WO2011148956A1 - 縮合イミダゾール誘導体 - Google Patents
縮合イミダゾール誘導体 Download PDFInfo
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- WO2011148956A1 WO2011148956A1 PCT/JP2011/061913 JP2011061913W WO2011148956A1 WO 2011148956 A1 WO2011148956 A1 WO 2011148956A1 JP 2011061913 W JP2011061913 W JP 2011061913W WO 2011148956 A1 WO2011148956 A1 WO 2011148956A1
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- trifluoromethoxyphenyl
- benzimidazole
- methyl
- ethoxy
- group
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- MOXBWSYIRUTLLI-UHFFFAOYSA-N CCOC(c1nc(cc(cc2)Br)c2[nH]1)c(cc1)ccc1OC(F)(F)F Chemical compound CCOC(c1nc(cc(cc2)Br)c2[nH]1)c(cc1)ccc1OC(F)(F)F MOXBWSYIRUTLLI-UHFFFAOYSA-N 0.000 description 1
- OZOKKZZRIIWXON-UHFFFAOYSA-N CCOC(c1nc(cc(cc2)F)c2[nH]1)c1ccc2OC(C)(C)Cc2c1 Chemical compound CCOC(c1nc(cc(cc2)F)c2[nH]1)c1ccc2OC(C)(C)Cc2c1 OZOKKZZRIIWXON-UHFFFAOYSA-N 0.000 description 1
- DPGKIHQVAOFIEU-UHFFFAOYSA-N COC(c1nc(cc(cc2)F)c2[nH]1)c(cc1)cc(C2CC2)c1OC(F)(F)F Chemical compound COC(c1nc(cc(cc2)F)c2[nH]1)c(cc1)cc(C2CC2)c1OC(F)(F)F DPGKIHQVAOFIEU-UHFFFAOYSA-N 0.000 description 1
- JDJKDJBBFOCVLN-UHFFFAOYSA-N FC(Oc1ccc(C(c2nc(cc(cc3)F)c3[nH]2)OC2C=CC=NC2)cc1)(F)F Chemical compound FC(Oc1ccc(C(c2nc(cc(cc3)F)c3[nH]2)OC2C=CC=NC2)cc1)(F)F JDJKDJBBFOCVLN-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/12—Radicals substituted by oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
Definitions
- the present invention relates to a condensed imidazole derivative having a T-type calcium channel antagonistic action and a medicine containing the same.
- Intracellular calcium is an important factor that causes various physiological responses such as nerve excitation, muscle contraction, hormone secretion, fertilization, immune response, cell motility, and cell death. It is a membrane voltage-dependent calcium channel and receptor-acting calcium. The concentration is adjusted by an ion channel such as a channel or a pump.
- Membrane voltage-dependent calcium channels are calcium channels that open and close in response to changes in the potential difference inside and outside the cell, and are present on the cell membrane of muscles and nerve cells. Membrane voltage-dependent calcium channels are currently classified into L-type, T-type, N-type, P / Q-type, and R-type calcium channels based on electrophysiological and pharmacological properties.
- the T-type calcium channel has a resting membrane potential. Since it is activated at a near potential, it acts as a trigger for intracellular calcium influx and is thought to be involved in pacemaker activity, production of low threshold calcium spikes, and burst firing.
- T-type calcium channels include three subtypes: Cav3.1 ( ⁇ 1G), Cav3.2 ( ⁇ 1H), Cav3.3 ( ⁇ 1I), brain, nervous tissue, heart, kidney, liver, pancreas, smooth muscle, Channel expression has been reported in testis and the like.
- Activation of T-type calcium channels in the above organs and tissue cells induces intracellular calcium overload, such as hypertension, tachyarrhythmia including atrial fibrillation, cardiac hypertrophy, heart failure, renal dysfunction, It has been suggested to be involved in the onset and progression of various pathological conditions such as cancer. Therefore, T-type calcium channel antagonists are considered to be effective for the treatment or prevention of these diseases (Non-Patent Documents 1 to 5).
- Mibefradil is known as a T-type calcium channel antagonist, but it is not currently marketed due to the problem of drug interaction.
- Patent Document 1 discloses 3,4-dihydroquinazoline derivatives
- Patent Document 2 discloses quinazoline derivatives
- Patent Document 3 discloses pyridylamide derivatives
- Patent Documents 4 and 5 describe 3-fluoropiperidine derivatives
- Patent Document 6 discloses. Indole derivatives, patent document 7 with oxadiazole derivatives, patent documents 8 and 9 with thiazole derivatives, patent document 10 with isoxazole derivatives, patent document 11 with 1,3-dioxoid indole derivatives with T-type calcium It is disclosed as a channel antagonist. However, these compounds have not been clinically used so far.
- An object of the present invention is to provide a novel compound having an antagonistic action on a T-type calcium channel and useful as a pharmaceutical product.
- the present inventors have synthesized various compounds and screened them using T-type calcium channel antagonistic activity as an index.
- compounds having an ⁇ -substituted benzyl group bonded to the 2-position of the condensed imidazole skeleton are excellent. It has been found that it has an antagonistic action and is useful as a preventive or therapeutic agent for various diseases such as hypertension and arrhythmia, and has completed the present invention.
- Ring Nn represents a condensed 6-membered aromatic ring optionally having a nitrogen atom
- Ring Np represents a 6-membered aromatic ring optionally having a nitrogen atom
- n represents the number of nitrogen atoms contained in the condensed 6-membered aromatic ring, and is 0, 1 or 2
- p represents the number of nitrogen atoms contained in the 6-membered aromatic ring, and is 0 or 1
- R 1 and R 2 are the same or different, (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxy group, (4) a cyano group, (5)
- R 6 and R 7 are the same or different and each represents
- this invention provides the pharmaceutical containing the compound represented with the said general formula (I), its pharmaceutically acceptable salt, or those solvates.
- the present invention also provides a compound represented by the above general formula (I), a pharmaceutically acceptable salt thereof, or a compound thereof, which is used for the treatment or prevention of a disease for which T-type calcium channel antagonism is effective.
- a solvate is provided.
- the present invention also provides a therapeutic or preventive agent for a disease in which the T-type calcium channel antagonistic action is effective of the compound represented by the above general formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. It provides use for the manufacture of medicines.
- the present invention also provides a T-type calcium channel antagonistic action characterized by administering an effective amount of the compound represented by the above general formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. Provides an effective method for treating or preventing a disease.
- the compound of the present invention has an excellent T-type calcium channel antagonistic action, high safety, and is useful as a prophylactic and therapeutic drug for various diseases in which the T-type calcium channel acts.
- diseases that can be prevented or treated by T-type calcium channel antagonism include hypertension, atrial fibrillation, arrhythmia, cardiac hypertrophy, heart failure, peripheral dysfunction, and cancer.
- ring Nn represents a condensed 6-membered aromatic ring which may have a nitrogen atom
- n represents the number of nitrogen atoms contained in the condensed 6-membered aromatic ring
- 0, 1 or 2 is there. That is,
- ring Np represents a 6-membered aromatic ring which may have a nitrogen atom
- p represents the number of nitrogen atoms contained in the 6-membered aromatic ring, and is 0 or 1. That is,
- the aromatic ring or non-aromatic ring may be benzene.
- substituent include a halogen atom and a C 1-6 alkyl group which may have a substituent.
- examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
- the “halogen atom” represented by R 1 , R 2 , and R 5 is preferably a fluorine atom, a chlorine atom, or a bromine atom, and more preferably a fluorine atom or a chlorine atom.
- C 1-6 alkyl group refers to a linear or branched or cyclic alkyl group having 1 to 6 carbon atoms and 3 to 6 carbon atoms.
- Examples of C 1-6 alkyl groups include methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n- Examples include a hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
- R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 may have a substituent represented by C 1-6 alkyl group “
- the “C 1-6 alkyl group” is preferably a C 1-4 alkyl group, more preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.
- C 1-6 alkyl group of R 1, R 2 a C 1-6 alkyl group optionally having a substituent represented by a methyl group is particularly preferred.
- C 1-6 alkyl group of the C 1-6 alkyl group optionally having a substituent represented by R 5
- n- propyl group a cyclopropyl group is particularly preferred.
- C 1-6 alkyl group of the C 1-6 alkyl group optionally having a substituent represented by R 6 include a methyl group, n- propyl group is particularly preferred.
- C 1-6 alkyl group of the C 1-6 alkyl group optionally having a substituent represented by R 9 is a methyl group, an ethyl group, an isopropyl group is particularly preferred.
- C 1-6 alkyl group of the C 1-6 alkyl group optionally having a substituent represented by R 3 include a methyl group, an ethyl group, an isopropyl group, isobutyl group and cyclohexyl group are preferable, methyl A group, an ethyl group and an isopropyl group are particularly preferred.
- C 2-6 alkenyl group refers to a linear or branched or cyclic alkenyl group having 2 to 6 carbon atoms or 3 to 6 carbon atoms.
- Examples of C 2-6 alkenyl groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl.
- the “aryl group” refers to a monocyclic or polycyclic aromatic ring group having 6 to 10 carbon atoms.
- Examples of the aryl group include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
- the “aryl group” of the aryl group which may have a substituent represented by R 3 or R 4 is preferably a phenyl group.
- heteroaryl group refers to a monocyclic or polycyclic aromatic ring group containing 1 to 3 oxygen atoms, nitrogen atoms or sulfur atoms.
- heteroaryl groups include pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, Examples include a pyrimidinyl group, a pyrazinyl group, a quinolyl group, an isoquinolyl group, a benzimidazolyl group, an indolyl group, a purinyl group, a benzisoxazolyl group, a benzoxazolyl group, a benzoisothiazolyl group, and a benzothiazolyl
- the “heteroaryl group” of the heteroaryl group which may have a substituent represented by R 3 or R 4 is preferably a 5- to 6-membered monocyclic heteroaryl group, More preferably, it is a pyridyl group.
- C 1-6 alkoxy group represents a group in which one hydrogen atom of the above “C 1-6 alkyl group” is substituted with an oxygen atom.
- Examples of C 1-6 alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclo Examples thereof include a propoxy group, a cyclopropylmethoxy group, a cyclobutoxy group, a cyclopentoxy group, and a cyclohexoxy group.
- R 1, R 2 have a substituent represented by R 5 is preferably a "C 1-6 alkoxy group" also a C 1-6 alkoxy group, C 1-4 And more preferably a methoxy group, an ethoxy group, an n-propoxy group, or an isopropoxy group.
- halo C 1-6 alkyl group refers to a group in which one or more hydrogen atoms of the “C 1-6 alkyl group” are substituted with a halogen atom.
- halo C 1-6 alkyl groups include chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, tribromomethyl, 2 -Chloroethyl group, 2,2-dichloroethyl group, 2,2,2-trichloroethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 1,1 , 2,2-tetrafluoroethyl group, pentafluoroethyl group, 2-bromoethyl group, 2,2,2-tribromoethyl group, 3,3,3-trichloropropyl
- the “halo C 1-6 alkyl group” represented by R 4 and R 10 is preferably a C 1-4 alkyl group substituted with one or more fluorine atoms, more preferably 2-fluoroethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, 3,3,3-trifluoropropyl group.
- halo C 1-6 alkoxy group refers to a group in which one or more hydrogen atoms of the “C 1-6 alkoxy group” are substituted with a halogen atom.
- halo C 1-4 alkoxy groups include chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, bromomethoxy, dibromomethoxy, tribromomethoxy, 2 -Chloroethoxy group, 2,2-dichloroethoxy group, 2,2,2-trichloroethoxy group, 2-fluoroethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 1, 1,2,2-tetrafluoroethoxy group, 1,1,2,2,2-pentafluoroethoxy group, 3,3,3-trichloropropoxy group, 3,3,3-trifluoropropoxy group, 3,3 , 3-t
- the “halo C 1-6 alkoxy group” represented by R 1 , R 2 , R 4 is preferably a C 1-4 alkoxy group substituted with one or more fluorine atoms, More preferred are a difluoromethoxy group, a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, and a 3,3,3-trifluoropropoxy group.
- aryloxy group refers to a group in which one hydrogen atom of the above “aryl group” is substituted with an oxygen atom.
- examples of the aryloxy group include phenoxy group, 1-naphthoxy group, and 2-naphthoxy group.
- heteroaryloxy group refers to a group in which one hydrogen atom of the carbon atom on the ring of the “heteroaryl group” is substituted with an oxygen atom.
- heteroaryloxy group include a 2-pyridyloxy group, a 3-pyridyloxy group, a 2-imidazolyloxy group, a 2-pyrimidinyloxy group, and a 1,2,4-triazol-5-yloxy group.
- the “aryloxy C 1-6 alkyl group” refers to a group in which one hydrogen atom of the “C 1-6 alkyl group” is substituted with an aryloxy group.
- Examples of the aryloxy C 1-6 alkyl group include a phenoxymethyl group, a phenoxyethyl group, a phenoxypropyl group, a phenoxybutyl group, a phenoxypentyl group, and a phenoxyhexyl group.
- aryloxy C 1-6 alkyl group of an aryloxy C 1-6 alkyl group optionally having a substituent represented by R 4, phenyloxy C 1-4
- An alkyl group more preferably a phenoxymethyl group or a phenoxyethyl group.
- the “aralkyl group” refers to a group in which one hydrogen atom of the “C 1-6 alkyl group” is substituted with an aryl group.
- aralkyl groups include benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, naphthylethyl, 3-phenylpropyl, 4-phenyl Examples include a butyl group and a 5-phenylpentyl group.
- the “aralkyl group” of the aralkyl group which may have a substituent represented by R 13 is preferably a phenyl C 1-6 alkyl group, a naphthyl C 1-6 alkyl group, More preferred are a benzyl group and a phenethyl group.
- the “aralkyloxy group” refers to a group in which one hydrogen atom of the “C 1-6 alkoxy group” is substituted with an aryl group.
- the aralkyloxy group include a benzyloxy group and a phenethyloxy group.
- the “aralkyloxy group” of the aralkyloxy group which may have a substituent represented by R 4 is preferably a phenyl C 1-6 alkyloxy group, more preferably benzyloxy It is a group.
- heteroaralkyloxy group refers to a group in which one hydrogen atom of the “C 1-6 alkoxy group” is substituted with a heteroaryl group.
- heteroaralkyloxy group include a pyridyl C 1-6 alkyloxy group.
- the “heteroaralkyloxy group” of the heteroaralkyloxy group which may have a substituent represented by R 4 is preferably a pyridylmethyloxy group or a pyridylethyloxy group, more preferably Are a 3-pyridylmethyloxy group, a 3-pyridylethyloxy group, a 2-pyridylmethyloxy group, and a 2-pyridylethyloxy group.
- non-aromatic heterocycle means a monocyclic, bicyclic or tricyclic and 3 to 10-membered ring containing at least one oxygen atom, nitrogen atom or sulfur atom.
- Non-aromatic heterocycle examples include azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring, hexamethyleneimine ring, heptamethyleneimine ring, homopiperazine ring, 2,5-diazabicyclo [2.2.1] heptane ring 1,6-diazepan ring, 2,5-diazabicyclo [2.2.2] octane ring, 1,6-diazabicyclo [3.2.1] octane ring, tetrahydrofuran ring, tetrahydropyran ring, morpholine ring, etc.
- “optionally substituted” means “unsubstituted” or 1 to 5, preferably 1 to 3 identical or different substituents at substitutable positions. It shows that it has.
- the substituent include a halogen atom, hydroxy group, cyano group, nitro group, C 1-6 alkyl group, C 1-6 alkoxy group, acyl group, formyl group, carboxyl group, C 1-6 alkylcarbonylamino group, C 1-6 alkoxycarbonyl group, carbamoyl group, sulfam
- the substituted C 1-6 alkyl group, C 2-6 alkenyl group, and C 1-6 alkoxy group include 1 to 5, preferably 1 to 3, halogen atoms, cyano group, hydroxy group, C 1 Those having a substituent of a -6 alkoxy group are preferred.
- R 1 as the C 1-6 alkyl group optionally having a substituent represented by R 2, unsubstituted or substituted by 1-5 C 1-6 alkyl group substituted by a halogen atom An unsubstituted C 1-6 alkyl group is particularly preferable.
- the C 1-6 alkyl group which may have a substituent represented by R 3 is unsubstituted or has 1 to 5 halogen atoms, C 1-6 alkoxy group, aryl group, hydroxy group A C 1-6 alkyl group substituted with is preferred, and an unsubstituted C 1-6 alkyl group is particularly preferred.
- An unsubstituted C 1-6 alkoxy group is particularly preferable. Others are preferably unsubstituted.
- An aryl group having a substituent, a heteroaryl group, an aryloxy group, a heteroaryloxy group, an aralkyl group, a heteroaralkyl group, an aralkyloxy group, a heteroaralkyloxy group, and an aryloxy C 1-6 alkyl group are And those having a substituent of 1 to 5, preferably 1 to 3, C 1-6 alkyl group, halogen atom, cyano group, hydroxy group, C 1-6 alkoxy group.
