound, where R1represents a heterocyclic group substituted by a Deputy selected from the group comprising (1) aryl, (2) heterocyclic group, (3) halogen, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted aryl, (8) lower quinil, optionally substituted aryl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl or aryl, (10) aryloxy and (11) amino, optionally substituted by protected carboxy, or lower alkyl, and its salt are more preferred.

One of them is particularly preferred group specifically represented by the following examples.

R1: 2-chloro-4-(2-furyl)phenyl, 2-chloro-4-(2-thienyl)phenyl, 2-chloro-4-(phenylethynyl)phenyl, 4-bromo-2-chlorophenyl, 3-R-4-((cyclohexyl)-metiloksi)phenyl, 4-benzyloxy-2-chlorophenyl, 2-chloro-4-(methylthio)-phenyl, 2-chloro-4-(trifluoromethyl)phenyl, 2-chloro-4-(phenoxymethyl)-phenyl, 2-chloro-4-nitrophenyl, 2-chloro-4-((E)-2-phenylethenyl)phenyl, 1-bromo-2-naphthyl,

R2: methyl,

R3: chlorine

R4: p-tolyl, (E)-2-phenylethenyl, pentyl, phenyl, 5-chloro-2-thienyl, 5-bromo-2-thienyl,

R6: 2-furyl, 2-thienyl, phenylethynyl, bromine, phenyl, 1-propoxy, 1-pentyloxy, (cyclopentyl)metiloksi, (cyclohexyl)metiloksi, benzyloxy, methylthio, trifluoromethyl, phenoxymethyl, nitro, (E)-2-phenylethenyl,

A: methylene

L: attilan.

Preferred specific compounds as the target compound (I) represented by the following examples.

(1) (E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(2) (2E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2 propenamide,

(3) (E)-3-(4-chloro-1-(2-chloro-4-(2-thienyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2 propenamide,

(4) (2E)-3-(4-chloro-1-(2-chloro-4-(2-thienyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2 propenamide,

(5) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2 Pro-2 propenamide,

(7) (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2 propenamide,

(8) (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2 propenamide,

(9) (E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-N- (1-pentanesulfonic)-2 propenamide,

(10) (E)-N-benzazolyl-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-2-propenamide,

(11) (E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(12) (E)-3-(4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(13) (E)-3-(4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl)-N-((5-chloro-2-thienyl)sulfonyl)-2-propenamide,

(14) (E)-N-((5-bromo-2-thienyl)sulfonyl)-3-(4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl)-2-propenamide,

(15) (E)-3-((4-chloro-1-(2-chloro-4-(1-propoxy)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(16) (E)-3-(4-chloro-1-(2-chloro-4-(1-propoxy)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(17) (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(18) (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-marked)-benzyl)-2-Mei-5-yl)-N-(1-pentanesulfonic)-2-propenamide,

(20) (E)-3-(4-chloro-1-(2-chloro-4-((cyclopentyl)metiloksi)-benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(21) (2E)-3-(4-chloro-1-(2-chloro-4-((cyclopentyl)metiloksi)-benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(22) (E)-3-(4-chloro-1-(2-chloro-4-((cyclohexyl)metiloksi)-benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(23) (2E)-3-(4-chloro-1-(2-chloro-4-((cyclohexyl)metiloksi)-benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(24) (E)-3-(1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(25) (E.)-3-(1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(26) (E)-3-(4-chloro-1-(2-chloro-4-(methylthio)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(27) (E)-3-(4-chloro-1-(2-chloro-4-(methylthio)benzyl)-2-methyl-imidazol-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(28) (E)-3-(4-chloro-1-(2-chloro-4-(trifluoromethyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(29) (E)-3-(4-chloro-1-(2-chloro-4-(trifluoromethyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(30) (E)-3-(4-chloro-1-(2-chloro-4-(phenoxymethyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(32) (E)-3-(4-chloro-1-(2-chloro-4-nitrobenzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(33) (E)-3-(4-chloro-1-(2-chloro-4-nitrobenzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(34) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(35) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide

(36) (E)-3-(1-(1-bromo-2-naphthyl)-4-chloro-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(37) (E)-3-(1-(1-bromo-2-naphthyl)-4-chloro-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(38) (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-(1-pentanesulfonic)-2-propenamide,

(39) (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

(40) (E)-N-(1-butanesulfonyl)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-propenamide,

(41) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-N-(1-pentanesulfonic)-2-propenamide,

(42) (E)-(3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

(43) (E)-N-(1-butenschon-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-N-(1-pentanesulfonic)-2-propenamide,

(45) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

(46) (E)-N-(1-butanesulfonyl)-3-(4-chloro-1-(2-chloro-4-(2-phenylethenyl)benzyl)-2-Mei-5-yl)-2-propenamide,

(47) (E)-3-(4-chloro-1-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-Mei-5-yl)-N-((E)-2-phenylacetylcarbinol)-2-propenamide,

(48) (E)-3-(4-chloro-1-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(49) (E)-3-(1-(4-(tert-butoxycarbonylamino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-(1-pentanesulfonic)-2-propenamide,

(50) (E.)-3-(1-(4-(tert-butoxycarbonylamino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

(51) (E)-3-(1-(4-(tert-butoxycarbonylamino)-2-Chlorobenzyl)4-chloro-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(52) (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(53) (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-ethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(54) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(55) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)of gasoline is 4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-2-propenamide,

(57) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-(1-pentanesulfonic)-2-propenamide,

(58) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

(59) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(60) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-N-(4-methylbenzenesulfonyl)-2-propenamide,

(61) (E)-N-(1-butanesulfonyl)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-2-propenamide,

(62) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-N-(1-pentanesulfonic)-2-propenamide,

(63) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

(64) (E)-3-(1-(4-bromo-2-Chlorobenzyl)-2,4-dimethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(65) (E)-3-(4-bromo-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(66) (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-4-ethyl-2-Mei-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(67) (E)-2-benzyl-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(69) (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-(3-pyridyl)methyl-N-((E)-2-phenylacetonitrile)-2-propenamide,

(70) (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-methyl-N-((E)-2-phenylacetonitrile)-2-propenamide,

(71) (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-methyl-N-((E)-2-phenylacetonitrile)-2-propenamide,

(72) 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-5-((E)-2-fenilatsetilenom)-1H-imidazole,

(73) (4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazol-5-yl) methyl N-(4-methylbenzenesulfonyl)carbamate,

(74) 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-5-((3-(4-methylbenzenesulfonyl)ureido)methyl)-2-methyl-1H-imidazole,

(75) 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-5-((3-(4-methylbenzenesulfonyl)-1-methylurea)methyl)-2-methyl-1H-imidazole, and

(76) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-1-penten-1-yl)-1-ylsulphonyl)-2-propenamide and its sodium salt.

Ways to obtain the target compound (I) are explained in detail next.

The method of obtaining 1

The target compound (I) and its salt can be prepared by the interaction of the compound (II) or a reactive derivative at carboxylate or its salt with the compound (III) Il is exigrep and compound (III) include those shown relative to the compound (I).

Preferred reactive derivative of carboxylate of compound (II) is gelegenheid acid, acid anhydride, including intramolecular acid anhydride, intermolecular anhydride acid and a mixed acid anhydride, active amide, active ester and the like. Preferred examples include the acid chloride of the acid, acid azide, mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphorous acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid and halogenated phosphoric acid), dialkylphosphorous acid, sulfurous acid, tisera acid, sulfuric acid, sulfonic acid (e.g., methanesulfonate acid), aliphatic carboxylic acid (e.g. acetic acid, propionic acid, butyric acid, somalina acid, trimethylhexane acid, pentane acid, isopentane acid, 2-ethylmalonate acid and trichloroacetic acid), aromatic carboxylic acid (e.g. benzoic acid) and the like; symmetric acid anhydride, active amide with imidazole, 4-ZAR, methoxymethyl ether, dimethylaminomethylene [(CH3)2N+=CH-] ester, vinyl ester, propargilovyh ether, p-nitrophenyloctyl ether, 2,4-dinitrophenoxy ether, trichloranisole ether, pentachlorphenol ether, methylphenylene ether, phenylazophenyl ether, phenylthio ether, p-nitrophenylthio ether, p-crazily ether, carboxymethylthio ether, paranjoy ether, pyridyloxy ether, piperidinyl ether and 8 finality ether); esters with N-hydroxy compound (e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-1H-pyridone, N-hydroxy-succinimide and 1-hydroxy-1H-benzotriazole) and the like. These reactive derivatives can be appropriately selected according to the type of compound (II).

Usually, the reaction proceeds in a conventional solvent such as water, alcohol (e.g. methanol and ethanol), acetone, dioxane, acetonitrile, chloroform, methylene chloride, telengard, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide and pyridine, or a mixture thereof or any other solvent which does not adversely affect the reaction. These solvents may be used alone or in combination.

When in this reaction, the compound (II) used in the form of free N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinobutyrophenone, N-cyclohexyl-N'-(4-diethylamino-cyclohexyl) carbodiimide, N,N'-diethylcarbamoyl, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, N,N'-carbonylbis(2-Mei), pentamethylene-N-cyclohexylamine, diphenylmethan-N-cyclohexylamine, ethoxyacetylene, 1-alkoxy-1-chlorethylene, trialkylphosphites, etiloleat, isopropylpalmitate, phosphorus oxychloride (phosphorylchloride), trichloride phosphorus, diphenylphosphoryl, diphenylchlorophosphine, diphenylphosphinyl chloride, thionyl chloride, oxacillin, lower alkylhalogenide (for example, ethylchloride and isopropylcarbamate), triphenylphosphine, salt of 2-ethyl-7-hydroxybenzotriazole, intramolecular salt of 2-ethyl-5-(m-sulfophenyl)isoxazole hydroxide, 1-(p-chlorobenzenesulfonate)-6-chloro-1H-benzotriazol, the so-called reagent of Vilsmeier (obtained by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethylcarbonate, phosphorus oxychloride, and the like) and the like.

The reaction can be performed in the presence of inorganic or organic bases such as bicarbonate of an alkali metal, three(lower)alkylamine, pyridine, 4-dimethylaminopyridine, n-(lower)alkalifree the>the temperature of the reaction is not particularly limited, and the reaction is usually carried out under conditions of from cooling to heating.

The above compounds can be converted in a preferred salt, if necessary, by conventional means. They can be cleaned, if necessary, in accordance with generally accepted methods used for the purification of organic compounds (i.e. precrystallization, column chromatography, thin-layer chromatography, high performance liquid chromatography, and the like). The connection can be identified by NMR spectral analysis, mass spectrometric analysis, IR spectroscopy, elemental analysis, determination of melting point and the like.

The compound of the present invention may have one or more chiral centers and therefore may be represented in the form of enantiomers and diastereomers. Some compounds containing alkenyl, can be represented in the form of CIS or TRANS isomers. In any case, the present invention covers such mixtures and the corresponding isomers.

The connection according to this invention and its salt can be in the form of MES, which is also covered by the real izobretaia data for compound (I) shown below to demonstrate the usefulness of the target compound (I).

Experimental example 1 (the activity of lowering blood sugar levels in db/db mice)

The analyzed compound a:

(E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-N-((4-methylbenzoyl)sulfonyl)-2-propenamide (compound of example 11)

Animal

Used female mice C57BL/KsJ-dbm db+/db+, C57BL/KsJ-dbm +m/+m (Jackson Laboratory) (aged 5 weeks) and were subjected to study after a 2-3-week period of acclimatization.

Receiving medication

The study drug was mixed in a mortar powder for food (CE-2, Clea Japan, Inc.). In the case of appointment of 100 mg/kg mixing ratio amounted to 0.1%, in the case of 30 mg/kg, the ratio was 0.03% and in the case of 10 mg/kg ratio was 0.01%. The diet was changed twice a week for each group. Registered number given food and the number of remaining determined consumption, calculating the difference.

Study design

Female mice db/db were gravirovali in accordance with body weight, blood sugar levels and concentrations of triglycerides in plasma. Then gave food, mixed with the drug for 14 days, during which the age of the mouse was from 8 to 10 weeks. In the morning at 7 and 14 day took the blood from the orbital venous plexus with ispolzovaniya plasma. The value of the blood sugar concentration of triglycerides in the plasma and the concentration of insulin in plasma were measured at day 0 and day 14 and the value of blood glucose and the concentration of triglycerides in plasma were changed on day 7. Body weight was measured at day 0, day 7 and 14. After the last screening blood samples of mice were sacrificially gas CO2.

The way of measuring

The value of the blood sugar was measured using 10-15 µl of plasma in accordance with the glucose oxydase method test (glucose CII-Test Wako, Wako Pure Chemicals Co., Ltd.). The concentration of triglycerides in plasma were measured using 10-15 µl of plasma and in accordance with the method of GPO-p-chlorophenol (triglyceride G-Test Wako), or using the GPO-DAOS (triglyceride E-Test Wako). The measurement was conducted immediately after taking the blood samples. The concentration of insulin in plasma was measured using 20 µl of plasma (stored at-20C) and in accordance with the method of the antibodies (Phadesef Insulin RIA kit, Kabi Pharmacia).

Result

Using the difference between mice db/db control group and mice +/+, the value of blood glucose and the concentration of triglycerides in the plasma as 100%, determined the proportion (%) lower values of blood sugar and the concentration of triglycerides in the plasma in the group that used the study drug. The results are shown the practical goals in the form of a pharmaceutical preparation. This pharmaceutical preparation that contains any compound (I) as an active substance in a mixture with pharmaceutically acceptable organic or inorganic excipient, which is solid, semisolid, or liquid and is suitable for oral, parenteral or external (local) application. Examples of the pharmaceutical preparation include capsules, tablets, pills, coated with sugar, granules, suppositories, liquid, lotion, suspension, emulsion, ointment, gel and the like. When required, these preparations can contain adjuvant, additional substance, stabilizer, wetting agent, emulsifier, buffer agent, and other conventional additives. Although the dose of compound (I) varies depending on the age and condition of the patient, for the treatment of the aforementioned diseases effective would be the average single dose of about 0,1, 1, 10, 50, 100, 250, 500 or 1000 mg of the compound (I). The daily dose is from 0.1 to about 1000 mg/patient.

The present invention is described in more detail in the following preparative examples and examples.

Preparative example 1-1

4,5-Dibromo-2-Mei (4,91 g) was dissolved in n, N-dimethylformamide (50 ml) and slowly added 60% hydride soda is ulali dropwise 2-(trimethylsilyl)ethoxymethylene (3.75 g) under ice cooling and the mixture was stirred over night at room temperature. The solvent was evaporated under reduced pressure and to the residue was added ethyl acetate. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and saline. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatographie on a column of silica gel (hexane/ethyl acetate=3/1) to give 4,5-dibromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)imidazole (7.6 g) as a colourless oil.

1H-NMR (CDCl3): 0,00(N, C) to 0.92(2H, t, J=8 Hz), 2,47(3H, s), 3,55(2H, t, J=8 Hz), of 5.24(2H, s).

Preparative example 1-2

4,5-Dibromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-imidazole (29,2 g) was dissolved in tetrahydrofuran (250 ml) and after 20 min was added dropwise a solution of 1.63 N. 1-utility/hexane (58,1 ml) at a temperature from -55 to-60C. The mixture was stirred at 60C for 30 min and was gradually added dropwise N/N-dimethylformamide (58 g) at temperatures from -55 to-60C. The mixture was stirred at room temperature for 1 h was Added a saturated saline solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography azole-5-carbaldehyde (18,5 g) as a pale yellow oil.

1H-NMR (CDCl3): 0,00(N, C) of 0.91(2H, t, J=8 Hz), 2,52(3H, s) to 3.58(2H, t, J=8 Hz), 5,70(2H, s), 9,71(1H, s).

Preparative example 1-3

4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-imidazole-5-carbaldehyde (18.5 g) was dissolved in ethanol (80 ml) was added 6N. hydrochloric acid (80 ml). The mixture was boiled under reflux for 1 h the Solvent was evaporated under reduced pressure and added saturated aqueous sodium hydrogen carbonate solution under ice cooling to obtain a slightly alkaline mixture. The precipitated crystals were collected by filtration and the crystals were washed with methanol and dried by heating under reduced pressure to obtain 5-bromo-2-Mei-4-carbaldehyde (9,17 g) as white crystals.

1H-NMR (CDCl3): of 2.45(3H, s), at 9.53(1H, s).

Preparative example 1-4

5-Bromo-2-Mei-4-carbaldehyde (400 mg) was dissolved in conc. hydrochloric acid (6 ml) and the mixture is boiled under reflux for 24 hours was Added saturated aqueous sodium hydrogen carbonate solution under ice cooling to obtain a slightly alkaline mixture and the mixture was twice extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then saturated saline solution. Organic is added hexane and the crystals were collected by filtration to obtain 5-chloro-2-Mei-4-carbaldehyde (222 mg) as yellow crystals.

1H-NMR (CDCl3): of 2.45(3H, s), 9,58(1H, s).

Preparative example 2

To a solution of 2-chloro-4-iodotoluene (to 7.59 g) in carbon tetrachloride (76 ml) was added N-bromosuccinimide (of 5.89 g) and 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (Wako V-70, 281 mg) at room temperature and the mixture was stirred at 55C for 3.5 hours the Reaction mixture was allowed to cool to room temperature and was added hexane (76 ml). Undissolved substance was filtered. The filtrate was concentrated and the residue was again dissolved in hexane. The mixture is then washed with water, 5% aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 2-chloro-4-jodensavanne (8,45 g) in the form of butter.

1H-NMR (CDCl3): to 4.52(2H, s), 7,16(1H, d, J=8 Hz), to 7.59(1H, DD, J=8 and 2 Hz), 7,76(1H, d, J=2 Hz).

Preparative example 3-1

To a suspension of tetrakis(triphenylphosphine)palladium (213 mg) in toluene (7 ml) was added 2-chloro-4-iodelay (2,33 g) at room temperature. The mixture was stirred at room temperature for 30 min and the solution was added to phenylboronic acid (1.35 g) in EtOH (2 ml) and 2M aqueous sodium carbonate solution (9,25 ml) is th. The aqueous layer was extracted with hexane (4 ml). The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate (4 ml) and saturated brine (4 ml) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated and to the residue (2,11 g) was added hexane (10 ml) and silica gel (4 g). The mixture was stirred at room temperature for 1 h, the Silica gel was filtered and the filtrate was concentrated to obtain 2-chloro-4-vinyltoluene in the form of a pale brown oil (1.86 g, 99.4 per cent).

1H-NMR (CDCl3): is 2.40(3H, s), 7.23 percent-of 7.60 (8H, m).

Preparative example 3-2

In the same manner as in the above preparative example 2, 2-chloro-4-phenylbenzoate was obtained as colorless crystals (3,22 g) of 2-chloro-4-vinyltoluene (3.6 g).

1H-NMR (CDCl3): with 4.64(2H, s), 7,35-7,63 (8H, m).

So pl. 73-S.

Preparative example 4-1

2-Chloro-4-iodelay (22,0 g) was dissolved in N,N-dimethylformamide (110 ml) was added copper iodide (I) (49,8 g), ethylchloroformiate (37,8 g) and potassium fluoride (15.2 g). The mixture was stirred at C for 70 hours, the Reaction mixture was filtered through celite. To the filtrate was added ice water (11 ml) and diethyl ether (110 ml) and the mixture was filtered, Cali and washed with saturated saline solution (110 ml), was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2-chloro-4-trifloromethyl (23,0 g) as a brown oil.

1H-NMR (CDCl3): 2,43(3H, s), 7,34(1H, d, J=8 Hz), 7,42 (1H, d, J=8 Hz), 7,60(1H, s).

Preparative example 4-2

In the same manner as in the above preparative example 2, 2-chloro-4-(trifluoromethyl)benzylbromide (6.20 g) was obtained as a pale-yellow oil from 2-chloro-4-trifloromethyl (10.0 g).

1H-NMR (CDCl3): 4,59(2H, s), 7,52(1H, d, J=8 Hz), EUR 7.57(1H, d, J=8 Hz), to 7.67(1H, s).

Preparative example 5-1

3-Chloro-4-METHYLPHENOL (2.00 g) was dissolved in N,N-dimethylformamide (10.0 ml) was added potassium carbonate (2.91 in g) and 1-propyliodide (2,62 g). The mixture was stirred at room temperature for 20 h and the reaction mixture was concentrated under reduced pressure. Added water and the mixture was extracted with AcOEt. The organic layer was sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was transferred to a chromatographic column with silica gel and was suirable hexane:ethyl acetate=5:1. The target fraction was concentrated under reduced pressure to obtain 2-chloro-4-(1-Pro is), 3,88(2H, t, J=7 Hz), of 6.71(1H, DD, J=8, 2 Hz), make 6.90(1H, d, J=2 Hz), to 7.09(1H, d, J=8 Hz).

Preparative example 5-2

In the same manner as in the above preparative example 2, 2-chloro-4-(1-propoxy)benzylbromide (of 2.26 g) was obtained as a pale-yellow oil from 2-chloro-4-(1-propoxy)toluene (2.14 g).

1H-NMR (CDCl3): of 1.03(3H, t, J=7 Hz), a 1.75-to 1.87 (2H, m), 3,90(2H, t, J=7 Hz), 4,59(2H, s), is 6.78(1H, DD, J=8, 2 Hz), 6,93(1H, d, J=2 Hz), 7,32(1H, d, J=8 Hz).

Preparative example 6-1

In the same manner as in the above preparative example 5-1, 2-chloro-4-(1-pentyloxy)toluene (16.3 g) was obtained as a pale-brown oil from 2-chloro-4-METHYLPHENOL (10.0 g).

1H-NMR (D13): of 0.93(3H, t, J=6 Hz), of 1.40(4H, m) of 1.76(2H, m) to 2.29(2H, s), 3,90(2H, t, J=6 Hz), 6,70(1H, DD, J=8, 2 Hz), make 6.90(1H, d, J=2 Hz), 7,10(1H, d, J=8 Hz).

Preparative example 6-2

In the same manner as in the above preparative example 2, 2-chloro-4-(1-pentyloxy)benzylbromide (of 21.9 g) was obtained as a pale-yellow solid from 2-chloro-4-(1-pentyloxy)toluene (16.2 g).

1H-NMR (CDCl3): of 0.93(3H, t, J=6 Hz), of 1.40(4H, m) of 1.76(2H, m), 3,93(2H, t, J=6 Hz), 4,58(2H, s), 6,77(1H, DD, J=8, 2 Hz), 6,92(1H, d, J=2 Hz), 7,32(1H, d, J=8 Hz).

Preparative example 7-1

To a solution of 3-chloro-4-METHYLPHENOL (1,00 g) in N,N-dimethylformamide (8 ml) we use,57 g) and the mixture was stirred at 120C for 3 hours The reaction mixture was cooled to room temperature. Added water and the mixture was extracted 3 times with hexane. The organic layers were combined and sequentially washed with 1N. aqueous solution of hydrochloride of sodium, water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by chromatography on a column (silica gel, hexane) to obtain 2-chloro-4-((cyclopentyl)metiloksi)toluene (1,46 g) as a colourless oil.

1H-NMR (CDCl3): 1,22-of 1.93 (8H, m) to 2.29(3H, s), 2,34(1H, Sept., J=7 Hz), of 3.78(2H, d, J=7 Hz), of 6.71(1H, DD, J=8 and 2 Hz), 6,91(1H, d, J=2 Hz), to 7.09(1H, d, J=8 Hz).

Preparative example 7-2

In the same manner as in the above preparative example 2, 2-chloro-4-((cyclopentyl)metiloksi)benzylbromide from 2.06 g) was obtained as an oil from 2-chloro-4-((cyclopentyl)-metiloksi)toluene (1.45 g).

