JP2003201271A - Lipid modulator - Google Patents
Lipid modulatorInfo
- Publication number
- JP2003201271A JP2003201271A JP2002310549A JP2002310549A JP2003201271A JP 2003201271 A JP2003201271 A JP 2003201271A JP 2002310549 A JP2002310549 A JP 2002310549A JP 2002310549 A JP2002310549 A JP 2002310549A JP 2003201271 A JP2003201271 A JP 2003201271A
- Authority
- JP
- Japan
- Prior art keywords
- chloro
- phenyl
- nitrophenyl
- carboxamide
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000002632 lipids Chemical class 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 451
- 239000003814 drug Substances 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 8
- 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 7
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims abstract description 6
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims abstract description 4
- -1 o Xazolyl group Chemical group 0.000 claims description 416
- 238000000034 method Methods 0.000 claims description 358
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 260
- 150000003857 carboxamides Chemical class 0.000 claims description 184
- 150000003839 salts Chemical class 0.000 claims description 39
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 125000003277 amino group Chemical group 0.000 claims description 20
- 239000000126 substance Substances 0.000 claims description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 10
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 7
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- BXGPFYRXFDHQAB-UHFFFAOYSA-N [4-[4-[(2-chloro-5-nitrobenzoyl)amino]phenyl]phenyl] acetate Chemical compound C1=CC(OC(=O)C)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl BXGPFYRXFDHQAB-UHFFFAOYSA-N 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000005462 imide group Chemical group 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical group C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 claims description 2
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical group C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
- RLZTXOHTNAJLEX-UHFFFAOYSA-N 2-chloro-n-[4-(1-hydroxyethyl)phenyl]-5-nitrobenzamide Chemical compound C1=CC(C(O)C)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl RLZTXOHTNAJLEX-UHFFFAOYSA-N 0.000 claims description 2
- UVMFZHOYNKFIDS-UHFFFAOYSA-N 2-chloro-n-[4-(diaminomethylideneamino)sulfonylphenyl]-5-nitrobenzamide Chemical compound C1=CC(S(=O)(=O)NC(=N)N)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl UVMFZHOYNKFIDS-UHFFFAOYSA-N 0.000 claims description 2
- QJHSQOZCXDOXAO-UHFFFAOYSA-N 2-chloro-n-[4-(ethylsulfonylamino)phenyl]-5-nitrobenzamide Chemical compound C1=CC(NS(=O)(=O)CC)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl QJHSQOZCXDOXAO-UHFFFAOYSA-N 0.000 claims description 2
- OHMAGUSIDSEVHO-UHFFFAOYSA-N 2-chloro-n-[4-(methanesulfonamido)phenyl]-5-nitrobenzamide Chemical compound C1=CC(NS(=O)(=O)C)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl OHMAGUSIDSEVHO-UHFFFAOYSA-N 0.000 claims description 2
- YQWTXGOINNHWJJ-UHFFFAOYSA-N 2-chloro-n-[4-[(6-hydroxy-2,5,7,8-tetramethyl-4-oxo-3h-chromen-2-yl)methoxy]phenyl]-5-nitrobenzamide Chemical compound C1C(=O)C=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl YQWTXGOINNHWJJ-UHFFFAOYSA-N 0.000 claims description 2
- AKOJMUWORICCLR-UHFFFAOYSA-N [2-[[4-[(2-chloro-5-nitrobenzoyl)amino]phenoxy]methyl]-2,5,7,8-tetramethyl-4-oxo-3h-chromen-6-yl] acetate Chemical compound C1C(=O)C2=C(C)C(OC(=O)C)=C(C)C(C)=C2OC1(C)COC(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl AKOJMUWORICCLR-UHFFFAOYSA-N 0.000 claims description 2
- 239000003741 agents affecting lipid metabolism Substances 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- 150000001669 calcium Chemical class 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- HTPHBIPIZQGVGQ-UHFFFAOYSA-N n-(4-acetamidophenyl)-2-chloro-5-nitrobenzamide Chemical compound C1=CC(NC(=O)C)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl HTPHBIPIZQGVGQ-UHFFFAOYSA-N 0.000 claims description 2
- QBAXAQDSFFIFQF-UHFFFAOYSA-N n-[4-(4-acetamidophenyl)phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(NC(=O)C)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl QBAXAQDSFFIFQF-UHFFFAOYSA-N 0.000 claims description 2
- RSDLMTSXLQWDBT-UHFFFAOYSA-N n-[4-(4-acetylpiperazin-1-yl)phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl RSDLMTSXLQWDBT-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000000565 sulfonamide group Chemical group 0.000 claims description 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims 2
- CPWZLBPJLKSCCN-UHFFFAOYSA-N (2-chloro-5-nitrophenyl)-(4-methylpiperazin-1-yl)methanone Chemical compound C1CN(C)CCN1C(=O)C1=CC([N+]([O-])=O)=CC=C1Cl CPWZLBPJLKSCCN-UHFFFAOYSA-N 0.000 claims 1
- MNHIASWCDSANIX-UHFFFAOYSA-N (2-chloro-5-nitrophenyl)-(4-phenylpiperazin-1-yl)methanone Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)N2CCN(CC2)C=2C=CC=CC=2)=C1 MNHIASWCDSANIX-UHFFFAOYSA-N 0.000 claims 1
- JTMXFDQIZASYIC-UHFFFAOYSA-N (2-chloro-5-nitrophenyl)-[4-[4-(dimethylamino)phenyl]piperazin-1-yl]methanone Chemical compound C1=CC(N(C)C)=CC=C1N1CCN(C(=O)C=2C(=CC=C(C=2)[N+]([O-])=O)Cl)CC1 JTMXFDQIZASYIC-UHFFFAOYSA-N 0.000 claims 1
- OIGUEMSERRIJBO-UHFFFAOYSA-N (2-chloro-5-nitrophenyl)-pyrrolidin-1-ylmethanone Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)N2CCCC2)=C1 OIGUEMSERRIJBO-UHFFFAOYSA-N 0.000 claims 1
- ZXNXJEVJKMJMBN-UHFFFAOYSA-N (4-benzylpiperazin-1-yl)-(2-chloro-5-nitrophenyl)methanone Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)N2CCN(CC=3C=CC=CC=3)CC2)=C1 ZXNXJEVJKMJMBN-UHFFFAOYSA-N 0.000 claims 1
- DYPULZFIMKOVQR-UHFFFAOYSA-N 2-chloro-5-nitro-n-(3-pyrrolidin-1-ylsulfonylphenyl)benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=C(C=CC=2)S(=O)(=O)N2CCCC2)=C1 DYPULZFIMKOVQR-UHFFFAOYSA-N 0.000 claims 1
- DJGIUIMZVFAPPS-UHFFFAOYSA-N 2-chloro-5-nitro-n-(4-pyrrolidin-1-ylsulfonylphenyl)benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)S(=O)(=O)N2CCCC2)=C1 DJGIUIMZVFAPPS-UHFFFAOYSA-N 0.000 claims 1
- NEROTJBRFMZDCW-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-(pyridin-3-ylcarbamothioylamino)phenyl]benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(NC(=S)NC=3C=NC=CC=3)=CC=2)=C1 NEROTJBRFMZDCW-UHFFFAOYSA-N 0.000 claims 1
- KUUXFFHOPUAORU-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-(pyridin-4-ylcarbamothioylamino)phenyl]benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(NC(=S)NC=3C=CN=CC=3)=CC=2)=C1 KUUXFFHOPUAORU-UHFFFAOYSA-N 0.000 claims 1
- PVYVIEMGRGJLQI-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-[2-(phenylcarbamothioylamino)ethyl]phenyl]benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(CCNC(=S)NC=3C=CC=CC=3)=CC=2)=C1 PVYVIEMGRGJLQI-UHFFFAOYSA-N 0.000 claims 1
- UYFCPKGWQCNQHL-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-[2-(phenylcarbamoylamino)ethyl]phenyl]benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(CCNC(=O)NC=3C=CC=CC=3)=CC=2)=C1 UYFCPKGWQCNQHL-UHFFFAOYSA-N 0.000 claims 1
- MGGYUUCKSZKPSF-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-[2-(pyridin-3-ylcarbamothioylamino)ethyl]phenyl]benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(CCNC(=S)NC=3C=NC=CC=3)=CC=2)=C1 MGGYUUCKSZKPSF-UHFFFAOYSA-N 0.000 claims 1
- OXMQUTYAGJAVHC-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-[4-(pyridin-4-ylcarbamothioylamino)phenyl]phenyl]benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)C=2C=CC(NC(=S)NC=3C=CN=CC=3)=CC=2)=C1 OXMQUTYAGJAVHC-UHFFFAOYSA-N 0.000 claims 1
- MGKKXVBMNGDYAU-UHFFFAOYSA-N 2-chloro-n-(1-methylbenzimidazol-2-yl)-5-nitrobenzamide Chemical compound N=1C2=CC=CC=C2N(C)C=1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl MGKKXVBMNGDYAU-UHFFFAOYSA-N 0.000 claims 1
- DRFKYUXGMFECFV-UHFFFAOYSA-N 2-chloro-n-(4-morpholin-4-ylsulfonylphenyl)-5-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)S(=O)(=O)N2CCOCC2)=C1 DRFKYUXGMFECFV-UHFFFAOYSA-N 0.000 claims 1
- VKZMVLDROWPQTP-UHFFFAOYSA-N 2-chloro-n-[3-(2-hydroxyethyl)phenyl]-5-nitrobenzamide Chemical compound OCCC1=CC=CC(NC(=O)C=2C(=CC=C(C=2)[N+]([O-])=O)Cl)=C1 VKZMVLDROWPQTP-UHFFFAOYSA-N 0.000 claims 1
- XRTNVRKTGCOIPS-UHFFFAOYSA-N 2-chloro-n-[4-[4-(2,5-dimethylpyrrol-1-yl)phenyl]phenyl]-5-nitrobenzamide Chemical compound CC1=CC=C(C)N1C1=CC=C(C=2C=CC(NC(=O)C=3C(=CC=C(C=3)[N+]([O-])=O)Cl)=CC=2)C=C1 XRTNVRKTGCOIPS-UHFFFAOYSA-N 0.000 claims 1
- JWQNAFPSIJEBFJ-UHFFFAOYSA-N 2-chloro-n-[4-[4-[(3-methoxyphenyl)carbamoylamino]phenyl]phenyl]-5-nitrobenzamide Chemical compound COC1=CC=CC(NC(=O)NC=2C=CC(=CC=2)C=2C=CC(NC(=O)C=3C(=CC=C(C=3)[N+]([O-])=O)Cl)=CC=2)=C1 JWQNAFPSIJEBFJ-UHFFFAOYSA-N 0.000 claims 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims 1
- 125000003943 azolyl group Chemical group 0.000 claims 1
- BSEUTKKMHWHNOY-UHFFFAOYSA-N ethyl n-[2-[4-[(2-chloro-5-nitrobenzoyl)amino]phenyl]ethylcarbamothioyl]carbamate Chemical compound C1=CC(CCNC(=S)NC(=O)OCC)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl BSEUTKKMHWHNOY-UHFFFAOYSA-N 0.000 claims 1
- XMPSAZDFGFKCTB-UHFFFAOYSA-N n-(3-acetylphenyl)-2-chloro-5-nitrobenzamide Chemical compound CC(=O)C1=CC=CC(NC(=O)C=2C(=CC=C(C=2)[N+]([O-])=O)Cl)=C1 XMPSAZDFGFKCTB-UHFFFAOYSA-N 0.000 claims 1
- DLDMGOQPCNYIMZ-UHFFFAOYSA-N n-(4-acetylphenyl)-2-chloro-5-nitrobenzamide Chemical compound C1=CC(C(=O)C)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl DLDMGOQPCNYIMZ-UHFFFAOYSA-N 0.000 claims 1
- HOILMFBWUNBECP-UHFFFAOYSA-N n-(6-acetamido-1,3-benzothiazol-2-yl)-2-chloro-5-nitrobenzamide Chemical compound S1C2=CC(NC(=O)C)=CC=C2N=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl HOILMFBWUNBECP-UHFFFAOYSA-N 0.000 claims 1
- XPSIJXOZHDNYHJ-UHFFFAOYSA-N n-[3-(2-acetamido-1,3-thiazol-4-yl)phenyl]-2-chloro-5-nitrobenzamide Chemical compound S1C(NC(=O)C)=NC(C=2C=C(NC(=O)C=3C(=CC=C(C=3)[N+]([O-])=O)Cl)C=CC=2)=C1 XPSIJXOZHDNYHJ-UHFFFAOYSA-N 0.000 claims 1
- CJAQZIGFVVVDRW-UHFFFAOYSA-N n-[4-(2-acetamido-1,3-thiazol-4-yl)phenyl]-2-chloro-5-nitrobenzamide Chemical compound S1C(NC(=O)C)=NC(C=2C=CC(NC(=O)C=3C(=CC=C(C=3)[N+]([O-])=O)Cl)=CC=2)=C1 CJAQZIGFVVVDRW-UHFFFAOYSA-N 0.000 claims 1
- OEAHLHBRQQLPAK-UHFFFAOYSA-N n-[4-(2-aminoethyl)phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(CCN)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl OEAHLHBRQQLPAK-UHFFFAOYSA-N 0.000 claims 1
- HFPUSJATYLBQNX-UHFFFAOYSA-N n-[4-(3-acetamidophenyl)-1,3-thiazol-2-yl]-2-chloro-5-nitrobenzamide Chemical compound CC(=O)NC1=CC=CC(C=2N=C(NC(=O)C=3C(=CC=C(C=3)[N+]([O-])=O)Cl)SC=2)=C1 HFPUSJATYLBQNX-UHFFFAOYSA-N 0.000 claims 1
- RZNQJFYKDAFOMU-UHFFFAOYSA-N n-[4-(4-acetamidophenyl)-1,3-thiazol-2-yl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(NC(=O)C)=CC=C1C1=CSC(NC(=O)C=2C(=CC=C(C=2)[N+]([O-])=O)Cl)=N1 RZNQJFYKDAFOMU-UHFFFAOYSA-N 0.000 claims 1
- GEZUGRGITXOLAO-UHFFFAOYSA-N n-[4-(butylcarbamoylsulfamoyl)phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(S(=O)(=O)NC(=O)NCCCC)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl GEZUGRGITXOLAO-UHFFFAOYSA-N 0.000 claims 1
- LNIKOTLBOJRLFN-UHFFFAOYSA-N n-[4-[2-(benzoylcarbamothioylamino)ethyl]phenyl]-2-chloro-5-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(CCNC(=S)NC(=O)C=3C=CC=CC=3)=CC=2)=C1 LNIKOTLBOJRLFN-UHFFFAOYSA-N 0.000 claims 1
- SUKWGOWFGOOHSJ-UHFFFAOYSA-N n-[4-[2-(carbamoylamino)ethyl]phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(CCNC(=O)N)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl SUKWGOWFGOOHSJ-UHFFFAOYSA-N 0.000 claims 1
- ZNVVZWYOUHGTJK-UHFFFAOYSA-N n-[4-[4-(benzylcarbamoylamino)phenyl]phenyl]-2-chloro-5-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)C=2C=CC(NC(=O)NCC=3C=CC=CC=3)=CC=2)=C1 ZNVVZWYOUHGTJK-UHFFFAOYSA-N 0.000 claims 1
- OQOHNIXBTACITJ-UHFFFAOYSA-N n-[4-[4-[bis(ethylsulfonyl)amino]phenyl]phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(N(S(=O)(=O)CC)S(=O)(=O)CC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl OQOHNIXBTACITJ-UHFFFAOYSA-N 0.000 claims 1
- IVNIHRFKDQSRSD-UHFFFAOYSA-N n-[6-(carbamoylamino)-1,3-benzothiazol-2-yl]-2-chloro-5-nitrobenzamide Chemical compound S1C2=CC(NC(=O)N)=CC=C2N=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl IVNIHRFKDQSRSD-UHFFFAOYSA-N 0.000 claims 1
- RHUZTELUFYMHDN-UHFFFAOYSA-N tert-butyl n-[2-[4-[(2-chloro-5-nitrobenzoyl)amino]phenyl]ethyl]carbamate Chemical compound C1=CC(CCNC(=O)OC(C)(C)C)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl RHUZTELUFYMHDN-UHFFFAOYSA-N 0.000 claims 1
- XKODFYWBJQJOPH-UHFFFAOYSA-N tert-butyl n-[4-[4-[(2-chloro-5-nitrobenzoyl)amino]phenyl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl XKODFYWBJQJOPH-UHFFFAOYSA-N 0.000 claims 1
- 229910002091 carbon monoxide Inorganic materials 0.000 abstract description 6
- 230000000069 prophylactic effect Effects 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 375
- 238000005160 1H NMR spectroscopy Methods 0.000 description 369
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 257
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 205
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 204
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 185
- OGLKKYALUKXVPQ-UHFFFAOYSA-N 2-chloro-5-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(Cl)=O)=C1 OGLKKYALUKXVPQ-UHFFFAOYSA-N 0.000 description 181
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 177
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 147
- 239000000243 solution Substances 0.000 description 136
- 238000006243 chemical reaction Methods 0.000 description 127
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 94
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 94
- 230000002829 reductive effect Effects 0.000 description 92
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 81
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 80
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 79
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
- 239000000203 mixture Substances 0.000 description 68
- 229910052739 hydrogen Inorganic materials 0.000 description 65
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 63
- 238000001914 filtration Methods 0.000 description 61
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 56
- 238000012360 testing method Methods 0.000 description 53
- 239000013078 crystal Substances 0.000 description 50
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 47
- 239000007787 solid Substances 0.000 description 46
- 235000017557 sodium bicarbonate Nutrition 0.000 description 43
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 43
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 42
- 229920006395 saturated elastomer Polymers 0.000 description 42
- 239000012044 organic layer Substances 0.000 description 41
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 38
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 210000004027 cell Anatomy 0.000 description 31
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 29
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 28
- 239000002609 medium Substances 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 24
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- 102000000536 PPAR gamma Human genes 0.000 description 22
- 108010016731 PPAR gamma Proteins 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 230000004069 differentiation Effects 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 208000001132 Osteoporosis Diseases 0.000 description 19
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 19
- 108020004414 DNA Proteins 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 18
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 210000001789 adipocyte Anatomy 0.000 description 16
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 16
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 16
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 14
- 229940126062 Compound A Drugs 0.000 description 13
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 12
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 12
- 108060001084 Luciferase Proteins 0.000 description 11
- 239000005089 Luciferase Substances 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- NFXMJUHGUXKRKJ-UHFFFAOYSA-N C1=CC(=C(C=C1[N+](=O)[O-])C(=O)N)Cl.Cl Chemical compound C1=CC(=C(C=C1[N+](=O)[O-])C(=O)N)Cl.Cl NFXMJUHGUXKRKJ-UHFFFAOYSA-N 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 10
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 10
- 239000005557 antagonist Substances 0.000 description 10
- 230000037396 body weight Effects 0.000 description 10
- 239000012141 concentrate Substances 0.000 description 10
- 235000008504 concentrate Nutrition 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000001963 growth medium Substances 0.000 description 10
- JARKCYVAAOWBJS-UHFFFAOYSA-N hexanal Chemical compound CCCCCC=O JARKCYVAAOWBJS-UHFFFAOYSA-N 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 239000013641 positive control Substances 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 102000016267 Leptin Human genes 0.000 description 9
- 108010092277 Leptin Proteins 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 125000005518 carboxamido group Chemical group 0.000 description 9
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 9
- 229940039781 leptin Drugs 0.000 description 9
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 9
- 239000013612 plasmid Substances 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- SDHXWAPVLOGAJR-UHFFFAOYSA-N 2-chloro-5-nitrobenzamide Chemical class NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl SDHXWAPVLOGAJR-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 8
- 239000012346 acetyl chloride Substances 0.000 description 8
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 150000002170 ethers Chemical class 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 230000001939 inductive effect Effects 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000004031 partial agonist Substances 0.000 description 8
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 8
- QUEKGYQTRJVEQC-UHFFFAOYSA-N 2516-96-3 Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl QUEKGYQTRJVEQC-UHFFFAOYSA-N 0.000 description 7
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 7
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 7
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 7
- 230000009471 action Effects 0.000 description 7
- 239000000556 agonist Substances 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 150000008282 halocarbons Chemical class 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 230000037356 lipid metabolism Effects 0.000 description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
- 230000001737 promoting effect Effects 0.000 description 7
- 108091008146 restriction endonucleases Proteins 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- BWWHTIHDQBHTHP-UHFFFAOYSA-N 2-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1C(Cl)=O BWWHTIHDQBHTHP-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 6
- 210000000988 bone and bone Anatomy 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 239000006285 cell suspension Substances 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 238000012258 culturing Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 230000036961 partial effect Effects 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 210000000636 white adipocyte Anatomy 0.000 description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 5
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 5
- 229920004890 Triton X-100 Polymers 0.000 description 5
- 239000013504 Triton X-100 Substances 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 239000013613 expression plasmid Substances 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 5
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 5
- 230000003449 preventive effect Effects 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000012192 staining solution Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 5
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 4
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- QUEKGYQTRJVEQC-UHFFFAOYSA-M 2-chloro-5-nitrobenzoate Chemical compound [O-]C(=O)C1=CC([N+]([O-])=O)=CC=C1Cl QUEKGYQTRJVEQC-UHFFFAOYSA-M 0.000 description 4
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000005916 2-methylpentyl group Chemical group 0.000 description 4
- 125000005917 3-methylpentyl group Chemical group 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 4
- 239000012981 Hank's balanced salt solution Substances 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- NIZHERJWXFHGGU-UHFFFAOYSA-N isocyanato(trimethyl)silane Chemical compound C[Si](C)(C)N=C=O NIZHERJWXFHGGU-UHFFFAOYSA-N 0.000 description 4
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 125000002971 oxazolyl group Chemical group 0.000 description 4
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 4
- 239000002304 perfume Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 4
- 125000004193 piperazinyl group Chemical group 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000001373 regressive effect Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 229940126585 therapeutic drug Drugs 0.000 description 4
- 150000001467 thiazolidinediones Chemical class 0.000 description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSJBFKREUBQANJ-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-(pyridin-3-ylcarbamoyl)phenyl]benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)C(=O)NC=2C=NC=CC=2)=C1 CSJBFKREUBQANJ-UHFFFAOYSA-N 0.000 description 3
- ZEBKGKSILFMYCO-UHFFFAOYSA-N 2-chloro-n-[4-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]-5-nitrobenzamide Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(C=2N=C(NC(=O)C=3C(=CC=C(C=3)[N+]([O-])=O)Cl)SC=2)=C1 ZEBKGKSILFMYCO-UHFFFAOYSA-N 0.000 description 3
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 3
- VMSZFBSYWXMXRF-UHFFFAOYSA-N 3-isothiocyanatopyridine Chemical compound S=C=NC1=CC=CN=C1 VMSZFBSYWXMXRF-UHFFFAOYSA-N 0.000 description 3
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 3
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 3
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010039984 Senile osteoporosis Diseases 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 210000000577 adipose tissue Anatomy 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 150000001718 carbodiimides Chemical class 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000013592 cell lysate Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000012937 correction Methods 0.000 description 3
- 230000000378 dietary effect Effects 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 3
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000001786 isothiazolyl group Chemical group 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 3
- 235000019426 modified starch Nutrition 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 102000006255 nuclear receptors Human genes 0.000 description 3
- 108020004017 nuclear receptors Proteins 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 3
- YHSREIRWPKNBCD-UHFFFAOYSA-N tert-butyl n-[3-[2-[(2-chloro-5-nitrobenzoyl)amino]-1,3-thiazol-4-yl]phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC(C=2N=C(NC(=O)C=3C(=CC=C(C=3)[N+]([O-])=O)Cl)SC=2)=C1 YHSREIRWPKNBCD-UHFFFAOYSA-N 0.000 description 3
- ZFTWHKJTOZSKGV-UHFFFAOYSA-N tert-butyl n-[4-[2-[(2-chloro-5-nitrobenzoyl)amino]-1,3-thiazol-4-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CSC(NC(=O)C=2C(=CC=C(C=2)[N+]([O-])=O)Cl)=N1 ZFTWHKJTOZSKGV-UHFFFAOYSA-N 0.000 description 3
- 125000004302 thioazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 3
- 210000002303 tibia Anatomy 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 210000000689 upper leg Anatomy 0.000 description 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 2
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- FRPJSHKMZHWJBE-UHFFFAOYSA-N 2-chloro-5-nitro-N-pyridin-4-ylbenzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CN=CC=2)=C1 FRPJSHKMZHWJBE-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- ASHGTJPOSUFTGB-UHFFFAOYSA-N 3-methoxyphenol Chemical compound COC1=CC=CC(O)=C1 ASHGTJPOSUFTGB-UHFFFAOYSA-N 0.000 description 2
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- KCJLDYVWDOTJKK-UHFFFAOYSA-N 4-isothiocyanatopyridine Chemical compound S=C=NC1=CC=NC=C1 KCJLDYVWDOTJKK-UHFFFAOYSA-N 0.000 description 2
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 2
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 2
- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 102000012422 Collagen Type I Human genes 0.000 description 2
- 108010022452 Collagen Type I Proteins 0.000 description 2
- 208000002249 Diabetes Complications Diseases 0.000 description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
- 206010012655 Diabetic complications Diseases 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 208000030814 Eating disease Diseases 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 208000019454 Feeding and Eating disease Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 101000741790 Homo sapiens Peroxisome proliferator-activated receptor gamma Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 201000001431 Hyperuricemia Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241001024304 Mino Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- OJGMBLNIHDZDGS-UHFFFAOYSA-N N-Ethylaniline Chemical compound CCNC1=CC=CC=C1 OJGMBLNIHDZDGS-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 108091008767 PPARγ2 Proteins 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 239000000883 anti-obesity agent Substances 0.000 description 2
- 229940125710 antiobesity agent Drugs 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000002785 azepinyl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000010241 blood sampling Methods 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 210000002798 bone marrow cell Anatomy 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- LIMQQADUEULBSO-UHFFFAOYSA-N butyl isothiocyanate Chemical compound CCCCN=C=S LIMQQADUEULBSO-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 235000014632 disordered eating Nutrition 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- BDTDECDAHYOJRO-UHFFFAOYSA-N ethyl n-(sulfanylidenemethylidene)carbamate Chemical compound CCOC(=O)N=C=S BDTDECDAHYOJRO-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 239000000834 fixative Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 208000018914 glucose metabolism disease Diseases 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 2
- BNTRVUUJBGBGLZ-UHFFFAOYSA-N hydron;pyridine-4-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=NC=C1 BNTRVUUJBGBGLZ-UHFFFAOYSA-N 0.000 description 2
- 125000002632 imidazolidinyl group Chemical group 0.000 description 2
- 125000002636 imidazolinyl group Chemical group 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000008011 inorganic excipient Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 230000005976 liver dysfunction Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 125000006501 nitrophenyl group Chemical group 0.000 description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- NUJGJRNETVAIRJ-UHFFFAOYSA-N octanal Chemical compound CCCCCCCC=O NUJGJRNETVAIRJ-UHFFFAOYSA-N 0.000 description 2
- 239000008012 organic excipient Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 210000000963 osteoblast Anatomy 0.000 description 2
- 230000004072 osteoblast differentiation Effects 0.000 description 2
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 2
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 2
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 2
- 229940117953 phenylisothiocyanate Drugs 0.000 description 2
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 238000003752 polymerase chain reaction Methods 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 2
- 125000002755 pyrazolinyl group Chemical group 0.000 description 2
- 125000001422 pyrrolinyl group Chemical group 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 150000004492 retinoid derivatives Chemical class 0.000 description 2
- 208000007442 rickets Diseases 0.000 description 2
- 102220240796 rs553605556 Human genes 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- ISTGQSQWSKCNFJ-UHFFFAOYSA-N tert-butyl n-ethylcarbamate Chemical compound CCNC(=O)OC(C)(C)C ISTGQSQWSKCNFJ-UHFFFAOYSA-N 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 125000004014 thioethyl group Chemical group [H]SC([H])([H])C([H])([H])* 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- 239000006163 transport media Substances 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- DOMQFIFVDIAOOT-ROUUACIJSA-N (2S,3R)-N-[4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1C=1C=NC=C(C=1)C)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)C DOMQFIFVDIAOOT-ROUUACIJSA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- GUHXYHYUBFCYGJ-UHFFFAOYSA-N (4-phenylphenyl)azanium;chloride Chemical compound [Cl-].C1=CC([NH3+])=CC=C1C1=CC=CC=C1 GUHXYHYUBFCYGJ-UHFFFAOYSA-N 0.000 description 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- UKGJZDSUJSPAJL-YPUOHESYSA-N (e)-n-[(1r)-1-[3,5-difluoro-4-(methanesulfonamido)phenyl]ethyl]-3-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]prop-2-enamide Chemical compound CCCC1=NC(C(F)(F)F)=CC=C1\C=C\C(=O)N[C@H](C)C1=CC(F)=C(NS(C)(=O)=O)C(F)=C1 UKGJZDSUJSPAJL-YPUOHESYSA-N 0.000 description 1
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 1
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 1
- QUKGLNCXGVWCJX-UHFFFAOYSA-N 1,3,4-thiadiazol-2-amine Chemical compound NC1=NN=CS1 QUKGLNCXGVWCJX-UHFFFAOYSA-N 0.000 description 1
- LQQKDSXCDXHLLF-UHFFFAOYSA-N 1,3-dibromopropan-2-one Chemical compound BrCC(=O)CBr LQQKDSXCDXHLLF-UHFFFAOYSA-N 0.000 description 1
- CMEPUAROFJSGJN-UHFFFAOYSA-N 1,4-dioxan-2-ylmethanol Chemical compound OCC1COCCO1 CMEPUAROFJSGJN-UHFFFAOYSA-N 0.000 description 1
- QGAVWEQSMLJGGG-UHFFFAOYSA-N 1,5-dimethyl-2h-pyrimidin-2-amine Chemical compound CN1C=C(C)C=NC1N QGAVWEQSMLJGGG-UHFFFAOYSA-N 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
- MJUVRTYWUMPBTR-MRXNPFEDSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-[1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide Chemical compound FC=1C=C2N(C[C@@H](O)CO)C(C(C)(CO)C)=CC2=CC=1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 MJUVRTYWUMPBTR-MRXNPFEDSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- QPXGLRJFCBZQNF-UHFFFAOYSA-N 1-[3-(hydroxymethyl)phenyl]-2-[(2-phenylmethoxyphenyl)methylamino]ethanol Chemical compound OCC1=CC=CC(C(O)CNCC=2C(=CC=CC=2)OCC=2C=CC=CC=2)=C1 QPXGLRJFCBZQNF-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006074 1-ethyl-2-butenyl group Chemical group 0.000 description 1
- 125000006075 1-ethyl-3-butenyl group Chemical group 0.000 description 1
- RIKWVZGZRYDACA-UHFFFAOYSA-N 1-fluoro-3-isocyanatobenzene Chemical compound FC1=CC=CC(N=C=O)=C1 RIKWVZGZRYDACA-UHFFFAOYSA-N 0.000 description 1
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 description 1
- UBUZJQPRFPSWHR-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene nitrobenzene Chemical compound FC1=CC=C(C=C1)[N+](=O)[O-].[N+](=O)([O-])C1=CC=CC=C1 UBUZJQPRFPSWHR-UHFFFAOYSA-N 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- JRVZITODZAQRQM-UHFFFAOYSA-N 1-isocyanato-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1N=C=O JRVZITODZAQRQM-UHFFFAOYSA-N 0.000 description 1
- NPOVTGVGOBJZPY-UHFFFAOYSA-N 1-isocyanato-3-methoxybenzene Chemical compound COC1=CC=CC(N=C=O)=C1 NPOVTGVGOBJZPY-UHFFFAOYSA-N 0.000 description 1
- 125000006025 1-methyl-1-butenyl group Chemical group 0.000 description 1
- 125000006019 1-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000006028 1-methyl-2-butenyl group Chemical group 0.000 description 1
- 125000006048 1-methyl-2-pentenyl group Chemical group 0.000 description 1
- 125000006021 1-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006030 1-methyl-3-butenyl group Chemical group 0.000 description 1
- 125000006052 1-methyl-3-pentenyl group Chemical group 0.000 description 1
- 125000006055 1-methyl-4-pentenyl group Chemical group 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- OWEMTCOXFULTNW-UHFFFAOYSA-N 2,3-dimethyl-2-propan-2-ylbutanoic acid Chemical compound CC(C)C(C)(C(C)C)C(O)=O OWEMTCOXFULTNW-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- QIJIUJYANDSEKG-UHFFFAOYSA-N 2,4,4-trimethylpentan-2-amine Chemical class CC(C)(C)CC(C)(C)N QIJIUJYANDSEKG-UHFFFAOYSA-N 0.000 description 1
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 1
- GFISDBXSWQMOND-UHFFFAOYSA-N 2,5-dimethoxyoxolane Chemical compound COC1CCC(OC)O1 GFISDBXSWQMOND-UHFFFAOYSA-N 0.000 description 1
- CHZXTOCAICMPQR-UHFFFAOYSA-N 2-(2-bromoethyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCBr)C(=O)C2=C1 CHZXTOCAICMPQR-UHFFFAOYSA-N 0.000 description 1
- SURCGQGDUADKBL-UHFFFAOYSA-N 2-(2-hydroxyethylamino)-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(NCCO)C2=O)=O)=C3C2=CC=CC3=C1 SURCGQGDUADKBL-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- SGFOGHSPQRYIEQ-UHFFFAOYSA-N 2-[3-(4-aminophenoxy)propyl]isoindole-1,3-dione Chemical compound C1=CC(N)=CC=C1OCCCN1C(=O)C2=CC=CC=C2C1=O SGFOGHSPQRYIEQ-UHFFFAOYSA-N 0.000 description 1
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 1
- UYPXQSLSPUBZQW-UHFFFAOYSA-N 2-bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone Chemical compound CC(C)(C)C1=CC(C(=O)CBr)=CC(C(C)(C)C)=C1O UYPXQSLSPUBZQW-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- WHPFDGIJCOQORR-UHFFFAOYSA-N 2-chloro-5-nitro-N-(4-pyridin-3-yl-1,3-thiazol-2-yl)benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2SC=C(N=2)C=2C=NC=CC=2)=C1 WHPFDGIJCOQORR-UHFFFAOYSA-N 0.000 description 1
- DESXUVPCYBWBRA-UHFFFAOYSA-N 2-chloro-5-nitro-n-(3-phenylphenyl)benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=C(C=CC=2)C=2C=CC=CC=2)=C1 DESXUVPCYBWBRA-UHFFFAOYSA-N 0.000 description 1
- LRWBDRVYKJKDLD-UHFFFAOYSA-N 2-chloro-5-nitro-n-(4-phenylphenyl)benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)C=2C=CC=CC=2)=C1 LRWBDRVYKJKDLD-UHFFFAOYSA-N 0.000 description 1
- IPAUNQQDMLQUTL-UHFFFAOYSA-N 2-chloro-5-nitro-n-(4-piperazin-1-ylphenyl)benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)N2CCNCC2)=C1 IPAUNQQDMLQUTL-UHFFFAOYSA-N 0.000 description 1
- MDCZABIHANYLGS-UHFFFAOYSA-N 2-chloro-5-nitro-n-(4-pyridin-2-ylphenyl)benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)C=2N=CC=CC=2)=C1 MDCZABIHANYLGS-UHFFFAOYSA-N 0.000 description 1
- XZGTUZMOJKKNJF-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-(4-pyrrol-1-ylphenyl)phenyl]benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)C=2C=CC(=CC=2)N2C=CC=C2)=C1 XZGTUZMOJKKNJF-UHFFFAOYSA-N 0.000 description 1
- VENANLXDCGGJHH-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-(propylamino)phenyl]benzamide Chemical compound C1=CC(NCCC)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl VENANLXDCGGJHH-UHFFFAOYSA-N 0.000 description 1
- DZWGRMNVRLNNKB-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-(pyridin-2-ylsulfamoyl)phenyl]benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 DZWGRMNVRLNNKB-UHFFFAOYSA-N 0.000 description 1
- AHQMGKKYIKRNKH-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-(pyrimidin-2-ylsulfamoyl)phenyl]benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CN=2)=C1 AHQMGKKYIKRNKH-UHFFFAOYSA-N 0.000 description 1
- SNQXKZOPPPWMSZ-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-[(2-phenylpyrazol-3-yl)sulfamoyl]phenyl]benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)S(=O)(=O)NC=2N(N=CC=2)C=2C=CC=CC=2)=C1 SNQXKZOPPPWMSZ-UHFFFAOYSA-N 0.000 description 1
- WDVXUXLNACCEJZ-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-[4-(octylamino)phenyl]phenyl]benzamide Chemical compound C1=CC(NCCCCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl WDVXUXLNACCEJZ-UHFFFAOYSA-N 0.000 description 1
- NKOSIXIRLZZIDT-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-[4-(pentylamino)phenyl]phenyl]benzamide Chemical compound C1=CC(NCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl NKOSIXIRLZZIDT-UHFFFAOYSA-N 0.000 description 1
- KWLXCNYUZFCYKE-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-[4-(propylamino)phenyl]phenyl]benzamide Chemical compound C1=CC(NCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl KWLXCNYUZFCYKE-UHFFFAOYSA-N 0.000 description 1
- CTVJHDFCIVBYFJ-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-[4-(pyridine-4-carbonyl)piperazin-1-yl]phenyl]benzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)N2CCN(CC2)C(=O)C=2C=CN=CC=2)=C1 CTVJHDFCIVBYFJ-UHFFFAOYSA-N 0.000 description 1
- LCORDMZBWKCRTD-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-[4-[octyl(propyl)amino]phenyl]phenyl]benzamide Chemical compound C1=CC(N(CCC)CCCCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl LCORDMZBWKCRTD-UHFFFAOYSA-N 0.000 description 1
- HSBQCGPURCABIC-UHFFFAOYSA-N 2-chloro-5-nitro-n-[4-[4-[pentyl(propyl)amino]phenyl]phenyl]benzamide Chemical compound C1=CC(N(CCC)CCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl HSBQCGPURCABIC-UHFFFAOYSA-N 0.000 description 1
- HBLVYPWUVLNREA-UHFFFAOYSA-N 2-chloro-n-(3-methylphenyl)-5-nitrobenzamide Chemical compound CC1=CC=CC(NC(=O)C=2C(=CC=C(C=2)[N+]([O-])=O)Cl)=C1 HBLVYPWUVLNREA-UHFFFAOYSA-N 0.000 description 1
- PTTCIOWGKHBWMF-UHFFFAOYSA-N 2-chloro-n-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-5-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)C=2N=C3C=CC=CN3C=2)=C1 PTTCIOWGKHBWMF-UHFFFAOYSA-N 0.000 description 1
- FKVWOXZMHFVJDM-UHFFFAOYSA-N 2-chloro-n-(4-methyl-1,3-thiazol-2-yl)-5-nitrobenzamide Chemical compound CC1=CSC(NC(=O)C=2C(=CC=C(C=2)[N+]([O-])=O)Cl)=N1 FKVWOXZMHFVJDM-UHFFFAOYSA-N 0.000 description 1
- PCTYWHPBLLIODL-UHFFFAOYSA-N 2-chloro-n-(4-methylphenyl)-5-nitrobenzamide Chemical compound C1=CC(C)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl PCTYWHPBLLIODL-UHFFFAOYSA-N 0.000 description 1
- NJWUYNONCVYHMV-UHFFFAOYSA-N 2-chloro-n-[2-[(5-methyl-1,2-oxazol-3-yl)sulfamoyl]phenyl]-5-nitrobenzamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC=CC=2)NC(=O)C=2C(=CC=C(C=2)[N+]([O-])=O)Cl)=N1 NJWUYNONCVYHMV-UHFFFAOYSA-N 0.000 description 1
- CLJADPZNYKVUGY-UHFFFAOYSA-N 2-chloro-n-[3-(1-hydroxyethyl)phenyl]-5-nitrobenzamide Chemical compound CC(O)C1=CC=CC(NC(=O)C=2C(=CC=C(C=2)[N+]([O-])=O)Cl)=C1 CLJADPZNYKVUGY-UHFFFAOYSA-N 0.000 description 1
- ORHOSZJHKWKAOY-UHFFFAOYSA-N 2-chloro-n-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-5-nitrobenzamide Chemical compound C1=CC(C(O)(C(F)(F)F)C(F)(F)F)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl ORHOSZJHKWKAOY-UHFFFAOYSA-N 0.000 description 1
- UWZHCSHBDGNVGH-UHFFFAOYSA-N 2-chloro-n-[4-(3-chloro-4-methylphenyl)-5-methyl-1,3-thiazol-2-yl]-5-nitrobenzamide Chemical compound N=1C(C=2C=C(Cl)C(C)=CC=2)=C(C)SC=1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl UWZHCSHBDGNVGH-UHFFFAOYSA-N 0.000 description 1
- VGWKCLAEUVWUBN-UHFFFAOYSA-N 2-chloro-n-[4-(dihexylamino)phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(CCCCCC)CCCCCC)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl VGWKCLAEUVWUBN-UHFFFAOYSA-N 0.000 description 1
- IMDUTFBPBARUFS-UHFFFAOYSA-N 2-chloro-n-[4-(ethylamino)phenyl]-5-nitrobenzamide;hydrochloride Chemical compound Cl.C1=CC(NCC)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl IMDUTFBPBARUFS-UHFFFAOYSA-N 0.000 description 1
- QDKOAZQREXYXRT-UHFFFAOYSA-N 2-chloro-n-[4-(hexylamino)phenyl]-5-nitrobenzamide Chemical compound C1=CC(NCCCCCC)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl QDKOAZQREXYXRT-UHFFFAOYSA-N 0.000 description 1
- DYUBZRLRKLELQF-UHFFFAOYSA-N 2-chloro-n-[4-[(4-methylbenzoyl)amino]phenyl]-5-nitrobenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl DYUBZRLRKLELQF-UHFFFAOYSA-N 0.000 description 1
- GQKWSVCLXLENFD-UHFFFAOYSA-N 2-chloro-n-[4-[(4-methylphenyl)sulfonylamino]phenyl]-5-nitrobenzamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl GQKWSVCLXLENFD-UHFFFAOYSA-N 0.000 description 1
- SJSRRRYUUMRQQM-UHFFFAOYSA-N 2-chloro-n-[4-[(5-methoxypyrimidin-2-yl)sulfamoyl]phenyl]-5-nitrobenzamide Chemical compound N1=CC(OC)=CN=C1NS(=O)(=O)C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl SJSRRRYUUMRQQM-UHFFFAOYSA-N 0.000 description 1
- WCKCHBXSCHJSGF-UHFFFAOYSA-N 2-chloro-n-[4-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfamoyl]phenyl]-5-nitrobenzamide Chemical compound S1C(C)=NN=C1NS(=O)(=O)C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl WCKCHBXSCHJSGF-UHFFFAOYSA-N 0.000 description 1
- BJDALFWNNFUXGH-UHFFFAOYSA-N 2-chloro-n-[4-[(6-chloropyridazin-3-yl)sulfamoyl]phenyl]-5-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=NC(Cl)=CC=2)=C1 BJDALFWNNFUXGH-UHFFFAOYSA-N 0.000 description 1
- PZHRXJXIQJWTGY-UHFFFAOYSA-N 2-chloro-n-[4-[4-(dihexylamino)phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(CCCCCC)CCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl PZHRXJXIQJWTGY-UHFFFAOYSA-N 0.000 description 1
- YXGAJDAWHFDWIX-UHFFFAOYSA-N 2-chloro-n-[4-[4-(dipentylamino)phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(CCCCC)CCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl YXGAJDAWHFDWIX-UHFFFAOYSA-N 0.000 description 1
- MFKBNSIZNSKQHJ-UHFFFAOYSA-N 2-chloro-n-[4-[4-(ethylamino)phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(NCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl MFKBNSIZNSKQHJ-UHFFFAOYSA-N 0.000 description 1
- UUYWSSKJTKIYLZ-UHFFFAOYSA-N 2-chloro-n-[4-[4-(ethylsulfonylamino)phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(NS(=O)(=O)CC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl UUYWSSKJTKIYLZ-UHFFFAOYSA-N 0.000 description 1
- NTMWTLOMLFFMIO-UHFFFAOYSA-N 2-chloro-n-[4-[4-(hexylamino)phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(NCCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl NTMWTLOMLFFMIO-UHFFFAOYSA-N 0.000 description 1
- WKCIBCFNHDFQOH-UHFFFAOYSA-N 2-chloro-n-[4-[4-(methanesulfonamido)phenyl]-1,3-thiazol-2-yl]-5-nitrobenzamide Chemical compound C1=CC(NS(=O)(=O)C)=CC=C1C1=CSC(NC(=O)C=2C(=CC=C(C=2)[N+]([O-])=O)Cl)=N1 WKCIBCFNHDFQOH-UHFFFAOYSA-N 0.000 description 1
- MVUUXSFKAKNNEB-UHFFFAOYSA-N 2-chloro-n-[4-[4-(methanesulfonamido)phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(NS(=O)(=O)C)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl MVUUXSFKAKNNEB-UHFFFAOYSA-N 0.000 description 1
- DDYQJISTMQMDDR-UHFFFAOYSA-N 2-chloro-n-[4-[4-(methylcarbamothioylamino)phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(NC(=S)NC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl DDYQJISTMQMDDR-UHFFFAOYSA-N 0.000 description 1
- FGANMJHRLWBNER-UHFFFAOYSA-N 2-chloro-n-[4-[4-[(4-methylphenyl)sulfonylamino]phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=CC=C(C=2C=CC(NC(=O)C=3C(=CC=C(C=3)[N+]([O-])=O)Cl)=CC=2)C=C1 FGANMJHRLWBNER-UHFFFAOYSA-N 0.000 description 1
- YWZLOIXTFLPGTI-UHFFFAOYSA-N 2-chloro-n-[4-[4-[ethyl(hexyl)amino]phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(CC)CCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl YWZLOIXTFLPGTI-UHFFFAOYSA-N 0.000 description 1
- LJJRVMVVUMWMMW-UHFFFAOYSA-N 2-chloro-n-[4-[4-[ethyl(octyl)amino]phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(CC)CCCCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl LJJRVMVVUMWMMW-UHFFFAOYSA-N 0.000 description 1
- JTQZSMXTBCQFIK-UHFFFAOYSA-N 2-chloro-n-[4-[4-[ethyl(pentyl)amino]phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(CC)CCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl JTQZSMXTBCQFIK-UHFFFAOYSA-N 0.000 description 1
- SOWLNSJEGDZHSJ-UHFFFAOYSA-N 2-chloro-n-[4-[4-[ethyl(propyl)amino]phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(CC)CCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl SOWLNSJEGDZHSJ-UHFFFAOYSA-N 0.000 description 1
- ZORTVAUMVOBJCS-UHFFFAOYSA-N 2-chloro-n-[4-[4-[hexyl(methyl)amino]phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(C)CCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl ZORTVAUMVOBJCS-UHFFFAOYSA-N 0.000 description 1
- VZLQALQQICTQBR-UHFFFAOYSA-N 2-chloro-n-[4-[4-[hexyl(octyl)amino]phenyl]phenyl]-5-nitrobenzamide;hydrochloride Chemical compound Cl.C1=CC(N(CCCCCC)CCCCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl VZLQALQQICTQBR-UHFFFAOYSA-N 0.000 description 1
- QQPLDOHXBJJBLS-UHFFFAOYSA-N 2-chloro-n-[4-[4-[hexyl(pentyl)amino]phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(CCCCC)CCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl QQPLDOHXBJJBLS-UHFFFAOYSA-N 0.000 description 1
- BQGDZIQDRCVGBT-UHFFFAOYSA-N 2-chloro-n-[4-[4-[hexyl(propyl)amino]phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(CCC)CCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl BQGDZIQDRCVGBT-UHFFFAOYSA-N 0.000 description 1
- TUGFDQBTFOIXMK-UHFFFAOYSA-N 2-chloro-n-[4-[4-[methyl(octyl)amino]phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(C)CCCCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl TUGFDQBTFOIXMK-UHFFFAOYSA-N 0.000 description 1
- MMPNANXFJGOAOI-UHFFFAOYSA-N 2-chloro-n-[4-[4-[methyl(pentyl)amino]phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(C)CCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl MMPNANXFJGOAOI-UHFFFAOYSA-N 0.000 description 1
- OOUQNTCHBJSNHD-UHFFFAOYSA-N 2-chloro-n-[4-[4-[methyl(propyl)amino]phenyl]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(C)CCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl OOUQNTCHBJSNHD-UHFFFAOYSA-N 0.000 description 1
- XAGLZOKBJLKRAT-UHFFFAOYSA-N 2-chloro-n-[4-[ethyl(hexyl)amino]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(CC)CCCCCC)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl XAGLZOKBJLKRAT-UHFFFAOYSA-N 0.000 description 1
- FNUPKXIODUNJJS-UHFFFAOYSA-N 2-chloro-n-[4-[ethyl(propyl)amino]phenyl]-5-nitrobenzamide Chemical compound C1=CC(N(CC)CCC)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl FNUPKXIODUNJJS-UHFFFAOYSA-N 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000006049 2-methyl-2-pentenyl group Chemical group 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006031 2-methyl-3-butenyl group Chemical group 0.000 description 1
- 125000006053 2-methyl-3-pentenyl group Chemical group 0.000 description 1
- 125000006056 2-methyl-4-pentenyl group Chemical group 0.000 description 1
- GPZXFICWCMCQPF-UHFFFAOYSA-N 2-methylbenzoyl chloride Chemical compound CC1=CC=CC=C1C(Cl)=O GPZXFICWCMCQPF-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 1
- 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- YGYGASJNJTYNOL-CQSZACIVSA-N 3-[(4r)-2,2-dimethyl-1,1-dioxothian-4-yl]-5-(4-fluorophenyl)-1h-indole-7-carboxamide Chemical compound C1CS(=O)(=O)C(C)(C)C[C@@H]1C1=CNC2=C(C(N)=O)C=C(C=3C=CC(F)=CC=3)C=C12 YGYGASJNJTYNOL-CQSZACIVSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 1
- NTQSKPCKGPEMBC-UHFFFAOYSA-N 3-amino-n-(3,5-ditert-butyl-4-hydroxyphenyl)benzenesulfonamide Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(NS(=O)(=O)C=2C=C(N)C=CC=2)=C1 NTQSKPCKGPEMBC-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- NXTNASSYJUXJDV-UHFFFAOYSA-N 3-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC(C(Cl)=O)=C1 NXTNASSYJUXJDV-UHFFFAOYSA-N 0.000 description 1
- MUNOBADFTHUUFG-UHFFFAOYSA-N 3-phenylaniline Chemical compound NC1=CC=CC(C=2C=CC=CC=2)=C1 MUNOBADFTHUUFG-UHFFFAOYSA-N 0.000 description 1
- 101710192523 30S ribosomal protein S9 Proteins 0.000 description 1
- JPZOAVGMSDSWSW-UHFFFAOYSA-N 4,6-dichloropyrimidin-2-amine Chemical compound NC1=NC(Cl)=CC(Cl)=N1 JPZOAVGMSDSWSW-UHFFFAOYSA-N 0.000 description 1
- NIGDWBHWHVHOAD-UHFFFAOYSA-N 4,6-dichloropyrimidin-5-amine Chemical compound NC1=C(Cl)N=CN=C1Cl NIGDWBHWHVHOAD-UHFFFAOYSA-N 0.000 description 1
- UCDDGMMXOQGZGJ-UHFFFAOYSA-N 4-(2-piperidin-1-ylphenyl)aniline Chemical compound C1=CC(N)=CC=C1C1=CC=CC=C1N1CCCCC1 UCDDGMMXOQGZGJ-UHFFFAOYSA-N 0.000 description 1
- UIPWYSFUWRTDOG-UHFFFAOYSA-N 4-(3-nitrophenyl)aniline Chemical compound C1=CC(N)=CC=C1C1=CC=CC([N+]([O-])=O)=C1 UIPWYSFUWRTDOG-UHFFFAOYSA-N 0.000 description 1
- CPJQKNUJNWPAPH-UHFFFAOYSA-N 4-(4-aminophenyl)benzonitrile Chemical compound C1=CC(N)=CC=C1C1=CC=C(C#N)C=C1 CPJQKNUJNWPAPH-UHFFFAOYSA-N 0.000 description 1
- YTISFYMPVILQRL-UHFFFAOYSA-N 4-(4-chlorophenoxy)aniline Chemical compound C1=CC(N)=CC=C1OC1=CC=C(Cl)C=C1 YTISFYMPVILQRL-UHFFFAOYSA-N 0.000 description 1
- VPCGOYHSWIYEMO-UHFFFAOYSA-N 4-(4-methylphenoxy)aniline Chemical compound C1=CC(C)=CC=C1OC1=CC=C(N)C=C1 VPCGOYHSWIYEMO-UHFFFAOYSA-N 0.000 description 1
- RIKJWJIWXCUKQV-UHFFFAOYSA-N 4-(4-nitrophenyl)-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=CC(=CC=2)[N+]([O-])=O)=C1 RIKJWJIWXCUKQV-UHFFFAOYSA-N 0.000 description 1
- GLYFJYOGOXQXGI-UHFFFAOYSA-N 4-(4-pyrrol-1-ylphenyl)aniline Chemical compound C1=CC(N)=CC=C1C1=CC=C(N2C=CC=C2)C=C1 GLYFJYOGOXQXGI-UHFFFAOYSA-N 0.000 description 1
- ZBOUWHQCVIPIGR-UHFFFAOYSA-N 4-(4-pyrrolidin-1-ylphenyl)aniline Chemical compound C1=CC(N)=CC=C1C1=CC=C(N2CCCC2)C=C1 ZBOUWHQCVIPIGR-UHFFFAOYSA-N 0.000 description 1
- VJPPLCNBDLZIFG-ZDUSSCGKSA-N 4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Chemical compound C(C#CC)(=O)N[C@@H]1CN(CCC1)C1=C2C(=C(NC2=C(C=C1F)C(=O)N)C)C VJPPLCNBDLZIFG-ZDUSSCGKSA-N 0.000 description 1
- LFJGGGIWERIGNX-UHFFFAOYSA-N 4-[2-(diethylamino)ethoxy]aniline Chemical compound CCN(CC)CCOC1=CC=C(N)C=C1 LFJGGGIWERIGNX-UHFFFAOYSA-N 0.000 description 1
- CCCVQPGAXZNTIL-UHFFFAOYSA-N 4-[2-(dimethylamino)ethoxy]aniline Chemical compound CN(C)CCOC1=CC=C(N)C=C1 CCCVQPGAXZNTIL-UHFFFAOYSA-N 0.000 description 1
- ZIUOGXYQWQLNQL-UHFFFAOYSA-N 4-[2-(dimethylamino)propoxy]aniline Chemical compound CN(C)C(C)COC1=CC=C(N)C=C1 ZIUOGXYQWQLNQL-UHFFFAOYSA-N 0.000 description 1
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 1
- XYWIPYBIIRTJMM-IBGZPJMESA-N 4-[[(2S)-2-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-5-methoxy-2-oxopyridin-1-yl]butanoyl]amino]-2-fluorobenzamide Chemical compound CC[C@H](N1C=C(OC)C(=CC1=O)C1=C(C=CC(Cl)=C1)N1C=C(N=N1)C(F)(F)F)C(=O)NC1=CC(F)=C(C=C1)C(N)=O XYWIPYBIIRTJMM-IBGZPJMESA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- CXEWEQXDQOCLHA-UHFFFAOYSA-N 4-amino-n-(3,5-ditert-butyl-4-hydroxyphenyl)benzenesulfonamide Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1 CXEWEQXDQOCLHA-UHFFFAOYSA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- QMPPRQRGWWBCTF-UHFFFAOYSA-N 4-amino-n-[4-[ethyl(propan-2-yl)amino]phenyl]benzenesulfonamide Chemical compound C1=CC(N(C(C)C)CC)=CC=C1NS(=O)(=O)C1=CC=C(N)C=C1 QMPPRQRGWWBCTF-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- OEQQFQXMCPMEIH-UHFFFAOYSA-N 4-chloro-1,3-benzothiazol-2-amine Chemical compound C1=CC=C2SC(N)=NC2=C1Cl OEQQFQXMCPMEIH-UHFFFAOYSA-N 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- 125000005274 4-hydroxybenzoic acid group Chemical class 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- OFBRKDXLBOTZNB-UHFFFAOYSA-N 4-methoxy-3-phenylaniline Chemical compound COC1=CC=C(N)C=C1C1=CC=CC=C1 OFBRKDXLBOTZNB-UHFFFAOYSA-N 0.000 description 1
- OUQMXTJYCAJLGO-UHFFFAOYSA-N 4-methyl-1,3-thiazol-2-amine Chemical compound CC1=CSC(N)=N1 OUQMXTJYCAJLGO-UHFFFAOYSA-N 0.000 description 1
- BXIJUQJYXZCOFB-UHFFFAOYSA-N 4-n-[2-(dimethylamino)ethyl]-4-n-methylbenzene-1,4-diamine Chemical compound CN(C)CCN(C)C1=CC=C(N)C=C1 BXIJUQJYXZCOFB-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- AXBVSRMHOPMXBA-UHFFFAOYSA-N 4-nitrothiophenol Chemical compound [O-][N+](=O)C1=CC=C(S)C=C1 AXBVSRMHOPMXBA-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- PBXBUVMSXRFGIX-UHFFFAOYSA-N 5-methoxy-2-phenylaniline Chemical compound NC1=CC(OC)=CC=C1C1=CC=CC=C1 PBXBUVMSXRFGIX-UHFFFAOYSA-N 0.000 description 1
- RLYUNPNLXMSXAX-UHFFFAOYSA-N 5-methylthiazole Chemical compound CC1=CN=CS1 RLYUNPNLXMSXAX-UHFFFAOYSA-N 0.000 description 1
- VMNXKIDUTPOHPO-UHFFFAOYSA-N 6-chloro-1,3-benzothiazol-2-amine Chemical compound C1=C(Cl)C=C2SC(N)=NC2=C1 VMNXKIDUTPOHPO-UHFFFAOYSA-N 0.000 description 1
- GPNAVOJCQIEKQF-UHFFFAOYSA-N 6-nitro-1,3-benzothiazol-2-amine Chemical compound C1=C([N+]([O-])=O)C=C2SC(N)=NC2=C1 GPNAVOJCQIEKQF-UHFFFAOYSA-N 0.000 description 1
- UNQYAAAWKOOBFQ-UHFFFAOYSA-N 7-[(4-chlorophenyl)methyl]-8-[4-chloro-3-(trifluoromethoxy)phenoxy]-1-(3-hydroxypropyl)-3-methylpurine-2,6-dione Chemical compound C=1C=C(Cl)C=CC=1CN1C=2C(=O)N(CCCO)C(=O)N(C)C=2N=C1OC1=CC=C(Cl)C(OC(F)(F)F)=C1 UNQYAAAWKOOBFQ-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102000005666 Apolipoprotein A-I Human genes 0.000 description 1
- 108010059886 Apolipoprotein A-I Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 0 B*C(C)(C)*NC(c(cc(cc1)[N+]([O-])=O)c1Cl)=O Chemical compound B*C(C)(C)*NC(c(cc(cc1)[N+]([O-])=O)c1Cl)=O 0.000 description 1
- 229920001342 Bakelite® Polymers 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- 101100439288 Bombyx mori nuclear polyhedrosis virus CG30 gene Proteins 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 206010068975 Bone atrophy Diseases 0.000 description 1
- 206010056809 Bone formation decreased Diseases 0.000 description 1
- PNVJLGMVRKXTGF-UHFFFAOYSA-N C(C1=CC=CC=C1)N1CCNCC1.N1CCNCC1 Chemical compound C(C1=CC=CC=C1)N1CCNCC1.N1CCNCC1 PNVJLGMVRKXTGF-UHFFFAOYSA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical class C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Chemical group CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- DNTSIBUQMRRYIU-UHFFFAOYSA-N GW 9662 Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC=CC=2)=C1 DNTSIBUQMRRYIU-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001131829 Homo sapiens P protein Proteins 0.000 description 1
- 101000879758 Homo sapiens Sjoegren syndrome nuclear autoantigen 1 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699673 Mesocricetus auratus Species 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 102100026933 Myelin-associated neurite-outgrowth inhibitor Human genes 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- XWBABSILBAABOK-UHFFFAOYSA-N N(=NC(=O)O)C(=O)O.C(C)C=1C(=C(C=CC1)P(C1=CC=CC=C1)C1=CC=CC=C1)CC Chemical compound N(=NC(=O)O)C(=O)O.C(C)C=1C(=C(C=CC1)P(C1=CC=CC=C1)C1=CC=CC=C1)CC XWBABSILBAABOK-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- FEYNFHSRETUBEM-UHFFFAOYSA-N N-[3-(1,1-difluoroethyl)phenyl]-1-(4-methoxyphenyl)-3-methyl-5-oxo-4H-pyrazole-4-carboxamide Chemical compound COc1ccc(cc1)N1N=C(C)C(C(=O)Nc2cccc(c2)C(C)(F)F)C1=O FEYNFHSRETUBEM-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 206010057178 Osteoarthropathies Diseases 0.000 description 1
- 206010031243 Osteogenesis imperfecta Diseases 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000012132 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 1
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 1
- 241000577218 Phenes Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 108010021757 Polynucleotide 5'-Hydroxyl-Kinase Proteins 0.000 description 1
- 102000008422 Polynucleotide 5'-hydroxyl-kinase Human genes 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 101001022386 Rattus norvegicus Leptin Proteins 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 102100037330 Sjoegren syndrome nuclear autoantigen 1 Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 208000037063 Thinness Diseases 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 229920000392 Zymosan Polymers 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- VSGDQOHHWSWGTD-UHFFFAOYSA-N [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)N2CCN(CC2)C(=O)C=2C=NC=CC=2)=C1 Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)N2CCN(CC2)C(=O)C=2C=NC=CC=2)=C1 VSGDQOHHWSWGTD-UHFFFAOYSA-N 0.000 description 1
- JLCHNBRGUPQWKF-UHFFFAOYSA-J [OH-].[C+4].[OH-].[OH-].[OH-] Chemical compound [OH-].[C+4].[OH-].[OH-].[OH-] JLCHNBRGUPQWKF-UHFFFAOYSA-J 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 125000004062 acenaphthenyl group Chemical group C1(CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000011759 adipose tissue development Effects 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- NMPVEAUIHMEAQP-UHFFFAOYSA-N alpha-bromo-acetaldehyde Natural products BrCC=O NMPVEAUIHMEAQP-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000004637 bakelite Substances 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical class C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- HFACYLZERDEVSX-UHFFFAOYSA-N benzidine Chemical compound C1=CC(N)=CC=C1C1=CC=C(N)C=C1 HFACYLZERDEVSX-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 230000003778 catagen phase Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- DGLFSNZWRYADFC-UHFFFAOYSA-N chembl2334586 Chemical compound C1CCC2=CN=C(N)N=C2C2=C1NC1=CC=C(C#CC(C)(O)C)C=C12 DGLFSNZWRYADFC-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 150000001868 cobalt Chemical class 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 239000005546 dideoxynucleotide Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- VLNZUSMTOFYNPS-UHFFFAOYSA-N diethylphosphorylformonitrile Chemical compound CCP(=O)(CC)C#N VLNZUSMTOFYNPS-UHFFFAOYSA-N 0.000 description 1
- BVTBRVFYZUCAKH-UHFFFAOYSA-L disodium selenite Chemical compound [Na+].[Na+].[O-][Se]([O-])=O BVTBRVFYZUCAKH-UHFFFAOYSA-L 0.000 description 1
- UKWLRLAKGMZXJC-QIECWBMSSA-L disodium;[4-chloro-3-[(3r,5s)-1-chloro-3'-methoxyspiro[adamantane-4,4'-dioxetane]-3'-yl]phenyl] phosphate Chemical compound [Na+].[Na+].O1OC2([C@@H]3CC4C[C@H]2CC(Cl)(C4)C3)C1(OC)C1=CC(OP([O-])([O-])=O)=CC=C1Cl UKWLRLAKGMZXJC-QIECWBMSSA-L 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 201000010063 epididymitis Diseases 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- ZRSDQBKGDNPFLT-UHFFFAOYSA-N ethanol;oxolane Chemical compound CCO.C1CCOC1 ZRSDQBKGDNPFLT-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- CDYVTVLXEWMCHU-UHFFFAOYSA-N ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate Chemical compound C1CCCC2=C1SC(N)=C2C(=O)OCC CDYVTVLXEWMCHU-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- VMVZGGPZNHFGKS-UHFFFAOYSA-N ethyl n-(oxomethylidene)carbamate Chemical compound CCOC(=O)N=C=O VMVZGGPZNHFGKS-UHFFFAOYSA-N 0.000 description 1
- YSPVHAUJXLGZHP-UHFFFAOYSA-N ethyl piperidine-1-carboxylate Chemical compound CCOC(=O)N1CCCCC1 YSPVHAUJXLGZHP-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- HKIOYBQGHSTUDB-UHFFFAOYSA-N folpet Chemical group C1=CC=C2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C2=C1 HKIOYBQGHSTUDB-UHFFFAOYSA-N 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000002301 glucosamine derivatives Chemical class 0.000 description 1
- 230000010030 glucose lowering effect Effects 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 150000004687 hexahydrates Chemical class 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000001245 hexylamino group Chemical group [H]N([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 102000047119 human OCA2 Human genes 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000019189 interleukin-1 beta production Effects 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- YDNLNVZZTACNJX-UHFFFAOYSA-N isocyanatomethylbenzene Chemical compound O=C=NCC1=CC=CC=C1 YDNLNVZZTACNJX-UHFFFAOYSA-N 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- QXXDTQJIPIKKGF-UHFFFAOYSA-N methanesulfonamide;dihydrochloride Chemical compound Cl.Cl.CS(N)(=O)=O QXXDTQJIPIKKGF-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000006626 methoxycarbonylamino group Chemical group 0.000 description 1
- IAGUPODHENSJEZ-UHFFFAOYSA-N methyl n-phenylcarbamate Chemical compound COC(=O)NC1=CC=CC=C1 IAGUPODHENSJEZ-UHFFFAOYSA-N 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- GAUSUDNBBOZKSB-UHFFFAOYSA-N methyl(phenyl)carbamic acid Chemical compound OC(=O)N(C)C1=CC=CC=C1 GAUSUDNBBOZKSB-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- MZVYSWVJXQYPOT-UHFFFAOYSA-N methylsulfanylimino(oxo)methane Chemical compound CSN=C=O MZVYSWVJXQYPOT-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical class C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 1
- UYUJNZVHPSXQRS-UHFFFAOYSA-N n-(3-aminophenyl)-3,5-ditert-butyl-4-hydroxybenzamide Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(C(=O)NC=2C=C(N)C=CC=2)=C1 UYUJNZVHPSXQRS-UHFFFAOYSA-N 0.000 description 1
- MMAWIRWXQLJLNK-UHFFFAOYSA-N n-(4-aminophenyl)-2-chloro-5-nitrobenzamide Chemical compound C1=CC(N)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl MMAWIRWXQLJLNK-UHFFFAOYSA-N 0.000 description 1
- HVMYDLMLZSWMLM-UHFFFAOYSA-N n-(4-aminophenyl)-2-chloro-5-nitrobenzamide;hydrochloride Chemical compound Cl.C1=CC(N)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl HVMYDLMLZSWMLM-UHFFFAOYSA-N 0.000 description 1
- QLTNXPAYDGYHTP-UHFFFAOYSA-N n-(4-aminophenyl)-3,5-ditert-butyl-4-hydroxybenzamide Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(C(=O)NC=2C=CC(N)=CC=2)=C1 QLTNXPAYDGYHTP-UHFFFAOYSA-N 0.000 description 1
- IMMSJZPDCYHUEG-UHFFFAOYSA-N n-(4-aminophenyl)-4-ethylbenzenesulfonamide Chemical compound C1=CC(CC)=CC=C1S(=O)(=O)NC1=CC=C(N)C=C1 IMMSJZPDCYHUEG-UHFFFAOYSA-N 0.000 description 1
- XKDFMOOUKPSLEM-UHFFFAOYSA-N n-(4-aminophenyl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=CC=C(N)C=C1 XKDFMOOUKPSLEM-UHFFFAOYSA-N 0.000 description 1
- AMRPBRJUQXFTEY-UHFFFAOYSA-N n-(4-benzamidophenyl)-2-chloro-5-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(NC(=O)C=3C=CC=CC=3)=CC=2)=C1 AMRPBRJUQXFTEY-UHFFFAOYSA-N 0.000 description 1
- FMASTMURQSHELY-UHFFFAOYSA-N n-(4-fluoro-2-methylphenyl)-3-methyl-n-[(2-methyl-1h-indol-4-yl)methyl]pyridine-4-carboxamide Chemical compound C1=CC=C2NC(C)=CC2=C1CN(C=1C(=CC(F)=CC=1)C)C(=O)C1=CC=NC=C1C FMASTMURQSHELY-UHFFFAOYSA-N 0.000 description 1
- YSAGBPKXODMPLA-UHFFFAOYSA-N n-(4-piperazin-1-ylphenyl)acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1N1CCNCC1 YSAGBPKXODMPLA-UHFFFAOYSA-N 0.000 description 1
- MYQTZORVIIUJAF-UHFFFAOYSA-N n-(4-piperazin-1-ylphenyl)methanesulfonamide Chemical compound C1=CC(NS(=O)(=O)C)=CC=C1N1CCNCC1 MYQTZORVIIUJAF-UHFFFAOYSA-N 0.000 description 1
- NXGZDEZWCOJXLG-UHFFFAOYSA-N n-[3-(2-amino-1,3-thiazol-4-yl)phenyl]-2-chloro-5-nitrobenzamide Chemical compound S1C(N)=NC(C=2C=C(NC(=O)C=3C(=CC=C(C=3)[N+]([O-])=O)Cl)C=CC=2)=C1 NXGZDEZWCOJXLG-UHFFFAOYSA-N 0.000 description 1
- HGZJLDIMWHDTQC-UHFFFAOYSA-N n-[4-(2-aminoethyl)phenyl]-2-chloro-5-nitrobenzamide;hydrochloride Chemical compound Cl.C1=CC(CCN)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl HGZJLDIMWHDTQC-UHFFFAOYSA-N 0.000 description 1
- XDXBUUJJESSSGS-UHFFFAOYSA-N n-[4-(4-aminophenyl)phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(N)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl XDXBUUJJESSSGS-UHFFFAOYSA-N 0.000 description 1
- LROXDBNIMAVJEJ-UHFFFAOYSA-N n-[4-(4-benzamidophenyl)phenyl]-2-chloro-5-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)C=2C=CC(NC(=O)C=3C=CC=CC=3)=CC=2)=C1 LROXDBNIMAVJEJ-UHFFFAOYSA-N 0.000 description 1
- MIOCKIYAHYTOJR-UHFFFAOYSA-N n-[4-(4-benzoylpiperazin-1-yl)phenyl]-2-chloro-5-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)N2CCN(CC2)C(=O)C=2C=CC=CC=2)=C1 MIOCKIYAHYTOJR-UHFFFAOYSA-N 0.000 description 1
- LDGRREQLCUIFGL-UHFFFAOYSA-N n-[4-(benzenesulfonamido)phenyl]-2-chloro-5-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(NS(=O)(=O)C=3C=CC=CC=3)=CC=2)=C1 LDGRREQLCUIFGL-UHFFFAOYSA-N 0.000 description 1
- PRKJSIBBLFZEIL-UHFFFAOYSA-N n-[4-[(2-chloro-5-nitrobenzoyl)amino]phenyl]pyridine-3-carboxamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(NC(=O)C=3C=NC=CC=3)=CC=2)=C1 PRKJSIBBLFZEIL-UHFFFAOYSA-N 0.000 description 1
- XRWVXMGRIUVWSR-UHFFFAOYSA-N n-[4-[(2-chloro-5-nitrobenzoyl)amino]phenyl]pyridine-4-carboxamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(NC(=O)C=3C=CN=CC=3)=CC=2)=C1 XRWVXMGRIUVWSR-UHFFFAOYSA-N 0.000 description 1
- IGARNHKUUDVIGH-UHFFFAOYSA-N n-[4-[2-(benzenesulfonamido)phenyl]phenyl]-2-chloro-5-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)C=2C(=CC=CC=2)NS(=O)(=O)C=2C=CC=CC=2)=C1 IGARNHKUUDVIGH-UHFFFAOYSA-N 0.000 description 1
- SDVWBQKZSAIVBM-UHFFFAOYSA-N n-[4-[4-(benzoylcarbamothioylamino)phenyl]phenyl]-2-chloro-5-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)C=2C=CC(NC(=S)NC(=O)C=3C=CC=CC=3)=CC=2)=C1 SDVWBQKZSAIVBM-UHFFFAOYSA-N 0.000 description 1
- BGKQEEPAUKTDCA-UHFFFAOYSA-N n-[4-[4-(butylamino)phenyl]phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(NCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl BGKQEEPAUKTDCA-UHFFFAOYSA-N 0.000 description 1
- IZJPAQVIUWZTTG-UHFFFAOYSA-N n-[4-[4-[(2-chloro-5-nitrobenzoyl)amino]phenyl]phenyl]pyridine-3-carboxamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)C=2C=CC(NC(=O)C=3C=NC=CC=3)=CC=2)=C1 IZJPAQVIUWZTTG-UHFFFAOYSA-N 0.000 description 1
- QWQQCKGWWBGSPV-UHFFFAOYSA-N n-[4-[4-[(2-chloro-5-nitrobenzoyl)amino]phenyl]phenyl]pyridine-4-carboxamide Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)NC=2C=CC(=CC=2)C=2C=CC(NC(=O)C=3C=CN=CC=3)=CC=2)=C1 QWQQCKGWWBGSPV-UHFFFAOYSA-N 0.000 description 1
- BZWCUPQIMOMBQR-UHFFFAOYSA-N n-[4-[4-[bis(methylsulfonyl)amino]phenyl]phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(N(S(=O)(=O)C)S(C)(=O)=O)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl BZWCUPQIMOMBQR-UHFFFAOYSA-N 0.000 description 1
- XRJSIKBVDREOEC-UHFFFAOYSA-N n-[4-[4-[butyl(hexyl)amino]phenyl]phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(N(CCCC)CCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl XRJSIKBVDREOEC-UHFFFAOYSA-N 0.000 description 1
- SIRRQSQDSIZRTR-UHFFFAOYSA-N n-[4-[4-[butyl(octyl)amino]phenyl]phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(N(CCCC)CCCCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl SIRRQSQDSIZRTR-UHFFFAOYSA-N 0.000 description 1
- OXGZTOHUBSOVID-UHFFFAOYSA-N n-[4-[4-[butyl(octyl)amino]phenyl]phenyl]-2-chloro-5-nitrobenzamide;hydrochloride Chemical compound Cl.C1=CC(N(CCCC)CCCCCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl OXGZTOHUBSOVID-UHFFFAOYSA-N 0.000 description 1
- MAWPBQJIAMVOST-UHFFFAOYSA-N n-[4-[4-[butyl(pentyl)amino]phenyl]phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(N(CCCC)CCCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl MAWPBQJIAMVOST-UHFFFAOYSA-N 0.000 description 1
- OPWIXOSRYGENDY-UHFFFAOYSA-N n-[4-[4-[butyl(propyl)amino]phenyl]phenyl]-2-chloro-5-nitrobenzamide Chemical compound C1=CC(N(CCC)CCCC)=CC=C1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl OPWIXOSRYGENDY-UHFFFAOYSA-N 0.000 description 1
- BPHRPPOQCQPNMB-UHFFFAOYSA-N n-carbamoyl-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC(N)=O)C=C1 BPHRPPOQCQPNMB-UHFFFAOYSA-N 0.000 description 1
- NNKPHNTWNILINE-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxopyrazin-1-yl]benzamide Chemical compound CNCCOC1=CC=CC=C1C1(NC=2C(N(C=3C(=C(F)C=C(C=3)C(=O)NC3CC3)C)C=CN=2)=O)CC1 NNKPHNTWNILINE-UHFFFAOYSA-N 0.000 description 1
- JLVDRILZZAPGNA-UHFFFAOYSA-N n-phenylthiophen-2-amine Chemical compound C=1C=CC=CC=1NC1=CC=CS1 JLVDRILZZAPGNA-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 150000002815 nickel Chemical class 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- HVZWVEKIQMJYIK-UHFFFAOYSA-N nitryl chloride Chemical compound [O-][N+](Cl)=O HVZWVEKIQMJYIK-UHFFFAOYSA-N 0.000 description 1
- 235000020925 non fasting Nutrition 0.000 description 1
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 238000013116 obese mouse model Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000003614 peroxisome proliferator Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940043274 prophylactic drug Drugs 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 1
- RVQZKNOMKUSGCI-UHFFFAOYSA-N pyridine-4-carbonyl chloride Chemical compound ClC(=O)C1=CC=NC=C1 RVQZKNOMKUSGCI-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003578 releasing effect Effects 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- NGHMEZWZOZEZOH-UHFFFAOYSA-N silicic acid;hydrate Chemical compound O.O[Si](O)(O)O NGHMEZWZOZEZOH-UHFFFAOYSA-N 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011781 sodium selenite Substances 0.000 description 1
- 235000015921 sodium selenite Nutrition 0.000 description 1
- 229960001471 sodium selenite Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Natural products CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- XOXHILFPRYWFOD-UHFFFAOYSA-N sulfachloropyridazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=C(Cl)N=N1 XOXHILFPRYWFOD-UHFFFAOYSA-N 0.000 description 1
- 229950008831 sulfachlorpyridazine Drugs 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- BRBKOPJOKNSWSG-UHFFFAOYSA-N sulfaguanidine Chemical compound NC(=N)NS(=O)(=O)C1=CC=C(N)C=C1 BRBKOPJOKNSWSG-UHFFFAOYSA-N 0.000 description 1
- 229960004257 sulfaguanidine Drugs 0.000 description 1
- 229960005158 sulfamethizole Drugs 0.000 description 1
- VACCAVUAMIDAGB-UHFFFAOYSA-N sulfamethizole Chemical compound S1C(C)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 VACCAVUAMIDAGB-UHFFFAOYSA-N 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- 229960004818 sulfaphenazole Drugs 0.000 description 1
- QWCJHSGMANYXCW-UHFFFAOYSA-N sulfaphenazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=NN1C1=CC=CC=C1 QWCJHSGMANYXCW-UHFFFAOYSA-N 0.000 description 1
- 229960002211 sulfapyridine Drugs 0.000 description 1
- GECHUMIMRBOMGK-UHFFFAOYSA-N sulfapyridine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=CC=N1 GECHUMIMRBOMGK-UHFFFAOYSA-N 0.000 description 1
- 229960001975 sulfisomidine Drugs 0.000 description 1
- YZMCKZRAOLZXAZ-UHFFFAOYSA-N sulfisomidine Chemical compound CC1=NC(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 YZMCKZRAOLZXAZ-UHFFFAOYSA-N 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- KQPVCFUTPHOFHQ-UHFFFAOYSA-N tert-butyl 4-(4-acetamidophenyl)piperazine-1-carboxylate Chemical compound C1=CC(NC(=O)C)=CC=C1N1CCN(C(=O)OC(C)(C)C)CC1 KQPVCFUTPHOFHQ-UHFFFAOYSA-N 0.000 description 1
- ZHFXMKLWVVBJRC-UHFFFAOYSA-N tert-butyl 4-[4-[(2-chloro-5-nitrobenzoyl)amino]phenyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(C=C1)=CC=C1NC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl ZHFXMKLWVVBJRC-UHFFFAOYSA-N 0.000 description 1
- SUPUIAUSUYHJPS-UHFFFAOYSA-N tert-butyl n-(2-amino-1,3-benzothiazol-6-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C2N=C(N)SC2=C1 SUPUIAUSUYHJPS-UHFFFAOYSA-N 0.000 description 1
- GPTXCAZYUMDUMN-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCO GPTXCAZYUMDUMN-UHFFFAOYSA-N 0.000 description 1
- BVQMUAAELWHQSF-UHFFFAOYSA-N tert-butyl n-[4-[(4-aminophenyl)methyl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1CC1=CC=C(N)C=C1 BVQMUAAELWHQSF-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000004862 thiobutyl group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000004035 thiopropyl group Chemical group [H]SC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012137 tryptone Substances 0.000 description 1
- 230000006433 tumor necrosis factor production Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は、PPARγモジュ
レーター活性を有する化合物及びそれらの用途に関す
る。TECHNICAL FIELD The present invention relates to compounds having PPARγ modulator activity and uses thereof.
【0002】より詳細には、本発明は、PPARγモジ
ュレーター活性を有する2−クロロ−5−ニトロフェニ
ルカルボキサミド誘導体及びその薬理上許容される塩並
びに、それを含有する、老人性骨粗鬆症、閉経後骨粗鬆
症、廃用性骨粗鬆症、ステロイド投与による骨粗鬆症、
骨折、骨形成不全、クル病、老年性骨関節疾患、肥満、
るい痩、I型糖尿病、II型糖尿病、動脈硬化症、脂質
代謝異常、膵炎、自己免疫疾患、糖代謝異常、糖尿病性
神経障害、糖尿病合併症、高尿酸血症、白血病、レチノ
イド関連受容体機能異常、肝機能異常、貧血、癌、炎
症、バセドウ氏病、心疾患、アルツハイマー病、摂食障
害、高血圧及び腎臓病の、治療薬または予防薬に関す
る。More specifically, the present invention provides a 2-chloro-5-nitrophenylcarboxamide derivative having a PPARγ modulator activity and a pharmacologically acceptable salt thereof, and senile osteoporosis, postmenopausal osteoporosis containing the same, Disused osteoporosis, osteoporosis caused by steroid administration,
Bone fracture, bone hypoplasia, rickets, senile bone joint disease, obesity,
Thinning, type I diabetes, type II diabetes, arteriosclerosis, dyslipidemia, pancreatitis, autoimmune disease, glucose metabolism disorder, diabetic neuropathy, diabetic complications, hyperuricemia, leukemia, retinoid-related receptor function The present invention relates to a therapeutic or prophylactic drug for abnormalities, liver dysfunction, anemia, cancer, inflammation, Graves' disease, heart disease, Alzheimer's disease, eating disorders, hypertension and kidney disease.
【0003】[0003]
【従来の技術】ペルオキシソームプロリフェレータ活性
化受容体(peroxisome proliferatoractivated recepto
r:PPAR)は核内レセプターファミリーの一員である。2. Description of the Related Art peroxisome proliferator activated recepto
r: PPAR) is a member of the nuclear receptor family.
【0004】一般に核内レセプター群には、アゴニス
ト、アンタゴニスト以外に、部分的アゴニストあるいは
部分的アンタゴニスト(これらは、総称して「モジュレ
ーター」といわれる)が存在することが知られている。
他の核内レセプターファミリーのモジュレーターの例と
しては、エストロゲンレセプターに対する部分的アゴニ
ストあるいは部分的アンタゴニストであるラロキシフェ
ンやタモキシフェンが知られている。部分的アゴニスト
はアゴニストに比較して、転写活性化量が小さいという
性質がある。また、部分的アンタゴニストはアゴニスト
存在時に同時に存在させると、アゴニストによる転写活
性化を抑制するが、その抑制の程度がアンタゴニストに
比べて小さいことが特徴である。また、一般的に部分的
アゴニストは部分的アンタゴニストの性質を示すことが
多い。It is generally known that in the nuclear receptor group, in addition to agonists and antagonists, there are partial agonists or partial antagonists (these are collectively referred to as "modulators").
As examples of modulators of other nuclear receptor families, raloxifene and tamoxifen, which are partial agonists or partial antagonists of estrogen receptors, are known. The partial agonist has a property that the transcription activation amount is smaller than that of the agonist. When a partial antagonist is present at the same time as an agonist is present, it suppresses transcriptional activation by the agonist, but is characterized in that the degree of the suppression is smaller than that of the antagonist. Further, in general, a partial agonist often exhibits the properties of a partial antagonist.
【0005】これら部分的アゴニストおよび部分的アン
タゴニストは、アゴニストおよびアンタゴニストが示す
組織特異的な望ましくない作用を抑制し、組織特異的な
望ましい作用を引き出すことを意図して作製される場合
が多い。These partial agonists and partial antagonists are often produced with the intention of suppressing the tissue-specific undesired effects of the agonists and antagonists and eliciting the tissue-specific desired effects.
【0006】ところで、種々のチアゾリジンジオン誘導
体は、インスリン非依存性糖尿病(NIDDM:non-insulin
-dependent diabetes melitus)のモデル動物で血糖降
下作用を示し、インスリン抵抗性解除作用を有する新し
いNIDDM治療薬として期待されている。これらチアゾリ
ジンジオン誘導体はまた、PPARγモジュレーターとして
作用し、PPARγを特異的に活性化することが最近の研究
で明らかとなった(Lehmannら,Journal of Biological
Chemistry,1995年,第270巻、p.12953-12956)。この
ようなチアゾリジンジオン誘導体のPPARγ活性化能と遺
伝性肥満マウスにおける血糖低下作用には強い相関が見
られることから、PPARγがチアゾリジンジオン誘導体の
薬理作用の標的分子であろうと考えられている(Willso
nら,Journal of Medicinal Chemistry,1996年,第39
巻,p.665-668)。[0006] By the way, various thiazolidinedione derivatives have been used in non-insulin-dependent diabetes mellitus (NIDDM).
-Dependent diabetes melitus) model animal shows hypoglycemic action and is expected as a new therapeutic drug for NIDDM having insulin resistance releasing action. Recent studies have revealed that these thiazolidinedione derivatives also act as PPARγ modulators and specifically activate PPARγ (Lehmann et al., Journal of Biological).
Chemistry, 1995, vol. 270, p.12953-12956). Since there is a strong correlation between the ability of thiazolidinedione derivatives to activate PPARγ and the blood glucose lowering effect in hereditary obese mice, it is considered that PPARγ is a target molecule for the pharmacological action of thiazolidinedione derivatives (Willso
n et al., Journal of Medicinal Chemistry, 1996, 39th.
Vol., P. 665-668).
【0007】これらの知見から、PPARγのモジュレータ
ーとして作用する化合物は、糖尿病治療薬として非常に
有効であると考えられている。From these findings, it is considered that the compound acting as a modulator of PPARγ is very effective as a therapeutic drug for diabetes.
【0008】又、骨塩量は男女とも加齢により減少し、
骨塩量が一定量以下(若年成人の70%未満)にまで減少
したときに骨粗鬆症と診断される。骨粗鬆症はその原因
となる基礎疾患の見られない原発性骨粗鬆症と、基礎疾
患がはっきりしている続発性骨粗鬆症に大別される。原
発性骨粗鬆症には閉経後女性にみられる閉経後骨粗鬆症
と老齢者にみられる老人性骨粗鬆症があり、この両者を
併せて退行期骨粗鬆症とよんでいる。Bone mineral content decreases with age in both men and women,
Osteoporosis is diagnosed when the amount of bone mineral drops below a certain level (less than 70% of young adults). Osteoporosis is roughly classified into primary osteoporosis in which the underlying disease that causes it is not seen and secondary osteoporosis in which the underlying disease is clear. Primary osteoporosis includes postmenopausal osteoporosis that occurs in postmenopausal women and senile osteoporosis that occurs in the elderly, and both are collectively referred to as catagen osteoporosis.
【0009】これまでに退行期骨粗鬆症患者の骨組織で
は健常人の骨組織にくらべて脂肪髄の割合が高いことが
報告されている(Burkuhardtら,Bone,1987年,第8
巻,p.157-164;Meunierら,Clin. Ortyop. Rel. Res,
1971年,第80巻,p.147-154)。また、不動化による骨
萎縮をきたした患者においても同様な変化が観察されて
いる(Minaireら,Calcified Tissue International,1
984年,第36巻,p.338-340;Calcified Tissue Interna
tional,1974年,第17巻,p.57-73)。It has been reported that the bone tissue of patients with regressive osteoporosis has a higher percentage of adipose pulp than that of healthy individuals (Burkuhardt et al., Bone, 1987, No. 8).
Volume, p.157-164; Meunier et al., Clin. Ortyop. Rel. Res,
1971, Volume 80, p.147-154). Similar changes were also observed in patients with bone atrophy due to immobilization (Minaire et al., Calcified Tissue International, 1
984, 36, 338-340; Calcified Tissue Interna
tional, 1974, Volume 17, p.57-73).
【0010】一方、PPARγは、脂肪細胞分化に深く関与
する因子であるとされている(Tontonozら,Genes and
Development,1994年,第8巻、p.1224-1234;Tontonoz
ら,Cell,1994年,第79巻、p.1147-1156)。On the other hand, PPARγ is said to be a factor deeply involved in adipocyte differentiation (Tontonoz et al., Genes and
Development, 1994, Volume 8, p.1224-1234; Tontonoz
Et al., Cell, 1994, Vol. 79, p. 1147-1156).
【0011】従って、骨髄細胞の脂肪細胞化を防ぐよう
なPPARγモジュレーターは、退行期骨粗鬆症に対する治
療薬として非常に有望である。Therefore, PPARγ modulators that prevent the bone marrow cells from becoming adipocytes are very promising as therapeutic agents for regressive osteoporosis.
【0012】更に、PPARγは細胞分化および脂質代謝を
転写レベルで調節し(Spiegelman,Eur. J. Med. Re
s.,1997年,第2巻,p.457-464;Tontonoz & Nagy,Cur
r. Opin. Lipidol,1999年,第10巻,p.485-490)、
又、PPREはapolipoprotein A-I[Stael,Atheroscleros
is,1998年,第137巻(suppulo),S19-S23]遺伝子やl
ipiprotein lipase[Schhnjans,EMBO J.,1996年,第1
5巻,p.5536-5548;Lefebvre,Arterio Thrombo Vasc.
Biol.,1997年,第17巻,p.1756-1764]などであり、血
清脂質プロファイルに影響を及ぼす脂質代謝関連遺伝子
プロモータである。従って、PPARγのモジュレーターは
脂質の代謝を調節し、脂質代謝異常に基づく疾患の治療
薬または予防薬(脂質調整薬)、高脂血症もしくは動脈
硬化症の治療薬または予防薬として期待される。In addition, PPARγ regulates cell differentiation and lipid metabolism at the transcriptional level (Spiegelman, Eur. J. Med. Re.
s., 1997, Volume 2, p.457-464; Tontonoz & Nagy, Cur
r. Opin. Lipidol, 1999, Volume 10, p.485-490),
PPRE is apolipoprotein AI [Stael, Atheroscleros
is, 1998, Volume 137 (suppulo), S19-S23] genes and l
ipiprotein lipase [Schhnjans, EMBO J., 1996, 1st
Volume 5, p. 5536-5548; Lefebvre, Arterio Thrombo Vasc.
Biol., 1997, Vol. 17, p. 1756-1764] and the like, which are lipid metabolism-related gene promoters that affect serum lipid profiles. Therefore, a modulator of PPARγ regulates lipid metabolism, and is expected as a therapeutic or preventive agent for diseases caused by abnormal lipid metabolism (lipid regulator), a therapeutic agent or preventive agent for hyperlipidemia or arteriosclerosis.
【0013】これまでクロロニトロフェニルカルボキサ
ミド誘導体が、PPARγのアゴニスト活性を有することが
報告されている(特許文献1、非特許文献1および2参
照)。It has been reported so far that chloronitrophenylcarboxamide derivatives have PPARγ agonist activity (see Patent Document 1, Non-Patent Documents 1 and 2).
【0014】[0014]
【特許文献1】国際公開第00/55118号パンフレ
ット[Patent Document 1] International Publication No. 00/55118 Pamphlet
【非特許文献1】L.M.Leesnitzer ら,Biochemistry,2
002年,第41巻,p.6640-6650。[Non-Patent Document 1] LM Leesnitzer et al., Biochemistry, 2
002, Volume 41, p.6640-6650.
【非特許文献2】G.L.Fabienne Elwood ら,The Journa
l of Biological Chemistry,2002年,第227巻,第22
号,p.19694-19657。[Non-Patent Document 2] GLFabienne Elwood et al., The Journa
l of Biological Chemistry, 2002, Volume 227, Volume 22
Issue, p.19694-19657.
【0015】[0015]
【発明が解決しようとする課題】従来、退行期骨粗鬆症
の治療薬としては、活性型ビタミンD製剤、ビタミン
K、カルシトニン、ビスフォスフォネートなどが用いら
れている。しかしながらこれらの薬剤は、亢進した骨吸
収に対する抑制作用がその薬理作用の主体であって、加
齢により低下した骨形成を回復・促進する作用を有する
薬剤はいまだ見出されていない。Conventionally, active vitamin D preparations, vitamin K, calcitonin, bisphosphonates and the like have been used as therapeutic agents for regressive osteoporosis. However, among these drugs, the suppressive action on the enhanced bone resorption is the main component of the pharmacological action, and no drug having the action of recovering / promoting the bone formation decreased with aging has been found yet.
【0016】本発明者等は、鋭意研究を行った結果、あ
る種の化合物がPPARγモジュレーター活性を有すること
を見出した。またこれらの化合物が、脂肪細胞分化亢進
の抑制作用、脂質調整作用および骨芽細胞の形成および
分化を促進する作用を有し、脂質代謝異常に基づく疾患
の治療薬または予防薬(脂質調整薬)、動脈硬化症、高
脂血症、骨粗鬆症もしくは糖尿病等の、治療薬または予
防薬として有用であることを見出し、本発明を完成し
た。As a result of intensive studies, the present inventors have found that certain compounds have PPARγ modulator activity. In addition, these compounds have an inhibitory effect on adipocyte differentiation promotion, a lipid regulating effect and an action promoting a formation and differentiation of osteoblasts, and a therapeutic or prophylactic agent for diseases caused by abnormal lipid metabolism (lipid regulating agent). The present invention has been completed based on the finding that it is useful as a therapeutic or preventive agent for arteriosclerosis, hyperlipidemia, osteoporosis, diabetes, etc.
