WO2012002527A1 - 複素環化合物及びp27Kip1分解阻害剤 - Google Patents
複素環化合物及びp27Kip1分解阻害剤 Download PDFInfo
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- WO2012002527A1 WO2012002527A1 PCT/JP2011/065148 JP2011065148W WO2012002527A1 WO 2012002527 A1 WO2012002527 A1 WO 2012002527A1 JP 2011065148 W JP2011065148 W JP 2011065148W WO 2012002527 A1 WO2012002527 A1 WO 2012002527A1
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Classifications
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- 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
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Definitions
- the present invention specifically binds to constitutive protein Skp2 of ubiquitin ligase (SCF Skp2 ) and suppresses dissociation of p27 Kip1 from, for example, the SCF Skp2 complex, resulting in the progress of ubiquitination of p27 Kip1.
- SCF Skp2 constitutive protein Skp2 of ubiquitin ligase
- a heterocyclic compound useful for suppressing degradation of p27 Kip1 by the proteasome a p27 Kip1 ubiquitination inhibitor (or p27 Kip1 degradation inhibitor) containing this compound, and prevention of cell proliferative diseases and And / or a therapeutic agent (for example, an anticancer agent).
- p27 Kip1 is a cyclin-dependent kinase inhibitor molecule (CDK Inhibitors) that is a factor that negatively regulates cell cycle progression.
- CDK Inhibitors cyclin-dependent kinase inhibitor molecule
- Clinical studies have shown that the expression level of p27 Kip1 is reduced due to increased degradation of p27 Kip1 in cancer cells with high malignancy.
- the decrease in the expression level of p27 Kip1 is closely related to the progress, recurrence, metastasis of cancer, and the decrease in the survival rate of cancer patients.
- p27 Kip1 is degraded mainly by the ubiquitin-proteasome system, and its expression level decreases. More specifically, when the 187th threonine of p27 Kip1 is phosphorylated, p27 Kip1 is released from the cyclin-CDK complex, and the Fbox of a ubiquitin ligase composed of SCF (Skp1 / Cullin1 / Fbox) complex. It specifically binds to a protein (Skp2). On the other hand, ubiquitin-binding enzyme (E2) is bound via Rbx1 in the ubiquitin ligase complex, and p27 Kip1 bound to Skp2 is ubiquitinated via this enzyme. By repeating this ubiquitination reaction, the polyubiquitinated p27 Kip1 is recognized by the proteasome and degraded.
- E2 ubiquitin-binding enzyme
- Patent Document 1 discloses a compound represented by the following formula, etc. as a physiologically active inhibitor of LPA that acts as an intercellular messenger.
- this compound is useful as a therapeutic or prophylactic agent for cell proliferative diseases, which are one of the diseases involving LPA receptors.
- cell proliferative diseases which are one of the diseases involving LPA receptors.
- the relationship with intracellular proteins is not described.
- an object of the present invention is to provide a novel heterocyclic compound or a salt thereof, a p27 Kip1 degradation inhibitor, a p27 Kip1 ubiquitination inhibitor, a prophylactic and / or therapeutic agent for cell proliferative diseases, and a pharmaceutical composition. There is to do.
- Another object of the present invention is useful novel heterocyclic compound or a salt thereof to selectively inhibit the degradation of p27 Kip1, p27 Kip1 degradation inhibitor p27 Kip1 ubiquitination inhibitor, cell proliferative disorder It is providing the preventive and / or therapeutic agent of this, and a pharmaceutical composition.
- Still another object of the present invention is useful novel heterocyclic compound or a salt thereof to selectively inhibit the ubiquitination of p27 Kip1, inhibitor of degradation of p27 Kip1, p27 Kip1 ubiquitination inhibitor, cell proliferation It is to provide a preventive and / or therapeutic agent for sexually transmitted diseases and a pharmaceutical composition.
- a heterocyclic compound in which a plurality of rings are bonded to each other via a specific linker or a salt thereof is (1) It binds specifically to the constituent protein Skp2 of the ubiquitin ligase (SCF Skp2 ), for example, by suppressing the dissociation of p27 Kip1 from the SCF Skp2 complex, thereby accompanying the ubiquitination of p27 Kip1 and this ubiquitination It is possible to inhibit the degradation of p27 Kip1 by the proteasome, and (2) selectively inhibit the degradation of p27 Kip1 with a high activity to restore the expression level of p27 Kip1 , thereby increasing non-selective expression of proteins other than p27 Kip1 (3) cells whose p27 Kip1 expression level is reduced (such as cancer cells) ) Was found to induce cell death (apoptosis), and the present invention was completed.
- SCF Skp2 ubiquitin ligase
- heterocyclic compound of the present invention or a salt thereof is a compound represented by the following formula (1) or a salt thereof.
- A represents an alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group, and the group A may have a substituent;
- ring B is a 5- to 8-membered monocyclic heterocyclic ring or A condensed ring including a monocyclic heterocyclic ring is represented, ring B may have a substituent;
- ring C represents an aromatic ring, ring C may have a substituent;
- the main chain has 3 to 5 atoms selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom, and has at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom
- n is 0 or 1;
- the group A is not a 2-methylaminopyrimidin-4-yl group, the ring C is not a 9-fluorenyl group, (Iv)
- the linker L is represented by the following formula (1-a2)
- X 1 represents a methyl group.
- ring C is a benzene ring having a halogen atom as a substituent
- ring B is not a 3,4-isoxazole-diyl group.
- the linker L may contain a urethane bond [—NH—C (O) —O— or —O—C (O) —NH—].
- a linker represented by any one of a1) to (1-a6) may be used.
- X 1 represents an alkyl group.
- the group A is an aryl group or a heterocyclic group having at least one substituent selected from a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a mercapto group, and an alkylthio group, for example, 2 It may be a phenyl group having a substituent at the -position and / or the 4-position.
- ring B is an aromatic heterocycle containing at least one heteroatom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S) as a constituent atom of the ring.
- ring B is selected from pyrrole ring, furan ring, thiophene ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, thiadiazole ring, pyridine ring, pyrimidine ring, and quinoline ring.
- aromatic heterocycle in particular, a 5- or 6-membered monocyclic heterocycle such as a thiazole ring, an isothiazole ring or a pyrazole ring).
- the aromatic ring represented by the ring C is not particularly limited, and for example, a monocyclic (non-condensed) arene ring having a substituent or a condensed optionally having a substituent In many cases, it is an arene ring, a monocyclic (non-condensed) or a condensed heterocyclic ring which may have a substituent.
- Ring C may be any of the following formulas (4-a) to (4-c), for example.
- Z 1 represents a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a mercapto group, an alkylthio group, an N-alkyl-substituted amino group (such as an N, N-dialkylamino group), or an N-acyl-substituted amino group
- Z 2 represents an alkyl group or an acyl group
- Z 3 represents an alkyl group or an acyl group
- ring C 1 represents a C 6-10 arene ring
- C 2 together with G 1 and G 2 , a 5- to 8-membered heterocyclic ring containing at least one hetero atom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S) as a constituent atom of the ring Ring
- C 3 contains, together with adjacent G 4 , at least one heteroatom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S)
- G 1 ⁇ G 3 is an aromatic or non-aromatic ring C 2, or in response to an aromatic or non-aromatic 5-membered ring adjacent to the ring C 3, nitrogen atom ( N), oxygen atom (O), sulfur atom (S), NH, CH or CH 2 ; G 4 depending on the aromaticity or non-aromaticity of the 5-membered ring adjacent to ring C 3 , A nitrogen atom (N), a carbon atom (C), or CH; p is an integer of 1 to 5, and q is an integer of 0 to 6. ]
- the 5-membered ring containing G 3, and G 4 a broken line, that the 5-membered ring may be aromatic rings or non-aromatic (aliphatic) ring Indicates.
- R 1 and R 2 are the same or different and each represents a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a mercapto group, or an alkylthio group;
- ring B represents a thiazole ring, an isothiazole ring or a pyrazole ring.
- Ring B may have at least one substituent selected from an alkyl group, a haloalkyl group, a cycloalkyl group, an aryl group, an aralkyl group, and an acyl group;
- L is a group represented by the formula (1-a1) ⁇ (1-a6) shows the kind of linker selected from;
- Z a is a hydroxyl group, an alkoxy group, a mercapto group, an alkylthio group, N- alkyl-substituted amino group (N, such as N- dialkylamino group), or An N-acyl-substituted amino group (such as N, N-diacylamino group);
- Z b represents a hydrogen atom, an alkyl group, a hydroxyl group, or an alkyl; Represents a alkoxy group;
- G 1 represents a nitrogen atom (N), CH, or CH 2 depending on the aromaticity or non-aromaticity of ring C
- A represents an alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group, and the group A may have a substituent;
- ring B is a 5- to 8-membered monocyclic heterocyclic ring or A condensed ring including a monocyclic heterocyclic ring is represented, ring B may have a substituent;
- ring C represents an aromatic ring, ring C may have a substituent;
- the main chain has 3 to 5 atoms selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom, and has at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom
- n is 0 or 1;
- ring B is a condensed ring containing a 5- to 8-membered monocyclic heterocycle
- ring C has a substituent.
- a salt thereof specifically binds to a constituent protein Skp2 of ubiquitin ligase (SCF Skp2 ) and suppresses dissociation of p27 Kip1 from the SCF Skp2 complex, for example, to prevent p27 Kip1 Ubiquitination and degradation of p27 Kip1 by the proteasome accompanying this ubiquitination can be effectively suppressed. Therefore, the present invention includes a p27 Kip1 ubiquitination inhibitor or degradation inhibitor containing the compound or a pharmaceutically (or physiologically) acceptable salt as an active ingredient.
- A represents an alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group, and the group A may have a substituent;
- ring B is a 5- to 8-membered monocyclic heterocyclic ring or A condensed ring including a monocyclic heterocyclic ring is represented, ring B may have a substituent;
- ring C represents an aromatic ring, ring C may have a substituent;
- the main chain has 3 to 5 atoms selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom, and has at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom
- n is 0 or 1;
- X 1 represents a methyl group.
- ring C is a benzene ring having a halogen atom as a substituent
- ring B is not a 3,4-isoxazole-diyl group.
- the present invention includes a prophylactic and / or therapeutic agent for cell proliferative diseases containing the compound or a pharmaceutically (or physiologically) acceptable salt thereof as an active ingredient.
- the compound of the present invention or a salt thereof specifically binds to constitutive protein Skp2 of ubiquitin ligase (SCF Skp2 ) and suppresses dissociation of p27 Kip1 from the SCF Skp2 complex, for example, thereby ubiquitination of p27 Kip1 And the degradation of p27 Kip1 by the proteasome accompanying this ubiquitination can be effectively suppressed.
- SCF Skp2 ubiquitin ligase
- it is possible to selectively inhibit the degradation of p27 Kip1 can avoid degradation or increased expression of proteins other than p27 Kip1.
- the compound of the present invention or a salt thereof is allowed to act on cells (for example, cancer cells) in which the expression of p27 Kip1 is decreased, the expression level of p27 Kip1 can be recovered and cell death (apoptosis) can be induced. It is useful for the prevention and / or treatment of proliferative diseases (eg, cancer, rheumatism, diabetes, obesity, endometriosis, benign prostatic hyperplasia, inflammation, etc.).
- proliferative diseases eg, cancer, rheumatism, diabetes, obesity, endometriosis, benign prostatic hyperplasia, inflammation, etc.
- FIG. 1 is a graph showing the results of Test Example 3 for the compound of Example 9-1.
- FIG. 2 is a view showing the results of Test Example 3 for the compounds of Examples 9-25.
- FIG. 3 shows the results of Test Example 3 for the compounds of Examples 9-94.
- FIG. 4 is a graph showing the results of Test Example 4 for the compound of Example 9-1.
- FIG. 5 is a graph showing the results of Test Example 4 for the compounds of Examples 9-25.
- FIG. 6 is a graph showing the results of Test Example 4 for the compounds of Examples 9-94.
- examples of the alkyl group represented by the group A include linear or methyl groups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, 2-ethylhexyl, heptyl, and octyl groups.
- examples thereof include a branched alkyl group (for example, a C 1-10 alkyl group, preferably a C 1-6 alkyl group, more preferably a C 1-4 alkyl group).
- Examples of the cycloalkyl group represented by the group A include C 3-10 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups (preferably C 4-8 cycloalkyl groups, more preferably C 5-6 cycloalkyl group); bridged cycloalkyl groups such as adamantyl group and norbornyl group (such as bi or tricycloalkyl group).
- Examples of the aryl group represented by the group A include C 6-10 aryl groups such as phenyl and naphthyl groups.
- the heterocyclic group represented by the group A includes various heterocyclic groups having an aromatic or non-aromatic 5- to 8-membered heterocyclic ring, for example, at least selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
- a heterocyclic group containing one hetero atom is included, and examples thereof include a 5- or 6-membered heterocyclic group, a condensed ring group of a 5- or 6-membered heterocyclic ring and a hydrocarbon ring, and the like.
- Examples of the 5- or 6-membered heterocyclic group include a heterocyclic group containing an oxygen atom as a hetero atom such as a furyl group (such as a 2- or 3-furyl group); a thienyl group (such as a 2- or 3-thienyl group), and the like A heterocyclic group containing a sulfur atom as a heteroatom; a heterocyclic ring containing a nitrogen atom such as a pyridyl group (such as a 2-, 3- or 4-pyridyl group) or a pyrazolyl group (such as a pyrazol-2-yl group) as a heteroatom And a heterocyclic group containing a sulfur atom and a nitrogen atom as a hetero atom, such as a group and a thiazolyl group (such as thiazol-5-yl group).
- a heterocyclic group containing an oxygen atom as a hetero atom such as a furyl group (such as a 2- or
- Examples of the condensed ring group of a 5- or 6-membered heterocyclic ring and a hydrocarbon ring include, for example, a benzothienyl group (or thianaphthenyl group) [benzo [b] thiophen-3-yl group (or thianaphthene-3- A heterocyclic ring containing a sulfur atom as a hetero atom and a hydrocarbon ring (such as a benzene ring); a nitrogen atom such as an isoquinolyl group [such as an isoquinolin-1-yl group] as a hetero atom
- a condensed ring group including a heterocyclic ring and a hydrocarbon ring such as a benzene ring
- a coumaryl group [coumaran-5- or 7-yl group, etc.], an alkylenedioxyphenyl group [2,3-ethylenedioxyphenyl group, etc.
- C 1-4 alkylenedioxyphenyl group etc.] and the like can be exemplified by a condensed ring group of a heterocycle containing an oxygen atom as a heteroatom and a hydrocarbon ring (benzene ring etc.)
- the group A may have a substituent.
- substituents include a halogen atom, an alkyl group, a cycloalkyl group, an aryl group, a hydroxyl group, an alkoxy group, a mercapto group, an alkylthio group, an amino group, and an N-substituted amino group. If necessary, these substituents may be further substituted with a substituent (such as a halogen atom) to form a haloalkyl group, a haloalkoxy group, or the like.
- halogen atom substituted for the group A examples include a fluorine atom and a chlorine atom.
- alkyl group substituted on the group A examples include the C 1-6 alkyl groups exemplified above (preferably C 1-4 alkyl groups).
- haloalkyl group substituted for the group A examples include a linear or branched halo C 1-6 alkyl group such as a fluoromethyl group (such as a trifluoromethyl group), a fluoroethyl group (2,2,2-trifluoro).
- Mono to perfluoro C 1-6 alkyl groups (preferably ethyl groups, perfluoroethyl groups, etc.), fluoropropyl groups (3,3,3,2,2-pentafluoropropyl groups, perfluoropropyl groups, etc.)
- Mono to perfluoro C 1-4 alkyl groups Mono to perfluoro C 1-4 alkyl groups), and chloroalkyl groups corresponding to these fluoroalkyl groups.
- Examples of the cycloalkyl group substituted on the group A include C 3-10 cycloalkyl groups such as cyclopentyl and cyclohexyl groups (preferably C 4-8 cycloalkyl groups, more preferably C 5-6 cycloalkyl groups).
- Examples of the aryl group include C 6-10 aryl groups such as phenyl and naphthyl groups.
- alkoxy group substituted for the group A examples include linear or branched alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy and t-butoxy groups (for example, C 1-10 alkoxy groups, preferably C 1-6 alkoxy group, more preferably C 1-4 alkoxy group).
- haloalkoxy group substituted for the group A examples include a linear or branched haloC 1-6 alkoxy group such as a fluoromethoxy group (such as a trifluoromethoxy group), a fluoroethoxy group (2,2,2-trimethyl).
- Mono to perfluoro C 1-6 alkoxy groups (preferably fluoroethoxy groups, perfluoroethoxy groups, etc.), fluoropropoxy groups (3,3,3,2,2-pentafluoropropoxy groups, perfluoropropoxy groups, etc.) Are mono to perfluoro C 1-4 alkoxy groups), and chloroalkoxy groups corresponding to these fluoroalkoxy groups.
- alkylthio group substituted for the group A examples include linear or branched alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, t-butylthio groups (for example, C 1-10 alkylthio groups, preferably C 1 -6 alkylthio group, more preferably C 1-4 alkylthio group).
- the N-substituted amino group substituted for the group A includes N-monosubstituted amino groups [for example, N-alkylamino groups such as N-methylamino and N-ethylamino groups (for example, N—C 1-6 alkylamino).
- N-acylamino groups eg N— (C 1-6 alkyl-carbonyl) amino groups, preferably N- (C 1-4 alkyl-carbonyl) amino group
- N-disubstituted amino group [eg, N, N-dimethylamino, N, N-diethylamino, N-methyl-N-ethylamino group] N, such as, N- dialkylamino group (e.g., N, N- di-C 1-6 alkylamino group, preferably N, N- di-C 1-4 alkylamino group)
- N, N- diacetylamino N such as, N- diacylamino group (e.g., N, N- di (C 1-6 alkyl - carbonyl) amino group, preferably N, N- di (C 1-4 al
- alkyl group having a substituent examples include an alkyl group having at least one substituent selected from a halogen atom and an aryl group, such as the halo C 1-6 alkyl group exemplified above (preferably a halo C 1-4 alkyl group). ), Arylalkyl groups (or aralkyl groups) [for example, C 6-10 aryl C 1-6 alkyl groups such as benzyl and phenethyl groups (preferably C 6-10 aryl C 1-4 alkyl groups)] and the like it can.
- cycloalkyl group having a substituent examples include alkyl cycloalkyl groups [for example, C 1-6 alkyl C 5-6 cycloalkyl groups such as 2-methylcyclohexyl group, 2-ethylcyclohexyl group, etc. (preferably C 1-4 alkyl C 5-6 cycloalkyl group) and the like].
- aryl group having a substituent for example, at least one kind of substitution selected from a halogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a mercapto group, an alkylthio group, and an N-substituted amino group
- aryl group having a group for example, a C 6-24 aryl group, preferably a C 6-20 aryl group, more preferably a C 6-18 aryl group
- the monosubstituted aryl group has, for example, one substituent selected from a halogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, and an N-alkyl-substituted amino group.
- An aryl group for example, a haloaryl group such as a 2-, 3- or 4-chlorophenyl group, 2-, 3- or 4-fluorophenyl group (such as a haloC 6-10 aryl group); 2-, 3- or 4- An alkylaryl group such as a methylphenyl group, 2-, 3- or 4-ethylphenyl group (C 1-6 alkyl C 6-10 aryl group, preferably C 1-4 alkyl C 6-10 aryl group etc.); 2 Mono to perhalo C 1-6 alkyl C 6-10 a such as-or 4-trifluoromethylphenyl group, 2- or 4-trichloromethylphenyl group Reel group (mono to perhalofluoro C 1-6 alkyl C 6-10 aryl group, preferably mono to perhalofluoro C 1-4 alkyl C 6-10 aryl group); 2- or 4-hydroxyphenyl group etc.
- a haloaryl group such as a 2-, 3- or 4-
- Hydroxyaryl groups (such as hydroxy C 6-10 aryl groups); alkoxyaryl groups such as 2- or 4-methoxyphenyl groups, 2- or 4-ethoxyphenyl groups, 2- or 4-propoxyphenyl groups (C 1- 6 alkoxy C 6-10 aryl group, preferably C 1-4 alkoxy C 6-10 aryl group, etc .; halo C 1-6 alkoxy C 6-10 aryl group (mono to perfluoro C 1-6 alkoxy C 6- 10 aryl group, preferably such as mono- to perfluoro C 1-4 alkoxy C 6-10 aryl group); 4- (N N- dimethylamino) N, such as a phenyl group, N- dialkylamino aryl group (N, N- di-C 1-6 alkylamino C 6-10 aryl group, preferably N, N- di-C 1-4 alkylamino C 6-10 aryl group, etc.)] and the like.
- alkoxyaryl groups such as
- disubstituted aryl group examples include, for example, an aryl group having two same or different substituents selected from a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a mercapto group, and an alkylthio group [for example, 2,3- 2,4- or 3,4-dichlorophenyl group, 2,3-, 2,4- or 3,4-difluorophenyl group, 2-chloro-4-fluorophenyl group, 2-fluoro-4-chlorophenyl group, etc.
- Dihaloaryl groups such as dihaloC 6-10 aryl groups
- dialkylaryl groups such as 2,3-, 2,4- or 2,5-dimethylphenyl groups (diC 1-6 alkyl C 6-10 aryl groups; preferably and di C 1-4 alkyl C 6-10 aryl group); 2,3, 2,4, di and 2,6 or 3,4-dihydroxyphenyl group Mud alkoxy (such as dihydroxy C 6-10 aryl group) an aryl group; 2,3-, 2,4-, 2,6- or 3,4-dimethoxy dialkoxy aryl group such as phenyl group (di-C 1-6 alkoxy C 6-10 aryl group, preferably diC 1-4 alkoxyphenyl group); 2-methyl-3- (or 4-) chlorophenyl group, 2-methyl-3- (or 4-) fluorophenyl group, etc.
- Alkyl-haloaryl groups (C 1-6 alkyl-halo C 6-10 aryl groups, preferably C 1-4 alkyl-halo C 6-10 aryl groups); 2-hydroxy-4-chlorophenyl group, 2-hydroxy- Hydroxy-haloaryl groups such as 4-fluorophenyl, 2-chloro-4-hydroxyphenyl, 2-fluoro-4-hydroxyphenyl, etc.
- Carboxymethyl - such as halo C 6-10 aryl group); 2-methoxy-4-chlorophenyl group, 2-methoxy-4-fluorophenyl group, 2-chloro-4-methoxyphenyl group, 2-fluoro-4-methoxyphenyl group Alkoxy-haloaryl groups such as (C 1-6 alkoxy-halo C 6-10 aryl group, preferably C 1-4 alkoxy-halo C 6-10 aryl group etc.); 2-methyl-3- (or 4-) Alkyl-hydroxyaryl groups such as hydroxyphenyl group and 2-hydroxy-4-methylphenyl group (C 1-6 alkyl-hydroxy C 6-10 aryl group, preferably C 1-4 alkyl-hydroxy C 6-10 aryl group 2-methyl-3- (or 4-) methoxyphenyl group, 2-methoxy-4-methylphenyl group, etc.
- Le - alkoxyaryl group (C 1-6 alkyl -C 1-6 alkoxy C 6-10 aryl
- the heterocyclic group having a substituent is a heterocyclic ring (for example, an aromatic heterocyclic ring) containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and includes a halogen atom, an alkyl group, A group having a heterocyclic ring having at least one substituent selected from a hydroxyl group, an alkoxy group, a mercapto group, and an alkylthio group (for example, a 5- to 8-membered ring, preferably a 5- to 7-membered heterocyclic group, more preferably Examples thereof include 5- or 6-membered heterocyclic groups.
- a heterocyclic group having a halogen atom and / or an alkyl group as a substituent for example, a heterocyclic group having a halogen atom as a substituent
- a halopyridyl group such as a 3-chloropyridin-2-yl group
- 5- or 6-membered heterocyclic groups containing nitrogen atoms as heteroatoms such as chloropyridyl groups and fluoropyridyl groups corresponding to these chloropyridyl groups
- halofuryl groups chlorofuryl such as 3-chlorofuran-2-yl groups
- Groups 5- or 6-membered heterocyclic groups containing oxygen atoms as heteroatoms such as fluorofuryl groups corresponding to these chlorofuryl groups
- halothienyl groups (3- or 5-chlorothiophen-2-yl groups, 3, Chlorothienyl groups such as 5-dichlorothiophen-2-yl group, fluor
- a 5- or 6-membered heterocyclic group containing a sulfur atom as a hetero atom, etc.], a heterocyclic group having an alkyl group as a substituent for example, an alkylpyridyl group (3-methylpyridin-2-yl group, 4-methylpyridine, etc.) Mono- or di-C 1-4 alkylpyridyl group such as a 3-yl group), mono- or di-C 1-4 alkyl pyrazolyl group such as an alkylpyrazolyl group ((1,4-dimethyl) pyrazol-2-yl group, etc.)
- a 5- or 6-membered heterocyclic group containing a nitrogen atom as a heteroatom such as an alkylthiazolyl group ((4-methyl) thiazol-5-yl group, (2,4-dimethyl) thiazol-5-yl group)
- mono- or di-C 1-4 alkylthiazolyl groups, etc. such as 5- or 6-membered hetero
- an aryl group or a heterocyclic group having a substituent for example, an aryl having at least one substituent selected from a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a mercapto group, and an alkylthio group) Group or heterocyclic group
- the number of substituents substituted on the aryl group or heterocyclic group depends on the kind of the aryl group or heterocyclic group, but is, for example, 1 to 5, preferably 1 to 4, more preferably 1 to 3 (for example, 1 Or it is about 2).
- the substitution position of the substituent with respect to the aryl group or heterocyclic group is not particularly limited.
- a phenyl group or a 5- or 6-membered heterocyclic group it may be 2-, 3-, 4-position and the like.
- the substitution position often includes at least the 2- and / or 4-position.
- Further preferred group A is a C 6-10 aryl group having a substituent, for example, a group represented by the following formula (2).
- R a to R e are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a mercapto group, or an alkylthio group, provided that R ( Except when all of a 1 to R e are hydrogen atoms)
- R except when all of a 1 to R e are hydrogen atoms
- the halogen atom, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, or alkylthio group represented by R a to R e the same halogen atom (fluorine atom, chlorine atom, etc.) as the substituent substituted on the group A ), C 1-4 alkyl group (such as C 1-2 alkyl group), fluoro C 1-4 alkyl group (such as fluoro C 1-2 alkyl group), C 1-4
- the group A is particularly preferably a mono- or di-substituted aryl group (such as a mono- or di-substituted C 6-10 aryl group), for example, a phenyl group having a substituent at the 2- and / or 4-position.
- R b , R d , and R e are hydrogen atoms, and at least one of R a and R c is a halogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, A group that is a haloalkoxy group, a mercapto group, or an alkylthio group
- R b , R d , and R e are hydrogen atoms
- R a , R c (halogen atom, halogen atom), (alkyl group, alkyl Group), (hydroxyl group, hydroxyl group), (alkoxy group, alkoxy group), (alkyl group, halogen atom), (hydroxyl group, halogen atom), (alkoxy group, halogen atom), (hydroxyl group, alkyl group) Or a group such as (alkoxy group, alkyl group)] is preferable.
- the group A is a 2,4-dihalophenyl group, a 2,4-diC 1-4 alkylphenyl group, a 2,4-dihydroxyphenyl group, a 2,4-diC 1-4 alkoxyphenyl group, 2 -C 1-4 alkyl-4-halophenyl group, 2-hydroxy-4-halophenyl group, 2-C 1-4 alkoxy-4-halophenyl group, 2-hydroxy-4-C 1-4 alkylphenyl group, 2- A C 1-4 alkoxy-4-C 1-4 alkylphenyl group and the like are preferable.
- n is 0 or 1 (the group A is not essential), and particularly preferably 1 (having the group A).
- the heterocyclic ring represented by ring B may be a non-aromatic heterocyclic ring or an aromatic heterocyclic ring, and may be a monocyclic heterocyclic ring or a condensed heterocyclic ring.
- the heterocyclic ring represented by ring B is not particularly limited, and for example, at least one heteroatom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S) is used as a constituent atom of the ring. May be a heterocyclic ring (for example, an aromatic heterocyclic ring).
- the number of heteroatoms is not particularly limited, and may be, for example, about 1 to 4 (preferably 1 to 3, particularly 1 to 2).
- the monocyclic heterocycle is, for example, a 5- to 8-membered heterocycle, preferably a 5- to 7-membered heterocycle, and more preferably a 5- or 6-membered heterocycle.
- a heterocycle pyrrole, furan, thiophene, etc.
- one heteroatom as a ring constituent atom, or a plurality (for example, 2 to 3) heteroatoms constituting a ring atom
- Heterocycles heterocycles containing nitrogen atoms such as imidazole, pyrazole, triazole, etc .
- heterocycles containing oxygen and nitrogen atoms such as oxazole, isoxazole, oxadiazole (or furazane); thiazoles, isothiazoles, thiadiazoles, etc.
- a hydrogenated product of these rings and the like.
- the 6-membered monocyclic heterocycle includes a heterocycle (pyridine, pyran) containing one heteroatom as a ring constituent atom, and a heterocycle containing multiple (for example, 2 to 4) heteroatoms as a ring constituent atom.
- heterocycles include rings (heterocycles containing nitrogen atoms such as pyridazine, pyrimidine, pyrazine, triazine, tetrazine, etc.), hydrogenated products of these rings, and the like.
- condensed heterocyclic ring examples include condensed rings containing the monocyclic 5- to 8-membered heterocyclic ring (for example, 6 to 15 membered ring, preferably 8 to 13 membered ring), such as a benzene ring and a C 4-8 aliphatic group.
- a condensed ring of a hydrocarbon ring or a 5- to 8-membered heterocycle containing at least an oxygen atom as a heteroatom and a 5- to 8-membered heterocycle containing at least a nitrogen atom as a heteroatom for example, a benzene ring and a cycloalkane ring (for example, C4-8 cycloalkane ring such as cyclohexane ring), cycloalkene ring (eg C 4-8 cycloalkene ring such as cyclohexene ring), chroman ring, isochroman ring, chromene ring, and isochromene ring
- a condensed ring of a 5- or 6-membered ring and a pyrrole ring for example, indenopyrazole, chromenopyrazole, etc., hydrogenated products of these rings, etc. It can be exemplified.
- the condensed heterocyclic ring may be formed by bonding two substituents substituted at the adjacent positions of the monocyclic 5- to 8-membered heterocyclic ring.
- the condensed heterocyclic ring may be formed by bonding a substituent of ring A and a substituent of the monocyclic 5- to 8-membered heterocyclic ring (in this case, n in the formula (1) is 0).
- the hetero atom (especially nitrogen atom) or carbon atom of ring B may be substituted with a substituent.
- substituents include an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, an acyl group, an amino group, and an N-substituted amino group. If necessary, these substituents are further substituted with a substituent [halogen atom, hydroxyl group, alkoxy group (such as linear or branched C 1-4 alkoxy group)], and a haloalkyl group, hydroxyaryl group , An alkoxyaryl group or the like may be formed. In many cases, the amino group and the N-substituted amino group are substituted with the carbon atoms of the heterocyclic ring constituting the ring B.
- alkyl group cycloalkyl group, aryl group or aralkyl group substituted on ring B, a linear or branched C 1-6 alkyl group, a C 3-10 cycloalkyl group similar to group A, respectively, Examples thereof include a C 6-10 aryl group and a C 6-10 aryl C 1-6 alkyl group.
- Examples of the acyl group substituted on ring B include linear or branched C 1-10 alkyl-carbonyl groups (preferably C 1-6 alkyl-carbonyl groups such as formyl group, acetyl, propionyl, butyryl group, more preferably C 1-4 alkyl - carbonyl group); C 6-10 such as a benzyl group; carbonyl group -; - C 6-10 aryl, such as benzoyl group carbonyl group C 3-10 cycloalkyl such as cyclohexyl group And aryl-C 1-4 alkylcarbonyl group.