1H-NMR (CDCl3): 1,23-of 1.92 (8H, m), 2,34(1H, Sept., J=7 Hz), 3,81(2H, d, J=7 Hz), 4,59(2H, s), is 6.78(1H, DD, J=9 and 2 Hz), 6,93(1H, d, J=2 Hz) to 7.32(1H, d, J=9 Hz).

Preparative example 8-1

In the same manner as in the above preparative example 5-1, 2-chloro-4-((cyclohexyl)metiloksi)toluene (1,41 g) was obtained as colorless crystals from 3-chloro-4-METHYLPHENOL (926 mg).

1H-NMR (CDCl3): 0,95-of 1.40 (5H), 1,64-1SS="ptx2">In the same manner as in the above preparative example 2, 2-chloro-4-((cyclohexyl)metiloksi)benzylbromide (1.35 g) was obtained as a pale yellow solid from 2-chloro-4-((cyclohexyl)metiloksi)toluene (1,00 g).

1H-NMR (CDCl3): 0,94-of 1.40(5H), 1, 63-1, 94 (6N), TO 3.73(2H, d, J=6 Hz), 4,59(2H, s), 6,79(1H, DD, J 8, 2 Hz), 6,93(1H, d, J=2 Hz), 7,32(1H, d, J=8 Hz).

Preparative example 9

To a solution of 4-bromo-2-chlorobenzylamino alcohol (of 3.56 g) and anhydrous triethylamine (3 ml) in anhydrous dichloromethane (36 ml) was added dropwise methanesulfonate (1.4 ml) under ice cooling in a nitrogen atmosphere. The mixture was stirred for 1 h and the reaction mixture is washed with water, saturated aqueous sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The filtrate was concentrated to obtain 4-bromo-2-chloro-1-((methanesulfonate)methyl)benzene as a pale brown product (4.77 g).

1H-NMR (CDCl3): 3,03(3H, s), from 5.29(2H, s), 7,37(1H, d, J=8 Hz), 7,47(1H, DD, J=8, 1 Hz), 7,60(1H, d, J=1 Hz).

Mass (ESI): m/z 298(M-1).

Preparative example 10-1

To a solution of methyl 4-bromo-2-chlorobenzoate (1.25 g) in N,N-dimethylformamide (10 ml) was added thiamethoxam sodium (459 mg) under ice cooling and the mixture was stirred vilovem ether. The organic layers were combined, sequentially washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue transferred to the chromatographic column with silica gel (hexane/ethyl acetate=10/1) to give methyl 2-chloro-4-(methylthio) benzoate (835 mg) as a colourless oil.

1H-NMR(CDCl3): 2,49(3H, s), 3,90(3H, s), 7,11(1H, d, J=8 Hz), 7.23 percent(1H, s), 7,78(1H, d, J=8 Hz).

Preparative example 10-2

To a suspension of lithium aluminum hydride (139 mg) in tetrahydrofuran (8 ml) was added dropwise methyl 2-chloro-4-(methylthio)benzoate (806 mg) under ice cooling and the mixture was stirred for 1 h, the Reaction mixture was diluted with diethyl ether and added dropwise 1N. hydrochloric acid (10 ml). The product was extracted 3 times with diethyl ether. The organic layers were combined and sequentially washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 2-chloro-4-(methylthio)benzyl alcohol (725 mg) as a colourless oil.

1H-NMR (CDCl3): 1,92(1H, user. t, J=7 Hz), 2,48(3H, s), to 4.73(2H, d, J=7 Hz), to 7.15(1H, d, J=8 Hz), 7.23 percent(1H, s), 7,37(1H, d, J=8 Hz).

Preparations)methyl)-4-(methylthio)benzene (1,02 g) was obtained as colorless oil from 2-chloro-4-(methylthio)benzyl alcohol (687 mg).

1H-NMR (CDCl3): 2,48(3H, s) of 3.00(3H, s), and 5.30(2H, s), to 7.15(1H, DD, J=8 and 2 Hz), 7,26(1H, d, J=2 Hz), 7,38(1H, d, J=8 Hz).

Preparative example 11

In the same manner as in the above preparative example 9, 2-chloro-1-((methanesulfonate)methyl)-4-nitrobenzene (of 3.56 g) was obtained as brown crystals of 2-chloro-4-nitrobenzyl alcohol (2.5 g).

1H-NMR (CDCl3): of 3.12(3H, s), of 5.40(2H, s), 7,73(1H, d, J=8 Hz), 8,18(1H, DD, J=2,8 Hz), 8,79(1H, d, J=2 Hz).

Preparative example 12-1

4-Amino-2-chlorbenzoyl acid (10,01 g) is homogeneous dissolved 12.5% sulfuric acid (400 ml) by heating to 70 C and cooled in ice. To this suspension was added dropwise an aqueous solution of sodium nitrite (4,24 g/12 ml of water) at not more than 8C for 5 min After 5 min the solution was partially poured into water (500 ml) at 80 ° C, the solution was vigorously foam and became red. The reaction mixture was stirred at 80 ° C for 1 h After cooling, the product was extracted 3 times with diethyl ether. The organic layers were combined and successively washed with diluted hydrochloric acid, water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated and to the residue was added a small amount disarray.

1H-NMR (CDCl3): 6,79(1H, DD, J=8 and 2 Hz), to 6.88(1H, d, J=2 Hz), to 7.77 (1H, d, J=8 Hz).

Macc (ESI): m/e 171(M-H)-.

Preparative example 12-2

To a solution of 2-chloro-4-hydroxybenzoic acid (695 mg) in N,N-dimethylformamide (3.5 ml) was added potassium carbonate (1,67 g) and benzylbromide (1.73 g) and the mixture was stirred at room temperature for 14 hours To the reaction mixture were added 1N. hydrochloric acid and the product was extracted 3 times with diethyl ether. The organic layers were combined and sequentially washed with water, saturated aqueous sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was recrystallized from diisopropyl ether/hexane to obtain benzyl 4-benzyloxy-2-chlorobenzoate (1.13 g) as a pale yellow powder.

1H-NMR (CDCl3): 5,09(2H, s), 5,32(2H, s), 6.87 in(1H, DD, J=8 and 2 Hz), 7,05(1H, d, J=2 Hz), 7.29 trend is 7.50 (10H, m), to $ 7.91(1H, d, J=8 Hz).

Macc (ESI): m/e 353(M+H)+.

Preparative example 12-3

To benzyl 4-benzyloxy-2-chlorobenzoate (1.12 g) was added ethanol (8,8 ml), 1,4-dioxane (2.2 ml) and 1N. an aqueous solution of sodium hydroxide (4,7 ml) and the mixture was stirred at 70 C for 1.5 h the Solvent was evaporated and to the residue add the precipitate was collected by filtration to obtain 4-benzyloxy-2-chlorbenzoyl acid (810 mg) as pale yellow powder.

1H-NMR (CDCl3): 5,20(2H, s), 7,06(1H, DD, J=8 and 2 Hz), 7,18(1H, d, J=2 Hz), 7.29 trend is 7.50(5H, m), 7,82(1H, d, J=8 Hz).

Macc (ESI): m/e 261(M-H)-.

Preparative example 12-4

To a solution of 4-benzyloxy-2-chlorbenzoyl acid (788 mg) in tetrahydrofuran (7.9 ml) was added dropwise porandamaterjalides complex (10,0 M, 0.6 ml) at room temperature under nitrogen atmosphere and the mixture is boiled under reflux for 2.5 hours the Reaction mixture was allowed to cool to room temperature and carefully added dropwise 1N. hydrochloric acid (1.5 ml). The mixture was stirred for 30 minutes To the reaction mixture were added water and the product was extracted 3 times with ethyl acetate. The organic layers were combined, sequentially washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 4-benzyloxy-2-chlorobenzylamino alcohol (778 mg) as a white powder.

1H-NMR (CDCl3): 1,83(1H, user. t, J=7 Hz), 4,70(2H, d, J=7 Hz), of 5.05(2H, s), to 6.88(1H, DD, J=8 and 2 Hz), 7,01(1H, d, J=2 Hz), 7,28-7,46 (6N, m).

Preparative example 12-5

In the same manner as in the above preparative example 9, 4-benzyloxy-2-chlorobenzylchloride (639 mg) Paluch(2H, C) of 5.05(2H, s), 6.87 in(1H, DD, J=8 and 2 Hz), 7,02(1H, d, J= 2 Hz), 7,28-7,44(6N, m).

Preparative example 13-1

To a solution of 4-bromo-2-chlorobenzylamino alcohol (14, 48mm g) in N,N-dimethylformamide (72 ml) was added imidazole (5.34 g) and tert-butylchloroformate (19,8 g) under ice cooling and the mixture was stirred for 1 h To the reaction mixture were added water and the resulting product was twice extracted with hexane. The organic layers were combined, sequentially washed with water, saturated aqueous sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue transferred to the chromatographic column with silica gel (hexane) to obtain 4-bromo-1-((tert-butyldiphenylsilyl)methyl)-2-chlorobenzene (29,22 g) as a colourless oil.

1H-NMR (CDCl3): 1,10(N, C), and 4.75(2H, s), 7,32 is 7.50 (8H, m), 7,55-7,72(5H, m).

Preparative example 13-2

To a solution of 4-bromo-1-((tert-butyldiphenylsilyl)-methyl)-2-chlorobenzene (8.65 g) in tetrahydrofuran (22 ml) was added a solution of 1-utility/hexane (1.54 M, 13.5 ml) under-75S in nitrogen atmosphere and the mixture was stirred for 15 minutes, the Reaction mixture was once heated to 10C and again cooled to-75S and after 10 min was added dropwise 1-formalpara the hydrated solution of ammonium chloride and the resulting product was twice extracted with hexane. The organic layers were combined, successively washed with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was transferred to a chromatographic column with silica gel (hexane/ethyl acetate=40/1) to obtain 4-((tert-butyldiphenylsilyl)methyl)-3-chlorobenzaldehyde (3,26 g) as a pale yellow oil.

1H-NMR (CDCl3): 1,14(N, (C), to 4.87(2H, s), 7,33-7,51 (6N, m), 7,63 to 7.75(4H, m), 7,81(1H, d, J=2 Hz), to 7.84(1H, DD, J=8 and 2 Hz), of 7.97(1H, d, J=8 Hz), becomes 9.97(1H, s).

Preparative example 13-3

To a suspension of 4-((tert-butyldiphenylsilyl)methyl)-3-chloro-benzaldehyde (3,24 g) in ethanol (32 ml) was added sodium borohydride (149 mg) under ice cooling and the mixture was stirred at room temperature for 3 hours the Reaction mixture was concentrated to half its quantity. Added water and the resulting product was twice extracted with diisopropyl ether. The organic layers were combined, sequentially washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatograph is(is 3.08 g) as a colourless oil.

1H-NMR (CDCl3): 1,12(N, C) to 1.70(1H, user. t, J=5 Hz), 4,69(2H, d, J=5 Hz), a 4.83(2H, s), 7,27-to 7.50 (8H, m), 7,65 for 7.78(5H, m).

Preparative example 13-4

In the same manner as in the above preparative example 9, 1-((tert-butyldiphenylsilyl)methyl)-2-chloro-4-(methane-sulfonyloxy) methyl)benzene (3.80 g) was obtained as colorless oil from 4-((tert-butyldiphenylsilyl)methyl)-3-chlorobenzylamino alcohol (3,05 g).

1H-NMR (DCl3): 1,12(N, C) of 2.97(3H, s), a 4.83(2H, s), a total of 5.21(2H, s), 7,33-to 7.50(8H, m), 7,63 to 7.75(4H, m), to 7.77-7,83(1H, m).

Preparative example 13-5

To a solution of phenol (969 mg) in N,N-dimethylformamide (27 ml) was added powdered potassium carbonate (1.92 g) and the mixture was stirred at room temperature for 5 minutes was Added 1-((tert-butyldiphenylsilyl)methyl)-2-chloro-4-((methanesulfonate)-methyl)benzene (3,39 g) and the mixture was stirred at 100C for 3 hours the Reaction mixture was allowed to cool to room temperature. Added water and the mixture was twice extracted with hexane. The organic layers were combined, sequentially washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by chromatography on a column (silica gel, hexane/ethyl acetate=50/1) to obtain 1-((tert-buildif the ): 1,12(N, C) a 4.83(2H, s), 5,04(2H, s), 6,93? 7.04 baby mortality(3H, m), 7,25 is 7.50(10H, m), 7,65-7,73(4H, m), 7,73-7,80(1H, m).

Preparative example 13-6

To a solution of 1-((tert-butyldiphenylsilyl)methyl)-2-chloro-4-(phenoxymethyl)benzene (2,84 g) in tetrahydrofuran (14 ml) solution was added to tetrabutylammonium/tetrahydrofuran (1.0 M, 7.0 ml) under ice cooling and the mixture was stirred for 1.5 hours To the reaction mixture were added water and the resulting product was twice extracted with ethyl acetate. The organic layers were combined, sequentially washed with 1N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate=5/1) to give 2-chloro-4-(phenoxymethyl)benzyl alcohol (1,38 g) as a white powder.

1H-NMR (CDCl3): 1,92(1H, user. t, J=6 Hz), 4,79(2H, d, J=6 Hz), of 5.05(2H, s), 6,88-7,06(3H, m), 7.23 percent-7,40(3H, m), 7,42-EUR 7.57(2H, m).

Preparative example 13-7

In the same manner as in the above preparative example 9, 2-chloro-1-((methanesulfonate)methyl)-4-(phenoxymethyl)-benzene (1,83 g) was obtained as an oil from 2-chloro-4-(phenoxymethyl)benzyl alcohol (1,36 g).

1H-NMR (CDCl3): the way, as in the above preparative example 12-4, 3-chloro-4-methylbenzylamine alcohol (23,0 g) was obtained as colorless oil from 3-chloro-4-methylbenzoic acid (25,0 g).

1H-NMR (CDCl3): a 2.36(3H, s) and 4.65(2H, s), 7,14(1H, d, J=8 Hz), 7.23 percent(1H, d, J=8 Hz), was 7.36(1H, s).

Preparative example 14-2

To a solution of 3-chloro-4-methylbenzylamino alcohol (2.00 g) and triethylamine (8,9 ml) in dimethyl sulfoxide (10 ml) was added to the complex of sulfur trioxide - pyridine (4,47 g) under cooling with water. The mixture was stirred at room temperature for 3 hours the Reaction mixture was poured into ice water and the mixture was extracted with diethyl ether. The organic layer was washed for 1H. hydrochloric acid, saturated saline solution and saturated aqueous sodium bicarbonate and dried over magnesium sulfate. The residue was concentrated to dryness under reduced pressure to obtain 3-chloro-4-methylbenzaldehyde (1.40 g) as a pale yellow oil.

1H-NMR (CDCl3): the 2.46(3H, s) and 4.65(2H, s), 7,40(1H, d, J=8 Hz), to 7.68(1H, d, J=8 Hz), 9,92(1H, s).

Preparative example 14-3

In the same manner as in preparative example 15-2, referred to hereinafter, (E)-2-chloro-4-(2-phenylethenyl)toluene (1.55 g) was obtained as a white powder from 3-chloro-4-methylbenzaldehyde (1.40 g) and dieterlen operativny example 14-4

In the same manner as in the above preparative example 2, (E)-2-chloro-4-(2-phenylethenyl)benzylbromide (309 mg) was obtained as a white powder from (E)-2-chloro-4-(2-phenylethenyl)-toluene (1.35 g).

1H-NMR (CDCl3): br4.61(2H, s), 7,01(1H, d, J=16 Hz), 7,14(1H, d, J=16 Hz), 7.24 to EUR 7.57 (8H).

Preparative example 15-1

To a solution of 5-chloro-2-Mei-4-carbaldehyde (433 mg) in N,N-dimethylformamide (4.3 ml) was added powdered potassium carbonate (616 mg) and 2-chloro-4-jodensavanne (1.2 equivalent) under ice cooling and the mixture was stirred at room temperature for 2.5 hours To the reaction mixture were added water and saturated saline solution, and the obtained product was twice extracted with ethyl acetate. The organic layers were combined, washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate=5/1) to obtain 4-chloro-1-(2-chloro-4-jobensis)-2-Mei-5-carbaldehyde (1.01 g) as a white powder.

1H-NMR (CDCl3): of 2.33(3H, s) to 5.56(2H, s), 6,21(1H, d, J=8 Hz), to 7.50(1H, DD, J=8 and 2 Hz), 7,78(1H, d, J=2 Hz), of 9.75(1H, s).

Macc (ESI): m/e 395(M+H)+.

Preparative example 15-2

To a solution of 4-chloro-1-(2-chloro-4-jobensis)-2-meth g) and the mixture is boiled under reflux for 4 hours The solvent was evaporated and the residue was purified column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl (E)-3-(4-chloro-1-(2-chloro-4-jobensis)-2-Mei-5-yl)-2-propenate (974 mg) as a white powder.

1H-NMR (CDCl3): of 2.33(3H, in), 3.75(3H, s), of 5.15(2H, s), 6,17(1H, d, J=8 Hz), of 6.49(1H, d, J 16 Hz), 7,28(1H, d, J=16 Hz), 7,53(1H, DD, J=8 and 2 Hz), 7,81(1H, d, J=2 Hz).

Mass (ESI): m/e 451(M+N)+.

Preparative example 15-3

A mixture of tetrakis(triphenylphosphine)palladium (0) (89 mg), methyl (E)-3-(4-chloro-1-(2-chloro-4-jobensis)-2-Mei-5-yl)-2-propenate (350 mg), 2-Puilboreau acid (135 mg), powdered potassium carbonate (321 mg) and N,N-dimethylformamide (3.5 ml) was stirred in nitrogen atmosphere at 80 ° C for 4 h the Reaction mixture was allowed to cool to room temperature and added water. The precipitate was collected by filtration. The residue was dissolved in chloroform, then washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by chromatography on a column of silica gel (chloroform/ethyl acetate=10/1) to give methyl (E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-Mei-5-yl)-2-propenate (336 mg) as pale yellow powder.

Macc (ESI): m/e 391(M+H)+.

Preparative example 15-4

To a suspension of methyl (E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-Mei-5-yl)-2-propenate (319 mg) in 1,4-dioxane (1.6 ml) was added 1N. an aqueous solution of sodium hydroxide (1.2 ml) and the mixture was stirred at 50C for 1 h, the Reaction mixture was cooled with ice and added dropwise 1N. hydrochloric acid (1.2 ml) to neutralize the mixture. The product was extracted 3 times with chloroform-methanol (4/1). The organic layers were combined, washed with saturated saline and dried over magnesium sulfate. The solvent was evaporated to obtain (E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-Mei-5-yl)-2-propanolol acid (310 mg) as a gray-white powder.

1H-NMR(DMCO-d6): of 2.34(3H, s) 5,41(2H, s), of 6.26(1H, d, J=16 Hz), to 6.58(1H, d, J=8 Hz), 6,62(1H, DD, J=3 and 2 Hz), to 7.09(1H, d, J=3 Hz), 7,22(1H, d, J=16 Hz), a 7.62(1H, DD, J=8 and 2 Hz), 7,79(1H, d, J=2 Hz), 7,88(1H, d, J=2 Hz).

Macc (ESI): m/e 375(M-H)-.

Preparative example 16-1

In the same manner as in the above preparative example 15-3, methyl (E)-3-(4-chloro-1-(2-chloro-4-(2-thienyl)benzyl)-2-Mei-5-yl)-2-propenal was obtained as a yellow oil (331 mg) from methyl (E)-3-(4-chloro-1-(2-chloro-4-jobensis)-2-Mei-5-yl)-2-propenate (360 mg,41(1H, DD, J=2, 8 Hz), 7,69(1H, d, J=2 Hz).

Macc (ESI): m/z 407(M+1).

Preparative example 16-2

In the same manner as in the above preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-(2-thienyl)benzyl)-2-Mei-5-yl)-2-propanolol acid was obtained as pale-yellow crystals (231 mg) from methyl (E)-3-(4-chloro-1-(2-chloro-4-(2-thienyl)benzyl)-2-Mei-5-yl)-2-propenate (281 mg).

1H-NMR (DMS O-d6): of 2.34(3H, s), 5,42(2H, s), 6,27(1H, d, J=16 Hz), 6,55(1H, d, J=8 Hz), 7,12-7,19(1H, m), 7,25(1H, d, J=16 Hz), 7,52 to 7.62 (3H, m), 7,87(1H, d, J=2 Hz).

Macc (ESI): m/z 391(M-1).

Preparative example 17-1

To a mixture of methyl (E)-3-(4-chloro-1-(2-chloro-4-jobensis)-2-Mei-5-yl)-2-propenate (360 mg), dichlorobis-(triphenylphosphine) palladium (II) (28 mg) and copper iodide (7,6 mg) was added to the solution of phenylacetylene (326 mg) in Diisopropylamine (20 ml) under nitrogen atmosphere and the mixture is boiled under reflux for 5 hours the Reaction mixture was allowed to cool. Added water and the mixture was twice extracted with chloroform. The organic layers were combined, washed with saturated aqueous sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The obtained product was filtered under reduced pressure and concentrated to obtain crude product. who-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-2-propenate in amorphous form brown (331 mg) of elyuirovaniya fraction hexane/ethyl acetate=5/1-1-1.

1H-NMR (CDCl3): 2,35(3H, in), 3.75(3H, s), 5,23(2H, s), of 6.45(1H, d, J=8 Hz), 6,50(1H, d, J=16 Hz), 7,27-7,40(5H, m), of 7.48-7,56(2H, m), 7,63(1H, s).

Macc (ESI): m/z 425(M+1).

Preparative example 17-2

In the same manner as in the above preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)-benzyl)-2-Mei-5-yl)-2-propanolol acid was obtained in the form of crystals pale ochre (283 mg) from methyl (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-2-propenate (413 mg).

1H-NMR (CDCl3): a 2.36(3H, s), 5,23(2H, s), of 6.45(1H, d, J=8 Hz), 6.48 in(1H, d, J=16 Hz), 7,32-7,41(5H, m), of 7.48-of 7.55(2H, m), of 7.64(1H, d, J=2 Hz).

Macc (ESI): m/z 409(M-1).

Preparative example 18-1

In the same manner as in the above preparative example 15-1, 1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-Mei-5-carbaldehyde (430 mg) was obtained as pale-yellow crystals from 4-chloro-2-Mei-5-carbaldehyde (200 mg) and 4-bromo-2-chloro-1-((methanesulfonate)-methyl)benzene (456 mg).

1H-NMR (CDCl3): of 2.33(3H, s) to 5.56(2H, s) 6,38(1H, d, J=8 Hz), 7,31(1H, DD, J=8, 2 Hz), 7,60(1H, d, J=2 Hz), of 9.75(1H, s).

Preparative example 18-2

In the same manner as in the above preparative example 15-2, methyl (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propenal (372 mg) was obtained in view of the OS-formanilide)acetate (606 mg).

1H-NMR (CDCl3): of 2.33(3H, in), 3.75(3H, s), 5,16(2H, s), 6,33(1H, d, J=8 Hz), 6,50(1H, d, J=15 Hz), 7,26(1H, d, J=2 Hz), 7,34(1H, DD, J=8, 2 Hz), 7,63(1H, d, J=2 Hz).

Preparative example 18-3

In the same manner as in the above preparative example 15-4, (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propanolol acid (338 mg) was obtained as pale-yellow crystals from methyl (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propenate (355 mg).

1H-NMR (DMCO-d6): 2,31(3H, s) 5,38(2H, s), of 6.26(1H, d, J=15 Hz), of 6.45(1H, d, J=8 Hz), 7,21(1H, d, J=15 Hz), 7,53(1H, DD, J=8, 2 Hz), 7,87(1H, d, J=2 Hz).