【0017】[0017]
【課題を解決するための手段】本発明は、(1)下記一
般式(I)The present invention includes (1) the following general formula (I)
【0018】[0018]
【化2】 [Chemical 2]
【0019】[式中、Aは、フェニル基、ナフチル基、
アセナフテニル基、ピリジル基、キノリル基、イソキノ
リル基、ピリミジニル基、フリル基、ベンゾフリル基、
ピラニル基、クロメニル基、チエニル基、ベンゾチエニ
ル基、ピロリル基、インドリル基、イソインドリル基、
イミダゾリル基、ピラゾリル基、ピリダジニル基、ピラ
ジニル基、オキサゾリル基、ピロリジニル基、ピペリジ
ル基、ピペラジニル基、イソオキサゾリル基、ベンゾオ
キサゾリル基、ベンゾイソオキサゾリル基、チアゾリル
基、イソチアゾリル基、ベンゾチアゾリル基、ベンゾイ
ソチアゾリル基又はビフェニル基(当該Aは、下記置換
基群αから選ばれる1個乃至2個以上の同一又は異なっ
た置換基により置換されていても良い)を示し、Bは、
アリール基、シクロアルキル基又は複素環基(当該B
は、下記置換基群α及び置換基群βから選ばれる1個乃
至2個以上の同一又は異なった置換基により置換されて
いても良い)を示し、Raは水素原子又はC1−C6アル
キル基を示し、Xは、結合手、酸素原子、硫黄原子、C
H2基、CO基、NH基、SO2NH基、NHSO2基、
CONH基、NHCO基又はOCH2基を示し、nは0
又は1を示す。
[置換基群α]C1−C20アルキル基、ニトロ基、シア
ノ基、カルボキシ基、カルボキシC2−C 7アルキル基、
C2−C7アルキルオキシカルボニル基、C3−C15アル
キルオキシカルボニルアルキル基、アミノ基(当該アミ
ノ基は、1個又は2個の同一又は異なったC1−C6アル
キル基若しくは1個のC3−C6アルケニル基により置換
されていても良い)、C1−C12アルキルアミノ基(当
該アルキルアミノ基は、アミノ基、C1−C12アルキル
アミノ基、C2−C6アルキルオキシカルボニル基、イミ
ド基又は置換カルバモイル基により置換されていても良
い)、水酸基(当該水酸基は、1個のC1−C6アルキル
基又は1個のC1−C6ハロアルキル基により置換されて
いても良い)、C1−C6アルコキシ基(当該アルコキシ
基は、アミノ基、C1−C12アルキルアミノ基、C2−C
6アルキルオキシカルボニル基、イミド基又は置換カル
バモイル基により置換されていても良い)、メルカプト
基(当該メルカプト基は、1個のC1−C6アルキル基に
より置換されていても良い)、及び、C1−C6アルキル
チオ基(当該アルキルチオ基は、アミノ基、C1−C12
アルキルアミノ基、C2−C6アルキルオキシカルボニル
基、イミド基又は置換カルバモイル基により置換されて
いても良い)。
[置換基群β]ハロゲン原子、スルホンアミド基、C1
−C6アルキルスルホンアミド基、アミジノアミノスル
ホニル基及びフェニル基]で表される化合物又はその薬
理上許容される塩、(2)上記(1)において、Aがフ
ェニル又はチアゾリル基である化合物又はその薬理上許
容される塩、(3)上記(1)又は(2)において、X
が結合手である化合物又はその薬理上許容される塩、
(4)上記(1)乃至(3)の何れかにおいて、nが1
である化合物又はその薬理上許容される塩、(5)上記
(1)乃至(4)の何れかにおける化合物又はその薬理
上許容される塩を含有する、脂質調整薬、(6)上記
(1)乃至(4)の何れかにおける化合物又はその薬理
上許容される塩を含有する、動脈硬化症治療薬、(7)
上記(1)乃至(4)の何れかにおける化合物又はその
薬理上許容される塩を含有する、高脂血症治療薬であ
る。[In the formula, A is a phenyl group, a naphthyl group,
Acenaphthenyl, pyridyl, quinolyl, isoquino
Ryl group, pyrimidinyl group, furyl group, benzofuryl group,
Pyranyl group, chromenyl group, thienyl group, benzothienyl
Group, pyrrolyl group, indolyl group, isoindolyl group,
Imidazolyl group, pyrazolyl group, pyridazinyl group, pyra
Dinyl group, oxazolyl group, pyrrolidinyl group, piperidi
Group, piperazinyl group, isoxazolyl group, benzoo group
Xazolyl group, benzisoxazolyl group, thiazolyl
Group, isothiazolyl group, benzothiazolyl group, benzoi
Sothiazolyl group or biphenyl group (the A is the following substitution
1 or 2 or more same or different selected from the group α
Optionally substituted by a substituent), B is
Aryl group, cycloalkyl group or heterocyclic group (the B
Is one selected from the following substituent group α and substituent group β
Substituted by up to two or more identical or different substituents
R)aIs a hydrogen atom or C1-C6Al
X represents a bond, an oxygen atom, a sulfur atom, C
H2Group, CO group, NH group, SO2NH group, NHSO2Base,
CONH group, NHCO group or OCH2Group, n is 0
Or 1 is shown.
[Substituent group α] C1-C20Alkyl group, nitro group, shear
Group, carboxy group, carboxy C2-C 7An alkyl group,
C2-C7Alkyloxycarbonyl group, C3-C15Al
Killoxycarbonylalkyl group, amino group
Group is 1 or 2 identical or different C1-C6Al
Kill group or 1 C3-C6Substitute with alkenyl group
C)1-C12Alkylamino group (this
The alkylamino group is an amino group, C1-C12Alkyl
Amino group, C2-C6Alkyloxycarbonyl group, imimi
May be substituted with a substituted group or a substituted carbamoyl group.
A hydroxyl group (the hydroxyl group is one C1-C6Alkyl
Group or 1 C1-C6Substituted by a haloalkyl group
C)1-C6Alkoxy group (the alkoxy
The group is an amino group, C1-C12Alkylamino group, C2-C
6Alkyloxycarbonyl group, imide group or substituted calcium
Which may be substituted by a vamoyl group), mercapto
A group (the mercapto group is one C1-C6On an alkyl group
May be further substituted), and C1-C6Alkyl
Thio group (the alkylthio group is an amino group, C1-C12
Alkylamino group, C2-C6Alkyloxycarbonyl
Substituted by groups, imido groups or substituted carbamoyl groups
You may stay).
[Substituent group β] halogen atom, sulfonamide group, C1
-C6Alkylsulfonamide group, amidinoaminosul
[Fonyl group and phenyl group] or its drug
(2) In the above (1), A is a salt
A compound having a phenyl or thiazolyl group or its pharmacological permission
An acceptable salt, (3) in the above (1) or (2), X
Is a bond or a pharmacologically acceptable salt thereof,
(4) In any one of (1) to (3) above, n is 1
Or a pharmacologically acceptable salt thereof, (5) above
The compound or pharmacology thereof according to any one of (1) to (4)
(6) The above lipid-modifying drug, containing an acceptable salt.
The compound or pharmacology thereof according to any one of (1) to (4)
A therapeutic agent for arteriosclerosis containing a salt which is acceptable above, (7)
The compound or the compound according to any one of (1) to (4) above
A therapeutic drug for hyperlipidemia containing a pharmacologically acceptable salt
It
【0020】本発明において、「アリール基」は、例え
ば、フェニル、インデニル、ナフチル、フェナンスレニ
ル、アントラセニルのような炭素数5乃至14個の芳香
族炭化水素基を挙げることができ、好適にはフェニル基
である。In the present invention, the "aryl group" may be, for example, an aromatic hydrocarbon group having 5 to 14 carbon atoms such as phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl, preferably a phenyl group. Is.
【0021】尚、上記「アリール基」は、炭素数3乃至
10個のシクロアルキル基と縮環していてもよく、例え
ば、2−インダニルのような基を挙げることができる。The above "aryl group" may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof include 2-indanyl.
【0022】本発明において、「シクロアルキル基」
は、例えば、シクロプロピル、シクロブチル、シクロペ
ンチル、シクロヘキシル、シクロヘプチル、ノルボルニ
ル、アダマンチルのような縮環していてもよい3乃至1
0員飽和環状炭化水素基を挙げることができ、好適に
は、5乃至10員飽和環状炭化水素基である。In the present invention, "cycloalkyl group"
Is an optionally condensed 3 to 1 such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl.
A 0-membered saturated cyclic hydrocarbon group can be mentioned, and a 5- to 10-membered saturated cyclic hydrocarbon group is preferable.
【0023】本発明において、「複素環基」は、硫黄原
子、酸素原子又は/及び窒素原子を1乃至3個含む5乃
至7員複素環基を示し、例えば、フリル、チエニル、ピ
ロリル、アゼピニル、ピラゾリル、イミダゾリル、オキ
サゾリル、イソキサゾリル、チアゾリル、イソチアゾリ
ル、1,2,3−オキサジアゾリル、トリアゾリル、テ
トラゾリル、チアジアゾリル、ピラニル、 ピリジル、ピ
リダジニル、ピリミジニル、ピラジニルのような芳香族
複素環基、及びモルホリニル、チオモルホリニル、ピロ
リジニル、ピロリニル、イミダゾリジニル、イミダゾリ
ニル、ピラゾリジニル、ピラゾリニル、ピペリジル、ピ
ペラジニルのようなこれらの基に対応する、部分若しく
は完全還元型の基を挙げることができる。好適には、窒
素原子を少なくとも1個含み、酸素原子又は硫黄原子を
含んでいてもよい5乃至7員複素環基であり、例えば、
ピロリル、アゼピニル、ピラゾリル、イミダゾリル、オ
キサゾリル、イソキサゾリル、チアゾリル、イソチアゾ
リル、1,2,3−オキサジアゾリル、トリアゾリル、
テトラゾリル、チアジアゾリル、ピリジル、ピリダジニ
ル、ピリミジニル、ピラジニルのような芳香族複素環
基、及びモルホリニル、チオモルホリニル、ピロリジニ
ル、ピロリニル、イミダゾリジニル、イミダゾリニル、
ピラゾリジニル、ピラゾリニル、ピペリジル、ピペラジ
ニルのようなこれらの基に対応する、部分若しくは完全
還元型の基をあげることができ、さらに好適には、イミ
ダゾリル、オキサゾリル、イソキサゾリル、チアゾリル
及びこれらの基に対応する、部分若しくは完全還元型の
基である。In the present invention, "heterocyclic group" means a 5- to 7-membered heterocyclic group containing 1 to 3 sulfur atom, oxygen atom and / or nitrogen atom, for example, furyl, thienyl, pyrrolyl, azepinyl, Aromatic heterocyclic groups such as pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and morpholinyl, thiomorpholinyl, pyrrolidinyl. , Pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, corresponding partially or fully reduced groups. Preferably, it is a 5- to 7-membered heterocyclic group containing at least one nitrogen atom and optionally an oxygen atom or a sulfur atom, for example,
Pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl,
Aromatic heterocyclic groups such as tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,
Examples thereof include partially or completely reduced groups corresponding to these groups such as pyrazolidinyl, pyrazolinyl, piperidyl and piperazinyl, and more preferably imidazolyl, oxazolyl, isoxazolyl, thiazolyl and these groups, It is a partially or completely reduced group.
【0024】尚、上記「複素環基」は、他の環式基と縮
環していてもよく、例えば、イソベンゾフラニル、ベン
ゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチア
ゾリル、ベンゾイソチアゾリル、クロメニル、クロマノ
ニル、キサンテニル、フェノキサチイニル、インドリジ
ニル、イソインドリル、インドリル、インダゾリル、プ
リニル、キノリジニル、イソキノリル、キノリル、フタ
ラジニル、ナフチリジニル、キノキサリニル、キナゾリ
ニル、カルバゾリル、カルボリニル、アクリジニル、イ
ソインドリニルのような基を挙げることができる。The above "heterocyclic group" may be condensed with another cyclic group, for example, isobenzofuranyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazo. Groups such as ril, chromenyl, chromanonyl, xanthenyl, phenoxathiynyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carborinyl, acridinyl, isoindolinyl. be able to.
【0025】本発明において、「C1−C6アルキル基」
は、例えば、メチル、エチル、プロピル、イソプロピ
ル、ブチル、イソブチル、s−ブチル、t−ブチル、ペ
ンチル、イソペンチル、2−メチルブチル、ネオペンチ
ル、1−エチルプロピル、ヘキシル、4−メチルペンチ
ル、3−メチルペンチル、2−メチルペンチル、1−メ
チルペンチル、3,3−ジメチルブチル、2,2−ジメ
チルブチル、1,1−ジメチルブチル、1,2−ジメチ
ルブチル、1,3−ジメチルブチル、2,3−ジメチル
ブチル及び2−エチルブチル基のような、炭素数1乃至
6個の直鎖又は分枝鎖アルキル基である。本発明におい
て、好適には、C1−C4アルキル基であり、更に好適に
は、メチル又はエチル基である。In the present invention, "C 1 -C 6 alkyl group"
Is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl. , 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3- It is a linear or branched alkyl group having 1 to 6 carbon atoms such as dimethylbutyl and 2-ethylbutyl groups. In the present invention, it is preferably a C 1 -C 4 alkyl group, and more preferably a methyl or ethyl group.
【0026】本発明において、「C1−C20アルキル
基」は、例えば、メチル、エチル、プロピル、イソプロ
ピル、ブチル、イソブチル、s−ブチル、t−ブチル、
ペンチル、イソペンチル、2−メチルブチル、ネオペン
チル、1−エチルプロピル、ヘキシル、4−メチルペン
チル、3−メチルペンチル、2−メチルペンチル、1−
メチルペンチル、3,3−ジメチルブチル、2,2−ジ
メチルブチル、1,1−ジメチルブチル、1,2−ジメ
チルブチル、1,3−ジメチルブチル、2,3−ジメチ
ルブチル、2−エチルブチル、ヘプチル、オクチル、ノ
ニル、デシル、ウンデシル、ドデシル、トリデシル、テ
トラデシル、ペンタデシル、ヘキサデシル、ヘプタデシ
ル、オクタデシル、ノナデシル及びイコシル基のよう
な、炭素数1乃至20個の直鎖又は分枝鎖アルキル基であ
る。本発明において、好適には、C1−C6アルキル基で
あり、更に好適には、C1−C4アルキル基であり、更に
より好適には、メチル又はエチル基である。In the present invention, "C 1 -C 20 alkyl group" means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl,
Pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-
Methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl , Octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and icosyl groups, which are straight or branched chain alkyl groups having 1 to 20 carbon atoms. In the present invention, a C 1 -C 6 alkyl group is preferred, a C 1 -C 4 alkyl group is more preferred, and a methyl or ethyl group is even more preferred.
【0027】本発明において、「カルボキシC2−C7ア
ルキル基」は、カルボキシ基の炭素原子が、前記「C1
−C6アルキル基」に結合した基である。In the present invention, the "carboxy C 2 -C 7 alkyl group" means that the carbon atom of the carboxy group is the above "C 1
-C 6 is a group attached to an alkyl group. "
【0028】本発明において、「C2−C7アルキルオキ
シカルボニル基」は、前記「C1−C6アルキル基」が、
−O−CO−基の酸素原子に結合した基である。In the present invention, the "C 2 -C 7 alkyloxycarbonyl group" means the above "C 1 -C 6 alkyl group".
It is a group bonded to an oxygen atom of a —O—CO— group.
【0029】本発明において、「C3−C15アルキルオ
キシカルボニルアルキル基」は、前記「カルボキシC2
−C7アルキル基」のカルボキシ基と後述の「C1−C8
アルキル基」がエステルを形成した基である。In the present invention, "C 3 -C 15 alkyloxycarbonylalkyl group" means the above "carboxy C 2
A carboxy group of "-C 7 alkyl group" and the below-mentioned "C 1 -C 8
An "alkyl group" is an ester-forming group.
【0030】「C1−C8アルキル基」は、例えば、メチ
ル、エチル、プロピル、イソプロピル、ブチル、イソブ
チル、s−ブチル、t−ブチル、ペンチル、イソペンチ
ル、2−メチルブチル、ネオペンチル、1−エチルプロ
ピル、ヘキシル、4−メチルペンチル、3−メチルペン
チル、2−メチルペンチル、1−メチルペンチル、3,
3−ジメチルブチル、2,2−ジメチルブチル、1,1
−ジメチルブチル、1,2−ジメチルブチル、1,3−
ジメチルブチル、2,3−ジメチルブチル、2−エチル
ブチル、ヘプチル及びオクチル基のような、炭素数1乃
至8個の直鎖又は分枝鎖アルキル基である。好適には、
C1−C6アルキル基であり、更に好適には、C1−C4ア
ルキル基である。"C 1 -C 8 alkyl group" means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl. , Hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,
3-dimethylbutyl, 2,2-dimethylbutyl, 1,1
-Dimethylbutyl, 1,2-dimethylbutyl, 1,3-
It is a linear or branched alkyl group having 1 to 8 carbon atoms such as dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl and octyl groups. Preferably,
C 1 -C 6 alkyl group, more preferably a C 1 -C 4 alkyl group.
【0031】本発明において、「ハロゲン原子」は、弗
素原子、塩素原子、臭素原子又は沃素原子である。In the present invention, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
【0032】本発明において、「C3−C6アルケニル
基」は、例えば、1−プロペニル、2−プロペニル、1
−メチル−2−プロペニル、1−メチル−1−プロペニ
ル、2−メチル−1−プロペニル、2−メチル−2−プ
ロペニル、2−エチル−2−プロペニル、1−ブテニ
ル、2−ブテニル、1−メチル−2−ブテニル、1−メ
チル−1−ブテニル、3−メチル−2−ブテニル、1−
エチル−2−ブテニル、3−ブテニル、1−メチル−3
−ブテニル、2−メチル−3−ブテニル、1−エチル−
3−ブテニル、1−ペンテニル、2−ペンテニル、1−
メチル−2−ペンテニル、2−メチル−2−ペンテニ
ル、3−ペンテニル、1−メチル−3−ペンテニル、2
−メチル−3−ペンテニル、4−ペンテニル、1−メチ
ル−4−ペンテニル、2−メチル−4−ペンテニル、1
−ヘキセニル、2−ヘキセニル、3−ヘキセニル、4−
ヘキセニル、5−ヘキセニルのような、炭素数3乃至6
個の直鎖又は分枝鎖アルケニル基である。本発明におい
て、好適には、C4−C6アルケニル基であり、更に好適
には、ブテニル又はペンテニル基である。In the present invention, "C 3 -C 6 alkenyl group" means, for example, 1-propenyl, 2-propenyl, 1
-Methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl -2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-
Ethyl-2-butenyl, 3-butenyl, 1-methyl-3
-Butenyl, 2-methyl-3-butenyl, 1-ethyl-
3-butenyl, 1-pentenyl, 2-pentenyl, 1-
Methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2
-Methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1
-Hexenyl, 2-hexenyl, 3-hexenyl, 4-
3 to 6 carbon atoms such as hexenyl and 5-hexenyl
Is a straight chain or branched chain alkenyl group. In the present invention, it is preferably a C 4 -C 6 alkenyl group, and more preferably a butenyl or pentenyl group.
【0033】本発明において、「アミノ基(当該アミノ
基は、1個又は2個の同一又は異なったC1−C6アルキ
ル基若しくは1個のC3−C6アルケニル基により置換さ
れていても良い)」は、アミノ基;メチルアミノ、エチ
ルアミノ、プロピルアミノ、ペンチルアミノ、ブチルア
ミノ、ペンチルアミノ及びヘキシルアミノ基のような、
1個の前記C1−C6アルキル基により置換されたアミノ
基;ジメチルアミノ、ジエチルアミノ、ジプロピルアミ
ノ、N−エチルメチルアミノ、N−メチルプロピルアミ
ノ及びN−メチルヘキシルアミノのような、同一又は異
なった2個の前記C1−C6アルキル基により置換された
アミノ基;または、アリルアミノ、ブテニルアミノ、ペ
ンテニルアミノ及びヘキセニルアミノのような、1個の
前記C3−C6アルケニル基により置換されたアミノ基で
ある。本発明において、好適には、アミノ基又は1個の
C1−C6アルキル基により置換されたアミノ基であり、
更に好適には、アミノ基、メチルアミノ基又はエチルア
ミノ基である。In the present invention, "an amino group (wherein the amino group may be substituted with one or two identical or different C 1 -C 6 alkyl groups or one C 3 -C 6 alkenyl group) Good) "is an amino group; such as methylamino, ethylamino, propylamino, pentylamino, butylamino, pentylamino and hexylamino groups,
An amino group substituted by one said C 1 -C 6 alkyl group; identical or identical, such as dimethylamino, diethylamino, dipropylamino, N-ethylmethylamino, N-methylpropylamino and N-methylhexylamino An amino group substituted by two different C 1 -C 6 alkyl groups; or substituted by one C 3 -C 6 alkenyl group such as allylamino, butenylamino, pentenylamino and hexenylamino It is an amino group. In the present invention, it is preferably an amino group or an amino group substituted by one C 1 -C 6 alkyl group,
More preferably, it is an amino group, a methylamino group or an ethylamino group.
【0034】本発明において、「C1−C12アルキル
基」は、例えば、メチル、エチル、プロピル、イソプロ
ピル、ブチル、イソブチル、s−ブチル、t−ブチル、
ペンチル、イソペンチル、2−メチルブチル、ネオペン
チル、1−エチルプロピル、ヘキシル、4−メチルペン
チル、3−メチルペンチル、2−メチルペンチル、1−
メチルペンチル、3,3−ジメチルブチル、2,2−ジ
メチルブチル、1,1−ジメチルブチル、1,2−ジメ
チルブチル、1,3−ジメチルブチル、2,3−ジメチ
ルブチル、2−エチルブチル、ヘプチル、オクチル、ノ
ニル、デシル、ウンデシル及びドデシル基のような、炭
素数1乃至12個の直鎖又は分枝鎖アルキル基である。
本発明において、好適には、C1−C6アルキル基であ
り、更に好適には、C1−C4アルキル基である。In the present invention, "C 1 -C 12 alkyl group" means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl,
Pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-
Methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl , Octyl, nonyl, decyl, undecyl and dodecyl groups, which are straight or branched chain alkyl groups having 1 to 12 carbon atoms.
In the present invention, it is preferably a C 1 -C 6 alkyl group, more preferably a C 1 -C 4 alkyl group.
【0035】本発明において、「C1−C12アルキルア
ミノ基」は、前記「C1−C12アルキル基」が、アミノ
基に結合した基である。In the present invention, the "C 1 -C 12 alkylamino group" is a group in which the above "C 1 -C 12 alkyl group" is bonded to an amino group.
【0036】本発明において、「C1−C5アルキル基」
は、例えば、メチル、エチル、プロピル、イソプロピ
ル、ブチル、イソブチル、s−ブチル、t−ブチル、ペ
ンチル、イソペンチル、2−メチルブチル、ネオペンチ
ル及び1−エチルプロピル基のような、炭素数1乃至5
個の直鎖又は分枝鎖アルキル基である。本発明におい
て、好適には、C1−C4アルキル基である。In the present invention, "C 1 -C 5 alkyl group"
Is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl and 1-ethylpropyl groups having 1 to 5 carbon atoms.
Is a straight chain or branched chain alkyl group. In the present invention, it is preferably a C 1 -C 4 alkyl group.
【0037】本発明において、「C2−C6アルキルオキ
シカルボニル基」は、前記「C1−C5アルキル基」が、
−O−CO−基の酸素原子に結合した基である。In the present invention, the "C 2 -C 6 alkyloxycarbonyl group" means the above "C 1 -C 5 alkyl group".
It is a group bonded to an oxygen atom of a —O—CO— group.
【0038】本発明において、「イミド基」は、スクシ
ンイミド、グルタルイミドまたはフタルイミド基のよう
なイミド結合を有する基であり、好適には、環状イミド
結合を有する基であり、更に好適には、フタルイミド基
である。In the present invention, the "imide group" is a group having an imide bond, such as a succinimide, glutarimide or phthalimide group, preferably a group having a cyclic imide bond, and more preferably phthalimide. It is a base.
【0039】本発明において、「置換カルバモイル基」
は、N−フェニルカルバモイル基のような1個の前記ア
リール基で置換されたカルバモイル基;N−ピリジルカ
ルバモイル基のような1個の前記複素環基で置換された
カルバモイル基;またはピロリジニルカルボニル、ピペ
リジニルカルボニル、モルホリニルカルボニル、ピペラ
ジニル、4−メチルピペラジニル、4−フェニルピペラ
ジニル及び4−t−ブトキシカルボニルピペラジニルカ
ルボニル基のような含窒素へテロシクリル基を有するカ
ルバモイル基であり、好適には含窒素へテロシクリル基
を有するカルバモイル基である。In the present invention, "substituted carbamoyl group"
Is a carbamoyl group substituted with one of the above aryl groups such as N-phenylcarbamoyl group; a carbamoyl group substituted with one of the above heterocyclic groups such as N-pyridylcarbamoyl group; or pyrrolidinylcarbonyl A carbamoyl group having a nitrogen-containing heterocyclyl group such as, piperidinylcarbonyl, morpholinylcarbonyl, piperazinyl, 4-methylpiperazinyl, 4-phenylpiperazinyl and 4-t-butoxycarbonylpiperazinylcarbonyl group. And is preferably a carbamoyl group having a nitrogen-containing heterocyclyl group.
【0040】本発明において、「水酸基(当該水酸基
は、1個のC1−C6アルキル基又は1個のC1−C6ハロ
アルキル基により置換されていても良い)」は、水酸
基;メトキシ、エトキシ、プロポキシ、ブトキシ、ペン
チルオキシ及びヘキシルオキシ基のような、炭素数1乃
至6個の直鎖又は分枝鎖C1−C6アルコキシ基;又は、
フルオロメトキシ、トリフルオロメトキシ及び2,2,
2−トリフルオロエトキシ基のような、炭素数1乃至6
個の直鎖又は分枝鎖C1−C6アルコキシ基に前記ハロゲ
ン原子が1個以上結合した基である。本発明において、
好適には、水酸基、メトキシ基、エトキシ基又はトリフ
ルオロメトキシ基である。In the present invention, "a hydroxyl group (the hydroxyl group may be substituted with one C 1 -C 6 alkyl group or one C 1 -C 6 haloalkyl group)" means a hydroxyl group; methoxy, A straight or branched C 1 -C 6 alkoxy group having 1 to 6 carbon atoms such as ethoxy, propoxy, butoxy, pentyloxy and hexyloxy groups; or
Fluoromethoxy, trifluoromethoxy and 2,2
1 to 6 carbon atoms such as 2-trifluoroethoxy group
This is a group in which one or more of the above halogen atoms are bonded to a straight or branched C 1 -C 6 alkoxy group. In the present invention,
It is preferably a hydroxyl group, a methoxy group, an ethoxy group or a trifluoromethoxy group.
【0041】本発明において、「C1−C6アルコキシ
基」は、前記「C1−C6アルキル基」が、酸素原子に結
合した基である。In the present invention, the "C 1 -C 6 alkoxy group" is a group in which the above "C 1 -C 6 alkyl group" is bonded to an oxygen atom.
【0042】本発明において、「メルカプト基(当該メ
ルカプト基は、1個のC1−C6アルキル基により置換さ
れていても良い)」は、メルカプト基又は、メチルチ
オ、エチルチオ、プロピルチオ、ブチルチオ、ペンチル
チオ及びヘキシルチオ基のような、炭素数1乃至6個の
直鎖又は分枝鎖C1−C6アルキルチオ基である。本発明
において、好適には、メルカプト、メチルチオ又はエチ
ルチオ基である。In the present invention, the "mercapto group (the mercapto group may be substituted with one C 1 -C 6 alkyl group)" means a mercapto group or methylthio, ethylthio, propylthio, butylthio, pentylthio. And a linear or branched C 1 -C 6 alkylthio group having 1 to 6 carbon atoms such as a hexylthio group. In the present invention, it is preferably a mercapto, methylthio or ethylthio group.
【0043】本発明において、「C1−C6アルキルチオ
基」は、前記「C1−C6アルキル基」が、硫黄原子に結
合した基である。In the present invention, the "C 1 -C 6 alkylthio group" is a group in which the above "C 1 -C 6 alkyl group" is bonded to a sulfur atom.
【0044】本発明において、「C1−C6アルキルスル
ホンアミド基」は、前記「C1−C6アルキル基」が、−
SO2−NH2−の硫黄原子または窒素原子に結合した基
である。In the present invention, the "C 1 -C 6 alkylsulfonamide group" is the above "C 1 -C 6 alkyl group".
It is a group bonded to a sulfur atom or a nitrogen atom of SO 2 —NH 2 —.
【0045】本発明において、nが1の場合、B−X−
A−で表される基は、B−A−基、B−O−A−基、B
−S−A−基、B−NH−A−、B−SO2NH−A−
基、B−NHSO2−A−基、B−CONH−A−基、
B−NHCO−A−基又はB−OCH2−A−基を示
す。In the present invention, when n is 1, B--X--
The group represented by A- is a B-A- group, a B-O-A- group, or a B
-S-A- group, B-NH-A-, B -SO 2 NH-A-
Group, B-NHSO 2 -A- group, B-CONH-A- group,
B-NHCO-A- represents a group or a B-OCH 2 -A- group.
【0046】本発明において、nが1の場合、B−X−
で表される基は、Aで表される基のいずれの置換位置に
置換していても良い。In the present invention, when n is 1, B--X--
The group represented by may be substituted at any substitution position of the group represented by A.
【0047】また、一般式(I)で表される化合物にお
いて、2−クロロ−5−ニトロフェニルカルボニルアミ
ノ基は、Aで表される基のいずれの置換位置に置換して
いても良い。In the compound represented by the general formula (I), the 2-chloro-5-nitrophenylcarbonylamino group may be substituted at any substitution position of the group represented by A.
【0048】さらに、nが1の場合、B−X−で表され
る基と2−クロロ−5−ニトロフェニルカルボニルアミ
ノ基との相対的な置換位置に関しても、いずれの相対的
な置換位置でも良い。好適には、Aがフェニル基の場合
は、パラ位であり、Aがピリジル基の場合は、基B−X
−が2位で2−クロロ−5−ニトロフェニルカルボニル
アミノ基が5位又は基B−X−が3位で2−クロロ−5
−ニトロフェニルカルボニルアミノ基が6位である。Further, when n is 1, the relative substitution position between the group represented by BX- and the 2-chloro-5-nitrophenylcarbonylamino group may be any relative substitution position. good. Suitably, when A is a phenyl group, it is in the para position, and when A is a pyridyl group, it is a group BX.
-Is 2-position and 2-chloro-5-nitrophenylcarbonylamino group is 5-position or group BX- is 3-position and 2-chloro-5
The -nitrophenylcarbonylamino group is in the 6-position.
【0049】本発明の化合物(I)は、常法に従って塩
にすることができ、それらの塩も本願発明に包含され
る。The compound (I) of the present invention can be converted into a salt according to a conventional method, and those salts are also included in the present invention.
【0050】そのような塩としては、例えば、ナトリウ
ム塩、カリウム塩、リチウム塩のようなアルカリ金属
塩;カルシウム塩、マグネシウム塩のようなアルカリ土
類金属塩;アルミニウム塩、鉄塩、亜鉛塩、銅塩、ニッ
ケル塩、コバルト塩等の金属塩;アンモニウム塩のよう
な無機塩基塩;t−オクチルアミン塩、ジベンジルアミ
ン塩、モルホリン塩、グルコサミン塩、フェニルグリシ
ンアルキルエステル塩、エチレンジアミン塩、N−メチ
ルグルカミン塩、グアニジン塩、ジエチルアミン塩、ト
リエチルアミン塩、ジシクロヘキシルアミン塩、N,
N’−ジベンジルエチレンジアミン塩、クロロプロカイ
ン塩、プロカイン塩、ジエタノールアミン塩、N−ベン
ジル−N−フェネチルアミン塩、ピペラジン塩、テトラ
メチルアンモニウム塩、トリス(ヒドロキシメチル)ア
ミノメタン塩のような有機アミン塩;弗化水素酸塩、塩
酸塩、臭化水素酸塩、沃化水素酸塩のようなハロゲン化
水素酸塩;硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無
機酸塩;メタンスルホン酸塩、トリフルオロメタンスル
ホン酸塩、エタンスルホン酸塩のような低級アルカンス
ルホン酸塩;ベンゼンスルホン酸塩、p-トルエンスルホ
ン酸塩のようなアリ−ルスルホン酸塩;酢酸塩、りんご
酸塩、フマ−ル酸塩、コハク酸塩、クエン酸塩、酒石酸
塩、蓚酸塩、マレイン酸塩等の有機酸塩;及び、オルニ
チン酸塩、グルタミン酸塩、アスパラギン酸塩のような
アミノ酸塩を挙げることができ、好適には、ハロゲン化
水素酸塩又は有機酸塩である。Examples of such salts include alkali metal salts such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts, iron salts, zinc salts, Metal salts such as copper salts, nickel salts and cobalt salts; inorganic base salts such as ammonium salts; t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N- Methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,
Organic amine salts such as N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-N-phenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt; Hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; inorganic salts such as nitrates, perchlorates, sulfates and phosphates; methanesulfonic acid Lower alkane sulfonates such as salts, trifluoromethane sulfonate, ethane sulfonate; aryl sulfonates such as benzene sulfonate, p-toluene sulfonate; acetate, malate, fumar Organic acid salts such as phosphates, succinates, citrates, tartrates, oxalates, and maleates; and ornithates, glutamate Salts, amino acid salts such as aspartate can be mentioned, preferably a hydrohalide salt or an organic acid salt.
【0051】又、本発明の化合物(I)は、大気中に放
置しておいたり、再結晶することにより、水分を吸収
し、吸着水が付いたり、水和物となる場合があり、それ
らの水和物も本発明に包含される。The compound (I) of the present invention may absorb water by adsorbing water or become a hydrate by being left in the air or recrystallized. The hydrate of is also included in the present invention.
【0052】更に、本発明の化合物(I)は、有機溶媒
を吸収し、溶媒和物となる場合があるが、それらの溶媒
和物も本発明に包含される。Further, the compound (I) of the present invention may absorb an organic solvent to form a solvate, and those solvates are also included in the present invention.
【0053】また、生体内において代謝されて本発明の
化合物(I)又はその薬理上許容される塩に変換される
化合物、いわゆるプロドラッグも全て本発明に包含され
る。The present invention also includes all compounds which are metabolized in vivo and converted into the compound (I) of the present invention or a pharmacologically acceptable salt thereof, so-called prodrugs.
【0054】[0054]
【発明の実施の形態】本発明の一般式(Ia)で表され
る2−クロロ−5−ニトロフェニルカルボキサミド誘導
体およびその薬理上許容される塩は、以下の方法に従っ
て容易に製造される。
(A法)BEST MODE FOR CARRYING OUT THE INVENTION The 2-chloro-5-nitrophenylcarboxamide derivative of the present invention represented by the general formula (Ia) and its pharmacologically acceptable salt are easily produced by the following method. (A method)
【0055】[0055]
【化3】 [Chemical 3]
【0056】(上記式中、A、B、X及びnは、前述し
たものと同意義を示す。)
(A工程)A工程は、前記一般式(Ia)で表される化
合物を製造する工程であり、前記一般式(II)で表さ
れるアミン化合物をアシル化することによって製造され
る。(In the above formula, A, B, X and n have the same meanings as described above.) (Step A) Step A is a step of producing a compound represented by the above general formula (Ia). And is produced by acylating the amine compound represented by the general formula (II).
【0057】本工程の原料である一般式(II)で表さ
れる化合物は、市販されているものを使用するか、又
は、例えばB法以下に記載した方法等の周知の方法にし
たがって製造することができる。The compound represented by the general formula (II), which is the raw material in this step, is commercially available or is produced according to a well-known method such as the method described below in Method B. be able to.
【0058】本反応は、有機合成化学において周知のア
ミド結合を形成させる反応であり、通常、溶剤の存在下
で好適に行われる。This reaction is a reaction for forming an amide bond, which is well known in synthetic organic chemistry, and is usually suitably carried out in the presence of a solvent.
【0059】使用される溶剤としては、本反応に影響を
与えなければ特に限定はなく、例えば不活性溶剤であり
得、好適には、ジクロロメタン、クロロホルムのような
ハロゲン化炭化水素類、酢酸エチルのようなエステル
類、テトラヒドロフラン、ジオキサンのようなエーテル
類、N、N−ジメチルアセトアミド、N、N−ジメチル
ホルムアミドのようなアミド類があげられる。The solvent to be used is not particularly limited as long as it does not affect the reaction, and may be, for example, an inert solvent, preferably halogenated hydrocarbons such as dichloromethane and chloroform, and ethyl acetate. Examples thereof include esters, ethers such as tetrahydrofuran and dioxane, and amides such as N, N-dimethylacetamide and N, N-dimethylformamide.
【0060】反応は、縮合剤で処理することにより行わ
れる。The reaction is carried out by treating with a condensing agent.
【0061】使用される縮合剤としては、 N、N−ジ
シクロヘキシルカルボジイミド、1−(3−ジメチルア
ミノプロピル)−3−エチルカルボジイミド・塩酸塩の
ようなカルボジイミド類;ジフェニルホスホリルアジ
ド、ジエチルホスホリルシアナイドのようなホスホリル
化合物;カルボニルジイミダゾール;トリフェニルホス
フィン−アゾジカルボン酸ジエチル;1−プロパンホス
フォン酸環状無水物;等があげられるが、好適には、カ
ルボニルジイミダゾールまたはカルボジイミド類であ
る。ホスホリル化合物を使用する場合には、トリエチル
アミン、N−メチルモルホリン等の三級アミンの存在下
で行なうのが好ましい。Examples of the condensing agent used include carbodiimides such as N, N-dicyclohexylcarbodiimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide / hydrochloride; diphenylphosphoryl azide and diethylphosphoryl cyanide. Examples thereof include phosphoryl compounds; carbonyldiimidazole; diethyl triphenylphosphine-azodicarboxylate; 1-propanephosphonic acid cyclic anhydride; and the like, with carbonyldiimidazole or carbodiimides being preferred. When a phosphoryl compound is used, it is preferably carried out in the presence of a tertiary amine such as triethylamine or N-methylmorpholine.
【0062】また、本反応は、本反応に使用するカルボ
ン酸またはその塩をクロルギ酸エチル、クロルギ酸イソ
ブチル等のクロルギ酸低級アルキルエステル類と、トリ
エチルアミン、N−メチルモルホリン等の三級アミンの
存在下で反応させ、混合酸無水物を形成させるか、ある
いは、本反応に使用するカルボン酸またはその塩をN−
ヒドロキシスクシンイミド、N−ヒドロキシベンズトリ
アゾール、p−ニトロフェノール等と、N、N−ジシク
ロヘキシルカルボジイミド等のカルボジイミド類の存在
下で反応させ、相当する活性エステルを形成させた後
に、これらをアミンと縮合させることによっても達成さ
れる。In this reaction, the carboxylic acid or its salt used in this reaction is prepared from the presence of lower alkyl alkyl chloroformates such as ethyl chloroformate and isobutyl chloroformate, and tertiary amines such as triethylamine and N-methylmorpholine. Or the carboxylic acid or salt thereof used in this reaction is reacted with N- to form a mixed acid anhydride.
Reacting with hydroxysuccinimide, N-hydroxybenztriazole, p-nitrophenol or the like in the presence of carbodiimides such as N, N-dicyclohexylcarbodiimide to form a corresponding active ester, and then condensing these with an amine. Also achieved by.
【0063】反応は通常、溶剤の存在下で好適に行われ
る。The reaction is usually suitably carried out in the presence of a solvent.
【0064】使用される溶剤としては、本反応に影響を
与えなければ特に限定はなく、例えば不活性溶剤であり
得、好適には、ジクロロメタン、クロロホルムのような
ハロゲン化炭化水素類、テトラヒドロフラン、ジオキサ
ンのようなエーテル類、ベンゼン、トルエンのような芳
香属炭化水素類をあげることができる。The solvent used is not particularly limited as long as it does not affect the reaction, and may be, for example, an inert solvent, and is preferably a halogenated hydrocarbon such as dichloromethane or chloroform, tetrahydrofuran, dioxane. And aromatic hydrocarbons such as benzene and toluene.
【0065】更にまた、本反応は対応するカルボン酸ク
ロリドなどのアシルハライドを、N、N−ジメチルアセ
トアミド中で上記アミン(II)と反応させることによ
っても達成され、場合によってはピリジン、トリエチル
アミンなどの塩基を存在させる必要がある。Furthermore, this reaction is also achieved by reacting the corresponding acyl halide such as carboxylic acid chloride with the above amine (II) in N, N-dimethylacetamide, and in some cases, such as pyridine, triethylamine and the like. Base must be present.
【0066】反応は通常、溶剤の存在下で好適に行われ
る。The reaction is usually suitably carried out in the presence of a solvent.
【0067】使用される溶剤としては、本反応に影響を
与えなければ特に限定はなく、例えば不活性溶剤であり
得、好適には、ジクロロメタンのようなハロゲン化炭化
水素類、テトラヒドロフラン、ジオキサンのようなエー
テル類、ベンゼン、トルエンのような芳香属炭化水素類
をあげることができる。The solvent used is not particularly limited as long as it does not affect the reaction, and may be, for example, an inert solvent, and is preferably a halogenated hydrocarbon such as dichloromethane, tetrahydrofuran or dioxane. Aromatic hydrocarbons such as various ethers, benzene and toluene can be mentioned.
【0068】反応温度は−20℃乃至100℃であり、
好適には、−5℃乃至50℃である。The reaction temperature is -20 ° C to 100 ° C,
It is preferably -5 ° C to 50 ° C.
【0069】反応時間は、反応試薬、反応温度、溶剤な
どによって異なるが、通常30分間乃至24時間であ
り、好適には、1時間乃至16時間である。
(B法)The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually 30 minutes to 24 hours, and preferably 1 hour to 16 hours. (Method B)
【0070】[0070]
【化4】 [Chemical 4]
【0071】(上記式中、A及びBは、前述したものと
同意義を示す。)
B法は、A工程の原料である化合物(II)において、
XがCONH、nが1である化合物(II−1)を製造
する方法である。
(B1工程)B1工程は、カルボン酸とアミンを縮合し
て、一般式(III−1)で表されるアミド結合を有す
るニトロアミド化合物を製造する工程である。(In the above formula, A and B have the same meanings as described above.) Method B is the same as compound (II) which is a raw material of step A.
It is a method for producing a compound (II-1) in which X is CONH and n is 1. (Step B1) Step B1 is a step of condensing a carboxylic acid and an amine to produce a nitroamide compound having an amide bond represented by the general formula (III-1).
【0072】本工程は、前記A工程に準じて行うことが
できる。
(B2工程)B2工程は、一般式(III−1)で表さ
れるニトロアミド化合物を還元して、一般式(II−
1)で表されるアミノ化合物を製造する工程である。This step can be carried out according to the above step A. (Step B2) In step B2, the nitroamide compound represented by the general formula (III-1) is reduced to give the general formula (II-
This is a step of producing an amino compound represented by 1).
【0073】本反応は、有機合成化学において周知の接
触水素添加反応であり、通常、溶剤の存在下で好適に行
われる。This reaction is a catalytic hydrogenation reaction well known in synthetic organic chemistry, and is usually suitably carried out in the presence of a solvent.
【0074】使用される触媒は、例えば、パラジウム−
炭素、水酸化パラジウム−炭素、パラジウム黒、酸化白
金、白金黒などがあげられ、好適には、パラジウム−炭
素である。The catalyst used is, for example, palladium-
Examples thereof include carbon, palladium hydroxide-carbon, palladium black, platinum oxide, platinum black, and the like, with palladium-carbon being preferred.
【0075】反応は通常、溶剤の存在下で好適に行われ
る。The reaction is usually suitably carried out in the presence of a solvent.
【0076】使用される溶剤としては、反応に影響を与
えなければ特に限定はなく、例えば、ベンゼン、トルエ
ン、キシレン、ヘキサン、ヘプタンのような炭化水素
類;クロロホルム、塩化メチレン、四塩化炭素のような
ハロゲン化炭化水素類;ジエチルエーテル、テトラヒド
ロフラン、ジオキサンのようなエーテル類;メタノー
ル、エタノール、イソプロパノールのようなアルコール
類;N、N−ジメチルホルムアミド、N、N−ジメチル
アセトアミド、ヘキサメチルリン酸トリアミドのような
アミド類;ギ酸、酢酸のようなカルボン酸類;またはこ
れらの混合溶剤であり得、好適には、アルコール類また
はエーテル類である。The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; chloroform, methylene chloride and carbon tetrachloride. Halogenated hydrocarbons; ethers such as diethyl ether, tetrahydrofuran, dioxane; alcohols such as methanol, ethanol, isopropanol; N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide Such amides; carboxylic acids such as formic acid and acetic acid; or a mixed solvent thereof, preferably alcohols or ethers.
【0077】反応温度は10℃乃至140℃であり、好
適には、20℃乃至120℃である。The reaction temperature is 10 ° C to 140 ° C, preferably 20 ° C to 120 ° C.
【0078】反応時間は、反応試薬、反応温度、溶剤な
どによって異なるが、通常30分間乃至3日間であり、
好適には、1時間乃至24時間である。The reaction time varies depending on the reaction reagent, reaction temperature, solvent, etc., but is usually 30 minutes to 3 days,
It is preferably 1 to 24 hours.
【0079】また、本工程は、例えば、塩化第二すず、
塩化ニッケル等の還元剤を用いて行うことができ、必要
に応じて水素化ホウ素ナトリウムなどの還元剤を共存さ
せる事ができる。Further, this step is carried out, for example, with stannic chloride,
This can be performed using a reducing agent such as nickel chloride, and if necessary, a reducing agent such as sodium borohydride can coexist.
【0080】反応は通常、溶剤の存在下で好適に行われ
る。The reaction is usually suitably carried out in the presence of a solvent.
【0081】使用される溶剤としては、反応に影響を与
えなければ特に限定はなく、例えば、ベンゼン、トルエ
ン、キシレン、ヘキサン、ヘプタンのような炭化水素
類;クロロホルム、塩化メチレン、四塩化炭素のような
ハロゲン化炭化水素類;ジエチルエーテル、テトラヒド
ロフラン、ジオキサンのようなエーテル類;メタノー
ル、エタノール、イソプロパノールのようなアルコール
類;N、N−ジメチルホルムアミド、N、N−ジメチル
アセトアミド、ヘキサメチルリン酸トリアミドのような
アミド類;ギ酸、酢酸のようなカルボン酸類;またはこ
れらの混合溶剤であり得、好適には、アルコール類若し
くはエーテル類である。The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; chloroform, methylene chloride and carbon tetrachloride. Halogenated hydrocarbons; ethers such as diethyl ether, tetrahydrofuran, dioxane; alcohols such as methanol, ethanol, isopropanol; N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide Such amides; carboxylic acids such as formic acid and acetic acid; or a mixed solvent thereof, preferably alcohols or ethers.
【0082】反応温度は10℃乃至140℃であり、好
適には、20℃乃至120℃である。The reaction temperature is 10 ° C to 140 ° C, preferably 20 ° C to 120 ° C.
【0083】反応時間は、反応試薬、反応温度、溶剤な
どによって異なるが、通常30分間乃至3日間であり、
好適には、1時間乃至24時間である。
(C法)The reaction time varies depending on the reaction reagent, reaction temperature, solvent, etc., but is usually 30 minutes to 3 days,
It is preferably 1 to 24 hours. (C method)
【0084】[0084]
【化5】 [Chemical 5]
【0085】(上記式中、A及びBは、前述したものと
同意義を示す。)
C法は、A工程の原料である化合物(II)において、
XがNHCO、nが1である化合物(II−2)を製造
する方法である。
(C1工程)C1工程は、アミンとカルボン酸を縮合し
て、一般式(III−2)で表されるアミド結合を有す
るニトロアミド化合物を製造する工程である。(In the above formula, A and B have the same meanings as described above.) Method C is the same as in the compound (II) which is a raw material in the step A.
A method for producing a compound (II-2) in which X is NHCO and n is 1. (Step C1) Step C1 is a step of condensing an amine and a carboxylic acid to produce a nitroamide compound having an amide bond represented by the general formula (III-2).
【0086】上記式中、A、B、およびXは、前述した
ものと同意義を示す。In the above formula, A, B and X have the same meanings as described above.
【0087】本工程は、前記A工程に準じて行うことが
できる。
(C2工程)C2工程は、一般式(III−2)で表さ
れるニトロアミド化合物を還元して一般式(II−2)
で表されるアミノ化合物を製造する工程である。This step can be carried out according to the above step A. (Step C2) In the step C2, the nitroamide compound represented by the general formula (III-2) is reduced to give the general formula (II-2).
Is a step of producing an amino compound represented by.
【0088】本工程は、前記B2工程に準じて行うこと
ができる。
(D法)This step can be carried out according to the above step B2. (D method)
【0089】[0089]
【化6】 [Chemical 6]
【0090】(上記式中、A及びBは、前述したものと
同意義を示す。)
D法は、A工程の原料である化合物(II)において、
XがNHSO2、nが1である化合物(II−3)を製
造する方法である。
(D1工程)D1工程は、アミンとスルホニルクロリド
とを縮合し、一般式(III−3)で表されるスルフォ
ンアミド結合を有するニトロスルフォンアミド化合物を
製造する工程である。(In the above formula, A and B have the same meanings as described above.) The method D is the same as in the compound (II) which is a raw material of the step A.
A method for producing a compound (II-3) in which X is NHSO 2 and n is 1. (Step D1) Step D1 is a step of condensing an amine and a sulfonyl chloride to produce a nitrosulfonamide compound having a sulfonamide bond represented by the general formula (III-3).
【0091】本反応は、有機合成化学において周知のス
ルフォンアミド結合を形成させる反応である。This reaction is a reaction for forming a sulfonamide bond which is well known in synthetic organic chemistry.
【0092】反応は通常、溶剤の存在下で好適に行われ
る。The reaction is usually suitably carried out in the presence of a solvent.
【0093】使用される溶剤としては、本反応に影響を
与えなければ特に限定はなく、例えば不活性溶剤であり
得、好適には、ジクロロメタンのようなハロゲン化炭化
水素類、テトラヒドロフラン、ジオキサンのようなエー
テル類、ベンゼン、トルエンのような芳香属炭化水素類
をあげることができる。The solvent used is not particularly limited as long as it does not affect the reaction, and may be, for example, an inert solvent, preferably halogenated hydrocarbons such as dichloromethane, tetrahydrofuran, dioxane and the like. Aromatic hydrocarbons such as various ethers, benzene and toluene can be mentioned.
【0094】反応温度は−20℃乃至100℃であり、
好適には、−5℃乃至50℃である。The reaction temperature is -20 ° C to 100 ° C,
It is preferably -5 ° C to 50 ° C.
【0095】反応時間は、反応試薬、反応温度、溶剤な
どによって異なるが、通常30分間乃至24時間であ
り、好適には、1時間乃至16時間である。
(D2工程)D2工程は、一般式(III−3)で表さ
れるニトロスルフォンアミド化合物を還元して、一般式
(II−3)で表されるアミノスルフォンアミド化合物
を製造する工程である。The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually 30 minutes to 24 hours, and preferably 1 hour to 16 hours. (Step D2) Step D2 is a step of reducing the nitrosulfonamide compound represented by the general formula (III-3) to produce an aminosulfonamide compound represented by the general formula (II-3).
【0096】本工程は、前記B2工程に準じて行うこと
ができる。
(E法)This step can be carried out according to the above step B2. (E method)
【0097】[0097]
【化7】 [Chemical 7]
【0098】(上記式中、A及びBは、前述したものと
同意義を示す。)
E法は、A工程の原料である化合物(II)において、
XがSO2NH、nが1である化合物(II−4)を製
造する方法である。
(E1工程)E1工程は、一般式(III−4)で表さ
れるスルフォンアミド結合を有するニトロスルフォンア
ミド化合物を製造する工程である。(In the above formula, A and B have the same meanings as described above.) Method E is the same as in the compound (II) which is a raw material of the step A.
A method for producing a compound (II-4) in which X is SO 2 NH and n is 1. (Step E1) Step E1 is a step of producing a nitrosulfonamide compound having a sulfonamide bond represented by the general formula (III-4).
【0099】本工程は、前記D1工程に準じて行うこと
ができる。
(E2工程)E2工程は、一般式(III−4)で表さ
れるニトロスルフォンアミド化合物を還元して、一般式
(II−4)で表されるアミノスルフォンアミド化合物
を製造する工程である。This step can be carried out according to the above-mentioned step D1. (Step E2) Step E2 is a step of reducing the nitrosulfonamide compound represented by the general formula (III-4) to produce an aminosulfonamide compound represented by the general formula (II-4).
【0100】本工程は、前記B2工程に準じて行うこと
ができる。
(F法)本発明化合物を製造する原料となる、下記一般
式(II−4)This step can be carried out according to the above step B2. (Method F) The following general formula (II-4) as a raw material for producing the compound of the present invention
【0101】[0101]
【化8】 [Chemical 8]
【0102】(上記式中、Bは前述したものと同意義を
示す。)で表される2−チアゾールアミン誘導体は、以
下の方法に従って容易に製造される。
(F1工程)F1工程は、一般式(II−4)で表され
る2−チアゾールアミン誘導体をメチルケトン化合物か
ら製造する工程である。(In the above formula, B has the same meaning as described above.) The 2-thiazoleamine derivative represented by the formula is easily produced by the following method. (Step F1) Step F1 is a step of producing a 2-thiazoleamine derivative represented by the general formula (II-4) from a methyl ketone compound.
【0103】[0103]
【化9】 [Chemical 9]
【0104】本工程は、J. Am. Chem. Soc.,第72巻,
p.3722-3725又はBull. Soc. Chim. Fr.,1958年,p.143
7−1439に記載の方法に準じて、メチルケトン化合物を
チオ尿素とヨウ素又は臭素存在下で加熱することによ
り、一般式(II−4)で表される2−チアゾールアミ
ン誘導体を製造する工程である。
(F2工程)This step is described in J. Am. Chem. Soc., Vol. 72,
p.3722-3725 or Bull. Soc. Chim. Fr., 1958, p.143
According to the method described in 7-1439, it is a step of producing a 2-thiazoleamine derivative represented by the general formula (II-4) by heating a methyl ketone compound in the presence of thiourea and iodine or bromine. . (F2 process)
【0105】[0105]
【化10】 [Chemical 10]
【0106】F2工程は、J. Indian Chem. Soc.,1974
年,第51巻,p.1031-1034に記載の方法に準じて、α−
ブロモメチルケトンをチオ尿素と反応させることによ
り、一般式(II−4)で表される2−チアゾールアミ
ン誘導体を製造する工程である。The F2 process is described in J. Indian Chem. Soc., 1974.
Year, Volume 51, p.1031-1034
This is a step of producing a 2-thiazoleamine derivative represented by the general formula (II-4) by reacting bromomethyl ketone with thiourea.
【0107】反応は、通常、溶剤の存在下で好適に行わ
れる。The reaction is usually suitably carried out in the presence of a solvent.
【0108】使用される溶剤としては、本反応に影響を
与えなければ特に限定はなく、例えば不活性溶剤であり
得、好適には、ジクロロメタン、クロロホルムのような
ハロゲン化炭化水素類、酢酸エチルのようなエステル
類、テトラヒドロフラン、ジオキサンのようなエーテル
類、N、N−ジメチルアセトアミド、N、N−ジメチル
ホルムアミドのようなアミド類、アセトン、メチルエチ
ルケトン等のケトン類があげられる。The solvent used is not particularly limited as long as it does not affect the reaction, and may be, for example, an inert solvent. Preferably, it is a halogenated hydrocarbon such as dichloromethane or chloroform, or ethyl acetate. Examples thereof include esters, tetrahydrofuran, ethers such as dioxane, amides such as N, N-dimethylacetamide, N, N-dimethylformamide, and ketones such as acetone and methyl ethyl ketone.
【0109】反応温度は−20℃乃至100℃であり、
好適には、−5℃乃至50℃である。The reaction temperature is -20 ° C to 100 ° C,
It is preferably -5 ° C to 50 ° C.
【0110】反応時間は反応試薬、反応温度、溶剤など
によって異なるが、通常30分間乃至24時間であり、
好適には、5時間乃至16時間である。A法乃至F法に
記載した各反応終了後、各反応の目的化合物は、常法に
従って、反応混合物から採取される。例えば、反応混合
物を適宜中和し、又、不溶物が存在する場合には濾過に
より除去した後、水と酢酸エチルのような水と混和しな
い有機溶媒を加え、目的化合物を含む有機層を分離し、
有機層を水等で洗浄し、無水硫酸マグネシウム、無水硫
酸ナトリウム若しくは無水炭酸水素ナトリウム等で乾燥
した後、溶剤を留去することによって、目的化合物は得
られる。得られた目的化合物は必要ならば、常法にした
がって、例えば、再結晶、再沈殿等の有機化合物の分離
精製に通常慣用されている方法を適宜用い、クロマトグ
ラフィーを適用し適切な溶離剤で溶出することによっ
て、分離、精製することができる。The reaction time varies depending on the reaction reagent, reaction temperature, solvent, etc., but is usually 30 minutes to 24 hours,
It is preferably 5 hours to 16 hours. After completion of each reaction described in Methods A to F, the target compound of each reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then water and an organic solvent immiscible with water such as ethyl acetate are added to separate the organic layer containing the target compound. Then
The target compound is obtained by washing the organic layer with water or the like, drying it over anhydrous magnesium sulfate, anhydrous sodium sulfate or anhydrous sodium hydrogen carbonate, and then distilling off the solvent. The obtained target compound is, if necessary, according to a conventional method, for example, by appropriately using a method usually used for separation and purification of an organic compound such as recrystallization, reprecipitation, and the like, by applying chromatography and applying an appropriate eluent. By eluting, it can be separated and purified.
【0111】本発明の前記一般式(I)を有する化合
物、又はその薬理上許容される塩を、治療薬又は予防薬
として使用する場合には、それ自体で温血動物(特に、
ヒト)に投与することができ、或は適宜の薬理学的に許
容される、賦形剤、希釈剤等と混合し、例えば、錠剤、
カプセル剤、顆粒剤、散剤若しくはシロップ剤等の製剤
として経口的に、又は注射剤若しくは坐剤等の製剤とし
て非経口的に、温血動物(特に、ヒト)に投与すること
ができる。When the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof is used as a therapeutic or prophylactic agent, a warm-blooded animal (particularly,
Human)) or is mixed with an appropriate pharmacologically acceptable excipient, diluent, etc., for example, tablets,
It can be administered to warm-blooded animals (particularly humans) orally as a preparation such as capsule, granule, powder or syrup, or parenterally as a preparation such as injection or suppository.
【0112】これらの製剤は、賦形剤、滑沢剤、滑沢
剤、結合剤、崩壊剤、安定剤、矯味矯臭剤、希釈剤等の
添加剤を用いて周知の方法で製造される。These formulations are manufactured by a known method using additives such as an excipient, a lubricant, a lubricant, a binder, a disintegrating agent, a stabilizer, a flavoring agent and a diluent.
【0113】賦形剤は、例えば、有機系賦形剤または無
機系賦形剤であり得る。有機系賦形剤は、例えば、乳
糖、白糖、葡萄糖、マンニトール、ソルビトールのよう
な糖誘導体;トウモロコシデンプン、バレイショデンプ
ン、α澱粉、デキストリンのような澱粉誘導体;結晶セ
ルロースのようなセルロース誘導体;アラビアゴム;デ
キストラン;またはプルラン等であり得る。無機系賦形
剤は、例えば、軽質無水珪酸、合成珪酸アルミニウム、
珪酸カルシウム、メタ珪酸アルミン酸マグネシウムのよ
うな珪酸塩誘導体;燐酸水素カルシウムのような燐酸
塩;炭酸カルシウムのような炭酸塩;または硫酸カルシ
ウムのような硫酸塩等であり得る。Excipients can be, for example, organic or inorganic excipients. Organic excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; corn starch, potato starch, α starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose; gum arabic. Dextran; or pullulan and the like. Inorganic excipients include, for example, light anhydrous silicic acid, synthetic aluminum silicate,
It may be a silicate derivative such as calcium silicate, magnesium aluminometasilicate; a phosphate such as calcium hydrogen phosphate; a carbonate such as calcium carbonate; or a sulfate such as calcium sulfate.
【0114】滑沢剤は、例えば、ステアリン酸、ステア
リン酸カルシウム、ステアリン酸マグネシウムのような
ステアリン酸金属塩;タルク;コロイドシリカ;ビーガ
ム、ゲイ蝋のようなワックス類;硼酸;アジピン酸;硫
酸ナトリウムのような硫酸塩;グリコール;フマル酸;
安息香酸ナトリウム;DLロイシン;脂肪酸ナトリウム
塩;ラウリル硫酸ナトリウム、ラウリル硫酸マグネシウ
ムのようなラウリル硫酸塩;無水珪酸、珪酸水和物のよ
うな珪酸類;または上記澱粉誘導体であり得る。Lubricants include, for example, stearic acid, metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as bee gum and gay wax; boric acid; adipic acid; sodium sulfate. Such sulfates; glycols; fumaric acid;
It may be sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid anhydride such as silicic acid anhydride and silicic acid hydrate; or the above starch derivative.
【0115】結合剤は、例えば、ヒドロキシプロピルセ
ルロース、ヒドロキシプロピルメチルセルロース、ポリ
ビニルピロリドン、マクロゴール、または上記賦形剤と
同様の化合物であり得る。The binder may be, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, or a compound similar to the above excipients.
【0116】崩壊剤は、例えば、低置換度ヒドロキシプ
ロピルセルロース、カルボキシメチルセルロース、カル
ボキシメチルセルロースカルシウム、内部架橋カルボキ
シメチルセルロースナトリウムのようなセルロース誘導
体;またはカルボキシメチルスターチ、カルボキシメチ
ルスターチナトリウム、架橋ポリビニルピロリドンのよ
うな化学修飾されたデンプン・セルロース類であり得
る。Disintegrators are, for example, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; or carboxymethylstarch, sodium carboxymethylstarch, crosslinked polyvinylpyrrolidone. It may be chemically modified starch / celluloses.
【0117】安定剤は、例えば、メチルパラベン、プロ
ピルパラベンのようなパラヒドロキシ安息香酸エステル
類;クロロブタノール、ベンジルアルコール、フェニル
エチルアルコールのようなアルコール類;塩化ベンザル
コニウム;フェノール、クレゾールのようなフェノール
類;チメロサール;デヒドロ酢酸;またはソルビン酸で
あり得る。Stabilizers include, for example, parahydroxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol such as phenol and cresol. Can be thimerosal; dehydroacetic acid; or sorbic acid.
【0118】矯味矯臭剤は、例えば、通常使用される、
甘味料、酸味料、香料等であり得る。Flavoring agents are, for example, commonly used,
It can be a sweetener, a sour agent, a flavoring agent and the like.
【0119】その使用量は症状、年齢、投与方法等によ
り異なるが、例えば、経口投与の場合には、1回当り、
下限として0.001mg/kg 体重(好ましくは、0.0
1mg/kg 体重)、上限として500mg/kg 体重(好まし
くは、50mg/kg 体重)を、静脈内投与の場合には、1
回当り、下限として0.001mg/kg 体重(好ましく
は、0.01mg/kg 体重)、上限として500mg/kg 体
重(好ましくは、50mg/kg 体重)を1日当り1乃至数
回、症状に応じて投与することができる。以下に、実施
例、参考例および試験例を示し、本発明を更に詳細に説
明するが、本発明の範囲はこれらに限定されるものでは
ない。The amount used varies depending on symptoms, age, administration method, etc., but, for example, in the case of oral administration,
The lower limit is 0.001 mg / kg body weight (preferably 0.0
1 mg / kg body weight), with an upper limit of 500 mg / kg body weight (preferably 50 mg / kg body weight).
The lower limit is 0.001 mg / kg body weight (preferably 0.01 mg / kg body weight) and the upper limit is 500 mg / kg body weight (preferably 50 mg / kg body weight) 1 to several times a day depending on the symptoms. It can be administered. Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples, but the scope of the present invention is not limited thereto.
【0120】[0120]
【実施例】下記実施例に置いて、特に記載が無い場合
は、NMR測定において内部標準物質として、テトラメ
チルシラン(TMS)を用いた。
(実施例1)N−(4−メチルフェニル)−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド
4−メチルアニリン0.330gをジメチルアセトアミ
ド(DMA)10mLに溶解し、2−クロロ−5−ニト
ロ安息香酸クロリド0.745gを室温で加え、3時間
攪拌した。反応溶液に酢酸エチル5mL及び飽和重曹水
30mLを加え、1時間攪拌し、酢酸エチルで抽出し
た。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリ
ウムで乾燥し、減圧下濃縮した。残渣をジイソプロピル
エーテル(IPE)で結晶化し、濾取して、標記目的化
合物0.759gを得た。EXAMPLES In the following examples, unless otherwise specified, tetramethylsilane (TMS) was used as an internal standard substance in NMR measurement. (Example 1) N- (4-methylphenyl)-(2-chloro-5-nitrophenyl) carboxamide 0.330 g of 4-methylaniline was dissolved in 10 mL of dimethylacetamide (DMA) to give 2-chloro-5-nitro. 0.745 g of benzoic acid chloride was added at room temperature and stirred for 3 hours. 5 mL of ethyl acetate and 30 mL of saturated aqueous sodium hydrogen carbonate were added to the reaction solution, stirred for 1 hour, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether (IPE) and collected by filtration to obtain the title compound (0.759 g).
【0121】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
2.36 (1H, s), 7.21 (1H, d, J=8.3Hz), 7.26 (1H, s),
7.51 (1H, d, J=8.3 Hz), 7.65 (1H, d, J=8.8 Hz),
7.77(1H, s), 8.26 (1H, dd, J=8.8, 2.7 Hz), 8.61 (1
H, d, J=2.7 Hz)。
(実施例2)N−(4−フェニルフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
4−フェニルアニリン・塩酸塩0.229gをピリジン
3mLに溶解し、2−クロロ−5−ニトロ安息香酸クロ
リド0.294gを室温で加え、一晩攪拌した。反応溶
液に酢酸エチル5mL及び飽和重曹水30mLを加え1
時間攪拌した後、水20mLを加え攪拌した。析出した
結晶を濾取し、乾燥して、標記目的化合物0.270g
の結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
2.36 (1H, s), 7.21 (1H, d, J = 8.3Hz), 7.26 (1H, s),
7.51 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 8.8 Hz),
7.77 (1H, s), 8.26 (1H, dd, J = 8.8, 2.7 Hz), 8.61 (1
H, d, J = 2.7 Hz). (Example 2) N- (4-phenylphenyl)-(2-chloro-5-nitrophenyl) carboxamide 0.229 g of 4-phenylaniline hydrochloride was dissolved in 3 mL of pyridine to prepare 2-chloro-5-nitrobenzoic acid. 0.294 g of acid chloride was added at room temperature and stirred overnight. Add 5 mL of ethyl acetate and 30 mL of saturated aqueous sodium hydrogen carbonate to the reaction solution, and add 1
After stirring for 20 hours, 20 mL of water was added and stirred. The precipitated crystals were collected by filtration and dried to give the title compound (0.270 g)
Was obtained.
【0122】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.34-7.81 (1H, m), 7.43-7.48 (2H,m), 7.59-7.74(7H,
m), 7.89 (1H, s), 8.28 (1H, dd, J=8.8, 2.7 Hz),
8.65(1H, d, J=2.7 Hz)。
(実施例3)N−(4−メチルチアゾール−2−イル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
2−アミノ−4−メチルチアゾール0.380g、2−
クロロ−5−ニトロ安息香酸0.671g及び1,1’
−カルボニルジイミダゾール(CDI)1.079gを
テトラヒドロフラン(THF)20mLに溶解し、16
時間加熱還流した。反応溶液をシリカゲルカラムクロマ
トグラフィ−(ヘキサン:酢酸エチル=3:2(v/
v))にて精製し、IPEで結晶化し、濾取して、標記
目的化合物0.155gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.34-7.81 (1H, m), 7.43-7.48 (2H, m), 7.59-7.74 (7H,
m), 7.89 (1H, s), 8.28 (1H, dd, J = 8.8, 2.7 Hz),
8.65 (1H, d, J = 2.7 Hz). (Example 3) N- (4-methylthiazol-2-yl)
-(2-Chloro-5-nitrophenyl) carboxamide 0.380 g of 2-amino-4-methylthiazole, 2-
Chloro-5-nitrobenzoic acid 0.671 g and 1,1 '
1.079 g of carbonyldiimidazole (CDI) was dissolved in 20 mL of tetrahydrofuran (THF),
Heated to reflux for hours. The reaction solution was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 2 (v /
Purified in v)), crystallized with IPE and collected by filtration to obtain 0.155 g of the title target compound as crystals.
【0123】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
2.00 (3H, s), 6.59 (1H, s), 7.62(1H, d, J=8.8 Hz),
8.28 (1H, dd, J=8.8, 2.7 Hz), 8.58 (1H, d, J=2.7
Hz),11.75 (1H, bs)。
(実施例4)N−(5−メチルチアゾール−2−イル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
2−アミノ−5−メチルチアゾール0.264g、DM
A5mLならびに2−クロロ−5−ニトロ安息香酸クロ
リド0.560gを使用して、実施例1に記載した方法
に従い、標記目的化合物0.619gの結晶を得た。1
H-NMR (400MHz, CDCl3, TMS): δ(ppm) 2.34 (3H, s),
6.32 (1H, s), 7.71 (1H, d, J=8.8 Hz), 8.35 (1H, d
d, J=8.8, 2.7 Hz), 8.57 (1H, d, J=2.7 Hz)。
(実施例5)N−(3−フェニルフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
3−フェニルアニリン・塩酸塩0.239g、ピリジン
5mLならびに2−クロロ−5−ニトロ安息香酸クロリ
ド0.307gを使用して、実施例1に記載した方法に
従い、標記目的化合物0.309gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
2.00 (3H, s), 6.59 (1H, s), 7.62 (1H, d, J = 8.8 Hz),
8.28 (1H, dd, J = 8.8, 2.7 Hz), 8.58 (1H, d, J = 2.7
Hz), 11.75 (1H, bs). (Example 4) N- (5-methylthiazol-2-yl)
-(2-chloro-5-nitrophenyl) carboxamide 2-amino-5-methylthiazole 0.264 g, DM
According to the method described in Example 1, using 5 mL of A and 0.560 g of 2-chloro-5-nitrobenzoic acid chloride, 0.619 g of the title object compound was obtained as crystals. 1 H-NMR (400MHz, CDCl 3 , TMS): δ (ppm) 2.34 (3H, s),
6.32 (1H, s), 7.71 (1H, d, J = 8.8 Hz), 8.35 (1H, d
d, J = 8.8, 2.7 Hz), 8.57 (1H, d, J = 2.7 Hz). (Example 5) N- (3-phenylphenyl)-(2-chloro-5-nitrophenyl) carboxamide 0.239 g of 3-phenylaniline.hydrochloride, 5 mL of pyridine and 2-chloro-5-nitrobenzoic acid chloride 0 According to the method described in Example 1, using 0.307 g, 0.309 g of the title object compound was obtained as crystals.
【0124】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.35-7.40 (1H, m), 7.41-7.52 (4H,m), 7.60-7.67(4H,
m), 7.86 (1H, s), 7.94 (1H, s), 8.26 (1H, dd, J=
8.8,2.7 Hz), 8.63 (1H, d, J=2.7 Hz)。
(実施例6)N−(4−メトキシ−3−フェニル)フェ
ニル−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
(4−メトキシ−3−フェニル)アニリン・塩酸塩0.
478g、ピリジン5mLならびに2−クロロ−5−ニ
トロ安息香酸クロリド0.535gを使用して、実施例
2に記載した方法に従い、標記目的化合物0.586g
の結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.35-7.40 (1H, m), 7.41-7.52 (4H, m), 7.60-7.67 (4H,
m), 7.86 (1H, s), 7.94 (1H, s), 8.26 (1H, dd, J =
8.8,2.7 Hz), 8.63 (1H, d, J = 2.7 Hz). (Example 6) N- (4-methoxy-3-phenyl) phenyl- (2-chloro-5-nitrophenyl) carboxamide (4-methoxy-3-phenyl) aniline.hydrochloride
According to the method described in Example 2, using 478 g, pyridine 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.535 g, the title object compound 0.586 g
Was obtained.
【0125】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
3.95 (3H, s), 7.31-7.46 (4H, m),7.63-7.69 (3H, m),
8.27 (1H, dd, J=8.8, 2.7 Hz), 8.67 (1H, d, J=2.7
Hz),8.54 (1H, d, 2.2 Hz)。
(実施例7)N−(2−フェニルフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
2−フェニルアニリン・塩酸塩0.251g、ピリジン
5mLならびに2−クロロ−5−ニトロ安息香酸クロリ
ド0.322gを使用して、実施例1に記載した方法に
従い、標記目的化合物0.323gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
3.95 (3H, s), 7.31-7.46 (4H, m), 7.63-7.69 (3H, m),
8.27 (1H, dd, J = 8.8, 2.7 Hz), 8.67 (1H, d, J = 2.7
Hz), 8.54 (1H, d, 2.2 Hz). (Example 7) N- (2-phenylphenyl)-(2-chloro-5-nitrophenyl) carboxamide 2-phenylaniline.hydrochloride 0.251 g, pyridine 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0 According to the method described in Example 1, using 0.322 g, 0.323 g of the title object compound was obtained as crystals.
【0126】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.27-7.34 (2H, m), 7.39-7.54 (7H,m), 7.90 (1H, s),
8.18 (1H, dd, J=8.8, 2.7 Hz), 8.45 (1H, d, J=8.1
Hz),8.53 (1H, d, J=2.7 Hz)。
(実施例8)N−[4−(2−ピリジル)フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
4−(2−ピリジル)アニリン・塩酸塩0.320g、
ピリジン5mLならびに2−クロロ−5−ニトロ安息香
酸クロリド0.347gを使用して、実施例1に記載し
た方法に従い、標記目的化合物0.388gの結晶を得
た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.27-7.34 (2H, m), 7.39-7.54 (7H, m), 7.90 (1H, s),
8.18 (1H, dd, J = 8.8, 2.7 Hz), 8.45 (1H, d, J = 8.1
Hz), 8.53 (1H, d, J = 2.7 Hz). (Example 8) N- [4- (2-pyridyl) phenyl]-
(2-chloro-5-nitrophenyl) carboxamide 4- (2-pyridyl) aniline.hydrochloride 0.320 g,
Following the method described in Example 1 using 5 mL of pyridine and 0.347 g of 2-chloro-5-nitrobenzoic acid chloride, 0.388 g of the title object compound was obtained as crystals.
【0127】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.22-7.26 (1H, m), 7.66 (1H, d, J=8.8 Hz), 7.72-7.
79 (4H, m), 8.05 (1H, d, J=8.8 Hz), 8.08 (1H, s),
8.27(1H, dd, J=8.8, 2.7 Hz), 8.63 (1H, d, J=2.7 H
z), 8.69 (1H, d, J=4.7 Hz)。
(実施例9)N−[4−(4−ニトロフェニル)フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
4−(4−ニトロフェニル)アニリン0.344g、D
MA5mLならびに2−クロロ−5−ニトロ安息香酸ク
ロリド0.424gを使用して、実施例2に記載した方
法に従い、標記目的化合物0.625gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.22-7.26 (1H, m), 7.66 (1H, d, J = 8.8 Hz), 7.72-7.
79 (4H, m), 8.05 (1H, d, J = 8.8 Hz), 8.08 (1H, s),
8.27 (1H, dd, J = 8.8, 2.7 Hz), 8.63 (1H, d, J = 2.7 H
z), 8.69 (1H, d, J = 4.7 Hz). (Example 9) N- [4- (4-nitrophenyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (4-nitrophenyl) aniline 0.344 g, D
According to the method described in Example 2, using 5 mL of MA and 0.424 g of 2-chloro-5-nitrobenzoic acid chloride, 0.625 g of the title object compound was obtained.
【0128】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.84-7.89 (4H, m), 7.92 (1H, d, J=8.8 Hz), 7.92 (2
H, d, J=8.8 Hz), 8.31 (2H, d, J=8.8 Hz), 8.36 (1H,
dd,J=8.8, 2.7 Hz), 8.52 (1H, d, J=2.7 Hz), 10.93
(1H, s)。
(実施例10)N−[4−(6−メチルベンゾチアゾー
ル−2−イル)フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
4−(6−メチルベンゾチアゾール−2−イル)アニリ
ン0.353g、DMA5mLならびに2−クロロ−5
−ニトロ安息香酸クロリド0.349gを使用して、実
施例1に記載した方法に従い、標記目的化合物0.61
4gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.84-7.89 (4H, m), 7.92 (1H, d, J = 8.8 Hz), 7.92 (2
H, d, J = 8.8 Hz), 8.31 (2H, d, J = 8.8 Hz), 8.36 (1H,
dd, J = 8.8, 2.7 Hz), 8.52 (1H, d, J = 2.7 Hz), 10.93
(1H, s). Example 10 N- [4- (6-Methylbenzothiazol-2-yl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (6-methylbenzothiazol-2-yl) aniline 0 .353 g, DMA 5 mL and 2-chloro-5
According to the method described in Example 1, using 0.349 g of -nitrobenzoic acid chloride, the title object compound 0.61 was prepared.
4 g of crystals were obtained.
【0129】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
2.47 (3H, s), 7.36 (1H, d, J=8.5 Hz), 7.89-7.94(2
H, m), 8.11 (1H, d, J=8.8 Hz), 8.37 (1H, dd, J=8.
8, 2.8 Hz), 8.55 (1H, d, J=2.8 Hz), 11.04 (1H,
s)。
(実施例11)N−(3−メチルフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
m−トルイジン0.269g、DMA5mLならびに2
−クロロ−5−ニトロ安息香酸クロリド0.663gを
使用して、実施例2に記載した方法に従い、標記目的化
合物0.677gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
2.47 (3H, s), 7.36 (1H, d, J = 8.5 Hz), 7.89-7.94 (2
H, m), 8.11 (1H, d, J = 8.8 Hz), 8.37 (1H, dd, J = 8.
8, 2.8 Hz), 8.55 (1H, d, J = 2.8 Hz), 11.04 (1H,
s). Example 11 N- (3-Methylphenyl)-(2-chloro-5-nitrophenyl) carboxamide m-toluidine 0.269 g, DMA 5 mL and 2
Following the procedure described in Example 2 using 0.663 g of -chloro-5-nitrobenzoic acid chloride, 0.677 g of the title compound was obtained as crystals.
【0130】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
2.40 (3H, s), 7.04 (1H, d, J=7.6Hz), 7.29 (1H, t,
J=7.9 Hz), 7.41 (1H, d, J=8.1 Hz), 7.74-7.84 (1H,
m),8.27 (1H, dd, J=8.8, 2.7 Hz), 8.61 (1H, d, J=2.
7 Hz)。
(実施例12)N−(4−エチルフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
4−エチルアニリン0.280g、DMA5mLならび
に2−クロロ−5−ニトロ安息香酸クロリド0.610
gを使用して、実施例2に記載した方法に従い、標記目
的化合物0.676gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
2.40 (3H, s), 7.04 (1H, d, J = 7.6Hz), 7.29 (1H, t,
J = 7.9 Hz), 7.41 (1H, d, J = 8.1 Hz), 7.74-7.84 (1H,
m), 8.27 (1H, dd, J = 8.8, 2.7 Hz), 8.61 (1H, d, J = 2.
7 Hz). Example 12 N- (4-Ethylphenyl)-(2-chloro-5-nitrophenyl) carboxamide 4-ethylaniline 0.280 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.610.
According to the method described in Example 2, using 0.6 g, 0.676 g of crystals of the title object compound was obtained.
【0131】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
1.25 (3H, t, J=7.6 Hz), 2.66 (2H,q, J=7.6 Hz), 7.2
4 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=8.4 Hz), 7.66
(1H,d, J=8.8 Hz), 8.26 (1H, dd, J=8.8, 2.7 Hz), 8.
61 (1H, d, J=2.7 Hz)。
(実施例13)N−(2−エチルフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
2−エチルアニリン0.269g、DMA5mLならび
に2−クロロ−5−ニトロ安息香酸クロリド0.586
gを使用して、実施例2に記載した方法に従い、標記目
的化合物0.667gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
1.25 (3H, t, J = 7.6 Hz), 2.66 (2H, q, J = 7.6 Hz), 7.2
4 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.66
(1H, d, J = 8.8 Hz), 8.26 (1H, dd, J = 8.8, 2.7 Hz), 8.
61 (1H, d, J = 2.7 Hz). Example 13 N- (2-Ethylphenyl)-(2-chloro-5-nitrophenyl) carboxamide 2-ethylaniline 0.269 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.586.
According to the method described in Example 2, using 0.6 g, 0.667 g of the title object compound was obtained as crystals.
【0132】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
1.28 (3H, t, J=7.6 Hz), 2.69 (2H,q, J=7.6 Hz), 7.2
1-7.33 (3H, m), 7.68 (1H, d, J=8.8 Hz), 7.80 (1H,
s),8.28 (1H, dd, J=8.8, 2.7 Hz), 8.67 (1H, d, J=2.
7 Hz)。
(実施例14)N−(3−エチルフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
3−エチルアニリン0.210g、DMA5mLならび
に2−クロロ−5−ニトロ安息香酸クロリド0.458
gを使用して、実施例2に記載した方法に従い、標記目
的化合物0.359gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
1.28 (3H, t, J = 7.6 Hz), 2.69 (2H, q, J = 7.6 Hz), 7.2
1-7.33 (3H, m), 7.68 (1H, d, J = 8.8 Hz), 7.80 (1H,
s), 8.28 (1H, dd, J = 8.8, 2.7 Hz), 8.67 (1H, d, J = 2.
7 Hz). Example 14 N- (3-Ethylphenyl)-(2-chloro-5-nitrophenyl) carboxamide 3-ethylaniline 0.210 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.458.
According to the method described in Example 2, using g, 0.359 g of the title object compound was obtained as crystals.
【0133】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
1.19 (3H, t, J=7.6 Hz), 2.61 (2H, q, J=7.6 Hz),
7.00 (1H, d, J=7.8 Hz), 7.28 (1H, t, J=7.8 Hz), 7.
51 (1H, d, J=7.8 Hz), 7.58 (1H, s), 7.89 (1H, d, J
=8.8 Hz), 8.34 (1H, dd, J=8.8, 2.7 Hz), 8.45 (1H,
d, J=2.7 Hz)。
(実施例15)N−(4−プロピルフェニル)−(2−
クロロ−5−ニトロフェニル)カルボキサミド
4−プロピルアニリン0.340g、DMA5mLなら
びに2−クロロ−5−ニトロ安息香酸クロリド0.66
4gを使用して、実施例2に記載した方法に従い、標記
目的化合物0.677gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
1.19 (3H, t, J = 7.6 Hz), 2.61 (2H, q, J = 7.6 Hz),
7.00 (1H, d, J = 7.8 Hz), 7.28 (1H, t, J = 7.8 Hz), 7.
51 (1H, d, J = 7.8 Hz), 7.58 (1H, s), 7.89 (1H, d, J
= 8.8 Hz), 8.34 (1H, dd, J = 8.8, 2.7 Hz), 8.45 (1H,
d, J = 2.7 Hz). (Example 15) N- (4-propylphenyl)-(2-
Chloro-5-nitrophenyl) carboxamide 4-propylaniline 0.340 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.66
According to the method described in Example 2, using 4 g, 0.677 g of the title target compound was obtained as crystals.
【0134】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
0.89 (3H, t, J=7.3 Hz), 1.58 (2H, m), 2.54 (2H,
t, J=7.6 Hz), 7.19 (2H, d, J=8.4 Hz), 7.60 (2H, d,
J=8.4 Hz), 7.89 (1H, d, J=8.8 Hz), 8.33 (1H, dd,
J=8.8, 2.7 Hz), 8.44 (1H, d, J=2.7 Hz), 10.62 (1H,
s)。
(実施例16)N−(4−ペンチルフェニル)−(2−
クロロ−5−ニトロフェニル)カルボキサミド
4−ペンチルアニリン0.300g、DMA5mLなら
びに2−クロロ−5−ニトロ安息香酸クロリド0.48
5gを使用して、実施例2に記載した方法に従い、標記
目的化合物0.514gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
0.89 (3H, t, J = 7.3 Hz), 1.58 (2H, m), 2.54 (2H,
t, J = 7.6 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.60 (2H, d,
J = 8.4 Hz), 7.89 (1H, d, J = 8.8 Hz), 8.33 (1H, dd,
J = 8.8, 2.7 Hz), 8.44 (1H, d, J = 2.7 Hz), 10.62 (1H,
s). (Example 16) N- (4-pentylphenyl)-(2-
Chloro-5-nitrophenyl) carboxamide 4-pentylaniline 0.300 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.48.
According to the method described in Example 2, using 5 g, 0.514 g of the title object compound was obtained as crystals.
【0135】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
0.90 (3H, t, J=6.9 Hz), 1.28-1.38(4H, m), 1.58-1.6
6 (2H, m), 2.61 (2H, t, J=7.7 Hz), 7.21 (2H, d, J=
8.4Hz), 7.53 (2H, d, J=8.5 Hz), 7.66 (1H, d, J=8.8
Hz), 7.77 (1H, s), 8.26(1H, dd, J=8.8, 2.8 Hz),
8.61 (1H, d, J=2.8 Hz)。
(実施例17)N−(4−ブチルオキシフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド
4−ブチルオキシアニリン0.267g、DMA5mL
ならびに2−クロロ−5−ニトロ安息香酸クロリド0.
427gを使用して、実施例2に記載した方法に従い、
標記目的化合物0.513gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
0.90 (3H, t, J = 6.9 Hz), 1.28-1.38 (4H, m), 1.58-1.6
6 (2H, m), 2.61 (2H, t, J = 7.7 Hz), 7.21 (2H, d, J =
8.4Hz), 7.53 (2H, d, J = 8.5 Hz), 7.66 (1H, d, J = 8.8
Hz), 7.77 (1H, s), 8.26 (1H, dd, J = 8.8, 2.8 Hz),
8.61 (1H, d, J = 2.8 Hz). (Example 17) N- (4-butyloxyphenyl)-
(2-chloro-5-nitrophenyl) carboxamide 4-butyloxyaniline 0.267 g, DMA 5 mL
And 2-chloro-5-nitrobenzoic acid chloride.
Following the procedure described in Example 2 using 427 g
Crystals of 0.513 g of the title object compound were obtained.
【0136】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
0.94 (3H, t, J=7.4 Hz), 1.39-1.48 (2H, m), 1.65-
1.73 (2H, m), 3.96 (2H, t, J=6.5 Hz), 6.94 (2H, d,
J=9.0 Hz), 7.60 (2H, d, J=9.0 Hz), 7.88 (1H, d, J
=8.8 Hz), 8.33 (1H, dd, J=8.8, 2.8 Hz), 8.43 (1H,
d, J=2.8 Hz), 10.54 (1H, s)。
(実施例18)N−(4−トリフルオロメチルオキシフ
ェニル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
4−トリフルオロメチルオキシアニリン0.310g、
DMA5mLならびに2−クロロ−5−ニトロ安息香酸
クロリド0.462gを使用して、実施例2に記載した
方法に従い、標記目的化合物0.541gの結晶を得
た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
0.94 (3H, t, J = 7.4 Hz), 1.39-1.48 (2H, m), 1.65-
1.73 (2H, m), 3.96 (2H, t, J = 6.5 Hz), 6.94 (2H, d,
J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz), 7.88 (1H, d, J
= 8.8 Hz), 8.33 (1H, dd, J = 8.8, 2.8 Hz), 8.43 (1H,
d, J = 2.8 Hz), 10.54 (1H, s). (Example 18) N- (4-trifluoromethyloxyphenyl)-(2-chloro-5-nitrophenyl) carboxamide 4-trifluoromethyloxyaniline 0.310 g,
According to the method described in Example 2, using 5 mL of DMA and 0.462 g of 2-chloro-5-nitrobenzoic acid chloride, 0.541 g of the title object compound was obtained as crystals.
【0137】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.40 (2H, d, J=8.5 Hz), 7.81 (2H, d, J=8.5 Hz),
7.90 (1H, d, J=8.8 Hz), 8.35 (1H, dd, J=8.8, 2.7 H
z), 8.50 (1H, d, J=2.7 Hz)。
(実施例19)N−(2−イソプロピル−6−メチルフ
ェニル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
2−イソプロピル−6−メチルアニリン0.309g、
DMA5mLならびに2−クロロ−5−ニトロ安息香酸
クロリド0.546gを使用して、実施例2に記載した
方法に従い反応を行った後、シリカゲルカラムクロマト
グラフィ−(ヘキサン:酢酸エチル=2:1(v/v))
にて精製し、IPEで固化し、濾取して、標記目的化合
物0.630gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.40 (2H, d, J = 8.5 Hz), 7.81 (2H, d, J = 8.5 Hz),
7.90 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 8.8, 2.7 H
z), 8.50 (1H, d, J = 2.7 Hz). (Example 19) N- (2-isopropyl-6-methylphenyl)-(2-chloro-5-nitrophenyl) carboxamide 2-isopropyl-6-methylaniline 0.309 g,
After performing the reaction according to the method described in Example 2 using 5 mL of DMA and 0.546 g of 2-chloro-5-nitrobenzoic acid chloride, silica gel column chromatography- (hexane: ethyl acetate = 2: 1 (v / v))
, Solidified with IPE and collected by filtration to obtain 0.630 g of the title target compound as crystals.
【0138】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
1.26 (6H, d, J=6.9 Hz), 3.23 (1H, sept, J=6.9 H
z), 7.17 (1H, m), 7.23-7.31 (2H, m), 7.45 (1H, b
s), 7.69(1H, d, J=8.8 Hz), 8.28 (1H, dd, J=8.8, 2.
8 Hz), 8.64 (1H, d, J=2.8 Hz)。
(実施例20)N−(4−シアノフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
4−シアノアニリン0.251g、DMA5mLならび
に2−クロロ−5−ニトロ安息香酸クロリド0.559
gを使用して、実施例2に記載した方法に従い、標記目
的化合物0.558gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
1.26 (6H, d, J = 6.9 Hz), 3.23 (1H, sept, J = 6.9 H)
z), 7.17 (1H, m), 7.23-7.31 (2H, m), 7.45 (1H, b
s), 7.69 (1H, d, J = 8.8 Hz), 8.28 (1H, dd, J = 8.8, 2.
8 Hz), 8.64 (1H, d, J = 2.8 Hz). Example 20 N- (4-Cyanophenyl)-(2-chloro-5-nitrophenyl) carboxamide 4-cyanoaniline 0.251 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.559.
According to the method described in Example 2, using 0.5 g, 0.558 g of the title object compound was obtained as crystals.
【0139】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.68-7.79 (3H, m), 7.81 (2H, d, J=8.6 Hz), 8.09 (1
H, s), 8.31 (1H, dd, J=8.8, 2.7 Hz), 8.63 (1H, d,
J=2.7Hz)。
(実施例21)N−(3−シアノフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
3−シアノアニリン0.255g、DMA5mLならび
に2−クロロ−5−ニトロ安息香酸クロリド0.559
gを使用して、実施例2に記載した方法に従い、標記目
的化合物0.616gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.68-7.79 (3H, m), 7.81 (2H, d, J = 8.6 Hz), 8.09 (1
H, s), 8.31 (1H, dd, J = 8.8, 2.7 Hz), 8.63 (1H, d,
J = 2.7Hz). Example 21 N- (3-Cyanophenyl)-(2-chloro-5-nitrophenyl) carboxamide 3-cyanoaniline 0.255 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.559.
According to the method described in Example 2, using 0.6 g, 0.616 g of the title object compound was obtained as crystals.
【0140】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.50-7.56 (2H, m), 7.70 (1H, d, J=8.8 Hz), 7.84-7.
87 (1H, m), 8.02 (1H, s), 8.07 (1H, s), 8.31 (1H,
dd, J=8.8, 2.7 Hz), 8.64 (1H, d, J=2.7 Hz)。
(実施例22)N−(2−シアノフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
2−シアノアニリン0.279g、DMA5mLならび
に2−クロロ−5−ニトロ安息香酸クロリド0.623
gを使用して、実施例2に記載した方法に従い、標記目
的化合物0.682gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.50-7.56 (2H, m), 7.70 (1H, d, J = 8.8 Hz), 7.84-7.
87 (1H, m), 8.02 (1H, s), 8.07 (1H, s), 8.31 (1H,
dd, J = 8.8, 2.7 Hz), 8.64 (1H, d, J = 2.7 Hz). Example 22 N- (2-Cyanophenyl)-(2-chloro-5-nitrophenyl) carboxamide 2-cyanoaniline 0.279 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.623.
Following the method described in Example 2 using 0.6 g, 0.682 g of the title object compound was obtained as crystals.
【0141】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.30 (1H, t, J=7.7 Hz), 7.66-7.72(3H, m), 8.33 (1
H, dd, J=8.8, 2.7 Hz), 8.50 (1H, s), 8.56 (1H, d,
J=8.4Hz), 8.71 (1H, d, J=2.7 Hz)。
(実施例23)N−(4−ニトロフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
4−ニトロアニリン0.285g、DMA5mLならび
に2−クロロ−5−ニトロ安息香酸クロリド0.545
gを使用して、実施例2に記載した方法に従い、標記目
的化合物0.619gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.30 (1H, t, J = 7.7 Hz), 7.66-7.72 (3H, m), 8.33 (1
H, dd, J = 8.8, 2.7 Hz), 8.50 (1H, s), 8.56 (1H, d,
J = 8.4Hz), 8.71 (1H, d, J = 2.7Hz). Example 23 N- (4-Nitrophenyl)-(2-chloro-5-nitrophenyl) carboxamide 4-nitroaniline 0.285 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.545.
According to the method described in Example 2, using 0.6 g, 0.619 g of the title object compound was obtained as crystals.
【0142】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.93 (1H, d, J=8.9 Hz), 7.96 (2H, d, J=9.2 Hz),
8.31 (2H, d, J=9.2 Hz), 8.38 (1H, dd, J=8.9, 2.7 H
z), 8.59 (1H, d, J=2.7 Hz), 11.32 (1H, s)。
(実施例24)N−(5−ニトロピリジン−2−イル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
2−アミノ−4−ニトロピリジン0.293g、DMA
5mLならびに2−クロロ−5−ニトロ安息香酸クロリ
ド0.556gを使用して、実施例1に記載した方法に
従い、標記目的化合物0.627gの結晶を得た.1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.89 (1H,
d, J=8.8 Hz), 8.36 (1H, dd, J=8.8, 2.8Hz), 8.42 (1
H, d, J=9.2 Hz), 8.58 (1H, d, J=2.8 Hz), 8.72 (1H,
dd, J=9.2, 2.5 Hz), 9.23 (1H, d, J=2.5 Hz), 12.00
(1H, s)。
(実施例25)N−(3−ニトロフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
3−ニトロアニリン0.274g、DMA5mLならび
に2−クロロ−5−ニトロ安息香酸クロリド0.524
gを使用して、実施例2に記載した方法に従い、標記目
的化合物0.638gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.93 (1H, d, J = 8.9 Hz), 7.96 (2H, d, J = 9.2 Hz),
8.31 (2H, d, J = 9.2 Hz), 8.38 (1H, dd, J = 8.9, 2.7 H
z), 8.59 (1H, d, J = 2.7 Hz), 11.32 (1H, s). (Example 24) N- (5-nitropyridin-2-yl)
-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4-nitropyridine 0.293 g, DMA
According to the method described in Example 1, using 5 mL and 0.556 g of 2-chloro-5-nitrobenzoic acid chloride, 0.627 g of the title object compound was obtained as crystals. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.89 (1H,
d, J = 8.8 Hz), 8.36 (1H, dd, J = 8.8, 2.8Hz), 8.42 (1
H, d, J = 9.2 Hz), 8.58 (1H, d, J = 2.8 Hz), 8.72 (1H,
dd, J = 9.2, 2.5 Hz), 9.23 (1H, d, J = 2.5 Hz), 12.00
(1H, s). Example 25 N- (3-Nitrophenyl)-(2-chloro-5-nitrophenyl) carboxamide 3-nitroaniline 0.274 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.524.
According to the method described in Example 2, using 0.6 g, 0.638 g of the title object compound was obtained as crystals.
【0143】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.70 (1H, t, J=8.2 Hz), 7.93 (1H, d, J=8.9 Hz),
8.00-8.04 (2H, m), 8.38 (1H, dd, J=8.9, 2.7 Hz),
8.58 (1H, d, J=2.7 Hz), 8.74 (1H, bs), 11.20 (1H,
s)。
(実施例26)N−(4−エトキシカルボニルフェニ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
4−アミノ安息香酸エチルエステル9.88g、DMA
50mLならびに2−クロロ−5−ニトロ安息香酸クロ
リド14.47gを使用して、実施例2に記載した方法
に従い、標記目的化合物20.33gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.70 (1H, t, J = 8.2 Hz), 7.93 (1H, d, J = 8.9 Hz),
8.00-8.04 (2H, m), 8.38 (1H, dd, J = 8.9, 2.7 Hz),
8.58 (1H, d, J = 2.7 Hz), 8.74 (1H, bs), 11.20 (1H,
s). (Example 26) N- (4-ethoxycarbonylphenyl)-(2-chloro-5-nitrophenyl) carboxamide 4-aminobenzoic acid ethyl ester 9.88 g, DMA
According to the method described in Example 2, using 50 mL and 14.47 g of 2-chloro-5-nitrobenzoic acid chloride, 20.33 g of the title object compound was obtained as crystals.
【0144】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
1.33 (1H, t, J=7.1 Hz), 4.31 (2H, q, J=7.1 Hz),
7.85 (2H, d, J=8.7 Hz), 7.91 (1H, d, J=8.8 Hz), 7.
99 (2H, d, J=8.7Hz), 8.36 (1H, dd, J=8.9, 2.8 Hz),
8.53 (1H, d, J=2.8 Hz), 11.05 (1H, s)。
(実施例27)4−[(2−クロロ−5−ニトロフェニ
ル)カルボニルアミノ]安息香酸
実施例26で製造したN−(4−エトキシカルボニルフ
ェニル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド19.55gを1,4−ジオキサン100mL
に溶解し、1N−水酸化ナトリウム水溶液84mLを加
え、3日間室温で放置した。反応溶液を減圧下濃縮した
後、水300mLを加え、氷水冷却下、1N−塩酸90
mLを滴加して攪拌した。生成した結晶を濾取し、乾燥
して、標記目的化合物17.59gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
1.33 (1H, t, J = 7.1 Hz), 4.31 (2H, q, J = 7.1 Hz),
7.85 (2H, d, J = 8.7 Hz), 7.91 (1H, d, J = 8.8 Hz), 7.
