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HK1043791B - Imidazole compounds and medicinal use thereof - Google Patents

Imidazole compounds and medicinal use thereof Download PDF

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Publication number
HK1043791B
HK1043791B HK02105326.2A HK02105326A HK1043791B HK 1043791 B HK1043791 B HK 1043791B HK 02105326 A HK02105326 A HK 02105326A HK 1043791 B HK1043791 B HK 1043791B
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HK
Hong Kong
Prior art keywords
chloro
benzyl
methylimidazol
acrylamide
substituted
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HK02105326.2A
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Chinese (zh)
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HK1043791A1 (en
Inventor
Kayakiri Hiroshi
Abe Yoshito
Hamashima Hitoshi
Sawada Hitoshi
Ishibashi Naoki
Setoi Hiroyuki
Oku Teruo
Yamasaki Noritsugu
Imoto Takafumi
Hiramura Takahiro
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安斯泰来制药有限公司
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Priority claimed from PCT/JP1999/007160 external-priority patent/WO2000039097A1/en
Publication of HK1043791A1 publication Critical patent/HK1043791A1/en
Publication of HK1043791B publication Critical patent/HK1043791B/en

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Description

Imidazole compounds and pharmaceutical use thereof
Technical Field
The present invention relates to a novel imidazole compound, more specifically to a novel imidazole compound having hypoglycemic activity or PDE-V inhibitory action, and a salt thereof. The present invention also relates to a process for producing the imidazole compound and salts thereof. The present invention also relates to a pharmaceutical composition containing the above imidazole compound or a salt thereof as an active ingredient.
Summary of The Invention
The object of the present invention is to provide a novel imidazole compound and a pharmaceutically acceptable salt thereof, and a pharmaceutical preparation for preventing or treating the following diseases, which contains the above imidazole compound or a pharmaceutically acceptable salt thereof as an active ingredient: impaired glucose tolerance, diabetes (type II diabetes and the like), gestational diabetes, diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatosis, diabetic psychosis, diabetic cataract, diabetic retinopathy and the like), insulin resistance syndrome (insulin receptor abnormality, Rabson-Mendenhall syndrome, lepigy syndrome, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly and the like), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases (angina pectoris, heart failure and the like), hyperglycemia (e.g., diseases characterized by abnormal sugar metabolism such as eating disorder), pancreatitis, osteoporosis, polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases (angina pectoris, heart failure and the like), hyperglycemia, and the like, Hyperuricemia, hypertension, inflammatory bowel disease, skin diseases accompanied by epidermal cell differentiation abnormality, angina pectoris based on cGMP-PDE (especially PDE-V) inhibitory action, smooth muscle relaxation action, bronchodilation action, vasodilation action, smooth muscle cell inhibitory action, allergy inhibitory action and the like, hypertension, pulmonary hypertension, congestive heart failure, glomerular disease (for example, diabetic glomerulosclerosis and the like), tubulointerstitial disease (for example, nephropathy and the like caused by FK506, cyclosporin and the like), renal failure, atherosclerosis, vascular stenosis (for example, vascular stenosis after percutaneous arterioplasty), non-tip vascular disease, cerebral hemorrhage, chronic occlusive disease (for example, bronchitis, asthma (chronic asthma, allergic asthma)), autoimmune disease, allergic rhinitis, Urticaria, glaucoma, diseases characterized by intestinal motility disorder (e.g., irritable bowel syndrome), impotence (e.g., organic impotence, psychogenic impotence, etc.), nephritis, cancer cachexia, or restenosis after PTCA, cachexia (e.g., progressive weight loss due to lipolysis, myolysis, anemia, edema, anorexia, etc. in chronic diseases such as cancer, tuberculosis, endocrine diseases, aids, etc.).
The novel compound of the present invention is an imidazole compound represented by the following general formula (I) [ hereinafter also referred to as object compound (I) ]:
in the formula, R1Is aryl or heterocyclyl, each of which may be substituted by a substituent selected from: (1) aryl, (2) heterocyclic group, (3) halogen, (4) halo (lower) alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl which may be substituted with aryl, (8) lower alkynyl which may be substituted with aryl, (9) lower alkoxy which may be substituted with cyclo (lower) alkyl or aryl, (10) aryloxy, and (11) amino which may be substituted with protected carboxy or lower alkyl;
R2is a lower alkyl group;
R3is hydrogen, halogen, lower alkyl or nitro;
R4is (1) lower alkenyl which may be substituted with aryl or heterocyclic group, (2) aryl which may be substituted with lower alkenyl, (3) lower alkyl, or (4) heterocyclic group which may be substituted with halogen;
a is lower alkylene;
l is a single bond, lower alkenyl or lower alkylene which may be substituted with aryl or heterocyclic group, or-X-CH2- (in which X is-O-, NR)5(in the formula, R5Is hydrogen or lower alkyl), or-S-).
Suitable salts of the object compound (I) are conventional salts which are nontoxic and pharmaceutically acceptable, for example, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, salts of ammonium salts with inorganic bases, organic amine salts such as triethylamine, pyridine, picoline, ethanolamine and triethanolamine, inorganic acid salts such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, organic carboxylic acid salts such as formic acid, acetic acid, trifluoroacetic acid, maleic acid and tartaric acid, sulfonic acid addition salts such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and salts or acid addition salts of basic or acidic amino acids such as arginine, aspartic acid and glutamic acid.
The object compound (I) and its salt of the present invention can be produced by a method represented by the following reaction formula.
The manufacturing method 1:
the symbols in the formula are the same as those described above.
The definitions of various terms in the above and below of the present specification are explained in detail below.
The term "lower" means 1 to 6 carbon atoms unless otherwise specified.
"alkyl" and "alkyl moiety" are straight or branched chain alkyl groups. Specific examples thereof include methyl group, ethyl group, 1-propyl group, isopropyl group, 1-butyl group, isobutyl group, tert-butyl group, sec-butyl group, 1-pentyl group, isopentyl group, sec-pentyl group, tert-pentyl group, methylbutyl group, 1-dimethylpropyl group, 1-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group, 3-ethylbutyl group, 1-dimethylbutyl group, 2-dimethylbutyl group, 3-dimethylbutyl group, 1-ethyl-1-methylpropyl group, 1-heptyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 2-methylhex, 1-ethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, 4-ethylpentyl group, 1-dimethylpentyl group, 2-dimethylpentyl group, 3-dimethylpentyl group, 4-dimethylpentyl group, 1-propylbutyl group, 1-octyl group, 1-methylheptyl group, 2-methylheptyl group, 3-methylheptyl group, 4-methylheptyl group, 5-methylheptyl group, 6-methylheptyl group, 1-ethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 5-ethylhexyl group, 1-dimethylhexyl group, 2-dimethylhexyl group, 3-dimethylhexyl group, 4-dimethylhexyl group, 5-dimethylhexyl group, 2-dimethylhexyl group, 3-dimethylhexyl group, 1-propylpentyl, 2-propylpentyl and the like.
Among them, preferred is an alkyl group having 1 to 6 carbon atoms.
Suitable examples of "alkenyl" and "alkenyl moiety" are straight or branched chain alkenyl groups such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1, 3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like.
Among them, an alkenyl group having 2 to 6 carbon atoms, particularly a vinyl group, is preferable.
The "cyclo (lower) alkyl group" is a cycloalkyl group having 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, and suitable examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and preferred examples thereof are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Suitable examples of the "lower alkylene group" include methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like, and particularly preferred is an alkylene group having 4 or less carbon atoms. Among them, methylene is particularly preferred.
Suitable examples of "lower alkynyl" are straight or branched alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-methyl-3-butynyl, 1-dimethyl-2-butynyl, 1-hexynyl, 5-hexynyl and the like.
Among them, particularly preferred is an alkynyl group having 2 to 6 carbon atoms, and particularly preferred is an ethynyl group.
Suitable examples of "lower alkenylene" are straight-chain or branched alkenylene groups such as vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene, methylvinylene, ethylvinylene, 1-pentylvinylene and the like.
Among them, an alkenylene group having 4 or less carbon atoms, particularly, a vinylene group is preferable.
"lower alkoxy" is a straight or branched alkoxy group having 6 or less carbon atoms. Suitable examples include methoxy, ethoxy, 1-propoxy, isopropoxy, 1-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 1-pentyloxy, isopentyloxy, sec-pentyloxy, tert-pentyloxy, 2-methylbutyloxy, 1-hexyloxy, isohexyloxy, tert-hexyloxy, sec-hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1-ethylbutoxy, 2-ethylbutoxy, 1-dimethylbutyloxy, 2-dimethylbutyloxy, 3-dimethylbutyloxy, and 1-ethyl-1-methylpropyloxy.
More preferred examples thereof include alkoxy groups having 5 or less carbon atoms such as methoxy, ethoxy, 1-propoxy, isopropoxy, 1-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and 1-pentoxy.
Examples of the "halogen" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
The "halo (lower) alkyl group" is a linear or branched alkyl group having 6 or less carbon atoms substituted with a fluorine atom, chlorine atom, bromine atom or iodine atom, and is preferably a linear or branched alkyl group having 6 or less carbon atoms substituted with a fluorine atom, chlorine atom or bromine atom. Examples thereof include fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, tribromomethyl group, 1-fluoroethyl group, 1-chloroethyl group, 1-bromoethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 1, 2-difluoroethyl group, 1, 2-dichloroethyl group, 1, 2-dibromoethyl group, 2, 2, 2-trifluoroethyl group, heptafluoroethyl group, 1-fluoropropyl group, 1-chloropropyl group, 1-bromopropyl group, 2-fluoropropyl group, 2-chloropropyl group, 2-bromopropyl group, 3-fluoropropyl group, 3-chloropropyl group, 3-bromopropyl group, 1, 2-difluoropropyl group, 1, 2-dichloropropyl group, 1, 2-dibromopropyl group, 2, 3-difluoropropyl group, 2, 3-dichloropropyl, 2, 3-dibromopropyl, 3, 3, 3-trifluoropropyl, 2, 3, 3, 3-pentafluoropropyl, 2-fluorobutyl, 2-chlorobutyl, 2-bromobutyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 4, 4, 4-trifluorobutyl, 2, 3, 3, 4, 4, 4-heptafluorobutyl, perfluorobutyl, 2-fluoropentyl, 2-chloropentyl, 2-bromopentyl, 5-fluoropentyl, 5-chloropentyl, perfluoropentyl, 2-fluorohexyl, 2-chlorohexyl, 2-bromohexyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, perfluorohexyl and the like.
"lower alkylthio" is a straight-chain or branched alkylthio group having 6 or less carbon atoms. Suitable examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, sec-pentylthio, tert-pentylthio, 2-methylbutylthio, n-hexylthio, isohexylthio, tert-hexylthio, sec-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1-dimethylbutylthio, 2-dimethylbutylthio, 3-dimethylbutylthio, and 1-ethyl-1-methylpropylthio.
More preferred is an alkylthio group having 4 or less carbon atoms, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.
In the present specification, the "aryl" and "aryl moiety" refer to an unsubstituted or alkyl-substituted aryl group. Suitable examples of the "unsubstituted aryl group" include C6-C10 aryl groups such as phenyl, naphthyl and pentalenyl groups, and among them, phenyl and naphthyl groups are preferred.
The term "alkyl-substituted aryl" refers to an aryl group substituted with at least 1 alkyl group. The number of substitution of the alkyl group is preferably 1 to 4. The aryl moiety of the "alkyl-substituted aryl" is the same as the above-mentioned unsubstituted aryl, and the "alkyl moiety" is the same as defined above, and is preferably a lower alkyl. Specific examples of the preferable alkyl-substituted aryl group include tolyl, xylyl, * -yl, ethylphenyl, propylphenyl and the like, and p-tolyl is more preferable.
The "heterocyclic group" is a saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least 1 hetero atom such as an oxygen atom, a sulfur atom, a nitrogen atom or a selenium atom, and among them, an unsaturated monocyclic heterocyclic group is preferable, heterocyclic groups described in the following (1), (7) and (9) are more preferable, and a pyridyl group, a thienyl group and a furyl group are more preferable.
Examples of the monocyclic heterocyclic group include the following:
(1) unsaturated 3-to 8-membered (preferably 5-to 6-membered) heteromonocyclic group having 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (for example, 4H-1, 2, 4-triazolyl, 1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl and the like), tetrazolyl (for example, 1H-tetrazolyl, 2H-tetrazolyl and the like);
(2) saturated 3-to 8-membered (preferably 5-to 6-membered) heteromonocyclic group containing 1-to 4-nitrogen atoms, for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
(3) unsaturated 3-to 8-membered (preferably 5-to 6-membered) heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (for example, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, etc.);
(4) saturated 3-to 8-membered (preferably 5-to 6-membered) heteromonocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, for example, morpholinyl, sdeskinyl and the like;
(5) unsaturated 3-to 8-membered (preferably 5-or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
(6) saturated 3-to 8-membered (preferably 5-to 6-membered) heteromonocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, such as thiazolidinyl, etc.;
(7) unsaturated 3-to 8-membered (preferably 5-to 6-membered) heteromonocyclic group containing 1 to 2 sulfur atoms, such as thienyl, dihydrodithiinyl, dihydrodithianyl and the like;
(8) saturated 3-to 8-membered (preferably 5-to 6-membered) heteromonocyclic group containing 1 to 2 oxygen atoms, for example, tetrahydrofuranyl, tetrahydropyranyl and the like;
(9) unsaturated 3-to 8-membered (preferably 5-to 6-membered) heteromonocyclic group containing 1 oxygen atom, for example, furyl group and the like;
(10) spiroheterocyclic groups containing 1 to 2 oxygen atoms, such as dioxaspiro undecyl (e.g., 1, 5-dioxaspiro [5, 5] undecyl, etc.);
(11) unsaturated 3-to 8-membered (preferably 5-to 6-membered) heteromonocyclic group containing 1 oxygen atom and 1-2 sulfur atoms, for example, dihydrooxathienylgroup and the like.
Examples of the polycyclic heterocyclic group include the following:
(12) saturated or unsaturated 7-to 12-membered (preferably 8-to 10-membered) polycyclic (preferably bicyclic) heterocyclic group having 1 to 4 nitrogen atoms.
Specific examples thereof include a benzimidazolyl group, an indolyl group, a 2, 3-dihydrobenzimidazolyl group, a pyrazolopyrimidinyl group such as a pyrazolo [1, 5-a ] pyrimidinyl group, a tetrahydropyrazolopyrimidinyl group such as a 4, 5, 6, 7-tetrahydropyrazolo [1, 5-a ] pyrimidinyl group, an imidazopyrazolyl group such as a 4H-imidazo [1, 2-b ] pyrazolyl group, a dihydroimidazopyrazolyl group such as a 2, 3-dihydroimidazo [1, 2-b ] pyrazolyl group, an imidazopyridinyl group such as an imidazo [1, 5-a ] (or [1, 2-a ], or [3, 4-a ]) pyridyl group, and a 1H (or 3H) -imidazo [4, 5-b ] (or [4, 5-c ]) pyridyl group, such as a 1H-pyrrolo [3, pyrrolopyridyl such as 2-b pyridyl, pyrazolopyridyl such as pyrazolo [1, 5-a ] (or [2, 3-a ] pyridyl or 1H (or 2H) -pyrazolo [4, 3-b ] pyridyl, benzopyrazolyl such as 1H (or 2H) -benzo [ c ] pyrazolyl, dihydrobenzimidazolyl, benzotriazolyl such as benzo [ d ] [1H-1, 2, 3] triazolyl, indolizinyl, isoindolyl such as 1H-isoindolyl, indazolyl such as 1H (or 2H or 3H) -indazolyl, indolinyl, isoindolyl, purinyl, quinolizinyl such as tetrah-quinolizinyl, isoquinolyl, quinolyl, 2, 3-naphthyridinyl, naphthylamino such as 1, 8-naphthylamino, Quinoxalinyl, dihydroquinoxalinyl such as 1, 2-dihydroquinoxalinyl, tetrahydroquinoxalinyl such as 1, 2, 3, 4-tetrahydroquinoxalinyl, quinazolinyl, dihydroquinazolinyl such as 1, 4- (or 3, 4) -dihydroquinazolinyl, tetrahydroquinazolinyl such as 1, 2, 3, 4-tetrahydroquinazolinyl, cinnolinyl, pteridinyl, pyrazinopyridazinyl such as pyrazino [2, 3-d ] pyridazinyl, imidazotriazinyl such as imidazo [1, 2-b ] [1, 2, 4] triazinyl, imidazopyrazinyl such as 1H-imidazo [4, 5-b ] pyrazinyl, imidazopyrimidinyl such as 3H-purine, imidazo [1, 5-a ] (or [3, 4-a ]) pyrimidine, imidazo [2, imidazopyridazinyl such as 3-b (or [3, 4-b ]) pyridazinyl, and 1H-1- (or 2) pyrimidinyl.
(13) A saturated or unsaturated 7-to 12-membered (preferably 8-to 10-membered) polycyclic (preferably bicyclic) heterocyclic group having 1 to 3 oxygen atoms.
Specific examples include: for example, a benzofuranyl group such as a benzo [ b ] (or [ c ]) furanyl group, an isobenzofuranyl group, a furopyridinyl group, a benzopyranyl group such as a 2H-benzopyranyl group, a chromanyl group, an isochromanyl group, a benzoxepin group such as a 3-benzoxepin group, a cyclopentopyranyl group such as a cyclopenta [ b ] pyranyl group, and a furopyranyl group such as a 2H-furo [3, 2-b ] pyranyl group.
(14) A saturated or unsaturated 7-to 12-membered (preferably 8-to 10-membered) polycyclic (preferably bicyclic) heterocyclic group containing 1 to 3 sulfur atoms.
Specific examples include: for example, a benzothiophenyl group such as a benzo [ b ] thiophenyl group, a dihydronaphthyridinyl group such as a 4H-1, 3-naphthyridinyl group, or a naphthyridinyl group such as a 1, 4-naphthyridinyl group.
(15) A saturated or unsaturated 7-to 12-membered (preferably 8-to 10-membered) polycyclic (preferably bicyclic) heterocyclic group containing 1 to 3 nitrogen atoms and 1 to 2 oxygen atoms.
Specific examples include: examples of the epidioxycyclopentenoimidazolyl group include an epidioxypentenoimidazolyl group such as a 4H-1, 3-epidioxypenteno [4, 5-d ] imidazolyl group, a benzoxazinyl group such as a 4H-3, 1-benzoxazinyl group, a pyridooxazinyl group such as a 5H-pyrido [2, 3-d ] oxazinyl group, a pyrazolooxazolyl group such as a 1H-pyrazolo [4, 3-d ] oxazolyl group, and a furopyridinyl group.
(16) A saturated or unsaturated 7-to 12-membered (preferably 8-to 10-membered) polycyclic (preferably bicyclic) heterocyclic group containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms.
Specific examples include: for example, a thienoimidazolyl group such as a thieno [2, 3-d ] imidazolyl group, a thienopyridyl group, a dithiadiazananyl group such as a 2, 3-dithia-1, 5-diazananyl group, and the like.
(17) A saturated or unsaturated 7-to 12-membered (preferably 8-to 10-membered) polycyclic (preferably bicyclic) heterocyclic group containing 1 to 3 oxygen atoms and 1 to 2 sulfur atoms.
Specific examples include: thienofuryl groups such as thieno [2, 3-b ] furyl group.
(18) A saturated or unsaturated 7-to 12-membered (preferably 8-to 10-membered) polycyclic (preferably bicyclic) heterocyclic group containing 1 nitrogen atom, 1 oxygen atom and 1 sulfur atom.
Specific examples include: for example, an oxathiolanopyrrolyl group such as a 4H [1, 3] -oxathiolato [5, 4-b ] pyrrolyl group.
(19) Saturated or unsaturated 7-to 12-membered (preferably 8-to 10-membered) polycyclic (preferably bicyclic) heterocyclic group containing 1 to 2 selenium atoms.
Specific examples include: a benzoselenophenyl group such as a benzo [ b ] (or [ c ]) selenophenyl group.
(20) Saturated or unsaturated 7-to 12-membered (preferably 8-to 10-membered) polycyclic (preferably bicyclic) heterocyclic group containing 1 to 2 selenium atoms and 1 to 3 nitrogen atoms.
Specific examples include: selenohexanopyridyl, such as selenohexano (seleno) [3, 2-b ] pyridyl.
As the "aryl moiety" in the "aryloxy group", there may be mentioned the "aryl moiety" mentioned hereinabove, and phenyl group is preferred.
Examples of the "protected carboxyl group" include esterified carboxyl groups.
Suitable examples of ester moieties of esterified carboxyl groups include: lower alkyl esters, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl esters, and the like, which may also have at least 1 suitable substituent, and examples thereof include: for example acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, trimethylacetoxymethyl ester, hexanoyloxymethyl ester, 1 (or 2) -acetoxyethyl ester, 1 (or 2 or 3) -acetoxypropyl ester, 1 (or 2 or 3 or 4) -acetoxybutyl ester, 1 (or 2) -propionyloxyethyl ester, lower alkanoyloxy (lower) alkyl esters such as 1 (or 2 or 3) -propionyloxypropyl ester, 1 (or 2) -butyryloxyethyl ester, 1 (or 2) -isobutyryloxyethyl ester, 1 (or 2) -trimethylacetoxyethyl ester, 1 (or 2) -hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3-dimethylbutyryloxymethyl ester, and 1 (or 2) -pentanoyloxyethyl ester; lower alkylsulfonyl (lower) alkyl esters such as 2-methanesulfonylethyl ester; mono (or di or tri) halo (lower) alkyl esters such as 2-iodoethyl ester, 2, 2, 2-trichloroethyl ester, and the like; lower alkoxycarbonyloxy (lower) alkyl esters such as methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester and the like; phthalylene (lower) alkyl esters; (5-lower alkyl-2-oxo-1, 3-dioxol-4-yl) (lower) alkyl esters such as (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl ester, (5-ethyl-2-oxo-1, 3-dioxol-4-yl) methyl ester, (5-propyl-2-oxo-1, 3-dioxol-4-yl) ethyl ester;
lower alkenyl esters such as vinyl esters, allyl esters, and the like;
lower alkynyl esters such as ethynyl ester and propynyl ester;
aryl (lower) alkyl esters which may have at least 1 suitable substituent such as mono (or di or tri) phenyl (lower) alkyl esters which may have at least 1 suitable substituent(s), for example, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3, 4-dimethoxybenzyl ester, 4-hydroxy-3, 5-di-tert-butylbenzyl ester, etc.;
for example, phenyl esters, 4-chlorophenyl esters, tolyl esters, t-butylphenyl esters, ditolyl esters, * -yl esters, cumenyl esters and the like may have at least 1 aryl ester of an appropriate substituent;
cyclo (lower) alkyl esters such as cyclohexyl ester;
2-benzo [ c ] furanone ester, and the like.
When the above substituents are substituted, the number of the substituents is 1 to 4, if not otherwise specified.
Preferable examples of the object compound (I) include compounds represented by the following general formula (IA):
in the formula, R2Is methyl;
R3is chlorine;
R4is (1) lower alkenyl which may be substituted with aryl, (2) aryl, (3) lower alkyl, or (4) heterocyclic group which may be substituted with halogen atom;
R6is (1) aryl, (2) heterocyclic group, (3) bromo, (4) halo (lower) alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl substituted with aryl, (8) lower alkynyl substituted with aryl, (9) lower alkoxy which may be substituted with cyclo (lower) alkyl or aryl, (10) lower alkyl which may be substituted with aryloxy, or (11) amino which may be substituted with protected carboxy or lower alkyl;
l is vinylidene.
In the above compound (IA), more preferably, R4Is aryl or lower alkenyl which may be substituted by aryl, R6Is bromine, lower alkenyl substituted with aryl, lower alkynyl substituted with aryl, or lower alkoxy which may be substituted with cyclo (lower) alkyl, or a salt thereof.
Among the above-mentioned compounds (I), R is particularly preferred1Is a heterocyclic group, a compound substituted with a substituent selected from the group consisting of: (1) aryl, (2) heterocyclic group, (3) halogen, (4) halo (lower) alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl which may be substituted with aryl, (8) lower alkynyl which may be substituted with aryl, (9) lower alkoxy which may be substituted with cyclo (lower) alkyl or aryl, (10) aryloxy, and (11) amino which may be substituted with protected carboxy or lower alkyl.
Among them, the following are particularly preferable.
R1: 2-chloro-4- (2-furyl) phenyl, 2-chloro-4- (2-thienyl) phenyl, 2-chloro-4- (2-phenylethynyl) phenyl, 4-bromo-2-chlorophenyl, 3-chloro-4-biphenyl, 2-chloro-4- (1-propoxy) phenyl, 2-chloro-4- (1-pentyloxy) phenyl, 2-chloro-4- ((cyclopentyl) methoxy) phenyl, 2-chloro-4- ((cyclohexyl) methoxy) phenyl, 4-benzyloxy-2-chlorophenyl, 2-chloro-4- (methylthio) phenyl, 2-chloro-4- (trifluoromethyl) phenyl, methyl-ethyl-phenyl, methyl-ethyl-phenyl, ethyl, 2-chloro-4- (phenoxy)Methyl) phenyl, 2-chloro-4-nitrophenyl, 2-chloro-4- ((E) -2-phenylvinyl) phenyl, 1-bromo-2-naphthyl;
R2: a methyl group;
R3: chlorine;
R4: p-tolyl, (E) -2-phenylvinyl, pentyl, phenyl, 5-chloro-2-thienyl, 5-bromo-2-thienyl;
R6: 2-furyl, 2-thienyl, phenylethynyl, bromo, phenyl, 1-propoxy, 1-pentoxy, (cyclopentyl) methoxy, (cyclohexyl) methoxy, benzyloxy, methylthio, trifluoromethyl, phenoxymethyl, nitro, (E) -2-phenylvinyl;
a: a methylene group;
l: vinylidene groups.
Preferred specific compounds of the object compound (I) are as follows.