Preparative example 19-1

In the same manner as in the above preparative example 15-1, 4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-carbaldehyde (1.23 g) was obtained as colorless oil from 5-chloro-2-Mei-4-carbaldehyde (600 mg) and 2-chloro-4-phenylendiamine (1.4 g).

1H-NMR (CDCl3): a 2.36(3H, s), 5,67(2H, s), 6,56(1H, d, J=8 Hz), 7,35-7,55(6N), THE 7.65(1H, s), 9,80(1H, s).

Preparative example 19-2

In the same manner as in the above preparative example 15-2, methyl (E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-2-propenal (1.13 g) was obtained as a white powder from 4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-carbaldehyde (1,23 g).

In the same manner as in the above preparative example 15-4, (E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-2-propanolol acid (1.18 g) was obtained as a white powder from methyl (E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-2-propenate (1.35 g).

1H-NMR (DMS O-d6): 2,35(3H, s), the 5.45(2H, s), 6,30(1H, d, J=16 Hz), to 6.58(1H, d, J=8 Hz), 7,25(1H, d, J=16 Hz), of 7.36-7,52(3H), A 7.62(1H, d, J=8 Hz), 7,69(2H, d, J=8 Hz), 7,86(1H, s).

Preparative example 20-1

In the same manner as in the above preparative example 15-1, 4-chloro-1-(2-chloro-4-(1-propoxy)benzyl)-2-Mei-5-carbaldehyde (376 mg) was obtained as pale-yellow crystals from 4-chloro-2-Mei-5-carbaldehyde (200 mg) and 2-chloro-4-(1-propoxy)benzylbromide (474 mg).

1H-NMR (CDCl3): of 1.02(3H, t, J=7 Hz), 1,73-of 1.85 (2H, m), 2,32(3H, s), a 3.87(2H, t, J=7 Hz), to 5.57(2H, s), 6,46(1H, d, J=8 Hz), 6,70(1H, DD, J=8, 2 Hz), of 6.96(1H, d, J=2 Hz), made up 9.77(1H, s).

Preparative example 20-2

In the same manner as in the above preparative example 15-2, methyl (E)-3-(4-chloro-1-(2-chloro-4-(1-propoxy)-benzyl)-2-Mei-5-yl)-2-propenal (348 mg) was obtained as colorless crystals from 4-chloro-1-(2-chloro-4-(1-propoxy)benzyl)-2-Mei-5-carbaldehyde (356 mg) and methyl (triphenylphosphorane)acetate (546 mg).

1H-YAM, the d, J=8, 2 Hz), of 6.99(1H, d, J=2 Hz), 7,34(1H, d, J=15 Hz).

Preparative example 20-3

In the same manner as in the above-mentioned preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-(1-propoxy)benzyl)-2-Mei-5-yl)-2-propanolol acid (305 mg) was obtained as colorless crystals from methyl (E)-3-(4-chloro-1-(2-chloro-4-(1-propoxy)benzyl)-2-Mei-5-yl)-2-propenate (332 mg).

1H-NMR (DMCO-d6): of 0.95(3H, t, J=7 Hz), 1, 64-1,75 (2H, m), 2,32(3H, s) to 3.92(2H, t, J=7 Hz), 5,31(2H, s), and 6.25(1H, d, J=15 Hz), 6,44(1H, d, J=8 Hz), to 6.88(1H, DD, J=8, 2 Hz), 7,13(1H, d, J=2 Hz), of 7.23(1H, d, J=15 Hz).

Preparative example 21-1

In the same manner as in the above preparative example 15-1, 4-chloro-1-[2-chloro-4-(1-pentyloxy)benzyl]-2-Mei-5-carbaldehyde (460 mg) was obtained as a pale-yellow oil from 5-chloro-2-Mei-4-carbaldehyde (200 mg) and 2-chloro-4-(1-pentyloxy)benzylbromide (378 mg).

1H-NMR (CDCl3): of 0.93(3H, t, J=6 Hz), of 1.40(4H, m) of 1.76(2H, m), 2,32(3H, s), 3,90(2H, t, J=6 Hz), to 5.57(2H, s), of 6.45(1H, d, J=8 Hz), 6,70(1H, DD, J=8, 2 Hz), to 6.95(1H, d, J=2 Hz), 9,76(1H, s).

Preparative example 21-2

In the same manner as in the above preparative example 15-2, methyl (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy) benzyl)-2-Mei-5-yl)-2-propenal received in the form of a milky white solid (427 m is: of 0.93(3H, t, J=7 Hz), 1.32 to-1,49(4H, m), 1,71 of-1.83(2H, m), of 2.34(3H, in), 3.75(3H, s) to 3.92(2H, t, J=7 Hz), further 5.15(2H, s), 6,37(1H, d, J=8 Hz), of 6.49(1H, d, J=16 Hz), 6,70(1H, DD, J=2, 8 Hz), of 6.99(1H, d, J=2 Hz), 7,34(1H, d, J=16 Hz).

Macc (ESI): m/z 411(M+1).

Preparative example 21-3

In the same manner as in the above preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-propanolol acid was obtained as thin yellow crystals (370 mg) from methyl (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-propenate (403 mg).

1H-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), 1,30-1,50(4H, m), 1.70 to to 1.83(2H, m), a 2.36(3H, s) to 3.92(2H, t, J=7 Hz), 5,16(2H, s) 6,38(1H, d, J=8 Hz), 6,47(1H, d, J=16 Hz), of 6.71(1 H, DD, J=2, 8 Hz), of 6.99(1H, d, J=2 Hz), 7,40(1H, d, J=16 Hz).

Macc (ESI): m/z 395(M-1).

Preparative example 22-1

In the same manner as in the above preparative example 15-1, 4-chloro-1-(2-chloro-4-((cyclopentyl)metiloksi)benzyl)-2-Mei-5-carbaldehyde (608 mg) was obtained as colorless oil from 5-chloro-2-Mei-4-carbaldehyde (300 mg) and 2-chloro-4-((cyclopentyl)metiloksi)benzylbromide (764 mg).

1H-NMR (CDCl3): 1,22-of 1.92(8H, m), 2,32(3H, s), 2,33(1H, Sept., J=7 Hz), of 3.78(2H, d, J=7 Hz), to 5.57(2H, s), of 6.45(1H, d, J=8 Hz), 6,70(1H, DD, J=9 and 2 Hz), of 6.96(1H, d, J=2 Hz), made up 9.77(1H, s).

Macc (ESI): m/e 367(M+H)+.

Preparative PR is lipantil)-metiloksi)benzyl)-2-Mei-5-yl)-2-propenal (563 mg) was obtained as a white powder from 4-chloro-1-(2-chloro-4-((cyclopentyl)metiloksi)benzyl)-2-Mei-5-carbaldehyde (577 mg) and methyl (triphenylphosphonium)acetate (788 mg).

1H-NMR (CDCl3): 1,24-of 1.92(8H, m), of 2.34(3H, s), 2,34(1H, Sept., J=7 Hz), 3,74(3H, s), with 3.79(2H, d, J=7 Hz), further 5.15(2H, s), 6,37(1H, d, J=8 Hz), of 6.49(1H, d, J=16 Hz), of 6.71(1H, DD, J=8 and 3 Hz), of 6.99(1H, d, J=3 Hz), 7,34(1H, d, J=16 Hz).

Macc (ESI): m/e 423(M+H)+.

Preparative example 22-3

In the same manner as in the above preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-((cyclopentyl)metiloksi)-benzyl)-2-Mei-5-yl)-2-propanolol acid (532 mg) was obtained as a white powder from methyl (E)-3-(4-chloro-1-(2-chloro-4-((cyclopentyl)metiloksi)benzyl)-2-Mei-5-yl)-2-propenate(535 mg).

1H-NMR (D13): 1,23-of 1.92(8H, m), 2,33(1H, Sept., J=7 Hz), to 2.35(3H, s), with 3.79(2H, d, J=7 Hz), further 5.15(2H, s), 6,37(1H, d, J=8 Hz), 6,46(1H, d, J=16 Hz), of 6.71(1H, DD, J=8 and 2 Hz), of 6.99(1H, d, J=2 Hz), 7,40(1H, d, J=16 Hz).

Macc (ESI): m/e 407(M-N)-.

Preparative example 23-1

In the same manner as in the above preparative example 15-1, 4-chloro-1-(2-chloro-4-((cyclohexyl)metiloksi)benzyl)-2-Mei-5-carbaldehyde was obtained as a yellow oil (410 mg) of 5-chloro-2-Mei-4-carbaldehyde (200 mg) and 2-chloro-4-((cyclohexyl)metiloksi)benzylbromide (659 mg).

1H-NMR (CDCl3): 0,95-1,10(2H, m), 1, 15-1, 39 (4H, m), 1,62-1,89(5H, m), 2,32(3H, s), 3,70(2H, d, J=7 Hz), to 5.57(2H, s), of 6.45(1H, d, J=8 Hz), 6,69(1H, DD, J=2, 8 Hz), to 6.95(1H, d, J=2 Hz), 9,76(1H, C).

1H-NMR (DCl3): 0,95-1,11 (2H, m), 1,15-to 1.38 (4H, m), 1,63-1,89 (5H, m), of 2.34(3H, s), 3,71(2H, d, J=7 Hz), 3,74(3H, s), of 5.15(2H, s), 6,36(1H, d, J=8 Hz), of 6.49(1H, d, J=16 Hz), 6,70(1H, DD, J=2, 8 Hz), 6,98(1H, d, J=2 Hz), 7,34(1H, d, J=16 Hz).

Macc (ESI): m/z 437(M+1).

Preparative example 23-3

In the same manner as in the above preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-((cyclohexyl)metiloksi)-benzyl)-2-Mei-5-yl)-2-propanolol acid was obtained as thin yellow crystals (375 mg) from methyl (E)-3-(4-chloro-1-(2-chloro-4-(cyclohexyl)metiloksi)benzyl)-2-Mei-5-yl)2-propenate(418 mg).

1H-NMR (CDCl3): 0,95-1,10(2H, m), 1,15-to 1.38 (4H, m), 1,64-1,89(5H, m) to 2.35(3H, s), 3,71(2H, d, J=7 Hz), 5,16(2H, s), 6,33(1H, d, J=8 Hz), 6,46(1H, d, J=16 Hz), 6,70(1H, DD, J=2, 8 Hz), 7,00(1H, d, J=2 Hz), 7,40(1H, d, J=16 Hz).

Mass (ESI): m/z 421(M-1).

Preparative example 24-1

In the same manner as in the above preparative example 15-1, 1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-carbaldehyde was obtained as a yellow oil (410 mg) of 5-chloro-2-Mei-4-carbaldehyde (200 mg) I), is 6.78(1H, DD, J=2, 8 Hz), 7,05(1H, d, J=2 Hz), 7,30 was 7.45 (5H, m), 9,76(1H, s).

Macc (ESI): m/z 375(M+1).

Preparative example 24-2

In the same manner as in the above preparative example 15-2, methyl (E)-3-(1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propenal was obtained as a colourless oil (384 mg) of 1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-carbaldehyde (389 mg).

1H-NMR (CDCl3): of 2.33(3H, in), 3.75(3H, s), of 5.03(2H, s), of 5.15(2H, s) 6,38(1H, d, J=8 Hz), 6,50(1H, d, J=16 Hz), 6,79(11-1, DD, J=2, 8 Hz), was 7.08(1H, d, J=2 Hz), 7,33(1H, d, J=16 Hz), 7,31-the 7.43 (5H, m).

Macc (ESI): m/z 431(M+1).

Preparative example 24-3

In the same manner as in the above preparative example 15-4, (E)-3-(1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propanolol acid was obtained as yellow crystals (296 mg) from methyl (E)-3-(1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propenate (375 mg).

1H-NMR (CDCl3): 2,35(3H, s), of 5.03(2H, s), 5,16(2H, s) 6,40(1H, d, J=8 Hz), 6,47(1H, d, J=16 Hz), to 6.80(1H, DD, J=2, 8 Hz), to 7.09(1H, d, J=2 Hz), 7,30 was 7.45(6N, m).

Macc (ESI): m/z 415 (M-1).

Preparative example 25-1

In the same manner as in the above preparative example 15-1, 4-chloro-1-(2-chloro-4-(methylthio)benzyl)-2-Mei-5-carbaldehyde was obtained as a colourless oil is(379 mg).

1H-NMR (CDCl3): 2,32(3H, s) to 2.46(3H, s), to 5.58(2H, s), to 6.43(1H, d, J=8 Hz), 7,03(1H, DD, J=2, 8 Hz), 7,26 (1H, overlapped CDCl3), 9,76(1H, s).

Mass (ESI): m/z 315(M+1).

Preparative example 25-2

In the same manner as in the above preparative example 15-2, methyl (E)-3-(4-chloro-1-(2-chloro-4-(methylthio)benzyl)-2-Mei-5-yl)-2-propenal was obtained as a yellow oil (384 mg) of 4-chloro-1-(2-chloro-4-(methylthio)benzyl)-2-Mei-5-carbaldehyde (336 mg).

1H-NMR (CDCl3): of 2.34(3H, s), 2,47(3H, in), 3.75(3H, s) to 5.17(2H, s), 6,36(1H, d, J=8 Hz), of 6.49(1H, d, J=16 Hz),? 7.04 baby mortality(1H, DD, J=2, 8 Hz), 7,30(1H, d, J=2 Hz), 7,32(1H, d, J=16 Hz).

Macc (ESI): m/z 371(M+1).

Preparative example 25-3

In the same manner as in the above preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-(methylthio)benzyl)-2-Mei-5-yl)-2-propanolol acid was obtained as thin yellow crystals (305 mg) from methyl (E)-3-(4-chloro-1-(2-chloro-4-(methylthio)benzyl)-2-Mei-5-yl)-2-propenate (374 mg).

1H-NMR (CDCl3): 2,35 (3H, s), 2,47(3H, s), is 5.18(2H, s) 6,38(1H, d, J=8 Hz), 6,47(1H, d, J=16 Hz), 7,05(1H, DD, J=2, 8 Hz), 7,30(1H, d, J=2 Hz), 7,37(1H, d, J=16 Hz),

Macc (ESI): m/z 357(M+1).

Preparative example 26-1

In the same manner as in the above preparative example 15-1, 4-chloro-1-(2-chloro-4-(trifluoromethyl)benzyl) is l-4-carbaldehyde (100 mg) and 2-chloro-4-(trifluoromethyl)benzyl bromide (378 mg).

1H-NMR (CDCl3): 2,35(3H, s), the 5.65(2H, s), 6,60(1H, d, J=8 Hz), was 7.45(1H, d, J=8 Hz), 7,71(1H, s), 9,76(1H, s).

Macc (ESI): m/e 337(M)+.

Preparative example 26-2

In the same manner as in the above preparative example 15-2, ethyl (E)-3-[4-chloro-1-(2-chloro-4-(trifluoromethyl)-benzyl)-2-Mei-5-yl]-2-propenal (207 mg) was obtained as colorless oil from 4-chloro-1-(2-chloro-4-(trifluoromethyl)-benzyl)-2-Mei-5-carbaldehyde (185 mg).

1H-NMR (CDCl3): of 1.30(3H, t, J=6 Hz), to 2.35(3H, s), 4,20(2H, q, J=6 Hz), are 5.36(2H, s), is 6.54(1H, d, J=16 Hz), 6,59(1H, d, J=8 Hz), 7,26(1H, d, J=16 Hz), of 7.48(1H, d, J=8 Hz), of 7.75(1H, s).

Macc (ESI): m/e 408(M+H)+.

Preparative example 26-3

In the same manner as in the above preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-(trifluoromethyl)-benzyl)-2-Mei-5-yl)-2-propanolol acid was obtained as colourless crystals (144 mg) of ethyl (E)-3-(4-chloro-1-(2-chloro-4-(trifluoromethyl)benzyl)-2-Mei-5-yl)-2-propenate (203 mg).

1H-NMR (CDCl3): a 2.36(3H, s), of 5.26(2H, s), of 6.49(1H, d, J=16 Hz), 6,60(1H, d, J=8 Hz), 7,33(1H, d, J=16 Hz), 7,49(1H, d, J=8 Hz), of 7.75(1H, s).

Macc (ESI): m/z 379(M+1).

Preparative example 27-1

In the same manner as in the above preparative example 15-1, 4-chloro-1-(2-chloro-4-(phenoxymethyl)benzyl)-2-Mei-5-((methanesulfonate)methyl)-4-(phenoxymethyl)benzene (605 mg).

1H-NMR (CDCl3): of 2.33(3H, s), free 5.01(2H, s), 5,63(2H, s), 6,51(1H, d, J=8 Hz), 6.90 to-7,03(3H, m), 7,20-to 7.35(3H, m), 7,53(1H, d, J=2 Hz), made up 9.77(1H, s).

Macc (ESI): m/e 375(M+H)+.

Preparative example 27-2

In the same manner as in the above preparative example 15-2, methyl (E)-3-(4-chloro-1-(2-chloro-4-(phenoxymethyl)-benzyl)-2-Mei-5-yl)-2-propenal (413 mg) was obtained as a white powder from 4-chloro-1-(2-chloro-4-(phenoxymethyl)-benzyl)-2-Mei-5-carbaldehyde (475 mg) and methyl (triphenylphosphorane)acetate (623 mg).

1H-NMR (CDCl3): of 2.34(3H, s), 3,74(3H, s), of 5.03(2H, s), with 5.22(2H, s), 6,47(1H, d, J=8 Hz), 6,50(1H, d, J=16 Hz), 6,91? 7.04 baby mortality(3H, m), 7,21-7,34(3H, m), 7,22(1H, d, J=16 Hz), EUR 7.57(1H, d, J=2 Hz).

Macc (ESI): m/e 431(M+H)+.

Preparative example 27-3

In the same manner as in the above preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-(phenoxymethyl)-benzyl)-2-Mei-5-yl)-2-propanolol acid (391 mg) was obtained as a white powder from methyl (E)-3-(4-chloro-1-(2-chloro-4-(phenoxymethyl)benzyl)-2-Mei-5-yl)-2-propenate (404 mg).

1H-NMR (CDCl3): of 2.34(3H, s), free 5.01(2H, s), a total of 5.21(2H, s), 6,46(1H, d, J=16 Hz), 6,47(1H, d, J=9 Hz), 6.89 in-7,02 (3H, m), 7,20-7,34(3H, m), 7,34(1H, d, J=16 Hz), 7,55(1H, d, J=2 Hz).

Macc (ESI): m/e 415(M-N)-.

Preparative example 28-1

In the same way as in the made in the form of pale yellow crystals of 4-chloro-2-Mei-5-carbaldehyde (200 mg) and 2-chloro-1-((methanesulfonate)methyl)-4-nitrobenzene (404 mg).

1H-NMR (CDCl3): is 2.37(3H, s), 5,67(2H, s), to 6.67(1H, d, J=8 Hz), of 8.06(1H, DD, J=8, 2 Hz), a 8.34(1H, d, J=2 Hz), of 9.75(1H, s).

Preparative example 28-2

In the same manner as in the above preparative example 15-2, methyl (E)-3-(4-chloro-1-(2-chloro-4-nitrobenzyl)-2-Mei-5-yl)-2-propenal (297 mg) was obtained as pale-yellow crystals from 4-chloro-1-(2-chloro-4-nitrobenzyl)-2-Mei-5-carbaldehyde (285 mg) and methyl (triphenyltin-formanilide)acetate (546 mg).

1H-NMR (CDCl3): 2,35(3H, s), 3,74(3H, s), from 5.29(2H, s), of 6.52(1H, d, J=15 Hz), of 6.65(1H, d, J=8 Hz), 7,27(1H, d, J=2 Hz), 8,08(1H, d, J=8, 2 Hz), at 8.36(1H, d, J=2 Hz).

Preparative example 28-3

In the same manner as in the above preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-nitrobenzyl)-2-Mei-5-yl)-2-propanolol acid (233 mg) was obtained as pale-orange crystals from methyl (E)-3-(4-chloro-1-(2-chloro-4-nitrobenzyl)-2-Mei-5-yl)-2-propenate (275 mg).

1H-NMR (DMS O-d6): 2,32(3H, s) to 5.56(2H, s), 6,28(1H, d, J=15 Hz), 6,77(1H, d, J=8 Hz), 7,22(1H, d, J=15 Hz), 8,16(1H, DD, J=8, 2 Hz), to 8.41(1H, d, J=2 Hz).

Preparative example 29-1

In the same manner as in the above preparative example 15-1, (E)-4-chloro-1-(2-chloro-4-(2-phenylethenyl)benzyl)-2-Mei-5-carbaldehyde was obtained as orange crystals1H-NMR (CDCl3): of 2.34(3H, s), 5,64(2H, s), of 6.50(1H, d, J=8 Hz), of 6.99(1H, d, J=16 Hz), 7,10(1H, d, J=16 Hz), 7,25-7,42 (4H, m) to 7.50(2H, d, J=8 Hz), 7,58(2H, s), 9,78(1H, s).

Macc (ESI): m/z 371(M+1).

Preparative example 29-2

In the same manner as in the above preparative example 15-2, methyl (2E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)-benzyl)-2-Mei-5-yl)-2-propenal received in the form of an amorphous product yellow (433 mg) from (E)-4-chloro-1-(2-chloro-4-(2-phenylethenyl)benzyl)-2-Mei-5-carbaldehyde (390 mg).

1H-NMR (CDCl3): a 2.36(3H, s), 3,74(3H, s), with 5.22(2H, s), of 6.45(1H, d, J=8 Hz), 6,51(1H, d, J=16 Hz), of 6.99(1H, d, J=16 Hz), 7,12(1H, d, J=16 Hz), 7,26-7,41(5H, m) to 7.50(2H, d, J=8 Hz), 7,60(1H, s).

Macc (ESI): m/z 427(M+1).

Preparative example 29-3

In the same manner as in the above preparative example 15-4, (2E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)-benzyl)-2-Mei-5-yl)-2-propanolol acid was obtained as colourless crystals (326 mg) of methyl (2E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)2-propenate (418 mg).

1H-NMR (DMS O-d6): of 2.34(3H, s) 5,41(2H, s), of 6.26(1H, d, J=16 Hz), 6,53(1H, d, J=8 Hz), 7.18 in-7,44(6N, m), 7,51(1H, d, J=8 Hz), 7,60(2H, d, J=8 Hz), to 7.84(1H, s).

Preparative example 30-1

In the same manner as in the above preparative example 15-1, 1-(1-brough the imidazole-5-carbaldehyde (200 mg) and 1-bromo-2-(methyl bromide)naphthalene (457 mg).

1H-NMR (CDCl3): 2,32(3H, s), 5,88(2H, s), to 6.58(1H, d, J=8 Hz), 7,56(1H, t, J=8 Hz), the 7.65(1H, t, J=8 Hz), 7,73(1H, d, J=8 Hz),of 7.82(1H, d, J=8 Hz), 8,35(1H, d, J=8 Hz), 9,82(1H, s).

Preparative example 30-2

In the same manner as in the above preparative example 15-2, methyl (E)-3-(1-(1-bromo-2-naphthyl)-4-chloro-2-Mei-5-yl)-2-propenal (413 mg) was obtained as pale-yellow crystals of 1-(1-bromo-2-naphthyl)-4-chloro-2-Mei-5-carbaldehyde (386 mg) and methyl (triphenylphosphorane-den)acetate (603 mg).

1H-NMR (CDCl3): a 2.36(3H, s), 3,70(3H, s), 5,44(2H, s), of 6.50(1H, d, J=8 Hz), 6,53(1H, d, J=2 Hz), 7,37(1H, d, J=15 Hz), EUR 7.57(1H, t, J=8 Hz), to 7.67(1H, t, J=8 Hz), of 7.75(1H, d, J=8 Hz), 7,83(1H, d, J=8 Hz), 8,35(1H, d, J=8 Hz).