99 (2H, d, J = 8.7Hz), 8.36 (1H, dd, J = 8.9, 2.8 Hz),
8.53 (1H, d, J = 2.8 Hz), 11.05 (1H, s). Example 27 4-[(2-chloro-5-nitrophenyl) carbonylamino] benzoic acid N- (4-ethoxycarbonylphenyl)-(2-chloro-5-nitrophenyl) carboxamide prepared in Example 26. 19.55 g of 1,4-dioxane 100 mL
, 1N-aqueous sodium hydroxide solution (84 mL) was added, and the mixture was left at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, 300 mL of water was added, and 1N-hydrochloric acid 90 was added under ice-water cooling.
mL was added dropwise and stirred. The produced crystal was collected by filtration and dried to obtain 17.59 g of the title object compound.
【0145】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.82 (2H, d, J=8.7 Hz), 7.91 (1H, d, J=8.8 Hz),
7.97 (2H, d, J=8.7 Hz), 8.36 (1H, dd, J=8.8, 2.8 H
z), 8.52 (1H, d, J=2.8 Hz), 11.01 (1H, s)。
(実施例28)N−(2−クロロ−5−ニトロフェニ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
2−クロロ−5−ニトロアニリン0.348g、DMA
5mLならびに2−クロロ−5−ニトロ安息香酸クロリ
ド0.532gを使用して、実施例2に記載した方法に
従い、標記目的化合物0.708gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.82 (2H, d, J = 8.7 Hz), 7.91 (1H, d, J = 8.8 Hz),
7.97 (2H, d, J = 8.7 Hz), 8.36 (1H, dd, J = 8.8, 2.8 H
z), 8.52 (1H, d, J = 2.8 Hz), 11.01 (1H, s). (Example 28) N- (2-chloro-5-nitrophenyl)-(2-chloro-5-nitrophenyl) carboxamide 2-chloro-5-nitroaniline 0.348 g, DMA
Following the method described in Example 2 using 5 mL and 0.532 g of 2-chloro-5-nitrobenzoic acid chloride, 0.708 g of the title object compound was obtained as crystals.
【0146】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.89 (1H, d, J=8.8 Hz), 7.91 (1H, d, J=8.8 Hz),
8.15 (1H, dd, J=8.8, 2.7 Hz), 8.37 (1H, dd, J=8.8,
2.7Hz), 8.65 (1H, d, J=2.7 Hz), 8.88 (1H, d, J=2.
7 Hz), 10.83 (1H, s)。
(実施例29)N−(3,5−ジ−t−ブチル−4−ヒ
ドロキシフェニル)−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
3,5−ジ−t−ブチル−4−ヒドロキシアニリン0.
500g、THF10mLならびに2−クロロ−5−ニ
トロ安息香酸クロリド0.538gを使用して、実施例
1に記載した方法に従い、標記目的化合物0.645g
の結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.89 (1H, d, J = 8.8 Hz), 7.91 (1H, d, J = 8.8 Hz),
8.15 (1H, dd, J = 8.8, 2.7 Hz), 8.37 (1H, dd, J = 8.8,
2.7Hz), 8.65 (1H, d, J = 2.7 Hz), 8.88 (1H, d, J = 2.
7 Hz), 10.83 (1H, s). (Example 29) N- (3,5-di-t-butyl-4-hydroxyphenyl)-(2-chloro-5-nitrophenyl) carboxamide 3,5-di-t-butyl-4-hydroxyaniline 0 .
0.645 g of the title object compound according to the method described in Example 1 using 500 g, 10 mL of THF and 0.538 g of 2-chloro-5-nitrobenzoic acid chloride.
Was obtained.
【0147】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
1.47 (6H, s), 5.20 (1H, s), 7.43(2H, s), 7.66 (1H,
d, J=8.8 Hz), 8.26 (1H, dd, J=8.8, 2.8 Hz), 8.62
(1H,d, J=2.7 Hz)。
(実施例30)N−(3−ベンゼンスルフォニルアミノ
フェニル)−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
3−ベンゼンスルフォニルアミノアニリン0.595
g、DMA5mLならびに2−クロロ−5−ニトロ安息
香酸クロリド0.633gを使用して、実施例1に記載
した方法に従い反応を行った後、シリカゲルカラムクロ
マトグラフィ−(ヘキサン:酢酸エチル=1:1(v/
v))にて精製し、IPEで固化し、濾取して、標記目的
化合物0.700gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
1.47 (6H, s), 5.20 (1H, s), 7.43 (2H, s), 7.66 (1H,
d, J = 8.8 Hz), 8.26 (1H, dd, J = 8.8, 2.8 Hz), 8.62
(1H, d, J = 2.7 Hz). (Example 30) N- (3-benzenesulfonylaminophenyl)-(2-chloro-5-nitrophenyl) carboxamide 3-benzenesulfonylaminoaniline 0.595
g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.633 g were used to carry out the reaction according to the method described in Example 1, followed by silica gel column chromatography (hexane: ethyl acetate = 1: 1 ( v /
Purified in v)), solidified with IPE, and collected by filtration to obtain 0.700 g of the title target compound as crystals.
【0148】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
6.87 (1H, d, J=8.1 Hz), 7.21 (1H,t, J=8.1 Hz), 7.3
8 (1H, d, J=8.1 Hz), 7.54-7.66 (4H, m), 7.80-7.82
(2H,m), 7.87 (1H, d, J=8.8 Hz), 8.33 (1H, dd, J=8.
8, 2.8 Hz), 8.44 (1H, d,J=2.8 Hz), 10.38 (1H, s),
10.69 (1H, s)。
(実施例31)N−[[3−(ピロリジン−1−イル)
カルボニル]フェニル]−(2−クロロ−5−ニトロフ
ェニル)カルボキサミド
[3−(ピロリジン−1−イル)カルボニル]アニリン
・塩酸塩0.244g、ピリジン5mLならびに2−ク
ロロ−5−ニトロ安息香酸クロリド0.300gを使用
して、実施例1に記載した方法に従い、標記目的化合物
0.319gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
6.87 (1H, d, J = 8.1 Hz), 7.21 (1H, t, J = 8.1 Hz), 7.3
8 (1H, d, J = 8.1 Hz), 7.54-7.66 (4H, m), 7.80-7.82
(2H, m), 7.87 (1H, d, J = 8.8 Hz), 8.33 (1H, dd, J = 8.
8, 2.8 Hz), 8.44 (1H, d, J = 2.8 Hz), 10.38 (1H, s),
10.69 (1H, s). (Example 31) N-[[3- (pyrrolidin-1-yl)
Carbonyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamido [3- (pyrrolidin-1-yl) carbonyl] aniline hydrochloride 0.244 g, pyridine 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0 According to the method described in Example 1, using 0.30 g, 0.319 g of the title object compound was obtained as crystals.
【0149】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
1.85-1.93 (4H, m), 3.36-3.45 (4H,m), 7.27 (1H, d,
J=8.1 Hz), 7.41 (1H, t, J=8.1 Hz), 7.65 (1H, d, J=
8.8Hz), 7.70 (1H, s), 7.91 (1H, d, J=8.1 Hz), 8.26
(1H, dd, J=8.8, 2.7 Hz),8.50 (1H, d, J=2.7 Hz),
9.09 (1H, s)。
(実施例32)N−[4−(4−メチルベンゼン)スル
フォニルアミノフェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
4−(p−トルエンスルフォニルアミノ)アニリン0.
308g、DMA5mLならびに2−クロロ−5−ニト
ロ安息香酸クロリド0.310gを使用して、実施例2
に記載した方法に従い、標記目的化合物0.516gの
結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
1.85-1.93 (4H, m), 3.36-3.45 (4H, m), 7.27 (1H, d,
J = 8.1 Hz), 7.41 (1H, t, J = 8.1 Hz), 7.65 (1H, d, J =
8.8Hz), 7.70 (1H, s), 7.91 (1H, d, J = 8.1 Hz), 8.26
(1H, dd, J = 8.8, 2.7 Hz), 8.50 (1H, d, J = 2.7 Hz),
9.09 (1H, s). (Example 32) N- [4- (4-methylbenzene) sulfonylaminophenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (p-toluenesulfonylamino) aniline
Example 2 using 308 g, 5 mL DMA and 0.310 g 2-chloro-5-nitrobenzoic acid chloride.
According to the method described in 1., 0.516 g of crystals of the title object compound was obtained.
【0150】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
2.34 (1H, s), 7.08 (2H, d, J=8.9 Hz), 7.35 (2H,
d, J=8.2 Hz), 7.54 (2H, d, J=8.9 Hz), 7.63 (2H, d,
J=8.2 Hz), 7.87 (1H, d, J=8.8 Hz), 8.32 (1H, dd,
J=8.8, 2.8 Hz), 8.42 (1H, d, J=2.8 Hz), 10.15 (1H,
s), 10.64 (1H, s)。
(実施例33)N−(ベンゾチアゾール−2−イル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド
2−アミノベンゾチアゾール0.312g、DMA5m
Lならびに2−クロロ−5−ニトロ安息香酸クロリド
0.503gを使用して、実施例2に記載した方法に従
い、標記目的化合物0.544gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
2.34 (1H, s), 7.08 (2H, d, J = 8.9 Hz), 7.35 (2H,
d, J = 8.2 Hz), 7.54 (2H, d, J = 8.9 Hz), 7.63 (2H, d,
J = 8.2 Hz), 7.87 (1H, d, J = 8.8 Hz), 8.32 (1H, dd,
J = 8.8, 2.8 Hz), 8.42 (1H, d, J = 2.8 Hz), 10.15 (1H,
s), 10.64 (1H, s). (Example 33) N- (benzothiazol-2-yl)-
(2-Chloro-5-nitrophenyl) carboxamide 2-aminobenzothiazole 0.312 g, DMA 5 m
According to the method described in Example 2, using L and 0.503 g of 2-chloro-5-nitrobenzoic acid chloride, 0.544 g of the title object compound was obtained.
【0151】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.58 (1H, t, J=7.1 Hz), 7.67 (2H, d, J=7.2 Hz),
7.75-7.79 (2H, m), 8.08 (1H, d, J=7.9 Hz), 8.19-8.
28 (2H, m), 8.77 (1H, d, J=2.8 Hz)。
(実施例34)N−(6−ニトロベンゾチアゾール−2
−イル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
2−アミノ−6−ニトロベンゾチアゾール0.421
g、DMA5mLならびに2−クロロ−5−ニトロ安息
香酸クロリド0.569gを使用して、実施例2に記載
した方法に従い、標記目的化合物0.755gの結晶を
得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.58 (1H, t, J = 7.1 Hz), 7.67 (2H, d, J = 7.2 Hz),
7.75-7.79 (2H, m), 8.08 (1H, d, J = 7.9 Hz), 8.19-8.
28 (2H, m), 8.77 (1H, d, J = 2.8 Hz). (Example 34) N- (6-nitrobenzothiazole-2)
-Yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-6-nitrobenzothiazole 0.421
Following the procedure described in Example 2 using 0.5 g of DMA, 5 mL of DMA and 0.569 g of 2-chloro-5-nitrobenzoic acid chloride, 0.755 g of the title compound of interest was obtained.
【0152】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.95 (2H, t, J=8.9 Hz), 8.32 (2H, dd, J=8.9, 2.4H
z), 8.41 (1H, dd, J=8.9, 2.8 Hz), 8.70 (1H, d, J=
2.8 Hz), 9.13 (1H, d, J=2.4 Hz)。
(実施例35)N−(4−フェニルチアゾール−2−イ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
2−アミノ−4−フェニルチアゾール・臭化水素酸塩
2.53g、ピリジン20mLならびに2−クロロ−5
−ニトロ安息香酸クロリド2.12gを使用して、実施
例1に記載した方法に従い反応を行った後、シリカゲル
カラムクロマトグラフィ−(ヘキサン:酢酸エチル=
3:2(v/v))にて精製し、IPEで固化し、濾取し
て、標記目的化合物0.240gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.95 (2H, t, J = 8.9 Hz), 8.32 (2H, dd, J = 8.9, 2.4H
z), 8.41 (1H, dd, J = 8.9, 2.8 Hz), 8.70 (1H, d, J =
2.8 Hz), 9.13 (1H, d, J = 2.4 Hz). (Example 35) N- (4-phenylthiazol-2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4-phenylthiazole.hydrobromide 2.53 g, pyridine 20 mL and 2-chloro-5
-Using 2.12 g of nitrobenzoic acid chloride, the reaction was carried out according to the method described in Example 1, and then silica gel column chromatography- (hexane: ethyl acetate =
3: 2 (v / v)), solidified with IPE, and collected by filtration to obtain the title object compound (0.240 g).
【0153】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.14-7.24 (5H, m), 7.43-7.45 (2H,m), 7.88 (1H, dd,
J=8.8, 2.7 Hz), 8.03 (1H, d, J=2.7 Hz)。
(実施例36)N−[4−(2−チエニル)チアゾール
−2−イル]−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド
2−アミノ−4−(2−チエニル)チアゾール1.03
g、THF20mL、CDI1.33gならびに2−ク
ロロ−5−ニトロ安息香酸1.10gを使用して、実施
例1に記載した方法に従い反応を行った後、シリカゲル
カラムクロマトグラフィ−(ヘキサン:酢酸エチル=
1:1(v/v))にて精製し、IPEで固化し、濾取し
て、標記目的化合物0.687gを得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.14-7.24 (5H, m), 7.43-7.45 (2H, m), 7.88 (1H, dd,
J = 8.8, 2.7 Hz), 8.03 (1H, d, J = 2.7 Hz). Example 36 N- [4- (2-thienyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4- (2-thienyl) thiazole 1.03
g, 20 mL of THF, 1.33 g of CDI and 1.10 g of 2-chloro-5-nitrobenzoic acid, the reaction was carried out according to the method described in Example 1, followed by silica gel column chromatography (hexane: ethyl acetate =
1: 1 (v / v)), solidified with IPE and collected by filtration to obtain 0.687 g of the title object compound.
【0154】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.12 (1H, d, J=5.1, 3.6 Hz), 7.52 (1H, d, J=5.1 H
z), 7.56 (1H, d, J=3.6 Hz), 7.90 (1H, d, J=8.8 H
z), 8.37 (1H, dd, J=8.8, 2.7 Hz), 8.60 (1H, d, J=
2.7 Hz)。
(実施例37)N−[4−(3−ピリジル)チアゾール
−2−イル]−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド
参考例2で製造した2−アミノ−4−(3−ピリジル)
チアゾール0.181g、DMA5mLならびに2−ク
ロロ−5−ニトロ安息香酸クロリド0.247gを使用
して、実施例1に記載した方法に従い、標記目的化合物
0.308gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.12 (1H, d, J = 5.1, 3.6 Hz), 7.52 (1H, d, J = 5.1 H
z), 7.56 (1H, d, J = 3.6 Hz), 7.90 (1H, d, J = 8.8 H
z), 8.37 (1H, dd, J = 8.8, 2.7 Hz), 8.60 (1H, d, J =
2.7 Hz). (Example 37) N- [4- (3-pyridyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4- (3-pyridyl) prepared in Reference Example 2.
Following the procedure described in Example 1 using 0.181 g of thiazole, 5 mL of DMA and 0.247 g of 2-chloro-5-nitrobenzoic acid chloride, 0.308 g of the title object compound was obtained.
【0155】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.49 (1H, dd, J=8.0, 4.8 Hz), 7.92 (1H, d, J=8.9H
z), 7.97 (1H, s), 8.27 (1H, dt, J=8.0, 2.0 Hz), 8.
38 (1H, dd, J=8.9, 1.6 Hz), 8.61 (1H,d, J=2.8 Hz),
9.15 (1H, d, J=1.6 Hz)。
(実施例38)N−[4−(2−ピリジル)チアゾール
−2−イル]−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド
2−アミノ−4−(2−ピリジル)チアゾール0.32
4g、DMA5mLならびに2−クロロ−5−ニトロ安
息香酸クロリド0.442gを使用して、実施例2に記
載した方法に従い、標記目的化合物0.491gを得
た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.49 (1H, dd, J = 8.0, 4.8 Hz), 7.92 (1H, d, J = 8.9H
z), 7.97 (1H, s), 8.27 (1H, dt, J = 8.0, 2.0 Hz), 8.
38 (1H, dd, J = 8.9, 1.6 Hz), 8.61 (1H, d, J = 2.8 Hz),
9.15 (1H, d, J = 1.6 Hz). (Example 38) N- [4- (2-pyridyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4- (2-pyridyl) thiazole 0.32
Following the method described in Example 2 using 4 g, 5 mL of DMA and 0.442 g of 2-chloro-5-nitrobenzoic acid chloride, 0.491 g of the title object compound was obtained.
【0156】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.34-7.37 (1H, m), 7.87-7.97 (4H, m), 8.38 (1H, d
t, J=8.9, 2.7 Hz), 8.61-8.63 (2H, m)。
(実施例39)N−[4−(2−メチルフェニル)チア
ゾール−2−イル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
2−アミノ−4−(2−メチルフェニル)チアゾール
0.398g、DMA5mLならびに2−クロロ−5−
ニトロ安息香酸クロリド0.385gを使用して、実施
例1に記載した方法に従い反応を行った後、シリカゲル
カラムクロマトグラフィ−(ヘキサン:酢酸エチル=
1:1(v/v))にて精製し、標記目的化合物0.452
gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.34-7.37 (1H, m), 7.87-7.97 (4H, m), 8.38 (1H, d
t, J = 8.9, 2.7 Hz), 8.61-8.63 (2H, m). (Example 39) N- [4- (2-methylphenyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4- (2-methylphenyl) thiazole 0.398 g , DMA 5 mL and 2-chloro-5-
After using 0.385 g of nitrobenzoic acid chloride to carry out the reaction according to the method described in Example 1, silica gel column chromatography- (hexane: ethyl acetate =
1: 1 (v / v)) and the title target compound 0.452
g was obtained.
【0157】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
2.45(1H, s), 7.23-7.31 (3H, m),7.42 (1H, s), 7.57
-7.60 (1H, m), 7.91 (1H, d, J=8.9 Hz), 8.37 (1H, d
d,J=8.9, 2.8 Hz), 8.59 (1H, d, J=2.8 Hz)。
(実施例40)N−[4−(3−メチルフェニル)チア
ゾール−2−イル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
2−アミノ−4−(3−メチルフェニル)チアゾール
0.303g、2−クロロ−5−ニトロ安息香酸0.2
47g、CDI0.640gならびにTHF10mLを
使用して、実施例3に記載した方法に従い反応を行った
後、シリカゲルカラムクロマトグラフィ−(ヘキサン:
酢酸エチル=1:1(v/v))にて精製し、標記目的化合
物0.105gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
2.45 (1H, s), 7.23-7.31 (3H, m), 7.42 (1H, s), 7.57
-7.60 (1H, m), 7.91 (1H, d, J = 8.9 Hz), 8.37 (1H, d
d, J = 8.9, 2.8 Hz), 8.59 (1H, d, J = 2.8 Hz). (Example 40) N- [4- (3-methylphenyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4- (3-methylphenyl) thiazole 0.303 g , 2-chloro-5-nitrobenzoic acid 0.2
The reaction was carried out according to the method described in Example 3 using 47 g, CDI (0.640 g) and THF (10 mL), followed by silica gel column chromatography (hexane:
Purification with ethyl acetate = 1: 1 (v / v)) gave 0.105 g of the title object compound.
【0158】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
2.32 (3H, s), 6.98 (1H, d, J=7.6Hz), 7.12 (1H, t,
J=7.7 Hz), 7.14(1H, s), 7.25-7.27 (2H, m), 7.30 (1
H, d, J=7.7 Hz), 7.93 (1H, dd, J=8.9, 2.7 Hz), 8.1
2 (1H, d, J=2.7 Hz)。
(実施例41)N−[4−(1−ナフチル)チアゾール
−2−イル]−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド
2−アミノ−4−(1−ナフチル)チアゾール0.37
8g、DMA5mLならびに2−クロロ−5−ニトロ安
息香酸クロリド0.404gを使用して、実施例1に記
載した方法に従い、標記目的化合物0.580gを得
た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
2.32 (3H, s), 6.98 (1H, d, J = 7.6Hz), 7.12 (1H, t,
J = 7.7 Hz), 7.14 (1H, s), 7.25-7.27 (2H, m), 7.30 (1
H, d, J = 7.7 Hz), 7.93 (1H, dd, J = 8.9, 2.7 Hz), 8.1
2 (1H, d, J = 2.7 Hz). (Example 41) N- [4- (1-naphthyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4- (1-naphthyl) thiazole 0.37
Following the procedure described in Example 1 using 8 g, 5 mL of DMA and 0.404 g of 2-chloro-5-nitrobenzoic acid chloride, 0.580 g of the title object compound was obtained.
【0159】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.02 (1H, d, J=8.8 Hz), 7.33-7.54(5H, m), 7.69 (1
H, d, J=8.2 Hz), 7.81 (1H, d, J=8.1 Hz), 7.84 (1H,
d, J=2.7 Hz), 8.16 (1H, d, J=8.6 Hz)。
(実施例42)N−[4−(2−ナフチル)チアゾール
−2−イル]−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド
2−アミノ−4−(2−ナフチル)チアゾール0.39
8g、DMA5mLならびに2−クロロ−5−ニトロ安
息香酸クロリド0.464gを使用して、実施例2に記
載した方法に従い、標記目的化合物0.566gを得
た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.02 (1H, d, J = 8.8 Hz), 7.33-7.54 (5H, m), 7.69 (1
H, d, J = 8.2 Hz), 7.81 (1H, d, J = 8.1 Hz), 7.84 (1H,
d, J = 2.7 Hz), 8.16 (1H, d, J = 8.6 Hz). (Example 42) N- [4- (2-naphthyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4- (2-naphthyl) thiazole 0.39
Following the procedure described in Example 2 using 8 g, 5 mL of DMA and 0.464 g of 2-chloro-5-nitrobenzoic acid chloride, 0.566 g of the title object compound was obtained.
【0160】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.49-7.56 (2H, m), 7.87-7.99 (5H, m), 8.09 (1H, d
d, J=8.6, 1.6 Hz), 8.36 (1H, dd, J=8.8, 2.7 Hz),
8.47(1H, s), 8.62 (1H, d, J=2.7 Hz)。
(実施例43)N−[4−(3,4−ジクロロフェニ
ル)チアゾール−2−イル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド
2−アミノ−4−(3,4−ジクロロフェニル)チアゾ
ール0.313g、DMA5mLならびに2−クロロ−
5−ニトロ安息香酸クロリド0.337gを使用して、
実施例2に記載した方法に従い、標記目的化合物0.4
49gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.49-7.56 (2H, m), 7.87-7.99 (5H, m), 8.09 (1H, d
d, J = 8.6, 1.6 Hz), 8.36 (1H, dd, J = 8.8, 2.7 Hz),
8.47 (1H, s), 8.62 (1H, d, J = 2.7 Hz). Example 43 N- [4- (3,4-Dichlorophenyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4- (3,4-dichlorophenyl) thiazole 0 .313 g, DMA 5 mL and 2-chloro-
Using 0.337 g of 5-nitrobenzoic acid chloride,
According to the method described in Example 2, the title object compound 0.4
49 g were obtained.
【0161】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.70 (1H, d, J=8.4 Hz), 7.86-7.93 (3H, m), 8.17(1
H, d, J=2.0 Hz), 8.34 (1H, dd, J=8.8, 2.8 Hz), 8.6
0 (1H, d, J=2.8 Hz)。
(実施例44)N−[4−(4−エチルフェニル)チア
ゾール−2−イル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
2−アミノ−4−(4−エチルフェニル)チアゾール
0.339g、DMA5mLならびに2−クロロ−5−
ニトロ安息香酸クロリド0.438gを使用して、実施
例1に記載した方法に従い、標記目的化合物0.393
gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.70 (1H, d, J = 8.4 Hz), 7.86-7.93 (3H, m), 8.17 (1
H, d, J = 2.0 Hz), 8.34 (1H, dd, J = 8.8, 2.8 Hz), 8.6
0 (1H, d, J = 2.8 Hz). (Example 44) N- [4- (4-ethylphenyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4- (4-ethylphenyl) thiazole 0.339 g , DMA 5 mL and 2-chloro-5-
Following the procedure described in Example 1 using 0.438 g of nitrobenzoic acid chloride, the title compound 0.393
g was obtained.
【0162】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
1.21 (3H, t, J=7.5 Hz), 2.63 (2H, q, J=7.5 Hz),
7.28 (1H, d, J=8.2 Hz), 7.71 (1H, s), 7.84 (1H, d,
J=8.2 Hz), 7.91 (1H, d, J=8.9 Hz), 8.38 (1H, dd,
J=8.9, 2.7 Hz), 8.61 (1H, d, J=2.7 Hz)。
(実施例45)N−[4−(tert−ブチルオキシカ
ルボニルアミノフェニル)]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド
(4−tert−ブチルオキシカルボニルアミノフェニ
ル)アミン(4.47g、21.5mmol)、DMA
(50mL)ならびに2−クロロ−5−ニトロ安息香酸
クロリド(5.19g、23.6mmol)を使用し
て、実施例2に記載した方法に従い、標記目的化合物
(6.96g、83%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.48 (9H, s), 7.
44 (2H, d, J=8.9 Hz),7.58 (2H, d, J=8.9 Hz), 7.88
(1H, d, J=8.8 Hz), 7.33 (1H, dd, J=2.8, 8.8Hz), 8.
43 (1H, d, J=2.8 Hz), 9.34 (1H, s), 10.58 (1H, s);
MS(FAB) m/z: 391 M+。
(実施例46)N−[4−(3−クロロ−4−メチルフ
ェニル)−5−メチルチアゾール−2−イル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド
2−アミノ−4−(3−クロロ−4−メチルフェニル)
−5−メチルチアゾール0.368g、DMA5mLな
らびに2−クロロ−5−ニトロ安息香酸クロリド0.4
07gを使用して、実施例1に記載した方法に従い、標
記目的化合物0.510gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
1.21 (3H, t, J = 7.5 Hz), 2.63 (2H, q, J = 7.5 Hz),
7.28 (1H, d, J = 8.2 Hz), 7.71 (1H, s), 7.84 (1H, d,
J = 8.2 Hz), 7.91 (1H, d, J = 8.9 Hz), 8.38 (1H, dd,
J = 8.9, 2.7 Hz), 8.61 (1H, d, J = 2.7 Hz). Example 45 N- [4- (tert-Butyloxycarbonylaminophenyl)]-(2-chloro-5-nitrophenyl) carboxamide (4-tert-butyloxycarbonylaminophenyl) amine (4.47 g, 21 .5 mmol), DMA
The title compound (6.96 g, 83%) was obtained according to the method described in Example 2 using (50 mL) and 2-chloro-5-nitrobenzoic acid chloride (5.19 g, 23.6 mmol). It was 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.48 (9H, s), 7.
44 (2H, d, J = 8.9 Hz), 7.58 (2H, d, J = 8.9 Hz), 7.88
(1H, d, J = 8.8 Hz), 7.33 (1H, dd, J = 2.8, 8.8 Hz), 8.
43 (1H, d, J = 2.8 Hz), 9.34 (1H, s), 10.58 (1H, s);
MS (FAB) m / z: 391 M + . (Example 46) N- [4- (3-chloro-4-methylphenyl) -5-methylthiazol-2-yl]-(2-
Chloro-5-nitrophenyl) carboxamide 2-amino-4- (3-chloro-4-methylphenyl)
0.368 g of 5-methylthiazole, 5 mL of DMA and 0.4 of 2-chloro-5-nitrobenzoic acid chloride
According to the method described in Example 1, using 07 g, 0.510 g of the title object compound was obtained.
【0163】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
2.39 (3H, s), 2.52 (3H, s), 7.47-7.52 (2H, m), 7.
64-7.69 (1H, m), 7.89 (1H, d, J=8.8 Hz), 8.36 (1H,
dd,J=8.8, 2.8 Hz), 8.56 (1H, d, J=2.8 Hz)。
(実施例47)N−[(4,5−ジメチル)チアゾール
−2−イル]−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド
2−アミノ−4,5−ジメチルチアゾール・塩酸塩0.
182g、ピリジン5mLならびに2−クロロ−5−ニ
トロ安息香酸クロリド0.304gを使用して、実施例
2に記載した方法に従い、標記目的化合物0.281g
を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
2.39 (3H, s), 2.52 (3H, s), 7.47-7.52 (2H, m), 7.
64-7.69 (1H, m), 7.89 (1H, d, J = 8.8 Hz), 8.36 (1H,
dd, J = 8.8, 2.8 Hz), 8.56 (1H, d, J = 2.8 Hz). Example 47 N-[(4,5-Dimethyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4,5-dimethylthiazole.hydrochloride.
0.281 g of the title object compound according to the method described in Example 2 using 182 g, 5 mL of pyridine and 0.304 g of 2-chloro-5-nitrobenzoic acid chloride.
Got
【0164】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
2.08 (3H, s), 2.31 (3H, s), 7.62 (1H, d, J=8.8 H
z), 8.27 (1H, dd, J=8.8, 2.7 Hz), 8.63 (1H, d, J=
2.7 Hz)。
(実施例48)N−(5−ブロモチアゾール−2−イ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
2−アミノ−5−ブロモチアゾール・臭化水素酸塩0.
677g、ピリジン5mLならびに2−クロロ−5−ニ
トロ安息香酸クロリド0.680gを使用して、実施例
1に記載した方法に従い、標記目的化合物0.428g
を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
2.08 (3H, s), 2.31 (3H, s), 7.62 (1H, d, J = 8.8 H
z), 8.27 (1H, dd, J = 8.8, 2.7 Hz), 8.63 (1H, d, J =
2.7 Hz). Example 48 N- (5-Bromothiazol-2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-5-bromothiazole.hydrobromide
According to the method described in Example 1, using 677 g, pyridine 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.680 g, the title object compound 0.428 g
Got
【0165】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.00 (1H, s), 7.74 (1H, d, J=8.8Hz), 8.38 (1H, dd,
J=8.8, 2.7 Hz), 8.68 (1H, d, J=2.7 Hz)。
(実施例49)N−(4−ピリジル)−(2−クロロ−
5−ニトロフェニル)カルボキサミド
4−アミノピリジン0.421g、DMA10mLなら
びに2−クロロ−5−ニトロ安息香酸クロリド1.08
gを使用して、実施例1に記載した方法に従い、標記目
的化合物0.788gを得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.00 (1H, s), 7.74 (1H, d, J = 8.8Hz), 8.38 (1H, dd,
J = 8.8, 2.7 Hz), 8.68 (1H, d, J = 2.7 Hz). (Example 49) N- (4-pyridyl)-(2-chloro-
5-nitrophenyl) carboxamide 4-aminopyridine 0.421 g, DMA 10 mL and 2-chloro-5-nitrobenzoic acid chloride 1.08
Following the procedure described in Example 1 using g, afford 0.788 g of the title object compound.
【0166】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
6.27 (2H, d, J=6.2 Hz), 7.92 (1H, d, J=8.8 Hz),
8.37 (1H, dd, J=8.8, 2.7 Hz), 8.52 (2H, d, J=6.2 H
z), 8.55 (1H, d, J=2.7 Hz), 11.10 (1H, s)。
(実施例50)N−(3−ピリジル)−(2−クロロ−
5−ニトロフェニル)カルボキサミド
3−アミノピリジン0.321g、DMA5mLならび
に2−クロロ−5−ニトロ安息香酸クロリド0.825
gを使用して、実施例1に記載した方法に従い、標記目
的化合物0.820gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
6.27 (2H, d, J = 6.2 Hz), 7.92 (1H, d, J = 8.8 Hz),
8.37 (1H, dd, J = 8.8, 2.7 Hz), 8.52 (2H, d, J = 6.2 H
z), 8.55 (1H, d, J = 2.7 Hz), 11.10 (1H, s). (Example 50) N- (3-pyridyl)-(2-chloro-
5-nitrophenyl) carboxamide 3-aminopyridine 0.321 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.825
Following the procedure described in Example 1 using 0.8 g, 0.820 g of the title object compound was obtained.
【0167】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.38 (1H, dd, J=4.8, 8.3 Hz), 7.69 (1H, d, J=8.8 H
z), 8.19 (1H, s), 8.28-8.31 (2H, m), 8.44 (1H, dd,
J=4.8, 1.4 Hz), 8.63 (1H, d, J=2.7 Hz), 8.68 (1H,
d, J=2.5 Hz)。
(実施例51)N−(6−メチルピリジン−2−イル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
2−アミノ−6−メチルピリジン0.314g、DMA
5mLならびに2−クロロ−5−ニトロ安息香酸クロリ
ド0.703gを使用して、実施例1に記載した方法に
従い、標記目的化合物0.632gを得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.38 (1H, dd, J = 4.8, 8.3 Hz), 7.69 (1H, d, J = 8.8 H
z), 8.19 (1H, s), 8.28-8.31 (2H, m), 8.44 (1H, dd,
J = 4.8, 1.4 Hz), 8.63 (1H, d, J = 2.7 Hz), 8.68 (1H,
d, J = 2.5 Hz). (Example 51) N- (6-methylpyridin-2-yl)
-(2-chloro-5-nitrophenyl) carboxamide 2-amino-6-methylpyridine 0.314 g, DMA
According to the method described in Example 1, using 5 mL and 0.703 g of 2-chloro-5-nitrobenzoic acid chloride, 0.632 g of the title object compound was obtained.
【0168】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
2.43 (3H, s), 7.07 (1H, d, J=7.8 Hz), 7.76 (1H,
d, J=7.8 Hz), 8.01 (1H, d, J=7.8 Hz), 8.31 (1H, d
d, J=8.8, 2.7 Hz), 8.42 (1H, d, J=2.7 Hz), 11.21
(1H, s)。
(実施例52)N−(5−メチルピリジン−2−イル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
2−アミノ−5−メチルピリジン0.367g、DMA
5mLならびに2−クロロ−5−ニトロ安息香酸クロリ
ド0.896gを使用して、実施例1に記載した方法に
従い反応を行った後、シリカゲルカラムクロマトグラフ
ィ−(ヘキサン:酢酸エチル=2:1(v/v))にて精製
し、標記目的化合物0.506gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
2.43 (3H, s), 7.07 (1H, d, J = 7.8 Hz), 7.76 (1H,
d, J = 7.8 Hz), 8.01 (1H, d, J = 7.8 Hz), 8.31 (1H, d
d, J = 8.8, 2.7 Hz), 8.42 (1H, d, J = 2.7 Hz), 11.21
(1H, s). (Example 52) N- (5-methylpyridin-2-yl)
-(2-chloro-5-nitrophenyl) carboxamide 2-amino-5-methylpyridine 0.367 g, DMA
The reaction was carried out according to the method described in Example 1 using 5 mL and 0.896 g of 2-chloro-5-nitrobenzoic acid chloride, followed by silica gel column chromatography (hexane: ethyl acetate = 2: 1 (v / Purified in v)) to obtain 0.506 g of the title object compound.
【0169】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
2.32 (3H, s), 7.61 (1H, dd, J=8.5, 1.9 Hz), 7.66
(1H, d, J=8.8 Hz), 8.05 (1H, bs), 8.24 (1H, d, J=
8.5 Hz), 8.28 (1H, dd, J=8.8, 2.7 Hz), 8.61 (1H,
d, J=2.7 Hz), 8.76 (1H, s)。
(実施例53)N−[4−(4−ジメチルアミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド
4−(4−ジメチルアミノフェニル)アニリン0.22
4g、DMA5mLならびに2−クロロ−5−ニトロ安
息香酸クロリド0.279gを使用して、実施例1に記
載した方法に従い、標記目的化合物0.389gの結晶
を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
2.32 (3H, s), 7.61 (1H, dd, J = 8.5, 1.9 Hz), 7.66
(1H, d, J = 8.8 Hz), 8.05 (1H, bs), 8.24 (1H, d, J =
8.5 Hz), 8.28 (1H, dd, J = 8.8, 2.7 Hz), 8.61 (1H,
d, J = 2.7 Hz), 8.76 (1H, s). Example 53 N- [4- (4-Dimethylaminophenyl) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide 4- (4-dimethylaminophenyl) aniline 0.22
According to the method described in Example 1, using 4 g of DMA, 5 mL of DMA and 0.279 g of 2-chloro-5-nitrobenzoic acid chloride, 0.389 g of the title object compound was obtained.
【0170】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
2.94 (6H, s), 6.80 (2H, d, J=8.9 Hz), 7.52 (2H,
d, J=8.9 Hz), 7.61 (2H, d, J=8.7 Hz), 7.73 (2H, d,
J=8.7 Hz), 7.90 (1H, d, J=8.8 Hz), 8.35 (1H, dd,
J=8.8, 2.7 Hz), 8.47 (1H, d, J=2.7 Hz), 10.72 (1H,
s)。
(実施例54)N−(アセナフテン−5−イル)−(2
−クロロ−5−ニトロフェニル)カルボキサミド
5−アミノアセナフテン0.326g、DMA5mLな
らびに2−クロロ−5−ニトロ安息香酸クロリド0.2
67gを使用して、実施例2に記載した方法に従い、標
記目的化合物0.335gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
2.94 (6H, s), 6.80 (2H, d, J = 8.9 Hz), 7.52 (2H,
d, J = 8.9 Hz), 7.61 (2H, d, J = 8.7 Hz), 7.73 (2H, d,
J = 8.7 Hz), 7.90 (1H, d, J = 8.8 Hz), 8.35 (1H, dd,
J = 8.8, 2.7 Hz), 8.47 (1H, d, J = 2.7 Hz), 10.72 (1H,
s). (Example 54) N- (acenaphthen-5-yl)-(2
-Chloro-5-nitrophenyl) carboxamide 5-aminoacenaphthene 0.326 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.2
Following the procedure described in Example 2 using 67 g, 0.335 g of the title object compound was obtained.
【0171】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
3.35-3.42 (4H, m), 7.34-7.37 (2H, m), 7.49-7.54
(1H, m), 7.78-7.83 (2H, m), 7.92 (1H, d, J=8.8 H
z), 8.36 (1H, dd, J=8.8, 2.7 Hz), 8.56(1H, d, J=2.
7 Hz), 10.63 (1H, s)。
(実施例55)N−(3−キノリル)−(2−クロロ−
5−ニトロフェニル)カルボキサミド
3−アミノキノリン0.377g、DMA5mLならび
に2−クロロ−5−ニトロ安息香酸クロリド0.633
gを使用して、実施例2に記載した方法に従い、標記目
的化合物0.555gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
3.35-3.42 (4H, m), 7.34-7.37 (2H, m), 7.49-7.54
(1H, m), 7.78-7.83 (2H, m), 7.92 (1H, d, J = 8.8 H
z), 8.36 (1H, dd, J = 8.8, 2.7 Hz), 8.56 (1H, d, J = 2.
7 Hz), 10.63 (1H, s). (Example 55) N- (3-quinolyl)-(2-chloro-
5-nitrophenyl) carboxamide 3-aminoquinoline 0.377 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.633
Following the method described in Example 2 using 0.5 g, 0.555 g of the title object compound is obtained.
【0172】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.62 (1H, d, J=8.0 Hz), 7.71 (1H, dd, J=6.8, 8.3
Hz), 7.94 (1H, d, J=8.8 Hz), 8.02 (2H, dd, J=8.8,
8.0Hz), 8.39 (1H, dd, J=8.8, 2.7 Hz), 8.61 (1H, d,
J=2.7 Hz), 8.86 (1H, d,J=2.4 Hz), 9.00 (1H, d, J=
2.4 Hz), 11.22 (1H, s)。
(実施例56)N−(5−キノリル)−(2−クロロ−
5−ニトロフェニル)カルボキサミド
5−アミノキノリン0.326g、DMA5mLならび
に2−クロロ−5−ニトロ安息香酸クロリド0.547
gを使用して、実施例2に記載した方法に従い、標記目
的化合物0.704gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.62 (1H, d, J = 8.0 Hz), 7.71 (1H, dd, J = 6.8, 8.3
Hz), 7.94 (1H, d, J = 8.8 Hz), 8.02 (2H, dd, J = 8.8,
8.0Hz), 8.39 (1H, dd, J = 8.8, 2.7 Hz), 8.61 (1H, d,
J = 2.7 Hz), 8.86 (1H, d, J = 2.4 Hz), 9.00 (1H, d, J =
2.4 Hz), 11.22 (1H, s). (Example 56) N- (5-quinolyl)-(2-chloro-
5-Nitrophenyl) carboxamide 5-aminoquinoline 0.326 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.547
Following the procedure as described in Example 2 using g, 0.704 g of the title object compound was obtained.
【0173】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.62 (1H, dd, J=8.6, 4.1 Hz), 7.81-7.99 (3H, m),
8.38 (1H, dd, J=8.8, 2.7 Hz), 8.59 (1H, d, J=8.6 H
z),8.67 (1H, d, J=2.6 Hz), 8.96 (2H, d, J=4.1 Hz),
10.88 (1H, s)。
(実施例57)N−(8−キノリル)−(2−クロロ−
5−ニトロフェニル)カルボキサミド
8−アミノキノリン0.326g、DMA5mLならび
に2−クロロ−5−ニトロ安息香酸クロリド0.525
gを使用して、実施例2に記載した方法に従い、標記目
的化合物0.634gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.62 (1H, dd, J = 8.6, 4.1 Hz), 7.81-7.99 (3H, m),
8.38 (1H, dd, J = 8.8, 2.7 Hz), 8.59 (1H, d, J = 8.6 H
z), 8.67 (1H, d, J = 2.6 Hz), 8.96 (2H, d, J = 4.1 Hz),
10.88 (1H, s). Example 57 N- (8-quinolyl)-(2-chloro-
5-nitrophenyl) carboxamide 8-aminoquinoline 0.326 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.525
Following the procedure described in Example 2 using 0.6 g, 0.634 g of the title object compound is obtained.
【0174】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.64-7.71 (2H, m), 7.81 (1H, d,J=7.1 Hz), 7.91(1
H, d, J=8.8 Hz), 8.86 (1H, dd, J=8.8, 2.7 Hz), 8.4
6 (1H, d, J=8.3 Hz), 8.55 (1H, d, J=2.7 Hz), 8.74
(1H, d, J=7.5 Hz), 8.93 (1H, d, J=4.2 Hz), 10.85
(1H, s)。
(実施例58)N−(4−アミノフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド・1塩酸塩
実施例45で製造したN−[4−(tert−ブチルオ
キシカルボニルアミノフェニル)]−(2−クロロ−5
−ニトロフェニル)カルボキサミド(5.60g、1
4.3mmol)、1,4−ジオキサン(65mL)及
び4N塩化水素−1,4−ジオキサン溶液(10mL)
を使用して、実施例8に記載した方法に従い、標記目的
化合物(4.62g、収率99%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.34 (2H, d, J=
8.8 Hz), 7.78 (2H, d, J=8.8 Hz), 7.99 (1H, d, J=8.
8 Hz), 8.35 (1H, dd, J=2.8, 8.8 Hz), 8.48 (1H, d,
J=2.7 Hz), 9.91 (1H, s), 10.89 (1H, s)。
(実施例59)N−(イソキノリン−1−イル)−(2
−クロロ−5−ニトロフェニル)カルボキサミド
1−アミノイソキノリン0.394g、DMA5mLな
らびに2−クロロ−5−ニトロ安息香酸クロリド0.7
52gを使用して、実施例2に記載した方法に従い、標
記目的化合物0.599gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.64-7.71 (2H, m), 7.81 (1H, d, J = 7.1 Hz), 7.91 (1
H, d, J = 8.8 Hz), 8.86 (1H, dd, J = 8.8, 2.7 Hz), 8.4
6 (1H, d, J = 8.3 Hz), 8.55 (1H, d, J = 2.7 Hz), 8.74
(1H, d, J = 7.5 Hz), 8.93 (1H, d, J = 4.2 Hz), 10.85
(1H, s). Example 58 N- (4-Aminophenyl)-(2-chloro-5-nitrophenyl) carboxamide monohydrochloride N- [4- (tert-Butyloxycarbonylaminophenyl)] prepared in Example 45 -(2-chloro-5
-Nitrophenyl) carboxamide (5.60 g, 1
4.3 mmol), 1,4-dioxane (65 mL) and 4N hydrogen chloride-1,4-dioxane solution (10 mL).
Was used according to the method described in Example 8 to give the title object compound (4.62 g, yield 99%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.34 (2H, d, J =
8.8 Hz), 7.78 (2H, d, J = 8.8 Hz), 7.99 (1H, d, J = 8.
8 Hz), 8.35 (1H, dd, J = 2.8, 8.8 Hz), 8.48 (1H, d,
J = 2.7 Hz), 9.91 (1H, s), 10.89 (1H, s). (Example 59) N- (isoquinolin-1-yl)-(2
-Chloro-5-nitrophenyl) carboxamide 1-aminoisoquinoline 0.394 g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.7
According to the method described in Example 2, using 52 g, 0.599 g of the title object compound was obtained.
【0175】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.80 (1H, d, J=8.8 Hz), 7.89-7.97 (2H, m), 8.03-
8.06 (1H, m), 8.22 (1H, dd, J=8.8, 2.7 Hz), 8.37
(1H, d, J=5.6 Hz), 8.56-8.59 (1H, m), 8.64-8.65 (1
H, m)。
(実施例60)N−(2−メトキシカルボニルピラジン
−3−イル)−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド
3−アミノピラジン−2−カルボン酸メチルエステル
0.338g、DMA5mLならびに2−クロロ−5−
ニトロ安息香酸クロリド0.583gを使用して、実施
例2に記載した方法に従い、標記目的化合物0.617
gを得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.80 (1H, d, J = 8.8 Hz), 7.89-7.97 (2H, m), 8.03-
8.06 (1H, m), 8.22 (1H, dd, J = 8.8, 2.7 Hz), 8.37
(1H, d, J = 5.6 Hz), 8.56-8.59 (1H, m), 8.64-8.65 (1
H, m). Example 60 N- (2-Methoxycarbonylpyrazin-3-yl)-(2-chloro-5-nitrophenyl) carboxamide 3-aminopyrazine-2-carboxylic acid methyl ester 0.338 g, DMA 5 mL and 2-chloro -5
Following the procedure described in Example 2 using 0.583 g of nitrobenzoic acid chloride, the title compound 0.617 is obtained.
g was obtained.
【0176】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
4.07 (3H, s), 7.67 (1H, d, J=8.8Hz), 8.30 (1H, dd,
J=8.8, 2.7 Hz), 8.49 (1H, d, J=2.3 Hz), 8.53 (1H,
d, J=2.7 Hz), 8.59 (1H, d, J=2.3 Hz), 11.32 (1H,
s)。
(実施例61)N−[4−(3−ニトロフェニル)チア
ゾール−2−イル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
2−アミノ−4−(3−ニトロフェニル)チアゾール
0.439g、DMA5mLならびに2−クロロ−5−
ニトロ安息香酸クロリド0.524gを使用して、実施
例2に記載した方法に従い、標記目的化合物0.728
gの結晶を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
4.07 (3H, s), 7.67 (1H, d, J = 8.8Hz), 8.30 (1H, dd,
J = 8.8, 2.7 Hz), 8.49 (1H, d, J = 2.3 Hz), 8.53 (1H,
d, J = 2.7 Hz), 8.59 (1H, d, J = 2.3 Hz), 11.32 (1H,
s). Example 61 N- [4- (3-Nitrophenyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4- (3-nitrophenyl) thiazole 0.439 g , DMA 5 mL and 2-chloro-5-
Following the procedure described in Example 2 using 0.524 g of nitrobenzoic acid chloride, the title compound 0.728 is obtained.
g crystals were obtained.
【0177】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.76 (1H, t, d=8.8 Hz), 7.92 (1H, d, J=8.8 Hz),
8.11 (1H, s), 8.20 (1H, dd, J=1.2, 8.8 Hz), 8.39
(2H, dd, J=2.8, 8.8 Hz), 8.63 (1H, d, J=2.8 Hz),
8.76 (1H, t, J=2.8 Hz)。
(実施例62)N−(6−クロロピリジン−3−イル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
5−アミノ−2−クロロピリジン0.257g、DMA
5mLならびに2−クロロ−5−ニトロ安息香酸クロリ
ド0.528gを使用して、実施例2に記載した方法に
従い、標記目的化合物0.554gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.76 (1H, t, d = 8.8 Hz), 7.92 (1H, d, J = 8.8 Hz),
8.11 (1H, s), 8.20 (1H, dd, J = 1.2, 8.8 Hz), 8.39
(2H, dd, J = 2.8, 8.8 Hz), 8.63 (1H, d, J = 2.8 Hz),
8.76 (1H, t, J = 2.8 Hz). (Example 62) N- (6-chloropyridin-3-yl)
-(2-chloro-5-nitrophenyl) carboxamide 5-amino-2-chloropyridine 0.257 g, DMA
Following the method described in Example 2 using 5 mL and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride, 0.554 g of the title object compound was obtained.
【0178】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.57 (1H, d, J=8.8 Hz), 7.92 (1H, d, J=8.8 Hz),
8.20 (1H, dd, J=2.9, 8.8 Hz), 8.37 (1H, dd, J=2.9,
8.8Hz), 8.56 (1H, d, J=2.9 Hz), 8.71 (1H, d, J=2.
9 Hz)。
(実施例63)N−(4−メチル−3−ニトロピリジン
−2−イル)−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド
2−アミノ−4−メチル−3−ニトロピリジン0.30
6g、DMA5mLならびに2−クロロ−5−ニトロ安
息香酸クロリド0.528gを使用して、実施例2に記
載した方法に従い、標記目的化合物0.482gの結晶
を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.57 (1H, d, J = 8.8 Hz), 7.92 (1H, d, J = 8.8 Hz),
8.20 (1H, dd, J = 2.9, 8.8 Hz), 8.37 (1H, dd, J = 2.9,
8.8Hz), 8.56 (1H, d, J = 2.9 Hz), 8.71 (1H, d, J = 2.
9 Hz). Example 63 N- (4-Methyl-3-nitropyridin-2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4-methyl-3-nitropyridine 0.30
According to the method described in Example 2, using 6 g, 5 mL of DMA, and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride, 0.482 g of the title object compound was obtained as crystals.
【0179】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.51 (1H, d, J=5.0 Hz), 7.90 (1H, d, J=8.8 Hz),
8.26 (1H, d, J=2.8 Hz), 8.38 (1H, dd, J=2.8, 8.8 H
z), 8.56 (1H, d, J=5.0 Hz)。
(実施例64)2,5−ビス(2−クロロ−5−ニトロ
ベンゾイルアミノ)ピリジン
2,5−ジアミノピリジン・2塩酸塩0.182g、ト
リエチルアミン0.335mL、DMA5mLならびに
2−クロロ−5−ニトロ安息香酸クロリド0.528g
を使用して、実施例2に記載した方法に従い、標記目的
化合物0.254gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.51 (1H, d, J = 5.0 Hz), 7.90 (1H, d, J = 8.8 Hz),
8.26 (1H, d, J = 2.8 Hz), 8.38 (1H, dd, J = 2.8, 8.8 H
z), 8.56 (1H, d, J = 5.0 Hz). (Example 64) 2,5-bis (2-chloro-5-nitrobenzoylamino) pyridine 2,5-diaminopyridine dihydrochloride 0.182 g, triethylamine 0.335 mL, DMA 5 mL and 2-chloro-5-nitro Benzoic acid chloride 0.528g
According to the method described in Example 2, using, was obtained 0.254 g of the title object compound as crystals.
【0180】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.87 (1H, d, J=8.8 Hz), 7.92 (1H, d, J=8.8 Hz),
8.17 (1H, dd, J=3.0, 8.8 Hz), 8.25 (1H, d, J=8.8 H
z), 8.33 (1H, dd, J=3.0, 8.8 Hz), 8.36 (1H, dd, J=
3.0, 8.8 Hz), 8.48 (1H, d,J=3.0 Hz), 8.54 (1H, d,
J=3.0 Hz), 8.71 (1H, s), 10.96 (1H, s), 11.30 (1H,
s)。
(実施例65)N−(4−メチルピリミジン−2−イ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
2−アミノ−4−メチルピリミジン0.218g、DM
A5mLならびに2−クロロ−5−ニトロ安息香酸クロ
リド0.528gを使用して、実施例2に記載した方法
に従い、標記目的化合物0.341gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.87 (1H, d, J = 8.8 Hz), 7.92 (1H, d, J = 8.8 Hz),
8.17 (1H, dd, J = 3.0, 8.8 Hz), 8.25 (1H, d, J = 8.8 H
z), 8.33 (1H, dd, J = 3.0, 8.8 Hz), 8.36 (1H, dd, J =
3.0, 8.8 Hz), 8.48 (1H, d, J = 3.0 Hz), 8.54 (1H, d,
J = 3.0 Hz), 8.71 (1H, s), 10.96 (1H, s), 11.30 (1H, s)
s). (Example 65) N- (4-methylpyrimidin-2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4-methylpyrimidine 0.218 g, DM
According to the method described in Example 2, using 5 mL of A and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride, 0.341 g of the title object compound was obtained as crystals.
【0181】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.10 (1H, s), 7.84 (1H, dd, J=3.0, 8.8 Hz), 8.30
(1H, dd, J=3.0, 8.8 Hz), 8.45 (1H, d, J=5.2 Hz), 1
1.39(1H, s)。
(実施例66)N−(2−メトキシカルボニルチオフェ
ン−3−イル)−(2−クロロ−5−ニトロフェニル)
カルボキサミド
3−アミノチオフェン−2−カルボン酸メチルエステル
0.314g、DMA5mLならびに2−クロロ−5−
ニトロ安息香酸クロリド0.528gを使用して、実施
例2に記載した方法に従い、標記目的化合物0.590
gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.10 (1H, s), 7.84 (1H, dd, J = 3.0, 8.8 Hz), 8.30
(1H, dd, J = 3.0, 8.8 Hz), 8.45 (1H, d, J = 5.2 Hz), 1
1.39 (1H, s). Example 66 N- (2-Methoxycarbonylthiophen-3-yl)-(2-chloro-5-nitrophenyl)
Carboxamide 3-aminothiophene-2-carboxylic acid methyl ester 0.314 g, DMA 5 mL and 2-chloro-5-
Following the procedure described in Example 2 using 0.528 g of nitrobenzoic acid chloride, 0.590 of the title object compound is obtained.
g crystals were obtained.
【0182】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.93 (1H, d, J=8.6 Hz), 7.96-8.03 (2H, m), 8.39(1
H, dd, J=3.0, 8.6 Hz), 8.56 (1H, d, J=3.0 Hz), 10.
67 (1H, s)。
(実施例67)N−(6−メトキシベンゾチアゾール−
2−イル)−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
2−アミノ−6−メトキシベンゾチアゾール0.360
g、DMA5mLならびに2−クロロ−5−ニトロ安息
香酸クロリド0.528gを使用して、実施例2に記載
した方法に従い、標記目的化合物0.577gの結晶を
得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.93 (1H, d, J = 8.6 Hz), 7.96-8.03 (2H, m), 8.39 (1
H, dd, J = 3.0, 8.6 Hz), 8.56 (1H, d, J = 3.0 Hz), 10.
67 (1H, s). (Example 67) N- (6-methoxybenzothiazole-
2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-6-methoxybenzothiazole 0.360
According to the method described in Example 2 using 0.5 g of DMA, 5 mL of DMA and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride, 0.577 g of the title compound of interest was obtained.
【0183】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.08 (1H, dd, J=2.8, 8.8 Hz), 7.65 (1H, d, J=2.8H
z), 7.71 (1H, d, J=8.8 Hz), 7.92 (1H, d, J=8.8 H
z), 8.39 (1H, dd, J=2.8, 8.8 Hz), 8.64 (1H, d, J=
2.8 Hz)。
(実施例68)N−(6−クロロベンゾチアゾール−2
−イル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
2−アミノ−6−クロロベンゾチアゾール0.368
g、DMA5mLならびに2−クロロ−5−ニトロ安息
香酸クロリド0.528gを使用して、実施例2に記載
した方法に従い、標記目的化合物0.751gの結晶を
得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.08 (1H, dd, J = 2.8, 8.8 Hz), 7.65 (1H, d, J = 2.8H
z), 7.71 (1H, d, J = 8.8 Hz), 7.92 (1H, d, J = 8.8 H
z), 8.39 (1H, dd, J = 2.8, 8.8 Hz), 8.64 (1H, d, J =
2.8 Hz). (Example 68) N- (6-chlorobenzothiazole-2)
-Yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-6-chlorobenzothiazole 0.368
According to the method described in Example 2, using 0.5 g of DMA, 5 mL of DMA and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride, 0.751 g of the title object compound was obtained.
【0184】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.52 (1H, dd, J=2.8, 8.8 Hz), 7.81 (1H, d, J=8.8H
z), 7.94 (1H, d, J=8.8 Hz), 8.22 (1H, d, J=2.8 H
z), 8.40 (1H, dd, J=3.0, 8.8 Hz), 8.66 (1H, d, J=
3.0 Hz)。
(実施例69)N−(4−クロロベンゾチアゾール−2
−イル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
2−アミノ−4−クロロベンゾチアゾール0.368
g、DMA5mLならびに2−クロロ−5−ニトロ安息
香酸クロリド0.528gを使用して、実施例2に記載
した方法に従い、標記目的化合物0.464gの結晶を
得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.52 (1H, dd, J = 2.8, 8.8 Hz), 7.81 (1H, d, J = 8.8H
z), 7.94 (1H, d, J = 8.8 Hz), 8.22 (1H, d, J = 2.8 H
z), 8.40 (1H, dd, J = 3.0, 8.8 Hz), 8.66 (1H, d, J =
3.0 Hz). (Example 69) N- (4-chlorobenzothiazole-2)
-Yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4-chlorobenzothiazole 0.368
g, 5 mL of DMA and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride were used according to the method described in Example 2 to obtain 0.464 g of the title object compound.
【0185】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.38 (1H, t, J=7.8 Hz), 7.59 (1H, d, J=7.8 Hz),
7.93 (1H, d, J=8.6 Hz), 8.06 (1H, d, J=7.8 Hz), 8.
40 (1H, dd, J=3.0, 8.6 Hz), 8.67 (1H, d, J=3.0 H
z)。
(実施例70)N−(6−フルオロベンゾチアゾール−
2−イル)−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
2−アミノ−6−フルオロベンゾチアゾール0.336
g、DMA5mLならびに2−クロロ−5−ニトロ安息
香酸クロリド0.528gを使用して、実施例2に記載
した方法に従い、標記目的化合物0.512gの結晶を
得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.38 (1H, t, J = 7.8 Hz), 7.59 (1H, d, J = 7.8 Hz),
7.93 (1H, d, J = 8.6 Hz), 8.06 (1H, d, J = 7.8 Hz), 8.
40 (1H, dd, J = 3.0, 8.6 Hz), 8.67 (1H, d, J = 3.0 H
z). (Example 70) N- (6-fluorobenzothiazole-
2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-6-fluorobenzothiazole 0.336
According to the method described in Example 2, using 0.5 g of DMA, 5 mL of DMA and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride, 0.512 g of the title object compound was obtained.
【0186】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.31-7.39 (1H, m), 7.80-7.88 (1H, m), 7.94 (1H,
d, J=8.8 Hz), 7.96 (1H, dd, J=3.0, 8.8 Hz), 8.40
(1H, dd, J=3.0, 8.8 Hz), 8.66 (1H, d, J=3.0 Hz)。
(実施例71)N−(4−エトキシカルボニルピラゾー
ル−3−イル)−(2−クロロ−5−ニトロフェニル)
カルボキサミド
3−アミノ−4−エトキシカルボニルピラゾール0.3
10g、DMA5mLならびに2−クロロ−5−ニトロ
安息香酸クロリド0.528gを使用して、実施例2に
記載した方法に従い、標記目的化合物0.579gの結
晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.31-7.39 (1H, m), 7.80-7.88 (1H, m), 7.94 (1H,
d, J = 8.8 Hz), 7.96 (1H, dd, J = 3.0, 8.8 Hz), 8.40
(1H, dd, J = 3.0, 8.8 Hz), 8.66 (1H, d, J = 3.0 Hz). Example 71 N- (4-Ethoxycarbonylpyrazol-3-yl)-(2-chloro-5-nitrophenyl)
Carboxamide 3-amino-4-ethoxycarbonylpyrazole 0.3
According to the method described in Example 2, 10 g of DMA, 5 mL of DMA and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride were used to obtain 0.579 g of the target compound.
【0187】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
1.29 (3H, t, J=7.2 Hz), 4.28 (2H, q, J=7.2 Hz),
6.11 (1H, s), 7.92 (1H, d, J=8.8 Hz), 8.38 (1H, d
d, J=2.9, 8.8 Hz), 8.66 (1H, d, J=2.9 Hz)。
(実施例72)N−(5−フェニルピラゾール−3−イ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
3−アミノ−5−フェニルピラゾール0.318g、D
MA5mLならびに2−クロロ−5−ニトロ安息香酸ク
ロリド0.528gを使用して、実施例2に記載した方
法に従い、標記目的化合物0.636gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
1.29 (3H, t, J = 7.2 Hz), 4.28 (2H, q, J = 7.2 Hz),
6.11 (1H, s), 7.92 (1H, d, J = 8.8 Hz), 8.38 (1H, d
d, J = 2.9, 8.8 Hz), 8.66 (1H, d, J = 2.9 Hz). (Example 72) N- (5-phenylpyrazol-3-yl)-(2-chloro-5-nitrophenyl) carboxamide 3-amino-5-phenylpyrazole 0.318 g, D
According to the method described in Example 2, using 5 mL of MA and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride, 0.636 g of the title object compound was obtained as crystals.
【0188】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.06 (1H, s), 7.34-7.52 (3H, m), 7.87 (1H, d, J=
8.8 Hz), 7.78 (2H, d, J=7.8 Hz), 8.32 (1H, dd, J=
3.0, 8.8 Hz), 8.41 (1H, s), 11.28 (1H, s)。
(実施例73)N−(3,5−ジメトキシピリミジン−
2−イル)−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
2−アミノ−3,5−ジメトキシピリミジン0.310
g、DMA5mLならびに2−クロロ−5−ニトロ安息
香酸クロリド0.528gを使用して、実施例2に記載
した方法に従い、標記目的化合物0.498gの結晶を
得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.06 (1H, s), 7.34-7.52 (3H, m), 7.87 (1H, d, J =
8.8 Hz), 7.78 (2H, d, J = 7.8 Hz), 8.32 (1H, dd, J =
3.0, 8.8 Hz), 8.41 (1H, s), 11.28 (1H, s). (Example 73) N- (3,5-dimethoxypyrimidine-
2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-3,5-dimethoxypyrimidine 0.310
g, 5 mL of DMA and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride were used according to the method described in Example 2 to obtain 0.498 g of the title object compound as crystals.
【0189】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
3.58 (6H, s), 5.90 (1H, s), 7.83 (1H, d, J=8.8 H
z), 8.26 (1H, dd, J=2.7, 8.8 Hz), 8.36 (1H, d, J=
2.7 Hz), 11.38 (1H, s)。
(実施例74)N−(3,5−ジメチルピリミジン−2
−イル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
2−アミノ−3,5−ジメチルピリミジン0.246
g、DMA5mLならびに2−クロロ−5−ニトロ安息
香酸クロリド0.528gを使用して、実施例2に記載
した方法に従い、標記目的化合物0.159gの結晶を
得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
3.58 (6H, s), 5.90 (1H, s), 7.83 (1H, d, J = 8.8 H
z), 8.26 (1H, dd, J = 2.7, 8.8 Hz), 8.36 (1H, d, J =
2.7 Hz), 11.38 (1H, s). (Example 74) N- (3,5-dimethylpyrimidine-2)
-Yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-3,5-dimethylpyrimidine 0.246
g, DMA 5 mL and 2-chloro-5-nitrobenzoic acid chloride 0.528 g were used according to the method described in Example 2 to obtain the title compound (0.159 g) as crystals.
【0190】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
2.25 (6H, s), 6.86 (1H, s), 7.80 (1H, d, J=8.8 H
z), 8.27-8.33 (2H, m), 11.28 (1H, s)。
(実施例75)N−(5−クロロベンゾオキサゾール−
2−イル)−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
2−アミノ−5−クロロベンゾオキサゾール0.336
g、DMA5mLならびに2−クロロ−5−ニトロ安息
香酸クロリド0.528gを使用して、実施例2に記載
した方法に従い、標記目的化合物0.583gの結晶を
得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
2.25 (6H, s), 6.86 (1H, s), 7.80 (1H, d, J = 8.8 H
z), 8.27-8.33 (2H, m), 11.28 (1H, s). (Example 75) N- (5-chlorobenzoxazole-
2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-5-chlorobenzoxazole 0.336
According to the method described in Example 2, using 0.5 g of DMA, 5 mL of DMA and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride, 0.583 g of the title object compound was obtained.
【0191】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.35 (1H, dd, J=2.2, 8.8 Hz), 7.69 (1H, s), 7.70
(1H, d, J=8.8 Hz), 7.91 (1H, d, J=8.8 Hz), 8.37 (1
H, dd, J=2.2, 8.8 Hz), 8.61 (1H, d, J=2.2 Hz)。
(実施例76)N−(4−メトキシカルボニルチオフェ
ン−3−イル)−(2−クロロ−5−ニトロフェニル)
カルボキサミド
3−アミノ−4−メトキシカルボニルチオフェン・塩酸
塩0.386g、トリエチルアミン0.335mL、D
MA5mLならびに2−クロロ−5−ニトロ安息香酸ク
ロリド0.528gを使用して、実施例2に記載した方
法に従い、標記目的化合物0.546gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.35 (1H, dd, J = 2.2, 8.8 Hz), 7.69 (1H, s), 7.70
(1H, d, J = 8.8 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.37 (1
H, dd, J = 2.2, 8.8 Hz), 8.61 (1H, d, J = 2.2 Hz). Example 76 N- (4-Methoxycarbonylthiophen-3-yl)-(2-chloro-5-nitrophenyl)
Carboxamide 3-amino-4-methoxycarbonylthiophene hydrochloride 0.386 g, triethylamine 0.335 mL, D
Following the method described in Example 2 using 5 mL of MA and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride, 0.546 g of the title object compound was obtained.
【0192】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
3.84 (3H, s), 7.92 (1H, d, J=8.7 Hz), 8.08 (1H,
d, J=2.9 Hz), 8.38 (1H, dd, J=2.9, 8.7 Hz), 8.44
(1H, d, J=2.9 Hz), 8.53 (1H, d, J=2.9 Hz), 10.54
(1H, s)。
(実施例77)N−(5−ブロモピリミジン−2−イ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
2−アミノ−5−ブロモピリミジン0.348g、DM
A5mLならびに2−クロロ−5−ニトロ安息香酸クロ
リド0.528gを使用して、実施例2に記載した方法
に従い、標記目的化合物0.541gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
3.84 (3H, s), 7.92 (1H, d, J = 8.7 Hz), 8.08 (1H,
d, J = 2.9 Hz), 8.38 (1H, dd, J = 2.9, 8.7 Hz), 8.44
(1H, d, J = 2.9 Hz), 8.53 (1H, d, J = 2.9 Hz), 10.54
(1H, s). Example 77 N- (5-Bromopyrimidin-2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-5-bromopyrimidine 0.348 g, DM
According to the method described in Example 2, using 5 mL of A and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride, 0.541 g of the title object compound was obtained.
【0193】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.84 (1H, d, J=8.8 Hz), 8.32 (1H, dd, J=2.9, 8.8H
z), 8.41 (1H, d, J=2.9 Hz), 8.83 (2H, s), 10.65 (1
H, s)。
(実施例78)N−(4−クロロ−6−メチルピリミジ
ン−2−イル)−(2−クロロ−5−ニトロフェニル)
カルボキサミド
2−アミノ−4−クロロ−6−メチルピリミジン0.2
87g、DMA5mLならびに2−クロロ−5−ニトロ
安息香酸クロリド0.528gを使用して、実施例2に
記載した方法に従い、標記目的化合物0.336gの結
晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.84 (1H, d, J = 8.8 Hz), 8.32 (1H, dd, J = 2.9, 8.8H
z), 8.41 (1H, d, J = 2.9 Hz), 8.83 (2H, s), 10.65 (1
H, s). Example 78 N- (4-chloro-6-methylpyrimidin-2-yl)-(2-chloro-5-nitrophenyl)
Carboxamide 2-amino-4-chloro-6-methylpyrimidine 0.2
According to the method described in Example 2, using 87 g, DMA (5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.528 g), 0.336 g of the title object compound was obtained as crystals.
【0194】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
2.34 (3H, s), 7.31 (1H, s), 7.83 (1H, d, J=8.8 H
z), 8.31 (1H, dd, J=2.9, 8.8 Hz), 8.39 (1H, d, J=
2.9 Hz), 10.67 (1H, s)。
(実施例79)N−(3−カルボエトキシ−4,5,
6,7−テトラヒドロベンゾ[b]チオフェン−2−イ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
2−アミノ−3−カルボエトキシ−4,5,6,7−テ
トラヒドロベンゾ[b]チオフェン0.451g、DM
A5mLならびに2−クロロ−5−ニトロ安息香酸クロ
リド0.528gを使用して、実施例2に記載した方法
に従い、標記目的化合物0.544gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
2.34 (3H, s), 7.31 (1H, s), 7.83 (1H, d, J = 8.8 H
z), 8.31 (1H, dd, J = 2.9, 8.8 Hz), 8.39 (1H, d, J =
2.9 Hz), 10.67 (1H, s). (Example 79) N- (3-carboethoxy-4,5,5
6,7-Tetrahydrobenzo [b] thiophen-2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-3-carbethoxy-4,5,6,7-tetrahydrobenzo [b] thiophene 0.451g, DM
According to the method described in Example 2, using 5 mL of A and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride, 0.544 g of the title object compound was obtained.
【0195】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
1.29 (3H, t, J=7.3 Hz), 1.70-1.82 (4H, m), 2.63-
2.80 (4H, m), 4.26 (2H, q, J=7.3 Hz), 7.94 (1H, d,
J=8.8 Hz), 8.40 (1H, dd, J=2.2, 8.8 Hz), 8.56 (1
H, d, J=2.2 Hz), 10.65 (1H,s)。
(実施例80)N−(3−ニトロピリジン−2−イル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
2−アミノ−3−ニトロピリジン0.278g、DMA
5mLならびに2−クロロ−5−ニトロ安息香酸クロリ
ド0.528gを使用して、実施例2に記載した方法に
従い、標記目的化合物0.405gの結晶を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
1.29 (3H, t, J = 7.3 Hz), 1.70-1.82 (4H, m), 2.63-
2.80 (4H, m), 4.26 (2H, q, J = 7.3 Hz), 7.94 (1H, d,
J = 8.8 Hz), 8.40 (1H, dd, J = 2.2, 8.8 Hz), 8.56 (1
H, d, J = 2.2 Hz), 10.65 (1H, s). (Example 80) N- (3-nitropyridin-2-yl)
-(2-chloro-5-nitrophenyl) carboxamide 2-amino-3-nitropyridine 0.278 g, DMA
Following the method described in Example 2 using 5 mL and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride, 0.405 g of the title object compound was obtained as crystals.
【0196】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.59 (1H, dd, J=4.8, 8.1 Hz), 7.92 (1H, d, J=8.8H
z), 8.32 (1H, d, J=2.9 Hz), 8.39 (1H, dd, J=2.9,
8.8 Hz), 8.51 (1H, d, J=8.1 Hz), 8.77 (1H, dd, J=
1.5, 4.8 Hz), 11.97 (1H, s)。
(実施例81)N−(4,6−ジクロロピリミジン−5
−イル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
5−アミノ−4,6−ジクロロピリミジン0.326
g、DMA5mLならびに2−クロロ−5−ニトロ安息
香酸クロリド0.528gを使用して、実施例2に記載
した方法に従い、標記目的化合物0.478gの結晶を
得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.59 (1H, dd, J = 4.8, 8.1 Hz), 7.92 (1H, d, J = 8.8H
z), 8.32 (1H, d, J = 2.9 Hz), 8.39 (1H, dd, J = 2.9,
8.8 Hz), 8.51 (1H, d, J = 8.1 Hz), 8.77 (1H, dd, J =
1.5, 4.8 Hz), 11.97 (1H, s). (Example 81) N- (4,6-dichloropyrimidine-5)
-Yl)-(2-chloro-5-nitrophenyl) carboxamide 5-amino-4,6-dichloropyrimidine 0.326
g, 5 mL of DMA and 0.528 g of 2-chloro-5-nitrobenzoic acid chloride were used according to the method described in Example 2 to obtain 0.478 g of the title object compound as crystals.
【0197】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.96 (1H, d, J=8.8 Hz), 8.35 (1H, d, J=2.9 Hz),
8.41 (1H, dd, J=2.9, 8.8 Hz), 8.96 (1H, s), 11.32
(1H,s)。
(実施例82)N−(1−メチルベンズイミダゾール−
2−イル)−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
2−アミノ−1−メチルベンズイミダゾール(アルドリ
ッチ、0.294g、2.0mmol)をDMA(5m
L)に溶解し、2−クロロ−5−ニトロ安息香酸クロリ
ド(0.528g、2.4mmol)を加えて、室温で
2.5時間攪拌した。反応溶液に飽和重曹水(5mL)
及び水(20mL)を加え、生じた固体を濾取し、水及
びジイソプロピルエーテルで洗浄し、減圧乾燥して、粗
製の標記目的化合物(0.438g)を得た。得られた
粗製の標記目的化合物(0.438g)をシリカゲルカ
ラムクロマトグラフィー(ヘキサン:酢酸エチル=2:
1(v/v))にて精製し、標記目的化合物(0.043
g、収率7%)を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.96 (1H, d, J = 8.8 Hz), 8.35 (1H, d, J = 2.9 Hz),
8.41 (1H, dd, J = 2.9, 8.8 Hz), 8.96 (1H, s), 11.32
(1H, s). (Example 82) N- (1-methylbenzimidazole-
2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-1-methylbenzimidazole (Aldrich, 0.294 g, 2.0 mmol) in DMA (5 m
L), 2-chloro-5-nitrobenzoic acid chloride (0.528 g, 2.4 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. Saturated sodium hydrogen carbonate solution (5 mL) in the reaction solution
And water (20 mL) were added, and the resulting solid was collected by filtration, washed with water and diisopropyl ether, and dried under reduced pressure to give a crude title compound (0.438 g). The obtained crude title compound (0.438 g) was subjected to silica gel column chromatography (hexane: ethyl acetate = 2:
1 (v / v)) and the title compound (0.043
g, yield 7%) was obtained.
【0198】Rf 0.40 (ヘキサン:酢酸エチル=1:1(v/
v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 3.68 (3H,
s), 7.24-7.34 (2H, m), 7.53-7.59 (2H, m), 7.80 (1
H, d, J=8.8 Hz), 8.25 (1H, dd, J=2.9, 8.8 Hz),8.66
(1H, d, J=2.9 Hz);
MS(EI) m/z: 330 M+。
(実施例83)N−(4,6−ジクロロピリミジン−2
−イル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
2−アミノ−4,6−ジクロロピリミジン(アルドリッ
チ、0.328g、2.0mmol)、DMA(5m
L)ならびに2−クロロ−5−ニトロ安息香酸クロリド
(0.528g、2.4mmol)を使用して、実施例
1に記載した方法に従い反応を行った。反応溶液に飽和
重曹水(5mL)及び水(20mL)を加え、生じた固
体を濾取し、水及びジイソプロピルエーテルで洗浄し、
減圧乾燥して、標記目的化合物(0.363g、収率5
2%)を得た。R f 0.40 (hexane: ethyl acetate = 1: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 3.68 (3H,
s), 7.24-7.34 (2H, m), 7.53-7.59 (2H, m), 7.80 (1
H, d, J = 8.8 Hz), 8.25 (1H, dd, J = 2.9, 8.8 Hz), 8.66
(1H, d, J = 2.9 Hz); MS (EI) m / z: 330 M + . (Example 83) N- (4,6-dichloropyrimidine-2)
-Yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4,6-dichloropyrimidine (Aldrich, 0.328 g, 2.0 mmol), DMA (5 m
L) and 2-chloro-5-nitrobenzoic acid chloride (0.528 g, 2.4 mmol) were used to carry out the reaction according to the method described in Example 1. Saturated aqueous sodium hydrogen carbonate (5 mL) and water (20 mL) were added to the reaction solution, the resulting solid was collected by filtration, washed with water and diisopropyl ether,
After drying under reduced pressure, the title object compound (0.363 g, yield 5
2%) was obtained.
【0199】Rf 0.61 (ヘキサン:酢酸エチル=1:1(v/
v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.71 (1H,
s), 7.85 (1H, d, J=8.8 Hz), 8.34 (1H, dd, J=2.9,
8.8 Hz), 8.45 (1H, d, J=2.9 Hz), 12.02 (1H,s);
MS(EI) m/z: 347 (M+H)+。
(実施例84)N−(5−ブロモ−3−ニトロピリジン
−2−イル)−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド
2−アミノ−5−ブロモ−3−ニトロピリジン(アルド
リッチ、0.436g、2.0mmol)、DMA(5
mL)ならびに2−クロロ−5−ニトロ安息香酸クロリ
ド(0.660g、3.0mmol)を使用して、実施
例2に記載した方法に従い、標記目的化合物(0.47
7g、収率59%)を得た。R f 0.61 (hexane: ethyl acetate = 1: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.71 (1H,
s), 7.85 (1H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 2.9,
8.8 Hz), 8.45 (1H, d, J = 2.9 Hz), 12.02 (1H, s); MS (EI) m / z: 347 (M + H) + . Example 84 N- (5-Bromo-3-nitropyridin-2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-5-bromo-3-nitropyridine (Aldrich, 0. 436 g, 2.0 mmol), DMA (5
mL) and 2-chloro-5-nitrobenzoic acid chloride (0.660 g, 3.0 mmol) according to the method described in Example 2 to give the title object compound (0.47).
7 g, yield 59%) was obtained.
【0200】Rf 0.20 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.92 (1H,
d, J=8.8 Hz), 8.33 (1H, d, J=2.9 Hz), 8.39 (1H, d
d, J=2.9, 8.8 Hz), 8.80 (1H, d, J=2.2 Hz), 8.95 (1
H, d, J=2.2 Hz),12.10 (1H, s);
MS(EI) m/z: 400 M+。
(実施例85)N−(1,3,4−チアジアゾール−2
−イル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
2−アミノ−1,3,4−チアジアゾール(東京化成、
0.202g、2.0mmol)、DMA(5mL)な
らびに2−クロロ−5−ニトロ安息香酸クロリド(0.
528g、2.4mmol)を使用して、実施例2に記
載した方法に従い、標記目的化合物(0.489g、収
率86%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.92 (1H,
d, J=8.8 Hz), 8.39 (1H, dd, J=2.9, 8.8 Hz), 8.65
(1H, d, J=2.9 Hz), 9.31 (1H, s);
MS(EI) m/z: 284 M+。
(実施例86)N−(2,1,3−ベンゾチアジアゾー
ル−4−イル)−(2−クロロ−5−ニトロフェニル)
カルボキサミド
4−アミノ−2,1,3−ベンゾチアジアゾール(東京
化成、0.302g、2.0mmol)、DMA(5m
L)ならびに2−クロロ−5−ニトロ安息香酸クロリド
(0.528g、2.4mmol)を使用して、実施例
2に記載した方法に従い、標記目的化合物(0.561
g、収率84%)を得た。1
H-NMR (400MHz, CDCl3, TMS): δ(ppm) 7.70 (1H, t,
J=8.8 Hz), 7.73 (1H,d, J=8.8 Hz), 7.80 (1H, d, J=
8.8 Hz), 8.33 (1H, dd, J=2.9, 8.8 Hz), 8.66 (1H,
d, J=8.8 Hz), 8.76 (1H, d, J=2.9 Hz), 9.39 (1H, b
r);
MS(EI) m/z: 334 M+。
(実施例87)N−[4−[4−(tert−ブトキシ
カルボニルアミノ)フェニル]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド
4−[4−(tert−ブトキシカルボニルアミノ)フ
ェニル]アニリン(Synth. Commun.,1998年,第28巻,
p.963)(0.284g、1.0mmol)、DMA
(5mL)ならびに2−クロロ−5−ニトロ安息香酸ク
ロリド(0.264g、1.2mmol)を使用して、
実施例2に記載した方法に従い、標記目的化合物(0.
335g、収率72%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.49 (9H,
s), 7.52-7.62 (4H, m), 7.65 (2H, d, J=8.8 Hz), 7.7
7 (2H, d, J=8.8 Hz), 7.90 (1H, d, J=8.8 Hz), 8.35
(1H, dd, J=2.2, 8.8 Hz), 8.49 (1H, d, J=2.2 Hz),
9.43 (1H, s), 10.77 (1H, s);
MS(EI) m/z: 467 (M + H)+。
(実施例88)N−[4−(4−アミノフェニル)フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキ
サミド・1塩酸塩
実施例87で製造した、N−[4−[4−(tert−
ブトキシカルボニルアミノ)フェニル]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(0.200g、0.427mmol)を1N塩化水素
−1,4−ジオキサン溶液(2mL)に懸濁させ、1週
間攪拌した。反応液をジエチルエーテルで希釈して、生
じた固体を濾取し、1,4−ジオキサン及びジエチルエ
ーテルで洗浄した。得られた固体を減圧乾燥して、標記
目的化合物(0.131g、収率76%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.32 (2H,
d, J=8.1 Hz), 7.70 (2H, d, J=8.8 Hz), 7.73 (2H, d,
J=8.1 Hz), 7.81 (2H, d, J=8.8 Hz), 7.91 (1H, d, J
=8.8 Hz), 8.36 (1H, dd, J=2.9, 8.8 Hz), 8.49 (1H,
d, J=2.9 Hz), 10.85 (1H, s);
MS(EI) m/z: 367 (M - HCl)+。
(実施例89)N−(6−クロロピリダジン−2−イ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
3−アミノ−6−クロロピリダジン(ランカスター、
0.259g、2.0mmol)、DMA(5mL)な
らびに2−クロロ−5−ニトロ安息香酸クロリド(0.
528g、2.4mmol)を使用して、実施例2に記
載した方法に従い、標記目的化合物(0.513g、収
率82%)を得た。R f 0.20 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.92 (1H,
d, J = 8.8 Hz), 8.33 (1H, d, J = 2.9 Hz), 8.39 (1H, d
d, J = 2.9, 8.8 Hz), 8.80 (1H, d, J = 2.2 Hz), 8.95 (1
H, d, J = 2.2 Hz), 12.10 (1H, s); MS (EI) m / z: 400 M + . (Example 85) N- (1,3,4-thiadiazole-2)
-Yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-1,3,4-thiadiazole (Tokyo Kasei,
0.202 g, 2.0 mmol), DMA (5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.
The title compound (0.489 g, yield 86%) was obtained according to the method described in Example 2 using 528 g (2.4 mmol). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.92 (1H,
d, J = 8.8 Hz), 8.39 (1H, dd, J = 2.9, 8.8 Hz), 8.65
(1H, d, J = 2.9 Hz), 9.31 (1H, s); MS (EI) m / z: 284 M + . (Example 86) N- (2,1,3-benzothiadiazol-4-yl)-(2-chloro-5-nitrophenyl)
Carboxamide 4-amino-2,1,3-benzothiadiazole (Tokyo Kasei, 0.302 g, 2.0 mmol), DMA (5 m
L) and 2-chloro-5-nitrobenzoic acid chloride (0.528 g, 2.4 mmol) according to the method described in Example 2 to give the title compound (0.561).
g, yield 84%). 1 H-NMR (400MHz, CDCl 3 , TMS): δ (ppm) 7.70 (1H, t,
J = 8.8 Hz), 7.73 (1H, d, J = 8.8 Hz), 7.80 (1H, d, J =
8.8 Hz), 8.33 (1H, dd, J = 2.9, 8.8 Hz), 8.66 (1H,
d, J = 8.8 Hz), 8.76 (1H, d, J = 2.9 Hz), 9.39 (1H, b
r); MS (EI) m / z: 334 M + . Example 87 N- [4- [4- (tert-Butoxycarbonylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- [4- (tert-Butoxycarbonylamino) phenyl] Aniline (Synth. Commun., 1998, Volume 28,
p.963) (0.284g, 1.0mmol), DMA
(5 mL) as well as 2-chloro-5-nitrobenzoic acid chloride (0.264 g, 1.2 mmol),
According to the method described in Example 2, the title object compound (0.
335 g, yield 72%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.49 (9H,
s), 7.52-7.62 (4H, m), 7.65 (2H, d, J = 8.8 Hz), 7.7
7 (2H, d, J = 8.8 Hz), 7.90 (1H, d, J = 8.8 Hz), 8.35
(1H, dd, J = 2.2, 8.8 Hz), 8.49 (1H, d, J = 2.2 Hz),
9.43 (1H, s), 10.77 (1H, s); MS (EI) m / z: 467 (M + H) + . (Example 88) N- [4- (4-aminophenyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide monohydrochloride N- [4- [4- ( tert-
Butoxycarbonylamino) phenyl] phenyl]-
(2-Chloro-5-nitrophenyl) carboxamide (0.200 g, 0.427 mmol) was suspended in a 1N hydrogen chloride-1,4-dioxane solution (2 mL) and stirred for 1 week. The reaction solution was diluted with diethyl ether, the resulting solid was collected by filtration, and washed with 1,4-dioxane and diethyl ether. The obtained solid was dried under reduced pressure to give the title object compound (0.131 g, yield 76%). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.32 (2H,
d, J = 8.1 Hz), 7.70 (2H, d, J = 8.8 Hz), 7.73 (2H, d,
J = 8.1 Hz), 7.81 (2H, d, J = 8.8 Hz), 7.91 (1H, d, J
= 8.8 Hz), 8.36 (1H, dd, J = 2.9, 8.8 Hz), 8.49 (1H,
d, J = 2.9 Hz), 10.85 (1H, s); MS (EI) m / z: 367 (M-HCl) + . (Example 89) N- (6-chloropyridazin-2-yl)-(2-chloro-5-nitrophenyl) carboxamide 3-amino-6-chloropyridazine (Lancaster,
0.259 g, 2.0 mmol), DMA (5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.
The title compound (0.513 g, yield 82%) was obtained according to the method described in Example 2 using 528 g (2.4 mmol).
【0201】Rf 0.46 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.90 (1H,
d, J=8.8 Hz), 8.00 (1H, d, J=8.8 Hz), 8.36 (1H, d
d, J=2.9, 8.8 Hz), 8.50 (1H, d, J=8.8 Hz), 8.58 (1
H, d, J=2.9 Hz), 12.10 (1H, s);
MS(FAB) m/z: 313 (M + H)+。
(実施例90)N−[6−(4−フルオロベンジル)ベ
ンゾチアゾール−2−イル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド
6−(4−フルオロベンジル)−2−アミノベンゾチア
ゾール(Chem. Pharm.Bull.,1992年,第40巻,p.205
5)(0.258g、1.0mmol)、DMA(5m
L)ならびに2−クロロ−5−ニトロ安息香酸クロリド
(0.264g、1.2mmol)を使用して、実施例
2に記載した方法に従い、標記目的化合物(0.315
g、収率36%)を得た。R f 0.46 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.90 (1H,
d, J = 8.8 Hz), 8.00 (1H, d, J = 8.8 Hz), 8.36 (1H, d
d, J = 2.9, 8.8 Hz), 8.50 (1H, d, J = 8.8 Hz), 8.58 (1
H, d, J = 2.9 Hz), 12.10 (1H, s); MS (FAB) m / z: 313 (M + H) + . Example 90 N- [6- (4-Fluorobenzyl) benzothiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 6- (4-fluorobenzyl) -2-aminobenzothiazole ( Chem. Pharm.Bull., 1992, Volume 40, p.205
5) (0.258 g, 1.0 mmol), DMA (5 m
L) and 2-chloro-5-nitrobenzoic acid chloride (0.264 g, 1.2 mmol) according to the method described in Example 2 to give the title compound (0.315).
g, yield 36%).
【0202】Rf 0.45 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 4.07 (2H,
s), 7.12 (1H, d, J=8.8 Hz), 7.14 (1H, d, J=8.8 H
z), 7.30-7.36 (3H, m), 7.72 (1H, d, J=8.1 Hz), 7.9
2 (1H, d, J=8.8 Hz), 8.39 (1H, dd, J=2.9, 8.8 Hz),
8.64 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 442 (M + H)+。
(実施例91)N−[4−(6−アセトキシ−2,5,
7,8−テトラメチル−4−オキソクロマン−2−イル
メトキシ)フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
4−(6−アセトキシ−2,5,7,8−テトラメチル
−4−オキソクロマン−2−イルメトキシ)アニリン
(0.787g、2.0mmol)、DMA(5mL)
ならびに2−クロロ−5−ニトロ安息香酸クロリド
(0.528g、2.4mmol)を使用して、実施例
2に記載した方法に従い、粗製の標記目的化合物(1.
17g)を得た。得られた粗製の標記目的化合物(0.
612g)をメタノール(5mL)に懸濁させ、1.5
時間攪拌した。生じた固体を濾取して、メタノールで洗
浄し、減圧乾燥して、標記目的化合物(0.486g、
収率43%)を得た。R f 0.45 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 4.07 (2H,
s), 7.12 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 8.8 H
z), 7.30-7.36 (3H, m), 7.72 (1H, d, J = 8.1 Hz), 7.9
2 (1H, d, J = 8.8 Hz), 8.39 (1H, dd, J = 2.9, 8.8 Hz),
8.64 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 442 (M + H) + . (Example 91) N- [4- (6-acetoxy-2,5,
7,8-Tetramethyl-4-oxochroman-2-ylmethoxy) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (6-acetoxy-2,5,7,8-tetramethyl-4-oxochroman 2-ylmethoxy) aniline (0.787 g, 2.0 mmol), DMA (5 mL)
And 2-chloro-5-nitrobenzoic acid chloride (0.528 g, 2.4 mmol) according to the method described in Example 2 to give the crude title compound (1.
17 g) was obtained. The resulting crude title compound (0.
612 g) in methanol (5 mL) and
Stir for hours. The resulting solid was collected by filtration, washed with methanol, and dried under reduced pressure to give the title object compound (0.486 g,
Yield 43%) was obtained.
【0203】Rf 0.14 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3, TMS): δ(ppm) 1.52 (3H, s),
2.09 (3H, s), 2.13(3H, s), 2.36 (3H, s), 2.42 (3
H, s), 2.71 (d, 1H, J=16.0 Hz), 3.10 (d, 1H, J=16.
0 Hz), 4.03 (d, 1H, J=10.3 Hz), 4.14 (d, 1H, J=10.
3 Hz), 6.93 (2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8
Hz), 7.65 (1H, d, J=8.8 Hz), 7.79 (1H, br), 8.26
(1H, dd, J=2.9, 8.8 Hz), 8.62 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 567 (M + H)+。
(実施例92)N−[4−(6−ヒドロキシ−2,5,
7,8−テトラメチル−4−オキソクロマン−2−イル
メトキシ)フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
実施例91で製造したN−[4−(6−アセトキシ−
2,5,7,8−テトラメチル−4−オキソクロマン−
2−イルメトキシ)フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド(0.342g、0.6
03mmol)をメタノール(6mL)に懸濁させ、2
5wt%ナトリウムメトキシド−メタノール溶液を少量
加えて21時間攪拌した。反応液に酢酸を加えて、酢酸
エチルで希釈した。有機層を水及び飽和食塩水で洗浄
し、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得
られた残渣をシリカゲルカラムクロマトグラフィー(ヘ
キサン:酢酸エチル=1:1(v/v))にて精製し、減圧
乾燥して、標記目的化合物(0.153g、収率48
%)を得た。R f 0.14 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 , TMS): δ (ppm) 1.52 (3H, s),
2.09 (3H, s), 2.13 (3H, s), 2.36 (3H, s), 2.42 (3
H, s), 2.71 (d, 1H, J = 16.0 Hz), 3.10 (d, 1H, J = 16.
0 Hz), 4.03 (d, 1H, J = 10.3 Hz), 4.14 (d, 1H, J = 10.
3 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.53 (2H, d, J = 8.8
Hz), 7.65 (1H, d, J = 8.8 Hz), 7.79 (1H, br), 8.26
(1H, dd, J = 2.9, 8.8 Hz), 8.62 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 567 (M + H) + . (Example 92) N- [4- (6-hydroxy-2,5,
7,8-Tetramethyl-4-oxochroman-2-ylmethoxy) phenyl]-(2-chloro-5-nitrophenyl) carboxamide Prepared in Example 91 N- [4- (6-acetoxy-
2,5,7,8-tetramethyl-4-oxochroman-
2-ylmethoxy) phenyl]-(2-chloro-5-nitrophenyl) carboxamide (0.342 g, 0.6
03 mmol) in methanol (6 mL),
A small amount of 5 wt% sodium methoxide-methanol solution was added and stirred for 21 hours. Acetic acid was added to the reaction solution and diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 (v / v)) and dried under reduced pressure to give the title object compound (0.153 g, yield 48).
%) Was obtained.
【0204】Rf 0.48 (ヘキサン:酢酸エチル, 1:1, v/
v);1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.40 (3H,
s), 2.05 (3H,s), 2.15(3H,s), 2.44 (3H,s), 2.69 (d,
1H, J=16.1 Hz), 3.00 (d, 1H, J=16.1 Hz), 4.09 (d,
1H, J=10.3 Hz), 4.13 (d, 1H, J=10.3 Hz), 6.97 (2
H, d, J=8.8 Hz),7.60 (2H, d, J=8.8 Hz), 7.88 (1H,
d, J=8.8 Hz), 7.92 (1H, br), 8.33 (1H, dd, J=2.9,
8.8 Hz), 8.44 (1H, d, J=2.9 Hz), 10.57 (1H, s);
MS(FAB) m/z: 525 (M + H)+。
(実施例93)N−[4−[4−(メタンスルホニルア
ミノ)フェニル]フェニル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド
実施例88で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド・1塩酸塩(0.404g、1.0mm
ol)をDMA(5mL)に溶解し、トリエチルアミン
(0.279mL,2.0mmol)及びメタンスルホ
ニルクロリド(0.116mL、1.5mmol)を加
えて室温で5時間攪拌した。反応溶液に飽和重曹水(4
mL)、水(20mL)及び酢酸エチル(20mL)を加
え、生じた固形物を濾取し、水及びジイソプロピルエー
テルで洗浄し、減圧乾燥して、標記目的化合物(0.2
38g、53%)を得た。R f 0.48 (hexane: ethyl acetate, 1: 1, v /
v); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.40 (3H,
s), 2.05 (3H, s), 2.15 (3H, s), 2.44 (3H, s), 2.69 (d,
1H, J = 16.1 Hz), 3.00 (d, 1H, J = 16.1 Hz), 4.09 (d,
1H, J = 10.3 Hz), 4.13 (d, 1H, J = 10.3 Hz), 6.97 (2
H, d, J = 8.8 Hz), 7.60 (2H, d, J = 8.8 Hz), 7.88 (1H,
d, J = 8.8 Hz), 7.92 (1H, br), 8.33 (1H, dd, J = 2.9,
8.8 Hz), 8.44 (1H, d, J = 2.9 Hz), 10.57 (1H, s); MS (FAB) m / z: 525 (M + H) + . Example 93 N- [4- [4- (Methanesulfonylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 88. ) Phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide monohydrochloride (0.404g, 1.0mm
was dissolved in DMA (5 mL), triethylamine (0.279 mL, 2.0 mmol) and methanesulfonyl chloride (0.116 mL, 1.5 mmol) were added, and the mixture was stirred at room temperature for 5 hours. Saturated sodium hydrogen carbonate solution (4
mL), water (20 mL) and ethyl acetate (20 mL) were added, the resulting solid was collected by filtration, washed with water and diisopropyl ether, and dried under reduced pressure to give the title object compound (0.2
38 g, 53%) was obtained.