(1) (E) -3- (4-chloro-1- (2-chloro-4- (2-furyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(2) (2E) -3- (4-chloro-1- (2-chloro-4- (2-furyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(3) (E) -3- (4-chloro-1- (2-chloro-4- (2-thienyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-toluene) sulfonyl) -2-acrylamide;
(4) (2E) -3- (4-chloro-1- (2-chloro-4- (2-thienyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(5) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(6) (2E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(7) (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(8) (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(9) (E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -N- (1-pentanesulfonyl) -2-acrylamide;
(10) (E) -N-benzenesulfonyl-3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -2-propenamide;
(11) (E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(12) (E) -3- (4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(13) (E) -3- (4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl) -N- ((5-chloro-2-thienyl) sulfonyl) -2-acrylamide;
(14) (E) -N- ((5-bromo-2-thienyl) sulfonyl) -3- (4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl) -2-acrylamide;
(15) (E) -3- (4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(16) (E) -3- (4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(17) (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(18) (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(19) (E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide;
(20) (E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(21) (2E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(22) (E) -3- (4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(23) (2E) -3- (4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(24) (E) -3- (1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- ((4-toluene) sulfonyl) -2-acrylamide;
(25) (E) -3- (1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(26) (E) -3- (4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazol-5-yl) -N- ((4-toluene) sulfonyl) -2-acrylamide;
(27) (E) -3- (4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(28) (E) -3- (4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(29) (E) -3- (4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(30) (E) -3- (4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(31) (E) -3- (4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylvinyl) sulfonyl) -2-acrylamide;
(32) (E) -3- (4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(33) (E) -3- (4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(34) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(35) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylvinyl) sulfonyl) -2-acrylamide;
(36) (E) -3- (1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazol-5-yl) -N- ((4-toluene) sulfonyl) -2-acrylamide;
(37) (E) -3- (1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(38) (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- (1-pentylsulfonyl) -2-acrylamide;
(39) (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide;
(40) (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-acrylamide;
(41) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide;
(42) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide;
(43) (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -2-acrylamide;
(44) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide;
(45) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide;
(46) (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- (2-phenylethynyl) benzyl) -2-methylimidazol-5-yl) -2-acrylamide;
(47) (E) -3- (4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(48) (E) -3- (4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(49) (E) -3- (1- (4- (tert-butoxycarbonylamino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide;
(50) (E) -3- (1- (4- (tert-butoxycarbonylamino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide;
(51) (E) -3- (1- (4- (tert-butoxycarbonylamino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(52) (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(53) (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-ethylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-acrylamide;
(54) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-acrylamide;
(55) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((4-toluene) sulfonyl) -2-acrylamide;
(56) (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -2-acrylamide;
(57) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide;
(58) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide;
(59) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(60) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- (4-toluenesulfonyl) -2-acrylamide;
(61) (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -2-acrylamide;
(62) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide;
(63) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide;
(64) (E) -3- (1- (4-bromo-2-chlorobenzyl) -2, 4-dimethylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-acrylamide;
(65) (E) -3- (4-bromo-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(66) (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -4-ethyl-2-methylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(67) (E) -2-benzyl-3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(68) (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (1-pentyl) -N- ((E) -2-phenylethenesulfonyl) -2-acrylamide;
(69) (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (3-pyridinyl) methyl-N- ((E) -2-phenylethenesulfonyl) -2-acrylamide;
(70) (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(71) (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-N- ((E) -2-phenylethenesulfonyl) -2-acrylamide;
(72) 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-5- ((E) -2-phenylethenesulfonylcarbamoyl) -1H-imidazole;
(73) (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazol-5-yl) methyl N- (4-tosyl) carbamate;
(74) 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -5- ((3- (4-tosyl) ureido) methyl) -2-methyl-1H-imidazole;
(75) 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -5- ((3- (4-tosyl) -1-methylureido) methyl) -2-methyl-1H-imidazole;
(76) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -1-penten-1-yl) -1-ylsulfonyl) -2-acrylamide; and sodium salts thereof.
The process for producing the object compound (I) will be described in detail below.
The manufacturing method 1:
the target compound (I) or a salt thereof can be produced by reacting the compound (II) or a reactive derivative thereof at a carboxyl group or a salt thereof with the compound (III) or a salt thereof.
Examples of suitable salts of the compound (II) or the reactive derivative at the carboxyl group thereof and the compound (III) include the same compounds as exemplified for the compound (I).
Suitable reactive derivatives at the carboxyl group of compound (II) include: acid halides, anhydrides including intramolecular anhydrides, intermolecular anhydrides, and mixed anhydrides, activated amides, activated esters, and the like. Preferred examples of the reactive derivative include: an acid chloride; acyl azides; mixed acid anhydrides with acids such as substituted phosphoric acids (e.g., dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acids (e.g., methanesulfonic acid, etc.), aliphatic carboxylic acids (e.g., acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acids (e.g., benzoic acid, etc.); a symmetric anhydride; an active amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; active esters (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [ (CH)3)2N+＝CH-]Esters, vinyl esters, propargyl esters, p-nitrophenyl esters, 2, 4-dinitrophenyl esters, trichlorophenyl esters, pentachlorophenyl esters, methanesulfonylphenyl esters, phenylazophenyl esters, thiophenyl esters, p-nitrophenylthio esters, p-tolylthioesters, carboxymethylthioesters, pyranyl esters, pyridyl esters, piperidyl esters, 8-quinolyl thioesters, etc.) or esters with N-hydroxy compounds (e.g., N-dimethylhydroxylamine, 1-hydroxy-2-1H-pyridone, N-hydroxysuccinimide, 1-hydroxy-1H-benzotriazole, etc.), etc. These reactive derivatives may be selected depending on the kind of the compound (II) to be usedAnd (d) a compound selected from the above compounds.
The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, N-dimethylformamide, pyridine, a mixture thereof or any other solvent which does not adversely affect the reaction. These conventional solvents may be used alone or in combination.
In this reaction, when the compound (II) is used in the form of a free acid or a salt thereof, it is preferable to carry out the reaction in the presence of a conventional condensing agent, and examples thereof include:
n, N ' -dicyclohexylcarbodiimide, N-cyclohexyl-N ' -morpholinoethylcarbodiimide, N-cyclohexyl-N ' - (4-diethylaminocyclohexyl) carbodiimide, N ' -diethylcarbodiimide, N ' -diisopropylcarbodiimide, N-ethyl-N ' - (3-dimethylaminopropyl) carbodiimide, N ' -carbonylbis (2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylmethanone-N-cyclohexylimine, ethoxyacetylene, 1-alkoxy-1-chloroethylene, trialkylphosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride (phosphoryl), Phosphorus trichloride, diphenylphosphoryl azide, diphenyl chlorophosphate, diphenylphosphinic acid chloride, thionyl chloride, oxalyl chloride, lower alkyl haloformates (e.g., ethyl chloroformate, isopropyl chloroformate, etc.), triphenylphosphine, 2-ethyl-7-hydroxybenzoisooxazolium salts, 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salts, 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole, Vilsmeier's reagent was prepared by reacting N, N-dimethylformamide with thionyl chloride, carbonyl chloride, trichloromethyl chloroformate, phosphoryl chloride, etc.).
The reaction may be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri-lower alkylamine, pyridine, 4-dimethylaminopyridine, N-lower alkylmorpholine, N-di-lower alkylaniline (e.g., N-dimethylaniline), N-di-lower alkylbenzylamine, or the like.
The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. The above compounds can be prepared into suitable salts by a usual method as required. Further, if necessary, the purification can be carried out by a common organic compound purification method, i.e., recrystallization, column chromatography, thin layer chromatography, high performance liquid chromatography, or the like. Identification of the compound can be performed by NMR spectroscopy, mass spectrometry, IR spectroscopy, elemental analysis, melting point measurement, or the like.
The compounds of the invention may also have more than 1 asymmetric center and, in addition, they may exist as enantiomers or diastereomers. Some of the alkenyl-containing compounds may exist in the cis or trans isomer form. In either case, the present invention includes mixtures thereof and each isomer.
The compound of the present invention or a salt thereof may sometimes take the form of a solvate, and such a form is also included in the scope of the present invention. Examples of the solvate include a hydrate and an ethanolate.
In order to prove the usefulness of the objective compound (I), the following pharmacological data are presented for the compound (I).
Test example 1 hypoglycemic Effect of db/db mice
Test compounds
A compound A:
(E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -N- ((4-methylbenzene) sulfonyl) -2-acrylamide; (Compound of example 11)
Animals were used:
female mice 5 weeks old, C57BL/KsJ-dbm db +/db +, C57BL/KsJ-dbm + m/+ m (Jackson laboratory), were purchased and acclimated for 2-3 weeks for testing.
Administration:
the sample was mixed with a powdery food (CE-2, japan クレア) using a mortar. The mixing ratio was 0.1% at 100mg/kg, 0.03% at 30mg/kg and 0.01% at 10 mg/kg. Each group was changed 2 times per week with a fresh food, and the amount of food given and the amount of food remaining were recorded, and the difference between the two was used to calculate the amount of food intake.
And (3) test planning:
female db/db mice were divided into groups according to body weight, blood glucose level and triglyceride concentration in plasma, and then the mice were fed the drug-mixed diet for 14 days (test period 8 weeks to 10 weeks old). In the morning of day 7 and 14, blood was collected from the orbital vein using heparin-treated glass capillaries (Chase healed Capillary Tubes) and plasma was obtained by centrifugation. Measurement items were, day 0 and day 14: blood glucose value, triglyceride concentration in plasma, plasma insulin concentration, day 7: blood glucose level, triglyceride concentration in plasma. In addition, body weight was measured on days 0, 7 and 14. After final blood collection, CO is used2The gas kills them.
The determination method comprises the following steps:
blood glucose levels were measured by glucose oxidase method (glucose CII-Test Wako, Wako pure chemical industries, Ltd.) using 10-15. mu.l of plasma. The triglyceride concentration in plasma was measured by the GPO-p-chlorophenol method (triglyceride G-TestWako) or the GPO-DAOS method (triglyceride E-Test Wako) using 10 to 15. mu.l of plasma. The above measurement was performed immediately after blood collection. Plasma insulin concentration was measured by the antibody method (Phadesef insulin RIA kit, Kabi Pharmacia) using 20. mu.l of plasma (which can be stored at-20 ℃).
As a result:
the difference between the blood glucose levels and the plasma triglyceride concentrations of the db/db mouse control group and the +/+ mice was defined as 100%, and the blood glucose level and the plasma triglyceride concentration reduction rate (%) of the test agent-administered group were determined. The results are shown in Table 1.
TABLE 1
Test compounds Dosage (mg/kg) Hypoglycemic Effect (%)
Compound A 3.2 63％
The compounds (I) of the present invention may be used for therapeutic purposes in the form of pharmaceutical preparations. The pharmaceutical preparation comprises the compound as an active ingredient in admixture with pharmaceutically acceptable organic or inorganic excipients in solid, semi-solid or liquid form suitable for oral, parenteral or topical (topical) administration. Examples of the pharmaceutical preparations include capsules, tablets, sugar-coated tablets, granules, suppositories, liquids, syrups, suspensions, emulsions, ointments, gels, and the like. Adjuvants, auxiliary substances, stabilizers, wetting or emulsifying agents, buffers and other customary additives may be incorporated into these preparations as required. The amount of compound (I) to be used varies depending on the age and symptoms of the patient, and for the treatment of the above-mentioned various diseases, an average per dose of compound (I) of about 0.1mg, 1mg, 10mg, 50mg, 100mg, 250mg, 500mg and 1000mg is effective. Generally, the daily amount administered will be between 0.1 mg/solid and 1000 mg/solid.
The present invention will be described in further detail below with reference to production examples and examples.
Production example 1-1
4, 5-dibromo-2-methylimidazole (4.91g) was dissolved in N, N-dimethylformamide (50ml), and 60% sodium hydride (901mg) was slowly added under ice-cooling. After stirring at room temperature for 1 hour, 2- (trimethylsilyl) ethoxymethyl chloride (3.75g) was slowly added dropwise under ice-cooling, and the mixture was stirred at room temperature overnight. After the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, which was then washed with a saturated aqueous sodium bicarbonate solution and then with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate ═ 3/1) to give 4, 5-dibromo-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) imidazole as a colorless oil (7.6 g).
1H-NMR(CDCl3)：0.00(9H，s)，0.92(2H，t，J＝8Hz)，2.47(3H，s)，3.55(2H，t，J＝8Hz)，5.24(2H，s).
Production examples 1 and 2
4, 5-dibromo-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) imidazole (29.2g) was dissolved in tetrahydrofuran (250ml), and a 1.63N 1-butyllithium/hexane solution (58.1ml) was added dropwise over 20 minutes at-55 ℃ to-60 ℃. After stirring at-60 ℃ for 30 minutes, N-dimethylformamide (58g) was slowly added dropwise at-55 ℃ to-60 ℃ and stirred at room temperature for 1 hour. Saturated brine was added, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate ═ 3/1) to give 4-bromo-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) imidazole-5-carbaldehyde as a pale yellow oil (18.5 g).
1H-NMR(CDCl3)：0.00(9H，s)，0.91(2H，t，J＝8Hz)，2.52(3H，s)，3.58(2H，t，J＝8Hz)，5.70(2H，s)，9.71(1H，s).
Production examples 1 to 3
4-bromo-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) imidazole-5-carbaldehyde (18.5g) was dissolved in ethanol (80ml), and 6N hydrochloric acid (80ml) was added to the solution, followed by heating and refluxing for 1 hour. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added under ice-cooling until the solution became weakly basic. The precipitated crystal was collected by filtration, washed with methanol and then dried under reduced pressure with heating to give 5-bromo-2-methylimidazole-4-carbaldehyde as white crystals (9.17 g).
1H-NMR(CDCl3)：2.45(3H，s)，9.53(1H，s).
Production examples 1 to 4
5-bromo-2-methylimidazole-4-carbaldehyde (400mg) was dissolved in concentrated hydrochloric acid (6ml), and the mixture was refluxed for 24 hours. Saturated aqueous sodium bicarbonate was added under ice cooling until becoming weakly basic, and extracted 2 times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, followed by brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the nematic residue, and crystals were collected by filtration to give yellow crystals of 5-chloro-2-methylimidazole-4-carbaldehyde (222 mg).
1H-NMR(CDCl3)：2.45(3H，s)，9.58(1H，s).
Production example 2
To a solution of 2-chloro-4-iodotoluene (7.59g) in carbon tetrachloride (76ml) was added N-bromosuccinimide (5.89g), 2' -azobis (4-methoxy-2, 4-dimethylvaleronitrile) (and light V-70, 281mg) at room temperature, and the mixture was stirred at 55 ℃ for 3.5 hours. After the reaction mixture was allowed to cool to room temperature, hexane (76ml) was added, and insoluble matter was removed by filtration. After concentrating the filtrate, the residue was again dissolved in hexane, washed with water, a 5% aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off to leave 2-chloro-4-iodobenzyl bromide as an oil (8.45 g).
1H-NMR(CDCl3): 4.52(2H, s), 7.16(1H, d, J ═ 8Hz), 7.59(1H, dd, J ═ 8 and 2Hz), 7.76(1H, d, J ═ 2Hz).
Production example 3-1
To a suspension of tetrakis (triphenylphosphine) palladium (213mg) in toluene (7ml) was added 2-chloro-4-iodotoluene (2.33g) at room temperature. After stirring at room temperature for 30 minutes, a solution of phenylboronic acid (1.35g) in EtOH (2ml) and 2M aqueous sodium carbonate (9.25ml) were added to the mixture, and the mixture was heated under reflux. After 3 hours, the reaction solution was cooled, and the organic layer was separated. The aqueous layer was extracted with hexane (4 ml). The organic layers were combined, washed with a saturated aqueous sodium hydrogencarbonate solution (4ml) and saturated brine (4ml), and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and hexane (10ml) and silica gel (4g) were added to the residue (2.11g), followed by stirring at room temperature for 1 hour. After filtering off the silica gel, the filtrate was concentrated to give 2-chloro-4-phenyltoluene as a pale brown oil (1.86g, 99.4%).
1H-NMR(CDCl3)：2.40(3H，s)，7.2 3-7.60(8H，m).
Production example 3-2
Colorless crystals (3.22g) of 2-chloro-4-phenylbenzyl bromide were obtained from 2-chloro-4-phenyltoluene (3.6g) in the same manner as in preparation example 2.
1H-NMR(CDCl3)：4.64(2H，s)，7.35-7.63(8H，m).
m.p.73-74℃.
Production example 4-1
2-chloro-4-iodotoluene (22.0g) was dissolved in N, N-dimethylformamide (110ml), and copper (I) iodide (49.8g), ethyl chlorodifluoroacetate (37.8g) and potassium fluoride (15.2g) were added to stir at an internal temperature of 116 ℃ for 70 hours. The reaction mixture was filtered through celite, and water (11ml) and diethyl ether (110ml) were added to the filtrate under ice-cooling, followed by filtration through celite. The filtrate was separated, the aqueous layer was re-extracted with diethyl ether (110ml), and the organic layers were combined, washed with saturated brine (110ml), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 2-chloro-4-trifluoromethyltoluene as a brown oil (23.0 g).
1H-NMR(CDCl3)：2.43(3H，s)，7.34(1H，d，J＝8Hz)，7.42(1H，d，J＝8Hz)，7.60(1H，s).
Production example 4-2
In the same manner as in production example 2 above, 2-chloro-4-trifluoromethyltoluene (10.0g) was used to give 2-chloro-4- (trifluoromethyl) benzyl bromide as a pale yellow oil (6.20 g).
1H-NMR(CDCl3)：4.59(2H，s)，7.52(1H，d，J＝8Hz)，7.57(1H，d，J＝8Hz)，7.67(1H，s).
Production example 5-1
3-chloro-4-cresol (2.00g) was dissolved in N, N-dimethylformamide (10.0ml), and potassium carbonate (2.91g) and 1-iodopropane (2.62g) were added. After stirring at room temperature for 20 hours, the reaction mixture was concentrated under reduced pressure, water was added, and extraction was performed with AcOEt. The organic layer was washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with hexane/ethyl acetate (5: 1), and the fractions of the objective compound were concentrated under reduced pressure to give 2-chloro-4- (1-propoxy) toluene as a colorless oil (2.18 g).
1H-NMR(CDCl3)：1.02(3H，t，J＝7Hz)，1.72-1.85(2H，m)，2.29(3H，s)，3.88(2H，t，J＝7Hz)，6.71(1H，dd，J＝8，2Hz)，6.90(1H，d，J＝2Hz)，7.09(1H，d，J＝8Hz).
Production example 5-2
In the same manner as in production example 2 above, 2-chloro-4- (1-propoxy) toluene (2.14g) was used to give 2-chloro-4- (1-propoxy) benzyl bromide as a pale yellow oil (2.26 g).
1H-NMR(CDCl3)：1.03(3H，t，J＝7Hz)，1.75-1.87(2H，m)，3.90(2H，t，J＝7Hz)，4.59(2H，s)，6.78(1H，dd，J＝8，2Hz)，6.93(1H，d，J＝2Hz)，7.32(1H，d，J＝8Hz).
Production example 6-1
In the same manner as in production example 5-1, 2-chloro-4-cresol (10.0g) was used to give 2-chloro-4- (1-pentyloxy) toluene as a pale brown oil (16.3 g).
1H-NMR(CDCl3)：0.93(3H，t，J＝6Hz)，1.40(4H，m)，1.76(2H，m)，2.29(2H，s)，3.90(2H，t，J＝6Hz)，6.70(1H，dd，J＝8，2Hz)，6.90(1H，d，J＝2Hz)，7.10(1H，d，J＝8Hz).
Production example 6-2
In the same manner as in production example 2 above, 2-chloro-4- (1-pentyloxy) toluene (16.2g) was used to give 2-chloro-4- (1-pentyloxy) benzyl bromide as a pale yellow solid (21.9 g).
1H-NMR(CDCl3)：0.93(3H，t，J＝6Hz)，1.40(4H，m)，1.76(2H，m)，3.93(2H，t，J＝6Hz)，4.58(2H，s)，6.77(1H，dd，J＝8，2Hz)，6.92(1H，d，J＝2Hz)，7.32(1H，d，J＝8Hz).
Production example 7-1
To a solution of 3-chloro-4-cresol (1.00g) in N, N-dimethylformamide (8ml), powdered potassium carbonate (1.44g) was added, and the mixture was heated to 80 ℃. Cyclopentyl methyl methanesulfonate (1.57g) was added thereto, and the mixture was stirred at 120 ℃ for 3 hours. The reaction mixture was allowed to cool to room temperature, water was added, and extraction was performed 3 times with hexane. The organic layers were combined, washed successively with a 1N aqueous solution of sodium hydroxide, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane) to give 2-chloro-4- ((cyclopentyl) methoxy) toluene as a colorless oil (1.46 g).
1H-NMR(CDCl3): 1.22-1.93(8H, m), 2.29(3H, s), 2.34(1H, sept, J ═ 7Hz), 3.78(2H, d, J ═ 7Hz), 6.71(1H, dd, J ═ 8 and 2Hz), 6.91(1H, d, J ═ 2Hz), 7.09(1H, d, J ═ 8Hz).
Production example 7-2
In the same manner as in production example 2 above, 2-chloro-4- ((cyclopentyl) methoxy) toluene (1.4g) was used to obtain 2-chloro-4- ((cyclopentyl) methoxy) benzyl bromide as an oil (2.06 g).
1H-NMR(CDCl3): 1.23-1.92(8H, m), 2.34(1H, sept, J ═ 7Hz), 3.81(2H, d, J ═ 7Hz), 4.59(2H, s), 6.78(1H, dd, J ═ 9 and 2Hz), 6.93(1H, d, J ═ 2Hz), 7.32(1H, d, J ═ 9Hz).
Production example 8-1
Colorless crystals of 2-chloro-4- ((cyclohexyl) methoxy) toluene (1.41g) were obtained from 3-chloro-4-cresol (926mg) in the same manner as in production example 5-1.
1H-NMR(CDCl3)：0.95-1.40(5H)，1.64-1.90(6H)，2.29(3H，s)，3.70(2H，d，J＝6Hz)，6.70(1H，dd，J＝8，2Hz)，6.89(1H，d，J＝2Hz)，7.08(1H，d，J＝8Hz).
Production example 8-2
In the same manner as in production example 2 above, 2-chloro-4- ((cyclohexyl) methoxy) toluene (1.00g) was used to give 2-chloro-4- ((cyclohexyl) methoxy) benzyl bromide as a pale yellow solid (1.35 g).
1H-NMR(CDCl3)：0.94-1.40(5H)，1.63-1.94(6H)，3.73(2H，d，J＝6Hz)，4.59(2Hs)，6.79(1H，dd，J＝8，2Hz)，6.93(1H，d，J＝2Hz)，7.32(1H，d，J＝8Hz).
Production example 9
Methanesulfonyl chloride (1.4 m) was added dropwise to a solution of 4-bromo-2-chlorobenzyl alcohol (3.56g) and triethylamine (3ml) in dry dichloromethane (36ml) under ice cooling in a nitrogen stream (after stirring for 1 hour), the reaction mixture was washed with water, a saturated aqueous sodium hydroxide solution and a saturated brine, dried over anhydrous magnesium sulfate, and the filtrate was concentrated to give a pale brown solid (4.77g) of 4-bromo-2-chloro-1- ((methanesulfonyloxy) methyl) benzene.
1H-NMR(CDCl3)：3.03(3H，s)，5.29(2H，s)，7.37(1H，d，J＝8Hz)，7.47(1H，dd，J＝8，1Hz)，7.60(1H，d，J＝1Hz).
Mass(ESI)：m/z 298(M-1).
Production example 10-1
Sodium thiomethoxide (459mg) was added to a solution of methyl 4-bromo-2-chlorobenzoate (1.25g) in N, N-dimethylformamide (10ml) under ice-cooling, and the mixture was stirred for 2 hours. 1N hydrochloric acid was added to the reaction solution, and the product was extracted 3 times with diethyl ether. The combined organic layers were washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off. Purification by silica gel column chromatography (hexane/ethyl acetate 10/1) gave methyl 2-chloro-4- (methylthio) benzoate as a colorless oil (835 mg).
1H-NMR(CDCl3)：2.49(3H，s)，3.90(3H，s)，7.11(1H，d，J＝8Hz)，7.23(1H，s)，7.78(1H，d，J＝8Hz).
Production example 10-2
To a suspension of lithium aluminum hydride (139mg) in tetrahydrofuran (8ml), methyl 2-chloro-4- (methylthio) benzoate (806mg) was added dropwise under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was diluted with diethyl ether, 1N hydrochloric acid (10ml) was added dropwise thereto, and the resultant was extracted with diethyl ether 3 times. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to leave 2-chloro-4- (methylthio) benzyl alcohol as a colorless oil (725 mg).
1H-NMR(CDCl3)：1.92(1H，br t，J＝7Hz)，2.48(3H，s)，4.73(2H，d，J＝7Hz)，7.15(1H，d，J＝8Hz)，7.23(1H，s)，7.37(1H，d，J＝8Hz).
Production example 10-3
In the same manner as in production example 9 above, 2-chloro-4- (methylthio) benzyl alcohol (687mg) was used to give 2-chloro-1- ((methanesulfonyloxy) methyl) -4- (methylthio) benzene as a colorless oil (1.02 g).
1H-NMR(CDCl3): 2.48(3H, s), 3.00(3H, s), 5.30(2H, s), 7.15(1H, dd, J ═ 8 and 2Hz), 7.26(1H, d, J ═ 2Hz), 7.38(1H, d, J ═ 8Hz).
Production example 11
From 2-chloro-4-nitrobenzyl alcohol (2.5g), brown crystals of 2-chloro-1- ((methanesulfonyloxy) methyl) -4-nitrobenzene (3.56g) were obtained in the same manner as in preparation example 9.
1H-NMR(CDCl3)：3.12(3H，s)，5.40(2H，s)，7.73(1H，d，J＝8Hz)，8.18(1H，dd，J＝2，8Hz)，8.79(1H， d，J＝2Hz).