Preparative example 30-3

In the same manner as in the above preparative example 15-4, (E)-3-(1-(1-bromo-2-naphthyl)-4-chloro-2-Mei-5-yl)-2-propanolol acid (389 mg) was obtained as colorless crystals from methyl (E)-3-(1-(1-bromo-2-naphthyl)-4-chloro-2-Mei-5-yl)-2-propenate (393 mg).

1H-NMR(DMS O-d6): is 2.37(3H, s), 5,61(2H, s), 6,24(1H, d, J=15 Hz), to 6.58(1H, d, J=8 Hz), 7,24(1H, d, J=15 Hz), the 7.65(1H, t, J=8 Hz), 7,76(1H, t, J=8 Hz), of 7.97(2H, t, J=8 Hz), 8,29(1H, d, J=8 Hz).

Preparative example 31-1

In the same manner as in preparative example 15-1, 4-chloro-1-((3-chloro-5-(trifluoromethyl)pyridine-2-Devida (271 mg) and 3-chloro-2-chloromethyl-5-(trifluoromethyl)pyridine (474 mg).

1H-NMR (DCl3): of 2.38(3H,s), USD 5.76(2H, s), of 7.97(1H, s), 8,58(1H, s), to 9.66(1H, s).

MS (ESI): m/z 336(M-1).

Preparative example 31-2

In the same manner as in preparative example 15-2, methyl (E)-3-(4-chloro-1-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)-methyl)-2-Mei-5-yl)-2-propenal was obtained as a yellow oil (342 mg) of 4-chloro-1-((3-chloro-5-(trifluoromethyl)-pyridine-2-yl)methyl)-2-Mei-5-carbaldehyde (430 mg).

1H-NMR (CDCl3): of 2.38(3H, s) of 2.75(3H, s), of 5.39(2H, s), is 6.54(1H, d, J=16 Hz), 7,34(1H, d, J=16 Hz), 8,00(1H, s), 8,66(1H, s).

MS (ESI): m/z 392(M-1).

Preparative example 31-3

In the same manner as in preparative example 15-4, (E)-3-(4-chloro-1-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-Mei-5-yl)-2-propanolol acid (240 mg) was obtained from methyl (E)-3-(4-chloro-1-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)-methyl)-2-Mei-5-yl)-2-propenate (335 mg).

1H-NMR (DMSO-d6): of 2.28(3H, s), of 5.68(2H, s), 6,28(1H, d, J=16 Hz), 7,26(1H, d, J=16 Hz), at 8.60(1H, s) 8,89(1H, s).

MS (ESI): m/z 380(M+1).

Preparative example 32-1

3-(4-(N,N-bis-(tert-butoxycarbonyl)amino)-2-Chlorobenzyl)-5-chloro-2-Mei-4-carbaldehyde (844 mg) was obtained as an amorphous white product of 5-chloro-2-Mei-4-carbaldehyde (340 mg) and 4-(N,N-bis-(tert-butoxycarbonyl)-AMD, J=8, 2 Hz), 7,26(1H, d, J=2 Hz), 9,76(1H, s).

Preparative example 32-2

Methyl (E)-3-(1-(4-(N,N-bis-(tert-butoxycarbonyl)amino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propenal (902 mg) was obtained as an amorphous white product of 3-(4-(N,N-bis-(tert-butoxycarbonyl)amino)-2-Chlorobenzyl)-5-chloro-2-Mei-4-carbaldehyde (834 mg).

1H-NMR (CDCl3): of 1.42(18H, s), of 2.34(3H, s), and 3.72(3H, s), 5,23(2H, s) of 6.45(1H, d, J=16 Hz), 6.48 in(1H, d, J=8 Hz), 7,01(1H, DD, J=8, 2 Hz), 7,30(1H, d, J=2 Hz), 7,33(1H, d, J=16 Hz).

MS (ESI): m/z 541 (M+1).

Preparative example 32-3

Methyl (E)-3-(1-(4-(N,N-bis-(tert-butoxycarbonyl) amino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propenal (882 mg) was dissolved in dioxane (8,8 ml) was added 1N. an aqueous solution of sodium hydroxide (5.0 ml). The mixture was stirred at 80 ° C for 5.5 hours To the reaction mixture were added 1N. an aqueous solution of sodium hydroxide (3.0 ml) and the mixture was stirred at 80 ° C for 18 h and was again added 1N. an aqueous solution of sodium hydroxide (1.0 ml). The reaction mixture was stirred at 80 ° C for 2 h and was heated under reflux for 3 h and neutralized under cooling with ice. The precipitate was collected by filtration and washed with water to obtain (E)-3-(1-(4-(tert-butoxycarbonyl)amino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-is, is), to 6.22(1H, d, J=16 Hz), 6,46(1H, d, J=8 Hz), 7,18(1H, d, J=16 Hz), 7,28(1H, DD, J=8, 2 Hz), 7,71(1H, d, J=2 Hz), for 9.64(1H, s).

MS (ESI): m/z 427 (M+1).

Preparative example 33-1

2-Ethylimidazole (1.0 g) was dissolved in dry ethanol (10 ml) was added dropwise bromine (1.2 ml) under ice cooling. The reaction mixture was stirred at the same temperature for 3 h and at room temperature for 3 h and left overnight at room temperature. After neutralization with 5 n aqueous sodium hydroxide solution was added sodium nitrite (1.4 g) and water (10 ml) and the mixture is boiled under reflux for 10 hours, the Reaction mixture was distributed between chloroform and water and the aqueous layer was twice extracted with chloroform. The organic layers were combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by chromatography on a column of silica gel (chloroform/methanol=98:2) to give 4-bromo-2-ethylimidazole (1,02 g) as a pale yellow solid.

1H-NMR (CDCl3): of 1.32(3H, t, J=6 Hz), a 2.75(2H, q, J=6 Hz), 6.89 in(1H,s).

MS (ESI): m/z 176 (M+1).

Preparative example 33-2

4-Bromo-2-ethylimidazole (24.4 g) was dissolved in ethanol (244 ml) was added aqueous sodium hydroxide solution (105 ml) and 37% formalin (15,6 drop ice and concentrated to dryness under reduced pressure. The residue was extracted with chloroform-methanol (4/1) and the insoluble substance was filtered. The residue was concentrated to dryness under reduced pressure. The residue was purified by chromatography on a column of silica gel (chloroform/methanol=49:1 to 19:1) to obtain 4-bromo-2-ethyl-5-(hydroxymethyl)imidazole (18,9 g) as a yellow powder.

1H-DMS O-d6): of 1.16(3H, t, J=6 Hz), to 2.55(2H, q, J=6 Hz), 4,30(2H, d, J=4 Hz), 5,14(1H, t, J=4 Hz).

Preparative example 33-3

4-Bromo-2-ethyl-5-(hydroxymethyl)imidazole (18,9 g) was dissolved in dry dimethylformamide (189 ml) and added dioxide, magnesium (80,1 g). The mixture was stirred at room temperature for 5 h and left overnight. The reaction mixture was filtered through celite and the insoluble substance was washed with chloroform. Filtrate and wash fractions were combined and concentrated to dryness under reduced pressure. The residue was washed with water to obtain 5-bromo-2-ethylimidazole-4-carbaldehyde (12.9 g) in the form Koricheva powder.

1H-NMR (CDCl3): of 1.37(3H, t, J=6 Hz), of 2.86(2H, q, J=6 Hz), 9,58(1H, s).

Preparative example 33-4

In the same manner as in preparative example 1-4, 5-chloro-2-ethylimidazole-4-carbaldehyde was obtained as orange crystals (6.6 g) of 5-bromo-2-ethylimidazole-4-LASS="ptx2">Preparative example 33-5

In the same manner as in preparative example 15-1, 4-chloro-1-(2-chloro-4-(n-pentyloxy)benzyl)-2-ethylimidazole-5-carbaldehyde was obtained as a pale yellow oil (260 mg) of 5-chloro-2-ethylimidazole-4-carbaldehyde (130 mg) and 2-chloro-4-(1-pentyloxy)benzylbromide (335 mg).

1H-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), 1,25(3H, t, J=7 Hz), 1.30 and for 1.49(4H, m), 1.70 to to 1.83(2H, m), 2,59(2H, q, J=7 Hz), 3,90(2H, t, J=7 Hz), to 5.57(2H, s), to 6.43(1H, d, J=8 Hz), of 6.68(1H, DD, J=8, 2 Hz), to 6.95(1H, d, J=2 Hz), made up 9.77(1H, s).

Mass (ESI): m/z 369(M-1).

Preparative example 33-6

In the same manner as in preparative example 15-2, methyl (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethylimidazole-5-yl)-2-propenal received in the form of solid yellow product (265 mg) of 4-chloro-1-(2-chloro-4-(1-pentyloxy) benzyl)-2-ethylimidazole-5-carbaldehyde (254 mg) and methyl (three-phenylphosphonite)acetate (354 mg).

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), of 1.27(3H, t, J=7 Hz), 1,31-1,49(4H, m), 1,71 of-1.83(2H, m), 2,61(2H, q, J=7 Hz), 3,74(3H, s), 3,90(2H, q, J=7 Hz), 5,16(2H, s), 6.35mm(1H, d, J=8 Hz), of 6.49(1H, d, J=15 Hz), 6,70(1H, DD, J=8, 2 Hz), 6,98(1H, d, J=2 Hz), 7,34(1H, d, J=15 Hz).

Mass (ESI): m/z 427(M+1).

Preparative example 33-7

In the same manner as in preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethylimidazole-5-yl)-2-prop is telemedical-5-yl)-2-propenate (254 mg).

1H-NMR(DMS O-d6): to 0.88(3H, t, J=7 Hz), to 1.14(3H, t, J=7 Hz), 1,25-of 1.44(4H, m), 1,63 is 1.75(2H, m), 2,65(2H, q, J=7 Hz), of 3.95(2H, q, J=7 Hz), 5,31(2H, s), 6,27(1H, d, J=15 Hz), 6,40(1H, d, J=8 Hz), to 6.67(1H, DD, J=8, 2 Hz), 7,13(1H, d, J=2 Hz), 7.23 percent(1H, d, J=15 Hz).

Mass (ESI): m/z 409(M-1).

Preparative example 34-1

In the same manner as in preparative example 15-1, 1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-ethylimidazole-5-carbaldehyde was obtained as a pale yellow solid (2.86 g) of 5-chloro-2-ethylimidazole-4-carbaldehyde (1.5 g) and 4-bromo-2-chlorobenzamide (3.77 g).

1H-NMR (CDCl3): of 1.28(3H, t, J=7 Hz), 2,58(2H, q, J=7 Hz), to 5.56(2H, s), 6.35mm(1H, d, J=8 Hz), 7,31(1H, DD, J=8, 1 Hz), 7,60(1H, d, J=1 Hz), 9,76(1H, s).

Mass (ESI): m/z 363(M+1).

Preparative example 34-2

In the same manner as in preparative example 15-2, methyl (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-ethylimidazole-5-yl)-2-propenal received in the form of a colourless solid (1.06 g) of 1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-ethylimidazole-5-carbaldehyde (1.0 g) and methyl (triphenylphosphonium)acetate (1.39 g).

1H-NMR (CDCl3): of 1.28(3H, t, J=7 Hz), 2,59(2H, q, J=7 Hz), of 3.75(3H, s), 5,16(2H, s), 6,32(1H, d, J=8 Hz), 6,50(1H, d, J=15 Hz), 7,29(1H, d, J=15 Hz), 7,34(1H, DD, J=8, 1 Hz), 7,63(1H, d, J=1 Hz).

Mass (ESI): m/z 419(M+1).

Preparative example 34-3

In the same way as in the pre colorless solid (228 mg) from methyl (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-ethylimidazole-5-yl)-2-propenate (260 mg).

1H-NMR (DMS O-d6): to 1.14(3H, t, J=7 Hz), 2,65(2H, q, J=7 Hz), 5,38(2H, s), 6,36(1H, d, J=15 Hz), to 6.43(1H, d, J=8 Hz), 7,20(1H, d, J=15 Hz), 7,52(1H, DD, J=8, 1 Hz), 7,87(1H, d, J=1 Hz).

Mass (ESI): m/z 403(M+1).

Preparative example 35-1

In the same manner as in preparative example 15-1, 4-chloro-1-(2-chloro-4-jobensis)-2-ethylimidazole-4-carbaldehyde was obtained as a pale yellow resin (2,68 g) of 5-chloro-2-ethylimidazole-4-carbaldehyde (1.2 g) and 2-chloro-4-jodensavanne (3,76 g).

1H-NMR (DCl3): of 1.28(3H, t, J=7 Hz), 2,58(2H, q, J=7 Hz), to 5.56(2H, s), of 6.20(1H, d, J=8 Hz), to 7.50(1H, DD, J=8, 1 Hz), 7,78(1H, d, J=1 Hz), of 9.75(1H, s).

Mass (ESI): m/z 409(M+1).

Preparative example 35-2

In the same manner as in preparative example 15-2, methyl (E)-3-(4-chloro-1-(2-chloro-4-jobensis)-2-ethylimidazole-5-yl)-2-propenal received in the form of pale yellow crystals (2,53 g) of 4-chloro-1-(2-chloro-4-jobensis)-2-ethylimidazole-5-carbaldehyde (2.65 g) and methyl (triphenylphosphonium)acetate (3.25 g).

1H-NMR (CDCl3): of 1.28(3H, t, J=7 Hz), 2,59(2H, q, J=7 Hz), of 3.75(3H, s), of 5.15(2H, s), 6,16(1H, d, J=8 Hz), of 6.49(1H, d, J=15 Hz), 7,27(1H, d, J=15 Hz), 7,51(1H, DD, J=8, 1 Hz), 7,81(1H, d, J=1 Hz).

Mass (ESI): m/z 465(M+1).

Preparative example 35-3

In the same manner as in preparative example 17-1, methyl (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Etzel)-2-ethylimidazole-5-yl)-2-propenate (600 mg) and phenylacetylene (439 mg).

1H-NMR (CDCl3): of 1.28(3H, t, J=7 Hz), 2,62(2H, q, J=7 Hz), of 3.75(3H, s), 5,23(2H, s), 6,44(1H, d, J=8 Hz), 6,50(1H, d, J=15 Hz), 7,28-7,40(4H, m), 7,47-of 7.55(2H, m), 7,63(1H, d, J=1 Hz).

Mass (ESI): m/z 439(M+1).

Preparative example 35-4

In the same manner as in preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-(phenylacetyl)benzyl)-2-ethylimidazole-5-yl)-2-propanolol acid was obtained in the form of grey crystals (410 mg) from methyl (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)-benzyl)-2-ethylimidazole-5-yl)-2-propenate (500 mg).

1H-NMR (DMS O-d6): to 1.15(3H, t, J=7 Hz), to 2.67(2H, q, J=7 Hz), 5,46(2H, s), 6,27(1H, d, J=15 Hz), is 6.54(1H, d, J=8 Hz), 7.23 percent(1H, d, J=15 Hz), 7,40-7,60(6N, m), 7,79(1H, d, J=1 Hz).

Mass (ESI): m/z 423(M-1).

Preparative example 36-1

A suspension of methyl (E)-3-(4-chloro-1-(2-chloro-4-jobensis)-2-ethylimidazole-5-yl)-2-propenate (600 mg), palladium acetate (600 mg) and tri-o-tolylphosphino (39 mg) in anhydrous triethylamine (5.4 ml) was stirred at room temperature under nitrogen atmosphere. Ten minutes later was added styrene (672 mg) and the reaction mixture was heated to 100C. After heating for 2 h the mixture was cooled with ice. Added water and the mixture was extracted with chloroform. The organic layers were washed with saturated saline, dried over anhydrous magnesium sulfate and filtered. The filtrate conc is an:ethyl acetate=10:1-7:1-5:1-4:1 gave a pale yellow resin (435 mg). It was led from isopropyl ether to obtain methyl (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-2-propenate in the form of pale yellow crystals (405 mg).

1H-NMR (CDCl3): of 1.29(3H, t, J=7 Hz), 2.63 in(2H, q, J=7 Hz), 3,74(3H, s), 5,23(2H, s), to 6.43(1H, d, J=8 Hz), 6,51(1H, d, J=15 Hz), of 6.99(1H, d, J=15 Hz), 7,21(1H, d, J=15 Hz), 7.24 to 7,41(5H, m), 7,51(2H, d, J=8 Hz) 7,60(1H, s).

Mass (ESI): m/z 441(M+1).

Preparative example 36-2

In the same manner as in preparative example 15-4, (E)3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-2-propanolol acid was obtained as pale-yellow crystals (363 mg) from methyl (E)-3-(4-chloro-1-(2-chlor-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-2-propenate (400 mg).

1H-NMR (DMS O-d6): of 1.16(3H, t, J=7 Hz), 2,68(2H, q, J=7 Hz), 5,42(2H, s), 6,27(1H, d, J=15 Hz), 6,50(1H, d, J=8 Hz), 7,28-7,44(6N, m), 7,52(1H, DD, J=8, 1 Hz), 7,60(2H, d, J=8 Hz), 7,83(1H, d, J=1 Hz).

Mass (ESI): m/z 425(M-1).

Preparative example 37-1

In the same manner as in preparative example 33-2, 2,4-dimethyl-5-(hydroxymethyl)imidazole (4,74 g) was obtained as a pale-yellow oil from 2,4-dimethylimidazole (2.6 g).

1H-NMR (DS-d6): of 2.20(3H, s) of 2.50(3H, s) to 4.41(2H, s).

Preparative example 37-2

In the same manner as in preparative example the tion of 2,4-dimethyl-5-(hydroxymethyl)imidazole (4,10 g).

Macc (ESI): m/z 123(M-H)-.

Preparative example 37-3

In the same manner as in preparative example 15-1, 1-(4-bromo-2-Chlorobenzyl)-2,4-dimethyl-1H-imidazole-5-carbaldehyde (481 mg) was obtained as pale-yellow crystals of 1-(4-bromo-2-Chlorobenzyl)-2,5-dimethyl-1H-imidazole-4-carbaldehyde (587 mg) was obtained as a pale-yellow oil from 2,4-dimethylimidazole-5-carbaldehyde (587 mg) and 4-bromo-2-chlorobenzenesulfonate (1.70 g).

1-(4-bromo-2-Chlorobenzyl)-2,4-dimethyl-1H-imidazole-5-carbaldehyde lH-NMR(CDCl3): 2,31(3H, s), 2,52(3H, s) 5,54(2H, s), of 6.31(1H, d, J=8 Hz), 7,27(1H, DD, J=8, 2 Hz), 7,58(1H, d, J=2 Hz), of 9.75(1H, s)

1-(4-bromo-2-Chlorobenzyl)-2,5-dimethyl-1H-imidazole-4-carbaldehyde 1H-NMR (CDCl3): of 2.33(3H, s), 2,43(3H, s), 5,07(2H, s), 6,23(1H, d, J=8 Hz), 7,34(1H, DD, J=8, 2 Hz), 7,63(1H, d, J=2 Hz), of 9.75(1H, s)

Preparative example 37-4

In the same manner as in preparative example 15-2, crudely purified product of methyl (E)-3-(1-(4-bromo-2-Chlorobenzyl)-2,4-dimethylimidazole-5-yl)-2-propenate (554 mg) was obtained as colorless crystals of 1-(4-bromo-2-Chlorobenzyl)-2,4-dimethyl-1H-imidazole-5-carbaldehyde (453 mg) and methyl (Trife-nilpotence)acetate (1.25 g).

1H-NMR (CDCl3): 2,32(3H, s), 2,42(3H, s), of 3.73(3H, s), 5,12(2H, s), of 5.89(1H, d, J=16 Hz), of 6.29(1H, d, J=8 Hz), 7,30(1H, DD, J=8, 2 Hz), 7,37-of 7.70(2H, m).

1H-NMR (DS-d6): of 2.26(3H, s), of 2.28(3H, s), 5,28(2H, s), of 5.75(1H, d, J=14 Hz), 6,32(1H, d, J=8 Hz), 7,27(1H, d, J=14 Hz), 7,52(1H, DD, J=8, 2 Hz), the 7.85(1H, d, J=2 Hz).

Preparative example 38-1

In the same manner as in preparative example 15-1, 4-bromo-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (9,11 g) was obtained as a pale yellow oil of 4-bromo-2-Mei-5-carbaldehyde (5,00 g) and 2-chloro-4-(1-pentyloxy)benzylbromide (9,26 g).

1H-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), 1,30-1,45 (4H, m), 1,70-1,80(2H, m), of 2.33(3H, s), 3,90(2H, t, J=7 Hz), to 5.58(2H, s), 6,44(1H, d, J=8 Hz), 6,70(1H, DD, J=8, 2 Hz), to 6.95(1H, d, J=2 Hz), 9,71(1H, C).

Preparative example 38-2

In the same manner as in preparative example 15-2, methyl (E)-3- (4-bromo-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-propenal (488 mg) was obtained as colorless crystals from 4-bromo-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (479 mg) and methyl (triphenyl-phosphoramidite)acetate (481 mg).

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), 1,33-of 1.45 (4H, m), 1,72 and 1.80(2H, m) to 2.35(3H, in), 3.75(3H, s) to 3.92(2H, t, J=7 Hz), to 5.17(2H, s), 6,36(1H, d, J=8 Hz), of 6.52(1H, d, J=15 Hz), of 6.71(1H, DD, J=8, 2 Hz), of 6.99(1H, d, J=2 Hz), 7,35(1H, d, J=15 Hz).

Preparative example 38-3

In the same manner as in preparative example 15-4, (E)-3-(4-bromo-1-(2-chloro-4-(1-Penta is 3-(4-bromo-1-(2-chloro-4-(1-pentyloxy) benzyl)-2-Mei-5-yl)-2-propenate (462 mg).

1H-NMR (DMS O-d6): to 0.88(3H, t, J=7 Hz), 1,25-of 1.42 (4H, m), 1,62-1,72(2H, m), of 2.33(3H, s), of 3.96(2H, t, J=7 Hz), 5,31(2H, s), of 6.29(1H. d, J=15 Hz), 6.42 per(1H, d, J=8 Hz), to 6.88(1H, DD, J=8, 2 Hz), 7,13(1H, d, J=2 Hz), 7,22(1H, d, J=15 Hz).

Preparative example 39-1

The lithium chloride (180 mg) suspended in 1,4-dioxane (10 ml) was added 4-bromo-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (707 mg), vinyltrimethylsilane (617 mg) and tetrakis (triphenylphosphine) palladium (0) (102 mg). The mixture was boiled under reflux for 12 hours To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The organic layers were washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The remainder went to the chromatographic column with silica gel and was suirable hexane/ethyl acetate=5/1. The target fraction was concentrated under reduced pressure to obtain 1-(2-chloro-4-(1-pentyloxy) benzyl)-4-ethynyl-2-methyl-1H-imidazole-5-carbaldehyde (538 mg) as a pale yellow resin.

1H-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), of 1.30 to 1.47 (4H, m), 1,70-1,80 (2H, m), of 2.34(3H, s), 3,90(2H, t, J=7 Hz), 5,54(1H, DD, J=8, 2 Hz), to 5.56(2H, s), of 6.26(1H, DD, J=15, 2 Hz), 6,40(1H, d, J=8 Hz), to 6.67(1H, DD, J=8, 2 Hz), 6,95-7,05(2H, m), for 9.90(1H, s).