- the aralkyloxy group or heteroaralkyloxy group which may have a substituent represented by R 4 is unsubstituted or has 1 to 3 halogen atoms, a C 1-6 alkyl group on the aromatic ring, Those substituted with a C 1-6 alkoxy group, a halo C 1-6 alkyl group or a halo C 1-6 alkoxy group are preferred. Others are preferably unsubstituted.
- n is preferably 0 or 1, more preferably 0. Therefore, the Nn ring is preferably a benzene ring or a pyridine ring, more preferably a benzene ring.
- p is preferably 0. Therefore, a benzene ring is preferable as the Np ring.
- R 1 and R 2 R 2 is a hydrogen atom, it is preferred that R 1 is a substituent other than hydrogen atom.
- R 1 (1) a halogen atom, (2) a C 1-6 alkyl group which may have a substituent, (3) an optionally substituted C 1-6 alkoxy group, Is preferred; (1) fluorine atom (2) chlorine atom (3) C 1-6 alkyl group (4) C 1-6 alkoxy group (5) halo C 1-6 alkoxy group is more preferred, Particularly preferred is a fluorine atom.
- n 0 or 1
- the condensed heterocyclic ring containing R 1 and Nn has the following formula
- R 3 Preferably as R 3 , (1) a hydrogen atom, (2) a C 1-6 alkyl group which may have a substituent, (3) an aryl group or a heteroaryl group which may have a substituent; More preferably, (1) a hydrogen atom, (2) a C 1-6 alkyl group, (3) a halo C 1-6 alkyl group, (4) an aryl group or a heteroaryl group; Particularly preferred are a hydrogen atom, a methyl group, an ethyl group, a 2-fluoroethyl group, and an isopropyl group.
- X is preferably an oxygen atom, —SO 2 — or —N (R 9 ) —; more preferably an oxygen atom.
- R 4 Preferably as R 4 , (1) a halo C 1-6 alkyl group, (2) a halo C 1-6 alkoxy group, (3) an aralkyl group which may have a substituent, (4) an aralkyloxy group which may have a substituent, (5) -SR 10 , (6) An aryl group or heteroaryl group which may have a substituent, More preferably, (1) Halo C 1-4 alkyl group, (2) Halo C 1-4 alkoxy group, (3) an aralkyloxy group which may have a substituent (4) -SR 10 , Is; More preferably, (1) a C 1-4 alkyl group substituted with a fluorine atom, (2) a C 1-4 alkoxy group substituted with a fluorine atom, (3) an aralkyloxy group substituted with a halogen atom; Particularly preferred is a trifluoromethoxy group.
- R 5 is (1) a hydrogen atom, (2) a halogen atom, Is; More preferably, it is a hydrogen atom.
- R 4 and R 5 together form a benzene ring or a dioxole ring which may have a substituent.
- the structural formula of a compound may represent a certain isomer for convenience, but in the present invention, all geometrical isomers generated from the structure of the compound, optical isomers based on asymmetric carbon, stereo It includes isomers such as isomers and tautomers, and isomer mixtures, and is not limited to the description of the formula for convenience, and may be either isomer or mixture.
- the compound of the present invention has an asymmetric carbon atom in the molecule and has optical isomers and racemates, but is not limited in the present invention and includes both.
- the present invention also includes a pharmaceutically acceptable salt of the compound (I) of the present invention.
- inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, formate, acetate, trichloroacetate, trifluoroacetate, propion Acid salt, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonic acid Salts, p-toluenesulfonate (4-methylbenzenesulfonate), aspartate, acid addition salts with organic acids such as glutamate, sodium salts, potassium salts, magnesium salts, calcium salts, aluminum salts, etc. And salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, ammonium salts
- the present invention includes pharmacologically acceptable prodrugs of the compound (I) of the present invention.
- a pharmacologically acceptable prodrug is a compound that undergoes enzymatic oxidation, reduction, and hydrolysis under physiological conditions in vivo to convert it into the compound (I) of the present invention.
- groups that form prodrugs include those described in Prog. Med. 5, 2157-2161 (1985) and “Development of pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198.
- the present invention may include hydrates, various solvates and crystal polymorphs of the compound (I) of the present invention and pharmaceutically acceptable salts thereof, but is not limited to any of them. These may be a single crystal form or a mixture of crystal forms, both of which are included. Furthermore, the present invention includes compounds obtained by labeling the compound (I) of the present invention with isotopes (eg, 2 H, 3 H, 14 C, 35 S, 125 I etc.) and the like.
- isotopes eg, 2 H, 3 H, 14 C, 35 S, 125 I etc.
- the compounds of the present invention and pharmaceutically acceptable salts thereof are produced by applying various per se known synthetic methods relating to the introduction of substituents and functional group transformations, utilizing characteristics based on the basic skeleton or the type of substituents. can do.
- reactive substituents such as amino groups, hydroxy groups, and carboxyl groups
- after introducing a protective group to the substituent as necessary after the target reaction is completed
- the desired compound can also be obtained by removing the protecting group.
- the selection of the protecting group, the introduction of the protecting group, and the removal of the protecting group can be carried out by appropriately selecting from the methods described in, for example, Greene and Wuts, “Protective Groups in Organic Synthesis (Third Edition)”.
- Examples of the method for producing the condensed imidazole derivative of the present invention include the following methods, but the method for producing the compound of the present invention is not limited thereto.
- R 1 , R 2 , R 3 , R 4 , R 5 , N n , N p , X are as defined above, L is a leaving group, and P represents a protecting group.
- Compound (III) can be produced by a condensation cyclization reaction of compound (II) and subsequent introduction of a protecting group.
- the condensed cyclization reaction is, for example, a method in which compound (II) and formic acid are heated and stirred in an aqueous hydrochloric acid solution, or compound (II) and ethyl orthoformate or methyl orthoformate are heated and stirred in microwave formic acid, etc. Can be performed.
- the reaction temperature is usually 40 to 200 ° C., preferably 40 to 150 ° C.
- the reaction time is usually 5 minutes to 48 hours, preferably 5 minutes to 6 hours.
- Compound (V) can be produced by reacting compound (III) and compound (IV) in the presence of an organolithium reagent in an inert solvent.
- an organolithium reagent for example, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide (LDA), lithium tetramethylpiperidide, lithium hexamethyldisilazide and the like are used.
- the amount of the organic lithium reagent to be used is generally 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (III).
- the inert solvent used in the reaction is not particularly limited as long as the reaction proceeds.
- reaction temperature is usually ⁇ 100 to 0 ° C., preferably ⁇ 78 to ⁇ 30 ° C.
- the reaction time is usually 0.5 to 24 hours, preferably 0.5 to 3 hours.
- Compound (VI) can be produced by reacting compound (V) with a leaving group introducing agent in the presence or absence of a base, in the absence of a solvent, or in an inert solvent.
- the leaving group introducing agent used include sulfonylating agents such as methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, and the like.
- the amount of the leaving group introducing agent to be used is generally 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (V).
- the inert solvent used in the reaction is not particularly limited as long as the reaction proceeds.
- diethyl ether, THF, dioxane, 1,2-dimethoxyethane, benzene, toluene, hexane, dichloromethane, chloroform, etc. may be used. it can. Two or more of these may be mixed and used at an appropriate ratio.
- the reaction temperature is usually ⁇ 30 ° C. to room temperature, preferably 0 ° C. to room temperature.
- the reaction time is usually 0.5 to 24 hours, preferably 0.5 to 3 hours.
- Compound (I) can be produced by reacting compound (VI) and compound (VII) in the presence or absence of a base in an inert solvent, followed by deprotection.
- Examples of compound (VII) include alcohols such as methanol and ethanol, amines such as dimethylamine, and thiols such as ethanethiol.
- the inert solvent used in the reaction between compound (VI) and compound (VII) is not particularly limited as long as the reaction proceeds. For example, chloroform, dichloromethane, diethyl ether, THF, benzene, toluene, xylene, N, N— Dimethylformamide (DMF), N, N-dimethylacetamide (DMA) and the like can be used.
- the amount of compound (VII) to be used is generally 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound (VI).
- the reaction temperature is usually ⁇ 20 ° C. to reflux temperature, preferably 0 ° C. to reflux temperature.
- the reaction time is usually 0.5 to 100 hours, preferably 1 to 48 hours.
- Compound (Ib) can be produced by deprotection of compound (V).
- Compound (Ib) can also be produced by a hydroxylation reaction of compound (Ia).
- the hydroxylation reaction is performed by, for example, a method of heating and stirring or microwave irradiation in a sulfuric acid aqueous solution, a hydrochloric acid aqueous solution, or a mixed solvent with THF, dioxane or the like.
- the reaction temperature is usually 40 to 200 ° C., preferably 80 to 180 ° C.
- the reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 3 hours.
- Compound (Ia) is produced by reacting Compound (V) with an alkylating agent in the presence of silver oxide in an inert solvent in the same manner as described in International Publication No. 2004/048335. it can.
- the inert solvent used for the reaction with the alkylating agent is not particularly limited as long as the reaction proceeds, and examples thereof include hydrocarbons such as benzene, toluene, cyclohexane and hexane, or a mixed solvent thereof.
- Examples of the alkylating agent to be used include alkyl iodides such as methyl iodide and ethyl iodide.
- the reaction temperature is ⁇ 20 ° C. to reflux temperature, preferably 0 ° C. to reflux temperature.
- the reaction time is usually 30 minutes to 10 hours, preferably 1 hour to 5 hours.
- compound (Ia) can be produced using compound (Ib) by a heating reaction with compound (IX) or microwave irradiation in the presence of an acid catalyst.
- the acid catalyst used include sulfuric acid and trifluoroacetic acid (TFA).
- Compound (IX) includes alcohols such as ethanol, isopropanol, cyclohexanol, benzyl alcohol, 2-methoxyethyl alcohol, phenol, 4-chlorophenol, 2-hydroxypyridine, 3-hydroxypyridine, 4-hydroxypyridine, and phenol.
- the reaction temperature is usually 100 ° C. to 250 ° C., preferably 150 ° C. to 200 ° C.
- the reaction time is usually 5 minutes to 3 hours, preferably 10 hours to 1 hour.
- compound (Ia) can be produced by an amide condensation reaction of compound (II) and compound (X) followed by a cyclization reaction.
- the amide condensation reaction is performed by reacting compound (II) and compound (X) in an inert solvent in the presence of a condensing agent and in the presence or absence of 1 to 5 equivalents of a base or the like. This reaction may be carried out in the presence of a catalytic amount to 5 equivalents of 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt) as necessary.
- HOBt 1-hydroxybenzotriazole
- HOAt 1-hydroxy-7-azabenzotriazole
- Examples of the condensing agent used in the reaction include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), diisopropylcarbodiimide (DIPC), and benzotriazol-1-yl.
- DCC dicyclohexylcarbodiimide
- EDC.HCl 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
- DIPC diisopropylcarbodiimide
- benzotriazol-1-yl examples of the condensing agent used in the reaction include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), diisopropylcarbodiimide (DIPC), and benzotriazol
- Oxytrisdimethylaminophosphonium hexafluorophosphide salt (BOP), diphenylphosphonyl azide (DPPA), N, N-carbodiimidazole (CDI), 2- (1H-7-azabenzotriazol-1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) or the like can be used.
- the amount of the condensing agent to be used is generally 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound (X).
- the inert solvent used in the reaction is not particularly limited as long as the reaction proceeds.
- dichloromethane, chloroform, DMF, DMA, THF, dimethoxyethane, acetonitrile, benzonitrile, ethyl acetate, and the like can be used. Two or more of these may be mixed and used at an appropriate ratio.
- a base used for the reaction pyridine, triethylamine, DMAP, DIPEA, or the like can be used.
- the reaction temperature is 0 ° C. to reflux temperature, preferably 0 ° C. to room temperature.
- the reaction time is usually 0.5 to 100 hours, preferably 1 to 48 hours.
- the subsequent cyclization reaction is carried out, for example, by acetic acid, formic acid, trifluoroacetic acid, or in a mixed solvent of these acids and alcohol, by heating and stirring, or by irradiation with microwaves.
- the amount of the acid used is 0.5 to 10 mL with respect to 1 mmol of the reaction substrate.
- the reaction temperature is usually 40 to 200 ° C, preferably 60 to 180 ° C.
- the reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 3 hours.
- compound (II) and compound (IV) used as a raw material compound in the manufacturing methods 1 and 2 can purchase a commercial item, or can manufacture it according to a well-known method.
- Compound (X) used as a raw material compound in Production Method 2 can be obtained by, for example, the method described in International Publication No. 2007/010516 pamphlet, CHIRALITY, Wiley-Liss, (USA), 2003, Vol. 15, p. According to the method described in 609-614, it can be produced from a benzaldehyde form as shown in the following formula.
- the compound (I) of the present invention thus obtained has excellent T-type calcium channel antagonism and high safety as shown in Test Examples described later. Accordingly, the compound (I) of the present invention is useful as a medicament for the prevention and treatment of diseases involving T-type calcium channels in animals including humans, particularly various diseases in which T-type calcium channel antagonistic action is effective. Examples of the disease include hypertension, atrial fibrillation, arrhythmia, cardiac hypertrophy, heart failure, renal dysfunction, cancer and the like.
- a pharmaceutical composition containing the compound (I) of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient is one or more of the compounds of the present invention and a pharmaceutical composition usually used for formulation.
- Administration is oral by tablet, pill, capsule, granule, powder, liquid, etc., or injection such as intravenous injection, intramuscular injection, suppository, nasal agent, transmucosal agent, transdermal agent, or inhalant Any form of parenteral administration, etc. may be used.
- the dosage is appropriately determined according to the individual case in consideration of the target disease or symptom, the age, weight, sex, etc. of the subject.
- the daily dose for an adult is suitably about 1 to 1000 mg, preferably about 3 to 300 mg, more preferably about 10 to 200 mg as the active ingredient (the compound of the present invention). Yes, this is administered once or divided into 2 to 4 times.
- the daily dose for an adult is usually about 0.01 to 100 mg, preferably about 0.01 to about 50 mg, more preferably about 0.01 to about 20 mg per kg body weight. It is appropriate to administer once to several times a day.
- Examples of the solid composition for oral administration according to the present invention include tablets, powders, granules and the like.
- one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, or metasilicic acid It can be manufactured by mixing with magnesium aluminate or the like.
- the solid composition may contain an additive other than an inert excipient, for example, a lubricant, a disintegrant, a stabilizer, a solubilizer or a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, or a gastric or enteric film.
- Liquid compositions for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and generally used inert diluents
- inert diluents For example, purified water and ethanol can be included.
- the composition may contain additives other than inert diluents, for example, adjuvants such as wetting agents, suspending agents, sweeteners, flavors, fragrances, or preservatives.
- the injection for parenteral administration can include a sterile aqueous or non-aqueous solution, suspension, or emulsion.
- the water-soluble solution or suspension can contain, for example, distilled water for injection and physiological saline as a diluent.
- the water-insoluble solution or suspension may contain, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 as a diluent.
- Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers, solubilizers and the like.
- a sterile solid composition can be produced and used by dissolving in sterile water or a sterile solvent for injection before use.
- Reference example 1 1-Dimethoxymethyl-5-fluoro-1H-benzimidazole mixture of positional isomers Under ice-cooling, 4-fluoro-1,2-phenylenediamine (21.0 g) was added with 4 mol / L hydrochloric acid (200 mL) and formic acid (38. 3 g) was sequentially added, and the mixture was stirred for 90 minutes under heating to reflux. Under ice cooling, a 10% aqueous sodium hydroxide solution was added to the reaction solution to make an alkaline solution, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was washed with diisopropyl ether to obtain 5-fluorobenzimidazole (19.7 g).
- the obtained 5-fluorobenzimidazole (19.7 g) was dissolved in toluene (500 mL), methyl orthoformate (38.7 g) and benzenesulfonic acid monohydrate (1.0 g) were sequentially added, and the mixture was heated under reflux. Stir for 40 hours. The solvent and methyl orthoformate were distilled off under reduced pressure, and the resulting residue was diluted with toluene.
- Table 1 shows compounds 2 and 3 produced by the same method as in Reference Example 1 using the corresponding raw materials.
- Reference example 4 (4-Benzyloxyphenyl)-(1-diethoxymethyl-5-methoxy-1H-benzimidazol-2-yl) methanol regioisomer mixture Under an argon atmosphere, the compound of Reference Example 3 (2.4 g) and 4 -Benzyloxybenzaldehyde (2.4 g) was dissolved in THF (30 mL), and about 1.14 mol / L LDA (hexane, THF solution) (10 mL) was added dropwise at a rate of 3 mL / min while cooling at -78 ° C. The mixture was stirred at the same temperature for 1 hour.