- C 1-10 alkyl-carbonyl groups preferably C 1-6 alkyl-carbonyl groups such as formyl group, acetyl, propionyl, butyryl group, more preferably C 1-4 alkyl - carbonyl group
- C 6-10 such as a benzyl group
- N-substituted amino group substituted on ring B the same N-monosubstituted amino group as the substituent substituted on group A [for example, N—C 1-6 alkylamino group, N— (C 1-6 alkyl) -Carbonyl) amino group and the like], N, N-disubstituted amino group [for example, N, N-diC 1-6 alkylamino group, N, N-di (C 1-6 alkyl-carbonyl) amino group and the like] Etc. can be exemplified.
- Examples of the haloalkyl group substituted on the ring B include the same linear or branched halo C 1-6 alkyl group as the group A.
- Examples of the hydroxyaryl group substituted on ring B include hydroxy C 6-10 aryl groups such as hydroxyphenyl and hydroxynaphthyl groups.
- Examples of alkoxyaryl groups include methoxyphenyl, methoxynaphthyl, ethoxyphenyl, ethoxynaphthyl and the like. Examples thereof include C 1-6 alkoxy C 6-10 aryl groups such as a group.
- an alkyl group, a haloalkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a hydroxyaryl group, an alkoxyaryl group, and an acyl group are preferable.
- the alkyl group is preferably a C 1-4 alkyl group such as a methyl, ethyl, propyl, or isopropyl group.
- the haloalkyl group is preferably a halo C 1-4 alkyl group such as a trihalomethyl group (eg, a mono to perfluoro C 1-3 alkyl group (eg, a mono to perfluoro C 1-2 alkyl group).
- the alkyl group is preferably a C 3-6 cycloalkyl group such as a cyclopropyl group
- the aryl group is preferably a C 6-10 aryl group such as a phenyl group
- the aralkyl group is a C benzyl group or the like.
- a 6-10 aryl C 1-4 alkyl group (for example, a C 6-10 aryl C 1-2 alkyl group) is preferred
- the hydroxyaryl group is preferably a hydroxy C 6-10 aryl group such as a hydroxyphenyl group.
- C 1-4 alkoxy such as methoxyphenyl group 6-10 aryl group (e.g., C 1-2 alkoxy C 6-10 aryl groups) include preferably the acyl group, C 1-4 alkyl such as acetyl group -.
- a carbonyl group e.g., C 1-2 alkyl - A carbonyl group is preferred.
- substitution position of the substituent is not particularly limited, and may vary depending on the type of ring B. For example, it may be 1-, 2-, 3-position, etc. based on a nitrogen atom, and may be a sulfur atom or an oxygen atom. It may be in the 3-, 4-position, etc. with respect to the atom. Substitution positions often include at least the 1- and / or 4-position.
- the bonding sites of A and L in ring B are not particularly limited, and may be adjacent positions, and may be non-adjacent positions (for example, 2,4-position, 2,5-position, 3, 5-position, 3,6-position, etc.) and are often 2,5-position, 3,5-position.
- Preferred ring B is a pyrrole ring, furan ring, thiophene ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, thiadiazole ring, pyridine ring, pyrimidine ring or quinoline ring.
- Specific examples include groups represented by the following formulas (3-1) to (3-18) (a linking unit or a linking unit).
- the left end may be connected to the linker L
- the right end may be connected to the ring A
- the left end is connected to the ring A
- the right end is connected to the linker L.
- These rings may have a substituent. That is, the hydrogen atom bonded to the carbon atom and / or the nitrogen atom constituting the ring is the above-exemplified substituent (for example, alkyl group, haloalkyl group, cycloalkyl group, aryl group, aralkyl group, acyl group, etc.). May be substituted.
- a group represented by any of the following formulas (3-a) to (3-p) is preferable.
- Y represents a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, an aryl group, an aralkyl group, or an acyl group.
- the left end is preferably connected to ring A and the right end is preferably connected to linker L.
- alkyl group haloalkyl group, cycloalkyl group, aryl group, aralkyl group, or acyl group represented by the group Y
- the group exemplified above as the substituent substituted on the ring B for example, C 1 -4 alkyl group, halo C 1-4 alkyl group (such as fluoro C 1-4 alkyl group), C 3-6 cycloalkyl group, C 6-10 aryl group, C 6-10 aryl C 1-4 alkyl group, Examples thereof include a C 1-4 alkyl-carbonyl group.
- the group Y is often an alkyl group or an acyl group.
- More preferable ring B is a 5-membered heterocyclic ring containing two or more heteroatoms as constituent atoms of the ring, and at least one heteroatom is a nitrogen atom, and in particular, a substituent (an alkyl group, an acyl group, etc.).
- a thiazole ring, an isothiazole ring, or a pyrazole ring [for example, a ring represented by the above formula (3-a), (3-b), or (3-f)].
- the aromatic ring represented by the ring C is not particularly limited, and may be a hydrocarbon ring or a heterocyclic ring.
- the aromatic hydrocarbon ring may be a monocyclic ring or a condensed cyclic arene ring (for example, a condensed bi- to tetracyclic arene ring).
- a condensed cyclic arene ring for example, a condensed bi- to tetracyclic arene ring.
- a C 6-24 arene ring preferably a C 6-20 arene ring, more preferably a C 6-18 arene ring.
- the aromatic heterocycle is not particularly limited, and usually contains at least one heteroatom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S) as a constituent atom of the ring.
- the aromatic heterocyclic ring may be a non-condensed ring (monocyclic heterocyclic ring) or a condensed ring (a condensed ring of a heterocyclic ring and a heterocyclic ring, or a condensed ring of a hydrocarbon ring and a heterocyclic ring). Good.
- non-fused rings include 5- to 8-membered heterocycles, preferably 5- to 7-membered heterocycles, and more preferably 5- or 6-membered heterocycles.
- Typical non-condensed rings include 5- or 6-membered rings containing a nitrogen atom as a heteroatom such as pyrrole, imidazole, pyrazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine; 5- or 6-membered ring containing as atoms; 5- or 6-membered ring containing sulfur atoms such as thiophene as heteroatoms; 5- or 6-membered rings containing nitrogen and oxygen atoms such as oxazole, isoxazole and oxazine as heteroatoms; thiazole And 5- or 6-membered rings containing nitrogen and sulfur atoms as heteroatoms, such as isothiazole and thiazine.
- a condensed ring for example, 6 to 15 membered ring, preferably 8 to 8 membered ring
- at least 5 to 8 membered monocyclic heterocyclic ring for example, 5 to 7 membered heterocyclic ring, particularly 5 or 6 membered heterocyclic ring
- a 13-membered ring can be exemplified.
- a condensed ring containing a 5- or 6-membered monocyclic heterocycle containing a nitrogen atom as a hetero atom eg, indole, indoline, isoindole, isoindoline, indolizine, indazole, benzimidazole, benzotriazole, purine , Quinoline, isoquinoline, quinolidine, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, pteridine, and other bicyclic fused rings;
- a tricyclic condensed ring such as azepine]
- a condensed ring containing a 5- or 6-membered monocyclic heterocycle containing an oxygen atom as a heteroatom eg, benzofuran, isobenzofuran, coumaran, coumarin, chromene, isochrome , Chroman, isochroman, bicyclic fused ring such
- tricyclic fused ring such as xanthene, hetero sulfur atom Fused rings containing 5- or 6-membered monocyclic heterocycles containing as atoms
- bicyclic condensed rings such as benzothiophene (or thianaphthene), alkylenedithiobenzene (C 1-4 alkylenedithiobenzene such as methylenedithiobenzene)
- a tricyclic condensed ring such as dibenzothiopyran and thianthrene]
- a condensed ring containing a 5- or 6-membered monocyclic heterocycle containing a nitrogen atom and an oxygen atom as a heteroatom for example, a bicyclic fused ring such as benzoxazole Ring: phenoxazine, oxadiazafluorene (or benzimidazomorpholine)
- a benzene ring and a heterocyclic ring containing at least one heteroatom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S) for example, 5 to 15 members
- a condensed ring with a ring, preferably a 5- to 10-membered ring for example, a bicyclic condensed ring with a benzene ring and a 5- to 8-membered monocyclic heterocycle, a benzene ring with 6 to 15 members (for example, 7 to 13)
- a 2-membered, preferably 8- to 10-membered bicyclic heterocycle such as a tricyclic condensed ring with a benzene
- Ring C may have a substituent.
- the ring C when the ring C is a monocyclic arene ring (for example, a benzene ring), it often has a substituent from the viewpoint of pharmacological activity. That is, the ring C is a monocyclic arene ring having a substituent, a condensed cyclic arene ring optionally having a substituent, a monocyclic or condensed ring heterocyclic ring optionally having a substituent. There are many cases.
- Substituents include halogen atoms, alkyl groups, cycloalkyl groups, aryl groups, hydroxyl groups, alkoxy groups, carboxyl groups, acyl groups, carbamoyl groups, N-substituted carbamoyl groups, dihydroxyboryl groups, mercapto groups, alkylthio groups, sulfones.
- Examples include acid groups, amino groups, N-substituted amino groups, cyano groups, nitro groups, and heterocyclic groups.
- substituents if necessary, further substituents [halogen atom, aryl group (C 6-10 aryl group etc.), hydroxyl group, alkoxy group (straight chain or branched C 1-4 alkoxy group etc.) , A mercapto group, an alkylthio group (such as a linear or branched C 1-4 alkylthio group) is substituted, and a haloalkyl group, a haloalkoxy group, an aralkyl group, an aryloxy group, an aralkyloxy group, a hydroxyalkyl group, An alkoxyalkyl group, an alkoxycarbonyl group, a mercaptoalkyl group, an alkylthioalkyl group, or the like may be formed.
- halogen atom alkyl group, cycloalkyl group, aryl group, alkoxy group or acyl group substituted on ring C
- the same halogen atom fluorine atom, chlorine atom as the substituent substituted on group A or ring B, respectively
- the N-substituted carbamoyl group substituted on ring C includes N-mono C 1-6 alkylcarbamoyl group, N-mono C 1-6 acyl-carbamoyl group, N, N-diC 1-6 alkylcarbamoyl group, N N-diC 1-6 acyl-carbamoyl group and the like.
- alkylthio group substituted on the ring C examples include a linear or branched C 1-6 alkylthio group (preferably a C 1-4 alkylthio group) similar to the substituent substituted on the group A.
- N-substituted amino group substituted on ring C the same N-monosubstituted amino group as the substituent substituted on group A [for example, N—C 1-6 alkylamino group, N— (C 1-6 alkyl) -Carbonyl) amino group and the like], N, N-disubstituted amino group [for example, N, N-diC 1-6 alkylamino group, N, N-di (C 1-6 alkyl-carbonyl) amino group and the like] Etc. can be exemplified.
- heterocyclic group substituted on ring C examples include various heterocyclic groups having an aromatic or non-aromatic 5- to 8-membered heterocyclic ring (for example, a 5- to 7-membered ring, preferably a 5- or 6-membered ring),
- nitrogen atom such as a morpholyl group (such as a 4-morpholyl group) and oxygen
- Examples include 5- or 6-membered heterocyclic groups containing atoms as heteroatoms; 5- or 6-membered heterocyclic groups containing boron and oxygen atoms as heteroatoms such as 1,3,2-dioxaborinan-2-yl groups, etc.] it can.
- haloalkyl group haloalkoxy group, or aralkyl group (arylalkyl group) substituted on ring C
- Alkyl groups preferably halo C 1-4 alkyl groups
- linear or branched halo C 1-6 alkoxy groups preferably mono to perfluoro C 1 such as difluoromethyloxy, trifluoromethyloxy groups, etc.
- C 6-10 aryl C 1-6 alkyl groups (preferably C 6-10 aryl C 1-4 An alkyl group).
- the aryloxy substituted on ring C, phenyloxy, etc. C 6-10 aryloxy group such as naphthyloxy group.
- Examples of the aralkyl group, C 6-10 aryl, such as benzyloxy, phenethyloxy examples thereof include a C 1-6 alkyloxy group (preferably a C 6-10 aryl C 1-4 alkyloxy group).
- hydroxyalkyl group substituted on the ring C examples include a hydroxy linear or branched C 1-6 alkyl group such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl group (preferably a hydroxy C 1-4 alkyl group). And the like.
- alkoxyalkyl group substituted on ring C examples include linear or branched C 1-6 alkoxy C 1-6 alkyl groups such as methoxymethyl, methoxyethyl, ethoxymethyl and ethoxyethyl groups (preferably C 1-4 Examples thereof include alkoxy C 1-4 alkyl groups and the like.
- alkoxycarbonyl group substituted on ring C examples include linear or branched C 1-6 alkoxy-carbonyl groups such as methoxycarbonyl and ethoxycarbonyl groups (preferably C 1-4 alkoxy-carbonyl groups and the like). it can.
- Examples of the mercaptoalkyl group substituted on the ring C include a mercapto linear or branched C 1-6 alkyl group corresponding to the hydroxyalkyl group, and the alkylthioalkyl group corresponds to the alkoxyalkyl group. Examples thereof include a linear or branched C 1-6 alkylthio C 1-6 alkyl group.
- Examples of the monocyclic or condensed cyclic arene ring having a substituent include a halogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, and an aryloxy group.
- substituents selected from aralkyloxy group, dihydroxyboryl group, carboxyl group, alkoxycarbonyl group, mercapto group, alkylthio group, nitro group, amino group, N-substituted amino group, and heterocyclic group
- rings C 6-24 arene rings such as benzene and naphthalene).
- the combination of substituents is not particularly limited.
- a disubstituted arene ring for example, 2 selected from a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a dihydroxyboryl group, and a nitro group. May be the same or different substituents.
- the combination of substituents may be, for example, three same or different substituents selected from a halogen atom, an alkyl group, a hydroxyl group, and an alkoxy group.
- the substitution position of the substituent is not particularly limited.
- benzene in the case of monosubstituted benzene, it may be 2-, 3-, 4-position, etc., and in the case of disubstituted benzene, 2,3-, 2,4 It may be in the-, 2,5-, 3,4-, 3,5-position, and in the case of trisubstituted benzene, it may be in the 2,3,4-, 3,4,5-position, etc. .
- the monocyclic heterocyclic ring having a substituent includes at least one kind of substituent selected from a hydroxyl group, an alkoxy group (such as a C 1-6 alkoxy group), a mercapto group, and an alkylthio group (such as a C 1-6 alkylthio group).
- 5- to 8-membered heterocycle having a group ⁇ eg, a 5- or 6-membered heterocycle containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom eg, alkoxypyridine (such as 2-methoxypyridine C 1-4 alkoxypyridine etc.)] ⁇ and the like.
- Examples of the condensed heterocyclic ring having a substituent include the above condensed heterocyclic rings having at least one substituent selected from an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxy group, and an acyl group.
- a monocyclic ring or a condensed ring having at least a benzene skeleton is preferable.
- any one of the following formulas (4-a) to (4-c) may be used.
- Z 1 represents a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a mercapto group, an alkylthio group, an N-alkyl-substituted amino group, or an N-acyl-substituted amino group
- Z 2 represents an alkyl group or a hydroxyalkyl group
- Z 3 represents an alkyl group, a hydroxyl group, an alkoxy group, or an acyl group
- ring C 1 represents a C 6-10 arene ring
- ring C 2 represents G 1 and A 5- to 8-membered heterocycle containing at least one heteroatom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S) as a ring-constituting atom together with G 2
- ring C 3 Includes at least one heteroatom selected from a nitrogen atom (N), an oxygen
- G 1 to G 3 represent aromatic or non-aromaticity of ring C 2 , or depending on aromaticity or non-aromaticity of the 5-membered ring adjacent to ring C 3 , Represents a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), NH, CH, or CH 2 ;
- G 4 is a 5-membered aromatic or non-aromatic ring adjacent to ring C 3 And represents a nitrogen atom (N), a carbon atom (C), or CH;
- p is an integer of 1 to 5
- q is an integer of 0 to 6.
- examples of the arene ring represented by the ring C 1 include C 6-10 arene rings such as benzene and naphthalene.
- halogen atom represented by Z 1 an alkyl group, an alkoxy group, an alkylthio group, an N-alkyl-substituted amino group, and an N-acyl-substituted amino group
- the above-described halogen atoms Fluorine atom, chlorine atom, etc.
- Z 1 an alkyl group, an alkoxy group, an alkylthio group, an N-alkyl-substituted amino group, and an N-acyl-substituted amino group
- types of Z 1 may be the same or different from each other.
- the substitution number p of Z 1 is about 1 to 5, preferably about 1 to 4, and more preferably about 1 to 3 (for example, 1 to 2). Further, the substitution position of Z 1 is not particularly limited.
- the substitution position of Z 1 may be 2-, 3-, 4-, 5-position when ring C 1 is a benzene ring, and is at least 3- and / or 4-position (particularly at least 4- Are preferred.
- Z a represents a hydroxyl group, an alkoxy group, a mercapto group, an alkylthio group, an N, N-dialkylamino group, or an N, N-diacylamino group
- Z b represents a hydrogen atom, an alkyl group, a hydroxyl group
- a group or an alkoxy group In the formula (4-a2), alkoxy group represented by Z a, an alkylthio group, N, N- dialkylamino group, or N, as the N- diacylamino group, similar to the illustration of groups C 1- 6 alkoxy groups (preferably C 1-4 alkoxy groups), C 1-6 alkylthio groups (preferably C 1-4 alkylthio groups), N, N-diC 1-6 alkylamino groups (preferably N, N— DiC 1-4 alkylamino group), N, N-di (C 1-6 alkyl-carbonyl) amino group [preferably N, N-di (C 1-6 alkyl
- Examples of the alkyl group or alkoxy group represented by Z b include the same C 1-6 alkyl group (preferably C 1-4 alkyl group) and C 1-6 alkoxy group (preferably C 1 ) as those exemplified above. -4 alkoxy group).
- Z b is often an alkyl group, a hydroxyl group, or an alkoxy group.
- the ring C 2 is a 5- to 8-membered heterocyclic ring containing G 1 and G 2 as constituent atoms (for example, a 5- to 7-membered heterocyclic ring, preferably a 5- or 6-membered heterocyclic ring).
- Ring which is usually a heterocyclic ring containing at least one heteroatom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S) as a constituent atom of the ring.
- the ring C 2 is, for example, a ring corresponding to the above-exemplified bicyclic condensed heterocyclic ring [that is, a benzene ring, a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S).
- a condensed ring with a heterocycle containing at least one heteroatom as a constituent atom of the ring eg, indole, indoline, isoindole, isoindoline, indazole, benzimidazole, benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine
- a nitrogen atom-containing heterocycle such as benzofuran, isobenzofuran, coumaran, coumarin, chromene, isochromene, chroman, isochroman, alkylene dioxybenzene, etc.
- the ring C 3 is a 5- to 8-membered ring (for example, a 5- to 7-membered ring) containing G 4 as a constituent atom of the ring, and usually a nitrogen atom (N), an oxygen atom (O) and a heterocycle containing at least one heteroatom selected from sulfur atoms (S) as a ring-constituting atom.
- N nitrogen atom
- O oxygen atom
- S sulfur atoms
- Ring C 3 is, for example, a ring corresponding to the above-mentioned exemplified tricyclic fused heterocycle ⁇ a tricyclic fused heterocycle having a benzene skeleton at the terminal, which is a benzene ring and a 5-membered monocyclic allotrope
- a tricyclic fused heterocycle of a ring or heterocycle and a 5- to 8-membered monocyclic heterocycle [eg, selected from benzene ring, imidazole ring, pyrrole ring, pyridine ring, azepine ring, and morpholine ring From a condensed ring (such as benzopyrroloimidazole, benzimidazopyridine, benzimidazoazepine, benzimidazomorpholine, etc.) or a hydrogenated product of these rings, etc. A residue excluding a ring, etc. ⁇ .
- Examples of the alkyl group or acyl group represented by Z 2 and Z 3 include the C 1-6 alkyl group (preferably C 1-4 alkyl group) exemplified above as a substituent substituted on ring C, and C 1 Examples include a -6 alkyl-carbonyl group (preferably a C 1-4 alkyl-carbonyl group) and the like.
- the hydroxyalkyl group and alkoxyalkyl group represented by Z 2 the hydroxy C 1-6 alkyl group (preferably hydroxy C 1-4 alkyl group) exemplified above as a substituent substituted on ring C, respectively, Examples thereof include 1-6 alkoxy C 1-6 alkyl group (preferably C 1-4 alkoxy C 1-4 alkyl group).
- Examples of the alkoxy group represented by Z 3 include the C 1-6 alkoxy groups exemplified above (preferably C 1-4 alkoxy groups) as substituents substituted on ring C. These substituents Z 2 and Z 3 are often alkyl groups, acyl groups, and the like. Incidentally, when q is an integer of 2 or more, the type of the substituent Z 2 (or Z 3) may be the same or different from each other.
- the substitution number q of Z 2 (or Z 3 ) is, for example, about 0 to 6, preferably about 0 to 4, more preferably about 0 to 3, particularly about 0 to 2.
- the group represented by the formula (4-b) includes a benzene ring and at least one heteroatom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S).
- Benzoxazolyl group for example, benzoxazol-6-yl group
- dihydrobenzoxazinyl group for example, 2,3-dihydro-1,4-benzoxazine-6-
- the group represented by the formula (4-c) includes a benzene ring and a 5-membered member containing at least one heteroatom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S). And a monocyclic heterocycle of 5 to 8 members containing at least one heteroatom selected from a nitrogen atom (N), an oxygen atom (O), and a sulfur atom (S)
- a cyclic group such as a benzene ring, an imidazole ring, and a condensed ring group selected from a pyrrole ring, a pyridine ring, an azepine ring, and a morpholine ring ⁇ for example, 2,3-dihydro-1H-benzo [ d] a benzopyrroloimidazolyl group such as a pyrrolo [1,2-a] imidazolyl group or a group composed of a hydrogenated product thereof; 1,2,3,4-tetrahydro
- ring C 2 together with G 1 and G 2 has at least one (for example, about 1 to 3) heteroatom selected from a nitrogen atom (N) and an oxygen atom (O) as a constituent atom of the ring.
- a 5- to 8-membered heterocyclic ring (for example, a 5- to 7-membered heterocyclic ring, preferably a 5- or 6-membered heterocyclic ring);
- ring C 3 together with the adjacent G 4 , a nitrogen atom (N) and an oxygen atom (O) at least one selected from (e.g., about 1 to 2) indicates a 5- to 8-membered heterocyclic ring containing a hetero atom as a constituent atom of the ring (e.g., 5- to 7-membered heterocyclic ring);
- G 2 represents an oxygen atom (O), a nitrogen atom (N), or NH, depending on the aromaticity and non-aromaticity of 2 ;
- G 4 represents a nitrogen atom (N);
- the broken line is adjacent to the ring C 3 , and the 5-membered ring containing G 3 and G 4 is an aromatic ring or a non-aromatic (aliphatic) ring. It is also good.
- G 5 represents N, NH, S, O, CH, or CH 2
- G 6 represents N, NH, S, or O
- G 7 represents N or NH
- G 8 represents N , NH, S, or O
- G 9 to G 11 represent N or NH
- G 12 represents CH or N
- G 13 represents N
- G 14 represents NH, O, S, or CH 2
- the groups represented by the above formulas (4-b3) to (4-b6), (4-c2), and (4-c3) may have a substituent. That is, a hydrogen atom bonded to a carbon atom and / or a nitrogen atom constituting the ring may be substituted with the exemplified substituent (for example, an alkyl group, an acyl group, etc.).
- Z represents a hydrogen atom, an alkyl group, or an acyl group.
- the alkyl group or acyl group represented by Z is a C 1-6 alkyl group exemplified above as a substituent substituted on ring C (preferably C 1-4 alkyl group), C 1-6 alkyl-carbonyl group (preferably C 1-4 alkyl-carbonyl group) and the like.
- the types of the two substituents Z may be the same or different from each other.
- the linker represented by L is not particularly limited as long as the ring B and the ring C can be connected.
- the main chain of the linker is a carbon atom (C) or a nitrogen atom. (N), an oxygen atom (O), and a sulfur atom (S), and have about 3 to 5 (particularly 4 to 5) atoms.
- the main chain of the linker is usually composed of at least one carbon atom and at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
- the hydrogen atom bonded to the nitrogen atom of the main chain may be substituted with one selected from an alkyl group and an acyl group.
- the bonding mode of these main chain atoms is not particularly limited, and examples thereof include linkers containing at least one chemical bond selected from amide bonds, urethane bonds, thioamide bonds, thiourethane bonds, and ether bonds. . Specifically, it may be a linker containing at least the basic skeleton represented by the following formulas (1-a) to (1-i).
- the hydrogen atom of the —NH— group may be substituted with an alkyl group or an acyl group.
- the alkyl group include a linear or branched C 1-6 alkyl group (preferably a C 1-4 alkyl group) similar to the group A.
- the acyl group include a linear or branched C 1-6 alkyl-carbonyl group (preferably a C 1-4 alkyl-carbonyl group) similar to the substituent substituted on ring B.
- X 1 represents an alkyl group
- X 2 represents an alkyl group or an acyl group.
- alkyl group for X 1 or X 2 include the same C 1-4 alkyl groups (C 1-2 alkyl group and the like) as those exemplified above
- examples of the acyl group for X 2 include the groups exemplified above. Examples thereof include C 1-4 alkyl-carbonyl groups (such as C 1-2 alkyl-carbonyl groups) and the like.
- the left end may be connected to ring C and the right end may be connected to ring B, but the left end is preferably connected to ring B and the right end is preferably connected to ring C. .
- linkers containing the basic skeleton represented by the above formulas (1-a) to (1-c) are preferable, and in particular, the urethane bond (—NHC ( A linker containing O) O— or —OC (O) NH—) [for example, a linker represented by the above formulas (1-a1) to (1-a6)] is preferable.
- the linker L is a linker represented by the above formula (1-a1)
- the group A is not a 2-methylaminopyrimidin-4-yl group
- the ring C is often not a 9-fluorenyl group.
- the linker L is a linker in which X 1 is a methyl group in the formula (1-a2) and the ring C is a benzene ring having a halogen atom as a substituent
- the ring B is an isoxazole-diyl group ( In particular, it is not often 3,4-isoxazole-diyl group).
- the heterocyclic compound represented by the formula (1) of the present invention or a salt thereof is novel.
- a heterocyclic compound or a pharmaceutically (or physiologically) acceptable salt thereof in which the groups (or biological equivalents) exemplified in the respective groups of group A, ring B, linker L, and ring C are arbitrarily combined.
- a heterocyclic compound or a pharmaceutically (or physiologically) acceptable salt thereof in which the groups (or biological equivalents) exemplified in the respective items of the group A, ring B, linker L and ring C are arbitrarily combined.
- the linker L is a linker in which X 1 is a methyl group in the formula (1-a2) and the ring C is a benzene ring having a halogen atom as a substituent
- the ring B is an isoxazole-diyl group ( In particular, it is not 3,4-isoxazole-diyl group).
- the compound represented by the formula (1) or a salt thereof is not particularly limited as long as it is a compound or a salt thereof in which the groups exemplified in each item of the group A, ring B, linker L, and ring C are arbitrarily combined.
- the following compounds or salts thereof are preferable.
- (1-1) A compound in which the linker L includes the basic skeleton of the formula (1-a) [for example, the linker L is any one of the formulas (1-a1) to (1-a6) and the group A is substituted.
- aryl group having a group such as a group represented by the formula (2), wherein ring B is an optionally substituted thiazole ring, isothiazole ring or pyrazole ring, and ring C is A compound (1) etc.
- linker L includes the basic skeleton of the formula (1-b) [for example, the linker L is the formula (1-b1) or (1-b2), and the group A has a substituent An aryl group (such as a group represented by the formula (2)), the ring B is an optionally substituted thiazole ring, pyrazole ring, or furan ring, and the ring C is the formula (4).
- a ring B is a thiazole ring, an isothiazole ring, a pyrazole ring, a pyrrole ring, an imidazole ring, or an oxazole ring which may have a substituent
- the ring C is the formula (4)
- An aryl group represented by -a) (wherein Z 1 may be a boronic acid group), or a heterocyclic group represented by the above formula (4-b) or (4-b2) A certain compound (1) etc.] or a salt thereof;
- (1-4) A compound in which the linker L includes the basic skeleton of the formula (1-d) [for example, the linker L is any one of the formulas (1-d1) to (1-d3) and the group A is substituted.
- An aryl group having a group (such as a group represented by the above formula (2)), ring B is an optionally substituted thiazole ring or pyrazole ring, and ring C is a group represented by the above formula (4- a compound (1) or the like which is an aryl group represented by a)] or a salt thereof; (1-5) A compound in which the linker L includes the basic skeleton of the formula (1-e) [for example, the linker L is the formula (1-e1) or (1-e2), and the group A has a substituent
- An aryl group (such as a group represented by the above formula (2)), ring B is an optionally substituted thiazole ring or pyrazole ring, and ring C is represented by the above formula (4-a) A compound (1) etc., which is an aryl group represented by (1-6) A compound in which the linker contains the basic skeleton of the formula (1-g) [for example, the linker L is the formula (1-g1) or (1-g
- a compound (1) etc. which is an aryl group, or a salt thereof;
- (1-7) A compound in which the linker includes the basic skeleton of the formula (1-h) [for example, the linker L is the formula (1-h1) and the group A is an aryl group having a substituent (the formula (2)
- the ring B is an optionally substituted thiazole ring or pyrazole ring, and the ring C is an aryl group represented by the formula (4-a).
- the linker includes the basic skeleton of the formula (1-h)
- the linker L is the formula (1-h1) and the group A is an aryl group having a substituent (the formula (2)
- the ring B is an optionally substituted thiazole ring or pyrazole ring
- the ring C is an aryl group represented by the formula (4-a). Compound (1) and the like].
- the compound represented by the formula (1) or a salt thereof is represented by any one of the following formulas (6-a) to (6-c) particularly from the viewpoint of p27 Kip1 degradation inhibitory ability and apoptosis-inducing ability. Or a salt thereof is preferred.
- R 1 and R 2 are the same or different and each represents a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a mercapto group, or an alkylthio group;
- ring B represents a thiazole ring, an isothiazole ring or a pyrazole ring.
- an alkyl group, a haloalkyl group, a cycloalkyl group, an aryl group may have at least one substituent selected from aralkyl and acyl groups,;
- Z a is a hydroxyl group, an alkoxy group, a mercapto group ,
- Z b represents a hydrogen atom or an alkyl group , hydroxyl group, or an alkoxy group;
- ring C 2 together with G 1 and G 2, nitrogen atoms (N), oxygen atom (O)
- a 5- to 8-membered ring for example, a 5- to 7-membered ring, preferably a 5- or 6-membered ring
- Examples of the halogen atom, alkyl group, alkoxy group, or alkylthio group represented by R 1 and R 2 include the same halogen atoms (fluorine atom, chlorine atom, etc.) as those exemplified for the group R, and C 1-6 alkyl groups. (C 1-4 alkyl group etc.), C 1-6 alkoxy group (C 1-4 alkoxy group etc.), C 1-6 alkylthio group (C 1-4 alkylthio group etc.) and the like.
- Specific examples of the compound represented by the formula (1) include compounds shown in Tables 2 to 4.
- the present invention also includes a salt of the compound represented by the formula (1) (such as a salt with a pharmacologically or physiologically acceptable acid or base).
- Acids that form such salts include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), organic acids (acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, oxalic acid, succinic acid) And organic carboxylic acids such as fumaric acid and maleic acid, oxycarboxylic acids such as lactic acid, malic acid, tartaric acid and citric acid, and sulfonic acids such as methanesulfonic acid and toluenesulfonic acid).