Preparative example 39-2

1-(2-Chloro-4-(1-alladi coal (50 mg). The mixture was stirred in an atmosphere of hydrogen for 1.5 hours, the Reaction mixture was filtered through celite. To the filtrate was added water and was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was transferred to a chromatographic column with silica gel and was suirable chloroform/ethyl acetate=2/1. The target fraction was concentrated under reduced pressure to obtain 1-(2-chloro-4-(1-pentyloxy) benzyl)-4-ethyl-2-methyl-1H-imidazole-5-carbaldehyde (283 mg) as a brown-black oil.

1H-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), of 1.35(3H, t, J=7 Hz), of 1.33 to 1.48(4H, m), 1,72 and 1.80(2H, m), 2,31(3H, s), 2,87(2H, q, J=7 Hz), 3,90(2H, t, J=7 Hz), of 5.55(2H, s) 6,38(1H, d, J=8 Hz), to 6.67(1H, DD, J=8, 2 Hz), 6,94(1H, d, J=2 Hz), made up 9.77(1H, s).

Preparative example 39-3

In the same manner as in preparative example 15-2, methyl (E)-3- (1-(2-chloro-4-(1-pentyloxy)benzyl)-4-ethyl-2-Mei-5-yl)-2-propenal (273 mg) was obtained as pale-yellow crystals of 1-(2-chloro-4-(1-pentyloxy)benzyl)-4-ethyl-2-methyl-1H-imidazole-5-carbaldehyde (265 mg) and methyl (triphenylphosphonium)acetate (940 mg).

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), is 1.31(3H, t, J=7 Hz), 1.32 to about 1.47(4H, m), 1.70 to is 1.81(2H, m), of 2.34(3H, s) of 2.75(2H,t).

Preparative example 39-4

In the same manner as in preparative example 15-4, (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-4-ethyl-2-Mei-5-yl)-2-propanolol acid (222 mg) was obtained as colorless powder from methyl (E)-3-(1-(2-chloro-4-(1-pentyloxy) benzyl)-4-ethyl-2-Mei-5-yl)-2-propenate (253 mg).

1H-NMR (DMS O-d6): to 0.88(3H, t, J=7 Hz), 1,19(3H, t, J=7 Hz), 1,28-of 1.42(4H, m), 1,63-of 1.73(2H, m), of 2.28(3H, s), 2,62(2H, q, J=7 Hz), of 3.95(2H, t, J=7 Hz), to 5.21(2H, s) 5,72(1H, d, J=15 Hz), 6,28(1H, d, J=8 Hz), 6.87 in(1H, DD, J=8, 2 Hz), 7,12(1H, d, J=2 Hz), 7,29(1H, d, J=15 Hz).

Preparative example 40-1

4-Bromo-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (of 4.00 g) was dissolved in a mixed solvent of methanol (20 ml) and 1,4-dioxane (20 ml) was added palladium on coal (400 mg) and potassium acetate (1.08 g). The reaction mixture was stirred in hydrogen atmosphere for 3 hours, the Reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. To the residue was added water and was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was transferred to a chromatographic column with silica gel and was suirable hexane/ethyl acetate=1/2H-imidazole-5-carbaldehyde (3,10 g) as a pale yellow oil.

1H-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), of 1.33 to 1.47 (4H, m), 1,72-to 1.82(2H, m) to 2.35(3H, s), 3,90(2H, t, J=7 Hz), 5,59(2H, s), 6,37(1H, d, J=8 Hz), to 6.67(1H, DD, J=8, 2 Hz), to 6.95(1H, d, J=2 Hz), 7,78(1H, C) 9,68(1H, s).

Preparative example 40-2

In the same manner as in preparative example 42-1 below, roughly purified product ethyl 2-benzyl-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-3-hydroxypropanoate was obtained as a brown oil from 1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (500 mg) and ethyl 3-phenylpropionate (361 mg).

Preparative example 40-3

In the same manner as in preparative example 42-2 below, ethyl (E)-2-benzyl-3-(1-(2-chloro-4-(1-pentyloxy) benzyl)-2-Mei-5-yl)-2-propenal (405 mg) was obtained as a pale-yellow oil from the roughly purified product ethyl 2-benzyl-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-3-hydroxypropanoate.

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), 1,19(3H, t, J=7 Hz), 1.32 to about 1.47 (4H, m), 1.70 to 1, 82 (2H, m), a 2.36(3H, s) to 3.92(2H, t, J=7 Hz), of 3.97(2H, s), 4,14(2H, q, J=7 Hz), to 5.17(2H, s), 6,32(1H, d, J=8 Hz), 6,69(1H, DD, J=8, 2 Hz), 6,98(1H, d, J=2 Hz), 7,13-7,28(6N, m), 7,46(1H, s).

Preparative example 40-4

In the same manner as in preparative example 15-4, (E)-2-benzyl-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methylimidazole)benzyl)-2-Mei-5-yl)-2-propenate (385 mg).

1H-NMR (DS-d6): to 0.88(3H, t, J=7 Hz), 1,27-1, 43 (4H, m), 1,65-of 1.74(2H, m) to 2.29(3H, s), 3,86(2H, s), of 3.96(2H, t, J=7 Hz), of 5.26(2H, s), of 6.31(1H, d, J=8 Hz), 6,85(1H, DD, J=8, 2 Hz), 7,07-7,30(7H, m), the 7.43(1H, s).

Preparative example 41-1

In the same manner as in preparative example 42-1, roughly purified product ethyl 3-(1-(2-chloro-4-(1-pentyloxy) benzyl)-2-Mei-5-yl)-3-hydroxy-2-(1-pentyl)propanate was obtained as a brown oil from 1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (500 mg) and ethyl n-heptanoate (321 mg).

Preparative example 41-2

In the same manner as in preparative example 42-2, ethyl (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-(1-pentyl)-2-propenal (425 mg) was obtained as a pale-yellow oil from the roughly purified product ethyl 3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-3-hydroxy-2-(1-pentyl)propanate.

1H-NMR (CDCl3): 0,87-0,94 (6N, m) of 1.27(3H, t, J=7 Hz), 1.32 to 1.55V(10H, m), 1,72-to 1.82(2H, m), is 2.37(3H, s) to 2.54(2H, t, J=7 Hz), 3,90(2H, t, J=7 Hz), 4,18(2H, q, J=7 Hz), 5,14(2H, s), of 6.31(1H, d, J=8 Hz), to 6.67(1H, DD, J=8, 2 Hz), of 6.96(1H, d, J=2 Hz), 7,19(1H, s), 7,31(1H, s).

Preparative example 41-3

In the same manner as in preparative example 15-4, (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-(1-pentyl)-2-propanolol acid (305 mg) half-propenate (405 mg).

1H-NMR (DMS O-d6): 0,85-0,87 (6N, m), 1, 20-1, 38 (10H, m), 1,62-1,72(2H, m), 2, 30(3H, s), 2,42(2H, t, J=7 Hz), of 3.94(2H, t, J=7 Hz), to 5.21(2H, s), 6,28(1H, d, J=8 Hz), 6,85(1H, DD, J=8, 2 Hz), 7,10(1H, d, J=2 Hz), 7,13(1H, s), 7,22(1H, s).

Preparative example 42-1

Diisopropylamine (237 mg) was dissolved in tetrahydrofuran (3 ml) was added a solution of 1.53 ml) 1.53 M n-utility in hexane under nitrogen atmosphere, cooling in a bath of dry ice - acetone. The mixture was stirred in a bath of ice water, and the solution was added methyl 3-(3-pyridyl)propionate (335 mg) in tetrahydrofuran (1 ml), cooling in a bath of dry ice - acetone. The mixture was stirred in a bath of dry ice - acetone for 1 h and the solution was added 1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (500 mg) in tetrahydrofuran (1 ml). The mixture was stirred in a bath of dry ice - acetone for 1 h and added a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated saline solution, dried by the addition of bezvodno magnesium sulfate and concentrated under reduced pressure to obtain crudely purified product methyl 3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-3-hydroxy-2-(3-pyridylmethyl)propagate in the form of a brown oil.

Preparative example 42-2

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), 1,32 is 1.48 (4H, m), 1,72-to 1.82(2H, m), a 2.36(3H, s), 3,70(3H, s) to 3.92(2H, t, J=7 Hz), 3,98(2H, s), is 5.18(2H, s), 6,30(1H, d, J=8 Hz), 6,69(1H, DD, J=8, 2 Hz), 6,98(1H, d, J=2 Hz), 7 the time as in preparative example 15-4, (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-(3-pyridylmethyl)-2-propanolol acid (502 mg) was obtained as a brown powder from methyl (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-(3-pyridylmethyl)-2-propenate (695 mg).

1H-NMR (DMS O-d6): to 0.88(3H, t, J=7 Hz), 1,27-of 1.44 (4H, m), 1,65-of 1.74(2H, m), 2,31(3H, s), a 3.87(2H, s), of 3.96(2H, t, J=7 Hz), at 5.27(2H, s), 6,32(1H, d, J=8 Hz), 6,34(1H, DD, J=8, 2 Hz), 7,12(1H, d, J=2 Hz), 7,19(1H, s), 7,27(1H, DD, J=8, 5 Hz), 7,41-7,44 (2H, m), at 8.36-to 8.40(2H, m).

Preparative example 43-1

In the same manner as in preparative example 42-1, roughly purified product ethyl 3-(1-(2-chloro-4-(1-pentyloxy) benzyl)-2-Mei-5-yl)-N-hydroxy-2-methylpropanoate was obtained as a brown oil from 1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (441 mg) and ethyl n-propionate (190 mg).

Preparative example 43-2

In the same manner as in preparative example 42-2, ethyl (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-methyl-2-propenal (449 mg) was obtained as a pale-yellow oil from the roughly purified product ethyl 3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-3-hydroxy-2-methylpropanoate

1H-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), of 1.28(3H, t, J=7 Hz), of 1.33 to 1.47(4H, m), 1,72-of 1.81 (2H, THE(1H, C).

Preparative example 43-3

In the same manner as in preparative example 15-4, (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-methyl-2-propanolol acid (253 mg) was obtained as colorless crystals from ethyl (E)-3-(1-(2-chloro-4-(1-pentyloxy) benzyl)-2-Mei-5-yl)-2-methyl-2-propenate (432 mg).

1H-NMR (DS-d6): of 1.09(3H, t, J=7 Hz), 1,47-of 1.64 (4H, m), 1.85 to 1,95(2H, m), of 2.21(3H, s), 2,52(3H, s) to 4.16(2H, t, J=7 Hz), 5,44(2H, s), 6.48 in(1H, d, J=8 Hz), 7,06(1H, DD, J=8, 2 Hz), 7,32(1H, d, J=2 Hz), 7,41(1H, s), 7,53(1H, s).

Preparative example 44-1

In the same manner as in preparative example 42-1, roughly purified product ethyl 3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-3-hydroxy-2-methylpropanoate was obtained as a brown oil from 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (441 mg) and ethyl n-propionate (400 mg).

Preparative example 44-2

In the same manner as in preparative example 42-2, ethyl (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-methyl-2-propenal (261 mg) was obtained as a pale-yellow oil from the roughly purified product ethyl 3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-3-hydroxy-2-methylpropanoate.

1H-NMR (CDCl3): to 0.92(3H, t, J=7 1H, DD, J=8, 2 Hz), to 6.95(1H, d, J=2 Hz), 7,06(1H, s).

Preparative example 44-3

In the same manner as in preparative example 15-4, (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-methyl-2-propanolol acid (140 mg) was obtained as colorless crystals from ethyl (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy) benzyl)-2-Mei-5-yl)-2-methyl-2-propenate (250 mg).

1H-NMR (DMS O-d6): to 0.88(3H, t, J=7 Hz), 1,25-1,40 (4H, m), 1,62-1,72(2H, m) of 1.76(3H, s), and 2.27(3H, s), of 3.95(2H, t, J=7 Hz), 5,12(2H, s), of 6.52(1H, d, J=8 Hz), 6,86(1H, DD, J=8, 2 Hz), 7,01(1H, s), 7,06(1H, d, J=2 Hz).

Preparative example 45

4-Chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (400 mg) was dissolved in tert-butanol (8 ml) and 2-methyl-2-butene (355 mg) was added an aqueous solution (2 ml) sodium dihydrogenphosphate (135 mg). To the reaction mixture after 2 minutes was added sodium chloride (356 mg) and the mixture was stirred at room temperature for 24 hours Under ice cooling was added 1N. hydrochloric acid and brought the pH to 4. Was added water (20 ml) and precipitated crystals were collected by filtration. The crystals were dried by heating under reduced pressure to obtain 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carboxylic acid (387 mg) as colorless crystals.

1, =8, 2 Hz), to 7.09(1H, d, J=2 Hz).

Preparative example 46

4-Chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (of 1.05 g) was dissolved in ethanol (10 ml) was added sodium borohydride (168 mg) under ice cooling. The mixture was stirred at room temperature for 3 hours To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added hexane (10 ml) and precipitated crystals were collected by filtration and dried by heating under reduced pressure to obtain 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-5-hydroxymethyl-2-methyl-1H-imidazole (786 mg) as colorless crystals.

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), of 1.30 to 1.48 (4H, m), 1,72-of 1.85 (2H, m), and 2.26(3H, s), 3,91(2H, t, J=7 Hz), 4,50(2H, s), is 5.18(2H, s) 6,40(1H, d, J=8 Hz), 6,70(1H, DD, J=8, 2 Hz), of 6.96(1H, d, J=2 Hz).

Preparative example 47-1

In the same manner as in preparative example 9, 4-chloro-5-chloromethyl-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole (707 mg) was obtained as a brown oil from 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-5-hydroxymethyl-methyl-1H-imidazole (611 mg).

1H-NMR (CDCl3): 0,93(3J=2 Hz).

Preparative example 47-2

A solution of 4-chloro-5-chloromethyl-1-(2-chloro-4-(1-pentyloxy) benzyl)-2-methyl-1H-imidazole (340 mg) in acetonitrile (3 ml) was gradually added to a mixed solvent of 28% aqueous ammonia solution (6 ml) and acetonitrile (6 ml) under cooling with ice. The reaction mixture was stirred at room temperature for 1 h was Added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was transferred to a chromatographic column with silica gel and was suirable chloroform/methanol=100/1. The target fraction was concentrated under reduced pressure to obtain 5-aminomethyl-4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole (82 mg) as a pale brown oil.

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), 1,32 is 1.48 (4H, m), 1,73 of-1.83(2H, m), and 2.26(3H, s), 3,70(2H, s), 3,91(2H, t, J=7 Hz), 5,19(2H, s), 6,37(1H, d, J=8 Hz), 6,70(1H, DD, J=8, 2 Hz), of 6.96(1H, d, J=2 Hz).

Preparative example 48

In the same manner as in preparative example 47-2, 5-(N-methylamino)methyl-4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole (85 mg) was obtained as pale to the NMR (CDCl3): of 0.93(3H, t, J=7 Hz), 1,30-1,45 (4H, m), 1,72-to 1.82 (2H, m), of 2.25(3H, s), a 2.36(3H, s), of 3.56(2H, s), 3,91(2H, t, J=7 Hz), 5,19(2H, s), 6,36(1H, d, J=8 Hz), 6,69(1H, DD, J=8, 2 Hz), to 6.95(1H, d, J=2 Hz).

Preparative example 49-1

4,5-Dibromo-2-ethylimidazole (451,3 g) was dissolved in N,N-dimethylformamide (2.25 l) was added potassium carbonate (368 g). Gradually dropwise added (chloromethyl)methyl ether (200 g) under ice cooling and the mixture was stirred at room temperature for 2 hours the Reaction mixture was poured into ice salt solution and the mixture was extracted with etilize-tatom. The organic layer was sequentially washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue was added hexane and the mixture was heated and cooled. Precipitated crystals were collected by filtration and dried by heating under reduced pressure to obtain 4,5-dibromo-2-ethyl-1-(methoxymethyl)imidazole (461,7 g) as brown crystals.

1H-NMR (CDCl3): of 1.33(3H, t, J=7 Hz), 2,77(2H, q, J=7 Hz), to 3.34(3H, s), 5,23(2N, C).

Preparative example 49-2

4,5-Dibromo-2-ethyl-1-(methoxymethyl)imidazole (461,1 g) was dissolved in tetrahydrofuran (2.3 l) was gradually added dropwise a solution of 1.57 M n-utility/getsid (599 ml) at-60C. The mixture was stirred at room temperature for 2 h and poured into ice-cold water. The reaction mixture was extracted with ethyl acetate and the organic layer was sequentially washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4-bromo-2-ethyl-1-(methoxymethyl)-imidazole-5-carboxyaldehyde (366,2 g) as a brown oil.

1H-NMR (CDCl3): of 1.37(3H, t, J=7 Hz), 2,80(2H, q, J=7 Hz), at 3.35(3H, s) 5,69(2H, s), 9,72(1H, s).

Preparative example 49-3

4-Bromo-2-ethyl-1-(methoxymethyl)imidazole-5-carbaldehyde (365 g) was dissolved in 35% conc. hydrochloric acid (1,8 L) and the mixture was heated at 90 °C for 20 hours, the Solvent was evaporated under reduced pressure and to the residue was added sodium hydrogen carbonate under ice cooling to purchase a mixture of weakly basic properties. The mixture was extracted with chloroform and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and to the residue was added diisopropyl ether. The mixture was heated and cooled. Precipitated crystals were collected by filtration and dried by heating under reduced pressure to obtain 4-chloro-2-ethylimidazole-5-carbaldehyde (of 211.5 g)

Example 1

To a suspension of (E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-Mei-5-yl)-2-propanolol acid (155 mg) in N,N-dimethylformamide (0.8 ml) was added 1,1'-carbonyldiimidazole (101 mg) at room temperature and the mixture was stirred for 1 h was Added (4-methylbenzoyl)sulfonamide (106 mg) and 1,8-diazabicyclo[5,4,0]-7-undecene (96 mg) and the mixture was stirred at 50°C for 5 h the Reaction mixture was cooled with ice and added dropwise hydrochloric acid (1.7 ml) until neutral solution. Was added water (4 ml) and the precipitate was collected by filtration. This crude product is recrystallized from acetone-water to obtain (E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)-benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide (152 mg) as a pale yellow powder.

1H-NMR (CDCl3): of 2.34(3H, s), is 2.40(3H, s) to 5.17(2H, s) 6,38(1H, d, J=8 Hz), of 6.49(1H, DD, J=3 and 2 Hz), 6,53(1H, d, J=16 Hz), of 6.68(1H, d, J=3 Hz), 7,31(2H, d, J=8 Hz), 7,35(1H, d, J=16 Hz), the 7.43(1H, DD, J=8 and 2 Hz), 7,49(1H, d, J=2 Hz), 7,74(1H, d, J=2 Hz), 7,92(2H, d, J=8 Hz).

Macc (ESI): m/e 528(M-H)-.

So pl. 242-S.

Example 2

In the same manner as in example 1, (2E)-3-(4-chloro-1-(2-chloro-4- (2-furyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide (159 mg) was obtained as pale yellow powder from (E)-3-(4-chloro-1-(2-chloro-lH-NMR (DMS O-d6): 2,31(3H, s), of 5.39(2H, s), 6,55(1H, d, J=8 Hz), is 6.61(1H, DD, J=3 and 2 Hz), 6,69(1H, d, J=16 Hz), 7,06(1H, d, J=3 Hz) 7,26(1H, d, J=16 Hz), 7,35 is 7.50(4H, m), 7,56(1H, d, J=16 Hz), to 7.59(1H, DD, J=8 and 2 Hz), to 7.67-to 7.77 (2H, m), 7,78(1H, d, J=2 Hz), 7,86(1H, d, J=2 Hz), 12,07(1H, user. C).

Macc (ESI): m/e 540(M-H)-.

So pl. 227-S.

Example 3

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(2-thienyl) benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide was obtained as colorless crystals (80 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(2-thienyl)-benzyl)-2-Mei-5-yl)-2-propanolol acid (100 mg) and (4-methylbenzoyl)sulfonamida (65 mg).

1H-NMR (CDCl3): of 2.34(3H, s), is 2.40(3H, s), 5,16(2H, s), 6,37(1H, d, J=8 Hz), is 6.54(1H, d, J=16 Hz), 7,06-7,11 (1H, m), 7,26-7,40(6N, m), the 7.65(1H, d, J=2 Hz), 7,92(2H, d, J=8 Hz).

Macc (ESI): m/z 544(M-1).

So pl. 235-S.

Example 4

In the same manner as in example 1, (2E)-3-(4-chloro-1-(2-chloro-4-(2-thienyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide was obtained as colorless crystals (105 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(2-thienyl)benzyl)-2-Mei-5-yl)-2-propanolol acid (100 mg) and (E)-(2-venilated)sulfonamida (70 mg).

1H-NMR (CDCl3): 2,32(3H, s), of 5.39(2H, s), of 6.52(1H, d, J=8 Hz), 6,69(1H, d, J 16 Hz), 7,11-7,17(1H, m), 7,26(1H, d, J=16 Hz), of 7.36-7,49(4H, m), 7,50-7,63(4H, m), 7,atom, as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide was obtained as thin yellow crystals (123 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl) benzyl)-2-Mei-5-yl)-2-propanolol acid (130 mg) and (4-methylbenzoyl)sulfonamida (81 mg).

1H-NMR (CDCl3): 2,32(3H, s) to 2.41(3H, s) to 5.17(2H, s), 6,34(1H, d, J=8 Hz), 6,56(1H, d, J=16 Hz), 7,27-7,40 (7H, m), of 7.48-of 7.55(2H, m), 7,60(1H, d, J=2 Hz), to 7.93(2H, d, J=8 Hz).

Macc (ESI): m/z 562(M-1).

So pl. 239-S.

Example 6

In the same manner as in example 1, (2E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide received in the form of thin crystals ochre (101 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-2-propanolol acid (130 mg) and (E)-(2-venilated)sulfonamida (87 mg).

1H-NMR (CDCl3): of 2.34(3H, s), 5,20(2H, s), to 6.39(1H, d, J=8 Hz), is 6.61(1H, d, J=16 Hz), 7,05(1H, d, J=16 Hz), 7,30(1H, DD, J=2, 8 Hz), 7,33-7,44(7H, m), 7,46-of 7.55(4H, m), 7,60(1H, d, J=2 Hz), 7,71 (1H, d, J=16 Hz).

Macc (ESI): m/z 574(M-1).

So pl. 220-S.

Example 7

In the same manner as in example 1, (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-((4-methylbenzoyl)-sulfonyl)-2-propenamide (162 mg) was obtained as colorless crystals from mg).

1H-NMR (CDCl3): 2,31(3H, s), 2,43(3H, s), 5,10(2H, s), 6,23(1H, d, J=8 Hz), to 6.58(1H, d, J=15 Hz), 7,25-7,33(4H, m), 7,58(1H, d, J=2 Hz), 7,92(2H, d, J=8 Hz).

Macc (ESI): m/z 542(M-H)-.

So pl. 233-S.

Example 8

In the same manner as in example 1, (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)-sulfonyl)-2-propenamide (172 mg) was obtained as colorless crystals from (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propanolol acid (168 mg) and (E)-(2-venilated)sulfonamida (118 mg).

1H-NMR (CDCl3): 2,32(3H, s), of 5.15(2H, s), 6,28(1H, d, J=8 Hz), 6,70 (1H, d, J=15 Hz), was 7.08(1H, d, J=15 Hz), 7, 31-7, 42 (5H, m), 7,49-7,53(2H, m), a 7.62(1H, d, J=2 Hz), 7,69(1H, d, J=15 Hz).

Macc (ESI): m/z 554(M-N)-.

So pl. 250-S.

Example 9

In the same manner as in example 1, (E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-N-(1-pentanesulfonic)-2-propenamide (134 mg) was obtained as colorless crystals from (E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-2-propanolol acid (150 mg).