- THF hexane, THF solution
- Table 2 shows compound 5 produced by the same method as in Reference Example 4 using the corresponding raw materials.
- Table 3 shows compounds 7 and 8 produced by the same method as in Reference Example 6 using the corresponding raw materials.
- Reference Example 9 (6-Chloro-1-methoxymethyl-1H-imidazo [4,5-b] pyridin-2-yl)-(4-trifluoromethoxyphenyl) methanol regioisomer mixture
- Compound of Reference Example 7 under argon atmosphere (700 mg) and 4-trifluoromethoxybenzaldehyde (800 mg) were dissolved in THF (12 mL), and about 1.14 mol / L LDA (hexane, THF solution) (3.7 mL) was added dropwise with cooling at ⁇ 78 ° C. The mixture was stirred at the same temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
- Table 4 shows compounds 10 to 20 produced by the same method as in Reference Example 9 using the corresponding raw materials.
- Reference Example 22 Ethoxy (4-hydroxyphenyl) acetic acid
- the compound of Reference Example 21 (39.3 g) was dissolved in ethanol (315 mL), 10% aqueous sodium hydroxide solution (156 mL) was added under ice cooling, and the mixture was stirred at room temperature for 4 hr.
- the reaction solution was acidified with 2 mol / L hydrochloric acid, ethanol was distilled off under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Reference Example 23 [4- (2,5-Difluorobenzyloxy) phenyl] ethoxyacetic acid
- the compound of Reference Example 21 (13.6 g) was dissolved in DMF (200 mL), and potassium carbonate (10.5 g) and 2,5 were dissolved under ice cooling.
- -Difluorobenzyl bromide (14.6 g) was added and stirred at room temperature for 6.5 hours.
- the solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution was added to the resulting residue, and the mixture was extracted with diethyl ether.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product.
- Table 5 shows compounds 24 to 30 produced by the same method as in Reference Example 23 using the corresponding raw materials.
- the organic layer was washed successively with water, a saturated aqueous sodium hydrogen carbonate solution and water and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product.
- the obtained crude product was dissolved in ethanol (26 mL), an ethanol solution (52 mL) of potassium hydroxide (7.4 g) was added dropwise, and the mixture was stirred for 3 hours with heating under reflux. Water was added to the reaction solution, which was washed with diethyl ether, 6 mol / L hydrochloric acid was added to make an acidic solution, and the mixture was extracted with ethyl acetate.
- Table 6 shows compounds 33 to 35 produced by the same method as in Reference Example 32 using the corresponding raw materials.
- Reference Example 36 Ethoxy (4-trifluoromethanesulfonylphenyl) acetic acid
- the compound of Reference Example 33 (3.4 g) was dissolved in TFA (50 mL), 30% aqueous hydrogen peroxide (11.0 g) was added under ice cooling, and the mixture was stirred at room temperature for 20 minutes. Stir for hours.
- the reaction solution was poured into ice water, neutralized with 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (10-100% ethyl acetate / hexane) to give a crude product (620 mg) of the title compound.
- Reference Example 38 [4- (tert-Butyldimethylsilyloxy) phenyl] ethoxyacetic acid
- the compound of Reference Example 22 (12.0 g) was dissolved in DMF (200 mL), and under ice cooling, imidazole (18.3 g), tert-butyldimethylsilyl.
- Chloride (TBDMSCl) (19.4 g) was added and stirred at room temperature for 5 hours. Water was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product (11.8 g) of the title compound.
- Reference Example 39 2- ⁇ [4- (tert-butyldimethylsilyloxy) phenyl] ethoxymethyl ⁇ -5-ethoxy-1H-benzimidazole
- the compound of Reference Example 38 (9.0 g) and 4-ethoxy-1,2-phenylenediamine ( The title compound (9.4 g) was obtained in the same manner as in Example 65 using 4.9 g).
- Reference Example 40 2- ⁇ [4- (tert-Butyldimethylsilyloxy) phenyl] ethoxymethyl ⁇ -5-ethoxybenzimidazole-1-carboxylic acid tert-butyl ester
- the compound of Reference Example 39 (9.4 g) was added to dichloromethane (440 mL). Dissolved, di-tert-butyl dicarbonate (5.3 g), triethylamine (8.5 g) and DMAP (215 mg) were successively added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes.
- Reference Example 41 5-Ethoxy-2- [ethoxy (4-hydroxyphenyl) methyl] benzimidazole-1-carboxylic acid tert-butyl ester
- THF 315 mL
- 1 mol / L tetra-n-butylammonium fluoride (TBAF) in THF (22.3 mL) was added, and the mixture was stirred at room temperature for 30 minutes.
- a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (25-50% ethyl acetate / hexane) to give the title compound (8.4 g) as a regioisomer mixture.
- Reference Example 44 4- [Ethoxy (5-ethoxy-1H-benzimidazol-2-yl) methyl] benzoic acid
- the compound of Reference Example 43 (300 mg) was dissolved in 1,4-dioxane (20 mL), and a 30% aqueous sodium hydroxide solution ( 10 mL) was added, and the mixture was stirred for 16 hours with heating under reflux.
- the reaction solution was washed with diethyl ether, 6 mol / L hydrochloric acid was added to make an acidic solution, and the mixture was extracted with ethyl acetate.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Reference Example 46 Hydroxy (4-trifluoromethoxyphenyl) acetic acid
- the compound of Reference Example 45 (10.0 g) was dissolved in ethanol (15 mL), 10% aqueous sodium hydroxide solution (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution, which was washed with diethyl ether, 6 mol / L hydrochloric acid was added to make an acidic solution, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (8.7 g) as a colorless solid.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was dissolved in THF (150 mL), 1 mol / L hydrochloric acid (150 mL) was added under ice cooling, and the mixture was stirred at room temperature for 4 hr.
- the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to make an alkaline solution, and the mixture was extracted with ethyl acetate.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Tables 7 and 8 show compounds 3 to 16 produced by the same method as in Example 1 using the corresponding starting materials.
- Example 1 The compound of Example 1 (444 mg) was dissolved in THF (7 mL), thionyl chloride (178 mg) and pyridine (247 mg) were added, and after stirring at room temperature for 30 minutes, ethanethiol (101 mg) and DIPEA (535 ⁇ L) were added. And stirred at room temperature for 1.5 hours. After the reaction solution was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to make an alkaline solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Example 1 The compound of Example 1 (150 mg) was dissolved in THF (5 mL), thionyl chloride (60 mg) and pyridine (146 mg) were added, and the mixture was stirred at room temperature for 30 minutes, and then 3-hydroxypyridine (87 mg), potassium hydroxide ( 65 mg) was added, and the mixture was stirred for 30 minutes under reflux. A 10% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Example 15 The compound of Example 15 (100 mg) was dissolved in THF (2 mL), thionyl chloride (40 mg) and pyridine (28 mg) were added, and the mixture was stirred at room temperature for 2 hours. A 20% ethanol solution (260 ⁇ L) of sodium ethoxide was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour and at 50 ° C. for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Example 17 The compound of Example 17 (100 mg) was dissolved in dichloromethane (3 mL), m-chloroperbenzoic acid (161 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hr. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to make an alkaline solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (33-100% ethyl acetate / hexane) to give the colorless amorphous title compound (62 mg).
- Example 2 The compound of Example 1 (123 mg) was dissolved in isopropanol (2 mL), concentrated sulfuric acid (41 mg) was added, and the mixture was heated in a microwave reactor at 140 ° C. for 1 hour and 160 ° C. for 2 hours. A 10% aqueous sodium hydroxide solution was added to the reaction solution to make an alkaline solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10-100% ethyl acetate / hexane) to give the title compound (66 mg) as a colorless solid.
- Tables 9 and 10 show compounds 23 to 33 produced by the same method as in Example 21 using the corresponding starting materials.
- the compound of Reference Example 4 (150 mg) was dissolved in dichloromethane, and triethylamine (98 mg) and methanesulfonyl chloride (56 mg) were sequentially added under ice cooling, followed by stirring at the same temperature for 30 minutes. While maintaining the same temperature, morpholine (85 mg) was added dropwise to the reaction solution and stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was dissolved in THF (4 mL), 1 mol / L hydrochloric acid (2 mL) was added under ice cooling, and the mixture was stirred at the same temperature for 30 min.
- a 1 mol / L aqueous sodium hydroxide solution was added to the reaction solution to make an alkaline solution, and the mixture was extracted with ethyl acetate.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by basic silica gel column chromatography (10-30% ethyl acetate / hexane) to give the colorless amorphous title compound (75 mg).
- Example 11 shows compounds 38 to 41 produced by the same method as in Example 35 using the corresponding starting materials.
- Example 37 The compound of Example 37 (30 mg) was dissolved in methanol (2 mL), water (1 mL) was added, Oxone (registered trademark, DuPont, 55 mg) was added, and the mixture was heated at 40 ° C. for 3 hr. Methanol was distilled off under reduced pressure, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (20-100% ethyl acetate / hexane) to give the title compound (10 mg) as a colorless solid.
- Example 11 The compound of Example 11 (200 mg) was dissolved in methanol (6 mL), 5% palladium on carbon (282 mg) was added, and the mixture was stirred at room temperature for 67 hours under a hydrogen stream (1 atm). The reaction solution was diluted with chloroform, filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (47-61% ethyl acetate / hexane) to give a yellow amorphous title compound (98 mg).
- the compound of Reference Example 9 (682 mg) was dissolved in THF (10 mL), 4.5 mL of 2 mol / L hydrochloric acid aqueous solution was added, and the mixture was stirred with a microwave reactor at 75 ° C. for 10 minutes and at 100 ° C. for 10 minutes. A 10% aqueous sodium hydroxide solution was added to the reaction solution to make an alkaline solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (3-20% methanol / chloroform).
- Example 45 to 50 Table 12 shows compounds 45 to 50 produced by the same method as in Example 44 using the corresponding starting materials.
- the compound of Reference Example 12 (300 mg) was dissolved in dichloromethane (6 mL), m-chloroperbenzoic acid (440 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to make the solution alkaline and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (12 to 90% ethyl acetate / hexane), and colorless amorphous [1-methoxymethyl-5- (propanyl-1-sulfonyl) -1H-benzimidazole-2- Yl]-(4-trifluoromethoxyphenyl) methanol (220 mg) was obtained.
- the obtained [1-methoxymethyl-5- (propanyl-1-sulfonyl) -1H-benzimidazol-2-yl]-(4-trifluoromethoxyphenyl) methanol (220 mg) was dissolved in ethanol (2 mL).
- the compound of Reference Example 14 (5.6 g) was dissolved in toluene (45 mL), silver (I) oxide (6.6 g) and iodoethane (5.6 mL) were added, and the mixture was heated at 70 ° C. for 1.5 hours.
- the reaction solution was diluted with chloroform, filtered through celite, and the solvent was evaporated under reduced pressure.
- the obtained residue was dissolved in ethanol (71 mL), concentrated sulfuric acid (1.5 g) was added, and the mixture was stirred with heating under reflux for 2 hr.
- a 10% aqueous sodium hydroxide solution was added to the reaction solution to make an alkaline solution, and the mixture was extracted with chloroform.
- Tables 13 and 14 show compounds 53 to 59 produced by the same method as in Example 52 using the corresponding starting materials.
- the compound of Reference Example 23 (2.0 g) was dissolved in dichloromethane (25 mL), and EDC (1.4 g), HOBt (1.1 g), 4-ethoxy-1,2-phenylenediamine (1. 0 g) was sequentially added and stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (20-50% ethyl acetate / hexane) to obtain an amide compound (2.3 g) as a regioisomer mixture.
- the obtained amide compound (2.3 g) was dissolved in acetic acid (40 mL) and heated at 100 ° C. for 30 minutes.
- the solvent was distilled off under reduced pressure, diluted with water, a saturated aqueous sodium hydrogen carbonate solution was added to make an alkaline solution, and extracted with ethyl acetate.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Example 61 to 64 Table 15 shows compounds 61 to 64 produced by the same method as in Example 60 using the corresponding starting materials.
- the compound of Reference Example 23 (300 mg) was dissolved in DMF (4 mL), and HATU (425 mg), 4-fluoro-1,2-phenylenediamine (129 mg) and DIPEA (289 mg) were sequentially added thereto, and the mixture was stirred at room temperature for 4 hours. Stir. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography (10-40% ethyl acetate / hexane) to obtain an amide compound as a regioisomer mixture.
- the obtained amide compound (377 mg) was dissolved in acetic acid (6 mL) and heated at 80 ° C. for 1 hour.
- the solvent was distilled off under reduced pressure, diluted with water, neutralized to alkaline by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Examples 72 to 94 Tables 16 to 20 show compounds 72 to 94 produced by the same method as in Example 65 using the corresponding starting materials.
- Example 96 to 100 Table 21 shows compounds 96 to 100 produced by the same method as in Example 95 using the corresponding starting materials.
- the obtained residue was purified by silica gel column chromatography (10 to 100% ethyl acetate / hexane) to give 5-ethoxy-2- ⁇ ethoxy [4- (3-fluorobenzyloxy) phenyl] methyl ⁇ benzimidazole-1 -Carboxylic acid tert-butyl ester (172 mg) was obtained.
- the obtained 5-ethoxy-2- ⁇ ethoxy [4- (3-fluorobenzyloxy) phenyl] methyl ⁇ benzimidazole-1-carboxylic acid tert-butyl ester (172 mg) was dissolved in dichloromethane (2 mL) and ice-cooled.
- Tables 22 and 23 show compounds 102 to 108 produced by the same method as in Example 101 using the corresponding raw materials.
- the compound of Reference Example 43 (100 mg) was dissolved in THF (2 mL), 2 mol / L benzylmagnesium chloride (THF solution) (1 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (10-100% ethyl acetate / hexane) to give the colorless amorphous title compound (110 mg).
- Example 112 The compound of Example 112 (300 mg) and zinc cyanide (364 mg) were suspended in DMF (4 mL), and argon bubbling was performed for 10 minutes. Tetrakistriphenylphosphine palladium (179 mg) was added to the reaction solution, and heated at 130 ° C. for 1 hour in a microwave reactor. A 28% aqueous ammonia solution (6 mL) was added to the reaction solution, filtered through a glass filter, and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Example 113 Using the compound of Example 113 (139 mg), the title compound (103 mg) as a colorless solid was obtained in the same manner as in Example 114.
- 1 H-NMR (CDCl 3 ) ⁇ : 1.33 (3H, t, J 7.1 Hz), 3.60-3.71 (2H, m), 5.72 (1H, s), 7.21 -7.25 (2H, m), 7.46-8.04 (5H, m), 9.77-9.81 (1H, br m).
- ESI-MS Found: m / z 362 (M + H) +
- the compound of Reference Example 44 (100 mg) was dissolved in THF (4 mL), EDC (56 mg), DIPEA (190 mg), DMAP (4 mg), and benzyl alcohol (159 mg) were sequentially added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (12-50% ethyl acetate / hexane) to give the colorless amorphous title compound (24 mg).
- the compound of Reference Example 44 (40 mg) was dissolved in THF (4 mL), HATU (67 mg), DIPEA (76 mg), and benzylamine (159 mg) were sequentially added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (12-50% ethyl acetate / hexane) to give the title compound (40 mg) as a colorless solid.
- Example 134 to 140 Table 26 shows compounds 134 to 140 produced by the same method as in Example 1 using the corresponding starting materials.
- Example 141 to 148 Table 27 shows compounds 141 to 148 produced by the same method as in Example 21 using the corresponding starting materials.
- Example 87 The compound of Example 87 (1.4 g) was dissolved in a mixed solution of 1,4-dioxane / water (1: 1) (18 mL), concentrated sulfuric acid (414 mg) was added, and the mixture was heated at 170 ° C. at 170 ° C. Heated for 5 hours. A 10% aqueous sodium hydroxide solution was added to the reaction solution to make an alkaline solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Examples 150 to 163 Tables 28 to 29 show compounds 150 to 163 produced by the same method as in Example 149 using the corresponding starting materials.
- Example 70 The compound of Example 70 (120 mg) was dissolved in 1,4-dioxane (2 mL), 2-fluoroethanol (22 mg) and concentrated sulfuric acid (99 mg) were sequentially added, and the mixture was heated at 180 ° C. for 5 minutes in a microwave reactor. did. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to make an alkaline solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (20-50% ethyl acetate / hexane) to give the title compound (63 mg) as a colorless solid.
- Example 165 to 170 Table 30 shows compounds 165 to 170 produced by the same method as in Example 164 using the corresponding starting materials.