Production example 12-1
4-amino-2-chlorobenzoic acid (10.01g) was heated to 70 ℃ in 12.5% sulfuric acid (400ml) to dissolve it uniformly, followed by ice-cooling. To this suspension was added dropwise an aqueous solution of sodium nitrite (4.24 g/water 12ml) at a temperature below 8 ℃ over 5 minutes. After 5 minutes, the solution was slowly poured into 80 ℃ water (500ml) and vigorously foamed to give a red solution. The reaction solution was further stirred at 80 ℃ for 1 hour. After cooling, the product was extracted 3 times with diethyl ether. The organic layers were combined, washed successively with dilute hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. After the solution was distilled off, a small amount of diisopropyl ether was added to the residue to crystallize it, whereby 2-chloro-4-hydroxybenzoic acid (6.32g) was obtained as an orange powder.
1H-NMR(DMSO-d6): 6.79(1H, dd, J ═ 8 and 2Hz), 6.88(1H, d, J ═ 2Hz), 7.77(1H, d, J ═ 8Hz).
Mass(ESI)：m/e 171(M-H)-.
Production example 12-2
To a solution of 2-chloro-4-hydroxybenzoic acid (695mg) in N, N-dimethylformamide (3.5ml) were added potassium carbonate (1.67g) and benzyl bromide (1.73g), and the mixture was stirred at room temperature for 14 hours. 1N hydrochloric acid was added to the reaction solution, and the product was extracted 3 times with diethyl ether. The organic layers were combined. The extract was washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine in this order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, it was recrystallized from diisopropyl ether/hexane to give benzyl 4-benzyloxy-2-chlorobenzoate as a pale yellow powder (1.13 g).
1H-NMR(CDCl3): 5.09(2H, s), 5.32(2H, s), 6.87(1H, dd, J ═ 8 and 2Hz), 7.05(1H, d, J ═ 2Hz), 7.29-7.50(10H, m), 7.91(1H, d, J ═ 8Hz).
Mass(ESI)：m/e 353(M+H)+.
Production example 12-3
To benzyl 4-benzyloxy-2-chlorobenzoate (1.12g) were added ethanol (8.8ml), 1, 4-dioxane (2.2ml) and 1N aqueous sodium hydroxide solution (4.7ml), and the mixture was stirred at 70 ℃ for 1.5 hours. After the solvent was distilled off, water was added to the residue to dissolve it, and the residue was washed with diethyl ether. The aqueous layer was made acidic with 1N hydrochloric acid, and the precipitated precipitate was collected by filtration to give 4-benzyloxy-2-chlorobenzoic acid as a pale yellow powder (810 mg).
1H-NMR(DMSO-d6): 5.20(2H, s), 7.06(1H, dd, J ═ 8 and 2Hz), 7.18(1H, d, J ═ 2Hz), 7.29 to 7.50(5H, m), 7.82(1H, d, J ═ 8Hz).
Mass(ESI)：m/e 261(M-H)-.
Production examples 12 to 4
To a solution of 4-benzyloxy-2-chlorobenzoic acid (788mg) in tetrahydrofuran (7.9ml) was added dropwise borane/dimethyl sulfide complex (10.0M, 0.6ml) under nitrogen atmosphere at room temperature, and the mixture was refluxed for 2.5 hours. The reaction mixture was allowed to cool to room temperature, and 1N hydrochloric acid (1.5ml) was added dropwise with caution, followed by stirring for 30 minutes. Water was added to the reaction solution, and the product was extracted 3 times with ethyl acetate. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to leave 4-benzyloxy-2-chlorobenzyl alcohol as a white powder (778 mg).
1H-NMR(CDCl3): 1.83(1H, br t, J ═ 7Hz), 4.70(2H, d, J ═ 7Hz), 5.05(2H, s), 6.88(1H, dd, J ═ 8 and 2Hz), 7.01(1H, d, J ═ 2Hz), 7.28-7.46(6H, m).
Production examples 12 to 5
In the same manner as in preparation example 9 above, 4-benzyloxy-2-chlorobenzyl alcohol (523mg) was used to give 4-benzyloxy-2-chlorobenzyl chloride as a colorless oil (639 mg).
1H-NMR(CDCl3): 4.67(2H, s), 5.05(2H, s), 6.87(1H, dd, J ═ 8 and 2Hz), 7.02(1H, d, J ═ 2Hz), 7.28-7.44(6H, m).
Production example 13-1
Imidazole (5.34g) and tert-butylchlorodiphenylsilane (19.8g) were added to a solution of 4-bromo-2-chlorobenzyl alcohol (14.48g) in N, N-dimethylformamide (72ml) under ice-cooling, and the mixture was stirred for 1 hour. Water was added to the reaction solution, and the product was extracted with hexane 2 times. The organic layers were combined, washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, it was purified by silica gel column chromatography (hexane) to give 4-bromo-1- ((tert-butyldiphenylsiloxy) methyl) -2-chlorobenzene as a colorless oil (29.22 g).
1H-NMR(CDCl3)：1.10(9H，s)，4.75(2H，s)，7.32-7.50(8H，m)，7.55-7.72(5H，m).
Production example 13-2
To a solution of 4-bromo-1- ((tert-butyldiphenylsiloxy) methyl) -2-chlorobenzene (8.65g) in tetrahydrofuran (22ml) was added a 1-butyllithium/hexane solution (1.54M, 13.5ml) under a stream of nitrogen and stirred at-75 ℃ for 15 minutes. The reaction solution was warmed to 10 ℃ and then cooled to-75 ℃ again, and 1-formylpiperidine (2.55g) was added dropwise over 10 minutes. The reaction solution was then warmed to room temperature over 3 hours. An aqueous ammonium chloride solution was added to the reaction solution, and the resultant was extracted 2 times with hexane. The organic layers were combined, washed successively with dilute hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane/ethyl acetate: 40/1) to give 4- ((tert-butyldiphenylsiloxy) methyl) -3-chlorobenzaldehyde as a pale yellow oil (3.26 g).
1H-NMR(CDCl3)：1.14(9H，s)，4.87(2HS), 7.33-7.51(6H, m), 7.63-7.75(4H, m), 7.81(1H, d, J ═ 2Hz), 7.84(1H, dd, J ═ 8 and 2Hz), 7.97(1H, d, J ═ 8Hz), 9.97(1H, s).
Production example 13-3
To a suspension of 4- ((tert-butyldiphenylsiloxy) methyl) -3-chlorobenzaldehyde (3.24g) in ethanol (32ml) was added sodium borohydride (149mg) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction mixture was concentrated to about half the amount, water was added and the resultant was extracted 2 times with diisopropyl ether. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane/ethyl acetate: 5/1) to give 4- ((tert-butyldiphenylsilyloxy) methyl) -3-chlorobenzyl alcohol as a colorless oil (3.08 g).
1H-NMR(CDCl3)：1.12(9H，s)，1.70(1H，br t，J＝5Hz)，4.69(2H，d，J＝5Hz)，4.83(2H，s)，7.27-7.50(8H，m)，7.65-7.78(5H，m).
Production examples 13 to 4
In the same manner as in production example 9 above, from 4- ((tert-butyldiphenylsiloxy) methyl) -3-chlorobenzyl alcohol (3.05g), a colorless oil of 1- ((tert-butyldiphenylsiloxy) methyl) -2-chloro-4- ((methanesulfonyloxy) methyl) benzene (3.80g) was obtained.
1H-NMR(CDCl3)：1.12(9H，s)，2.97(3H，s)，4.83(2H，s)，5.21(2H，s)，7.33-7.50(8H，m)，7.63-7.75(4H，m)，7.77-7.83(1H，m).
Production examples 13 to 5
To a solution of phenol (969mg) in N, N-dimethylformamide (27ml) was added powdered potassium carbonate (1.92g), and after stirring at room temperature for 5 minutes, 1- ((tert-butyldiphenylsilyloxy) methyl) -2-chloro-4- ((methanesulfonyloxy) methyl) benzene (3.39g) was added and stirred at 100 ℃ for 3 hours. The reaction mixture was allowed to cool to room temperature, water was added, and extraction was performed 2 times with hexane. The organic layers were combined, washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate ═ 50/1) to give 1- ((tert-butyldiphenylsilyloxy) methyl) -2-chloro-4- (phenoxymethyl) benzene as a colorless oil (2.65 g).
1H-NMR(CDCl3)：1.12(9H，s)，4.83(2H，s)，5.04(2H，s)，6.93-7.04(3H，m)，7.25-7.50(10H，m)，7.65-7.73(4H，m)，7.73-7.80(1H，m).
Production examples 13 to 6
A tetrabutylammonium fluoride/tetrahydrofuran solution (1.0M, 7.0ml) was added to a tetrahydrofuran (14ml) solution of 1- ((tert-butyldiphenylsiloxy) methyl) -2-chloro-4- (phenoxymethyl) benzene (2.84g) under ice-cooling, and the mixture was stirred for 1.5 hours. The reaction mixture was added with water, and the product was extracted with ethyl acetate 2 times, washed successively with 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane/ethyl acetate 5/1) to obtain 2-chloro-4- (phenoxymethyl) benzyl alcohol as a white powder (1.38 g).
1H-NMR(CDCl3)：1.92(1H，br t，J＝6Hz)，4.79(2H，d，J＝6Hz)，5.05(2H，s)，6.88-7.06(3H，m)，7.23-7.40(3H，m)，7.42-7.57(2H，m).
Production examples 13 to 7
In the same manner as in production example 9 above, 2-chloro-4- (phenoxymethyl) benzyl alcohol (1.36g) was used to give 2-chloro-1- ((methanesulfonyloxy) methyl) -4- (phenoxymethyl) benzene as an oily substance (1.83 g).
1H-NMR(CDCl3)：3.03(3H，s)，5.07(2H，s)，5.35(2H，s)，6.91-7.04(3H，m)，7.25-7.42(3H，m)，7.44-7.67(2H，m).
Production example 14-1
From 3-chloro-4-methylbenzoic acid (25.0g), 3-chloro-4-methylbenzyl alcohol (23.0g) was obtained as a colorless oil in the same manner as in production example 12-4.
1H-NMR(CDCl3)：2.36(3H，s)，4.65(2H，s)，7.14(1H，d，J＝8Hz)，7.23(1H，d，J＝8Hz)，7.36(1H，s).
Production example 14-2
To a solution of 3-chloro-4-methylbenzyl alcohol (2.00g) and triethylamine (8.9ml) in dimethylsulfoxide (10ml) was added sulfur trioxide-pyridine complex (4.47g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with diethyl ether. The organic layer was washed with 1N hydrochloric acid, saturated brine and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to dryness to give 3-chloro-4-methylbenzaldehyde as a pale yellow oil (1.40 g).
1H-NMR(CDCl3)：2.46(3H，s)，4.65(2H，s)，7.40(1H，d，J＝8Hz)，7.68(1H，d，J＝8Hz)，9.92(1H，s).
Production example 14-3
In the same manner as in production example 15-2 below, from 3-chloro-4-methylbenzaldehyde (1.40g) and diethyl benzylphosphate (2.27g), white powder (1.55g) of (E) -2-chloro-4- (2-phenylvinyl) toluene was obtained.
1H-NMR(CDCl3)：2.38(3H，s)，7.00(1H，d，J＝16Hz)，7.08(1H，d，J＝16Hz)，7.18-7.53(8H).
Production example 14-4
In the same manner as in production example 2 above, white powder (309mg) of (E) -2-chloro-4- (2-phenylvinyl) benzyl bromide was obtained from (E) -2-chloro-4- (2-phenylvinyl) toluene (1.35 g).
1H-NMR(CDCl3)：4.61(2H，s)，7.01(1H，d，J＝16Hz)，7.14(1H， d，J＝16Hz)，7.24-7.57(8H).
Production example 15-1
To a solution of 5-chloro-2-methylimidazole-4-carbaldehyde (433mg) in N, N-dimethylformamide (4.3ml) were added potassium carbonate powder (616mg) and 2-chloro-4-iodobenzyl bromide (1.2 eq) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture were added water and saturated brine, and the product was extracted 2 times with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane/ethyl acetate: 5/1) to give 4-chloro-1- (2-chloro-4-iodobenzyl) -2-methylimidazole-5-carbaldehyde as a white powder (1.01 g).
1H-NMR(CDCl3): 2.33(3H, s), 5.56(2H, s), 6.21(1H, d, J ═ 8Hz), 7.50(1H, dd, J ═ 8 and 2Hz), 7.78(1H, d, J ═ 2Hz), 9.75(1H, s).
Mass(ESI)：m/e 395(M+H)+.
Production example 15-2
To a solution of 4-chloro-1- (2-chloro-4-iodobenzyl) -2-methylimidazole-5-carbaldehyde (1.01g) in tetrahydrofuran (10ml) was added methyl (triphenylphosphoranylidene) acetate (1.27g), and the mixture was refluxed for 4 hours. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane/ethyl acetate 3/1) to give methyl (E) -3- (4-chloro-1- (2-chloro-4-iodobenzyl) -2-methylimidazol-5-yl) -2-acrylate as a white powder (974 mg).
1H-NMR(CDCl3): 2.33(3H, s), 3.75(3H, s), 5.15(2H, s), 6.17(1H, d, J ═ 8Hz), 6.49(1H, d, J ═ 16Hz), 7.28(1H, d, J ═ 16Hz), 7.53(1H, dd, J ═ 8 and 2Hz), 7.81(1H, d, J ═ 2H2).
Mass(ESI)：m/e 451(M+H)+.
Production examples 15 to 3
A mixture of tetrakis (triphenylphosphine) palladium (0) (89mg), (E) -3- (4-chloro-1- (2-chloro-4-iodobenzyl) -2-methylimidazol-5-yl) -2-propenoic acid methyl ester (350mg), 2-furylboronic acid (135mg), powdered potassium carbonate (321mg) and N, N-dimethylformamide (3.5ml) was stirred under nitrogen at 80 ℃ for 4 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the precipitate was filtered off. The precipitate was dissolved in chloroform, washed with a saturated aqueous sodium bicarbonate solution and a saturated brine in this order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform/ethyl acetate 10/1) to give (E) -3- (4-chloro-1- (2-chloro-4- (2-furyl) benzyl) -2-methylimidazol-5-yl) -2-acrylic acid methyl ester as a pale yellow powder (336 mg).
1H-NMR(CDCl3)：2.36(3H，s)，3.74(3H，s)，5.22(2H，s)，6.44-6.50(2H，m)，6.50(1H，d，J＝16Hz)，6.68(1H，d，J＝3Hz)，7.34(1H，d，J＝16Hz)，7.43-7.50(2H，m)，7.76(1H，d，J＝2Hz).
Mass(ESI)：m/e 391(M+H)+.
Production examples 15 to 4
To a suspension of methyl (E) -3- (4-chloro-1- (2-chloro-4- (2-furyl) benzyl) -2-methylimidazol-5-yl) -2-propenoate (319mg) in 1, 4-dioxane (1.6ml) was added 1N aqueous sodium hydroxide solution (1.2ml), and the mixture was stirred at 50 ℃ for 1 hour. After the reaction mixture was ice-cooled, 1N hydrochloric acid (1.2ml) was added dropwise for neutralization, and the product was extracted 3 times with chloroform-methanol (4/1). The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off to leave (E) -3- (4-chloro-1- (2-chloro-4- (2-furyl) benzyl) -2-methylimidazol-5-yl) -2-acrylic acid as an off-white powder (310 mg).
1H-NMR(DMSO-d6): 2.34(3H, s), 5.41(2H, s), 6.26(1H, d, J ═ 16Hz), 6.58(1H, d, J ═ 8Hz), 6.62(1H, dd, J ═ 3 and 2Hz), 7.09(1H, d, J ═ 3Hz), 7.22(1H, d, J ═ 16Hz), 7.62(1H, dd, J ═ 8 and 2Hz), 7.79(1H, d, J ═ 2Hz), 7.88(1H, d, J ═ 2Hz).
Mass(ESI)：m/e 375(M-H)-.
Production example 16-1
In the same manner as in production example 15-3 above, methyl (E) -3- (4-chloro-1- (2-chloro-4-iodobenzyl) -2-methylimidazol-5-yl) -2-propenoate (360mg) was used to obtain methyl (E) -3- (4-chloro-1- (2-chloro-4- (2-thienyl) benzyl) -2-methylimidazol-5-yl) -2-propenoate as a yellow oil (331mg).
1H-NMR(CDCl3)：2.36(3H，s)，3.74(3H，s)，5.23(2H，s)，6.47(1H，d，J＝8Hz)，6.51(1H，d，J＝16Hz)，7.07-7.11(1H，m)，7.29-7.38(3H，m)，7.41(1H，dd，J＝2，8Hz)，7.69(1H，d，J＝2Hz).
Mass(ESI)：m/z 407(M+1).
Production example 16-2
In the same manner as in production example 15-4 above, methyl (E) -3- (4-chloro-1- (2-chloro-4- (2-thienyl) benzyl) -2-methylimidazol-5-yl) -2-propenoate (281mg) was used to obtain (E) -3- (4-chloro-1- (2-chloro-4- (2-thienyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid as pale yellow crystals (231 mg).
1H-NMR(DMSO-d6)：2.34(3H，s)，5.42(2H，s)，6.27(1H，d，J＝16Hz)，6.55(1H，d，J＝8Hz)，7.12-7.19(1H，m)，7.25(1H，d，J＝16Hz)，7.52-7.62(3H，m)，7.87(1H，d，J＝2Hz).
Mass(ESI)：m/z 391(M-1).
Production example 17-1
To a mixture of (E) -methyl 3- (4-chloro-1- (2-chloro-4-iodobenzyl) -2-methylimidazol-5-yl) -2-propenoate (360mg), dichlorobis (triphenylphosphine) palladium (II) (28mg) and copper iodide (7.6mg) was added a solution of phenylacetylene (326mg) in diisopropylamine (20ml) in a nitrogen stream, and the mixture was refluxed for 5 hours. The reaction solution was cooled, water was added thereto, extraction was performed with chloroform 2 times, and organic layers were combined, washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained crude product was applied to flash silica gel column chromatography (10 g of silica gel), and eluted with hexane/ethyl acetate of 5/1 to 1/1 to give a brown amorphous product of (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid methyl ester (331mg).
1H-NMR(CDCl3)：2.35(3H，s)，3.75(3H，s)，5.23(2H，s)，6.45(1H，d，J＝8Hz)，6.50(1H，d，J＝16Hz)，7.27-7.40(5H，m)，7.48-7.56(2H，m)，7.63(1H，s).
Mass(ESI)：m/z 425(M+1).
Production example 17-2
In the same manner as in production example 15-4 above, methyl (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -2-propenoate (413mg) was used to obtain pale yellowish crystals of (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (283 mg).
1H-NMR(CDCl3)：2.36(3H，s)，5.23(2H，s)，6.45(1H，d，J＝8Hz)，6.48(1H，d，J＝16Hz)，7.32-7.41(5H，m)，7.48-7.55(2H，m)，7.64(1H，d，J＝2Hz).
Mass(ESI)：m/z 409(M-1).
Production example 18-1
In the same manner as in production example 15-1 above, from 4-chloro-2-methylimidazole-5-carbaldehyde (200mg) and 4-bromo-2-chloro-1- ((methanesulfonyloxy) methyl) benzene (456mg), pale yellow crystals of 1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazole-5-carbaldehyde (430mg) were obtained.
1H-NMR(CDCl3)：2.33(3H，s)，5.56(2H，s)，6.38(1H，d，J＝8Hz)，7.31(1H，dd，J＝8，2Hz)，7.60(1H，d，J＝2Hz)，9.75(1H，s).
Production example 18-2
In the same manner as in production example 15-2 above, from 1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazole-5-carbaldehyde (394mg) and methyl (triphenylphosphoranylidene) acetate (606mg), colorless crystals of (E) -methyl 3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-acrylate (372mg) were obtained.
1H-NMR(CDCl3)：2.33(3H，s)，3.75(3H，s)，5.16(2H，s)，6.33(1H，d，J＝8Hz)，6.50(1H，d，J＝15Hz)，7.26(1H，d，J＝2Hz)，7.34(1H，dd，J＝8，2Hz)，7.63(1H，d，J＝2Hz).
Production example 18-3
In the same manner as in production example 15-4 above, methyl (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoate (355mg) was used to obtain (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid as pale yellow crystals (338 mg).
1H-NMR(DMSO-d6)：2.31(3H，s)，5.38(2H，s)，6.26(1H，d，J＝15Hz)，6.45(1H，d，J＝8Hz)，7.21(1H，d，J＝15Hz)，7.53(1H，dd，J＝8，2Hz)，7.87(1H，d，J＝2Hz).
Production example 19-1
In the same manner as in production example 15-1 above, from 5-chloro-2-methylimidazole-4-carbaldehyde (600mg) and 2-chloro-4-phenylbenzylbromide (1.4g), 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazole-5-carbaldehyde was obtained as a colorless oil (1.23 g).
1H-NMR(CDCl3)：2.36(3H，s)，5.67(2H，s)，6.56(1H，d，J＝8Hz)，7.35-7.55(6H)，7.65(1H，s)，9.80(1H，s).
Production example 19-2
In the same manner as in production example 15-2 above, from 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazole-5-carbaldehyde (1.23g), methyl (E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -2-acrylate was obtained as a white powder (1.13 g).
1H-NMR(CDCl3)：2.37(3H，s)，3.74(3H，s)，5.25(2H，s)，6.46-6.57(2H)，7.30-7.55(7H)，7.68(1H，s).
Production example 19-3
In the same manner as in production example 15-4 above, methyl (E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -2-propenoate (1.35g) was used to obtain (E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -2-propenoic acid as a white powder (1.18 g).
1H-NMR(DMSO-d6)：2.35(3H，s)，5.45(2H，s)，6.30(1H，d，J＝16Hz)，6.58(1H，d，J＝8Hz)，7.25(1H，d，J＝16Hz)，7.36-7.52(3H)，7.62(1H，d，J＝8Hz)，7.69(2H，d，J＝8Hz)，7.86(1H，s).
Production example 20-1
In the same manner as in production example 15-1 above, from 4-chloro-2-methylimidazole-5-carbaldehyde (200mg) and 2-chloro-4- (1-propoxy) benzyl bromide (474mg), pale yellow crystals of 4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazole-5-carbaldehyde (376mg) were obtained.
1H-NMR(CDCl3)：1.02(3H，t，J＝7Hz)，1.73-1.85(2H，m)，2.32(3H，s)，3.87(2H，t，J＝7Hz)，5.57(2H，s)，6.46(1H，d，J＝8Hz)，6.70(1H，dd，J＝8，2Hz)，6.96(1H，d，J＝2Hz)，9.77(1H，s).
Production example 20-2
In the same manner as in production example 15-2 above, from 4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazole-5-carbaldehyde (356mg) and methyl (triphenylphosphoranylidene) acetate (546mg), colorless crystals of methyl (E) -3- (4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoate (348mg) were obtained.
1H-NMR(CDCl3)：1.02(3H，t，J＝7Hz)，1.74-1.85(2H，m)，2.34(3H，s)，3.75(3H，s)，3.89(2H，t，J＝7Hz)，5.15(2H，s)，6.37(1H，d，J＝8Hz)，6.49(1H，d，J＝15Hz)，6.71(1H，dd，J＝8，2Hz)，6.99(1H，d，J＝2Hz)，7.34(1H，d，J＝15Hz).
Production example 20-3
In the same manner as in production example 15-4 above, methyl (E) -3- (4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoate (332mg) was used to obtain colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (305 mg).
1H-NMR(DMSO-d6)：0.95(3H，t，J＝7Hz)，1.64-1.75(2H，m)，2.32(3H，s)，3.92(2H，t，J＝7Hz)，5.31(2H，s)，6.25(1H，d，J＝15Hz)，6.44(1H，d，J＝8Hz)，6.88(1H，dd，J＝8，2Hz)，7.13(1H，d，J＝2Hz)，7.23(1H，d，J＝15Hz).
Production example 21-1
In the same manner as in preparation example 15-1 above, from 5-chloro-2-methylimidazole-4-carbaldehyde (200mg) and 2-chloro-4- (1-pentyloxy) benzyl bromide (378mg), 4-chloro-1- [ 2-chloro-4- (1-pentyloxy) benzyl ] -2-methylimidazole-5-carbaldehyde was obtained as a pale yellow oil (460 mg).
1H-NMR(CDCl3)：0.93(3H，t，J＝6Hz)，1.40(4H，m)，1.76(2H，m)，2.32(3H，s)，3.90(2H，t，J＝6Hz)，5.57(2H，s)，6.45(1H，d，J＝8Hz)，6.70(1H，dd，J＝8，2Hz)，6.95(1H，d，J＝2Hz)，9.76(1H，s).
Production example 21-2
In the same manner as in production example 15-2 above, from 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazole-5-carbaldehyde (439mg), methyl (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoate was obtained as a milky white solid (427 mg).
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.32-1.49(4H，m)，1.71-1.83(2H，m)，2.34(3H，s)，3.75(3H，s)，3.92(2H，t，J＝7Hz)，5.15(2H，s)，6.37(1H，d，J＝8Hz)，6.49(1H，d，J＝16Hz)，6.70(1H，dd，J＝2，8Hz)，6.99(1H，d，J＝2Hz)，7.34(1H，d，J＝16Hz).
Mass(ESI)：m/z 411(M+1).
Production examples 21 to 3
In the same manner as in production example 15-4 above, methyl (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoate (403mg) was used to obtain (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid as pale yellow crystals (370 mg).
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.30-1.50(4H，m)，1.70-1.83(2H，m)，2.36(3H，s)，3.92(2H，t，J＝7Hz)，5.16(2H，s)，6.38(1H，d，J＝8Hz)，6.47(1H，d，J＝16Hz)，6.71(1H，dd，J＝2，8Hz)，6.99(1H，d，J＝2Hz)，7.40(1H，d，J＝16Hz).
Mass(ESI)：m/z 395(M-1).
Production example 22-1
The same procedures as in production example 15-1 above were repeated except for using 5-chloro-2-methylimidazole-4-carbaldehyde (300mg) and 2-chloro-4- ((cyclopentyl) methoxy) benzyl bromide (764mg) to give 4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazole-5-carbaldehyde as a colorless oil (608 mg).
1H-NMR(CDCl3): 1.22-1.92(8H, m), 2.32(3H, s), 2.33(1H, sept, J ═ 7Hz), 3.78(2H, d, J ═ 7Hz), 5.57(2H, s), 6.45(1H, d, J ═ 8Hz), 6.70(1H, dd, J ═ 9 and 2Hz), 6.96(1H, d, J ═ 2Hz), 9.77(1H, s).