【0205】Rf 0.51 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 3.02 (3H,
s), 7.30 (2H, d, J=8.8 Hz), 7.66 (2H, d, J=8.8 H
z), 7.68 (2H, d, J=8.8 Hz), 7.79 (2H, d, J=8.8 H
z), 7.91 (1H, d, J=8.8 Hz), 8.35 (1H, dd, J=2.9,
8.8 Hz), 8.49 (1H, d, J=2.9 Hz), 9.83 (1H, s), 10.
80 (1H, s);
MS(FAB) m/z: 446 (M + H)+。
(実施例94)N−[4−[4−(4−トルエンスルホ
ニルアミノ)フェニル]フェニル]−(2−クロロ−5
−ニトロフェニル)カルボキサミド
実施例88で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド・1塩酸塩(0.404g、1.0mm
ol)をDMA(5mL)に溶解し、トリエチルアミン
(0.279mL,2.0mmol)及び4−トルエン
スルホニルクロリド(0.286g、1.5mmol)
を加えて室温で4.5時間攪拌した。反応溶液に飽和重
曹水(4mL)、水(20mL)及び酢酸エチル(20m
L)を加え、有機層を分離した。有機層を無水硫酸ナト
リウムで乾燥し、減圧下濃縮した。得られた固形物を濾
取し、水及びジイソプロピルエーテルで洗浄し、減圧乾
燥して、標記目的化合物(0.365g、70%)を得
た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.34 (3H,
s), 7.17 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 H
z), 7.55 (2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 H
z), 7.69 (2H, d, J=8.8 Hz), 7.75 (2H, d, J=8.8 H
z), 7.90 (1H, d, J=8.8 Hz), 8.35 (1H, dd, J=2.9,
8.8 Hz), 8.48 (1H, d, J=2.9 Hz), 10.34 (1H,s), 10.
77 (1H, s);
MS(FAB) m/z: 522 (M + H)+。
(実施例95)N−[4−[(ピリミジン−2−イル)
アミノスルホニル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド
スルファジアジン(アルドリッチ、0.250g、1.
0mmol)、DMA(9mL)ならびに2−クロロ−
5−ニトロ安息香酸クロリド(0.264g、1.2m
mol)を使用して、実施例2に記載した方法に従い、
標記目的化合物(0.208g、収率48%)を得た。R f 0.51 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 3.02 (3H,
s), 7.30 (2H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 H
z), 7.68 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 H
z), 7.91 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 2.9,
8.8 Hz), 8.49 (1H, d, J = 2.9 Hz), 9.83 (1H, s), 10.
80 (1H, s); MS (FAB) m / z: 446 (M + H) + . Example 94 N- [4- [4- (4-toluenesulfonylamino) phenyl] phenyl]-(2-chloro-5
-Nitrophenyl) carboxamide N- [4- (4-aminophenyl) phenyl]-(2-chloro-5-nitrophenyl) prepared in Example 88.
Carboxamide monohydrochloride (0.404g, 1.0mm
ol) in DMA (5 mL) and triethylamine (0.279 mL, 2.0 mmol) and 4-toluenesulfonyl chloride (0.286 g, 1.5 mmol).
Was added and the mixture was stirred at room temperature for 4.5 hours. Saturated aqueous sodium hydrogen carbonate (4 mL), water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution.
L) was added and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained solid was collected by filtration, washed with water and diisopropyl ether, and dried under reduced pressure to give the title object compound (0.365 g, 70%). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.34 (3H,
s), 7.17 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 H
z), 7.55 (2H, d, J = 8.8 Hz), 7.61 (2H, d, J = 8.8 H
z), 7.69 (2H, d, J = 8.8 Hz), 7.75 (2H, d, J = 8.8 H
z), 7.90 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 2.9,
8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 10.34 (1H, s), 10.
77 (1H, s); MS (FAB) m / z: 522 (M + H) + . Example 95 N- [4-[(pyrimidin-2-yl)
Aminosulfonyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide sulfadiazine (Aldrich, 0.250 g, 1.
0 mmol), DMA (9 mL) and 2-chloro-
5-Nitrobenzoic acid chloride (0.264g, 1.2m
mol) according to the method described in Example 2,
The title object compound (0.208 g, yield 48%) was obtained.
【0206】Rf 0.07 (ヘキサン:酢酸エチル=1:1(v/
v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.06 (1H,
t, J=5.1 Hz), 7.87 (2H, d, J=8.8 Hz), 7.90 (2H, d,
J=8.8 Hz), 8.01 (2H, d, J=8.8 Hz), 8.36 (1H, dd,
J=2.2, 8.8 Hz), 8.51 (2H, d, J=5.1 Hz), 8.52 (1H,
m), 11.09 (1H,br), 11.76 (1H, br);
MS(FAB) m/z: 434 (M + H)+。
(実施例96)N−[4−(チアゾール−2−イル)ア
ミノスルホニル]フェニル−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
4−[(チアゾ−ル−2−イル)アミノスルホニル]フ
ェニルアミン(メルク、0.510g、2.0mmo
l)、DMA(5mL)ならびに2−クロロ−5−ニト
ロ安息香酸クロリド(0.528g、2.4mmol)
を使用して、実施例2に記載した方法に従い、標記目的
化合物(0.843g、収率97%)を得た。R f 0.07 (hexane: ethyl acetate = 1: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.06 (1H,
t, J = 5.1 Hz), 7.87 (2H, d, J = 8.8 Hz), 7.90 (2H, d,
J = 8.8 Hz), 8.01 (2H, d, J = 8.8 Hz), 8.36 (1H, dd,
J = 2.2, 8.8 Hz), 8.51 (2H, d, J = 5.1 Hz), 8.52 (1H,
m), 11.09 (1H, br), 11.76 (1H, br); MS (FAB) m / z: 434 (M + H) + . Example 96 N- [4- (thiazol-2-yl) aminosulfonyl] phenyl- (2-chloro-5-nitrophenyl) carboxamide 4-[(thiazol-2-yl) aminosulfonyl] phenylamine (Merck, 0.510g, 2.0mmo
l), DMA (5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.528 g, 2.4 mmol).
Was used according to the method described in Example 2 to give the title object compound (0.843 g, yield 97%).
【0207】Rf 0.58 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 6.84 (1H,
d, J=4.4 Hz), 7.26 (1H, d, J=4.4 Hz), 7.84 (4H,
m), 7.90 (1H, d, J=8.8 Hz), 8.35 (1H, dd, J=2.9,
8.8 Hz), 8.51 (1H, d, J=2.9 Hz), 11.04 (1H, s);
MS(FAB) m/z: 439 (M + H)+。
(実施例97)N−[4−(4,5−ジメチルオキサゾ
ール−2−イル)アミノスルホニル]フェニル−(2−
クロロ−5−ニトロフェニル)カルボキサミド
4−[(4,5−ジメチルオキサゾル−2−イル)アミ
ノスルホニル]アニリン(シグマ、0.534g、2.
0mmol)、DMA(5mL)ならびに2−クロロ−
5−ニトロ安息香酸クロリド(0.528g、2.4m
mol)を使用して、実施例2に記載した方法に従い、
標記目的化合物(0.763g、収率85%)を得た。R f 0.58 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 6.84 (1H,
d, J = 4.4 Hz), 7.26 (1H, d, J = 4.4 Hz), 7.84 (4H,
m), 7.90 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 2.9,
8.8 Hz), 8.51 (1H, d, J = 2.9 Hz), 11.04 (1H, s); MS (FAB) m / z: 439 (M + H) + . Example 97 N- [4- (4,5-Dimethyloxazol-2-yl) aminosulfonyl] phenyl- (2-
Chloro-5-nitrophenyl) carboxamide 4-[(4,5-dimethyloxazol-2-yl) aminosulfonyl] aniline (Sigma, 0.534 g, 2.
0 mmol), DMA (5 mL) and 2-chloro-
5-Nitrobenzoic acid chloride (0.528 g, 2.4 m
mol) according to the method described in Example 2,
The title object compound (0.763 g, yield 85%) was obtained.
【0208】Rf 0.68 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.95 (3H,
s), 2.06 (3H, s), 7.83 (2H, d, J=8.8 Hz), 7.87 (2
H, d, J=8.8 Hz), 7.91 (1H, d, J=8.8 Hz), 8.36 (1H,
dd, J=2.9, 8.8 Hz), 8.52 (1H, d, J=2.9 Hz), 11.02
(1H, s), 11.78(1H, s);
MS(FAB) m/z: 451 (M + H)+。
(実施例98)N−[[4−(2,6−ジメチルピリミ
ジン−4−イル)アミノスルホニル]フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド
スルフィソミジン(和光純薬、0.278g、1.0m
mol)、DMA(2.5mL)ならびに2−クロロ−
5−ニトロ安息香酸クロリド(0.264g、1.2m
mol)を使用して、実施例2に記載した方法に従い、
標記目的化合物(0.054g、収率12%)を得た。R f 0.68 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.95 (3H,
s), 2.06 (3H, s), 7.83 (2H, d, J = 8.8 Hz), 7.87 (2
H, d, J = 8.8 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.36 (1H,
dd, J = 2.9, 8.8 Hz), 8.52 (1H, d, J = 2.9 Hz), 11.02
(1H, s), 11.78 (1H, s); MS (FAB) m / z: 451 (M + H) + . Example 98 N-[[4- (2,6-Dimethylpyrimidin-4-yl) aminosulfonyl] phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide sulfisomidine (Wako Pure Chemical, 0.278 g, 1.0 m
mol), DMA (2.5 mL) and 2-chloro-
5-Nitrobenzoic acid chloride (0.264g, 1.2m
mol) according to the method described in Example 2,
The title object compound (0.054 g, yield 12%) was obtained.
【0209】Rf 0.55 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.28 (3H,
s), 2.36 (3H, s), 7.82-7.94 (6H, m), 8.35 (1H, dd,
J=2.9, 8.8 Hz), 8.51 (1H, d, J=2.9 Hz), 11.03 (1
H, s);
MS(FAB) m/z: 462 (M + H)+。
(実施例99)N−[[(5−メチルイソキサゾール−
3−イル)アミノスルホニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
スルファメトキサゾール(東京化成、0.253g、
1.0mmol)、DMA(2.5mL)ならびに2−
クロロ−5−ニトロ安息香酸クロリド(0.264g、
1.2mmol)を使用して、実施例2に記載した方法
に従い、標記目的化合物(0.325g、収率74%)
を得た。R f 0.55 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.28 (3H,
s), 2.36 (3H, s), 7.82-7.94 (6H, m), 8.35 (1H, dd,
J = 2.9, 8.8 Hz), 8.51 (1H, d, J = 2.9 Hz), 11.03 (1
H, s); MS (FAB) m / z: 462 (M + H) + . (Example 99) N-[[(5-methylisoxazole-
3-yl) aminosulfonyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide sulfamethoxazole (Tokyo Kasei, 0.253 g,
1.0 mmol), DMA (2.5 mL) and 2-
Chloro-5-nitrobenzoic acid chloride (0.264 g,
1.2 mmol) and according to the method described in Example 2 to obtain the title compound (0.325 g, yield 74%).
Got
【0210】Rf 0.70 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.30 (3H,
s), 6.16 (1H, s), 7.85-7.92 (5H, m), 7.91 (1H, d,
J=8.8 Hz), 8.36 (1H, dd, J=2.9, 8.8 Hz), 8.53 (1H,
d, J=2.9 Hz), 11.14 (1H, s), 11.40 (1H, s);
MS(FAB) m/z: 437 (M + H)+。
(実施例100)N−[4−[(ピリジン−2−イル)
アミノスルホニル]フェニル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド
スルファピリジン(東京化成、0.278g、1.0m
mol)、DMA(2.5mL)ならびに2−クロロ−
5−ニトロ安息香酸クロリド(0.264g、1.2m
mol)を使用して、実施例2に記載した方法に従い、
標記目的化合物(0.408g、収率94%)を得た。R f 0.70 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.30 (3H,
s), 6.16 (1H, s), 7.85-7.92 (5H, m), 7.91 (1H, d,
J = 8.8 Hz), 8.36 (1H, dd, J = 2.9, 8.8 Hz), 8.53 (1H,
d, J = 2.9 Hz), 11.14 (1H, s), 11.40 (1H, s); MS (FAB) m / z: 437 (M + H) + . (Example 100) N- [4-[(pyridin-2-yl)
Aminosulfonyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide sulfapyridine (Tokyo Kasei, 0.278 g, 1.0 m
mol), DMA (2.5 mL) and 2-chloro-
5-Nitrobenzoic acid chloride (0.264g, 1.2m
mol) according to the method described in Example 2,
The title object compound (0.408 g, yield 94%) was obtained.
【0211】Rf 0.57 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 6.88 (1H,
m), 7.15 (1H, d, J=8.8 Hz), 7.72 (1H, ddd, J=1.5,
8.8, 8.8 Hz), 7.84 (2H, d, J=8.8 Hz), 7.90(2H, d,
J=8.8 Hz), 7.90 (1H, d, J=8.8 Hz), 8.03 (1H, m),
8.35 (1H, dd, J=2.9, 8.8 Hz), 8.51 (1H, d, J=2.9 H
z), 11.03 (1H, s);
MS(FAB) m/z: 433 (M + H)+。
(実施例101)N−[4−[(5−メチル−[1,3,
4]チアジアゾール−2−イル)アミノスルホニル]フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
スルファメチゾール(東京化成、0.270g、1.0
mmol)、DMA(2.5mL)ならびに2−クロロ
−5−ニトロ安息香酸クロリド(0.264g、1.2
mmol)を使用して、実施例2に記載した方法に従
い、標記目的化合物(0.060g、収率13%)を得
た。R f 0.57 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 6.88 (1H,
m), 7.15 (1H, d, J = 8.8 Hz), 7.72 (1H, ddd, J = 1.5,
8.8, 8.8 Hz), 7.84 (2H, d, J = 8.8 Hz), 7.90 (2H, d,
J = 8.8 Hz), 7.90 (1H, d, J = 8.8 Hz), 8.03 (1H, m),
8.35 (1H, dd, J = 2.9, 8.8 Hz), 8.51 (1H, d, J = 2.9 H
z), 11.03 (1H, s); MS (FAB) m / z: 433 (M + H) + . (Example 101) N- [4-[(5-methyl- [1,3,
4] Thiadiazol-2-yl) aminosulfonyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide sulfamethizole (Tokyo Kasei, 0.270 g, 1.0
mmol), DMA (2.5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.264 g, 1.2).
was used according to the method described in Example 2 to give the title object compound (0.060 g, yield 13%).
【0212】Rf 0.47 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.46 (3H,
s), 7.81 (2H, d, J=8.8Hz), 7.86 (2H, d, J=8.8 Hz),
7.91 (1H, d, J=8.8 Hz), 8.36 (1H, dd, J=2.9, 8.8
Hz), 8.51 (1H, d, J=2.9 Hz), 11.07 (1H, s);
MS(FAB) m/z: 454 (M + H)+。
(実施例102)N−[4−[(6−クロロピリダジン
−3−イル)アミノスルホニル]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド
スルファクロロピリダジン(シグマ、0.284g、
1.0mmol)、DMA(2.5mL)ならびに2−
クロロ−5−ニトロ安息香酸クロリド(0.264g、
1.2mmol)を使用して、実施例2に記載した方法
に従い、標記目的化合物(0.454g、収率97%)
を得た。R f 0.47 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.46 (3H,
s), 7.81 (2H, d, J = 8.8Hz), 7.86 (2H, d, J = 8.8 Hz),
7.91 (1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 2.9, 8.8
Hz), 8.51 (1H, d, J = 2.9 Hz), 11.07 (1H, s); MS (FAB) m / z: 454 (M + H) + . Example 102 N- [4-[(6-chloropyridazin-3-yl) aminosulfonyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide sulfachloropyridazine (Sigma, 0.284 g,
1.0 mmol), DMA (2.5 mL) and 2-
Chloro-5-nitrobenzoic acid chloride (0.264 g,
1.2 mmol) and according to the method described in Example 2 to obtain the title object compound (0.454 g, yield 97%).
Got
【0213】Rf 0.54 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.77-7.97
(7H, m, J=8.8 Hz), 8.36(1H, dd, J=2.9, 8.8 Hz), 8.
51 (1H, d, J=2.9 Hz), 11.11 (1H, s);
MS(FAB) m/z: 468 (M + H)+。
(実施例103)N−[4−[(1H−インダゾール−
6−イル)アミノスルホニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
6−スルファニルアミドインダゾール(アルドリッチ、
0.288g、1.0mmol)、DMA(2.5m
L)ならびに2−クロロ−5−ニトロ安息香酸クロリド
(0.264g、1.2mmol)を使用して、実施例
2に記載した方法に従い、標記目的化合物(0.454
g、収率97%)を得た。R f 0.54 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.77-7.97
(7H, m, J = 8.8 Hz), 8.36 (1H, dd, J = 2.9, 8.8 Hz), 8.
51 (1H, d, J = 2.9 Hz), 11.11 (1H, s); MS (FAB) m / z: 468 (M + H) + . (Example 103) N- [4-[(1H-indazole-
6-yl) aminosulfonyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide 6-sulfanilamide indazole (Aldrich,
0.288 g, 1.0 mmol), DMA (2.5 m
L) and 2-chloro-5-nitrobenzoic acid chloride (0.264 g, 1.2 mmol) according to the method described in Example 2 to give the title compound (0.454).
g, yield 97%).
【0214】Rf 0.71 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 6.90 (1H, d
d, J=2.2, 8.8 Hz), 7.27 (1H, d, J=2.2 Hz), 7.61 (1
H, d, J=8.8 Hz), 7.79 (2H, d, J=8.8 Hz), 7.82 (2H,
d, J=8.8 Hz), 7.88 (1H, d, J=8.8 Hz), 7.94 (1H,
s), 8.34 (1H, dd,J=2.9, 8.8 Hz), 8.50 (1H, d, J=2.
9 Hz), 10.38 (1H, s), 11.05 (1H, s);
MS(FAB) m/z: 472 (M + H)+。
(実施例104)N−[4−[(3,4−ジメチルイソ
キサゾール−6−イル)アミノスルホニル]フェニル]
−(2−クロロ−5−ニトロフェニル)カルボキサミド
スルファイソキサゾール(シグマ、0.267g、1.
0mmol)、DMA(2.5mL)ならびに2−クロ
ロ−5−ニトロ安息香酸クロリド(0.264g、1.
2mmol)を使用して、実施例2に記載した方法に従
い、標記目的化合物(0.364g、収率81%)を得
た。
Rf 0.41 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.68 (3H,
s), 2.10 (3H, s), 7.79 (2H, d, J=8.8 Hz), 7.91 (2
H, d, J=8.8 Hz), 7.91 (1H, d, J=8.8 Hz), 8.36 (1H,
dd, J=2.9, 8.8 Hz), 8.56 (1H, d, J=2.9 Hz), 11.15
(1H, s);
MS(FAB) m/z: 451 (M + H)+。
(実施例105)N−[4−[(5−メトキシピリミジ
ン−2−イル)アミノスルホニル]フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
スルファメテール(シグマ、0.280g、1.0mm
ol)、DMA(2.5mL)ならびに2−クロロ−5
−ニトロ安息香酸クロリド(0.264g、1.2mm
ol)を使用して、実施例2に記載した方法に従い、標
記目的化合物(0.377g、収率97%)を得た。R f 0.71 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 6.90 (1H, d
d, J = 2.2, 8.8 Hz), 7.27 (1H, d, J = 2.2 Hz), 7.61 (1
H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 7.82 (2H,
d, J = 8.8 Hz), 7.88 (1H, d, J = 8.8 Hz), 7.94 (1H,
s), 8.34 (1H, dd, J = 2.9, 8.8 Hz), 8.50 (1H, d, J = 2.
9 Hz), 10.38 (1H, s), 11.05 (1H, s); MS (FAB) m / z: 472 (M + H) + . (Example 104) N- [4-[(3,4-dimethylisoxazol-6-yl) aminosulfonyl] phenyl]
-(2-Chloro-5-nitrophenyl) carboxamide sulfisoxazole (Sigma, 0.267 g, 1.
0 mmol), DMA (2.5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.264 g, 1.
2 mmol) and according to the method described in Example 2 to obtain the title object compound (0.364 g, yield 81%). R f 0.41 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.68 (3H,
s), 2.10 (3H, s), 7.79 (2H, d, J = 8.8 Hz), 7.91 (2
H, d, J = 8.8 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.36 (1H,
dd, J = 2.9, 8.8 Hz), 8.56 (1H, d, J = 2.9 Hz), 11.15
(1H, s); MS (FAB) m / z: 451 (M + H) + . Example 105 N- [4-[(5-Methoxypyrimidin-2-yl) aminosulfonyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide sulfametate (Sigma, 0.280 g, 1. 0 mm
ol), DMA (2.5 mL) and 2-chloro-5
-Nitrobenzoic acid chloride (0.264g, 1.2mm
was used according to the method described in Example 2 to give the title object compound (0.377 g, yield 97%).
【0215】Rf 0.71 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 3.80 (3H,
s), 7.87 (2H, d, J=8.8Hz), 7.91 (1H, d, J=8.8 Hz),
7.98 (2H, d, J=8.8 Hz), 8.30 (2H, s), 8.36(1H, d
d, J=2.2, 8.8 Hz), 8.52 (1H, d, J=2.2 Hz), 11.09
(1H, s), 11.46 (1H, br);
MS(FAB) m/z: 464 (M + H)+。
(実施例106)N−[4−(アミジノアミノスルホニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド
スルファグアニジン(シグマ、0.214g、1.0m
mol)、DMA(2.5mL)ならびに2−クロロ−
5−ニトロ安息香酸クロリド(0.242g、1.1m
mol)を使用して、実施例2に記載した方法に従い、
標記目的化合物(0.280g、収率70%)を得た。R f 0.71 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 3.80 (3H,
s), 7.87 (2H, d, J = 8.8Hz), 7.91 (1H, d, J = 8.8 Hz),
7.98 (2H, d, J = 8.8 Hz), 8.30 (2H, s), 8.36 (1H, d
d, J = 2.2, 8.8 Hz), 8.52 (1H, d, J = 2.2 Hz), 11.09
(1H, s), 11.46 (1H, br); MS (FAB) m / z: 464 (M + H) + . Example 106 N- [4- (amidinoaminosulfonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide sulfaguanidine (Sigma, 0.214 g, 1.0 m)
mol), DMA (2.5 mL) and 2-chloro-
5-Nitrobenzoic acid chloride (0.242 g, 1.1 m
mol) according to the method described in Example 2,
The title object compound (0.280 g, yield 70%) was obtained.
【0216】Rf 0.24 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS):δ (ppm) 6.70 (4H, b
r), 7.77 (2H, d, J=8.8Hz), 7.81 (2H, d, J=8.8 Hz),
7.91 (1H, d, J=8.8 Hz), 8.36 (1H, dd, J=2.2, 8.8
Hz), 8.51 (1H, d, J=2.2 Hz), 10.98 (1H, s);
MS(FAB) m/z: 398 (M + H)+。
(実施例107)N−[4−(ブチルアミノカルボニル
アミノスルホニル)フェニル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド
1−ブチル−3−スルファニルイルウレア(アルドリッ
チ、0.271g、1.0mmol)、DMA(2.5
mL)ならびに2−クロロ−5−ニトロ安息香酸クロリ
ド(0.264g、1.2mmol)を使用して、実施
例2に記載した方法に従い、標記目的化合物(0.34
6g、収率76%)を得た。R f 0.24 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 6.70 (4H, b
r), 7.77 (2H, d, J = 8.8Hz), 7.81 (2H, d, J = 8.8 Hz),
7.91 (1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 2.2, 8.8
Hz), 8.51 (1H, d, J = 2.2 Hz), 10.98 (1H, s); MS (FAB) m / z: 398 (M + H) + . Example 107 N- [4- (Butylaminocarbonylaminosulfonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 1-Butyl-3-sulfanylylurea (Aldrich, 0.271 g, 1.0 mmol ), DMA (2.5
mL) and 2-chloro-5-nitrobenzoic acid chloride (0.264 g, 1.2 mmol) according to the method described in Example 2 to give the title object compound (0.34
6 g, yield 76%) was obtained.
【0217】Rf 0.24 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 0.82 (3H,
t, J=7.3 Hz), 1.18 (1H,m), 1.31 (1H, m), 2.94 (1H,
m), 6.44 (1H, m), 7.90-7.93 (5H, m), 8.36 (1H, d
d, J=2.8, 8.8 Hz), 8.54 (1H, d, J=2.8 Hz), 10.48
(1H, br), 11.12 (1H, s);
MS(FAB) m/z: 455 (M + H)+。
(実施例108)N−[4−[(2−フェニル−(2
H)−ピラゾール−3−イル)アミノスルホニル]フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
スルファフェナゾール(シグマ、0.314g、1.0
mmol)、DMA(2.5mL)ならびに2−クロロ
−5−ニトロ安息香酸クロリド(0.264g、1.2
mmol)を使用して、実施例2に記載した方法に従
い、標記目的化合物(0.428g、収率86%)を得
た。R f 0.24 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 0.82 (3H,
t, J = 7.3 Hz), 1.18 (1H, m), 1.31 (1H, m), 2.94 (1H, m)
m), 6.44 (1H, m), 7.90-7.93 (5H, m), 8.36 (1H, d
d, J = 2.8, 8.8 Hz), 8.54 (1H, d, J = 2.8 Hz), 10.48
(1H, br), 11.12 (1H, s); MS (FAB) m / z: 455 (M + H) + . (Example 108) N- [4-[(2-phenyl- (2
H) -Pyrazol-3-yl) aminosulfonyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide sulfaphenazole (Sigma, 0.314 g, 1.0)
mmol), DMA (2.5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.264 g, 1.2).
was used according to the method described in Example 2 to give the title object compound (0.428 g, yield 86%).
【0218】Rf 0.63 (塩化メチレン:メタノール=7:1
(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 5.89 (1H,
d, J=1.8 Hz), 7.40 (1H,m), 7.48 (4H, m), 7.59 (1H,
d, J=1.8 Hz), 7.69 (2H, d, J=8.8 Hz), 7.85(2H, d,
J=8.8 Hz), 7.93 (1H, d, J=8.8 Hz), 8.37 (1H, dd,
J=2.9, 8.8 Hz),8.56 (1H, d, J=2.9 Hz), 11.13 (1H,
s);
MS(FAB) m/z: 498 (M + H)+。
(実施例109)N−(4−フェニル−5−テトラデシ
ルチアゾール−2−イル)−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
2−アミノ−4−フェニル−5−テトラデシルチアゾー
ル(アルドリッチ、0.373g、1.0mmol)、
DMA(2.5mL)ならびに2−クロロ−5−ニトロ
安息香酸クロリド(0.264g、1.2mmol)を
使用して、実施例2に記載した方法に従い、標記目的化
合物(0.311g、収率56%)を得た。R f 0.63 (methylene chloride: methanol = 7: 1
(v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 5.89 (1H,
d, J = 1.8 Hz), 7.40 (1H, m), 7.48 (4H, m), 7.59 (1H,
d, J = 1.8 Hz), 7.69 (2H, d, J = 8.8 Hz), 7.85 (2H, d,
J = 8.8 Hz), 7.93 (1H, d, J = 8.8 Hz), 8.37 (1H, dd,
J = 2.9, 8.8 Hz), 8.56 (1H, d, J = 2.9 Hz), 11.13 (1H,
s); MS (FAB) m / z: 498 (M + H) + . (Example 109) N- (4-phenyl-5-tetradecylthiazol-2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4-phenyl-5-tetradecylthiazole (Aldrich, 0.373 g, 1.0 mmol),
Following the method described in Example 2 using DMA (2.5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.264 g, 1.2 mmol), the title compound (0.311 g, yield) was obtained. 56%).
【0219】Rf 0.59 (ヘキサン:酢酸エチル=3:1(v/
v));1
H-NMR (400MHz, CDCl3, TMS): δ(ppm) 0.88 (3H, t,
J=7.3 Hz), 1.10-1.47 (10H, m), 1.71 (2H, m), 2.85
(2H, t, J=7.8 Hz), 7.16-7.28 (5H, m), 7.33 (1H, d,
J=8.6 Hz), 8.05 (1H, dd, J=2.7, 8.6 Hz), 8.07 (1
H, d, J=2.7 Hz);
MS(FAB) m/z: 566 (M + H)+。
(実施例110)N−(5−フェニル−1,3,4−チ
アジアゾール−2−イル)−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
2−アミノ−5−フェニル−1,3,4−チアジアゾー
ル・硫酸塩(アルドリッチ、0.177g、1.0mm
ol)、DMA(2.5mL)ならびに2−クロロ−5
−ニトロ安息香酸クロリド(0.264g、1.2mm
ol)を使用して、実施例2に記載した方法に従い、標
記目的化合物(0.141g、収率39%)を得た。R f 0.59 (hexane: ethyl acetate = 3: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 , TMS): δ (ppm) 0.88 (3H, t,
J = 7.3 Hz), 1.10-1.47 (10H, m), 1.71 (2H, m), 2.85
(2H, t, J = 7.8 Hz), 7.16-7.28 (5H, m), 7.33 (1H, d,
J = 8.6 Hz), 8.05 (1H, dd, J = 2.7, 8.6 Hz), 8.07 (1
H, d, J = 2.7 Hz); MS (FAB) m / z: 566 (M + H) + . (Example 110) N- (5-phenyl-1,3,4-thiadiazol-2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-5-phenyl-1,3,4- Thiadiazole / Sulfate (Aldrich, 0.177g, 1.0mm
ol), DMA (2.5 mL) and 2-chloro-5
-Nitrobenzoic acid chloride (0.264g, 1.2mm
was used according to the method described in Example 2 to give the title object compound (0.141 g, yield 39%).
【0220】Rf 0.59 (ヘキサン:酢酸エチル=3:1(v/
v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.56 (3H,
m), 7.93 (1H, d, J=8.8Hz), 8.01 (2H, m), 8.40 (1H,
dd, J=2.9, 8.8 Hz), 8.68 (1H, d, J=2.9 Hz);
MS(EI) m/z: 360 M+。
(実施例111)N−[4−(3,4−ジフルオロフェ
ニル)チアゾール−2−イル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド
2−アミノ−4−(3,4−ジフルオロフェニル)チア
ゾール(メイブリッジ、0.212g、1.0mmo
l)、DMA(2.5mL)ならびに2−クロロ−5−
ニトロ安息香酸クロリド(0.264g、1.2mmo
l)を使用して、実施例2に記載した方法に従い、標記
目的化合物(0.361g、収率91%)を得た。R f 0.59 (hexane: ethyl acetate = 3: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.56 (3H,
m), 7.93 (1H, d, J = 8.8Hz), 8.01 (2H, m), 8.40 (1H,
dd, J = 2.9, 8.8 Hz), 8.68 (1H, d, J = 2.9 Hz); MS (EI) m / z: 360 M + . Example 111 N- [4- (3,4-Difluorophenyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide 2-amino-4- (3,4-difluorophenyl) Thiazole (Maybridge, 0.212g, 1.0mmo
l), DMA (2.5 mL) and 2-chloro-5-
Nitrobenzoyl chloride (0.264g, 1.2mmo
The title compound (0.361 g, yield 91%) was obtained according to the method described in Example 2 using l).
【0221】Rf 0.43 (ヘキサン:酢酸エチル=3:1(v/
v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.52 (1H, d
dd, J=2.2, 8.8, 8.8 Hz), 7.79 (1H, m), 7.88 (1H,
s), 7.91 (1H, d, J=8.8 Hz), 7.94 (1H, ddd, J=2.2,
2.2, 8.8 Hz), 8.38 (1H, dd, J=2.9, 8.8 Hz), 8.61
(1H, d, J=2.9 Hz);
MS(EI) m/z: 395 M+。
(実施例112)N−[3−(2−メチルピリミジン−
4−イル)フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
4−(3−アミノフェニル)−2−メチルピリミジン
(メイブリッジ、0.185g、1.0mmol)、D
MA(2.5mL)ならびに2−クロロ−5−ニトロ安
息香酸クロリド(0.264g、1.2mmol)を使
用して、実施例2に記載した方法に従い、標記目的化合
物(0.198g、収率52%)を得た。R f 0.43 (hexane: ethyl acetate = 3: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.52 (1H, d
dd, J = 2.2, 8.8, 8.8 Hz), 7.79 (1H, m), 7.88 (1H,
s), 7.91 (1H, d, J = 8.8 Hz), 7.94 (1H, ddd, J = 2.2,
2.2, 8.8 Hz), 8.38 (1H, dd, J = 2.9, 8.8 Hz), 8.61
(1H, d, J = 2.9 Hz); MS (EI) m / z: 395 M + . (Example 112) N- [3- (2-methylpyrimidine-
4-yl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (3-aminophenyl) -2-methylpyrimidine (Maybridge, 0.185 g, 1.0 mmol), D
Following the method described in Example 2 using MA (2.5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.264 g, 1.2 mmol), the title object compound (0.198 g, yield) was obtained. 52%).
【0222】Rf 0.06 (ヘキサン:酢酸エチル=3:1(v/
v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.69 (3H,
s), 7.57 (1H, dd, J=8.1, 8.1 Hz), 7.84 (1H, d, J=
5.1 Hz), 7.90-7.96 (3H, m), 8.36 (1H, dd, J=2.9,
8.8 Hz), 8.53 (1H, d, J=2.9 Hz), 8.54 (1H, m), 8.7
8 (1H, d, J=5.9 Hz), 10.94 (1H, s);
MS(EI) m/z: 368 M+。
(実施例113)N−[4−(モルホリン−4−イル)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
N−(4−アミノフェニル)モルホリン(メイブリッ
ジ、0.179g、1.0mmol)、DMA(2.5
mL)ならびに2−クロロ−5−ニトロ安息香酸クロリ
ド(0.264g、1.2mmol)を使用して、実施
例2に記載した方法に従い、標記目的化合物(0.28
8g、収率80%)を得た。R f 0.06 (hexane: ethyl acetate = 3: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.69 (3H,
s), 7.57 (1H, dd, J = 8.1, 8.1 Hz), 7.84 (1H, d, J =
5.1 Hz), 7.90-7.96 (3H, m), 8.36 (1H, dd, J = 2.9,
8.8 Hz), 8.53 (1H, d, J = 2.9 Hz), 8.54 (1H, m), 8.7
8 (1H, d, J = 5.9 Hz), 10.94 (1H, s); MS (EI) m / z: 368 M + . (Example 113) N- [4- (morpholin-4-yl)
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) morpholine (Maybridge, 0.179 g, 1.0 mmol), DMA (2.5
mL) and 2-chloro-5-nitrobenzoic acid chloride (0.264 g, 1.2 mmol) according to the method described in Example 2 to give the title object compound (0.28
8 g, yield 80%) was obtained.
【0223】Rf 0.06 (ヘキサン:酢酸エチル=3:1(v/
v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 3.08 (4H,
t, J=4.8 Hz), 3.74 (4H,t, J=4.8 Hz), 6.96 (2H, d,
J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.88 (1H,d, J=
8.8 Hz), 8.32 (1H, dd, J=2.9, 8.8 Hz), 8.42 (1H,
d, J=2.9 Hz), 10.49 (1H, s);
MS(EI) m/z: 361 M+。
(実施例114)N−[4−(ピペリジン−1−イル)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
N−(4−アミノフェニル)ピペリジン(メイブリッ
ジ、0.176g、1.0mmol)、DMA(2.5
mL)ならびに2−クロロ−5−ニトロ安息香酸クロリ
ド(0.264g、1.2mmol)を使用して、実施
例2に記載した方法に従い、標記目的化合物(0.24
9g、収率69%)を得た。R f 0.06 (hexane: ethyl acetate = 3: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 3.08 (4H,
t, J = 4.8 Hz), 3.74 (4H, t, J = 4.8 Hz), 6.96 (2H, d,
J = 8.8 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.88 (1H, d, J =
8.8 Hz), 8.32 (1H, dd, J = 2.9, 8.8 Hz), 8.42 (1H,
d, J = 2.9 Hz), 10.49 (1H, s); MS (EI) m / z: 361 M + . (Example 114) N- [4- (piperidin-1-yl)
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) piperidine (Maybridge, 0.176 g, 1.0 mmol), DMA (2.5
mL) and 2-chloro-5-nitrobenzoic acid chloride (0.264 g, 1.2 mmol) according to the method described in Example 2 to give the title compound (0.24
9 g, yield 69%) was obtained.
【0224】Rf 0.06 (ヘキサン:酢酸エチル=3:1(v/
v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.55 (2H,
m), 1.62 (4H, m), 3.10(4H, t, J=5.6 Hz), 6.94 (2H,
d, J=9.1 Hz), 7.54 (2H, d, J=9.1 Hz), 7.88(1H, d,
J=8.8 Hz), 8.33 (1H, dd, J=2.8, 8.8 Hz), 8.41 (1
H, d, J=2.8 Hz),10.42 (1H, s);
MS(EI) m/z: 359 M+。
(実施例115)N−(4−エチルアミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩
実施例58で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩(0.583g、2.0mmol)をメタノー
ル(10mL)に懸濁させ、シアノ水素化ホウ素ナトリ
ウム(251mg、4.0mmol)及びアセトアルデ
ヒド(0.224mL、4.0mmol)を加えて、0
℃で30分間攪拌した。反応溶液に水(20mL)及び
飽和重曹水(1mL)を加え、生じた固形物を濾取し、
水で洗浄した後、酢酸エチルに溶解した。溶液を無水硫
酸ナトリウムで乾燥し、濃縮し、得られた残渣をシリカ
ゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル
=3:1−1:1(v/v))にて精製し、標記目的化合物
(0.263g、収率41%)を得た。
Rf 0.38 (ヘキサン:酢酸エチル=1:1(v/v));1
H-NMR (400MHz, CDCl3, TMS): δ(ppm) 1.27 (3H, t,
J=7.3 Hz), 3.17 (2H, q, J=7.3 Hz), 6.62 (2H, d, J=
8.8 Hz), 7.41 (2H, d, J=8.8 Hz), 7.64 (1H, d, J=8.
8 Hz), 7.66 (1H, br), 8.24 (1H, dd, J=2.2, 8.8 H
z), 8.60 (1H, d, J=2.2 Hz);
MS(FAB) m/z: 319 M+。
(実施例116)N−[4−(4−トルエンスルホニル
アミノ)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
実施例58で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩(0.291g、1.0mmol)、DMA
(5mL)、トリエチルアミン(0.209mL,1.
5mmol)及び4−トルエンスルホニルクロリド
(0.286g、1.5mmol)を使用して、実施例
36に記載した方法に従い、標記目的化合物(0.24
9g、収率29%)を得た。
Rf 0.64 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.35 (3H,
s), 7.08 (2H, d, J=8.8Hz), 7.35 (2H, d, J=8.8 Hz),
7.54 (2H, d, J=8.8 Hz), 7.63 (2H, d, J=8.8Hz), 7.
87 (1H, d, J=8.8 Hz), 8.32 (1H, dd, J=2.9, 8.8 H
z), 8.42 (1H, d,J=2.9 Hz), 10.14 (1H, s), 10.63 (1
H, s);
MS(FAB) m/z: 446 (M + H)+。
(実施例117)N−(4−アセチルアミノフェニル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例58で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩(0.291g、1.0mmol)、DMA
(3mL)及びアセチルクロリド(0.078mL、
1.1mmol)を使用して、実施例2に記載した方法
に従い、標記目的化合物(0.255g、収率76%)
を得た。
Rf 0.54 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.04 (3H,
s), 7.57 (2H, d, J=8.8Hz), 7.62 (2H, d, J=8.8 Hz),
7.89 (1H, d, J=8.8 Hz), 8.33 (1H, dd, J=2.9, 8.8
Hz), 8.44 (1H, d, J=2.9 Hz), 9.95 (1H, s), 10.63
(1H, s);
MS(FAB) m/z: 334 (M + H)+。
(実施例118)N−[4−(4−アセチルアミノフェ
ニル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
実施例88で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド・1塩酸塩(0.303g、0.75m
mol)、DMA(4mL)、トリエチルアミン(0.
627mL,4.5mmol)及びアセチルクロリド
(0.117mL、1.65mmol)を使用して、実
施例2に記載した方法に従い、標記目的化合物(0.2
63g、収率86%)を得た。
Rf 0.56 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.07 (3H,
s), 7.62 (2H, d, J=8.8Hz), 7.67 (2H, d, J=8.8 Hz),
7.67 (2H, d, J=8.8 Hz), 7.78 (2H, d, J=8.8Hz), 7.
91 (1H, d, J=8.8 Hz), 8.35 (1H, dd, J=2.9, 8.8 H
z), 8.49 (1H, d,J=2.9 Hz), 10.02 (1H, s), 10.78 (1
H, s);
MS(FAB) m/z: 410 (M + H)+。
(実施例119)N−(4−ベンゾイルアミノフェニ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
実施例58で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩(0.291g、1.0mmol)、DMA
(3mL)及びベンゾイルクロリド(0.128mL、
1.1mmol)を使用して、実施例2に記載した方法
に従い、標記目的化合物(0.317g、収率80%)
を得た。
Rf 0.67 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.50-7.63
(3H, m), 7.69 (2H, d, J=8.8 Hz), 7.79 (2H, d, J=8.
8 Hz), 7.90 (1H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8
Hz), 8.34 (1H, dd, J=2.9, 8.8 Hz), 8.47 (1H, d, J=
2.9 Hz), 10.28 (1H, s), 10.70 (1H, s);
MS(FAB) m/z: 396 (M + H)+。
(実施例120)N−[4−(4−ベンゾイルアミノフ
ェニル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
実施例88で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド・1塩酸塩(0.303g、0.75m
mol)、DMA(3mL)、トリエチルアミン(0.
314mL,2.25mmol)及びベンゾイルクロリ
ド(0.096mL、0.83mmol)を使用して、
実施例2に記載した方法に従い、標記目的化合物(0.
312g、収率88%)を得た。
Rf 0.73 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.52-7.62
(3H, m), 7.69 (4H, m),7.80 (2H, d, J=8.7 Hz), 7.90
(3H, m), 7.98 (2H, m), 8.36 (1H, dd, J=2.9,8.8 H
z), 8.49 (1H, d, J=2.9 Hz), 10.35 (1H, s), 10.80
(1H, s);
MS(FAB) m/z: 472 (M + H)+。
(実施例121)N−[4−(4−メチルベンゾイル)
アミノフェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
実施例58で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩(0.291g、1.0mmol)、DMA
(3mL)及び4−メチルベンゾイルクロリド(0.1
45mL、1.1mmol)を使用して、実施例2に記
載した方法に従い、標記目的化合物(0.302g、収
率74%)を得た。
Rf 0.55 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.40 (3H,
s), 7.34 (2H, d, J=8.1Hz), 7.68 (2H, d, J=8.8 Hz),
7.78 (2H, d, J=8.8 Hz), 7.89 (2H, d, J=8.1Hz), 7.
90 (1H, d, J=8.8 Hz), 8.34 (1H, dd, J=2.9, 8.8 H
z), 8.47 (1H, d,J=2.9 Hz), 10.19 (1H, s), 10.69 (1
H, s);
MS(FAB) m/z: 410 (M + H)+。
(実施例122)N−[4−(4−メチルベンゾイルア
ミノ)フェニル]フェニル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド
実施例88で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド・1塩酸塩(0.303g、0.75m
mol)、DMA(3mL)、トリエチルアミン(0.
314mL,2.25mmol)及び4−メチルベンゾ
イルクロリド(0.109mL、0.83mmol)を
使用して、実施例2に記載した方法に従い、標記目的化
合物(0.309g、収率85%)を得た。
Rf 0.72 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.40 (3H,
s), 7.35 (2H, d, J=8.8Hz), 7.68 (2H, d, J=8.8 Hz),
7.71 (2H, d, J=8.8 Hz), 7.80 (2H, d, J=8.8Hz), 7.
87-7.93 (5H, m), 8.36 (1H, dd, J=2.9, 8.8 Hz), 8.4
9 (1H, d, J=2.9Hz), 10.25 (1H, s), 10.79 (1H, s);
MS(FAB) m/z: 468 (M + H)+。
(実施例123)N−[4−(ピリジン−3−イルカル
ボニルアミノ)フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
実施例58で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩(0.291g、1.0mmol)、DMA
(3mL)及びニコチノイルクロリド・塩酸塩(0.3
36g、1.9mmol)を使用して、実施例2に記載
した方法に従い、標記目的化合物(0.149g、収率
38%)を得た。
Rf 0.29 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.58 (1H, d
d, J=2.9, 8.0 Hz), 7.71 (2H, d, J=8.8 Hz), 7.78 (2
H, d, J=8.8 Hz), 7.90 (1H, d, J=8.8 Hz), 8.31 (1H,
ddd, J= 1.5, 2.2, 8.0 Hz), 8.35 (1H, dd, J=2.9,
8.8 Hz), 8.48 (1H, d, J=2.9 Hz), 8.77 (1H, dd, J=
1.5, 5.1 Hz), 9.12 (1H, d, J=2.2 Hz), 10.48 (1H,
s), 10.73 (1H, s);
MS(EI) m/z: 396 M+。
(実施例124)N−[4−[4−(ピリジン−3−イ
ルカルボニルアミノ)フェニル]フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
実施例88で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド・1塩酸塩(0.303g、0.75m
mol)、DMA(3mL)、トリエチルアミン(0.
314mL,2.25mmol)及びニコチノイルクロ
リド・塩酸塩(0.294g、1.65mmol)を使
用して、実施例2に記載した方法に従い、標記目的化合
物(0.263g、収率74%)を得た。
Rf 0.55 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.59 (1H, d
d, J=2.9, 7.3 Hz), 7.70-7.74 (4H, m), 7.80 (2H, d,
J=8.8 Hz), 7.89 (2H, d, J=8.8 Hz), 7.91 (1H, d, J
=8.8 Hz), 8.32 (1H, ddd, J= 2.2, 2.2, 8.1 Hz), 8.3
6 (1H, dd, J=2.9, 8.8 Hz), 8.50 (1H, d, J=2.9 Hz),
8.78 (1H, m), 9.14 (1H, d, J=1.5 Hz),10.54 (1H,
s), 10.81 (1H, s);
MS(EI) m/z: 472 (M + H)+。
(実施例125)N−[4−(ピリジン−4−イルカル
ボニルアミノ)フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
実施例58で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩(0.291g、1.0mmol)、DMA
(3mL)及びイソニコチノイルクロリド・塩酸塩
(0.356g、2.0mmol)を使用して、実施例
2に記載した方法に従い、標記目的化合物(0.216
g、収率59%)を得た。
Rf 0.48 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.71 (2H,
d, J=8.8 Hz), 7.79 (2H,d, J=8.8 Hz), 7.88 (2H, d,
J=5.9 Hz), 7.90 (1H, d, J=8.8 Hz), 8.34 (1H,dd, J=
2.9, 8.8 Hz), 8.48 (1H, d, J=2.9 Hz), 8.79 (1H, d,
J=5.9 Hz), 10.55 (1H, s), 10.74 (1H, s);
MS(EI) m/z: 396 M+。
(実施例126)N−[4−[4−(ピリジン−4−イ
ルカルボニルアミノ)フェニル]フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
実施例88で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド・1塩酸塩(0.303g、0.75m
mol)、DMA(3mL)、トリエチルアミン(0.
314mL,2.25mmol)及びイソニコチノイル
クロリド・塩酸塩(0.267g、1.5mmol)を
使用して、実施例2に記載した方法に従い、標記目的化
合物(0.256g、収率72%)を得た。
Rf 0.53 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.70-7.74
(4H, m), 7.81 (2H, d, J=8.8 Hz), 7.87-7.93 (5H,
m), 8.36 (1H, dd, J=2.9, 8.8 Hz), 8.50 (1H, d,J=2.
9 Hz), 8.81 (2H, d, J=6.6 Hz), 10.60 (1H, s), 10.8
1 (1H, s);
MS(EI) m/z: 472 M+。
(実施例127)N−(4−ベンゼンスルホニルアミノ
フェニル)−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
実施例58で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩(0.291g、1.0mmol)、DMA
(3mL)、トリエチルアミン(0.279mL、2.
0mmol)及びベンゼンスルホニルクロリド(0.1
53mL、1.2mmol)を使用して、実施例2に記
載した方法に従い、標記目的化合物(0.139g、収
率32%)を得た。
Rf 0.68 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.09 (2H,
d, J=8.8 Hz), 7.53-7.62(5H, m), 7.75 (2H, d, J=7.3
Hz), 7.87 (1H, d, J=8.8 Hz), 8.32 (1H, dd,J=2.9,
8.8 Hz), 8.42 (1H, d, J=2.9 Hz), 10.21 (1H, s), 1
0.64 (1H, s);
MS(FAB) m/z: 432 (M + H)+。
(実施例128)N−[4−(ベンゼンスルホニルアミ
ノフェニル)フェニル]−(2−クロロ−5−ニトロフ
ェニル)カルボキサミド
実施例88で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド・1塩酸塩(0.303g、0.75m
mol)、DMA(3mL)、トリエチルアミン(0.
209mL,1.5mmol)及びベンゼンスルホニル
クロリド(0.119mL、0.9mmol)を使用し
て、実施例2に記載した方法に従い、標記目的化合物
(0.308g、収率75%)を得た。
Rf 0.70 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ 7.18 (2H, d, J=
8.8 Hz), 7.53-7.95 (12H, m), 7.89 (1H, d, J=8.8 H
z), 8.35 (1H, dd, J=2.9, 8.8 Hz), 8.48 (1H, d,J=2.
9 Hz), 9.40 (1H, br), 10.76 (1H, s);
MS(FAB) m/z: 508 (M + H)+。
(実施例129)N−(4−エタンスルホニルアミノフ
ェニル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
実施例58で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩(0.291g、1.0mmol)をピリジン
(3mL)に溶解し、エタンスルホニルクロリド(0.
153mL、1.2mmol)を加えて室温で6時間攪
拌した。反応溶液に飽和重曹水(3mL)、水(20m
L)及び酢酸エチル(1mL)を加え、生じた固形物を
濾取し、水及びジイソプロピルエーテルで洗浄し、減圧
乾燥して、標記目的化合物(0.254g、収率66
%)を得た。
Rf 0.34 (塩化メチレン:メタノール=20:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.20 (3H,
t, J=7.3 Hz), 3.06 (2H,q, J=7.3 Hz), 7.23 (2H, d,
J=8.8 Hz), 7.65 (2H, d, J=8.8 Hz), 7.89 (1H,d, J=
8.8 Hz), 8.34 (1H, dd, J=2.9, 8.8 Hz), 8.45 (1H,
d, J=2.9 Hz), 9.73 (1H, s), 10.69 (1H, s);
MS(FAB) m/z: 384 (M + H)+。
(実施例130)N−[4−(4−エタンスルホニルア
ミノフェニル)フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
実施例88で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド・1塩酸塩(0.303g、0.75m
mol)、DMA(3mL)及びエタンスルホニルクロ
リド(0.085mL、0.90mmol)を使用し
て、実施例50に記載した方法に従い、標記目的化合物
(0.267g、収率77%)を得た。
Rf 0.32 (塩化メチレン:メタノール=20:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.21 (3H,
t, J=7.3 Hz), 3.12 (2H,q, J=7.3 Hz), 7.30 (2H, d,
J=8.8 Hz), 7.65 (2H, d, J=8.8 Hz), 7.67 (2H,d, J=
8.8 Hz), 7.79 (2H, d, J=8.8 Hz), 7.91 (1H, d, J=8.
8 Hz), 8.35 (1H,dd, J=2.9, 8.8 Hz), 8.49 (1H, d, J
=2.9 Hz), 9.88 (1H, s), 10.80 (1H, s);
MS(FAB) m/z: 460 (M + H)+。
(実施例131)N−(4−ジエチルアミノ−2−メチ
ルフェニル)−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド
2−アミノ−5−(ジエチルアミノ)トルエン・塩酸塩
(東京化成、0.429g、2.0mmol)、DMA
(5mL)、トリエチルアミン(0.335mL、2.
4mmol)ならびに2−クロロ−5−ニトロ安息香酸
クロリド(0.528g、2.4mmol)を使用し
て、実施例2に記載した方法に従い、標記目的化合物
(0.431g、収率60%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.09 (6H,
t, J=7.0 Hz), 2.22 (3H,s), 3.33 (4H, m), 6.53 (2H,
m), 7.17 (1H, d, J=8.8 Hz), 7.87 (1H, d, J=8.8 H
z), 8.32 (1H, dd, J=2.9, 8.8 Hz), 8.39 (1H, d, J=
2.9 Hz), 9.86 (1H,s);
MS(FAB) m/z: 361 M+。
(実施例132)N−[4−(4−tert−ブトキシ
カルボニルピペラジン−1−イル)フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド4−(4
−アミノフェニル)ピペラジン−1−カルボン酸 te
rt−ブチルエステル(Tetrahedron Lett., 2000年,
第41巻,p.385)(5.08g、18.3mmol)、
DMA(50mL)ならびに2−クロロ−5−ニトロ安
息香酸クロリド(4.84g、22.0mmol)を使
用して、実施例2に記載した方法に従い、標記目的化合
物(7.62g、収率90%)を得た。
Rf 0.56 (ヘキサン:酢酸エチル=1:1(v/v));1
H-NMR (400MHz, CDCl3, TMS): δ(ppm) 1.49 (9H, s),
3.13 (4H, t, J=5.1 Hz), 3.59 (4H, t, J=5.1 Hz),
6.94 (2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8 Hz), 7.
64 (1H, d, J=8.8 Hz), 7.86 (1H, br), 8.24 (1H, dd,
J=2.9, 8.8 Hz),8.59 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 460 M+。
(実施例133)N−[4−(ピペラジン−1−イル)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
実施例132で製造した、N−[4−(4−tert−
ブトキシカルボニルピペラジン−1−イル)フェニル]
−(2−クロロ−5−ニトロフェニル)カルボキサミド
(6.15g、13.3mmol)を2N塩化水素−
1,4−ジオキサン溶液(40mL)に懸濁させ、20
時間攪拌した。反応液をジエチルエーテルで希釈して、
固形物を濾取し、1,4−ジオキサン及びジエチルエー
テルで洗浄した。得られた固体を減圧乾燥して、標記目
的化合物(5.17g、収率90%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 3.23 (4H,
m), 3.37 (4H, m), 7.04(2H, d, J=8.8 Hz), 7.62 (2H,
d, J=8.8 Hz), 7.88 (1H, d, J=8.8 Hz), 8.33(1H, d
d, J=2.9, 8.8 Hz), 8.42 (1H, d, J=2.9 Hz), 9.40 (1
H, m), 10.62 (1H, s);
MS(FAB) m/z: 361 (M + H)+。
(実施例134)N−[4−(4−アセトキシフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド
(134a)4−(4−アセトキシフェニル)アニリン
4−(4−アセトキシフェニル)ニトロベンゼン(J. A
m. Chem. Soc., 1944年,第66巻,p.1245)(0.86
0g、3.34mmol)をエタノール(9mL)に溶
解し,5%パラジウム−カーボン(0.18g)を加
え、水素雰囲気下、室温で2時間攪拌した。触媒を濾去
した後、濾液を減圧下濃縮した。得られた残渣をシリカ
ゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル
=1:1(v/v))にて精製し、標記目的化合物(0.6
99g、収率92%)を得た。
Rf 0.11 (ヘキサン:酢酸エチル=3:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.32 (3H,
s), 3.73 (2H, br), 6.75(2H, d, J=8.6 Hz), 7.11 (2
H, d, J=8.7 Hz), 7.38 (2H, d, J=8.6 Hz), 7.52(2H,
d, J=8.7 Hz)。
(134b)N−[4−(4−アセトキシフェニル)フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
実施例134aで製造した4−(4−アセトキシフェニ
ル)アニリン(0.694g、3.05mmol)、D
MA(7mL)ならびに2−クロロ−5−ニトロ安息香
酸クロリド(0.873g、3.97mmol)を使用
して、実施例2に記載した方法に従い、標記目的化合物
(1.03g、収率82%)を得た。
Rf 0.16 (ヘキサン:酢酸エチル=2:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.30 (3H,
s), 7.22 (2H, d, J=8.8Hz), 7.71 (2H, d, J=8.8 Hz),
7.71 (2H, d, J=8.8 Hz), 7.81 (2H, d, J=8.8Hz), 7.
91 (1H, d, J=8.8 Hz), 8.36 (1H, dd, J=2.9, 8.8Hz),
8.49 (1H, d, J=2.9Hz), 10.82 (1H, s);
MS(FAB) m/z: 411 (M + H)+。
(実施例135)N−[4−(4−ヒドロキシフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド
実施例134で製造したN−[4−(4−アセトキシフ
ェニル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド(0.882g、2.14mmo
l)をメタノール(18mL)に懸濁させ、25wt%
ナトリウムメトキシド−メタノール溶液を少量加えて、
22時間攪拌した。反応溶液に酢酸を加えてpHを4に
して、生じた固形物を濾取した。得られた固形物をメタ
ノールで洗浄し、減圧乾燥して、粗製の標記目的化合物
(0.728g)を得た。得られた粗製の標記目的化合
物(0.728g)をエタノールに溶解し、3日間放置
した。生じた固体を濾去し、濾液を濃縮し、残渣を減圧
乾燥して、標記目的化合物(0.269g、収率34
%)を得た。
Rf 0.09 (ヘキサン:酢酸エチル=1:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 6.85 (2H,
d, J=8.8 Hz), 7.49 (2H,d, J=8.8 Hz), 7.60 (2H, d,
J=8.8 Hz), 7.75 (2H, d, J=8.8 Hz), 7.90 (1H,d, J=
8.8 Hz), 8.35 (1H, dd, J=2.9, 8.8Hz), 8.48 (1H, d,
J=2.9 Hz), 9.53(1H, s), 10.75 (1H, s);
MS(FAB) m/z: 369 (M + H)+。
(実施例136)N−(4−メタンスルホニルアミノフ
ェニル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
実施例58で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩(0.291g、1.0mmol)をDMA
(5mL)に溶解し、トリエチルアミン(0.209m
L,1.5mmol)及びメタンスルホニルクロリド
(0.116mL、1.5mmol)を加えて室温で2
0時間攪拌した。反応溶液に飽和重曹水(1.5mL)
及び水(15mL)を加え、生じた固形物を濾取した。
得られた固体を水及びジイソプロピルエーテルで洗浄
し、減圧乾燥して、標記目的化合物(0.210g、5
7%)を得た。
Rf 0.64 (塩化メチレン:メタノール=7:1(v/v));1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.97 (3H,
s), 7.23 (2H, d, J=8.8Hz), 7.67 (2H, d, J=8.8 Hz),
7.89 (1H, d, J=8.8 Hz), 8.34 (1H, dd, J=2.9, 8.8
Hz), 8.45 (1H, d, J=2.9 Hz), 9.65 (1H, s), 10.71
(1H, s);
MS(FAB) m/z: 370 (M + H)+。
(実施例137)N−(4−n−ヘキシルアミノフェニ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
実施例58で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩(0.583g、2.0mmol)、メタノー
ル(10mL)、シアノ水素化ホウ素ナトリウム(13
8mg、1.1mmol)及びn−ヘキサナール(0.
288mL、2.4mmol)を使用して、実施例11
5に記載した方法に従い、高極性化合物として、標記目
的化合物(0.247g、収率33%)を得た。
Rf 0.56 (ヘキサン:酢酸エチル=1:1(v/v));1
H-NMR (400MHz, CDCl3, TMS): δ(ppm) 0.91 (3H, t,
J=7.3 Hz), 1.30-1.65(8H, m), 3.12 (2H, t, J=7.3 H
z), 6.62 (2H, d, J=6.6 Hz), 7.40 (2H, d, J=6.6 H
z), 7.64 (1H, d, J=8.8 Hz), 7.66 (1H, br), 8.24 (1
H, dd, J=2.2, 8.8 Hz), 8.60 (1H, d, J=2.2 Hz);
MS(FAB) m/z: 375 M+。
(実施例138)N−[4−(N、N−ジ−n−ヘキシ
ルアミノ)フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
実施例137において、低極性化合物として、標記目的
化合物(0.162g、収率18%)を得た。
Rf 0.79 (ヘキサン:酢酸エチル=1:1(v/v));1
H-NMR (400MHz, CDCl3, TMS): δ(ppm) 0.90 (6H, m),
1.26-1.38 (12H, m), 1.52-1.62 (4H, m), 3.26 (4H,
t, J=7.3 Hz), 6.63 (2H, d, J=9.2 Hz), 7.42 (2H, d,
J=9.2 Hz), 7.62 (1H, br), 7.63 (1H, d, J=8.8 Hz),
8.24 (1H, dd, J=2.9, 8.8 Hz), 8.60 (1H, d, J=2.9
Hz)。
(実施例139)N−[4−(3,5−ジ−tert−
ブチル−4−ヒドロキシフェニル)チアゾール−2−イ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
(139a)2−アミノ−5−(3,5−ジ−tert
−ブチル−4−ヒドロキシフェニル)チアゾール
1−(3,5−ジ−tert−ブチル−4−ヒドロキシ
フェニル)−2−ブロモエタン−1−オン(9.81
g、30mmol)をアセトン50mLに溶解し、チオ
ウレア(4.56g、60mmol)を加え、一晩攪拌
した。反応溶液を濃縮した後、飽和重曹水及びヘキサン
を加え攪拌した。析出した固体を濾取し、水洗した後、
乾燥して、標記目的化合物(8.92g、収率98%)
を得た。R f 0.06 (hexane: ethyl acetate = 3: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.55 (2H,
m), 1.62 (4H, m), 3.10 (4H, t, J = 5.6 Hz), 6.94 (2H,
d, J = 9.1 Hz), 7.54 (2H, d, J = 9.1 Hz), 7.88 (1H, d,
J = 8.8 Hz), 8.33 (1H, dd, J = 2.8, 8.8 Hz), 8.41 (1
H, d, J = 2.8 Hz), 10.42 (1H, s); MS (EI) m / z: 359 M + . (Example 115) N- (4-ethylaminophenyl)-
(2-chloro-5-nitrophenyl) carboxamide
Monohydrochloride N- (4-aminophenyl) -prepared in Example 58
(2-chloro-5-nitrophenyl) carboxamide
Monohydrochloride (0.583 g, 2.0 mmol) was suspended in methanol (10 mL), sodium cyanoborohydride (251 mg, 4.0 mmol) and acetaldehyde (0.224 mL, 4.0 mmol) were added and 0
The mixture was stirred at 0 ° C for 30 minutes. Water (20 mL) and saturated aqueous sodium hydrogen carbonate (1 mL) were added to the reaction solution, and the resulting solid matter was collected by filtration.
After washing with water, it was dissolved in ethyl acetate. The solution was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-1: 1 (v / v)) to give the title compound (0 .263 g, yield 41%) was obtained. R f 0.38 (hexane: ethyl acetate = 1: 1 (v / v)); 1 H-NMR (400MHz, CDCl 3 , TMS): δ (ppm) 1.27 (3H, t,
J = 7.3 Hz), 3.17 (2H, q, J = 7.3 Hz), 6.62 (2H, d, J =
8.8 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.64 (1H, d, J = 8.
8 Hz), 7.66 (1H, br), 8.24 (1H, dd, J = 2.2, 8.8 H
z), 8.60 (1H, d, J = 2.2 Hz); MS (FAB) m / z: 319 M + . Example 116 N- [4- (4-toluenesulfonylamino) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 58.
(2-chloro-5-nitrophenyl) carboxamide
Monohydrochloride (0.291 g, 1.0 mmol), DMA
(5 mL), triethylamine (0.209 mL, 1.
5 mmol) and 4-toluenesulfonyl chloride (0.286 g, 1.5 mmol) according to the method described in Example 36.
9 g, yield 29%) was obtained. R f 0.64 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.35 (3H,
s), 7.08 (2H, d, J = 8.8Hz), 7.35 (2H, d, J = 8.8 Hz),
7.54 (2H, d, J = 8.8 Hz), 7.63 (2H, d, J = 8.8Hz), 7.
87 (1H, d, J = 8.8 Hz), 8.32 (1H, dd, J = 2.9, 8.8 H
z), 8.42 (1H, d, J = 2.9 Hz), 10.14 (1H, s), 10.63 (1
H, s); MS (FAB) m / z: 446 (M + H) + . (Example 117) N- (4-acetylaminophenyl)
-(2-Chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 58
(2-chloro-5-nitrophenyl) carboxamide
Monohydrochloride (0.291 g, 1.0 mmol), DMA
(3 mL) and acetyl chloride (0.078 mL,
1.1 mmol) and according to the method described in Example 2 to give the title object compound (0.255 g, yield 76%).
Got R f 0.54 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.04 (3H,
s), 7.57 (2H, d, J = 8.8Hz), 7.62 (2H, d, J = 8.8 Hz),
7.89 (1H, d, J = 8.8 Hz), 8.33 (1H, dd, J = 2.9, 8.8
Hz), 8.44 (1H, d, J = 2.9 Hz), 9.95 (1H, s), 10.63
(1H, s); MS (FAB) m / z: 334 (M + H) + . Example 118 N- [4- (4-Acetylaminophenyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-Aminophenyl) phenyl] prepared in Example 88. -(2-chloro-5-nitrophenyl)
Carboxamide monohydrochloride (0.303g, 0.75m
mol), DMA (4 mL), triethylamine (0.
627 mL, 4.5 mmol) and acetyl chloride (0.117 mL, 1.65 mmol) according to the method described in Example 2 to give the title object compound (0.2
63 g, yield 86%) was obtained. R f 0.56 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.07 (3H,
s), 7.62 (2H, d, J = 8.8Hz), 7.67 (2H, d, J = 8.8 Hz),
7.67 (2H, d, J = 8.8 Hz), 7.78 (2H, d, J = 8.8 Hz), 7.
91 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 2.9, 8.8 H
z), 8.49 (1H, d, J = 2.9 Hz), 10.02 (1H, s), 10.78 (1
H, s); MS (FAB) m / z: 410 (M + H) + . Example 119 N- (4-benzoylaminophenyl)-(2-chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 58.
(2-chloro-5-nitrophenyl) carboxamide
Monohydrochloride (0.291 g, 1.0 mmol), DMA
(3 mL) and benzoyl chloride (0.128 mL,
1.1 mmol) and according to the method described in Example 2 to obtain the title object compound (0.317 g, yield 80%).
Got R f 0.67 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.50-7.63
(3H, m), 7.69 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.
8 Hz), 7.90 (1H, d, J = 8.8 Hz), 7.97 (2H, d, J = 8.8
Hz), 8.34 (1H, dd, J = 2.9, 8.8 Hz), 8.47 (1H, d, J =
2.9 Hz), 10.28 (1H, s), 10.70 (1H, s); MS (FAB) m / z: 396 (M + H) + . Example 120 N- [4- (4-benzoylaminophenyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-aminophenyl) phenyl] prepared in Example 88. -(2-chloro-5-nitrophenyl)
Carboxamide monohydrochloride (0.303g, 0.75m
mol), DMA (3 mL), triethylamine (0.
314 mL, 2.25 mmol) and benzoyl chloride (0.096 mL, 0.83 mmol),
According to the method described in Example 2, the title object compound (0.
(312 g, yield 88%) was obtained. R f 0.73 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.52-7.62
(3H, m), 7.69 (4H, m), 7.80 (2H, d, J = 8.7 Hz), 7.90
(3H, m), 7.98 (2H, m), 8.36 (1H, dd, J = 2.9,8.8 H
z), 8.49 (1H, d, J = 2.9 Hz), 10.35 (1H, s), 10.80
(1H, s); MS (FAB) m / z: 472 (M + H) + . (Example 121) N- [4- (4-methylbenzoyl)
Aminophenyl]-(2-chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 58
(2-chloro-5-nitrophenyl) carboxamide
Monohydrochloride (0.291 g, 1.0 mmol), DMA
(3 mL) and 4-methylbenzoyl chloride (0.1
The title compound (0.302 g, yield 74%) was obtained according to the method described in Example 2 using 45 mL (1.1 mmol). R f 0.55 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.40 (3H,
s), 7.34 (2H, d, J = 8.1Hz), 7.68 (2H, d, J = 8.8 Hz),
7.78 (2H, d, J = 8.8 Hz), 7.89 (2H, d, J = 8.1Hz), 7.
90 (1H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 2.9, 8.8 H
z), 8.47 (1H, d, J = 2.9 Hz), 10.19 (1H, s), 10.69 (1
H, s); MS (FAB) m / z: 410 (M + H) + . Example 122 N- [4- (4-methylbenzoylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 88. Phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide monohydrochloride (0.303g, 0.75m
mol), DMA (3 mL), triethylamine (0.
314 mL, 2.25 mmol) and 4-methylbenzoyl chloride (0.109 mL, 0.83 mmol) were used according to the method described in Example 2 to obtain the title object compound (0.309 g, yield 85%). It was R f 0.72 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.40 (3H,
s), 7.35 (2H, d, J = 8.8Hz), 7.68 (2H, d, J = 8.8 Hz),
7.71 (2H, d, J = 8.8Hz), 7.80 (2H, d, J = 8.8Hz), 7.
87-7.93 (5H, m), 8.36 (1H, dd, J = 2.9, 8.8 Hz), 8.4
9 (1H, d, J = 2.9Hz), 10.25 (1H, s), 10.79 (1H, s); MS (FAB) m / z: 468 (M + H) + . Example 123 N- [4- (pyridin-3-ylcarbonylamino) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 58.
(2-chloro-5-nitrophenyl) carboxamide
Monohydrochloride (0.291 g, 1.0 mmol), DMA
(3 mL) and nicotinoyl chloride hydrochloride (0.3 mL)
The title compound (0.149 g, yield 38%) was obtained according to the method described in Example 2 using 36 g, 1.9 mmol). R f 0.29 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.58 (1H, d
d, J = 2.9, 8.0 Hz), 7.71 (2H, d, J = 8.8 Hz), 7.78 (2
H, d, J = 8.8 Hz), 7.90 (1H, d, J = 8.8 Hz), 8.31 (1H,
ddd, J = 1.5, 2.2, 8.0 Hz), 8.35 (1H, dd, J = 2.9,
8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 8.77 (1H, dd, J =
1.5, 5.1 Hz), 9.12 (1H, d, J = 2.2 Hz), 10.48 (1H,
s), 10.73 (1H, s); MS (EI) m / z: 396 M + . Example 124 N- [4- [4- (Pyridin-3-ylcarbonylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (Prepared in Example 88 4-Aminophenyl) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide monohydrochloride (0.303g, 0.75m
mol), DMA (3 mL), triethylamine (0.
314 mL, 2.25 mmol) and nicotinoyl chloride hydrochloride (0.294 g, 1.65 mmol) according to the method described in Example 2 to give the title object compound (0.263 g, 74% yield). Obtained. R f 0.55 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.59 (1H, d
d, J = 2.9, 7.3 Hz), 7.70-7.74 (4H, m), 7.80 (2H, d,
J = 8.8 Hz), 7.89 (2H, d, J = 8.8 Hz), 7.91 (1H, d, J
= 8.8 Hz), 8.32 (1H, ddd, J = 2.2, 2.2, 8.1 Hz), 8.3
6 (1H, dd, J = 2.9, 8.8 Hz), 8.50 (1H, d, J = 2.9 Hz),
8.78 (1H, m), 9.14 (1H, d, J = 1.5 Hz), 10.54 (1H,
s), 10.81 (1H, s); MS (EI) m / z: 472 (M + H) + . Example 125 N- [4- (pyridin-4-ylcarbonylamino) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 58
(2-chloro-5-nitrophenyl) carboxamide
Monohydrochloride (0.291 g, 1.0 mmol), DMA
(3 mL) and isonicotinoyl chloride hydrochloride (0.356 g, 2.0 mmol) according to the method described in Example 2 to obtain the title compound (0.216).
g, yield 59%). R f 0.48 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.71 (2H,
d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 7.88 (2H, d,
J = 5.9 Hz), 7.90 (1H, d, J = 8.8 Hz), 8.34 (1H, dd, J =
2.9, 8.8 Hz), 8.48 (1H, d, J = 2.9 Hz), 8.79 (1H, d,
J = 5.9 Hz), 10.55 (1H, s), 10.74 (1H, s); MS (EI) m / z: 396 M + . Example 126 N- [4- [4- (Pyridin-4-ylcarbonylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (Prepared in Example 88 4-Aminophenyl) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide monohydrochloride (0.303g, 0.75m
mol), DMA (3 mL), triethylamine (0.
314 mL, 2.25 mmol) and isonicotinoyl chloride hydrochloride (0.267 g, 1.5 mmol) according to the method described in Example 2 to give the title object compound (0.256 g, yield 72%). Got R f 0.53 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.70-7.74
(4H, m), 7.81 (2H, d, J = 8.8 Hz), 7.87-7.93 (5H,
m), 8.36 (1H, dd, J = 2.9, 8.8 Hz), 8.50 (1H, d, J = 2.
9 Hz), 8.81 (2H, d, J = 6.6 Hz), 10.60 (1H, s), 10.8
1 (1H, s); MS (EI) m / z: 472 M + . Example 127 N- (4-benzenesulfonylaminophenyl)-(2-chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 58.
(2-chloro-5-nitrophenyl) carboxamide
Monohydrochloride (0.291 g, 1.0 mmol), DMA
(3 mL), triethylamine (0.279 mL, 2.
0 mmol) and benzenesulfonyl chloride (0.1
The title compound (0.139 g, yield 32%) was obtained according to the method described in Example 2 using 53 mL, 1.2 mmol). R f 0.68 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.09 (2H,
d, J = 8.8 Hz), 7.53-7.62 (5H, m), 7.75 (2H, d, J = 7.3
Hz), 7.87 (1H, d, J = 8.8 Hz), 8.32 (1H, dd, J = 2.9,
8.8 Hz), 8.42 (1H, d, J = 2.9 Hz), 10.21 (1H, s), 1
0.64 (1H, s); MS (FAB) m / z: 432 (M + H) + . Example 128 N- [4- (benzenesulfonylaminophenyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-aminophenyl) phenyl]-prepared in Example 88. (2-chloro-5-nitrophenyl)
Carboxamide monohydrochloride (0.303g, 0.75m
mol), DMA (3 mL), triethylamine (0.
209 mL, 1.5 mmol) and benzenesulfonyl chloride (0.119 mL, 0.9 mmol) were followed according to the method described in Example 2 to obtain the title object compound (0.308 g, yield 75%). R f 0.70 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ 7.18 (2H, d, J =
8.8 Hz), 7.53-7.95 (12H, m), 7.89 (1H, d, J = 8.8 H
z), 8.35 (1H, dd, J = 2.9, 8.8 Hz), 8.48 (1H, d, J = 2.
9 Hz), 9.40 (1H, br), 10.76 (1H, s); MS (FAB) m / z: 508 (M + H) + . Example 129 N- (4-ethanesulfonylaminophenyl)-(2-chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 58
(2-chloro-5-nitrophenyl) carboxamide
The monohydrochloride (0.291 g, 1.0 mmol) was dissolved in pyridine (3 mL) and ethanesulfonyl chloride (0.
(153 mL, 1.2 mmol) was added and the mixture was stirred at room temperature for 6 hours. Saturated sodium hydrogen carbonate solution (3 mL) and water (20 m
L) and ethyl acetate (1 mL) were added, the resulting solid was collected by filtration, washed with water and diisopropyl ether, and dried under reduced pressure to give the title object compound (0.254 g, yield 66).
%) Was obtained. R f 0.34 (methylene chloride: methanol = 20: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.20 (3H,
t, J = 7.3 Hz), 3.06 (2H, q, J = 7.3 Hz), 7.23 (2H, d,
J = 8.8 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.89 (1H, d, J =
8.8 Hz), 8.34 (1H, dd, J = 2.9, 8.8 Hz), 8.45 (1H,
d, J = 2.9 Hz), 9.73 (1H, s), 10.69 (1H, s); MS (FAB) m / z: 384 (M + H) + . Example 130 N- [4- (4-ethanesulfonylaminophenyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-aminophenyl) phenyl prepared in Example 88. ]-(2-Chloro-5-nitrophenyl)
Carboxamide monohydrochloride (0.303g, 0.75m
mol), DMA (3 mL) and ethanesulfonyl chloride (0.085 mL, 0.90 mmol) according to the method described in Example 50 to give the title object compound (0.267 g, yield 77%). . R f 0.32 (methylene chloride: methanol = 20: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.21 (3H,
t, J = 7.3 Hz), 3.12 (2H, q, J = 7.3 Hz), 7.30 (2H, d,
J = 8.8 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.67 (2H, d, J =
8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 7.91 (1H, d, J = 8.
8 Hz), 8.35 (1H, dd, J = 2.9, 8.8 Hz), 8.49 (1H, d, J
= 2.9 Hz), 9.88 (1H, s), 10.80 (1H, s); MS (FAB) m / z: 460 (M + H) + . (Example 131) N- (4-diethylamino-2-methylphenyl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-5- (diethylamino) toluene hydrochloride (Tokyo Kasei, 0.429 g, 2.0 mmol), DMA
(5 mL), triethylamine (0.335 mL, 2.
4 mmol) and 2-chloro-5-nitrobenzoic acid chloride (0.528 g, 2.4 mmol) according to the method described in Example 2 to give the title object compound (0.431 g, yield 60%). Obtained. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.09 (6H,
t, J = 7.0 Hz), 2.22 (3H, s), 3.33 (4H, m), 6.53 (2H,
m), 7.17 (1H, d, J = 8.8 Hz), 7.87 (1H, d, J = 8.8 H
z), 8.32 (1H, dd, J = 2.9, 8.8 Hz), 8.39 (1H, d, J =
2.9 Hz), 9.86 (1H, s); MS (FAB) m / z: 361 M + . Example 132 N- [4- (4-tert-Butoxycarbonylpiperazin-1-yl) phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide 4- (4
-Aminophenyl) piperazine-1-carboxylic acid te
rt-butyl ester (Tetrahedron Lett., 2000,
Volume 41, p.385) (5.08 g, 18.3 mmol),
Following the method described in Example 2 using DMA (50 mL) and 2-chloro-5-nitrobenzoic acid chloride (4.84 g, 22.0 mmol), the title object compound (7.62 g, yield 90%) was obtained. ) Got. R f 0.56 (hexane: ethyl acetate = 1: 1 (v / v)); 1 H-NMR (400MHz, CDCl 3 , TMS): δ (ppm) 1.49 (9H, s),
3.13 (4H, t, J = 5.1 Hz), 3.59 (4H, t, J = 5.1 Hz),
6.94 (2H, d, J = 8.8 Hz), 7.53 (2H, d, J = 8.8 Hz), 7.
64 (1H, d, J = 8.8 Hz), 7.86 (1H, br), 8.24 (1H, dd,
J = 2.9, 8.8 Hz), 8.59 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 460 M + . (Example 133) N- [4- (piperazin-1-yl)
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide prepared in Example 132, N- [4- (4-tert-
Butoxycarbonylpiperazin-1-yl) phenyl]
-(2-chloro-5-nitrophenyl) carboxamide (6.15 g, 13.3 mmol) in 2N hydrogen chloride-
Suspend in 1,4-dioxane solution (40 mL), 20
Stir for hours. Dilute the reaction solution with diethyl ether,
The solid was collected by filtration and washed with 1,4-dioxane and diethyl ether. The obtained solid was dried under reduced pressure to give the title object compound (5.17 g, yield 90%). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 3.23 (4H,
m), 3.37 (4H, m), 7.04 (2H, d, J = 8.8 Hz), 7.62 (2H,
d, J = 8.8 Hz), 7.88 (1H, d, J = 8.8 Hz), 8.33 (1H, d
d, J = 2.9, 8.8 Hz), 8.42 (1H, d, J = 2.9 Hz), 9.40 (1
H, m), 10.62 (1H, s); MS (FAB) m / z: 361 (M + H) + . Example 134 N- [4- (4-acetoxyphenyl) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (134a) 4- (4-acetoxyphenyl) aniline 4- (4-acetoxyphenyl) nitrobenzene (J.A.
m. Chem. Soc., 1944, Volume 66, p.1245) (0.86)
0 g, 3.34 mmol) was dissolved in ethanol (9 mL), 5% palladium-carbon (0.18 g) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 (v / v)) to give the title object compound (0.6
99g, yield 92%) was obtained. R f 0.11 (hexane: ethyl acetate = 3: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.32 (3H,
s), 3.73 (2H, br), 6.75 (2H, d, J = 8.6 Hz), 7.11 (2
H, d, J = 8.7 Hz), 7.38 (2H, d, J = 8.6 Hz), 7.52 (2H,
d, J = 8.7 Hz). (134b) N- [4- (4-acetoxyphenyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (4-acetoxyphenyl) aniline prepared in Example 134a (0.694 g, 3. 05 mmol), D
Following the method described in Example 2 using MA (7 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.873 g, 3.97 mmol), the title object compound (1.03 g, yield 82%) was obtained. ) Got. R f 0.16 (hexane: ethyl acetate = 2: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.30 (3H,
s), 7.22 (2H, d, J = 8.8Hz), 7.71 (2H, d, J = 8.8 Hz),
7.71 (2H, d, J = 8.8Hz), 7.81 (2H, d, J = 8.8Hz), 7.
91 (1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 2.9, 8.8 Hz),
8.49 (1H, d, J = 2.9Hz), 10.82 (1H, s); MS (FAB) m / z: 411 (M + H) + . (Example 135) N- [4- (4-hydroxyphenyl) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide N- [4- (4-acetoxyphenyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide prepared in Example 134 (0.882 g, 2.14 mmo).
l) is suspended in methanol (18 mL), and 25 wt%
Add a small amount of sodium methoxide-methanol solution,
It was stirred for 22 hours. Acetic acid was added to the reaction solution to adjust the pH to 4, and the resulting solid was collected by filtration. The obtained solid was washed with methanol and dried under reduced pressure to give a crude title compound (0.728 g). The obtained crude title compound (0.728 g) was dissolved in ethanol and left for 3 days. The generated solid was filtered off, the filtrate was concentrated, and the residue was dried under reduced pressure to give the title object compound (0.269 g, yield 34%).
%) Was obtained. R f 0.09 (hexane: ethyl acetate = 1: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 6.85 (2H,
d, J = 8.8 Hz), 7.49 (2H, d, J = 8.8 Hz), 7.60 (2H, d,
J = 8.8 Hz), 7.75 (2H, d, J = 8.8 Hz), 7.90 (1H, d, J =
8.8 Hz), 8.35 (1H, dd, J = 2.9, 8.8Hz), 8.48 (1H, d,
J = 2.9 Hz), 9.53 (1H, s), 10.75 (1H, s); MS (FAB) m / z: 369 (M + H) + . Example 136 N- (4-methanesulfonylaminophenyl)-(2-chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 58.
(2-chloro-5-nitrophenyl) carboxamide
DMAC of monohydrochloride (0.291 g, 1.0 mmol)
(5 mL), triethylamine (0.209 m
L, 1.5 mmol) and methanesulfonyl chloride (0.116 mL, 1.5 mmol) and added at room temperature to 2
Stir for 0 hours. Saturated sodium hydrogen carbonate solution (1.5 mL) in the reaction solution
And water (15 mL) were added, and the resulting solid was collected by filtration.
The obtained solid was washed with water and diisopropyl ether and dried under reduced pressure to give the title object compound (0.210 g, 5
7%). R f 0.64 (methylene chloride: methanol = 7: 1 (v / v)); 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.97 (3H,
s), 7.23 (2H, d, J = 8.8Hz), 7.67 (2H, d, J = 8.8 Hz),
7.89 (1H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 2.9, 8.8
Hz), 8.45 (1H, d, J = 2.9 Hz), 9.65 (1H, s), 10.71
(1H, s); MS (FAB) m / z: 370 (M + H) + . Example 137 N- (4-n-hexylaminophenyl)-(2-chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 58
(2-chloro-5-nitrophenyl) carboxamide
Monohydrochloride (0.583 g, 2.0 mmol), methanol (10 mL), sodium cyanoborohydride (13
8 mg, 1.1 mmol) and n-hexanal (0.
288 mL, 2.4 mmol) and used in Example 11
According to the method described in 5, the title object compound (0.247 g, yield 33%) was obtained as a highly polar compound. R f 0.56 (hexane: ethyl acetate = 1: 1 (v / v)); 1 H-NMR (400MHz, CDCl 3 , TMS): δ (ppm) 0.91 (3H, t,
J = 7.3 Hz), 1.30-1.65 (8H, m), 3.12 (2H, t, J = 7.3 H
z), 6.62 (2H, d, J = 6.6 Hz), 7.40 (2H, d, J = 6.6 H
z), 7.64 (1H, d, J = 8.8 Hz), 7.66 (1H, br), 8.24 (1
H, dd, J = 2.2, 8.8 Hz), 8.60 (1H, d, J = 2.2 Hz); MS (FAB) m / z: 375 M + . (Example 138) N- [4- (N, N-di-n-hexylamino) phenyl]-(2-chloro-5-nitrophenyl) carboxamide In Example 137, the title compound ( 0.162 g, yield 18%) was obtained. R f 0.79 (hexane: ethyl acetate = 1: 1 (v / v)); 1 H-NMR (400MHz, CDCl 3 , TMS): δ (ppm) 0.90 (6H, m),
1.26-1.38 (12H, m), 1.52-1.62 (4H, m), 3.26 (4H,
t, J = 7.3 Hz), 6.63 (2H, d, J = 9.2 Hz), 7.42 (2H, d,
J = 9.2 Hz), 7.62 (1H, br), 7.63 (1H, d, J = 8.8 Hz),
8.24 (1H, dd, J = 2.9, 8.8 Hz), 8.60 (1H, d, J = 2.9
Hz). (Example 139) N- [4- (3,5-di-tert-
Butyl-4-hydroxyphenyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide (139a) 2-amino-5- (3,5-di-tert.
-Butyl-4-hydroxyphenyl) thiazol 1- (3,5-di-tert-butyl-4-hydroxyphenyl) -2-bromoethan-1-one (9.81)
g, 30 mmol) was dissolved in 50 mL of acetone, thiourea (4.56 g, 60 mmol) was added, and the mixture was stirred overnight. The reaction solution was concentrated, saturated aqueous sodium hydrogen carbonate and hexane were added, and the mixture was stirred. The precipitated solid was collected by filtration and washed with water,
Dry to give the title compound (8.92 g, 98% yield).
Got
【0225】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
1.40 (9H, s), 6.71 (1H, s), 6.96 (2H, s), 6.97
(1H, s), 7.52 (2H, s)。
(139b)N−[4−(3,5−ジ−tert−ブチ
ル−4−ヒドロキシフェニル)チアゾール−2−イル]
−(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例139aで製造した2−アミノ−5−(3,5−
ジ−tert−ブチチル−4−ヒドロキシフェニル)チ
アゾール(0.32g、1.03mmol)、DMA
(5mL)ならびに2−クロロ−5−ニトロ安息香酸ク
ロリド(0.25g、1.13mmol)を使用して、
実施例2に記載した方法に従い、標記目的化合物(0.
446g、収率88%)を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
1.40 (9H, s), 6.71 (1H, s), 6.96 (2H, s), 6.97
(1H, s), 7.52 (2H, s). (139b) N- [4- (3,5-di-tert-butyl-4-hydroxyphenyl) thiazol-2-yl]
-(2-Chloro-5-nitrophenyl) carboxamide 2-amino-5- (3,5- prepared in Example 139a.
Di-tert-butytyl-4-hydroxyphenyl) thiazole (0.32 g, 1.03 mmol), DMA
(5 mL) as well as 2-chloro-5-nitrobenzoic acid chloride (0.25 g, 1.13 mmol),
According to the method described in Example 2, the title object compound (0.
446 g, yield 88%) was obtained.
【0226】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
1.42(9H, s), 7.11 (1H, s), 7.53 (1H, s) , 7.65
(1H, s) , 7.90 (1H, d, J=8.9 Hz) , 8.37 (1H, dd,
J=2.8, 8.9 Hz) , 8.59 (1H, d, J=2.8)。
(実施例140)N−(ピラジン−2−イル)−(2−
クロロ−5−ニトロフェニル)カルボキサミド
2−アミノピラジン(0.297g、3.13mmo
l)、DMA(5mL)ならびに2−クロロ−5−ニト
ロ安息香酸クロリド(0.833g、3.79mmo
l)を使用して、実施例1に記載した方法に従い反応を
行った。反応溶液に飽和重曹水(10mL)及び水(1
0mL)を加え、酢酸エチル(20mL)で抽出した。
有機層を飽和食塩水(10mL×2)で洗浄し、無水硫
酸ナトリウムで乾燥し、減圧下濃縮して、粗製の標記目
的化合物を得た。得られた粗製の標記目的化合物を、シ
リカゲルカラムクロマトグラフィー(塩化メチレン:酢
酸エチル=1:5(v/v))にて精製し、標記目的化合物
(0.27g)を得た。これをジイソプロピルエーテル
で固化させ、濾取し、乾燥して、標記目的化合物(0.
18g、収率21%)を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
1.42 (9H, s), 7.11 (1H, s), 7.53 (1H, s), 7.65
(1H, s), 7.90 (1H, d, J = 8.9 Hz), 8.37 (1H, dd,
J = 2.8, 8.9 Hz), 8.59 (1H, d, J = 2.8). (Example 140) N- (pyrazin-2-yl)-(2-
Chloro-5-nitrophenyl) carboxamide 2-aminopyrazine (0.297 g, 3.13 mmo
l), DMA (5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.833 g, 3.79 mmo).
The reaction was carried out according to the method described in Example 1 using 1). Saturated aqueous sodium hydrogen carbonate (10 mL) and water (1
0 mL) was added, and the mixture was extracted with ethyl acetate (20 mL).
The organic layer was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude title compound. The obtained crude title compound was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 1: 5 (v / v)) to obtain the title compound (0.27 g). This was solidified with diisopropyl ether, collected by filtration and dried to give the title object compound (0.
18 g, yield 21%) was obtained.
【0227】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
7.71 (1H, d, J=8.8 Hz), 8.31-8.35(2H, m), 8.47 (1
H, d, J=2.5 Hz), 8.62 (1H, bs), 8.68 (1H, d, J=2.7
Hz),9.68 (1H, bs)。
(実施例141)N−(6−メチルベンゾチアゾール−
2−イル)−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
2−アミノ−6−メチルベンゾチアゾール(0.30
g、1.80mmol)をDMA(5mL)に溶解し、
ジフェニルホスホリルアジド(DPPA)(0.44m
L、2.0mmol)、トリエチルアミン(0.28m
L、2.0mmol)及び2−クロロ−5−ニトロ安息
香酸(0.37g、1.82mmol)を加え、室温で
一晩攪拌した。実施例62に記載した方法と同様に処理
して、粗製の標記目的化合物を得た。得られた粗製の標
記目的化合物を、シリカゲルカラムクロマトグラフィー
(ヘキサン:酢酸エチル=5:1(v/v))にて精製し、
標記目的化合物(0.19g)を得た。これをジイソプ
ロピルエーテルで固化させ、濾取し、乾燥して、標記目
的化合物(0.14g、収率21%)を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
7.71 (1H, d, J = 8.8 Hz), 8.31-8.35 (2H, m), 8.47 (1
H, d, J = 2.5 Hz), 8.62 (1H, bs), 8.68 (1H, d, J = 2.7
Hz), 9.68 (1H, bs). (Example 141) N- (6-methylbenzothiazole-
2-yl)-(2-chloro-5-nitrophenyl) carboxamide 2-amino-6-methylbenzothiazole (0.30
g, 1.80 mmol) in DMA (5 mL),
Diphenylphosphoryl azide (DPPA) (0.44m
L, 2.0 mmol), triethylamine (0.28 m
L, 2.0 mmol) and 2-chloro-5-nitrobenzoic acid (0.37 g, 1.82 mmol) were added, and the mixture was stirred at room temperature overnight. Work up as in Example 62 to give the crude title compound. The resulting crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 (v / v)),
The title object compound (0.19 g) was obtained. This was solidified with diisopropyl ether, collected by filtration and dried to give the title object compound (0.14 g, yield 21%).
【0228】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
2.44 (3H, s), 7.30 (1H, d, J=8.3 Hz), 7.69 (1H,
d, J=8.3 Hz), 7.84 (1H, s), 7.92 (1H, d, J=8.9 H
z), 8.39 (1H, dd, J=2.8, 8.9 Hz), 8.64 (1H, d, J=
2.8 Hz)。
(実施例142)N−[3−(4−トリルアミノスルホ
ニル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
3−(4−トリルアミノスルホニル)アニリン(0.4
0g、1.52mmol)、DMA(5mL)ならびに
2−クロロ−5−ニトロ安息香酸クロリド(0.39
g)を使用して、実施例2に記載した方法に従い、標記
目的化合物(0.65g、収率96%)を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
2.44 (3H, s), 7.30 (1H, d, J = 8.3 Hz), 7.69 (1H,
d, J = 8.3 Hz), 7.84 (1H, s), 7.92 (1H, d, J = 8.9 H
z), 8.39 (1H, dd, J = 2.8, 8.9 Hz), 8.64 (1H, d, J =
2.8 Hz). Example 142 N- [3- (4-Tolylaminosulfonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 3- (4-Tolylaminosulfonyl) aniline (0.4
0 g, 1.52 mmol), DMA (5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.39
The title compound (0.65 g, yield 96%) was obtained according to the method described in Example 2 using g).
【0229】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
2.78 (3H, s), 6.62 (1H, s), 6.95(2H, d, J=8.4 Hz),
7.05 (2H, d, J=8.4 Hz), 7.43-7.50 (2H, m), 7.66
(1H,d, J=8.8 Hz), 7.94 (1H, s), 8.02-8.05 (1H, m),
8.26-8.30 (2H, m), 8.58 (1H, d, J=2.7 Hz)。
(実施例143)3−(2−クロロ−5−ニトロベンゾ
イルアミノ)安息香酸メチルエステル
N−[3−(メトキシカルボニル)フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド−3−ア
ミノ安息香酸メチルエステル(5.3g、35mmo
l)、DMA(50mL)ならびに2−クロロ−5−ニ
トロ安息香酸クロリド(8.49g)を使用して、実施
例2に記載した方法に従い、標記目的化合物(10.8
9g、収率93%)を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
2.78 (3H, s), 6.62 (1H, s), 6.95 (2H, d, J = 8.4 Hz),
7.05 (2H, d, J = 8.4 Hz), 7.43-7.50 (2H, m), 7.66
(1H, d, J = 8.8 Hz), 7.94 (1H, s), 8.02-8.05 (1H, m),
8.26-8.30 (2H, m), 8.58 (1H, d, J = 2.7 Hz). (Example 143) 3- (2-chloro-5-nitrobenzoylamino) benzoic acid methyl ester N- [3- (methoxycarbonyl) phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide-3-aminobenzoic acid methyl ester (5.3 g, 35 mmo
1), DMA (50 mL) and 2-chloro-5-nitrobenzoic acid chloride (8.49 g) according to the method described in Example 2 to give the title compound (10.8).
9 g, yield 93%) was obtained.
【0230】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
3.94 (3H, s), 7.51 (1H, t, J=7.9Hz), 7.68 (1H, d,
J=8.8 Hz), 7.89 (1H, d, J=7.9 Hz), 8.04 (1H, d, J=
8.8Hz), 8.15 (1H, bs), 8.29 (1H, dd, J=8.8, 2.7 H
z), 8.64 (1H, d, J=2.7 Hz)。
(実施例144)N−[4−(4−トリルアミノスルホ
ニル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
4−(4−トリルアミノスルホニル)アニリン(0.2
63g、1.00mmol)、DMA(5mL)ならび
に2−クロロ−5−ニトロ安息香酸クロリド(0.24
3g)を使用して、実施例2に記載した方法に従い、標
記目的化合物(0.375g、収率84%)を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
3.94 (3H, s), 7.51 (1H, t, J = 7.9Hz), 7.68 (1H, d,
J = 8.8 Hz), 7.89 (1H, d, J = 7.9 Hz), 8.04 (1H, d, J =
8.8Hz), 8.15 (1H, bs), 8.29 (1H, dd, J = 8.8, 2.7 H
z), 8.64 (1H, d, J = 2.7 Hz). Example 144 N- [4- (4-Tolylaminosulfonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (4-Tolylaminosulfonyl) aniline (0.2
63 g, 1.00 mmol), DMA (5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.24
The title compound (0.375 g, yield 84%) was obtained according to the method described in Example 2 using 3 g).