1H-NMR (CDCl3): of 0.87(3H, t, J=8 Hz), 1,24-of 1.45(4H, m), 1,75-1,89(2H, m), is 2.40(3H, s), 3,38-3,47(2H, m), of 5.26(2H, s), of 6.50 (1H, d, J=8 Hz), to 6.57(1H, d, J=15 Hz), 7,35-7,58 (7H, m), 7,68(1H, d, J=2 Hz), 8,18(1H, user. C).

Macc (ESI): m/z 520(M+1).

So pl. 203-S.

Example 10

In the same way as in pide colorless crystals from (E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-2-propanolol acid (150 mg).

1H-NMR (CDCl3): a 2.36(3H, s), 5,20(2H, s), to 6.43(1H, d, J=8 Hz), to 6.57(1H, d, J=15 Hz), 7,31-7,55(N, m), to 7.59(1H, d, J=8 Hz), to 7.64(1H, d, J=2 Hz), with 8.05(2H, d, J=8 Hz), 8,54(1H, user. C).

Macc (ESI): m /z 526(M+1).

So pl. 245-S.

Example 11

In the same manner as in example 1, (E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-N-((4-methylbenzoyl)-sulfonyl)-2-propenamide (137 mg) was obtained as colorless crystals from (E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-2-propanolol acid (150 mg).

1H-NMR (CDCl3): 2,35(3H, s), is 2.40(3H, s), 5,19(2H, s), to 6.43(1H, d, J=8 Hz), to 6.57(1H, d, J=15 Hz), 7.24 to at 7.55(8H, m), the 7.65(1H, d, J=1 Hz), 7,92(2H, d, J=8 Hz), to 8.41(1H, user. C).

Macc (ESI): m/z 540(M+1).

So pl. 229-232C.

Example 12

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)-sulfonyl)-2-propenamide (132 mg) was obtained as colorless crystals from (E)-3-(4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl)-2-propanolol acid (150 mg) and (E)-(2-venilated)sulfonamida (106 mg).

1H-NMR (CDCl3): is 2.37(3H, s), with 5.22(2H, s), 6,47(1H, d, J=8 Hz), to 6.57(1H, d, J=15 Hz), 7,03(1H, d, J=15 Hz), 7,37-7,54 (N, m), the 7.65(1H, s), 7,71(1H, d, J=15 Hz).

Mass (ESI): m/z 554(M+H)+.

So pl. 240-S.

Example 13

In the same manner as in example 1, (E)-3-(4-chloro-etnich crystals from (E)-3-(4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl)-2-propanolol acid (150 mg) and 5-chlorothiophene-2-sulfonamida (115 mg).

1H-NMR (CDCl3): is 2.37(3H, s), a total of 5.21(2H, s), 6,46(1H, d, J=8 Hz), 6,60(1H, d, J=15 Hz), make 6.90(1H, d, J=4 Hz), 7,37-7,53(7H, m), of 7.64-7,66(2H, m).

Mass (ESI): m/z 566(M+N)+.

So pl. 229-S.

Example 14

In the same manner as in example 1, (E)-N-((5-bromo-2-thienyl)sulfonyl)-3-(4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl)-2-propenamide (155 mg) was obtained as colorless crystals from (E)-3-(4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl)-2-propanolol acid (150 mg) and 5-bromothiophene-2-sulfonamida (141 mg).

1H-NMR (CDCl3): is 2.37(3H, s), a total of 5.21(2H, s), 6,46(1H, d, J=8 Hz), 6,59(1H, d, J=15 Hz),? 7.04 baby mortality(1H, d, J=4 Hz), of 7.36-of 7.55 (7H, m), to 7.61(1H, d, J=4 Hz), 7,66(1H, d, J=2 Hz).

Macc (ESI): m/z 612(M+H)+.

So pl. 234-C.

Example 15

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(1-propoxy)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide (155 mg) was obtained as colorless crystals from (E)-3-(4-chloro-1-(2-chloro-4-(1-propoxy)-benzyl)-2-Mei-5-yl)-2-propanolol acid (145 mg) and (4-methylbenzoyl)sulfonamida (96 mg).

1H-NMR (CDCl3CD3OD): of 1.02(3H, t, J=7 Hz), 1,73-of 1.85 (2H, m), is 2.30(3H, s) to 2.41(3H, s), 3,88(2H, t, J=7 Hz), 5,10(2H, s), 6,27(1H, d, J=8 Hz), only 6.64(1H, d, J=15 Hz), of 6.68(1H, DD, J=8, 2 Hz), 6,97(1H, d, J=2 Hz), 7,27-7,33 (3H, m), 7,92(2H, d, J=8 Hz).

Macc (ESI): m/z 520(M-H)-.

1H-NMR (CDCl3CD3OD): of 1.02(3H, t, J=7 Hz), 1,73-of 1.85 (2H, m), 2,32(3H, s), 3,88(2H, t, J=7 Hz), further 5.15(2H, s), 6,33(1H, d, J=8 Hz), 6,69(1H, d, J=15 Hz), 6,70(1H, DD, J=8, 2 Hz), 6,98(1H, d, J=2 Hz), to 7.09(1H, d, J=15 Hz), 7,35-7,42 (4H, m), 7,50-rate of 7.54 (2H, m), 7,68(1H, d, J=15 Hz).

Macc (ESI): m/z 532(M-H)-.

So pl. 199-S.

Example 17

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide was obtained as colorless crystals (60 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-propanolol acid (100 mg) and (4-methylbenzoyl)sulfonamida (65 mg).

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), 1,30-1,50 (4H, m), 1.70 to of 1.84 (2H, m), 2,32(3H, s), 2,42(3H, s), 3,90(2H, t, J=7 Hz), 5,09(2H, s), 6,27(1H, d, J=8 Hz), 6,53(1H, d, J=16 Hz), to 6.67(1H, DD, J=2, 8 Hz), of 6.96(1H, d, J=2 Hz), 7,28-7,39 (3H, m), to 7.93(2H, d, J=8 Hz).

Macc (ESI): m/z 548(M-1).

So pl. 195-S.

Example 18

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide was obtained as colorless crystals (84 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-propanolol acid (100 mg) and (E)-(2-venilated)sulfonamida (69 mg).

1H-NMR (DCl3): to 0.92(3H, t, J=7 Hz), 1.30 and for 1.49(4H, m), the C), 7,35-7,56(6N, m), 7,72(1H, d, J=16 Hz).

Macc (ESI): m/z 560(M-1).

So pl. 196-S.

Example 19

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-((cyclopentyl)metiloksi)benzyl)-2-Mei-5-yl)-N-(1-pentanesulfonic)-2-propenamide (82 mg) was obtained as a white powder from (E)-3-(4-chloro-1-(2-chloro-4-((cyclopentyl)-metiloksi)benzyl)-2-Mei-5-yl)-2-propanolol acid (164 mg) and 1-pentanesulfonate (90 mg).

1H-NMR (CDCl3): of 0.90(3H, t, J=7 Hz), 1,25-1, 92 (14N, m), 2,34(1H, Sept, J=7 Hz), is 2.37(3H, s), 3,38-3,50(2H, m), 3,80(2H, d, J=7 Hz), 5,16(2H, s), 6,34(1H, d, J=8 Hz), 6,51(1H, d, J=15 Hz), 6,72(1H, DD, J=8 and 2 Hz), 7,00(1H, d, J=2 Hz), 7,44(1H, d, J=16 Hz).

Macc (ESI): m/e 540 (M-N)-.

So pl. 177-S.

Example 20

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-((cyclopentyl)metiloksi)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide (135 mg) was obtained as a white powder from (E)-3-(4-chloro-1-(2-chloro-4-((cyclopentyl)-metiloksi)benzyl)-2-Mei-5-yl)-2-propanolol acid (163 mg) and (4-methylbenzoyl)sulfonamida (106 mg).

1H-NMR (CDCl3): 1,25-of 1.92 (8H, m), 2,32(3H, s), 2,33(1H. Sept, J=7 Hz), 2,42(3H, s), of 3.78(2H, d, J=7 Hz), 5,09(2H, s), 6,27(1H, d, J=8 Hz), of 6.52(1H, d, J=16 Hz), of 6.68(1H, DD, J=8 and 2 Hz), 6,97(1H, d, J=2 Hz), 7,32(2H, d, J=8 Hz), 7,34(1H, d, J=16 Hz), 7,94(2H, d, J=8 Hz).

Macc (ESI): m/e 564-((cyclopentyl)metiloksi)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide (128 mg) was obtained as a white powder from (E)-3-(4-chloro-1-(2-chloro-4-((cyclopentyl)metiloksi)benzyl)-2-Mei-5-yl)-2-propanolol acid (164 mg) and (E)-(2-venilated)sulfonamida (99 mg).

1H-NMR (CDCl3): 1,23-of 1.92 (8H, m), 2,32(1H, Sept, J=7 Hz), of 2.33(3H, s), of 3.77(2H, d, J=7 Hz), 5,12(2H, s), 6,32(1H, d, J=8 Hz), 6,60(1H, d, J=16 Hz), of 6.68(1H, DD, J=8 and 2 Hz), of 6.96(1H, d, J=2 Hz), was 7.08(1H. d, J=16 Hz), 7,33-7,56 (5H, m), 7,40(1H, d, J=16 Hz), of 7.70(1H, d, J=16 Hz).

Macc (ESI): m/e 572(M-H)-.

So pl. 200-S.

Example 22

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-((cyclohexyl)metiloksi)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide was obtained as colorless crystals (61 mg) from (E)-3-(4-chloro-1-(2-chloro-4-((cyclohexyl)metiloksi)benzyl)-2-Mei-5-yl)-2-propanolol acid (85 mg) and (4-methylbenzoyl)sulfonamida (52 mg).

1H-NMR (CDCl3): 0,95-1,89 (11N, m), 2,32(3H, s), 2,42(3H, s), 3,70(2H, d, J=7 Hz), 5,10(2H, s), from 6.22(1H, d, J=8 Hz), 6,50(1H, d, J=16 Hz), to 6.67(1H, DD, J=2, 8 Hz), 6,97(1H, d, J=2 Hz), 7,30-7,38 (3H, m), 7,94(2H, d, J=8 Hz).

Mass (ESI): m/z 574(M-1).

So pl. 214-S.

Example 23

In the same manner as in example 1, (2E)-3-(4-chloro-1-(2-chloro-4-((cyclohexyl)metiloksi)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide was obtained as colorless crystals (63 mg) from (E)-3-(4-chloro-1-(2-chloro-4-((cyclohexyl)metiloksi)benzyl)-2-Mei-5-yl)-2-propanolol acid (85 mg) and (E)-(2-venilated)sulfonamida (55 mg).

1H-NMR (CDCl3): of 0.95 to 1.37 (6N, m)16 Hz), 7,37 was 7.45(4H, m), 7,49-rate of 7.54 (2H, m), 7,72(1H, d, J=16 Hz).

Mass (ESI): m/z 586(M-1).

So pl. 210-S.

Example 24

In the same manner as in example 1, (E)-3-(1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide was obtained as colorless crystals (83 mg) from (E)-3-(1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propanolol acid (90 mg) and (4-methylbenzoyl)sulfonamida (55 mg).

1H-NMR (CDCl3): 2,32(3H, s), 2,42(3H, s), of 5.03(2H, s), 5,10(2H, s), of 6.29(1H, d, J=8 Hz), 6,51(1H, d, J=16 Hz), to 6.75(1H, DD, J=2, 8 Hz), 7,06(1H, d, J=2 Hz), 7,29-7,44 (8H, m), 7,95(2H, d, J=8 Hz).

Macc (ESI): m/z 568(M-1).

So pl. 226-S.

Example 25

In the same manner as in example 1, (E)-3-(1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide was obtained as colorless crystals (73 mg) from (E)-3-(1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propanolol acid (90 mg) and (E)-(2-venilated)sulfonamida (59 mg).

1H-NMR (CDCl3): of 2.34(3H, s), 5,02(2H, s), 5,14(2H, s), 6,34(1H, d, J=8 Hz), 6,56(1H, d, J=16 Hz), 6,77(1H, DD, J=2, 8 Hz), 7,02-7,10(2H, m), 7,31-7,55(11N, m), 7,73(1H, d, J=16 Hz).

Macc (ESI): m/z 580(M-1).

So pl. 225-S.

Example 26

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(methylthio)benzyl)-2-the 4-chloro-1-(2-chloro-4-(methylthio)-benzyl)-2-Mei-5-yl)-2-propanolol acid (90 mg) and (4-methylbenzoyl)sulfonamida (65 mg).

lH-NMR(CDCl3): 2,32(3H, s), 2,42(3H, s), 2,47(3H, s), 5,11(2H, s), of 6.26(1H, d, J=8 Hz), of 6.52(1H, d, J=16 Hz), 7,00(1H, DD, J=2, 8 Hz), 7,26 and 7.36(4H, m), 7,94(2H, d, J=8 Hz).

Macc (ESI): m/z 508(M-1).

So pl. 228-230S.

Example 27

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(methylthio)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide was obtained as colorless crystals (97 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(methylthio)benzyl)-2-Mei-5-yl)-2-propanolol acid (90 mg) and (E)-(2-venilated)sulfonamida (69 mg).

1H-NMR (CDCl3): of 2.34(3H, s) to 2.46(3H, s), of 5.15(2H, s), of 6.31(1H, d, J=8 Hz), to 6.57(1H, d, J=16 Hz), 7,00(1H, d, J=2 Hz), 7,05(1H, d, J=16 Hz), 7,29(1H, d, J=2 Hz), 7,35-7,45(4H, m), 7,49-of 7.55(2H, m), 7,72(1H, d, J=16 Hz).

Macc (ESI): m/z 520(M-1).

So pl. 237-S.

Example 28

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(trifluoromethyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide was obtained as thin yellow crystals (14 mg) from (E)-3-(4-chloro-1-(2-chloro-4(trifluoromethyl)benzyl)-2-Mei-5-yl)-2-propanolol acid (30 mg) and (4-methylbenzoyl)sulfonamida (20 mg).

1H-NMR (CDCl3): of 2.33(3H, s), 2,42(3H, s), 5,20(2H, s), 6.48 in(1H, d, J=8 Hz), 6,60(1H, d, J=16 Hz), 7.23 percent-of 7.35(3H, m), 7,44(1H, d, J=8 Hz), 7,72(1H, s), 7,92(2H, d, J=8 Hz).

Macc (ESI): m/z 530(M-1).

So pl. 223-S.idazole-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide was obtained as colorless crystals (90 mg) from (E)-3-(4-chloro-1-(2-chloro-4(trifluoromethyl)benzyl)-2-Mei-5-yl)-2-propanolol acid (100 mg) and (E)-(2-venilated)sulfonamida (72 mg).

lH-NMR (DMSO-d6): 2,30(3H, s), of 5.48(2H, s), 6,63 to 6.75(2H, m), 7,24(1H, d, J=16 Hz), 7,37-7,51(4H, m), EUR 7.57(1H, d, J=16 Hz), 7,66(1H, d, J=8 Hz), 7,73(2H, d, J=8 Hz), to 7.99(1H, s).

Macc (ESI): m/z 542(M-1).

So pl. 261-S.

Example 30

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(phenoxymethyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide (207 mg) was obtained as a white powder from (E)-3-(4-chloro-1-(2-chloro-4-(phenoxymethyl)-benzyl)-2-Mei-5-yl)-2-propanolol acid (191 mg) and (4-methylbenzoyl)sulfonamida (118 mg).

1H-NMR (CDCl3): 2,32(3H, s), 2,42(3H, s), 5,02(2H, s), 5,16(2H, s) 6,38(1H, d, J=8 Hz), is 6.54(1H, d, J=15 Hz), 6.89 in? 7.04 baby mortality (3H, m), 7.18 in-7,38 (6N, m), 7,54(1H, d, J=2 Hz), to 7.93(2H, d, J=8 Hz).

Macc (ESI): m/e 568(M-N)-.

So pl. 236-S.

Example 31

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(phenoxymethyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide (219 mg) was obtained as a white powder from (E)-3-(4-chloro-1-(2-chloro-4-(phenoxymethyl)-benzyl)-2-Mei-5-yl)-2-propanolol acid (189 mg) and (E)-(2-venilated)sulfonamida (128 mg).

1H-NMR (CDCl3): 2,30(3H, s), 5,07(2H, s), of 5.39(2H, s), of 6.50(1H, d, J=8 Hz), 6,70(1H, d, J=16 Hz), 6,88-7,02(MN, m), 7,22(1H, d, J=16 Hz) 7,26-of 7.48(7H, m), 7,56(1H, d, J=16 Hz), a 7.62(1H, d, J=2 Hz), 7,68-7,80(2H, m), 12,08(1H, user. C).

Macc (2-chloro-4-nitrobenzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)-sulfonyl)-2-propenamide (63 mg) was obtained as pale-yellow crystals from (E)-3-(4-chloro-1-(2-chloro-4-nitrobenzyl)-2-Mei-5-yl)-2-propanolol acid (105 mg) and (4-methylbenzoyl)sulfonamida (76 mg).

1H-NMR (CDCl3CD3OD): 2,32(3H, s) to 2.41(3H, s), of 5.24(2H, s), 6,55(1H, d, J=8 Hz), of 6.68(1H, d, J=15 Hz), 7,22(1H, d, J=15 Hz), 7,30(2H, d, J=8 Hz), of 7.90(2H, d, J=8 Hz), 8,03(1H, DD, J=8, 2 Hz), with 8.33(1H, d, J=2 Hz).

Macc (ESI): m/z 507(M-N)-.

So pl. 241-S.

Example 33

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-nitrobenzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)-sulfonyl)-2-propenamide (78 mg) was obtained as pale-yellow crystals from (E)-3-(4-chloro-1-(2-chloro-4-nitrobenzyl)-2-Mei-5-yl)-2-propanolol acid (105 mg) and (E)-(2-venilated)sulfonamida (81 mg).

1H-NMR (CDCl3CD3D): WAS 2.34(3H, s), from 5.29(2H, s), 6,59(1H, d, J=8 Hz), 6.73 x(1H, d, J=15 Hz), 7,06(1H, d, J=15 Hz), 7,30(1H, t, J=8 Hz), 7,37 was 7.45(3H, m), 7,50-7,52(2H, m), 7,68(1H, d, J=15 Hz), with 8.05(1H, DD, J=8, 2 Hz), a 8.34(1H, d, J=2 Hz).

Macc (ESI): m/z 519(M-H)-.

So pl. 199-S.

Example 34

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide was obtained as thin yellow crystals (81 mg) from (E)-3-(4-chloro-1-(2-chloro-4- ((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-2-propanolol acid (150 mg) and (4-methylbenzoyl)sulfonamida (93 mg).

1H-NMR (CDCl3): of 2.33(3H, s), 2,39(3H, s), of 5.15 (2H, s), 6.35mm(1H, d, J=8 Hz), is 6.54(1H, d, J=16 Hz), 6,97(1H, d, J=16 Hz), 7,CLASS="ptx2">Example 35

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide was obtained as colorless crystals (86 mg) from (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-2-propanolol acid (150 mg) and (E)-(2-venilated)sulfonamida (100 mg).

1H-NMR (Dl3): a 2.36(3H, s), 5,20(2H, s) 6,40 (1H, d, J=8 Hz), to 6.58(1H, d, J=16 Hz), of 6.96(1H, d, J=16 Hz),? 7.04 baby mortality(1H, d, J=16 Hz), was 7.08(1H, d, J=16 Hz), 7,26-7,54(N, m), 7,58(1H, d, J=2 Hz), of 7.70(1H, d, J=16 Hz).

Macc (ESI): m/z 576(M-1).

So pl. 230-232C.

Example 36

In the same manner as in example 1, (E)-3-(1-(1-bromo-2-naphthyl)-4-chloro-2-Mei-5-yl)-N-((4-methylbenzoyl)-sulfonyl)-2-propenamide (182 mg) was obtained as colorless crystals from (E)-3-(1-(1-bromo-2-naphthyl)-4-chloro-2-methylimidazol-5-yl)-2-propanolol acid (175 mg) and (4-methylbenzoyl)-sulfonamida (111 mg).

1H-NMR (CDCl3): 2,30(3H, s), of 2.38(3H, s) 5,33(2H, s), 6.42 per(1H, d, J=8 Hz), of 6.52(1H, d, J=15 Hz), 7.23 percent-7,26(2H, m), 7,37(1H, d, J=15 Hz), EUR 7.57(1H, t, J=8 Hz), the 7.65(1H, d, J=8 Hz), of 7.70(1H, d, J=8 Hz), 7,80(1H, d, J=8 Hz), 7,88(2H, d, J=8 Hz), 8,31(1H, d, J=8 Hz), 8,69(1H, user. C).

Macc (ESI): m/z 558(M-H)-.

So pl. 260-C.

Example 37

In the same manner as in example 1, (E)-3-(1-(1-bromo-2-naphthyl)-4-chloro-2-Mei-5-yl)-N--4-chloro-2-Mei-5-yl)-2-propanolol acid (175 mg) and (E)-(2-venilated)-sulfonamida (119 mg).

1H-NMR (DMS O-d6): of 2.33(3H, s) 5,59(2H, s), 6,56(1H, d, J=8 Hz), 6,70(1H, d, J=15 Hz), 7,27(1H, d, J=15 Hz), 7,37-of 7.48(4H, m), 7,53(1H, d, J=15 Hz), to 7.64(1H, t, J=8 Hz), 7,69 to 7.75(3H, m), 7,94(2H, t, J=8 Hz), compared to 8.26(1H, d, J=8 Hz).

Macc (ESI): m/z 570(M-H)-.

So pl. 264-S.

Example 38

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-(1-pentanesulfonic)-2-propenamide (135 mg) was obtained as colorless crystals from (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy) benzyl)-2-Mei-5-yl)-2-propanolol acid (150 mg) and 1-pentanesulfonate (86 mg).

So pl. 175-S

lH-NMR (CDCl3): to 0.89(3H, t, J=6 Hz), of 0.93(3H, t, J=6 Hz), of 1.25 to 1.48(8H), 1.70 TO A 1.88 (4H), A 2.36(3H, s), of 3.45(2H, t, J=6 Hz), to 3.92(2H, t, J=6 Hz), further 5.15(2H, s), 6.35mm(1H, d, J=8 Hz), of 6.52(1H, d, J=16 Hz), of 6.71(DD, J=8, 2 Hz), of 6.99(1H, d, J=2 Hz), 7,44(1H, d, J=16 Hz), 8,03(1H, user. C).

MS (ESI): m/z 529(M-1).

Example 39

(E)-3-(4-Chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-propanolol acid (150 mg) was dissolved in N,N-dimethylformamide (1.5 ml) was added carbonyldiimidazole. The mixture was stirred at room temperature for 3 hours To the reaction mixture were added sodium salt of (E)-1-penten-1-ralfinamide (97 mg) and the mixture was stirred at room temperature for 3 h and left for one day. The reaction mixture is to collected by filtration and washed with water. The resulting white powder suspended in ethanol (0.75 ml) and was heated. The mixture was stirred at room temperature for 30 minutes the Precipitate was collected by filtration, washed with ethanol and dissolved in N,N-dimethylformamide (0.75 ml) at 80 ° C. Was added water (0.25 ml) at the same temperature and the mixture was stirred at room temperature for 1 h the Precipitated crystals were collected by filtration, washed with a solution of N,N-dimethylformamide-water (1:1) and then with water to obtain (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide (160 mg) as colorless crystals.