Mass(ESI)：m/e 367(M+H)+.
Production example 22-2
In the same manner as in production example 15-2 above, methyl 4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazole-5-carbaldehyde (577mg) and methyl (triphenylphosphoranylidene) acetate (788mg) were used to obtain a white powder (563mg) of methyl (E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoate.
NMR(CDCl3)：1.24-1.92(8H，m)，2.34(3H，s)，2.34(1H，sept，J＝7Hz)，3.74(3H，s)，3.79(2H，d，J＝7Hz)，5.15(2H，s)，6.37(1H，d，J＝8Hz)，649(1H, d, J ═ 16Hz), 6.71(1H, dd, J ═ 8 and 3Hz), 6.99(1H, d, J ═ 3Hz), 7.34(1H, d, J ═ 16Hz).
Mass(ESI)：m/e 423(M+H)+.
Production example 22-3
In the same manner as in production example 15-4 above, methyl (E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoate (535mg) was used to obtain (E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid as a white powder (532 mg).
1H-NMR(CDCl3): 1.23-1.92(8H, m), 2.33(1H, sept, J ═ 7Hz), 2.35(3H, s), 3.79(2H, d, J ═ 7Hz), 5.15(2H, s), 6.37(1H, d, J ═ 8Hz), 6.46(1H, d, J ═ 16Hz), 6.71(1H, dd, J ═ 8 and 2Hz), 6.99(1H, d, J ═ 2Hz), 7.40(1H, d, J ═ 16Hz).
Mass(ESI)：m/e 407(M-H)-.
Production example 23-1
In the same manner as in production example 15-1 above, from 5-chloro-2-methylimidazole-4-carbaldehyde (200mg) and 2-chloro-4- ((cyclohexyl) methoxy) benzyl bromide (659mg), 4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazole-5-carbaldehyde was obtained as a yellow oil (410 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＝7Hz)，5.57(2H，s)，6.45(1H，d，J＝8Hz)，6.69(1H，dd，J＝2，8Hz)，6.95(1H，d，J＝2Hz)，9.76(1H，s).
Mass(ESI)：m/z 381(M+1).
Production example 23-2
In the same manner as in production example 15-2 above, 4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazole-5-carbaldehyde (405mg) was used to give methyl (E) -3- (4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazol-5-yl) -2-acrylate as a yellow oily substance (419 mg).
1H-NMR(CDCl3)：0.95-1.11(2H，m)，1.15-1.38(4H，m)，1.63-1.89(5H，m)，2.34(3H，s)，3.71(2H，d，J＝7Hz)，3.74(3H，s)，5.15(2H，s)，6.36(1H，d，J＝8Hz)，6.49(1H，d，J＝16Hz)，6.70(1H，dd，J＝2，8Hz)，6.98(1H，d，J＝2Hz)，7.34(1H，d，J＝16Hz).
Mass(ESI)：m/z 437(M+1).
Production example 23-3
In the same manner as in production example 15-4 above, methyl (E) -3- (4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoate (418mg) was used to obtain (E) -3- (4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid as pale yellow crystals (375 mg).
1H-NMR(CDCl3)：0.95-1.10(2H，m)，1.15-1.38(4H，m)，1.64-1.89(5H，m)，2.35(3H，s)，3.71(2H，d，J＝7Hz)，5.16(2H，s)，6.33(1H，d，J＝8Hz)，6.46(1H，d，J＝16Hz)，6.70(1H，dd，J＝2，8Hz)，7.00(1H，d，J＝2Hz)，7.40(1H，d，J＝16Hz).
Mass(ESI)：m/z 421(M-1).
Production example 24-1
In the same manner as in production example 15-1 above, from 5-chloro-2-methylimidazole-4-carbaldehyde (200mg) and 4-benzyloxy-2-chlorobenzyl chloride (480mg), 1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazole-5-carbaldehyde was obtained as a yellow oil (410 mg).
1H-NMR(CDCl3)：2.32(3H，s)，5.02(2H，s)，5.57(2H，s)，6.47(1H，d，J＝8Hz)，6.78(1H，dd，J＝2，8Hz)，7.05(1H，d，J＝2Hz)，7.30-7.45(5H，m)，9.76(1H，s).
Mass(ESI)：m/z 375(M+1).
Production example 24-2
In the same manner as in production example 15-2 above, 1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazole-5-carbaldehyde (389mg) was used to give methyl (E) -3- (1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-acrylate as a colorless oil (384 mg).
1H-NMR(CDCl3)：2.33(3H，s)，3.75(3H，s)，5.03(2H，s)，5.15(2H，s)，6.38(1H，d，J＝8Hz)，6.50(1H，d，J＝16Hz)，6.79(1H，dd，J＝2，8Hz)，7.08(1H，d，J＝2Hz)，7.33(1H，d，J＝16Hz)，7.31-7.43(5H，m).
Mass(ESI)：m/z 431(M+1).
Production example 24-3
In the same manner as in production example 15-4 above, methyl (E) -3- (1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoate (375mg) was used to give (E) -3- (1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid as yellow crystals (296 mg).
1H-NMR(CDCl3)：2.35(3H，s)，5.03(2H，s)，5.16(2H，s)，6.40(1H，d，J＝8Hz)，6.47(1H，d，J＝16Hz)，6.80(1H，dd，J＝2，8Hz)，7.09(1H，d，J＝2Hz)，7.30-7.45(6H，m).
Mass(ESI)：m/z 415(M-1).
Production example 25-1
In the same manner as in production example 15-1 above, 5-chloro-2-methylimidazole-4-carbaldehyde (200mg) and 2-chloro-1- ((methanesulfonyloxy) methyl) -4- (methylthio) benzene (379mg) were used to give 4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazole-5-carbaldehyde as a colorless oil (344 mg).
1H-NMR(CDCl3)：2.32(3H，s)，2.46(3H，s)，5.58(2H，s)，6.43(1H，d，J＝8Hz)，7.03(1H，dd，J＝2，8Hz)，7.26(1H，overlapped with CDCl3)，9.76(1H，s).
Mass(ESI)：m/z 315(M+1).
Production example 25-2
In the same manner as in production example 15-2 above, from 4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazole-5-carbaldehyde (336mg), methyl (E) -3- (4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazol-5-yl) -2-acrylate was obtained as a yellow oil (384 mg).
1H-NMR(CDCl3)：2.34(3H，s)，2.47(3H，s)，3.75(3H，s)，5.17(2H，s)，6.36(1H，d，J＝8Hz)，6.49(1H，d，J＝16Hz)，7.04(1H，dd，J＝2，8Hz)，7.30(1H，d，J＝2Hz)，7.32(1H，d，J＝16Hz).
Mass(ESI)：m/z 371(M+1).
Production example 25-3
In the same manner as in production example 15-4 above, methyl (E) -3- (4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazol-5-yl) -2-propenoate (374mg) was used to obtain (E) -3- (4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid as pale yellow crystals (305 mg).
1H-NMR(CDCl3)：2.35(3H，s)，2.47(3H，s)，5.18(2H，s)，6.38(1H，d，J＝8Hz)，6.47(1H，d，J＝16Hz)，7.05(1H，dd，J＝2，8Hz)，7.30(1H，d，J＝2Hz)，7.37(1H，d，J＝16Hz).
Mass(ESI)：m/z 357(M+1).
Production example 26-1
In the same manner as in production example 15-1 above, from 5-chloro-2-methylimidazole-4-carbaldehyde (100mg) and 2-chloro-4- (trifluoromethyl) benzyl bromide (378mg), 4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazole-5-carbaldehyde was obtained as a pale yellow solid (189 mg).
1H-NMR(CDCl3)：2.35(3H，s)，5.65(2H，s)，6.60(1H，d，J＝8Hz)，7.45(1H，d，J＝8Hz)，7.71(1H，s)，9.76(1H，s).
Mass(ESI)：m/e 337(M)+.
Production example 26-2
In the same manner as in production example 15-2 above, from 4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazole-5-carbaldehyde (185mg), ethyl (E) -3- [ 4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazol-5-yl ] -2-acrylate was obtained as a colorless oil (207 mg).
1H-NMR(CDCl3)：1.30(3H，t，J＝6Hz)，2.35(3H，s)，4.20(2H，q，J＝6Hz)，5.36(2H，s)，6.54(1H，d，J＝16Hz)，6.59(1H，d，J＝8Hz)，7.26(1H，d，J＝16Hz)，7.48(1H，d，J＝8Hz)，7.75(1H，s).
Mass(ESI)：m/e 408(M+H)+.
Production example 26-3
In the same manner as in production example 15-4 above, ethyl (E) -3- (4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazol-5-yl) -2-propenoate (203mg) was used to obtain colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (144 mg).
1H-NMR(CDCl3)：2.36(3H，s)，5.26(2H，s)，6.49(1H，d，J＝16Hz)，6.60(1H，d，J＝8Hz)，7.33(1H，d，J＝16Hz)，7.49(1H，d，J＝8Hz)，7.75(1H，s).
Mass(ESI)：m/z 379(M+1).
Production example 27-1
In the same manner as in production example 15-1 above, 5-chloro-2-methylimidazole-4-carbaldehyde (216mg) and 2-chloro-1- ((methanesulfonyloxy) methyl) -4- (phenoxymethyl) benzene (605mg) were used to give 4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazole-5-carbaldehyde as a colorless oil (482 mg).
1H-NMR(CDCl3)：2.33(3H，s)，5.01(2H，s)，5.63(2H，s)，6.51(1H，d，J＝8Hz)，6.90-7.03(3H，m)，7.20-7.35(3H，m)，7.53(1H，d，J＝2Hz)，9.77(1H，s).
Mass(ESI)：m/e 375(M+H)+.
Production example 27-2
In the same manner as in production example 15-2 above, methyl 4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazole-5-carbaldehyde (475mg) and methyl (triphenylphosphoranylidene) acetate (623mg) were used to give methyl (E) -3- (4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazol-5-yl) -2-propenoate as a white powder (413 mg).
1H-NMR(CDCl3)：2.34(3H，s)，3.74(3H，s)，5.03(2H，s)，5.22(2H，s)，6.47(1H，d，J＝8Hz)，6.50(1H，d，J＝16Hz)，6.91-7.04(3H，m)，7.21-7.34(3H，m)，7.22(1H，d，J＝16Hz)，7.57(1H，d，J＝2Hz).
Mass(ESI)：m/e 431(M+H)+.
Production example 27-3
In the same manner as in production example 15-4 above, methyl (E) -3- (4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazol-5-yl) -2-propenoate (404mg) was used to obtain (E) -3- (4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid as a white powder (391 mg).
1H-NMR(CDCl3)：2.34(3H，s)，5.01(2H，s)，5.21(2H，s)，6.46(1H，d，J＝16Hz)，6.47(1H，d，J＝9Hz)，6.89-7.02(3H，m)，7.20-7.34(3H，m)，7.34(1H，d，J＝16Hz)，7.55(1H，d，J＝2Hz).
Mass(ESI)：m/e 415(M-H)-.
Production example 28-1
In the same manner as in production example 15-1 above, 4-chloro-2-methylimidazole-5-carbaldehyde (200mg) and 2-chloro-1- ((methanesulfonyloxy) methyl) -4-nitrobenzene (404mg) were used to give 4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazole-5-carbaldehyde as pale yellow crystals (304 mg).
1H-NMR(CDCl3)：2.37(3H，s)，5.67(2H，s)，6.67(1H，d，J＝8Hz)，8.06(1H，dd，J＝8，2Hz)，8.34(1H，d，J＝2Hz)，9.75(1H，s).
Production example 28-2
In the same manner as in production example 15-2 above, methyl 4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazole-5-carbaldehyde (285mg) and methyl (triphenylphosphoranylidene) acetate (546mg) were combined to give methyl (E) -3- (4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazol-5-yl) -2-propenoate as pale yellow crystals (297 mg).
1H-NMR(CDCl3)：2.35(3H，s)，3.74(3H，s)，5.29(2H，s)，6.52(1H，d，J＝15Hz)，6.65(1H，d，J＝8Hz)，7.27(1H，d，J＝2Hz)，8.08(1H，d，J＝8，2Hz)，8.36(1H，d，J＝2Hz).
Production example 28-3
In the same manner as in production example 15-4 above, methyl (E) -3- (4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazol-5-yl) -2-propenoate (275mg) was used to give pale orange crystals of (E) -3- (4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazol-5-yl) -2-propenoic acid (233 mg).
1H-NMR(DMSO-d6)：2.32(3H，s)，5.56(2H，s)，6.28(1H，d，J＝15Hz)，6.77(1H，d，J＝8Hz)，7.22(1H，d，J＝15Hz)，8.16(1H，dd，J＝8，2Hz)，8.41(1H，d，J＝2Hz).
Production example 29-1
In the same manner as in production example 15-1 above, from 5-chloro-2-methylimidazole-4-carbaldehyde (209mg) and (E) -2-chloro-4- (2-phenylvinyl) benzyl bromide (489mg), orange crystals of (E) -4-chloro-1- (2-chloro-4- (2-phenylvinyl) benzyl) -2-methylimidazole-5-carbaldehyde (471mg) were obtained.
1H-NMR(CDCl3)：2.34(3H，s)，5.64(2H，s)，6.50(1H，d，J＝8Hz)，6.99(1H，d，J＝16Hz)，7.10(1H，d，J＝16Hz)，7.25-7.42(4H，m)，7.50(2H，d，J＝8Hz)，7.58(2H，s)，9.78(1H，s).
Mass(ESI)：m/z 371(M+1).
Production example 29-2
In the same manner as in production example 15-2 above, methyl (2E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -2-acrylate was obtained as a yellow amorphous substance (433mg) from (E) -4-chloro-1- (2-chloro-4- (2-phenylvinyl) benzyl) -2-methylimidazole-5-carbaldehyde (390 mg).
1H-NMR(CDCl3)：2.36(3H，s)，3.74(3H，s)，5.22(2H，s)，6.45(1H，d，J＝8Hz)，6.51(1H，d，J＝16Hz)，6.99(1H，d，J＝16Hz)，7.12(1H，d，J＝16Hz)，7.26-7.41(5H，m)，7.50(2H，d，J＝8Hz)，7.60(1H，s).
Mass(ESI)：m/z 427(M+1).
Production example 29-3
In the same manner as in production example 15-4 above, methyl (2E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -2-propenoate (418mg) was used to obtain colorless crystals of (2E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (326 mg).
1H-NMR(DMSO-d6)：2.34(3H，s)，5.41(2H，s)，6.26(1H，d，J＝16Hz)，6.53(1H，d，J＝8Hz)，7.18-7.44(6H，m)，7.51(1H，d，J＝8Hz)，7.60(2H，d，J＝8Hz)，7.84(1H，s).
Production example 30-1
In the same manner as in production example 15-1 above, 4-chloro-2-methylimidazole-5-carbaldehyde (200mg) and 1-bromo-2- (bromomethyl) naphthalene (457mg) were used to give 1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazole-5-carbaldehyde as pale yellow crystals (379 mg).
1H-NMR(CDCl3)：2.32(3H，s)，5.88(2H，s)，6.58(1H，d，J＝8Hz)，7.56(1H，t，J＝8Hz)，7.65(1H，t，J＝8Hz)，7.73(1H，d，J＝8Hz)，7.82(1H，d，J＝8Hz)，8.35(1H，d，J＝8Hz)，9.82(1H，s).
Production example 30-2
In the same manner as in production example 15-2 above, methyl 1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazole-5-carbaldehyde (386mg) and methyl (triphenylphosphoranylidene) acetate (603mg) were combined to give methyl (E) -3- (1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoate as pale yellow crystals (413 mg).
1H-NMR(CDCl3)：2.36(3H，s)，3.70(3H，s)，5.44(2H，s)，6.50(1H，d，J＝8Hz)，6.53(1H，d，J＝2Hz)，7.37(1H，d，J＝15Hz)，7.57(1H，t，J＝8Hz)，7.67(1H，t，J＝8Hz)，7.75(1H，d，J＝8Hz)，7.83(1H，d，J＝8Hz)，8.35(1H，d，J＝8Hz).
Production example 30-3
In the same manner as in production example 15-4 above, methyl (E) -3- (1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoate (393mg) was used to obtain colorless crystals of (E) -3- (1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid (389 mg).
1H-NMR(DMSO-d6)：2.37(3H，s)，5.61(2H，s)，6.24(1H，d，J＝15Hz)，6.58(1H，d，J＝8Hz)，7.24(1H，d，J＝15Hz)，7.65(1H，t，J＝8Hz)，7.76(1H，t，J＝8Hz)，7.97(2H，t，J＝8Hz)，8.29(1H，d，J＝8Hz).
Production example 31-1
In the same manner as in production example 15-1 above, 5-chloro-2-methylimidazole-4-carbaldehyde (271mg) and 3-chloro-2-chloromethyl-5- (trifluoromethyl) pyridine (474mg) were used to give 4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazole-5-carbaldehyde as a yellow oily substance (440 mg).
1H-NMR(CDCl3)：2.38(3H，s)，5.76(2H，s)，7.97(1H，s)，8.58(1H，s)，9.66(1H，s).
MS(ESI)：m/z 336(M-1).
Production example 31-2
In the same manner as in production example 15-2 above, 4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazole-5-carbaldehyde (430mg) was used to give methyl (E) -3- (4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazol-5-yl) -2-acrylate as a yellow oily substance (342 mg).
1H-NMR(CDCl3)：2.38(3H，s)，2.75(3H，s)，5.39(2H，s)，6.54(1H，d，J＝16Hz)，7.34(1H，d，J＝16Hz)，8.00(1H，s)，8.66(1H，s).
MS(ESI)：m/z 392(M-1).
Production example 31-3
In the same manner as in production example 15-4 above, (E) -3- (4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazol-5-yl) -2-acrylic acid methyl ester (335mg) was obtained as (240mg) 3- (4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazol-5-yl) -2-acrylic acid.
1H-NMR(DMSO-d6)：2.28(3H，s)，5.68(2H，s)，6.28(1H，d，J＝16Hz)，7.26(1H，d，J＝16Hz)，8.60(1H，s)，8.89(1H，s).
MS(ESI)：m/z 380(M+1).
Production example 32-1
From 5-chloro-2-methylimidazole-4-carbaldehyde (340mg) and 4- (N, N-di- (tert-butoxycarbonyl) amino) -2-chlorobenzyl bromide (1.19g), 3- (4- (N, N-di- (tert-butoxycarbonyl) amino) -2-chlorobenzyl) -5-chloro-2-methylimidazole-4-carbaldehyde was obtained as a white amorphous substance (844 mg).
1H-NMR(CDCl3)：1.42(18H，s)，2.30(3H，s)，5.65(2H，s)，6.52(1H，d，J＝8Hz)，6.99(1H，dd，J＝8，2Hz)，7.26(1H，d，J＝2Hz)，9.76(1H，s).
Production example 32-2
From 3- (4- (N, N-bis- (tert-butoxycarbonyl) amino) -2-chlorobenzyl) -5-chloro-2-methylimidazole-4-carbaldehyde (834mg), a white amorphous substance of (E) -methyl 3- (1- (4- (N, N-bis- (tert-butoxycarbonyl) amino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-acrylate (902mg) was obtained.
1H-NMR(CDCl3)：1.42(18H，s)，2.34(3H，s)，3.72(3H，s)，5.23(2H，s)，6.45(1H，d，J＝16Hz)，6.48(1H，d，J＝8Hz)，7.01(1H，dd，J＝8，2Hz)，7.30(1H，d，J＝2Hz)，7.33(1H，d，J＝16Hz).
MS(ESI)：m/z 541(M+1)
Production example 32-3
Methyl (E) -3- (1- (4- (N, N-di- (tert-butoxycarbonyl) amino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoate (882mg) was dissolved in dioxane (8.8ml), and 1N aqueous sodium hydroxide solution (5.0ml) was added to stir at 80 ℃ for 5.5 hours. To the reaction mixture was added a 1N aqueous solution (3.0ml) of sodium hydroxide, and the mixture was stirred at 80 ℃ for 18 hours, followed by adding a 1N aqueous solution (1.0ml) of sodium hydroxide again. The reaction mixture was stirred at 80 ℃ for 2 hours, stirred at reflux for 3 hours, and then neutralized under ice-cooling. The precipitated precipitate was collected by filtration and washed with water to give (E) -3- (1- (4- (tert-butoxycarbonyl) amino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid as a white powder (452 mg).
1H-NMR(DMSO-d6)：1.45(18H，s)，2.31(3H，s)，5.28(2H，s)，6.22(1H，d，J＝16Hz)，6.46(1H，d，J＝8Hz)，7.18(1H，d，J＝16Hz)，7.28(1H，dd，J＝8，2Hz)，7.71(1H，d，J＝2Hz)，9.64(1H，s).
MS(ESI)：m/z 427(M+1)
Production example 33-1
2-Ethylimidazole (1.0g) was dissolved in anhydrous ethanol (10ml), and bromine (1.2ml) was added dropwise under ice-cooling. The reaction mixture was stirred at this temperature for 3 hours, at room temperature for 3 hours, and then left at room temperature overnight. After neutralization with a 5N aqueous solution of sodium hydroxide, sodium sulfite (1.4g) and water (10ml) were added, and the mixture was refluxed for 10 hours. The reaction solution was partitioned between chloroform and water, and the aqueous layer was extracted 2 times with chloroform. The organic layers were combined, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol 98/2) to give 4-bromo-2-ethylimidazole as a pale yellow solid (1.02 g).
1H-NMR(CDCl3)：1.32(3H，t，J＝6Hz)，2.75(2H，q，J＝6Hz)，6.89(1H，s).
MS(ESI)：m/z 176(M+1)
Production example 33-2
4-bromo-2-ethylimidazole (24.4g) was dissolved in ethanol (244ml), and a 1N aqueous solution of sodium hydroxide (105ml) and 37% formalin (15.6ml) were added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was neutralized under ice-cooling, concentrated under reduced pressure and dried. The residue was extracted with chloroform-methanol (4/1), and insoluble matter was filtered off, followed by concentration under reduced pressure and drying. The residue was purified by silica gel column chromatography (chloroform/methanol ═ 49: 1 to 19: 1) to give 4-bromo-2-ethyl-5- (hydroxymethyl) imidazole as a yellow powder (18.9 g).
1H-NMR(DMSO-d6)：1.16(3H，t，J＝6Hz)，2.55(2H，q，J＝6Hz)，4.30(2H，d，J＝4Hz)，5.14(1H，t，J＝4Hz).
Production example 33-3
4-bromo-2-ethyl-5- (hydroxymethyl) imidazole (18.9g) was dissolved in anhydrous dimethylformamide (189ml), and manganese dioxide (80.1g) was added thereto, and the mixture was stirred at room temperature for 5 hours and then allowed to stand overnight. The reaction mixture was filtered through celite, and the insoluble material was washed with chloroform. The filtrate and the washing liquid were combined, concentrated under reduced pressure to dry the residue, and then the residue was washed with water to give 5-bromo-2-ethylimidazole-4-carbaldehyde as a brown powder (12.9 g).
1H-NMR(CDCl3)：1.37(3H，t，J＝6Hz)，2.86(2H，q，J＝6Hz)，9.58(1H，s).
Production example 33-4
In the same manner as in production examples 1 to 4, orange crystals (6.6g) of 5-chloro-2-ethylimidazole-4-carbaldehyde (12g) were obtained as 5-bromo-2-ethylimidazole-4-carbaldehyde.
1H-NMR(DMSO-d6)：1.20(3H，t，J＝7Hz)，2.66(2H，q，J＝7Hz)，9.59(1H，s).
MASS(ESI)：m/z 157(M-1).
Production example 33-5
In the same manner as in production example 15-1 above, from 5-chloro-2-ethylimidazole-4-carbaldehyde (130mg) and 2-chloro-4- (1-pentyloxy) benzyl bromide (335mg), 4-chloro-1- (2-chloro-4- (n-pentyloxy) benzyl) -2-ethylimidazole-5-carbaldehyde was obtained as a pale yellow oil (260 mg).
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.25(3H，t，J＝7Hz)，1.30-1.49(4H，m)，1.70-1.83(2H，m)，2.59(2H，q，J＝7Hz)，3.90(2H，t，J＝7Hz)，5.57(2H，s)，6.43(1H，d，J＝8Hz)，6.68(1H，dd，J＝8，2Hz)，6.95(1H，d，J＝2Hz)，9.77(1H，s).
MASS(ESI)：m/z 369(M-1).
Production example 33-6
In the same manner as in production example 15-2 above, methyl 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-ethylimidazole-5-carbaldehyde (254mg) and methyl (triphenylphosphoranylidene) acetate (354mg) were used to give methyl (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-ethylimidazol-5-yl) -2-propenoate as a yellow solid (265 mg).
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.27(3H，t，J＝7Hz)，1.31-1.49(4H，m)，1.71-1.83(2H，m)，2.61(2H，q，J＝7Hz)，3.74(3H，s)，3.90(2H，q，J＝7Hz)，5.16(2H，s)，6.35(1H，d，J＝8Hz)，6.49(1H，d，J＝15Hz)，6.70(1H，dd，J＝8，2Hz)，6.98(1H，d，J＝2Hz)，7.34(1H，d，J＝15Hz).
MASS(ESI)：m/z 427(M+1).
Production examples 33 to 7
In the same manner as in production example 15-4 above, methyl (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-ethylimidazol-5-yl) -2-propenoate (254mg) was used to obtain colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (178 mg).
1H-NMR(DMSO-d6)：0.88(3H，t，J＝7Hz)，1.14(3H，t，J＝7Hz)，1.25-1.44(4H，m)，1.63-1.75(2H，m)，2.65(2H，q，J＝7Hz)，3.95(2H，q，J＝7Hz)，5.31(2H，s)，6.27(1H，d，J＝15Hz)，6.40(1H，d，J＝8Hz)，6.67(1H，dd，J＝8，2Hz)，7.13(1H，d，J＝2Hz)，7.23(1H，d，J＝15Hz).
MASS(ESI)：m/z 409(M-1).
Production example 34-1
In the same manner as in production example 15-1 above, from 5-chloro-2-ethylimidazole-4-carbaldehyde (1.5g) and 4-bromo-2-chlorobenzyl bromide (3.77g), 1- (4-bromo-2-chlorobenzyl) -4-chloro-2-ethylimidazole-5-carbaldehyde was obtained as a pale yellow solid (2.86 g).