【0231】1H-NMR (400MHz, CDCl3, TMS): δ(ppm)
2.29 (3H, s), 6.36 (1H, s), 6.96(2H, d, J=8.3 Hz),
7.07 (2H, d, J=8.3 Hz), 7.67-7.70 (5H, m), 8.09
(1H,m), 8.30 (1H, dd, J=2.7, 8.8 Hz), 8.61 (1H, d,
J=2.7 Hz)。
(実施例145)3−(2−クロロ−5−ニトロベンゾ
イルアミノ)安息香酸
実施例143で製造した3−(2−クロロ−5−ニトロ
ベンゾイルアミノ)安息香酸メチルエステル(10.3
2g、30.8mmol)を1,4−ジオキサン(10
0mL)に溶解し、1N水酸化ナトリウム水溶液(46
mL)を加え24時間攪拌した。反応溶液を濃縮した
後、氷水冷却下、1N塩酸(50mL)を攪拌下にて滴
加した。析出した結晶を濾取し、水洗し、乾燥して、標
記目的化合物(9.72g、収率98%)を得た。 1 H-NMR (400 MHz, CDCl 3 , TMS): δ (ppm)
2.29 (3H, s), 6.36 (1H, s), 6.96 (2H, d, J = 8.3 Hz),
7.07 (2H, d, J = 8.3 Hz), 7.67-7.70 (5H, m), 8.09
(1H, m), 8.30 (1H, dd, J = 2.7, 8.8 Hz), 8.61 (1H, d,
J = 2.7 Hz). Example 145 3- (2-chloro-5-nitrobenzoylamino) benzoic acid 3- (2-chloro-5-nitrobenzoylamino) benzoic acid methyl ester prepared in Example 143 (10.3
2 g, 30.8 mmol) was added to 1,4-dioxane (10
0 mL) and dissolved in 1N aqueous sodium hydroxide solution (46
(mL) was added and stirred for 24 hours. After concentrating the reaction solution, 1N hydrochloric acid (50 mL) was added dropwise with stirring under cooling with ice water. The precipitated crystals were collected by filtration, washed with water, and dried to give the title object compound (9.72 g, yield 98%).
【0232】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.51 (1H, t, J=8.0 Hz), 7.71-7.74 (1H, m), 7.89
-7.92 (2H, m), 8.33-8.42 (2H, m), 8.52 (1H, d, J
=2.7Hz), 10.90 (1H, s)。
(実施例146)N−(ピリジン−4−イル)−(2−
クロロ−5−ニトロフェニル)カルボキサミド・塩酸塩
4−アミノピリジン(0.421g)、DMA(10m
L)ならびに2−クロロ−5−ニトロ安息香酸クロリド
(1.08g)を使用して、実施例1に記載した方法に
従い、0.788gのN−(ピリジン−4−イル)−
(2−クロロ−5−ニトロフェニル)カルボキサミドを
得た。得られたN−(ピリジン−4−イル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド(0.65
7g、2.37mmol)を、1.4−ジオキサン(1
0mL)に溶解し、4N塩化水素−1.4−ジオキサン
溶液を滴加し、1時間攪拌した。ジエチルエーテル(1
0mL)を加え、析出した結晶を濾取し、乾燥して、標
記目的化合物(0.73g、収率98%)を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.51 (1H, t, J = 8.0 Hz), 7.71-7.74 (1H, m), 7.89
-7.92 (2H, m), 8.33-8.42 (2H, m), 8.52 (1H, d, J
= 2.7Hz), 10.90 (1H, s). (Example 146) N- (pyridin-4-yl)-(2-
Chloro-5-nitrophenyl) carboxamide hydrochloride 4-aminopyridine (0.421 g), DMA (10 m
L) as well as 2-chloro-5-nitrobenzoic acid chloride (1.08 g) according to the method described in Example 1 0.788 g of N- (pyridin-4-yl)-
(2-Chloro-5-nitrophenyl) carboxamide was obtained. Obtained N- (pyridin-4-yl)-(2-chloro-5-nitrophenyl) carboxamide (0.65
7 g, 2.37 mmol) and 1.4-dioxane (1
0 mL), a 4N hydrogen chloride-1.4-dioxane solution was added dropwise, and the mixture was stirred for 1 hour. Diethyl ether (1
0 mL) was added, and the precipitated crystals were collected by filtration and dried to give the title object compound (0.73 g, yield 98%).
【0233】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.96 (1H, d, J=8.8 Hz), 8.20 (2H, d, J=7.0 Hz),
8.42 (1H, dd, J=2.8, 8.8 Hz), 8.68 (1H, d, J=2.8 H
z), 8.80 (2H, d, J=7.0 Hz), 12.25 (1H, s)。
(実施例147)N−[4−(ピリジン−2−イル)フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド・塩酸塩
4−[(ピリジン−2−イル)フェニル]アニリン・塩
酸塩0.320g、ピリジン5mL及び2−クロロ−5
−ニトロ安息香酸クロリド0.347gを使用して、実
施例68に記載した方法に従い、N−[4−(ピリジン
−2−イル)フェニル]−(2−クロロ−5−ニトロフ
ェニル)カルボキサミド(0.388g)を得た。得ら
れたN−[4−(ピリジン−2−イル)フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(0.522g、1.474mmol)、1,4−ジオ
キサン(10mL)及び4N塩化水素−1,4−ジオキ
サン(0.46mL)を使用して、実施例68に記載し
た方法に従い、標記目的化合物(0.57g、収率99
%)を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.96 (1H, d, J = 8.8 Hz), 8.20 (2H, d, J = 7.0 Hz),
8.42 (1H, dd, J = 2.8, 8.8 Hz), 8.68 (1H, d, J = 2.8 H
z), 8.80 (2H, d, J = 7.0 Hz), 12.25 (1H, s). (Example 147) N- [4- (pyridin-2-yl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide hydrochloride 4-[(pyridin-2-yl) phenyl] aniline hydrochloride 0.320 g, pyridine 5 mL and 2-chloro-5
According to the method described in Example 68, using 0.347 g of -nitrobenzoic acid chloride, N- [4- (pyridin-2-yl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide (0 .388 g) was obtained. Obtained N- [4- (pyridin-2-yl) phenyl]-
Performed using (2-chloro-5-nitrophenyl) carboxamide (0.522 g, 1.474 mmol), 1,4-dioxane (10 mL) and 4N hydrogen chloride-1,4-dioxane (0.46 mL). According to the method described in Example 68, the title object compound (0.57 g, yield 99
%) Was obtained.
【0234】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.6-7.73 (1H, m), 7.92 (2H, d,J=8.8 Hz), 7.93 (2
H, d, J=8.8), 8.16 (2H, d, J=8.8 Hz), 8.23-8.26 (1
H,m), 8.30-8.34 (1H, m), 8.37 (1H, dd, J=2.8, 8.
8 Hz), 8.53 (1H, d, J=2.8 Hz), 8.77-8.79 (1H, m),
11.09 (1H, s)。
(実施例148)N−[4−(ピリジン−3−イルアミ
ノカルボニル)フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
(148a)N−(4−エトキシカルボニルフェニル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
4−アミノ安息香酸エチルエステル(9.88g)、D
MA(50mL)ならびに2−クロロ−5−ニトロ安息
香酸クロリド(14.47g)を使用して、実施例2に
記載した方法に従い、標記目的化合物20.33gの結
晶を得た.1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.33 (1H,
t, J=7.1 Hz), 4.31 (2H, q, J=7.1 Hz), 7.85 (2H, d,
J=8.7 Hz), 7.91 (1H, d, J=8.8 Hz), 7.99 (2H, d, J
=8.7 Hz), 8.36 (1H, dd, J=8.9, 2.8 Hz), 8.53 (1H,
d, J=2.8 Hz), 11.05 (1H, s)。
(148b)4−[(2−クロロ−5−ニトロフェニ
ル)カルボニルアミノ]安息香酸
実施例148aで製造したN−(4−エトキシカルボニ
ルフェニル)−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド(19.55g)を1,4−ジオキサン
(100mL)に溶解し、1N−水酸化ナトリウム水溶
液(84mL)を加え、室温で3日間放置した。反応液
を減圧下濃縮した後、水(300mL)を加え、氷水冷
却下、1N−塩酸(90mL)を滴加し攪拌した。生じ
た結晶を濾取し、乾燥して、標記目的化合物(17.5
9g)を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.6-7.73 (1H, m), 7.92 (2H, d, J = 8.8 Hz), 7.93 (2
H, d, J = 8.8), 8.16 (2H, d, J = 8.8 Hz), 8.23-8.26 (1
H, m), 8.30-8.34 (1H, m), 8.37 (1H, dd, J = 2.8, 8.
8 Hz), 8.53 (1H, d, J = 2.8 Hz), 8.77-8.79 (1H, m),
11.09 (1H, s). Example 148 N- [4- (pyridin-3-ylaminocarbonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide (148a) N- (4-ethoxycarbonylphenyl)
-(2-Chloro-5-nitrophenyl) carboxamide 4-aminobenzoic acid ethyl ester (9.88 g), D
According to the method described in Example 2, using MA (50 mL) and 2-chloro-5-nitrobenzoic acid chloride (14.47 g), 20.33 g of the title target compound was obtained as crystals. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.33 (1H,
t, J = 7.1 Hz), 4.31 (2H, q, J = 7.1 Hz), 7.85 (2H, d,
J = 8.7 Hz), 7.91 (1H, d, J = 8.8 Hz), 7.99 (2H, d, J
= 8.7 Hz), 8.36 (1H, dd, J = 8.9, 2.8 Hz), 8.53 (1H,
d, J = 2.8 Hz), 11.05 (1H, s). (148b) 4-[(2-chloro-5-nitrophenyl) carbonylamino] benzoic acid N- (4-ethoxycarbonylphenyl)-(2-chloro-5-nitrophenyl) carboxamide (19 prepared in Example 148a. 0.55 g) was dissolved in 1,4-dioxane (100 mL), 1N-sodium hydroxide aqueous solution (84 mL) was added, and the mixture was left at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, water (300 mL) was added, and 1N-hydrochloric acid (90 mL) was added dropwise under ice-water cooling and the mixture was stirred. The crystals formed were collected by filtration and dried to give the title object compound (17.5
9 g) was obtained.
【0235】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.82 (2H, d, J=8.7 Hz), 7.91 (1H, d, J=8.8Hz), 7.
97 (2H, d, J=8.7 Hz), 8.36 (1H, dd, J=8.8, 2.8 H
z), 8.52 (1H, d, J=2.8 Hz),11.01 (1H, s)。
(148c) N−[4−(ピリジン−3−イルアミノカ
ルボニル)フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
実施例148bで製造した4−[(2−クロロ−5−ニ
トロフェニル)カルボニルアミノ]安息香酸(0.52
3g、1.63mmol)をジメチルホルムアミド(D
MF)(10mL)に溶解し、1−エチル−3−(3−
ジメチルアミノプロピル)カルボジイミド(WSC)
(0.39g)及び3−アミノピリジン(0.15g)
を加え、室温で4時間攪拌した。反応溶液に飽和重曹水
(30mL)を加え、酢酸エチル(50mL)で抽出し
た。有機層を飽和食塩水(20mL×2)で洗浄し、無
水硫酸ナトリウムで乾燥し、減圧下濃縮して、粗製の標
記目的化合物を得た。得られた粗製の標記目的化合物を
シリカゲルカラムクロマトグラフィー(塩化メチレン:
メタノール=20:1(v/v))にて精製した後、酢酸エ
チルで固化させ、濾取し、乾燥して、標記目的化合物
(0.30g、収率46%)を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.82 (2H, d, J = 8.7 Hz), 7.91 (1H, d, J = 8.8Hz), 7.
97 (2H, d, J = 8.7 Hz), 8.36 (1H, dd, J = 8.8, 2.8 H
z), 8.52 (1H, d, J = 2.8 Hz), 11.01 (1H, s). (148c) N- [4- (pyridin-3-ylaminocarbonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4-[(2-chloro-5-nitrophenyl) prepared in Example 148b. Carbonylamino] benzoic acid (0.52
3 g, 1.63 mmol) was added to dimethylformamide (D
MF) (10 mL) and dissolved in 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide (WSC)
(0.39 g) and 3-aminopyridine (0.15 g)
Was added, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude title compound. The obtained crude title compound was subjected to silica gel column chromatography (methylene chloride:
After purification by methanol (20: 1 (v / v)), the solid was solidified with ethyl acetate, collected by filtration and dried to obtain the title object compound (0.30 g, yield 46%).
【0236】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
7.40 (1H, dd, J=4.7, 8.3 Hz), 7.87 (1H, d, J=8.7
Hz), 7.92 (1H,d , J=8.8 Hz), 8.04 (2H, d, J=8.7 H
z), 8.18-8.22 (1H, m), 8.32 (1H, dd, J=4.7, 1.4 H
z), 8.37 (1H, dd, J=2.7, 8.8Hz), 8.54 (1H, d, J=2.
7 Hz), 8.94 (1H, d, J=2.4 Hz), 10.39 (1H, s), 11.0
2 (1H, s)。
(実施例149)N−[2−(4−メチルベンゾイルア
ミノ)ベンゾチアゾール−6−イル]−(2−クロロ−
5−ニトロフェニル)カルボキサミド
(149a)2−(4−メチルベンゾイルアミノ)−6
−ニトロベンゾチアゾール
2−アミノ−6−ニトロベンゾチアゾール(6.44
g、33mmol)、DMA(45mL)ならびに4−
メチル安息香酸クロリド(4.80mL)を使用して、
実施例2に記載した方法に従い、標記目的化合物(9.
88g、収率96%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.41 (3H,
s), 7.39 (2H, d, J=8.2Hz), 7.90 (1H, d, J=8.9 Hz),
8.08 (2H, d, J=8.2 Hz), 8.25 (1H, bs), 8.30(1H, d
d, J=2.4, 8.9 Hz), 9.06 (1H, d, J=2.4 Hz)。
(149b)6−アミノ−2−(4−メチルベンゾイル
アミノ)ベンゾチアゾール
実施例149aで製造した2−(4−メチルベンゾイル
アミノ)−6−ニトロベンゾチアゾール(3.20g、
10.2mmol)をTHF(150mL)に溶解し、
塩化ニッケル(II)六水和物(4.85g)及び水素
化ホウ素ナトリウム(1.55g)を氷水冷却下で加
え、30分間攪拌した。反応液を濃縮した後、酢酸エチ
ル(200mL)及び飽和重曹水(200mL)を加
え、30分間攪拌した後、不溶物を濾去した。濾液の有
機層を分離し、飽和食塩水(20mL×2)で洗浄し、
無水硫酸ナトリウムで乾燥し、減圧下濃縮して、粗製の
標記目的化合物を得た。得られた粗製の標記目的化合物
をジイソプロピルエーテルで固化し、濾取し、乾燥し
て、標記目的化合物(1.50g、収率52%)を得
た。 1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.40 (3H,
s), 5.20 (2H, bs), 6.74(1H, dd, J=2.2, 8.6 Hz), 7.
04 (1H, d, J=2.2 Hz), 7.36 (2H, d, J=8.2 Hz), 7.45
(1H, d, J=8.6 Hz), 8.01 (2H, d, J=8.2 Hz)。
(149c)N−[2−(4−メチルベンゾイルアミ
ノ)ベンゾチアゾール−6−イル]−(2−クロロ−5
−ニトロフェニル)カルボキサミド
実施例149bで製造した6−アミノ−2−(4−メチ
ルベンゾイルアミノ)ベンゾチアゾール(0.30g、
1.04mmol)、DMA(5mL)ならびに2−ク
ロロ−5−ニトロ安息香酸クロリド(0.26g、1.
20mmol)を使用して、実施例2に記載した方法に
従い、標記目的化合物(0.41g、収率86%)を得
た。1
H-NMR (400MHz, DMSO-d6, TMS):δ (ppm) 2.40 (3H,
s), 7.36 (2H, d, J=8.1Hz), 7.64 (1H, dd, J=2.0, 8.
7 Hz), 7.75 (1H, d, J=8.7 Hz), 7.91 (1H, d,J=8.9 H
z), 8.05 (2H, d, J=8.1 Hz), 8.36 (1H, dd, J=2.8,
8.9 Hz), 8.43 (1H, d, J=2.0 Hz), 8.50 (1H, d, J=2.
8 Hz), 10.86 (1H, s)。
(実施例150)N−[4−(4−エチルベンゼンスル
ホニルアミノ)フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
4−(4−エチルベンゼンスルホニルアミノ)アニリン
(0.37g、1.35mmol)、DMA(5mL)
ならびに2−クロロ−5−ニトロ安息香酸クロリド
(0.33g、1.48mmol)を使用して、実施例
2に記載した方法に従い、標記目的化合物(0.56
g、収率90%)を得た。[0236]1H-NMR (400MHz, DMSO-d6, TMS): δ (ppm)
7.40 (1H, dd, J = 4.7, 8.3 Hz), 7.87 (1H, d, J = 8.7
Hz), 7.92 (1H, d, J = 8.8 Hz), 8.04 (2H, d, J = 8.7 H
z), 8.18-8.22 (1H, m), 8.32 (1H, dd, J = 4.7, 1.4 H
z), 8.37 (1H, dd, J = 2.7, 8.8Hz), 8.54 (1H, d, J = 2.
7 Hz), 8.94 (1H, d, J = 2.4 Hz), 10.39 (1H, s), 11.0
2 (1H, s).
(Example 149) N- [2- (4-methylbenzoylurea
Mino) benzothiazol-6-yl]-(2-chloro-
5-nitrophenyl) carboxamide
(149a) 2- (4-methylbenzoylamino) -6
-Nitrobenzothiazole
2-Amino-6-nitrobenzothiazole (6.44
g, 33 mmol), DMA (45 mL) and 4-
Using methyl benzoyl chloride (4.80 mL),
According to the method described in Example 2, the title object compound (9.
88 g (96% yield) were obtained.1
H-NMR (400MHz, DMSO-d6, TMS): δ (ppm) 2.41 (3H,
s), 7.39 (2H, d, J = 8.2Hz), 7.90 (1H, d, J = 8.9 Hz),
8.08 (2H, d, J = 8.2 Hz), 8.25 (1H, bs), 8.30 (1H, d
d, J = 2.4, 8.9 Hz), 9.06 (1H, d, J = 2.4 Hz).
(149b) 6-amino-2- (4-methylbenzoyl)
Amino) benzothiazole
2- (4-methylbenzoyl) prepared in Example 149a
Amino) -6-nitrobenzothiazole (3.20 g,
10.2 mmol) in THF (150 mL),
Nickel (II) chloride hexahydrate (4.85 g) and hydrogen
Sodium borohydride (1.55g) was added under ice water cooling.
And stirred for 30 minutes. After concentrating the reaction mixture,
(200 mL) and saturated aqueous sodium hydrogen carbonate (200 mL)
After stirring for 30 minutes, the insoluble matter was filtered off. Existence of filtrate
The organic layer was separated, washed with saturated saline (20 mL x 2),
Dry over anhydrous sodium sulfate and concentrate under reduced pressure to give the crude
The title object compound was obtained. The crude title compound obtained
Solidified with diisopropyl ether, collected by filtration and dried.
To give the title object compound (1.50 g, yield 52%)
It was 1
H-NMR (400MHz, DMSO-d6, TMS): δ (ppm) 2.40 (3H,
s), 5.20 (2H, bs), 6.74 (1H, dd, J = 2.2, 8.6 Hz), 7.
04 (1H, d, J = 2.2 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.45
(1H, d, J = 8.6 Hz), 8.01 (2H, d, J = 8.2 Hz).
(149c) N- [2- (4-methylbenzoylami)
No) benzothiazol-6-yl]-(2-chloro-5
-Nitrophenyl) carboxamide
The 6-amino-2- (4-methyl ester prepared in Example 149b.
Rubenzoylamino) benzothiazole (0.30 g,
1.04 mmol), DMA (5 mL) and 2-
Lolo-5-nitrobenzoic acid chloride (0.26 g, 1.
20 mmol) in the method described in Example 2.
Therefore, the title compound (0.41 g, yield 86%) was obtained.
It was1
H-NMR (400MHz, DMSO-d6, TMS): δ (ppm) 2.40 (3H,
s), 7.36 (2H, d, J = 8.1Hz), 7.64 (1H, dd, J = 2.0, 8.
7 Hz), 7.75 (1H, d, J = 8.7 Hz), 7.91 (1H, d, J = 8.9 H
z), 8.05 (2H, d, J = 8.1 Hz), 8.36 (1H, dd, J = 2.8,
8.9 Hz), 8.43 (1H, d, J = 2.0 Hz), 8.50 (1H, d, J = 2.
8 Hz), 10.86 (1H, s).
(Example 150) N- [4- (4-ethylbenzenesulfur)
Phenylamino) phenyl]-(2-chloro-5-nitro
Phenyl) carboxamide
4- (4-ethylbenzenesulfonylamino) aniline
(0.37 g, 1.35 mmol), DMA (5 mL)
And 2-chloro-5-nitrobenzoic acid chloride
(0.33 g, 1.48 mmol)
According to the method described in 2, the title compound (0.56
g, yield 90%) was obtained.
【0237】1H-NMR (400MHz, DMSO-d6, TMS): δ(ppm)
1.16 (3H, t, J=7.6 Hz), 2.65 (2H, q, J=7.6 Hz),
7.10 (2H, d, J=8.9 Hz), 7.39 (2H, d, J= 8.4 Hz),
7.55(2H, d, J=8.9 Hz), 7.66 (2H, d, J=8.4 Hz), 7.8
7 (1H, d, J=8.8 Hz), 8.32(1H, dd, J=2.7, 8.8 Hz),
8.42 (1H, d, J=2.7 Hz), 10.16 (1H, s), 10.63 (1H,
s)。
(実施例151)N−[4−(ピペリジルスルホニル)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
4−(ピペリジルスルホニル)アニリン(0.27g、
1.12mmol)、DMA(5mL)ならびに2−ク
ロロ−5−ニトロ安息香酸クロリド(0.27g、1.
24mmol)を使用して、実施例2に記載した方法に
従い、標記目的化合物(0.32g、収率68%)を得
た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.36-1.39
(2H, m), 1.52-1.58 (4H,m), 2.88 (4H, t, J=5.3 Hz),
7.75 (2H, d, J=8.9 Hz), 7.92 (1H, d, J=8.8Hz), 7.
94 (2H, d, J=8.8 Hz), 8.37 (1H, dd, J=2.7, 8.9 H
z), 8.54 (1H, d,J=2.7 Hz)。
(実施例152)N−[4−(ピロリジニルスルホニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド
4−(ピロリジニルスルホニル)アニリン(0.27
g、1.19mmol)、DMA(4mL)ならびに2
−クロロ−5−ニトロ安息香酸クロリド(0.31g、
1.43mmol)を使用して、実施例2に記載した方
法に従い、標記目的化合物(0.46g、収率94%)
を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.63-1.68
(4H, m), 3.14 (4H, t,J=6.7 Hz), 7.83 (2H, d, J=8.
8 Hz), 7.92 (2H, d, J=8.8 Hz), 7.94 (1H, d,J=8.9 H
z), 8.37 (1H, dd, J=2.8, 8.9 Hz), 8.55 (1H, d, J=
2.8 Hz), 11.13 (1H, s)。
(実施例153)N−[4−(モルホリン−4−イルス
ルホニル)フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
4−(モルホリン−4−イル−スルホニル)アニリン
(0.28g、1.17mmol)、DMA(4mL)
ならびに2−クロロ−5−ニトロ安息香酸クロリド
(0.31g、1.40mmol)を使用して、実施例
2に記載した方法に従い、標記目的化合物(0.36
g、収率73%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.87 (4H,
t, J=4.6 Hz), 3.64 (4H,t, J=4.6 Hz), 7.77 (2H, d,
J=8.8 Hz), 7.92 (1H, d, J=8.8 Hz), 7.98 (2H,d, J=
8.8 Hz), 8.37 (1H, dd, J=2.7, 8.8 Hz), 8.55 (1H,
d, J=2.7 Hz)。
(実施例154)N−[3−(ピロリジルスルホニル)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
3−(ピロリジルスルホニル)アニリン(0.23g、
1.02mmol)、DMA(4mL)ならびに2−ク
ロロ−5−ニトロ安息香酸クロリド(0.27g、1.
23mmol)を使用して、実施例2に記載した方法に
従い、標記目的化合物(0.39g、収率93%)を得
た。1
H-NMR (400MHz, CDCl3, TMS): δ(ppm) 1.77-1.81 (4
H, m), 3.24 (4H, t, J=6.8 Hz), 7.55-7.62 (2H, m),
7.68 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=7.6 Hz), 8.
29 (1H, dd, J=2.7, 8.8 Hz), 8.59 (1H, d, J=2.7 H
z)。
(実施例155)N−(4−アセチルフェニル)−(2
−クロロ−5−ニトロフェニル)カルボキサミド
4−アセチルアニリン(7.04g、52.1mmo
l)、DMA(70mL)ならびに2−クロロ−5−ニ
トロ安息香酸クロリド(13.2g、60mmol)を
使用して、実施例2に記載した方法に従い、標記目的化
合物(16.4g、収率99%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.61 (3H,
s), 7.68 (1H, d, J=8.8Hz), 7.77 (2H, d, J=8.6 Hz),
8.01 (2H, d, J=8.7 Hz), 8.14 (1H, bs), 8.29(1H, d
d, J=2.7, 8.8 Hz), 8.63 (1H, d, J=2.7 Hz)。
(実施例156)N−(3−アセチルフェニル)−(2
−クロロ−5−ニトロフェニル)カルボキサミド
3−アセチルアニリン(7.44g、55.0mmo
l)、DMA(75mL)ならびに2−クロロ−5−ニ
トロ安息香酸クロリド(13.9g、63.3mmo
l)を使用して、実施例2に記載した方法に従い、標記
目的化合物(17.4g、収率99%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.63 (3H,
s), 7.53 (1H, t, J=7.9Hz), 7.69 (1H, d, J=8.8 Hz),
7.80 (1H, d, J=7.9 Hz), 8.03-8.06 (1H, m),8.11 (1
H, bs), 8.13 (1H, bs), 8.29 (1H, dd, J=2.7, 8.8 H
z), 8.64 (1H, d,J=2.7 Hz)。
(実施例157)N−[4−[(3,5−ジ−tert
−ブチル−4−ヒドロキシベンゾイル)アミノ]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
4−[(3,5−ジ−tert−ブチル−4−ヒドロキ
シベンゾイル)アミノ]アニリン(0.44g、1.2
9mmol)、DMA(5mL)ならびに2−クロロ−
5−ニトロ安息香酸クロリド(0.34g、1.54m
mol)を使用して、実施例2に記載した方法に従い、
標記目的化合物(0.63g、収率93%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.44 (18H,
s), 7.51 (1H, bs), 7.65-7.73 (6H, m), 7.90 (1H,
d, J=8.9 Hz), 8.34 (1H, dd, J=2.7, 8.8 Hz), 8.47
(1H, d, J=2.7 Hz), 10.06 (1H, s), 10.68 (1H, s);
MS(FAB) m/z: 524 (M + H)+。
(実施例158)N−[4−(モルホリン−4−イル−
カルボニル)フェニル]−(2−クロロ−5−ニトロフ
ェニル)カルボキサミド
4−(モルホリン−4−イル−カルボニル)アニリン
(0.31g、1.50mmol)、DMA(5mL)
ならびに2−クロロ−5−ニトロ安息香酸クロリド
(0.40g、1.80mmol)を使用して、実施例
2に記載した方法に従い、標記目的化合物(0.57
g、収率97%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 3.48-3.61
(8H, m), 7.45 (2H, d, J=8.5 Hz), 7.77 (2H, d, J=8.
6 Hz), 7.91 (1H, d, J=8.8 Hz), 8.35 (1H, dd,J=2.7,
8.8 Hz), 8.49 (1H, d, J=2.7 Hz), 10.90 (1H, s);
MS(FAB) m/z: 390 (M + H)+。
(実施例159)N−[4−(ピペリジルカルボニル)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
4−(ピペリジルカルボニル)アニリン(0.31g、
1.50mmol)、DMA(5mL)ならびに2−ク
ロロ−5−ニトロ安息香酸クロリド(0.40g、1.
80mmol)を使用して、実施例2に記載した方法に
従い、標記目的化合物(0.49g、収率85%)を得
た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.51 (4H,
m), 1.62 (2H, m), 3.50-3.56 (4H, m), 7.41 (2H, d,
J=8.4 Hz), 7.76 (2H, d, J=8.4 Hz), 7.91 (1H,d, J=
8.8 Hz), 8.35 (1H, dd, J=2.7, 8.8 Hz), 8.49 (1H,
d, J=2.7 Hz), 10.88 (1H, s);
MS(FAB) m/z: 388 (M + H)+。
(実施例160)N−[4−(1−ピロリジニルカルボ
ニル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
4−(1−ピロリジニルカルボニル)アニリン(0.2
9g、1.50mmol)、DMA(5mL)ならびに
2−クロロ−5−ニトロ安息香酸クロリド(0.40
g、1.80mmol)を使用して、実施例2に記載し
た方法に従い、標記目的化合物(0.47g、収率83
%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 3.31-3.40
(4H, m), 3.40-3.49 (4H,m), 7.56 (2H, d, J=8.5 Hz),
7.76 (2H, d, J=8.5 Hz), 7.91 (1H, d, J=8.8Hz), 8.
35 (1H, dd, J=2.6, 8.8 Hz), 8.50 (1H, d, J=2.6 H
z);
MS(FAB) m/z: 374 (M + H)+。
(実施例161)N−[3−[(3,5−ジ−tert
−ブチル−4−ヒドロキシフェニル)アミノスルホニ
ル]フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド
3−[(3,5−ジ−tert−ブチル−4−ヒドロキ
シフェニル)アミノスルホニル]アニリン(0.36
g、0.95mmol)、DMA(4mL)ならびに2
−クロロ−5−ニトロ安息香酸クロリド(0.25g、
1.14mmol)を使用して、実施例2に記載した方
法に従い、標記目的化合物(0.46g、収率87%)
を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.32 (18H, s), 6.3
0 (1H, s), 6.76 (2H, s), 7.44-7.48 (2H, m), 7.67
(1H, d, J=8.8 Hz), 8.10 (1H, d, J=7.7 Hz), 8.29 (1
H, dd, J=2.7, 8.8 Hz), 8.29 (1H, bs), 8.58 (1H, d,
J=2.7 Hz)。
(実施例162)N−[3−[(3,5−ジ−tert
−ブチル−4−ヒドロキシベンゾイル)アミノ]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
3−[(3,5−ジ−tert−ブチル−4−ヒドロキ
シベンゾイル)アミノ]アニリン(0.48g、1.4
0mmol)、DMA(5mL)ならびに2−クロロ−
5−ニトロ安息香酸クロリド(0.37g、1.68m
mol)を使用して、実施例2に記載した方法に従い、
標記目的化合物(0.66g、収率90%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.49 (18H,
s), 5.65 (1H, s), 7.38-7.40 (2H, m), 7.53-7.55 (1
H, m), 7.60 (1H, d, J=8.8 Hz), 7.64 (2H, s),7.78
(1H, s), 8.08 (1H, s), 8.19 (1H, dd, J=2.7, 8.8 H
z), 8.26 (1H, bs),8.53 (1H, d, J=2.7 Hz)。
(実施例163)4−[4−[(2−クロロ−5−ニト
ロフェニル)カルボニルアミノ]フェニル]フェニル−
(2−クロロ−5−ニトロフェニル)カルボキサミド
4―(4−アミノフェニル)アニリン(0.875g、
4.75mmol)、DMA(10mL)ならびに2−
クロロ−5−ニトロ安息香酸クロリド(2.30g、1
0.5mmol)を使用して、実施例2に記載した方法
に従い、標記目的化合物(2.49g、収率95%)を
得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.72 (4H,
d, J=8.7 Hz), 7.81 (4H,d, J=8.7 Hz), 7.91 (2H, d,
J=8.8 Hz), 8.36 (2H, dd, J=2.8, 8.8 Hz), 8.49 (2H,
d, J=2.8 Hz), 10.81 (2H, s);
MS(FAB) m/z: 551 (M + H)+。
(実施例164)N−[4−(4−メチルピペラジン−
1−イルカルボニル)フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド
4−(4−メチルピペラジン−1−イルカルボニル)ア
ニリン(0.33g、1.50mmol)、DMA(5
mL)ならびに2−クロロ−5−ニトロ安息香酸クロリ
ド(0.40g、1.80mmol)を使用して、実施
例2に記載した方法に従い、標記目的化合物(0.54
g、収率89%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.32 (4H,
m), 3.34-3.59 (4H, m),7.42 (2H, d, J=8.6 Hz), 7.77
(2H, d, J=8.6 Hz), 7.91 (1H, d, J=8.8 Hz),8.35 (1
H, dd, J=2.7, 8.8 Hz), 8.49 (1H, d, J=2.7 Hz), 10.
89 (1H, s);
MS(FAB) m/z: 403 (M + H)+。
(実施例165)N−[4−(4−フェニルピペラジン
−1−イルカルボニル)フェニル]−(2−クロロ−5
−ニトロフェニル)カルボキサミド
4−(4−フェニルピペラジン−1−イルカルボニル)
アニリン(0.42g、1.50mmol)、DMA
(5mL)ならびに2−クロロ−5−ニトロ安息香酸ク
ロリド(0.40g、1.80mmol)を使用して、
実施例2に記載した方法に従い、標記目的化合物(0.
66g、収率95%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 3.18 (4H, b
s), 3.55-3.74 (4H, m),6.82 (1H, t, J=7.2 Hz), 6.97
(2H, d, J=8.7 Hz), 7.21-7.27 (2H, m), 7.49(2H, d,
J=8.5 Hz), 7.79 (2H, d, J=8.5 Hz), 7.91 (1H, d, J
=8.8 Hz), 8.36(1H, dd, J=2.8, 8.8 Hz), 8.51 (1H,
d, J=2.8 Hz), 10.91 (1H, s);
MS(FAB) m/z: 465 (M + H)+。
(実施例166)N−[4−(4−tert−ブトキシ
カルボニルピペラジン−1−イルカルボニル)フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
4−(4−tert−ブトキシカルボニルピペラジン−
1−イルカルボニル)アニリン(0.46g、1.50
mmol)、DMA(5mL)ならびに2−クロロ−5
−ニトロ安息香酸クロリド(0.40g、1.80mm
ol)を使用して、実施例2に記載した方法に従い、標
記目的化合物(0.70g、収率95%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.41 (9H,
s), 3.32-3.55 (8H, m),7.45 (2H, d, J=8.5 Hz), 7.77
(2H, d, J=8.5 Hz), 7.91 (1H, d, J=8.8 Hz),8.36 (1
H, dd, J=2.7, 8.8 Hz), 8.50 (1H, d, J=2.7 Hz), 10.
90 (1H, s);
MS(FAB) m/z: 489 (M + H)+。
(実施例167)N−[4−(2−tert−ブトキシ
カルボニルアミノエチル)フェニル]−(2−クロロ−
5−ニトロフェニル)カルボキサミド
4−(2−tert−ブトキシカルボニルアミノエチ
ル)アニリン(5.66g、24mmol)、DMA
(50mL)ならびに2−クロロ−5−ニトロ安息香酸
クロリド(6.32g、28.8mmol)を使用し
て、実施例2に記載した方法に従い、標記目的化合物
(10.0g、収率99%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.37 (9H,
s), 2.67 (2H, t, J=7.5Hz), 3.10-3.13 (2H, m), 7.19
(2H, d, J=8.4 Hz), 7.61 (2H, d, J=8.4 Hz),7.89 (1
H, d, J=8.8 Hz), 8.34 (1H, dd, J=2.8, 8.8 Hz), 8.4
4 (1H, d, J=2.8Hz), 10.64 (1H, s);
MS(FAB) m/z: 420 (M + H)+。
(実施例168)[4−(2−クロロ−5−ニトロベン
ゾイルアミノ)フェニル]酢酸 エチルエステル
4−アミノフェニル酢酸 エチルエステル(4.58
g、25mmol)、DMA(70mL)ならびに2−
クロロ−5−ニトロ安息香酸クロリド(6.60g、3
0mmol)を使用して、実施例2に記載した方法に従
い、標記目的化合物(8.20g、収率90%)を得
た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.19 (3H,
t, J=7.1 Hz), 3.64 (2H,s), 4.08 (2H, q, J=7.1 Hz),
7.27 (2H, d, J=8.5 Hz), 7.65 (2H, d, J=8.5Hz), 7.
89 (1H, d, J=8.8 Hz), 8.34 (1H, dd, J=2.8, 8.8 H
z), 8.46 (1H, d,J=2.8 Hz), 10.76 (1H, s);
MS(FAB) m/z: 401 (M + H)+。
(実施例169)N−[4−(2−アミノエチル)フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキ
サミド・塩酸塩 0.2水和物
実施例167で製造したN−[4−(2−tert−ブ
トキシカルボニルアミノエチル)フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド(8.73
g、20.8mmol)、1,4−ジオキサン(90m
L)及び4N塩化水素−1,4−ジオキサン溶液(10
mL)を使用して、実施例88に記載した方法に従い、
標記目的化合物(6.87g、収率84%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.86 (2H,
t, J=7.8 Hz), 3.02 (2H,bs), 7.27 (2H, d, J=7.9 H
z), 7.67 (2H, d, J=7.9 Hz), 7.89 (2H, d, J=8.8Hz),
7.96-8.00 (2H, m), 8.33-8.37 (1H, m), 8.43 (1H,
d, J=1.5 Hz), 10.74 (1H, s);
MS(FAB) m/z: 320 (M + H)+。
(実施例170)[4−(2−クロロ−5−ニトロベン
ゾイルアミノ)フェニル]酢酸
実施例168で製造した[4−(2−クロロ−5−ニト
ロベンゾイルアミノ)フェニル]酢酸 エチルエステル
(7.02g、19.3mmol)、THF(50m
L)ならびに1N水酸化ナトリウム水溶液(39mL)
を使用して、実施例145に記載した方法に従い反応し
た。1N塩酸(40mL)を使用して、実施例67に記
載した方法に従い反応溶液を処理して、標記目的化合物
(6.47g、収率99%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 3.55 (2H,
s), 7.26 (2H, d, J=8.5Hz), 7.64 (2H, d, J=8.5 Hz),
7.89 (1H, d, J=8.8 Hz), 8.34 (1H, dd, J=2.7, 8.8
Hz), 8.45 (1H, d, J=2.7 Hz), 10.69 (1H, s), 12.31
(1H, s);
MS(FAB) m/z: 335 (M + H)+。
(実施例171)N−[4−[4−(ピロリジン−1−
イルアミノ)フェニル]フェニル]−(2−クロロ−5
−ニトロフェニル)カルボキサミド
4−(4−ピロリジニルフェニル)アニリン(0.26
g、1.1mmol)、DMA(5mL)ならびに2−
クロロ−5−ニトロ安息香酸クロリド(0.28g、
1.28mmol)を使用して、実施例2に記載した方
法に従い、標記目的化合物(0.45g、収率99%)
を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.95-1.99
(4H, m), 3.26-3.29 (4H,m), 6.62 (2H, d, J=8.7 Hz),
7.51 (2H, d, J=8.6 Hz), 7.59 (2H, d, J=8.6Hz), 7.
72 (2H, d, J=8.7 Hz), 7.91 (1H, d, J=8.8 Hz), 8.35
(1H, dd, J=2.7, 8.8 Hz), 8.47 (1H, d, J=2.7 Hz),
10.71 (1H, s);
MS(FAB) m/z: 421 (M + H)+。
(実施例172)N−(4−ジエチルアミノフェニル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
4−ジエチルアミノアニリン(0.42g、2.58m
mol)、DMA(5mL)ならびに2−クロロ−5−
ニトロ安息香酸クロリド(0.62g、2.82mmo
l)を使用して、実施例2に記載した方法に従い、標記
目的化合物(0.66g、収率73%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.08 (6H,
t, J=7.0 Hz), 3.32 (4H,q, J=7.0 Hz), 6.67 (2H, d,
J=9.1 Hz), 7.48 (2H, d, J=9.1 Hz), 7.87 (1H,d, J=
8.79 Hz), 8.31 (1H, dd, J=2.8, 8.8 Hz), 8.38 (1H,
d, J=2.8 Hz), 10.33 (1H, s);
MS(FAB) m/z: 347 M+, 348(M + H)+。
(実施例173)N−(4−ジメチルアミノフェニル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
4−ジメチルアミノアニリン(0.33g、2.43m
mol)、DMA(5mL)ならびに2−クロロ−5−
ニトロ安息香酸クロリド(0.59g、2.67mmo
l)を使用して、実施例2に記載した方法に従い、標記
目的化合物(0.66g、収率85%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.88 (6H,
s), 6.74 (2H, d, J=9.1Hz), 7.52 (2H, d, J=9.1 Hz),
7.87 (1H, d, J=8.8 Hz), 8.32 (1H, dd, J=2.8, 8.8
Hz), 8.40 (1H, d, J=2.8 Hz), 10.38 (1H, s);
MS(FAB) m/z: 319 M+, 320 (M + H)+。
(実施例174)N−[4−(イミダゾール−1−イ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド
4−(イミダゾール−1−イル)アニリン(0.35
g、2.18mmol)、DMA(5mL)ならびに2
−クロロ−5−ニトロ安息香酸クロリド(0.55g、
2.50mmol)を使用して、実施例2に記載した方
法に従い、標記目的化合物(0.69g、収率92%)
を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.12 (1H, b
s), 7.67 (2H, d, J=9.0Hz), 7.73 (1H, bs), 7.83 (2
H, d, J=8.9 Hz), 7.91 (1H, d, J=8.9 Hz), 8.24 (1H,
bs), 8.36 (1H, dd, J=2.8, 8.9 Hz), 8.51 (1H, d, J
=2.8 Hz), 10.87(1H, s);
MS(FAB) m/z: 343 (M + H)+。
(実施例175)N−[4−[(3,5−ジ−tert
−ブチル−4−ヒドロキシフェニル)アミノスルホニ
ル]フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド
4−[(3,5−ジ−tert−ブチル−4−ヒドロキ
シフェニル)アミノスルホニル]アニリン(0.27
g、0.72mmol)、DMA(3mL)ならびに2
−クロロ−5−ニトロ安息香酸クロリド(0.17g、
0.80mmol)を使用して、実施例2に記載した方
法に従い、標記目的化合物(0.32g、収率80%)
を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.27 (18H,
s), 6.76 (2H, s), 6.83(1H, s), 7.66 (2H, d, J=8.6
Hz), 7.82 (2H, d, J=8.6 Hz), 7.90 (1H, d, J=8.8 H
z), 8.33-8.37 (1H, m), 8.49 (1H, d, J=2.7 Hz), 9.5
6-9.59 (1H, m),11.05 (1H, s);
MS(FAB) m/z: 559 M+。
(実施例176)N−(3−ジメチルアミノ)フェニル
−(2−クロロ−5−ニトロフェニル)カルボキサミド
3−ジメチルアミノアニリン・二塩酸塩(0.511
g、2.45mmol)、THF(10mL)、ピリジ
ン(2mL)ならびに2−クロロ−5−ニトロ安息香酸
クロリド(0.59g、2.70mmol)を使用し
て、実施例2に記載した方法に従い反応した。反応溶液
に飽和重曹水(30mL)を加え、酢酸エチル(30m
L)で抽出した。有機層を分離し、飽和食塩水(20m
L×2)で洗浄し、無水硫酸ナトリウムで乾燥し、減圧
下濃縮して、粗製の標記目的化合物を得た。得られた粗
製の標記目的化合物を、シリカゲルカラムクロマトグラ
フィー(ヘキサン:酢酸エチル=1:1(v/v))にて精
製した後、ジイソプロピルエーテルで固化させ、濾取
し、乾燥して、標記目的化合物(0.38g、収率49
%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 2.99 (6H,
s), 6.58 (1H, dd, J=2.2, 8.3 Hz), 6.84 (1H, dd, J=
1.7, 7.8 Hz), 7.16 (1H, t, J=2.2 Hz), 7.23 (1H, t,
J=8.3 Hz), 7.65 (1H, d, J=8.8 Hz), 7.74 (1H, bs),
8.25 (1H, dd, J=2.7, 8.8 Hz);
MS(FAB) m/z: 319 M+ , 320 (M + H)+。
(実施例177)N−[4−[4−(ピペリジン−1−
イル)フェニル]フェニル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド
4−(ピペリジニルフェニル)アニリン(0.25g、
1.0mmol)、DMA(10mL)ならびに2−ク
ロロ−5−ニトロ安息香酸クロリド(0.26g、1.
2mmol)を使用して、実施例2に記載した方法に従
い、標記目的化合物(0.41g、収率94%)を得
た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 1.55-1.58
(2H, m), 1.61-1.66 (4H,m), 3.19 (4H, t, J=5.2 Hz),
7.00 (2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7Hz), 7.
62 (2H, d, J=8.6 Hz), 7.74 (2H, d, J=8.6 Hz), 7.91
(1H, d, J=8.8Hz), 8.35 (1H, dd, J=2.7, 8.8 Hz),
8.47 (1H, d, J=2.7 Hz), 10.74 (1H, s);
MS(FAB) m/z: 435 M+, 436 (M + H)+。
(実施例178)N−[4−[(ピペリジン−1−イ
ル)アミノスルホニル]フェニル]−(2−クロロ−5
−ニトロフェニル)カルボキサミド
4−[(ピペリジン−1−イル)アミノスルホニル]ア
ニリン(0.57g、2.27mmol)、DMA(5
mL)ならびに2−クロロ−5−ニトロ安息香酸クロリ
ド(0.29g、1.33mmol)を使用して、実施
例2に記載した方法に従い、標記目的化合物(0.30
g、収率31%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 7.30 (1H, d
d, J=4.7, 8.3 Hz), 7.50-7.54 (1H, m), 7.78 (2H, d,
J=8.8 Hz), 7.86 (2H, d, J=8.8 Hz), 7.90 (1H, d, J
=8.8 Hz), 8.26 (1H, d, J=4.7 Hz), 8.29 (1H, d, J=
2.5 Hz), 8.35 (1H, dd, J=2.7, 8.8 Hz), 8.52 (1H,
d, J=2.7 Hz), 10.52 (1H, s), 11.09 (1H,s)。
(実施例179)N−[4−[4−(モルホリン−4−
イル)フェニル]アミノスルホニル]フェニル−(2−
クロロ−5−ニトロフェニル)カルボキサミド
[4−[4−(モルホリン−4−イル)フェニル]アミ
ノスルホニル]アニリン(0.40g、1.21mmo
l)、DMA(5mL)ならびに2−クロロ−5−ニト
ロ安息香酸クロリド(0.29g、1.33mmol)
を使用して、実施例2に記載した方法に従い、標記目的
化合物(0.51g、収率81%)を得た。1
H-NMR (400MHz, DMSO-d6, TMS): δ(ppm) 3.01 (4H,
t, J=4.8 Hz), 3.69 (4H,t, J=4.8 Hz), 6.83 (2H, d,
J=9.1 Hz), 6.94 (2H, d, J=9.1 Hz), 7.72 (2H,d, J=
8.7 Hz), 7.82 (2H, d, J=8.7 Hz), 7.90 (1H, d, J=8.
8 Hz), 8.35 (1H,dd, J=2.7, 8.8 Hz), 8.52 (1H, d, J
=2.7 Hz), 9.79 (1H, s), 11.05 (1H, s);
MS(FAB) m/z: 516 M+, 517 (M + H)+。
(実施例180)N−(4−アミノフェニル)−(2−
クロロ−5−ニトロフェニル)カルボキサミド
実施例58で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩(4.89g、14.9mmol)を飽和重曹
水(200mL)及び水(100mL)に懸濁させ、2
時間攪拌した。生じた結晶を濾取し、水洗した後、乾燥
して、標記目的化合物(4.29g、収率99%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 4.99 (1H, bs),
6.55 (2H, d, J= 8.8 Hz), 7.34 (2H, d, J= 8.8 Hz),
7.86 (1H, d, J= 8.8 Hz), 8.31 (1H, dd, J= 8.8, 2.8
Hz), 8.37 (1H, d, J= 2.8 Hz), 10.26 (1H, s);
MS(FAB) m/z: 292 (M + H)+。
(実施例181)N−[4−(N−プロピルアミノ)フ
ェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド実施例180で
製造したN−(4−アミノフェニル)−(2−クロロ−
5−ニトロフェニル)カルボキサミド(0.583g、
2.00mmol)、メタノール(10mL)、シアノ
水素化ホウ素ナトリウム(0.151g、2.40mm
ol)及びプロピオンアルデヒド(0.289mL、
4.00mmol)を使用して、実施例115に記載し
た方法に従い、高極性化合物として、標記目的化合物
(0.307g、収率46%)を得た。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
1.16 (3H, t, J = 7.6 Hz), 2.65 (2H, q, J = 7.6 Hz),
7.10 (2H, d, J = 8.9 Hz), 7.39 (2H, d, J = 8.4 Hz),
7.55 (2H, d, J = 8.9 Hz), 7.66 (2H, d, J = 8.4 Hz), 7.8
7 (1H, d, J = 8.8 Hz), 8.32 (1H, dd, J = 2.7, 8.8 Hz),
8.42 (1H, d, J = 2.7 Hz), 10.16 (1H, s), 10.63 (1H,
s). (Example 151) N- [4- (piperidylsulfonyl)
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (piperidylsulfonyl) aniline (0.27 g,
1.12 mmol), DMA (5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.27 g, 1.
The title compound (0.32 g, yield 68%) was obtained according to the method described in Example 2 using 24 mmol). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.36-1.39
(2H, m), 1.52-1.58 (4H, m), 2.88 (4H, t, J = 5.3 Hz),
7.75 (2H, d, J = 8.9 Hz), 7.92 (1H, d, J = 8.8Hz), 7.
94 (2H, d, J = 8.8 Hz), 8.37 (1H, dd, J = 2.7, 8.9 H
z), 8.54 (1H, d, J = 2.7 Hz). Example 152 N- [4- (Pyrrolidinylsulfonyl) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide 4- (pyrrolidinylsulfonyl) aniline (0.27
g, 1.19 mmol), DMA (4 mL) and 2
-Chloro-5-nitrobenzoic acid chloride (0.31 g,
1.43 mmol) according to the method described in Example 2 to give the title object compound (0.46 g, 94% yield).
Got 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.63-1.68
(4H, m), 3.14 (4H, t, J = 6.7 Hz), 7.83 (2H, d, J = 8.
8 Hz), 7.92 (2H, d, J = 8.8 Hz), 7.94 (1H, d, J = 8.9 H
z), 8.37 (1H, dd, J = 2.8, 8.9 Hz), 8.55 (1H, d, J =
2.8 Hz), 11.13 (1H, s). Example 153 N- [4- (morpholin-4-ylsulfonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (morpholin-4-yl-sulfonyl) aniline (0.28 g, 1 .17 mmol), DMA (4 mL)
And 2-chloro-5-nitrobenzoic acid chloride (0.31 g, 1.40 mmol) according to the method described in Example 2 to obtain the title compound (0.36 g).
g, yield 73%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.87 (4H,
t, J = 4.6 Hz), 3.64 (4H, t, J = 4.6 Hz), 7.77 (2H, d,
J = 8.8 Hz), 7.92 (1H, d, J = 8.8 Hz), 7.98 (2H, d, J =
8.8 Hz), 8.37 (1H, dd, J = 2.7, 8.8 Hz), 8.55 (1H,
d, J = 2.7 Hz). (Example 154) N- [3- (pyrrolidylsulfonyl)
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide 3- (pyrrolidylsulfonyl) aniline (0.23 g,
1.02 mmol), DMA (4 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.27 g, 1.
23 mmol) according to the method described in Example 2 to obtain the title object compound (0.39 g, yield 93%). 1 H-NMR (400MHz, CDCl 3 , TMS): δ (ppm) 1.77-1.81 (4
H, m), 3.24 (4H, t, J = 6.8 Hz), 7.55-7.62 (2H, m),
7.68 (1H, d, J = 8.8 Hz), 8.19 (1H, d, J = 7.6 Hz), 8.
29 (1H, dd, J = 2.7, 8.8 Hz), 8.59 (1H, d, J = 2.7 H
z). (Example 155) N- (4-acetylphenyl)-(2
-Chloro-5-nitrophenyl) carboxamide 4-acetylaniline (7.04 g, 52.1 mmo)
1), DMA (70 mL) and 2-chloro-5-nitrobenzoic acid chloride (13.2 g, 60 mmol) according to the method described in Example 2 to give the title object compound (16.4 g, yield 99). %) Was obtained. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.61 (3H,
s), 7.68 (1H, d, J = 8.8Hz), 7.77 (2H, d, J = 8.6 Hz),
8.01 (2H, d, J = 8.7 Hz), 8.14 (1H, bs), 8.29 (1H, d
d, J = 2.7, 8.8 Hz), 8.63 (1H, d, J = 2.7 Hz). (Example 156) N- (3-acetylphenyl)-(2
-Chloro-5-nitrophenyl) carboxamide 3-acetylaniline (7.44 g, 55.0 mmo
l), DMA (75 mL) and 2-chloro-5-nitrobenzoic acid chloride (13.9 g, 63.3 mmo).
The title compound (17.4 g, yield 99%) was obtained according to the method described in Example 2 using l). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.63 (3H,
s), 7.53 (1H, t, J = 7.9Hz), 7.69 (1H, d, J = 8.8 Hz),
7.80 (1H, d, J = 7.9 Hz), 8.03-8.06 (1H, m), 8.11 (1
H, bs), 8.13 (1H, bs), 8.29 (1H, dd, J = 2.7, 8.8 H
z), 8.64 (1H, d, J = 2.7 Hz). (Example 157) N- [4-[(3,5-di-tert)
-Butyl-4-hydroxybenzoyl) amino] phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4-[(3,5-di-tert-butyl-4-hydroxybenzoyl) amino] aniline (0.44 g , 1.2
9 mmol), DMA (5 mL) and 2-chloro-
5-Nitrobenzoyl chloride (0.34g, 1.54m
mol) according to the method described in Example 2,
The title object compound (0.63 g, yield 93%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.44 (18H,
s), 7.51 (1H, bs), 7.65-7.73 (6H, m), 7.90 (1H,
d, J = 8.9 Hz), 8.34 (1H, dd, J = 2.7, 8.8 Hz), 8.47
(1H, d, J = 2.7 Hz), 10.06 (1H, s), 10.68 (1H, s); MS (FAB) m / z: 524 (M + H) + . (Example 158) N- [4- (morpholin-4-yl-
Carbonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (morpholin-4-yl-carbonyl) aniline (0.31 g, 1.50 mmol), DMA (5 mL).
And 2-chloro-5-nitrobenzoic acid chloride (0.40 g, 1.80 mmol) according to the method described in Example 2 to give the title compound (0.57
g, yield 97%). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 3.48-3.61
(8H, m), 7.45 (2H, d, J = 8.5 Hz), 7.77 (2H, d, J = 8.
6 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 2.7,
8.8 Hz), 8.49 (1H, d, J = 2.7 Hz), 10.90 (1H, s); MS (FAB) m / z: 390 (M + H) + . (Example 159) N- [4- (piperidylcarbonyl)
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (piperidylcarbonyl) aniline (0.31 g,
1.50 mmol), DMA (5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.40 g, 1.
80 mmol) was used and the title compound (0.49 g, yield 85%) was obtained according to the method described in Example 2. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.51 (4H,
m), 1.62 (2H, m), 3.50-3.56 (4H, m), 7.41 (2H, d,
J = 8.4 Hz), 7.76 (2H, d, J = 8.4 Hz), 7.91 (1H, d, J =
8.8 Hz), 8.35 (1H, dd, J = 2.7, 8.8 Hz), 8.49 (1H,
d, J = 2.7 Hz), 10.88 (1H, s); MS (FAB) m / z: 388 (M + H) + . (Example 160) N- [4- (1-pyrrolidinylcarbonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (1-pyrrolidinylcarbonyl) aniline (0.2
9 g, 1.50 mmol), DMA (5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.40
g, 1.80 mmol) according to the method described in Example 2 (0.47 g, yield 83).
%) Was obtained. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 3.31-3.40
(4H, m), 3.40-3.49 (4H, m), 7.56 (2H, d, J = 8.5 Hz),
7.76 (2H, d, J = 8.5 Hz), 7.91 (1H, d, J = 8.8Hz), 8.
35 (1H, dd, J = 2.6, 8.8 Hz), 8.50 (1H, d, J = 2.6 H
z); MS (FAB) m / z: 374 (M + H) + . (Example 161) N- [3-[(3,5-di-tert)
-Butyl-4-hydroxyphenyl) aminosulfonyl] phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide 3-[(3,5-di-tert-butyl-4-hydroxyphenyl) aminosulfonyl] aniline (0.36
g, 0.95 mmol), DMA (4 mL) and 2
-Chloro-5-nitrobenzoic acid chloride (0.25 g,
The target compound (0.46 g, yield 87%) was prepared according to the method described in Example 2 using 1.14 mmol).
Got 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.32 (18H, s), 6.3
0 (1H, s), 6.76 (2H, s), 7.44-7.48 (2H, m), 7.67
(1H, d, J = 8.8 Hz), 8.10 (1H, d, J = 7.7 Hz), 8.29 (1
H, dd, J = 2.7, 8.8 Hz), 8.29 (1H, bs), 8.58 (1H, d,
J = 2.7 Hz). (Example 162) N- [3-[(3,5-di-tert)
-Butyl-4-hydroxybenzoyl) amino] phenyl]-(2-chloro-5-nitrophenyl) carboxamide 3-[(3,5-di-tert-butyl-4-hydroxybenzoyl) amino] aniline (0.48 g , 1.4
0 mmol), DMA (5 mL) and 2-chloro-
5-Nitrobenzoyl chloride (0.37g, 1.68m
mol) according to the method described in Example 2,
The title object compound (0.66 g, yield 90%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.49 (18H,
s), 5.65 (1H, s), 7.38-7.40 (2H, m), 7.53-7.55 (1
H, m), 7.60 (1H, d, J = 8.8 Hz), 7.64 (2H, s), 7.78
(1H, s), 8.08 (1H, s), 8.19 (1H, dd, J = 2.7, 8.8 H
z), 8.26 (1H, bs), 8.53 (1H, d, J = 2.7 Hz). Example 163 4- [4-[(2-chloro-5-nitrophenyl) carbonylamino] phenyl] phenyl-
(2-chloro-5-nitrophenyl) carboxamide 4- (4-aminophenyl) aniline (0.875 g,
4.75 mmol), DMA (10 mL) and 2-
Chloro-5-nitrobenzoic acid chloride (2.30 g, 1
The title compound (2.49 g, yield 95%) was obtained according to the method described in Example 2 using 0.5 mmol). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.72 (4H,
d, J = 8.7 Hz), 7.81 (4H, d, J = 8.7 Hz), 7.91 (2H, d,
J = 8.8 Hz), 8.36 (2H, dd, J = 2.8, 8.8 Hz), 8.49 (2H,
d, J = 2.8 Hz), 10.81 (2H, s); MS (FAB) m / z: 551 (M + H) + . (Example 164) N- [4- (4-methylpiperazine-
1-ylcarbonyl) phenyl]-(2-chloro-5-
Nitrophenyl) carboxamide 4- (4-methylpiperazin-1-ylcarbonyl) aniline (0.33 g, 1.50 mmol), DMA (5
mL) and 2-chloro-5-nitrobenzoic acid chloride (0.40 g, 1.80 mmol) according to the method described in Example 2 to give the title compound (0.54).
g, yield 89%). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.32 (4H,
m), 3.34-3.59 (4H, m), 7.42 (2H, d, J = 8.6 Hz), 7.77
(2H, d, J = 8.6 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.35 (1
H, dd, J = 2.7, 8.8 Hz), 8.49 (1H, d, J = 2.7 Hz), 10.
89 (1H, s); MS (FAB) m / z: 403 (M + H) + . Example 165 N- [4- (4-phenylpiperazin-1-ylcarbonyl) phenyl]-(2-chloro-5
-Nitrophenyl) carboxamide 4- (4-phenylpiperazin-1-ylcarbonyl)
Aniline (0.42g, 1.50mmol), DMA
(5 mL) as well as 2-chloro-5-nitrobenzoic acid chloride (0.40 g, 1.80 mmol),
According to the method described in Example 2, the title object compound (0.
66 g, yield 95%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 3.18 (4H, b
s), 3.55-3.74 (4H, m), 6.82 (1H, t, J = 7.2 Hz), 6.97
(2H, d, J = 8.7 Hz), 7.21-7.27 (2H, m), 7.49 (2H, d,
J = 8.5 Hz), 7.79 (2H, d, J = 8.5 Hz), 7.91 (1H, d, J
= 8.8 Hz), 8.36 (1H, dd, J = 2.8, 8.8 Hz), 8.51 (1H,
d, J = 2.8 Hz), 10.91 (1H, s); MS (FAB) m / z: 465 (M + H) + . (Example 166) N- [4- (4-tert-butoxycarbonylpiperazin-1-ylcarbonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (4-tert-butoxycarbonylpiperazine-
1-ylcarbonyl) aniline (0.46 g, 1.50
mmol), DMA (5 mL) and 2-chloro-5
-Nitrobenzoic acid chloride (0.40 g, 1.80 mm
was used according to the method described in Example 2 to give the title object compound (0.70 g, yield 95%). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.41 (9H,
s), 3.32-3.55 (8H, m), 7.45 (2H, d, J = 8.5 Hz), 7.77
(2H, d, J = 8.5 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.36 (1
H, dd, J = 2.7, 8.8 Hz), 8.50 (1H, d, J = 2.7 Hz), 10.
90 (1H, s); MS (FAB) m / z: 489 (M + H) + . (Example 167) N- [4- (2-tert-butoxycarbonylaminoethyl) phenyl]-(2-chloro-
5-Nitrophenyl) carboxamide 4- (2-tert-butoxycarbonylaminoethyl) aniline (5.66 g, 24 mmol), DMA
(50 mL) and 2-chloro-5-nitrobenzoic acid chloride (6.32 g, 28.8 mmol) according to the method described in Example 2 to give the title compound (10.0 g, 99% yield). Got 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.37 (9H,
s), 2.67 (2H, t, J = 7.5Hz), 3.10-3.13 (2H, m), 7.19
(2H, d, J = 8.4 Hz), 7.61 (2H, d, J = 8.4 Hz), 7.89 (1
H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 2.8, 8.8 Hz), 8.4
4 (1H, d, J = 2.8Hz), 10.64 (1H, s); MS (FAB) m / z: 420 (M + H) + . (Example 168) [4- (2-chloro-5-nitrobenzoylamino) phenyl] acetic acid ethyl ester 4-aminophenylacetic acid ethyl ester (4.58)
g, 25 mmol), DMA (70 mL) and 2-
Chloro-5-nitrobenzoic acid chloride (6.60 g, 3
(0 mmol) according to the method described in Example 2 to obtain the title object compound (8.20 g, yield 90%). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.19 (3H,
t, J = 7.1 Hz), 3.64 (2H, s), 4.08 (2H, q, J = 7.1 Hz),
7.27 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.5Hz), 7.
89 (1H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 2.8, 8.8 H
z), 8.46 (1H, d, J = 2.8 Hz), 10.76 (1H, s); MS (FAB) m / z: 401 (M + H) + . Example 169 N- [4- (2-aminoethyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide hydrochloride 0.2 hydrate N- [4-prepared in Example 167. (2-tert-Butoxycarbonylaminoethyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide (8.73)
g, 20.8 mmol), 1,4-dioxane (90 m
L) and 4N hydrogen chloride-1,4-dioxane solution (10
mL) according to the method described in Example 88,
The title object compound (6.87 g, yield 84%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.86 (2H,
t, J = 7.8 Hz), 3.02 (2H, bs), 7.27 (2H, d, J = 7.9 H
z), 7.67 (2H, d, J = 7.9 Hz), 7.89 (2H, d, J = 8.8Hz),
7.96-8.00 (2H, m), 8.33-8.37 (1H, m), 8.43 (1H,
d, J = 1.5 Hz), 10.74 (1H, s); MS (FAB) m / z: 320 (M + H) + . Example 170 [4- (2-chloro-5-nitrobenzoylamino) phenyl] acetic acid [4- (2-chloro-5-nitrobenzoylamino) phenyl] acetic acid ethyl ester prepared in Example 168 (7. 02g, 19.3mmol), THF (50m
L) and 1N aqueous sodium hydroxide solution (39 mL)
Was used according to the method described in Example 145. The reaction solution was treated according to the method described in Example 67 using 1N hydrochloric acid (40 mL) to obtain the title object compound (6.47 g, yield 99%). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 3.55 (2H,
s), 7.26 (2H, d, J = 8.5Hz), 7.64 (2H, d, J = 8.5 Hz),
7.89 (1H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 2.7, 8.8
Hz), 8.45 (1H, d, J = 2.7 Hz), 10.69 (1H, s), 12.31
(1H, s); MS (FAB) m / z: 335 (M + H) + . (Example 171) N- [4- [4- (pyrrolidine-1-
Ilamino) phenyl] phenyl]-(2-chloro-5
-Nitrophenyl) carboxamide 4- (4-pyrrolidinylphenyl) aniline (0.26
g, 1.1 mmol), DMA (5 mL) and 2-
Chloro-5-nitrobenzoic acid chloride (0.28 g,
The title compound (0.45 g, yield 99%) according to the method described in Example 2 using 1.28 mmol).
Got 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.95-1.99
(4H, m), 3.26-3.29 (4H, m), 6.62 (2H, d, J = 8.7 Hz),
7.51 (2H, d, J = 8.6Hz), 7.59 (2H, d, J = 8.6Hz), 7.
72 (2H, d, J = 8.7 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.35
(1H, dd, J = 2.7, 8.8 Hz), 8.47 (1H, d, J = 2.7 Hz),
10.71 (1H, s); MS (FAB) m / z: 421 (M + H) + . (Example 172) N- (4-diethylaminophenyl)
-(2-Chloro-5-nitrophenyl) carboxamide 4-diethylaminoaniline (0.42 g, 2.58 m
mol), DMA (5 mL) and 2-chloro-5-
Nitrobenzoyl chloride (0.62g, 2.82mmo
According to the method described in Example 2 using 1), the title object compound (0.66 g, yield 73%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.08 (6H,
t, J = 7.0 Hz), 3.32 (4H, q, J = 7.0 Hz), 6.67 (2H, d,
J = 9.1 Hz), 7.48 (2H, d, J = 9.1 Hz), 7.87 (1H, d, J =
8.79 Hz), 8.31 (1H, dd, J = 2.8, 8.8 Hz), 8.38 (1H,
d, J = 2.8 Hz), 10.33 (1H, s); MS (FAB) m / z: 347 M + , 348 (M + H) + . (Example 173) N- (4-dimethylaminophenyl)
-(2-Chloro-5-nitrophenyl) carboxamide 4-dimethylaminoaniline (0.33 g, 2.43 m
mol), DMA (5 mL) and 2-chloro-5-
Nitrobenzoyl chloride (0.59g, 2.67mmo
According to the method described in Example 2 using l), the title object compound (0.66 g, yield 85%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.88 (6H,
s), 6.74 (2H, d, J = 9.1Hz), 7.52 (2H, d, J = 9.1 Hz),
7.87 (1H, d, J = 8.8 Hz), 8.32 (1H, dd, J = 2.8, 8.8
Hz), 8.40 (1H, d, J = 2.8 Hz), 10.38 (1H, s); MS (FAB) m / z: 319 M + , 320 (M + H) + . Example 174 N- [4- (imidazol-1-yl) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide 4- (imidazol-1-yl) aniline (0.35
g, 2.18 mmol), DMA (5 mL) and 2
-Chloro-5-nitrobenzoic acid chloride (0.55 g,
2.50 mmol) according to the method described in Example 2 to give the title object compound (0.69 g, yield 92%).
Got 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.12 (1H, b
s), 7.67 (2H, d, J = 9.0Hz), 7.73 (1H, bs), 7.83 (2
H, d, J = 8.9 Hz), 7.91 (1H, d, J = 8.9 Hz), 8.24 (1H,
bs), 8.36 (1H, dd, J = 2.8, 8.9 Hz), 8.51 (1H, d, J
= 2.8 Hz), 10.87 (1H, s); MS (FAB) m / z: 343 (M + H) + . (Example 175) N- [4-[(3,5-di-tert.
-Butyl-4-hydroxyphenyl) aminosulfonyl] phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide 4-[(3,5-di-tert-butyl-4-hydroxyphenyl) aminosulfonyl] aniline (0.27
g, 0.72 mmol), DMA (3 mL) and 2
-Chloro-5-nitrobenzoic acid chloride (0.17 g,
0.80 mmol) according to the method described in Example 2 to give the title object compound (0.32 g, yield 80%).
Got 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.27 (18H,
s), 6.76 (2H, s), 6.83 (1H, s), 7.66 (2H, d, J = 8.6
Hz), 7.82 (2H, d, J = 8.6 Hz), 7.90 (1H, d, J = 8.8 H
z), 8.33-8.37 (1H, m), 8.49 (1H, d, J = 2.7 Hz), 9.5
6-9.59 (1H, m), 11.05 (1H, s); MS (FAB) m / z: 559 M + . (Example 176) N- (3-dimethylamino) phenyl- (2-chloro-5-nitrophenyl) carboxamide 3-dimethylaminoaniline dihydrochloride (0.511)
g, 2.45 mmol), THF (10 mL), pyridine (2 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.59 g, 2.70 mmol) according to the method described in Example 2. did. Saturated aqueous sodium hydrogen carbonate (30 mL) was added to the reaction solution, and ethyl acetate (30 m
L). The organic layer was separated and saturated brine (20 m
Wash with L × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude title compound. The resulting crude title compound was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 (v / v)), solidified with diisopropyl ether, collected by filtration, dried, and dried. Target compound (0.38 g, yield 49
%) Was obtained. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 2.99 (6H,
s), 6.58 (1H, dd, J = 2.2, 8.3 Hz), 6.84 (1H, dd, J =
1.7, 7.8 Hz), 7.16 (1H, t, J = 2.2 Hz), 7.23 (1H, t,
J = 8.3 Hz), 7.65 (1H, d, J = 8.8 Hz), 7.74 (1H, bs),
8.25 (1H, dd, J = 2.7, 8.8 Hz); MS (FAB) m / z: 319 M + , 320 (M + H) + . (Example 177) N- [4- [4- (piperidine-1-
Iyl) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (piperidinylphenyl) aniline (0.25 g,
1.0 mmol), DMA (10 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.26 g, 1.
2 mmol) and according to the method described in Example 2 to obtain the title object compound (0.41 g, yield 94%). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.55-1.58
(2H, m), 1.61-1.66 (4H, m), 3.19 (4H, t, J = 5.2 Hz),
7.00 (2H, d, J = 8.7Hz), 7.52 (2H, d, J = 8.7Hz), 7.
62 (2H, d, J = 8.6 Hz), 7.74 (2H, d, J = 8.6 Hz), 7.91
(1H, d, J = 8.8Hz), 8.35 (1H, dd, J = 2.7, 8.8 Hz),
8.47 (1H, d, J = 2.7 Hz), 10.74 (1H, s); MS (FAB) m / z: 435 M + , 436 (M + H) + . Example 178 N- [4-[(piperidin-1-yl) aminosulfonyl] phenyl]-(2-chloro-5
-Nitrophenyl) carboxamide 4-[(piperidin-1-yl) aminosulfonyl] aniline (0.57 g, 2.27 mmol), DMA (5
mL) and 2-chloro-5-nitrobenzoic acid chloride (0.29 g, 1.33 mmol) according to the method described in Example 2 to give the title compound (0.30).
g, yield 31%). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 7.30 (1H, d
d, J = 4.7, 8.3 Hz), 7.50-7.54 (1H, m), 7.78 (2H, d,
J = 8.8 Hz), 7.86 (2H, d, J = 8.8 Hz), 7.90 (1H, d, J
= 8.8 Hz), 8.26 (1H, d, J = 4.7 Hz), 8.29 (1H, d, J =
2.5 Hz), 8.35 (1H, dd, J = 2.7, 8.8 Hz), 8.52 (1H,
d, J = 2.7 Hz), 10.52 (1H, s), 11.09 (1H, s). (Example 179) N- [4- [4- (morpholine-4-
Yl) phenyl] aminosulfonyl] phenyl- (2-
Chloro-5-nitrophenyl) carboxamide [4- [4- (morpholin-4-yl) phenyl] aminosulfonyl] aniline (0.40 g, 1.21 mmo
l), DMA (5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.29 g, 1.33 mmol).
Was used according to the method described in Example 2 to give the title object compound (0.51 g, yield 81%). 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 3.01 (4H,
t, J = 4.8 Hz), 3.69 (4H, t, J = 4.8 Hz), 6.83 (2H, d,
J = 9.1 Hz), 6.94 (2H, d, J = 9.1 Hz), 7.72 (2H, d, J =
8.7 Hz), 7.82 (2H, d, J = 8.7 Hz), 7.90 (1H, d, J = 8.
8 Hz), 8.35 (1H, dd, J = 2.7, 8.8 Hz), 8.52 (1H, d, J
= 2.7 Hz), 9.79 (1H, s), 11.05 (1H, s); MS (FAB) m / z: 516 M + , 517 (M + H) + . (Example 180) N- (4-aminophenyl)-(2-
Chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 58
(2-chloro-5-nitrophenyl) carboxamide
The monohydrochloride (4.89 g, 14.9 mmol) was suspended in saturated aqueous sodium hydrogen carbonate (200 mL) and water (100 mL), and 2
Stir for hours. The resulting crystals were collected by filtration, washed with water, and dried to give the title object compound (4.29 g, yield 99%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 4.99 (1H, bs),
6.55 (2H, d, J = 8.8 Hz), 7.34 (2H, d, J = 8.8 Hz),
7.86 (1H, d, J = 8.8 Hz), 8.31 (1H, dd, J = 8.8, 2.8
Hz), 8.37 (1H, d, J = 2.8 Hz), 10.26 (1H, s); MS (FAB) m / z: 292 (M + H) + . Example 181 N- [4- (N-propylamino) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- (4-aminophenyl)-(2-chloro-) prepared in Example 180.
5-nitrophenyl) carboxamide (0.583 g,
2.00 mmol), methanol (10 mL), sodium cyanoborohydride (0.151 g, 2.40 mm)
ol) and propionaldehyde (0.289 mL,
(4.00 mmol) and following the method described in Example 115 to give the title object compound (0.307 g, yield 46%) as a highly polar compound.
【0238】Rf 0.20 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 1.01 (3H, t, J=7.3
Hz), 1.66 (2H, tq, J=7.3 Hz), 3.10 (2H, t, J=7.3
Hz), 6.62 (2H, d, J=8.8 Hz), 7.41 (2H, d, J=8.8 H
z), 7.63 (1H, br), 7.64 (1H, d, J=8.8 Hz), 8.24 (1
H, dd, J=8.8, 2.9Hz), 8.61 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 333 M+。
(実施例182)N−[4−(N、N−ジプロピルアミ
ノ)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド
実施例181において、低極性化合物として、標記目的
化合物(0.099g、収率13%)を得た。R f 0.20 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.01 (3H, t, J = 7.3
Hz), 1.66 (2H, tq, J = 7.3 Hz), 3.10 (2H, t, J = 7.3
Hz), 6.62 (2H, d, J = 8.8 Hz), 7.41 (2H, d, J = 8.8 H
z), 7.63 (1H, br), 7.64 (1H, d, J = 8.8 Hz), 8.24 (1
H, dd, J = 8.8, 2.9Hz), 8.61 (1H, d, J = 2.9Hz); MS (FAB) m / z: 333 M + . Example 182 N- [4- (N, N-dipropylamino) phenyl]-(2-chloro-5-nitrophenyl)
In Carboxamide Example 181, the title compound (0.099 g, yield 13%) was obtained as a low-polarity compound.
【0239】Rf 0.47 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.93 (6H, t, J=7.3
Hz), 1.61 (4H, tq, J=7.3 Hz), 3.24 (4H, t, J=7.3
Hz), 6.64 (2H, d, J=8.8 Hz), 7.42 (2H, d, J=8.8 H
z), 7.62 (1H, br), 7.63 (1H, d, J=8.8 Hz), 8.24 (1
H, dd, J=8.8, 2.9Hz), 8.61 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 375 M+。
(実施例183)N−[4−(4−アセチルピペラジン
−1−イル)フェニル]−(2−クロロ−5−ニトロフ
ェニル)カルボキサミド
実施例133で製造したN−[(4−ピペラジン−1−
イル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド・2塩酸塩(0.200g、0.4
61mmol)をピリジン(2mL)に溶解し、無水酢
酸(0.131mL、1.18mmol)を加えて、室
温で1時間攪拌した。反応溶液に飽和重曹水(2m
L)、水(20mL)を加え、生じた固形物を濾取し、
水及びジイソプロピルエーテルで洗浄し、減圧乾燥し
て、標記目的化合物(0.164g、収率88%)を得
た。1
H-NMR (400MHz, CDCl3): δ(ppm) 2.15 (3H, s), 3.14
(2H, t, J=5.5 Hz), 3.19 (2H, t, J=5.5 Hz), 3.64
(2H, t, J=5.1 Hz), 3.78 (2H, t, J=5.1 Hz), 6.96 (2
H, d, J=8.8 Hz), 7.55 (2H, d, J=8.8 Hz), 7.66 (1H,
d, J=8.8 Hz), 7.81 (1H, br), 8.26 (1H, dd, J=8.8,
2.9 Hz), 8.61 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 403 (M + H)+。
(実施例184)N−[4−(4−ベンゾイルピペラジ
ン−1−イル)フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
実施例133で製造したN−[(4−ピペラジン−1−
イル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド・2塩酸塩(0.200g、0.4
61mmol)、安息香酸クロリド(0.107mL、
0.922mmol)及びピリジン(2mL)を使用し
て、実施例183に記載した方法に従い、標記目的化合
物(0.020g、収率9%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 3.20 (4H, m), 3.62
(2H, m), 3.95 (2H, m), 6.96 (2H, d, J=8.8 Hz), 7.
44 (5H, m), 7.55 (2H, d, J=8.8 Hz), 7.66 (1H, d, J
=8.8 Hz), 7.77 (1H, br), 8.26 (1H, dd, J=8.8, 2.9
Hz), 8.61 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 465 (M + H)+。
(実施例185)N−[4−[4−(N、N−ジオクチ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド・塩酸塩
4−[4−(N、N−ジオクチルアミノ)フェニル]ア
ニリン(0.31g、0.75mmol)、DMA(1
0mL)ならびに2−クロロ−5−ニトロ安息香酸クロ
リド(0.20g、0.91mmol)を使用して、実
施例2に記載した方法に従い、油状物質を得た。得られ
た油状物質を、実施例146に記載した方法に従い、4
N塩化水素−1,4−ジオキサン溶液0.4mLで処理
して、標記目的化合物(0.47g、収率99%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 0.83 (6H, t, J=
6.7 Hz), 1.12-1.80 (24H, m), 4.7-5.2 (4H, m), 7.7-
7.9 (8H, m), 7.91 (2H, d, J= 8.8 Hz), 8.36 (1H, d
d, J= 2.7, 8.8 Hz), 8.49 (1H, d, J= 2.7 Hz), 10.88
(1H,s);
MS(FAB) m/z: 591 M+, 592 (M + H)+。
(実施例186)N−[4−[4−(ピロール−1−イ
ル)フェニル]フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
(186a)4−[4−(ピロール−1−イル)フェニ
ル]ニトロベンゼン
4−(4−ニトロフェニル)アニリン(8.49g、3
9.6mmol)の酢酸(40mL)懸濁液に2,5−
ジメトキシテトラヒドロフラン(10.47g、79.
2mmol)を加え、5時間加熱還流した。反応液を冷
却した後、ジエチルエーテル(200mL)を加えて攪
拌し、生じた結晶を濾取し、乾燥して、標記目的化合物
(9.65g、収率92%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 6.32 (2H, t, J=
2.2 Hz), 7.49 (2H, t,J= 2.2 Hz), 7.76 (2H, d, J=
8.7 Hz), 7.90 (2H, d, J= 8.7 Hz), 8.02 (2H,d, J=
8.8 Hz), 8.31 (2H, d, J= 8.8 Hz), 10.82 (1H,s)。
(186b)4−[4−(ピロール−1−イル)フェニ
ル]アニリン
実施例186aで製造した4−[(4−ピロール−1−
イル)フェニル]ニトロベンゼン(9.65g、36.
5mmol)の1,4−ジオキサン−メタノール(2:
1(v/v)、300mL)の溶液にニッケルクロリド6水
和物(17.36g、73.0mmol)を加えた後、
氷水冷却下にて水素化ホウ素ナトリウム(5.53g、
146mmol)を徐々に加えた。反応液を濃縮し、飽
和重曹水(400mL)及び酢酸エチル(400mL)
を加えて、30分間攪拌した後、不溶物を濾別した。濾
液を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し
た後、無水硫酸ナトリウムで乾燥し、濾過し、濃縮し
て、標記目的化合物(6.67g、収率78%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 5.25 (2H, bs),
6.26 (2H, t, J=2.2 Hz),6.65 (2H, d, J=8.6 Hz), 7.3
7 (2H, d, J=2.2 Hz), 7.39 (2H, d, J=8.6 Hz),7.56
(2H, d, J=8.8 Hz), 7.65 (2H, d, J=8.8 Hz)。
(186c)N−[4−[4−(ピロール−1−イル)
フェニル]フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
実施例186bで製造した[4−(4−ピロール−1−
イル)フェニル]アニリン(0.47g、2.0mmo
l)、DMA(10mL)ならびに2−クロロ−5−ニ
トロ安息香酸クロリド(0.53g、2.40mmo
l)を使用して、実施例2に記載した方法に従い、標記
目的化合物(0.75g、収率90%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 6.30 (2H, t, J=
2.0 Hz), 7.43 (2H, t, J=2.0 Hz), 7.67 (2H, d, J=8.
6 Hz), 7.7-7.83 (6H, m), 7.92 (1H, d, J=8.5 Hz),
8.36 (1H, dd, J=8.5, 2.7 Hz), 8.50 (1H, d, J=2.7 H
z), 10.82 (1H, s);MS(FAB) m/z: 418 (M + H)+。
(実施例187)N−[[4−[4−(イミダゾール−
1−イル)フェニル]アミノスルホニル]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
4−[[4−(イミダゾール−1−イル)フェニル]ア
ミノスルホニル]アニリン(0.31g、1.0mmo
l)、DMA(10mL)ならびに2−クロロ−5−ニ
トロ安息香酸クロリド(0.26g、1.2mmol)
を使用して、実施例2に記載した方法に従い、標記目的
化合物(0.30g、収率61%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.06 (1H, s), 7.
21 (2H, d, J=8.7 Hz),7.53 (2H, d, J=8.7 Hz), 7.63
(1H, s), 7.80 (2H, d, J=8.8 Hz), 7.85 (2H,d, J=8.8
Hz), 7.89 (1H, d, J=8.8 Hz), 7.96-8.03 (1H, m),
8.13 (1H, s), 8.35 (1H, dd, J=8.8, 2.7 Hz), 8.51
(1H, d, J=2.7 Hz), 10.44 (1H, bs), 11.08 (1H, s);
MS(FAB) m/z: 498 (M + H)+。
(実施例188)N−[4−(N−エチル−N−ヘキシ
ルアミノ)フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
実施例115で製造したN−[4−(N−エチルアミ
ノ)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.062g、0.195mmo
l)、メタノール(1.2mL)、シアノ水素化ホウ素
ナトリウム(0.015g、0.234mmol)及び
ヘキサナール(0.035mL、0.293mmol)
を使用して、実施例115に記載した方法に従い、標記
目的化合物(0.019g、収率25%)を得た。R f 0.47 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.93 (6H, t, J = 7.3
Hz), 1.61 (4H, tq, J = 7.3 Hz), 3.24 (4H, t, J = 7.3
Hz), 6.64 (2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.8 H
z), 7.62 (1H, br), 7.63 (1H, d, J = 8.8 Hz), 8.24 (1
H, dd, J = 8.8, 2.9 Hz), 8.61 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 375 M + . Example 183 N- [4- (4-Acetylpiperazin-1-yl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N-[(4-Piperazin-1-
Iyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide dihydrochloride (0.200 g, 0.4
61 mmol) was dissolved in pyridine (2 mL), acetic anhydride (0.131 mL, 1.18 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Saturated sodium hydrogen carbonate solution (2m
L) and water (20 mL) were added, the resulting solid matter was collected by filtration,
It was washed with water and diisopropyl ether, and dried under reduced pressure to give the title object compound (0.164 g, yield 88%). 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 2.15 (3H, s), 3.14
(2H, t, J = 5.5 Hz), 3.19 (2H, t, J = 5.5 Hz), 3.64
(2H, t, J = 5.1 Hz), 3.78 (2H, t, J = 5.1 Hz), 6.96 (2
H, d, J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz), 7.66 (1H,
d, J = 8.8 Hz), 7.81 (1H, br), 8.26 (1H, dd, J = 8.8,
2.9 Hz), 8.61 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 403 (M + H) + . Example 184 N- [4- (4-Benzoylpiperazin-1-yl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N-[(4-Piperazin-1-) prepared in Example 133.
Iyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide dihydrochloride (0.200 g, 0.4
61 mmol), benzoic acid chloride (0.107 mL,
According to the method described in Example 183 using 0.922 mmol) and pyridine (2 mL), the title object compound (0.020 g, yield 9%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 3.20 (4H, m), 3.62
(2H, m), 3.95 (2H, m), 6.96 (2H, d, J = 8.8 Hz), 7.
44 (5H, m), 7.55 (2H, d, J = 8.8 Hz), 7.66 (1H, d, J
= 8.8 Hz), 7.77 (1H, br), 8.26 (1H, dd, J = 8.8, 2.9
Hz), 8.61 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 465 (M + H) + . Example 185 N- [4- [4- (N, N-Dioctylamino) phenyl] phenyl]-(2-chloro-5-
Nitrophenyl) carboxamide hydrochloride 4- [4- (N, N-dioctylamino) phenyl] aniline (0.31 g, 0.75 mmol), DMA (1
0 mL) as well as 2-chloro-5-nitrobenzoic acid chloride (0.20 g, 0.91 mmol) were used according to the method described in Example 2 to give an oil. The resulting oily material was treated with 4 according to the method described in Example 146.
Treatment with 0.4 mL of N hydrogen chloride-1,4-dioxane solution gave the title object compound (0.47 g, yield 99%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 0.83 (6H, t, J =
6.7 Hz), 1.12-1.80 (24H, m), 4.7-5.2 (4H, m), 7.7-
7.9 (8H, m), 7.91 (2H, d, J = 8.8 Hz), 8.36 (1H, d
d, J = 2.7, 8.8 Hz), 8.49 (1H, d, J = 2.7 Hz), 10.88
(1H, s); MS (FAB) m / z: 591 M + , 592 (M + H) + . Example 186 N- [4- [4- (Pyrrol-1-yl) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide (186a) 4- [4- (pyrrol-1-yl) ) Phenyl] nitrobenzene 4- (4-nitrophenyl) aniline (8.49 g, 3
9.5 mmol) in acetic acid (40 mL) suspension in 2,5-
Dimethoxytetrahydrofuran (10.47 g, 79.
2 mmol) was added and the mixture was heated under reflux for 5 hours. After cooling the reaction solution, diethyl ether (200 mL) was added and the mixture was stirred, and the resulting crystals were collected by filtration and dried to give the title object compound (9.65 g, yield 92%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 6.32 (2H, t, J =
2.2 Hz), 7.49 (2H, t, J = 2.2 Hz), 7.76 (2H, d, J =
8.7 Hz), 7.90 (2H, d, J = 8.7 Hz), 8.02 (2H, d, J =
8.8 Hz), 8.31 (2H, d, J = 8.8 Hz), 10.82 (1H, s). (186b) 4- [4- (Pyrrol-1-yl) phenyl] aniline 4-[(4-pyrrole-1-) prepared in Example 186a.
Ill) phenyl] nitrobenzene (9.65 g, 36.
5 mmol of 1,4-dioxane-methanol (2:
1 (v / v), 300 mL) solution was added with nickel chloride hexahydrate (17.36 g, 73.0 mmol),
Sodium borohydride (5.53 g,
146 mmol) was added slowly. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate (400 mL) and ethyl acetate (400 mL).
Was added and stirred for 30 minutes, and then the insoluble matter was filtered off. The filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title object compound (6.67 g, yield 78%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 5.25 (2H, bs),
6.26 (2H, t, J = 2.2 Hz), 6.65 (2H, d, J = 8.6 Hz), 7.3
7 (2H, d, J = 2.2 Hz), 7.39 (2H, d, J = 8.6 Hz), 7.56
(2H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.8 Hz). (186c) N- [4- [4- (pyrrol-1-yl)
Phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide [4- (4-pyrrole-1-) prepared in Example 186b.
Il) phenyl] aniline (0.47 g, 2.0 mmo
l), DMA (10 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.53 g, 2.40 mmo).
The title compound (0.75 g, yield 90%) was obtained according to the method described in Example 2 using l). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 6.30 (2H, t, J =
2.0 Hz), 7.43 (2H, t, J = 2.0 Hz), 7.67 (2H, d, J = 8.
6 Hz), 7.7-7.83 (6H, m), 7.92 (1H, d, J = 8.5 Hz),
8.36 (1H, dd, J = 8.5, 2.7 Hz), 8.50 (1H, d, J = 2.7 H)
z), 10.82 (1H, s); MS (FAB) m / z: 418 (M + H) + . (Example 187) N-[[4- [4- (imidazole-
1-yl) phenyl] aminosulfonyl] phenyl]-
(2-chloro-5-nitrophenyl) carboxamide 4-[[4- (imidazol-1-yl) phenyl] aminosulfonyl] aniline (0.31 g, 1.0 mmo
l), DMA (10 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.26 g, 1.2 mmol).
Was used according to the method described in Example 2 to give the title object compound (0.30 g, yield 61%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.06 (1H, s), 7.
21 (2H, d, J = 8.7 Hz), 7.53 (2H, d, J = 8.7 Hz), 7.63
(1H, s), 7.80 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8
Hz), 7.89 (1H, d, J = 8.8 Hz), 7.96-8.03 (1H, m),
8.13 (1H, s), 8.35 (1H, dd, J = 8.8, 2.7 Hz), 8.51
(1H, d, J = 2.7 Hz), 10.44 (1H, bs), 11.08 (1H, s); MS (FAB) m / z: 498 (M + H) + . Example 188 N- [4- (N-ethyl-N-hexylamino) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (N-ethylamino) prepared in Example 115. ) Phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.062g, 0.195mmo
l), methanol (1.2 mL), sodium cyanoborohydride (0.015 g, 0.234 mmol) and hexanal (0.035 mL, 0.293 mmol).
According to the method described in Example 115, was obtained the title object compound (0.019 g, yield 25%).
【0240】Rf 0.52 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.90 (3H, t, J=7.3
Hz), 1.15 (3H, t, J=7.3 Hz), 1.32 (6H, m), 1.58
(2H, m), 3.25 (2H, t, J=7.3 Hz), 3.37 (2H, q,J=7.3
Hz), 6.65 (2H, d, J=8.8 Hz), 7.42 (2H, d, J=8.8 H
z), 7.62 (1H, d,J=8.8 Hz), 7.69 (1H, br), 8.22 (1
H, dd, J=8.8, 2.9 Hz), 8.58 (1H, m);
MS(FAB) m/z: 403 M+。
(実施例189)N−[4−(N−エチル−N−プロピ
ルアミノ)フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
実施例181で製造したN−[4−(N−プロピルアミ
ノ)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.056g、0.168mmo
l)、メタノール(2mL)、シアノ水素化ホウ素ナト
リウム(0.021g、0.294mmol)及びアセ
トアルデヒド(0.016mL、0.294mmol)
を使用して、実施例115に記載した方法に従い、標記
目的化合物(0.029g、収率54%)を得た。R f 0.52 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.90 (3H, t, J = 7.3
Hz), 1.15 (3H, t, J = 7.3 Hz), 1.32 (6H, m), 1.58
(2H, m), 3.25 (2H, t, J = 7.3 Hz), 3.37 (2H, q, J = 7.3
Hz), 6.65 (2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.8 H
z), 7.62 (1H, d, J = 8.8 Hz), 7.69 (1H, br), 8.22 (1
H, dd, J = 8.8, 2.9 Hz), 8.58 (1H, m); MS (FAB) m / z: 403 M + . Example 189 N- [4- (N-ethyl-N-propylamino) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (N-propylamino) prepared in Example 181. ) Phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.056g, 0.168mmo
l), methanol (2 mL), sodium cyanoborohydride (0.021 g, 0.294 mmol) and acetaldehyde (0.016 mL, 0.294 mmol).
Was used according to the method described in Example 115 to give the title object compound (0.029 g, yield 54%).