- the base examples include inorganic bases (alkali metal hydroxides such as ammonia, sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as alkali metal carbonate, calcium hydroxide and magnesium hydroxide, calcium carbonate) Alkaline earth metal carbonates, etc.), organic bases [aliphatic amines (alkylamines such as triethylamine, alkanolamines such as ethanolamine, polyamines such as alkylenediamine), alicyclic amines (dicyclohexyl, etc.) Dicycloalkylamines such as amines), aromatic amines (such as N-alkyl-substituted anilines such as N, N-dimethylaniline), heterocyclic amines (such as 5- or 6-membered rings such as pyrrolidine, pyridine, morpholine, etc.) )] And the like. These acids or bases can be used alone or in combination of two or more.
- the compound of the present invention or a salt thereof may be an anhydride or a hydrate, and may be a solvate (such as a solvate by an organic solvent such as ethanol).
- a solvate such as a solvate by an organic solvent such as ethanol.
- an isolated crystal such as a polymorphic substance.
- the compound of the present invention or a salt thereof includes a tautomer of the compound of the formula (1) or a salt thereof, an optically active substance having an asymmetric carbon atom ((R) form, (S) form, diastereomer). Etc.), a racemate, or a mixture thereof.
- prodrug form or active metabolite in which terminal groups, heterocyclic groups, etc. are modified to express activity in vivo.
- prodrug form include compounds that exhibit activity by metabolism such as hydrolysis, oxidation, reduction, transesterification (ester form, ether form, alcohol form, amide form, etc. of the compound of formula (1)).
- the compound of the present invention or a salt thereof has high safety.
- the compound represented by the formula (1) or a salt thereof can be produced by linking the units represented by the group A, ring B, linker L, and ring C, and the linking order is not particularly limited. Can be produced according to the following reaction process formula (i).
- L 1 and L 2 represent groups capable of reacting with each other to form a linker L, and groups A, ring B, rings C, L, and n are the same as described above.
- the groups represented by L 1 and L 2 are not particularly limited as long as they can react with each other to form the linker L, and are appropriately selected depending on the type of the linker L. It may be a functional group itself that can react with each other to form a bond, or may be a group having the functional group (terminal group).
- Examples of the functional group include a haloalkyl group, a hydroxyl group, an aldehyde group (formyl group), a carboxyl group, a carbazoyl group, a hydroxamic acid group, an amino group, a hydrazino group, an aminocyano group, an isocyanate group, and an isothiocyanato group.
- examples of the residue excluding the functional group include an alkylene group.
- the compound represented by the formula (1) or a salt thereof can be prepared, for example, according to the following reaction process formula (ii).
- L 1a and L 2a are the same or different and represent an alkylene group; L 3 represents a linker represented by the following formulas (1-a) to (1-i); j and k are The same or different, 0 or 1; the group A, ring B, ring C, and n are as defined above.
- groups represented by J and K are not particularly limited as long as they can react with each other to link a compound having a ring B and a compound having a ring C, and the linker L [ -(L 1a ) j -L 3- (L 2a ) k- ] is appropriately selected according to the type of the basic skeleton L 3 .
- Specific examples of combinations of the group J and the group K corresponding to the basic skeleton L 3 of the linker L are shown in Table 5.
- alkylene group including alkylidene group
- alkylidene group examples include methylene, 1,1-ethanediyl, ethylene (1,2-ethanediyl), 1,1-propanediyl, propylene (1,2- Propanediyl), linear or branched alkylene groups such as trimethylene and tetramethylene groups (for example, C 1-4 alkylene groups, preferably C 1-2 alkylene groups) and the like.
- trimethylene and tetramethylene groups for example, C 1-4 alkylene groups, preferably C 1-2 alkylene groups
- the ratio (use ratio) of compound (7-a) [or compound (7-c)] to compound (7-b) [or compound (7-d)] is L 1 (terminal
- the ratio in which the group J) and L 2 (terminal group K) are approximately equivalent, for example, the former / the latter (molar ratio) 2/1 to 1/2, preferably 1.5 / 1 to 1 / 1.5. More preferably, it may be about 1.2 / 1 to 1 / 1.2.
- the linker formation reaction may be performed in the presence of a solvent.
- the solvent is not particularly limited as long as it is inert to the reaction, and can be appropriately selected according to the type of the raw material compounds (7-a) to (7-d), the type of reaction, and the like.
- aliphatic hydrocarbons such as pentane and hexane
- alicyclic hydrocarbons such as cyclohexane
- aromatic hydrocarbons such as benzene, toluene and xylene
- halogenated solvents for example, methylene chloride, chloroform, carbon tetrachloride, bromoform
- Halogenated hydrocarbons such as ethylene chloride
- alcohols alkanols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and t-butanol
- glycols such as ethylene glycol and propylene glycol
- ethers For example, ethyl ether, isopropyl ether, etc.
- Jo ethers dioxane, tetrahydrofuran, cyclic ethers such as tetrahydropyran
- cellosolves methyl cellosolve, ethyl cellosolve C 1-4 alkyl cellosolve such as cellosolve, etc.
- C 1-4 such as cellosolve acetates (ethyl cellosolve acetate Alkyl cellosolve acetates), carbitols (such as methyl carbitol), ketones (such as dialkyl ketones such as acetone, methyl ethyl ketone, diisopropyl ketone, isobutyl methyl ketone), organic carboxylic acids (such as acetic acid), esters (for example, methyl acetate, ethyl acetate, acetic acid esters such as butyl acetate), amides (e.g., formamide; N- methylformamide, N, such as N- di
- N- mono- or di-C 1-4 alkyl acetamide such as N- dimethylacetamide
- pyridines pyridine, pyridine borane, etc.
- nitriles acetonitrile, benzonitrile
- solvents can be used alone or as a mixed solvent.
- the linker formation reaction may be performed in the presence of a catalyst.
- the catalyst include acid catalysts [for example, inorganic acids (such as sulfuric acid), organic acids (such as p-toluenesulfonic acid), Lewis acids, etc.], base catalysts ⁇ inorganic bases [for example, metal hydroxide (sodium hydroxide) Alkali metal or alkaline earth metal hydroxide, etc.), metal carbonate (alkali metal such as sodium carbonate or alkaline earth metal carbonate, etc.)], organic base [eg, aliphatic amine [first to third] Secondary aliphatic amines, for example, aliphatic tertiary amines such as tri-C 1-4 alkylamines (triethylamine, diethylmethylamine, diisopropylethylamine, tri-n-propylamine, tributylamine, etc.), aromatic amines (primary To tertiary aromatic amines, for example, aromatic ter
- the amount of the catalyst used is, for example, 0.0001 to 5 with respect to 1 mol of compound (7-a) [or compound (7-c)] or compound (7-b) [or compound (7-d)]. Mole, preferably about 0.001 to 1 mol.
- the linker formation reaction may be performed at room temperature or under heating.
- the reaction can be performed in air or under an inert gas atmosphere (nitrogen, helium, argon gas, etc.), and may be performed under atmospheric pressure or under pressure.
- the reaction time is not particularly limited, and may be, for example, about 0.1 to 60 hours, preferably about 0.5 to 50 hours.
- the compound represented by the above formula (1) [or the above formula (7-e)] or a salt thereof is subjected to a conventional separation or purification (or isolation) method, for example, filtration, distillation, concentration, precipitation. May be separated or purified from the reaction mixture by crystallization, recrystallization, decantation, extraction, drying, washing, chromatography, and combinations thereof.
- the method for connecting the group A and the ring B is not particularly limited, and a conventional addition reaction, substitution reaction, coupling reaction (for example, a cross coupling reaction such as a Suzuki coupling reaction). Etc.) can be used.
- Examples of the compound represented by the formula (8-a) include compounds in which A 2 is a boronic acid group, for example, arylboronic acids [for example, halo-alkoxyarylboron such as 4-chloro-2-methoxyphenylboronic acid Acid (preferably halo-C 1-6 alkoxy C 6-10 arylboronic acid) and the like].
- arylboronic acids for example, halo-alkoxyarylboron such as 4-chloro-2-methoxyphenylboronic acid Acid (preferably halo-C 1-6 alkoxy C 6-10 arylboronic acid) and the like.
- Examples of the compound represented by the formula (8-b) include compounds in which A 3 is a halogen atom and L 1 is an alkoxycarbonyl group [for example, 4-bromo-1-methyl-1H-pyrrole-2- 4-halo-1-alkyl-1H-pyrrole-2-carboxylic acid alkyl esters such as ethyl carboxylic acid (preferably 4-halo-1-C 1-4 alkyl-1H-pyrrole-2-carboxylic acid C 1- 4- alkyl ester) and the like].
- a 3 is a halogen atom
- L 1 is an alkoxycarbonyl group
- the reaction between the compound (8-a) and the compound (8-b) may be performed in the presence of an inorganic base.
- the inorganic base include metal carbonates (for example, alkali metal carbonates such as potassium carbonate and sodium carbonate). These inorganic bases can be used alone or in combination of two or more.
- the proportion of inorganic base (use proportion) is, for example, about 0.1 to 10 mol, preferably about 0.5 to 5 mol, relative to 1 mol in total of compound (8-a) and compound (8-b). There may be.
- the reaction between the compound (8-a) and the compound (8-b) may be performed in the presence of a catalyst (for example, a palladium-based catalyst such as tetrakistriphenylphosphine palladium).
- a catalyst for example, a palladium-based catalyst such as tetrakistriphenylphosphine palladium.
- the ratio (use ratio) of the catalyst is 0.1 mol or less, preferably 0.1 mol or less with respect to 1 mol in total of the compound represented by the formula (8-a) and the compound represented by the formula (8-b). It may be 0.01 mol or less (for example, about 0.001 to 0.01 mol).
- the reaction of compound (8-a) and compound (8-b) may be performed in the presence of a solvent.
- the solvent is not particularly limited as long as it is inert to the reaction, and water, hydrocarbons (for example, aliphatic hydrocarbons such as pentane and hexane; alicyclic hydrocarbons such as cyclohexane; benzene, toluene, xylene, etc.
- Aromatic hydrocarbons amides (eg, formamide; N-mono or di C 1-4 alkylformamide such as N-methylformamide, N, N-dimethylformamide; N-methylacetamide, N, N-dimethylacetamide, etc.
- N-mono or di-C 1-4 alkylacetamide, etc. These solvents can be used alone or as a mixed solvent.
- the reaction between the compound (8-a) and the compound (8-b) can be performed at room temperature or under heating, for example, at about 10 to 150 ° C. (preferably 20 to 100 ° C.).
- the reaction can be carried out in air or under an inert gas atmosphere (nitrogen, helium, argon gas, etc.).
- the reaction may be performed under atmospheric pressure or under pressure.
- the reaction time is not particularly limited, and may be, for example, about 0.1 to 20 hours, preferably 0.5 to 15 hours, and more preferably about 1 to 10 hours.
- the method for forming the ring B is not particularly limited, and is a known method for producing a heterocyclic ring (for example, 4th edition, Experimental Chemistry Course 24, Organic Synthesis VI, heteroelements and typical metal element compounds). , Edited by The Chemical Society of Japan, Maruzen Co., Ltd., p. 463-549, etc.) can be used.
- Etc. thiosemicarbazides (or semicarbazides) and acid halides, hydroxyiminoacetonitriles and thioglycolic acid alkyl esters, and the like.
- Table 6 shows representative examples of combinations of the compound (8-c) and the compound (8-d) and the compound (7-a) in this cyclization reaction.
- Halo represents a halogen atom (chlorine atom, bromine atom, etc.), and the group A, the group L 1 , and n are the same as described above.
- the method for forming the ring B is not particularly limited, and is a known method for producing a heterocyclic ring (for example, 4th edition, Experimental Chemistry Course 24, Organic Synthesis VI, heteroelement, typical metal element compound). , Edited by The Chemical Society of Japan, Maruzen Co., Ltd., p463-549, etc.), for example, ⁇ , ⁇ -unsaturated ketones (or 1,2-diketones) and hydrazines (or hydroxylamine). And amides).
- Table 7 shows representative examples of combinations of the compound (8-e) and the compound (8-f) and the compound (7-a) in this cyclization reaction.
- group A, group L 1, and n is as defined above.
- the reaction steps (iv) and (v) may be performed in the presence of a solvent.
- the solvent is not particularly limited as long as it is inert to the reaction.
- Hydrocarbons for example, aliphatic hydrocarbons such as pentane and hexane; alicyclic hydrocarbons such as cyclohexane; aromatics such as benzene, toluene and xylene
- alcohols for example, alkanols such as methanol and ethanol
- These solvents can be used alone or as a mixed solvent. Of these solvents, C 1-4 alkanols such as ethanol are widely used.
- the reaction steps (iv) and (v) can be performed at room temperature or under heating, for example, at about 10 to 150 ° C. (preferably 20 to 100 ° C.).
- the reaction can be carried out in air or under an inert gas atmosphere (nitrogen, helium, argon gas, etc.).
- the reaction may be performed under atmospheric pressure or under pressure.
- the reaction time is not particularly limited, and may be, for example, about 1 to 50 hours, preferably about 5 to 40 hours, and more preferably about 10 to 30 hours.
- the compound represented by the formula (7-b) may be, for example, any one of the following formulas (7-b1) to (7-b3).
- the compound represented by the formula (7-b1) may be synthesized by a conventional method, but a commercially available product may be used.
- a compound corresponding to the ring represented by the formula (4-a) for example, a compound in which the terminal group (group K) of L 2 is a hydroxyl group
- an aralkyl alcohol such as benzyl alcohol (preferably Is a C 6-10 aryl C 1-4 alkyl alcohol); a haloaralkyl alcohol such as 4-fluorobenzyl alcohol (preferably a halo C 6-10 aryl C 1-4 alkyl alcohol); 4-methoxybenzyl alcohol, 4-methoxy Alkoxy-aralkyl alcohols such as phenethyl alcohol (preferably C 1-4 alkoxy-C 6-10 aryl C 1-4 alkyl alcohol); Alkylthio-aralkyl alcohols such as 4-methylthiobenzyl alcohol (preferably C 1-4 alkylthio- C 6-10 aryl C 1-4 alkyl alcohols; N, N-dialkyl-aralkyl alcohols such as 3- or 4- (N, N-dimethyl)
- the compound represented by the formula (7-b2) or (7-b3) a commercially available product may be used, and a known method for producing a heterocyclic ring (for example, 4th edition, Experimental Chemistry Course 24, Organic Synthesis) VI Heteroelements / Typical metal element compounds, edited by The Chemical Society of Japan, Maruzen Co., Ltd., methods described on pages 463-549, methods described in J. Chem. Soc., 1963, 4666-4669, J. Chem. Soc. Perkin I, 1979, 1056-1062, etc.).
- the compound represented by the formula (7-b2) or (7-b3) can be prepared according to the following reaction process formula (vi) or (vii).
- C 2a represents a component for forming ring C 2 ; groups L 2 , ring C 2 , ring C 3 , and G 1 to G 4 are the same as described above.
- the broken line indicates that G 1 to G 3 may be bonded to a hydrogen atom depending on the type of G 1 to G 3 .
- the compound (9-b) is not particularly limited as long as it is a component for forming the ring C 2 , but usually at least an acid component (organic acid) is used.
- the acid component include alkanoic acids such as formic acid, acetic acid and propionic acid (C 1-6 alkanoic acid and the like), and anhydrides of these acids.
- nitrous acid or a salt thereof an alkali metal salt such as a sodium salt
- an ester thereof a nitrous acid C 1 ⁇ such as isoamyl nitrite 6 alkyl esters
- Table 8 shows representative examples of combinations of the compound (9-a) and the compound (9-b).
- an organic acid such as formic acid also acts as a reaction solvent
- the compound (9-c) is cyclized in the molecule in the presence of a peroxide (such as aqueous hydrogen peroxide) and an organic acid (such as formic acid), so that A 5-membered ring adjacent to both 3 is formed.
- a peroxide such as aqueous hydrogen peroxide
- an organic acid such as formic acid
- cyclization reaction (vi) and (vii) in presence of a solvent.
- the solvent include hydrocarbons (for example, aliphatic hydrocarbons such as pentane and hexane; alicyclic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene), and halogenated solvents (for example, methylene chloride).
- Halogenated hydrocarbons such as chloroform, carbon tetrachloride, bromoform and ethylene chloride), ethers (eg, chain ethers such as ethyl ether and isopropyl ether; cyclic ethers such as dioxane, tetrahydrofuran and tetrahydropyran), etc. It can be illustrated. These solvents may be used alone or as a mixed solvent.
- the cyclization reaction (vi) and (vii) can be performed at room temperature or under heating, for example, at about 10 to 150 ° C. (preferably 20 to 100 ° C.).
- the reaction can be carried out in air or under an inert gas atmosphere (nitrogen, helium, argon gas, etc.).
- the reaction may be performed under atmospheric pressure or under pressure.
- the reaction time is not particularly limited, and may be, for example, about 1 minute to 50 hours, preferably about 5 minutes to 40 hours, and more preferably about 10 minutes to 30 hours.
- L 1 (terminal group J) or L 2 (terminal group K) May be a group capable of directly reacting to form a linker, or may be a precursor group of a group capable of forming a linker.
- the precursor group can be converted to a target group by using a known reaction (oxidation reaction, reduction reaction, addition reaction, condensation reaction, hydrolysis reaction, rearrangement reaction, etc.).
- an alkoxycarbonyl group can be converted to a carboxyl group by a hydrolysis reaction
- a carboxyl group can be converted to an acid azide group by reacting with (a) diarylphosphoryl azide
- an acid azide group can be converted to an isocyanate group by a Curtius rearrangement reaction.
- (B) can be converted to a carbazoyl group by reacting with hydrazine
- (c) can be converted to a carbamoyl group by reacting with ammonia
- the carbamoyl group can be converted to an isothiocyanato group by reacting with thionyl chloride
- Can be converted to an aldehyde group by a reduction reaction the aldehyde group can be converted to an alkyl group by (d1) clementene reduction, converted to a haloalkyl group by halogenating the alkyl group, and (d2) aminosia by reacting with hydrazine. It is converted to the group.
- the reaction for converting L 1 (terminal group J) or L 2 (terminal group K) to the target group and the formation reaction of linker L may be performed in separate reaction systems, but in the same reaction system You may go.
- the ratio (use ratio) of the carboxylic acid represented by the formula (7-f) and the alcohol represented by the formula (7-g) is not particularly limited, and the carboxyl group and the hydroxyl group are approximately equivalent.
- the former / the latter (molar ratio) 2/1 to 1/2, preferably 1.5 / 1 to 1 / 1.5, more preferably about 1.2 / 1 to 1 / 1.2. It may be.
- the ratio (use ratio) of diarylphosphoryl azide is, for example, 0.1 to 2 mol, preferably 0.5 to 1.5 mol, relative to 1 mol of the carboxylic acid represented by the formula (7-f). More preferably, it may be about 0.8 to 1.2 mol.
- the base may be a basic inorganic compound, but is usually a basic organic compound.
- basic organic compounds tertiary amines are widely used.
- aliphatic amines for example, tri-C 1-6 alkylamines such as trimethylamine and triethylamine; N, N, N ′, N′-tetramethylethylenediamine) N, N, N ′, N′-tetramethylpropanediamine and the like, N, N, N ′, N′- tetraC 1-4 alkylC 1-4alkanediamine and the like
- alicyclic amines for example, Tri-C 5-6 cycloalkylamine such as tricyclohexylamine; di-C 5-6 cycloalkyl C 1-4 alkylamine such as dicyclohexylethylamine; di-C 1-4 alkyl C 5-6 cycloalkylamine such as diethylcyclohexylamine Etc.
- the ratio of the base is, for example, 0 with respect to 1 mol in total of the carboxylic acid represented by the formula (7-f), the alcohol represented by the formula (7-g), and the diarylphosphoryl azide. .01 to 1 mol, preferably about 0.1 to 0.5 mol.
- the reaction of the compound (7-f) and the compound (7-g) may be performed in the presence of a solvent.
- the solvent is not particularly limited as long as it is inert to the reaction.
- Hydrocarbons for example, aliphatic hydrocarbons such as pentane and hexane; alicyclic hydrocarbons such as cyclohexane; aromatics such as benzene, toluene and xylene
- Hydrocarbons for example, aliphatic hydrocarbons such as pentane and hexane; alicyclic hydrocarbons such as cyclohexane; aromatics such as benzene, toluene and xylene
- Hydrocarbons eg, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, bromoform, ethylene chloride
- ethers eg, chain ethers such as ethyl ether, isopropyl ether; dio
- the reaction between the compound (7-f) and the compound (7-g) can be performed at room temperature or under heating, for example, at about 10 to 150 ° C. (preferably 20 to 100 ° C.).
- the reaction can be carried out in air or under an inert gas atmosphere (nitrogen, helium, argon gas, etc.).
- the reaction may be performed under atmospheric pressure or under pressure.
- the reaction time is not particularly limited, and may be, for example, about 0.1 to 20 hours, preferably 0.5 to 15 hours, and more preferably about 1 to 10 hours.
- the compound represented by the above formula (7-h) or a salt thereof is converted into a conventional separation or purification (or isolation) method such as filtration, distillation, concentration, precipitation, crystallization, recrystallization, decane.
- the reaction mixture may be separated or purified, for example, by filtration, extraction, drying, washing, chromatography, and combinations thereof.
- the compound of the present invention or a salt thereof can specifically bind to the constituent protein Skp2 of ubiquitin ligase, it is useful as a p27 Kip1 ubiquitination inhibitor, for example, suppressing the dissociation of p27 Kip1 from the SCF Skp2 complex.
- By inhibiting the ubiquitination of p27 Kip1 with high activity it is possible to effectively inhibit the degradation of p27 Kip1 by the proteasome, so that it is also useful as a p27 Kip1 degradation inhibitor.
- the compounds or salts thereof of the present invention by inhibiting the degradation of p27 Kip1, to recover the expression level of p27 Kip1, for cell death (apoptosis) can be derived efficiently also useful as cell death-inducing agent It is useful as a preventive and / or therapeutic agent for cell proliferative diseases such as cancer, rheumatism, diabetes, obesity, endometriosis, benign prostatic hyperplasia, inflammation and the like.
- the compound of the present invention or a salt thereof can be used for various cancers [for example, solid cancer (eg, brain tumor, oral cancer, pharyngeal cancer, laryngeal cancer, lung cancer, digestive organ cancer (esophageal cancer, stomach cancer, colon cancer, liver cancer, pancreatic cancer).
- Urinary cancer (kidney cancer, bladder cancer, prostate cancer, etc.), breast cancer, uterine (cervical) cancer, ovarian cancer, skin cancer, thyroid cancer, osteosarcoma, etc., blood system cancer (leukemia, malignant lymphoma, etc.), etc. It is useful as a preventive and / or therapeutic agent.
- the compound of the present invention or a salt thereof is highly malignant (or refractory) cancer such as brain tumor, oral squamous cell carcinoma, lung cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, prostate cancer (endocrine therapy).
- Refractory prostate cancer, etc.), breast cancer, uterine (cervical) cancer, ovarian cancer, hematological cancer and the like are useful as preventive and / or therapeutic agents.
- Such a preventive and / or therapeutic agent for cancer can be suitably used for preventing the occurrence and growth (progress, recurrence, metastasis, etc.) of cancer.
- the compound may be used alone as a medicine, or may be used as a pharmaceutical composition (or preparation) in combination with a carrier (such as a pharmacologically or physiologically acceptable carrier).
- a carrier such as a pharmacologically or physiologically acceptable carrier.
- the carrier is appropriately selected according to the form (ie, dosage form), dosage form, use, etc. of the pharmaceutical composition (or formulation).
- the dosage form is not particularly limited, and is a solid preparation (powder, powder, granule (granule, fine granule, etc.), pill, pill, tablet, capsule (soft capsule, hard capsule, etc.), dry syrup, Suppositories, etc.), semi-solid preparations (creams, ointments, gels, gummies, film preparations, sheet preparations, etc.), liquids (solutions, suspensions, emulsions, syrups, elixirs, lotions) , Injections, etc.). Also included are sprays such as the powders and / or liquids, aerosols and the like.
- the capsule may be a liquid-filled capsule or a capsule filled with a solid agent such as a granule.
- the preparation may be a lyophilized preparation.
- the preparation of the present invention may be a preparation with controlled drug release rate (sustained release preparation, immediate release preparation).
- the preparation may be an oral administration preparation or a parenteral administration preparation (nasal drops, inhalants, transdermal preparations, etc.).
- the preparation may be a topical preparation (solutions such as injections (aqueous injections, non-aqueous injections, etc.), suspensions, ointments, patches, cataplasms, etc.).
- the preparations of the present invention are often solid preparations (particularly oral preparations) and liquid preparations (parenteral preparations such as injections).
- the content of the compound of the present invention or a salt thereof in the preparation is not particularly limited and varies depending on the dosage form.
- it can be selected from the range of about 0.0001 to 99% by weight, and is usually a solid preparation or a semisolid.
- a preparation it is about 0.005 to 60% by weight (for example, 0.01 to 50% by weight), and in the case of a liquid preparation, it is about 0.001 to 30% by weight (for example, 0.005 to 20% by weight). It is.
- the carrier examples include Japanese Pharmacopoeia (Pharmacopoeia), (1) Pharmaceutical Additives Handbook, Maruzen Co., Ltd., (1989), (2) “Pharmaceutical Additives Dictionary 2000” (Pharmaceutical Daily Inc., 2002) Issued in March), (3) “Pharmaceutical Additives Dictionary 2005” (Pharmaceutical Daily Report, published in May 2005), (4) Pharmacology, Revised 5th Edition, Nanedo Co., Ltd. (1997), and (5) Among ingredients (for example, excipients, binders, disintegrants, lubricants, coating agents, etc.) listed in Pharmaceutical Additives Standard 2003 (Pharmaceutical Daily, August 2003), etc. It can select suitably according to a formulation use. For example, as a carrier for a solid preparation, at least one carrier selected from excipients, binders and disintegrants is often used.
- the pharmaceutical composition may contain a lipid.
- excipient examples include lactose, sucrose, glucose, sucrose, saccharides such as mannitol, sorbitol, and xylitol or sugar alcohols; starch such as corn starch; polysaccharides such as crystalline cellulose (including microcrystalline cellulose); Examples thereof include silicon oxide such as anhydrous silicic acid and synthetic aluminum silicate, or silicate.
- Binders include soluble starches such as pregelatinized starch and partially pregelatinized starch; polysaccharides such as agar, gum arabic, dextrin, sodium alginate, tragacanth gum, xanthan gum, hyaluronic acid, sodium chondroitin sulfate; polyvinylpyrrolidone, polyvinyl alcohol, carboxy Synthetic polymers such as vinyl polymer, polyacrylic acid polymer, polylactic acid, polyethylene glycol; methyl cellulose (MC), ethyl cellulose (EC), carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose ( Examples thereof include cellulose ethers such as HPC) and hydroxypropylmethylcellulose (HPMC).
- polysaccharides such as agar, gum arabic, dextrin, sodium alginate, tragacanth gum, xanthan gum, hyaluronic acid, sodium
- Disintegrants include calcium carbonate, sodium carboxymethyl starch, carboxymethyl cellulose or a salt thereof (carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, etc.), cross-linked polyvinyl pyrrolidone (crospopidone), low-substituted hydroxypropyl cellulose Etc. can be exemplified. These carriers can be used alone or in combination of two or more.
- the coating agent examples include saccharides, cellulose derivatives such as ethyl cellulose and hydroxyethyl cellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, and Eudragit (Metal). Acrylic acid / acrylic acid copolymer).
- the coating agent may be an enteric component such as cellulose phthalate, hydroxypropylmethylcellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, or a polymer containing a basic component such as dialkylaminoalkyl (meth) acrylate ( Gastric soluble components composed of Eudragit etc.).
- the preparation may also be a capsule containing these enteric components and gastric components in the skin.
- oily carriers include animal and vegetable oils (vegetable oils such as jojoba oil, olive oil, palm oil, and cottonseed oil; animal oils such as squalane) and mineral oils (liquid paraffin, silicone oil, etc.) Etc. can be exemplified.
- aqueous carrier examples include water (purified or sterile water, distilled water for injection, etc.), physiological saline, Ringer's solution, glucose solution, water-soluble organic solvents [lower aliphatic alcohols such as ethanol and isopropanol; (poly) alkylene glycols ( Ethylene glycol, polyethylene glycol and the like); glycerin and the like], dimethylisosorbide, dimethylacetamide and the like.
- the semi-solid carrier may be selected from the solid pharmaceutical carrier and / or the liquid carrier.
- the carrier of the semisolid agent may contain a lipid.
- Lipids include waxes (beeswax, carnauba wax, lanolin, paraffin, petrolatum, etc.), long chain fatty acid esters (saturated or unsaturated fatty acid alkyl esters, fatty acids and polyhydric alcohols (poly C 2-4 alkylene glycol, glycerin or Polyglycerin, etc.) and esters (such as glycerides), hydrogenated oils, higher alcohols (saturated fatty alcohols such as stearyl alcohol, unsaturated aliphatic alcohols such as oleyl alcohol), higher fatty acids (linoleic acid, linolenic acid, Stearic acid, oleic acid and the like), metal soaps (for example, fatty acid metal salts such as sodium coconut oil fatty acid and calcium stearate) and the like.
- waxes beeswax, carnauba wax, lanolin, paraffin, petrolatum, etc.
- long chain fatty acid esters saturated
- additives can be appropriately used depending on the administration route, dosage form and the like.
- additives include lubricants (for example, talc, magnesium stearate, polyethylene glycol 6000), disintegration aids, antioxidants or antioxidants, and emulsifiers (for example, nonionic surfactants).
- Surfactants dispersants, suspending agents, solubilizers, solubilizers, thickeners (water-soluble polymers such as carboxyvinyl polymer, polyvinyl alcohol, carrageenan, gelatin; cellulose such as carboxymethylcellulose) Ethers, etc.), pH adjusters or buffers (citric acid-sodium citrate buffer, etc.), stabilizers, preservatives or preservatives (parabens, such as methylparaben and butylparaben), fungicides or antibacterial agents (benzoic acid) Benzoic acids such as sodium acid), antistatic agents, flavoring agents or masking agents (for example, Etc.
- Taste agents coloring agents (such as dyes and pigments such as red iron oxide), such as flavoring agents, or perfumes (fragrances), fresheners, defoamers, isotonic agents, soothing agents.
- coloring agents such as dyes and pigments such as red iron oxide
- perfumes fragments
- fresheners such as peppers and peppers
- isotonic agents such as sodium tartrate
- soothing agents such as sodium tartrate, sodium tartrate, sodium tartrate, sodium tartrate, sodium stearate, sodium stearate, sodium stearate, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stevia, sodium stearate, sodium stearate, sodium steacetate
- a solubilizer In injections, usually, a solubilizer, a solubilizer, a suspending agent, a buffer, a stabilizer, a preservative, and the like are often used as the additive.
- powder injections lyophilized preparations
- infusion preparations physiological saline, glucose solution, Ringer's solution, etc.
- Conventional additives can be used.
- topical administration agents such as inhalants and transdermal absorption agents, dissolution aids, stabilizers, buffers, suspending agents, emulsifiers, preservatives and the like are usually used as the above additives. .
- the pharmaceutical composition of the present invention is prepared by a conventional formulation method, for example, a production method described in the Japanese Pharmacopoeia or the production method described in the 15th revision of the Japanese Pharmacopoeia, using an active ingredient, a carrier component, and additives as necessary. Can be prepared by different methods.
- the compound of the present invention or a salt thereof can be used in humans and non-human animals, usually mammals.
- Safe oral or parenteral administration eg rectal administration, intravenous administration, intramuscular administration
- animals eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.
- Subcutaneous administration etc.
- the dose of the compound of the present invention or a salt thereof depends on the subject to be administered, age, weight, sex and condition (general condition, medical condition, presence or absence of complications, etc.), administration time, dosage form, administration method, etc. Can be selected as appropriate.
- the dose to humans is usually about 0.01 to 1,000 mg, preferably about 0.1 to 700 mg, more preferably, in a free form of the compound or a salt thereof. Is about 0.2 to 500 mg.