- Example 128 The compound of Example 128 (366 mg) and zinc cyanide (410 mg) were suspended in DMF (4 mL), and argon bubbling was performed for 10 minutes. Tetrakis (triphenylphosphine) palladium (100 mg) was added to the reaction solution and heated at 130 ° C. for 60 minutes in a microwave reactor. Concentrated aqueous ammonia was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Example 128 Under an argon atmosphere, the compound of Example 128 (96 mg) was dissolved in a toluene / water (2: 1) mixed solution (3.3 mL), cesium carbonate (373 mg), cyclopropylboronic acid (48 mg), tetrakis (triphenyl) Phosphine) palladium (27 mg) was sequentially added and heated in a microwave reactor at 130 ° C. for 60 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- Example 70 The compound of Example 70 (1.0 g) was dissolved in isopropanol (6 mL), maleic acid (344 mg) was added, and the mixture was stirred at room temperature for 5 minutes. After precipitation of the solid, diisopropyl ether (6 ml) was added to the reaction mixture, and the mixture was filtered through a glass filter to give the title compound (0.9 g) as a colorless solid.
- Example 70 The compound of Example 70 (176 mg) was dissolved in isopropanol (1.5 mL), oxalic acid (49 mg) was added, and the mixture was stirred at room temperature for 18 hours. After the solid precipitated, diisopropyl ether was added to the reaction mixture, and the mixture was collected by filtration with a glass filter to obtain the title compound (142 mg) as a colorless solid.
- Example 70 The compound of Example 70 (177 mg) was dissolved in isopropanol (1.2 mL), 4-methylbenzenesulfonic acid (344 mg) was added, and the mixture was stirred at room temperature for 52 hours. After precipitation of the solid, diethyl ether was added to the reaction solution, which was collected by filtration with a glass filter to give the title compound (246 mg) as a colorless solid.
- Example 70 The compound of Example 70 (173 mg) was dissolved in isopropanol (1.5 mL), benzenesulfonic acid (344 mg) was added, and the mixture was stirred at room temperature for 18 hours. After the solid precipitated, diisopropyl ether was added to the reaction solution, and the mixture was collected by filtration with a glass filter to obtain the title compound (153 mg) as a colorless solid.
- Example 70 The compound of Example 70 (1.0 g) was dissolved in THF (6 mL), phosphoric acid (325 mg) was added thereto, and the mixture was stirred at room temperature for 2.5 hours. After precipitation of the solid, diethyl ether was added to the reaction mixture, and the mixture was collected by filtration with a glass filter to give the title compound (1.2 g) as a colorless solid.
- Test example 1 Representative compounds of the present invention were tested for selective antagonism against T-type calcium channel (Cav3.2) according to the following test examples.
- human fetal kidney cells HEK293 cells
- HEK293 cells stably expressing human T-type calcium channels
- human Cav3.2 human Cav3.2
- FBS fetal bovine serum
- penicillin 100 U / mL
- streptomycin 100 ⁇ g / mL
- G418 250 ⁇ g / mL
- the cells were suspended in a culture solution, seeded in a 96-well plate, and then cultured for 24 hours. Excluding the culture solution, 5% (v / v) FBS, calcium chloride (0.5 mmol / L), L-glutamine (2 mmol / L), L-alanine (8.9 ng / mL), L-asparagine (13.
- assay buffer 140 mmol / L sodium chloride, 5 mmol / L potassium chloride, 0.5 mmol / L magnesium chloride, 0.5 mmol / L calcium chloride, 10 mmol / L glucose, 0 ° C.
- assay buffer 140 mmol / L sodium chloride, 5 mmol / L potassium chloride, 0.5 mmol / L magnesium chloride, 0.5 mmol / L calcium chloride, 10 mmol / L glucose, 0 ° C.
- an assay buffer in which Fura2-AM, a fluorescent Ca 2+ indicator, was dissolved in 5 ⁇ M was added, and 37 Incubated for 30 minutes at ° C.
- the assay buffer in which Fura2 was dissolved was removed, and after washing with the assay buffer, the assay buffer to which the test compound was added was added and incubated for 15 minutes. After setting the plate in a fluorescence measuring device (FLex Station II, Molecular Devices) and measuring the baseline, the change in intracellular calcium concentration induced when assay buffer added with 100 mmol / L calcium chloride was added. Measured (340 nm, 380 nm excitation, 510 nm detection), and the fluorescence intensity ratio obtained from each wavelength was calculated.
- test compound solution was prepared with an assay buffer so that each test compound was dissolved in DMSO so as to be 10 mmol / L, and then at a set concentration. DMSO was used instead of the test compound in the control solution.
- the inhibitory activity value (%) of the test compound is obtained by subtracting the average value of the fluorescence intensity ratio for 0 to 20 seconds from the start of measurement from the average value of the fluorescence intensity ratio for 45 to 50 seconds after the start of measurement, and obtaining the value in the control solution
- the maximum activity of Cav3.2 was calculated by comparing with the activity in the presence of the test compound.
- IC 50 value The inhibitory activity of the test compound was measured at concentrations of 0.3, 0.5, 1, 3, 5, 10 and 30 ⁇ mol / L, respectively, and the curve fit equation (Model) of Assay Explorer (Symyx) was measured. 08: sigmoidal inhibition curve) was calculated and IC 50 values with.
- Curve fitting formula (Model08: Sigma Inhibition Carve, Vmax + Y2 to Y2)
- HC average LC of RFU value 25-30 seconds after addition of Ca 2+ -containing assay buffer after treatment with control solution (45-50 seconds after measurement start): 25-30 after addition of assay buffer without Ca 2+ after treatment with control solution
- the RFU in the average expression of the RFU values for 2 seconds represents the relative fluorescence intensity (Relational Fluorescence Unit).
- Test Example 2 Electrophysiological test (Patch clamp method) Representative compounds of the present invention were tested for selective antagonism against T-type calcium channel (Cav3.2) according to the following test examples.
- human fetal kidney cells HEK293 cells
- human Cav3.2 human T-type calcium channels
- HEK293 cells stably expressing human Cav3.2 were supplemented with 10% (v / v) fetal bovine serum (FBS), penicillin (100 U / mL), streptomycin (100 ⁇ g / mL), G418 (250 ⁇ g / mL) at 37 ° C.
- the cells were cultured in Alpha-MEM.
- the cells were collected by an actase (SIGMA) treatment and suspended in a culture solution.
- Measurement inner solution 50 mmol / L CsCl, 10 mmol / L NaCl, 60 mmol / L CsF, 2 mmol / L MgCl 2 , 20 mmol / L EGTA, 10 mmol / L HEPES / CsOH pH 7.2
- measurement outer solution 80 mmol / L NaCl, 1 mmol / L TEACl, 3 mmol / L KCl, 35 mmol / L CaCl 2 , 10 mmol / L MgCl 2 , 10 mmol / L HEPES, pH 7.2
- the calcium current was measured.
- the holding potential was fixed at ⁇ 80 mV, and ⁇ 20 mV pulses were applied to the cells at 5-second intervals, and the inhibitory effect of the compound on the peak current was measured.
- the current was measured by sequentially exchanging with an external solution (1 ⁇ mol / L, 3 ⁇ mol / L, 10 ⁇ mol / L, 50 ⁇ mol / L) containing the compound.
- the inhibition rate was calculated from the peak current value, and the IC 50 value was calculated from an approximate expression derived by linear regression after the inhibition rate was converted by the probit method. The results are shown in Table 31.
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Abstract
Description
下記の一般式(I)
環Nnは窒素原子を有していてもよい縮合6員芳香環を示し;
環Npは窒素原子を有していても良い6員芳香環を示し;
nは縮合6員芳香環に含まれる窒素原子の数を示し、0、1又は2であり;
pは6員芳香環に含まれる窒素原子の数を示し、0又は1であり;
R1及びR2は同一又は異なって、
(1)水素原子、
(2)ハロゲン原子、
(3)ヒドロキシ基、
(4)シアノ基、
(5)ニトロ基、
(6)置換基を有していてもよいC1-6アルキル基、
(7)置換基を有していてもよいC1-6アルコキシ基、
(8)-SR6、
(9)-SO2R6
(10)-SO2NR6R7
(11)-(C=O)-R6、又は
(12)アミノ基
を示し;
R6及びR7は同一又は異なって、置換基を有していてもよいC1-6アルキル基を示し;
R3は、
(1)水素原子、
(2)置換基を有していてもよいC1-6アルキル基、
(3)-(C=O)-R8、又は
(4)置換基を有していてもよいアリール基又はヘテロアリール基
を示し;
R8は、置換基を有していてもよいC1-6アルキル基を示し;
Xは、酸素原子、硫黄原子、-SO2-、-N(R9)-を示し;
R9は、置換基を有していてもよいC1-6アルキル基を示すか、又はR3及び隣接する窒素原子と一緒になって置換基を有していてもよい非芳香族複素環を形成してもよく;
R4は、
(1)ハロC1-6アルキル基、
(2)置換基を有していてもよいC2-6アルケニル基
(3)ハロC1-6アルコキシ基、
(4)置換基を有していてもよいアラルキル基、
(5)置換基を有していてもよいアラルキルオキシ基、
(6)置換基を有していてもよいヘテロアラルキルオキシ基、
(7)置換基を有していてもよいアリールオキシC1-6アルキル基、
(8)-SR10、
(9)-SO2R10、
(10)-SO2NR11R12、
(11)-NR12R13、
(12)-(C=O)-R13、
(13)-(C=O)-OR13、
(14)-(C=O)-NR12R13、又は
(15)置換基を有していてもよいアリール基又はヘテロアリール基
を示し;
R10はハロC1-6アルキル基を示し;
R11は置換基を有していてもよいアリール基又はヘテロアリール基を示し;
R12は水素原子又は置換基を有していてもよいC1-6アルキル基を示し;
R13は置換基を有していてもよいアラルキル基を示し;
R5は、
(1)水素原子、
(2)ハロゲン原子、
(3)ヒドロキシ基、
(4)ニトロ基、
(5)シアノ基、
(6)置換基を有していてもよいC1-6アルキル基、又は
(7)置換基を有していてもよいC1-6アルコキシ基
を示し;
R4とR5は一緒になって置換基を有していてもよい芳香環又は非芳香環を形成してもよく;
ただし、R4が置換基を有さないアラルキルオキシ基であり、nが0の場合、XR3はOHではない]
で表される化合物、その薬学的に許容される塩、又はそれらの溶媒和物を提供するものである。
また、本発明は上記一般式(I)で表される化合物、その薬学的に許容される塩、又はそれらの溶媒和物を含有する医薬を提供するものである。
また、本発明は、T型カルシウムチャネル拮抗作用が有効な疾患の治療又は予防のために使用される上記一般式(I)で表される化合物、その薬学的に許容される塩、又はそれらの溶媒和物を提供するものである。
また、本発明は、上記一般式(I)で表される化合物、その薬学的に許容される塩、又はそれらの溶媒和物の、T型カルシウムチャネル拮抗作用が有効な疾患の治療薬又は予防薬製造のための使用を提供するものである。
また、本発明は、上記一般式(I)で表される化合物、その薬学的に許容される塩、又はそれらの溶媒和物の有効量を投与すること特徴とする、T型カルシウムチャネル拮抗作用が有効な疾患の治療方法又は予防方法を提供するものである。
R1、R2で示される置換基を有していてもよいC1-6アルキル基としては、無置換であるか、または1~5個のハロゲン原子で置換されたC1-6アルキル基が好ましく、無置換のC1-6アルキル基が特に好ましい。R3で示される置換基を有していてもよいC1-6アルキル基としては、無置換であるか、または1~5個のハロゲン原子、C1-6アルコキシ基、アリール基、ヒドロキシ基で置換されたC1-6アルキル基が好ましく、無置換のC1-6アルキル基が特に好ましい。R1、R2で示される置換基を有していてもよいC1-6アルコキシ基としては、無置換であるか、または1~5個のハロゲン原子で置換されたC1-6アルコキシ基が好ましく、無置換のC1-6アルコキシ基が特に好ましい。その他としては、無置換のものが好ましい。
置換基を有するアリール基、ヘテロアリール基、アリールオキシ基、ヘテロアリールオキシ基、アラルキル基、ヘテロアラルキル基、アラルキルオキシ基、ヘテロアラルキルオキシ基、アリールオキシC1-6アルキル基としては、芳香環上に1~5個、好ましくは1~3個のC1-6アルキル基、ハロゲン原子、シアノ基、ヒドロキシ基、C1-6アルコキシ基の置換基を有するものが好ましい。
R4で示される置換基を有していてもよいアラルキルオキシ基又はヘテロアラルキルオキシ基としては、無置換であるか、芳香環上に1~3個のハロゲン原子、C1-6アルキル基、C1-6アルコキシ基、ハロC1-6アルキル基、ハロC1-6アルコキシ基で置換されたものが好ましい。その他としては、無置換のものが好ましい。
<1>nは好ましくは0又は1であり、より好ましくは0である。従って、Nn環としてはベンゼン環又はピリジン環が好ましく、より好ましくはベンゼン環である。
R1としては、
(1)ハロゲン原子、
(2)置換基を有していてもよいC1-6アルキル基、
(3)置換基を有していてもよいC1-6アルコキシ基、
が好ましく;
(1)フッ素原子
(2)塩素原子
(3)C1-6アルキル基
(4)C1-6アルコキシ基
(5)ハロC1-6アルコキシ基
がさらに好ましく、
特に好ましくは、フッ素原子である。
(1)水素原子、
(2)置換基を有していてもよいC1-6アルキル基、
(3)置換基を有していてもよいアリール基若しくはヘテロアリール基
であり;
より好ましくは、
(1)水素原子、
(2)C1-6アルキル基、
(3)ハロC1-6アルキル基、
(4)アリール基若しくはヘテロアリール基
であり;
特に好ましくは、水素原子、メチル基、エチル基、2-フルオロエチル基、イソプロピル基である。
(1)ハロC1-6アルキル基、
(2)ハロC1-6アルコキシ基、
(3)置換基を有していてもよいアラルキル基、
(4)置換基を有していてもよいアラルキルオキシ基、
(5)-SR10、
(6)置換基を有していてもよいアリール基若しくはヘテロアリール基
であり、
より好ましくは、
(1)ハロC1-4アルキル基、
(2)ハロC1-4アルコキシ基、
(3)置換基を有していてもよいアラルキルオキシ基
(4)-SR10、
であり;
さらに好ましくは、
(1)フッ素原子で置換されたC1-4アルキル基、
(2)フッ素原子で置換されたC1-4アルコキシ基、
(3)ハロゲン原子で置換されたアラルキルオキシ基
であり;
特に好ましくは、トリフルオロメトキシ基である。
(1)水素原子、
(2)ハロゲン原子、
であり;
より好ましくは、水素原子である。
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメチルスルファニルフェニル)メタノール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメチルフェニル)メタノール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-[3-フルオロ-4-(トリフルオロメチル)フェニル]メタノール;
2-[エトキシ(4-トリフルオロメチルフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-[4-(1,1,2,2-テトラフルオロエトキシ)フェニル]メタノール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(ナフタレン-2-イル)メタノール;