【0241】Rf 0.26 (ヘキサン:酢酸エチル=9:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.94 (3H, t, J=7.3
Hz), 1.16 (3H, t, J=7.3 Hz), 1.62 (2H, tq, J=7.3
Hz), 3.22 (2H, t, J=7.3 Hz), 3.38 (2H, q, J=7.3 H
z), 6.65 (2H, d, J=8.8 Hz), 7.41 (2H, d, J=8.8 H
z), 7.62 (1H, d, J=8.8 Hz), 7.69 (1H, br), 8.22 (1
H, dd, J=8.8, 2.9 Hz), 8.58 (1H, d, J=2.9Hz);
MS(FAB) m/z: 361 M+。
(実施例190)N−[4−(4−tert−ブトキシ
カルボニルアミノフェニル)チアゾール−2−イル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(190a)2−アミノ−4−(4−tert−ブトキ
シカルボニルアミノフェニル)チアゾール
2−アミノ−4−(4−アミノフェニル)チアゾール
(2.15g、11.2mmol)のメタノール(30
mL)溶液にジ−tert−ブチルジカーボネート
(2.94g、13.5mmol)を加え、一晩放置し
た。反応溶液を濃縮し、飽和重曹水(50mL)及び酢
酸エチル(50mL)を加え、1時間攪拌した。反応液
を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した
後、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をジ
イソプロピルエーテル(IPE)で結晶化し、濾取し
て、標記目的化合物(1.80g、収率55%)を得
た。(190b)N−[4−(4−tert−ブトキシ
カルボニルアミノフェニル)チアゾール−2−イル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド実
施例190aで製造した2−アミノ−4−(4−ter
t−ブトキシカルボニルアミノフェニル)チアゾール
(0.49g、1.67mmol)、DMA(5mL)
ならびに2−クロロ−5−ニトロ安息香酸クロリド
(0.40g、1.84mmol)を使用して、実施例
2に記載した方法に従い、標記目的化合物(0.55
g、収率69%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.52 (2H, d, J=
8.7 Hz), 7.56 (1H, s),7.81 (2H, d, J=8.7 Hz), 7.88
(1H, d, J=8.8 Hz), 8.35 (1H, dd, J=8.8, 2.7Hz),
9.46 (1H, s);
MS(FAB) m/z: 475 (M + H)+。
(実施例191)N−(3−ヒドロキシフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド
3−アミノフェノール(1.09g、10.0mmo
l)、DMA(20mL)ならびに2−クロロ−5−ニ
トロ安息香酸クロリド(2.31g、10.5mmo
l)を使用して、実施例2に記載した方法に従い、標記
目的化合物(2.19g、収率75%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 6.52-6.55 (1H,
m), 7.04-7.07 (1H, m),7.14 (1H, t, J=8.0 Hz), 7.30
(1H, t, J=2.1 Hz), 7.88 (1H, d, J=8.9 Hz),8.33 (1
H, dd, J=8.9, 2.8 Hz), 8.43 (1H, d, J=2.8 Hz), 9.4
9 (1H, s), 10.57 (1H, s) ;
MS(FAB) m/z: 292 (M + H)+。
(実施例192)N−[4−(4−アミノフェニル)フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
実施例87で製造したN−[4−[4−(N−tert
−ブトキシカルボニル)アミノフェニル]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(4.37g、9.34mmol)の塩化メチレン(1
00mL)溶液にアニソール(1mL)及びトリフルオ
ロ酢酸(10mL)を加え、2時間攪拌した。反応液を
濃縮した後、飽和重曹水(300mL)及び水(200
mL)を加え1時間攪拌した。ジイソプロピルエーテル
(50mL)を加え30分間攪拌した。析出した固体を
濾取し、乾燥して、標記目的化合物(3.38g、収率
98%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 5.19 (1H, d, J=
8.2 Hz), 6.64 (2H, d, J=8.5 Hz), 7.36 (2H, d, J=8.
5 Hz), 7.55 (2H, d, J=8.7 Hz), 7.71 (2H, d, J=8.7
Hz), 7.90 (1H, d, J=8.8 Hz), 8.34 (1H, dd, J=8.8,
2.8 Hz), 8.47 (1H, d, J=2.8 Hz), 10.70 (1H, s);
MS(FAB) m/z: 367 M+, 368 (M + H)+。
(実施例193)N−(4−ヒドロキシフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド
4−アミノフェノール(3.52g、32.3mmo
l)、DMA(50mL)ならびに2−クロロ−5−ニ
トロ安息香酸クロリド(7.45g、33.9mmo
l)を使用して、実施例2に記載した方法に従い、標記
目的化合物(6.29g、収率74%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 6.76 (2H, d, J=
8.8 Hz), 7.49 (2H, d, J=8.8 Hz), 7.88 (1H, d, J=8.
8 Hz), 8.32 (1H, d, J=8.8, 2.7 Hz), 8.41 (1H,d, J=
2.7 Hz), 9.34 (1H, s), 10.45 (1H, s);
MS(FAB) m/z: 292 M+。
(実施例194)N−[4−[4−(N、N−ジプロピ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド
4−[4−(N、N−ジプロピルアミノ)フェニル]ア
ニリン(0.045g、0.17mmol)、DMA
(5mL)ならびに2−クロロ−5−ニトロ安息香酸ク
ロリド(0.044g、0.2mmol)を使用して、
実施例2に記載した方法に従い、標記目的化合物(72
mg、収率96%)を得た。R f 0.26 (hexane: ethyl acetate = 9: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.94 (3H, t, J = 7.3
Hz), 1.16 (3H, t, J = 7.3 Hz), 1.62 (2H, tq, J = 7.3
Hz), 3.22 (2H, t, J = 7.3 Hz), 3.38 (2H, q, J = 7.3 H
z), 6.65 (2H, d, J = 8.8 Hz), 7.41 (2H, d, J = 8.8 H
z), 7.62 (1H, d, J = 8.8 Hz), 7.69 (1H, br), 8.22 (1
H, dd, J = 8.8, 2.9 Hz), 8.58 (1H, d, J = 2.9Hz); MS (FAB) m / z: 361 M + . (Example 190) N- [4- (4-tert-butoxycarbonylaminophenyl) thiazol-2-yl]-
(2-chloro-5-nitrophenyl) carboxamide (190a) 2-amino-4- (4-tert-butoxycarbonylaminophenyl) thiazole 2-amino-4- (4-aminophenyl) thiazole (2.15 g, 11 0.2 mmol of methanol (30
(mL) solution was added with di-tert-butyl dicarbonate (2.94 g, 13.5 mmol) and left overnight. The reaction solution was concentrated, saturated aqueous sodium hydrogen carbonate (50 mL) and ethyl acetate (50 mL) were added, and the mixture was stirred for 1 hr. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was crystallized from diisopropyl ether (IPE) and collected by filtration to give the title object compound (1.80 g, yield 55%). (190b) N- [4- (4-tert-butoxycarbonylaminophenyl) thiazol-2-yl]-
(2-Chloro-5-nitrophenyl) carboxamide 2-amino-4- (4-ter) prepared in Example 190a.
t-butoxycarbonylaminophenyl) thiazole (0.49 g, 1.67 mmol), DMA (5 mL)
And 2-chloro-5-nitrobenzoic acid chloride (0.40 g, 1.84 mmol) according to the method described in Example 2 to give the title compound (0.55
g, yield 69%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.52 (2H, d, J =
8.7 Hz), 7.56 (1H, s), 7.81 (2H, d, J = 8.7 Hz), 7.88
(1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 8.8, 2.7Hz),
9.46 (1H, s); MS (FAB) m / z: 475 (M + H) + . (Example 191) N- (3-hydroxyphenyl)-
(2-Chloro-5-nitrophenyl) carboxamide 3-aminophenol (1.09 g, 10.0 mmo
l), DMA (20 mL) and 2-chloro-5-nitrobenzoic acid chloride (2.31 g, 10.5 mmo).
According to the method described in Example 2 using l), the title object compound (2.19 g, yield 75%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 6.52-6.55 (1H,
m), 7.04-7.07 (1H, m), 7.14 (1H, t, J = 8.0 Hz), 7.30
(1H, t, J = 2.1 Hz), 7.88 (1H, d, J = 8.9 Hz), 8.33 (1
H, dd, J = 8.9, 2.8 Hz), 8.43 (1H, d, J = 2.8 Hz), 9.4
9 (1H, s), 10.57 (1H, s); MS (FAB) m / z: 292 (M + H) + . Example 192 N- [4- (4-aminophenyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-tert) prepared in Example 87.
-Butoxycarbonyl) aminophenyl] phenyl]-
(2-Chloro-5-nitrophenyl) carboxamide (4.37 g, 9.34 mmol) in methylene chloride (1
Anisole (1 mL) and trifluoroacetic acid (10 mL) were added to the solution (00 mL) and the mixture was stirred for 2 hours. After the reaction solution was concentrated, saturated aqueous sodium hydrogen carbonate (300 mL) and water (200 mL) were added.
(mL) was added and stirred for 1 hour. Diisopropyl ether (50 mL) was added and stirred for 30 minutes. The precipitated solid was collected by filtration and dried to give the title object compound (3.38 g, yield 98%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 5.19 (1H, d, J =
8.2 Hz), 6.64 (2H, d, J = 8.5 Hz), 7.36 (2H, d, J = 8.
5 Hz), 7.55 (2H, d, J = 8.7 Hz), 7.71 (2H, d, J = 8.7
Hz), 7.90 (1H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 8.8,
2.8 Hz), 8.47 (1H, d, J = 2.8 Hz), 10.70 (1H, s); MS (FAB) m / z: 367 M + , 368 (M + H) + . (Example 193) N- (4-hydroxyphenyl)-
(2-Chloro-5-nitrophenyl) carboxamide 4-aminophenol (3.52 g, 32.3 mmo
l), DMA (50 mL) and 2-chloro-5-nitrobenzoic acid chloride (7.45 g, 33.9 mmo).
By using l) and following the method described in Example 2, the title object compound (6.29 g, yield 74%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 6.76 (2H, d, J =
8.8 Hz), 7.49 (2H, d, J = 8.8 Hz), 7.88 (1H, d, J = 8.
8 Hz), 8.32 (1H, d, J = 8.8, 2.7 Hz), 8.41 (1H, d, J =
2.7 Hz), 9.34 (1H, s), 10.45 (1H, s); MS (FAB) m / z: 292 M + . Example 194 N- [4- [4- (N, N-dipropylamino) phenyl] phenyl]-(2-chloro-5-
Nitrophenyl) carboxamide 4- [4- (N, N-dipropylamino) phenyl] aniline (0.045 g, 0.17 mmol), DMA
(5 mL) as well as 2-chloro-5-nitrobenzoic acid chloride (0.044 g, 0.2 mmol),
According to the method described in Example 2, the title compound (72
mg, yield 96%).
【0242】1H-NMR (400MHz, DMSO-d6): δ(ppm) 0.90
(6H, t, J=7.4 Hz), 1.50-1.60 (4H, m), 3.27 (4H,
t, J=7.4 Hz), 6.70 (2H, d, J=8.8 Hz), 7.47 (2H, d,
J=8.8 Hz), 7.58 (2H, d, J=8.7 Hz), 7.72 (2H, d, J
=8.7 Hz), 7.90 (1H, d, J=8.8 Hz), 8.35 (1H, dd, J=
8.8, 2.8 Hz), 8.47 (1H, d, J=2.8 Hz), 10.71 (1H,
s);
MS(FAB) m/z: 452 (M + H)+。
(実施例195)N−[4−[4−(N−ヘキシルアミ
ノ)フェニル]フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(2.04g、5.55mmol)をメ
タノール(40mL)に懸濁させ、シアノ水素化ホウ素
ナトリウム(0.698g、11.1mmol)及びヘ
キサナール(1.33mL、11.1mmol)を加え
て、0℃で4時間、室温で12時間攪拌した。反応溶液
に飽和重曹水(200mL)を加え、生じた固形物を濾
取し、水及びジイソプロピルエーテルで洗浄し、減圧乾
燥して、標記目的化合物(2.02g、収率82%)を
得た。 1 H-NMR (400 MHz, DMSO-d 6 ): δ (ppm) 0.90
(6H, t, J = 7.4 Hz), 1.50-1.60 (4H, m), 3.27 (4H,
t, J = 7.4 Hz), 6.70 (2H, d, J = 8.8 Hz), 7.47 (2H, d,
J = 8.8 Hz), 7.58 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J
= 8.7 Hz), 7.90 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J =
8.8, 2.8 Hz), 8.47 (1H, d, J = 2.8 Hz), 10.71 (1H,
s); MS (FAB) m / z: 452 (M + H) + . Example 195 N- [4- [4- (N-hexylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-amino) prepared in Example 192. Phenyl) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (2.04 g, 5.55 mmol) was suspended in methanol (40 mL), sodium cyanoborohydride (0.698 g, 11.1 mmol) and hexanal (1.33 mL, 11.1 mmol) were added to 0. The mixture was stirred at 4 ° C for 4 hours and at room temperature for 12 hours. Saturated aqueous sodium hydrogen carbonate (200 mL) was added to the reaction solution, the resulting solid was collected by filtration, washed with water and diisopropyl ether, and dried under reduced pressure to give the title object compound (2.02 g, yield 82%). .
【0243】Rf 0.83 (ヘキサン:酢酸エチル=1:1(v/
v));1
H-NMR (400MHz, DMSO-d6): δ(ppm) 0.88 (3H, t, J=
6.6 Hz), 1.26-1.42 (6H,m), 1.56 (2H, m), 3.25 (2H,
t, J=7.3 Hz), 5.75 (1H, br), 6.63 (2H, d, J=8.8 H
z), 7.41 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 H
z), 7.71 (2H, d, J=8.8 Hz), 7.90 (1H, d, J=8.8 H
z), 8.35 (1H, dd, J=8.8, 2.9 Hz), 8.47 (1H, d, J=
2.9 Hz), 10.70 (1H, s);
MS(FAB) m/z: 451 M+。
(実施例196)N−[4−[4−(N−ヘキシル−N
−メチルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例195で製造したN−[4−[4−(N−ヘキシ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.200g、0.
433mmol)をDMF(2mL)に溶解させ、水素
化ナトリウム(0.021g、0.487mmol)を
加えた。0℃で30分間攪拌した後、ヨウ化メチル
(0.033mL、0.531mmol)を加えて15
分間攪拌した。反応溶液に水(20mL)及び飽和重曹
水(1mL)を加え、酢酸エチルで抽出した。有機層を
無水硫酸ナトリウムで乾燥し、濃縮した。得られた残渣
をシリカゲルカラムクロマトグラフィー(ヘキサン:酢
酸エチル=3:1(v/v))にて精製し、標記目的化合物
(0.185g、収率90%)を得た。R f 0.83 (hexane: ethyl acetate = 1: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 0.88 (3H, t, J =
6.6 Hz), 1.26-1.42 (6H, m), 1.56 (2H, m), 3.25 (2H,
t, J = 7.3 Hz), 5.75 (1H, br), 6.63 (2H, d, J = 8.8 H
z), 7.41 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 H
z), 7.71 (2H, d, J = 8.8 Hz), 7.90 (1H, d, J = 8.8 H
z), 8.35 (1H, dd, J = 8.8, 2.9 Hz), 8.47 (1H, d, J =
2.9 Hz), 10.70 (1H, s); MS (FAB) m / z: 451 M + . (Example 196) N- [4- [4- (N-hexyl-N
-Methylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-hexylamino) phenyl] phenyl]-(2-chloro- prepared in Example 195. 5-
Nitrophenyl) carboxamide (0.200 g, 0.
433 mmol) was dissolved in DMF (2 mL) and sodium hydride (0.021 g, 0.487 mmol) was added. After stirring at 0 ° C. for 30 minutes, methyl iodide (0.033 mL, 0.531 mmol) was added and the mixture was added to 15
Stir for minutes. Water (20 mL) and saturated aqueous sodium hydrogen carbonate (1 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 (v / v)) to give the title object compound (0.185 g, yield 90%).
【0244】Rf 0.43 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.89 (3H, t, J=6.6
Hz), 1.30-1.45 (6H, m), 1.56 (2H, tt, J=7.3 Hz),
3.11 (2H, t, J=7.3 Hz), 3.53 (3H, s), 3.76 (1H, b
r), 6.60 (2H, d, J=8.8 Hz), 7.13 (2H, d, J=8.1 H
z), 7.31 (2H, d, J=8.1 Hz), 7.36 (3H, m), 7.96 (1
H, dd, J=8.8, 2.9 Hz), 8.06 (1H, d, J=2.9Hz);
MS(FAB) m/z: 465 M+。
(実施例197)N−[4−[4−(N−エチル−N−
ヘキシルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例195で製造したN−[4−[4−(N−ヘキシ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.169g、0.
352mmol)をメタノール(2mL)に懸濁させ、
シアノ水素化ホウ素ナトリウム(0.150g、2.3
9mmol)、アセトアルデヒド(0.500mL、
8.94mmol)及び触媒量の濃硫酸を加えて、0℃
で4時間、室温で14時間攪拌した。反応溶液に飽和重
曹水(2mL)及び水(20mL)を加え、生じた固形
物を濾取し、水及びジイソプロピルエーテルで洗浄し、
減圧乾燥して、標記目的化合物(0.112g、収率6
2%)を得た。R f 0.43 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.89 (3H, t, J = 6.6
Hz), 1.30-1.45 (6H, m), 1.56 (2H, tt, J = 7.3 Hz),
3.11 (2H, t, J = 7.3 Hz), 3.53 (3H, s), 3.76 (1H, b
r), 6.60 (2H, d, J = 8.8 Hz), 7.13 (2H, d, J = 8.1 H
z), 7.31 (2H, d, J = 8.1 Hz), 7.36 (3H, m), 7.96 (1
H, dd, J = 8.8, 2.9 Hz), 8.06 (1H, d, J = 2.9Hz); MS (FAB) m / z: 465 M + . (Example 197) N- [4- [4- (N-ethyl-N-
Hexylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-hexylamino) phenyl] phenyl]-(2-chloro-5 prepared in Example 195. −
Nitrophenyl) carboxamide (0.169 g, 0.
352 mmol) in methanol (2 mL),
Sodium cyanoborohydride (0.150 g, 2.3
9 mmol), acetaldehyde (0.500 mL,
8.94 mmol) and a catalytic amount of concentrated sulfuric acid,
The mixture was stirred at room temperature for 4 hours and at room temperature for 14 hours. Saturated aqueous sodium hydrogen carbonate (2 mL) and water (20 mL) were added to the reaction solution, the resulting solid was collected by filtration, washed with water and diisopropyl ether,
After drying under reduced pressure, the title compound (0.112 g, yield 6
2%) was obtained.
【0245】Rf 0.19 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, DMSO-d6): δ(ppm) 0.88 (3H, t, J=
6.2 Hz), 1.10 (3H, t, J=7.3 Hz), 1.31 (6H, m), 1.5
5 (2H, m), 3.27 (2H, m), 3.38 (2H, q, J=7.3 Hz),
6.71 (2H, d, J=8.8 Hz), 7.49 (2H, d, J=8.8 Hz), 7.
59 (2H, d, J=8.8 Hz), 7.72 (2H, d, J=8.8 Hz), 7.90
(1H, d, J=8.8 Hz), 8.35 (1H, dd, J=8.8,2.9 Hz),
8.47 (1H, d, J=2.9 Hz), 10.71 (1H, s);
MS(FAB) m/z: 479 M+。
(実施例198)N−[4−[4−(N−ヘキシル−N
−プロピルアミノ)フェニル]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド
実施例195で製造したN−[4−[4−(N−ヘキシ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.200g、0.
433mmol)をTHF(4mL)に溶解させ、プロ
ピオンアルデヒド(0.128mL、1.77mmo
l)、酢酸(0.203mL、3.54mmol)及び
トリアセトキシ水素化ホウ素ナトリウム(0.375
g、1.77mmol)を加え、0℃で1.5時間攪拌
した。反応溶液に飽和重曹水(10mL)及び水(20
mL)を加え、酢酸エチルで抽出した。有機層を無水硫
酸ナトリウムで乾燥し、濃縮し、減圧乾燥した。得られ
た残渣をエタノール(2mL)に溶解させ、過剰の水を
加えた。生じた固形物を濾取し、水及びジイソプロピル
エーテルで洗浄した後、減圧乾燥して、標記目的化合物
(0.158g、収率72%)を得た。R f 0.19 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 0.88 (3H, t, J =
6.2 Hz), 1.10 (3H, t, J = 7.3 Hz), 1.31 (6H, m), 1.5
5 (2H, m), 3.27 (2H, m), 3.38 (2H, q, J = 7.3 Hz),
6.71 (2H, d, J = 8.8 Hz), 7.49 (2H, d, J = 8.8 Hz), 7.
59 (2H, d, J = 8.8 Hz), 7.72 (2H, d, J = 8.8 Hz), 7.90
(1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 8.8,2.9 Hz),
8.47 (1H, d, J = 2.9 Hz), 10.71 (1H, s); MS (FAB) m / z: 479 M + . Example 198 N- [4- [4- (N-hexyl-N
-Propylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-hexylamino) phenyl] phenyl]-(2-chloro- prepared in Example 195. 5-
Nitrophenyl) carboxamide (0.200 g, 0.
433 mmol) was dissolved in THF (4 mL) and propionaldehyde (0.128 mL, 1.77 mmo) was added.
l), acetic acid (0.203 mL, 3.54 mmol) and sodium triacetoxyborohydride (0.375
g, 1.77 mmol) was added, and the mixture was stirred at 0 ° C. for 1.5 hours. Saturated aqueous sodium hydrogen carbonate (10 mL) and water (20 mL) were added to the reaction solution.
mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated, and dried under reduced pressure. The obtained residue was dissolved in ethanol (2 mL), and excess water was added. The resulting solid was collected by filtration, washed with water and diisopropyl ether, and dried under reduced pressure to give the title object compound (0.158 g, yield 72%).
【0246】Rf 0.29 (ヘキサン:酢酸エチル=3:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.90 (3H, t, J=6.6
Hz), 1.02 (3H, t, J=7.3 Hz), 1.28-1.45 (6H, m),
1.60 (2H, m), 1.71 (2H, m), 3.12 (2H, t, J=7.0 H
z), 3.92 (2H, t, J=7.3 Hz), 6.61 (2H, d, J=8.8 H
z), 7.14 (2H, d, J=8.8 Hz), 7.32 (2H, d, J=8.8 H
z), 7.37 (3H, m), 7.94 (1H, dd, J=8.8, 2.9 Hz), 8.
01 (1H, d, J=2.9 Hz)。
(実施例199)N−[4−[4−(N−ブチル−N−
ヘキシルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例195で製造したN−[4−[4−(N−ヘキシ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.200g、0.
433mmol)、ブチルアルデヒド(0.160m
L、1.77mmol)、酢酸(0.203mL、3.
54mmol)、トリアセトキシ水素化ホウ素ナトリウ
ム(0.375g、1.77mmol)及びTHF(4
mL)を使用して、実施例198に記載した方法に従
い、標記目的化合物(0.175g、収率78%)を得
た。R f 0.29 (hexane: ethyl acetate = 3: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.90 (3H, t, J = 6.6
Hz), 1.02 (3H, t, J = 7.3 Hz), 1.28-1.45 (6H, m),
1.60 (2H, m), 1.71 (2H, m), 3.12 (2H, t, J = 7.0 H
z), 3.92 (2H, t, J = 7.3 Hz), 6.61 (2H, d, J = 8.8 H
z), 7.14 (2H, d, J = 8.8 Hz), 7.32 (2H, d, J = 8.8 H
z), 7.37 (3H, m), 7.94 (1H, dd, J = 8.8, 2.9 Hz), 8.
01 (1H, d, J = 2.9 Hz). (Example 199) N- [4- [4- (N-butyl-N-
Hexylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-hexylamino) phenyl] phenyl]-(2-chloro-5 prepared in Example 195. −
Nitrophenyl) carboxamide (0.200 g, 0.
433 mmol), butyraldehyde (0.160 m
L, 1.77 mmol), acetic acid (0.203 mL, 3.
54 mmol), sodium triacetoxyborohydride (0.375 g, 1.77 mmol) and THF (4
(mL) and according to the method described in Example 198 to give the title object compound (0.175 g, yield 78%).
【0247】Rf 0.31 (ヘキサン:酢酸エチル=1:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.91 (3H, t, J=6.6
Hz), 0.97 (3H, t, J=7.3 Hz), 1.30-1.44 (6H, m),
1.54-1.66 (6H, m), 3.31 (4H, m), 6.71 (2H, d,J=8.8
Hz), 7.47 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 H
z), 7.64 (2H, d,J=8.8 Hz), 7.66 (1H, d, J=8.8 Hz),
7.84 (1H, br), 8.26 (1H, dd, J=8.8,2.9 Hz), 8.62
(1H, d, J=2.9 Hz);
MS(FAB) m/z: 508 (M + H)+。
(実施例200)N−[4−[4−(N−ヘキシル−N
−ペンチルアミノ)フェニル]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド
実施例195で製造したN−[4−[4−(N−ヘキシ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.200g、0.
433mmol)、n−吉草アルデヒド(0.188m
L、1.77mmol)、酢酸(203mL、3.54
mmol)、トリアセトキシ水素化ホウ素ナトリウム
(0.375g、1.77mmol)及びTHF(4m
L)を使用して、実施例198に記載した方法に従い、
標記目的化合物(0.212g、収率92%)を得た。R f 0.31 (hexane: ethyl acetate = 1: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.91 (3H, t, J = 6.6
Hz), 0.97 (3H, t, J = 7.3 Hz), 1.30-1.44 (6H, m),
1.54-1.66 (6H, m), 3.31 (4H, m), 6.71 (2H, d, J = 8.8
Hz), 7.47 (2H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.8 H
z), 7.64 (2H, d, J = 8.8 Hz), 7.66 (1H, d, J = 8.8 Hz),
7.84 (1H, br), 8.26 (1H, dd, J = 8.8,2.9 Hz), 8.62
(1H, d, J = 2.9 Hz); MS (FAB) m / z: 508 (M + H) + . (Example 200) N- [4- [4- (N-hexyl-N
-Pentylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-hexylamino) phenyl] phenyl]-(2-chloro- prepared in Example 195. 5-
Nitrophenyl) carboxamide (0.200 g, 0.
433 mmol), n-valeraldehyde (0.188 m
L, 1.77 mmol), acetic acid (203 mL, 3.54
mmol), sodium triacetoxyborohydride (0.375 g, 1.77 mmol) and THF (4 m
L) using the method described in Example 198
The title object compound (0.212 g, yield 92%) was obtained.
【0248】Rf 0.34 (ヘキサン:酢酸エチル=1:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.91 (5H, m), 1.32
-1.44 (8H, m), 1.52-1.68 (6H, m), 3.30 (4H, t, J=
7.3 Hz), 6.71 (2H, d, J=8.8 Hz), 7.47 (2H, d,J=8.8
Hz), 7.58 (2H, d, J=8.8 Hz), 7.65 (2H, d, J=8.8 H
z), 7.66 (1H, d,J=8.8 Hz), 7.84 (1H, br), 8.27 (1
H, dd, J=8.8, 2.9 Hz), 8.63 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 522 (M + H)+。
(実施例201)N−[4−[4−(N、N−ジヘキシ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド
実施例195で製造したN−[4−[4−(N−ヘキシ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.200g、0.
433mmol)、ヘキサナール(0.212mL、
1.77mmol)、酢酸(0.203mL、3.54
mmol)、トリアセトキシ水素化ホウ素ナトリウム
(0.375g、1.77mmol)及びTHF(4m
L)を使用して、実施例198に記載した方法に従い、
標記目的化合物(0.128g、収率54%)を得た。R f 0.34 (hexane: ethyl acetate = 1: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.91 (5H, m), 1.32
-1.44 (8H, m), 1.52-1.68 (6H, m), 3.30 (4H, t, J =
7.3 Hz), 6.71 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8
Hz), 7.58 (2H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.8 H
z), 7.66 (1H, d, J = 8.8 Hz), 7.84 (1H, br), 8.27 (1
H, dd, J = 8.8, 2.9 Hz), 8.63 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 522 (M + H) + . Example 201 N- [4- [4- (N, N-dihexylamino) phenyl] phenyl]-(2-chloro-5-
Nitrophenyl) carboxamide N- [4- [4- (N-hexylamino) phenyl] phenyl]-(2-chloro-5-prepared in Example 195.
Nitrophenyl) carboxamide (0.200 g, 0.
433 mmol), hexanal (0.212 mL,
1.77 mmol), acetic acid (0.203 mL, 3.54
mmol), sodium triacetoxyborohydride (0.375 g, 1.77 mmol) and THF (4 m
L) using the method described in Example 198
The title object compound (0.128 g, yield 54%) was obtained.
【0249】Rf 0.35 (ヘキサン:酢酸エチル=1:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.91 (6H, t, J=6.6
Hz), 1.28-1.42 (12H,m),1.61 (4H, m), 3.30 (4H, t,
J=7.3 Hz), 6.71 (2H, d, J=8.8 Hz), 7.47 (2H, d, J
=8.8 Hz), 7.58 (2H, d, J=8.8 Hz), 7.65 (2H, d, J=
8.8 Hz), 7.66 (1H, d, J=8.8 Hz), 7.84 (1H, br), 8.
27 (1H, dd, J=8.8, 2.9 Hz), 8.63 (1H,d, J=2.9 Hz);
MS(FAB) m/z: 536 (M + H)+。
(実施例202)N−[4−[4−(N−ペンチルアミ
ノ)フェニル]フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(1.50g、4.08mmol)をメ
タノール(30mL)に懸濁させ、トリアセトキシ水素
化ホウ素ナトリウム(0.950g、4.49mmo
l)及びn−吉草アルデヒド(0.477mL、4.4
9mmol)を加えて、0℃で4時間攪拌した。反応溶
液に飽和重曹水(100mL)を加え、酢酸エチルで抽
出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリ
ウムで乾燥し、濃縮した。得られた残渣をシリカゲルカ
ラムクロマトグラフィー(ヘキサン:酢酸エチル=3:
1(v/v))にて精製し、粗製の標記目的化合物(1.1
5g)を得た。得られた粗製の標記目的化合物をエタノ
ールに加熱溶解させて、不溶物を濾別した。濾液を濃縮
して、残渣をシリカゲルカラムクロマトグラフィー(ヘ
キサン:酢酸エチル=3:1(v/v))にて精製し、標記
目的化合物(0.143g、8%)を得た。R f 0.35 (hexane: ethyl acetate = 1: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.91 (6H, t, J = 6.6
Hz), 1.28-1.42 (12H, m), 1.61 (4H, m), 3.30 (4H, t,
J = 7.3 Hz), 6.71 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J
= 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.65 (2H, d, J =
8.8 Hz), 7.66 (1H, d, J = 8.8 Hz), 7.84 (1H, br), 8.
27 (1H, dd, J = 8.8, 2.9 Hz), 8.63 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 536 (M + H) + . Example 202 N- [4- [4- (N-pentylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-amino) prepared in Example 192. Phenyl) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (1.50 g, 4.08 mmol) was suspended in methanol (30 mL) and sodium triacetoxyborohydride (0.950 g, 4.49 mmo).
1) and n-valeraldehyde (0.477 mL, 4.4
9 mmol) was added and the mixture was stirred at 0 ° C. for 4 hours. Saturated aqueous sodium hydrogen carbonate (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
1 (v / v)) to give the crude title compound (1.1
5 g) was obtained. The obtained crude title compound was dissolved in ethanol by heating, and the insoluble material was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 (v / v)) to give the title object compound (0.143 g, 8%).
【0250】Rf 0.74 (ヘキサン:酢酸エチル=1:1(v/
v));1
H-NMR (400MHz, DMSO-d6): δ(ppm) 0.90 (3H, t, J=
7.0 Hz), 1.35 (4H, m),1.56 (2H, m), 3.02 (2H, t, J
=7.3 Hz), 5.72 (1H, br), 6.63 (2H, d, J=8.8Hz), 7.
41 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz), 7.71
(2H, d, J=8.8Hz), 7.90 (1H, d, J=8.8 Hz), 8.34 (1
H, dd, J=8.8, 2.9 Hz), 8.47 (1H, d,J=2.9 Hz), 10.7
0 (1H, s);
MS(FAB) m/z: 437 M+。
(実施例203)N−[4−[4−(N−ブチルアミ
ノ)フェニル]フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(1.50g、4.08mmol)、メ
タノール(30mL)、シアノ水素化ホウ素ナトリウム
(1.54g、24.5mmol)及びブチルアルデヒ
ド(2.20mL、24.5mmol)を使用して、実
施例195に記載した方法に従い、標記目的化合物
(1.50g、収率86%)を得た。R f 0.74 (hexane: ethyl acetate = 1: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 0.90 (3H, t, J =
7.0 Hz), 1.35 (4H, m), 1.56 (2H, m), 3.02 (2H, t, J
= 7.3 Hz), 5.72 (1H, br), 6.63 (2H, d, J = 8.8Hz), 7.
41 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.71
(2H, d, J = 8.8Hz), 7.90 (1H, d, J = 8.8 Hz), 8.34 (1
H, dd, J = 8.8, 2.9 Hz), 8.47 (1H, d, J = 2.9 Hz), 10.7
0 (1H, s); MS (FAB) m / z: 437 M + . Example 203 N- [4- [4- (N-butylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-amino) prepared in Example 192. Phenyl) phenyl]-(2-chloro-5-nitrophenyl)
Example 195 using carboxamide (1.50 g, 4.08 mmol), methanol (30 mL), sodium cyanoborohydride (1.54 g, 24.5 mmol) and butyraldehyde (2.20 mL, 24.5 mmol). According to the method described in (1), the title object compound (1.50 g, yield 86%) was obtained.
【0251】Rf 0.69 (ヘキサン:酢酸エチル=1:1(v/
v));1
H-NMR (400MHz, DMSO-d6):δ(ppm) 0.93 (3H, t, J=7.
3 Hz), 1.40 (2H, tq, J=7.3, 7.3 Hz), 1.54 (2H, tt,
J=7.0, 7.3 Hz), 3.03 (2H, t, J=7.0 Hz), 5.74 (1H,
br), 6.64 (2H, d, J=8.4 Hz), 7.42 (2H, d, J=8.4 H
z), 7.56 (2H, d,J=8.4 Hz), 7.71 (2H, d, J=8.4 Hz),
7.90 (1H, d, J=8.8 Hz), 8.35 (1H, dd, J=8.8, 2.9
Hz), 8.47 (1H, d, J=2.9 Hz), 10.70 (1H, s);
MS(FAB) m/z: 423 M+。
(実施例204)N−[4−[4−(N−プロピルアミ
ノ)フェニル]フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(1.00g、2.71mmol)、メ
タノール(20mL)、シアノ水素化ホウ素ナトリウム
(1.03g、16.3mmol)及びプロピオンアル
デヒド(1.18mL、16.3mmol)を使用し
て、実施例195に記載した方法に従い、標記目的化合
物(0.988g、収率89%)を得た。R f 0.69 (hexane: ethyl acetate = 1: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 0.93 (3H, t, J = 7.
3 Hz), 1.40 (2H, tq, J = 7.3, 7.3 Hz), 1.54 (2H, tt,
J = 7.0, 7.3 Hz), 3.03 (2H, t, J = 7.0 Hz), 5.74 (1H,
br), 6.64 (2H, d, J = 8.4 Hz), 7.42 (2H, d, J = 8.4 H
z), 7.56 (2H, d, J = 8.4 Hz), 7.71 (2H, d, J = 8.4 Hz),
7.90 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 8.8, 2.9
Hz), 8.47 (1H, d, J = 2.9 Hz), 10.70 (1H, s); MS (FAB) m / z: 423 M + . Example 204 N- [4- [4- (N-propylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-amino) prepared in Example 192. Phenyl) phenyl]-(2-chloro-5-nitrophenyl)
Example 195 using carboxamide (1.00 g, 2.71 mmol), methanol (20 mL), sodium cyanoborohydride (1.03 g, 16.3 mmol) and propionaldehyde (1.18 mL, 16.3 mmol). According to the method described in (1), the title object compound (0.988 g, yield 89%) was obtained.
【0252】Rf 0.67 (ヘキサン:酢酸エチル=1:1(v/
v));1
H-NMR (400MHz, DMSO-d6): δ(ppm) 0.95 (3H, t, J=
7.3 Hz), 1.58 (2H, tq,J=7.3, 7.3 Hz), 3.01 (2H, t,
J=7.3 Hz), 5.78 (1H, br), 6.64 (2H, d, J=8.8 Hz),
7.42 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz),
7.71 (2H, d, J=8.8 Hz), 7.90 (1H, d, J=8.8 Hz), 8.
35 (1H, dd, J=8.8, 2.9 Hz), 8.47 (1H, d, J=2.9 H
z), 10.70 (1H, s);
MS(FAB) m/z: 409 M+。
(実施例205)N−[4−[4−(N−エチルアミ
ノ)フェニル]フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(1.00g、2.71mmol)、メ
タノール(20mL)、シアノ水素化ホウ素ナトリウム
(1.03g、16.3mmol)及びアセトアルデヒ
ド(0.92mL、16.3mmol)を使用して、実
施例195に記載した方法に従い、標記目的化合物
(0.714g、収率66%)を得た。R f 0.67 (hexane: ethyl acetate = 1: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 0.95 (3H, t, J =
7.3 Hz), 1.58 (2H, tq, J = 7.3, 7.3 Hz), 3.01 (2H, t,
J = 7.3 Hz), 5.78 (1H, br), 6.64 (2H, d, J = 8.8 Hz),
7.42 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz),
7.71 (2H, d, J = 8.8 Hz), 7.90 (1H, d, J = 8.8 Hz), 8.
35 (1H, dd, J = 8.8, 2.9 Hz), 8.47 (1H, d, J = 2.9 H
z), 10.70 (1H, s); MS (FAB) m / z: 409 M + . Example 205 N- [4- [4- (N-ethylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-amino) prepared in Example 192. Phenyl) phenyl]-(2-chloro-5-nitrophenyl)
Using carboxamide (1.00 g, 2.71 mmol), methanol (20 mL), sodium cyanoborohydride (1.03 g, 16.3 mmol) and acetaldehyde (0.92 mL, 16.3 mmol) in Example 195. The title compound (0.714 g, yield 66%) was obtained according to the method described.
【0253】Rf 0.65 (ヘキサン:酢酸エチル=1:1(v/
v));1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.18 (3H, t, J=
7.3 Hz), 3.10 (2H, q, J=7.0 Hz), 5.72 (1H, br), 6.
63 (2H, d, J=8.8 Hz), 7.42 (2H, d, J=8.8 Hz),7.56
(2H, d, J=8.8 Hz), 7.71 (2H, d, J=8.8 Hz), 7.90 (1
H, d, J=8.8 Hz),8.34 (1H, dd, J=8.8, 2.9 Hz), 8.47
(1H, d, J=2.9 Hz), 10.70 (1H, s);
MS(FAB) m/z: 395 (M + H)+。
(実施例206)N−[4−[4−(N−ブチル−N−
ペンチルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例203で製造したN−[4−[4−(N−ブチル
アミノ)フェニル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド(0.200g、0.4
72mmol)、n−吉草アルデヒド(0.201m
L、1.89mmol)、酢酸(0.216mL、3.
77mmol)、トリアセトキシ水素化ホウ素ナトリウ
ム(0.400g、1.89mmol)及びTHF(4
mL)を使用して、実施例198に記載した方法に従
い、標記目的化合物(0.133g、収率57%)を得
た。R f 0.65 (hexane: ethyl acetate = 1: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.18 (3H, t, J =
7.3 Hz), 3.10 (2H, q, J = 7.0 Hz), 5.72 (1H, br), 6.
63 (2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.8 Hz), 7.56
(2H, d, J = 8.8 Hz), 7.71 (2H, d, J = 8.8 Hz), 7.90 (1
H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 8.8, 2.9 Hz), 8.47
(1H, d, J = 2.9 Hz), 10.70 (1H, s); MS (FAB) m / z: 395 (M + H) + . (Example 206) N- [4- [4- (N-butyl-N-
Pentylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-butylamino) phenyl] phenyl]-(2-chloro-5) prepared in Example 203. -Nitrophenyl) carboxamide (0.200 g, 0.4
72 mmol), n-valeric aldehyde (0.201 m
L, 1.89 mmol), acetic acid (0.216 mL, 3.
77 mmol), sodium triacetoxyborohydride (0.400 g, 1.89 mmol) and THF (4
(mL) and according to the method described in Example 198 to give the title object compound (0.133 g, yield 57%).
【0254】Rf 0.36 (ヘキサン:酢酸エチル=3:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.93 (3H, t, J=7.3
Hz), 0.97 (3H, t, J=7.3 Hz), 1.30-1.42 (6H, m),
1.56-1.68 (4H, m), 3.30 (4H, m), 6.71 (2H, d,J=8.8
Hz), 7.47 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8 H
z), 7.65 (2H, d,J=8.8 Hz), 7.66 (1H, d, J=8.8 Hz),
7.84 (1H, br), 8.27 (1H, dd, J=8.8,2.9 Hz), 8.63
(1H, d, J=2.9 Hz);
MS(FAB) m/z: 493 M+。
(実施例207)N−[4−[4−(N、N−ジブチル
アミノ)フェニル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド
実施例203で製造したN−[4−[4−(N−ブチル
アミノ)フェニル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド(0.200g、0.4
72mmol)、ブチルアルデヒド(0.170mL、
1.89mmol)、酢酸(0.216mL、3.77
mmol)、トリアセトキシ水素化ホウ素ナトリウム
(0.400g、1.89mmol)及びTHF(4m
L)を使用して、実施例198に記載した方法に従い、
標記目的化合物(0.202g、収率89%)を得た。R f 0.36 (hexane: ethyl acetate = 3: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.93 (3H, t, J = 7.3
Hz), 0.97 (3H, t, J = 7.3 Hz), 1.30-1.42 (6H, m),
1.56-1.68 (4H, m), 3.30 (4H, m), 6.71 (2H, d, J = 8.8
Hz), 7.47 (2H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.8 H
z), 7.65 (2H, d, J = 8.8 Hz), 7.66 (1H, d, J = 8.8 Hz),
7.84 (1H, br), 8.27 (1H, dd, J = 8.8,2.9 Hz), 8.63
(1H, d, J = 2.9 Hz); MS (FAB) m / z: 493 M + . Example 207 N- [4- [4- (N, N-dibutylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4 -(N-Butylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide (0.200 g, 0.4
72 mmol), butyraldehyde (0.170 mL,
1.89 mmol), acetic acid (0.216 mL, 3.77)
mmol), sodium triacetoxyborohydride (0.400 g, 1.89 mmol) and THF (4 m
L) using the method described in Example 198
The title object compound (0.202 g, yield 89%) was obtained.
【0255】Rf 0.32 (ヘキサン:酢酸エチル=3:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.97 (6H, t, J=7.3
Hz),1.38 (4H, tq, J=7.3 Hz), 1.60 (4H, m), 3.31
(4H, t, J=7.7 Hz), 6.71 (2H, d, J=8.8 Hz), 7.47 (2
H, d, J=8.8 Hz), 7.58 (2H, d, J=8.0 Hz), 7.65 (2H,
d, J=8.0 Hz), 7.66 (1H, d, J=8.8 Hz), 7.84 (1H, b
r), 8.26 (1H, dd, J=8.8, 2.9 Hz), 8.63(1H, d, J=2.
9 Hz);
MS(FAB) m/z: 479 (M + H)+。
(実施例208)N−[4−[4−(N−ブチル−N−
プロピルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例203で製造したN−[4−[4−(N−ブチル
アミノ)フェニル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド(0.200g、0.4
72mmol)、プロピオンアルデヒド(0.136m
L、1.89mmol)、酢酸(0.216mL、3.
77mmol)、トリアセトキシ水素化ホウ素ナトリウ
ム(0.400g、1.89mmol)及びTHF(4
mL)を使用して、実施例198に記載した方法に従
い、標記目的化合物(0.123g、収率56%)を得
た。R f 0.32 (hexane: ethyl acetate = 3: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.97 (6H, t, J = 7.3
Hz), 1.38 (4H, tq, J = 7.3 Hz), 1.60 (4H, m), 3.31
(4H, t, J = 7.7 Hz), 6.71 (2H, d, J = 8.8 Hz), 7.47 (2
H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.0 Hz), 7.65 (2H,
d, J = 8.0 Hz), 7.66 (1H, d, J = 8.8 Hz), 7.84 (1H, b
r), 8.26 (1H, dd, J = 8.8, 2.9 Hz), 8.63 (1H, d, J = 2.
9 Hz); MS (FAB) m / z: 479 (M + H) + . (Example 208) N- [4- [4- (N-butyl-N-
Propylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-butylamino) phenyl] phenyl]-(2-chloro-5 prepared in Example 203. -Nitrophenyl) carboxamide (0.200 g, 0.4
72 mmol), propionaldehyde (0.136 m
L, 1.89 mmol), acetic acid (0.216 mL, 3.
77 mmol), sodium triacetoxyborohydride (0.400 g, 1.89 mmol) and THF (4
(mL), and according to the method described in Example 198, the title object compound (0.123 g, yield 56%) was obtained.
【0256】Rf 0.29 (ヘキサン:酢酸エチル=3:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.96 (6H, m),1.38
(2H, tq, J=7.3, 7.3 Hz), 1.62 (4H, m), 3.30 (4H,
m), 6.71 (2H, d, J=8.8 Hz), 7.47 (2H, d, J=8.8 H
z), 7.58 (2H, d, J=8.0 Hz), 7.65 (2H, d, J=8.0 H
z), 7.66 (1H, d, J=8.8 Hz), 7.84 (1H, br), 8.27 (1
H, dd, J=8.8, 2.9 Hz), 8.64 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 465 M+。
(実施例209)N−[4−[4−(N−ブチル−N−
エチルアミノ)フェニル]フェニル]−(2−クロロ−
5−ニトロフェニル)カルボキサミド
実施例203で製造したN−[4−[4−(N−ブチル
アミノ)フェニル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド(0.200g、0.4
72mmol)、アセトアルデヒド(0.106mL、
1.89mmol)、酢酸(0.216mL、3.77
mmol)、トリアセトキシ水素化ホウ素ナトリウム
(0.400g、1.89mmol)及びTHF(4m
L)を使用して、実施例198に記載した方法に従い、
標記目的化合物(0.120g、収率56%)を得た。R f 0.29 (hexane: ethyl acetate = 3: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.96 (6H, m), 1.38
(2H, tq, J = 7.3, 7.3 Hz), 1.62 (4H, m), 3.30 (4H,
m), 6.71 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8 H
z), 7.58 (2H, d, J = 8.0 Hz), 7.65 (2H, d, J = 8.0 H
z), 7.66 (1H, d, J = 8.8 Hz), 7.84 (1H, br), 8.27 (1
H, dd, J = 8.8, 2.9 Hz), 8.64 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 465 M + . (Example 209) N- [4- [4- (N-butyl-N-
Ethylamino) phenyl] phenyl]-(2-chloro-
5-Nitrophenyl) carboxamide N- [4- [4- (N-butylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide prepared in Example 203 (0.200 g, 0.4
72 mmol), acetaldehyde (0.106 mL,
1.89 mmol), acetic acid (0.216 mL, 3.77)
mmol), sodium triacetoxyborohydride (0.400 g, 1.89 mmol) and THF (4 m
L) using the method described in Example 198
The title object compound (0.120 g, yield 56%) was obtained.
【0257】Rf 0.27 (ヘキサン:酢酸エチル=3:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.98 (3H, t, J=7.3
Hz), 1.19 (3H, t, J=7.3 Hz), 1.39 (2H, tq, J=7.3,
7.3 Hz), 1.56-1.66 (4H, m), 3.30 (2H, t, J=7.3 H
z), 3.41 (2H, q, J=7.3 Hz), 6.73 (2H, d, J=8.8 H
z), 7.47 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.0 H
z), 7.65 (2H, d, J=8.0 Hz), 7.66 (1H, d, J=8.8 H
z), 7.84 (1H, br), 8.27 (1H, dd, J=8.8, 2.9 Hz),
8.63 (1H, d, J=2.9Hz);
MS(FAB) m/z: 451 M+。
(実施例210)N−[4−[4−(N−ブチル−N−
メチルアミノ)フェニル]フェニル]−(2−クロロ−
5−ニトロフェニル)カルボキサミド
実施例203で製造したN−[4−[4−(N−ブチル
アミノ)フェニル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド(0.200g、0.4
72mmol)をDMF(2mL)に溶解させ、水素化
ナトリウム(0.023g、0.519mmol)を加
えた。0℃で30分間攪拌した後、ヨウ化メチル(0.
035mL、0.566mmol)を加えて1時間攪拌
した。反応液に水(20mL)を加えて酢酸エチルで抽
出し、有機層を水で3回、飽和食塩水で1回洗浄した。
有機層を無水硫酸ナトリウムで乾燥し、濃縮し、減圧乾
燥した。得られた残渣をエタノール(2mL)に溶解し
て放置した。析出した結晶を濾取し、減圧乾燥して、標
記目的化合物(0.120g、収率58%)を得た。R f 0.27 (hexane: ethyl acetate = 3: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.98 (3H, t, J = 7.3
Hz), 1.19 (3H, t, J = 7.3 Hz), 1.39 (2H, tq, J = 7.3,
7.3 Hz), 1.56-1.66 (4H, m), 3.30 (2H, t, J = 7.3 H
z), 3.41 (2H, q, J = 7.3 Hz), 6.73 (2H, d, J = 8.8 H
z), 7.47 (2H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.0 H
z), 7.65 (2H, d, J = 8.0 Hz), 7.66 (1H, d, J = 8.8 H
z), 7.84 (1H, br), 8.27 (1H, dd, J = 8.8, 2.9 Hz),
8.63 (1H, d, J = 2.9Hz); MS (FAB) m / z: 451 M + . (Example 210) N- [4- [4- (N-butyl-N-
Methylamino) phenyl] phenyl]-(2-chloro-
5-Nitrophenyl) carboxamide N- [4- [4- (N-butylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide prepared in Example 203 (0.200 g, 0.4
72 mmol) was dissolved in DMF (2 mL) and sodium hydride (0.023 g, 0.519 mmol) was added. After stirring at 0 ° C. for 30 minutes, methyl iodide (0.
(035 mL, 0.566 mmol) was added and stirred for 1 hour. Water (20 mL) was added to the reaction solution and the mixture was extracted with ethyl acetate, and the organic layer was washed 3 times with water and once with saturated brine.
The organic layer was dried over anhydrous sodium sulfate, concentrated, and dried under reduced pressure. The obtained residue was dissolved in ethanol (2 mL) and left to stand. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title object compound (0.120 g, yield 58%).
【0258】Rf 0.41 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.96 (3H, t, J=7.3
Hz), 1.43 (2H, tq, J=7.3, 7.3 Hz), 1.60 (2H, tt,
J=7.3, 7.3 Hz), 3.13 (2H, t, J=7.3 Hz), 3.53(3H,
s), 6.61 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 H
z), 7.32 (2H, d, J=8.0 Hz), 7.37 (2H, d, J=8.0 H
z), 7.38 (1H, d, J=8.8 Hz), 7.97 (1H, dd,J=8.8, 2.
9 Hz), 8.06 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 438 (M + H)+。
(実施例211)N−[4−[4−(N−ペンチル−N
−プロピルアミノ)フェニル]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド
実施例204で製造したN−[4−[4−(N−プロピ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.200g、0.
488mmol)、n−吉草アルデヒド(0.208m
L、1.95mmol)、酢酸(0.223mL、3.
90mmol)、トリアセトキシ水素化ホウ素ナトリウ
ム(0.414g、1.95mmol)及びTHF(4
mL)を使用して、実施例198に記載した方法に従
い、標記目的化合物(0.179g、収率77%)を得
た。R f 0.41 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.96 (3H, t, J = 7.3
Hz), 1.43 (2H, tq, J = 7.3, 7.3 Hz), 1.60 (2H, tt,
J = 7.3, 7.3 Hz), 3.13 (2H, t, J = 7.3 Hz), 3.53 (3H,
s), 6.61 (2H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.8 H
z), 7.32 (2H, d, J = 8.0 Hz), 7.37 (2H, d, J = 8.0 H
z), 7.38 (1H, d, J = 8.8 Hz), 7.97 (1H, dd, J = 8.8, 2.
9 Hz), 8.06 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 438 (M + H) + . Example 211 N- [4- [4- (N-pentyl-N
-Propylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-propylamino) phenyl] phenyl]-(2-chloro- prepared as in Example 204. 5-
Nitrophenyl) carboxamide (0.200 g, 0.
488 mmol), n-valeraldehyde (0.208 m
L, 1.95 mmol), acetic acid (0.223 mL, 3.
90 mmol), sodium triacetoxyborohydride (0.414 g, 1.95 mmol) and THF (4
(mL) and according to the method described in Example 198 to give the title object compound (0.179 g, yield 77%).
【0259】Rf 0.60 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.92 (3H, t, J=7.3
Hz), 0.95 (3H, t, J=7.3 Hz), 1.35 (4H, m), 1.63
(4H, m), 3.29 (4H, m), 6.61 (2H, d, J=8.8 Hz), 7.4
7 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.64
(2H, d, J=8.8 Hz), 7.66 (1H, d, J=8.8 Hz), 7.83 (1
H, br), 8.26 (1H, dd, J=8.8, 2.9 Hz), 8.63 (1H, d,
J=2.9 Hz)。
(実施例212)N−[4−[4−(N−エチル−N−
プロピルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例204で製造したN−[4−[4−(N−プロピ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.200g、0.
488mmol)をTHF(4mL)に溶解させ、アセ
トアルデヒド(0.109mL、1.95mmol)、
酢酸(0.223mL、3.90mmol)及びトリア
セトキシ水素化ホウ素ナトリウム(0.414g、1.
95mmol)を加え、0℃で1.5時間攪拌した。反
応溶液に飽和重曹水(10mL)及び水(20mL)加
え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄
し、無水硫酸ナトリウムで乾燥し、濃縮し、減圧乾燥し
た。得られた残渣をエタノール(2mL)に溶解して放
置した。析出した結晶を濾取し、減圧乾燥して、標記目
的化合物(0.124g、収率58%)を得た。R f 0.60 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.92 (3H, t, J = 7.3
Hz), 0.95 (3H, t, J = 7.3 Hz), 1.35 (4H, m), 1.63
(4H, m), 3.29 (4H, m), 6.61 (2H, d, J = 8.8 Hz), 7.4
7 (2H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.64
(2H, d, J = 8.8 Hz), 7.66 (1H, d, J = 8.8 Hz), 7.83 (1
H, br), 8.26 (1H, dd, J = 8.8, 2.9 Hz), 8.63 (1H, d,
J = 2.9 Hz). (Example 212) N- [4- [4- (N-ethyl-N-
Propylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-propylamino) phenyl] phenyl]-(2-chloro-5) prepared in Example 204. −
Nitrophenyl) carboxamide (0.200 g, 0.
488 mmol) in THF (4 mL), acetaldehyde (0.109 mL, 1.95 mmol),
Acetic acid (0.223 mL, 3.90 mmol) and sodium triacetoxyborohydride (0.414 g, 1.
95 mmol) was added and the mixture was stirred at 0 ° C. for 1.5 hours. Saturated aqueous sodium hydrogen carbonate (10 mL) and water (20 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and dried under reduced pressure. The obtained residue was dissolved in ethanol (2 mL) and left to stand. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title object compound (0.124 g, yield 58%).
【0260】Rf 0.41 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.96 (3H, t, J=7.3
Hz), 1.19 (3H, t, J=7.3 Hz), 1.66 (2H, tq, J=7.3,
7.3 Hz), 3.27 (2H, t, J=7.3 Hz), 3.42 (2H,q, J=7.
3 Hz), 6.73 (2H, d, J=8.8 Hz), 7.47 (2H, d, J=8.8
Hz), 7.58 (2H,d, J=8.8 Hz), 7.65 (2H, d, J=8.8 H
z), 7.66 (1H, d, J=8.8 Hz), 7.85 (1H,br), 8.26 (1
H, dd, J=8.8, 2.9 Hz), 8.63 (1H, d, J=2.9 Hz)。
(実施例213)N−[4−[4−(N−メチル−N−
プロピルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例204で製造したN−[4−[4−(N−プロピ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.200g、0.
488mmol)をDMF(2mL)に溶解させ、水素
化ナトリウム(0.023g、0.537mmol)を
加えた。0℃で30分間攪拌した後、ヨウ化メチル
(0.037mL、0.586mmol)を加えて1時
間攪拌した。反応液に水(20mL)を加えて酢酸エチ
ルで抽出し、有機層を水で3回、飽和食塩水で1回洗浄
した。有機層を無水硫酸ナトリウムで乾燥し、濃縮し、
減圧乾燥した。生じた固体を濾取してエタノールで洗浄
した後、減圧乾燥して、標記目的化合物(0.119
g、収率58%)を得た。R f 0.41 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.96 (3H, t, J = 7.3
Hz), 1.19 (3H, t, J = 7.3 Hz), 1.66 (2H, tq, J = 7.3,
7.3 Hz), 3.27 (2H, t, J = 7.3 Hz), 3.42 (2H, q, J = 7.
3 Hz), 6.73 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8
Hz), 7.58 (2H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.8 H
z), 7.66 (1H, d, J = 8.8 Hz), 7.85 (1H, br), 8.26 (1
H, dd, J = 8.8, 2.9 Hz), 8.63 (1H, d, J = 2.9 Hz). (Example 213) N- [4- [4- (N-methyl-N-
Propylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-propylamino) phenyl] phenyl]-(2-chloro-5) prepared in Example 204. −
Nitrophenyl) carboxamide (0.200 g, 0.
488 mmol) was dissolved in DMF (2 mL) and sodium hydride (0.023 g, 0.537 mmol) was added. After stirring at 0 ° C. for 30 minutes, methyl iodide (0.037 mL, 0.586 mmol) was added and the mixture was stirred for 1 hour. Water (20 mL) was added to the reaction solution and the mixture was extracted with ethyl acetate, and the organic layer was washed 3 times with water and once with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated,
It was dried under reduced pressure. The resulting solid was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title object compound (0.119).
g, yield 58%) was obtained.
【0261】Rf 0.31 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 1.00 (3H, t, J=7.3
Hz), 1.65 (2H, tq, J=7.3, 7.3 Hz), 3.10 (2H, t, J
=7.3 Hz), 3.53 (3H, s), 3.78 (1H, br), 6.61(2H, d,
J=8.8 Hz), 7.13 (2H, d, J=8.8 Hz), 7.32 (2H, d, J
=8.8 Hz), 7.37(2H, d, J=8.8 Hz), 7.38 (1H, d, J=8.
8 Hz), 7.98 (1H, dd, J=8.8, 2.9 Hz),8.06 (1H, d, J
=2.9 Hz)。
(実施例214)N−[4−[4−(N、N−ジペンチ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド
実施例202で製造したN−[4−[4−(N−ペンチ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.086g、0.
197mmol)、n−吉草アルデヒド(0.084m
L、0.789mmol)、酢酸(0.090mL、
1.58mmol)、トリアセトキシ水素化ホウ素ナト
リウム(0.167g、0.789mmol)及びTH
F(1.5mL)を使用して、実施例198に記載した
方法に従い、標記目的化合物(0.034g、収率34
%)を得た。R f 0.31 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.00 (3H, t, J = 7.3
Hz), 1.65 (2H, tq, J = 7.3, 7.3 Hz), 3.10 (2H, t, J
= 7.3 Hz), 3.53 (3H, s), 3.78 (1H, br), 6.61 (2H, d,
J = 8.8 Hz), 7.13 (2H, d, J = 8.8 Hz), 7.32 (2H, d, J
= 8.8 Hz), 7.37 (2H, d, J = 8.8 Hz), 7.38 (1H, d, J = 8.
8 Hz), 7.98 (1H, dd, J = 8.8, 2.9 Hz), 8.06 (1H, d, J
= 2.9 Hz). Example 214 N- [4- [4- (N, N-dipentylamino) phenyl] phenyl]-(2-chloro-5-
Nitrophenyl) carboxamide N- [4- [4- (N-pentylamino) phenyl] phenyl]-(2-chloro-5-prepared in Example 202
Nitrophenyl) carboxamide (0.086 g, 0.
197 mmol), n-valeraldehyde (0.084 m
L, 0.789 mmol), acetic acid (0.090 mL,
1.58 mmol), sodium triacetoxyborohydride (0.167 g, 0.789 mmol) and TH
The title compound (0.034 g, yield 34) was obtained according to the method described in Example 198 using F (1.5 mL).
%) Was obtained.
【0262】Rf 0.65 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.93 (6H, t, J=7.3
Hz), 1.36 (8H, m), 1.62 (4H, m), 3.30 (4H, t, J=
7.3 Hz), 6.71 (2H, d, J=8.8 Hz), 7.47 (2H, d,J=8.8
Hz), 7.58 (2H, d, J=8.8 Hz), 7.65 (2H, d, J=8.8 H
z), 7.66 (1H, d,J=8.8 Hz), 8.27 (1H, dd, J=8.8, 2.
9 Hz), 8.64 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 507 M+。
(実施例215)N−[4−[4−(N−メチル−N−
ペンチルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例202で製造したN−[4−[4−(N−ペンチ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.175g、0.
400mmol)、水素化ナトリウム(0.019g、
0.440mmol)、ヨウ化メチル(0.030m
L、0.480mmol)及びDMF(2mL)を使用
して、実施例210に記載した方法に従い、標記目的化
合物(0.142g、収率79%)を得た。R f 0.65 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.93 (6H, t, J = 7.3
Hz), 1.36 (8H, m), 1.62 (4H, m), 3.30 (4H, t, J =
7.3 Hz), 6.71 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8
Hz), 7.58 (2H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.8 H
z), 7.66 (1H, d, J = 8.8 Hz), 8.27 (1H, dd, J = 8.8, 2.
9 Hz), 8.64 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 507 M + . (Example 215) N- [4- [4- (N-methyl-N-
Pentylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-pentylamino) phenyl] phenyl]-[2-chloro-5 prepared in Example 202. −
Nitrophenyl) carboxamide (0.175 g, 0.
400 mmol), sodium hydride (0.019 g,
0.440 mmol), methyl iodide (0.030 m
L, 0.480 mmol) and DMF (2 mL) were used to give the title object compound (0.142 g, yield 79%) according to the method described in Example 210.
【0263】Rf 0.42 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.92 (3H, t, J=7.3
Hz), 1.37 (4H, m), 1.62 (2H, m), 3.12 (2H, t, J=
7.3 Hz), 3.54 (3H, s), 6.61 (2H, d, J=8.8 Hz), 7.1
4 (2H, d, J=8.8 Hz), 7.32 (2H, d, J=8.0 Hz), 7.37
(2H, d, J=8.0 Hz), 7.38 (1H, d, J=8.8 Hz), 7.97 (1
H, dd, J=2.2, 8.8 Hz), 8.06 (1H, d, J=2.2 Hz);
MS(FAB) m/z: 451 M+。
(実施例216)N−[4−[4−(N−エチル−N−
ペンチルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例205で製造したN−[4−[4−(N−エチル
アミノ)フェニル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド(0.139g、0.3
51mmol)、n−吉草アルデヒド(0.149m
L、1.40mmol)、酢酸(0.161mL、2.
81mmol)、トリアセトキシ水素化ホウ素ナトリウ
ム(0.298g、1.40mmol)及びTHF
(2.8mL)を使用して、実施例198に記載した方
法に従い、標記目的化合物(0.130g、収率79
%)を得た。R f 0.42 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.92 (3H, t, J = 7.3
Hz), 1.37 (4H, m), 1.62 (2H, m), 3.12 (2H, t, J =
7.3 Hz), 3.54 (3H, s), 6.61 (2H, d, J = 8.8 Hz), 7.1
4 (2H, d, J = 8.8 Hz), 7.32 (2H, d, J = 8.0 Hz), 7.37
(2H, d, J = 8.0 Hz), 7.38 (1H, d, J = 8.8 Hz), 7.97 (1
H, dd, J = 2.2, 8.8 Hz), 8.06 (1H, d, J = 2.2 Hz); MS (FAB) m / z: 451 M + . (Example 216) N- [4- [4- (N-ethyl-N-
Pentylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-ethylamino) phenyl] phenyl]-(2-chloro-5) prepared in Example 205. -Nitrophenyl) carboxamide (0.139 g, 0.3
51 mmol), n-valeric aldehyde (0.149 m
L, 1.40 mmol), acetic acid (0.161 mL, 2.
81 mmol), sodium triacetoxyborohydride (0.298 g, 1.40 mmol) and THF.
The title compound (0.130 g, yield 79) was obtained according to the method described in Example 198 using (2.8 mL).
%) Was obtained.
【0264】Rf 0.38 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.93 (3H, t, J=7.3
Hz), 1.19 (3H, t, J=7.3 Hz), 1.35 (4H, m), 1.63
(2H, m), 3.29 (2H, t, J=7.3 Hz), 3.41 (2H, q,J=7.3
Hz), 6.73 (2H, d, J=8.8 Hz), 7.47 (2H, d, J=8.8 H
z), 7.58 (2H, d,J=8.0 Hz), 7.65 (2H, d, J=8.0 Hz),
7.66 (1H, d, J=8.8 Hz), 8.26 (1H, dd, J=8.8, 2.9
Hz), 8.63 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 465 M+。
(実施例217)N−[4−[4−(N、N−ジエチル
アミノ)フェニル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド
実施例205で製造したN−[4−[4−(N−エチル
アミノ)フェニル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド(0.200g、0.5
05mmol)をTHF(4mL)に溶解させ、アセト
アルデヒド(0.113mL、2.02mmol)、酢
酸(0.231mL、4.04mmol)及びトリアセ
トキシ水素化ホウ素ナトリウム(0.428g、2.0
2mmol)を加え、0℃で1.5時間攪拌した。反応
溶液に飽和重曹水(10mL)及び水(20mL)加
え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄
し、無水硫酸ナトリウムで乾燥し、濃縮し、減圧乾燥し
た。生じた固体を濾取し、ジイソプロピルエーテルで洗
浄した後、減圧乾燥して、標記目的化合物(0.186
g、収率87%)を得た。R f 0.38 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.93 (3H, t, J = 7.3
Hz), 1.19 (3H, t, J = 7.3 Hz), 1.35 (4H, m), 1.63
(2H, m), 3.29 (2H, t, J = 7.3 Hz), 3.41 (2H, q, J = 7.3
Hz), 6.73 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8 H
z), 7.58 (2H, d, J = 8.0 Hz), 7.65 (2H, d, J = 8.0 Hz),
7.66 (1H, d, J = 8.8 Hz), 8.26 (1H, dd, J = 8.8, 2.9
Hz), 8.63 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 465 M + . Example 217 N- [4- [4- (N, N-diethylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-Ethylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide (0.200 g, 0.5
05 mmol) in THF (4 mL), acetaldehyde (0.113 mL, 2.02 mmol), acetic acid (0.231 mL, 4.04 mmol) and sodium triacetoxyborohydride (0.428 g, 2.0).
2 mmol) was added and the mixture was stirred at 0 ° C. for 1.5 hours. Saturated aqueous sodium hydrogen carbonate (10 mL) and water (20 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and dried under reduced pressure. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give the title object compound (0.186
g, yield 87%).
【0265】Rf 0.25 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 1.20 (6H, t, J=7.3
Hz), 3.40 (4H, q, J=7.3 Hz), 6.75 (2H, d, J=8.8 H
z), 7.48 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.0 H
z), 7.65 (2H, d, J=8.0 Hz), 7.67 (1H, d, J=8.8 H
z), 8.26 (1H, dd, J=8.8, 2.9 Hz), 8.63 (1H, d, J=
2.9 Hz);MS(FAB) m/z: 423 M+。
(実施例218)N−[4−[4−(N−エチル−N−
メチルアミノ)フェニル]フェニル]−(2−クロロ−
5−ニトロフェニル)カルボキサミド
実施例205で製造したN−[4−[4−(N−エチル
アミノ)フェニル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド(0.202g、0.5
05mmol)、水素化ナトリウム(0.024g、
0.555mmol)、ヨウ化メチル(0.038m
L、0.606mmol)及びDMF(2mL)を使用
して、実施例210に記載した方法に従い、標記目的化
合物(0.141g、収率68%)を得た。R f 0.25 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.20 (6H, t, J = 7.3
Hz), 3.40 (4H, q, J = 7.3 Hz), 6.75 (2H, d, J = 8.8 H
z), 7.48 (2H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.0 H
z), 7.65 (2H, d, J = 8.0 Hz), 7.67 (1H, d, J = 8.8 H
z), 8.26 (1H, dd, J = 8.8, 2.9 Hz), 8.63 (1H, d, J =
2.9 Hz); MS (FAB) m / z: 423 M + . (Example 218) N- [4- [4- (N-ethyl-N-
Methylamino) phenyl] phenyl]-(2-chloro-
5-Nitrophenyl) carboxamide N- [4- [4- (N-ethylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide prepared in Example 205 (0.202 g, 0.5
05 mmol), sodium hydride (0.024 g,
0.555 mmol), methyl iodide (0.038 m
L, 0.606 mmol) and DMF (2 mL) were used according to the method described in Example 210 to give the title object compound (0.141 g, yield 68%).
【0266】Rf 0.32 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 1.26 (3H, t, J=7.3
Hz), 3.18 (2H, q, J=7.3 Hz), 3.54 (3H, s), 6.62
(2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 7.32 (2
H, d, J=8.0 Hz), 7.38 (3H, m), 7.97 (1H, dd, J=8.
8, 2.9 Hz), 8.06 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 409 M+。
(実施例219)N−[4−[4−(N−オクチルアミ
ノ)フェニル]フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(1.50g、4.08mmol)をメ
タノール(30mL)に懸濁させ、シアノ水素化ホウ素
ナトリウム(1.54g、14.4mmol)及びオク
タナール(3.82mL、14.4mmol)を加え
て、室温で12時間攪拌した。生じた固形物を濾取し、
メタノール、ジイソプロピルエーテル及び水で洗浄し、
減圧乾燥して、標記目的化合物(1.20g、収率61
%)を得た。R f 0.32 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.26 (3H, t, J = 7.3
Hz), 3.18 (2H, q, J = 7.3 Hz), 3.54 (3H, s), 6.62
(2H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.32 (2
H, d, J = 8.0 Hz), 7.38 (3H, m), 7.97 (1H, dd, J = 8.
8, 2.9 Hz), 8.06 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 409 M + . Example 219 N- [4- [4- (N-octylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-amino) prepared in Example 192. Phenyl) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (1.50 g, 4.08 mmol) was suspended in methanol (30 mL), sodium cyanoborohydride (1.54 g, 14.4 mmol) and octanal (3.82 mL, 14.4 mmol) were added, and room temperature was added. It was stirred for 12 hours. The resulting solid matter is collected by filtration,
Wash with methanol, diisopropyl ether and water,
After drying under reduced pressure, the title object compound (1.20 g, yield 61) was obtained.
%) Was obtained.
【0267】Rf 0.79 (ヘキサン:酢酸エチル=1:1(v/
v));1
H-NMR (400MHz, DMSO-d6): δ(ppm) 0.87 (3H, t, J=
6.6 Hz), 1.20-1.40 (10H, m), 1.55 (2H, m), 3.02 (2
H, t, J=7.0 Hz), 5.75 (1H, br), 6.63 (2H, d,J=8.8
Hz), 7.41 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 H
z), 7.71 (2H, d,J=8.8 Hz), 7.90 (1H, d, J=8.8 Hz),
8.34 (1H, dd, J=8.8, 2.9 Hz), 8.47 (1H, d, J=2.9
Hz), 10.70 (1H, s);
MS(FAB) m/z: 479 M+。
(実施例220)N−[4−[4−(N−ヘキシル−N
−オクチルアミノ)フェニル]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド・1塩酸塩
実施例219で製造したN−[4−[4−(N−オクチ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.150g、0.
313mmol)をTHF(3mL)に溶解させ、ヘキ
サナール(0.150mL、1.25mmol)、酢酸
(0.143mL、2.50mmol)及びトリアセト
キシ水素化ホウ素ナトリウム(0.265g、1.25
mmol)を加え、0℃で2時間攪拌した。反応溶液に
飽和重曹水(10mL)及び水(20mL)を加え、酢
酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾
燥し、濃縮し、減圧乾燥した。得られた残渣をエタノー
ル(2mL)に溶解させ、過剰の水を加えた。生じた固
形物を濾取し、シリカゲルカラムクロマトグラフィー
(ヘキサン:酢酸エチル=4:1(v/v))にて精製し
た。得られた化合物をジエチルエーテル(4mL)に溶
解し、1N塩酸−ジエチルエーテル溶液(0.5mL)
を加え、生じた固体を濾取し、減圧乾燥して、標記目的
化合物(0.102g、収率54%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 0.83 (6H, m), 1.
21 (18H, m), 1.66 (2H,m), 3.91 (4H, m), 7.70-8.00
(8H, m), 7.91 (1H, d, J=8.8 Hz), 8.36(1H, dd, J=8.
8, 2.9 Hz), 8.50 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 564 (M - Cl)+。
(実施例221)N−[4−[4−(N−オクチル−N
−ペンチルアミノ)フェニル]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド・1塩酸塩
実施例219で製造したN−[4−[4−(N−オクチ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.150g、0.
313mmol)、n−吉草アルデヒド(0.133m
L、1.25mmol)、酢酸(0.143mL、2.
50mmol)、トリアセトキシ水素化ホウ素ナトリウ
ム(0.265g、1.25mmol)及びTHF(3
mL)を使用して、実施例220に記載した方法に従
い、標記目的化合物(0.060g、収率33%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 0.82 (6H, m), 1.
21 (16H, m), 1.65 (2H,m), 3.77 (4H, m), 7.70-8.00
(8H, m), 7.91 (1H, d, J=8.8 Hz), 8.36(1H, dd, J=8.
8, 2.9 Hz), 8.49 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 550 (M - Cl)+。
(実施例222)N−[4−[4−(N−ブチル−N−
オクチルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例219で製造したN−[4−[4−(N−オクチ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.150g、0.
313mmol)、ブチルアルデヒド(0.113m
L、1.25mmol)、酢酸(0.143mL、2.
50mmol)、トリアセトキシ水素化ホウ素ナトリウ
ム(0.265g、1.25mmol)及びTHF(3
mL)を使用して、実施例198に記載した方法に従
い、標記目的化合物(0.091g、収率54%)を得
た。R f 0.79 (hexane: ethyl acetate = 1: 1 (v /
v)); 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 0.87 (3H, t, J =
6.6 Hz), 1.20-1.40 (10H, m), 1.55 (2H, m), 3.02 (2
H, t, J = 7.0 Hz), 5.75 (1H, br), 6.63 (2H, d, J = 8.8
Hz), 7.41 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 H
z), 7.71 (2H, d, J = 8.8 Hz), 7.90 (1H, d, J = 8.8 Hz),
8.34 (1H, dd, J = 8.8, 2.9 Hz), 8.47 (1H, d, J = 2.9
Hz), 10.70 (1H, s); MS (FAB) m / z: 479 M + . (Example 220) N- [4- [4- (N-hexyl-N
-Octylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide monohydrochloride N- [4- [4- (N-octylamino) phenyl] phenyl]-(prepared in Example 219. 2-chloro-5
Nitrophenyl) carboxamide (0.150 g, 0.
313 mmol) in THF (3 mL) and hexanal (0.150 mL, 1.25 mmol), acetic acid (0.143 mL, 2.50 mmol) and sodium triacetoxyborohydride (0.265 g, 1.25).
mmol) was added and the mixture was stirred at 0 ° C. for 2 hours. Saturated aqueous sodium hydrogen carbonate (10 mL) and water (20 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated, and dried under reduced pressure. The obtained residue was dissolved in ethanol (2 mL), and excess water was added. The resulting solid matter was collected by filtration and purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 (v / v)). The obtained compound was dissolved in diethyl ether (4 mL), and 1N hydrochloric acid-diethyl ether solution (0.5 mL)
The resulting solid was collected by filtration and dried under reduced pressure to give the title object compound (0.102 g, yield 54%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 0.83 (6H, m), 1.
21 (18H, m), 1.66 (2H, m), 3.91 (4H, m), 7.70-8.00
(8H, m), 7.91 (1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 8.
8, 2.9 Hz), 8.50 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 564 (M-Cl) + . (Example 221) N- [4- [4- (N-octyl-N
-Pentylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide monohydrochloride N- [4- [4- (N-octylamino) phenyl] phenyl]-] prepared in Example 219. 2-chloro-5
Nitrophenyl) carboxamide (0.150 g, 0.
313 mmol), n-valeraldehyde (0.133 m)
L, 1.25 mmol), acetic acid (0.143 mL, 2.
50 mmol), sodium triacetoxyborohydride (0.265 g, 1.25 mmol) and THF (3
(mL) and according to the method described in Example 220 to give the title object compound (0.060 g, yield 33%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 0.82 (6H, m), 1.
21 (16H, m), 1.65 (2H, m), 3.77 (4H, m), 7.70-8.00
(8H, m), 7.91 (1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 8.
8, 2.9 Hz), 8.49 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 550 (M-Cl) + . (Example 222) N- [4- [4- (N-butyl-N-
Octylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-octylamino) phenyl] phenyl]-(2-chloro-5) prepared in Example 219. −
Nitrophenyl) carboxamide (0.150 g, 0.
313 mmol), butyraldehyde (0.113 m
L, 1.25 mmol), acetic acid (0.143 mL, 2.
50 mmol), sodium triacetoxyborohydride (0.265 g, 1.25 mmol) and THF (3
(mL) and according to the method described in Example 198 to give the title object compound (0.091 g, yield 54%).
【0268】Rf 0.65 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.90 (3H, m), 0.97
(3H, t, J=7.3 Hz), 1.24 - 1.42 (12H, m), 1.60 (4
H, m), 3.30 (4H, m), 6.71 (2H, d, J=8.8 Hz),7.47
(2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8 Hz), 7.65 (2
H, d, J=8.8 Hz),7.66 (1H, d, J=8.8 Hz), 7.84 (1H,
br), 8.27 (1H, dd, J=8.8, 2.9 Hz), 8.64 (1H, d, J=
2.9 Hz);
MS(FAB) m/z: 535 M+。
(実施例223)N−[4−[4−(N−ブチル−N−
オクチルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド・1塩酸塩
実施例222で製造したN−[4−[4−(N−ブチル
−N−オクチルアミノ)フェニル]フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド(0.0
34g、0.063mmol)をジエチルエーテル(1
mL)に溶解し、1N塩酸−ジエチルエーテル溶液
(0.2mL)を加えた。生じた固体を濾取し、減圧乾
燥して、標記目的化合物(0.028g、収率77%)
を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 0.82 (6H, m), 1.
21 (14H, m), 1.64 (2H,m), 3.74 (4H, m), 7.70-8.00
(8H, m), 7.91 (1H, d, J=8.8 Hz), 8.36(1H, dd, J=8.
8, 2.9 Hz), 8.49 (1H, m);
MS(FAB) m/z: 536 (M - Cl)+。
(実施例224)N−[4−[4−(N−オクチル−N
−プロピルアミノ)フェニル]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド
実施例219で製造したN−[4−[4−(N−オクチ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.150g、0.
313mmol)、プロピオンアルデヒド(0.090
mL、1.25mmol)、酢酸(0.143mL、
2.50mmol)、トリアセトキシ水素化ホウ素ナト
リウム(0.265g、1.25mmol)及びTHF
(3mL)を使用して、実施例198に記載した方法に
従い、標記目的化合物(0.103g、収率63%)を
得た。R f 0.65 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.90 (3H, m), 0.97
(3H, t, J = 7.3 Hz), 1.24-1.42 (12H, m), 1.60 (4
H, m), 3.30 (4H, m), 6.71 (2H, d, J = 8.8 Hz), 7.47
(2H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.65 (2
H, d, J = 8.8 Hz), 7.66 (1H, d, J = 8.8 Hz), 7.84 (1H,
br), 8.27 (1H, dd, J = 8.8, 2.9 Hz), 8.64 (1H, d, J =
2.9 Hz); MS (FAB) m / z: 535 M + . (Example 223) N- [4- [4- (N-butyl-N-
Octylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide monohydrochloride N- [4- [4- (N-butyl-N-octylamino) phenyl] phenyl prepared in Example 222 ]-(2-
Chloro-5-nitrophenyl) carboxamide (0.0
34 g, 0.063 mmol) in diethyl ether (1
mL), and 1N hydrochloric acid-diethyl ether solution (0.2 mL) was added. The resulting solid was collected by filtration and dried under reduced pressure to give the title object compound (0.028 g, yield 77%).
Got 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 0.82 (6H, m), 1.
21 (14H, m), 1.64 (2H, m), 3.74 (4H, m), 7.70-8.00
(8H, m), 7.91 (1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 8.
8, 2.9 Hz), 8.49 (1H, m); MS (FAB) m / z: 536 (M-Cl) + . (Example 224) N- [4- [4- (N-octyl-N
-Propylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-octylamino) phenyl] phenyl]-(2-chloro- prepared in Example 219. 5-
Nitrophenyl) carboxamide (0.150 g, 0.
313 mmol), propionaldehyde (0.090
mL, 1.25 mmol), acetic acid (0.143 mL,
2.50 mmol), sodium triacetoxyborohydride (0.265 g, 1.25 mmol) and THF
The title compound (0.103 g, yield 63%) was obtained according to the method described in Example 198 using (3 mL).
【0269】Rf 0.63 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.89 (3H, t, J=7.3
Hz), 0.95 (3H, t, J=7.3 Hz), 1.24-1.38 (10H, m),
1.63 (4H, m), 3.28 (4H, m), 6.71 (2H, d, J=8.8 H
z), 7.47 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 H
z), 7.64 (2H, d, J=8.8 Hz), 7.65 (1H, d, J=8.8 H
z), 7.86 (1H, br), 8.25 (1H, dd, J=8.8, 2.9Hz), 8.
62 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 521 M+。
(実施例225)N−[4−[4−(N−エチル−N−
オクチルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例219で製造したN−[4−[4−(N−オクチ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.150g、0.
313mmol)、アセトアルデヒド(0.078m
L、1.25mmol)、酢酸(0.143mL、2.
50mmol)、トリアセトキシ水素化ホウ素ナトリウ
ム(0.265g、1.25mmol)及びTHF(3
mL)を使用して、実施例217に記載した方法に従
い、標記目的化合物(0.097g、収率61%)を得
た。R f 0.63 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.89 (3H, t, J = 7.3
Hz), 0.95 (3H, t, J = 7.3 Hz), 1.24-1.38 (10H, m),
1.63 (4H, m), 3.28 (4H, m), 6.71 (2H, d, J = 8.8 H
z), 7.47 (2H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.8 H
z), 7.64 (2H, d, J = 8.8 Hz), 7.65 (1H, d, J = 8.8 H
z), 7.86 (1H, br), 8.25 (1H, dd, J = 8.8, 2.9Hz), 8.
62 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 521 M + . (Example 225) N- [4- [4- (N-ethyl-N-
Octylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-octylamino) phenyl] phenyl]-(2-chloro-5) prepared in Example 219. −
Nitrophenyl) carboxamide (0.150 g, 0.
313 mmol), acetaldehyde (0.078 m
L, 1.25 mmol), acetic acid (0.143 mL, 2.
50 mmol), sodium triacetoxyborohydride (0.265 g, 1.25 mmol) and THF (3
(mL) according to the method described in Example 217 to give the title object compound (0.097 g, yield 61%).
【0270】Rf 0.61 (ヘキサン:酢酸エチル=2:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.89 (3H, t, J=7.3
Hz), 1.19 (3H, t, J=7.3 Hz), 1.24-1.38 (10H, m),
1.62 (2H, m), 3.29 (2H, t, J=7.3 Hz), 3.41 (2H, q,
J=7.3 Hz), 6.73 (2H, d, J=8.8 Hz), 7.48 (2H, d, J
=8.8 Hz), 7.58 (2H, d, J=8.8 Hz), 7.65 (2H, d, J=
8.8 Hz), 7.66(1H, d, J=8.8 Hz), 7.83 (1H, br), 8.2
7 (1H, dd, J=8.8, 2.9 Hz), 8.64 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 507 (M + H)+。
(実施例226)N−[4−[4−(N−メチル−N−
オクチルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例219で製造したN−[4−[4−(N−オクチ
ルアミノ)フェニル]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド(0.150g、0.
313mmol)、水素化ナトリウム(0.015g、
0.345mmol)、ヨウ化メチル(0.023m
L、0.375mmol)及びDMF(2mL)を使用
して、実施例210に記載した方法に従い、標記目的化
合物(0.101g、収率66%)を得た。R f 0.61 (hexane: ethyl acetate = 2: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.89 (3H, t, J = 7.3
Hz), 1.19 (3H, t, J = 7.3 Hz), 1.24-1.38 (10H, m),
1.62 (2H, m), 3.29 (2H, t, J = 7.3 Hz), 3.41 (2H, q,
J = 7.3 Hz), 6.73 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J
= 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.65 (2H, d, J =
8.8 Hz), 7.66 (1H, d, J = 8.8 Hz), 7.83 (1H, br), 8.2
7 (1H, dd, J = 8.8, 2.9 Hz), 8.64 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 507 (M + H) + . (Example 226) N- [4- [4- (N-methyl-N-
Octylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- [4- (N-octylamino) phenyl] phenyl]-(2-chloro-5) prepared in Example 219. −
Nitrophenyl) carboxamide (0.150 g, 0.
313 mmol), sodium hydride (0.015 g,
0.345 mmol), methyl iodide (0.023 m
L, 0.375 mmol) and DMF (2 mL) were used to give the title object compound (0.101 g, yield 66%) according to the method described in Example 210.
【0271】Rf 0.31 (ヘキサン:酢酸エチル=3:1(v/
v));1
H-NMR (400MHz, CDCl3): δ(ppm) 0.88 (3H, t, J=7.3
Hz), 1.25-1.45 (10H,m), 1.50-1.65 (4H, m), 3.12
(2H, t, J=7.3 Hz), 3.53 (3H, s), 6.61 (2H, d, J=8.
8 Hz), 7.14 (2H, d, J=8.8 Hz), 7.32 (2H, d, J=8.0
Hz), 7.37 (2H, d, J=8.0 Hz), 7.38 (1H, d, J=8.8 H
z), 7.97 (1H, dd, J=8.8, 2.2 Hz), 8.06(1H, d, J=2.
2 Hz);
MS(FAB) m/z: 494 (M + H)+。
(実施例227)N−[4−[4−(ピリジン−3−イ
ルカルボニル)ピペラジン−1−イル]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例133で製造したN−[4−(ピペラジン−1−
イル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド・2塩酸塩(0.200g、0.4
61mmol)、ニコチン酸クロリド・塩酸塩(0.1
23g、0.692mmol)及びピリジン(2mL)
を使用して、実施例183に記載した方法に従い、標記
目的化合物(0.140g、収率65%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 3.20 (4H, m), 3.62
(2H, m), 3.95 (2H, m), 6.94 (2H, d, J=8.8 Hz), 7.
39 (1H, dd, J=5.1, 8.0 Hz), 7.55 (2H, d, J=8.8 H
z), 7.62 (1H, d, J=8.8 Hz), 7.79 (1H, m), 8.14 (1
H, br), 8.22 (1H, dd, J=8.8, 2.1 Hz), 8.55 (1H, d,
J=2.1 Hz), 8.68 (2H, m);
MS(FAB) m/z: 466 (M + H)+。
(実施例228)N−[4−[4−(ピリジン−4−イ
ルカルボニル)ピペラジン−1−イル]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例133で製造したN−[4−(ピペラジン−1−
イル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド・2塩酸塩(0.200g、0.4
61mmol)、イソニコチン酸クロリド・塩酸塩
(0.123g、0.692mmol)及びピリジン
(2mL)を使用して、実施例183に記載した方法に
従い、標記目的化合物(0.205g、収率96%)を
得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 3.12 (2H, m), 3.27
(2H, m), 3.54 (2H, m), 3.95 (2H, m), 6.93 (2H, d,
J=8.8 Hz), 7.32 (2H, d, J=5.8 Hz), 7.55 (2H, d, J
=8.8 Hz), 7.64 (1H, d, J=8.8 Hz), 8.00 (1H, br),
8.24 (1H, dd, J=8.8, 2.1 Hz), 8.58 (1H, d, J=2.1 H
z), 8.72 (2H, d, J=5.8 Hz);
MS(FAB) m/z: 466 (M + H)+。
(実施例229)N−(2−エトキシフェニル)−(2
−クロロ−5−ニトロフェニル)カルボキサミド
2−エトキシアニリン(0.33g、2.40mmo
l)、DMA(4mL)ならびに2−クロロ−5−ニト
ロ安息香酸クロリド(0.58g、2.64mmol)
を使用して、実施例2に記載した方法に従い、標記目的
化合物(0.41g、収率54%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.35 (3H, t, J=
7.0 Hz), 4.10 (2H, q, J=7.0 Hz), 6.98 (1H, t, J=7.
5 Hz), 7.09 (1H, d, J=7.5 Hz), 7.18 (1H, t, J=7.5
Hz), 7.87 (1H, d, J=7.5 Hz), 7.87 (1H, d, J=8.6 H
z), 8.33 (1H, dd,J=8.6, 2.7 Hz), 8.41 (1H, d, J=2.
7 Hz), 9.91 (1H, s);
MS(FAB) m/z: 320 (M + H)+。
(実施例230)N−[4−(2−ヒドロキシエチル)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
4−(2−ヒドロキシエチル)アニリン(5.02g、
36.6mmol)、DMA(50mL)ならびに2−
クロロ−5−ニトロ安息香酸クロリド(8.45g、3
8.4mmol)を使用して、実施例2に記載した方法
に従い、標記目的化合物(9.18g、収率78%)を
得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.70 (2H, t, J=
7.1 Hz), 3.56-3.61 (2H,m), 4.64 (1H, t, J=5.2 Hz),
7.22 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4Hz), 7.
89 (1H, d, J=8.8 Hz), 8.33 (1H, dd, J=8.8, 2.8 H
z), 8.43 (1H, d,J=2.8 Hz), 10.63 (1H, s);
MS(FAB) m/z: 321 (M + H)+。
(実施例231)N−[[3−[4−(イミダゾール−
1−イル)フェニル]アミノカルボニル]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
3−アミノ−N−[4−(イミダゾール−1−イル)フ
ェニル]ベンズアミド(0.28g、1.0mmo
l)、DMA(10mL)ならびに2−クロロ−5−ニ
トロ安息香酸クロリド(0.26g、1.20mmo
l)を使用して、実施例2に記載した方法に従い、標記
目的化合物(0.41g、収率89%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.11 (1H, s), 7.
57 (1H, t, J=7.9 Hz),7.65 (2H, d, J=8.9 Hz), 7.72
(1H, s), 7.77 (1H, d, J=7.6 Hz), 7.90-7.95(4H, m),
8.22-8.26 (2H, s), 8.51 (1H, d, J=2.7 Hz), 10.49
(1H, s), 10.94(1H, s);
MS(FAB) m/z: 462 (M + H)+。
(実施例232)N−[[4−[4−(N−エチル−N
−イソプロピルアミノ)フェニル]アミノスルホニル]
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
4−[4−(N−エチル−N−イソプロピルアミノ)フ
ェニルアミノスルホニル]アニリン(0.33g、1.
0mmol)、DMA(10mL)ならびに2−クロロ
−5−ニトロ安息香酸クロリド(0.26g、1.20
mmol)を使用して、実施例2に記載した方法に従
い、標記目的化合物(0.42g、収率81%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.03 (3H, t, J=
6.9 Hz), 1.08 (6H, d, J=3.3 Hz), 3.14 (2H, q, J=6.
9 Hz), 3.8-4.0 (1H, m), 6.57 (2H, d, J=9.1 Hz), 6.
85 (2H, d, J=9.1 Hz), 7.69 (2H, d, J=8.8 Hz), 7.82
(2H, d, J=8.8 Hz), 7.90 (1H, d, J=8.8 Hz), 8.35
(1H, dd, J=8.8, 2.7 Hz), 8.52 (1H, d, J=2.7 Hz), 1
1.05 (1H, s);
MS(FAB) m/z: 516 M+, 517 (M + H)+。
(実施例233)N−[3−(2−アミノチアゾール−
4−イル)フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
実施例156で製造したN−(3−アセチルフェニル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
(1.91g、6.0mmol)、チオウレア(0.9
1g、12mmol)ならびに沃素(1.52g、6.
0mmol)を使用して、参考例2に記載した方法に従
い、標記目的化合物(2.06g、収率91%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.01 (1H, s), 7.
40 (1H, t, J=7.9 Hz),7.53-7.58 (2H, m), 7.90 (1H,
d), 8.19 (1H, t, J=1.7 Hz), 8.35 (1H, dd, J=8.8,
2.7 Hz), 8.47 (1H, d, J=2.7 Hz), 10.77 (1H, s);
MS(FAB) m/z: 375 (M + H)+。
(実施例234)N−[4−(3−tert−ブトキシ
カルボニルアミノフェニル)チアゾール−2−イル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(234a)2−アミノ−4−(3−tert−ブトキ
シカルボニルアミノフェニル)チアゾール
2−アミノ−(3−アミノフェニル)チアゾール(1.
43g、7.47mmol)、メタノール(30mL)
ならびにジ−tert−ブチルジカーボネート(1.8
0g、8.24mmol)を使用して、実施例190a
に記載した方法に従い、標記目的化合物(2.10g、
収率97%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 6.86 (1H, s), 7.
03 (2H, s), 7.18-7.26(2H, m), 7.36-7.38 (1H, m),
8.01 (1H, s), 9.33 (1H, s)。
(234b)N−[4−(3−tert−ブトキシカル
ボニルアミノフェニル)チアゾール−2−イル]−(2
−クロロ−5−ニトロフェニル)カルボキサミド
実施例234aで製造した2−アミノ−4−(3−te
rt−ブトキシカルボニルアミノフェニル)チアゾール
(0.29g、1.0mmol)、DMA(5mL)な
らびに2−クロロ−5−ニトロ安息香酸クロリド(0.
26g、1.2mmol)を使用して、実施例2に記載
した方法に従い、標記目的化合物(0.45g、収率9
5%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.26-7.33 (2H,
m), 7.51 (1H, dd, J=1.7, 6.8 Hz), 7.65 (1H, s), 7.
91 (1H, d, J=8.8 Hz), 8.22 (1H, s), 8.37 (1H,dd, J
=8.8, 2.7 Hz), 8.60 (1H, d, J=2.7 Hz), 9.43 (1H,
s);
MS(FAB) m/z: 475 (M + H)+。
(実施例235)N−[4−[4−(N、N−ジメタン
スルホニルアミノ)フェニル]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)のTH
F(10mL)溶液にトリエチルアミン(0.55m
L、4.0mmol)及びメタンスルホニルクロリド
(0.17mL、2.2mmol)を加え3時間攪拌し
た。反応溶液に飽和重曹水及び酢酸エチルを加え、1時
間攪拌した後、酢酸エチルで抽出した。有機層を飽和重
硫酸カリウム水溶液及び飽和食塩水で洗浄し、無水硫酸
ナトリウムで乾燥し、濃縮した。残渣をジイソプロピル
エーテル及びヘキサンで固化させ、生じた固形物を濾取
して、標記目的化合物(0.44g、収率83%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.56 (6H, s), 7.
60 (2H, d, J=8.4 Hz),7.78 (2H, d, J=8.8 Hz), 7.78
(2H, d, J=8.4 Hz), 7.84 (2H, d, J=8.8 Hz),7.92 (1
H, d, J=8.8 Hz), 8.36 (1H, dd, J=8.8, 2.7 Hz), 8.5
0 (1H, d,J= 2.7Hz), 10.86 (1H, s);
MS(FAB) m/z: 524 (M + H)+。
(実施例236)N−[4−[4−(メチルアミノチオ
カルボニルアミノ)フェニル]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)のTH
F(5mL)溶液にメチルチオイソシアネート(0.1
8g、2.5mmol)を加え、一晩攪拌した。反応溶
液にメタノール(0.2mL)を加え、1時間攪拌し、
反応液を濃縮した。残渣に水(10mL)及びヘキサン
(5mL)を加え攪拌した後、析出した固体を濾取し、
乾燥して、標記目的化合物(0.42g、収率96%)
を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.33 (2H, d, J=
8.5 Hz), 7.49 (2H, d, J=8.5 Hz), 7.54 (2H, d, J=8.
7 Hz), 7.65 (2H, d, J=8.7 Hz), 7.76 (1H, d, J=8.8
Hz), 8.21 (1H, dd, J=8.8, 2.8 Hz), 8.34 (1H, d, J=
2.8 Hz), 9.52 (1H, bs), 10.79 (1H, s);
MS(FAB) m/z: 440 M+。
(実施例237)N−[4−(2,2,2−トリフルオ
ロ−1−ヒドロキシ−1−トリフルオロメチルエチル)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
4−(2,2,2−トリフルオロ−1−ヒドロキシ−1
−トリフルオロメチル−エチル)アニリン(0.44
g、1.69mmol)、DMA(5mL)ならびに2
−クロロ−5−ニトロ安息香酸クロリド(0.41g、
1.86mmol)を使用して、実施例2に記載した方
法に従い、標記目的化合物(0.62g、収率82%)
を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 5.43 (1H, bs),
7.69 (2H, d, J=8.7 Hz),7.84 (2H, d, J=8.7 Hz), 7.9
1 (1H, d, J=8.8 Hz), 8.36 (1H, dd, J=8.8, 2.7 Hz),
8.50 (1H, d, J=2.7 Hz), 10.94 (1H, s);
MS(FAB) m/z: 443 (M + H)+。
(実施例238)N−[4−(1−ヒドロキシエチル)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
実施例155で製造したN−(4−アセチルフェニル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
(0.32g、1.0mmol)のTHF−水(9:1
(v/v)、5mL)溶液に、水素化ホウ素ナトリウム
(0.04g、1.0mmol)を加え、室温で1時間
攪拌した。反応液に飽和重曹水を加え、酢酸エチルで抽
出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリ
ウムで乾燥し、濃縮した。残渣にヘキサンを加え、生じ
た固体を濾取し、乾燥して、標記目的化合物(0.24
g、収率76%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.31 (3H, d, J=
6.4 Hz), 4.67-4.73 (1H,m), 5.13 (1H, d, J=4.7 Hz),
7.33 (2H, d, J=8.5 Hz), 7.63 (2H, d, J=8.5Hz), 7.
89 (1H, d, J=8.8 Hz), 8.34 (1H, dd, J=8.8, 2.8 H
z), 8.44 (1H, d,J=2.8 Hz), 10.65 (1H, s);
MS(FAB) m/z: 321 (M + H)+。
(実施例239)N−[3−(1−ヒドロキシエチル)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
実施例156で製造したN−(3−アセチルフェニル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
(0.32g、1.0mmol)、THF−水(9:1
(v/v)、5mL)ならびに水素化ホウ素ナトリウム
(0.04g、1.0mmol)を使用して、実施例2
38に記載した方法に従い、標記目的化合物(0.24
g、収率74%)を得た。R f 0.31 (hexane: ethyl acetate = 3: 1 (v /
v)); 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 0.88 (3H, t, J = 7.3
Hz), 1.25-1.45 (10H, m), 1.50-1.65 (4H, m), 3.12
(2H, t, J = 7.3 Hz), 3.53 (3H, s), 6.61 (2H, d, J = 8.