1H-NMR(CDCl3)：1.28(3H，t，J＝7Hz)，2.58(2H，q，J＝7Hz)，5.56(2H，s)，6.35(1H，d，J＝8Hz)，7.31(1H，dd，J＝8，1Hz)，7.60(1H，d，J＝1Hz)，9.76(1H，s).
MASS(ESI)：m/z 363(M+1).
Production example 34-2
In the same manner as in production example 15-2 above, from 1- (4-bromo-2-chlorobenzyl) -4-chloro-2-ethylimidazole-5-carbaldehyde (1.0g) and methyl (triphenylphosphoranylidene) acetate (1.39g), methyl (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-ethylimidazol-5-yl) -2-propenoate was obtained as a colorless solid (1.06 g).
1H-NMR(CDCl3)：1.28(3H，t，J＝7Hz)，2.59(2H，q，J＝7Hz)，3.75(3H，s)，5.16(2H，s)，6.32(1H，d，J＝8Hz)，6.50(1H，d，J＝15Hz)，7.29(1H，d，J＝15Hz)，7.34(1H，dd，J＝8，1Hz)，7.63(1H，d，J＝1Hz).
MASS(ESI)：m/z 419(M+1).
Production example 34-3
In the same manner as in production example 15-4 above, methyl (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-ethylimidazol-5-yl) -2-propenoate (260mg) was used to obtain (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-ethylimidazol-5-yl) -2-propenoic acid as a colorless solid (228 mg).
1H-NMR(DMSO-d6)：1.14(3H，t，J＝7Hz)，2.65(2H，q，J＝7Hz)，5.38(2H，s)，6.36(1H，d，J＝15Hz)，6.43(1H，d，J＝8Hz)，7.20(1H，d，J＝15Hz)，7.52(1H，dd，J＝8，1Hz)，7.87(1H，d，J＝1Hz).
MASS(ESI)：m/z 403(M+1).
Production example 35-1
In the same manner as in production example 15-1 above, 5-chloro-2-ethylimidazole-4-carbaldehyde (1.2g) and 2-chloro-4-iodobenzyl bromide (3.76g) were used to give 4-chloro-1- (2-chloro-4-iodobenzyl) -2-ethylimidazole-4-carbaldehyde as a pale yellow colloid (2.68 g).
1H-NMR(CDCl3)：1.28(3H，t，J＝7Hz)，2.58(2H，q，J＝7Hz)，5.56(2H，s)，6.20(1H，d，J＝8Hz)，7.50(1H，dd，J＝8，1Hz)，7.78(1H，d，J＝1Hz)，9.75(1H，s).
MASS(ESI)：m/z 409(M+1).
Production example 35-2
In the same manner as in production example 15-2 above, methyl 4-chloro-1- (2-chloro-4-iodobenzyl) -2-ethylimidazole-5-carbaldehyde (2.65g) and methyl (triphenylphosphoranylidene) acetate (3.25g) were used to give methyl (E) -3- (4-chloro-1- (2-chloro-4-iodobenzyl) -2-ethylimidazol-5-yl) -2-propenoate as pale yellow crystals (2.52 g).
1H-NMR(CDCl3)：1.28(3H，t，J＝7Hz)，2.59(2H，q，J＝7Hz)，3.75(3H，s)，5.15(2H，s)，6.16(1H，d，J＝8Hz)，6.49(1H，d，J＝15Hz)，7.27(1H，d，J＝15Hz)，7.51(1H，dd，J＝8，1Hz)，7.81(1H，d，J＝1Hz).
MASS(ESI)：m/z 465(M+1).
Production example 35-3
In the same manner as in production example 17-1 above, methyl (E) -3- (4-chloro-1- (2-chloro-4-iodobenzyl) -2-ethylimidazol-5-yl) -2-acrylate (600mg) and phenylacetylene (439mg) were used to obtain gray crystals of methyl (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -2-acrylate (522 mg).
1H-NMR(CDCl3)：1.28(3H，t，J＝7Hz)，2.62(2H，q，J＝7Hz)，3.75(3H，s)，5.23(2H，s)，6.44(1H，d，J＝8Hz)，6.50(1H，d，J＝15Hz)，7.28-7.40(4H，m)，7.47-7.55(2H，m)，7.63(1H，d，J＝1Hz).
MASS(ESI)：m/z 439(M+1).
Production example 35-4
In the same manner as in production example 15-4 above, methyl (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoate (500mg) was used to obtain gray crystals of (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (410 mg).
1H-NMR(DMSO-d6)：1.15(3H，t，J＝7Hz)，2.67(2H，q，J＝7Hz)，5.46(2H，s)，6.27(1H，d，J＝15Hz)，6.54(1H，d，J＝8Hz)，7.23(1H，d，J＝15Hz)，7.40-7.60(6H，m)，7.79(1H，d，J＝1Hz).
MASS(ESI)：m/z 423(M-1).
Production example 36-1
A suspension of (E) -methyl 3- (4-chloro-1- (2-chloro-4-iodobenzyl) -2-ethylimidazol-5-yl) -2-acrylate (600mg), palladium acetate (600mg), tri-o-tolylphosphine (39mg) in anhydrous triethylamine (5.4ml) was stirred under a stream of nitrogen at room temperature. After 10 minutes, styrene (672mg) was added and the reaction was heated to 100 ℃. After heating for 2 hours, the mixture was ice-cooled, water was added, and extraction was performed with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate, dried, and filtered. The filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (silica gel, 150 ml). Eluting with hexane and ethyl acetate at a ratio of 10: 1-7: 1-5: 1-4: 1 to obtain pale yellow colloid (435 mg). This was crystallized from isopropyl ether to give methyl (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoate as pale yellow crystals (405 mg).
1H-NMR(CDCl3)：1.29(3H，t，J＝7Hz)，2.63(2H，q，J＝7Hz)，3.74(3H，s)，5.23(2H，s)，6.43(1H，d，J＝8Hz)，6.51(1H，d，J＝15Hz)，6.99(1H，d，J＝15Hz)，7.21(1H，d，J＝15Hz)，7.24-7.41(5H，m)，7.51(2H，d，J＝8Hz)，7.60(1H，s).
MASS(ESI)：m/z 441(M+1).
Production example 36-2
In the same manner as in production example 15-4 above, methyl (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoate (400mg) was used to obtain (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid as pale yellow crystals (363 mg).
1H-NMR(DMSO-d6)：1.16(3H，t，J＝7Hz)，2.68(2H，q，J＝7Hz)，5.42(2H，s)，6.27(1H，d，J＝15Hz)，6.50(1H，d，J＝8Hz)，7.28-7.44(6H，m)，7.52(1H，dd，J＝8，1Hz)，7.60(2H，d，J＝8Hz)，7.83(1H，d，J＝1Hz).
MASS(ESI)：m/z 425(M-1).
Production example 37-1
In the same manner as in production example 33-2 above, 2, 4-dimethyl-5- (hydroxymethyl) imidazole (2.6g) was used to give 2, 4-dimethyl-5- (hydroxymethyl) imidazole as a pale yellow oil (4.74 g).
1H-NMR(DMSO-d6)：2.20(3H，s)，2.50(3H，s)，4.41(2H，s)
Production example 37-2
In the same manner as in production example 33-3 above, 2, 4-dimethyl-5- (hydroxymethyl) imidazole (4.10g) was used to obtain a crude purified product (3.00g) of 2, 4-dimethylimidazole-5-carbaldehyde as a yellow solid.
Mass(ESI)：m/z 123(M-H)-
Production example 37-3
In the same manner as in production example 15-1 above, from 2, 4-dimethylimidazole-5-aldehyde (587mg) and 4-bromo-2-chlorobenzyl iodoformate (1.70g), pale yellow crystals of 1- (4-bromo-2-chlorobenzyl) -2, 4-dimethyl-1H-imidazole-5-aldehyde (481mg) and pale yellow oil of 1- (4-bromo-2-chlorobenzyl) -2, 5-dimethyl-1H-imidazole-4-aldehyde (587mg) were obtained.
1- (4-bromo-2-chlorobenzyl) -2, 4-dimethyl-1H-imidazole-5-aldehyde
1H-NMR(CDCl3)：2.31(3H，s)，2.52(3H，s)，5.54(2H，s)，6.31(1H，d，J＝8Hz)，7.27(1H，dd，J＝8，2Hz)，7.58(1H，d，J＝2Hz)，9.75(1H，s)
1- (4-bromo-2-chlorobenzyl) -2, 5-dimethyl-1H-imidazole-4-aldehyde
1H-NMR(CDCl3)：2.33(3H，s)，2.43(3H，s)，5.07(2H，s)，6.23(1H，d，J＝8Hz)，7.34(1H，dd，J＝8，2Hz)，7.63(1H，d，J＝2Hz)，9.75(1H，s)
Production example 37-4
A colorless crystalline crude purified product (554mg) of methyl (E) -3- (1- (4-bromo-2-chlorobenzyl) -2, 4-dimethylimidazol-5-yl) -2-propenoate was obtained from 1- (4-bromo-2-chlorobenzyl) -2, 4-dimethyl-1H-imidazole-5-carbaldehyde (453mg) and methyl (triphenylphosphoranylidene) acetate (1.25g) in the same manner as in production example 15-2.
1H-NMR(CDCl3)：2.32(3H，s)，2.42(3H，s)，3.73(3H，s)，5.12(2H，s)，5.89(1H，d，J＝16Hz)，6.29(1H，d，J＝8Hz)，7.30(1H，dd，J＝8，2Hz)，7.37-7.70(2H，m)
Production examples 37 to 5
In the same manner as in production example 15-4 above, methyl (E) -3- (1- (4-bromo-2-chlorobenzyl) -2, 4-dimethylimidazol-5-yl) -2-propenoate (554mg) was used to obtain colorless crystals of (E) -3- (1- (4-bromo-2-chlorobenzyl) -2, 4-dimethylimidazol-5-yl) -2-propenoic acid (158 mg).
1H-NMR(DMSO-d6)：2.26(3H，s)，2.28(3H，s)，5.28(2H，s)，5.75(1H，d，J＝14Hz)，6.32(1H，d，J＝8Hz)，7.27(1H，d，J＝14Hz)，7.52(1H，dd，J＝8，2Hz)，7.85(1H，d，J＝2Hz)
Production example 38-1
In the same manner as in production example 15-1 above, from 4-bromo-2-methylimidazole-5-carbaldehyde (5.00g) and 2-chloro-4- (1-pentyloxy) benzyl bromide (9.26g), 4-bromo-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carbaldehyde was obtained as a pale yellow oil (9.11 g).
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.30-1.45(4H，m)，1.70-1.80(2H，m)，2.33(3H，s)，3.90(2H，t，J＝7Hz)，5.58(2H，s)，6.44(1H，d，J＝8Hz)，6.70(1H，dd，J＝8，2Hz)，6.95(1H，d，J＝2Hz)，9.71(1H，s)
Production example 38-2
In the same manner as in production example 15-2 above, colorless crystals of methyl (E) -3- (4-bromo-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoate (488mg) were obtained from 4-bromo-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carbaldehyde (479mg) and methyl (triphenylphosphoranylidene) acetate (481 mg).
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.33-1.45(4H，m)，1.72-1.80(2H，m)，2.35(3H，s)，3.75(3H，s)，3.92(2H，t，J＝7Hz)，5.17(2H，s)，6.36(1H，d，J＝8Hz)，6.52(1H，d，J＝15Hz)，6.71(1H，dd，J＝8，2Hz)，6.99(1H，d，J＝2Hz)，7.35(1H，d，J＝15Hz)
Production example 38-3
In the same manner as in production example 15-4 above, methyl (E) -3- (4-bromo-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoate (462mg) was used to obtain (E) -3- (4-bromo-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid as a colorless powder (447 mg).
1H-NMR(DMSO-d6)：0.88(3H，t，J＝7Hz)，1.25-1.42(4H，m)，1.62-1.72(2H，m)，2.33(3H，s)，3.96(2H，t，J＝7Hz)，5.31(2H，s)，6.29(1H，d，J＝15Hz)，6.42(1H，d，J＝8Hz)，6.88(1H，dd，J＝8，2Hz)，7.13(1H，d，J＝2Hz)，7.22(1H，d，J＝15Hz)
Production example 39-1
Lithium chloride (180mg) was suspended in 1, 4-dioxane (10ml), and 4-bromo-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carbaldehyde (707mg), vinyltributyltin (617mg), and tetrakis (triphenylphosphine) palladium (O) (102mg) were added to the suspension and the mixture was refluxed for 12 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which was eluted with hexane/ethyl acetate 5/1 and the objective fraction was concentrated under reduced pressure to give 1- (2-chloro-4- (1-pentyloxy) benzyl) -4-vinyl-2-methyl-1H-imidazole-5-carbaldehyde as a pale yellow gum (538 mg).
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.30-1.47(4H，m)，1.70-1.80(2H，m)，2.34(3H，s)，3.90(2H，t，J＝7Hz)，5.54(1H，dd，J＝8，2Hz)，5.56(2H，s)，6.26(1H，dd，J＝15，2Hz)，6.40(1H，d，J＝8Hz)，6.67(1H，dd，J＝8，2Hz)，6.95-7.05(2H，m)，9.90(1H，s)
Production example 39-2
1- (2-chloro-4- (1-pentyloxy) benzyl) -4-vinyl-2-methyl-1H-imidazole-5-carbaldehyde (575mg) was dissolved in 1, 4-dioxane (6ml), and palladium on charcoal (50mg) was added to stir under a hydrogen atmosphere for 1.5 hours. After filtration through celite, water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with chloroform/ethyl acetate 2/1, and the objective fraction was concentrated under reduced pressure to give 1- (2-chloro-4- (1-pentyloxy) benzyl) -4-ethyl-2-methyl-1H-imidazole-5-carbaldehyde as a dark brown oil (283 mg).
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.35(3H，t，J＝7Hz)，1.33-1.48(4H，m)，1.72-1.80(2H，m)，2.31(3H，s)，2.87(2H，q，J＝7Hz)，3.90(2H，t，J＝7Hz)，5.55(2H，s)，6.38(1H，d，J＝8Hz)，6.67(1H，dd，J＝8，2Hz)，6.94(1H，d，J＝2Hz)，9.77(1H，s)
Production example 39-3
In the same manner as in production example 15-2 above, methyl 1- (2-chloro-4- (1-pentyloxy) benzyl) -4-ethyl-2-methyl-1H-imidazole-5-carbaldehyde (265mg) and methyl (triphenylphosphoranylidene) acetate (940mg) were used to give methyl (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -4-ethyl-2-methylimidazol-5-yl) -2-propenoate as pale yellow crystals (273 mg).
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.31(3H，t，J＝7Hz)，1.32-1.47(4H，m)，1.70-1.81(2H，m)，2.34(3H，s)，2.75(2H，q，J＝7Hz)，3.73(3H，s)，3.91(2H，t，J＝7Hz)，5.14(2H，s)，5.86(1H，d，J＝15Hz)，6.32(1H，d，J＝8Hz)，6.68(1H，dd，J＝8，2Hz)，6.98(1H，d，J＝2Hz)，7.45(1H，d，J＝15Hz)
Production example 39-4
In the same manner as in production example 15-4 above, methyl (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -4-ethyl-2-methylimidazol-5-yl) -2-propenoate (253mg) was used to obtain (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -4-ethyl-2-methylimidazol-5-yl) -2-propenoic acid as a colorless powder (222 mg).
1H-NMR(DMSO-d6)：0.88(3H，t，J＝7Hz)，1.19(3H，t，J＝7Hz)，1.28-1.42(4H，m)，1.63-1.73(2H，m)，2.28(3H，s)，2.62(2H， q，J＝7Hz)，3.95(2H，t，J＝7Hz)，5.21(2H，s)，5.72(1H，d，J＝15Hz)，6.28(1H，d，J＝8Hz)，6.87(1H，dd，J＝8，2Hz)，7.12(1H，d，J＝2Hz)，7.29(1H，d，J＝15Hz)
Production example 40-1
4-bromo-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carbaldehyde (4.00g) was dissolved in a mixed solvent of methanol (20ml) and 1, 4-dioxane (20ml), and palladium on charcoal (400mg) and potassium acetate (1.08g) were added. After the reaction mixture was stirred under hydrogen atmosphere for 3 hours, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. To the residue was added water, followed by extraction with ethyl acetate and washing of the organic layer with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the residue was applied to a silica gel column chromatography, eluted with hexane/ethyl acetate 1/2, and the objective fraction was concentrated under reduced pressure to give 1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carbaldehyde as a pale yellow oil (3.10 g).
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.33-1.47(4H，m)，1.72-1.82(2H，m)，2.35(3H，s)，3.90(2H，t，J＝7Hz)，5.59(2H，s)，6.37(1H，d，J＝8Hz)，6.67(1H，dd，J＝8，2Hz)，6.95(1H，d，J＝2Hz)，7.78(1H，s)，9.68(1H，s)
Production example 40-2
In the same manner as in production example 42-1 below, from 1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carbaldehyde (500mg) and ethyl 3-phenylpropionate (361mg), a crude purified product of ethyl 2-benzyl-3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -3-hydroxypropionate was obtained as a brown oil.
Production example 40-3
In the same manner as in production example 42-2 below, a crude pure extract of ethyl 2-benzyl-3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -3-hydroxypropionate gave ethyl (E) -2-benzyl-3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propionate as a pale yellow oil (405 mg).
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.19(3H，t，J＝7Hz)，1.32-1.47(4H，m)，1.70-1.82(2H，m)，2.36(3H，s)，3.92(2H，t，J＝7Hz)，3.97(2H，s)，4.14(2H，q，J＝7Hz)，5.17(2H，s)，6.32(1H，d，J＝8Hz)，6.69(1H，dd，J＝8，2Hz)，6.98(1H，d，J＝2Hz)，7.13-7.28(6H，m)，7.46(1H，s)
Production example 40-4
In the same manner as in production example 15-4 above, ethyl (E) -2-benzyl-3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoate (385mg) was used to obtain (E) -2-benzyl-3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid as a pale yellow powder (308 mg).
1H-NMR(DMSO-d6)：0.88(3H，t，J＝7Hz)，1.27-1.43(4H，m)，1.65-1.74(2H，m)，2.29(3H，s)，3.86(2H，s)，3.96(2H，t，J＝7Hz)，5.26(2H，s)，6.31(1H，d，J＝8Hz)，6.85(1H，dd，J＝8，2Hz)，7.07-7.30(7H，m)，7.43(1H，s)
Production example 41-1
In the same manner as in production example 42-1, from 1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carbaldehyde (500mg) and ethyl n-heptanoate (321mg), a crude purified product of ethyl 3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -3-hydroxy-2- (1-pentyl) propionate was obtained as a brown oil.
Production example 41-2
In the same manner as in production example 42-2, a crude purified product of ethyl 3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -3-hydroxy-2- (1-pentyl) propionate gave ethyl (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (1-pentyl) -2-acrylate as a pale yellow oil (425 mg).
1H-NMR(CDCl3)：0.87-0.94(6H，m)，1.27(3H，t，J＝7Hz)，1.32-1.55(10H，m)，1.72-1.82(2H，m)，2.37(3H，s)，2.54(2H，t，J＝7Hz)，3.90(2H，t，J＝7Hz)，4.18(2H，q，J＝7Hz)，5.14(2H，s)，6.31(1H，d，J＝8Hz)，6.67(1H，dd，J＝8，2Hz)，6.96(1H，d，J＝2Hz)，7.19(1H，s)，7.31(1H，s)
Production example 41-3
In the same manner as in production example 15-4, ethyl (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (1-pentyl) -2-propenoate (405mg) was used to obtain (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (1-pentyl) -2-propenoic acid as a pale yellow powder (305 mg).
1H-NMR(DMSO-d6)：0.85-0.87(6H，m)，1.20-1.38(10H，m)，1.62-1.72(2H，m)，2.30(3H，s)，2.42(2H，t，J＝7Hz)，3.94(2H，t，J＝7Hz)，5.21(2H，s)，6.28(1H，d，J＝8Hz)，6.85(1H，dd，J＝8，2Hz)，7.10(1H，d，J＝2Hz)，7.13(1H，s)，7.22(1H，s)
Production example 42-1
Diisopropylamine (237mg) was dissolved in tetrahydrofuran (3ml), and a 1.53M n-butyllithium hexane solution (1.53ml) was added under a nitrogen atmosphere while cooling on a dry ice-acetone bath. After stirring in an ice water bath for 30 minutes, a tetrahydrofuran (1ml) solution of methyl 3- (3-pyridyl) propionate (335mg) was added while cooling in a dry ice-acetone bath. After stirring for 1 hour on a dry ice-acetone bath, a solution of 1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carbaldehyde (500mg) in tetrahydrofuran (1ml) was added. After stirring for 1 hour on a dry ice-acetone bath, saturated aqueous ammonium chloride solution was added. Extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give methyl 3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -3-hydroxy-2- (3-pyridylmethyl) propionate as a crude purified brown oil.
Production example 42-2
The crude purified methyl 3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -3-hydroxy-2- (3-pyridylmethyl) propionate was dissolved in dichloromethane (8ml), acetic anhydride (0.88ml) and 4-dimethylaminopyridine (76mg) were added. After stirring at room temperature for 14 hours, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was stirred for 15 minutes. Extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (8ml), and 1, 8-diazabicyclo [5, 4, 0] undec-7-ene (0.58ml) was added. After heating in an oil bath at 100 ℃ for 4 minutes, a saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform/methanol 100/1 and the fractions of the objective compound were concentrated under reduced pressure to give methyl (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (3-pyridylmethyl) -2-acrylate as a pale yellow oil (713 mg).
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.32-1.48(4H，m)，1.72-1.82(2H，m)，2.36(3H，s)，3.70(3H，s)，3.92(2H，t，J＝7Hz)，3.98(2H，s)，5.18(2H，s)，6.30(1H，d，J＝8Hz)，6.69(1H，dd，J＝8，2Hz)，6.98(1H，d，J＝2Hz)，7.18(1H，dd，J＝8，5Hz)，7.24(1H，s)，7.44(1H，d，J＝8Hz)，7.51(1H，s)，8.44-8.46(2H，m)
Production example 42-3
In the same manner as in production example 15-4, methyl (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (3-pyridylmethyl) -2-propenoate (695mg) was used to obtain (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (3-pyridylmethyl) -2-propenoic acid as a brown powder (502 mg).
1H-NMR(DMSO-d6)：0.88(3H，t，J＝7Hz)，1.27-1.44(4H，m)，1.65-1.74(2H，m)，2.31(3H，s)，3.87(2H，s)，3.96(2H，t，J＝7Hz)，5.27(2H，s)，6.32(1H，d，J＝8Hz)，6.34(1H，dd，J＝8，2Hz)，7.12(1H，d，J＝2Hz)，7.19(1H，s)，7.27(1H，dd，J＝8，5Hz)，7.41-7.44(2H，m)，8.36-8.40(2H，m)
Production example 43-1
In the same manner as in production example 42-1, from 1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carbaldehyde (441mg) and ethyl n-propionate (190mg), a crude purified product of ethyl 3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -3-hydroxy-2-methylpropionate was obtained as a brown oil.
Production example 43-2
In the same manner as in production example 42-2, a pale yellow oily substance of ethyl (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-2-acrylate (449mg) was obtained from the crude pure product of ethyl 3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -3-hydroxy-2-methylpropionate.
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.28(3H，t，J＝7Hz)，1.33-1.47(4H，m)，1.72-1.81(2H，m)，2.12(3H，s)，2.38(3H，s)，3.90(2H，t，J＝7Hz)，4.18(2H，q，J＝7Hz)，5.15(2H，s)，6.30(1H，d，J＝2Hz)，6.67(1H，dd，J＝8，2Hz)，6.96(1H，d，J＝2Hz)，7.26(1H，s)，7.34(1H，s)
Production example 43-3
In the same manner as in production example 15-4, ethyl (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-2-propenoate (432mg) was used to obtain colorless crystals of (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-2-propenoic acid (253 mg).
1H-NMR(DMSO-d6)：1.09(3H，t，J＝7Hz)，1.47-1.64(4H，m)，1.85-1.95(2H，m)，2.21(3H，s)，2.52(3H，s)，4.16(2H，t，J＝7Hz)，5.44(2H，s)，6.48(1H，d，J＝8Hz)，7.06(1H，dd，J＝8，2Hz)，7.32(1H，d，J＝2Hz)，7.41(1H，s)，7.53(1H，s)
Production example 44-1
In the same manner as in production example 42-1, from 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carbaldehyde (441mg) and ethyl n-propionate (400mg), a crude brown oily purification product of ethyl 3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -3-hydroxy-2-methylpropionate was obtained.
Production example 44-2
In the same manner as in production example 42-2, crude pure ethyl 3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -3-hydroxy-2-methylpropionate gave (E) -ethyl 3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-2-acrylate as a pale yellow oil (261 mg).
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.30(3H，t，J＝7Hz)，1.32-1.47(4H，m)，1.70-1.80(2H，m)，1.97(3H，s)，2.31(3H，s)，3.92(2H，t，J＝7Hz)，4.21(2H，q，J＝7Hz)，5.02(2H，s)，6.42(1H，d，J＝8Hz)，6.72(1H，dd，J＝8，2Hz)，6.95(1H，d，J＝2Hz)，7.06(1H，s)
Production example 44-3
In the same manner as in production example 15-4, ethyl (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-2-propenoate (250mg) was used to obtain colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-2-propenoic acid (140 mg).
1H-NMR(DMSO-d6)：0.88(3H，t，J＝7Hz)，1.25-1.40(4H，m)，1.62-1.72(2H，m)，1.76(3H，s)，2.27(3H，s)，3.95(2H，t，J＝7Hz)，5.12(2H，s)，6.52(1H，d，J＝8Hz)，6.86(1H，dd，J＝8，2Hz)，7.01(1H，s)，7.06(1H，d，J＝2Hz)
Production example 45
4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carbaldehyde (400mg) was dissolved in tert-butanol (8ml), and 2-methyl-2-butene (355mg) and an aqueous solution (2ml) of sodium dihydrogen phosphate (135mg) were added. Sodium chlorite (356mg) was added to the reaction solution for 2 minutes, and the mixture was stirred at room temperature for 24 hours. 1N hydrochloric acid was added to the reaction solution under ice cooling to adjust the pH to 4, water (20ml) was added, and precipitated crystals were collected by filtration. The crystals were dried under reduced pressure with heating to give colorless crystals (387mg) of 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carboxylic acid.