(2,2-ジフルオロベンゾ[1,3]ジオキソール-5-イル)-(5-フルオロ-1H-ベンズイミダゾール-2-イル)メタノール;
5-フルオロ-2-[イソプロポキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
5-フルオロ-2-[(2-メトキシエトキシ)-(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
(6-クロロ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(6-フルオロ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-[4-(4-メチルベンジルオキシ)フェニル]メタノール;
6-クロロ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-3H-イミダゾ[4,5-b]ピリジン;
6-クロロ-2-{エトキシ[4-(4-メチルベンジルオキシ)フェニル]メチル}-3H-イミダゾ[4,5-b]ピリジン;
2-{エトキシ[4-(4-メチルベンジルオキシ)フェニル]メチル}-6-フルオロ-3H-イミダゾ[4,5-b]ピリジン;
6-クロロ-2-{エトキシ[4-(4-フルオロベンジルオキシ)フェニル]メチル}-3H-イミダゾ[4,5-b]ピリジン;
2-{エトキシ[4-(4-フルオロベンジルオキシ)フェニル]メチル}-6-フルオロ-3H-イミダゾ[4,5-b]ピリジン;
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-エトキシ-1H-ベンズイミダゾール;
5-クロロ-2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-1H-ベンズイミダゾール;
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-トリフルオロメチル-1H-ベンズイミダゾール;
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-メトキシ-1H-ベンズイミダゾール;
5-エトキシ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール;
5-エトキシ-2-[メトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-メチル-1H-ベンズイミダゾール;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-メトキシ-1H-ベンズイミダゾール;
5-クロロ-2-[メトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
5-フルオロ-2-[メトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
5-エトキシ-2-[エトキシ(4-トリフルオロメチルスルファニルフェニル)メチル]-1H-ベンズイミダゾール;
5-エトキシ-2-{エトキシ[4-(4-メチルベンジルオキシ)フェニル]メチル}-1H-ベンズイミダゾール;
2-{[4-(2,4-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-エトキシ-1H-ベンズイミダゾール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-[3-フルオロ-4-(トリフルオロメトキシ)フェニル]メタノール;
[3-ブロモ-4-(トリフルオロメトキシ)フェニル]-(5-フルオロ-1H-ベンズイミダゾール-2-イル)メタノール;
2-[エトキシ(3-フルオロ-4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-[4-(2,2,2-トリフルオロエトキシ)フェニル]メタノール;
5-フルオロ-2-{メトキシ[4-(2,2,2-トリフルオロエトキシ)フェニル]メチル}-1H-ベンズイミダゾール;
2-{エトキシ[4-(2,2,2-トリフルオロエトキシ)フェニル]メチル}-5-フルオロ-1H-ベンズイミダゾール;
2-[(2,2-ジフルオロベンゾ[1,3]ジオキソール-5-イル)エトキシメチル]-5-フルオロ-1H-ベンズイミダゾール;
2-[(2,2-ジフルオロベンゾ[1,3]ジオキソール-5-イル)メトキシメチル]-5-フルオロ-1H-ベンズイミダゾール;
(5-ニトロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
5-クロロ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(5-プロピルスルファニル-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(6-クロロ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-(2,2-ジフルオロベンゾ[1,3]ジオキソール-5-イル)メタノール;
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-フルオロ-1H-ベンズイミダゾール;
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-ニトロ-1H-ベンズイミダゾール;
5-エトキシ-2-{エトキシ[4-(4-フルオロベンジルオキシ)フェニル]メチル}-1H-ベンズイミダゾール;
5-エトキシ-2-{エトキシ[4-(3-フルオロベンジルオキシ)フェニル]メチル}-1H-ベンズイミダゾール;
5-エトキシ-2-{エトキシ[4-(2-フルオロベンジルオキシ)フェニル]メチル}-1H-ベンズイミダゾール;
2-{[4-(3,5-ジメトキシベンジルオキシ)フェニル]エトキシメチル}-5-エトキシ-1H-ベンズイミダゾール;
5-エトキシ-2-{エトキシ[4-(4-トリフルオロメトキシベンジルオキシ)フェニル]メチル}-1H-ベンズイミダゾール;
(5-ブロモ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
5-ブロモ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[ヒドロキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール-5-カルボニトリル;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール-5-カルボニトリル;
6-クロロ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-4-フルオロ-1H-ベンズイミダゾール;
6-クロロ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール-4-イルアミン;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5,6-ジフルオロ-1H-ベンズイミダゾール;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-6-フルオロ-3H-イミダゾ[4,5-b]ピリジン;
6-ブロモ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-3H-イミダゾ[4,5-b]ピリジン;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-トリフルオロメトキシ-1H-ベンズイミダゾール;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-トリフルオロメチル-1H-ベンズイミダゾール;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-4-フルオロ-1H-ベンズイミダゾール;
5-ジフルオロメトキシ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[(3-ブロモ-4-トリフルオロメトキシフェニル)メトキシメチル]-5-フルオロ-1H-ベンズイミダゾール;
2-[(3-ブロモ-4-トリフルオロメトキシフェニル)メトキシメチル]-1H-ベンズイミダゾール;
2-[(3-ブロモ-4-トリフルオロメトキシフェニル)メトキシメチル]-5-メトキシ-1H-ベンズイミダゾール;
2-[(3-ブロモ-4-トリフルオロメトキシフェニル)メトキシメチル]-5-エトキシ-1H-ベンズイミダゾール;
5-ジフルオロメトキシ-2-[エトキシ(4-トリフルオロメチルフェニル)メチル]-1H-ベンズイミダゾール;
5-ジフルオロメトキシ-2-[メトキシ(4-トリフルオロメチルフェニル)メチル]-1H-ベンズイミダゾール;
(1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(5-ジフルオロメトキシ-1H-ベンズイミダゾール-2-イル)-(4-ジフルオロメトキシフェニル)メタノール;
(5-ジフルオロメトキシ-1H-ベンズイミダゾール-2-イル)-[4-(2,2,2-トリフルオロエトキシ)フェニル]メタノール;
(5-ジフルオロメトキシ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメチルフェニル)メタノール;
(3-クロロ-4-トリフルオロメトキシフェニル)-(5-フルオロ-1H-ベンズイミダゾール-2-イル)メタノール;
(1H-ベンズイミダゾール-2-イル)-(3-クロロ-4-トリフルオロメトキシフェニル)メタノール;
(3-クロロ-4-トリフルオロメトキシフェニル)-(5-メトキシ-1H-ベンズイミダゾール-2-イル)メタノール;
2-[メトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[プロポキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[イソプロポキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[(3-クロロ-4-トリフルオロメトキシフェニル)エトキシメチル]-5-フルオロ-1H-ベンズイミダゾール;
2-[(3-クロロ-4-トリフルオロメトキシフェニル)エトキシメチル]-1H-ベンズイミダゾール;
2-[(3-クロロ-4-トリフルオロメトキシフェニル)エトキシメチル]-5-メトキシ-1H-ベンズイミダゾール;
(5-メトキシ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
2-[イソプロポキシ(4-トリフルオロメトキシフェニル)メチル]-3H-イミダゾ[4,5-b]ピリジン;
(5-クロロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(5-ジフルオロメトキシ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
2-[ヒドロキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール-5-オール;
(6-クロロ-4-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(5-トリフルオロメトキシ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(4-トリフルオロメトキシフェニル)-(5-トリフルオロメチル-1H-ベンズイミダゾール-2-イル)メタノール;
(4-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(1H-ベンズイミダゾール-2-イル)-(3-ブロモ-4-トリフルオロメトキシフェニル)メタノール;
(3-ブロモ-4-トリフルオロメトキシフェニル)-(5-メトキシ-1H-ベンズイミダゾール-2-イル)メタノール;
(3-ブロモ-4-トリフルオロメトキシフェニル)-(5-エトキシ-1H-ベンズイミダゾール-2-イル)メタノール;
(5,6-ジフルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(3-イソプロピル-4-トリフルオロメトキシフェニル)メタノール;
(6-フルオロ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(6-ブロモ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
5-フルオロ-2-[(2-フルオロエトキシ)-(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メトキシ]エタノール;
5-フルオロ-2-[プロポキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[イソプロポキシ(4-トリフルオロメトキシフェニル)メチル]-5-メトキシ-1H-ベンズイミダゾール;
5-エトキシ-2-[イソプロポキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
5-クロロ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
5-フルオロ-2-[メトキシ(4-トリフルオロメチルフェニル)メチル]-1H-ベンズイミダゾール;
5-[(5-フルオロ-1H-ベンズイミダゾール-2-イル)メトキシメチル]-2-トリフルオロメトキシベンゾニトリル;
2-[(3-シクロプロピル-4-トリフルオロメトキシフェニル)メトキシメチル]-5-フルオロ-1H-ベンズイミダゾール。
さらに、本発明には、本発明化合物(I)を同位元素(例、2H、3H、14C、35S、125I等)等でラベル化した化合物を包含する。
また、化合物(Ib)は、化合物(Ia)のヒドロキシル化反応によっても製造できる。ヒドロキシル化反応は、例えば、硫酸水溶液、塩酸水溶液中、あるいはTHF、ジオキサン等との混合溶媒中で加熱撹拌あるいはマイクロウェーブ照射する方法などにより行われる。反応温度は、通常40~200℃であり、好ましくは80~180℃である。反応時間は、通常5分~24時間であり、好ましくは5分~3時間である。
化合物(Ia)は、国際公開2004/048335号パンフレット記載の方法と同様に、不活性溶媒中、酸化銀の存在下、化合物(V)と、アルキル化剤を反応させた後、脱保護によって製造できる。アルキル化剤との反応に用いる不活性溶媒としては、反応が進行する限り特に限定されないが、例えばベンゼン、トルエン、シクロヘキサン、ヘキサン等の炭化水素類、又はこれらの混合溶媒等が挙げられる。用いるアルキル化剤としては、例えば、ヨウ化メチル、ヨウ化エチル等のヨウ化アルキルが挙げられる。反応温度は、-20℃~環流温度であり、好ましくは0℃~環流温度である。反応時間は通常30分~10時間であり、好ましくは1時間~5時間である。
製造法2において原料化合物として用いられる化合物(X)は、例えば国際公開2007/010516号パンフレット記載の方法や、CHIRALITY,Wiley-Liss,(米国),2003年,15巻,p.609-614に記載の方法に従って、次式に示すようにベンズアルデヒド体から製造することができる。
1-ジメトキシメチル-5-フルオロ-1H-ベンズイミダゾールの位置異性体混合物
氷冷下、4-フルオロ-1,2-フェニレンジアミン(21.0g)に4mol/L塩酸(200mL)、ギ酸(38.3g)を順次加え、加熱還流下90分間撹拌した。氷冷下、反応溶液に10%水酸化ナトリウム水溶液を加え、アルカリ性溶液とし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をジイソプロピルエーテルで洗浄し、5-フルオロベンズイミダゾール(19.7g)を得た。得られた5-フルオロベンズイミダゾール(19.7g)をトルエン(500mL)に溶解し、オルトギ酸メチル(38.7g)、ベンゼンスルホン酸一水和物(1.0g)を順次加え、加熱還流下40時間撹拌した。減圧下に溶媒及びオルトギ酸メチルを留去し、得られた残渣をトルエンで希釈し、氷冷下、ジイソプロピルアミン(1mL)、飽和炭酸水素ナトリウム水溶液を順次加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣を塩基性シリカゲルクロマトグラフィー(20~100% 酢酸エチル/ヘキサン)にて精製し、表題化合物(25.2g)を得た。
(4-ベンジルオキシフェニル)-(1-ジエトキシメチル-5-メトキシ-1H-ベンズイミダゾール-2-イル)メタノールの位置異性体混合物
アルゴン雰囲気下、参考例3の化合物(2.4g)と4-ベンジルオキシベンズアルデヒド(2.4g)をTHF(30mL)に溶解し、-78℃冷却下、約1.14mol/LのLDA(ヘキサン、THF溶液)(10mL)を毎分3mLの速度で滴下し、同温で1時間撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(20~100% 酢酸エチル/ヘキサン)にて精製し、表題化合物(3.3g)を得た。
1-メトキシメチル-1H-イミダゾ[4,5-b]ピリジンの位置異性体混合物
4-アザベンズイミダゾール(7.5g)をDMF(125mL)に溶解し、炭酸セシウム(68g)を加えた後に、氷冷下、クロロメチルメチルエーテル(7.0mL)を滴下し、室温で1時間撹拌した。クロロメチルメチルエーテル(1.9mL)を追加し、室温で12時間撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(0~15% メタノール/クロロホルム)にて精製し、表題化合物(5.7g)を得た。
(6-クロロ-1-メトキシメチル-1H-イミダゾ[4,5-b]ピリジン-2-イル)-(4-トリフルオロメトキシフェニル)メタノールの位置異性体混合物
アルゴン雰囲気下、参考例7の化合物(700mg)と4-トリフルオロメトキシベンズアルデヒド(800mg)をTHF(12mL)に溶解し、-78℃冷却下、約1.14mol/LのLDA(ヘキサン、THF溶液)(3.7mL)を滴下し、同温で2時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(25~75% 酢酸エチル/ヘキサン)にて精製し、表題化合物(682mg)を得た。
エトキシ(4-ヒドロキシフェニル)酢酸エチルエステル
DL-4-ヒドロキシマンデル酸(25.5g)をエタノール(227mL)に溶解し、氷冷下、濃硫酸(4.5mL)を加え、室温で数分間撹拌した後、加熱還流下21時間撹拌した。減圧下に溶媒を留去し、得られた残渣を氷水に注ぎ、飽和炭酸水素ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をジイソプロピルエーテルで洗浄し、乾燥し、表題化合物(26.3g)を得た。
1H-NMR(CDCl3)δ:1.21(3H,t,J=6.3Hz),1.26(3H,t,J=6.1Hz),3.44-3.63(2H,m),4.10-4.25(2H,m),4.80(1H,s),6.81(2H,d,J=9.2Hz),7.32(2H,d,J=9.2Hz).
ESI-MS Found:m/z 223(M-H)-
エトキシ(4-ヒドロキシフェニル)酢酸
参考例21の化合物(39.3g)をエタノール(315mL)に溶解し、氷冷下、10%水酸化ナトリウム水溶液(156mL)を加え、室温で4時間撹拌した。反応溶液に2mol/L塩酸を加えて酸性にした後、減圧下にエタノールを留去し、水で希釈し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をジエチルエーテルで洗浄し、酢酸エチルで再結晶を行い、表題化合物(26.3g)を得た。
1H-NMR(DMSO-d6)δ:1.11(3H,t,J=7.0Hz),3.35(1H,m),3.48(1H,m),4.69(1H,s),6.72(2H,d,J=9.1Hz),7.17(2H,d,J=9.1Hz),9.46(1H,br s),12.58(1H,br s).
ESI-MS Found:m/z 195(M-H)-
[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシ酢酸
参考例21の化合物(13.6g)をDMF(200mL)に溶解し、氷冷下、炭酸カリウム(10.5g)と2,5-ジフルオロベンジルブロミド(14.6g)を加え、室温で6.5時間撹拌した。減圧下に溶媒を留去し、得られた残渣に飽和塩化アンモニウム水溶液を加え、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、粗生成物を得た。
得られた粗生成物をエタノール(300mL)に溶解し、氷冷下、10%水酸化ナトリウム水溶液(100mL)を加え、室温で11時間撹拌した。減圧下に溶媒を留去して得られた残渣に、2mol/L塩酸を加え、酸性溶液とし、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(4~10% メタノール/クロロホルム)にて精製し、表題化合物(20.0g)を得た。
1H-NMR(CDCl3)δ:1.27(3H,t,J=7.0Hz),3.52-3.62(2H m),4.84(1H,s),5.11(2H,s),6.94-7.09(4H,m),7.19-7.25(1H,m),7.35-7.38(2H,m).
ESI-MS Found:m/z 321(M-H)-
エトキシ(4-トリフルオロメトキシフェニル)酢酸
4-トリフルオロメトキシベンズアルデヒド(5.0g)とクロロホルム(7.2g)をDMF(16mL)に溶解し、氷冷下、水酸化カリウム(1.2g)のメタノール溶液(4.5mL)を滴下し、同温で2時間撹拌した。1mol/L塩酸(36mL)とトルエン(36mL)を加え、室温で13時間撹拌した。有機層と水層を分離し、水層をトルエンで抽出した。有機層を水、飽和炭酸水素ナトリウム水溶液、水で順次洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、粗生成物を得た。
得られた粗生成物をエタノール(26mL)に溶解し、水酸化カリウム(7.4g)のエタノール溶液(52mL)を滴下し、加熱還流下3時間撹拌した。反応溶液に水を加え、ジエチルエーテルで洗浄した後、6mol/L塩酸を加え、酸性溶液とし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(0~20% メタノール/クロロホルム)にて精製し、黄色油状の表題化合物(3.2g)を得た。
1H-NMR(CDCl3)δ:1.30(3H,t,J=7.0Hz),3.54-3.69(2H,m),4.90(1H,s),7.22-7.25(2H,m),7.47-7.50(2H,m).
ESI-MS Found:m/z 263(M-H)-
メトキシ(4-トリフルオロメトキシフェニル)酢酸
4-トリフルオロメトキシベンズアルデヒド(25.0g)をメタノール/1,4-ジオキサン1:1混合溶液(500mL)に溶解し、氷冷下、ブロモホルム(30.3g)を加えた後、水酸化カリウム(3.3g)のメタノール溶液(150mL)を滴下し、室温で22時間撹拌した。減圧下溶媒を留去し、得られた残渣を水で希釈し、3mol/L塩酸を加えて酸性とし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(50~100% 酢酸エチル/ヘキサン)にて精製し、粗生成物として表題化合物(29.4g)を得た。
エトキシ(4-トリフルオロメタンスルホニルフェニル)酢酸
参考例33の化合物(3.4g)をTFA(50mL)に溶解し、氷冷下、30%過酸化水素水(11.0g)を加え、室温で20時間撹拌した。反応溶液を氷水に注ぎ、10%水酸化ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(10~100% 酢酸エチル/ヘキサン)にて精製し、表題化合物の粗生成物(620mg)を得た。
4-[エトキシ(5-エトキシ-1H-ベンズイミダゾール-2-イル)メチル]フェノール
参考例22の化合物(300mg)と4-エトキシ-1,2-フェニレンジアミン(134mg)を用いて、実施例65と同様の方法により表題化合物(57mg)を得た。
1H-NMR(DMSO-d6)δ:1.18(3H,t,J=7.0Hz),1.30-1.33(3H,m),3.41-3.51(2H,m),3.96-4.01(2H,m),5.48-5.50(1H,m),6.70-7.38(7H,m),9.41(1H,s),12.13-12.16(1H,m).