8 Hz), 7.14 (2H, d, J = 8.8 Hz), 7.32 (2H, d, J = 8.0
Hz), 7.37 (2H, d, J = 8.0 Hz), 7.38 (1H, d, J = 8.8 H
z), 7.97 (1H, dd, J = 8.8, 2.2 Hz), 8.06 (1H, d, J = 2.
2 Hz); MS (FAB) m / z: 494 (M + H) + . Example 227 N- [4- [4- (Pyridin-3-ylcarbonyl) piperazin-1-yl] phenyl]-
(2-Chloro-5-nitrophenyl) carboxamide N- [4- (piperazine-1-) prepared in Example 133.
Iyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide dihydrochloride (0.200 g, 0.4
61 mmol), nicotinic acid chloride / hydrochloride (0.1
23 g, 0.692 mmol) and pyridine (2 mL)
Was used according to the method described in Example 183 to give the title object compound (0.140 g, yield 65%). 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 3.20 (4H, m), 3.62
(2H, m), 3.95 (2H, m), 6.94 (2H, d, J = 8.8 Hz), 7.
39 (1H, dd, J = 5.1, 8.0 Hz), 7.55 (2H, d, J = 8.8 H
z), 7.62 (1H, d, J = 8.8 Hz), 7.79 (1H, m), 8.14 (1
H, br), 8.22 (1H, dd, J = 8.8, 2.1 Hz), 8.55 (1H, d,
J = 2.1 Hz), 8.68 (2H, m); MS (FAB) m / z: 466 (M + H) + . Example 228 N- [4- [4- (Pyridin-4-ylcarbonyl) piperazin-1-yl] phenyl]-
(2-Chloro-5-nitrophenyl) carboxamide N- [4- (piperazine-1-) prepared in Example 133.
Iyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide dihydrochloride (0.200 g, 0.4
61 mmol), isonicotinic acid chloride.hydrochloride (0.123 g, 0.692 mmol) and pyridine (2 mL) according to the method described in Example 183, the title object compound (0.205 g, yield 96%). ) Got. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 3.12 (2H, m), 3.27
(2H, m), 3.54 (2H, m), 3.95 (2H, m), 6.93 (2H, d,
J = 8.8 Hz), 7.32 (2H, d, J = 5.8 Hz), 7.55 (2H, d, J
= 8.8 Hz), 7.64 (1H, d, J = 8.8 Hz), 8.00 (1H, br),
8.24 (1H, dd, J = 8.8, 2.1 Hz), 8.58 (1H, d, J = 2.1 H
z), 8.72 (2H, d, J = 5.8 Hz); MS (FAB) m / z: 466 (M + H) + . (Example 229) N- (2-ethoxyphenyl)-(2
-Chloro-5-nitrophenyl) carboxamide 2-ethoxyaniline (0.33 g, 2.40 mmo
l), DMA (4 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.58 g, 2.64 mmol).
Was used according to the method described in Example 2 to give the title object compound (0.41 g, yield 54%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.35 (3H, t, J =
7.0 Hz), 4.10 (2H, q, J = 7.0 Hz), 6.98 (1H, t, J = 7.
5 Hz), 7.09 (1H, d, J = 7.5 Hz), 7.18 (1H, t, J = 7.5
Hz), 7.87 (1H, d, J = 7.5 Hz), 7.87 (1H, d, J = 8.6 H
z), 8.33 (1H, dd, J = 8.6, 2.7 Hz), 8.41 (1H, d, J = 2.
7 Hz), 9.91 (1H, s); MS (FAB) m / z: 320 (M + H) + . (Example 230) N- [4- (2-hydroxyethyl)
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (2-hydroxyethyl) aniline (5.02 g,
36.6 mmol), DMA (50 mL) and 2-
Chloro-5-nitrobenzoic acid chloride (8.45 g, 3
(8.4 mmol) and according to the method described in Example 2 to obtain the title object compound (9.18 g, yield 78%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.70 (2H, t, J =
7.1 Hz), 3.56-3.61 (2H, m), 4.64 (1H, t, J = 5.2 Hz),
7.22 (2H, d, J = 8.4 Hz), 7.60 (2H, d, J = 8.4Hz), 7.
89 (1H, d, J = 8.8 Hz), 8.33 (1H, dd, J = 8.8, 2.8 H
z), 8.43 (1H, d, J = 2.8 Hz), 10.63 (1H, s); MS (FAB) m / z: 321 (M + H) + . (Example 231) N-[[3- [4- (imidazole-
1-yl) phenyl] aminocarbonyl] phenyl]-
(2-Chloro-5-nitrophenyl) carboxamide 3-amino-N- [4- (imidazol-1-yl) phenyl] benzamide (0.28 g, 1.0 mmo
l), DMA (10 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.26 g, 1.20 mmo.
By using l) and following the method described in Example 2, the title object compound (0.41 g, yield 89%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.11 (1H, s), 7.
57 (1H, t, J = 7.9 Hz), 7.65 (2H, d, J = 8.9 Hz), 7.72
(1H, s), 7.77 (1H, d, J = 7.6 Hz), 7.90-7.95 (4H, m),
8.22-8.26 (2H, s), 8.51 (1H, d, J = 2.7 Hz), 10.49
(1H, s), 10.94 (1H, s); MS (FAB) m / z: 462 (M + H) + . (Example 232) N-[[4- [4- (N-ethyl-N
-Isopropylamino) phenyl] aminosulfonyl]
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- [4- (N-ethyl-N-isopropylamino) phenylaminosulfonyl] aniline (0.33 g, 1.
0 mmol), DMA (10 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.26 g, 1.20).
was used according to the method described in Example 2 to give the title object compound (0.42 g, yield 81%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.03 (3H, t, J =
6.9 Hz), 1.08 (6H, d, J = 3.3 Hz), 3.14 (2H, q, J = 6.
9 Hz), 3.8-4.0 (1H, m), 6.57 (2H, d, J = 9.1 Hz), 6.
85 (2H, d, J = 9.1 Hz), 7.69 (2H, d, J = 8.8 Hz), 7.82
(2H, d, J = 8.8 Hz), 7.90 (1H, d, J = 8.8 Hz), 8.35
(1H, dd, J = 8.8, 2.7 Hz), 8.52 (1H, d, J = 2.7 Hz), 1
1.05 (1H, s); MS (FAB) m / z: 516 M + , 517 (M + H) + . (Example 233) N- [3- (2-aminothiazole-
4-yl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- (3-acetylphenyl) prepared in Example 156
-(2-chloro-5-nitrophenyl) carboxamide (1.91 g, 6.0 mmol), thiourea (0.9
1 g, 12 mmol) and iodine (1.52 g, 6.
Was used according to the method described in Reference Example 2 to give the title object compound (2.06 g, yield 91%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.01 (1H, s), 7.
40 (1H, t, J = 7.9 Hz), 7.53-7.58 (2H, m), 7.90 (1H,
d), 8.19 (1H, t, J = 1.7 Hz), 8.35 (1H, dd, J = 8.8,
2.7 Hz), 8.47 (1H, d, J = 2.7 Hz), 10.77 (1H, s); MS (FAB) m / z: 375 (M + H) + . (Example 234) N- [4- (3-tert-butoxycarbonylaminophenyl) thiazol-2-yl]-
(2-chloro-5-nitrophenyl) carboxamide (234a) 2-amino-4- (3-tert-butoxycarbonylaminophenyl) thiazole 2-amino- (3-aminophenyl) thiazole (1.
43 g, 7.47 mmol), methanol (30 mL)
And di-tert-butyl dicarbonate (1.8
0g, 8.24mmol) was used for Example 190a.
According to the method described in 1., the title compound (2.10 g,
Yield 97%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 6.86 (1H, s), 7.
03 (2H, s), 7.18-7.26 (2H, m), 7.36-7.38 (1H, m),
8.01 (1H, s), 9.33 (1H, s). (234b) N- [4- (3-tert-butoxycarbonylaminophenyl) thiazol-2-yl]-(2
-Chloro-5-nitrophenyl) carboxamide 2-amino-4- (3-te) prepared in Example 234a.
rt-Butoxycarbonylaminophenyl) thiazole (0.29 g, 1.0 mmol), DMA (5 mL) and 2-chloro-5-nitrobenzoic acid chloride (0.
26 g, 1.2 mmol) and according to the method described in Example 2 (0.45 g, yield 9).
5%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.26-7.33 (2H,
m), 7.51 (1H, dd, J = 1.7, 6.8 Hz), 7.65 (1H, s), 7.
91 (1H, d, J = 8.8 Hz), 8.22 (1H, s), 8.37 (1H, dd, J
= 8.8, 2.7 Hz), 8.60 (1H, d, J = 2.7 Hz), 9.43 (1H,
s); MS (FAB) m / z: 475 (M + H) + . Example 235 N- [4- [4- (N, N-Dimethanesulfonylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4-Prepared in Example 192 (4-Aminophenyl) phenyl]-(2-chloro-5-nitrophenyl)
TH of carboxamide (0.37 g, 1.0 mmol)
To the F (10 mL) solution, triethylamine (0.55 m
L, 4.0 mmol) and methanesulfonyl chloride (0.17 mL, 2.2 mmol) were added, and the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the reaction solution, the mixture was stirred for 1 hr, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium bisulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was solidified with diisopropyl ether and hexane, and the resulting solid was collected by filtration to give the title object compound (0.44 g, yield 83%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 3.56 (6H, s), 7.
60 (2H, d, J = 8.4 Hz), 7.78 (2H, d, J = 8.8 Hz), 7.78
(2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.8 Hz), 7.92 (1
H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 8.8, 2.7 Hz), 8.5
0 (1H, d, J = 2.7Hz), 10.86 (1H, s); MS (FAB) m / z: 524 (M + H) + . Example 236 N- [4- [4- (methylaminothiocarbonylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- [4- (4- Aminophenyl) phenyl]-(2-chloro-5-nitrophenyl)
TH of carboxamide (0.37 g, 1.0 mmol)
F (5 mL) solution was added with methylthioisocyanate (0.1
8 g, 2.5 mmol) was added and stirred overnight. Add methanol (0.2 mL) to the reaction solution, stir for 1 hour,
The reaction solution was concentrated. Water (10 mL) and hexane (5 mL) were added to the residue and stirred, and then the precipitated solid was collected by filtration,
Dry to give the title object compound (0.42 g, 96% yield).
Got 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.33 (2H, d, J =
8.5 Hz), 7.49 (2H, d, J = 8.5 Hz), 7.54 (2H, d, J = 8.
7 Hz), 7.65 (2H, d, J = 8.7 Hz), 7.76 (1H, d, J = 8.8
Hz), 8.21 (1H, dd, J = 8.8, 2.8 Hz), 8.34 (1H, d, J =
2.8 Hz), 9.52 (1H, bs), 10.79 (1H, s); MS (FAB) m / z: 440 M + . Example 237 N- [4- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide 4- (2,2,2-trifluoro-1-hydroxy-1)
-Trifluoromethyl-ethyl) aniline (0.44
g, 1.69 mmol), DMA (5 mL) and 2
-Chloro-5-nitrobenzoic acid chloride (0.41 g,
1.86 mmol) according to the method described in Example 2 to give the title object compound (0.62 g, yield 82%).
Got 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 5.43 (1H, bs),
7.69 (2H, d, J = 8.7 Hz), 7.84 (2H, d, J = 8.7 Hz), 7.9
1 (1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 8.8, 2.7 Hz),
8.50 (1H, d, J = 2.7 Hz), 10.94 (1H, s); MS (FAB) m / z: 443 (M + H) + . (Example 238) N- [4- (1-hydroxyethyl)
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- (4-acetylphenyl) prepared in Example 155
-(2-Chloro-5-nitrophenyl) carboxamide (0.32 g, 1.0 mmol) in THF-water (9: 1)
(v / v), 5 mL) solution was added sodium borohydride (0.04 g, 1.0 mmol) and stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Hexane was added to the residue, and the resulting solid was collected by filtration and dried to give the title object compound (0.24
g, yield 76%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.31 (3H, d, J =
6.4 Hz), 4.67-4.73 (1H, m), 5.13 (1H, d, J = 4.7 Hz),
7.33 (2H, d, J = 8.5 Hz), 7.63 (2H, d, J = 8.5Hz), 7.
89 (1H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 8.8, 2.8 H
z), 8.44 (1H, d, J = 2.8 Hz), 10.65 (1H, s); MS (FAB) m / z: 321 (M + H) + . (Example 239) N- [3- (1-hydroxyethyl)
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide N- (3-acetylphenyl) prepared in Example 156.
-(2-chloro-5-nitrophenyl) carboxamide (0.32 g, 1.0 mmol), THF-water (9: 1)
(v / v), 5 mL) and sodium borohydride (0.04 g, 1.0 mmol), Example 2
According to the method described in No. 38, the title compound (0.24
g, yield 74%).
【0272】1H-NMR (400MHz, DMSO-d6): δ(ppm) 1.31
(3H, d, J=6.4 Hz), 4.66-4.73 (1H, m), 5.18 (1H,
d, J=4.1 Hz), 7.09 (1H, d, J=7.7 Hz), 7.29 (1H, t,
J=7.7 Hz), 7.54-7.57 (1H, m), 7.70 (1H, bs), 7.87
(1H, dd, J=8.8 Hz), 8.32 (1H, dd, J=8.8, 2.7 Hz),
8.43 (1H, d, J=2.7 Hz), 10.67 (1H, s);
MS(FAB) m/z: 320 M+。
(実施例240)N−[4−(5,7,7,10,10
−ペンタメチル−7,8,9,10−テトラヒドロ−5
H−5,13−ジアザ−ベンゾ[4,5]シクロヘプタ
[1,2−b]ナフタレン−12−イル)フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(240a)4−(5,7,7,10,10−ペンタメ
チル−7,8,9,10−テトラヒドロ−5H−5,1
3−ジアザベンゾ[4,5]シクロヘプタ[1,2−
b]ナフタレン−12−イル)アニリン4−(5,7,
7,10,10−ペンタメチル−7,8,9,10−テ
トラヒドロ−5H−5,13−ジアザベンゾ[4,5]
シクロヘプタ[1,2−b]ナフタレン−12−イル)
安息香酸(0.97g、2.21mmol)、tert
−ブチルアルコール(10mL)、DPPA(0.59
mL、2.74mmol)ならびにトリエチルアミン
(0.38mL、2.74mmol)から製造される4
−(5,7,7,10,10−ペンタメチル−7,8,
9,10−テトラヒドロ−5H−5,13−ジアザベン
ゾ[4,5]シクロヘプタ[1,2−b]ナフタレン−
12−イル)アニリンのBOC体(0.59g、1.1
5mmol)及び4N塩化水素−1,4−ジオキサン溶
液(2mL)を使用して、実施例88に記載した方法に
従い、標記目的化合物の塩酸塩(0.50g)を得た。
得られた塩酸塩に飽和重曹水を加えて、酢酸エチルで抽
出した。有機層を無水硫酸ナトリウムで乾燥し、濃縮し
て、標記目的化合物(0.41g、収率87%)を油状
物質として得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.05 (3H, s), 1.
17 (3H, s), 1.25 (3H,s), 1.29 (3H, s), 1.60-1.65
(4H, m), 3.16 (3H, s), 5.67 (2H, s), 6.57 (2H, d,
J=8.7 Hz), 6.96 (1H, s), 6.99-7.10 (4H, m), 7.01
(1H, s), 7.42 (2H, d, J=8.7)。
(240b)N−[4−(5,7,7,10,10−ペ
ンタメチル−7,8,9,10−テトラヒドロ−5H−
5,13−ジアザベンゾ[4,5]シクロヘプタ
[1,2−b]ナフタレン−12−イル)フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例240aで製造した4−(5,7,7,10,1
0−ペンタメチル−7,8,9,10−テトラヒドロ−
5H−5,13−ジアザベンゾ[4,5]シクロヘプタ
[1,2−b]ナフタレン−12−イル)アニリン
(0.41g、1.00mmol)、DMA(5mL)
ならびに2−クロロ−5−ニトロ安息香酸クロリド
(0.25g、1.13mmol)を使用して、実施例
2に記載した方法に従い、標記目的化合物(0.45
g、収率76%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.04 (3H, s), 1.
16 (3H, s), 1.26 (3H,s), 1.31 (3H, s), 1.57-1.66
(4H, m), 3.21 (3H, s), 6.95 (1H, s), 7.06 (1H, s),
7.06-7.19 (4H, m), 7.73 (2H, d, J=8.8 Hz), 7.82
(2H, d, J=8.8 Hz), 7.91 (1H, d, J=8.8 Hz), 8.36 (1
H, dd, J=8.8, 2.7 Hz), 8.54 (1H, d, J=2.7 Hz), 10.
96 (1H, s);
MS(FAB) m/z: 592 M+, 593 (M + H)+。
(実施例241)N−[4−(4−アミノフェニル)チ
アゾール−2−イル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
実施例190で製造したN−[4−(4−tert−ブ
トキシカルボニルアミノフェニル)チアゾール−2−イ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド(0.36g、0.75mmol)、塩化メチレン
(10mL)、アニソール(0.1mL)ならびにトリ
フルオロ酢酸(1mL)を使用して、実施例192に記
載した方法に従い、標記目的化合物(0.24g、収率
86%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 5.26-5.27 (2H,
m), 6.59 (2H, d, J=8.6Hz), 7.34 (1H, s), 7.59 (2H,
d, J=8.6 Hz), 7.90 (1H, d, J=8.9 Hz), 8.37(1H, d
d, J=8.9, 2.8 Hz), 8.58 (1H, d, J=2.8 Hz);
MS(FAB) m/z: 375 (M + H)+。
(実施例242)N−[4−[4−(フェニルアミノカ
ルボニルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(5mL)ならびにフェニルイソシアネート(0.1
3mL、1.2mmol)を使用して、実施例236に
記載した方法に従い、標記目的化合物(0.45g、収
率93%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 6.98 (1H, t, J=
7.7 Hz), 7.29 (2H, d, J=7.7 Hz), 7.47 (2H, d, J=7.
7 Hz), 7.55 (2H, d, J=8.3 Hz), 7.62 (2H, d, J=8.4
Hz), 7.67 (2H, d, J=8.4 Hz), 7.78 (2H, d, J=8.3 H
z), 7.91 (1H, d, J=8.8 Hz), 7.35 (1H, d, J=8.8 H
z), 8.49 (1H, bs), 8.69 (1H, s), 8.77 (1H,s), 10.7
8 (1H, s);
MS(FAB) m/z: 487 (M + H)+。
(実施例243)N−[4−[4−(アミノカルボニル
アミノ)フェニル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(5mL)ならびにトリメチルシリルイソシアネート
(0.16mL、1.2mmol)を使用して、実施例
236に記載した方法に従い、標記目的化合物(0.3
7g、収率90%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 5.87 (1H, s), 7.
48 (2H, d, J=8.8 Hz),7.55 (2H, d, J=8.8 Hz), 7.64
(2H, d, J=8.7 Hz), 7.76 (2H, d, J=8.7 Hz),7.91 (1
H, d, J=8.8 Hz), 8.35 (1H, dd, J=8.8, 2.8 Hz), 8.4
8 (1H, d, J=2.8Hz), 8.61 (1H, s), 10.77 (1H, s);
MS(FAB) m/z: 411 (M + H)+。
(実施例244)N−[4−[4−(エトキシカルボニ
ルアミノカルボニルアミノ)フェニル]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(5mL)ならびにエトキシカルボニルイソシアネー
ト(0.12mL、1.2mmol)を使用して、実施
例236に記載した方法に従い、標記目的化合物(0.
47g、収率97%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.14 (3H, t, J=
7.1 Hz), 4.20 (2H, q, J=7.1 Hz), 7.60 (2H, d, J=8.
8 Hz), 7.65 (2H, d, J=8.8 Hz), 7.68 (2H, d, J=8.7
Hz), 7.79 (2H, d, J=8.7 Hz), 7.91 (1H, d, J=8.8 H
z), 8.35 (1H, dd,J=8.8, 2.8 Hz), 8.49 (1H, d, J=2.
8 Hz), 9.93 (1H, s), 10.38 (1H, s), 10.79 (1H, s);
MS(FAB) m/z: 483 (M + H)+。
(実施例245)N−[4−[4−[(3−フルオロフ
ェニル)アミノチオカルボニルアミノ]フェニル]フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキ
サミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(5mL)ならびに3−フルオロフェニルイソシアネ
ート(0.15mL、1.2mmol)を使用して、実
施例236に記載した方法に従い、標記目的化合物
(0.49g、収率95%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 6.92-6.98 (1H,
m), 7.28 (1H, d, J=8.1Hz), 7.34-7.40 (1H, m), 7.58
(1H, d, J=8.4 Hz), 7.59 (1H, s), 7.67 (2H,d, J=8.
7 Hz), 7.71 (2H, d, J=8.7 Hz), 7.80 (2H, d, J=8.7
Hz), 7.91 (1H,d, J=8.8 Hz), 8.36 (1H, dd, J=8.8,
2.8 Hz), 8.49 (1H, d, J=2.8 Hz), 10.01 (1H, s), 1
0.81 (1H, s);
MS(FAB) m/z: 521 (M + H)+。
(実施例246)N−[4−(4−ニトロフェニル)チ
アゾール−2−イル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
2−アミノ−4−(4−ニトロフェニル)チアゾール
(0.40g、1.82mmol)、DMA(5mL)
ならびに2−クロロ−5−ニトロ安息香酸クロリド
(0.47g、2.13mmol)を使用して、実施例
2に記載した方法に従い、標記目的化合物(0.71
g、収率96%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.91 (1H, d, J=
8.8 Hz), 8.12 (1H, bs),8.20 (2H, d, J=9.0 Hz), 8.3
2 (2H, d, J=9.0 Hz), 8.37 (1H, dd, J=8.8, 2.7 Hz),
8.62 (1H, d, J=2.7 Hz);MS(FAB) m/z: 405 (M +
H)+。
(実施例247)N−[4−[4−[(3−メトキシフ
ェニル)アミノカルボニルアミノ]フェニル]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(5mL)ならびに3−メトキシフェニルイソシアネ
ート(0.16mL、1.2mmol)を使用して、実
施例236に記載した方法に従い、標記目的化合物
(0.50g、収率97%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.74 (3H, s), 6.
55-6.58 (1H, m), 6.93-6.96 (1H, m), 7.16-7.21 (2H,
m), 7.54 (2H, d, J=8.7 Hz), 7.61 (1H, d, J=8.7 H
z), 7.67 (2H, d, J=8.7 Hz), 7.78 (2H, d, J=8.7 H
z), 7.91 (1H, d, J=8.8 Hz), 8.35 (1H, dd, J=8.8,
2.8 Hz), 8.49 (1H, d, J=2.8 Hz), 8.71 (1H,s), 8.76
(1H, s), 10.78 (1H, s);
MS(FAB) m/z: 517 (M + H)+。
(実施例248)N−[4−[4−(ベンジルアミノカ
ルボニルアミノ)フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(5mL)ならびにベンジルイソシアネート(0.1
5mL、1.2mmol)を使用して、実施例236に
記載した方法に従い、標記目的化合物(0.49g、収
率98%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 4.32 (2H, d, J=
5.8 Hz), 6.65 (1H, t, J=5.8 Hz), 7.23-7.27 (1H,
m), 7.32-7.37 (4H, m), 7.50 (2H, d, J=8.7 Hz),7.56
(2H, d, J=8.7 Hz), 7.65 (2H, d, J=8.7 Hz), 7.76
(2H, d, J=8.7 Hz),7.91 (1H, d, J=8.8 Hz), 8.35 (1
H, dd, J=8.8, 2.7 Hz), 8.48 (1H, d, J=2.7Hz), 8.67
(1H, s), 10.76 (1H, s);
MS(FAB) m/z: 501 (M + H)+。
(実施例249)N−[4−[4−[(2,4−ジフル
オロフェニル)アミノカルボニルアミノ]フェニル]フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(5mL)ならびに2,4−ジフルオロフェニルイソ
シアネート(0.19g、1.2mmol)を使用し
て、実施例236に記載した方法に従い、標記目的化合
物(0.50g、収率96%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.00-7.06 (1H,
m), 7.29 (1H, ddd, J=11.4, 8.9, 2.7 Hz), 7.51 (2H,
d, J=8.7 Hz), 7.60 (2H, d, J=8.7 Hz), 7.65 (2H,
d, J=8.7 Hz), 7.75 (2H, d, J=8.7 Hz), 8.04 - 8.12
(1H, m), 8.32 (1H,dd, J=8.8, 2.7 Hz), 8.46 (1H, d,
J=2.7 Hz) , 8.51 (1H, s), 9.10 (1H, bs), 10.75 (1
H, s);
MS(FAB) m/z: 523 (M + H)+。
(実施例250)N−[4−[4−(ベンゾイルアミノ
チオカルボニルアミノ)フェニル]フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(5mL)ならびにベンゾイルイソチオシアネート
(0.16mL、1.2mmol)を使用して、実施例
236に記載した方法に従い、標記目的化合物(0.5
1g、収率96%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.56 (2H, t, J=
7.5 Hz), 7.68 (1H, t, J=7.5 Hz), 7.74-7.76 (4H,
m), 7.81-7.83 (4H, m), 7.92 (1H, d, J=8.8 Hz),8.00
(2H, d, J=7.5 Hz), 8.36 (1H, dd, J=8.8, 2.8 Hz),
8.50 (1H, d, J=2.8Hz), 10.83 (1H, s), 11.60 (1H,
s);
MS(FAB) m/z: 531 (M + H)+。
(実施例251)N−[4−[4−(エトキシカルボニ
ルアミノチオカルボニルアミノ)フェニル]フェニル]
−(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(5mL)ならびにエトキシカルボニルイソチオシア
ネート(0.14mL、1.2mmol)を使用して、
実施例236に記載した方法に従い、標記目的化合物
(0.48g、収率96%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.27 (3H, t, J=
7.1 Hz), 4.23 (2H, q, J=7.1 Hz), 7.71 (4H, s), 7.7
3 (2H, d, J=8.8 Hz), 7.81 (2H, d, J=8.8 Hz),7.91
(1H, d, J=8.8 Hz), 8.36 (1H, dd, J=8.8, 2.7 Hz),
8.50 (1H, d, J=2.7Hz), 10.82 (1H, s), 11.29 (1H,
s), 11.61 (1H, s);MS(FAB) m/z: 499 (M + H)+。
(実施例252)N−[4−[4−(フェニルアミノチ
オカルボニルアミノ)フェニル]フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(5mL)ならびにフェニルイソチオシアネート
(0.24mL、2.0mmol)を使用して、実施例
236に記載した方法に従い、標記目的化合物(0.4
5g、収率89%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.14 (1H, t, J=
7.4 Hz), 7.35 (2H, t, J=7.9 Hz), 7.49-7.53 (2H,
m), 7.57-7.61 (2H, m), 7.66 (2H, d, J=8.7 Hz),7.70
(2H, d, J=8.7 Hz), 7.80 (2H, d, J=8.7 Hz), 7.91
(1H, d, J=8.8 Hz),8.35 (1H, dd, J=8.8, 2.7 Hz), 8.
49 (1H, d, J=2.7 Hz), 9.84 (1H, s), 9.89(1H, bs),
10.81 (1H, s);MS(FAB) m/z: 503 (M + H)+。
(実施例253)N−[4−(3−アミノフェニル)チ
アゾール−2−イル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
実施例234で製造したN−[4−(3−tert−ブ
トキシカルボニルアミノフェニル)チアゾール−2−イ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド(0.20g、0.43mmol)、塩化メチレン
(5mL)、アニソール(0.05mL)及びトリフル
オロ酢酸(1mL)を使用して、実施例192に記載し
た方法に従い、標記目的化合物(0.12g、収率78
%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 5.15 (2H, bs),
6.52-6.55 (1H, m), 7.06(1H, s), 7.06-7.12 (2H, m),
7.54 (1H, s), 7.91 (1H, d, J=8.9 Hz), 8.37(1H, d
d, J=8.9, 2.8 Hz), 8.59 (1H, d, J=2.8 Hz);MS(FAB)
m/z: 374 M+, 375 (M + H)+。
(実施例254)N−[4−[4−(2−ニトロフェニ
ルアミノカルボニルアミノ)フェニル]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(5mL)ならびに2−ニトロフェニルイソシアネー
ト(0.20g、1.2mmol)を使用して、実施例
236に記載した方法に従い、標記目的化合物(0.4
8g、収率90%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.20-7.25 (1H,
m), 7.59 (2H, d, J=8.8Hz), 7.65 (2H, d, J=8.8 Hz),
7.69 (2H, d, J=8.8 Hz), 7.70-7.74 (1H, m),7.79 (2
H, d, J=8.8 Hz), 7.91 (1H, d, J=8.8 Hz), 8.11 (1H,
dd, J=8.4, 1.5Hz), 8.32 (1H, dd, J=8.4, 1.5 Hz),
8.35 (1H, dd, J=8.8, 2.8 Hz), 8.49 (1H, d, J=2.8 H
z), 9.64 (1H, bs), 9.95 (1H, bs);MS(FAB) m/z: 532
(M + H)+。
(実施例255)N−[4−(2−アミノチアゾール−
4−イル)フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
実施例155で製造したN−(4−アセチルフェニル)
−(2−クロロ−5−ニトロフェニル)カルボキサミド
(4.78g、15.0mmol)、チオウレア(0.
91g、12mmol)ならびに沃素(1.52g、
6.0mmol)を使用して、参考例2に記載した方法
に従い、標記目的化合物(3.49g、収率62%)を
得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 6.95 (1H, s), 7.
04 (2H, bs), 7.70 (2H,d, J=8.7 Hz), 7.80 (2H, d, J
=8.7 Hz), 7.90 (1H, d, J=8.8 Hz), 8.34 (1H,dd, J=
8.8, 2.7 Hz), 8.48 (1H, d, J=2.7 Hz), 10.75 (1H,
s);
MS(FAB) m/z: 375 (M + H)+。
(実施例256)N−[4−[4−[(ピリジン−3−
イル)アミノチオカルボニルアミノ]フェニル]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(5mL)ならびに3−ピリジニルイソチオシアネー
ト(0.16g、1.2mmol)を使用して、実施例
236に記載した方法に従い、標記目的化合物(0.4
5g、収率89%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.38 (1H, dd, J=
8.5, 4.8 Hz), 7.58 (2H, d, J=8.6 Hz), 7.68 (2H, d,
J=8.6 Hz), 7.71 (2H, d, J=8.7 Hz), 7.80 (2H, d, J
=8.7 Hz), 7.91 (1H, d, J=8.9 Hz), 7.96-7.98 (1H,
m), 8.33 (1H, dd,J=4.8, 1.4 Hz), 8.36 (1H, dd, J=
8.9, 2.8 Hz), 8.49 (1H, d, J=2.8 Hz), 8.63 (1H, d,
J=2.4 Hz), 9.92 (1H, bs), 10.11 (1H, s), 10.81 (1
H, s);
MS(FAB) m/z: 504 (M + H)+。
(実施例257)N−[4−[(ピリジン−3−イル)
アミノチオカルボニルアミノ]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド
実施例180で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(0.29g、1.0mmol)、THF(5mL)な
らびに3−ピリジニルイソチオシアネート(0.16
g、1.2mmol)を使用して、実施例236に記載
した方法に従い、標記目的化合物(0.39g、収率9
1%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.37 (1H, dd, J=
8.1, 4.7 Hz), 7.46 (2H, d, J=8.6 Hz), 7.68 (2H, d,
J=8.6 Hz), 7.90 (1H, d, J=8.8 Hz), 7.95 (1H, d, J
=7.9 Hz), 8.31-8.36 (2H, m), 8.46 (1H, d, J=2.7 H
z), 8.61 (1H, d,J=2.1 Hz), 9.80 (1H, bs), 10.00 (1
H, s) , 10.74 (1H, s);
MS(FAB) m/z: 428 (M + H)+。
(実施例258)N−[4−[4−[(ピリジン−4−
イル)アミノチオカルボニルアミノ]フェニル]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.15g、0.40mmol)、T
HF(5mL)ならびに4−ピリジニルイソチオシアネ
ート(0.16g、1.2mmol)を使用して、実施
例236に記載した方法に従い、標記目的化合物(0.
19g、収率94%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.59 (2H, d, J=
8.6 Hz), 7.64 (2H, d, J=5.2 Hz), 7.68 (2H, d, J=8.
6 Hz), 7.71 (2H, d, J=8.7 Hz), 7.80 (2H, d, J=8.7
Hz), 7.91 (1H, d, J=8.8 Hz), 8.36 (1H, dd, J=8.8,
2.7 Hz), 8.42 (2H, d, J=5.2 Hz), 8.49 (1H, d, J=2.
7 Hz), 10.23 (1H, bs), 10.81 (1H, s);
MS(FAB) m/z: 504 (M + H)+。
(実施例259)N−[4−[(ピリジン−4−イル)
アミノチオカルボニルアミノ]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド
実施例180で製造したN−(4−アミノフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(0.12g、0.40mmol)、THF(5mL)
ならびに4−ピリジニルイソチオシアネート(0.16
g、1.2mmol)を使用して、実施例236に記載
した方法に従い、標記目的化合物(0.16g、収率9
4%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.47 (2H, d, J=
8.8 Hz), 7.64 (2H, d, J=6.0 Hz), 7.69 (2H, d, J=8.
8 Hz), 7.90 (1H, d, J=8.8 Hz), 8.35 (1H, dd,J=8.8,
2.8 Hz), 8.42 (2H, d, J=6.0 Hz), 8.46 (1H, d, J=
2.8 Hz), 10.11 (1H, s), 10.19 (1H, s), 10.75 (1H,
s);
MS(FAB) m/z: 428 (M + H)+。
(実施例260)N−[(6−tert−ブトキシカル
ボニルアミノ)ベンゾチアゾール−2−イル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド
2−アミノ−6−tert−ブトキシカルボニルアミノ
ベンゾチアゾール(4.23g、15.9mmol)、
DMA(40mL)ならびに2−クロロ−5−ニトロ安
息香酸クロリド(4.21g、19.1mmol)を使
用して、実施例2に記載した方法に従い、標記目的化合
物(6.09g、収率85%)を得た。 1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.50 (9H, s), 7.
43 (1H, dd, J=8.7, 2.1Hz), 7.66 (1H, d, J=8.7 Hz),
7.90 (1H, d, J=8.9 Hz), 8.18 (1H, bs), 8.37 (1H,
dd, J=8.9, 2.7 Hz), 8.62 (1H, d, J=2.7 Hz), 9.54
(1H, bs);
MS(FAB) m/z: 449 (M + H)+。
(実施例261)N−(6−アミノベンゾチアゾール−
2−イル)−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
実施例260で製造したN−[(6−tert−ブトキ
シカルボニルアミノ)ベンゾチアゾール−2−イル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(5.46g、12.2mmol)、アニソール(1m
L)及びトリフルオロ酢酸(11mL)を使用して、実
施例192に記載した方法に従い、標記目的化合物
(4.14g、収率97%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.08 (1H, dd, J=
8.6, 2.0 Hz), 7.55 (1H, bs), 7.68 (1H, d, J=8.6 H
z), 7.92 (1H, d, J=8.9 Hz), 8.39 (1H, dd, J=8.9,
2.7 Hz), 8.62 (1H, d, J=2.7 Hz);
MS(FAB) m/z: 348 M+, 349 (M + H)+。
(実施例262)N−[4−(4−メタンスルホニルア
ミノフェニル)チアゾール−2−イル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例241で製造したN−[4−(4−アミノフェニ
ル)チアゾール−2−イル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド(0.50g、1.32m
mol)、メタンスルホニルクロリド(0.11mL、
1.45mmol)及びピリジン(5mL)を使用し
て、実施例2に記載した方法に従い、標記目的化合物
(0.59g、収率99%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.03 (3H, s), 7.
27 (2H, d, J=8.7 Hz),7.69 (1H, s), 7.89 (2H, d, J=
8.7 Hz), 7.91 (1H, d, J=8.9 Hz), 8.38 (1H,dd, J=8.
9, 2.7 Hz), 8.60 (1H, d, J=2.7 Hz), 9.88 (1H, s);
MS(FAB) m/z: 453 (M + H)+。
(実施例263)N−[4−(4−アセチルアミノフェ
ニル)チアゾール−2−イル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド
実施例241で製造したN−[4−(4−アミノフェニ
ル)チアゾール−2−イル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド(0.33g、0.88m
mol)、アセチルクロリド(0.07mL、0.96
mmol)及びDMA(4mL)を使用して、実施例2
に記載した方法に従い、標記目的化合物(0.35g、
収率96%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.06 (3H, s), 7.
64 (2H, d, J=8.7 Hz),7.84 (2H, d, J=8.7 Hz), 8.37
(1H, dd, J=8.8, 2.8 Hz), 8.59 (1H, d, J=2.8Hz), 1
0.03 (1H, s);
MS(FAB) m/z: 417 (M + H)+。
(実施例264)N−[4−[(4−アミノカルボニ
ル)ピペラジン−1−イル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例133で製造したN−[4−(ピペラジン−1−
イル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド・2塩酸塩(0.24g、0.65
mmol)、トリメチルシリルイソシアネート(0.1
1mL、0.78mmol)及びTHF(5mL)を使
用して、実施例236に記載した方法に従い、標記目的
化合物(0.22g、収率84%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.05 (4H, m), 3.
43 (4H, m), 6.05 (2H,bs), 6.98 (2H, d, J=8.4 Hz),
7.56 (2H, d, J=8.4 Hz), 7.88 (1H, d, J=8.8Hz), 8.3
3 (1H, d, J=8.8 Hz), 8.41 (1H, s), 10.49 (1H, s)。
(実施例265)N−[4−(2−アセチルアミノチア
ゾール−4−イル)フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド
実施例255で製造したN−[4−(2−アミノチアゾ
ール−4−イル)フェニル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド(0.19g、0.50m
mol)、アセチルクロリド(0.04mL、0.55
mmol)及びDMA(5mL)を使用して、実施例2
に記載した方法に従い、標記目的化合物(0.16g、
収率78%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.17 (3H, s), 7.
54 (1H, s), 7.77 (2H,d, J=8.7 Hz), 7.79-7.93 (3H,
m), 8.35 (1H, dd, J=8.9, 2.8 Hz), 8.49 (1H,d, J=2.
8 Hz), 10.81 (1H, s)。
(実施例266)N−[3−(2−アセチルアミノチア
ゾール−4−イル)フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド
実施例233で製造したN−[3−(2−アミノチアゾ
ール−4−イル)フェニル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド(0.12g、0.33m
mol)、アセチルクロリド(0.03mL)及びDM
A(5mL)を使用して、実施例2に記載した方法に従
い、標記目的化合物(0.10g、収率70%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.17 (3H, s), 7.
43 (1H, t, J=7.9 Hz),7.49-7.52 (1H, m), 7.56 (1H,
s), 7.65-7.68 (1H, m), 7.91 (1H, d, J=8.8 Hz), 8.3
5 (1H, dd, J=8.8, 2.7 Hz), 8.41-8.42 (1H, m), 8.49
(1H, d, J=2.7Hz), 10.78 (1H, s)。
(実施例267)N−[4−(2−アミノエチル)フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキ
サミド
実施例169で製造したN−[4−(2−アミノエチ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド塩酸塩・0.2水和物(3.74g、1
0mmol)を飽和重曹水(20mL)、水(80m
L)及びヘキサン(10mL)に懸濁させ、1時間攪拌
した。生じた固形物を濾取し、水洗し、乾燥して、標記
目的化合物(3.05g、収率96%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.63-2.70 (1H,
m), 2.79 (27H, t, J=7.0Hz), 3.12-3.18 (1H, m), 7.2
1 (2H, d, J=8.4 Hz), 7.62 (2H, d, J=8.4 Hz),7.89
(1H, d, J=8.8 Hz), 8.33 (1H, dd, J=8.8, 2.7 Hz),
8.43 (1H, d, J=2.7 Hz),10.65 (1H, s);
MS(FAB) m/z: 320 (M + H)+。
(実施例268)N−[4−(2−フェニルアミノカル
ボニルアミノエチル)フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド
実施例267で製造したN−[4−(2−アミノエチ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.32g、1.0mmol)、TH
F(5mL)ならびにフェニルイソシアネート(0.1
3mL、1.2mmol)を使用して、実施例236に
記載した方法に従い、標記目的化合物(0.35g、収
率79%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.86 (2H, t, J=
7.3 Hz), 3.66-3.71 (2H,m), 6.88 (1H, t, J=7.3 Hz),
7.21 (2H, t, J=8.3 Hz), 7.37 (2H, d, J=7.7Hz), 7.
64 (2H, d, J=8.3 Hz), 7.89 (1H, d, J=8.9 Hz), 8.34
(1H, dd, J=8.9, 2.7 Hz), 8.44 (1H, d, J=2.7 Hz),
8.46 (1H, s), 10.66 (1H, s);
MS(FAB) m/z: 439 (M + H)+。
(実施例269)N−[4−(2−フェニルアミノチオ
カルボニルアミノエチル)フェニル]−(2−クロロ−
5−ニトロフェニル)カルボキサミド
実施例267で製造したN−[4−(2−アミノエチ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.32g、1.0mmol)、TH
F(5mL)ならびにフェニルイソチオシアネート
(0.15mL、2.0mmol)を使用して、実施例
236に記載した方法に従い、標記目的化合物(0.3
5g、収率78%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.87 (2H, t, J=
7.3 Hz), 3.70-3.72 (2H,m), 7.11 (1H, t, J=6.2 Hz),
7.26-7.37 (6H, m), 7.66 (2H, d, J=8.4 Hz),7.72 (1
H, bs), 7.90 (1H, d, J=8.8 Hz), 8.35 (1H, dd, J=8.
8, 2.8 Hz), 8.45 (1H, d, J=2.8 Hz), 9.57 (1H, bs),
10.67 (1H, s);
MS(FAB) m/z: 455 (M + H)+。
(実施例270)N−[4−(2−アミノカルボニルア
ミノエチル)フェニル]−(2−クロロ−5−ニトロフ
ェニル)カルボキサミド
実施例267で製造したN−[4−(2−アミノエチ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.32g、1.0mmol)、TH
F(5mL)ならびにトリメチルシリルイソシアネート
(0.16mL、1.2mmol)を使用して、実施例
236に記載した方法に従い、標記目的化合物(0.2
8g、収率77%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.65 (2H, t, J=
7.2 Hz), 3.16-3.22 (2H,m), 5.42 (2H, s), 5.89 (1H,
t, J=5.5 Hz), 7.21 (2H, d, J=8.3 Hz), 7.62(2H, d,
J=8.3 Hz), 7.89 (1H, d, J=8.8 Hz), 8.34 (1H, dd,
J=8.8, 2.7 Hz),8.44 (1H, d, J=2.7 Hz), 10.63 (1H,
s);
MS(FAB) m/z: 363 (M + H)+。
(実施例271)N−[4−(2−フェニルカルボニル
アミノチオカルボニルアミノエチル)フェニル]−(2
−クロロ−5−ニトロフェニル)カルボキサミド
実施例267で製造したN−[4−(2−アミノエチ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.32g、1.0mmol)、TH
F(5mL)ならびにベンゾイルイソチオシアネート
(0.16mL、1.2mmol)を使用して、実施例
236に記載した方法に従い、標記目的化合物(0.4
0g、収率84%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.96 (2H, t, J=
7.1 Hz), 3.83-3.89 (2H,m), 7.30 (2H, d, J=8.4 Hz),
7.51 (2H, t, J=7.7 Hz), 7.61-7.67 (3H, m),7.87-7.
93 (3H, m), 8.33 (1H, dd, J=8.8, 2.8 Hz), 8.45 (1
H, d, J=2.8 Hz),10.68 (1H, s), 10.93 (1H, s), 11.3
3 (1H, s);
MS(FAB) m/z: 483 (M + H)+。
(実施例272)N−[4−(2−エトキシカルボニル
アミノチオカルボニルアミノエチル)フェニル]−(2
−クロロ−5−ニトロフェニル)カルボキサミド
実施例267で製造したN−[4−(2−アミノエチ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.32g、1.0mmol)、TH
F(5mL)ならびにエトキシカルボニルイソチオシア
ネート(0.14mL、1.2mmol)を使用して、
実施例236に記載した方法に従い、標記目的化合物
(0.41g、収率92%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.21 (3H, t, J=
7.1 Hz), 2.89 (2H, t, J=7.2 Hz), 3.76-3.81 (2H,
m), 4.14 (2H, q, J=7.1 Hz), 7.26 (2H, d, J=8.4Hz),
7.64 (2H, d, J=8.4 Hz), 7.89 (1H, d, J=8.8 Hz),
8.34 (1H, dd, J=8.8, 2.7 Hz), 8.45 (1H, d, J=2.7 H
z), 9.91 (1H, bs), 10.67 (1H, s), 10.96 (1H, s);
MS(FAB) m/z: 451 (M + H)+。
(実施例273)N−[4−[2−(ピリジン−3−イ
ル)アミノチオカルボニルアミノエチル]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例267で製造したN−[4−(2−アミノエチ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.32g、1.0mmol)、TH
F(5mL)及び3−ピリジルイソチオシアネート
(0.16g、1.2mmol)を使用して、実施例2
36に記載した方法に従い、標記目的化合物(0.41
g、収率90%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.87 (2H, t, J=
7.3 Hz), 3.66-3.77 (2H,m), 7.27 (2H, d, J=8.3 Hz),
7.36 (1H, dd, J=8.1, 4.7 Hz), 7.65 (2H, d,J=8.3 H
z), 7.89 (1H, d, J=8.8 Hz), 7.91-7.98 (2H, m), 8.3
0 (1H, d, J=4.7Hz), 8.34 (1H, dd, J=8.8, 2.7 Hz),
8.44 (1H, d, J=2.7 Hz), 8.57 (1H, d,J=2.2 Hz), 9.7
0 (1H, bs), 10.67 (1H, s);
MS(FAB) m/z: 456 (M + H)+。
(実施例274)N−[4−(イミダゾ[1,2−a]
ピリジン−2−イル)フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド
4−(イミダゾ[1,2−a]ピリジン−2−イル)ア
ニリン(0.22g、1.07mmol)、DMA(3
mL)ならびに2−クロロ−5−ニトロ安息香酸クロリ
ド(0.26g、1.18mmol)を使用して、実施
例2に記載した方法に従い、標記目的化合物(0.39
g、収率92%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 6.89 (1H, m), 7.
22-7.26 (1H, m), 7.57(1H, d, J=9.3 Hz), 7.79 (2H,
d, J=8.6 Hz), 7.91 (1H, d, J=8.9 Hz), 7.98(2H, d,
J=8.6 Hz), 8.35 (1H, dd, J=8.9, 2.8 Hz), 8.50 (1H,
d, J=2.8 Hz),
8.53 (1H, d, J=6.7 Hz), 10.80 (1H, s)。
(実施例275)N−[3−(2−ヒドロキシエチル)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
N−3−(2−ヒドロキシエチル)アニリン(2.56
g、18.7mmol)、DMA(25mL)ならびに
2−クロロ−5−ニトロ安息香酸クロリド(4.31
g、19.6mmol)を使用して、実施例2に記載し
た方法に従い、標記目的化合物(3.81g、収率64
%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.72 (2H, t, J=
7.0 Hz), 3.61 (2H, q, J=7.0 Hz), 4.66 (1H, t, J=7.
0 Hz), 7.00 (1H, d, J=7.8 Hz), 7.27 (1H, d, J=7.8
Hz), 7.54 (1H, d, J=7.8 Hz), 7.57 (1H, s), 7.89 (1
H, d, J=8.8 Hz),8.34 (1H, dd, J=8.8, 2.8 Hz), 8.44
(1H, d, J=2.7 Hz), 10.64 (1H, s);MS(FAB) m/z: 321
(M + H)+。
(実施例276)N−[4−[4−(N、N−ジエタン
スルホニルアミノ)フェニル]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド
実施例192で製造したN−[4−(4−アミノフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.37g、1.0mmol)、TH
F(10mL)、トリエチルアミン(0.55mL、
4.0mmol)ならびにエタンスルホニルクロリド
(0.31mL、2.2mmol)を使用して、実施例
235に記載した方法に従い、標記目的化合物(0.2
2g、収率40%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.36 (6H, t, J=
7.1 Hz), 3.68 (4H, q, J=7.1 Hz), 7.55 (2H, d, J=7.
7 Hz), 7.60-7.85 (6H, m), 7.92 (1H, d, J=8.2Hz),
8.66 (1H, d, J=8.2 Hz), 8.50 (1H, s), 10.86 (1H,
s);
MS(FAB) m/z: 552 (M + H)+。
(実施例277)N−[4−(3−アセチルアミノフェ
ニル)チアゾール−2−イル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド
実施例253で製造したN−[4−(3−アミノフェニ
ル)チアゾール−2−イル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド(0.22g、0.60m
mol)、アセチルクロリド(0.05mL、0.7m
mol)及びDMA(5mL)を使用して、実施例2に
記載した方法に従い、標記目的化合物(0.22g、収
率86%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.06 (3H, s), 7.
35 (1H, t, J=8.0 Hz),7.44 (1H, d, J=8.0 Hz), 7.58
(1H, d, J=8.0 Hz), 7.67 (1H, s), 7.91 (1H,d, J=8.8
Hz), 8.26 (1H, bs), 8.37 (1H, dd, J=8.8, 2.7 Hz),
8.60 (1H, d,J=2.7 Hz), 10.01 (1H, s);
MS(FAB) m/z: 417 (M + H)+。
(実施例278)N−[4−(3−メタンスルホニルア
ミノフェニル)チアゾール−2−イル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド
実施例260で製造したN−[4−(3−アミノフェニ
ル)チアゾール−2−イル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド(0.22g、0.60m
mol)、メタンスルホニルクロリド(0.05mL、
0.7mmol)及びピリジン(5mL)を使用して、
実施例2に記載した方法に従い、標記目的化合物(0.
18g、収率65%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.01 (3H, s), 7.
17 (1H, d, J=7.6 Hz),7.41 (1H, t, J=7.6 Hz), 7.66
(1H, d, J=7.6 Hz), 7.74 (1H, s), 7.81 (1H,s), 7.91
(1H, d, J=8.4 Hz), 8.38 (1H, d, J=8.4 Hz), 8.61
(1H, bs), 9.84(1H, s);
MS(FAB) m/z: 452 (M + H)+。
(実施例279)N−[4−[4−(2,5−ジメチル
ピロール−1−イル)フェニル]フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
4−[4−(2,5−ジメチルピロール−1−イル)フ
ェニル]アニリン(0.12g、0.45mmol)、
DMA(5mL)ならびに2−クロロ−5−ニトロ安息
香酸クロリド(0.11g、0.53mmol)を使用
して、実施例2に記載した方法に従い、標記目的化合物
(0.17g、収率85%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.01 (6H, s), 5.
82 (2H, s), 7.35 (2H,d, J=8.4 Hz), 7.77-7.85 (6H,
m), 7.92 (1H, d, J=8.8 Hz), 8.36 (1H, dd, J=8.8,
2.7 Hz), 8.51 (1H, d, J=2.7 Hz), 10.85 (1H, s);
MS(FAB) m/z: 262 M+。
(実施例280)N−(6−アセチルアミノベンゾチア
ゾール−2−イル)−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
実施例261で製造したN−(6−アミノベンゾチアゾ
ール−2−イル)−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド(0.28g、0.80mmo
l)、アセチルクロリド(0.06mL、0.9mmo
l)及びDMA(5mL)を使用して、実施例2に記載
した方法に従い、標記目的化合物(0.22g、収率6
9%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.09 (3H, s), 7.
53 (1H, d, J=8.7 Hz),7.72 (1H, d, J=8.3 Hz), 7.92
(1H, dd, J=8.8, 1.7 Hz), 8.37-8.40 (2H, m),8.64 (1
H, d, J=1.7 Hz);
MS(FAB) m/z: 391 (M + H)+。
(実施例281)N−(6−アミノカルボニルアミノベ
ンゾチアゾール−2−イル)−(2−クロロ−5−ニト
ロフェニル)カルボキサミド
実施例261で製造したN−(6−アミノベンゾチアゾ
ール−2−イル)−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド(0.22g、0.60mmo
l)、トリメチルシリルイソシアネート(0.01m
L、0.7mmol)及びTHF(5mL)を使用し
て、実施例236に記載した方法に従い、標記目的化合
物(0.18g、収率77%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 5.91 (2H, bs),
7.36 (1H, dd, J=8.8, 2.2 Hz), 7.64-7.68 (1H, m),
7.92 (1H, d, J=8.8 Hz), 8.18 (1H, bs), 8.38 (1H, d
d, J=8.8, 2.5 Hz), 8.63 (1H, d, J=2.5 Hz), 8.72 (1
H, bs);
MS(FAB) m/z: 392 (M + H)+。
(実施例282)N−フェニル−N−エチル−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
N−エチルアニリン(0.30g、2.48mmo
l)、2−クロロ−5−ニトロ安息香酸クロリド(0.
60g、2.73mmol)及びDMA(3mL)を使
用して、実施例1に記載した方法に従い、標記目的化合
物(0.58g、収率76%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.28 (3H, t, J=7.2
Hz), 4.00 (2H, q, J=7.2 Hz), 7.14-7.25 (5H, m),
7.37 (1H, d, J=8.7 Hz), 7.95 (1H, dd, J=2.7,8.7 H
z), 7.98 (1H, d, J=2.7 Hz)。
(実施例283)N−[4−[4−[[(ブチルアミ
ノ)チオカルボニル]アミノ]フェニル]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
N−[4−(4−アミノフェニル)フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド(0.3
67g、1.00mmol)をTHF(5mL)に溶解
させ、ブチルイソチオシアネート(0.145mL、
1.20mmol)を加えて、室温で22時間攪拌し
た。反応溶液にメタノールを加えて攪拌した後、減圧濃
縮した。得られた固体をジイソプロピルエーテルで洗浄
し、減圧乾燥して、標記目的化合物(0.395g、収
率82%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 0.92 (3H, t, J=
7.3 Hz), 1.33 (2H, m),1.54 (2H, m), 3.47 (2H, m),
5.33 (1H, bs), 7.51 (2H, m), 7.63 (2H, d, J=8.0 H
z), 7.71 (2H, m), 7.79 (2H, d, J=8.0 Hz), 7.90 (1
H, m), 8.35 (1H, m), 8.47 (1H, m), 9.52 (1H, bs),
10.70 (1H, bs);
MS(FAB) m/z: 483 (M + H)+。
(実施例284)N−[4−(3−ニトロフェニル)フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
4−(3−ニトロフェニル)アニリン(0.22g、
1.00mmol)、2−クロロ−5−ニトロ安息香酸
クロリド(0.24g、1.11mmol)及びDMA
(4mL)を使用して、実施例1に記載した方法に従
い、標記目的化合物(0.35g、収率87%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.77 (1H, t, J=
8.0 Hz), 7.86 (4H, Abq,J=9.3 Hz), 7.92 (1H, d, J=
8.9 Hz), 8.16-8.22 (2H, m), 8.36 (1H, dd, J=2.8,
8.9 Hz), 8.46 (1H, t, J=2.0 Hz), 8.51 (1H, d, J=2.
8 Hz), 10.89 (1H,s);
MS(FAB) m/z: 397 M+。
(実施例285)N−[4−(4−シアノフェニル)フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
4−(4−シアノフェニル)アニリン(1.06g、
5.46mmol)、2−クロロ−5−ニトロ安息香酸
クロリド(1.44g、6.55mmol)及びDMA
(10mL)を使用して、実施例1に記載した方法に従
い、標記目的化合物(2.00g、収率97%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.84 (4H, ABq, J
=9.0, 16.5 Hz), 7.90-7.94 (5H, m), 8.36 (1H, dd, J
=2.7, 8.8 Hz), 8.51 (1H, d, J=2.7 Hz), 10.89(1H,
s);
MS(FAB) m/z: 378 (M + H)+。
(実施例286)N−[4−(フェニルメチル)フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
4−(フェニルメチル)アニリン(0.183g、1.
00mmol)、2−クロロ−5−ニトロ安息香酸クロ
リド(0.330g、1.50mmol)及びDMA
(2mL)を使用して、実施例1に記載した方法に従
い、標記目的化合物(0.225g、収率61%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.93 (2H, s), 7.
18-7.31 (7H, m), 7.62(2H, d, J=8.8 Hz), 7.88 (1H,
d, J=8.8 Hz), 8.33 (1H, dd, J=2.9, 8.8 Hz),8.43 (1
H, d, J=2.9 Hz), 10.65 (1H, bs);
MS(FAB) m/z: 367 (M + H)+。
(実施例287)N−[4−[[4−[(tert−ブ
トキシカルボニル)アミノ]フェニル]メチル]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
4−[[4−[(tert−ブトキシカルボニル)アミ
ノ]フェニル]メチル]アニリン(2.98g、10.
0mmol)、2−クロロ−5−ニトロ安息香酸クロリ
ド(2.64g、12.0mmol)及びDMA(30
mL)を使用して、実施例1に記載した方法に従い、標
記目的化合物(4.60g、収率95%)を得た。1
H NMR (400MHz, CDCl3): δ(ppm) 1.51 (9H, s), 3.93
(2H, s), 6.43 (1H, bs), 7.10 (2H, d, J=8.0 Hz),
7.20 (2H, d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz), 7.
53 (2H, d, J=8.0 Hz), 7.64 (1H, d, J=8.8 Hz), 7.82
(1H, bs), 8.25 (1H, dd, J=2.9, 8.8 Hz), 8.59 (1H,
d, J=2.9 Hz);
MS(FAB) m/z: 481 M+。
(実施例288)N−[4−[(4−アミノフェニル)
メチル]フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
実施例287で製造したN−[4−[[4−[(ter
t−ブトキシカルボニル)アミノ]フェニル]メチル]
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド(3.51g、7.28mmol)を1,4
−ジオキサン(50mL)に懸濁させ、4N塩化水素−
1,4−ジオキサン溶液(25mL)を加えて、室温で
3日間攪拌した。反応溶液をジエチルエーテルで希釈し
て、生じた固体を濾取し、減圧乾燥して、標記目的化合
物(2.78g、収率91%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.95 (2H, s), 7.
23 (2H, m), 7.28 (2H,m), 7.33 (2H, m), 7.63 (2H,
m), 7.88 (1H, d, J=8.8 Hz), 8.33 (1H, dd, J=2.9,
8.8 Hz), 8.42 (1H, d, J=2.9 Hz), 10.70 (1H, bs);
MS(ESI) m/z: 382 ((M-HCl) + H)+。
(実施例289)N−[4−[2−[[(3−メトキシ
フェニルアミノ)カルボニル]アミノ]エチル]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
実施例267で製造したN−[4−(2−アミノエチ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド(0.319g、1.00mmol)を
THF(5mL)に溶解させ、3−メトキシフェニルイ
ソシアネート(0.157mL、1.20mmol)を
加え、室温で22時間攪拌した。反応溶液にメタノール
を加えて攪拌した後、減圧濃縮した。得られた固体をジ
イソプロピルエーテルで洗浄し、減圧乾燥して、標記目
的化合物(0.458g、98%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.73 (2H, t, J=
7.0 Hz), 3.70 (3H, s),3.68-3.72 (2H, m), 6.46 (1H,
m), 6.84 (1H, d, J=8.0 Hz), 7.20-7.07 (2H,m), 7.2
5 (2H, d, J=8.4 Hz), 7.64 (2H, d, J=8.4 Hz), 7.89
(1H, d, J=8.8 Hz), 8.34 (1H, dd, J=2.2, 8.8 Hz),
8.44 (1H, d, J=2.2 Hz), 8.51 (1H, bs),10.66 (1H, b
s);
MS(FAB) m/z: 469 (M + H)+。
(実施例290)N−(4−フェノキシフェニル)−
(2−クロロ−5−ニトロフェニル)カルボキサミド
4−フェノキシアニリン(0.185g、1.00mm
ol)、2−クロロ−5−ニトロ安息香酸クロリド
(0.330g、1.50mmol)及びDMA(2m
L)を使用して、実施例1に記載した方法に従い、標記
目的化合物(0.249g、収率68%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.00 (2H, d, J=
8.0 Hz), 7.07 (2H, d, J=8.8 Hz), 7.13 (1H, m), 7.3
9 (2H, t, J=8.0 Hz), 7.73 (2H, d, J=8.8 Hz),7.90
(1H, d, J=8.8 Hz), 8.35 (1H, dd, J=2.9, 8.8 Hz),
8.47 (1H, d, J=2.9Hz), 10.74 (1H, bs);
MS(FAB) m/z: 369 (M + H)+。
(実施例291)N−[3−[4−[(tert−ブト
キシカルボニル)アミノ]フェニル]フェニル]−(2
−クロロ−5−ニトロフェニル)カルボキサミド3−
[4−[(tert−ブトキシカルボニル)アミノ]フ
ェニル]フェニルアミン(1.44g、5.06mmo
l)、2−クロロ−5−ニトロ安息香酸クロリド(1.
23g、5.59mmol)及びDMA(5mL)を使
用して、実施例1に記載した方法に従い、標記目的化合
物(2.07g、収率87%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.49 (9H, s), 7.
37-7.46 (4H, ABq J=9.0, 12.9 Hz), 7.66 (1H, dd, J=
1.7, 7.6 Hz), 7.91 (1H, d, J=8.8 Hz), 7.95 (1H, t,
J=1.7 Hz), 8.35 (1H, dd, J=2.7, 8.8 Hz), 8.49 (1
H, d, J=2.7 Hz),9.47 (1H, s), 10.78 (1H, s);
MS(FAB) m/z: 467 (M + H)+。
(実施例292)N−[3−(4−アミノフェニル)フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
実施例291で製造したN−[3−[4−[(tert
−ブトキシカルボニル)アミノ]フェニル]フェニル]
−(2−クロロ−5−ニトロフェニル)カルボキサミド
(1.67g、3.58mmol)を塩化メチレン(2
0mL)に溶解させ、p−アニソール(1滴)及びトリ
フルオロ酢酸(2mL)を加えて、室温で17時間攪拌
した。反応溶液に飽和重曹水(20mL)、水(20m
L)及びジイソプロピルエーテル(10mL)を加え、
2時間攪拌した。生じた結晶を濾取し、水及びジイソプ
ロピルエーテルで洗浄し、減圧乾燥して、標記目的化合
物(1.31g、収率99%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 5.26 (2H, s), 6.
65 (2H, d, J=8.5 Hz),7.30-7.39 (4H, m), 7.55 (1H,
d, J=8.0 Hz), 7.89 (1H, s), 7.90 (1H, d, J=8.7 H
z), 8.35 (1H, dd, J=2.7, 8.7 Hz), 8.48 (1H, d, J=
2.7 Hz), 10.70 (1H, s);
MS(FAB) m/z: 367 M+。
(実施例293)N−[(5−メトキシ−2−フェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド
(5−メトキシ−2−フェニル)フェニルアミン・1塩
酸塩(0.28g、1.19mmol)、2−クロロ−
5−ニトロ安息香酸クロリド(0.39g、1.79m
mol)及びピリジン(5mL)を使用して、実施例1
に記載した方法に従い、標記目的化合物(0.28g、
収率62%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.84 (3H, s), 7.
00 (1H, dd, J=2.6, 8.5Hz), 7.23 (1H, d, J=2.6 Hz),
7.32 (1H, d, J=8.5 Hz), 7.34-7.44 (5H, m),7.81 (1
H, d, J=8.8 Hz), 8.24 (1H, d, J=2.7 Hz), 8.28 (1H,
dd, J=2.7, 8.8 Hz), 10.19 (1H, s)。
(実施例294)N−[4−(4−メチルフェノキシ)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
4−(4−メチルフェノキシ)アニリン(0.199
g、1.00mmol)、2−クロロ−5−ニトロ安息
香酸クロリド(0.330g、1.50mmol)及び
DMA(2mL)を使用して、実施例1に記載した方法
に従い、標記目的化合物(0.235g、収率61%)
を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.29 (3H, s), 6.
91 (2H, d, J=8.4 Hz),7.02 (2H, d, J=8.4 Hz), 7.19
(2H, d, J=8.4 Hz), 7.70 (2H, d, J=8.4 Hz),7.90 (1
H, d, J=8.8 Hz), 8.34 (1H, dd, J=2.9, 8.8 Hz), 8.4
6 (1H, d, J=2.9Hz), 10.71 (1H, bs);
MS(FAB) m/z: 383 (M + H)+。
(実施例295)N−[4−(4−クロロフェノキシ)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
4−(4−クロロフェノキシ)アニリン(0.219
g、1.00mmol)、2−クロロ−5−ニトロ安息
香酸クロリド(0.330g、1.50mmol)及び
DMA(2mL)を使用して、実施例1に記載した方法
に従い、標記目的化合物(0.274g、収率68%)
を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 7.02 (2H, d, J=
8.8 Hz), 7.10 (2H, d, J=8.8 Hz), 7.43 (2H, d, J=8.
8 Hz), 7.74 (2H, d, J=8.8 Hz), 7.90 (1H, d, J=8.8
Hz), 8.35 (1H, dd, J=2.9, 8.8 Hz), 8.47 (1H, d, J=
2.9 Hz), 10.76 (1H, bs);
MS(FAB) m/z: 403 (M + H)+。
(実施例296)N−[4−[2−(1,3−ジオキソ
イソインドール−2−イル)エトキシ]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(296a)2−[2−(4−ニトロフェノキシ)エチ
ル]イソインドール−1,3−ジオン
ナトリウム p−ニトロフェノキシド・2水和物(0.
986g、5.0mmol)をDMF(30mL)に溶
解させ、N−(2−ブロモエチル)フタルイミド(1.
91g、7.5mmol)を加え、70℃で18時間攪
拌した。反応溶液を室温まで放冷した後、酢酸エチルで
希釈し、不溶物を濾別した。濾液を減圧下濃縮して、得
られた残渣をシリカゲルカラムクロマトグラフィー(ヘ
キサン:酢酸エチル=1:1(v/v))にて精製し、標記
目的化合物(0.650g、収率42%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 4.04 (2H, t, J=5.8
Hz), 4.23 (2H, t, J=5.8 Hz), 6.84 (2H, d, J=8.8 H
z), 7.64 (2H, m), 7.77 (2H, m), 8.07 (2H,d,J=8.8 H
z)。
(296b)2−[2−(4−アミノフェノキシ)エチ
ル]イソインドール−1,3−ジオン
実施例296aで製造した2−[2−(4−ニトロフェ
ノキシ)エチル]イソインドール−1,3−ジオン
(0.650g、2.08mmol)と10%パラジウ
ム−炭素(0.130g)をエタノール−THF(1:
1(v/v)、13mL)に加え、水素雰囲気下、室温で3
時間攪拌した。反応溶液から触媒を濾別して、濾液を減
圧下濃縮した。得られた残渣をシリカゲルカラムクロマ
トグラフィー(ヘキサン:酢酸エチル=1:1(v/v))
にて精製し、標記目的化合物(0.447g、収率76
%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 3.42 (2H, bs), 4.0
9 (2H, t, J=5.9 Hz),4.15 (2H, t, J=5.9 Hz), 6.59
(2H, d, J=8.8 Hz), 6.70 (2H, d, J=8.8 Hz),7.71 (2
H, m), 7.86 (2H, m)。
(296c)N−[4−[2−(1,3−ジオキソイソ
インドール−2−イル)エトキシ]フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド
実施例296bで製造した2−[2−(4−アミノフェ
ノキシ)エチル]イソインドール−1,3−ジオン
(0.425g、1.51mmol)、2−クロロ−5
−ニトロ安息香酸クロリド(0.397g、1.81m
mol)及びDMA(4mL)を使用して、実施例1に
記載した方法に従い、標記目的化合物(0.627g、
収率89%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.97 (2H, t, J=
5.9 Hz), 4.21 (2H, t, J=5.9 Hz), 6.91 (2H, d, J=8.
8 Hz), 7.58 (2H, d, J=8.8 Hz), 7.88 (5H, m),8.32
(1H, dd, J=2.7, 8.8 Hz), 8.43 (1H, d, J=2.9 Hz), 1
0.55 (1H, bs);
MS(FAB) m/z: 466 (M + H)+。
(実施例297)N−[4−(2−アミノエトキシ)フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
実施例296cで製造したN−[4−[2−(1,3−
ジオキソイソインドール−2−イル)エトキシ]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド(0.102g、0.219mmol)をエタノー
ル(2mL)に溶解させ、ヒドラジン・1水和物(0.
053mL、1.09mmol)を加えて、室温で5時
間攪拌した。反応溶液に1N水酸化ナトリウム水溶液を
滴下して塩基性とし、水を加えて酢酸エチルで抽出し
た。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮
した。得られた残渣をシリカゲルカラムクロマトグラフ
ィー(メタノール:塩化メチレン=1:1(v/v))にて
精製し、標記目的化合物(0.034g、収率46%)
を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 3.08 (2H, t, J=5.1
Hz), 3.98 (2H, t, J=5.1 Hz), 6.90 (2H, d, J=8.8 H
z), 7.52 (2H, d, J=8.8 Hz), 7.63 (1H, d, J=8.8 H
z), 8.15 (1H, bs), 8.23 (1H, dd, J=2.8, 8.8 Hz),
8.55 (1H, d, J=2.8 Hz);
MS(FAB) m/z: 336 (M + H)+。
(実施例298)N−[4−[2−(tert−ブトキ
シカルボニルアミノ)エトキシ]フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
実施例193で製造したN−(4−ヒドロキシフェニ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド(0.293g、1.0mmol)及びN−(2−
ヒドロキシエチル)カルバミン酸 tert−ブチルエ
ステル(0.501mL、2.0mmol)をトルエン
(1mL)に溶解させ、氷冷下、トリフェニルホスフィ
ン(0.525g、2.0mmol)及びジエチルアゾ
ジカルボキシレート(DEAD)−40%トルエン溶液
(0.788mL、2.0mmol)を加えて、室温で
20時間攪拌した。反応溶液を減圧下濃縮し、残渣をシ
リカゲルカラムクロマトグラフィー(クロロホルム:メ
タノール=2:1(v/v))にて精製し、標記目的化合物
(0.084g、収率19%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.45 (9H, s), 3.54
(2H, m), 4.02 (2H, t,J=5.1 Hz), 5.01 (1H, bs), 6.
91 (2H, d, J=9.0 Hz), 7.54 (2H, d, J=9.0 Hz), 7.64
(1H, d, J=8.8 Hz), 7.91 (1H, bs), 8.25 (1H, dd, J
=2.2, 8.8 Hz),8.58 (1H, d, J=2.2 Hz);
MS(FAB) m/z: 435 M+。
(実施例299)N−[4−[2−(ジメチルアミノ)
エトキシ]フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
(299a)4−[2−(ジメチルアミノ)エトキシ]
ニトロベンゼン
4−ニトロフェノール(1.39g、10.0mmo
l)をDMA(25mL)に溶解させ、N,N−ジメチ
ルアミノプロピルクロリド・1塩酸塩(1.85g、1
1.0mmol)及び炭酸カリウム(4.15g、3
0.0mmol)を加えて、60℃で2日間攪拌した。
反応溶液を室温まで放冷した後、炭酸カリウムを濾去し
た。濾液を酢酸エチル(80mL)で希釈して、水(5
0mLx4)及び飽和重曹水で洗浄した。有機層を無水
硫酸ナトリウムで乾燥し、減圧下濃縮し、減圧乾燥し
て、標記目的化合物(1.05g、収率50%)を得
た。1
H-NMR (400MHz, CDCl3): δ(ppm) 2.35 (6H, s), 2.77
(2H, t, J=5.9 Hz), 4.16 (2H, t, J=5.9 Hz), 6.98
(2H, d, J=8.8 Hz), 8.20 (2H, d, J=8.8 Hz)。
(299b)4−[2−(ジメチルアミノ)エトキシ]
アニリン
実施例299aで製造した4−[2−(ジメチルアミ
ノ)エトキシ]ニトロベンゼン(0.650g、2.0
8mmol)、5%パラジウム−炭素(0.191g)
及びエタノール(10mL)を使用して、実施例296
bに記載した方法に従い、標記目的化合物(0.721
g、収率88%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 2.32 (6H, s), 2.69
(2H, t, J=5.9 Hz), 3.28 (2H, bs), 3.99 (2H, t, J=
5.9 Hz), 6.40 (2H, d, J=8.8 Hz), 6.76 (2H, d, J=8.
8 Hz)。
(299c)N−[4−[2−(ジメチルアミノ)エト
キシ]フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
実施例299bで製造した4−[2−(ジメチルアミ
ノ)エトキシ]アニリン(0.716g、3.97mm
ol)、2−クロロ−5−ニトロ安息香酸クロリド
(1.05g、4.77mmol)及びDMA(10m
L)を使用して、実施例1に記載した方法に従い、標記
目的化合物(0.883g、収率61%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 2.34 (6H, s), 2.74
(2H, t, J=5.9 Hz), 4.08 (2H, t, J=5.9 Hz), 6.95
(2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8 Hz), 7.65 (1
H, d, J=8.8 Hz), 7.79 (1H, bs), 8.25 (1H, dd, J=2.
9, 8.8 Hz), 8.60(1H, d, J=2.9 Hz);
MS(FAB) m/z: 364 (M + H)+。
(実施例300)N−[4−[2−(ジエチルアミノ)
エトキシ]フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド
実施例299a及び299bと同様の方法に従い製造し
た4−[2−(ジエチルアミノ)エトキシ]アニリン
(1.48g、7.11mmol)、2−クロロ−5−
ニトロ安息香酸クロリド(1.88g、8.53mmo
l)及びDMA(20mL)を使用して、実施例1に記
載した方法に従い、標記目的化合物(1.71g、収率
61%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.08 (6H, t, J=7.3
Hz), 2.65 (4H, q, J=7.3 Hz), 2.88 (2H, t, J=6.2 H
z), 4.06 (2H, t, J=6.2 Hz), 6.92 (2H, d, J=9.0 H
z), 7.53 (2H, d, J=9.0 Hz), 7.64 (1H, d, J=8.8 H
z), 7.80 (1H, bs), 8.24 (1H, dd, J=2.9, 8.8 Hz),
8.59 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 392 (M + H)+。
(実施例301)N−[4−[3−(1,3−ジオキソ
イソインドール−2−イル)プロポキシ]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例296a及び299bと同様の方法に従い製造し
た2−[3−(4−アミノフェノキシ)プロピル]イソ
インドール−1,3−ジオン(0.90g、3.04m
mol)、2−クロロ−5−ニトロ安息香酸クロリド
(0.80g、3.64mmol)及びDMA(8m
L)を使用して、実施例1に記載した方法に従い、標記
目的化合物(1.14g、収率78%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 2.20 (2H, tt, J=6.
6, 6.6 Hz), 3.92 (2H,t, J=6.6 Hz), 4.04 (2H, t, J=
6.6 Hz), 6.83 (2H, d, J=9.2 Hz), 7.50 (2H,d, J=9.2
Hz), 7.65 (1H, d, J=8.8 Hz), 7.73 (2H, m), 7.84
(2H, m), 8.25 (1H, dd, J=2.9, 8.8 Hz), 8.60 (1H,
d, J=2.9 Hz);
MS(FAB) m/z: 480 (M + H)+。
(実施例302)N−[4−(3−アミノプロポキシ)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド
実施例301で製造したN−[4−[2−(1,3−ジ
オキソイソインドール−2−イル)プロポキシ]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド(0.480g、1.00mmol)、ヒドラジン
・1水和物(0.146mL、3.00mmol)及び
エタノール(10mL)を使用して、実施例297に記
載した方法に従い、標記目的化合物(0.077g、収
率22%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.81 (2H, tt, J=
6.6 Hz), 2.72 (2H, m),4.02 (2H, t, J=6.6 Hz), 6.95
(2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz),7.88 (1
H, d, J=8.8 Hz), 8.33 (1H, dd, J=2.9, 8.8 Hz), 8.4
3 (1H, d, J=2.9 Hz), 10.56 (1H, bs);
MS(FAB) m/z: 350 (M + H)+。
(実施例303)N−[4−[3−(ジメチルアミノ)
プロポキシ]フェニル]−(2−クロロ−5−ニトロフ
ェニル)カルボキサミド
実施例299a及び299bと同様の方法に従い製造し
た4−[2−(ジメチルアミノ)プロポキシ]アニリン
(1.14g、5.87mmol)、2−クロロ−5−
ニトロ安息香酸クロリド(1.55g、7.04mmo
l)及びDMA(15mL)を使用して、実施例1に記
載した方法に従い、標記目的化合物(1.27g、収率
57%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.96 (2H, tt, J=6.
6, 6.6 Hz), 2.26 (6H,s), 2.46 (2H, t, J=6.6 Hz),
4.03 (2H, t, J=6.6 Hz), 6.93 (2H, d, J=8.8 Hz), 7.
52 (2H, d, J=8.8 Hz), 7.65 (1H, d, J=8.8 Hz), 7.79
(1H, bs), 8.25(1H, dd, J=2.9, 8.8 Hz), 8.60 (1H,
d, J=2.9 Hz);
MS(FAB) m/z: 378 (M + H)+。
(実施例304)N−[4−[4−(1,3−ジオキソ
イソインドール−2−イル)ブトキシ]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例296a及び296bと同様の方法に従い製造し
た2−[4−(アミノフェノキシ)ブチル]イソインド
ール−1,3−ジオン(0.99g、3.19mmo
l)、2−クロロ−5−ニトロ安息香酸クロリド(0.
84g、3.83mmol)及びDMA(8mL)を使
用して、実施例1に記載した方法に従い、標記目的化合
物(1.40g、収率89%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.87 (4H, m), 3.78
(2H, t, J=6.6 Hz), 4.01 (2H, t, J=6.6 Hz), 6.91
(2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 7.65 (1
H, d, J=8.8 Hz), 7.72 (2H, m), 7.85 (2H, m), 8.25
(1H, dd, J=2.9, 8.8 Hz), 8.60 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 494 (M + H)+。
(実施例305)N−[4−(4−アミノブトキシ)フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
実施例304で製造したN−[4−[2−(1,3−ジ
オキソイソインドール−2−イル)ブトキシ]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド(0.494g、1.00mmol)、ヒドラジン
・1水和物(0.146mL、3.00mmol)及び
エタノール(10mL)を使用して、実施例297に記
載した方法に従い、標記目的化合物(0.061g、収
率17%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.49 (2H, m), 1.
73 (2H, m), 2.60 (2H,t, J=7.0 Hz), 3.95 (2H, t, J=
6.6 Hz), 6.94 (2H, d, J=8.8 Hz), 7.60 (2H,d, J=8.8
Hz), 7.88 (1H, d, J=8.8 Hz), 8.33 (1H, dd, J=2.9,
8.8 Hz), 8.43(1H, d, J=2.9 Hz);
MS(FAB) m/z: 364 (M + H)+。
(実施例306)N−[4−[2−(1,3−ジオキソ
イソインドール−2−イル)エチルチオ]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(306a)2−[4−(4−ニトロフェニル)チオエ
チル]−1H−イソインドール−1,3−ジオン
4−ニトロチオフェノール(22.3g、144mmo
l)をDMF(440mL)に溶解させ、氷冷下、55
%水素化ナトリウム(6.90g、158mmol)を
加えて30分間攪拌した。反応液にN−(2−ブロモエ
チル)フタルイミド(40.2g、158mmol)の
DMF溶液(440mL)を滴下し、0℃で3時間攪拌
した。反応溶液を氷−飽和重曹水中に注ぎ込み、生じた
固体を濾取した。得られた固体を水及びジイソプロピル
エーテルで洗浄し、減圧乾燥して、標記目的化合物(4
1.0g、収率87%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 3.35 (2H, t, J=7.3
Hz), 4.00 (2H, t, J=7.3 Hz), 7.47 (2H, d, J=8.8 H
z), 7.73 (2H, m), 7.84 (2H, m), 8.10 (2H, d,J=8.8
Hz)。
(306b)2−[4−(4−アミノフェニル)チオエ
チル]イソインドール−1,3−ジオン
実施例306aで製造した2−[4−(4−ニトロフェ
ニル)チオエチル]−1H−イソインドール−1,3−
ジオン(6.57g、20.0mmol)及び塩化ニッ
ケル(II)・6水和物(9.51g、40.0mmo
l)をTHF(200mL)に懸濁させ、氷冷下、水素
化ホウ素ナトリウム(3.03g、80.0mmol)
を2時間かけて加えた。反応溶液を濃縮し、残渣に飽和
重曹水を加えてセライト濾過し、濾液を酢酸エチルで抽
出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリ
ウムで乾燥し、減圧下濃縮し、減圧乾燥して、標記目的
化合物(3.56g、収率60%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 3.09 (2H, t, J=7.0
Hz), 3.68 (2H, bs), 3.87 (2H, t, J=7.0 Hz), 6.59
(2H, d, J=8.8 Hz), 7.31 (2H, d, J=8.8 Hz), 7.70 (2
H, m), 7.82 (2H, m)。
(306c)N−[4−[2−(1,3−ジオキソイソ
インドール−2−イル)エチルチオ]フェニル]−(2
−クロロ−5−ニトロフェニル)カルボキサミド実施例
306bで製造した2−[2−(4−アミノフェニル)
チオエチル]イソインドール−1,3−ジオン(0.4
70g、1.58mmol)、2−クロロ−5−ニトロ
安息香酸クロリド(0.416g、1.89mmol)
及びDMA(5mL)を使用して、実施例1に記載した
方法に従い、標記目的化合物(0.669g、収率88
%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.24 (2H, t, J=
7.0 Hz), 3.79 (2H, t, J=7.0 Hz), 7.39 (2H, d, J=8.
8 Hz), 7.61 (2H, d, J=8.8 Hz), 7.84 (4H, m),7.90
(1H, d, J=8.8 Hz), 8.35 (1H, dd, J=2.9, 8.8 Hz),
8.45 (1H, d, J=2.9Hz), 10.70 (1H, bs);
MS(FAB) m/z: 482 (M + H)+。
(実施例307)N−[4−[2−(tert−ブトキ
シカルボニルアミノ)エチルチオ]フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド
4−[2−(tert−ブトキシカルボニルアミノ)エ
チル]チオフェニルアミン(0.451g、1.68m
mol)、2−クロロ−5−ニトロ安息香酸クロリド
(0.444g、2.02mmol)及びDMA(5m
L)を使用して、実施例1に記載した方法に従い、標記
目的化合物(0.624g、収率76%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.44 (9H, s), 3.03
(2H, m), 3.33 (2H, m), 4.90 (1H, bs), 7.43 (2H,
d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.67 (1H, d,
J=8.8 Hz), 7.88 (1H, bs), 8.27 (1H, dd, J=2.9, 8.
8 Hz), 8.61 (1H,d, J=2.9 Hz);
MS(FAB) m/z: 451 M+。
(実施例308)N−[[4−(2−アミノエチル)チ
オ]フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド・1塩酸塩
実施例307で製造したN−[4−[2−(tert−
ブトキシカルボニルアミノ)エチルチオ]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(0.502g、1.11mmol)を1,4−ジオキ
サン(3mL)に懸濁させ、4N塩化水素−1,4−ジ
オキサン溶液(3mL)を加えて、室温で3日間攪拌し
た。反応溶液をジエチルエーテルで希釈して、生じた固
体を濾取し、減圧乾燥して、標記目的化合物(0.40
0g、収率93%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.93 (2H, m), 3.
19 (2H, t, J=7.3 Hz),7.47 (2H, d, J=8.8 Hz), 7.73
(2H, d, J=8.8 Hz), 7.90 (1H, d, J=8.8 Hz),8.18 (2
H, bs), 8.35 (1H, dd, J=2.9, 8.8 Hz), 8.47 (1H, d,
J=2.9 Hz), 10.88 (1H, bs);
MS(FAB) m/z: 352 (M + H)+。
(実施例309)N−[4−[3−(1,3−ジオキソ
イソインドール−2−イル)プロピルチオ]フェニル]
−(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例306a及び306bと同様の方法に従い製造し
た2−[3−(4−アミノフェニル)チオプロピル]イ
ソインドール−1,3−ジオン(0.475g、1.5
2mmol)、2−クロロ−5−ニトロ安息香酸クロリ
ド(0.401g、1.82mmol)及びDMA(5
mL)を使用して、実施例1に記載した方法に従い、標
記目的化合物(0.620g、収率82%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 2.00 (2H, tt, J=7.
3 Hz), 2.94 (2H, t, J=7.3 Hz), 3.83 (2H, t, J=7.3
Hz), 7.41 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 H
z), 7.65 (1H, d, J=8.8 Hz), 7.72 (2H, m), 7.85 (2
H, m), 8.26 (1H, dd, J=2.9, 8.8 Hz), 8.60 (1H, d,
J=2.9 Hz);
MS(FAB) m/z: 496 (M + H)+。
(実施例310)N−[[4−(3−アミノプロピル)
チオ]フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド
実施例309で製造したN−[4−[3−(1,3−ジ
オキソイソインドール−2−イル)プロピルチオ]フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキ
サミド(0.496g、1.00mmol)をエタノー
ル(5mL)に懸濁させ、n−ブチルアミン(0.40
mL、4.00mmol)を加えて、室温で2日間攪拌
した。反応溶液を減圧下濃縮し、残渣をシリカゲルカラ
ムクロマトグラフィー(クロロホルム:メタノール=
3:1(v/v))にて精製し、標記目的化合物(0.03
3g、収率9%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.82 (2H, tt, J=
7.3 Hz), 2.87 (2H, t,J=7.3 Hz), 3.02 (2H, t, J=7.3
Hz), 7.40 (2H, d, J=8.8 Hz), 7.69 (2H, d,J=8.8 H
z), 7.70 (2H, bs), 7.90 (1H, d, J=8.8 Hz), 8.35 (1
H, dd, J=2.9, 8.8 Hz), 8.46 (1H, d, J=2.9 Hz), 10.
82 (1H, bs);
MS(FAB) m/z: 366 (M + H)+。
(実施例311)N−[4−[4−(1,3−ジオキソ
イソインドール−2−イル)ブチルチオ]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
実施例306a及び306bと同様の方法に従い製造し
た2−[4−(4−アミノフェニル)チオブチル]イソ
インドール−1,3−ジオン(2.57g、7.87m
mol)、2−クロロ−5−ニトロ安息香酸クロリド
(2.08g、9.45mmol)及びDMA(26m
L)を使用して、実施例1に記載した方法に従い、標記
目的化合物(3.46g、収率86%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.68 (2H, tt, J=7.
3, 7.3 Hz), 1.84 (2H,tt, J=7.3, 7.3 Hz), 2.96 (2H,
t, J=7.3 Hz), 3.70 (2H, t, J=7.3 Hz), 7.36(2H, d,
J=8.8 Hz), 7.55 (2H, d, J=8.8 Hz), 7.66 (1H, d, J
=8.8 Hz), 7.72(2H, m), 7.84 (3H, m), 8.27 (1H, dd,
J=2.9, 8.8 Hz), 8.60 (1H, d, J=2.9Hz);
MS(FAB) m/z: 510 (M + H)+。
(実施例312)N−[4−[(4−アミノブチル)チ
オ]フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド
実施例311で製造したN−[4−[4−(1,3−ジ
オキソイソインドール−2−イル)ブチルチオ]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド(1.00g、1.96mmol)、ヒドラジン・
1水和物(0.476mL、9.80mmol)及びエ
タノール(20mL)を使用して、実施例297に記載
した方法に従い、標記目的化合物(0.210g、収率
28%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.45 (2H, tt, J=
7.3, 7.3 Hz), 1.58 (2H, tt, J=7.3, 7.3 Hz), 2.53
(2H, t, J=7.3 Hz), 2.93 (2H, t, J=7.3 Hz), 7.36 (2
H, d, J=8.8 Hz), 7.66 (2H, d, J=8.8 Hz), 7.89 (1H,
d, J=8.8 Hz), 8.34 (1H, dd, J=2.9, 8.8 Hz), 8.46
(1H, d, J=2.9 Hz);
MS(FAB) m/z: 380 (M + H)+。
(実施例313)N−[4−[[2−(tert−ブト
キシカルボニルアミノ)エチル]スルホニル]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
実施例307で製造したN−[4−[2−(tert−
ブトキシカルボニルアミノ)エチルチオ]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(0.226g、0.500mmol)を酢酸(1m
L)に溶解させ、70℃で31%過酸化水素水(0.2
0mL)を加えた。90℃で2時間攪拌した後、室温ま
で放冷した。反応溶液にジエチルエーテル(5mL)及
び水(5mL)を加え、生じた固体を濾取し、水及びジ
エチルエーテルで洗浄し、減圧乾燥して、標記目的化合
物(0.096g、収率40%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.32 (9H, s) 3.2
0 (2H, m), 3.38 (2H, m), 6.83 (1H, m), 7.89-7.98
(5H, m), 8.37 (1H, dd, J=2.9, 8.8 Hz), 8.54 (1H,
d, J=2.9 Hz), 11.18 (1H, bs);
MS(FAB) m/z: 484 (M + H)+。
(実施例314)N−[4−[(2−アミノエチル)ス
ルホニル]フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド・1塩酸塩
実施例313で製造したN−[4−[[2−(tert
−ブトキシカルボニルアミノ)エチル]スルホニル]フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド(0.060g、0.124mmol)、4N
塩化水素−1,4−ジオキサン溶液(0.3mL)及び
1,4−ジオキサン(0.9mL)を使用して、実施例
288に記載した方法に従い、標記目的化合物(0.0
44g、収率84%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.04 (2H, m), 3.
63 (2H, t, J=7.7 Hz),6.93 (1H, d, J=8.8 Hz), 7.97
(2H, d, J=8.8 Hz), 8.01 (2H, d, J=8.8 Hz),8.08 (2
H, bs), 8.38 (1H, dd, J=2.9, 8.8 Hz), 8.54 (1H, d,
J=2.9 Hz), 11.29 (1H, bs);
MS(FAB) m/z: 384 ((M-HCl) + H)+。
(実施例315)N−[4−[[4−(1,3−ジオキ
ソイソインドール−2−イル)ブチル]スルホニル]フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
実施例311で製造したN−[4−[4−(1,3−ジ
オキソイソインドール−2−イル)ブチルチオ]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド(0.510g、1.00mmol)、酢酸(2m
L)及び31%過酸化水素水(0.39mL)を使用し
て、実施例313に記載した方法に従い、標記目的化合
物(0.366g、68%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.77 (4H, m), 3.17
(2H, t, J=7.3 Hz), 3.69 (2H, m), 7.69 (1H, d, J=
8.8 Hz), 7.72 (2H, m), 7.83 (2H, m), 7.86 (2H, d,
J=9.2 Hz), 7.91 (2H, d, J=9.2 Hz), 8.27 (1H, bs),
8.30 (1H, dd, J=2.2, 8.8 Hz), 8.62 (1H, d, J=2.2 H
z);
MS(FAB) m/z: 542 (M + H)+。
(実施例316)N−[4−[[2−(tert−ブト
キシカルボニルアミノ)エチル]アミノ]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド・
1塩酸塩
(316a)N−(4−ニトロフェニル)エタンジアミ
ン
4−フルオロニトロベンゼン(5.00mL、47.1
mmol)及びエチレンジアミン(15.8mL、23
5.6mmol)をエタノール(50mL)に溶解さ
せ、4.5時間加熱還流した。反応溶液を氷冷し、生じ
た結晶を濾取し、減圧乾燥して、標記目的化合物(5.
32g、収率62%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 3.02 (2H, t, J=5.9
Hz), 3.26 (2H, dt, J=5.9, 5.9 Hz), 5.09 (1H, bs),
6.56 (2H, d, J=8.8 Hz), 8.06 (2H, d, J=8.8Hz)。
(316b)2−(4−ニトロアニリノ)エチルカルバ
ミン酸 tert−ブチルエステル
実施例316aで製造したN−(4−ニトロフェニル)
エタンジアミン(5.14g、28.4mmol)をメ
タノール(100mL)に溶解させ、ジ−tert−ブ
チルジカーボネート(18.6g、88.1mmol)
を加えて、室温で24時間攪拌した。反応溶液を減圧下
濃縮し、残渣をシリカゲルカラムクロマトグラフィー
(ヘキサン:酢酸エチル=3:1(v/v))にて精製し、
標記目的化合物(5.43g、収率68%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.46 (9H, s), 3.33
(2H, m), 3.43 (2H, m), 4.85 (1H, bs), 5.39 (1H, b
s), 6.52 (2H, d, J=9.2 Hz), 8.08 (2H, d, J=9.2 H
z)。
(316c)2−(4−アミノアニリノ)エチルカルバ
ミン酸 tert−ブチルエステル
実施例316bで製造した2−(4−ニトロアニリノ)
エチルカルバミン酸tert−ブチルエステル(2.0
0g、7.11mmol)、10%パラジウム−炭素
(0.2g)及びエタノール(40mL)を使用して、
実施例296bに記載した方法に従い、標記目的化合物
(1.83g、収率100%)を得た。 1
H-NMR (400MHz, CDCl3): δ(ppm) 1.45 (9H, s), 3.19
(2H, m), 3.33 (2H, m), 4.83 (1H, bs), 6.52 (2H,
d, J=8.7 Hz), 6.61 (2H, d, J=8.7 Hz)。
(316d)N−[4−[[2−(tert−ブトキシ
カルボニルアミノ)エチル]アミノ]フェニル]−(2
−クロロ−5−ニトロフェニル)カルボキサミド・1塩
酸塩
実施例316cで製造した2−(4−アミノアニリノ)
エチルカルバミン酸tert−ブチルエステル(1.8
3g、7.28mmol)をDMA(20mL)に溶解
させ、2−クロロ−5−ニトロ安息香酸クロリド(1.
76g、8.01mmol)を加えて、室温で24時間
攪拌した。反応溶液に飽和重曹水及び水を加えて、酢酸
エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥
し、減圧下濃縮した。得られた残渣をシリカゲルカラム
クロマトグラフィー(ヘキサン:酢酸エチル=1:1(v
/v))にて精製し、粗製のN−[4−[[2−(ter
t−ブトキシカルボニルアミノ)エチル]アミノ]フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキ
サミド(1.13g)を得た。[0272] 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.31
(3H, d, J = 6.4 Hz), 4.66-4.73 (1H, m), 5.18 (1H,
d, J = 4.1 Hz), 7.09 (1H, d, J = 7.7 Hz), 7.29 (1H, t,
J = 7.7 Hz), 7.54-7.57 (1H, m), 7.70 (1H, bs), 7.87
(1H, dd, J = 8.8 Hz), 8.32 (1H, dd, J = 8.8, 2.7 Hz),
8.43 (1H, d, J = 2.7 Hz), 10.67 (1H, s); MS (FAB) m / z: 320 M + . (Example 240) N- [4- (5,7,7,10,10)
-Pentamethyl-7,8,9,10-tetrahydro-5
H-5,13-diaza-benzo [4,5] cyclohepta
[1,2-b] Naphthalen-12-yl) phenyl]-
(2-chloro-5-nitrophenyl) carboxamide (240a) 4- (5,7,7,10,10-pentame
Chill-7,8,9,10-tetrahydro-5H-5,1
3-diazabenzo [4,5] cyclohepta [1,2-
b] naphthalen-12-yl) aniline 4- (5,7,
7,10,10-pentamethyl-7,8,9,10-te
Trahydro-5H-5,13-diazabenzo [4,5]
Cyclohepta [1,2-b] naphthalen-12-yl)
Benzoic acid (0.97 g, 2.21 mmol), tert
-Butyl alcohol (10 mL), DPPA (0.59
mL, 2.74 mmol) and triethylamine
4 produced from (0.38 mL, 2.74 mmol)
-(5,7,7,10,10-pentamethyl-7,8,
9,10-Tetrahydro-5H-5,13-diazaben
Zo [4,5] cyclohepta [1,2-b] naphthalene-
BOC form of 12-yl) aniline (0.59 g, 1.1
5 mmol) and 4N hydrogen chloride-1,4-dioxane dissolved
Using the liquid (2 mL), follow the procedure described in Example 88.
Accordingly, the hydrochloride (0.50 g) of the title object compound was obtained.
Saturated aqueous sodium hydrogen carbonate was added to the obtained hydrochloride and extracted with ethyl acetate.
I put it out. The organic layer was dried over anhydrous sodium sulfate and concentrated.
To give the title compound (0.41 g, yield 87%) as an oil.
Obtained as a substance. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.05 (3H, s), 1.