- the dose is usually about 0.01 to 200 mg, preferably about 0.05 to 100 mg, more preferably about 1 to 200 mg per day with the compound or salt thereof in a free form. About 0.1 to 80 mg.
- Step 1-1-2 4-methylamino-3-nitrobenzoic acid ethyl ester
- 4-fluoro-3-nitrobenzoic acid ethyl ester (10.0 g, 46.9 mmol) prepared in step 1-1-1 above was dissolved in methanol (40 ml), triethylamine (10 ml, 70.4 mmol) was added, A 40% methylamine-methanol solution (5.50 g, 70.4 mmol) was added under ice cooling. After stirring for 1 hour under ice cooling, ice water was added, and the precipitate was collected by filtration and washed with water. By air drying overnight, the title compound (10.4 g, 99%) was obtained as a yellow powder.
- Step 1-1-3 3-Amino-4-methylaminobenzoic acid ethyl ester
- Lithium aluminum hydride (9.70 g, 256 mmol) was suspended in tetrahydrofuran (100 ml) under an argon gas stream, and 1-methyl-1H-benzimidazole-5 prepared in Step 1-1-4 above was cooled with ice.
- a tetrahydrofuran solution (100 ml) of carboxylic acid ethyl ester (26.1 g, 128 mmol) was slowly added. The mixture was further stirred for 1 hour under ice cooling. Saturated aqueous sodium bicarbonate was slowly added under ice cooling. The precipitate was filtered off and concentrated. Dissolved in chloroform, washed with saturated aqueous sodium bicarbonate, and concentrated.
- Examples 1-2 to 1-6 Example 1-1 except that the compounds shown in the following table were used instead of the 40% methylamine-methanol solution as the ring-forming component or 4-fluoro-3-nitrobenzoic acid ethyl ester as the monocyclic compound
- the target bicyclic compound was obtained by operating in the same manner as above.
- Step 2-1-2 (1,2-Dimethyl-1H-benzimidazol-5-yl) methanol
- Examples 2-2 to 2-4 The same procedure as in Example 2-1 was performed except that the compounds shown in the following table were used instead of acetic anhydride as a ring-forming component or 3-amino-4-methylaminobenzoic acid ethyl ester as a monocyclic compound. As a result, the desired bicyclic compound was obtained.
- Step 1-1-1 4-Fluoro-3-nitrobenzoic acid ethyl ester (160 g, 0.752 mol) prepared in Step 1-1-1 was suspended in ethanol (500 ml), triethylamine (91.4 g, 0.903 mol) was added, and iced. Piperidine (76.9 g, 0.903 mol) was slowly added under cooling. After stirring at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated.
- 3-amino-4-piperidin-1-ylbenzoic acid ethyl ester (5.38 g, 21.7 mmol) prepared in Step 3-1-2 above was dissolved in formic acid (90%, 40 ml), and hydrogen peroxide solution was added. (20 ml) was added and heated under reflux for 40 minutes. After cooling, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate and 25% aqueous ammonia, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated.
- Lithium aluminum hydride (1.97 g, 51.9 mmol) was suspended in tetrahydrofuran (30 ml), and 1,2,3,4-tetrahydrobenzo [4,5 prepared in Step 3-1-3 above under ice cooling.
- a tetrahydrofuran solution (20 ml) of imidazo [1,2-a] pyridine-7-carboxylic acid ethyl ester (6.34 g, 26.0 mmol) was slowly added dropwise. After stirring for 1 hour under ice-cooling, saturated sodium hydrogen carbonate solution (5 ml) was slowly added at the same temperature while paying attention to exotherm. Further ethyl acetate was added slowly. It returned to room temperature and filtered. Washed with chloroform.
- Examples 3-2 to 3-7 The target tricyclic compound was obtained in the same manner as in Example 3-1, except that the N-containing monocyclic compound shown in the following table was used instead of piperidine.
- Step 4-1-3 1-methyl-1H-indazole-5-carboxylic acid ethyl ester and 2-methyl-2H-indazole-5-carboxylic acid ethyl ester
- Lithium aluminum hydride (300 mg, 7.83 mmol) is suspended in tetrahydrofuran (20 ml), and 1-methyl-1H-indazole-5-carboxylic acid ethyl ester prepared in Step 4-1-3-A is prepared under ice cooling.
- Examples 4-3-4-7 Instead of methyl iodide as the alkylating component or 4-amino-3-methylbenzoic acid as the monocyclic compound, the compounds shown in the following table were used, and according to the production method shown in the following table, A cyclic compound was obtained.
- 3-amino-4-ethylaminobenzoic acid ethyl ester (1.80 g, 9.27 mmol) prepared in the same manner as in Step 1-1-3 was dissolved in acetic acid (5 ml), and sodium nitrite (1 .28 g, 18.5 mmol) was added in small portions. The mixture was cooled with water and stirred for 10 minutes. The mixture was ice-cooled again, neutralized with 25% aqueous ammonia, ethyl acetate was added, and the mixture was washed with saturated brine and water. The extract was dried over anhydrous magnesium sulfate and concentrated.
- Step 6-1-2 (2,3-Dimethylquinoxalin-6-yl) methanol
- R represents a homocyclic group or heterocyclic group which may have a substituent (a halogen atom, an alkyl group, an alkoxy group, etc.), and R ′ represents a hydrogen atom, an alkyl group, a haloalkyl group or a cyclo group. Represents an alkyl group]
- Example 7-1 Step 7-1-1 4-chloro-2-methoxybenzamide
- Step 7-1-3 2- (4-Chloro-2-methoxyphenyl) -4-methylthiazole-5-carboxylic acid ethyl ester
- Step 7-1-4 2- (4-Chloro-2-methoxyphenyl) -4-methylthiazole-5-carboxylic acid
- Example 7-2 to 7-25, 7-27 to 7-41 The same procedure as in Example 7-1 was performed except that 4-chloro-2-methoxybenzoic acid as the carboxylic acid component or 2-chloroacetoacetic acid ethyl ester as the ring-forming component was used instead of the compounds shown in the following table. Thus, the target compound was obtained.
- R represents a homocyclic group or a heterocyclic group which may have a substituent (halogen atom, alkyl group, haloalkyl group, alkoxy group, amino group, N-alkyl-substituted amino group, etc.)
- R ′ represents a hydrogen atom, an alkyl group, or an aralkyl group
- Step 8-1-2 5- (2,4-Dichlorophenyl) -2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester and 5- (2,4-dichlorophenyl) -1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester
- Examples 8-3 to 8-29, 8-31 to 8-35 instead of 2 ′, 4′-dichloroacetophenone as the carbonyl compound or methylhydrazine as the ring-forming component, the compound shown in the following table was used, and the target compound was obtained according to the production method shown in the following table.
- Ar represents a thiazole ring or a pyrazole ring optionally substituted by a homocyclic group or a heterocyclic group
- R and R ′ are the same or different and represent a hydrogen atom, a halogen atom, an alkyl group, or a haloalkyl.
- R ′′ represents a group, an alkoxy group, an amino group, or an N-alkyl-substituted amino group, and R ′′ may have a substituent (an alkyl group, a hydroxyl group, an alkoxy group, an alkoxyalkyl group, an alkylthio group, etc.) A cyclic group or a heterocyclic group, and R ′ ′′ represents an alkyl group]
- Example 9-1 Step 9-1 [2- (4-Chloro-2-methoxyphenyl) -4-methylthiazol-5-yl] carbamic acid 1,2,3,4-tetrahydrobenzo [4,5] imidazo [1,2-a] pyridine- 7-ylmethyl ester
- Examples 9-2 to 9-377 2- (4-Chloro-2-methoxyphenyl) -4-methylthiazole-5-carboxylic acid or (1,2,3,4-tetrahydrobenzo [4,5] imidazo [1,2-a] pyridine-7 -Yl)
- the target compound was obtained in the same manner as in Example 9-1 except that carboxylic acid or hydroxy compound shown in the following table was used instead of methanol.
- R represents an aryl group which may have a substituent (halogen atom, alkoxy group, etc.), R ′ represents an alkyl group, and R ′′ represents a substituent (alkyl group, alkoxy group, etc.).
- N-methylpyrrole (8.10 g, 100 mmol) was dissolved in methylene chloride (100 ml), trichloroacetic acid chloride (20.00 g, 115 mmol) was added, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution is added, and the organic phase is separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to remove 2,2,2-trichloro-1- (methyl-1H-pyrrole-2 -Yl) ethanone (16.3 g, 72%) was obtained.
- Step 10-1-2 4-Bromo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
- Step 10-1-3 4- (4-Chloro-2-methoxyphenyl) -1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
- Step 10-1-4 [4- (4-Chloro-2-methoxyphenyl) -1-methyl-1H-pyrrol-2-yl] carbamic acid 4-methoxybenzyl ester
- Step 10-1-3 4- (4-chloro-2-methoxyphenyl) -1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester prepared in Step 10-1-3, the same procedure as in Step 7-1-4 was performed.
- the carboxylic acid obtained by hydrolysis is used in place of 2- (4-chloro-2-methoxyphenyl) -4-methylthiazole-5-carboxylic acid, and (1,2,3,4-tetrahydrobenzo [4,5] imidazo [1,2-a] pyridin-7-yl)
- the title compound was obtained in the same manner as in Example 9-1 except that 4-methoxybenzyl alcohol was used instead of methanol. .
- Example 10-2 [4- (4-Chloro-2-methoxyphenyl) -1-methyl-1H-pyrrol-2-yl] carbamic acid 1-methyl-1H-benzimidazol-5-ylmethyl ester
- R and R ′ are the same or different and each represents a hydrogen atom, an alkyl group or an alkoxyalkyl group, and R and R ′ are bonded to each other to form a 5- to 7-membered member together with the adjacent nitrogen and carbon atoms. A ring may be formed)
- Example 11-1 Step 11-1 1-methyl-1H-benzimidazole-5-carboxylic acid
- Step 1-1-4 1-Methyl-1H-benzimidazole-5-carboxylic acid ethyl ester (800 mg, 3.92 mmol) prepared in Step 1-1-4 was suspended in 2-propanol (10 ml), and 1 mol / L aqueous sodium hydroxide solution ( 10 ml) was added and heated to reflux for 1 hour. After cooling, the mixture was neutralized with 1 mol / L hydrochloric acid. Further acidified with citric acid. The product was collected by filtration, washed with a small amount of water, and then air-dried overnight to obtain the title compound (595 mg, 86%) as a gray powder.
- Example 11-2 to 11-15 The same operation as in Example 11-1 was carried out except that the ester compound obtained based on the production method A shown in the following table was used instead of 1-methyl-1H-benzimidazole-5-carboxylic acid ethyl ester. The target compound was obtained.
- R represents a homocyclic group or heterocyclic group which may have a substituent (such as a halogen atom, an alkyl group, or an alkoxy group), and R ′ represents a hydrogen atom or an alkyl group]
- R represents a homocyclic group or heterocyclic group which may have a substituent (such as a halogen atom, an alkyl group, or an alkoxy group)
- R ′ represents a hydrogen atom or an alkyl group
- Lithium aluminum hydride (380 mg, 10.0 mmol) was suspended in tetrahydrofuran (10 ml), and 2- (4-chloro-2-methoxyphenyl) -4-methylthiazole-prepared in Example 7-1 at room temperature there.
- a suspension of 5-carboxylic acid (1.42 g, 5.00 mmol) in tetrahydrofuran (10 ml) was added and stirred for 3 hours at room temperature. Under ice-cooling, 5 drops of saturated aqueous sodium bicarbonate were slowly added dropwise. Ethyl acetate was added, and 5 drops of saturated aqueous sodium hydrogen carbonate was added. The precipitate was removed by filtration, and the solid collected by filtration with chloroform was washed.
- Examples 12-2 to 12-17, 12-19 to 12-25, 12-30, 12-32 to 12-34 The same operation as in Example 12-1 except that instead of 2- (4-chloro-2-methoxyphenyl) -4-methylthiazole-5-carboxylic acid, the carboxylic acid of the example shown in the following table was used. This gave the desired compound.
- Ar represents a thiazole ring or a pyrazole ring optionally substituted by a homocyclic group or a heterocyclic group
- R and R ′ are the same or different and represent a hydrogen atom, a halogen atom, an alkyl group, or Represents an alkoxy group
- R ′′ represents a homocyclic group or a heterocyclic group which may have a substituent (a halogen atom, an alkyl group, an alkoxy group, an alkoxyalkyl group, etc.)
- Example 13-1 Step 13-1 (1-Methyl-1H-benzimidazol-5-yl) carbamic acid 4-methyl-2- (2-methylphenyl) thiazol-5-ylmethyl ester
- Examples 13-2 to 13-150 Instead of [2- (2-methylphenyl) -4-methylthiazol-5-yl] methanol or 1-methyl-1H-benzimidazole-5-carboxylic acid, known or obtained in the examples shown in the following table
- the target compound was obtained in the same manner as in Example 13-1, except that the obtained hydroxy compound or carboxylic acid was used.
- Tetrahydrofuran (40 ml) was added to lithium aluminum hydride (1.94 g), and the mixture was gently heated and stirred under an argon atmosphere to prepare 4-methoxybenzoic acid N-methylhydrazide (4.78 g) prepared in Step 14-1-1 above.
- Examples 14-3 to 14-7 The target compound was obtained in the same manner as in Example 14-1, except that the acid chloride component shown in the following table was used instead of 4-methoxybenzoyl chloride.
- N-aminophthalimide (1.62 g) and 4-methoxy-3-methylbenzaldehyde (1.50 g) were added to ethanol (20 ml), and the mixture was stirred overnight with heating under reflux. After bringing to room temperature, the precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to obtain the title compound (2.50 g, 84%).
- Step 15-1-3 2-[(4-Methoxy-3-methylbenzyl) methylamino] isoindole-1,3-dione
- R and R ′ ′′ are the same or different and each represents an aryl group which may have a substituent (a halogen atom, an alkyl group, an alkoxy group, etc.), and R ′ and R ′′ represent The same or different and represents a hydrogen atom or an alkyl group]
- Example 16-1 2- (4-Chloro-2-methoxyphenyl) -4-methylthiazole-5-carboxylic acid N ′-(4-methoxybenzyl) -N′-methylhydrazide
- Examples 16-2 to 16-25 instead of 2- (4-chloro-2-methoxyphenyl) -4-methylthiazole-5-carboxylic acid or N- (4-methoxybenzyl) -N-methylhydrazine, the carboxylic acid or hydrazine compound shown in the following table The compound of interest was obtained by the same procedures as in Example 16-1 except that was used.
- R and R ′ ′′ are the same or different and each represents an aryl group or a heterocyclic group which may have a substituent (a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, etc.); 'And R ′′ are the same or different and each represents a hydrogen atom or an alkyl group]
- Example 17-1 Step 17-1 2- (4-Chloro-2-methoxyphenyl) -4-methylthiazole-5-carboxylic acid N ′-(1-methyl-1H-indol-5-ylmethyl) hydrazide
- Example 17-3 was used instead of 2- (4-chloro-2-methoxyphenyl) -4-methylthiazole-5-carboxylic acid N ′-(1-methyl-1H-indol-5-ylmethyl) hydrazide.
- the title compound was obtained in the same manner as the Example 17-2 except that it was used.
- R and R ′′ are the same or different and each represents an aryl group which may have a substituent (such as a halogen atom or an alkoxy group), and R ′ represents an alkyl group]
- R and R ′′ are the same or different and each represents an aryl group which may have a substituent (such as a halogen atom or an alkoxy group), and R ′ represents an alkyl group]
- Example 18-1 Step 18-1-1 4- (4-Chloro-2-methoxyphenyl) -2,4-dioxobutyric acid methyl ester
- Hydrazine monohydrate was prepared by dissolving methyl 4- (4-chloro-2-methoxyphenyl) -2,4-dioxobutyrate (2.47 g) obtained in Step 18-1-1 in ethanol (15 ml). (457 mg) was added and heated to reflux. After 19 hours, the temperature was returned to room temperature, and the crystals were collected by filtration to obtain the title compound (1.8 g, 74%).
- Step 18-1-3 5- (4-Chloro-2-methoxyphenyl) -2H-pyrazole-3-carboxylic acid
- Step 18-1-4 5- (4-Chloro-2-methoxyphenyl) -2H-pyrazole-3-carboxylic acid N ′-(4-methoxybenzyl) -N′-methylhydrazide
- Example 18-1 The title compound was obtained in the same manner as the Example 18-1, except that the compound of Example 14-5 was used instead of N- (4-methoxybenzyl) -N-methylhydrazine.
- R and R ′′ are the same or different and each represents an aryl group which may have a substituent (such as a halogen atom or an alkoxy group), and R ′ represents an alkyl group]
- R ′ represents an alkyl group
- Example 19-1 The title compound was obtained in the same manner as the Example 19-1, except that the compound of Example 14-5 was used instead of N- (4-methoxybenzyl) -N-methylhydrazine.
- R and R ′′ are the same or different and each represents an aryl group which may have a substituent (a halogen atom, an alkyl group, an alkoxy group, etc., and R ′ represents an alkyl group)]
- Example 20-1 Step 20-1-1 2- [2- (2-Methoxyphenyl) -2-oxoethyl-3-oxobutyric acid ethyl ester
- Step 20-1-4 (2-methoxyphenyl) -2-methylfuran-3-carboxylic acid N ′-(4-methoxybenzyl) -N′-methylhydrazide
- Example 20-1 except that 5- (2,4-dichlorophenyl) -2-methylfuran-3-carboxylic acid was used instead of 5- (2-methoxyphenyl) -2-methylfuran-3-carboxylic acid The title compound was obtained by operating in the same manner as above.
- R represents an aryl group which may have a substituent (halogen atom, alkoxy group, etc.), and R ′ represents a substituent (halogen atom, alkyl group, hydroxyl group, alkoxy group, nitro group, etc.) And R ′′ represents a hydrogen atom or an alkyl group]
- R represents an aryl group which may have a substituent (halogen atom, alkoxy group, etc.)
- R ′ represents a substituent (halogen atom, alkyl group, hydroxyl group, alkoxy group, nitro group, etc.)
- R ′′ represents a hydrogen atom or an alkyl group
- Example 21-1 except that the carbonyl compound or carboxylic acid shown in the following table was used instead of 2,4-dihydroxybenzaldehyde or 5- (2,4-dichlorophenyl) -2H-pyrazole-3-carboxylic acid To obtain the desired compound.
- Step 22-1-4 (2-Chlorophenyl) -2H-pyrazole-3-carboxylic acid [1- (3-hydroxy-4-methoxyphenyl) methylidene] hydrazide
- Examples 22-2 to 22-10 By operating in the same manner as in Example 22-1 except that an aldehyde compound or a ketone compound shown in the following table is used instead of 3-hydroxy-4-methoxybenzaldehyde or 1- (2-chlorophenyl) ethanone, A compound was obtained.
- R represents an alkyl group or a homocyclic group or heterocyclic group which may have a substituent (a halogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, etc.), and R ′ represents a hydrogen atom.
- An atom, an alkyl group, a haloalkyl group, or a cycloalkyl group or an aryl group which may have a substituent (such as an alkoxy group) is represented, and R ′′ represents a substituent (a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group).
- Step 23-1-2 (2,4-Dichlorophenyl) -4-methylthiazole-5-carboxylic acid hydrazide
- Step 23-1-3 (2,4-Dichlorophenyl) -4-methylthiazole-5-carboxylic acid [1- (3-hydroxy-4-methoxyphenyl) methylidene] hydrazide
- Examples 23-2 to 23-165, 23-171 to 23-172 instead of using 2,4-dichlorothiobenzamide as a thioamide compound, 3-hydroxy-4-methoxybenzaldehyde as an aldehyde compound, or ethyl 2-chloroacetoacetate as a ring-forming component, the compounds shown in the following table are used. The target compound was obtained in the same manner as in Example 23-1.
- Boc represents a protecting group (t-butoxycarbonyl group), and R and R ′ are the same or different and may have a substituent (an alkyl group, a hydroxyl group, an alkoxy group, etc.) Show group]
- Example 24-1 Step 24-1-1 4-Bromo-1H-pyrrole-2-ethyl carboxylate
- Step 24-1-3 4- (2,3-Dimethylphenyl) -1H-pyrrole-2-carboxylic acid ethyl ester
- Step 24-1-4 (2,3-Dimethylphenyl) -1H-pyrrole-2-carboxylic acid hydrazide
- Step 24-1-5 4- (2,3-Dimethylphenyl) -1H-pyrrole-2-carboxylic acid [1- (4-hydroxy-3,5-dimethylphenyl) methylidene] hydrazide
- Step 24-1-3 4-chlorophenylboronic acid is used instead of 2,3-dimethylphenylboronic acid, and 4-hydroxy-3,5-dimethylbenzaldehyde is used instead of 3-hydroxy-4-methoxybenzaldehyde.
- the title compound was obtained in the same manner as the Example 24-1 except for the above.
- R and R ′′ are the same or different and each represents an aryl group which may have a substituent (a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, etc.), and R ′ represents a hydrogen atom or Represents an alkyl group]
- R and R ′′ are the same or different and each represents an aryl group which may have a substituent (a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, etc.), and R ′ represents a hydrogen atom or Represents an alkyl group]
- Example 25-1 Step 25-1-1 2- (4-Chlorophenyl) -1H-imidazole-4-carboxylic acid hydrazide
- Step 22-1-3 except that 2- (4-chlorophenyl) -1H-imidazole-4-carboxylic acid methyl ester was used instead of 5- (2-chlorophenyl) -2H-pyrazole-3-carboxylic acid methyl ester
- the title compound was obtained by operating in the same manner as above.
- Step 25-1-2 2- (4-Chlorophenyl) -3H-imidazole-4-carboxylic acid [1- (3-hydroxy-4-methoxyphenyl) methylidene] hydrazide
- Example 25-2 (2-Methylphenyl) -3H-imidazole-4-carboxylic acid [1- (4-hydroxy-3,5-dimethylphenyl) methylidene] hydrazide
- Example 25-1 except that 2- (2-methylphenyl) -1H-imidazole-4-carboxylic acid methyl ester was used instead of 2- (4-chlorophenyl) -1H-imidazole-4-carboxylic acid methyl ester
- the title compound was obtained by operating in the same manner as above.
- R and R ′′ are the same or different and each represents an aryl group which may have a substituent (halogen atom, alkyl group, hydroxyl group, alkoxy group, etc.), and R ′ represents an alkyl group.
- R and R ′′ are the same or different and each represents an aryl group which may have a substituent (halogen atom, alkyl group, hydroxyl group, alkoxy group, etc.), and R ′ represents an alkyl group.
- Step 22-1- except that 2- (4-chlorophenyl) -4-methyloxazole-5-carboxylic acid methyl ester was used instead of 5- (2-chlorophenyl) -2H-pyrazole-3-carboxylic acid methyl ester
- the title compound was obtained in the same manner as in 3.
- Step 26-1-2 2- (4-Chlorophenyl) -4-methyloxazole-5-carboxylic acid N ′-(4-hydroxy-3,5-dimethylbenzyl) -N′-methylhydrazide
- R and R ′ are the same or different and each represents an aryl group or a heterocyclic group which may have a substituent (halogen atom, alkyl group, hydroxyl group, alkoxy group, haloalkoxy group, etc.) , Ts represents a tosyl group]
- Example 27-1 Step 27-1-1 (2,4-Dichlorophenyl) -hydroxyiminoacetonitrile
- Step 27-1-2 (2,4-Dichlorophenyl) -O- (p-toluenesulfonyl) hydroxyiminoacetonitrile
- Step 27-1-3 4-Amino-3- (2,4-dichlorophenyl) isothiazole-5-carboxylic acid ethyl ester
- Step 27-1-4 (2,4-Dichlorophenyl) isothiazole-5-carboxylic acid ethyl ester
- Step 27-1-5 (2,4-Dichlorophenyl) isothiazole-5-carboxylic acid hydrazide
- Step 27-1-6 (2,4-Dichlorophenyl) isothiazole-5-carboxylic acid [1- (4-dimethylaminophenyl) methylidene] hydrazide
- Examples 27-2 to 27-13 The target compound was obtained in the same manner as in Example 27-1, except that the aldehyde compound or acetonitrile compound shown in the following table was used instead of 4-dimethylaminobenzaldehyde or 2,4-dichlorophenylacetonitrile.