ESI-MS Found:m/z 313(M+H)+
[4-(tert-ブチルジメチルシリルオキシ)フェニル]エトキシ酢酸
参考例22の化合物(12.0g)をDMF(200mL)に溶解し、氷冷下、イミダゾール(18.3g)、tert-ブチルジメチルシリルクロリド(TBDMSCl)(19.4g)を加え、室温で5時間撹拌した。反応溶液に水を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、表題化合物の粗生成物(11.8g)を得た。
2-{[4-(tert-ブチルジメチルシリルオキシ)フェニル]エトキシメチル}-5-エトキシ-1H-ベンズイミダゾール
参考例38の化合物(9.0g)と4-エトキシ-1,2-フェニレンジアミン(4.9g)を用いて、実施例65と同様の方法により表題化合物(9.4g)を得た。
1H-NMR(CDCl3)δ:0.17(6H,s),0.96(9H,s),1.27(3H,t,J=7.0Hz),1.42(3H,t,J=7.0Hz),3.52-3.67(2H,m),4.00-4.07(2H,m),5.61(1H,s),6.77-6.89(4H,m),7.20-7.60(3H,m),9.30-9.35(1H,br m).
ESI-MS Found:m/z 427(M+H)+
2-{[4-(tert-ブチルジメチルシリルオキシ)フェニル]エトキシメチル}-5-エトキシベンズイミダゾール-1-カルボン酸tert-ブチルエステル
参考例39の化合物(9.4g)をジクロロメタン(440mL)に溶解し、氷冷下、二炭酸ジ-tert-ブチル(5.3g)、トリエチルアミン(8.5g)、DMAP(215mg)を順次加え、室温で30分間撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加え、ジクロロメタンで抽出し、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(15~25% 酢酸エチル/ヘキサン)にて精製し、位置異性体混合物として表題化合物(11.5g)を得た。
5-エトキシ-2-[エトキシ(4-ヒドロキシフェニル)メチル]ベンズイミダゾール-1-カルボン酸tert-ブチルエステル
参考例40の化合物(11.5g)をTHF(315mL)に溶解し、氷冷下、1mol/Lのフッ化テトラ-n-ブチルアンモニウム(TBAF)のTHF溶液(22.3mL)を加え、室温で30分間撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(25~50% 酢酸エチル/ヘキサン)にて精製し、位置異性体混合物として表題化合物(8.4g)を得た。
(4-シアノフェニル)エトキシ酢酸
4-シアノベンズアルデヒド(3.0g)をエタノール/1,4-ジオキサン1:1混合溶液(80mL)に溶解し、氷冷下、ブロモホルム(7.0g)を加えた後、水酸化カリウム(7.6g)のエタノール溶液(40mL)を慎重に加え、室温で6時間撹拌した。減圧下溶媒を留去し、得られた残渣を水で希釈し、2mol/L塩酸を加え、酸性溶液とし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(50~100% 酢酸エチル/ヘキサン)にて精製し、粗生成物として表題化合物(2.6g)を得た。
4-[エトキシ(5-エトキシ-1H-ベンズイミダゾール-2-イル)メチル]ベンゾニトリル
参考例42の化合物(1.1g)と4-エトキシ-1,2-フェニレンジアミン(912mg)を用いて、実施例65と同様の方法により無色固体の表題化合物(870mg)を得た。
1H-NMR(CDCl3)δ:1.33(3H,t,J=7.0Hz),1.43(3H,t,J=7.0Hz),3.66(2H,q,J=7.0Hz),4.05(2H,q,J=7.0Hz),5.72(1H,s),6.87-7.31(3H,m),7.63(4H,q,J=8.5Hz),9.19(1H,s).
ESI-MS Found:m/z 322(M+H)+
4-[エトキシ(5-エトキシ-1H-ベンズイミダゾール-2-イル)メチル]安息香酸
参考例43の化合物(300mg)を1,4-ジオキサン(20mL)に溶解させ、30%水酸化ナトリウム水溶液(10mL)を加え、加熱還流下16時間撹拌した。反応溶液をジエチルエーテルで洗浄後、6mol/L塩酸を加え、酸性溶液とし、酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(10~40% メタノール/クロロホルム)にて精製し、表題化合物(130mg)を得た。
1H―NMR(DMSO-d6)δ:1.21(3H,t,J=7.0Hz),1.32(3H,t,J=7.0Hz),3.54(2H,q,J=7.0Hz),3.99(2H,q,J=7.0Hz),5.72(1H,s),6.75(1H,d,J=7.7Hz),6.87-7.10(1H,m),7.30-7.44(1H,m),7.54(2H,d,J=8.1Hz),7.92(2H,d,J=8.1Hz),12.24-13.11(1H,br m).
ESI-MS Found:m/z 339(M-H)-
ヒドロキシ(4-トリフルオロメトキシフェニル)酢酸エチルエステル
4-トリフルオロメトキシベンズアルデヒド(10.0g)をジクロロメタン(105mL)に溶解し、トリメチルシリルシアニド(7.0g)、トリエチルアミン(530mg)を加え、室温で4時間撹拌した。反応溶液を減圧留去し、(4-トリフルオロメトキシフェニル)トリメチルシリルオキシアセトニトリル(15.0g)を得た。
得られた(4-トリフルオロメトキシフェニル)トリメチルシリルオキシアセトニトリル(15.0g)をジエチルエーテル(100mL)に溶解し、2mol/Lの塩化水素エタノール溶液(100mL)を加え、室温で65時間撹拌した。反応溶液を減圧留去した後、水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、表題化合物(13.0g)を得た。
1H-NMR(CDCl3)δ:1.24(3H,t,J=7.1Hz),3.51(1H,br s),4.14-4.32(2H,m),5.17(1H,s),7.21(2H,d,J=8.6Hz),7.47(2H,d,J=8.6Hz).
ヒドロキシ(4-トリフルオロメトキシフェニル)酢酸
参考例45の化合物(10.0g)をエタノール(15mL)に溶解し、10%水酸化ナトリウム水溶液(50mL)を加え、室温で2時間撹拌した。反応溶液に水を加え、ジエチルエーテルで洗浄した後、6mol/L塩酸を加え、酸性溶液とし、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、無色固体の表題化合物(8.7g)を得た。
1H-NMR(CDCl3)δ:5.27(1H,s),7.23(2H,d,J=7.9Hz),7.47-7.52(2H,m).
ESI-MS Found:m/z 235(M-H)-
1-(4-フルオロベンジル)-1H-インドール-5-カルボアルデヒド
インドール-5-カルボアルデヒド(1.0g)をDMF(14mL)に溶解し、氷冷下、水酸化カリウム(460mg)と4-フルオロベンジルブロミド(1.4g)を順次加え、室温で65時間撹拌した。反応液に水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(20~50% 酢酸エチル/ヘキサン)にて精製し、淡黄色固体の表題化合物(1.2g)を得た。
1H-NMR(CDCl3)δ:5.34(2H,s),6.72(1H,dd,J=3.3,0.9Hz),6.98-7.11(4H,m),7.21(1H,d,J=3.3Hz),7.36(1H,d,J=8.6Hz),7.76(1H,dd,J=8.6,1.6Hz),8.18(1H,d,J=0.9Hz),10.03(1H,s).
ESI-MS Found:m/z 254(M+H)+
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール
1H-NMR(CDCl3)δ:6.05(1H,s),6.94-7.03(1H,m),7.15-7.22(3H,m),7.44-7.50(3H,m).
ESI-MS Found:m/z 327(M+H)+
(5-エトキシ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール
1H-NMR(CDCl3)δ:1.38(3H,t,J=7.0Hz),3.91(2H,q,J=7.0Hz),5.98(1H,s),6.81-6.83(2H,m),7.04-7.07(2H,m),7.25-7.39(3H,m).
ESI-MS Found:m/z 353(M+H)+
対応する原料を用いて、実施例1と同様の方法により製造した化合物3~16を表7、8に示す。
2-[エチルスルファニル(4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.26(3H,t,J=7.3Hz),2.46-2.64(2H,m),5.46(1H,s),6.98-7.72(7H,m),9.63(1H,br s)
ESI-MS Found:m/z 371(M+H)+
5-フルオロ-2-[ピリジン-3-イルオキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:6.61(1H,s),6.98-7.05(1H,m),7.22-7.27(4H,m),7.36-7.40(1H,m),7.47-7.55(1H,m),7.58(2H,d,J=8.8Hz),8.17(1H,d,J=2.6Hz),8.26(1H,d,J=4.2Hz).
ESI-MS Found:m/z 404(M+H)+
2-[(2,2-ジメチル-2,3-ジヒドロベンゾフラン-5-イル)エトキシメチル]-5-フルオロ-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.27(3H,t,J=7.0Hz),1.43(6H,s),2.92(2H,s),3.51-3.68(2H,m),5.58(1H,s),6.67(1H,d,J=8.8Hz),6.93-7.16(4H,m),7.29-7.66(1H,m),9.81(1H,br s).
ESI-MS Found:m/z 341(M+H)+
2-[エタンスルホニル(4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.39(3H,t,J=7.5Hz),3.01-3.26(2H,m),5.97(1H,s),7.03-7.10(1H,m),7.27(2H,d,J=8.8Hz),7.41-7.59(1.5H,m),7.77(2H,d,J=8.8Hz),8.00-8.12(0.5H,m),10.45(1H,br s).
ESI-MS Found:m/z 404(M+H)+
5-フルオロ-2-[イソプロポキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.24-1.28(6H,m),3.76-3.84(1H,m),5.81(1H,s),6.95-7.04(1H,m),7.11(0.5H,dd,J=8.6,2.4Hz),7.20(2H,d,J=8.4Hz),7.32-7.41(1H,m),7.50(2H,d,J=8.4Hz),7.61-7.66(0.5H,m),9.44(1H,br s).
ESI-MS Found:m/z 369(M+H)+
2-[ベンジルオキシ(4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:4.57(1H,d,J=11.5Hz),4.67(1H,d,J=11.5Hz),5.79(1H,s),6.97-7.03(1H,m),7.08-7.11(0.5H,m),7.22(2H,d,J=8.5Hz),7.32-7.41(6H,m),7.50(2H,d,J=8.5Hz),7.60-7.68(0.5H,m),9.49(1H,br s).
ESI-MS Found:m/z 417(M+H)+
対応する原料を用いて、実施例21と同様の方法により製造した化合物23~33を表9、10に示す。
(4-ベンジルオキシフェニル)-(5-メトキシ-1H-ベンズイミダゾール-2-イル)メタノール
1H-NMR(CDCl3)δ:3.83(3H,s),5.06(2H,s),5.98(1H,s),6.85-7.45(12H,m).
ESI-MS Found:m/z 361(M+H)+
2-[(4-ベンジルオキシフェニル)モルホリン-4-イルメチル]-5-メトキシ-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:2.32-2.42(2H,m),2.51-2.58(2H,m),3.70-3.75(4H,m),3.82(3H,s),4.64(1H,s),5.02(2H,s),6.83-7.58(12H,m),9.37-9.41(1H,br m).
ESI-MS Found:m/z 430(M+H)+
2-[(4-ベンジルオキシフェニル)ピロリジン-1-イルメチル]-5-メトキシ-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.62-1.68(2H,m),1.77-1.83(2H,m),2.45-2.52(2H,m),2.53-2.58(2H,m),3.82(3H,s),4.62(1H,s),5.02(2H,s),6.82-7.57(12H,m),9.42(1H,br s).
ESI-MS Found:m/z 412(M-H)-
2-[(4-ベンジルオキシフェニル)エチルスルファニルメチル]-5-メトキシ-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.24(3H,t,J=7.4Hz),2.53(2H,q,J=7.4Hz),3.83(3H,s),5.02(2H,s),5.44(1H,s),6.86-7.40(12H,m).
ESI-MS Found:m/z 405(M+H)+
対応する原料を用いて、実施例35と同様の方法により製造した化合物38~41を表11に示す。
2-[(4-ベンジルオキシフェニル)エタンスルホニルメチル]-5-メトキシ-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.37(3H,t,J=7.4Hz),3.07(2H,q,J=7.4Hz),3.84(3H,s),5.05(2H,s),5.73(1H,s),6.90-7.62(12H,m),10.08(1H,br s).
ESI-MS Found:m/z 437(M+H)+
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-フェネチルフェニル)メタノール
1H-NMR(CDCl3)δ:2.88(4H,s),6.01(1H,s),6.92-6.99(1H,m),7.12-7.25(7H,m),7.26-7.43(4H,m).
ESI-MS Found:m/z 347(M+H)+
(6-クロロ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-(4-トリフルオロメトキシフェニル)メタノール
1H-NMR(DMSO-d6)δ:5.99(1H,s),6.75(1H,br s),7.35(2H,d,J=8.4Hz),7.62(2H,d,J=8.4Hz),7.91-8.07(1H,m),8.29(1H,s),12.92-13.38(1H,m).
ESI-MS Found:m/z 342(M-H)-
対応する原料を用いて、実施例44と同様の方法により製造した化合物45~50を表12に示す。
[5-(プロパン-1-スルホニル)-1H-ベンズイミダゾール-2-イル]-(4-トリフルオロメトキシフェニル)メタノール
得られた[1-メトキシメチル-5-(プロパニル-1-スルホニル)-1H-ベンズイミダゾール-2-イル]-(4-トリフルオロメトキシフェニル)メタノール(220mg)をエタノール(2mL)に溶解し、濃硫酸(45mg)を加え、加熱還流下3時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、アルカリ性溶液とし、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(33~100% 酢酸エチル/ヘキサン)にて精製し、無色固体の表題化合物(71mg)を得た。
1H-NMR(DMSO-d6)δ:0.86(3H,t,J=7.2Hz),1.45-1.55(2H,m),3.15-3.29(2H,m),6.03-6.06(1H,m),6.78-6.85(1H,m),7.36(2H,d,J=8.4Hz),7.60-7.77(4H,m),7.92-8.02(1H,m),13.02-13.04(1H,br m).
ESI-MS Found:m/z 413(M-H)―
2-{エトキシ[4-(4-フルオロベンジルオキシ)フェニル]メチル}-3H-イミダゾ[4,5-b]ピリジン
1H-NMR(DMSO-d6)δ:1.17-1.23(3H,m),3.47-3.56(2H,m),5.05(2H,s),5.60-5.69(1H,m),6.99(2H,d,J=8.2Hz),7.16-7.22(3H,m),7.37-7.49(4H,m),7.80-7.94(1H,m),8.24-8.32(1H,m),12.66-13.13(1H,m).
ESI-MS Found:m/z 378(M+H)+
対応する原料を用いて、実施例52と同様の方法により製造した化合物53~59を表13、14に示す。
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-エトキシ-1H-ベンズイミダゾール
得られたアミド体(2.3g)を酢酸(40mL)に溶解し、100℃で30分間加熱した。減圧下に溶媒を留去し、水で希釈し、飽和炭酸水素ナトリウム水溶液を加え、アルカリ性溶液とし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー(10~35% 酢酸エチル/ヘキサン)にて精製し、無色固体の表題化合物(1.5g)を得た。
1H-NMR(CDCl3)δ:1.28(3H,t,J=7.1Hz),1.42(3H,t,J=7.0Hz),3.53-3.69(2H,m),4.04(2H,q,J=7.0Hz),5.07(2H,s),5.62(1H,s),6.87-7.51(10H,m),9.34(1H,br).
ESI-MS Found:m/z 439(M+H)+
対応する原料を用いて、実施例60と同様の方法により製造した化合物61~64を表15に示す。
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-フルオロ-1H-ベンズイミダゾール
得られたアミド体(377mg)を酢酸(6mL)に溶解し、80℃で1時間加熱した。減圧下に溶媒を留去し、水で希釈し、飽和炭酸水素ナトリウム水溶液を加えて中性からアルカリ性とし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(10~40% 酢酸エチル/ヘキサン)にて精製し、無色固体の表題化合物(300mg)を得た。
1H-NMR(CDCl3)δ:1.29(3H,t,J=7.0Hz),3.53-3.69(2H,m),5.08(2H,s),5.63(1H,s),6.93-7.11(5H,m),7.18-7.23(1H,m),7.31-7.65(4H,m),9.49(1H,br).
ESI-MS Found:m/z 413(M+H)+
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-メトキシ-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.29(3H,t,J=7.1Hz),3.53-3.69(2H,m),3.83(3H,s),5.08(2H,s),5.63(1H,s),6.84-7.23(7H,m),7.28-7.61(3H,m),9.31-9.35(1H,br).
ESI-MS Found:m/z 425(M+H)+
8-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-7H-プリン
1H-NMR(CDCl3)δ:1.33(3H,t,J=7.1Hz),3.60-3.78(2H,m),5.08(2H,s),5.72(1H,s),6.96-7.07(4H,m),7.16-7.22(1H,m),7.42-7.45(2H,m),9.02(1H,s),9.09(1H,s),12.12(1H,br).
ESI-MS Found:m/z 397(M+H)+
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-3H-イミダゾ[4,5-c]ピリジン
1H-NMR(CDCl3)δ:1.30(3H,t,J=7.0Hz),3.55-3.71(2H,m),5.08(2H,s),5.69(1H,s),6.91-7.07(4H,m),7.18-7.23(1H,m),7.30-7.61(3H,m),8.39-8.41(1H,m),9.02(1H,br s),10.01(1H,br s).