1H-NMR (CDCl3): to 0.92(3H, t, J=6 Hz), were 0.94(3H, t, J=6 Hz), 1,30-1,60(6N), OF 1.78(2H, m), of 2.25(2H, q, J=6 Hz), to 2.35(3H, s) to 3.92(2H, t, J=6 Hz), further 5.15(2H, s), 6,33(1H, d, J=8 Hz), of 6.49(1H, d, J=16 Hz), is 6.54(1H, d, J=16 Hz), 6,70(DD, J=8, 2 Hz), of 6.99(1H, d, J=2 Hz),? 7.04 baby mortality(1H, dt, J=16.6 Hz), 7,41(1H, d, J=16 Hz), 8,00(1H, user. C).

MS (ESI): m/z 528(M-1).

Example 40

In the same manner as in example 1, (E)-N-(1-butanesulfonyl)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-propenamide (132 mg) was obtained as colorless crystals from (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-propanolol acid (150 mg) and 1-butanesulfinamide (78 mg).

So pl. 182-S

MS (ESI): m/z 515(M-1).

Example 41

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-N-(1-pentanesulfonic)-2-propenamide was obtained as colorless crystals (116 mg) from (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)-benzyl)-2-Mei-5-yl)-2-propanolol acid (140 mg) and 1-pentanesulfonate (77 mg).

1H-NMR (CDCl3): of 0.87(3H, t, J=7 Hz), 1,24-of 1.45 (4H, m), 1,75-of 1.88(2H, m), of 2.38(3H, s), 3,39-of 3.46(2H, m), with 5.22(2H, s), 6.42 per(1H, d, J=8 Hz), is 6.54(1H, d, J=16 Hz), 7,00(1H, d, J=16 Hz), 7,12(1H, d, J=16 Hz), 7,27-rate of 7.54(7H, m), 7,60(1H, d, J=1 Hz).

MS (ESI): m/z 544(M-1).

So pl. 215-S.

Example 42

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide was obtained as colorless crystals (117 mg) from (E)-3-(4-chloro-1-(2-chloro-4-((E)-(2-phenylethenyl))benzyl)-2-Mei-5-yl)-(E)-2-propanolol acid (150 mg) and (E)-1-penten-1-ralfinamide (81 mg).

1H-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), 1,43-of 1.57(2H, m), 2,14-of 2.30(2H, m), is 2.37(3H, s), a total of 5.21(2H, s) 6,40(1H, d, J=8 Hz), 6.48 in(1H, d, J=16 Hz), to 6.57(1H, d, J=16 Hz), 6,95-to 7.15(3H, m), 7,26-of 7.55(7H, m), of 7.60(1H, d, J=1 Hz).

MS (ESI): m/z 542(M-1).

So pl. 226-S.enyl)-benzyl)-2-Mei-5-yl)-2-propenamide (148 mg) was obtained as colorless crystals from (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-2-propanolol acid (150 mg) and 1-butanesulfinamide (75 mg).

So pl. 213-S

1H-NMR (CDCl3): to 0.92(3H, t, J=6 Hz), of 1.44(2H, m), of 1.80(2H, m), 2,48(3H, s), 3,44(2H, t, J=6 Hz), with 5.22(2H, s), 6.42 per(1H, d, J=8 Hz), 6,59(1H, d, J=16 Hz), 7,00(1H, d, J=16 Hz), 7,11(1H, d, J=16 Hz), 7,25-of 7.55 (7H), 7,60(1H, d, J=2 Hz), 8,40(1H, user. C).

MS (ESI): m/z 531(M-1).

Example 44

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-N-(1-pentane-sulfonyl)-2-propenamide was obtained as colorless crystals (100 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)-benzyl)2-Mei-5-yl)-2-propanolol acid (135 mg) and pentanesulfonate (74 mg).

1H-NMR (CDCl3): to 0.89(3H, t, J=7 Hz), of 1.25 to 1.47 (4H, m), 1,75-1,90(2H, m), of 2.38(3H, s), 3,40-3,47 (2H, m), 5,23(2H, s), 6.42 per(1H, d, J=8 Hz), 6,55(1H, d, J=16 Hz), 7,31-7,40(3H, m), 7,42(1H, d, J=16 Hz), of 7.48-of 7.55(2H, m), 7,63(1H, d, J=1 Hz), 7,87(1H, s).

MS (ESI): m/z 542(M-1).

So pl. 207-S.

Example 45

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide was obtained as colorless crystals (84 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)-benzyl)-2-Mei-5-yl)-2-propanolol acid (125 mg) and (E)-1-penten-1-ralfinamide (68 mg).

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), 1,45-of 1.57 (2H, m), 2,20-of 2.30 (2H, m), a 2.36(3H, s), with 5.22(2H, s) 6,40(1H, d, J=8 Hz), 6.48 in(1H, d, J=16 Hz), 6.

Example 46

In the same manner as in example 1, (E)-N-(1-butanesulfonyl)-3-(4-chloro-1-(2-chloro-4-(2-phenylethynyl)-benzyl)-2-Mei-5-yl)-2-propenamide (79 mg) was obtained as colorless crystals from (E)-3-(4-chloro-1-(2-chloro-4-(2-phenylethenyl)benzyl)-2-Mei-5-yl)-2-propanolol acid (87 mg) and 1-butanesulfinamide (44 mg).

So pl. 217-S

lH-NMR (CDCl3): of 0.94(3H, t, J=6 Hz), to 1.45(2H, m), of 1.80(2H, m), 2,47(3H, s), 3,44(2H, t, J=6 Hz), 5,23(2H, s), 6.42 per(1H, d, J=8 Hz), 6,56(1H, d, J=16 Hz), 7,30-of 7.55(7H), A 7.62(1H, d, J=2 Hz), to 8.14(1H, user. C).

MS (ESI): m/z 529(M-1).

Example 47

In the same manner as in example 1, (E)-3-(4-chloro-1-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-Mei-5-yl)-N-((E)-2-phenylacetylcarbinol)-2-propenamide received in the form of pale yellow crystals (60 mg) from (E)-3-(4-chloro-1-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-Mei-5-yl)-2-propanolol acid (120 mg) and (E)-(2-venilated)-sulfonamida (87 mg).

1H-NMR (DMS O-d6): of 2.26(3H, s), the 5.65(2H, s), of 6.66(1H, d, J=16 Hz), 7,27(1H, d, J=16 Hz), 7,38-of 7.48(4H, m), EUR 7.57(1H, d, J=16 Hz), 7,70 for 7.78(2H, m), 8,56(1H, d, J=1 Hz), cent to 8.85(1H, s).

MS (ESI): m/z 545(M+1).

So pl. 249-S.

Example 48

In the same manner as in example 1, (E)-3-(4-chloro-1-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-Mei-yl)-N-((4-methylbenzoyl)sulfonyl)-2-bpd)-2-Mei-5-yl)-propanolol acid (100 mg) and (4-methylbenzoyl)sulfonamida (68 mg).

1H-NMR (CDCl3): of 2.34(3H, s), 2,42(3H, s) 5,33(2H, s), 5,62(1H, d, J=16 Hz), 7,26 and 7.36(3H, m), 7,94(2H, d, J=8 Hz), at 8.60(2H, s).

MS (ESI): m/z 533(M+1).

So pl. 239-S.

Example 49

In the same manner as in example 1, (E)-3-(1-(4-(tert-butoxycarbonylamino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-(1-pentanesulfonic)-2-propenamide was obtained as colorless crystals (64 mg) from (E)-3-(1-(4-(tert-butoxy-carbylamine)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propanolol acid (150 mg) and 1-pentanesulfonate (80 mg).

1H-NMR (CDCl3): to 0.89(3H, t, J=7 Hz), 1,28 of 1.46 (4H, m) and 1.51(N, C), a 1.75-1,89(2H, m), a 2.36(3H, s), 3,40-of 3.48(2H, m), 5,16(2H, s), 6.35mm(1H, d, J=8 Hz), 6,50(1H, d, J=16 Hz), 6,55(1H, s), 7,03(1H, DD, J=1, 8 Hz), the 7.43(1H, d, J=16 Hz).

MS (ESI): m/z 557(M-1).

So pl. 202-S.

Example 50

In the same manner as in example 1, (E)-3-(1-(4-(tert-butoxycarbonylamino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide was obtained as colorless crystals (59 mg) from (E)-3-(1-(4-(tert-butoxycarbonylamino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propanolol acid (130 mg) and (E)-1-penten-1-ralfinamide (68 mg).

1H-NMR (DMS O-d6): 0,84(3H, t, J=7 Hz), 1,35-1,49(2H, m), 1,46(N, C), 2,15 was 2.25(2H, m), 2,31(3H, s), and 5.30(2H, s), 6,47(1H, d, J=8 Hz), of 6.65(1H, d, J=16 Hz), to 6.67(1H, d, J=16 Hz), 6.75 in-6,86(1H, m), 7,24 the same way as in example 1, (E)-3-(1-(4-(tert-butoxycarbonylamino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide received in the form of a pale yellow powder (81 mg) from (E)-3-(1-(4-(tert-butoxycarbonylamino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-2-propanolol acid (200 mg) and (E)-(2-venilated)-sulfonamida (129 mg).

1H-NMR (DS-d6): 1,46(N, C) to 2.29(3H, s), from 5.29(2H, s), 6,46(1H, d, J=8 Hz), of 6.68(1H, d, J=16 Hz), 7,20-7,30(2H, m), 7,39-to 7.50(4H, m), 7,58(1H, d, J=16 Hz), to 7.67-7,80(2H, m).

MS (ESI): m/z 589(M-1).

Example 52

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(n-pentyloxy)benzyl)-2-ethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide was obtained as colorless crystals (139 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy) benzyl)-2-ethylimidazole-5-yl)-2-propanolol acid (160 mg) and (E)-2-phenylacetophenone (107 mg).

So pl. 174-175°C.

lH-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), of 1.26(3H, t, J=7 Hz), is 1.31 to 1.48(4H, m), 1,69-to 1.82(2H, m), 2,61(2H, q, J=7 Hz), 3,90(2H, q, J=7 Hz), 5,14(2H, s), 6,30(1H, d, J=8 Hz), 6,56(1H, d, J=15 Hz), to 6.67(1H, DD, J=8, 2 Hz), 6,97(1H, d, J=2 Hz), 7,06(1H, d, J=15 Hz), of 7.36-7,55(6N, m), 7,72(1H, d, J=15 Hz).

Example 53

In the same manner as in example 1, (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-ethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide received in videi (E)-2-phenylacetophenone (136 mg).

So pl. 209-S

1H-NMR(CDCl3): of 1.27(3H, t, J=7 Hz), 2,59(2H, q, J=7 Hz), 5,14(2H, s), 6,28(1H, d, J=8 Hz), 6,62(1H, d, J=15 Hz), 7,05(1H, d, J=15 Hz), 7.24 to 7,55(6N, m), 7,60(1H, d, J=1 Hz), 7,72(1H, d, J=15 Hz), a 8.34(1H, s).

Mass (ESI): m/z 568(M-1).

Example 54

In the same manner as in example 1, (E)-3-(4-chloro-1- (2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide received in the form of pale yellow crystals(120 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-2-propanolol acid (170 mg) and (E)-2-phenylacetophenone (109 mg).

So pl. 233-234°C

1H-NMR (CDCl3): of 1.27(3H, t, J=7 Hz), 2,61(2H, q, J=7 Hz), to 5.21(2H, s) 6,38(1H, d, J=8 Hz), 6,60(1H, d, J=15 Hz), 7,05(1H, d, J=15 Hz), 7,30(1H, DD, J=8, 1 Hz), 7,43-7,55(11N, m), to 7.59(1H, d, J=1 Hz), 7,71(1H, d, J=15 Hz).

Mass (ESI): m/z 588(M-1).

Example 55

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-{(4-methylbenzoyl)sulfonyl)-2-propenamide was obtained as colorless crystals (161 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)-benzyl)-2-ethylimidazole-5-yl)-2-propanolol acid (170 mg) and 4-(methylbenzoyl)sulfonamida (103 mg).

So pl. 250-S

1H-NMR (CDCl3): of 1.26(3H, t, J=7 Hz), 2,58(2H, q, J=7 Hz), to 5.17(2H, s), 6,33(1H, d, J=8 Hz), 6,56(1H, d, J=15 Hz), 7,25-7,40(7H, m), of 7.48-of 7.55(2H, m), 7,58 (who in example 1, (E)-N-(l-butanesulfonyl)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-2-propenamide was obtained as colorless crystals (107 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)-benzyl)-2-ethylimidazole-5-yl)-2-propanolol acid (130 mg) 1-butanesulfinamide (63 mg).

lH-NMR(CDCl3): of 0.93(3H, t, J=7 Hz), of 1.29(3H, t, J=7 Hz), 1,38-of 1.53(2H, m), a 1.75-to 1.86(2H, m), 2.63 in(2H, d, J=7 Hz), 3,40-to 3.49(2H, m), of 5.24(2H, s) 6,41(1H, d, J=8 Hz), 6,56(1H, d, J=16 Hz), 7,30-7,40 (4H, m), the 7.43(1H, d, J=16 Hz), 7,47-of 7.55 (2H, m), 7,63(1H, d, J=1 Hz).

MS (ESI): m/z 542(M-1).

So pl. 165-S.

Example 57

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-(1-pentanesulfonic)-2-propenamide was obtained as colorless crystals (93 mg) from (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-2-propanolol acid (130 mg) and 1-pentanesulfonate (69 mg).

1H-NMR (CDCl3): to 0.88(3H, t, J=7 Hz), of 1.29 (3H, t, J=7 Hz), 1,24 of 1.46(4H, m), 1,75-of 1.88(2H, m), 2.63 in(2H, d, J=7 Hz), 3,38-3,47(2H, m), of 5.24(2H, s) 6,40(1H, d, J=8 Hz), 6,56(1H, d, J=16 Hz), 7,30-7,40(4H, m), the 7.43(1H, d, J=16 Hz), of 7.48-of 7.55(2H, m), a 7.62(1H, d, J=1 Hz).

MS (ESI): m/z 556(M-1).

So pl. 161-163C.

Example 58

In the same manner as in example 39, (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide received in the slots (130 mg) and sodium (E)-1-penten-1-ralfinamide (78 mg).

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), of 1.28(3H, t, J=7 Hz), 1,45-1,55(2H, m), 2,19-of 2.30 (2H, m), 2,62(2H, d, J=7 Hz), with 5.22(2H, s) 6,40(1H, d, J=8 Hz), 6.48 in(1H, d, J=16 Hz), to 6.58(1H, d, J=16 Hz), 6,98-7,10(1H, m), 7.29 trend was 7.45(5H, m), 7,47-7,56(2H, m), a 7.62(1H, d, J=1 Hz).

MS (ESI): m/z 554(M-1).

So pl. 173-S.

Example 59

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide was obtained as colorless crystals (180 mg) from (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-2-propanolol acid (170 mg) and (E)-2-phenylacetophenone (109 mg).

So pl. 218-220C

1H-NMR (CDCl3CD3OD): a 1.25(3H, t, J=7 Hz), 2,62(2H, q, J=7 Hz), with 5.22(2H, s) 6,38(1H, d, J=8 Hz), 6.90 to(1H, d, J=15 Hz), 6,98(1H, d, J=15 Hz),? 7.04 baby mortality-7,14(2H, m), 7.24 to 7,44(7H, m), 7,46-7,53(4H, m), 7,58(1H, d, J=1 Hz), to 7.68(1H, d, J=15 Hz).

Mass (ESI): m/z 425(M-1).

Example 60

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-N-(4-methylbenzenesulfonyl)-2-propenamide was obtained as colorless crystals (153 mg) from (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-2-propanolol acid (170 mg) and 4-(methylbenzoyl)sulfonamida (102 mg).

So pl. 250-S

1H-NMR (CDCl3): of 1.24(3H, t, J=7 Hz), 2,60(2H, q, J=7 Hz), 5, ,47 (1H, user. C).

Mass (ESI): m/z 580 (M-1).

Example 61

In the same manner as in example 1, (E)-N-(l-butanesulfonyl)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)-benzyl)-2-ethylimidazole-5-yl)-2-propenamide was obtained as colorless crystals (146 mg) from (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-2-propanolol acid (150 mg) and 1-butanesulfinamide (72 mg).

1H-NMR (DCl3): to 0.92(3H, t, J=7 Hz), of 1.30(3H, t, J=7 Hz), 1,35-of 1.55(2H, m), 1,74-of 1.85(2H, m), 2,65(2H, d, J=7 Hz), 3,39-of 3.48(2H, m), 5,23(2H, s) 6,41(1H, d, J=8 Hz), 6,55(1H, d, J=16 Hz), of 6.99(1H, d, J=16 Hz), 7,11(1H, d, J=16 Hz), 7,27 to 7.62(8H, m).

MS (ESI): m/z 544 (M-1).

So pl. 210-S.

Example 62

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-N-(1-pentanesulfonic)-2-propenamide was obtained as colorless crystals (138 mg) from (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-2-propanolol acid (150 mg) and 1-pentanesulfonate (80 mg).

lH-NMR (CDCl3): of 0.87(3H, t, J=7 Hz), 1,23-of 1.45(4H, m) of 1.30(3H, t, J=7 Hz), 1,75-of 1.88 (2H, m), 2,65(2H, d, J=7 Hz), 3,38-of 3.46(2H, m), 5,23(2H, s) 6,40(1H, d, J=8 Hz), 6,55(1H, d, J=16 Hz), 6,98(1H, d, J=16 Hz), 7,11(1H, d, J=16 Hz), 7,26-7,66 (8H, m).

MS (ESI): m/z 558 (M-1).

So pl. 197-200C.

Example 63

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-Chetnik crystals (109 mg) from (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-2-propanolol acid (150 mg) and (E)-1-penten-1-ralfinamide (79 mg).

1H-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), of 1.29(3H, t, J=7 Hz), 1,43-of 1.56(2H, m), 2,18-of 2.28(2H, m), 2.63 in(2H, d, J=7 Hz), to 5.21(2H, s) 6,40(1H, d, J=8 Hz), 6.48 in(1H, d, J=16 Hz), to 6.57(1H, d, J=16 Hz), 6,95-to 7.15(3H, m), 7,25-to 7.61(8H, m).

MS (ESI): m/z 556(M-1).

So pl. 197-200C.

Example 64

In the same manner as in example 1, (E)-3-(1-(4-bromo-2-Chlorobenzyl)-2,4-dimethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propanamide (150 mg) was obtained as colorless powder from (E)-3-(1-(4-bromo-2-Chlorobenzyl)-2,4-dimethylimidazole-5-yl)-2-propanolol acid (140 mg) and (E)-2-Penilaian-sulfonamida (104 mg).

1H-NMR (CDCl3CD3OD): to 2.29(3H, s), is 2.40(3H, s), 5,12(2H, s), 6,04(1H, d, J=15 Hz), 6,23(1H, d, J=8 Hz), was 7.08(1H, d, J=15 Hz), 7,28(1H, DD, J=8, 2 Hz), 7,45-7,53(6N, m) to 7.61(1H, d, J=2 Hz), to 7.67(1H, d, J=16 Hz).

Macc (ESI): m/z 534(M-N)-.

So pl. 251-S.

Example 65

In the same manner as in example 1, (E)-3-(4-bromo-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide (218 mg) was obtained as colorless crystals from (E)-3-(4-bromo-1-(2-chloro-4-(1-pentyloxy) benzyl)-2-Mei-5-yl)-2-propanolol acid (200 mg) and (E)-2-phenylacetophenone (124 mg).

1H-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), 1.32 to about 1.47(4H, m), 1,72-of 1.81(2H, m) to 2.35(3H, s), 3,90(2H, t, J=7 Hz), 5,14(2H, s), 6,32(1H, d, J=8 Hz), 6,63(1H, d, J=15 Hz), of 6.68(1H, DD, J=8, 2 Hz), 6,97(1H, d, J=2 the ptx2">Example 66

In the same manner as in example 1, (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-4-ethyl-2-Mei-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide (102 mg) was obtained as colorless powder from (E)-3-(1-(2-chloro-4-(1-pentyloxy) benzyl)-4-ethyl-2-Mei-5-yl)-2-propanolol acid (150 mg) and (E)-2-phenylacetophenone (105 mg).

1H-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), of 1.26(3H, t, J=7 Hz), 1.32 to the 1.45(4H, m), 1,70-1,80(2H, m), of 2.33(3H, s), of 2.72(2H, q, J=7 Hz), with 3.89(2H, t, J=7 Hz), 5,11(2H, s), of 5.84(1H, d, J=15 Hz), 6,30(1H, d, J=8 Hz), to 6.67(1H, DD, J=8, 2 Hz), of 6.96(1H, d, J=2 Hz), 7,06(1H, d, J=15 Hz), of 7.36-7,44 (3H, m), 7,46-to 7.59 (3H, m), 7,68(1H, d, J=15 Hz).

Mass (ESI): m/z 554(M-N)-.

Example 67

In the same manner as in example 1, (E)-2-benzyl-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide (138 mg) was obtained as colorless crystals from (E)-2-benzyl-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-propanolol acid (200 mg) and (E)-2-phenylacetophenone (121 mg).

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), 1.32 to about 1.47 (4H, m), 1,72-to 1.82 (2H, m) to 2.35(3H, s), 3,90(2H, t, J=7 Hz), of 3.96(2H, s), of 5.15(2H, s), 6,30(1H, d, J=8 Hz), to 6.67(1H, DD, J=8, 2 Hz), 6,92-6,98 (2H, m), for 7.12(2H, d, J=8 Hz), 7,20-to 7.32 (5H, m), 7,35-7,45(5H, m), 7,58(1H, d, J=8 Hz).

Mass (ESI): m/z 616(M-N)-.

So pl. 171-S.

Example 68

The same is sulfonyl)-2-propenamide (123 mg) was obtained as colorless crystals from (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-(1-pentyl)-2-propanolol acid (200 mg) and (E)-2-phenylacetophenone (127 mg).

1H-NMR (CDCl3): to 0.88(3H, t, J=7 Hz), to 0.92(3H, t, J=7 Hz), 1,25-of 1.55(10H, m), 1,70-1,80(2H, m), is 2.37(3H, s), 2,48(2H, t, J=7 Hz), with 3.89(2H, t, J=7 Hz), 5,12(2H, s), 6,32(1H, d, J=8 Hz), to 6.67(1H, DD, J=8, 2 Hz), 6,95-6,97(2H, m), 7,12(1H, d, J=15 Hz), 7,27(1H, d, J=9 Hz), 7,37-7, 47 (3H, m), 7,50-7,53 (2H, m), 7,72(1H, d, J=15 Hz).

Macc (ESI): m/z 596(M-H)-.

So pl. 168 -169 PAGES.

Example 69

In the same manner as in example 1, (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-((3-pyridyl)-methyl)-N-((E)-2-phenylacetonitrile)-2-propenamide (139 mg) was obtained as colorless crystals from (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-(3-pyridyl)methyl-2-propanolol acid (230 mg) and (E)-2-phenylacetophenone (139 mg).

1H-NMR (CDCl3): of 0.94(3H, t, J=7 Hz), 1,32 is 1.48 (4H, m), 1,72-to 1.82(2H, m), of 2.38(3H, s), 3,86(2H, t, J=7 Hz), of 3.97(2H, s) to 5.00(2H, s), 6,37(1H, d, J=8 Hz), is 6.61(1H, d, J=8, 2 Hz), 6,92(1H, d, J=2 Hz), to 6.95(1H, s), 6,98(1H, d, J=15 Hz), 7.18 in-7,27(2H, m), 7,32 was 7.45(5H, m), 7,56-7,63(2H, m), of 8.09(1H, s), 8,48(1H, d, J=5 Hz).

Macc (ESI): m/z 617(M-N)-.

So pl. 156-S.