- Step 28-1-3 2- (4-Chloro-2-methoxyphenyl) -5-isocyanate-4-methylthiazole
- Step 28-1-4 [2- (4-Chloro-2-methoxyphenyl) -4-methylthiazol-5-yl] thiocarbamic acid O- (4-methoxybenzyl) ester
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Abstract
Description
(ii)環Cが単環式アレーン環であるとき、環Cは置換基を有しており、
(iii)リンカーLが下記式(1-a1)
(iv)リンカーLが下記式(1-a2)
で表されるリンカーであり、環Cがハロゲン原子を置換基として有するベンゼン環であるとき、環Bは3,4-イソオキサゾール-ジイル基ではない。]
前記式(1)において、リンカーLは、ウレタン結合[-NH-C(O)-O-又は-O-C(O)-NH-]を含んでいてもよく、例えば、下記式(1-a1)~(1-a6)のいずれかで表されるリンカーであってもよい。
前記式(1)において、基Aは、ハロゲン原子、アルキル基、ヒドロキシル基、アルコキシ基、メルカプト基、及びアルキルチオ基から選択された少なくとも一種の置換基を有するアリール基又は複素環基、例えば、2-位及び/又は4-位に置換基を有するフェニル基であってもよい。
なお、環C3に隣接し、G3及びG4を含む5員環において、破線は、この5員環が芳香族性環又は非芳香族性(脂肪族性)環であってもよいことを示す。
本発明の医薬組成物は、前記化合物又はその薬学的(又は生理学的)に許容される塩と、担体とを含んでいる。
(ii)環Cが単環式アレーン環であるとき、環Cは置換基を有している。]
で表される複素環化合物又はその塩は、ユビキチンリガーゼ(SCFSkp2)の構成タンパク質Skp2に特異的に結合して、例えば、SCFSkp2複合体からのp27Kip1の解離を抑制することにより、p27Kip1のユビキチン化、及びこのユビキチン化に伴うプロテアソームによるp27Kip1の分解を有効に抑制できる。そのため、本発明には、前記化合物又はその薬学的(又は生理学的)に許容される塩を有効成分として含有するp27Kip1ユビキチン化阻害剤又は分解阻害剤が含まれる。
(ii)環Cが単環式アレーン環であるとき、環Cは置換基を有しており、
(iii)リンカーLが下記式(1-a2)
で表されるリンカーであり、環Cがハロゲン原子を置換基として有するベンゼン環であるとき、環Bは3,4-イソオキサゾール-ジイル基ではない。]
で表される複素環化合物又はその塩は、p27Kip1の分解を有効に抑制し、p27Kip1の発現量を回復できるため、細胞増殖性疾患(例えば、癌、リウマチ、糖尿病、肥満、子宮内膜症、前立腺肥大症、炎症など)の予防及び/又は治療として有効である。そのため、本発明には、前記化合物又はその薬学的(又は生理学的)に許容される塩を有効成分として含有する細胞増殖性疾患の予防及び/又は治療剤が含まれる。
Ra~Reで表されるハロゲン原子、アルキル基、ハロアルキル基、アルコキシ基、ハロアルコキシ基、又はアルキルチオ基としては、基Aに置換する置換基と同様のハロゲン原子(フッ素原子、塩素原子など)、C1-4アルキル基(C1-2アルキル基など)、フルオロC1-4アルキル基(フルオロC1-2アルキル基など)、C1-4アルコキシ基(C1-2アルコキシ基など)、フルオロC1-4アルコキシ基(フルオロC1-2アルコキシ基など)、C1-4アルキルチオ基(C1-2アルキルチオ基など)などが例示できる。
なお、上記式(3-a)~(3-p)において、左端は環Aに連結し、右端はリンカーLに連結するのが好ましい。
なお、前記式(4-c)において、下記で表される化学結合
前記式(4-a2)において、Zaで表されるアルコキシ基、アルキルチオ基、N,N-ジアルキルアミノ基、又はN,N-ジアシルアミノ基としては、前記例示の基と同様のC1-6アルコキシ基(好ましくはC1-4アルコキシ基)、C1-6アルキルチオ基(好ましくはC1-4アルキルチオ基)、N,N-ジC1-6アルキルアミノ基(好ましくはN,N-ジC1-4アルキルアミノ基)、N,N-ジ(C1-6アルキル-カルボニル)アミノ基[好ましくはN,N-ジ(C1-4アルキル-カルボニル)アミノ基]などが例示できる。Zbで表されるアルキル基、又はアルコキシ基としては、前記例示の基と同様のC1-6アルキル基(好ましくはC1-4アルキル基)、C1-6アルコキシ基(好ましくはC1-4アルコキシ基)などが例示できる。
なお、前記式(4-c2)において、破線は、環C3に隣接し、G3及びG4を含む5員環が芳香族性環又は非芳香族性(脂肪族性)環であってもよいことを示す。
上記式(4-b3)~(4-b6)、(4-c2)、及び(4-c3)で表される基は、置換基を有していてもよい。すなわち、前記環を構成する炭素原子及び/又は窒素原子に結合する水素原子は、前記例示の置換基(例えば、アルキル基、アシル基など)で置換されていてもよい。
前記式(5-a)~(5-e)において、Zで表されるアルキル基又はアシル基としては、それぞれ、環Cに置換する置換基として前記に例示のC1-6アルキル基(好ましくはC1-4アルキル基)、C1-6アルキル-カルボニル基(好ましくはC1-4アルキル-カルボニル基)などが挙げられる。なお、前記式(5-a)において、2つの置換基Zの種類は、互いに同一又は異なっていてもよい。
(1-1)リンカーLが前記式(1-a)の基本骨格を含む化合物[例えば、リンカーLが前記式(1-a1)~(1-a6)のいずれかであり、基Aが置換基を有するアリール基(前記式(2)で表される基など)であり、環Bが置換基を有していてもよいチアゾール環、イソチアゾール環又はピラゾール環であり、かつ環Cが前記式(4-a)~(4-c)のいずれかである化合物(1)など]又はその塩;
(1-2)リンカーLが前記式(1-b)の基本骨格を含む化合物[例えば、リンカーLが前記式(1-b1)又は(1-b2)であり、基Aが置換基を有するアリール基(前記式(2)で表される基など)であり、環Bが置換基を有していてもよいチアゾール環、ピラゾール環、又はフラン環であり、かつ環Cが前記式(4-a)で表されるアリール基、又は前記式(4-b)若しくは(4-b2)で表される複素環基である化合物(1)など]又はその塩;
(1-3)リンカーLが前記式(1-c)の基本骨格を含む化合物[例えば、リンカーLが前記式(1-c1)~(1-c3)のいずれかであり、環Aが無置換のアリール基、置換基を有するアリール基(前記式(2)で表される基など)、又は置換基を有する複素環基(ピリジル基などの少なくとも窒素原子をヘテロ原子として含む5~8員複素環基など)であり、環Bが置換基を有していてもよいチアゾール環、イソチアゾール環、ピラゾール環、ピロール環、イミダゾール環、又はオキサゾール環であり、かつ環Cが前記式(4-a)で表されるアリール基(なお、式中、Z1はボロン酸基であってもよい)、又は前記式(4-b)若しくは(4-b2)で表される複素環基である化合物(1)など]又はその塩;
(1-4)リンカーLが前記式(1-d)の基本骨格を含む化合物[例えば、リンカーLが前記式(1-d1)~(1-d3)のいずれかであり、基Aが置換基を有するアリール基(前記式(2)で表される基など)であり、環Bが置換基を有していてもよいチアゾール環又はピラゾール環であり、かつ環Cが前記式(4-a)で表されるアリール基である化合物(1)など]又はその塩;
(1-5)リンカーLが前記式(1-e)の基本骨格を含む化合物[例えば、リンカーLが前記式(1-e1)又は(1-e2)であり、基Aが置換基を有するアリール基(前記式(2)で表される基など)であり、環Bが置換基を有していてもよいチアゾール環又はピラゾール環であり、かつ環Cが前記式(4-a)で表されるアリール基である化合物(1)など]又はその塩;
(1-6)リンカーが前記式(1-g)の基本骨格を含む化合物[例えば、リンカーLが前記式(1-g1)又は(1-g2)であり、基Aが置換基を有するアリール基(前記式(2)で表される基など)であり、環Bが置換基を有していてもよいチアゾール環又はピラゾール環であり、かつ環Cが前記式(4-a)で表されるアリール基である化合物(1)など]又はその塩;
(1-7)リンカーが前記式(1-h)の基本骨格を含む化合物[例えば、リンカーLが前記式(1-h1)であり、基Aが置換基を有するアリール基(前記式(2)で表される基など)であり、環Bが置換基を有していてもよいチアゾール環又はピラゾール環であり、かつ環Cが前記式(4-a)で表されるアリール基である化合物(1)など]。
R1及びR2で表されるハロゲン原子、アルキル基、アルコキシ基、又はアルキルチオ基としては、基Rで例示の基と同様のハロゲン原子(フッ素原子、塩素原子など)、C1-6アルキル基(C1-4アルキル基など)、C1-6アルコキシ基(C1-4アルコキシ基など)、C1-6アルキルチオ基(C1-4アルキルチオ基など)などが例示できる。
前記式(1)で表される化合物又はその塩は、基A、環B、リンカーL、及び環Cで表される各ユニットを連結することにより製造でき、連結順序は特に限定されないが、例えば、下記の反応工程式(i)に従って製造できる。
前記反応工程(i)において、L1及びL2で表される基は、互いに反応してリンカーLを形成可能な限り、特に限定されず、リンカーLの種類に応じて適宜選択され、例えば、互いに反応して結合形成可能な官能基そのものであってもよく、前記官能基(末端基)を有する基であってもよい。前記官能基としては、ハロアルキル基、ヒドロキシル基、アルデヒド基(ホルミル基)、カルボキシル基、カルバゾイル基、ヒドロキサム酸基、アミノ基、ヒドラジノ基、アミノシアノ基、イソシアネート基、イソチオシアナト基などが例示できる。前記官能基を有する基において、前記官能基を除いた残基としては、アルキレン基などが挙げられる。
前記反応工程(ii)において、J及びKで表される基は、互いに反応して、環Bを有する化合物と環Cを有する化合物とを連結可能である限り、特に限定されず、リンカーL[-(L1a)j-L3-(L2a)k-]の基本骨格L3の種類に応じて適宜選択される。リンカーLの基本骨格L3に対応する基J及び基Kの組合せの具体例を表5に示す。
前記式(7-a)で表される化合物は、慣用の方法、例えば、下記の反応工程式(iii)~(v)のいずれかに従って調製できる。
前記反応工程(iii)において、基Aと環Bとを連結する方法としては、特に限定されず、慣用の付加反応、置換反応、カップリング反応(例えば、鈴木カップリング反応などのクロスカップリング反応など)などが利用できる。A2及びA3の組合せとしては、例えば、A2がボロン酸基[-B(OH)2]であり、A3がハロゲン原子であると、双方の基が互いに反応して、A1(=A)が環Bと連結し、前記式(7-a)で表される化合物が得られる。
前記式(7-b)で表される化合物は、例えば、下記式(7-b1)~(7-b3)のいずれかであってもよい。
前記式(7-b1)で表される化合物は、慣用の方法により合成してもよいが、市販品を使用してもよい。具体的には、前記式(4-a)で表される環に対応する化合物、例えば、L2の末端基(基K)がヒドロキシル基である化合物[例えば、ベンジルアルコールなどのアラルキルアルコール(好ましくはC6-10アリールC1-4アルキルアルコール);4-フルオロベンジルアルコールなどのハロアラルキルアルコール(好ましくはハロC6-10アリールC1-4アルキルアルコール);4-メトキシベンジルアルコール、4-メトキシフェネチルアルコールなどのアルコキシ-アラルキルアルコール(好ましくはC1-4アルコキシ-C6-10アリールC1-4アルキルアルコール);4-メチルチオベンジルアルコールなどのアルキルチオ-アラルキルアルコール(好ましくはC1-4アルキルチオ-C6-10アリールC1-4アルキルアルコール;3-又は4-(N,N-ジメチル)-ベンジルアルコールなどのN,N-ジアルキル-アラルキルアルコール(好ましくはN,N-ジC1-4アルキル-C6-10アリールC1-4アルキルアルコール);3-フルオロ-4-メトキシベンジルアルコールなどのハロ-アルコキシ-アラルキルアルコール(好ましくはハロ-C1-4アルコキシ-C6-10アリールC1-4アルキルアルコール)など]、これらの化合物に対応し、L2の末端基(基K)がホルミル基、カルボキシル基、カルバゾイル基などである化合物などが例示できる。
なお、前記式(9-a)及び(9-b)において、破線は、G1~G3の種類に応じて、G1~G3が水素原子と結合していてもよいことを示す。
に従って、塩基の存在下、前記式(7-f)で表されるカルボン酸と、前記式(7-g)で表されるアルコールと、ジアリールホスホリルアジド(ジフェニルホスホリルアジドなどのジC6-10アリールホスホリルアジド)とを反応させることにより、前記式(7-h)で表される化合物が得られる。より詳細には、下記の反応工程式に従って、前記式(7-h)で表される化合物が得られる。
すなわち、塩基の存在下、前記式(7-f)で表されるカルボン酸とジアリールホスホリルアジドとを反応させて、前記式(7-i)で表されるカルボン酸アジドを生成する工程と、前記カルボン酸アジドの酸アジド基がクルチウス転位によりイソシアネート基へと変換して、前記式(7-j)で表されるイソシアネートを生成する工程と、前記イソシアネートと、前記式(7-g)で表されるアルコールとを反応させる工程とを経ることにより、前記式(7-h)で表される化合物が得られる。
本発明の化合物又はその塩は、ユビキチンリガーゼの構成タンパク質Skp2に特異的に結合できるため、p27Kip1ユビキチン化阻害剤として有用であり、例えば、SCFSkp2複合体からのp27Kip1の解離を抑制することによりp27Kip1のユビキチン化を高い活性で阻害することによって、プロテアソームによるp27Kip1の分解を有効に阻害できるため、p27Kip1分解阻害剤としても有用である。また、本発明の化合物又はその塩は、p27Kip1の分解を抑制することにより、p27Kip1の発現量を回復し、細胞死(アポトーシス)を効率よく誘導できるため、細胞死誘導剤としても有用であり、細胞増殖性疾患、例えば、癌、リウマチ、糖尿病、肥満、子宮内膜症、前立腺肥大症、炎症などの予防及び/又は治療剤として有用である。本発明の化合物又はその塩は、種々の癌[例えば、固形癌(例えば、脳腫瘍、口腔癌、咽頭癌、喉頭癌、肺癌、消化器癌(食道癌、胃癌、大腸癌、肝臓癌、膵臓癌など)、泌尿器癌(腎臓癌、膀胱癌、前立腺癌など)、乳癌、子宮(頚)癌、卵巣癌、皮膚癌、甲状腺癌、骨肉腫など)、血液系癌(白血病、悪性リンパ腫など)など]の予防及び/又は治療剤として有用である。特に、本発明の化合物又はその塩は、悪性度の高い(又は難治性の)癌、例えば、脳腫瘍、口腔扁平上皮癌、肺癌、胃癌、大腸癌、肝臓癌、膀胱癌、前立腺癌(内分泌療法不応性前立腺癌など)、乳癌、子宮(頚)癌、卵巣癌、血液系癌などの予防及び/又は治療剤として有用である。このような癌の予防及び/又は治療剤は、癌の発生増殖(進展、再発、転移など)を防止するために好適に利用できる。
実施例1-1
ステップ1-1-1
4-フルオロ-3-ニトロ安息香酸エチルエステル
1H-NMR(DMSO-d6)δ:8.56(dd,J=2.3,7.3Hz,1H),8.35-8.31(m,1H),7.76-7.71(m,1H),4.37(q,J=7.3Hz,2H),1.35(t,J=7.3Hz,3H)。
Mass,m/z:213(M+),185,168(base)。
4-メチルアミノ-3-ニトロ安息香酸エチルエステル
1H-NMR(CDCl3)δ:8.87(d,J=1.9Hz,1H),8.33(brs,1H),8.08(dd,J=1.9,9.2Hz,1H),6.87-6.84(m,1H),4.35(q,J=6.9Hz,2H),3.08(d,J=5.0Hz,3H),1.38(t,J=6.9Hz,3H)。
Mass,m/z:224(M+),179,105(base)。
3-アミノ-4-メチルアミノ安息香酸エチルエステル
1H-NMR(CDCl3)δ:7.92(dd,J=1.9,8.5Hz,1H),7.40(d,J=1.9Hz,1H),6.58(d,J=8.5Hz,1H),4.31(q,J=7.3Hz,2H),3.99(brs,1H),3.22(brs,2H),2.19(s,3H),1.36(t,J=7.3Hz,3H)。
Mass,m/z:194(M+,base),149。
1-メチル-1H-ベンゾイミダゾール-5-カルボン酸エチルエステル
1H-NMR(CDCl3)δ:8.52(d,J=1.5Hz,1H),8.04(dd,J=1.5,8.5Hz,1H),7.92(s,1H),7.39(d,J=8.5Hz,1H),4.40(q,J=7.3Hz,2H),3.86(s,3H),1.41(t,J=7.3Hz,3H)。
Mass,m/z:204(M+),159(base)。
(1-メチル-1H-ベンゾイミダゾール-5-イル)メタノール
1H-NMR(CDCl3)δ:7.85(s,1H),7.77(s,1H),7.37-7.34(m,2H),4.80(s,2H),3.84(s,3H),1.92(brs,1H)。
Mass,m/z:162(M+),133(base)。
環形成成分としての40%メチルアミン-メタノール溶液、又は単環式化合物としての4-フルオロ-3-ニトロ安息香酸エチルエステルの代わりに、下記の表に示す化合物を用いる以外、実施例1-1と同様に操作することで、目的の二環式化合物を得た。
実施例2-1
ステップ2-1-1
1,2-ジメチル-1H-ベンゾイミダゾール-5-カルボン酸エチルエステル
1H-NMR(CDCl3)δ:8.39(d,J=1.5Hz,1H),7.98(dd,J=1.5,8.5Hz,1H),7.28(d,J=8.5Hz,1H),4.39(q,J=6.9Hz,2H),3.75(s,3H),2.62(s,3H),1.41(t,J=6.9Hz,3H)。
Mass,m/z:218(M+),173(base)。
(1,2-ジメチル-1H-ベンゾイミダゾール-5-イル)メタノール
1H-NMR(DMSO-d6)δ:7.44(d,J=0.7Hz,1H),7.39(d,J=8.5Hz,1H),7.14(dd,J=1.5,8.5Hz,1H),5.09(t,J=5.8Hz,1H),4.56(d,J=5.8Hz,2H),3.71(s,3H),2.50(s,3H)。
Mass,m/z:176(M+),147(base)。
環形成成分としての無水酢酸、又は単環式化合物としての3-アミノ-4-メチルアミノ安息香酸エチルエステルの代わりに、下記の表に示す化合物を用いる以外、実施例2-1と同様に操作することで、目的の二環式化合物を得た。
実施例3-1
ステップ3-1-1
3-ニトロ-4-ピペリジン-1-イル安息香酸エチルエステル
1H-NMR(DMSO-d6)δ:8.26(d,J=2.3Hz,1H),7.98(dd,J=2.3,8.9Hz,1H),7.31(d,J=9.2Hz,1H),4.30(q,J=7.3Hz,2H),3.13(brs,4H),1.60(brs,6H),1.31(t,J=7.3Hz,3H)。
Mass,m/z:278(M+),261(base)。
3-アミノ-4-ピペリジン-1-イル安息香酸エチルエステル
1H-NMR(CDCl3)δ:7.43(dd,J=2.3,8.1Hz,1H),7.38(d,J=2.3Hz,1H),6.95(d,J=8.1Hz,1H),4.32(q,J=7.3Hz,2H),3.95(brs,2H),2.95-2.80(m,4H),1.72-1.68(m,4H),1.61-1.57(m,2H),1.36(t,J=7.3Hz,3H)。
Mass,m/z:248(M+,base)。
1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピリジン-7-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:8.13(d,J=1.2Hz,1H),7.84(dd,J=1.5,8.1Hz,1H),7.57-7.54(m,1H),4.32(q,J=6.9Hz,2H),4.16-4.13(m,2H),3.02-2.98(m,2H),2.09-2.03(m,2H),1.98-1.92(m,2H),1.35(t,J=6.9Hz,3H)。
Mass,m/z:244(M+),199(base)。
(1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピリジン-7-イル)メタノール
1H-NMR(DMSO-d6)δ:7.45(d,J=0.7Hz,1H),7.37(d,J=8.1Hz,1H),7.13(dd,J=1.2,8.1Hz,1H),5.08(t,J=5.8Hz,1H),4.57(d,J=5.8Hz,2H),4.08-4.05(m,2H),2.96-2.93(m,2H),2.07-2.01(m,2H),1.96-1.90(m,2H)。
Mass,m/z:202(M+,base),185。
ピペリジンの代わりに、下記の表に示すN含有単環式化合物を用いる以外、実施例3-1と同様に操作することで、目的の三環式化合物を得た。
7-ヒドロキシメチル-1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピリジン-3-オール
1H-NMR(DMSO-d6)δ:7.45(s,1H),7.38(d,J=8.5Hz,1H),7.14(dd,J=1.2,8.1Hz,1H),5.62(d,J=3.5Hz,1H),5.08(t,J=5.8Hz,1H),4.57(d,J=5.8Hz,2H),4.29-4.23(m,1H),4.12-4.07(m,2H),3.13(dd,J=4.2,17.0Hz,1H),2.87(dd,J=5.4,17.0Hz,1H),2.18-1.91(m,2H)。
Mass,m/z:218(M+,base)。
実施例4-1
ステップ4-1-1
4-アミノ-3-メチル安息香酸エチルエステル
1H-NMR(CDCl3)δ:7.74(d,J=2.3Hz,1H),7.72(d,J=1.9Hz,1H),6.62(d,J=8.1Hz,1H),4.30(q,J=7.3Hz,2H),4.00(brs,2H),2.17(s,3H),1.35(t,J=7.3Hz,3H)。
Mass,m/z:179(M+),134(base)。
1H-インダゾール-5-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:13.38(s,1H),8.49(s,1H),7.92(dd,J=1.5,8.9Hz,1H),7.62(d,J=8.9Hz,1H),4.33(q,J=7.3Hz,2H),1.35(t,J=7.3Hz,3H)。
Mass,m/z:190(M+),145(base)。
1-メチル-1H-インダゾール-5-カルボン酸エチルエステルおよび2-メチル-2H-インダゾール-5-カルボン酸エチルエステル
4-1-3-A:1-メチル-1H-インダゾール-5-カルボン酸エチルエステル
1H-NMR(CDCl3)δ:8.51(d,J=1.5Hz,1H),8.08(d,J=1.2Hz,1H),8.07(dd,J=1.5,8.9Hz,1H),7.39(dd,J=0.8,8.9Hz,1H),4.40(q,J=6.9Hz,2H),4.10(s,3H),1.42(t,J=6.9Hz,3H)。
Mass,m/z:204(M+),159(base)。
4-1-3-B:2-メチル-2H-インダゾール-5-カルボン酸エチルエステル
1H-NMR(CDCl3)δ:8.48(s,1H),8.03(s,1H),7.90(dd,J=1.5,9.2Hz,1H),7.68(d,J=8.9Hz,1H),4.38(q,J=7.3Hz,2H),4.24(s,3H),1.40(t,J=7.3Hz,3H)。
Mass,m/z:204(M+),159(base)。
(1-メチル-1H-インダゾール-5-イル)メタノール
1H-NMR(CDCl3)δ:7.95(s,1H),7.69(s,1H),7.43-7.37(m,2H),4.78(d,J=5.8Hz,H),4.07(s,3H)。
Mass,m/z:162(M+,base)。
ステップ4-1-5
(2-メチル-2H-インダゾール-5-イル)メタノール
1H-NMR(DMSO-d6)δ:8.25(s,1H),7.57(d,J=1.5Hz,1H),7.53(d,J=8.9Hz,1H),7.18(dd,J=1.5,8.9Hz,1H),5.10(t,J=5.8Hz,1H),4.52(d,J=5.8Hz,2H),4.14(s,3H)。
Mass,m/z:162(M+,base)。
アルキル化成分としてのヨウ化メチル、又は単環式化合物としての4-アミノ-3-メチル安息香酸の代わりに、下記の表に示す化合物を用い、下記の表に示す製造方法に従って、目的の二環式化合物を得た。
実施例5-1
ステップ5-1-1
1-エチル-5-ベンゾトリアゾールカルボン酸エチルエステル
1H-NMR(CDCl3)δ:8.63(s,1H),8.10(dd,J=1.5,8.9Hz,1H),8.02(d,J=8.6Hz,1H),4.49(q,J=7.3Hz,2H),4.38(q,J=6.9Hz,2H),1.54(t,J=7.3Hz,3H),1.37(t,J=6.9Hz,3H)。
Mass,m/z:219(M+),118(base)。
(1-エチル-1H-ベンゾトリアゾール-5-イル)メタノール
1H-NMR(CDCl3)δ:8.00(d,J=1.2Hz,1H),7.52(t,J=1.2Hz,2H),4.85(d,J=3.1Hz,1H),4.68(q,J=7.3Hz,2H),1.62(t,J=7.3Hz,3H)。
Mass,m/z:177(M+),104(base)。
ステップ6-1-1
2,3-ジメチルキノキサリン-6-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:8.52(d,J=1.5Hz,1H),8.19(dd,J=1.9,8.5Hz,1H),8.07(d,J=8.5Hz,1H),4.40(q,J=6.9Hz,2H),2.72(s,3H),2.72(s,3H)。
Mass,m/z:230(M+),185(base)。
(2,3-ジメチルキノキサリン-6-イル)メタノール
1H-NMR(DMSO-d6)δ:8.31(s,1H),7.91(d,J=8.5Hz,1H),7.86(d,J=1.2Hz,1H),7.66(dd,J=1.9,8.5Hz,1H),6.29(brs,1H),4.71(d,J=5.8Hz,1H),2.67(s,3H),2.67(s,3H)。
Mass,m/z:188(M+),159(base)。
実施例7-1
ステップ7-1-1
4-クロロ-2-メトキシベンザミド
1H-NMR(DMSO-d6)δ:7.79(d,J=8.1Hz,1H),7.58(d,J=12.3Hz,1H),7.22(d,J=1.9Hz,1H),3.91(s,3H)。
Mass,m/z:187&185(M+),165(base)。
4-クロロ-2-メトキシチオベンザミド
1H-NMR(CDCl3)δ:8.89(brs,1H),8.60(d,J=8.5Hz,1H),7.96(brs,1H),7.04(dd,J=1.9,8.5Hz,1H),6.95(d,J=1.9Hz,1H),3.97(s,3H)。
Mass,m/z:201&203(M+),168(base)。
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:8.31(d,J=8.9Hz,1H),7.41(d,J=1.9Hz,1H),7.20(dd,J=1.9,8.5Hz,1H),4.31(q,J=7.3Hz,2H),4.09(s,3H),2.70(s,3H),1.32(t,J=7.3Hz,3H)。
Mass,m/z:311(M+),71(base)。
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸
1H-NMR(DMSO-d6)δ:8.29(d,J=8.5Hz,1H),7.38(d,J=1.9Hz,1H),7.19(dd,J=1.9,8.5Hz,1H),4.08(s,3H),2.67(s,3H)。
Mass,m/z:283&285(M+),144(base)。
カルボン酸成分としての4-クロロ-2-メトキシ安息香酸、又は環形成成分としての2-クロロアセト酢酸エチルエステルの代わりに、下記の表に示す化合物を用いる以外、実施例7-1と同様に操作することで、目的の化合物を得た。
2,4-ジメチルチアゾール-5-カルボン酸
1H-NMR(DMSO-d6)δ:13.13(brs,1H),2.62(s,3H),2.56(s,3H)。
Mass,m/z:157(M+,base)。
実施例8-1
ステップ8-1-1
4-(2,4-ジクロロフェニル)-2,4-ジオキソブチル酸エチルエステル
1H-NMR(DMSO-d6)δ:7.85-7.74(m,1H),7.70-7.62(m,1H),7.58-7.55(m,2H),6.53(brs,1H),4.29-4.21(m,2H),1.29-1.25(m,3H)。
Mass,m/z:288(M+),215(base)。
5-(2,4-ジクロロフェニル)-2-メチル-2H-ピラゾール-3-カルボン酸エチルエステルおよび5-(2,4-ジクロロフェニル)-1-メチル-1H-ピラゾール-3-カルボン酸エチルエステル
8-1-2-A:5-(2,4-ジクロロフェニル)-2-メチル-2H-ピラゾール-3-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:7.83(d,J=8.5Hz,1H),7.73(d,J=1.9Hz,1H),7.51(dd,J=1.9,8.5Hz,1H),7.31(s,1H),4.34(q,J=7.3Hz,2H),4.17(s,3H),1.33(t,J=7.3Hz,3H)。
Mass,m/z:298(M+),55(base)。
8-1-2-B:5-(2,4-ジクロロフェニル)-1-メチル-1H-ピラゾール-3-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:7.87(d,J=1.9Hz,1H),7.62-7.56(m,2H),6.86(s,1H),4.29(q,J=6.9Hz,2H),3.72(s,3H),1.30(t,J=6.9Hz,3H)。
Mass,m/z:298(M+),226(base)。
5-(2,4-ジクロロフェニル)-2-メチル-2H-ピラゾール-3-カルボン酸
1H-NMR(DMSO-d6)δ:13.54(brs,1H),7.83(d,J=8.5Hz,1H),7.72(d,J=2.3Hz,1H),7.51(dd,J=2.3,8.5Hz,1H),7.27(s,1H),4.16(s,3H)。
Mass,m/z:270(M+,base)。
5-(2,4-ジクロロフェニル)-1-メチル-1H-ピラゾール-3-カルボン酸
1H-NMR(DMSO-d6)δ:12.75(brs,1H),7.86(d,J=1.9Hz,1H),7.61-7.55(m,2H),6.80(s,1H),3.71(s,3H)。
Mass,m/z:270(M+,base)。
カルボニル化合物としての2’,4’-ジクロロアセトフェノン、又は環形成成分としてのメチルヒドラジンの代わりに、下記の表に示す化合物を用い、下記の表に示す製造方法に従って、目的の化合物を得た。
2,5-ジメチル-2H-ピラゾール-3-カルボン酸
1H-NMR(DMSO-d6)δ:13.16(brs,1H),6.58(s,1H),3.98(s,3H),2.16(s,3H)。
Mass,m/z:140(M+,base)。
実施例9-1
ステップ9-1
[2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-イル]カルバミン酸 1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピリジン-7-イルメチルエステル
1H-NMR(DMSO-d6)δ:10.08(brs,1H),8.16(d,J=8.5Hz,1H),7.62(s,1H),7.47(d,J=8.1Hz,1H),7.30(d,J=1.9Hz,1H),7.27(d,J=7.7Hz,1H),7.12(dd,J=1.9,8.5Hz,1H),5.29(s,2H),4.11-4.08(m,2H),4.02(s,3H),2.98-2.95(m,2H),2.31(s,3H),2.07-2.04(m,2H),1.97-1.92(m,2H)。
Mass,m/z:482(M+),438,280,202(base)。
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸又は(1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピリジン-7-イル)メタノールの代わりに、下記の表に示すカルボン酸又はヒドロキシ化合物を用いる以外、実施例9-1と同様に操作することで、目的の化合物を得た。
実施例10-1
ステップ10-1-1
1-(4-ブロモ-1-メチル-1H-ピロール-2-イル)-2,2,2-トリクロロエタノン
1H-NMR(DMSO-d6)δ:7.66(d,J=1.5Hz,1H),7.43(d,J=1.5Hz,1H),3.91(s,3H)。
4-ブロモ-1-メチル-1H-ピロール-2-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:7.28(d,J=2.3Hz,1H),6.85(d,J=1.9Hz,1H),4.21(q,J=7.3Hz,2H),3.84(s,3H),1.27(t,J=7.3Hz,3H)。
Mass,m/z:231(M+)。
4-(4-クロロ-2-メトキシフェニル)-1-メチル-1H-ピロール-2-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:7.59-7.56(m,2H),7.25(d,J=2.3Hz,1H),7.11(d,J=1.9Hz,1H),6.98(dd,J=1.9,8.1Hz,1H),4.24(q,J=7.3Hz,2H),3.89(s,3H),3.89(s,3H),1.30(t,J=7.3Hz,3H)。
Mass,m/z:293(M+.base)。
[4-(4-クロロ-2-メトキシフェニル)-1-メチル-1H-ピロール-2-イル]カルバミン酸 4-メトキシベンジルエステル
1H-NMR(DMSO-d6)δ:9.00(brs,1H),7.45(d,J=8.1Hz,1H),7.35(d,J=6.6Hz,2H),7.12(d,J=1.9Hz,1H),6.95-6.93(m,3H),6.25(s,1H),5.05(s,2H),3.86(s,3H),3.76(s,3H),3.41(s,3H)。
Mass,m/z:400(M+),356,235,121(base)。
[4-(4-クロロ-2-メトキシフェニル)-1-メチル-1H-ピロール-2-イル]カルバミン酸 1-メチル-1H-ベンゾイミダゾール-5-イルメチルエステル
1H-NMR(DMSO-d6)δ:9.04(brs,1H),8.20(s,1H),7.75-7.65(m,1H),7.58(d,J=8.1Hz,1H),7.45(d,J=8.5Hz,1H),7.33(d,J=6.6Hz,1H),7.13(d,J=1.9Hz,1H),7.04(d,J=1.9Hz,1H),6.94(dd,J=1.9,8.5Hz,1H),6.26(s,1H),5.23(s,3H),3.86(s,3H),3.84(s,3H),3.42(s,3H)。
Mass,m/z:424(M+),380,262,145(base)。
実施例11-1
ステップ11-1
1-メチル-1H-ベンゾイミダゾール-5-カルボン酸
1H-NMR(DMSO-d6)δ:12.74(brs,1H),8.33(s,1H),8.29(s,1H),7.90(dd,J=1.5,8.5Hz,1H),7.65(d,J=8.5Hz,1H),3.88(s,3H)。
Mass,m/z:176(M+,base),159。
1-メチル-1H-ベンゾイミダゾール-5-カルボン酸エチルエステルの代わりに、下記の表に示す製造方法Aに基づいて得られたエステル化合物を用いる以外、実施例11-1と同様に操作することで、目的の化合物を得た。
実施例12-1
ステップ12-1
[2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-イル]メタノール