ESI-MS Found:m/z 396(M+H)+
5-エトキシ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.31(3H,t,J=7.0Hz),1.43(3H,t,J=7.0Hz),3.58-3.68(2H,m),4.04(2H,q,J=7.0Hz),5.68(1H,s),6.87-7.21(4H,m),7.28-7.61(3H,m),9.28-9.34(1H,br m).
ESI-MS Found:m/z 381(M+H)+
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.31(3H,t,J=7.0Hz),3.59-3.69(2H,m),5.68(1H,s),6.96-7.03(1H,m),7.08-7.13(0.5H,m),7.20(2H,d,J=8.5Hz),7.32-7.40(1H,m),7.48(2H,d,J=8.5Hz),7.60-7.67(0.5H,m),9.55(1H,br s).
ESI-MS Found:m/z 355(M+H)+
5-エトキシ-2-[メトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.42(3H,t,J=7.0Hz),3.47(3H,s),4.04(2H,q,J=7.0Hz),5.56(1H,s),6.85-7.62(7H,m),9.36(1H,br s).
ESI-MS Found:m/z 367(M+H)+
対応する原料を用いて、実施例65と同様の方法により製造した化合物72~94を表16~20に示す。
2-[(4-ベンジルオキシフェニル)エトキシメチル]-5-エトキシ-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.28(3H,t,J=7.0Hz),1.42(3H,t,J=7.0Hz),3.59-3.63(2H,m),4.04(2H,q,J=7.0Hz),5.04(2H,s),5.62(1H,s),6.85-7.22(4H,m),7.31-7.61(8H,m),9.21(1H,br s).
ESI-MS Found:m/z 403(M+H)+
対応する原料を用いて、実施例95と同様の方法により製造した化合物96~100を表21に示す。
5-エトキシ-2-{エトキシ[4-(3-フルオロベンジルオキシ)フェニル]メチル}-1H-ベンズイミダゾール
得られた5-エトキシ-2-{エトキシ[4-(3-フルオロベンジルオキシ)フェニル]メチル}ベンズイミダゾール-1-カルボン酸tert-ブチルエステル(172mg)をジクロロメタン(2mL)に溶解し、氷冷下、TFA(2mL)を加え、室温で1.5時間撹拌した。溶媒を減圧留去し、得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(10~100% 酢酸エチル/ヘキサン)にて精製し、無色固体の表題化合物(82mg)を得た。
1H-NMR(CDCl3)δ:1.29(3H,t,J=7.0Hz),1.42(3H,t,J=7.0Hz),3.55-3.66(2H,m),4.04(2H,q,J=7.0Hz),5.03(2H,s),5.62(1H,s),6.85-7.60(11H,m),9.26-9.32(1H,br m).
ESI-MS Found:m/z 421(M+H)+
5-エトキシ-2-[エトキシ(4-フェニルオキシフェニル)メチル]-1H-ベンズイミダゾール
得られた5-エトキシ-2-[エトキシ(4-フェニルオキシフェニル)メチル]ベンズイミダゾール-1-カルボン酸tert-ブチルエステル(237mg)をジクロロメタン(2mL)に溶解し、氷冷下、TFA(2mL)を加え、室温で1.5時間撹拌した。溶媒を減圧留去し、得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(10~100% 酢酸エチル/ヘキサン)にて精製し、無色固体の表題化合物(38mg)を得た。
1H-NMR(CDCl3)δ:1.30(3H,t,J=7.0Hz),1.43(3H,t,J=7.0Hz),3.55-3.69(2H,m),4.05(2H,q,J=7.0Hz),5.65(1H,s),6.86-7.61(12H,m),9.25-9.31(1H,br m).
ESI-MS Found:m/z 389(M+H)+
5-エトキシ-2-[エトキシ(4-フェネチルオキシフェニル)メチル]-1H-ベンズイミダゾール
得られた5-エトキシ-2-[エトキシ(4-フェネチルオキシフェニル)メチル]ベンズイミダゾール-1-カルボン酸tert-ブチルエステル(199mg)から実施例109と同様にして、無色固体の表題化合物(24mg)を得た。
1H-NMR(CDCl3)δ:1.28(3H,t,J=7.0Hz),1.42(3H,t,J=7.0Hz),3.08(2H,t,J=7.1Hz),3.54-3.65(2H,m),4.04(2H,q,J=7.0Hz),4.15(2H,t,J=7.1Hz),5.61(1H,s),6.86-7.61(12H,m),9.20(1H,br s).
ESI-MS Found:m/z 417(M+H)+
1-{4-[エトキシ(5-エトキシ-1H-ベンズイミダゾール-2-イル)メチル]フェニル}-2-フェニルエタノン
1H-NMR(CDCl3)δ:1.30(3H,t,J=7.0Hz),1.42(3H,t,J=7.0Hz),3.64(2H,m),4.03(2H,q,J=7.0Hz),4.24(2H,s),5.71(1H,s),6.80-7.40(7H,m),7.54-7.66(3H,m),7.99(2H,d,J=8.4Hz),9.26-9.32(1H,br m).
ESI-MS Found:m/z 415(M+H)+
(5-ブロモ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール
1H-NMR(CDCl3)δ:6.01(1H,s),7.13(2H,d,J=8.4Hz),7.27-7.32(2H,m),7.39(2H,d,J=8.4Hz),7.57(1H,s).
ESI-MS Found:m/z 387(M+H)+
5-ブロモ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:1.31(3H,t、J=7.1Hz),3.58-3.69(2H,m),5.69(1H,s),7.20(2H,d,J=8.4Hz),7.24-7.36(2H,m),7.47(2H,d,J=8.4Hz),7.57-7.86(1H,m),9.53(1H,br s).
ESI-MS Found:m/z 415(M+H)+
2-[ヒドロキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール-5-カルボニトリル
1H-NMR(DMSO-d6)δ:6.02(1H,d,J=4.0Hz),6.79(1H,d,J=4.0Hz),7.35(2H,d,J=8.2Hz),7.51-7.72(4H,m),7.89-8.07(1H,m),13.01(1H,br s).
ESI-MS Found:m/z 334(M+H)+
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール-5-カルボニトリル
1H-NMR(CDCl3)δ:1.33(3H,t,J=7.1Hz),3.60-3.71(2H,m),5.72(1H,s),7.21-7.25(2H,m),7.46-8.04(5H,m),9.77-9.81(1H,br m).
ESI-MS Found:m/z 362(M+H)+
4-[エトキシ(5-エトキシ-1H-ベンズイミダゾール-2-イル)メチル]安息香酸ベンジル
1H-NMR(CDCl3)δ:1.29(3H,t,J=7.0Hz),1.41(3H,t,J=7.0Hz),3.63(2H,q,J=7.0Hz),4.02(2H,q,J=7.0Hz),5.34(2H,s),5.71(1H,s),6.80-7.25(2H,m),7.26-7.59(8H,m),8.04(2H,d,J=8.2Hz),9.41(1H,br s).
ESI-MS Found:m/z 431(M+H)+
N-ベンジル-4-[エトキシ(5-エトキシ-1H-ベンズイミダゾール-2-イル)メチル]ベンズアミド
1H-NMR(CDCl3)δ:1.25(3H,t,J=7.0Hz),1.39(3H,t,J=7.0Hz),3.57(2H,q,J=7.0Hz),3.98(2H,q,J=7.0Hz),4.59(2H,d,J=5.9Hz),5.61(1H,s),6.82-6.86(2H,m),6.96(1H,br s),7.22-7.48(8H,m),7.66(2H,d,J=8.4Hz),10.13(1H,br s).
ESI-MS Found:m/z 430(M+H)+
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-[1-(4-フルオロベンジル)-1H-インドール-5-イル]メタノール
1H-NMR(CDCl3)δ:5.26(2H,s),6.10(1H,s),6.53(1H,d,J=3.2Hz),6.92-6.99(3H,m),7.03-7.08(2H,m),7.14(1H,d,J=3.2Hz),7.18-7.25(3H,m),7.43(1H,s),7.71(1H,s).
ESI-MS Found:m/z 390(M+H)+
[実施例119~133]
対応する原料を用いて、実施例65と同様の方法により製造した化合物119~133を表24~25に示す。
対応する原料を用いて、実施例1と同様の方法により製造した化合物134~140を表26に示す。
対応する原料を用いて、実施例21と同様の方法により製造した化合物141~148を表27に示す。
(5-メトキシ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール
1H-NMR(CDCl3)δ:3.75(3H,s),6.00(1H,s),6.80-6.88(2H,m),7.09(2H,d,J=8.2Hz),7.31(1H,d,J=8.8Hz),7.39(2H,d,J=8.2Hz).
ESI-MS Found:m/z 339(M+H)+
対応する原料を用いて、実施例149と同様の方法により製造した化合物150~163を表28~29に示す。
5-フルオロ-2-[(2-フルオロエトキシ)-(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:3.74-3.94(2H,m),4.52-4.79(2H,m),5.77(1H,s),6.96-7.04(1H,m),7.17-7.26(3H,m),7.46-7.54(3H,m),9.72(1H,br s).
ESI-MS Found:m/z 373(M+H)+
対応する原料を用いて、実施例164と同様の方法により製造した化合物165~170を表30に示す。
5-[(5-フルオロ-1H-ベンズイミダゾール-2-イル)メトキシメチル]-2-トリフルオロメトキシベンゾニトリル
1H-NMR(CDCl3)δ:3.53(3H,s),5.60-5.61(1H,m),6.98-7.08(1H,m),7.11-7.15(0.5H,m),7.34-7.40(2H,m),7.62-7.67(0.5H,m),7.72-7.77(1H,m),7.85(1H,d,J=2.2Hz),9.52(1H,br s).
ESI-MS Found:m/z 366(M+H)+
2-[(3-シクロプロピル-4-トリフルオロメトキシフェニル)メトキシメチル]-5-フルオロ-1H-ベンズイミダゾール
1H-NMR(CDCl3)δ:0.63-0.69(2H,m),0.95-1.01(2H,m),2.05-2.15(1H,m),3.45(3H,s),5.50(1H,s),6.95-7.10(2.5H,m),7.16-7.24(2H,m),7.29-7.40(1H,m),7.61-7.65(0.5H,m),9.58(1H,br s).
ESI-MS Found:m/z 381(M+H)+
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール マレイン酸塩
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール シュウ酸塩
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール 4-メチルベンゼンスルホン酸塩
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール ベンゼンスルホン酸塩
1H-NMR(DMSO-d6)δ:1.24(3H,t,J=7.0Hz),3.57-3.68(2H,m),6.02(1H,s),7.28-7.33(4H,m),7.44(2H,d,J=8.6Hz),7.50-7.54(1H,m),7.58-7.64(4H,m),7.68-7.73(1H,m).
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール リン酸塩
1H-NMR(DMSO-d6)δ:1.21(3H,t,J=7.0Hz),3.55(2H,q,J=7.0Hz),5.75(1H,s),6.97-7.04(1H,m),7.26-7.29(1H,m),7.36(2H,d,J=8.7Hz),7.48(1H,brs),7.57(2H,d,J=8.7Hz),12.56(1H,brs).
本発明の代表的な化合物について、下記の試験例により、T型カルシウムチャネル(Cav3.2)に対する選択的拮抗作用について試験した。各試験にはヒトT型カルシウムチャネル(ヒトCav3.2)を安定発現させたヒト胎児腎臓細胞(HEK293細胞)を用いた。
ヒトCav3.2が安定発現したHEK293細胞は37℃で10%(v/v)ウシ胎仔血清(FBS)、ペニシリン(100U/mL)、ストレプトマイシン(100μg/mL)、G418(250μg/mL)を加えたAlpha-MEMにて培養した。細胞は培養液で懸濁し、96穴プレ-トに播種した後、24時間培養した。培養液を除き、5%(v/v)FBS、塩化カルシウム(0.5mmol/L)、L-グルタミン(2mmol/L),L-アラニン(8.9ng/mL)、L-アスパラギン(13.2ng/mL)、L-アスパラギン酸(1.33ng/mL)、L-グルタミン酸(1.47ng/mL)、グリシン(7.5ng/mL)、L-プロリン(11.5ng/mL)、L-セリン(10.5ng/mL)、ペニシリン(100U/mL)、ストレプトマイシン(100μg/mL)を加えたS-MEMに交換し、さらに24時間培養した。再び培養液を除き、37℃に保温したアッセイバッファー(140mmol/L塩化ナトリウム、5mmol/L塩化カリウム、0.5mmol/L塩化マグネシウム、0.5mmol/L塩化カルシウム、10mmol/Lグルコ-ス、0.4mmol/L硫酸マグネシウム、10mmol/L HEPES、250μmol/Lスルフィンピラゾン、pH7.4)にて洗浄した後、蛍光Ca2+指示薬であるFura2-AMを5μMに溶解させたアッセイバッファーを加え、37℃で30分間培養した。Fura2が溶解しているアッセイバッファーを除き、アッセイバッファーにて洗浄した後、試験化合物を添加したアッセイバッファーを加え、15分間培養した。蛍光測定装置(FLex Station II、Molecular Devices社)にプレートを設置し、ベースラインを測定した後、100mmol/L塩化カルシウムを加えたアッセイバッファーを添加した際に誘起される細胞内カルシウム濃度の変化を測定し(340nm、380nm励起、510nm検出)、各波長より得られる蛍光強度比を算出した。
Y=Vmax ×(1-(Xn/(Kn+Xn)))+Y2
・X=Concentrarion
・Y=%阻害値
・%阻害値=(RFU(化合物)-RFU(LC))/(RFU(HC)-RFU(LC))
HC:コントロール溶液処理後のCa2+含有アッセイバッファー添加後25~30秒間(測定開始後45~50秒間)のRFU値の平均
LC:コントロール溶液処理後のCa2+非含有アッセイバッファー添加後25~30秒間(測定開始後45~50秒間)のRFU値の平均
式中のRFUは相対的蛍光強度(Relative Fluorescence Unit)を表す。
本発明の代表的な化合物について、下記の試験例により、T型カルシウムチャネル(Cav3.2)に対する選択的拮抗作用について試験した。各試験にはヒトT型カルシウムチャネル(ヒトCav3.2)を安定発現させたヒト胎児腎臓細胞(HEK293細胞)を用いた。
ヒトCav3.2が安定発現したHEK293細胞は37℃で10%(v/v)ウシ胎仔血清(FBS)、ペニシリン(100U/mL)、ストレプトマイシン(100μg/mL)、G418(250μg/mL)を加えたAlpha-MEMにて培養した。細胞はアクターゼ(SIGMA社)処理により回収し、培養液中に懸濁して使用した。測定内液(50mmol/L CsCl、10mmol/L NaCl、60mmol/L CsF、2mmol/L MgCl2、20mmol/L EGTA、10mmol/L HEPES/CsOH pH7.2)、測定外液(80mmol/L NaCl、1mmol/L TEACl、3mmol/L KCl、35mmol/L CaCl2、10mmol/L MgCl2、10mmol/L HEPES、pH7.2)を使用し、オートパッチクランプシステム(port-a-patch,Nanion社)によりカルシウム電流を測定した。
保持電位は-80mVに固定し、-20mVのパルスを5秒間隔で細胞に与え、ピーク電流に対する化合物の阻害作用を測定した。化合物評価は、化合物を含む外液(1μmol/L、3μmol/L、10μmol/L、50μmol/L)に順次交換して電流測定を行った。阻害率はピーク電流値から算出し、IC50値は阻害率をプロビット法による変換を行った後、線形回帰により導出された近似式より算出した。
結果を表31に示す。
Claims (17)
- 一般式(I)
環Nnは窒素原子を有していてもよい縮合6員芳香環を示し、
環Npは窒素原子を有していてもよい6員芳香環を示し、
nは縮合6員芳香環に含まれる窒素原子の数を示し、0、1又は2であり;
pは6員芳香環に含まれる窒素原子の数を示し、0又は1であり;
R1及びR2は同一又は異なって、
(1)水素原子、
(2)ハロゲン原子、
(3)ヒドロキシ基、
(4)シアノ基、
(5)ニトロ基、
(6)置換基を有していてもよいC1-6アルキル基、
(7)置換基を有していてもよいC1-6アルコキシ基、
(8)-SR6、
(9)-SO2R6
(10)-SO2NR6R7
(11)-(C=O)-R6、又は
(12)アミノ基
を示し;
R6及びR7は同一又は異なって、置換基を有していてもよいC1-6アルキル基を示し;
R3は、
(1)水素原子、
(2)置換基を有していてもよいC1-6アルキル基、
(3)-(C=O)-R8、又は
(4)置換基を有していてもよいアリール基又はヘテロアリール基
を示し;
R8は置換基を有していてもよいC1-6アルキル基を示し;
Xは酸素原子、硫黄原子、-SO2-、又は-N(R9)-を示し;
R9は置換基を有していてもよいC1-6アルキル基を示すか、又はR3及び隣接する窒素原子と一緒になって置換基を有していてもよい非芳香族複素環を形成してもよく;
R4は、
(1)ハロC1-6アルキル基、
(2)置換基を有していてもよいC2-6アルケニル基、
(3)ハロC1-6アルコキシ基、
(4)置換基を有していてもよいアラルキル基、
(5)置換基を有していてもよいアラルキルオキシ基、
(6)置換基を有していてもよいヘテロアラルキルオキシ基、
(7)置換基を有していてもよいアリールオキシC1-6アルキル基、
(8)-SR10、
(9)-SO2R10、
(10)-SO2NR11R12、
(11)-NR12R13、
(12)-(C=O)-R13、
(13)-(C=O)-OR13、
(14)-(C=O)-NR12R13、又は
(15)置換基を有していてもよいアリール基又はヘテロアリール基
を示し;
R10はハロC1-6アルキル基を示し;
R11は置換基を有していてもよいアリール基又はヘテロアリール基を示し;
R12は水素原子又は置換基を有していてもよいC1-6アルキル基を示し;
R13は置換基を有していてもよいアラルキル基を示し;
R5は、
(1)水素原子、
(2)ハロゲン原子、
(3)ヒドロキシ基、
(4)ニトロ基、
(5)シアノ基、
(6)置換基を有していてもよいC1-6アルキル基、又は
(7)置換基を有していてもよいC1-6アルコキシ基
を示し;
R4とR5は一緒になって置換基を有していてもよい芳香環又は非芳香環を形成してもよく;
ただし、R4が置換基を有さないアラルキルオキシ基であり、nが0の場合、XR3はOHではない]
で表される化合物、その薬学的に許容される塩、又はそれらの溶媒和物。 - Xが酸素原子である請求項1記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物。
- R2が水素原子である請求項1~2のいずれか1項記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物。
- 一般式(I)中のNp環がベンゼン環であり、Nn環がベンゼン環又はピリジン環である請求項1~3のいずれか1項記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物。
- R4が、
(1)ハロC1-6アルキル基、
(2)ハロC1-6アルコキシ基、
(3)置換基を有していてもよいアラルキルオキシ基、又は
(4)-SR10
であり、
R5が、
(1)水素原子、又は
(2)ハロゲン原子
であるか、
又はR4とR5が一緒になって置換基を有していてもよいベンゼン環、ジオキソール環を形成している請求項1~5のいずれか1項記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物。 - (5-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメチルスルファニルフェニル)メタノール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメチルフェニル)メタノール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-[3-フルオロ-4-(トリフルオロメチル)フェニル]メタノール;