1H-NMR(DMSO-d6)：0.88(3H，t，J＝7Hz)，1.27-1.42(4H，m)，1.65-1.75(2H，m)，2.25(3H，s)，3.95(2H，t，J＝7Hz)，5.51(2H，s)，6.32(1H，d，J＝8Hz)，6.86(1H，dd，J＝8，2Hz)，7.09(1H，d，J＝2Hz)
Production example 46
4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carbaldehyde (1.05g) was dissolved in ethanol (10ml), and sodium borohydride (168mg) was added thereto under ice-cooling, followed by stirring at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate, washing of the organic layer with saturated brine, drying over anhydrous magnesium sulfate, and concentration under reduced pressure. Hexane (10ml) was added to the residue, and the precipitated crystals were collected by filtration and dried under reduced pressure under heating to give 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -5-hydroxymethyl-2-methyl-1H-imidazole as colorless crystals (786 mg).
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.30-1.48(4H，m)，1.72-1.85(2H，m)，2.26(3H，s)，3.91(2H，t，J＝7Hz)，4.50(2H，s)，5.18(2H，s)，6.40(1H，d，J＝8Hz)，6.70(1H，dd，J＝8，2Hz)，6.96(1H，d，J＝2Hz)
Production example 47-1
In the same manner as in production example 9, from 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -5-hydroxymethyl-2-methyl-1H-imidazole (611mg), 4-chloro-5-chloromethyl-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole was obtained as a brown oil (707 mg).
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.32-1.48(4H，m)，1.73-1.82(2H，m)，2.33(3H，s)，3.92(2H，t，J＝7Hz)，4.48(2H，s)，5.17(2H，s)，6.46(1H，d，J＝8Hz)，6.73(1H，dd，J＝8，2Hz)，6.97(1H，d，J＝2Hz)
Production example 47-2
To a mixed solution of 28% aqueous ammonia (6ml) and acetonitrile (6ml) was slowly added a solution of 4-chloro-5-chloromethyl-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole (340mg) in acetonitrile (3ml) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour, and then a saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform/methanol 100/1, and the objective fraction was concentrated under reduced pressure to give 5-aminomethyl-4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole as a pale brown oil (82 mg).
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.32-1.48(4H，m)，1.73-1.83(2H，m)，2.26(3H，s)，3.70(2H，s)，3.91(2H，t，J＝7Hz)，5.19(2H，s)，6.37(1H，d，J＝8Hz)，6.70(1H，dd，J＝8，2Hz)，6.96(1H，d，J＝2Hz)
Production example 48
In the same manner as in production example 47-2, from 4-chloro-5-chloromethyl-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole (340mg), 5- (N-methylamino) methyl-4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole was obtained as a pale brown oil (85 mg).
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.30-1.45(4H，m)，1.72-1.82(2H，m)，2.25(3H，s)，2.36(3H，s)，3.56(2H，s)，3.91(2H，t，J＝7Hz)，5.19(2H，s)，6.36(1H，d，J＝8Hz)，6.69(1H，dd，J＝8，2Hz)，6.95(1H，d，J＝2Hz)
Production example 49-1
4, 5-dibromo-2-ethylimidazole (451.3g) was dissolved in N, N-dimethylformamide (2.25L), potassium carbonate (368g) was added, and then (chloromethyl) methyl ether (200g) was slowly added dropwise under ice cooling. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice-cold brine and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane was added to the residue, which was then heated and cooled, and the precipitated crystal was collected by filtration and dried under reduced pressure by heating to give brown crystals of 4, 5-dibromo-2-ethyl-1- (methoxymethyl) imidazole (461.7 g).
1H-NMR(CDCl3)：1.33(3H，t，J＝7Hz)，2.77(2H，q，J＝7Hz)，3.34(3H，s)，5.23(2H，s)
Production example 49-2
4, 5-dibromo-2-ethyl-1- (methoxymethyl) imidazole (461.1g) was dissolved in tetrahydrofuran (2.3L), and a 1.57M n-butyllithium/hexane solution (1.084L) was slowly added dropwise at-60 ℃. After the reaction mixture was stirred at-60 ℃ for 30 minutes, N-dimethylformamide (599ml) was added dropwise at-60 ℃. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine in this order and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 4-bromo-2-ethyl-1- (methoxymethyl) imidazole-5-carbaldehyde (カルボキシアルデヒド) as a brown oil (366.2 g).
1H-NMR(CDCl3)：1.37(3H，t，J＝7Hz)，2.80(2H，q，J＝7Hz)，3.35(3H，s)，5.69(2H，s)，9.72(1H，s)
Production example 49-3
4-bromo-2-ethyl-1- (methoxymethyl) imidazole-5-carbaldehyde (365g) was dissolved in 35% concentrated hydrochloric acid (1.8L) and heated at 90 ℃ for 20 hours. The solvent was distilled off under reduced pressure, and sodium hydrogencarbonate was added to the residue under ice-cooling until the residue became weakly alkaline. Chloroform was added thereto for extraction, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, which was then heated and cooled, and the precipitated crystal was collected by filtration and dried under reduced pressure by heating to give brown crystals (211.5g) of 4-chloro-2-ethylimidazole-5-carbaldehyde.
1H-NMR(CDCl3)：1.37(3H，t，J＝7Hz)，2.85(2H，q，J＝7Hz)，9.63(1H，s)，11.30(1H，brs)
Example 1
To a suspension of (E) -3- (4-chloro-1- (2-chloro-4- (2-furyl) benzyl) -2-methylimidazol-5-yl) -2-acrylic acid (155mg) in N, N-dimethylformamide (0.8ml) was added 1, 1' -carbonyldiimidazole (101mg) at room temperature, which was stirred for 1 hour. (4-toluene) sulfonamide (106mg) and 1, 8-diazabicyclo [5.4.0] -7-undecene (96mg) were further added to the solution, and the mixture was stirred at 50 ℃ for 5 hours. After the reaction mixture was ice-cooled, 1N hydrochloric acid (1.7ml) was added dropwise for neutralization, water (4ml) was further added thereto, and the precipitated precipitate was collected by filtration. The crude product was recrystallized from acetone-water to give (E) -3- (4-chloro-1- (2-chloro-4- (2-furyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide as a pale yellow powder (152 mg).
1H-NMR(CDCl3): 2.34(3H, s), 2.40(3H, s), 5.17(2H, s), 6.38(1H, d, J ═ 8Hz), 6.49(1H, dd, J ═ 3 and 2Hz), 6.53(1H, d, J ═ 16Hz), 6.68(1H, d, J ═ 3Hz), 7.31(2H, d, J ═ 8Hz), 7.35(1H, d, J ═ 16Hz), 7.43(1H, dd, J ═ 8 and 2Hz), 7.49(1H, d, J ═ 2Hz), 7.74(1H, d, J ═ 2Hz), 7.92(2H, d, J ═ 8Hz).
Mass(ESI)：m/e 528(M-H)-.
m.p.242-243℃.
Example 2
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (2-furyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (148mg) and (E) - (2-phenylethene) sulfonamide (108mg), a pale yellow powder of (2E) -3- (4-chloro-1- (2-chloro-4- (2-furyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-propenamide (159mg) was obtained.
1H-NMR(DMSO-d6): 2.31(3H, s), 5.39(2H, s), 6.55(1H, d, J ═ 8Hz), 6.61(1H, dd, J ═ 3 and 2Hz), 6.69(1H, d, J ═ 16Hz), 7.06(1H, d, J ═ 3Hz), 7.26(1H, d, J ═ 16Hz), 7.35-7.50(4H, m), 7.56(1H, d, J ═ 16Hz), 7.59(1H, dd, J ═ 8 and 2Hz), 7.67-7.77(2H, m), 7.78(1H, d, J ═ 2Hz), 7.86(1H, d, J ═ 2Hz), 12.07(1H, br s).
Mass(ESI)：m/e 540(M-H)-.
m.p.227-228℃.
Example 3
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (2-thienyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (100mg) and (4-methylbenzene) sulfonamide (65mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (2-thienyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-toluene) sulfonyl) -2-propenamide (80mg) were obtained.
1H-NMR(CDCl3)：2.34(3H，s)，2.40(3H，s)，5.16(2H，s)，6.37(1H，d，J＝8Hz)，6.54(1H，d，J＝16Hz)，7.06-7.11(1H，m)，7.26-7.40(6H，m)，7.65(1H，d，J＝2Hz)，7.92(2H，d，J＝8Hz).
Mass(ESI)：m/z 544(M-1).
m.p.235-237℃.
Example 4
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (2-thienyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (100mg) and (E) - (2-phenylethene) sulphonamide (70mg), colorless crystals of (2E) -3- (4-chloro-1- (2-chloro-4- (2-thienyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulphonyl) -2-propenamide (105mg) were obtained.
1H-NMR(DMSO-d6)：2.32(3H，s)，5.39(2H，s)，6.52(1H，d，J＝8Hz)，6.69(1H，d，J＝16Hz)，7.11-7.17(1H，m)，7.26(1H，d，J＝16Hz)，7.36-7.49(4H，m)，7.50-7.63(4H，m)，7.72(2H，dd，J＝2，8Hz)，7.84(1H，d，J＝2Hz).
Mass(ESI)：m/z 556(M-1).
m.p.246-248℃.
Example 5
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (130mg) and (4-toluene) sulfonamide (81mg), pale yellow crystals of (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-propenamide (123mg) were obtained.
1H-NMR(CDCl3)：2.32(3H，s)，2.41(3H，s)，5.17(2H，s)，6.34(1H，d，J＝8Hz)，6.56(1H，d，J＝16Hz)，7.27-7.40(7H，m)，7.48-7.55(2H，m)，7.60(1H，d，J＝2Hz)，7.93(2H，d，J＝8Hz).
Mass(ESI)：m/z 562(M-1).
m.p.239-241℃.
Example 6
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (130mg) and (E) - (2-phenylethene) sulphonamide (87mg), pale yellowish brown crystals of (2E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulphonyl) -2-propenamide (101mg) were obtained.
1H-NMR(CDCl3)：2.34(3H，s)，5.20(2H，s)，6.39(1H，d，J＝8Hz)，6.61(1H，d，J＝16Hz)，7.05(1H，d，J＝16Hz)，7.30(1H，dd，J＝2，8Hz)，7.33-7.44(7H，m)，7.46-7.55(4H，m)，7.60(1H，d，J＝2Hz)，7.71(1H，d，J＝16Hz).
Mass(ESI)：m/z 574(M-1).
m.p.220-222℃.
Example 7
In the same manner as in example 1, from (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid (150mg) and (4-toluene) sulfonamide (99mg), colorless crystals of (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- ((4-methylbenzyl) sulfonyl) -2-propenamide (162mg) were obtained.
1H-NMR(CDCl3)：2.31(3H，s)，2.43(3H，s)，5.10(2H，s)，6.23(1H，d，J＝8Hz)，6.58(1H，d，J＝15Hz)，7.25-7.33(4H，m)，7.58(1H，d，J＝2Hz)，7.92(2H，d，J＝8Hz).
Mass(ESI)：m/z 542(M-H)-.
m.p.233-235℃.
Example 8
In the same manner as in example 1, from (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid (168mg) and (E) - (2-phenylethene) sulphonamide (118mg), colorless crystals of (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulphonyl) -2-propenamide (172mg) were obtained.
1H-NMR(CDCl3-CD3OD)：2.32(3H，s)，5.15(2H，s)，6.28(1H，d，J＝8Hz)，6.70(1H，d，J＝15Hz)，7.08(1H，d，J＝15Hz)，7.31-7.42(5H，m)，7.49-7.53(2H，m)，7.62(1H，d，J＝2Hz)，7.69(1H，d，J＝15Hz).
Mass(ESI)：m/z 554(M-H)-.
m.p.250-251℃.
Example 9
In the same manner as in example 1, from (E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -2-propenoic acid (150mg), colorless crystals of (E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -N- (1-pentanesulfonyl) -2-propenamide (134mg) were obtained.
1H-NMR(CDCl3)：0.87(3H，t，J＝8Hz)，1.24-1.45(4H，m)，1.75-1.89(2H，m)，2.40(3H，s)，3.38-3.47(2H，m)，5.26(2H，s)，6.50(1H，d，J＝8Hz)，6.57(1H，d，J＝15Hz)，7.35-7.58(7H，m)，7.68(1H，d，J＝2Hz)，8.18(1H，br s).
Mass(ESI)：m/z 520(M+1).
m.p.203-204℃.
Example 10
In the same manner as in example 1, from (E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -2-propenoic acid (150mg), colorless crystals of (E) -N-benzenesulfonyl-3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -2-propenamide (141mg) were obtained.
1H-NMR(CDCl3)：2.36(3H，s)，5.20(2H，s)，6.43(1H，d，J＝8Hz)，6.57(1H，d，J＝15Hz)，7.31-7.55(9H，m)，7.59(1H，d，J＝8Hz)，7.64(1H，d，J＝2Hz)，8.05(2H，d，J＝8Hz)，8.54(1H，br s).
Mass(ESI)：m/z 526(M+1).
m.p.245-247℃.
Example 11
In the same manner as in example 1, from (E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -2-propenoic acid (150mg), colorless crystals of (E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -N- ((4-methylbenzene) sulfonyl) -2-propenoic acid amine (137mg) were obtained.
1H-NMR(CDCl3)：2.35(3H，s)，2.40(3H，s)，5.19(2H，s)，6.43(1H，d，J＝8Hz)，6.57(1H，d，J＝15Hz)，7.24-7.55(8H，m)，7.65(1H，d，J＝1Hz)，7.92(2H，d，J＝8Hz)，8.41(1H，br s).
Mass(ESI)：m/z 540(M+1).
m.p.229-232℃.
Example 12
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl) -2-propenoic acid (150mg) and (E) - (2-phenylethene) sulfonamide (106mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-propenamide (132mg) were obtained.
1H-NMR(CDCl3)：2.37(3H，s)，5.22(2H，s)，6.47(1H，d，J＝8Hz)，6.57(1H，d，J＝15Hz)，7.03(1H，d，J＝15Hz)，7.37-7.54(12H，m)，7.65(1H，s)，7.71(1H，d，J＝15Hz).
Mass(ESI)：m/z 554(M+H)+.
m.p.240-241℃.
Example 13
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl) -2-propenoic acid (150mg) and 5-chlorothiophene-2-sulphonamide (115mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl) -N- ((5-chloro-2-thienyl) sulfonyl) -2-propenamide (126mg) were obtained.
1H-NMR(CDCl3)：2.37(3H，s)，5.21(2H，s)，6.46(1H，d，J＝8Hz)，6.60(1H，d，J＝15Hz)，6.90(1H，d，J＝4Hz)，7.37-7.53(7H，m)，7.64-7.66(2H，m).
Mass(ESI)：m/z 566(M+H)+.
m.p.229-233℃.
Example 14
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl) -2-propenoic acid (150mg) and 5-bromothiophene-2-sulphonamide (141mg), colorless crystals of (E) -N- ((5-bromo-2-thienyl) sulfonyl) -3- (4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl) -2-propenamide (155mg) were obtained.
1H-NMR(CDCl3)：2.37(3H，s)，5.21(2H，s)，6.46(1H，d，J＝8Hz)，6.59(1H，d，J＝15Hz)，7.04(1H，d，J＝4Hz)，7.36-7.55(7H，m)，7.61(1H，d，J＝4Hz)，7.66(1H，d，J＝2Hz).
Mass(ESI)：m/z 612(M+H)+.
m.p.234-235℃.
Example 15
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (145mg) and (4-methylbenzene) sulfonamide (96mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-propenamide (155mg) were obtained.
1H-NMR(CDCl3-CD3OD)：1.02(3H，t，J＝7Hz)，1.73-1.85(2H，m)，2.30(3H，s)，2.41(3H，s)，3.88(2H，t，J＝7Hz)，5.10(2H，s)，6.27(1H，d，J＝8Hz)，6.64(1H，d，J＝15Hz)，6.68(1H，dd，J＝8，2Hz)，6.97(1H，d，J＝2Hz)，7.27-7.33(3H，m)，7.92(2H，d，J＝8Hz).
Mass(ESI)：m/z 520(M-H)-.
m.p.226-228℃.
Example 16
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (143mg) and (E) - (2-phenylethene) sulfonamide (106mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-propenamide (164mg) were obtained.
1H-NMR(CDCl3-CD3OD)：1.02(3H，t，J＝7Hz)，1.73-1.85(2H，m)，2.32(3H，s)，3.88(2H，t，J＝7Hz)，5.15(2H，s)，6.33(1H，d，J＝8Hz)，6.69(1H，d，J＝15Hz)，6.70(1H，dd，J＝8，2Hz)，6.98(1H，d，J＝2Hz)，7.09(1H，d，J＝15Hz)，7.35-7.42(4H，m)，7.50-7.54(2H，m)，7.68(1H，d，J＝15Hz).
Mass(ESI)：m/z 532(M-H)-.
m.p.199-201℃.
Example 17
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (100mg) and (4-toluene) sulfonamide (65mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-propenamide (60mg) were obtained.
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.30-1.50(4H，m)，1.70-1.84(2H，m)，2.32(3H，s)，2.42(3H，s)，3.90(2H，t，J＝7Hz)，5.09(2H，s)，6.27(1H，d，J＝8Hz)，6.53(1H，d，J＝16Hz)，6.67(1H，dd，J＝2，8Hz)，6.96(1H，d，J＝2Hz)，7.28-7.39(3H，m)，7.93(2H，d，J＝8Hz).
Mass(ESI)：m/z 548(M-1).
m.p.195-197℃.
Example 18
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (100mg) and (E) - (2-phenylethene) sulfonamide (69mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-propenamide (84mg) were obtained.
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.30-1.49(4H，m)，1.69-1.72(2H，m)，2.34(3H，s)，3.90(2H，t，J＝7Hz)，5.13(2H，s)，6.32(1H，d，J＝8Hz)，6.56(1H，d，J＝16Hz)，6.68(1H，dd，J＝2，8Hz)，6.96(1H，d，J＝2Hz)，7.06(1H，d，J＝16Hz)，7.35-7.56(6H，m)，7.72(1H，d，J＝16Hz).
Mass(ESI)：m/z 560(M-1).
m.p.196-199℃.
Example 19
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (164mg) and 1-pentanesulfonamide (90mg), a white powder of (E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-propenamide (82mg) was obtained.
1H-NMR(CDCl3): 0.90(3H, t, J ═ 71Hz), 1.25-1.92(14H, m), 2.34(1H, sept, J ═ 7Hz), 2.37(3H, s), 3.38-3.50(2H, m), 3.80(2H, d, J ═ 7Hz), 5.16(2H, s), 6.34(1H, d, J ═ 8Hz), 6.51(1H, d, J ═ 15Hz), 6.72(1H, dd, J ═ 8 and 2Hz), 7.00(1H, d, J ═ 2Hz), 7.44(1H, d, J ═ 16Hz).
Mass(ESI)：m/e 540(M-H)-.
m.p.177-178℃.
Example 20
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (163mg) and (4-methylbenzene) sulfonamide (106mg), a white powder of (E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-propenamide (135mg) was obtained.
1H-NMR(CDCl3): 1.25-1.92(8H, m), 2.32(3H, s), 2.33(1H, sept, J ═ 7Hz), 2.42(3H, s), 3.78(2H, d, J ═ 7Hz), 5.09(2H, s), 6.27(1H, d, J ═ 8Hz), 6.52(1H, d, J ═ 16Hz), 6.68(1H, dd, J ═ 8 and 2Hz), 6.97(1H, d, J ═ 2Hz), 7.32(2H, d, J ═ 8Hz), 7.34(1H, d, J ═ 16Hz), 7.94(2H, d, J ═ 8Hz).
Mass(ESI)：m/e 560(M-H)-.
m.p.217-218℃.
Example 21
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (164mg) and (E) - (2-phenylethene) sulphonamide (99mg), a white powder of (2E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulphonyl) -2-propenamide (128mg) was obtained.
1H-NMR(CDCl3): 1.23-1.92(8H, m), 2.32(1H, sept, J ═ 7Hz), 2.33(3H, s), 3.77(2H, d, J ═ 7Hz), 5.12(2H, s), 6.32(1H, d, J ═ 8Hz), 6.60(1H, d, J ═ 16Hz), 6.68(1H, dd, J ═ 8 and 2Hz), 6.96(1H, d, J ═ 2Hz), 7.08(1H, d, J ═ 16Hz), 7.33-7.56(5H, m), 7.40(1H, d, J ═ 16Hz), 7.70(1H, d, J ═ 16Hz).
Mass(ESI)：m/e 572(M-H)-.
m.p.200-201℃.
Example 22
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (85mg) and (4-toluene) sulfonamide (52mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-propenamide (61mg) were obtained.
1H-NMR(CDCl3)：0.95-1.89(11H，m)，2.32(3H，s)，2.42(3H，s)，3.70(2H，d，J＝7Hz)，5.10(2H，s)，6.22(1H，d，J＝8Hz)，6.50(1H，d，J＝16Hz)，6.67(1H，dd，J＝2，8Hz)，6.97(1H，d，J＝2Hz)，7.30-7.38(3H，m)，7.94(2H，d，J＝8Hz).
Mass(ESI)：m/z 574(M-1).
m.p.214-216℃.
Example 23
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (85mg) and (E) - (2-phenylethene) sulphonamide (55mg), colorless crystals of (2E) -3- (4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulphonyl) -2-propenamide (63mg) were obtained.
1H-NMR(CDCl3)：0.95-1.37(6H，m)，1.65-1.88(5H，m)，2.35(3H，s)，3.70(2H，d，J＝7Hz)，5.13(2H，s)，6.31(1H，d，J＝8Hz)，6.54(1H，d，J＝16Hz)，6.68(1H，dd，J＝2，8Hz)，6.98(1H，d，J＝2Hz)，7.06(1H，d，J＝16Hz)，7.37-7.45(4H，m)，7.49-7.54(2H，m)，7.72(1H，d，J＝16Hz).
Mass(ESI)：m/z 586(M-1).
m.p.210-212℃.
Example 24
In the same manner as in example 1, from (E) -3- (1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid (90mg) and (4-toluene) sulfonamide (55mg), colorless crystals of (E) -3- (1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-propenamide (83mg) were obtained.
1H-NMR(CDCl3)：2.32(3H，s)，2.42(3H，s)，5.03(2H，s)，5.10(2H，s)，6.29(1H，d，J＝8Hz)，6.51(1H，d，J＝16Hz)，6.75(1H，dd，J＝2，8Hz)，7.06(1H，d，J＝2Hz)，7.29-7.44(8H，m)，7.95(2H，d，J＝8Hz).
Mass(ESI)：m/z 568(M-1).
m.p.226-228℃.
Example 25
In the same manner as in example 1, from (E) -3- (1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid (90mg) and (E) - (2-phenylethene) sulphonamide (59mg), colorless crystals of (E) -3- (1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulphonyl) -2-propenamide (73mg) were obtained.
1H-NMR(CDCl3)：2.34(3H，s)，5.02(2H，s)，5.14(2H，s)，6.34(1H，d，J＝8Hz)，6.56(1H，d，J＝16Hz)，6.77(1H，dd，J＝2，8Hz)，7.02-7.10(2H，m)，7.31-7.55(11H，m)，7.73(1H，d，J＝16Hz).
Mass(ESI)：m/z 580(M-1).
m.p.225-227℃.
Example 26
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (90mg) and (4-toluene) sulfonamide (65mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazol-5-yl) -N- ((4-toluene) sulfonyl) -2-propenamide (83mg) were obtained.
1H-NMR(CDCl3)：2.32(3H，s)，2.42(3H，s)，2.47(3H，s)，5.11(2H，s)，6.26(1H，d，J＝8Hz)，6.52(1H，d，J＝16Hz)，7.00(1H，dd，J＝2，8Hz)，7.26-7.36(4H，m)，7.94(2H，d，J＝8Hz).
Mass(ESI)：m/z 508(M-1).
m.p.228-230℃.
Example 27
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (90mg) and (E) - (2-phenylethene) sulfonamide (69mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-propenamide (97mg) were obtained.
1H-NMR(CDCl3)：2.34(3H，s)，2.46(3H，s)，5.15(2H，s)，6.31(1H，d，J＝8Hz)，6.57(1H，d，J＝16Hz)，7.00(1H，d，J＝2Hz)，7.05(1H，d，J＝16Hz)，7.29(1H，d，J＝2Hz)，7.35-7.45(4H，m)，7.49-7.55(2H，m)，7.72(1H，d，J＝16Hz).
Mass(ESI)：m/z 520(M-1).
m.p.237-238℃.
Example 28
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (30mg) and (4-toluene) sulfonamide (20mg), pale yellow crystals of (E) -3- (4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-propenamide (14mg) were obtained.
1H-NMR(CDCl3)：2.33(3H，s)，2.42(3H，s)，5.20(2H，s)，6.48(1H，d，J＝8Hz)，6.60(1H，d，J＝16Hz)，7.23-7.35(3H，m)，7.44(1H，d，J＝8Hz)，7.72(1H，s)，7.92(2H，d，J＝8Hz).
Mass(ESI)：m/z 530(M-1).
m.p.223-225℃.
Example 29
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (100mg) and (E) - (2-phenylethene) sulphonamide (72mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulphonyl) -2-propenamide (90mg) were obtained.
1H-NMR(DMSO-d6)：2.30(3H，s)，5.48(2H，s)，6.63-6.75(2H，m)，7.24(1H，d，J＝16Hz)，7.37-7.51(4H，m)，7.57(1H，d，J＝16Hz)，7.66(1H，d，J＝8Hz)，7.73(2H，d，J＝8Hz)，7.99(1H，s).
Mass(ESI)：m/z 542(M-1).
m.p.261-263℃.
Example 30
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (191mg) and (4-methylbenzene) sulfonamide (118mg), white powder of (E) -3- (4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-propenamide (207mg) was obtained.