1H-NMR(DMSO-d6)δ:8.21(d,J=8.5Hz,1H),7.32(d,J=1.2Hz,1H),7.14(dd,J=1.5,8.5Hz,1H),5.44(t,J=5.4Hz,1H),4.65(d,J=5.4Hz,1H),4.03(s,3H),2.35(s,3H)。
Mass,m/z:269(M+,base),130。
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸の代わりに、下記の表に示す実施例のカルボン酸を用いる以外、実施例12-1と同様に操作することで、目的の化合物を得た。
[5-(2-メトキシ-4-メチルフェニル)-1-メチル-1H-ピラゾール-3-イル]メタノール
1H-NMR(DMSO-d6)δ:7.11(d,J=7.7Hz,1H),6.98(s,1H),6.85(d,J=7.3Hz,1H),6.12(s,1H),4.94(t,J=5.8Hz,1H),4,39(d,J=5.8Hz,2H),3.78(s,3H),3.54(s,3H),2.37(s,3H)。
Mass,m/z:232(M+,base)。
1-エチル-[5-(4-フルオロ-2-メトキシフェニル)-1H-ピラゾール-3-イル]メタノール
1H-NMR(DMSO-d6)δ:7.25(dd,J=6.9,8.5Hz,1H),7.07(dd,J=2.3,11.2Hz,1H),6.87(dt,J=2.3,8.5Hz,1H),6.11(s,1H),5.00(brs,1H),4,41(d,J=4.2Hz,2H),3,79(s,3H),3.78(q,J=7.3Hz,2H),1.22(t,J=7.3Hz,3H)。
Mass,m/z:250(M+,base)。
1-エチル-[5-(2-メトキシフェニル)-1H-ピラゾール-3-イル]メタノール
1H-NMR(DMSO-d6)δ:7.45(dt,J=1.9,7.7Hz,1H),7.22(dd,J=1.9,7.7Hz,1H),7.15(d,J=8.1Hz,1H),7.06-7.02(m,1H),6.12(s,1H),4.97(t,J=5.8Hz,1H),4,42(d,J=5.4Hz,2H),3,80(q,J=7.3Hz,2H),3.78(s,3H),1.22(t,J=7.3Hz,3H)。
Mass,m/z:232(M+,base)。
[5-(4-クロロ-2-メトキシフェニル)-1-エチル-1H-ピラゾール-3-イル]メタノール
1H-NMR(DMSO-d6)δ:7.25-7.23(m,2H),7.11(dd,J=1.9,8.1Hz,1H),6.13(s,1H),4.98(t,J=5.8Hz,1H),4,41(d,J=5.8Hz,2H),3,82-3.77(m,5H),1.22(t,J=7.3Hz,3H)。
Mass,m/z:266(M+,base)。
1-エチル-[5-(2-メトキシ-4-メチルフェニル)-1H-ピラゾール-3-イル]メタノール
1H-NMR(DMSO-d6)δ:7.08(d,J=7.7Hz,1H),6.97(s,1H),6.85(dd,J=0.8,7.3Hz,1H),6.08(s,1H),4.95(t,J=5.8Hz,1H),4,40(d,J=5.8Hz,2H),3.82-3.76(m,2H),3.76(s,3H),2.37(s,3H),1.21(t,J=7.3Hz,3H)。
Mass,m/z:246(M+,base)。
[5-(2,4-ジメチルフェニル)-1-メチル-1H-ピラゾール-3-イル]メタノール
1H-NMR(DMSO-d6)δ:7.17(s,1H),7.11(s,2H),6.14(s,1H),4.97(t,J=5.8Hz,1H),4,41(d,J=5.8Hz,2H),3.51(s,3H),2.33(s,3H),2.10(s,3H)。
Mass,m/z:216(M+,base)。
実施例13-1
ステップ13-1
(1-メチル-1H-ベンゾイミダゾール-5-イル)カルバミン酸 4-メチル-2-(2-メチルフェニル)チアゾール-5-イルメチルエステル
1H-NMR(DMSO-d6)δ:9.71(brs,1H),8.11(s,1H),7.81(s,1H),7.72(d,J=7.3Hz,1H),7.46(d,J=8.5Hz,1H),7.40-7.35(m,2H),7.33-7.29(m,2H),5.34(s,2H),3.80(s,3H),2.54(s,3H),2.50(s,3H)。
Mass,m/z:348(M+-44),173(base)。
[2-(2-メチルフェニル)-4-メチルチアゾール-5-イル]メタノール又は1-メチル-1H-ベンゾイミダゾール-5-カルボン酸の代わりに、下記の表に示す公知の又は実施例で得られたヒドロキシ化合物又はカルボン酸を用いる以外、実施例13-1と同様に操作することで、目的の化合物を得た。
実施例14-1
ステップ14-1-1
4-メトキシ安息香酸 N-メチルヒドラジド
1H-NMR(CDCl3)δ:7.54(d,J=8.9Hz,2H),7.45(d,J=8.1Hz,2H),3.83(s,3H),3.24(s,3H)。
Mass,m/z:180(M+),135(base)。
N-(4-メトキシベンジル)-N-メチルヒドラジン
1H-NMR(CDCl3)δ:7.70(d,J=8.5Hz,2H),7.23(d,J=8.5Hz,2H),3.80(s,3H),3.56(s,2H),2.49(s,3H)。
Mass,m/z:166(M+),121(base)。
N-エチル-N-(4-メトキシベンジル)ヒドラジン
1H-NMR(CDCl3)δ:7.24(d,J=8.1Hz,2H),6.87(d,J=8.9Hz,2H),3.80(s,3H),3.61(s,2H),2.59(q,J=7.3Hz,2H),1.15(t,J=7.3Hz,3H)。
Mass,m/z:180(M+),121(base)。
4-メトキシベンゾイルクロリドの代わりに、下記の表に示す酸クロリド成分を用いる以外、実施例14-1と同様に操作することで、目的の化合物を得た。
実施例15-1
ステップ15-1-1
2-{[1-(4-メトキシ-3-メチルフェニル)-メチリデン]アミノ}イソインドール-1,3-ジオン
1H-NMR(CDCl3)δ:9.19(s,1H),7.90(dd,J=3.1Hz,5.4Hz,2H),7.77(brs,1H),7.76(dd,J=3.1Hz,5.4Hz,2H),7.64(dd,J=2.3Hz,8.5Hz,1H),6.87(d,J=8.5Hz,1H),3.89(s,3H),2.26(s,3H)。
Mass,m/z:294(M+),147(base)。
2-(4-メトキシ-3-メチルベンジルアミノ)イソインドール-1,3-ジオン
1H-NMR(CDCl3)δ:7.83(dd,J=3.1Hz,5.4Hz,2H),7.72(dd,J=3.1Hz,5.4Hz,2H),7.23~7.20(m,2H),6.76(d,J=8.9Hz,1H),4.68(brd,J=5.0Hz,1H),4.10(d,J=5.0Hz,2H),3.80(s,3H),2.19(s,3H)。
Mass,m/z:296(M+),135(base)。
2-[(4-メトキシ-3-メチルベンジル)メチルアミノ]イソインドール-1,3-ジオン
1H-NMR(CDCl3)δ:7.74(dd,J=3.1Hz,5.4Hz,2H),7.66(dd,J=3.1Hz,5.4Hz,2H),7.16~7.12(m,2H),6.66(d,J=8.8Hz,1H),4.31(s,2H),3.74(s,3H),3.06(s,3H),2.11(s,3H)。
Mass,m/z:310(M+),135(base)。
N-(4-メトキシ-3-メチルベンジル)-N-メチルヒドラジン
1H-NMR(CDCl3)δ:7.12~7.08(m,2H),6.78(d,J=8.5Hz,1H),3.82(s,3H),3.57(s,2H),3.27(brs,2H),2.52(s,3H),2.20(s,3H)。
Mass,m/z:180(M+),135(base)。
2-メトキシ-5-(N-メチルヒドラジノメチル)フェノール
1H-NMR(CDCl3)δ:6.91(d,J=1.5Hz,1H),6.81~6.79(m,2H),3.88(s,3H),3.53(s,2H),2.49(s,3H)。
Mass,m/z:182(M+),137(base)。
実施例16-1
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸 N’-(4-メトキシベンジル)-N’-メチルヒドラジド
1H-NMR(DMSO-d6)δ:9.17,8.81(two s,1H),8.29,8.25(two d,J=8.1Hz,1H),7.37(brs,1H),7.29(d,J=8.5Hz,2H),7.18(dd,J=2.0Hz,8.5Hz,1H),6.86(d,J=8.5Hz,2H),4.07(s,3H),3.91~3.79(m,2H),3.72(s,3H),2.63,2.60(two s,3H),2.53,2.41(two s,3H)。
Mass,m/z:431(M+),121(base)。
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸又はN-(4-メトキシベンジル)-N-メチルヒドラジンの代わりに、下記の表に示すカルボン酸又はヒドラジン化合物を用いる以外、実施例16-1と同様に操作することで、目的の化合物を得た。
実施例17-1
ステップ17-1
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸 N’-(1-メチル-1H-インドール-5-イルメチル)ヒドラジド
1H-NMR(DMSO-d6)δ:7.78(d,J=8.5Hz,1H),7.53(s,1H),7.50(s,1H),7.42~7.34(m,2H),7.30(d,J=3.1Hz,1H),7.19(brd,J=8.5Hz,1H),6.39(d,J=2.7Hz,1H),4.04,3.90(two d,J=5.8Hz,2H),3.78,3.76(two s,3H),2.64,2.55(two s,6H)。
Mass,m/z:424(M+),144(base)。
ステップ17-2
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸 N’-メチル-N’-(1-メチル-1H-インドール-5-イルメチル)ヒドラジド
1H-NMR(DMSO-d6)δ:9.21,8.89(two s,1H),7.80(d,J=8.5Hz,1H),7.50(brs,2H),7.42(dd,J=1.6Hz,8.5Hz,1H),7.31(d,J=8.5Hz,1H),7.28(d,J=3.1Hz,1H),7.15(brd,J=8.5Hz,1H),6.35(d,J=2.7Hz,1H),4.03,3.92(two s,2H),3.75(s,3H),2.64,2.57(two s,3H),2.56,2.42(two s,3H),2.53(s,3H)。
Mass,m/z:438(M+),144(base)。
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸 N’-(4-ヒドロキシ-3,5-ジメチルベンジル)ヒドラジド
1H-NMR(DMSO-d6)δ:8.27(d,J=8.5Hz,1H),8.09(s,1H),7.38(brs,1H),7.18(dd,J=1.6Hz,8.5Hz,1H),6.91(s,2H),4.07,3.97(two s,3H),3.79(d,J=3.8Hz,2H),2.60,2.54(two s,3H),2.16,2.12(two s,6H)。
Mass,m/z:431(M+),135(base)。
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸 N’-(4-ヒドロキシ-3,5-ジメチルベンジル)-N’-メチルヒドラジド
1H-NMR(DMSO-d6)δ:9.14,8.71(two s,1H),8.29,8.26(two d,J=8.5Hz,1H),8.09,8.07(two s,1H),7.38(d,J=1.5Hz,1H),7.18(dd,J=1.9Hz,8.5Hz,1H),6.91,6.82(two s,2H),4.07,4.03(two s,3H),3.79,3.68(two s,2H),2.59,2.55(two s,3H),2.55,2.46(two s,3H),2.14,2.05(two s,6H)。
Mass,m/z:445(M+),135(base)。
実施例18-1
ステップ18-1-1
4-(4-クロロ-2-メトキシフェニル)-2,4-ジオキソ酪酸メチル
1H-NMR(CDCl3)δ:15.21(s,1H),7.85(d,J=8.7Hz,1H),7.04(dd,J=1.9,8.2Hz,1H),6.99(d,J=1.9Hz,1H),3.95(s,3H),3.92(s,3H)。
Mass,m/z:270(M+),211,169(base)。
5-(4-クロロ-2-メトキシフェニル)-2H-ピラゾール-3-カルボン酸メチル
1H-NMR(DMSO-d6)δ:14.14 and 13.64(two s,1H),7.94 and 7.76(two d,J=8.5Hz,1H),7.26 and 7.23(two d,J=1.9Hz,1H),7.21 and 7.16(two d,J=2.3Hz,1H),7.13 and 7.08(two dd,J=1.9,8.5Hz,1H),3.95 and 3.93(two s,3H),3.87 and 3.83(two s,3H)。
Mass,m/z:266(M+)(base),235,178,148,115。
5-(4-クロロ-2-メトキシフェニル)-2H-ピラゾール-3-カルボン酸
1H-NMR(DMSO-d6)δ:7.83(d,J=6.9Hz,1H),7.22(d,J=1.5Hz,1H),7.10(dd,J=1.9,7.5Hz,1H),3.93(s,3H)。
Mass,m/z:252(M+)(base)。
5-(4-クロロ-2-メトキシフェニル)-2H-ピラゾール-3-カルボン酸 N’-(4-メトキシベンジル)-N’-メチルヒドラジド
1H-NMR(DMSO-d6)δ:13.58 and 13.27(two brs,1H),9.44 and 8.90(two brs,1H), 7.89 and 7.69(two d,J=8.5Hz,1H),7.29(d,J=8.5Hz,2H),7.24(s,1H),7.19 and 6.97(two s,1H),7.12 and 7.05(two d,J=8.5Hz,1H),6.85(d,J=8.5Hz,2H),3.92(s,5H),3.72(s,3H),2.65 and 2.61(two s,3H)。
Mass,m/z:400(M+),385,235,150,121(base)。
5-(4-クロロ-2-メトキシフェニル)-2H-ピラゾール-3-カルボン酸 N’-エチル-N’-(4-メトキシベンジル)ヒドラジド
1H-NMR(DMSO-d6)δ:13.55 and 13.26(two brs,1H),9.20 and 8.63(two brs,1H), 7.89 and 7.69(two d,J=8.1Hz,1H),7.30(d,J=8.5Hz,2H),7.24(s,1H),7.19 and 6.96(two s,1H),7.12 and 7.06(two d,J=8.5Hz,1H),6.84(d,J=8.5Hz,2H),3.94(s,2H),3.92(s,3H),3.71(s,3H),2.96-2.81(m,2H),1.02(brt,J=6.9Hz,3H)。
Mass,m/z:414(M+),399,235,164,121(base)。
実施例19-1
3-(4-クロロ-2-メトキシフェニル)イソチアゾール-5-カルボン酸 N’-(4-メトキシベンジル)-N’-メチルヒドラジド
1H-NMR(CDCl3)δ:8.47(s,1H),7.96(d,J=8.1Hz,1H),7.28(d,J=8.5Hz,2H),7.04(dd,J=1.9,8.1Hz,1H),6.99(d,J=1.9Hz,1H),6.89(d,J=8.9Hz,2H),6.49(s,1H),3.96(d,J=13.1Hz,1H),3.91(s,3H),3.88(d,J=12.7Hz,1H),3.80(s,3H),2.63(s,3H)。
Mass,m/z:417(M+),149,121(base)。
3-(4-クロロ-2-メトキシフェニル)イソチアゾール-5-カルボン酸 N’-(4-メトキシベンジル)-N’-エチルヒドラジド
1H-NMR(CDCl3)δ:8.48(s,1H),7.97(d,J=8.5Hz,1H),7.26(d,J=8.5Hz,2H),7.04(dd,J=1.9,8.5Hz,1H),6.99(d,J=1.9Hz,1H),6.88(d,J=8.9Hz,2H),6.32(s,1H),3.99(d,J=13.1Hz,1H),3.93(d,J=12.7Hz,1H),3.92(s,3H),3.79(s,3H),3.05-2.96(m,1H),2.68-2.59(m,1H),1.17(t,J=7.3Hz,3H)。
Mass,m/z:431(M+),163,121(base)。
実施例20-1
ステップ20-1-1
2-[2-(2-メトキシフェニル)-2-オキソエチル-3-オキソブチル酸エチルエステル
1H-NMR(CDCl3)δ:7.75(dd,J=1.5,7.7Hz,1H),7.47(ddd,J=1.5,7.3,9.2Hz,1H),7.01~6.96(m,2H),4.21(q,J=7.3Hz,2H),4.17(dd,J=5.8,8.1Hz,1H),3.70(dd,J=8.1,9.3Hz,1H),3.55(dd,J=5.8,8.5Hz,1H),2.40(s,3H),1.28(t,J=7.3Hz,3H)。
Mass,m/z:278(m+),135(base)。
5-(2-メトキシフェニル)-2-メチルフラン-3-カルボン酸エチルエステル
1H-NMR(CDCl3)δ:7.80(dd,J=1.9,7.7Hz,1H),7.27~7.22(m,1H),7.13(s,1H),7.03~6.95(m,2H),4.32(q,J=6.9Hz,2H),3.95(s,3H),2.64(s,3H),1.37(t,J=6.9Hz,3H)。
Mass,m/z:260(m+),231(base)。
5-(2-メトキシフェニル)-2-メチルフラン-3-カルボン酸
1H-NMR(CDCl3)δ:7.81(dd,J=1.5,7.7Hz,1H),7.28~7.24(m,1H),7.18(s,1H),7.01(dt,J=1.2,7.7Hz,1H),6.97(d,J=8.5Hz,1H),3.95(s,3H),2.68(s,3H)。
Mass,m/z:232(m+,base)。
5-(2-メトキシフェニル)-2-メチルフラン-3-カルボン酸 N’-(4-メトキシベンジル)-N’-メチルヒドラジド
1H-NMR(CDCl3)δ:7.79(d,J=5.8Hz,1H),7.29~7.21(m,2H),7.19(d,J=8.9Hz,2H),7.03~6.85(m,2H),6.85(d,J=8.9Hz,2H),3.94(s,2H),3.81(s,3H),3.79(s,3H),2.99,2.76(two s,3H),2.60(s,3H)。
Mass,m/z:380(m+),121(base)。
5-(2,4-ジクロロフェニル)-2-メチルフラン-3-カルボン酸 N’-(4-メトキシベンジル)-N’-メチルヒドラジド
1H-NMR(CDCl3)δ:7.75(d,J=8.5Hz,1H),7.44(s,1H),7.29(d,J=8.5Hz,2H),7.25~7.18(m,1H),6.87(d,J=8.5Hz,2H),4.03(s,2H),3.81(s,3H),3.79(s,3H),2.95,2.87(two s,3H),2.58(s,3H)。
Mass,m/z:418(m+),121(base)。
5-(2,4-ジクロロフェニル)-2-メチルフラン-3-カルボン酸 N’-(4-メトキシ-3,5-ジメチルベンジル)-N’-メチルヒドラジド
1H-NMR(CDCl3)δ:7.76(d,J=8.5Hz,1H),7.45(s,1H),7.35~7.23(m,1H),6.99(s,2H),3.97(s,2H),3.71(s,3H),2.74,2.59(two s,3H),2.50(s,3H),2.69(s,6H)。
Mass,m/z:446(m+),149(base)。
実施例21-1
ステップ21-1-1
5-(2,4-ジクロロフェニル)-2H-ピラゾール-3-カルボン酸ヒドラジド
1H-NMR(DMSO-d6)δ:13.88(brs,1H),9.85 and 9.44(two brs,1H),7.90-7.60(m,2H),7.52(s,1H),7.38(s,1H),4.50(brs,2H)。
Mass,m/z:270(M+),239(base)。
5-(2,4-ジクロロフェニル)-2H-ピラゾール-3-カルボン酸[1-(2,4-ジヒドロキシフェニル)メチリデン]ヒドラジド
1H-NMR(DMSO-d6)δ:14.15 and 13.84(two brs,1H),11.92(brs,1H),11.57 and 11.14(two brs,1H),9.93(s,1H),8.58 and 8.53(s,1H),7.98-7.07(m,5H),6.37(dd,J=1.6,8.5Hz,1H),6.32(s,1H)。
Mass,m/z:390(M+),239(base)。
2,4-ジヒドロキシベンズアルデヒド又は5-(2,4-ジクロロフェニル)-2H-ピラゾール-3-カルボン酸の代わりに、下記の表に示すカルボニル化合物又はカルボン酸を用いる以外、実施例21-1と同様に操作することで、目的の化合物を得た。
実施例22-1
ステップ22-1-1
4-(2-クロロフェニル)-2,4-ジオキソ酪酸メチルエステル
Mass,m/z:240(M+),181(base)。
5-(2-クロロフェニル)-2H-ピラゾール-3-カルボン酸メチルエステル
Mass,m/z:236(M+),148(base)。
5-(2-クロロフェニル)-2H-ピラゾール-3-カルボン酸ヒドラジド
1H-NMR(DMSO-d6)δ:13.67(brs,1H),9.79(brs,1H),7.74(s,1H),7.60(d,J=6.2Hz,1H),7.50-7.00(m,3H),4.47(brs,2H)。
Mass,m/z:236(M+),205(base)。
5-(2-クロロフェニル)-2H-ピラゾール-3-カルボン酸[1-(3-ヒドロキシ-4-メトキシフェニル)メチリデン]ヒドラジド
1H-NMR(DMSO-d6)δ:14.04( and 13.74(two s,1H),11.73 and 11.55(two s,1H),9.30 and 9.27(two s,1H),8.39 and 8.30(two s,1H),7.73-7.60(m,1H),7.60-7.36(m,3H),7.32-7.24(m,1H),7.14-6.95(m,3H),3.82 and 3.81(two s,3H)。
Mass,m/z:370(M+),205(base)。
3-ヒドロキシ-4-メトキシベンズアルデヒド又は1-(2-クロロフェニル)エタノンの代わりに、下記の表に示すアルデヒド化合物又はケトン化合物を用いる以外、実施例22-1と同様に操作することで、目的の化合物を得た。
実施例23-1
ステップ23-1-1
2-(2,4-ジクロロフェニル)-4-メチルチアゾール-5-カルボン酸エチルエステル
1H-NMR(CDCl3)δ:8.08(d,J=1.9Hz,1H),7.76(dd,J=2.0,8.5Hz,1H),7.51(d,J=8.1Hz,1H),4.35(q,J=7.3Hz,2H),1.38(t,J=7.3Hz,3H)。
Mass,m/z:315(M+),71(base)。
2-(2,4-ジクロロフェニル)-4-メチルチアゾール-5-カルボン酸ヒドラジド
1H-NMR(DMSO-d6)δ:9.62(brs,1H),8.13(d,J=1.9Hz,1H),7.89(dd,J=2.3,8.5Hz,1H),7.78(d,J=8.5Hz,1H),4.56(brs,2H),2.60(s,3H)。
Mass,m/z:301(M+),71(base)。
2-(2,4-ジクロロフェニル)-4-メチルチアゾール-5-カルボン酸[1-(3-ヒドロキシ-4-メトキシフェニル)メチリデン]ヒドラジド
1H-NMR(DMSO-d6)δ:11.74(s,1H),9.39(s,1H),8.21(s,1H),8.00(d,J=7.3Hz,1H),7.99(s,1H),7.82(d,J=8.5Hz,1H),7.31(s,1H),7.09(dd,J=1.5,8.5Hz,1H),7.00(d,J=8.5Hz,1H),3.82(s,3H),2.77(s,3H)。
Mass,m/z:435(M+),71(base)。
チオアミド化合物としての2,4-ジクロロチオベンズアミド、アルデヒド化合物としての3-ヒドロキシ-4-メトキシベンズアルデヒド、又は環形成成分としての2-クロロアセト酢酸エチルの代わりに、下記の表に示す化合物を用いる以外、実施例23-1と同様に操作することで、目的の化合物を得た。
5-(4-クロロフェニル)-2-メチルフラン-3-カルボン酸 [1-(3-ヒドロキシ-4-メトキシフェニル)メチリデン]ヒドラジド
1H-NMR(DMSO-d6)δ:11.29(s,1H),9.28(s,1H),8.25(s,1H),7.67(d,J=8.1Hz,2H),7.53(d,J=8.5Hz,2H),7.36(s,1H),7.26(brs,1H),7.06(d,J=8.1Hz,1H),6.98(d,J=8.5Hz,1H),3.82(s,3H),2.63(s,3H)。
Mass,m/z:384(M+),219(base)。
5-(4-クロロフェニル)-2-メチルフラン-3-カルボン酸 [1-(4-ヒドロキシ-3,5-ジメチルフェニル)メチリデン]ヒドラジド
1H-NMR(DMSO-d6)δ:11.26(s,1H),8.71(s,1H),8.22(s,1H),7.68(d,J=8.1Hz,2H),7.53(d,J=8.9Hz,2H),7.36(s,1H),7.30(s,2H),2.62(s,3H),2.21(s,6H)。
Mass,m/z:382(M+),219(base)。
4-(4-クロロ-2-メトキシフェニル)-1-メチル-1H-ピロール-2-カルボン酸 (4-メトキシベンジリデン)ヒドラジド
1H-NMR(DMSO-d6)δ:11.37(brs,1H),8.31(brs,1H),7.65(d,J=8.9Hz,2H),7.52(s,1H),7.39(s,1H),7.12(d,J=1.9Hz,1H),7.06~7.01(m,3H),3.91(s,6H),3.82(s,3H)。
Mass,m/z:397(m+),248(base)。
4-(4-クロロ-2-メトキシフェニル)-1-メチル-1H-ピロール-2-カルボン酸 (4-ヒドロキシ-3,5-ジメチルベンジリデン)ヒドラジド
1H-NMR(DMSO-d6)δ:11.29(brs,1H),8.67(s,1H),8.19(s,1H),7.51(d,J=2.7Hz,1H),7.28(s,2H),7.12(d,J=2.3Hz,2H),7.03(dd,J=2.3,8.5Hz,1H),3.91(s,3H),2.21(s,3H)。
Mass,m/z:411(m+),248(base)。
4-(4-クロロ-2-メトキシフェニル)-1-メチル-1H-ピロール-2-カルボン酸 (3-ヒドロキシ-4-メトキシベンジリデン)ヒドラジド
1H-NMR(DMSO-d6)δ:11.31(brs,1H),9.24(s,1H),8.22(s,1H),7.52(s,1H),7.37(s,1H),7.24(d,J=1.5Hz,1H),7.12(d,J=1.9Hz,1H),7.04(d,J=2.3Hz,1H),7.02(d,J=1.9Hz,1H),6.98(d,J=8.5Hz,1H),3.91(s,6H),3.81(s,3H)。
Mass,m/z:413(m+),248(base)。
実施例24-1
ステップ24-1-1
4-ブロモ-1H-ピロール-2-カルボン酸エチル
1H-NMR(CDCl3)δ:9.16(brs,1H),6.93(dd,J=1.5,2.7Hz,1H),6.89(dd,J=1.5,2.7Hz,1H),4.31(q,J=6.9Hz,2H),1.35(t,J=6.9Hz,3H)。
Mass,m/z:217(M+),189,173(base)。
4-ブロモピロール-1,2-ジカルボン酸 1-tert-ブチルエステル 2-エチルエステル
1H-NMR(CDCl3)δ:7.29(d,J=1.9Hz,1H),6.78(d,J=1.9Hz,1H),4.29(q,J=7.3Hz,2H),1.57(s,9H),1.34(t,J=7.3Hz,3H)。
Mass,m/z:317(M+),297,217,57(base)。
4-(2,3-ジメチルフェニル)-1H-ピロール-2-カルボン酸エチル
1H-NMR(DMSO-d6)δ:11.98(brs,1H),7.12-7.03(m,4H),6.84(dd,J=1.5,2.7Hz,1H),4.26(q,J=6.9Hz,2H),2.27(s,3H),2.24(s,3H),1.30(t,J=6.9Hz,3H)。
Mass,m/z:243(M+)(base),197,129。
4-(2,3-ジメチルフェニル)-1H-ピロール-2-カルボン酸ヒドラジド
1H-NMR(DMSO-d6)δ:11.56(brs,1H),9.29(brs,1H),7.09-7.03(m,3H),6.92(dd,J=1.5,2.7Hz,1H),6.87(s,1H),4.32(d,J=3.9Hz,2H),2.27(s,3H),2.24(s,3H)。
Mass,m/z:229(M+),198(base)。
4-(2,3-ジメチルフェニル)-1H-ピロール-2-カルボン酸[1-(4-ヒドロキシ-3,5-ジメチルフェニル)メチリデン]ヒドラジド
1H-NMR(DMSO-d6)δ:11.81(brs,1H),11.25(s,1H),8.68(s,1H),8.20(brs,1H),7.30(s,2H),7.20-6.97(m,5H),2.30(s,6H),2.21(s,6H)。
Mass,m/z:361(M+),164(base)。
4-(4-クロロフェニル)-1H-ピロール-2-カルボン酸 [1-(3-ヒドロキシ-4-メトキシフェニル)メチリデン]ヒドラジド
1H-NMR(DMSO-d6)δ:11.93(s,1H),11.35(s,1H),9.27(s,1H),8.22(s,1H),7.60(d,J=8.1Hz,2H),7.49(dd,J=1.5,2.7Hz,1H),7.40(d,J=8.5Hz,2H),7.27(brd,J=1.2Hz,1H),7.06(dd,J=1.9,8.5Hz,1H),6.99(d,J=8.5Hz,1H),3.82(s,3H)。
Mass,m/z:369(M+),166(base)。
4-(4-クロロフェニル)-1H-ピロール-2-カルボン酸 [1-(4-ヒドロキシ-3,5-ジメチルフェニル)メチリデン]ヒドラジド
1H-NMR(DMSO-d6)δ:11.92(s,1H),11.31(s,1H),8.69(s,1H),8.19(s,1H),7.60(d,J=8.5Hz,2H),7.49(s,1H),7.40(d,J=8.9Hz,2H),7.31(s,3H),2.22(s,6H)。
Mass,m/z:367(M+),164(base)。
実施例25-1
ステップ25-1-1
2-(4-クロロフェニル)-1H-イミダゾール-4-カルボン酸ヒドラジド
1H-NMR(CDCl3)δ:7.75(d,J=8.9Hz,2H),7.44(d,J=8.5Hz,2H),7.01(s,1H),4.03(brs,2H)。
Mass,m/z:236(M+),205(base)。
2-(4-クロロフェニル)-3H-イミダゾール-4-カルボン酸 [1-(3-ヒドロキシ-4-メトキシフェニル)メチリデン]ヒドラジド
1H-NMR(CDCl3)δ:13.18(brs,1H),11.18(s,1H),9.26(s,1H),8.40(s,1H),8.06(d,J=8.5Hz,2H),7.95(s,1H),7.59(d,J=8.9Hz,2H),7.26(s,1H),7.04(dd,J=1.9,8.5Hz,1H),6.98(d,J=8.9Hz,1H),3.81(s,3H)。
Mass,m/z:370(M+),166(base)。
2-(2-メチルフェニル)-3H-イミダゾール-4-カルボン酸 [1-(4-ヒドロキシ-3,5-ジメチルフェニル)メチリデン]ヒドラジド
1H-NMR(CDCl3)δ:12.76(brs,1H),11.05(s,1H),8.66(s,1H),8.34(s,1H),7.90(s,1H),7.59(d,J=7.3Hz,1H),7.35-7.27(m,5H),2.50(s,6H),2.21(s,3H)。
Mass,m/z:348(M+),164(base)。
2-(2-メチルフェニル)-3H-イミダゾール-4-カルボン酸 [1-(3-ヒドロキシ-4-メトキシフェニル)メチリデン]ヒドラジド
1H-NMR(CDCl3)δ:12.78(brs,1H),11.09(s,1H),9.25(s,1H),8.38(s,1H),7.91(s,1H),7.59(d,J=6.9Hz,1H),7.35-7.25(m,4H),7.03-6.96(m,2H),3.81(s,3H),2.53(s,3H)。
Mass,m/z:350(M+),164(base)。
2-(2-メチルフェニル)-3H-イミダゾール-4-カルボン酸 [1-(4-ヒドロキシ-3-メチルフェニル)メチリデン]ヒドラジド
1H-NMR(CDCl3)δ:12.76(brs,1H),11.04(s,1H),9.75(s,1H),8.37(s,1H),7.90(s,1H),7.59(d,J=7.3Hz,1H),7.44(s,1H),7.35-7.30(m,3H),6.84(d,J=8.1Hz,1H),2.53(s,3H),2.16(s,3H)。
Mass,m/z:334(M+),185(base)。
2-(4-クロロフェニル)-3H-イミダゾール-4-カルボン酸 [1-(3-ヒドロキシ-4-メトキシフェニル)メチリデン]ヒドラジド
1H-NMR(CDCl3)δ:12.88(brs,1H),11.03(s,1H),9.25(s,1H),8.38(s,1H),8.02(d,J=8.1Hz,2H),7.58(d,J=8.5Hz,2H),7.24(d,J=1.9Hz,1H),7.02(dd,J=1.9,8.5Hz,1H),6.98(d,J=8.1Hz,1H),3.81(s,3H),2.56(s,3H)。
Mass,m/z:384(M+),166(base)。
実施例26-1
ステップ26-1-1
2-(4-クロロフェニル)-4-メチルオキサゾール-5-カルボン酸ヒドラジド
1H-NMR(CDCl3)δ:9.89(brs,1H),8.17(d,J=8.5Hz,2H),7.64(d,J=8.5Hz,2H),4.50(brs,2H),2.44(s,3H)。
Mass,m/z:251(M+),164(base)。
2-(4-クロロフェニル)-4-メチルオキサゾール-5-カルボン酸 N’-(4-ヒドロキシ-3,5-ジメチルベンジル)-N’-メチルヒドラジド
1H-NMR(CDCl3)δ:11.63(brs,1H),8.77(s,1H),8.35(s,1H),8.20(d,J=8.5Hz,2H),7.69(d,J=8.5Hz,2H),7.32(s,1H),2.50(s,6H),2.22(s,3H)。
Mass,m/z:383(M+),236(base)。
2-(2-メトキシフェニル)-4-メチルオキサゾール-5-カルボン酸 N’-(3-ヒドロキシ-4-メトキシベンジル)-N’-メチルヒドラジド
1H-NMR(CDCl3)δ:11.52(brs,1H),9.29(s,1H),8.36(brs,1H),8.04(d,J=8.1Hz,1H),7.60-7.55(m,1H),7.26-7.23(m,2H),7.13(t,J=7.3Hz,1H),7.06(dd,J=1.9,8.5Hz,1H),6.99(d,J=8.5Hz,1H),3.90(s,3H),3.82(s,3H),2.47(s,3H)。
Mass,m/z:381(M+),160(base)。
2-(2-メトキシフェニル)-4-メチルオキサゾール-5-カルボン酸 N’-(3-メチル-4-メトキシベンジル)-N’-メチルヒドラジド