2-[エトキシ(4-トリフルオロメチルフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-[4-(1,1,2,2-テトラフルオロエトキシ)フェニル]メタノール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(ナフタレン-2-イル)メタノール;
(2,2-ジフルオロベンゾ[1,3]ジオキソール-5-イル)-(5-フルオロ-1H-ベンズイミダゾール-2-イル)メタノール;
5-フルオロ-2-[イソプロポキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
5-フルオロ-2-[(2-メトキシエトキシ)-(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
(6-クロロ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(6-フルオロ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-[4-(4-メチルベンジルオキシ)フェニル]メタノール;
6-クロロ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-3H-イミダゾ[4,5-b]ピリジン;
6-クロロ-2-{エトキシ[4-(4-メチルベンジルオキシ)フェニル]メチル}-3H-イミダゾ[4,5-b]ピリジン;
2-{エトキシ[4-(4-メチルベンジルオキシ)フェニル]メチル}-6-フルオロ-3H-イミダゾ[4,5-b]ピリジン;
6-クロロ-2-{エトキシ[4-(4-フルオロベンジルオキシ)フェニル]メチル}-3H-イミダゾ[4,5-b]ピリジン;
2-{エトキシ[4-(4-フルオロベンジルオキシ)フェニル]メチル}-6-フルオロ-3H-イミダゾ[4,5-b]ピリジン;
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-エトキシ-1H-ベンズイミダゾール;
5-クロロ-2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-1H-ベンズイミダゾール;
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-トリフルオロメチル-1H-ベンズイミダゾール;
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-メトキシ-1H-ベンズイミダゾール;
5-エトキシ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール;
5-エトキシ-2-[メトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-メチル-1H-ベンズイミダゾール;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-メトキシ-1H-ベンズイミダゾール;
5-クロロ-2-[メトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
5-フルオロ-2-[メトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
5-エトキシ-2-[エトキシ(4-トリフルオロメチルスルファニルフェニル)メチル]-1H-ベンズイミダゾール;
5-エトキシ-2-{エトキシ[4-(4-メチルベンジルオキシ)フェニル]メチル}-1H-ベンズイミダゾール;
2-{[4-(2,4-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-エトキシ-1H-ベンズイミダゾール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-[3-フルオロ-4-(トリフルオロメトキシ)フェニル]メタノール;
[3-ブロモ-4-(トリフルオロメトキシ)フェニル]-(5-フルオロ-1H-ベンズイミダゾール-2-イル)メタノール;
2-[エトキシ(3-フルオロ-4-トリフルオロメトキシフェニル)メチル]-5-フルオロ-1H-ベンズイミダゾール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-[4-(2,2,2-トリフルオロエトキシ)フェニル]メタノール;
5-フルオロ-2-{メトキシ[4-(2,2,2-トリフルオロエトキシ)フェニル]メチル}-1H-ベンズイミダゾール;
2-{エトキシ[4-(2,2,2-トリフルオロエトキシ)フェニル]メチル}-5-フルオロ-1H-ベンズイミダゾール;
2-[(2,2-ジフルオロベンゾ[1,3]ジオキソール-5-イル)エトキシメチル]-5-フルオロ-1H-ベンズイミダゾール;
2-[(2,2-ジフルオロベンゾ[1,3]ジオキソール-5-イル)メトキシメチル]-5-フルオロ-1H-ベンズイミダゾール;
(5-ニトロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
5-クロロ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(5-プロピルスルファニル-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(6-クロロ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-(2,2-ジフルオロベンゾ[1,3]ジオキソール-5-イル)メタノール;
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-フルオロ-1H-ベンズイミダゾール;
2-{[4-(2,5-ジフルオロベンジルオキシ)フェニル]エトキシメチル}-5-ニトロ-1H-ベンズイミダゾール;
5-エトキシ-2-{エトキシ[4-(4-フルオロベンジルオキシ)フェニル]メチル}-1H-ベンズイミダゾール;
5-エトキシ-2-{エトキシ[4-(3-フルオロベンジルオキシ)フェニル]メチル}-1H-ベンズイミダゾール;
5-エトキシ-2-{エトキシ[4-(2-フルオロベンジルオキシ)フェニル]メチル}-1H-ベンズイミダゾール;
2-{[4-(3,5-ジメトキシベンジルオキシ)フェニル]エトキシメチル}-5-エトキシ-1H-ベンズイミダゾール;
5-エトキシ-2-{エトキシ[4-(4-トリフルオロメトキシベンジルオキシ)フェニル]メチル}-1H-ベンズイミダゾール;
(5-ブロモ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
5-ブロモ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[ヒドロキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール-5-カルボニトリル;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール-5-カルボニトリル;
6-クロロ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-4-フルオロ-1H-ベンズイミダゾール;
6-クロロ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール-4-イルアミン;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5,6-ジフルオロ-1H-ベンズイミダゾール;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-6-フルオロ-3H-イミダゾ[4,5-b]ピリジン;
6-ブロモ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-3H-イミダゾ[4,5-b]ピリジン;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-トリフルオロメトキシ-1H-ベンズイミダゾール;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-5-トリフルオロメチル-1H-ベンズイミダゾール;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-4-フルオロ-1H-ベンズイミダゾール;
5-ジフルオロメトキシ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[(3-ブロモ-4-トリフルオロメトキシフェニル)メトキシメチル]-5-フルオロ-1H-ベンズイミダゾール;
2-[(3-ブロモ-4-トリフルオロメトキシフェニル)メトキシメチル]-1H-ベンズイミダゾール;
2-[(3-ブロモ-4-トリフルオロメトキシフェニル)メトキシメチル]-5-メトキシ-1H-ベンズイミダゾール;
2-[(3-ブロモ-4-トリフルオロメトキシフェニル)メトキシメチル]-5-エトキシ-1H-ベンズイミダゾール;
5-ジフルオロメトキシ-2-[エトキシ(4-トリフルオロメチルフェニル)メチル]-1H-ベンズイミダゾール;
5-ジフルオロメトキシ-2-[メトキシ(4-トリフルオロメチルフェニル)メチル]-1H-ベンズイミダゾール;
(1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(5-ジフルオロメトキシ-1H-ベンズイミダゾール-2-イル)-(4-ジフルオロメトキシフェニル)メタノール;
(5-ジフルオロメトキシ-1H-ベンズイミダゾール-2-イル)-[4-(2,2,2-トリフルオロエトキシ)フェニル]メタノール;
(5-ジフルオロメトキシ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメチルフェニル)メタノール;
(3-クロロ-4-トリフルオロメトキシフェニル)-(5-フルオロ-1H-ベンズイミダゾール-2-イル)メタノール;
(1H-ベンズイミダゾール-2-イル)-(3-クロロ-4-トリフルオロメトキシフェニル)メタノール;
(3-クロロ-4-トリフルオロメトキシフェニル)-(5-メトキシ-1H-ベンズイミダゾール-2-イル)メタノール;
2-[メトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[プロポキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[イソプロポキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[(3-クロロ-4-トリフルオロメトキシフェニル)エトキシメチル]-5-フルオロ-1H-ベンズイミダゾール;
2-[(3-クロロ-4-トリフルオロメトキシフェニル)エトキシメチル]-1H-ベンズイミダゾール;
2-[(3-クロロ-4-トリフルオロメトキシフェニル)エトキシメチル]-5-メトキシ-1H-ベンズイミダゾール;
(5-メトキシ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
2-[イソプロポキシ(4-トリフルオロメトキシフェニル)メチル]-3H-イミダゾ[4,5-b]ピリジン;
(5-クロロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(5-ジフルオロメトキシ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
2-[ヒドロキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール-5-オール;
(6-クロロ-4-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(5-トリフルオロメトキシ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(4-トリフルオロメトキシフェニル)-(5-トリフルオロメチル-1H-ベンズイミダゾール-2-イル)メタノール;
(4-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(1H-ベンズイミダゾール-2-イル)-(3-ブロモ-4-トリフルオロメトキシフェニル)メタノール;
(3-ブロモ-4-トリフルオロメトキシフェニル)-(5-メトキシ-1H-ベンズイミダゾール-2-イル)メタノール;
(3-ブロモ-4-トリフルオロメトキシフェニル)-(5-エトキシ-1H-ベンズイミダゾール-2-イル)メタノール;
(5,6-ジフルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(3-イソプロピル-4-トリフルオロメトキシフェニル)メタノール;
(6-フルオロ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
(6-ブロモ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-(4-トリフルオロメトキシフェニル)メタノール;
5-フルオロ-2-[(2-フルオロエトキシ)-(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[(5-フルオロ-1H-ベンズイミダゾール-2-イル)-(4-トリフルオロメトキシフェニル)メトキシ]エタノール;
5-フルオロ-2-[プロポキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
2-[イソプロポキシ(4-トリフルオロメトキシフェニル)メチル]-5-メトキシ-1H-ベンズイミダゾール;
5-エトキシ-2-[イソプロポキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
5-クロロ-2-[エトキシ(4-トリフルオロメトキシフェニル)メチル]-1H-ベンズイミダゾール;
5-フルオロ-2-[メトキシ(4-トリフルオロメチルフェニル)メチル]-1H-ベンズイミダゾール;
5-[(5-フルオロ-1H-ベンズイミダゾール-2-イル)メトキシメチル]-2-トリフルオロメトキシベンゾニトリル;
及び2-[(3-シクロプロピル-4-トリフルオロメトキシフェニル)メトキシメチル]-5-フルオロ-1H-ベンズイミダゾールから選ばれる化合物、その薬学的に許容される塩又はそれらの溶媒和物。 - 請求項1~7のいずれか1項記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物を含有する医薬。
- 請求項1~7のいずれか1項記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物を含有するT型カルシウムチャネル拮抗作用が有効な疾患の治療薬又は予防薬。
- 請求項1~7のいずれか1項記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物を含有する高血圧、心房細動、不整脈、心肥大、心不全、腎機能障害又は癌の治療薬若しくは予防薬。
- さらに薬学的に許容される担体を含有する請求項8~10のいずれか1項記載の医薬。
- T型カルシウムチャネル拮抗作用が有効な疾患の治療又は予防のために使用される請求項1~7のいずれか1項記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物。
- 高血圧、心房細動、不整脈、心肥大、心不全、腎機能障害又は癌の治療若しくは予防のために使用される、請求項1~7のいずれか1項記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物。
- 請求項1~7のいずれか1項記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物の、T型カルシウムチャネル拮抗作用が有効な疾患の治療薬又は予防薬製造のための使用。
- 請求項1~7のいずれか1項記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物の、高血圧、心房細動、不整脈、心肥大、心不全、腎機能障害又は癌の治療薬若しくは予防薬製造のための使用。
- 請求項1~7のいずれか1項記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物の有効量を投与することを特徴とするT型カルシウムチャネル拮抗作用が有効な疾患の治療方法又は予防方法。
- 請求項1~7のいずれか1項記載の化合物、その薬学的に許容される塩、又はそれらの溶媒和物の有効量を投与することを特徴とする高血圧、心房細動、不整脈、心肥大、心不全、腎機能障害又は癌の治療方法若しくは予防方法。
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JP2012517286A JP5892550B2 (ja) | 2010-05-24 | 2011-05-24 | 縮合イミダゾール誘導体 |
EP11786655.8A EP2578573A4 (en) | 2010-05-24 | 2011-05-24 | CONDENSATE IMIDAZOLE DERIVATIVE |
CN2011800254638A CN102906074A (zh) | 2010-05-24 | 2011-05-24 | 稠合咪唑衍生物 |
US13/699,692 US9096531B2 (en) | 2010-05-24 | 2011-05-24 | Fused imidazole derivative |
CA2800521A CA2800521A1 (en) | 2010-05-24 | 2011-05-24 | Fused imidazole derivative |
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US (1) | US9096531B2 (ja) |
EP (1) | EP2578573A4 (ja) |
JP (1) | JP5892550B2 (ja) |
CN (1) | CN102906074A (ja) |
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WO2015182724A1 (ja) * | 2014-05-28 | 2015-12-03 | トーアエイヨー株式会社 | 置換トロパン誘導体 |
JP2016535042A (ja) * | 2013-10-30 | 2016-11-10 | ノバルティス アーゲー | 2−ベンジル−ベンゾイミダゾール補体因子b阻害剤およびその使用 |
US10011594B2 (en) | 2015-06-03 | 2018-07-03 | Bristol-Myers Squibb Company | 4-hydroxy-3-(heteroaryl)pyridine-2-one APJ agonists |
JP2021522262A (ja) * | 2018-05-03 | 2021-08-30 | ジエンス ヘンルイ メデイシンカンパニー リミテッドJiangsu Hengrui Medicine Co.,Ltd. | レチノイド関連オルファン受容体ガンマ(RORγ)のモジュレーターとしてのベンジイミダゾール誘導体およびそれらの医薬品用途 |
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US10913736B2 (en) * | 2014-08-22 | 2021-02-09 | University Of Washington | Specific inhibitors of methionyl-tRNA synthetase |
WO2019027856A1 (en) * | 2017-08-02 | 2019-02-07 | Merck Sharp & Dohme Corp. | NOVEL SUBSTITUTED PYRIDINE COMPOUNDS AS INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE (IDO) |
MX2022005260A (es) * | 2019-10-31 | 2022-06-09 | Jiangsu Hengrui Medicine Co | Sal de adicion acida de regulador rorgamma. |
CN112745268B (zh) * | 2019-10-31 | 2022-09-16 | 江苏恒瑞医药股份有限公司 | 苯并咪唑衍生物的晶型及制备方法 |
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JPWO2015182724A1 (ja) * | 2014-05-28 | 2017-04-20 | トーアエイヨー株式会社 | 置換トロパン誘導体 |
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Also Published As
Publication number | Publication date |
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US20130065896A1 (en) | 2013-03-14 |
JP5892550B2 (ja) | 2016-03-23 |
EP2578573A4 (en) | 2014-08-06 |
EP2578573A1 (en) | 2013-04-10 |
CA2800521A1 (en) | 2011-12-01 |
JPWO2011148956A1 (ja) | 2013-07-25 |
CN102906074A (zh) | 2013-01-30 |
US9096531B2 (en) | 2015-08-04 |
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