1H-NMR(CDCl3)：2.32(3H，s)，2.42(3H，s)，5.02(2H，s)，5.16(2H，s)，6.38(1H，d，J＝8Hz)，6.54(1H，d，J＝15Hz)，6.89-7.04(3H，m)，7.18-7.38(6H，m)，7.54(1H，d，J＝2Hz)，7.93(2H，d，J＝8Hz).
Mass(ESI)：m/e 568(M-H)-.
m.p.236-237℃.
Example 31
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (189mg) and (E) - (2-phenylethene) sulfonamide (128mg), white powder of (E) -3- (4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-propenamide (219mg) was obtained.
1H-NMR(CDCl3)：2.30(3H，s)，5.07(2H，s)，5.39(2H，s)，6.50(1H，d，J＝8Hz)，6.70(1H，d，J＝16Hz)，6.88-7.02(3H，m)，7.22(1H，d，J＝16Hz)，7.26-7.48(7H，m)，7.56(1H，d，J＝16Hz)，7.62(1H，d，J＝2Hz)，7.68-7.80(2H，m)，12.08(1H，brs).
Mass(ESI)：m/e 580(M-H)-.
m.p.202-203℃.
Example 32
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazol-5-yl) -2-propenoic acid (105mg) and (4-toluene) sulfonamide (76mg), pale yellow crystals of (E) -3- (4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzyl) sulfonyl) -2-propenamide (63mg) were obtained.
1H-NMR(CDCl3-CD3OD)：2.32(3H，s)，2.41(3H，s)，5.24(2H，s)，6.55(1H，d，J＝8Hz)，6.68(1H，d，J＝15Hz)，7.22(1H，d，J＝15Hz)，7.30(2H，d，J＝8Hz)，7.90(2H，d，J＝8Hz)，8.03(1H，dd，J＝8，2Hz)，8.33(1H，d，J＝2Hz).
Mass(ESI)：m/z 507(M-H)-.
m.p.241-243℃.
Example 33
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazol-5-yl) -2-propenoic acid (105mg) and (E) - (2-phenylethene) sulphonamide (81mg), pale yellow crystals of (E) -3- (4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulphonyl) -2-propenamide (78mg) were obtained.
1H-NMR(CDCl3-CD3OD)：2.34(3H，s)，5.29(2H，s)，6.59(1H，d，J＝8Hz)，6.73(1H，d，J＝15Hz)，7.06(1H，d，J＝15Hz)，7.30(1H，t，J＝8Hz)，7.37-7.45(3H，m)，7.50-7.52(2H，m)，7.68(1H，d，J＝15Hz)，8.05(1H，dd，J＝8，2Hz)，8.34(1H，d，J＝2Hz).
Mass(ESI)：m/z 519(M-H)-.
m.p.199-201℃.
Example 34
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (105mg) and (4-toluene) sulfonamide (93mg), pale yellow crystals of (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-propenamide (81mg) were obtained.
1H-NMR(CDCl3)：2.33(3H，s)，2.39(3H，s)，5.15(2H，s)，6.35(1H，d，J＝8Hz)，6.54(1H，d，J＝16Hz)，6.97(1H，d，J＝16Hz)，7.08(1H，d，J＝16Hz)，7.21-7.41(7H，m)，7.50(2H，d，J＝8Hz)，7.55(1H，d，J＝2Hz)，7.92(1H，d，J＝8Hz).
Mass(ESI)：m/z 564(M-1).
m.p.237-239℃.
Example 35
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (150mg) and (E) - (2-phenylethene) sulfonamide (100mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -N- ((((E) -2-phenylvinyl) sulfonyl) -2-propenamide (86mg) were obtained.
1H-NMR(CDCl3)：2.36(3H，s)，5.20(2H，s)，6.40(1H，d，J＝8Hz)，6.58(1H，d，J＝16Hz)，6.96(1H，d，J＝16Hz)，7.04(1H，d，J＝16Hz)，7.08(1H，d，J＝16Hz)，7.26-7.54(12H，m)，7.58(1H，d，J＝2Hz)，7.70(1H，d，J＝16Hz).
Mass(ESI)：m/z 576(M-1).
m.p.230-232℃.
Example 36
In the same manner as in example 1, from (E) -3- (1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid (175mg) and (4-methylbenzene) sulfonamide (111mg), colorless crystals of (E) -3- (1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-propenamide (182mg) were obtained.
1H-NMR(CDCl3)：2.30(3H，s)，2.38(3H，s)，5.33(2H，s)，6.42(1H，d，J＝8Hz)，6.52(1H，d，J＝15Hz)，7.23-7.26(2H，m)，7.37(1H，d，J＝15Hz)，7.57(1H，t，J＝8Hz)，7.65(1H，d，J＝8Hz)，7.70(1H，d，J＝8Hz)，7.80(1H，d，J＝8Hz)，7.88(2H，d，J＝8Hz)，8.31(1H，d，J＝8Hz)，8.69(1H，br s).
Mass(ESI)：m/z 558(M-H)-.
m.p.260-262℃.
Example 37
In the same manner as in example 1, from (E) -3- (1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid (175mg) and (E) - (2-phenylethene) sulphonamide (119mg), colorless crystals of (E) -3- (1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulphonyl) -2-propenamide (188mg) were obtained.
1H-NMR(DMSO-d6)：2.33(3H，s)，5.59(2H，s)，6.56(1H，d，J＝8Hz)，6.70(1H，d，J＝15Hz)，7.27(1H，d，J＝15Hz)，7.37-7.48(4H，m)，7.53(1H，d，J＝15Hz)，7.64(1H，t，J＝8Hz)，7.69-7.75(3H，m)，7.94(2H，t，J＝8Hz)，8.26(1H，d，J＝8Hz).
Mass(ESI)：m/z 570(M-H)-.
m.p.264-265℃.
Example 38
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (150mg) and 1-pentanesulfonamide (86mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- (1-pentylsulfonyl) -2-propenamide (135mg) were obtained.
1H-NMR(CDCl3)：0.89(3H，t，J＝6Hz)，0.93(3H，t，J＝6Hz)，1.25-1.48(8H)，1.70-1.88(4H)，2.36(3H，s)，3.45(2H，t，J＝6Hz)，3.92(2H，t，J＝6Hz)，5.15(2H，s)，6.35(1H，d，J＝8Hz)，6.52(1H，d，J＝16Hz)，6.71(dd，J＝8，2Hz)，6.99(1H，d，J＝2Hz)，7.44(1H，d，J＝16Hz)，8.03(1H，br.s).
MS(ESI)：m/z 529(M-1).
Example 39
(E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (150mg) was dissolved in N, N-dimethylformamide (1.5ml), carbonyldiimidazole was added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added (E) -1-penten-1-ylsulfonamide sodium salt (97mg), and the mixture was stirred at room temperature for 3 hours and then allowed to stand for one day. The reaction mixture was diluted with water (1.5ml), and the pH was adjusted to 4 with 1N hydrochloric acid under ice-cooling, and the precipitated powder was collected by filtration and washed with water. The obtained white powder was suspended in ethanol (0.75mg), heated, and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with ethanol, dissolved in N, N-dimethylformamide (0.75ml) at 80 ℃ and water (0.25ml) was added thereto at that temperature, followed by stirring at room temperature for 1 hour. The precipitated crystal was collected by filtration, washed with N, N-dimethylformamide-water (1: 1) and then with water to give colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide (160 mg).
1H-NMR(CDCl3)：0.92(3H，t，J＝6Hz)，0.94(3H，t，J＝6Hz)，1.30-1.60(6H)，1.78(2H，m)，2.25(2H，q，J＝6Hz)，2.35(3H，s)，3.92(2H，t，J＝6Hz)，5.15(2H，s)，6.33(1H，d，J＝8Hz)，6.49(1H，d，J＝16Hz)，6.54(1H，d，J＝16Hz)，6.70(dd，J＝8，2Hz)，6.99(1H，d，J＝2Hz)，7.04(1H，dt，J＝16，6Hz)，7.41(1H，d，J＝16Hz)，8.00(1H，br.s).
MS(ESI)：m/z 528(M-1).
Example 40
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (150mg) and 1-butanesulfonamide (78mg), colorless crystals of (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenamide (132mg) were obtained.
m.p.182-183℃
1H-NMR(CDCl3)：0.93(3H，t，J＝6Hz)，0.94(3H，t，J＝6Hz)，1.30-1.53(6H)，1.70-1.87(4H)，2.36(3H，s)，3.45(2H，t，J＝6Hz)，3.92(2H，t，J＝6Hz)，5.15(2H，s)，6.35(1H，d，J＝8Hz)，6.54(1H，d，J＝16Hz)，6.71(1H，dd，J＝8，2Hz)，6.99(1H，d，J＝2Hz)，7.44(1H，d，J＝16Hz)，8.17(1H，br.s).
MS(ESI)：m/z 515(M-1).
EXAMPLE 41
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (140mg) and 1-pentanesulfonamide (77mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-propenamide (116mg) were obtained.
1H-NMR(CDCl3)：0.87(3H，t，J＝7Hz)，1.24-1.45(4H，m)，1.75-1.88(2H，m)，2.38(3H，s)，3.39-3.46(2H，m)，5.22(2H，s)，6.42(1H，d，J＝8Hz)，6.54(1H，d，J＝16Hz)，7.00(1H，d，J＝16Hz)，7.12(1H，d，J＝16Hz)，7.27-7.54(7H，m)，7.60(1H，d，J＝1Hz).
MS(ESI)：m/z 544(M-1).
m.p.215-216℃.
Example 42
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) - (E) -2-acrylic acid (150mg) and (E) -1-penten-1-ylsulfonamide (81mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -N- (E) -1-penten-1-ylsulfonyl) -2-acrylamide (117mg) were obtained.
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.43-1.57(2H，m)，2.14-2.30(2H，m)，2.37(3H，s)，5.21(2H，s)，6.40(1H，d，J＝8Hz)，6.48(1H，d，J＝16Hz)，6.57(1H，d，J＝16Hz)，6.95-7.15(3H，m)，7.26-7.55(7H，m)，7.60(1H，d，J＝1Hz).
MS(ESI)：m/z 542(M-1).
m.p.226-228℃.
Example 43
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (150mg) and 1-butanesulfonamide (75mg), colorless crystals of (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -2-propenamide (148mg) were obtained.
m.p.213-214℃
1H-NMR(CDCl3)：0.92(3H，t，J＝6Hz)，1.44(2H，m)，1.80(2H，m)，2.48(3H，s)，3.44(2H，t，J＝6Hz)，5.22(2H，s)，6.42(1H，d，J＝8Hz)，6.59(1H，d，J＝16Hz)，7.00(1H，d，J＝16Hz)，7.11(1H，d，J＝16Hz)，7.25-7.55(7H)，7.60(1H，d，J＝2Hz)，8.40(1H，br.s).
MS(ESI)：m/z 531(M-1).
Example 44
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (135mg) and 1-pentanesulfonamide (74mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N-1-pentanesulfonyl) -2-propenamide (100mg) were obtained.
1H-NMR(CDCl3)：0.89(3H，t，J＝7Hz)，1.25-1.47(4H，m)，1.75-1.90(2H，m)，2.38(3H，s)，3.40-3.47(2H，m)，5.23(2H，s)，6.42(1H，d，J＝8Hz)，6.55(1H，d，J＝16Hz)，7.31-7.40(3H，m)，7.42(1H，d，J＝16Hz)，7.48-7.55(2H，m)，7.63(1H，d，J＝1Hz)，7.87(1H，s).
MS(ESI)：m/z 542(M-1).
m.p.207-209℃.
Example 45
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (125mg) and (E) -1-penten-1-ylsulfonamide (68mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-propenamide (84mg) were obtained.
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.45-1.57(2H，m)，2.20-2.30(2H，m)，2.36(3H，s)，5.22(2H，s)，6.40(1H，d，J＝8Hz)，6.48(1H，d，J＝16Hz)，6.57(1H，d，J＝16Hz)，6.98-7.10(1H，m)，7.30-7.43(4H，m)，7.48-7.55(2H，m)，7.63(1H，d，J＝1Hz)，7.87(1H，s).
MS(ESI)：m/z 540(M-1).
m.p.207-210℃.
Example 46
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (2-phenylethynyl) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (87mg) and 1-butanesulfonamide (44mg), colorless crystals of (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- (2-phenylethynyl) benzyl) -2-methylimidazol-5-yl) -2-propenamide (79mg) were obtained.
m.p.217-218℃
1H-NMR(CDCl3)：0.94(3H，t，J＝6Hz)，1.45(2H，m)，1.80(2H，m)，2.47(3H，s)，3.44(2H，t，J＝6Hz)，5.23(2H，s)，6.42(1H，d，J＝8Hz)，6.56(1H，d，J＝16Hz)，7.30-7.55(7H)，7.62(1H，d，J＝2Hz)，8.14(1H，br.s).
MS(ESI)：m/z 529(M-1).
Example 47
In the same manner as in example 1, from (E) -3- (4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazol-5-yl) -2-propenoic acid (120mg) and (E) - (2-phenylethene) sulfonamide (87mg), pale yellow crystals of (E) -3- (4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-propenamide (60mg) were obtained.
1H-NMR(DMSO-d6)：2.26(3H，s)，5.65(2H，s)，6.66(1H，d，J＝16Hz)，7.27(1H，d，J＝16Hz)，7.38-7.48(4H，m)，7.57(1H，d，J＝16Hz)，7.70-7.78(2H，m)，8.56(1H，d，J＝1Hz)，8.85(1H，s).
MS(ESI)：m/z 545(M+1).
m.p.249-252℃.
Example 48
In the same manner as in example 1, from (E) -3- (4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazol-5-yl) -2-propenoic acid (100mg) and (4-methylbenzene) sulfonamide (68mg), pale yellow crystals of (E) -3- (4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-propenamide (38mg) were obtained.
1H-NMR(CDCl3)：2.34(3H，s)，2.42(3H，s)，5.33(2H，s)，5.62(1H，d，J＝16Hz)，7.26-7.36(3H，m)，7.94(2H，d，J＝8Hz)，8.60(2H，s).
MS(ESI)：m/z 533(M+1).
m.p.239-241℃.
Example 49
In the same manner as in example 1, from (E) -3- (1- (4- (tert-butoxycarbonylamino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid (150mg) and 1-pentanesulfonamide (80mg), colorless crystals of (E) -3- (1- (4- (tert-butoxycarbonylamino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-propenamide (64mg) were obtained.
1H-NMR(CDCl3)：0.89(3H，t，J＝7Hz)，1.28-1.46(4H，m)，1.51(9H，s)，1.75-1.89(2H，m)，2.36(3H，s)，3.40-3.48(2H，m)，5.16(2H，s)，6.35(1H，d，J＝8Hz)，6.50(1H，d，J＝16Hz)，6.55(1H，s)，7.03(1H，dd，J＝1，8Hz)，7.43(1H，d，J＝16Hz).
MS(ESI)：m/z 557(M-1).
m.p.202-204℃.
Example 50
In the same manner as in example 1, from (E) -3- (1- (4- (tert-butoxycarbonylamino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid (130mg) and (E) -1-penten-1-ylsulfonamide (68mg), colorless crystals of (E) -3- (1- (4- (tert-butoxycarbonylamino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-propenamide (59mg) were obtained.
1H-NMR(DMSO-d6)：0.84(3H，t，J＝7Hz)，1.35-1.49(2H，m)，1.46(9H，s)，2.15-2.25(2H，m)，2.31(3H，s)，5.30(2H，s)，6.47(1H，d，J＝8Hz)，6.65(1H，d，J＝16Hz)，6.67(1H，d，J＝16Hz)，6.75-6.86(1H，m)，7.24(1H，d，J＝16Hz)，7.29(1H，dd，J＝1，8Hz)，7.71(1H，s).
MS(ESI)：m/z 555(M-1).
m.p.209-210℃.
Example 51
In the same manner as in example 1, from (E) -3- (1- (4- (tert-butoxycarbonylamino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -2-propenoic acid (200mg) and (E) - (2-phenylethene) sulfonamide (129mg), pale yellow powder of (E) -3- (1- (4- (tert-butoxycarbonylamino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-propenamide (81mg) was obtained.
1H-NMR(DMSO-d6)：1.46(9H，s)，2.29(3H，s)，5.29(2H，s)，6.46(1H，d，J＝8Hz)，6.68(1H，d，J＝16Hz)，7.20-7.30(2H，m)，7.39-7.50(4H，m)，7.58(1H，d，J＝16Hz)，7.67-7.80(2H，m).
MS(ESI)：m/z 589(M-1).
Example 52
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (160mg) and (E) -2-phenylethenesulfonamide (107mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (N-pentyloxy) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-propenamide (139mg) were obtained.
m.p.174-175℃
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.26(3H，t，J＝7Hz)，1.31-1.48(4H，m)，1.69-1.82(2H，m)，2.61(2H，q，J＝7Hz)，3.90(2H，q，J＝7Hz)，5.14(2H，s)，6.30(1H，d，J＝8Hz)，6.56(1H，d，J＝15Hz)，6.67(1H，dd，J＝8，2Hz)，6.97(1H，d，J＝2Hz)，7.06(1H，d，J＝15Hz)，7.36-7.55(6H，m)，7.72(1H，d，J＝15Hz).
Example 53
In the same manner as in example 1, from (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-ethylimidazol-5-yl) -2-propenoic acid (200mg) and (E) -2-phenylethenesulfonamide (136mg), colorless crystals of (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-ethylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-propenamide (175mg) were obtained.
m.p.209-210℃
1H-NMR(CDCl3)：1.27(3H，t，J＝7Hz)，2.59(2H，q，J＝7Hz)，5.14(2H，s)，6.28(1H，d，J＝8Hz)，6.62(1H，d，J＝15Hz)，7.05(1H，d，J＝15Hz)，7.24-7.55(6H，m)，7.60(1H，d，J＝1Hz)，7.72(1H，d，J＝15Hz)，8.34(1H，s).
MASS(ESI)：m/z 568(M-1).
Example 54
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (170mg) and (E) -2-phenylethenesulfonamide (109mg), pale yellow crystals of (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-propenamide (120mg) were obtained.
m.p.233-234℃
1H-NMR(CDCl3)：1.27(3H，t，J＝7Hz)，2.61(2H，q，J＝7Hz)，5.21(2H，s)，6.38(1H，d，J＝8Hz)，6.60(1H，d，J＝15Hz)，7.05(1H，d，J＝15Hz)，7.30(1H，dd，J＝8，1Hz)，7.43-7.55(11H，m)，7.59(1H，d，J＝1Hz)，7.71(1H，d，J＝15Hz).
MASS(ESI)：m/z 588(M-1).
Example 55
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (170mg) and 4- (toluene) sulphonamide (103mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-propenamide (161mg) were obtained.
m.p.250-252℃
1H-NMR(CDCl3)：1.26(3H，t，J＝7Hz)，2.58(2H，q，J＝7Hz)，5.17(2H，s)，6.33(1H，d，J＝8Hz)，6.56(1H，d，J＝15Hz)，7.25-7.40(7H，m)，7.48-7.55(2H，m)，7.58(1H，d，J＝1Hz)，7.92(1H，d，J＝8Hz)，8.41(1H，br s).
MASS(ESI)：m/z 576(M-1).
Example 56
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (130mg) and 1-butanesulfonamide (63mg), colorless crystals of (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -2-propenamide (107mg) were obtained.
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.29(3H，t，J＝7Hz)，1.38-1.53(2H，m)，1.75-1.86(2H，m)，2.63(2H，d，J＝7Hz)，3.40-3.49(2H，m)，5.24(2H，s)，6.41(1H，d，J＝8Hz)，6.56(1H，d，J＝16Hz)，7.30-7.40(4H，m)，7.43(1H，d，J＝16Hz)，7.47-7.55(2H，m)，7.63(1H，d，J＝1Hz).
MS(ESI)：m/z 542(M-1).
m.p.165-167℃.
Example 57
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (130mg) and 1-pentanesulfonamide (69mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-propenamide (93mg) were obtained.
1H-NMR(CDCl3)：0.88(3H，t，J＝7Hz)，1.29(3H，t，J＝7Hz)，1.24-1.46(4H，m)，1.75-1.88(2H，m)，2.63(2H，d，J＝7Hz)，3.38-3.47(2H，m)，5.24(2H，s)，6.40(1H，d，J＝8Hz)，6.56(1H，d，J＝16Hz)，7.30-7.40(4H，m)，7.43(1H，d，J＝16Hz)，7.48-7.55(2H，m)，7.62(1H，d，J＝1Hz).
MS(ESI)：m/z 556(M-1).
m.p.161-163℃.
Example 58
In the same manner as in example 39, from (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (130mg) and (E) -1-penten-1-ylsulfonamide sodium salt (78mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-propenamide (106mg) were obtained.
1H-NMR(CDCl3)：0.93(3H，t，J＝71Hz)，1.28(3H，t，J＝7Hz)，1.45-1.55(2H，m)，2.19-2.30(2H，m)，2.62(2H，d，J＝7Hz)，5.22(2H，s)，6.40(1H，d，J＝8Hz)，6.48(1H，d，J＝16Hz)，6.58(1H，d，J＝16Hz)，6.98-7.10(1H，m)，7.29-7.45(5H，m)，7.47-7.56(2H，m)，7.62(1H，d，J＝1Hz).
MS(ESI)：m/z 554(M-1).
m.p.173-175℃.
Example 59
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (170mg) and (E) -2-phenylvinylsulfonamide (109mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-propenamide (180mg) were obtained.
m.p.218-220℃
1H-NMR(CDCl3-CD3OD)：1.25(3H，t，J＝7Hz)，2.62(2H，q，J＝7Hz)，5.22(2H，s)，6.38(1H，d，J＝8Hz)，6.90(1H，d，J＝15Hz)，6.98(1H，d，J＝15Hz)，7.04-7.14(2H，m)，7.24-7.44(7H，m)，7.46-7.53(4H，m)，7.58(1H，d，J＝1Hz)，7.68(1H，d，J＝15Hz).
MASS(ESI)：m/z 425(M-1).
Example 60
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (170mg) and 4- (toluene) sulphonamide (102mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- (4-toluenesulfonyl) -2-propenamide (153mg) were obtained.
m.p.250-252℃
1H-NMR(CDCl3)：1.24(3H，t，J＝7Hz)，2.60(2H，q，J＝7Hz)，5.16(2H，s)，6.34(1H，d，J＝8Hz)，6.54(1H，d，J＝15Hz)，6.96(1H，d，J＝15Hz)，7.19(1H，d，J＝15Hz)，7.21-7.41(7H，m)，7.50(2H，d，J＝8Hz)，7.56(1H，s)，7.92(2H，d，J＝8Hz)，8.47(1H，br s).
MASS(ESI)：m/z 580(M-1).
Example 61
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (150mg) and 1-butanesulfonamide (72mg), colorless crystals of (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -2-propenamide (146mg) were obtained.
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.30(3H，t，J＝7Hz)，1.35-1.55(2H，m)，1.74-1.85(2H，m)，2.65(2H，d，J＝7Hz)，3.39-3.48(2H，m)，5.23(2H，s)，6.41(1H，d，J＝8Hz)，6.55(1H，d，J＝16Hz)，6.99(1H，d，J＝16Hz)，7.11(1H，d，J＝16Hz)，7.27-7.62(8H，m).
MS(ESI)：m/z 544(M-1).
m.p.210-213℃.
Example 62
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (150mg) and 1-butanesulfonamide (80mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-propenamide (138mg) were obtained.
1H-NMR(CDCl3)：0.87(3H，t，J＝7Hz)，1.23-1.45(4H，m)，1.30(3H，t，J＝7Hz)，1.75-1.88(2H，m)，2.65(2H，d，J＝7Hz)，3.38-3.46(2H，m)，5.23(2H，s)，6.40(1H，d，J＝8Hz)，6.55(1H，d，J＝16Hz)，6.98(1H，d，J＝16Hz)，7.11(1H，d，J＝16Hz)，7.26-7.66(8H，m).
MS(ESI)：m/z 558(M-1).
m.p.197-200℃.
Example 63
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -2-propenoic acid (150mg) and (E) -1-penten-1-ylsulfonamide (79mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-propenamide (109mg) were obtained.
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.29(3H，t，J＝7Hz)，1.43-1.56(2H，m)，2.18-2.28(2H，m)，2.63(2H，d，J＝7Hz)，5.21(2H，s)，6.40(1H，d，J＝8Hz)，6.48(1H，d，J＝16Hz)，6.57(1H，d，J＝16Hz)，6.95-7.15(3H，m)，7.25-7.61(8H，m).
MS(ESI)：m/z 556(M-1).
m.p.197-200℃.
Example 64
In the same manner as in example 1, from (E) -3- (1- (4-bromo-2-chlorobenzyl) -2, 4-dimethylimidazol-5-yl) -2-propenoic acid (140mg) and (E) -2-phenylethenesulfonamide (104mg), a colorless powder of (E) -3- (1- (4-bromo-2-chlorobenzyl) -2, 4-dimethylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-propenamide (150mg) was obtained.
1H-NMR(CDCl3-CD3OD)：2.29(3H，s)，2.40(3H，s)，5.12(2H，s)，6.04(1H，d，J＝15Hz)，6.23(1H，d，J＝8Hz)，7.08(1H，d，J＝15Hz)，7.28(1H，dd，J＝8，2Hz)，7.45-7.53(6H，m)，7.61(1H，d，J＝2Hz)，7.67(1H，d，J＝16Hz)
Mass(ESI)：m/z 534(M-H)-
m.p.251-253℃
Example 65
In the same manner as in example 1, from (E) -3- (4-bromo-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (200mg) and (E) -2-phenylethenesulfonamide (124mg), colorless crystals of (E) -3- (4-bromo-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-propenamide (218mg) were obtained.
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.32-1.47(4H，m)，1.72-1.81(2H，m)，2.35(3H，s)，3.90(2H，t，J＝7Hz)，5.14(2H，s)，6.32(1H，d，J＝8Hz)，6.63(1H，d，J＝15Hz)，6.68(1H，dd，J＝8，2Hz)，6.97(1H，d，J＝2Hz)，7.06(1H，d，J＝15Hz)，7.42-7.45(4H，m)，7.50-7.53(2H，m)，7.72(1H，d，J＝15Hz)
Mass(ESI)：m/z 606(M-H)-
m.p.208-209℃
Example 66
In the same manner as in example 1, from (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -4-ethyl-2-methylimidazol-5-yl) -2-propenoic acid (150mg) and (E) -2-phenylethenesulfonamide (105mg), a colorless powder of (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -4-ethyl-2-methylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-propenamide (102mg) was obtained.