1H-NMR(CDCl3)δ:11.49(brs,1H),9.84(s,1H),8.36(brs,1H),8.03(d,J=7.3Hz,1H),7.59-7.55(m,1H),7.47(s,1H),7.37(d,J=7.3Hz,1H),7.24(d,J=8.1Hz,1H),7.12(t,J=7.3Hz,1H),6.85(d,J=8.1Hz,1H),3.90(s,3H),2.47(s,3H),2.16(s,3H)。
Mass,m/z:365(M+),160(base)。
実施例27-1
ステップ27-1-1
(2,4-ジクロロフェニル)-ヒドロキシイミノアセトニトリル
1H-NMR(DMSO-d6)δ:7.70(d,J=8.9Hz,1H),7.48(d,J=2.3Hz,1H),7.32(dd,J=2.3,8.5Hz,1H)。
(2,4-ジクロロフェニル)-O-(p-トルエンスルホニル)ヒドロキシイミノアセトニトリル
4-アミノ-3-(2,4-ジクロロフェニル)イソチアゾール-5-カルボン酸 エチルエステル
3-(2,4-ジクロロフェニル)イソチアゾール-5-カルボン酸 エチルエステル
1H-NMR(DMSO-d6)δ:8.25(s,1H),7.82(d,J=2.3Hz,1H),7.80(d,J=8.1Hz,1H),7.59(dd,J=2.3Hz,1H),4.40(q,J=7.3Hz,1H),1.34(t,J=7.3Hz,1H)。
Mass,m/z:301(M+,base)。
3-(2,4-ジクロロフェニル)イソチアゾール-5-カルボン酸ヒドラジド
1H-NMR(CDCl3)δ:10.29 and 9.48(two brs,1H),8.24 and 8.22(two s,1H),7.81-7.76(m,2H),7.60-7.54(m,1H),5.26 and 4.68(two brs,2H)。
Mass,m/z:287(M+),256(base)。
3-(2,4-ジクロロフェニル)イソチアゾール-5-カルボン酸 [1-(4-ジメチルアミノフェニル)メチリデン]ヒドラジド
1H-NMR(DMSO-d6)δ:12.17(s,1H),8.36(s,1H),8.08(s,1H),7.84(d,J=8.5Hz,1H),7.81(d,J=2.3Hz,1H),7.68(d,J=8.9Hz,2H),7.59(dd,J=2.3,8.5Hz,1H),6.84(d,J=8.9Hz,2H),3.26(s,6H)。
Mass,m/z:418(M+),256,162,146(base)。
4-ジメチルアミノベンズアルデヒド又は2,4-ジクロロフェニルアセトニトリルの代わりに、下記の表に示すアルデヒド化合物又はアセトニトリル化合物を用いる以外、実施例27-1と同様に操作することで、目的の化合物を得た。
4-アミノ-3-(2,4-ジクロロフェニル)イソチアゾール-5-カルボン酸 [1-(4-ヒドロキシ-3-メチルフェニル)メチリデン]ヒドラジド
1H-NMR(DMSO-d6)δ:11.72(s,1H),9.90(s,1H),8.00(s,1H),7.79(d,J=1.9Hz,1H),7.57(dd,J=1.9,8.5Hz,1H),7.53(s,1H),7.51(d,J=8.1Hz,1H),7.48(d,J=8.5Hz,1H),6.91(d,1H),6.47(s,2H),2.19(s,3H)。
Mass,m/z:420(M+),271,235,150,72(base)。
4-アミノ-3-(2,4-ジクロロフェニル)イソチアゾール-5-カルボン酸 [1-(4-ヒドロキシ-3,5-ジメチルフェニル)メチリデン]ヒドラジド
1H-NMR(DMSO-d6)δ:11.72(s,1H),9.81(s,1H),7.98(s,1H),7.79(d,J=1.9Hz,1H),7.56(d,J=2.3Hz,1H),7.48(d,J=8.1Hz,1H),7.41(s,2H),6.47(s,2H),2.23(s,6H)。
Mass,m/z:434(M+),271,235,164,72(base)。
実施例28-1
ステップ28-1-1
[2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-イル]カルバミン酸 tert-ブチルエステル
1H-NMR(DMSO-d6)δ:8.16(d,J=8.5Hz,1H),7.34-7.27(m,1H),7.17-7.12(m,1H),4.02(s,3H),2.32(s,3H),1.94(s,9H)。
Mass,m/z:354(M+),298。
5-アミノ-2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール
1H-NMR(DMSO-d6)δ:8.04(d,J=8.5Hz,1H),7.20(d,J=2.3Hz,1H),7.05(dd,J=2.3,8.5Hz,1H),5.36(brs,2H),3.96(s,3H),2.18(s,3H)。
Mass,m/z:254(M+)。
2-(4-クロロ-2-メトキシフェニル)-5-イソシアネート-4-メチルチアゾール
1H-NMR(DMSO-d6)δ:8.21(d,J=8.9Hz,1H),7.38(d,J=2.3Hz,1H),7.19(dd,J=1.9,8.5Hz,1H),4.06(s,3H),2.42(s,3H)。
Mass,m/z:296(M+,base)。
[2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-イル]チオカルバミン酸 O-(4-メトキシベンジル)エステル
1H-NMR(DMSO-d6)δ:8.21(d,J=8.5Hz,1H),7.32-7.28(m,1H),7.23(d,J=8.9Hz,2H),7.13(dd,J=1.9,8.5Hz,1H),6.88(d,J=8.9Hz,2H),4.16(s,2H),4.04(s,3H),3.28(s,3H),2.34(s,3H)。
Mass,m/z:434(M+),121(base)。
実施例29-1
ステップ29-1-1
3-ブロモ-4-オキソペンタン酸
1H-NMR(CDCl3)δ:4.61(dd,J=5.4,8.9Hz,1H),3.32(dd,J=8.9,17.7Hz,1H),2.94(dd,J=5.4,17.7Hz,1H),2.42(s,3H)。
Mass,m/z:194(M+),55(base)。
3-ブロモ-4-オキソペンタン酸エチル
1H-NMR(CDCl3)δ:4.64(dd,J=5.8,8.9Hz,1H),4.14(q,J=7.3Hz,2H),3.25(dd,J=8.9,17.0Hz,1H),2.88(dd,J=5.8,17.0Hz,1H),2.41(s,3H),1.25(t,J=7.3Hz,3H)。
Mass,m/z:221(M+),101(base)。
[2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-イル]酢酸エチル
1H-NMR(CDCl3)δ:9.31(d,J=8.5Hz,1H),7.28(dd,J=1.9,8.5Hz,1H),7.08(d,J=1.9Hz,1H),4.27(q,J=7.3Hz,2H),4.10(s,3H),3.84(s,2H),2.82(s,3H),1.33(t,J=7.3Hz,3H)。
Mass,m/z:325(M+),252(base)。
[2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-イル]酢酸ヒドラジド
1H-NMR(DMSO-d6)δ:9.27(s,1H),8.20(d,J=8.5Hz,1H),7.32(d,J=1.9Hz,1H),7.13(dd,J=1.9Hz,8.5Hz,1H),4.27(s,2H),4.03(s,3H),3.58(s,3H),2.50(s,3H)。
Mass,m/z:311(M+),252(base)。
2-(4-クロロ-2-メトキシフェニル)-5-[2-(4-メトキシベンジルオキシ)エチル]-4-メチルチアゾール
1H-NMR(DMSO-d6)δ:11.52 and 11.36(two s,1H),8.22 and 8.21(two d,J=8.5Hz,1H),8.18 and 7.98(two s,1H),7.70 and 7.64(two d,J=8.9Hz,2H),7.32 and 7.28(d,J=2.3Hz,1H),7.14 and 7.13(two dd,J=2.3,8.5Hz,1H),7.04 and 7.01(d,J=8.9Hz,2H),4.16 and 4.03(two s,2H),3.92 and 3.78(two s,3H),3.82 and 3.80(two s,3H),2.41 and 2.40(s,3H)。
Mass,m/z:429(M+),295,252,128,85(base)。
2-(4-クロロ-2-メトキシフェニル)-5-[2-(4-メトキシベンジルオキシ)エチル]-4-メチルチアゾール
1H-NMR(DMSO-d6)δ:11.43 and 11.26(two s,1H),8.71(s,1H),8.22 and 8.21(two d,J=8.5Hz,1H),8.04 and 7.87(two s,1H),7.33-7.27(m,3H),7.14 and 7.13(two dd,J=2.3,8.5Hz,1H),4.15 and 4.03(two s,2H),3.93 and 3.76(two s,3H),2.41 and 2.39(two s,3H),2.21 and 2.19(two s,6H)。
Mass,m/z:443(M+),295,252,128,85(base)。
実施例30-1
ステップ30-1-1
1-[2-(4-クロロフェニル)-4-メチルチアゾール-5-イル]-エタノン
1H-NMR(CDCl3)δ:8.02(dt,J=1.9,2.7,8.5Hz,2H),7.60(dt,J=1.9,2.3,2.7,8.8Hz,2H),2.72(s,3H),2.58(s,3H)。
Mass,m/z:251(M+),236(base)。
{1-[2-(4-クロロフェニル)-4-メチルチアゾール-5-イル]エチリデン}-ヒドラジン
1H-NMR(DMSO-d6)δ:7.88(dt,J=1.9,2.7,8.5Hz,2H),7.53(dt,J=1.9,2.7,8.5Hz,2H),6.59(br,2H),2.53(s,3H),2.11(s,3H)。
Mass,m/z:265(M+)(base)。
4-{[1-[2-(4-クロロフェニル)-4-メチルチアゾール-5-イル]エチリデン]ヒドラゾノメチル}-2,6-ジメチル-フェノール
1H-NMR(DMSO-d6)δ:8.92(s,1H),8.35(s,1H),7.98(dt,J=1.9,2.7,8.5Hz,2H),7.57(dt,J=1.9,2.7,8.5Hz,2H),7.48(s,2H),2.71(s,3H),2.59(s,3H),2.22(s,6H)。
Mass,m/z:397(M+),150(base)。
4-{[1-[2-(4-クロロフェニル)-4-メチルチアゾール-5-イル]エチリデン]ヒドラゾノメチル}-2,6-ジメチル-フェノール
1H-NMR(DMSO-d6)δ:9.31(s,1H),8.38(s,1H),7.98(dt,J=2.0,2.3,2.7,8.5Hz,2H),7.58(dt,J=1.9,2.7,8.5Hz,2H),7.41(d,J=1.9Hz,1H),7.26(dd,J=1.9,8.1Hz,1H),7.03(d,J=8.5Hz,1H),3.84(s,3H),2.72(s,3H),2.59(s,3H)。
Mass,m/z:399(M+),248(base)。
2-メトキシ-5-{[1-[2-(2-メトキシフェニル)-4-メチルチアゾール-5-イル]エチリデン]ヒドラゾノメチル}フェノール
1H-NMR(DMSO-d6)δ:9.29(s,1H),8.41(s,1H),8.31(dd,J=1.6Hz,J=7.7Hz,1H),7.50(ddd,J=1.6Hz,J=7.3Hz,J=8.5Hz,1H),7.41(d,J=2.3Hz,1H),7.26(dd,J=2.0Hz,J=8.5Hz,2H),7.12(td,J=0.8Hz,J=8.1Hz,1H),7.03(d,J=8.5Hz,1H),4.05(s,3H),3.84(s,3H),2.72(s,3H),2.59(s,3H)。
Mass,m/z:395(M+)(base)。
ステップ31-1-1
1-[2-(2,4-ジメチルフェニル)-4-メチルチアゾール-5-イル]エタノン
1H-NMR(CDCl3)δ:8.11(d,J=7.7Hz,1H),7.25(d,J=6.2Hz,1H),7.19(s,1H),3.08(s,3H),2.65(s,3H),2.63(s,3H),2.39(s,3H)。
Mass,m/z:245(M+,base)。
2-[2-(2,4-ジメチルフェニル)-4-メチルチアゾール-5-イル]-2,2-ジメトキシエタノール
1H-NMR(CDCl3)δ:7.64,7.63(two d,J=7.7Hz,1H),7.07(s,1H),7.05(dd,J=1.2,7.7Hz,1H),3.89(d,J=6.6Hz,2H),3.31(s,6H),2.54(s,3H),2.48(s,3H),2.34(s,3H),1.74(t,J=6.6Hz,1H)。
Mass,m/z:307(M+),276(base)。
5-[1,1-ジメトキシ-2-(4-メトキシベンジルオキシ)エチル]-2-(2,4-ジメチルフェニル)-4-メチルチアゾール
1H-NMR(CDCl3)δ:7.64(d,J=7.7Hz,1H),7.09~7.04(m,4H),6.78(d,J=8.8Hz,2H),4.40(s,2H),3.76(s,3H),3.70(s,2H),3.27(s,6H),2.56(s,3H),2.34(s,6H)。
Mass,m/z:427(M+),121(base)。
1-[2-(2,4-ジメチルフェニル)-4-メチルチアゾール-5-イル]-2-(4-メトキシベンジルオキシ)エタノン
1H-NMR(CDCl3)δ:7.71(d,J=8.1Hz,1H),7.32(d,J=8.5Hz,2H),7.11(s,1H),7.09(d,J=8.1Hz,1H),6.89(d,J=8.9Hz,2H),4.61(s,2H),4.41(s,2H),3.81(s,3H),2.80(s,3H),2.56(s,3H),2.36(s,3H)。
Mass,m/z:383(M+),245(base)。
ステップ32-1
5-(2,4-ジクロロフェニル)-2H-ピラゾール-3-カルボン酸 [2-(4-ヒドロキシフェニル)-エチル]-アミド
1H-NMR(DMSO-d6):13.84 and 13.62(two s,1H),9.15 and 9.14(two s,1H),8.62 and 8.16(t,J=5.4Hz,1H),7.86 and 7.68(two d,J=8.5Hz,1H),7.80 and 7.70(two d,J=2.3Hz,1H),7.58 and 7.50(two dd,J=1.9,8.5Hz,1H),7.40 and 6.98(two d,J=1.6Hz,1H),7.03(d,J=8.5Hz,2H),6.68(d,J=8.5Hz,2H),3.42(q,J=7.3Hz,2H),2.73(q,J=7.7Hz,2H)。
Mass,m/z:375(M+),120(base)。
実施例33-1
ステップ33-1
3-ヒドロキシ-4-メトキシ-安息香酸 N’-[2-(4-クロロフェニル)-4-メチルチアゾール-5-カルボニル]ヒドラジド
1H-NMR(DMSO-d6):10.32(s,1H),10.26(s,1H),9.28(s,1H),8.00(d,J=8.5Hz,2H),7.60(d,J=8.5Hz,2H),7.42(dd,J=1.5,8.1Hz,1H),7.37(s,1H),7.04(d,J=8.5Hz,1H),3.84(s,3H),2.68(s,3H)。
Mass,m/z:417(M+),151(base)。
実施例34-1
ステップ34-1
N-[2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-イル]-3-(4-メトキシフェニル)アクリルアミド
1H-NMR(CDCl3)δ:8.25(d,J=8.5Hz,1H),7.79(d,J=15.4Hz,1H),7.53(s,1H),7.51(d,8.5Hz,2H),7.02(dd,J=1.9,8.5Hz,1H),6.98(d,J=1.9Hz,1H),6.91(d,J=8.9Hz,2H),6.48(d,J=15.4Hz,1H),4.01(s,3H),3.84(s,3H),2.47(s,3H)。
Mass,m/z:414(M+),161(base)。
ステップ35-1-1
5-(2,4-ジクロロフェニル)-[1,3,4]チアジアゾール-2-イルアミン
1H-NMR(DMSO-d6)δ:8.03(d,J=8.9Hz,1H),7.79(d,J=2.3Hz,1H),7.55(dd,J=2.3,8.5Hz,1H),7.49(s,2H)。
Mass,m/z:245,247(M+),74(base)。
[5-(2,4-ジクロロフェニル)-[1,3,4]チアジアゾール-2-イル]カルバミン酸 1-メチル-1H-ベンゾイミダゾール-5-イルメチルエステル
1H-NMR(DMSO-d6)δ:12.47(brs,1H),8.22(s,1H),8.13(d,J=8.5Hz,1H),7.88(d,J=2.3Hz,1H),7.76(s,1H),7.61(dd,J=2.3,8.5Hz,1H),7.60(d,J=8.1Hz,1H),7.38(dd,J=1.5,8.5Hz,1H),5.40(s,2H),3.85(s,3H)。
Mass,m/z:389(M+-44),133(base)。
[5-(2,4-ジクロロフェニル)-[1,3,4]チアジアゾール-2-イル]カルバミン酸 1-メチル-1H-インダゾール-5-イルメチルエステル
1H-NMR(DMSO-d6)δ:12.47(brs,1H),8.13(d,J=8.5Hz,1H),8.09(d,J=8.5Hz,1H),7.89(d,J=2.3Hz,1H),7.86(s,1H),7.68(d,J=8.9Hz,1H),7.62(dd,J=2.3,8.5Hz,1H),7.49(dd,J=1.5,8.5Hz,1H),5.39(s,2H),4.06(s,3H)。
Mass,m/z:433(M+),389,145(base)。
実施例36-1
ステップ36-1-1
2-アミノベンゾチアゾール-6-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:8.28(d,J=1.5Hz,1H),7.87(brs,2H),7.82(dd,J=1.9,8.5Hz,1H),7.37(d,J=8.5Hz,1H),4.29(q,J=6.9Hz,2H),1.32(t,J=6.9Hz,3H)。
Mass,m/z:222(M+),177(base)。
ベンゾチアゾール-6-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:9.60(s,1H),8.84(d,J=1.5Hz,1H),8.29(d,J=8.5Hz,1H),8.11(d,J=8.5Hz,1H),4.37(q,J=7.3Hz,2H),1.36(t,J=7.3Hz,3H)。
Mass,m/z:207(M+),162。
ベンゾチアゾール-6-イルメタノール
1H-NMR(DMSO-d6)δ:9.33(s,1H),8.08(s,1H),8.03(d,J=8.5Hz,1H),7.49(dd,J=1.5,8.1Hz,1H),5.33(t,J=5.8Hz,1H),4.65(d,J=5.8Hz,2H)。
Mass,m/z:165(M+),136(base)。
[2-(4-クロロ-2-メチルフェニル)-4-メチルチアゾール-5-イル]カルバミン酸 ベンゾチアゾール-6-イルメチルエステル
1H-NMR(DMSO-d6)δ:10.16(brs,1H),9.43(s,1H),8.26(s,1H),8.17(d,J=8.5Hz,1H),8.13(d,J=8.5Hz,1H),7.63(d,J=8.5Hz,1H),7.30(d,J=1.9Hz,1H),7.12(dd,J=1.9,8.5Hz,1H),5.36(s,2H),4.01(s,3H),2.32(s,3H)。
Mass,m/z:445(M+),401。
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸又は(1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピリジン-7-イル)メタノールの代わりに、下記の表に示す実施例又はステップで得られたカルボン酸又はヒドロキシ化合物を用いる以外、実施例9-1と同様に操作することで、目的の化合物を得た。
実施例37-1
ステップ37-1-1
2-メチルベンゾチアゾール-5-カルボン酸
1H-NMR(DMSO-d6)δ:13.09(brs,1H),8.40(d,J=1.5Hz,1H),8.16(d,J=8.1Hz,1H),7.95(dd,J=1.5,8.5Hz,1H),2.84(s,3H)。
Mass,m/z:193(M+,base)。
(2-メチルベンゾチアゾール-5-イル)メタノール
1H-NMR(DMSO-d6)δ:7.95(d,J=8.1Hz,1H),7.84(d,J=0.8Hz,1H),7.35(dd,J=1.5,8.1Hz,1H),5.28(brs,1H),4.63(s,2H)。
Mass,m/z:179(M+),150(base)。
[2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-イル]カルバミン酸 2-メチルベンゾチアゾール-5-イルメチルエステル
1H-NMR(DMSO-d6)δ: 10.16(s,1H),8.17(d,J=8.5Hz,1H),8.06(d,J=8.1Hz,1H),7.99(s,1H),7.47(d,J=8.1Hz,1H),7.30(d,J=1.9Hz,1H),7.12(dd,J=1.9,8.5Hz,1H),5.34(s,2H),4.02(s,3H),2.81(s,3H),2.32(s,3H)。
Mass,m/z:459(M+),415,162(base)。
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸又は(1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピリジン-7-イル)メタノールの代わりに、下記の表に示す実施例又はステップで得られたカルボン酸又はヒドロキシ化合物を用いる以外、実施例9-1と同様に操作することで、目的の化合物を得た。
実施例38-1
ステップ38-1-1
4-(4-エトキシカルボニル-2-ニトロフェニル)ピペリジン-1-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:8.31(d,J=2.3Hz,1H),8.04(dd,J=1.9,8.9Hz,1H),7.36(d,J=8.9Hz,1H),4.31(q,J=6.9Hz,1H),4.07(q,J=6.9Hz,2H),3.53-3.50(m,4H),3.20-3.18(m,4H),1.32(t,J=6.9Hz,3H),1.20(t,J=6.9Hz,3H)。
Mass,m/z:351(M+)。
4-(2-アミノ-4-エトキシカルボニルフェニル)ピペラジンー1-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:7.33(d,J=1.9Hz,1H),7.18(dd,J=1.9,8.1Hz,1H),6.93(d,J=8.1Hz,1H),5.03(s,2H),4.24(q,J=6.9Hz,2H),4.07(q,J=6.9Hz,2H),3.56-3.53(m,4H),2.81(t,J=5.0Hz,4H),1.29(t,J=6.9Hz,3H),1.20(t,J=6.9Hz,3H)。
Mass,m/z:321(M+,base)。
3,4-ジヒドロ-1H-ベンゾ[4,5]イミダゾ[1,2-a]ピラジン-2,8-ジカルボン酸ジエチルエステル
1H-NMR(DMSO-d6)δ:8.19(d,J=0.8Hz,1H),7.89(dd,J=1.5,8.5Hz,1H),7.63(d,J=8.5Hz,1H),4.87(s,2H),4.33(t,J=7.3Hz,2H),4.25(t,J=5.4Hz,2H),4.14(t,J=6.9Hz,2H),1.35(t,J=7.3Hz,3H),1.24(t,J=6.9Hz,3H)。
Mass,m/z:317(M+),288(base)。
1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピラジン-8-カルボン酸
1H-NMR(DMSO-d6)δ:8.13(d,J=1.5Hz,1H),7.84(dd,J=1.5,8.5Hz,1H),7.54(d,J=8.5Hz,1H),4.10-4.08(m,4H),3.21(t,J=5.4Hz,2H)。
Mass,m/z:217(M+,base)。
1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピラジン-8-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:8.15(d,J=1.2Hz,1H),7.85(dd,J=1.5,8.5Hz,1H),7.58(d,J=8.5Hz,1H),4.33(t,J=6.9Hz,2H),4.11-4.08(m,4H),3.22-3.19(m,2H),1.35(t,J=6.9Hz,3H)。
Mass,m/z:245(M+,base)。
2-メチル-1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピラジン-8-カルボン酸エチルエステル
1H-NMR(CDCl3)δ:8.42(d,J=1.2Hz,1H),7.89(dd,J=1.5,8.5Hz,1H),7.32(d,J=8.5Hz,1H),4.39(t,J=6.9Hz,2H),4.16(t,J=5.4Hz,2H),3.88(s,2H),2.98(t,J=5.4Hz,2H),2.55(s,3H),1.41(t,J=6.9Hz,3H)。
Mass,m/z:259(M+,base)。
(2-メチル-1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピラジン-8-イル)メタノール
1H-NMR(DMSO-d6)δ:7.49(s,1H),7.41(d,J=8.1Hz,1H),7.17(dd,J=1.2,8.1Hz,1H),5.10(t,J=5.8Hz,1H),4.58(d,J=5.8Hz,2H),4.11(t,J=5.4Hz,2H),3.74(s,2H),2.92(t,J=5.4Hz,2H),2.45(s,3H)。
Mass,m/z:217(M+)。
[2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-イル]カルバミン酸 2-メチル-1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピラジン-8-イルメチルエステル
1H-NMR(DMSO-d6)δ:10.11(brs,1H),8.32(s,1H),8.16(d,J=8.5,1H),7.66(s,1H),7.51(d,J=8.5Hz,1H),7.32-7.30(m,2H),7.12(dd,J=1.9,8.5Hz,1H),5.30(s,2H),4.14(t,J=5.8Hz,2H),4.01(s,3H),3.76(s,2H),2.94(t,J=5.8Hz,2H),2.45(s,3H),2.31(s,3H)。
Mass,m/z:454(M+-44),260(base)。
[2-(2-メトキシ-4-メチルフェニル)-4-メチルチアゾール-5-イル]カルバミン酸 2-メチル-1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピラジン-8-イルメチルエステル
1H-NMR(DMSO-d6)δ:9.96(brs,1H),8.04(d,J=8.1Hz,1H),7.65(s,1H),7.51(d,J=8.5Hz,1H),7.30(d,J=8.1Hz,1H),7.02(s,1H),6.87(d,J=8.1Hz,1H),5.29(s,2H),4.13(t,J=5.8Hz,2H),3.96(s,3H),3.75(s,2H),2.93(t,J=5.8Hz,2H),2.45(s,3H),2.35(s,3H),1.99(s,3H)。
Mass,m/z:477(M+),433,260(base)。
[2-(2,4-ジチルフェニル)-4-メチルチアゾール-5-イル]カルバミン酸 2-メチル-1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピラジン-8-イルメチルエステル
1H-NMR(DMSO-d6)δ:10.11(brs,1H),7.65(s,1H),7.55(d,J=8.1Hz,1H),7.50(d,J=8.5Hz,1H),7.30(d,J=8.1Hz,1H),7.14(s,1H),7.09(d,J=8.1Hz,1H),5.29(s,2H),4.14(t,J=5.8Hz,2H),3.76(s,3H),2.93(t,J=5.8Hz,2H),2.45(s,3H),2.31(s,6H)。
Mass,m/z:417(M+-44),244(base)。
ステップ39-1-1
(8-ヒドロキシメチル-3,4-ジヒドロ-1H-ベンゾ[4,5]イミダゾ[1,2-a]ピラジン-2-カルボン酸 tert-ブチルエステル
1H-NMR(DMSO-d6)δ:7.52(s,1H),7.43(d,J=8.5Hz,1H),7.19(dd,J=1.5,8.5Hz,1H),5.12(t,J=5.8Hz,1H),4.67(s,2H),4.58(d,J=5.8Hz,2H),4.15(t,J=5.4Hz,2H),3.91(t,J=5.4Hz,2H),1.46(s,9H)。
Mass,m/z:303(M+),246(base)。
8-[2-(2-メトキシ-4-メチルフェニル)-4-メチルチアゾール-5-イルカルバモイルメチル]-3,4-ジヒドロ-1H-ベンゾ[4,5]イミダゾ[1,2-a]ピラジン-2-カルボン酸 tert-ブチルエステル
1H-NMR(DMSO-d6)δ:9.94(brs,1H),8.04(d,J=7.7Hz,1H),7.68(s,1H),7.53(d,J=8.5Hz,1H),7.32(d,J=8.5Hz,1H),7.02(s,1H),6.87(d,J=7.7Hz,1H),5.29(s,2H),4.79(s,2H),4.79-4.59(m,2H),3.96(s,3H),3.93-3.91(m,2H),2.35(s,3H),2.28(s,3H),1.46(s,9H)。
Mass,m/z:563(M+),519,260(base)。
[2-(2-メトキシ-4-メチルフェニル)-4-メチルチアゾール-5-イル]カルバミン酸 1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピラジン-8-イルメチルエステル
1H-NMR(DMSO-d6)δ:9.96(brs,1H),8.04(d,J=7.7Hz,1H),7.64(s,1H),7.49(d,J=8.1Hz,1H),7.29(d,J=7.7Hz,1H),7.02(s,1H),6.87(d,J=8.1Hz,1H),5.28(s,2H),4.06(brs,3H),3.96(s,3H),3.32-3.29(m,2H),3.20(t,J=5.4Hz,2H),2.35(s,3H),2.28(s,3H)。
Mass,m/z:463(M+),260(base)。
実施例40-1
ステップ40-1-1
チオモルホリン-3-オン
1H-NMR(DMSO-d6)δ:7.79(brs,1H),3.41-3.38(m,2H),3.15(s,2H),2.76(t,J=5.8Hz,2H)。
Mass,m/z:117(M+,base)。
3-ニトロ-4-(3-オキソチオモルホリン-4-イル)安息香酸エチルエステル
1H-NMR(DMSO-d6)δ:8.39(d,J=1.9Hz,1H),8.30(dd,J=1.9,8.5Hz,1H),7.76(d,J=8.1Hz,1H),4.38(q,J=6.9Hz,2H),4.14(brs,2H),3.44(s,2H),3.13(t,J=5.4Hz,2H),1.35(t,J=6.9Hz,3H)。
Mass,m/z:310(M+),264(base)。
3,4-ジヒドロ-1H-2-チア-4a,9-ジアザフルオレン-7-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:8.17(d,J=1.5Hz,1H),7.88(dd,J=1.5,8.5Hz,1H),7.61(d,J=8.5Hz,1H),4.40(t,J=5.8Hz,2H),4.33(q,J=6.9Hz,2H),4.14(s,2H),3.27(t,J=5.8Hz,2H),1.35(t,J=6.9Hz,3H)。
Mass,m/z:262(M+),217(base)。
(3,4-ジヒドロ-1H-2-チア-4a,9-ジアザフルオレン-7-イル)メタノール
1H-NMR(DMSO-d6)δ:7.50(s,1H),7.42(d,J=8.1Hz,1H),7.19(dd,J=1.2,8.5Hz,1H),5.12(t,J=5.8Hz,1H),4.59(d,J=5.8Hz,2H),4.32(t,J=5.8Hz,2H),4.08(s,2H),3.24(t,J=5.8Hz,2H)。
Mass,m/z:220(M+,base),191。
[2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-イル]カルバミン酸 3,4-ジヒドロ-1H-2-チア-4a,9-ジアザフルオレン-7-イルメチルエステル
1H-NMR(DMSO-d6)δ:10.10(brs,1H),8.16(d,J=8.5Hz,1H),7.67(s,1H),7.52(d,J=8.5Hz,1H),7.33(d,J=8.1Hz,1H),7.29(d,J=1.9Hz,1H),7.12(dd,J=1.9,8.5Hz,1H),5.30(s,2H),4.35(t,J=5.8Hz,2H),4.10(s,2H),4.02(s,3H),3.30-3.17(m,4H),2.31(s,3H)。
Mass,m/z:500(M+),456,280,220(base)。
[2-(2-メトキシ-4-メチルフェニル)-4-メチルチアゾール-5-イル]カルバミン酸 3,4-ジヒドロ-1H-2-チア-4a,9-ジアザフルオレン-7-イルメチルエステル
1H-NMR(DMSO-d6)δ:9.95(brs,1H),8.04(d,J=7.7Hz,1H),7.66(s,1H),7.52(d,J=8.1Hz,1H),7.32(d,J=8.1Hz,1H),7.02(s,1H),6.87(d,J=8.1Hz,1H),5.29(s,2H),4.35(t,J=5.8Hz,2H),4.10(s,2H),3.96(s,3H),3.31-3.24(m,4H),2.35(s,3H),2.28(s,3H)。
Mass,m/z:480(M+),436,260(base)。
[2-(4-クロロ-2-メチルフェニル)-4-メチルチアゾール-5-イル]カルバミン酸 3,4-ジヒドロ-1H-2-チア-4a,9-ジアザフルオレン-7-イルメチルエステル
1H-NMR(DMSO-d6)δ:10.24(brs,1H),7.71-7.68(m,1H),7.55-7.44(m,3H),7.36-7.32(m,2H),5.31(s,2H),4.36(t,J=5.8Hz,2H),4.11(s,2H),3.32-3.25(m,4H),2.53(s,3H),2.32(s,3H)。
Mass,m/z:265,220。
ステップ41-1-1
ベンゾチアゾール-6-カルボン酸
1H-NMR(DMSO-d6)δ:13.11(brs,1H),9.58(s,1H),8.81(d,J=1.5Hz,1H),8.17(d,J=8.5Hz,1H),8.09(dd,J=1.5,8.5Hz,1H)。
Mass,m/z:179(M+,base),162。
ベンゾチアゾール-6-イルカルバミン酸 2-(2,4-ジメチルフェニル)-4-メチルチアゾール-5-イルメチルエステル