Example 70

In the same manner as in example 1, (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-methyl-N-((E)-2-phenylacetonitrile)-2-propenamide (183 mg) was obtained as colorless crystals from (E)-3-(1-(2-chloro-4-(1-pentyloxy) benzyl)-2-Mei-5-yl)-2-methyl-2-propanolol acid (200 mg) and (E)-36(3H, C) to 3.89(2H, t, J=7 Hz), 5,13(2H, s), of 6.29(1H, d, J=8 Hz), of 6.66(1H, DD, J=8, 2 Hz), 7,08-to 7.15(2H, m), 7,33(1H, s), of 7.36-7,47(3H, m), 7,49-7,53(2H, m), of 7.70(1H, d, J=15 Hz).

Macc (ESI): m/z 540(M-H)-.

So pl. 143-S.

Example 71

In the same manner as in example 1, (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy) benzyl)-2-Mei-5-yl)-2-methyl-N-((E)-2-phenylacetonitrile)-2-propenamide (90 mg) was obtained as colorless crystals from (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-methyl-2-propanolol acid (120 mg) and (E)-2-phenylacetophenone (80 mg).

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), 1,32 is 1.48 (4H, m), 1,72-to 1.82 (2H, m) to 1.99(3H, s), 2,31(3H, s), 3,91(2H, t, J=7 Hz), 5,00 (2H, s) 6,40(1H, d, J=2 Hz), 6,70(1H, DD, J=8, 2 Hz), 6,92-6,94(2H, m), 7,11(1H, d, J=15 Hz), 7,38 was 7.45(3H, m), 7,52-of 7.55(2H, m), 7,73(1H, d, J=15 Hz), 8,32(1H, user. C).

Macc (ESI): m/z 574(M-N)-.

So pl. 156-S.

Example 72

In the same manner as in example 1, 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-5-((E)-2-fenilatsetilenom)-lH-imidazole (108 mg) was obtained as colorless crystals from 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carboxylic acid (200 mg) and (E)-2-phenylacetophenone (148 mg).

1H-NMR (CDCl3): of 0.91(3H, t, J=7 Hz), of 1.28 to 1.37 (4H, m), 1,60-1,70(2H, m), 2,02(3H, s), 3,62(2H, t, J=7 Hz), 5,32(2H, s), 6,32(1H, d, J=8 Hz), 6,44(1H, d, J=8 Hz-chloro-4-(1-pentyloxy)benzyl)-5-hydroxymethyl-2-methyl-1H-imidazole (150 mg) was dissolved in 1,4-dioxane (1.5 ml) and at room temperature was added p-toluensulfonate (99 mg). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. To the residue was added ethanol (5 ml) and precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate (2 ml) and was added hexane (13 ml) in an oil bath at 70 ° C. The mixture was cooled and the precipitated crystals were collected by filtration. The crystals were dried by heating under reduced pressure to obtain (4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazol-5-yl)methyl N-(4-methylbenzenesulfonyl)-carbamate (176 mg) as colorless crystals.

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), 1,32 of 1.50 (4H, m), 1,73 of-1.83(2H, m) to 2.29(3H, s), a 2.45(3H, s), 3,93(2H, t, J=7 Hz), is 4.93(2H, s), 5,02(2H, s), of 6.31(1H, d, J=8 Hz), of 6.68(1H, DD, J=8, 2 Hz), 6,94(1H, d, J=2 Hz), 7,32(2H, d, J=8 Hz), 7,95(2H, d, J=8 Hz).

Macc (ESI): m/z 552(M-N)-.

So pl. 109-S.

Example 74

In the same manner as in example 73, 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-5-((3-(4-methylbenzenesulfonyl)-freedomites)-2-methyl-1H-imidazole (41 mg) was obtained as colorless crystals from 5-aminomethyl-4-chloro-1-(2-chloro-4-(1-pentyloxy) benzyl)-2-methyl-1H-imidazole (70 mg) and p-toluensulfonate (43 mg).

1H-NMR (CDCl3): to 0.92(3H, t, J=7 Hz), of 1.30 to 1.47 (4H, m), 1,70-1,80(2H, m), of 2.34(3H, s), 2,43(3H, s), 3,90(2H, t, J=7 Hz), -.

So pl. 165-S.

Example 75

In the same manner as in example 73, 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-5-((3-(4-methylbenzenesulfonyl)-1-methylurea)methyl)-2-methyl-1H-imidazole (60 mg) was obtained as colorless powder from 5-(N-methylamino)methyl-4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole (70 mg) and p-toluensulfonate (41 mg).

1H-NMR (CDCl3): of 0.93(3H, t, J=7 Hz), of 1.30 to 1.48 (4H, m), 1,72-to 1.82 (2H, m), is 2.09(3H, s), of 2.38(3H, s), of 2.72(3H, s), 3,88(2H, t, J=7 Hz), to 4.41(2H, s), 4,99(2H, s), x 6.15(1H, d, J=8 Hz), is 6.61(1H, DD, J=8, 2 Hz), PC 6.82(1H, d, J=2 Hz), 7,13(2H, d, J=8 Hz), of 7.70(2H, d, J=8 Hz).

Macc (ESI): m/z 565(M-H)-.

Example 76

(E)-3-(4-Chloro-1-(2-chloro-4-(phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-1-penten-1-yl)sulfonyl-2-propenamide (853 mg) suspended in ethanol (7 ml) was added 1N. an aqueous solution of sodium hydroxide (1,53 ml). The solvent was evaporated under reduced pressure. To the residue was added ethyl acetate (17 ml) and the mixture was heated and filtered hot. The filtrate was allowed to cool and the precipitated powder was collected by filtration and dried by heating under reduced pressure to obtain sodium salt of (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-1-penten-1-yl)sulfonyl)-2-propenamide (737 mg) as colorless powder.

0,85(3H, t, J=7 Hz), of 1.13(3H, t, J=7 Hz), 1.30 and USD 1.43(2H, m), 2,02(2H, q, J=7 Hz), to 2.57(2H, q, J=7 Hz), of 5.34(2H, s), 6,20-6,30(2H, m), 6,47(1H, d, J=7 Hz), 6,55(1H, d, J=15 Hz), 6,93(1H, d, J=15 Hz), 7,41 was 7.45(3H, m), of 7.48(1H, DD, J=8, 2 Hz), 7,54-7,58(2H, m), 7,78(1H, d, J=2 Hz)

Macc (ESI): m/z 554 (M-N)-.

Industrial applicability

The above-mentioned imidazole derivatives and pharmaceutically acceptable salts of the present invention can be used as pharmaceutical drugs whose action is based on the hypoglycemic activity, can be used for the prevention and treatment of, for example, disorders associated with deterioration of glucose tolerance, diabetes (e.g. type II diabetes), diabetes, pregnant, diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, and the like), syndrome of insulin resistance (e.g., abnormalities of the insulin receptor (Rabson-Mendenhall syndrome, leprechaunism syndrome Kobberling-Dunnigan syndrome Seip syndrome Lawrence, Cushing's syndrome, acromegaly, etc.), syndrome of polycystic yaichnitsei and the like), hyperglycemia (e.g., characterized by abnormal metabolism of sugar, such as eating disorders), pancreatitis, osteoporosis, hyperuricemia, hypertension, inflammatory bowel disease and skin diseases associated with abnormal differentiation of epidermal cells; and based on the inhibitory activity of cGMP-PDE (especially PDE-V), relaxing effect on the smooth musculature, bronchodilatory action, vasodilating action, overwhelming effect on smooth muscle cells, suppression effect on allergies and the like, can be used for angina, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis), tubulointerstitial disorders (e.g., kidney disease, induced by FK506, cyclosporin and the like), renal failure, atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty), peripheral vascular disease, cerebral apoplexy, chronic reversible obstructive lesions (e.g., bronchitis, asthma including chronic and allergic asthma), autoimmune diseases, allergic rhinitis, urticaria, glaucoma, impotencia (for example, organic impotence, physical impotence, and the like), nephritis, cancer cachexia, or restenosis after RTSA, exhaustion (e.g., progressive weight loss due to lipolysis, myolysis, anemia, edema, anorexia and the like in case of chronic diseases, such as cancer, tuberculosis, endocrine diseases and AIDS, and the like). The combination of the compounds of formula (I) or its pharmaceutically acceptable salts and retinoid can be used for the treatment of diseases caused by uncontrolled cell proliferation, including cancer, restenosis and atherosclerosis.

This application is based on applications NN10-367362 and 11-228838, filed in Japan on 24 December 1998 and August 12, 1999, respectively, the contents of which are incorporated herein by reference.

1. Derived imidazole of the formula (I)

where R1represents phenyl or pyridinyl, substituted by substituents selected from the group comprising (1) phenyl, (2) furyl, thienyl, (3) halogen, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted phenyl, (8) lower quinil, optionally substituted phenyl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl is on carboxyla;

R2represents lower alkyl;

R3represents halogen or lower alkyl;

R4represents (1) lower alkenyl, optionally substituted phenyl, (2) phenyl, optionally substituted lower alkyl or lower alkenyl, (3) lower alkyl or (4) thienyl, optionally substituted with halogen;

And represents the lowest alkylen;

L represents a simple bond, a lower albaniles or lower alkylene, optionally substituted phenyl or pyridinyl, or-X-CH2- where X represents O or NR5where R5represents hydrogen or lower alkyl,

or its salt.

2. A derivative of imidazole under item 1 of formula (IA)

where R2represents methyl;

R3represents chlorine;

R4represents (1) lower alkenyl, optionally substituted phenyl, (2) phenyl, (3) lower alkyl, or (4) thienyl, optionally substituted with halogen;

R6represents (1) phenyl, (2) furyl, thienyl, (3) bromine, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, substituted phenyl, (8) lower quinil, substituted phenyl, (9) lower alkoxy, optionally Thames battelino substituted protected carboxyla;

L represents attilan,

or its salt.

3. A derivative of imidazole under item 2, where R4represents phenyl or lower alkenyl, optionally substituted phenyl, R6represents bromine, lower alkenyl, substituted phenyl, lower quinil, substituted phenyl, or lower alkoxy, optionally substituted cyclo(lower)alkyl, or its salt.

4. A derivative of imidazole under item 1, where R1represents pyridinyl, substituted by substituents selected from the group comprising (1) phenyl, (2) furyl, thienyl, (3) halogen, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted phenyl, (8) lower quinil, optionally substituted phenyl, (9) lower alkoxy optionally substituted cyclo(lower)alkyl or phenyl, (10) lower alkyl, optionally substituted, phenyloxy, and (11) amino, optionally substituted protected carboxyla, or its salt.

5. A derivative of imidazole under item 1, which is a

(1) (E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(2) (2E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(5) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(6) (2E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(7) (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(8) (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(9) (E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-N-(1-pentanesulfonic)-2-propenamide,

(10) (E)-N-benzazolyl-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-2-propenamide,

(11) (E)-3-[4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl]-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(12) (E)-3-(4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(13) (E)-3-(4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl)-N-((5-chloro-2-thienyl)sulfonyl)-2-propenamide,

(14) (E)-N-((5-bromo-2-thienyl)sulfonyl)-3-(4-chloro-1-(2-chloro-4-phenylbenzyl)-2-Mei-5-yl)-2-propenamide,

(15) (E)-3-((4-chloro-1-(2-chloro-4-(1-propoxy)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(16) (E)-3-(4-chloro-1-(2-chloro-4-(1-propoxy)benzyl)-2-madilim eliminator-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(18) (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(19) (E)-3-(4-chloro-1-(2-chloro-4-((cyclopentyl)metiloksi)benzyl)-2-Mei-5-yl)-N-(1-pentanesulfonic)-2-propenamide,

(20) (E)-3-(4-chloro-1-(2-chloro-4-((cyclopentyl)metiloksi)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(21) (2E)-3-(4-chloro-1-(2-chloro-4-((cyclopentyl)metiloksi)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(22) (E)-3-(4-chloro-1-(2-chloro-4-((cyclohexyl)metiloksi)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(23) (2E)-3-(4-chloro-1-(2-chloro-4-((cyclohexyl)metiloksi)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(24) (E)-3-(1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(25) (E.)-3-(1-(4-benzyloxy-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(26) (E)-3-(4-chloro-1-(2-chloro-4-(methylthio)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(27) (E)-3-(4-chloro-1-(2-chloro-4-(methylthio)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(28) (E)-3-(4-chloro-1-(2-chloro-4-(trifloromethyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(30) (E)-3-(4-chloro-1-(2-chloro-4-(phenoxymethyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(31) (E)-3-(4-chloro-1-(2-chloro-4-(phenoxymethyl)benzyl)-2-Mei-5-yl)-N-((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(32) (E)-3-(4-chloro-1-(2-chloro-4-nitrobenzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(33) (E)-3-(4-chloro-1-(2-chloro-4-nitrobenzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(34) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(35) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide

(36) (E)-3-(1-(1-bromo-2-naphthyl)-4-chloro-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(37) (E)-3-(1-(1-bromo-2-naphthyl)-4-chloro-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(38) (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-(1-pentanesulfonic)-2-propenamide,

(39) (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

(40) (E)-N-(1-butanesulfonyl)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei - 5-yl)-2-propenamide,

(41) (E)-3-(4-chlorine is-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

(43) (E)-N-(1-butanesulfonyl)-3-(4-chloro-1-(2-chloro-4-(((E)-2-phenylethenyl)benzyl)-2-Mei-5-yl)-2-propenamide,

(44) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-N - (1-pentanesulfonic)-2-propenamide,

(45) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-Mei-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

(46) (E)-N-(1-butanesulfonyl)-3-(4-chloro-1-(2-chloro-4-(2-phenyl-ethinyl)benzyl)-2-Mei-5-yl)-2-propenamide,

(47) (E)-3-(4-chloro-1-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-Mei-5-yl)-N-((E)-2-phenylacetylcarbinol)-2-propenamide,

(48) (E)-3-(4-chloro-1-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-Mei-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(49) (E)-3-(1-(4-(tert-butoxycarbonylamino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-(1-pentanesulfonic)-2-propenamide,

(50) (E.)-3-(1-(4-(tert-butoxycarbonylamino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

(51) (E)-3-(1-(4-(tert-butoxycarbonylamino)-2-Chlorobenzyl)-4-chloro-2-Mei-5-yl)-N-(((E)-2-phenylethenyl)sulfonyl)-2-propenamide,

(52) (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(53) (E)-3-(1-(4-bromo-2-Chlorobenzyl)-4-chloro-2-this is imidazol-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(55) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(56) (E)-N-(1-butanesulfonyl)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-2-propenamide,

(57) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-(1-pentanesulfonic)-2-propenamide,

(58) (E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

(59) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(60) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-N-(4-methylbenzenesulfonyl)-2-propenamide,

(61) (E)-N-(1-butanesulfonyl)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-2-propenamide,

(62) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-N-(1-pentanesulfonic)-2-propenamide,

(63) (E)-3-(4-chloro-1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

(64) (E)-3-(1-(4-bromo-2-Chlorobenzyl)-2,4-dimethylimidazole-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(65) (E)-3-(4-bromo-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(66) (E)-3-(1-(2-�SIL-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(68) (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-(1 pentyl)-N-((E)-2-phenylacetonitrile)-2-propenamide,

(69) (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-(3-pyridyl)methyl-N-((E)-2-phenylacetonitrile)-2-propenamide,

(70) (E)-3-(1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-methyl-N-((E)-2-phenylacetonitrile)-2-propenamide,

(71) (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-Mei-5-yl)-2-methyl-N-((E)-2-phenylacetonitrile)-2-propenamide,

(72) 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-5-((E)-2-fenilatsetilenom)-1H-imidazole,

(73) (4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazol-5-yl)methyl N-(4-methylbenzenesulfonyl)carbamate,

(74) 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-5-((3-(4-methylbenzenesulfonyl)ureido)methyl)-2-methyl-1H-imidazole,

(75) 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-5-((3-(4-methylbenzenesulfonyl)-1-methylurea)methyl)-2-methyl-1H-imidazole or

(76) 3-(4-chloro-1-(2-chloro-4-(phenylacetyl)benzyl)-2-ethylimidazole-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-(E)-2-propenamide,

or its salt.

6. A derivative of imidazole under item 1, which is a

(E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-imidazol-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propane is UNAMID,

(E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethylimidazole-5-yl)-N-((4-methylbenzoyl)sulfonyl)-2-propenamide,

(E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethyl-imidazol-5-yl)-N-(1-pentanesulfonic)-2-propenamide or

(E)-3-(4-chloro-1-(2-chloro-4-(phenylethynyl)benzyl)-2-ethyl-imidazol-5-yl)-N-((E)-1-penten-1-ylsulphonyl)-2-propenamide,

or its salt.

7. Pharmaceutical composition having hypoglycemic activity, containing a derivative of imidazole under item 1 or its pharmaceutically acceptable salt.

8. Pharmaceutical drug, possess hypoglycemic activity, containing a derivative of imidazole under item 1 or its pharmaceutically acceptable salt that can be used as tools for the prevention and/or treatment of disorders associated with deterioration of glucose tolerance, diabetes, diabetes in pregnancy, diabetes complications, syndrome of insulin resistance, polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases, hyperglycemia, pancreatitis, osteoporosis, hyperuricemia, hypertension, inflammatory bowel disease, skin diseases associated with abnormal differentiation of epidermal cells.

9. P is ACTICE and/or treatment of disorders related deterioration in glucose tolerance, diabetes, diabetes in pregnancy, diabetes complications, syndrome of insulin resistance, polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases, hyperglycemia, pancreatitis, osteoporosis, hyperuricemia, hypertension, inflammatory bowel disease, skin diseases associated with abnormal differentiation of epidermal cells.

10. The method of prevention and/or treatment of disorders associated with deterioration of glucose tolerance, diabetes, diabetes in pregnancy, diabetes complications, syndrome of insulin resistance, polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases, hyperglycemia, pancreatitis, osteoporosis, hyperuricemia, hypertension, inflammatory bowel disease, skin diseases associated with abnormal differentiation epidemal cells, which includes the introduction of a derivative of imidazole under item 1 or its pharmaceutically acceptable salt.

11. Derived imidazole of the formula

where R2represents lower alkyl;

R3represents halogen or lower alkyl;

RR6represents (1) phenyl, (2) furyl, thienyl, (3) bromine, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted phenyl, (8) lower quinil, optionally substituted phenyl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl or phenyl, (10) lower alkyl, optionally substituted, phenyloxy, or (11) amino, optionally substituted lower alkoxycarbonyl;

L represents (1) lower albaniles or lower alkylene, optionally substituted phenyl or pyridinyl, (2) -O-CH2or (3) -NR5-CH2- where R5represents hydrogen or lower alkyl;

or its salt.

12. A derivative of imidazole under item 11, where R3represents chlorine, and L represents attilan.

13. A derivative of imidazole under item 12, where R6represents a lower alkenyl, optionally substituted phenyl, or lower quinil, optionally substituted phenyl.

14. The method of obtaining the derivative of imidazole of the formula (I) described in paragraph 1, or its salt, including interaction of the compounds of formula (II):

where R1

where R4as mentioned in paragraph 1,

or its salt.

Priority on the grounds of:

24.12.98 all signs of the formula, except for R1represents phenyl, substituted lower alkyl, optionally substituted, phenoxy, R4represents phenyl, optionally substituted lower alkyl, L represents a simple bond;

12.08.1999 - L represents a simple bond;

24.07.2001 - R1represents phenyl, substituted lower alkyl, optionally substituted, phenoxy, R4represents phenyl, optionally substituted lower alkyl.

 

Same patents:

The invention relates to compounds of formula (I)

in which f represents phenylenebis radical, a represents the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; R11represents a hydrogen atom, an unbranched or branched alkyl radical having from 1 to 6 carbon atoms, or the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; b is a thiophene; W is absent or represents an Association or S; X represents a bond or a radical -(CH2)k-NR16-, -O-, -CO-, -NR16-CO-, and so forth, and k is 0 or 1; Y represents a bond or a radical selected from the radicals -(CH2)m-, -(CH2)m-O-(CH2)n, -(CH-Q-(CH2)n; and Q represents pieperazinove radical, m and n are equal to integers from 0 to 6; R16, R17, R18represent independently a hydrogen atom, or a salt of the compounds

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to new derivatives of N, S-substituted N'-1-[(hetero)aryl] -N'-[(hetero)aryl] methylisothiazoline General formula I or their salts with pharmacologically acceptable acids HX in the form of a racemic mixture or in the form of a mixture of stereoisomers, which can be used for the treatment and prevention of diseases associated with dysfunction glutamatergic nanoperiodic

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to new derivatives of 2-aminopyridine F.-ly (1) where denotes unsubstituted or substituted phenyl, pyridyl, thienyl, thiazolyl, hinely, cinoxacin-2-yl or Antonelliana derivatives; D is unsubstituted or substituted phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, hinely, triazolyl, oxazolyl, isoxazolyl or Antonelliana derivatives, provided that C and D are not simultaneously have the following values: S - phenyl, and D is phenyl, S - phenyl, and D - pyridyl, With - pyridyl and D - phenyl, - pyridyl and D - pyridyl; R1- R4- hydrogen, NO2or NH2

The invention relates to the field of organic chemistry, specifically to new connections: dicyanodiamide, namely aralen-bis(2-aminothiophene-3-carbonitrile)am General formula

where R represents

Connection most effectively can be used as monomers for obtaining polyamides, polyazomethines and politician with phenylanaline groups with high values of viscosity and conductivity

The invention relates to new substituted phenyl derivatives, which are strong blockers chlorine ion channels and as such are useful in the treatment of sickle cell anemia, cerebral edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and to reduce the intraocular pressure for the treatment of disorders such as glaucoma

The invention relates to piperazine derivatives of General formula I, in which R1denotes pyridyl or phenyl, unsubstituted or once substituted Ph or 2 - or 3-Tiepolo, R2indicates Ph1or Het

The invention relates to new derivatives of arylsulfonamides having, in particular, valuable pharmacological properties, more particularly to a derivative of arylsulfonamides General formula (I)

< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene pentamethylbenzyl, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl, phenyl, disubstituted by chlorine atoms or methoxypropane,

R2a hydrogen atom, methyl,

R3pyridyl,

R4and R5hydrogen atoms or together denote a carbon-uglerodnoi communication,

R6hydroxyl, methoxyl,

A group of the formula

< / BR>
where R7and R8a hydrogen atom or together denote a methylene or ethylene group

X N-methyl-aminogroup or sulfur atom, and the group-CHR7associated with the group-NR2-,

B a carbon-carbon bond or unbranched Allenova group with 2-4 carbon atoms,

their mixtures, isomers or individual isomers and physiologically tolerated additive salts with bases, if R6means hydroxyl, which

The invention relates to new substituted phenyl derivatives, which are strong blockers chlorine ion channels and as such are useful in the treatment of sickle cell anemia, cerebral edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and to reduce the intraocular pressure for the treatment of disorders such as glaucoma

The invention relates to new triazinyl compounds of formulas Ia and Ib:

< / BR>
or their salts, where in the formula Ia W represents N or C-CO-R, where R denotes HE OC1-C6alkyl or NR3R4where R3and R4- N or C1-C6alkyl, or formula Ib Az denotes imidazopyridine and in both formulas Ia and Ib R1represents C1-C4alkyl, R2denotes phenyl fragment or 2,5-cyclohexadiene-3,4-ridin-1 silt fragment

The invention relates to new 1-(biphenyl-4-yl)methyl-1H-1, 2,4-triazole compounds and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole compounds, and each of them has as a substituent in the 2'-position (2,4-dioxopyrimidine-5-ilidene)methyl or (2,4-dioxotetrahydrofuran-5-ilidene)methyl, and their salts
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