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.26(3H，t，J＝7Hz)，1.32-1.45(4H，m)，1.70-1.80(2H，m)，2.33(3H，s)，2.72(2H，q，J＝7Hz)，3.89(2H，t，J＝7Hz)，5.11(2H，s)，5.84(1H，d，J＝15Hz)，6.30(1H，d，J＝8Hz)，6.67(1H，dd，J＝8，2Hz)，6.96(1H，d，J＝2Hz)，7.06(1H，d，J＝15Hz)，7.36-7.44(3H，m)，7.46-7.59(3H，m)，7.68(1H，d，J＝15Hz)
Mass(ESI)：m/z 554(M-H)-
Example 67
In the same manner as in example 1, from (E) -2-benzyl-3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-propenoic acid (200mg) and (E) -2-phenylethenesulfonamide (121mg), colorless crystals of (E) -2-benzyl-3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-propenamide (138mg) were obtained.
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.32-1.47(4H，m)，1.72-1.82(2H，m)，2.35(3H，s)，3.90(2H，t，J＝7Hz)，3.96(2H，s)，5.15(2H，s)，6.30(1H，d，J＝8Hz)，6.67(1H，dd，J＝8，2Hz)，6.92-6.98(2H，m)，7.12(2H，d，J＝8Hz)，7.20-7.32(5H，m)，7.35-7.45(5H，m)，7.58(1H，d，J＝8Hz)
Mass(ESI)：m/z 616(M-H)-
m.p.171-172℃
Example 68
In the same manner as in example 1, from (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (1-pentyl) -2-propenoic acid (200mg) and (E) -2-phenylethenesulfonamide (127mg), colorless crystals of (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (1-pentyl) -N- ((E) -2-phenylethenesulfonyl) -2-propenamide (123mg) were obtained.
1H-NMR(CDCl3)：0.88(3H，t，J＝7Hz)，0.92(3H，t，J＝7Hz)，1.25-1.55(10H，m)，1.70-1.80(2H，m)，2.37(3H，s)，2.48(2H，t，J＝7Hz)，3.89(2H，t，J＝7Hz)，5.12(2H，s)，6.32(1H，d，J＝8Hz)，6.67(1H，dd，J＝8，2Hz)，6.95-6.97(2H，m)，7.12(1H，d，J＝15Hz)，7.27(1H，d，J＝9Hz)，7.37-7.47(3H，m)，7.50-7.53(2H，m)，7.72(1H，d，J＝15Hz)
Mass(ESI)：m/z 596(M-H)-
m.p.168-169℃
Example 69
In the same manner as in example 1, from (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (3-pyridinyl) methyl-2-propenoic acid (230mg) and (E) -2-phenylethenesulfonamide (139mg), colorless crystals of (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- ((3-pyridinyl) methyl) -N- ((E) -2-phenylethenesulfonyl) -2-propenamide (139mg) were obtained.
1H-NMR(CDCl3)：0.94(3H，t，J＝7Hz)，1.32-1.48(4H，m)，1.72-1.82(2H，m)，2.38(3H，s)，3.86(2H，t，J＝7Hz)，3.97(2H，s)，5.00(2H，s)，6.37(1H，d，J＝8Hz)，6.61(1H，d，J＝8，2Hz)，6.92(1H，d，J＝2Hz)，6.95(1H，s)，6.98(1H，d，J＝15Hz)，7.18-7.27(2H，m)，7.32-7.45(5H，m)，7.56-7.63(2H，m)，8.09(1H，s)，8.48(1H，d，J＝5Hz)
Mass(ESI)：m/z 617(M-H)-
m.p.156-158℃
Example 70
In the same manner as in example 1, from (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-2-propenoic acid (200mg) and (E) -2-phenylethenesulfonamide (146mg), colorless crystals of (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-N- ((E) -2-phenylethenesulfonyl) -2-propenamide (183mg) were obtained.
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.30-1.47(4H，m)，1.71-1.80(2H，m)，2.12(3H，s)，2.36(3H，s)，3.89(2H，t，J＝7Hz)，5.13(2H，s)，6.29(1H，d，J＝8Hz)，6.66(1H，dd，J＝8，2Hz)，7.08-7.15(2H，m)，7.33(1H，s)，7.36-7.47(3H，m)，7.49-7.53(2H，m)，7.70(1H，d，J＝15Hz)
Mass(ESI)：m/z 540(M-H)-
m.p.143-145℃
Example 71
In the same manner as in example 1, from (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-2-propenoic acid (120mg) and (E) -2-phenylethenesulfonamide (80mg), colorless crystals of (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-N- ((E) -2-phenylethenesulfonyl) -2-propenamide (90mg) were obtained.
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.32-1.48(4H，m)，1.72-1.82(2H，m)，1.99(3H，s)，2.31(3H，s)，3.91(2H，t，J＝7Hz)，5.00(2H，s)，6.40(1H，d，J＝2Hz)，6.70(1H，dd，J＝8，2Hz)，6.92-6.94(2H，m)，7.11(1H，d，J＝15Hz)，7.38-7.45(3H，m)，7.52-7.55(2H，m)，7.73(1H，d，J＝15Hz)，8.32(1H，br s)
Mass(ESI)：m/z 574(M-H)-
m.p.156-157℃
Example 72
In the same manner as in example 1, from 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole-5-carboxylic acid (200mg) and (E) -2-phenylethenesulfonamide (148mg), colorless crystals of 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-5- ((E) -2-phenylethenesulfonylcarbamoyl) -1H-imidazole (108mg) were obtained.
1H-NMR(CDCl3)：0.91(3H，t，J＝7Hz)，1.28-1.37(4H，m)，1.60-1.70(2H，m)，2.02(3H，s)，3.62(2H，t，J＝7Hz)，5.32(2H，s)，6.32(1H，d，J＝8Hz)，6.44(1H，d，J＝8Hz)，6.58-6.64(2H，m)，7.05-7.20(6H，m)
Mass(ESI)：m/z 534(M-H)-
m.p.107-110℃
Example 73
4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -5-hydroxymethyl-2-methyl-1H-imidazole (150mg) was dissolved in 1, 4-dioxane (1.5ml), and p-toluenesulfonyl isocyanate (99mg) was added at room temperature. After the reaction mixture was stirred at room temperature for 1 hour, the mixture was concentrated under reduced pressure, ethanol (5ml) was added to the residue, and precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate (2ml), and hexane (13ml) was added to an oil bath at 70 ℃ to cool the solution, followed by filtration to collect the precipitated crystals. The crystals were dried under reduced pressure with heating to give colorless crystals of (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazol-5-yl) methyl N- (4-methylbenzenesulfonyl) carbamate (176 mg).
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.32-1.50(4H，m)，1.73-1.83(2H，m)，2.29(3H，s)，2.45(3H，s)，3.93(2H，t，J＝7Hz)，4.93(2H，s)，5.02(2H，s)，6.31(1H，d，J＝8Hz)，6.68(1H，dd，J＝8，2Hz)，6.94(1H，d，J＝2Hz)，7.32(2H，d，J＝8Hz)，7.95(2H，d，J＝8Hz)
Mass(ESI)：m/z 552(M-H)-
m.p.109-111℃
Example 74
In the same manner as in example 73, from 5-aminomethyl-4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole (70mg) and p-toluenesulfonyl isochlorate (43mg), colorless crystals of 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -5- ((3- (4-methylphenylsulfonyl) ureidomethyl) -2-methyl-1H-imidazole (41mg) were obtained.
1H-NMR(CDCl3)：0.92(3H，t，J＝7Hz)，1.30-1.47(4H，m)，1.70-1.80(2H，m)，2.34(3H，s)，2.43(3H，s)，3.90(2H，t，J＝7Hz)，4.24(2H，d，J＝7Hz)，5.06(2H，s)，6.25(1H，d，J＝8Hz)，6.65-6.68(2H，m)，6.93(1H，d，J＝2Hz)，7.28(2H，d，J＝8Hz)，7.68(2H，d，J＝8Hz)
Mass(ESI)：m/z 551(M-H)-
m.p.165-166℃
Example 75
In the same manner as in example 73, 5- (N-methylamino) methyl-4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazole (70mg) and p-toluenesulfonyl isocyanate (41mg) were combined to give 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -5- ((3- (4-toluenesulfonyl) -1-methylurea) methyl-2-methyl-1H-imidazole (60mg) as a colorless powder.
1H-NMR(CDCl3)：0.93(3H，t，J＝7Hz)，1.30-1.48(4H，m)，1.72-1.82(2H，m)，2.09(3H，s)，2.38(3H，s)，2.72(3H，s)，3.88(2H，t，J＝7Hz)，4.41(2H，s)，4.99(2H，s)，6.15(1H，d，J＝8Hz)，6.61(1H，dd，J＝8，2Hz)，6.82(1H，d，J＝2Hz)，7.13(2H，d，J＝8Hz)，7.70(2H，d，J＝8Hz)
Mass(ESI)：m/z 565(M-H)-
Example 76
(E) -3- (4-chloro-1- (2-chloro-4- (phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -1-penten-1-yl) sulfonyl-2-acrylamide (853mg) was suspended in ethanol (7ml), a 1N aqueous sodium hydroxide solution (1.53ml) was added, and the solvent was distilled off under reduced pressure. To the residue was added ethyl acetate (17ml), which was then heated and filtered. The filtrate was allowed to cool, and the precipitated powder was collected by filtration and dried under reduced pressure by heating to give a colorless powder of (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -1-penten-1-yl) sulfonyl-2-acrylamide sodium salt (737 mg).
IR(KBr)：2958，2227，2202，1635，1552，1498，1460，1383，1335，1296，1263，1238，1101，1066，1049，966，866，839cm-1
1H-NMR(DESO-d6)：0.85(3H，t，J＝7Hz)，1.13(3H，t，J＝7Hz)，1.30-1.43(2H，m)，2.02(2H，q，J＝7Hz)，2.57(2H，q，J＝7Hz)，5.34(2H，s)，6.20-6.30(2H，m)，6.47(1H，d，J＝7Hz)，6.55(1H，d，J＝15Hz)，6.93(1H，d，J＝15Hz)，7.41-7.45(3H，m)，7.48(1H，dd，J＝8，2Hz)，7.54-7.58(2H，m)，7.78(1H，d，J＝2Hz)
Mass(ESI)：m/z 554(M-H)-
Application in industry
The imidazole compounds of the present invention and pharmaceutically acceptable salts thereof described above can be used for the prevention or treatment of the following diseases based on hypoglycemic activity: impaired glucose tolerance, diabetes (type II diabetes and the like), gestational diabetes, diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatosis, diabetic psychosis, diabetic cataract, diabetic retinopathy and the like), insulin resistance syndrome (insulin receptor abnormality, Rabson-Mendenhall syndrome, lepigy syndrome, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly and the like), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases (angina pectoris, heart failure and the like), hyperglycemia (e.g., diseases characterized by abnormal glucose metabolism such as eating disorder), pancreatitis, osteoporosis, polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases (angina pectoris, heart failure and the like), hyperglycemia (e.g., diseases characterized by abnormal glucose metabolism such as eating disorder and the like), and the like, Hyperuricemia, hypertension, inflammatory bowel disease, skin diseases accompanied by epidermal cell differentiation abnormality, angina pectoris based on cGMP-PDE (especially PDE-V) inhibitory action, smooth muscle relaxation action, bronchodilator action, vasodilator action, smooth muscle cell inhibitory action, allergy inhibitory action and the like, hypertension, pulmonary hypertension, congestive heart failure, glomerular disease (for example, diabetic glomerulosclerosis and the like), tubulointerstitial disease (for example, nephropathy and the like caused by FK506, cyclosporin and the like), renal failure, atherosclerosis, vascular stenosis (for example, vascular stenosis after percutaneous angioplasty), non-tip vascular disease, cerebral hemorrhage, chronic occlusive disease (for example, bronchitis, asthma (chronic asthma, allergic asthma)), autoimmune disease, Allergic rhinitis, urticaria, glaucoma, diseases characterized by intestinal motility disorder (e.g., irritable bowel syndrome), impotence (e.g., organic impotence, psychogenic impotence, etc.), nephritic carcinemia, or restenosis after PTCA, cachexia (e.g., progressive weight loss due to lipolysis, myolysis, anemia, edema, anorexia, etc. in chronic diseases such as cancer, tuberculosis, endocrine diseases, aids, etc.). In addition, it can be used for treating diseases accompanied by abnormal cell proliferation including cancer, restenosis and atherosclerosis by combining with retinal derivative.
This application is based on Japanese application No. Hei 10-367362 and No. Hei 11-228838, filed 24/1998 and 8/12/1999, the contents of which are also included in this specification.

Claims (11)

1. An imidazole compound represented by the general formula (I):
in the formula
R1Is phenyl, (C1-C6) alkyl substituted phenyl, naphthyl or pyridyl, each of which is substituted with a substituent selected from the group consisting of: (1) phenyl, (2) furyl or thienyl, (3) halogen, (4) halo (C1-C6) alkyl, (5) C1-C6 alkylthio, (6) nitro, (7) optionally substituted by phenylSubstituted (C2-C6) alkenyl, (8) alkynyl (C2-C6) which may be substituted with phenyl, (9) alkoxy (C1-C6) which may be substituted with cyclo (C3-C10) alkyl or phenyl, (10) phenoxy, and (11) amino which may be substituted with (C1-C6) alkoxycarbonyl or (C1-C6) alkyl;
R2is (C1-C6) alkyl;
R3is hydrogen, halogen, or (C1-C6) alkyl;
R4is (1) a (C2-C6) alkenyl group which may be substituted with a phenyl group, (2) a phenyl group or a (C1-C6) alkyl-substituted phenyl group, either of which may be substituted with a (C2-C6) alkenyl group, (3) (C1-C6) alkyl group, or (4) a thienyl group which may be substituted with a halogen;
a is (C1-C4) alkylene;
l is (1) a single bond, (2) a (C2-C6) alkenylene group or (C1-C6) alkylene group which may be substituted with a phenyl group or a pyridyl group, or (3) -X-CH2-, in which X is-O-or-NR5-, in the formula, R5Is hydrogen or (C1-C6) alkyl.
2. The imidazole compound or a salt thereof according to claim 1, which is represented by the following general formula (IA):
in the formula
R2Is methyl;
R3is chlorine;
R4is (1) a (C2-C6) alkenyl group which may be substituted with a phenyl group, (2) a phenyl group or a (C1-C6) alkyl-substituted phenyl group, (3) (C1-C6) alkyl group, or (4) a thienyl group which may be substituted with a halogen;
R6is (1) phenyl, (2) furyl or thienyl, (3) bromo, (4) halo (C1-C6) alkyl, (5) C1-C6 alkylthio, (6) nitro, (7) (C2-C6) alkenyl which may be substituted by phenyl, (8) alkynyl (C2-C6) which may be substituted by phenyl, (9) (C1-C6) alkoxy which may be substituted by cyclo (C3-C10) alkyl or phenyl, (10) alkyl (C1-C6) which may be substituted by phenoxy, and (11) amino which may be substituted by (C1-C6) alkoxycarbonyl or (C1-C6) alkyl;
l is vinylidene.
3. The imidazole compound or a salt thereof according to claim 2, wherein,
R4is phenyl, (C1-C6) alkyl-substituted phenyl, or (C2-C6) alkenyl which may be substituted with phenyl;
R6is bromo, (C2-C6) alkenyl which may be substituted by phenyl, (C2-C6) alkynyl which may be substituted by phenyl, or (C1-C6) alkoxy which may be substituted by cyclo (C3-C10) alkyl.
4. The imidazole compound or a salt thereof according to claim 1, wherein R is1Is a pyridyl group, which is substituted with a substituent selected from the group consisting of: (1) phenyl, (2) furyl or thienyl, (3) halogen, (4) halo (C1-C6) alkyl, (5) C1-C6 alkylthio, (6) nitro, (7) phenyl-substituted (C2-C6) alkenyl, (8) phenyl-substituted (C2-C6) alkynyl, (9) ring (C3-C10) alkyl-or phenyl-substituted (C1-C6) alkoxy, (10) phenoxy, and (11) amino-substituted by (C1-C6) alkoxycarbonyl or (C1-C6) alkyl.
5. The imidazole compound or a salt thereof according to claim 1, wherein the compound is:
(1) (E) -3- (4-chloro-1- (2-chloro-4- (2-furyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(2) (2E) -3- (4-chloro-1- (2-chloro-4- (2-furyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(3) (E) -3- (4-chloro-1- (2-chloro-4- (2-thienyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(4) (2E) -3- (4-chloro-1- (2-chloro-4- (2-thienyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(5) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(6) (2E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(7) (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(8) (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(9) (E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -N- (1-pentanesulfonyl) -2-acrylamide;
(10) (E) -N-benzenesulfonyl-3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -2-propenamide;
(11) (E) -3- [ 4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl ] -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(12) (E) -3- (4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(13) (E) -3- (4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl) -N- ((5-chloro-2-thienyl) sulfonyl) -2-acrylamide;
(14) (E) -N- ((5-bromo-2-thienyl) sulfonyl) -3- (4-chloro-1- (2-chloro-4-phenylbenzyl) -2-methylimidazol-5-yl) -2-acrylamide;
(15) (E) -3- (4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(16) (E) -3- (4-chloro-1- (2-chloro-4- (1-propoxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(17) (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(18) (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(19) (E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide;
(20) (E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(21) (2E) -3- (4-chloro-1- (2-chloro-4- ((cyclopentyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(22) (E) -3- (4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(23) (2E) -3- (4-chloro-1- (2-chloro-4- ((cyclohexyl) methoxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(24) (E) -3- (1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(25) (E) -3- (1- (4-benzyloxy-2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(26) (E) -3- (4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(27) (E) -3- (4-chloro-1- (2-chloro-4- (methylthio) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(28) (E) -3- (4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(29) (E) -3- (4-chloro-1- (2-chloro-4- (trifluoromethyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(30) (E) -3- (4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(31) (E) -3- (4-chloro-1- (2-chloro-4- (phenoxymethyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylvinyl) sulfonyl) -2-acrylamide;
(32) (E) -3- (4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(33) (E) -3- (4-chloro-1- (2-chloro-4-nitrobenzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(34) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(35) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylvinyl) sulfonyl) -2-acrylamide;
(36) (E) -3- (1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(37) (E) -3- (1- (1-bromo-2-naphthyl) -4-chloro-2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(38) (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- (1-pentylsulfonyl) -2-acrylamide;
(39) (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide;
(40) (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-acrylamide;
(41) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide;
(42) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide;
(43) (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-methylimidazol-5-yl) -2-acrylamide;
(44) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide;
(45) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide;
(46) (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- (2-phenylethynyl) benzyl) -2-methylimidazol-5-yl) -2-acrylamide;
(47) (E) -3- (4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(48) (E) -3- (4-chloro-1- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) methyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(49) (E) -3- (1- (4- (tert-butoxycarbonylamino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide;
(50) (E) -3- (1- (4- (tert-butoxycarbonylamino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide;
(51) (E) -3- (1- (4- (tert-butoxycarbonylamino) -2-chlorobenzyl) -4-chloro-2-methylimidazol-5-yl) -N- (((E) -2-phenylethenyl) sulfonyl) -2-acrylamide;
(52) (E) -3- (4-chloro-1- (2-chloro-4- (N-pentyloxy) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(53) (E) -3- (1- (4-bromo-2-chlorobenzyl) -4-chloro-2-ethylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-acrylamide;
(54) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-acrylamide;
(55) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(56) (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -2-acrylamide;
(57) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide;
(58) (E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide;
(59) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(60) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- (4-methylbenzenesulfonyl) -2-acrylamide;
(61) (E) -N- (1-butanesulfonyl) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -2-acrylamide;
(62) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide;
(63) (E) -3- (4-chloro-1- (2-chloro-4- ((E) -2-phenylvinyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -1-penten-1-ylsulfonyl) -2-acrylamide;
(64) (E) -3- (1- (4-bromo-2-chlorobenzyl) -2, 4-dimethylimidazol-5-yl) -N- ((E) -2-phenylethenesulfonyl) -2-acrylamide;
(65) (E) -3- (4-bromo-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(66) (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -4-ethyl-2-methylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(67) (E) -2-benzyl-3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(68) (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (1-pentyl) -N- ((E) -2-phenylethenesulfonyl) -2-acrylamide;
(69) (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2- (3-pyridinyl) methyl-N- ((E) -2-phenylethenesulfonyl) -2-acrylamide;
(70) (E) -3- (1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-N- ((E) -2-phenylvinylsulfonyl) -2-acrylamide;
(71) (E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -2-methyl-N- ((E) -2-phenylethenesulfonyl) -2-acrylamide;
(72) 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-5- ((E) -2-phenylethenesulfonylcarbamoyl) -1H-imidazole;
(73) 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methyl-1H-imidazol-5-yl) N- (4-toluenesulfonyl) carbamate;
(74) 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -5- ((3- (4-tosyl) ureido) methyl) -2-methyl-1H-imidazole;
(75) 4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -5- ((3- (4-tosyl) -1-methylureido) methyl) -2-methyl-1H-imidazole; or
(76)3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -1-penten-1-yl) sulfonyl) - (E) -2-acrylamide.
6. The imidazole compound or a salt thereof according to claim 1, wherein the compound is:
(E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-methylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(E) -3- (4-chloro-1- (2-chloro-4- (1-pentyloxy) benzyl) -2-methylimidazol-5-yl) -N- (((E) -2-phenylvinyl) sulfonyl) -2-acrylamide;
(E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((4-methylbenzene) sulfonyl) -2-acrylamide;
(E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- (1-pentanesulfonyl) -2-acrylamide; or
(E) -3- (4-chloro-1- (2-chloro-4- (phenylethynyl) benzyl) -2-ethylimidazol-5-yl) -N- ((E) -1-penten-1-yl) sulfonyl) -2-acrylamide.
7. A pharmaceutical composition comprising the imidazole compound according to claim 1 or a pharmaceutically acceptable salt thereof.
8. A process for producing an imidazole compound represented by the general formula (I) or a salt thereof according to claim 1, which comprises reacting a compound represented by the general formula (II) or a reactive derivative of a carboxyl group thereof or a salt thereof with a compound represented by the general formula (III) or a salt thereof,
in the formula (I), the compound is shown in the specification,
R1is phenyl, (C1-C6) alkyl substituted phenyl, naphthyl or pyridyl, each of which is substituted with a substituent selected from the group consisting of: (1) phenyl, (2) furyl or thienyl, (3) halogen, (4) halo (C1-C6) alkyl, (5) C1-C6 alkylthio, (6) nitro, (7) phenyl-substituted (C2-C6) alkenyl, (8) phenyl-substituted (C2-C6) alkynyl, (9) ring (C3-C10) alkyl-or phenyl-substituted (C1-C6) alkoxy, (10) phenoxy, and (11) amino-substituted by (C1-C6) alkoxycarbonyl or (C1-C6) alkyl;
R2is (C1-C6) alkyl;
R3is hydrogen, halogen or (C1-C6) alkyl;
a is (C1-C4) alkylene;
l is (1) a single bond, (2) a (C2-C6) alkenylene group or (C1-C6) alkylene group which may be substituted with a phenyl group or a pyridyl group, or (3) -X-CH2-, in which X is-O-or-NR5-, in the formula, R5Is hydrogen or (C1-C6) alkyl;
R4-SO2NH2 (III)
in the formula (I), the compound is shown in the specification,
R4is (1) a (C2-C6) alkenyl group which may be substituted with a phenyl group, (2) a phenyl group or a (C1-C6) alkyl-substituted phenyl group, any of which may be substituted with a (C2-C6) alkenyl group, (3) (C1-C6) alkyl group, or (4) a thienyl group which may be substituted with a halogen.
9. The imidazole compound or a salt thereof according to claim 1, which has the following general formula:
wherein R is2Is (C1-C6) alkyl;
R3is hydrogen, halogen or (C1-C6) alkyl;
R4is (1) a (C2-C6) alkenyl group which may be substituted with a phenyl group or a (C1-C6) alkyl-substituted phenyl group, (2) a phenyl group or a (C1-C6) alkyl-substituted alkyl groupPhenyl which may be substituted with (C2-C6) alkenyl, (3) (C1-C6) alkyl, or (4) thienyl which may be substituted with halogen;
R6is (1) phenyl, (2) furyl or thienyl, (3) bromo, (4) halo (C1-C6) alkyl, (5) C1-C6 alkylthio, (6) nitro, (7) (C2-C6) alkenyl which may be substituted by phenyl, (8) alkynyl (C2-C6) which may be substituted by phenyl, (9) (C1-C6) alkoxy which may be substituted by cyclo (C3-C10) alkyl or phenyl, (10) alkyl (C1-C6) which may be substituted by phenoxy, and (11) amino which may be substituted by (C1-C6) alkoxycarbonyl or (C1-C6) alkyl;
l is (1) a single bond, (2) a (C2-C6) alkenylene group or (C1-C6) alkylene group which may be substituted with a phenyl group or a pyridyl group, or (3) -X-CH2-, in which X is-O-or-NR5-, in the formula, R5Is hydrogen or (C1-C6) alkyl.
10. A compound as claimed in claim 9, characterized in that R3Is chlorine and L is vinylidene.
11. A compound as claimed in claim 10, characterized in that R6Is (C2-C6) alkenyl which may be substituted by phenyl, or (C2-C6) alkynyl which may be substituted by phenyl.
HK02105326.2A 1998-12-24 1999-12-20 Imidazole compounds and medicinal use thereof HK1043791B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP367362/1998 1998-12-24
JP36736298 1998-12-24
JP228838/1999 1999-08-12
JP22883899 1999-08-12
PCT/JP1999/007160 WO2000039097A1 (en) 1998-12-24 1999-12-20 Imidazole compounds and medicinal use thereof

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HK1043791A1 HK1043791A1 (en) 2002-09-27
HK1043791B true HK1043791B (en) 2005-06-03

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