1H-NMR(DMSO-d6)δ:10.09(brs,1H),9.23(s,1H),8.32(d,J=0.8Hz,1H),7.99(d,J=8.9Hz,1H),7.62(d,J=7.7Hz,1H),7.54(d,J=8.1Hz,1H),7.17(s,1H),7.12(d,J=8.1Hz,1H),5.41(s,2H),2.50(s,6H),2.32(s,3H)。
Mass,m/z:409(M+),365,216(base)。
実施例42-1
ステップ42-1-1
(2-メチルベンゾチアゾール-5-イル)カルバミン酸 2-(2,4-ジメチルフェニル)-4-メチルチアゾール-5-イルメチルエステル
1H-NMR(DMSO-d6)δ:9.98(brs,1H),8.10(s,1H),7.90(d,J=8.9Hz,1H),7.62(d,J=8.1Hz,1H),7.46(dd,J=1.9,8.5Hz,1H),7.17(s,1H),7.12(d,J=7.3Hz,1H),5.40(s,2H),2.77(s,3H),2.47(s,3H),2.50(s,3H),2.32(s,3H)。
Mass,m/z:423(M+),379,216(base)。
(2-メチルベンゾチアゾール-5-イル)カルバミン酸 2-(4-クロロー2-メチルフェニル)-4-メチルチアゾール-5-イルメチルエステル
1H-NMR(DMSO-d6)δ:9.99(brs,1H),8.10(d,J=0.8Hz,1H),7.90(d,J=8.5Hz,1H),7.76(d,J=8.1Hz,1H),7.48-7.44(m,2H),7.38(d,J=8.9Hz,1H),5.41(s,2H),2.77(s,3H),2.55(s,3H),2.50(s,3H)。
Mass,m/z:443(M+),399,236(base)。
実施例43-1
ステップ43-1-1
3,4-ジヒドロ-1H-2-チア-4a,9-ジアザフルオレン-7-カルボン酸
1H-NMR(DMSO-d6)δ:12.70(brs,1H),8.15(d,J=1.2Hz,1H),7.87(dd,J=1.5Hz,8.5Hz,1H),7.58(d,J=8.5Hz,1H),4.40(t,J=5。8Hz,1H),4.13(s,2H),3.27(t,J=5.8Hz,2H)。
Mass,m/z:234(M+,base)。
(3,4-ジヒドロ-1H-2-チア-4a,9-ジアザフルオレン-7-イル)カルバミン酸 2-(4-フルオロ-2-メチルフェニル)-4-メチルチアゾール-5-イルメチルエステル
1H-NMR(DMSO-d6)δ:9.71(brs,1H),7.79-7.75(m,2H),7.39(d,J=8.5Hz,1H),7.29-7.23(m,2H),7.15(dt,J=2.7,8.5Hz,1H),5.38(s,2H),4.29(t,J=5.8Hz,2H),4.06(s,2H),3.30-3.22(m,4H),2.54(s,3H),2.50(s,3H)。
Mass,m/z:468(M+),424,231(base)。
[2-(2-メチルフェニル)-4-メチルチアゾール-5-イル]メタノール又は1-メチル-1H-ベンゾイミダゾール-5-カルボン酸の代わりに、下記の表に示す実施例又はステップで得られたヒドロキシ化合物又はカルボン酸を用いる以外、実施例13-1と同様に操作することで、目的の化合物を得た。
実施例44-1
ステップ44-1-1
5-(4-クロロ-2-メトキシフェニル)-[1,3,4]オキサチアゾール-2-オン
1H-NMR(DMSO-d6)δ:7.76(d,J=8.5Hz,1H),7.36(d,J=1.9Hz,1H),7.18(dd,J=1.9,8.5Hz,1H),3.30(s,3H)。
Mass,m/z:243(M+),169(base)。
3-(4-クロロ-2-メトキシフェニル)イソチアゾール-5-カルボン酸 エチルエステルおよび3-(4-クロロ-2-メトキシフェニル)イソチアゾール-4-カルボン酸エチルエステル
44-1-2-A:3-(4-クロロ-2-メトキシフェニル)イソチアゾール-5-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:8.25(s,1H),7.93(d,J=8.5Hz,1H),7.30(d,J=1.9Hz,1H),7.16(dd,J=1.9,8.3Hz,1H),4.39(q,J=7.3Hz,2H),3.29(s,3H),1.34(t,J=7.3Hz,3H)。
Mass,m/z:297(M+),268(base)。
44-1-2-B:3-(4-クロロ-2-メトキシフェニル)イソチアゾール-4-カルボン酸エチルエステル
1H-NMR(DMSO-d6)δ:9.60(s,1H),7.41(d,J=8.1Hz,1H),7.18(d,J=1.9Hz,1H),7.11(dd,J=1.9,8.1Hz,1H),4.14(q,J=7.3Hz,2H),3.71(s,3H),1.13(t,J=7.3Hz,3H)。
Mass,m/z:297(M+),224(base)。
3-(4-クロロ-2-メトキシフェニル)イソチアゾール-5-カルボン酸
1H-NMR(DMSO-d6)δ:14.11(brs,1H),8.20(s,1H),7.94(d,J=8.5Hz,1H),7.30(d,J=1.9Hz,1H),7.16(dd,J=1.9,8.1Hz,1H),3.95(s,3H)。
Mass,m/z:269(M+),240(base)。
ステップ44-1-4
3-(4-クロロ-2-メトキシフェニル)イソチアゾール-4-カルボン酸
1H-NMR(DMSO-d6)δ:14.11(brs,1H),8.20(s,1H),7.94(d,J=8.5Hz,1H),7.30(d,J=1.9Hz,1H),7.16(dd,J=1.9,8.1Hz,1H),3.95(s,3H)。
Mass,m/z:269(M+),240(base)。
3-(2-メトキシ-4-メチルフェニル)イソチアゾール-5-カルボン酸
1H-NMR(DMSO-d6)δ:8.19(s,1H),7.83(d,J=7.8Hz,1H),7.03(s,1H),6.90(d,J=7.7Hz,1H),3.90(s,3H),2.37(s,1H)。
Mass,m/z:249(M+),220(base)。
3-(2-メトキシフェニル)イソチアゾール-5-カルボン酸
1H-NMR(DMSO-d6)δ:14.05(brs,1H),8.22(s,1H),7.91(dd,J=1.5,7.7Hz,1H),7.48(t,J=8.9Hz,1H),7.21(d,J=8.1Hz,1H),7.09(t,J=7.7Hz,1H),3.92(s,3H)。
Mass,m/z:235(M+),206(base)。
3-(2-メトキシフェニル)イソチアゾール-4-カルボン酸
1H-NMR(DMSO-d6)δ:12.70(brs,1H),9.51(s,1H),7.44-7.35(m,2H),7.08-6.99(m,2H),3.69(s,3H)。
Mass,m/z:235(M+,base)。
実施例45-1~45-7
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸又は(1,2,3,4-テトラヒドロベンゾ[4,5]イミダゾ[1,2-a]ピリジン-7-イル)メタノールの代わりに、下記の表に示す実施例で得られたカルボン酸又はヒドロキシ化合物を用いる以外、実施例9-1と同様に操作することで、目的の化合物を得た。
実施例46-1~46-4
2-(4-クロロ-2-メトキシフェニル)-4-メチルチアゾール-5-カルボン酸の代わりに、下記の表に示す実施例で得られたカルボン酸又はエステルを用いる以外、実施例12-1と同様に操作することで、目的の化合物を得た。
実施例47-1~47-12
[2-(2-メチルフェニル)-4-メチルチアゾール-5-イル]メタノール又は1-メチル-1H-ベンゾイミダゾール-5-カルボン酸の代わりに、下記の表に示す実施例で得られたヒドロキシ化合物又はカルボン酸を用い、下記の表に示す実施例の製造方法に従って、目的の化合物を得た。
実施例48-1
ステップ48-1-1
1-エチル-1H-インダゾール-5-カルバルデヒド
1H-NMR(DMSO-d6)δ:10.03(s,1H),8.43(s,1H),8.33(s,1H),7.85(m,2H),4.49(m,2H),1.42(t,J=6.9Hz,3H)。
Mass,m/z:174(M+),159(base)。
3,4-ジヒドロ-1H-2-オキサ-4a,9-ジアザフルオレン-7-カルバルデヒド
1H-NMR(DMSO-d6)δ:10.06(s,1H),8.19(s,1H),7.82(d,J=8.5Hz,1H),7.72(d,J=8.1Hz,1H),5.01(s,2H),4.28(t,J=5.2Hz,2H),4.19(t,J=5.4Hz,2H)。
Mass,m/z:202(M+,base)。
実施例49-1
ステップ49-1-1
3-(4-クロロ-2-メトキシフェニル)イソチアゾール-5-カルボン酸ヒドラジド
1H-NMR(DMSO-d6)δ:10.27 and 9.40(two brs,1H),8.34(d,J=17.0Hz,1H),7.95(t,J=8.5Hz,1H),7.29-7.26(m,1H),7.16-7.12(m,1H),5.19(s,1H),4.66(s,1H),3.95(s,3H)。
Mass,m/z:283(M+),252(base)。
3-(4-クロロ-2-メトキシフェニル)イソチアゾール-5-カルボン酸 [1-メチル-1H-ベンゾイミダゾール-5-イル)メチリデン]ヒドラジド
1H-NMR(CD3CO2D)δ:9.01(s,1H),8.63(s,1H),8.33-8.25(m,3H),7.99(d,J=8.5Hz,1H),7.86(d,J=8.9Hz,1H),7.11(d,J=1.9Hz,1H),7.07(dd,J=1.9,8.5Hz,1H),4.09(s,3H),3.97(s,3H)。
Mass,m/z:425(M+),157(base)。
3-(2-メトキシフェニル)イソチアゾール-5-カルボン酸 [1-(1-メチル-1H-ベンゾイミダゾール-5-イル)メチリデン]ヒドラジド
1H-NMR(CD3CO2D)δ:9.02(s,1H),8.65(d,J=2.3Hz,1H),8.33-8.28(m,3H),8.00(dd,J=1.5,7.7Hz,1H),7.87(d,J=8.5Hz,1H),7.44-7.39(m,1H),7.11-7.04(m,2H),4.10(s,3H),3.95(s,3H)。
Mass,m/z:391(M+),204(base)。
3-(2,4-ジクロロフェニル)イソチアゾール-5-カルボン酸 [3,4-ジヒドロ-1H-2-オキサ-4a,9-ジアザフルオレン-7-イル)メチリデン]ヒドラジド
1H-NMR(CD3CO2D)δ:12.39(s,1H),8.40(s,1H),8.35(s,1H),8.05(s,1H),7.84(m,2H),7.72(d,J=8.10Hz,1H),7.60(d,J=8.2Hz,1H),5.00(s,2H),4.26(m,2H),4.19(m,2H)。
Mass,m/z:471(M+),199(base)。
3-(2-メトキシフェニル)イソチアゾール-5-カルボン酸 [1-(3,4-ジヒドロ-1H-2-オキサ-4a,9-ジアザフルオレン-7-イル)メチリデン]ヒドラジド
1H-NMR(CD3CO2D)δ:8.63(s,1H),8.28(s,1H),8.18(d,J=8.5Hz,1H),8.14(s,1H),8.00(d,J=7.7Hz,1H),7.71(d,J=8.5Hz,1H),7.42(t,J=7.7Hz,1H),7.11-7.04(m,2H),5.17(s,2H),4.33-4.27(m,4H),3.95(s,3H)。
Mass,m/z:433(M+),205(base)。
3-(4-クロロ-2-メトキシフェニル)イソチアゾール-5-カルボン酸 [1-(3,4-ジヒドロ-1H-2-オキサ-4a,9-ジアザ-フルオレン-7-イル)メチリデン]ヒドラジド
1H-NMR(CD3CO2D)δ:8.64(s,1H),8.32(s,1H),8.21-8.18(m,2H),8.00(d,J=8.1Hz,1H),7.73(d,J=8.9Hz,1H),7.12(d,J=1.2Hz,1H),7.08(dd,J=1.7,8.3Hz,1H),5.18(s,2H),4.35-4.27(m,4H),3.97(s,3H)。
Mass,m/z:467(M+),199(base)。
3-(2,4-ジクロロフェニル)イソチアゾール-5-カルボン酸 [1-(1-エチル-1H-インダゾール-5-イル)メチリデン]ヒドラジド
1H-NMR(CD3CO2D)δ:8.54(s,1H),8.29(s,1H),8.25(s,1H),8.23(dd,J=1.5Hz,J=9.1Hz,1H),8.17(s,1H),7.81(d,J=8.5Hz,1H),7.72(d,J=8.9Hz,1H),7.59(d,J=2.3Hz,1H),7.44(dd,J=1.9,8.5Hz,1H),4.55(q,J=7.3Hz,2H),1.50(t,J=7.3Hz,3H)。
Mass,m/z:443(M+),171(base)。
3-(2-メトキシフェニル)イソチアゾール-5-カルボン酸 [1-(1-エチル-1H-インダゾール-5-イル)メチリデン]ヒドラジド
1H-NMR(CD3CO2D)δ:8.64(s,1H),8.27-8.24(m,3H),8.16(s,1H),7.99(dd,J=1.7,7.5Hz,1H),7.72(d,J=8.9Hz,1H),7.42(m,1H),7.10(d,J=8.9Hz,1H),7.06(d,J=7.7Hz,1H),4.54(q,J=7.3Hz,2H),3.95(s,3H),1.50(t,J=7.3Hz,3H)。
Mass,m/z:405(M+),171(base)。
3-(4-クロロ-2-メトキシフェニル)イソチアゾール-5-カルボン酸 [1-エチル-1H-インダゾール-5-イル)メチリデン]ヒドラジド
1H-NMR(CD3CO2D)δ:8.63(s,1H),8.27-8.22(m,3H),8.16(s,1H),8.00(d,J=8.1Hz,1H),7.72(d,J=8.9Hz,1H),7.11(s,1H),7.08(dd,J=1.5,9.2Hz,1H),4.54(q,J=7.3Hz,2H),3.97(s,3H),1.50(t,J=7.3Hz,3H)。
Mass,m/z:439(M+),171(base)。
以下に、本発明の複素環化合物又はその塩の有効性に関する薬理試験の方法及び結果について説明する。
前記式(1)で表される化合物又はその塩の細胞死誘導活性を次のように測定した。
実施例9-15、9-16、9-24、9-25、9-38、9-39、9-40、9-42、9-48、9-49、9-58、9-59、9-60、9-61、9-62、9-63、9-64、9-92、9-93、9-94、9-96、9-98、9-103、9-128、9-129、9-136、9-137、9-165、9-169、9-181、9-221、9-222、9-223、9-224、9-226、9-227、9-228、9-233、9-235、9-247、9-249、9-280、9-300、9-344、9-372、13-10、13-26、13-80、13-84、13-85、13-86、13-88、13-89、13-90、13-92、13-97、13-99、13-100、13-101、13-103、13-106、13-108、13-109、13-110、13-111、13-112、13-113、13-118、13-133、47-3、47-4、47-7、47-9。
実施例9-1、9-13、9-14、9-17、9-19、9-20、9-22、9-23、9-26、9-27、9-28、9-33、9-36、9-37、9-41、9-47、9-56、9-57、9-67、9-71、9-76、9-77、9-78、9-81、9-82、9-86、9-87、9-91、9-95、9-97、9-102、9-106、9-107、9-108、9-113、9-130、9-134、9-135、9-138、9-139、9-140、9-141、9-143、9-144、9-145、9-147、9-150、9-153、9-154、9-155、9-160、9-161、9-163、9-164、9-166、9-167、9-170、9-171、9-172、9-173、9-174、9-176、9-182、9-207、9-208、9-209、9-213、9-217、9-218、9-219、9-229、9-230、9-234、9-239、9-245、9-248、9-250、9-251、9-258、9-259、9-260、9-261、9-262、9-267、9-281、9-283、9-291、9-292、9-301、9-340、9-341、9-345、9-346、9-349、9-357、9-358、9-359、9-360、9-362、9-364、9-365、9-373、9-377、13-8、13-9、13-11、13-15、13-16、13-17、13-18、13-24、13-25、13-28、13-34、13-35、13-50、13-55、13-76、13-81、13-82、13-83、13-87、13-95、13-98、13-102、13-104、13-105、13-107、13-116、13-119、13-120、13-121、13-122、13-123、13-129、13-149、13-150、17-2、23-46、23-92、23-171、40-1、40-2、43-2、47-6、49-1、49-2。
実施例9-3、9-18、9-35、9-46、9-53、9-68、9-70、9-75、9-79、9-80、9-83、9-88、9-90、9-100、9-101、9-104、9-111、9-112、9-115、9-120、9-126、9-127、9-131、9-133、9-142、9-146、9-152、9-156、9-157、9-162、9-168、9-175、9-177、9-185、9-210、9-214、9-215、9-220、9-236、9-242、9-243、9-246、9-252、9-253、9-256、9-257、9-268、9-269、9-270、9-271、9-284、9-285、9-286、9-290、9-293、9-295、9-302、9-343、9-348、9-350、9-352、9-353、9-356、9-361、9-366、9-368、9-370、9-374、9-375、9-376、13-1、13-3、13-5、13-12、13-13、13-21、13-30、13-33、13-44、13-45、13-48、13-49、13-53、13-54、13-56、13-67、13-77、13-78、13-91、13-96、13-114、13-115、13-117、13-127、13-135、16-1、16-6、16-8、16-11、16-13、16-19、16-20、16-24、16-25、17-1、21-25、22-9、22-10、23-2、23-4、23-7、23-12、23-14、23-15、23-16、23-17、23-44、23-48、23-50、23-53、23-68、23-70、23-73、23-74、23-78、23-79、23-82、23-83、23-84、23-88、23-90、23-91、23-93、23-95、23-97、23-98、23-120、23-122、23-123、23-124、23-145、23-149、23-153、23-156、23-157、23-158、23-159、23-160、24-3、27-7、27-8、27-10、27-13、37-1、39-1、40-3、43-1、43-3、45-5、45-7、47-1、47-5、47-11。
実施例9-2、9-12、9-30、9-31、9-32、9-43、9-44、9-45、9-54、9-66、9-69、9-72、9-74、9-84、9-85、9-99、9-109、9-110、9-121、9-122、9-125、9-148、9-149、9-151、9-158、9-183、9-184、9-186、9-192、9-193、9-200、9-203、9-205、9-216、9-231、9-240、9-244、9-254、9-255、9-263、9-264、9-265、9-266、9-274、9-275、9-276、9-279、9-288、9-289、9-294、9-296、9-303、9-304、9-305、9-342、9-347、9-351、9-354、9-355、9-363、9-367、9-369、9-371、10-2、13-19、13-20、13-23、13-27、13-31、13-39、13-41、13-57、13-68、13-71、13-72、13-93、13-94、13-125、13-128、13-130、13-131、13-132、16-3、16-4、16-7、16-10、16-12、16-15、16-16、16-17、16-18、16-21、16-22、16-23、17-3、18-1、18-2、21-7、21-9、21-11、21-19、21-20、21-21、21-22、22-3、22-6、22-8、23-8、23-13、23-22、23-23、23-26、23-28、23-34、23-38、23-41、23-43、23-45、23-47、23-52、23-55、23-61、23-65、23-66、23-67、23-71、23-72、23-75、23-76、23-77、23-80、23-85、23-89、23-94、23-100、23-104、23-106、23-110、23-115、23-116、23-117、23-118、23-121、23-125、23-126、23-127、23-128、23-130、23-131、23-134、23-135、23-136、23-137、23-139、23-140、23-141、23-142、23-143、23-147、23-161、23-162、23-165、23-166、23-167、23-168、23-171、23-172、24-1、24-2、27-4、27-5、27-9、27-12、29-1、29-2、30-2、34-1、36-1、36-2、37-2、37-3、37-4、38-1、42-1、42-2、43-4、45-2、45-6、47-2、47-8、49-5、49-6、49-7、49-8。
実施例9-5、9-7、9-8、9-11、9-21、9-29、9-50、9-55、9-116、9-118、9-119、9-124、9-178、9-179、9-191、9-195、9-196、9-204、9-211、9-212、9-238、9-241、9-273、9-277、9-278、9-297、9-298、9-306、9-309、9-311、9-313、9-320、9-321、9-324、9-335、9-337、9-338、9-339、13-22、13-36、13-46、13-61、13-66、13-70、13-73、13-124、13-126、13-137、13-141、13-144、16-2、16-5、16-9、16-14、17-4、19-1、19-2、20-1、21-2、21-6、21-8、21-13、21-15、21-17、21-18、22-1、22-4、22-7、23-1、23-5、23-6、23-10、23-11、23-18、23-19、23-20、23-21、23-24、23-27、23-30、23-35、23-40、23-42、23-51、23-57、23-59、23-60、23-81、23-86、23-101、23-102、23-103、23-105、23-107、23-108、23-113、23-119、23-129、23-132、23-133、23-138、23-150、23-152、23-154、23-163、23-169、23-170、25-1、25-2、25-3、25-4、25-5、26-1、26-2、26-3、27-1、27-2、27-3、27-6、27-11、27-14、27-15、27-16、28-1、30-1、31-1、36-3、36-4、36-5、38-2、38-3、41-1、45-1、45-3、45-4、47-10、47-12、49-3、49-4。
ヒト前立腺癌細胞株(PC-3細胞)及びヒト線維肉腫細胞株(HT1080細胞)を96穴マイクロプレートに各々1,300及び3,100細胞/wellの密度になるように播種し、5%CO2存在下37℃で各々48及び24時間培養後、各wellに被験物質を添加した。尚、薬剤のコントロールにはDMSOを添加した。いずれの細胞も被験物質を添加後72時間継続培養した後、1mg/mLの3’-[1-(フェニルアミノカルボニル)-3,4-テトラゾリウム]-ビス(4-メトキシ-6-ニトロ)ベンゼンスルホン酸ナトリウム水和物(XTT)を含むXTT標識試薬と1.25mMのN-メチルジベンゾピラジンメチル硫酸塩(PMS)を含む電子カップリング試薬とを50:1で混合したXTT標識混合液を各wellに対して各々50μL添加し、さらに4時間培養した。被験物質含有の培養液をブランクとして、XTT標識混合液を含む培養液を測定波長(450nm)及び対照波長(650nm)で、各々の吸光度をプレートリーダーにて測定し、その吸光度の差を生細胞由来のミトコンドリアの脱水素酵素の活性とした。IC50は、下記のシグモイド曲線のモデル式に対して、吸光度の差と回帰予測値の残差平方和を最小にする各変数(gain、range、base及びα)の収束解を求めた後、各被験物質のIC50(=eα)を算出した。
p21Cip1、p57Kip2及びCyclinD1は、かつてSCFSkp2の基質蛋白である可能性が報告されたものであるが、一方で別のE3の基質である可能性を示唆する報告もある。Nrf2は、その発現亢進が既存薬(抗癌剤)による耐性獲得の指標となること、及び別のE3の基質蛋白であること、が各々示唆されている。そこで、前記式(1)で表される化合物又はその塩が、p27Kip1選択的分解阻害剤であることを検証するためにp27Kip1を含むこれら分子を解析対象とした。
図1~図3から明らかな通り、前記式(1)で表される化合物又はその塩は、解析した他の基質蛋白の発現量に影響を及ぼさず、経時的にp27Kip1の発現量のみを増加させた。
対数増殖期(播種後48時間)のヒト前立腺癌細胞株(PC-3細胞)を、前記式(1)で表される化合物又はその塩で処理した後、経時的に細胞を回収し、70%エタノールに懸濁した後、-20℃に一晩以上放置し、細胞を固定化した。固定化した細胞をPBSにて2回洗浄した後、192mmol/L リン酸水素二ナトリウム、4mmol/L クエン酸溶液を100μL加えて懸濁し、室温で30分間穏やかに撹拌した。遠心し、上清を除去した後、100μg/mL RNase/PBS溶液を100μL加えて懸濁し、37℃で30分間インキュベートした。PBSを850μL加えた後、1mg/mL ヨウ化プロピジウム/PBS溶液を50μL加えて転倒混和し、穏やかに撹拌しながら室温で30分間反応させた後、メッシュフィルターに通して解析サンプルとした。フローサイトメーターを用いて、アポトーシス細胞の指標となるsub-G1細胞*比率の解析を行った。
(この論文でsub-G1細胞が、アポトーシス細胞の指標となることが定義されている)
結果
図1~図6から明らかな通り、前記式(1)で表される化合物又はその塩は、選択的にp27Kip1の発現量を増加させた後、アポトーシスを誘導することが示唆された。
ヒト前立腺癌細胞株PC-3を雄性6週齢ヌードマウスの右腋下部皮下に0.1mL移植(2×105cells/body)した。移植3日後よりVehicle又は下記化合物を1日2回/11日間反復経口投与した。移植14日後に腫瘍の長径及び短径を測定し、腫瘍体積(長径×短径×高さ×0.5236)を用いて薬効を評価した。
下記に示す化合物(実施例番号)は1mg/kg以下の用量において、Vehicle群と比較して抑制率50%以上の抗腫瘍効果を示した。
経口投与用の固形製剤
処方例: mg/錠
活性成分 5.0
でん粉 10.0
乳糖 73.0
カルボキシメチルセルロースカルシウム 10.0
タルク 1.0
ステアリン酸マグネシウム 1.0
全量 100.0
顆粒剤
活性成分[前記式(1)で表される化合物又はその塩]を70μm以下の粒度に粉砕し、でん粉、乳糖及びカルボキシメチルセルロースカルシウムを加えてよく混合した後、この混合粉体に10%のでん粉のりを加えて撹拌混合し、湿式造粒して顆粒剤を得た。
上記で得られた顆粒の粒径を1000μm前後に整粒し、これにタルク及びステアリン酸マグネシウムを混合し、打錠することにより、錠剤を得た。
上記で得られた顆粒を硬カプセルに充填することにより、カプセル剤を得た。
活性成分[前記式(1)で表される化合物又はその塩]50mgを可溶化剤としてエタノールを含有する生理食塩水100mLに溶解し、容器に充填密封後、滅菌を行って、注射剤を得た。
Claims (16)
- 下記式(1)
[式中、Aはアルキル基、シクロアルキル基、アリール基、又は複素環基を示し、基Aは置換基を有していてもよく;環Bは5~8員単環式複素環又はこの単環式複素環を含む縮合環を示し、環Bは置換基を有していてもよく;環Cは芳香族性環を示し、環Cは置換基を有していてもよく;Lは、主鎖が炭素原子、窒素原子、酸素原子、及び硫黄原子から選択された3~5つの原子を有し、かつ窒素原子、酸素原子、及び硫黄原子から選択された少なくとも1つのヘテロ原子を有するリンカーを示し、リンカーLは置換基を有していてもよく;nは0又は1である。
但し、(i)nが0のとき、環Bは5~8員単環式複素環を含む縮合環であり、
(ii)環Cが単環式アレーン環であるとき、環Cは置換基を有しており、
(iii)リンカーLが下記式(1-a1)
で表されるリンカーであるとき、基Aは2-メチルアミノピリミジン-4-イル基ではなく、環Cは9-フルオレニル基ではなく、
(iv)リンカーLが下記式(1-a2)
(式中、X1はメチル基を示す。)
で表されるリンカーであり、環Cがハロゲン原子を置換基として有するベンゼン環であるとき、環Bは3,4-イソオキサゾール-ジイル基ではない。]
で表される化合物又はその塩。 - 前記式(1)において、リンカーLがウレタン結合を含む請求項1記載の化合物又はその塩。
- 前記式(1)において、基Aが、ハロゲン原子、アルキル基、ヒドロキシル基、アルコキシ基、メルカプト基、及びアルキルチオ基から選択された少なくとも一種の置換基を有するアリール基又は複素環基である請求項1~3のいずれかに記載の化合物又はその塩。
- 前記式(1)において、基Aが、2-位及び/又は4-位に置換基を有するフェニル基である請求項4記載の化合物又はその塩。
- 前記式(1)において、環Bが、窒素原子、酸素原子、及び硫黄原子から選択された少なくとも一種のヘテロ原子を環の構成原子として含む芳香族複素環である請求項1~5のいずれかに記載の化合物又はその塩。
- 前記式(1)において、環Bが、ピロール環、フラン環、チオフェン環、イミダゾール環、ピラゾール環、チアゾール環、イソチアゾール環、オキサゾール環、イソオキサゾール環、チアジアゾール環、ピリジン環、ピリミジン環、及びキノリン環から選択された一種の芳香族複素環である請求項1~6のいずれかに記載の化合物又はその塩。
- 前記式(1)において、環Bが、チアゾール環、イソチアゾール環又はピラゾール環である請求項1~7のいずれかに記載の化合物又はその塩。
- 前記式(1)において、環Cが、置換基を有する単環式アレーン環、置換基を有していてもよい縮合アレーン環、及び置換基を有していてもよい単環式又は縮合複素環から選択された一種である請求項1~8のいずれかに記載の化合物又はその塩。
- 前記式(1)において、環Cが下記式(4-a)~(4-c)
[式中、Z1はハロゲン原子、アルキル基、ヒドロキシル基、アルコキシ基、メルカプト基、アルキルチオ基、N-アルキル置換アミノ基、又はN-アシル置換アミノ基を示し;Z2はアルキル基、又はアシル基を示し;Z3はアルキル基、又はアシル基を示し;環C1はC6-10アレーン環を示し;環C2はG1及びG2とともに、N、O、及びSから選択された少なくとも一種のヘテロ原子を環の構成原子として含む5~8員複素環を示し;環C3は隣接するG4とともに、N、O、及びSから選択された少なくとも一種のヘテロ原子を環の構成原子として含む5~8員複素環を示し;G1~G3は、環C2の芳香族性又は非芳香族性、又は環C3に隣接する5員環の芳香族性又は非芳香族性に応じて、N、O、S、NH、CH、又はCH2を示し;G4は、環C3に隣接する5員環の芳香族性又は非芳香族性に応じて、N、C、又はCHを示し;pは1~5の整数であり、qは0~6の整数である。]
のいずれかである請求項1~9のいずれかに記載の化合物又はその塩。 - 下記式(6-a)~(6-c)
のいずれかで表される化合物又はその塩。 - 請求項1~11のいずれかに記載の化合物又はその薬学的に許容される塩と、担体とを含む医薬組成物。
- 下記式(1)
[式中、Aはアルキル基、シクロアルキル基、アリール基、又は複素環基を示し、基Aは置換基を有していてもよく;環Bは5~8員単環式複素環又はこの単環式複素環を含む縮合環を示し、環Bは置換基を有していてもよく;環Cは芳香族性環を示し、環Cは置換基を有していてもよく;Lは、主鎖が炭素原子、窒素原子、酸素原子、及び硫黄原子から選択された3~5つの原子を有し、かつ窒素原子、酸素原子、及び硫黄原子から選択された少なくとも1つのヘテロ原子を有するリンカーを示し、リンカーLは置換基を有していてもよく;nは0又は1である。
但し、(i)nが0のとき、環Bは5~8員単環式複素環を含む縮合環であり、
(ii)環Cが単環式アレーン環であるとき、環Cは置換基を有している。]
で表される化合物又はその薬学的に許容される塩を有効成分として含有するp27Kip1ユビキチン化阻害剤。 - 請求項13記載の化合物又はその薬学的に許容される塩を有効成分として含有するp27Kip1分解阻害剤。
- 下記式(1)
[式中、Aはアルキル基、シクロアルキル基、アリール基、又は複素環基を示し、基Aは置換基を有していてもよく;環Bは5~8員単環式複素環又はこの単環式複素環を含む縮合環を示し、環Bは置換基を有していてもよく;環Cは芳香族性環を示し、環Cは置換基を有していてもよく;Lは、主鎖が炭素原子、窒素原子、酸素原子、及び硫黄原子から選択された3~5つの原子を有し、かつ窒素原子、酸素原子、及び硫黄原子から選択された少なくとも1つのヘテロ原子を有するリンカーを示し、リンカーLは置換基を有していてもよく;nは0又は1である。
但し、(i)nが0のとき、環Bは5~8員単環式複素環を含む縮合環であり、
(ii)環Cが単環式アレーン環であるとき、環Cは置換基を有しており、
(iii)リンカーLが下記式(1-a2)
(式中、X1はメチル基を示す。)
で表されるリンカーであり、環Cがハロゲン原子を置換基として有するベンゼン環であるとき、環Bは3,4-イソオキサゾール-ジイル基ではない。]
で表される化合物又はその薬学的に許容される塩を有効成分として含有する細胞増殖性疾患の予防及び/又は治療剤。 - 細胞増殖性疾患が、癌、リウマチ、糖尿病、肥満、子宮内膜症、前立腺肥大症及び炎症から選択された少なくとも一種である請求項15記載の予防及び/又は治療剤。
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Also Published As
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CN102985405A (zh) | 2013-03-20 |
JPWO2012002527A1 (ja) | 2013-08-29 |
EP2594555A1 (en) | 2013-05-22 |
CN105753858A (zh) | 2016-07-13 |
CN105753858B (zh) | 2019-04-30 |
US20130079306A1 (en) | 2013-03-28 |
CN102985405B (zh) | 2016-07-06 |
KR101844615B1 (ko) | 2018-05-14 |
JP5944823B2 (ja) | 2016-07-05 |
CA2804225C (en) | 2018-05-01 |
KR20130041115A (ko) | 2013-04-24 |
EP2594555A4 (en) | 2013-11-27 |
CA2804225A1 (en) | 2012-01-05 |
EP2594555B1 (en) | 2018-03-07 |
US9200008B2 (en) | 2015-12-01 |
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