17 (3H, s), 1.25 (3H, s), 1.29 (3H, s), 1.60-1.65
(4H, m), 3.16 (3H, s), 5.67 (2H, s), 6.57 (2H, d,
J = 8.7 Hz), 6.96 (1H, s), 6.99-7.10 (4H, m), 7.01
(1H, s), 7.42 (2H, d, J = 8.7). (240b) N- [4- (5,7,7,10,10-pe
N-methyl-7,8,9,10-tetrahydro-5H-
5,13-diazabenzo [4,5] cyclohepta [1,2-b] naphthalen-12-yl) phenyl]-
(2-Chloro-5-nitrophenyl) carboxamide 4- (5,7,7,10,1) prepared in Example 240a.
0-pentamethyl-7,8,9,10-tetrahydro-
5H-5,13-diazabenzo [4,5] cyclohepta
[1,2-b] Naphthalen-12-yl) aniline
(0.41 g, 1.00 mmol), DMA (5 mL)
And 2-chloro-5-nitrobenzoic acid chloride
(0.25 g, 1.13 mmol)
According to the method described in 2, the title object compound (0.45
g, yield 76%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.04 (3H, s), 1.
16 (3H, s), 1.26 (3H, s), 1.31 (3H, s), 1.57-1.66
(4H, m), 3.21 (3H, s), 6.95 (1H, s), 7.06 (1H, s),
7.06-7.19 (4H, m), 7.73 (2H, d, J = 8.8 Hz), 7.82
(2H, d, J = 8.8 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.36 (1
H, dd, J = 8.8, 2.7 Hz), 8.54 (1H, d, J = 2.7 Hz), 10.
96 (1H, s); MS (FAB) m / z: 592 M + , 593 (M + H) + . (Example 241) N- [4- (4-aminophenyl) thio
Azol-2-yl]-(2-chloro-5-nitrofe
Nyl) carboxamide N- [4- (4-tert-butene) prepared in Example 190
Toxycarbonylaminophenyl) thiazol-2-i
]-(2-Chloro-5-nitrophenyl) carboxa
Mido (0.36 g, 0.75 mmol), methylene chloride
(10 mL), anisole (0.1 mL) and chicken
Fluoroacetic acid (1 mL) was used as described in Example 192.
According to the method described, the title object compound (0.24 g, yield
86%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 5.26-5.27 (2H,
m), 6.59 (2H, d, J = 8.6Hz), 7.34 (1H, s), 7.59 (2H,
d, J = 8.6 Hz), 7.90 (1H, d, J = 8.9 Hz), 8.37 (1H, d
d, J = 8.9, 2.8 Hz), 8.58 (1H, d, J = 2.8 Hz); MS (FAB) m / z: 375 (M + H) + . (Example 242) N- [4- [4- (phenylaminoca
Rubonylamino) phenyl] phenyl]-(2-chloro
-5-Nitrophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (5 mL) and phenyl isocyanate (0.1
3 mL, 1.2 mmol) to Example 236
According to the method described, the title compound (0.45 g, yield
Rate 93%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 6.98 (1H, t, J =
7.7 Hz), 7.29 (2H, d, J = 7.7 Hz), 7.47 (2H, d, J = 7.
7 Hz), 7.55 (2H, d, J = 8.3 Hz), 7.62 (2H, d, J = 8.4
Hz), 7.67 (2H, d, J = 8.4 Hz), 7.78 (2H, d, J = 8.3 H
z), 7.91 (1H, d, J = 8.8 Hz), 7.35 (1H, d, J = 8.8 H
z), 8.49 (1H, bs), 8.69 (1H, s), 8.77 (1H, s), 10.7
8 (1H, s); MS (FAB) m / z: 487 (M + H) + . (Example 243) N- [4- [4- (aminocarbonyl
Amino) phenyl] phenyl]-(2-chloro-5-di
Trophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (5 mL) and trimethylsilyl isocyanate
(0.16 mL, 1.2 mmol) using
According to the method described in 236, the title compound (0.3
7 g, yield 90%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 5.87 (1H, s), 7.
48 (2H, d, J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz), 7.64
(2H, d, J = 8.7 Hz), 7.76 (2H, d, J = 8.7 Hz), 7.91 (1
H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 8.8, 2.8 Hz), 8.4
8 (1H, d, J = 2.8Hz), 8.61 (1H, s), 10.77 (1H, s); MS (FAB) m / z: 411 (M + H) + . (Example 244) N- [4- [4- (ethoxycarbonyl
Luaminocarbonylamino) phenyl] phenyl]-
(2-Chloro-5-nitrophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (5 mL) and ethoxycarbonyl isocyanate
Performed using a solution (0.12 mL, 1.2 mmol)
According to the method described in Example 236, the title object compound (0.
47 g, yield 97%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.14 (3H, t, J =
7.1 Hz), 4.20 (2H, q, J = 7.1 Hz), 7.60 (2H, d, J = 8.
8 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.68 (2H, d, J = 8.7
Hz), 7.79 (2H, d, J = 8.7 Hz), 7.91 (1H, d, J = 8.8 H
z), 8.35 (1H, dd, J = 8.8, 2.8 Hz), 8.49 (1H, d, J = 2.
8 Hz), 9.93 (1H, s), 10.38 (1H, s), 10.79 (1H, s); MS (FAB) m / z: 483 (M + H) + . (Example 245) N- [4- [4-[(3-fluorophenyl
Phenyl) aminothiocarbonylamino] phenyl] phen
Nyl]-(2-chloro-5-nitrophenyl) carboxy
N- [4- (4-aminophenenyl) prepared in Samide Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (5 mL) and 3-fluorophenylisocyanate
(0.15 mL, 1.2 mmol)
According to the method described in Example 236, the title compound
(0.49 g, yield 95%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 6.92-6.98 (1H,
m), 7.28 (1H, d, J = 8.1Hz), 7.34-7.40 (1H, m), 7.58
(1H, d, J = 8.4 Hz), 7.59 (1H, s), 7.67 (2H, d, J = 8.
7 Hz), 7.71 (2H, d, J = 8.7 Hz), 7.80 (2H, d, J = 8.7
Hz), 7.91 (1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 8.8,
2.8 Hz), 8.49 (1H, d, J = 2.8 Hz), 10.01 (1H, s), 1
0.81 (1H, s); MS (FAB) m / z: 521 (M + H) + . (Example 246) N- [4- (4-nitrophenyl) thio
Azol-2-yl]-(2-chloro-5-nitrofe
Nyl) carboxamide 2-amino-4- (4-nitrophenyl) thiazole
(0.40 g, 1.82 mmol), DMA (5 mL)
And 2-chloro-5-nitrobenzoic acid chloride
(0.47 g, 2.13 mmol)
According to the method described in 2, the title object compound (0.71
g, yield 96%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.91 (1H, d, J =
8.8 Hz), 8.12 (1H, bs), 8.20 (2H, d, J = 9.0 Hz), 8.3
2 (2H, d, J = 9.0 Hz), 8.37 (1H, dd, J = 8.8, 2.7 Hz),
8.62 (1H, d, J = 2.7 Hz); MS (FAB) m / z: 405 (M +
H) + . (Example 247) N- [4- [4-[(3-methoxyphenol
Phenyl) aminocarbonylamino] phenyl] phenyl
]-(2-Chloro-5-nitrophenyl) carboxa
The N- [4- (4-aminophenenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (5 mL) and 3-methoxyphenyl isocyanate
(0.16 mL, 1.2 mmol)
According to the method described in Example 236, the title compound
(0.50 g, yield 97%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 3.74 (3H, s), 6.
55-6.58 (1H, m), 6.93-6.96 (1H, m), 7.16-7.21 (2H,
m), 7.54 (2H, d, J = 8.7 Hz), 7.61 (1H, d, J = 8.7 H
z), 7.67 (2H, d, J = 8.7 Hz), 7.78 (2H, d, J = 8.7 H
z), 7.91 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 8.8,
2.8 Hz), 8.49 (1H, d, J = 2.8 Hz), 8.71 (1H, s), 8.76
(1H, s), 10.78 (1H, s); MS (FAB) m / z: 517 (M + H) + . (Example 248) N- [4- [4- (benzylaminoca
Rubonylamino) phenyl] phenyl]-(2-chloro
-5-Nitrophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (5 mL) and benzyl isocyanate (0.1
5 mL, 1.2 mmol) to Example 236
According to the method described, the target compound (0.49 g, yield
Rate of 98%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 4.32 (2H, d, J =
5.8 Hz), 6.65 (1H, t, J = 5.8 Hz), 7.23-7.27 (1H,
m), 7.32-7.37 (4H, m), 7.50 (2H, d, J = 8.7 Hz), 7.56
(2H, d, J = 8.7 Hz), 7.65 (2H, d, J = 8.7 Hz), 7.76
(2H, d, J = 8.7 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.35 (1
H, dd, J = 8.8, 2.7 Hz), 8.48 (1H, d, J = 2.7Hz), 8.67
(1H, s), 10.76 (1H, s); MS (FAB) m / z: 501 (M + H) + . (Example 249) N- [4- [4-[(2,4-diflu
Orophenyl) aminocarbonylamino] phenyl] f
]-(2-Chloro-5-nitrophenyl) carbo
N- [4- (4-aminophenenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (5 mL) and 2,4-difluorophenyliso
Using cyanate (0.19 g, 1.2 mmol)
According to the method described in Example 236.
The product (0.50 g, yield 96%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.00-7.06 (1H,
m), 7.29 (1H, ddd, J = 11.4, 8.9, 2.7 Hz), 7.51 (2H,
d, J = 8.7 Hz), 7.60 (2H, d, J = 8.7 Hz), 7.65 (2H,
d, J = 8.7 Hz), 7.75 (2H, d, J = 8.7 Hz), 8.04-8.12
(1H, m), 8.32 (1H, dd, J = 8.8, 2.7 Hz), 8.46 (1H, d,
J = 2.7 Hz), 8.51 (1H, s), 9.10 (1H, bs), 10.75 (1
H, s); MS (FAB) m / z: 523 (M + H) + . Example 250 N- [4- [4- (benzoylamino
Thiocarbonylamino) phenyl] phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (5 mL) and benzoyl isothiocyanate
(0.16 mL, 1.2 mmol) using
According to the method described in 236, the title compound (0.5
1 g, yield 96%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.56 (2H, t, J =
7.5 Hz), 7.68 (1H, t, J = 7.5 Hz), 7.74-7.76 (4H,
m), 7.81-7.83 (4H, m), 7.92 (1H, d, J = 8.8 Hz), 8.00
(2H, d, J = 7.5 Hz), 8.36 (1H, dd, J = 8.8, 2.8 Hz),
8.50 (1H, d, J = 2.8Hz), 10.83 (1H, s), 11.60 (1H,
s); MS (FAB) m / z: 531 (M + H) + . (Example 251) N- [4- [4- (ethoxycarbonyl
Luaminothiocarbonylamino) phenyl] phenyl]
-(2-Chloro-5-nitrophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (5 mL) and ethoxycarbonyl isothiocyanate
Nate (0.14 mL, 1.2 mmol),
According to the method described in Example 236, the title object compound was obtained.
(0.48 g, yield 96%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.27 (3H, t, J =
7.1 Hz), 4.23 (2H, q, J = 7.1 Hz), 7.71 (4H, s), 7.7
3 (2H, d, J = 8.8 Hz), 7.81 (2H, d, J = 8.8 Hz), 7.91
(1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 8.8, 2.7 Hz),
8.50 (1H, d, J = 2.7Hz), 10.82 (1H, s), 11.29 (1H,
s), 11.61 (1H, s); MS (FAB) m / z: 499 (M + H) + . (Example 252) N- [4- [4- (phenylaminothiophene)
Ocarbonylamino) phenyl] phenyl]-(2-q
Lolo-5-nitrophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (5 mL) and phenylisothiocyanate
(0.24 mL, 2.0 mmol) using
According to the method described in 236, the title compound (0.4
5 g, yield 89%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.14 (1H, t, J =
7.4 Hz), 7.35 (2H, t, J = 7.9 Hz), 7.49-7.53 (2H,
m), 7.57-7.61 (2H, m), 7.66 (2H, d, J = 8.7 Hz), 7.70
(2H, d, J = 8.7 Hz), 7.80 (2H, d, J = 8.7 Hz), 7.91
(1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 8.8, 2.7 Hz), 8.
49 (1H, d, J = 2.7 Hz), 9.84 (1H, s), 9.89 (1H, bs),
10.81 (1H, s); MS (FAB) m / z: 503 (M + H) + . (Example 253) N- [4- (3-aminophenyl) thio
Azol-2-yl]-(2-chloro-5-nitrofe
Nyl) carboxamide N- [4- (3-tert-butane prepared in Example 234.
Toxycarbonylaminophenyl) thiazol-2-i
]-(2-Chloro-5-nitrophenyl) carboxa
Mido (0.20 g, 0.43 mmol), methylene chloride
(5 mL), anisole (0.05 mL) and triflu
Described in Example 192 using oroacetic acid (1 mL).
According to the above method, the title compound (0.12 g, yield 78
%) Was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 5.15 (2H, bs),
6.52-6.55 (1H, m), 7.06 (1H, s), 7.06-7.12 (2H, m),
7.54 (1H, s), 7.91 (1H, d, J = 8.9 Hz), 8.37 (1H, d
d, J = 8.9, 2.8 Hz), 8.59 (1H, d, J = 2.8 Hz); MS (FAB)
m / z: 374 M + , 375 (M + H) + . (Example 254) N- [4- [4- (2-nitropheny
Luaminocarbonylamino) phenyl] phenyl]-
(2-Chloro-5-nitrophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (5 mL) and 2-nitrophenyl isocyanate
(0.20 g, 1.2 mmol)
According to the method described in 236, the title compound (0.4
8 g, yield 90%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.20-7.25 (1H,
m), 7.59 (2H, d, J = 8.8Hz), 7.65 (2H, d, J = 8.8 Hz),
7.69 (2H, d, J = 8.8 Hz), 7.70-7.74 (1H, m), 7.79 (2
H, d, J = 8.8 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.11 (1H,
dd, J = 8.4, 1.5Hz), 8.32 (1H, dd, J = 8.4, 1.5Hz),
8.35 (1H, dd, J = 8.8, 2.8 Hz), 8.49 (1H, d, J = 2.8 H
z), 9.64 (1H, bs), 9.95 (1H, bs); MS (FAB) m / z: 532
(M + H) + . (Example 255) N- [4- (2-aminothiazole-
4-yl) phenyl]-(2-chloro-5-nitrofe
Nyl) carboxamide N- (4-acetylphenyl) prepared in Example 155
-(2-chloro-5-nitrophenyl) carboxamide
(4.78 g, 15.0 mmol), thiourea (0.
91 g, 12 mmol) and iodine (1.52 g,
6.0 mmol) using the method described in Reference Example 2.
According to the above, the title object compound (3.49 g, yield 62%) was obtained.
Obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 6.95 (1H, s), 7.
04 (2H, bs), 7.70 (2H, d, J = 8.7 Hz), 7.80 (2H, d, J
= 8.7 Hz), 7.90 (1H, d, J = 8.8 Hz), 8.34 (1H, dd, J =
8.8, 2.7 Hz), 8.48 (1H, d, J = 2.7 Hz), 10.75 (1H,
s); MS (FAB) m / z: 375 (M + H) + . (Example 256) N- [4- [4-[(pyridine-3-
Ile) aminothiocarbonylamino] phenyl] phenyl
]-(2-Chloro-5-nitrophenyl) carboxa
The N- [4- (4-aminophenenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (5 mL) and 3-pyridinyl isothiocyanate
(0.16 g, 1.2 mmol) using
According to the method described in 236, the title compound (0.4
5 g, yield 89%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.38 (1H, dd, J =
8.5, 4.8 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.68 (2H, d,
J = 8.6 Hz), 7.71 (2H, d, J = 8.7 Hz), 7.80 (2H, d, J
= 8.7 Hz), 7.91 (1H, d, J = 8.9 Hz), 7.96-7.98 (1H,
m), 8.33 (1H, dd, J = 4.8, 1.4 Hz), 8.36 (1H, dd, J =
8.9, 2.8 Hz), 8.49 (1H, d, J = 2.8 Hz), 8.63 (1H, d,
J = 2.4 Hz), 9.92 (1H, bs), 10.11 (1H, s), 10.81 (1
H, s); MS (FAB) m / z: 504 (M + H) + . (Example 257) N- [4-[(pyridin-3-yl)
Aminothiocarbonylamino] phenyl]-(2-chloro
(5--5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 180
(2-chloro-5-nitrophenyl) carboxamide
(0.29 g, 1.0 mmol), THF (5 mL)
Rabini 3-pyridinyl isothiocyanate (0.16
g, 1.2 mmol) as described in Example 236.
According to the method described above, the title compound (0.39 g, yield 9
1%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.37 (1H, dd, J =
8.1, 4.7 Hz), 7.46 (2H, d, J = 8.6 Hz), 7.68 (2H, d,
J = 8.6 Hz), 7.90 (1H, d, J = 8.8 Hz), 7.95 (1H, d, J
= 7.9 Hz), 8.31-8.36 (2H, m), 8.46 (1H, d, J = 2.7 H
z), 8.61 (1H, d, J = 2.1 Hz), 9.80 (1H, bs), 10.00 (1
H, s), 10.74 (1H, s); MS (FAB) m / z: 428 (M + H) + . (Example 258) N- [4- [4-[(pyridine-4-
Ile) aminothiocarbonylamino] phenyl] phenyl
]-(2-Chloro-5-nitrophenyl) carboxa
The N- [4- (4-aminophenenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.15 g, 0.40 mmol), T
HF (5 mL) and 4-pyridinyl isothiocyanate
Carried out using a salt (0.16 g, 1.2 mmol).
According to the method described in Example 236, the title object compound (0.
19 g (94% yield) were obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.59 (2H, d, J =
8.6 Hz), 7.64 (2H, d, J = 5.2 Hz), 7.68 (2H, d, J = 8.
6 Hz), 7.71 (2H, d, J = 8.7 Hz), 7.80 (2H, d, J = 8.7
Hz), 7.91 (1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 8.8,
2.7 Hz), 8.42 (2H, d, J = 5.2 Hz), 8.49 (1H, d, J = 2.
7 Hz), 10.23 (1H, bs), 10.81 (1H, s); MS (FAB) m / z: 504 (M + H) + . (Example 259) N- [4-[(pyridin-4-yl)
Aminothiocarbonylamino] phenyl]-(2-chloro
(5--5-nitrophenyl) carboxamide N- (4-aminophenyl) -prepared in Example 180
(2-chloro-5-nitrophenyl) carboxamide
(0.12 g, 0.40 mmol), THF (5 mL)
And 4-pyridinyl isothiocyanate (0.16
g, 1.2 mmol) as described in Example 236.
According to the method described above, the title compound (0.16 g, yield 9
4%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.47 (2H, d, J =
8.8 Hz), 7.64 (2H, d, J = 6.0 Hz), 7.69 (2H, d, J = 8.
8 Hz), 7.90 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 8.8,
2.8 Hz), 8.42 (2H, d, J = 6.0 Hz), 8.46 (1H, d, J =
2.8 Hz), 10.11 (1H, s), 10.19 (1H, s), 10.75 (1H,
s); MS (FAB) m / z: 428 (M + H) + . (Example 260) N-[(6-tert-butoxycal
Bonylamino) benzothiazol-2-yl]-(2-
Chloro-5-nitrophenyl) carboxamide 2-amino-6-tert-butoxycarbonylamino
Benzothiazole (4.23 g, 15.9 mmol),
DMA (40 mL) and 2-chloro-5-nitro ammonium
Using benzoic acid chloride (4.21 g, 19.1 mmol)
According to the method described in Example 2,
The product (6.09 g, yield 85%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.50 (9H, s), 7.
43 (1H, dd, J = 8.7, 2.1Hz), 7.66 (1H, d, J = 8.7 Hz),
7.90 (1H, d, J = 8.9 Hz), 8.18 (1H, bs), 8.37 (1H,
dd, J = 8.9, 2.7 Hz), 8.62 (1H, d, J = 2.7 Hz), 9.54
(1H, bs); MS (FAB) m / z: 449 (M + H) + . (Example 261) N- (6-aminobenzothiazole-
2-yl)-(2-chloro-5-nitrophenyl) calc
Voxamide N-[(6-tert-butoxyl prepared in Example 260
Cycarbonylamino) benzothiazol-2-yl]-
(2-chloro-5-nitrophenyl) carboxamide
(5.46 g, 12.2 mmol), anisole (1 m
L) and trifluoroacetic acid (11 mL),
According to the method described in Example 192, the title object compound was obtained.
(4.14 g, yield 97%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.08 (1H, dd, J =
8.6, 2.0 Hz), 7.55 (1H, bs), 7.68 (1H, d, J = 8.6 H
z), 7.92 (1H, d, J = 8.9 Hz), 8.39 (1H, dd, J = 8.9,
2.7 Hz), 8.62 (1H, d, J = 2.7 Hz); MS (FAB) m / z: 348 M + , 349 (M + H) + . (Example 262) N- [4- (4-methanesulfonyla
Minophenyl) thiazol-2-yl]-(2-chloro
-5-Nitrophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 241
Lu) thiazol-2-yl]-(2-chloro-5-nit
Rophenyl) carboxamide (0.50g, 1.32m
mol), methanesulfonyl chloride (0.11 mL,
1.45 mmol) and pyridine (5 mL)
According to the method described in Example 2,
(0.59 g, yield 99%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 3.03 (3H, s), 7.
27 (2H, d, J = 8.7 Hz), 7.69 (1H, s), 7.89 (2H, d, J =
8.7 Hz), 7.91 (1H, d, J = 8.9 Hz), 8.38 (1H, dd, J = 8.
9, 2.7 Hz), 8.60 (1H, d, J = 2.7 Hz), 9.88 (1H, s); MS (FAB) m / z: 453 (M + H) + . (Example 263) N- [4- (4-acetylaminophen)
Nyl) thiazol-2-yl]-(2-chloro-5-di
Trophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 241
Lu) thiazol-2-yl]-(2-chloro-5-nit
Rophenyl) carboxamide (0.33g, 0.88m
mol), acetyl chloride (0.07 mL, 0.96)
mmol) and DMA (4 mL), Example 2
According to the method described in 1., the title compound (0.35 g,
Yield 96%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.06 (3H, s), 7.
64 (2H, d, J = 8.7 Hz), 7.84 (2H, d, J = 8.7 Hz), 8.37
(1H, dd, J = 8.8, 2.8 Hz), 8.59 (1H, d, J = 2.8Hz), 1
0.03 (1H, s); MS (FAB) m / z: 417 (M + H) + . (Example 264) N- [4-[(4-aminocarbonyl
Lu) piperazin-1-yl] phenyl]-(2-chloro
-5-Nitrophenyl) carboxamide N- [4- (piperazine-1-) prepared in Example 133.
Iyl) phenyl]-(2-chloro-5-nitrophenyl
Le) carboxamide dihydrochloride (0.24 g, 0.65)
mmol), trimethylsilyl isocyanate (0.1
1 mL, 0.78 mmol) and THF (5 mL).
According to the method described in Example 236
A compound (0.22 g, yield 84%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 3.05 (4H, m), 3.
43 (4H, m), 6.05 (2H, bs), 6.98 (2H, d, J = 8.4 Hz),
7.56 (2H, d, J = 8.4 Hz), 7.88 (1H, d, J = 8.8Hz), 8.3
3 (1H, d, J = 8.8 Hz), 8.41 (1H, s), 10.49 (1H, s). (Example 265) N- [4- (2-acetylaminothia)
Zol-4-yl) phenyl]-(2-chloro-5-di
Trophenyl) carboxamide N- [4- (2-aminothiazo) prepared in Example 255
4-4-yl) phenyl]-(2-chloro-5-nit
Rophenyl) carboxamide (0.19g, 0.50m
mol), acetyl chloride (0.04 mL, 0.55
mmol) and DMA (5 mL), Example 2
According to the method described in 1., the title compound (0.16 g,
Yield 78%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.17 (3H, s), 7.
54 (1H, s), 7.77 (2H, d, J = 8.7 Hz), 7.79-7.93 (3H,
m), 8.35 (1H, dd, J = 8.9, 2.8 Hz), 8.49 (1H, d, J = 2.
8 Hz), 10.81 (1H, s). (Example 266) N- [3- (2-acetylaminothia)
Zol-4-yl) phenyl]-(2-chloro-5-di
Trophenyl) carboxamide N- [3- (2-aminothiazo) prepared in Example 233
4-4-yl) phenyl]-(2-chloro-5-nit
Rophenyl) carboxamide (0.12g, 0.33m
mol), acetyl chloride (0.03 mL) and DM
Follow the procedure described in Example 2 using A (5 mL).
The title object compound (0.10 g, yield 70%) was obtained.
It was 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.17 (3H, s), 7.
43 (1H, t, J = 7.9 Hz), 7.49-7.52 (1H, m), 7.56 (1H,
s), 7.65-7.68 (1H, m), 7.91 (1H, d, J = 8.8 Hz), 8.3
5 (1H, dd, J = 8.8, 2.7 Hz), 8.41-8.42 (1H, m), 8.49
(1H, d, J = 2.7Hz), 10.78 (1H, s). (Example 267) N- [4- (2-aminoethyl) phene
Nyl]-(2-chloro-5-nitrophenyl) carboxy
Samide N- [4- (2-aminoethyl) prepared in Example 169
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide hydrochloride 0.2 hydrate (3.74 g, 1
0 mmol) saturated aqueous sodium hydrogen carbonate (20 mL), water (80 m)
L) and hexane (10 mL) and stirred for 1 hour
did. The resulting solid is collected by filtration, washed with water, dried and
The target compound (3.05 g, yield 96%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.63-2.70 (1H,
m), 2.79 (27H, t, J = 7.0Hz), 3.12-3.18 (1H, m), 7.2
1 (2H, d, J = 8.4 Hz), 7.62 (2H, d, J = 8.4 Hz), 7.89
(1H, d, J = 8.8 Hz), 8.33 (1H, dd, J = 8.8, 2.7 Hz),
8.43 (1H, d, J = 2.7 Hz), 10.65 (1H, s); MS (FAB) m / z: 320 (M + H) + . Example 268 N- [4- (2-phenylaminocal
Bonylaminoethyl) phenyl]-(2-chloro-5-
Nitrophenyl) carboxamide N- [4- (2-aminoethyl) prepared in Example 267
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.32 g, 1.0 mmol), TH
F (5 mL) and phenyl isocyanate (0.1
3 mL, 1.2 mmol) to Example 236
According to the method described, the title compound (0.35 g, yield
Rate 79%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.86 (2H, t, J =
7.3 Hz), 3.66-3.71 (2H, m), 6.88 (1H, t, J = 7.3 Hz),
7.21 (2H, t, J = 8.3 Hz), 7.37 (2H, d, J = 7.7Hz), 7.
64 (2H, d, J = 8.3 Hz), 7.89 (1H, d, J = 8.9 Hz), 8.34
(1H, dd, J = 8.9, 2.7 Hz), 8.44 (1H, d, J = 2.7 Hz),
8.46 (1H, s), 10.66 (1H, s); MS (FAB) m / z: 439 (M + H) + . (Example 269) N- [4- (2-phenylaminothio)
Carbonylaminoethyl) phenyl]-(2-chloro-
5-Nitrophenyl) carboxamide N- [4- (2-aminoethyl) prepared in Example 267
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.32 g, 1.0 mmol), TH
F (5 mL) and phenylisothiocyanate
(0.15 mL, 2.0 mmol) using
According to the method described in 236, the title compound (0.3
5 g, yield 78%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.87 (2H, t, J =
7.3 Hz), 3.70-3.72 (2H, m), 7.11 (1H, t, J = 6.2 Hz),
7.26-7.37 (6H, m), 7.66 (2H, d, J = 8.4 Hz), 7.72 (1
H, bs), 7.90 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 8.
8, 2.8 Hz), 8.45 (1H, d, J = 2.8 Hz), 9.57 (1H, bs),
10.67 (1H, s); MS (FAB) m / z: 455 (M + H) + . (Example 270) N- [4- (2-aminocarbonyla)
Minoethyl) phenyl]-(2-chloro-5-nitrof
N- [4- (2-aminoethyl) prepared in Example 267.
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.32 g, 1.0 mmol), TH
F (5 mL) and trimethylsilyl isocyanate
(0.16 mL, 1.2 mmol) using
According to the method described in 236, the title compound (0.2
8 g, yield 77%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.65 (2H, t, J =
7.2 Hz), 3.16-3.22 (2H, m), 5.42 (2H, s), 5.89 (1H,
t, J = 5.5 Hz), 7.21 (2H, d, J = 8.3 Hz), 7.62 (2H, d,
J = 8.3 Hz), 7.89 (1H, d, J = 8.8 Hz), 8.34 (1H, dd,
J = 8.8, 2.7 Hz), 8.44 (1H, d, J = 2.7 Hz), 10.63 (1H,
s); MS (FAB) m / z: 363 (M + H) + . (Example 271) N- [4- (2-phenylcarbonyl)
Aminothiocarbonylaminoethyl) phenyl]-(2
-Chloro-5-nitrophenyl) carboxamide N- [4- (2-aminoethyl) prepared in Example 267
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.32 g, 1.0 mmol), TH
F (5 mL) and benzoyl isothiocyanate
(0.16 mL, 1.2 mmol) using
According to the method described in 236, the title compound (0.4
0 g, yield 84%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.96 (2H, t, J =
7.1 Hz), 3.83-3.89 (2H, m), 7.30 (2H, d, J = 8.4 Hz),
7.51 (2H, t, J = 7.7 Hz), 7.61-7.67 (3H, m), 7.87-7.
93 (3H, m), 8.33 (1H, dd, J = 8.8, 2.8 Hz), 8.45 (1
H, d, J = 2.8 Hz), 10.68 (1H, s), 10.93 (1H, s), 11.3
3 (1H, s); MS (FAB) m / z: 483 (M + H) + . (Example 272) N- [4- (2-ethoxycarbonyl)
Aminothiocarbonylaminoethyl) phenyl]-(2
-Chloro-5-nitrophenyl) carboxamide N- [4- (2-aminoethyl) prepared in Example 267
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.32 g, 1.0 mmol), TH
F (5 mL) and ethoxycarbonyl isothiocyanate
Nate (0.14 mL, 1.2 mmol),
According to the method described in Example 236, the title object compound was obtained.
(0.41 g, yield 92%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.21 (3H, t, J =
7.1 Hz), 2.89 (2H, t, J = 7.2 Hz), 3.76-3.81 (2H,
m), 4.14 (2H, q, J = 7.1 Hz), 7.26 (2H, d, J = 8.4Hz),
7.64 (2H, d, J = 8.4 Hz), 7.89 (1H, d, J = 8.8 Hz),
8.34 (1H, dd, J = 8.8, 2.7 Hz), 8.45 (1H, d, J = 2.7 H
z), 9.91 (1H, bs), 10.67 (1H, s), 10.96 (1H, s); MS (FAB) m / z: 451 (M + H) + . (Example 273) N- [4- [2- (pyridin-3-i
Le) Aminothiocarbonylaminoethyl] phenyl]-
(2-Chloro-5-nitrophenyl) carboxamide N- [4- (2-aminoethyl) prepared in Example 267
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.32 g, 1.0 mmol), TH
F (5 mL) and 3-pyridyl isothiocyanate
Example 2 using (0.16 g, 1.2 mmol)
According to the method described in 36, the title compound (0.41
g, yield 90%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.87 (2H, t, J =
7.3 Hz), 3.66-3.77 (2H, m), 7.27 (2H, d, J = 8.3 Hz),
7.36 (1H, dd, J = 8.1, 4.7 Hz), 7.65 (2H, d, J = 8.3 H
z), 7.89 (1H, d, J = 8.8 Hz), 7.91-7.98 (2H, m), 8.3
0 (1H, d, J = 4.7Hz), 8.34 (1H, dd, J = 8.8, 2.7 Hz),
8.44 (1H, d, J = 2.7 Hz), 8.57 (1H, d, J = 2.2 Hz), 9.7
0 (1H, bs), 10.67 (1H, s); MS (FAB) m / z: 456 (M + H) + . (Example 274) N- [4- (imidazo [1,2-a]
Pyridin-2-yl) phenyl]-(2-chloro-5-
Nitrophenyl) carboxamide 4- (imidazo [1,2-a] pyridin-2-yl) a
Niline (0.22 g, 1.07 mmol), DMA (3
mL) and 2-chloro-5-nitrobenzoic acid chloride
Carried out using a solution (0.26 g, 1.18 mmol).
According to the method described in Example 2, the title object compound (0.39
g, yield 92%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 6.89 (1H, m), 7.
22-7.26 (1H, m), 7.57 (1H, d, J = 9.3 Hz), 7.79 (2H,
d, J = 8.6 Hz), 7.91 (1H, d, J = 8.9 Hz), 7.98 (2H, d,
J = 8.6 Hz), 8.35 (1H, dd, J = 8.9, 2.8 Hz), 8.50 (1H,
d, J = 2.8 Hz), 8.53 (1H, d, J = 6.7 Hz), 10.80 (1H, s). (Example 275) N- [3- (2-hydroxyethyl)
Phenyl]-(2-chloro-5-nitrophenyl) calc
Voxamide N-3- (2-hydroxyethyl) aniline (2.56
g, 18.7 mmol), DMA (25 mL) and
2-Chloro-5-nitrobenzoic acid chloride (4.31)
g, 19.6 mmol) was used and described in Example 2.
According to the above method, the title object compound (3.81 g, yield 64)
%) Was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.72 (2H, t, J =
7.0 Hz), 3.61 (2H, q, J = 7.0 Hz), 4.66 (1H, t, J = 7.
0 Hz), 7.00 (1H, d, J = 7.8 Hz), 7.27 (1H, d, J = 7.8
Hz), 7.54 (1H, d, J = 7.8 Hz), 7.57 (1H, s), 7.89 (1
H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 8.8, 2.8 Hz), 8.44
(1H, d, J = 2.7 Hz), 10.64 (1H, s); MS (FAB) m / z: 321
(M + H) + . (Example 276) N- [4- [4- (N, N-diethane
Sulfonylamino) phenyl] phenyl]-(2-chloro
Lo-5-nitrophenyl) carboxamide N- [4- (4-aminophenyl) prepared in Example 192
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.37 g, 1.0 mmol), TH
F (10 mL), triethylamine (0.55 mL,
4.0 mmol) and ethanesulfonyl chloride
(0.31 mL, 2.2 mmol)
According to the method described in 235, the title compound (0.2
2 g, yield 40%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.36 (6H, t, J =
7.1 Hz), 3.68 (4H, q, J = 7.1 Hz), 7.55 (2H, d, J = 7.
7 Hz), 7.60-7.85 (6H, m), 7.92 (1H, d, J = 8.2Hz),
8.66 (1H, d, J = 8.2 Hz), 8.50 (1H, s), 10.86 (1H,
s); MS (FAB) m / z: 552 (M + H) + . (Example 277) N- [4- (3-acetylaminophen)
Nyl) thiazol-2-yl]-(2-chloro-5-di
Trophenyl) carboxamide N- [4- (3-aminophenyl) prepared in Example 253
Lu) thiazol-2-yl]-(2-chloro-5-nit
Rophenyl) carboxamide (0.22g, 0.60m
mol), acetyl chloride (0.05 mL, 0.7 m
mol) and DMA (5 mL) to give Example 2.
According to the method described, the title compound (0.22 g, yield
Rate 86%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.06 (3H, s), 7.
35 (1H, t, J = 8.0 Hz), 7.44 (1H, d, J = 8.0 Hz), 7.58
(1H, d, J = 8.0 Hz), 7.67 (1H, s), 7.91 (1H, d, J = 8.8
Hz), 8.26 (1H, bs), 8.37 (1H, dd, J = 8.8, 2.7 Hz),
8.60 (1H, d, J = 2.7 Hz), 10.01 (1H, s); MS (FAB) m / z: 417 (M + H) + . (Example 278) N- [4- (3-methanesulfonylaurea
Minophenyl) thiazol-2-yl]-(2-chloro
-5-Nitrophenyl) carboxamide N- [4- (3-aminophenyl) prepared in Example 260
Lu) thiazol-2-yl]-(2-chloro-5-nit
Rophenyl) carboxamide (0.22g, 0.60m
mol), methanesulfonyl chloride (0.05 mL,
0.7 mmol) and pyridine (5 mL),
According to the method described in Example 2, the title object compound (0.
18 g, yield 65%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 3.01 (3H, s), 7.
17 (1H, d, J = 7.6 Hz), 7.41 (1H, t, J = 7.6 Hz), 7.66
(1H, d, J = 7.6 Hz), 7.74 (1H, s), 7.81 (1H, s), 7.91
(1H, d, J = 8.4 Hz), 8.38 (1H, d, J = 8.4 Hz), 8.61
(1H, bs), 9.84 (1H, s); MS (FAB) m / z: 452 (M + H) + . (Example 279) N- [4- [4- (2,5-dimethyl
Pyrrol-1-yl) phenyl] phenyl]-(2-q
Lolo-5-nitrophenyl) carboxamide 4- [4- (2,5-dimethylpyrrol-1-yl) fluoro
Phenyl] aniline (0.12 g, 0.45 mmol),
DMA (5 mL) and 2-chloro-5-nitrobenzoate
Using perfume chloride (0.11g, 0.53mmol)
Then, according to the method described in Example 2, the title compound
(0.17 g, yield 85%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.01 (6H, s), 5.
82 (2H, s), 7.35 (2H, d, J = 8.4 Hz), 7.77-7.85 (6H,
m), 7.92 (1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 8.8,
2.7 Hz), 8.51 (1H, d, J = 2.7 Hz), 10.85 (1H, s); MS (FAB) m / z: 262 M + . (Example 280) N- (6-acetylaminobenzothia
Zol-2-yl)-(2-chloro-5-nitropheni
L) carboxamide N- (6-aminobenzothiazo prepared in Example 261)
R-2-yl)-(2-chloro-5-nitrophenyl
Le) carboxamide (0.28 g, 0.80 mmo
l), acetyl chloride (0.06 mL, 0.9 mmo
1) and DMA (5 mL), described in Example 2
According to the method described above, the title compound (0.22 g, yield 6
9%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.09 (3H, s), 7.
53 (1H, d, J = 8.7 Hz), 7.72 (1H, d, J = 8.3 Hz), 7.92
(1H, dd, J = 8.8, 1.7 Hz), 8.37-8.40 (2H, m), 8.64 (1
H, d, J = 1.7 Hz); MS (FAB) m / z: 391 (M + H) + . (Example 281) N- (6-aminocarbonylamino)
Nzothiazol-2-yl)-(2-chloro-5-nit
Rophenyl) carboxamide N- (6-aminobenzothiazo prepared in Example 261
R-2-yl)-(2-chloro-5-nitrophenyl
Le) carboxamide (0.22 g, 0.60 mmo
l), trimethylsilyl isocyanate (0.01 m
L, 0.7 mmol) and THF (5 mL)
According to the method described in Example 236.
The product (0.18 g, yield 77%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 5.91 (2H, bs),
7.36 (1H, dd, J = 8.8, 2.2 Hz), 7.64-7.68 (1H, m),
7.92 (1H, d, J = 8.8 Hz), 8.18 (1H, bs), 8.38 (1H, d
d, J = 8.8, 2.5 Hz), 8.63 (1H, d, J = 2.5 Hz), 8.72 (1
H, bs); MS (FAB) m / z: 392 (M + H) + . (Example 282) N-phenyl-N-ethyl- (2-q
Lolo-5-nitrophenyl) carboxamide N-ethylaniline (0.30 g, 2.48 mmo
l), 2-chloro-5-nitrobenzoic acid chloride (0.
60 g, 2.73 mmol) and DMA (3 mL)
According to the method described in Example 1,
The product (0.58 g, yield 76%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.28 (3H, t, J = 7.2
Hz), 4.00 (2H, q, J = 7.2 Hz), 7.14-7.25 (5H, m),
7.37 (1H, d, J = 8.7 Hz), 7.95 (1H, dd, J = 2.7,8.7 H
z), 7.98 (1H, d, J = 2.7 Hz). (Example 283) N- [4- [4-[[(butylamine
No) Thiocarbonyl] amino] phenyl] phenyl]-
(2-chloro-5-nitrophenyl) carboxamide N- [4- (4-aminophenyl) phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide (0.3
67 g, 1.00 mmol) dissolved in THF (5 mL)
Butyl isothiocyanate (0.145 mL,
1.20 mmol) and stirred at room temperature for 22 hours
It was Add methanol to the reaction solution and stir, then concentrate under reduced pressure.
Contracted. The obtained solid is washed with diisopropyl ether
And dried under reduced pressure to give the title compound (0.395 g, yield
82%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 0.92 (3H, t, J =
7.3 Hz), 1.33 (2H, m), 1.54 (2H, m), 3.47 (2H, m),
5.33 (1H, bs), 7.51 (2H, m), 7.63 (2H, d, J = 8.0 H
z), 7.71 (2H, m), 7.79 (2H, d, J = 8.0 Hz), 7.90 (1
H, m), 8.35 (1H, m), 8.47 (1H, m), 9.52 (1H, bs),
10.70 (1H, bs); MS (FAB) m / z: 483 (M + H) + . (Example 284) N- [4- (3-nitrophenyl) phenyl
]-(2-Chloro-5-nitrophenyl) carbo
Xamide 4- (3-nitrophenyl) aniline (0.22 g,
1.00 mmol), 2-chloro-5-nitrobenzoic acid
Chloride (0.24 g, 1.11 mmol) and DMA
(4 mL) using the method described in Example 1.
The title compound (0.35 g, yield 87%) was obtained.
It was 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.77 (1H, t, J =
8.0 Hz), 7.86 (4H, Abq, J = 9.3 Hz), 7.92 (1H, d, J =
8.9 Hz), 8.16-8.22 (2H, m), 8.36 (1H, dd, J = 2.8,
8.9 Hz), 8.46 (1H, t, J = 2.0 Hz), 8.51 (1H, d, J = 2.
8 Hz), 10.89 (1H, s); MS (FAB) m / z: 397 M + . (Example 285) N- [4- (4-cyanophenyl) phenyl]
]-(2-Chloro-5-nitrophenyl) carbo
Xamide 4- (4-cyanophenyl) aniline (1.06 g,
5.46 mmol), 2-chloro-5-nitrobenzoic acid
Chloride (1.44 g, 6.55 mmol) and DMA
(10 mL) using the method described in Example 1.
The title object compound (2.00 g, yield 97%) was obtained.
It was 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.84 (4H, ABq, J
= 9.0, 16.5 Hz), 7.90-7.94 (5H, m), 8.36 (1H, dd, J
= 2.7, 8.8 Hz), 8.51 (1H, d, J = 2.7 Hz), 10.89 (1H,
s); MS (FAB) m / z: 378 (M + H) + . (Example 286) N- [4- (phenylmethyl) phenyi
]-(2-Chloro-5-nitrophenyl) carboxa
Mido 4- (phenylmethyl) aniline (0.183 g, 1.
00 mmol), 2-chloro-5-nitrobenzoic acid chloride
Lido (0.330 g, 1.50 mmol) and DMA
(2 mL) using the method described in Example 1.
The target compound (0.225 g, yield 61%) was obtained.
It was 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 3.93 (2H, s), 7.
18-7.31 (7H, m), 7.62 (2H, d, J = 8.8 Hz), 7.88 (1H,
d, J = 8.8 Hz), 8.33 (1H, dd, J = 2.9, 8.8 Hz), 8.43 (1
H, d, J = 2.9 Hz), 10.65 (1H, bs); MS (FAB) m / z: 367 (M + H) + . (Example 287) N- [4-[[4-[(tert-
Toxycarbonyl) amino] phenyl] methyl] phenyl
]-(2-Chloro-5-nitrophenyl) carboxa
Mid 4-[[4-[(tert-butoxycarbonyl) ami
No] phenyl] methyl] aniline (2.98 g, 10.
0 mmol), 2-chloro-5-nitrobenzoic acid chloride
De (2.64 g, 12.0 mmol) and DMA (30
mL) according to the method described in Example 1.
The target compound (4.60 g, yield 95%) was obtained. 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 1.51 (9H, s), 3.93
(2H, s), 6.43 (1H, bs), 7.10 (2H, d, J = 8.0 Hz),
7.20 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.
53 (2H, d, J = 8.0 Hz), 7.64 (1H, d, J = 8.8 Hz), 7.82
(1H, bs), 8.25 (1H, dd, J = 2.9, 8.8 Hz), 8.59 (1H,
d, J = 2.9 Hz); MS (FAB) m / z: 481 M + . (Example 288) N- [4-[(4-aminophenyl)
Methyl] phenyl]-(2-chloro-5-nitrophenyl
L) carboxamide N- [4-[[4-[(ter
t-butoxycarbonyl) amino] phenyl] methyl]
Phenyl]-(2-chloro-5-nitrophenyl) calc
Voxamide (3.51 g, 7.28 mmol) in 1,4
-Suspended in dioxane (50 mL), 4N hydrogen chloride-
Add 1,4-dioxane solution (25 mL) at room temperature
Stir for 3 days. Dilute the reaction solution with diethyl ether.
The resulting solid was collected by filtration, dried under reduced pressure, and combined with the title compound.
The product (2.78 g, yield 91%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 3.95 (2H, s), 7.
23 (2H, m), 7.28 (2H, m), 7.33 (2H, m), 7.63 (2H, m
m), 7.88 (1H, d, J = 8.8 Hz), 8.33 (1H, dd, J = 2.9,
8.8 Hz), 8.42 (1H, d, J = 2.9 Hz), 10.70 (1H, bs); MS (ESI) m / z: 382 ((M-HCl) + H) + . (Example 289) N- [4- [2-[[(3-methoxy
Phenylamino) carbonyl] amino] ethyl] pheny
]-(2-Chloro-5-nitrophenyl) carboxa
The N- [4- (2-aminoethyl) prepared in Example 267
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (0.319 g, 1.00 mmol)
Dissolve in THF (5 mL) and add 3-methoxyphenyl
Socyanate (0.157 mL, 1.20 mmol)
In addition, the mixture was stirred at room temperature for 22 hours. Methanol in the reaction solution
After adding and stirring, the mixture was concentrated under reduced pressure. The resulting solid is
Wash with isopropyl ether and dry under reduced pressure.
Compound (0.458 g, 98%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.73 (2H, t, J =
7.0 Hz), 3.70 (3H, s), 3.68-3.72 (2H, m), 6.46 (1H,
m), 6.84 (1H, d, J = 8.0 Hz), 7.20-7.07 (2H, m), 7.2
5 (2H, d, J = 8.4 Hz), 7.64 (2H, d, J = 8.4 Hz), 7.89
(1H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 2.2, 8.8 Hz),
8.44 (1H, d, J = 2.2 Hz), 8.51 (1H, bs), 10.66 (1H, b
s); MS (FAB) m / z: 469 (M + H) + . (Example 290) N- (4-phenoxyphenyl)-
(2-Chloro-5-nitrophenyl) carboxamide 4-phenoxyaniline (0.185 g, 1.00 mm
ol), 2-chloro-5-nitrobenzoic acid chloride
(0.330 g, 1.50 mmol) and DMA (2 m
L) according to the method described in Example 1
The target compound (0.249 g, yield 68%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.00 (2H, d, J =
8.0 Hz), 7.07 (2H, d, J = 8.8 Hz), 7.13 (1H, m), 7.3
9 (2H, t, J = 8.0 Hz), 7.73 (2H, d, J = 8.8 Hz), 7.90
(1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 2.9, 8.8 Hz),
8.47 (1H, d, J = 2.9Hz), 10.74 (1H, bs); MS (FAB) m / z: 369 (M + H) + . (Example 291) N- [3- [4-[(tert-but
Xycarbonyl) amino] phenyl] phenyl]-(2
-Chloro-5-nitrophenyl) carboxamide 3-
[4-[(tert-butoxycarbonyl) amino] fu
Phenyl] phenylamine (1.44g, 5.06mmo
l), 2-chloro-5-nitrobenzoic acid chloride (1.
23 g, 5.59 mmol) and DMA (5 mL).
According to the method described in Example 1,
The product (2.07 g, yield 87%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.49 (9H, s), 7.
37-7.46 (4H, ABq J = 9.0, 12.9 Hz), 7.66 (1H, dd, J =
1.7, 7.6 Hz), 7.91 (1H, d, J = 8.8 Hz), 7.95 (1H, t,
J = 1.7 Hz), 8.35 (1H, dd, J = 2.7, 8.8 Hz), 8.49 (1
H, d, J = 2.7 Hz), 9.47 (1H, s), 10.78 (1H, s); MS (FAB) m / z: 467 (M + H) + . (Example 292) N- [3- (4-aminophenyl) phenyl
]-(2-Chloro-5-nitrophenyl) carbo
N-amide prepared in Example 291. N- [3- [4-[(tert
-Butoxycarbonyl) amino] phenyl] phenyl]
-(2-chloro-5-nitrophenyl) carboxamide
(1.67 g, 3.58 mmol) was added to methylene chloride (2
0 mL), p-anisole (1 drop) and tri-
Add fluoroacetic acid (2 mL) and stir at room temperature for 17 hours
did. Saturated aqueous sodium hydrogen carbonate (20 mL) and water (20 m) were added to the reaction solution.
L) and diisopropyl ether (10 mL) were added,
Stir for 2 hours. The crystals formed are filtered off and washed with water and diisoprene.
Wash with ropyl ether, dry under reduced pressure, and then
The product (1.31 g, yield 99%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 5.26 (2H, s), 6.
65 (2H, d, J = 8.5 Hz), 7.30-7.39 (4H, m), 7.55 (1H,
d, J = 8.0 Hz), 7.89 (1H, s), 7.90 (1H, d, J = 8.7 H
z), 8.35 (1H, dd, J = 2.7, 8.7 Hz), 8.48 (1H, d, J =
2.7 Hz), 10.70 (1H, s); MS (FAB) m / z: 367 M + . (Example 293) N-[(5-methoxy-2-phenyl
Lu) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide (5-methoxy-2-phenyl) phenylamine 1 salt
Acid salt (0.28 g, 1.19 mmol), 2-chloro-
5-Nitrobenzoic acid chloride (0.39 g, 1.79 m)
mol) and pyridine (5 mL), Example 1
According to the method described in 1., the title compound (0.28 g,
Yield 62%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 3.84 (3H, s), 7.
00 (1H, dd, J = 2.6, 8.5Hz), 7.23 (1H, d, J = 2.6 Hz),
7.32 (1H, d, J = 8.5 Hz), 7.34-7.44 (5H, m), 7.81 (1
H, d, J = 8.8 Hz), 8.24 (1H, d, J = 2.7 Hz), 8.28 (1H,
dd, J = 2.7, 8.8 Hz), 10.19 (1H, s). (Example 294) N- [4- (4-methylphenoxy)
Phenyl]-(2-chloro-5-nitrophenyl) calc
Voxamide 4- (4-methylphenoxy) aniline (0.199
g, 1.00 mmol), 2-chloro-5-nitrobenzoate
Perfume chloride (0.330 g, 1.50 mmol) and
The method described in Example 1 using DMA (2 mL)
According to the above, the title object compound (0.235 g, yield 61%)
Got 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.29 (3H, s), 6.
91 (2H, d, J = 8.4 Hz), 7.02 (2H, d, J = 8.4 Hz), 7.19
(2H, d, J = 8.4 Hz), 7.70 (2H, d, J = 8.4 Hz), 7.90 (1
H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 2.9, 8.8 Hz), 8.4
6 (1H, d, J = 2.9Hz), 10.71 (1H, bs); MS (FAB) m / z: 383 (M + H) + . (Example 295) N- [4- (4-chlorophenoxy)
Phenyl]-(2-chloro-5-nitrophenyl) calc
Voxamide 4- (4-chlorophenoxy) aniline (0.219
g, 1.00 mmol), 2-chloro-5-nitrobenzoate
Perfume chloride (0.330 g, 1.50 mmol) and
The method described in Example 1 using DMA (2 mL)
According to the above, the title compound (0.274 g, yield 68%)
Got 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 7.02 (2H, d, J =
8.8 Hz), 7.10 (2H, d, J = 8.8 Hz), 7.43 (2H, d, J = 8.
8 Hz), 7.74 (2H, d, J = 8.8 Hz), 7.90 (1H, d, J = 8.8
Hz), 8.35 (1H, dd, J = 2.9, 8.8 Hz), 8.47 (1H, d, J =
2.9 Hz), 10.76 (1H, bs); MS (FAB) m / z: 403 (M + H) + . (Example 296) N- [4- [2- (1,3-dioxo
Isoindol-2-yl) ethoxy] phenyl]-
(2-Chloro-5-nitrophenyl) carboxamide (296a) 2- [2- (4-nitrophenoxy) ethyl
] Isoindole-1,3-dione sodium p-nitrophenoxide dihydrate (0.
986 g, 5.0 mmol) in DMF (30 mL)
And N- (2-bromoethyl) phthalimide (1.
91 g, 7.5 mmol) was added and the mixture was stirred at 70 ° C. for 18 hours.
I stirred. The reaction solution was allowed to cool to room temperature and then with ethyl acetate.
It was diluted and the insoluble material was filtered off. The filtrate is concentrated under reduced pressure to obtain
The residue obtained is subjected to silica gel column chromatography (
Xane: ethyl acetate = 1: 1 (v / v))
The target compound (0.650 g, yield 42%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 4.04 (2H, t, J = 5.8
Hz), 4.23 (2H, t, J = 5.8 Hz), 6.84 (2H, d, J = 8.8 H
z), 7.64 (2H, m), 7.77 (2H, m), 8.07 (2H, d, J = 8.8 H
z). (296b) 2- [2- (4-aminophenoxy) ethyl
L] isoindole-1,3-dione 2- [2- (4-nitrophe) prepared in Example 296a
(Noxy) ethyl] isoindole-1,3-dione
(0.650 g, 2.08 mmol) and 10% parasiodium
Mu-carbon (0.130 g) was added to ethanol-THF (1:
1 (v / v), 13 mL), and 3 at room temperature under hydrogen atmosphere.
Stir for hours. Filter off the catalyst from the reaction solution and reduce the filtrate.
It was concentrated under pressure. The residue obtained is chromatographed on a silica gel column.
Tography (hexane: ethyl acetate = 1: 1 (v / v))
The title compound (0.447 g, yield 76
%) Was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 3.42 (2H, bs), 4.0
9 (2H, t, J = 5.9 Hz), 4.15 (2H, t, J = 5.9 Hz), 6.59
(2H, d, J = 8.8 Hz), 6.70 (2H, d, J = 8.8 Hz), 7.71 (2
H, m), 7.86 (2H, m). (296c) N- [4- [2- (1,3-dioxoiso
Indole-2-yl) ethoxy] phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide 2- [2- (4-aminophene) prepared in Example 296b.
(Noxy) ethyl] isoindole-1,3-dione
(0.425 g, 1.51 mmol), 2-chloro-5
-Nitrobenzoic acid chloride (0.397 g, 1.81 m)
mol) and DMA (4 mL) in Example 1
According to the method described, the title compound (0.627 g,
Yield 89%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 3.97 (2H, t, J =
5.9 Hz), 4.21 (2H, t, J = 5.9 Hz), 6.91 (2H, d, J = 8.
8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.88 (5H, m), 8.32
(1H, dd, J = 2.7, 8.8 Hz), 8.43 (1H, d, J = 2.9 Hz), 1
0.55 (1H, bs); MS (FAB) m / z: 466 (M + H) + . (Example 297) N- [4- (2-aminoethoxy) phenyl]
]-(2-Chloro-5-nitrophenyl) carbo
N- [4- [2- (1,3-) prepared in Xamide Example 296c.
Dioxoisoindol-2-yl) ethoxy] phenyl
]-(2-Chloro-5-nitrophenyl) carboxa
Add amide (0.102g, 0.219mmol) to ethanol.
Hydrazine monohydrate (0.
053 mL, 1.09 mmol) at room temperature at 5 o'clock
It was stirred for a while. 1N sodium hydroxide aqueous solution to the reaction solution
Add basic water by dropping, add water and extract with ethyl acetate.
It was The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure.
did. The resulting residue is silica gel column chromatograph
(Methanol: methylene chloride = 1: 1 (v / v))
Purify and title compound (0.034 g, yield 46%)
Got 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 3.08 (2H, t, J = 5.1
Hz), 3.98 (2H, t, J = 5.1 Hz), 6.90 (2H, d, J = 8.8 H
z), 7.52 (2H, d, J = 8.8 Hz), 7.63 (1H, d, J = 8.8 H
z), 8.15 (1H, bs), 8.23 (1H, dd, J = 2.8, 8.8 Hz),
8.55 (1H, d, J = 2.8 Hz); MS (FAB) m / z: 336 (M + H) + . (Example 298) N- [4- [2- (tert-butoki)
Cycarbonylamino) ethoxy] phenyl]-(2-q
Lolo-5-nitrophenyl) carboxamide N- (4-hydroxyphenyl) prepared in Example 193
)-(2-Chloro-5-nitrophenyl) carboxa
Mido (0.293 g, 1.0 mmol) and N- (2-
Hydroxyethyl) carbamic acid tert-butyl ester
Stell (0.501 mL, 2.0 mmol) in toluene
Dissolve in (1 mL) and cool with triphenylphosphine under ice-cooling.
(0.525 g, 2.0 mmol) and diethylazo
Dicarboxylate (DEAD) -40% toluene solution
(0.788 mL, 2.0 mmol) at room temperature
Stir for 20 hours. The reaction solution is concentrated under reduced pressure and the residue is filtered.
Rica gel column chromatography (chloroform: me
Tanol = 2: 1 (v / v)) and the title compound
(0.084 g, yield 19%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.45 (9H, s), 3.54
(2H, m), 4.02 (2H, t, J = 5.1 Hz), 5.01 (1H, bs), 6.
91 (2H, d, J = 9.0 Hz), 7.54 (2H, d, J = 9.0 Hz), 7.64
(1H, d, J = 8.8 Hz), 7.91 (1H, bs), 8.25 (1H, dd, J
= 2.2, 8.8 Hz), 8.58 (1H, d, J = 2.2 Hz); MS (FAB) m / z: 435 M + . (Example 299) N- [4- [2- (dimethylamino)
Ethoxy] phenyl]-(2-chloro-5-nitrophe
Nyl) carboxamide (299a) 4- [2- (dimethylamino) ethoxy]
Nitrobenzene 4-nitrophenol (1.39g, 10.0mmo
l) is dissolved in DMA (25 mL) and N, N-dimethyl
Luaminopropyl chloride monohydrochloride (1.85 g, 1
1.0 mmol) and potassium carbonate (4.15 g, 3
0.0 mmol) was added and the mixture was stirred at 60 ° C. for 2 days.
After allowing the reaction solution to cool to room temperature, potassium carbonate was filtered off.
It was The filtrate was diluted with ethyl acetate (80 mL) and washed with water (5
It was washed with 0 mL × 4) and saturated aqueous sodium hydrogen carbonate. Anhydrous organic layer
Dry over sodium sulfate, concentrate under reduced pressure, and dry under reduced pressure.
To give the title object compound (1.05 g, yield 50%)
It was 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 2.35 (6H, s), 2.77
(2H, t, J = 5.9 Hz), 4.16 (2H, t, J = 5.9 Hz), 6.98
(2H, d, J = 8.8 Hz), 8.20 (2H, d, J = 8.8 Hz). (299b) 4- [2- (dimethylamino) ethoxy]
Aniline 4- [2- (dimethylamido) prepared in Example 299a
No) ethoxy] nitrobenzene (0.650 g, 2.0
8 mmol), 5% palladium-carbon (0.191 g)
296 using ethanol and ethanol (10 mL).
According to the method described in b., the title compound (0.721
g, yield 88%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 2.32 (6H, s), 2.69
(2H, t, J = 5.9 Hz), 3.28 (2H, bs), 3.99 (2H, t, J =
5.9 Hz), 6.40 (2H, d, J = 8.8 Hz), 6.76 (2H, d, J = 8.
8 Hz). (299c) N- [4- [2- (dimethylamino) eth]
Xy] phenyl]-(2-chloro-5-nitrophenyl
4-) 2- (dimethylamido) prepared in Example 299b.
No) ethoxy] aniline (0.716 g, 3.97 mm)
ol), 2-chloro-5-nitrobenzoic acid chloride
(1.05 g, 4.77 mmol) and DMA (10 m
L) according to the method described in Example 1
The target compound (0.883 g, yield 61%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 2.34 (6H, s), 2.74
(2H, t, J = 5.9 Hz), 4.08 (2H, t, J = 5.9 Hz), 6.95
(2H, d, J = 8.8 Hz), 7.53 (2H, d, J = 8.8 Hz), 7.65 (1
H, d, J = 8.8 Hz), 7.79 (1H, bs), 8.25 (1H, dd, J = 2.
9, 8.8 Hz), 8.60 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 364 (M + H) + . (Example 300) N- [4- [2- (diethylamino)
Ethoxy] phenyl]-(2-chloro-5-nitrophe
Nil) carboxamide prepared according to a method similar to Examples 299a and 299b.
4- [2- (diethylamino) ethoxy] aniline
(1.48 g, 7.11 mmol), 2-chloro-5-
Nitrobenzoyl chloride (1.88g, 8.53mmo
1) and DMA (20 mL) were used and described in Example 1.
According to the method described, the title object compound (1.71 g, yield
61%). 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.08 (6H, t, J = 7.3
Hz), 2.65 (4H, q, J = 7.3 Hz), 2.88 (2H, t, J = 6.2 H
z), 4.06 (2H, t, J = 6.2 Hz), 6.92 (2H, d, J = 9.0 H
z), 7.53 (2H, d, J = 9.0 Hz), 7.64 (1H, d, J = 8.8 H
z), 7.80 (1H, bs), 8.24 (1H, dd, J = 2.9, 8.8 Hz),
8.59 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 392 (M + H) + . (Example 301) N- [4- [3- (1,3-dioxo
Isoindol-2-yl) propoxy] phenyl]-
(2-chloro-5-nitrophenyl) carboxamide Prepared according to a method similar to that of Example 296a and 299b.
2- [3- (4-aminophenoxy) propyl] iso
Indole-1,3-dione (0.90g, 3.04m
mol), 2-chloro-5-nitrobenzoic acid chloride
(0.80 g, 3.64 mmol) and DMA (8 m
L) according to the method described in Example 1
The target compound (1.14 g, yield 78%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 2.20 (2H, tt, J = 6.
6, 6.6 Hz), 3.92 (2H, t, J = 6.6 Hz), 4.04 (2H, t, J =
6.6 Hz), 6.83 (2H, d, J = 9.2 Hz), 7.50 (2H, d, J = 9.2
Hz), 7.65 (1H, d, J = 8.8 Hz), 7.73 (2H, m), 7.84
(2H, m), 8.25 (1H, dd, J = 2.9, 8.8 Hz), 8.60 (1H,
d, J = 2.9 Hz); MS (FAB) m / z: 480 (M + H) + . Example 302 N- [4- (3-aminopropoxy)
Phenyl]-(2-chloro-5-nitrophenyl) calc
Voxamide N- [4- [2- (1,3-di) prepared in Example 301
Oxoisoindol-2-yl) propoxy] pheny
]-(2-Chloro-5-nitrophenyl) carboxa
Mido (0.480 g, 1.00 mmol), hydrazine
-Monohydrate (0.146 mL, 3.00 mmol) and
Using ethanol (10 mL), describe in Example 297.
According to the method described, the title compound (0.077 g, yield
22%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.81 (2H, tt, J =
6.6 Hz), 2.72 (2H, m), 4.02 (2H, t, J = 6.6 Hz), 6.95
(2H, d, J = 8.8 Hz), 7.61 (2H, d, J = 8.8 Hz), 7.88 (1
H, d, J = 8.8 Hz), 8.33 (1H, dd, J = 2.9, 8.8 Hz), 8.4
3 (1H, d, J = 2.9 Hz), 10.56 (1H, bs); MS (FAB) m / z: 350 (M + H) + . (Example 303) N- [4- [3- (dimethylamino)
Propoxy] phenyl]-(2-chloro-5-nitrof
Phenyl) carboxamide prepared according to a method similar to that of Examples 299a and 299b.
4- [2- (dimethylamino) propoxy] aniline
(1.14 g, 5.87 mmol), 2-chloro-5-
Nitrobenzoyl chloride (1.55g, 7.04mmo
1) and DMA (15 mL), using the procedure described in Example 1.
According to the method described, the target compound (1.27 g, yield
57%). 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.96 (2H, tt, J = 6.
6, 6.6 Hz), 2.26 (6H, s), 2.46 (2H, t, J = 6.6 Hz),
4.03 (2H, t, J = 6.6 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.
52 (2H, d, J = 8.8 Hz), 7.65 (1H, d, J = 8.8 Hz), 7.79
(1H, bs), 8.25 (1H, dd, J = 2.9, 8.8 Hz), 8.60 (1H,
d, J = 2.9 Hz); MS (FAB) m / z: 378 (M + H) + . (Example 304) N- [4- [4- (1,3-dioxo
Isoindol-2-yl) butoxy] phenyl]-
(2-chloro-5-nitrophenyl) carboxamide Prepared according to a method similar to that of Example 296a and 296b.
2- [4- (aminophenoxy) butyl] isoindo
1,3-dione (0.99 g, 3.19 mmo)
l), 2-chloro-5-nitrobenzoic acid chloride (0.
84 g, 3.83 mmol) and DMA (8 mL).
According to the method described in Example 1,
The product (1.40 g, yield 89%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.87 (4H, m), 3.78
(2H, t, J = 6.6 Hz), 4.01 (2H, t, J = 6.6 Hz), 6.91
(2H, d, J = 8.8 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.65 (1
H, d, J = 8.8 Hz), 7.72 (2H, m), 7.85 (2H, m), 8.25
(1H, dd, J = 2.9, 8.8 Hz), 8.60 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 494 (M + H) + . (Example 305) N- [4- (4-aminobutoxy) phenyl]
]-(2-Chloro-5-nitrophenyl) carbo
N- [4- [2- (1,3-di) prepared in Xamide Example 304.
Oxoisoindol-2-yl) butoxy] pheny
]-(2-Chloro-5-nitrophenyl) carboxa
Mido (0.494 g, 1.00 mmol), hydrazine
-Monohydrate (0.146 mL, 3.00 mmol) and
Using ethanol (10 mL), describe in Example 297.
According to the method described, the title compound (0.061 g, yield
Rate 17%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.49 (2H, m), 1.
73 (2H, m), 2.60 (2H, t, J = 7.0 Hz), 3.95 (2H, t, J =
6.6 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.60 (2H, d, J = 8.8
Hz), 7.88 (1H, d, J = 8.8 Hz), 8.33 (1H, dd, J = 2.9,
8.8 Hz), 8.43 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 364 (M + H) + . (Example 306) N- [4- [2- (1,3-dioxo
Isoindol-2-yl) ethylthio] phenyl]-
(2-Chloro-5-nitrophenyl) carboxamide (306a) 2- [4- (4-nitrophenyl) thioe
Cyl] -1H-isoindole-1,3-dione 4-nitrothiophenol (22.3 g, 144 mmo
l) was dissolved in DMF (440 mL) and cooled under ice-cooling to 55
% Sodium hydride (6.90 g, 158 mmol)
In addition, the mixture was stirred for 30 minutes. N- (2-bromoe
Chill) phthalimide (40.2 g, 158 mmol)
DMF solution (440 mL) was added dropwise, and the mixture was stirred at 0 ° C for 3 hours.
did. The reaction solution was poured into ice-saturated sodium hydrogen carbonate solution to generate.
The solid was filtered off. The solid obtained is treated with water and diisopropyl.
Wash with ether and dry under reduced pressure to give the title compound (4
1.0 g, yield 87%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 3.35 (2H, t, J = 7.3
Hz), 4.00 (2H, t, J = 7.3 Hz), 7.47 (2H, d, J = 8.8 H
z), 7.73 (2H, m), 7.84 (2H, m), 8.10 (2H, d, J = 8.8
Hz). (306b) 2- [4- (4-aminophenyl) thioe
Cyl] isoindole-1,3-dione 2- [4- (4-nitrophene) prepared in Example 306a
Nyl) thioethyl] -1H-isoindole-1,3-
Dione (6.57 g, 20.0 mmol) and nitric chloride
Kell (II) hexahydrate (9.51 g, 40.0 mmo
l) was suspended in THF (200 mL), and hydrogen was added under ice cooling.
Sodium borohydride (3.03g, 80.0mmol)
Was added over 2 hours. Concentrate the reaction solution and saturate the residue
Aqueous sodium bicarbonate was added and the mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate.
I put it out. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
Dried under vacuum, concentrated under reduced pressure, dried under reduced pressure, and
A compound (3.56 g, yield 60%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 3.09 (2H, t, J = 7.0
Hz), 3.68 (2H, bs), 3.87 (2H, t, J = 7.0 Hz), 6.59
(2H, d, J = 8.8 Hz), 7.31 (2H, d, J = 8.8 Hz), 7.70 (2
H, m), 7.82 (2H, m). (306c) N- [4- [2- (1,3-dioxoiso
Indole-2-yl) ethylthio] phenyl]-(2
-Chloro-5-nitrophenyl) carboxamide Example
2- [2- (4-aminophenyl) prepared in 306b
Thioethyl] isoindole-1,3-dione (0.4
70 g, 1.58 mmol), 2-chloro-5-nitro
Benzoic acid chloride (0.416 g, 1.89 mmol)
And DMA (5 mL) as described in Example 1.
According to the method, the title object compound (0.669 g, yield 88
%) Was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 3.24 (2H, t, J =
7.0 Hz), 3.79 (2H, t, J = 7.0 Hz), 7.39 (2H, d, J = 8.
8 Hz), 7.61 (2H, d, J = 8.8 Hz), 7.84 (4H, m), 7.90
(1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 2.9, 8.8 Hz),
8.45 (1H, d, J = 2.9Hz), 10.70 (1H, bs); MS (FAB) m / z: 482 (M + H) + . (Example 307) N- [4- [2- (tert-butoki)
Cycarbonylamino) ethylthio] phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide 4- [2- (tert-butoxycarbonylamino) e
Chill] thiophenylamine (0.451g, 1.68m
mol), 2-chloro-5-nitrobenzoic acid chloride
(0.444 g, 2.02 mmol) and DMA (5 m
L) according to the method described in Example 1
The target compound (0.624 g, yield 76%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.44 (9H, s), 3.03
(2H, m), 3.33 (2H, m), 4.90 (1H, bs), 7.43 (2H, m
d, J = 8.4 Hz), 7.60 (2H, d, J = 8.4 Hz), 7.67 (1H, d,
J = 8.8 Hz), 7.88 (1H, bs), 8.27 (1H, dd, J = 2.9, 8.
8 Hz), 8.61 (1H, d, J = 2.9 Hz); MS (FAB) m / z: 451 M + . (Example 308) N-[[4- (2-aminoethyl) thio
O] phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide monohydrochloride N- [4- [2- (tert-
Butoxycarbonylamino) ethylthio] phenyl]-
(2-chloro-5-nitrophenyl) carboxamide
(0.502 g, 1.11 mmol) was added to 1,4-diox
Suspended in sun (3 mL), 4N hydrogen chloride-1,4-di
Add oxane solution (3 mL) and stir at room temperature for 3 days.
It was The reaction solution was diluted with diethyl ether and the resulting solid
The body was collected by filtration and dried under reduced pressure to give the title object compound (0.40
0 g, yield 93%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.93 (2H, m), 3.
19 (2H, t, J = 7.3 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.73
(2H, d, J = 8.8 Hz), 7.90 (1H, d, J = 8.8 Hz), 8.18 (2
H, bs), 8.35 (1H, dd, J = 2.9, 8.8 Hz), 8.47 (1H, d,
J = 2.9 Hz), 10.88 (1H, bs); MS (FAB) m / z: 352 (M + H) + . (Example 309) N- [4- [3- (1,3-dioxo
Isoindol-2-yl) propylthio] phenyl]
-(2-Chloro-5-nitrophenyl) carboxamide Prepared according to a method similar to Examples 306a and 306b.
2- [3- (4-aminophenyl) thiopropyl] i
Soindole-1,3-dione (0.475g, 1.5
2 mmol), 2-chloro-5-nitrobenzoic acid chloride
(0.401 g, 1.82 mmol) and DMA (5
mL) according to the method described in Example 1.
The target compound (0.620 g, yield 82%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 2.00 (2H, tt, J = 7.
3 Hz), 2.94 (2H, t, J = 7.3 Hz), 3.83 (2H, t, J = 7.3
Hz), 7.41 (2H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.8 H
z), 7.65 (1H, d, J = 8.8 Hz), 7.72 (2H, m), 7.85 (2
H, m), 8.26 (1H, dd, J = 2.9, 8.8 Hz), 8.60 (1H, d,
J = 2.9 Hz); MS (FAB) m / z: 496 (M + H) + . (Example 310) N-[[4- (3-aminopropyl)
Thio] phenyl]-(2-chloro-5-nitrophenyl
L) carboxamide N- [4- [3- (1,3-di) prepared in Example 309
Oxoisoindol-2-yl) propylthio] fe
Nyl]-(2-chloro-5-nitrophenyl) carboxy
Samide (0.496 g, 1.00 mmol) in ethanol
Suspension (5 mL) and n-butylamine (0.40
(mL, 4.00 mmol) and stirred at room temperature for 2 days
did. The reaction solution was concentrated under reduced pressure and the residue was washed with silica gel.
Chromatography (chloroform: methanol =
3: 1 (v / v)) to give the title compound (0.03
3 g, yield 9%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.82 (2H, tt, J =
7.3 Hz), 2.87 (2H, t, J = 7.3 Hz), 3.02 (2H, t, J = 7.3
Hz), 7.40 (2H, d, J = 8.8 Hz), 7.69 (2H, d, J = 8.8 H
z), 7.70 (2H, bs), 7.90 (1H, d, J = 8.8 Hz), 8.35 (1
H, dd, J = 2.9, 8.8 Hz), 8.46 (1H, d, J = 2.9 Hz), 10.
82 (1H, bs); MS (FAB) m / z: 366 (M + H) + . (Example 311) N- [4- [4- (1,3-dioxo
Isoindol-2-yl) butylthio] phenyl]-
(2-Chloro-5-nitrophenyl) carboxamide Prepared according to a method similar to Examples 306a and 306b.
2- [4- (4-aminophenyl) thiobutyl] iso
Indole-1,3-dione (2.57g, 7.87m)
mol), 2-chloro-5-nitrobenzoic acid chloride
(2.08 g, 9.45 mmol) and DMA (26 m
L) according to the method described in Example 1
The target compound (3.46 g, yield 86%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.68 (2H, tt, J = 7.
3, 7.3 Hz), 1.84 (2H, tt, J = 7.3, 7.3 Hz), 2.96 (2H,
t, J = 7.3 Hz), 3.70 (2H, t, J = 7.3 Hz), 7.36 (2H, d,
J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz), 7.66 (1H, d, J
= 8.8 Hz), 7.72 (2H, m), 7.84 (3H, m), 8.27 (1H, dd,
J = 2.9, 8.8 Hz), 8.60 (1H, d, J = 2.9Hz); MS (FAB) m / z: 510 (M + H) + . (Example 312) N- [4-[(4-aminobutyl) thio]
O] phenyl]-(2-chloro-5-nitrophenyl)
N- [4- [4- (1,3-dicarboxamide prepared in Example 311
Oxoisoindol-2-yl) butylthio] phenyl
]-(2-Chloro-5-nitrophenyl) carboxa
Mido (1.00 g, 1.96 mmol), hydrazine
Monohydrate (0.476 mL, 9.80 mmol) and
Described in Example 297 using tanol (20 mL)
According to the method described above, the title compound (0.210 g, yield
28%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.45 (2H, tt, J =
7.3, 7.3 Hz), 1.58 (2H, tt, J = 7.3, 7.3 Hz), 2.53
(2H, t, J = 7.3 Hz), 2.93 (2H, t, J = 7.3 Hz), 7.36 (2
H, d, J = 8.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.89 (1H,
d, J = 8.8 Hz), 8.34 (1H, dd, J = 2.9, 8.8 Hz), 8.46
(1H, d, J = 2.9 Hz); MS (FAB) m / z: 380 (M + H) + . (Example 313) N- [4-[[2- (tert-but
Xycarbonylamino) ethyl] sulfonyl] phenyl
]-(2-Chloro-5-nitrophenyl) carboxa
Mido prepared in Example 307 N- [4- [2- (tert-
Butoxycarbonylamino) ethylthio] phenyl]-
(2-chloro-5-nitrophenyl) carboxamide
(0.226 g, 0.500 mmol) was added to acetic acid (1 m
L) and 31% hydrogen peroxide solution (0.2
0 mL) was added. After stirring at 90 ° C for 2 hours, allow to reach room temperature.
I left it to cool. Add diethyl ether (5 mL) to the reaction solution.
Water and water (5 mL) were added, and the resulting solid was collected by filtration, washed with water and diluted with water.
Wash with ethyl ether, dry under reduced pressure, and then
The product (0.096 g, yield 40%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.32 (9H, s) 3.2
0 (2H, m), 3.38 (2H, m), 6.83 (1H, m), 7.89-7.98
(5H, m), 8.37 (1H, dd, J = 2.9, 8.8 Hz), 8.54 (1H,
d, J = 2.9 Hz), 11.18 (1H, bs); MS (FAB) m / z: 484 (M + H) + . (Example 314) N- [4-[(2-aminoethyl) su]
Rufonyl] phenyl]-(2-chloro-5-nitrophe
Nyl) carboxamide monohydrochloride N- [4-[[2- (tert
-Butoxycarbonylamino) ethyl] sulfonyl] f
]-(2-Chloro-5-nitrophenyl) carbo
Xamide (0.060 g, 0.124 mmol), 4N
Hydrogen chloride-1,4-dioxane solution (0.3 mL) and
Example using 1,4-dioxane (0.9 mL)
288 according to the method described in 288.
44 g, yield 84%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 3.04 (2H, m), 3.
63 (2H, t, J = 7.7 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.97
(2H, d, J = 8.8 Hz), 8.01 (2H, d, J = 8.8 Hz), 8.08 (2
H, bs), 8.38 (1H, dd, J = 2.9, 8.8 Hz), 8.54 (1H, d,
J = 2.9 Hz), 11.29 (1H, bs); MS (FAB) m / z: 384 ((M-HCl) + H) + . (Example 315) N- [4-[[4- (1,3-dioki
Soisoindol-2-yl) butyl] sulfonyl] f
]-(2-Chloro-5-nitrophenyl) carbo
N- [4- [4- (1,3-di) prepared in Example 311.
Oxoisoindol-2-yl) butylthio] phenyl
]-(2-Chloro-5-nitrophenyl) carboxa
Mido (0.510 g, 1.00 mmol), acetic acid (2 m
L) and 31% hydrogen peroxide solution (0.39 mL)
According to the method described in Example 313.
The product (0.366 g, 68%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.77 (4H, m), 3.17
(2H, t, J = 7.3 Hz), 3.69 (2H, m), 7.69 (1H, d, J =
8.8 Hz), 7.72 (2H, m), 7.83 (2H, m), 7.86 (2H, d,
J = 9.2 Hz), 7.91 (2H, d, J = 9.2 Hz), 8.27 (1H, bs),
8.30 (1H, dd, J = 2.2, 8.8 Hz), 8.62 (1H, d, J = 2.2 H
z); MS (FAB) m / z: 542 (M + H) + . (Example 316) N- [4-[[2- (tert-but
Xycarbonylamino) ethyl] amino] phenyl]-
(2-chloro-5-nitrophenyl) carboxamide
Monohydrochloride (316a) N- (4-nitrophenyl) ethanediami
4-fluoronitrobenzene (5.00 mL, 47.1
mmol) and ethylenediamine (15.8 mL, 23
5.6 mmol) dissolved in ethanol (50 mL)
And heated to reflux for 4.5 hours. Cool the reaction solution with ice
The crystals were collected by filtration and dried under reduced pressure to give the title object compound (5.
32 g, yield 62%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 3.02 (2H, t, J = 5.9
Hz), 3.26 (2H, dt, J = 5.9, 5.9 Hz), 5.09 (1H, bs),
6.56 (2H, d, J = 8.8 Hz), 8.06 (2H, d, J = 8.8 Hz). (316b) 2- (4-nitroanilino) ethylcarba
Minic acid tert-butyl ester N- (4-nitrophenyl) prepared in Example 316a
Ethanediamine (5.14 g, 28.4 mmol) was added to the
Dissolve in tanol (100 mL) and di-tert-but
Chillidicarbonate (18.6 g, 88.1 mmol)
Was added and the mixture was stirred at room temperature for 24 hours. Reaction solution under reduced pressure
Concentrate and concentrate the residue on silica gel column chromatography
Purify with (hexane: ethyl acetate = 3: 1 (v / v)),
The title object compound (5.43 g, yield 68%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.46 (9H, s), 3.33
(2H, m), 3.43 (2H, m), 4.85 (1H, bs), 5.39 (1H, b
s), 6.52 (2H, d, J = 9.2 Hz), 8.08 (2H, d, J = 9.2 H
z). (316c) 2- (4-aminoanilino) ethylcarba
Minic acid tert-butyl ester 2- (4-nitroanilino) prepared in Example 316b
Ethylcarbamic acid tert-butyl ester (2.0
0 g, 7.11 mmol), 10% palladium-carbon
(0.2 g) and ethanol (40 mL),
According to the method described in Example 296b, the title compound
(1.83 g, yield 100%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.45 (9H, s), 3.19
(2H, m), 3.33 (2H, m), 4.83 (1H, bs), 6.52 (2H, m
d, J = 8.7 Hz), 6.61 (2H, d, J = 8.7 Hz). (316d) N- [4-[[2- (tert-butoxy
Carbonylamino) ethyl] amino] phenyl]-(2
-Chloro-5-nitrophenyl) carboxamide-1 salt
2- (4-Aminoanilino) prepared in Example 316c
Ethylcarbamic acid tert-butyl ester (1.8
3 g, 7.28 mmol) dissolved in DMA (20 mL)
2-chloro-5-nitrobenzoic acid chloride (1.
76 g, 8.01 mmol) and added at room temperature for 24 hours.
It was stirred. Saturated aqueous sodium hydrogen carbonate and water were added to the reaction solution, and acetic acid was added.
Extracted with ethyl. Dry the organic layer over anhydrous sodium sulfate
And concentrated under reduced pressure. The residue obtained is a silica gel column.
Chromatography (hexane: ethyl acetate = 1: 1 (v
/ v)) and the crude N- [4-[[2- (ter
t-butoxycarbonylamino) ethyl] amino] phen
Nyl]-(2-chloro-5-nitrophenyl) carboxy
Samide (1.13 g) was obtained.
【0273】得られた粗製の化合物を1,4−ジオキサ
ン(10mL)に溶解し、氷冷下、4N塩化水素−1,
4−ジオキサン溶液(1mL)を加えた。反応溶液にジ
エチルエーテル(20mL)を加え、生じた白色固体を
濾取し、減圧乾燥して、標記目的化合物(0.491
g、収率15%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.40 (9H, s), 3.
19 (4H, m), 6.90 (2H,d, J=8.8 Hz), 7.06 (2H, m),
7.63 (2H, m), 7.89 (1H, d, J=8.8 Hz), 8.33 (1H, d
d, J=2.9, 8.8 Hz), 8.43 (1H, d, J=2.9 Hz), 10.66
(1H, bs);
MS(FAB) m/z: 435 ((M-HCl) + H)+。
(実施例317)N−[4−[(2−アミノエチル)ア
ミノ]フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド・2塩酸塩
実施例316で製造したN−[4−[[2−(tert
−ブトキシカルボニルアミノ)エチル]アミノ]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド・1塩酸塩(0.300g、0.636mmo
l)、4N塩化水素−1,4−ジオキサン溶液(3m
L)及び1,4−ジオキサン(3mL)を使用して、実
施例288に記載した方法に従い、標記目的化合物
(0.221g、収率85%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.05 (2H, m), 3.
37 (2H, m), 6.88 (2H,d, J=8.8 Hz), 7.56 (2H, d, J=
8.8 Hz), 7.88 (1H, d, J=8.8 Hz), 8.19 (2H,bs), 8.3
2 (1H, dd, J=2.9, 8.8 Hz), 8.41 (1H, d, J=2.9 Hz),
10.56 (1H, bs);
MS(FAB) m/z: 335 ((M-2HCl) + H)+。
(実施例318)N−[4−[[(2−ジメチルアミ
ノ)エチル](メチル)アミノ]フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド
(318a)4−[[(2−ジメチルアミノ)エチル]
(メチル)アミノ]ニトロベンゼン
4−フルオロニトロベンゼン(1.00mL、9.43
mmol)及びN,N,N’−トリメチルエチレンジア
ミン(2.89g、28.3mmol)をエタノール
(20mL)に溶解させ、9時間加熱還流した。反応溶
液を室温まで放冷した後、減圧下濃縮した。得られた残
渣をシリカゲルカラムクロマトグラフィー(ヘキサン:
酢酸エチル=1:1(v/v))にて精製し、標記目的化合
物(2.04g、収率97%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 2.30 (6H, s), 2.50
(2H, t, J=7.0 Hz), 3.10 (3H, s), 3.56 (2H, t, J=
7.0 Hz), 6.11 (2H, d, J=8.8 Hz), 8.11 (2H, d,J=8.8
Hz)。
(318b)4−[[2−(ジメチルアミノ)エチル]
(メチル)アミノ]アニリン
実施例318aで製造した4−[[(2−ジメチルアミ
ノ)エチル](メチル)アミノ]ニトロベンゼン(2.
04g、9.14mmol)、10%パラジウム−炭素
(0.20g)及びエタノール(40mL)を使用し
て、実施例296bに記載した方法に従い、標記目的化
合物(1.73g、収率98%)を得た。 1
H-NMR (400MHz, CDCl3): δ(ppm) 2.27 (6H, s), 2.44
(2H, t, J=7.0 Hz), 2.84 (3H, s), 3.31 (2H, t, J=
7.0 Hz), 6.66 (4H, s)。
(318c)N−[4−[[(2−ジメチルアミノ)エ
チル](メチル)アミノ]フェニル]−(2−クロロ−
5−ニトロフェニル)カルボキサミド
実施例318bで製造した4−[[2−(ジメチルアミ
ノ)エチル](メチル)アミノ]アニリン(1.72
g、8.90mmol)をDMA(17mL)に溶解さ
せ、2−クロロ−5−ニトロ安息香酸クロリド(2.3
5g、10.7mmol)を加えて、室温で24時間攪
拌した。反応溶液に飽和重曹水及び水を加えて、酢酸エ
チルで抽出した。有機層を無水硫酸ナトリウムで乾燥
し、減圧下濃縮し、減圧乾燥して、標記目的化合物
(3.12g、収率92%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.18 (6H, s), 2.
36 (2H, t, J=7.0 Hz),2.89 (3H, s), 3.40 (2H, t, J=
7.0 Hz), 6.69 (2H, d, J=8.8 Hz), 7.49 (2H,d, J=8.8
Hz), 7.87 (1H, d, J=8.8 Hz), 8.31 (1H, dd, J=2.9,
8.8 Hz), 8.39(1H, d, J=2.9 Hz), 10.36 (1H, bs);
MS(FAB) m/z: 377 (M + H)+。
(実施例319)N−[4−[[3−(tert−ブト
キシカルボニルアミノ)プロピル]アミノ]フェニル]
−(2−クロロ−5−ニトロフェニル)カルボキサミド
・1塩酸塩
実施例316a、316b及び316cと同様の方法に
従い製造した4−[[3−(tert−ブトキシカルボ
ニルアミノ)プロピル]アミノ]アニリン(1.45
g、5.46mmol)、2−クロロ−5−ニトロ安息
香酸クロリド(1.44g、6.58mmol)及びD
MA(20mL)を使用して、実施例316に記載した
方法に従い、標記目的化合物(0.346g、収率13
%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.38 (9H, s), 1.
77 (2H, m), 3.02 (2H,m), 3.21 (2H, m), 6.97 (1H,
m), 7.41 (2H, m), 7.78 (2H, d, J=8.8 Hz), 7.90 (1
H, d, J=8.8 Hz), 8.35 (1H, dd, J=2.9, 8.8 Hz), 8.4
7 (1H, d, J=2.9 Hz), 10.90 (1H, bs);
MS(FAB) m/z: 449 ((M-HCl) + H)+。
(実施例320)N−[4−[(3−アミノプロピル)
アミノ]フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド・2塩酸塩
実施例319で製造したN−[4−[[3−(tert
−ブトキシカルボニルアミノ)プロピル]アミノ]フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキ
サミド・1塩酸塩(0.150g、0.309mmo
l)、4N塩化水素−1,4−ジオキサン溶液(1.5
mL)及び1,4−ジオキサン(1.5mL)を使用し
て、実施例288に記載した方法に従い、標記目的化合
物(0.108g、収率83%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.93 (2H, m), 2.
90 (2H, m), 3.27 (2H,m), 7.66 (2H, m), 7.89 (1H,
d, J=8.8 Hz), 7.97 (2H, m), 8.34 (1H, dd, J=2.9,
8.8 Hz), 8.44 (1H, d, J=2.9 Hz), 10.71 (1H, bs);
MS(FAB) m/z: 349 ((M-2HCl) + H)+。
(実施例321)N−[4−[[(3−ジメチルアミ
ノ)プロピル](メチル)アミノ]フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド
実施例318a及び318bと同様の方法に従い製造し
た4−[[3−(ジメチルアミノ)プロピル](メチ
ル)アミノ]アニリン(1.82g、8.78mmo
l)をDMA(20mL)に溶解させ、2−クロロ−5
−ニトロ安息香酸クロリド(2.32g、10.5mm
ol)を加えて、室温で24時間攪拌した。反応溶液に
飽和重曹水及び水を加えて、酢酸エチルで抽出した。有
機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
得られた残渣をシリカゲルカラムクロマトグラフィー
(ヘキサン:酢酸エチル=1:1(v/v))にて精製し、
標記目的化合物(2.26g、収率66%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.74 (2H, tt, J=7.
3 Hz), 2.24 (6H, s), 2.29 (2H, t, J=7.3 Hz), 2.94
(3H, s), 3.38 (2H, t, J=7.3 Hz), 6.71 (2H, d, J=8.
8 Hz), 7.44 (2H, d, J=8.8 Hz), 7.63 (1H, d, J=8.8
Hz), 7.73 (1H, bs), 8.23 (1H, dd, J=2.9, 8.8 Hz),
8.59 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 391 (M + H)+。
(実施例322)N−[4−[[(3−ジメチルアミ
ノ)プロピル](メチル)アミノ]フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド・2塩酸
塩
実施例321で製造したN−[4−[[(3−ジメチル
アミノ)プロピル](メチル)アミノ]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド
(0.50g、1.28mmol)をジエチルエーテル
(5mL)に懸濁させ、1N塩化水素−ジエチルエーテ
ル溶液(3.84mL)を加えて3時間攪拌した。反応
溶液を減圧下濃縮し、減圧乾燥して、標記目的化合物
(0.545g、92%)を得た。1
H-NMR (400MHz,DMSO-d6): δ(ppm) 1.91 (2H, m), 2.7
3 (6H, s), 2.99 (3H, bs), 3.10 (2H, m), 3.47 (2H,
m), 7.68 (4H, m), 7.89 (1H, d, J=8.8 Hz), 8.34 (1
H, dd, J=2.9, 8.8 Hz), 8.43 (1H, d, J=2.9 Hz), 10.
38 (1H, bs);MS(FAB) m/z: 391 ((M-2HCl) + H)+。
(実施例323)N−[4−[[4−(tert−ブト
キシカルボニルアミノ)ブトキシ]アミノ]フェニル]
−(2−クロロ−5−ニトロフェニル)カルボキサミド
・1塩酸塩
実施例318a及び318bと同様の方法に従い製造し
た4−[[4−(tert−ブトキシカルボニルアミ
ノ)ブチル]アミノ]アニリン(0.450g、1.6
1mmol)、2−クロロ−5−ニトロ安息香酸クロリ
ド(0.354g、1.61mmol)及びDMA(5
mL)を使用して、実施例316に記載した方法に従
い、標記目的化合物(0.160g、収率20%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.38 (9H, s), 1.
45 (2H, m), 1.61 (2H,m), 2.92 (2H, m), 3.21 (2H,
m), 6.85 (1H, m), 7.41 (2H, m), 7.78 (2H, d,J=8.0
Hz), 7.90 (1H, d, J=8.8 Hz), 8.35 (1H, dd, J=2.9,
8.8 Hz), 8.47 (1H, d, J=2.9 Hz), 10.90 (1H, bs);
MS(FAB) m/z: 463 ((M-HCl) + H)+。
(実施例324)N−[4−[(4−アミノブトキシ)
アミノ]フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド・2塩酸塩
実施例323で製造したN−[4−[[4−(tert
−ブトキシカルボニルアミノ)ブチル]アミノ]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド・1塩酸塩(0.100g、0.200mmo
l)、4N塩化水素−1,4−ジオキサン溶液(1m
L)及び1,4−ジオキサン(1mL)を使用して、実
施例288に記載した方法に従い、標記目的化合物
(0.084g、収率96%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.70 (4H, m), 2.
81 (2H, m), 3.24 (2H,m), 7.37 (2H, m), 7.90 (1H,
d, J=8.8 Hz), 7.98 (2H, m), 8.35 (1H, dd, J=2.2,
8.8 Hz), 8.46 (1H, d, J=2.2 Hz), 10.86 (1H, bs);
MS(FAB) m/z: 363 ((M-2HCl) + H)+。
(実施例325)N−[4−(4−メタンスルホニル−
1−ピペラジニル)フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド
N−[4−(1−ピペラジニル)フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド(0.20
0g、0.461mmol)をピリジン(2mL)に溶
解させ、メタンスルホニルクロリド(0.054mL、
0.692mmol)を加えて4時間攪拌した。反応溶
液に飽和重曹水(6mL)及び水(20mL)を加え、
生じた固体を濾取し、水及びジイソプロピルエーテルで
洗浄し、減圧乾燥して、標記目的化合物(0.144
g、収率72%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.84 (3H, s), 3.
29 (4H, m), 3.41 (4H,m), 6.97 (2H, d, J=8.8 Hz),
7.56 (2H, d, J=8.8 Hz), 7.66 (1H, d, J=8.8 Hz), 7.
72 (1H, bs), 8.27 (1H, dd, J=2.9, 8.8 Hz), 8.63 (1
H, d, J=2.9 Hz);MS(FAB) m/z: 439 (M + H)+。
(実施例326)N−[4−(4−フェニルスルホニル
−1−ピペラジニル)フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド
実施例133で製造したN−[4−(ピペラジン−1−
イル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド(0.200g、0.461mmo
l)、ベンゼンスルホニルクロリド(0.088mL、
0.692mmol)及びピリジン(2mL)を使用し
て、実施例325に記載した方法に従い、標記目的化合
物(0.194g、収率84%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 3.19 (4H, m), 3.
25 (4H, m), 6.90 (2H,d, J=9.2 Hz), 7.50-7.66 (5H,
m), 7.70 (1H, bs), 7.81 (2H, d, J=9.2 Hz),8.26 (1
H, dd, J=2.9, 8.8 Hz), 8.61 (1H, d, J=2.9 Hz);
MS(FAB) m/z: 501 (M + H)+。
(実施例327)4−(2−クロロ−5−ニトロベンゾ
イル)−1−ピペリジンカルボン酸 エチルエステル
N−エトキシカルボニルピペリジン(10.97g、6
9.3mmol)、2−クロロ−5−ニトロ安息香酸ク
ロリド(18.31g、83.2mmol)、トリエチ
ルアミン(15mL)及びTHF(100mL)を使用
して、実施例1に記載した方法に従い反応した。反応溶
液を濃縮し、酢酸エチルで希釈し、飽和重曹水及び飽和
食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥
し、減圧下濃縮し、減圧乾燥した。残渣をジイソプロピ
ルエーテルで固化させ、標記目的化合物(19.94
g、収率85%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.26 (3H, t, J=7.1
Hz), 3.17-3.29 (2H, m), 3.45-3.67 (4H, m), 3.74-
3.90 (2H, m), 4.17 (2H, q, J=7.1 Hz), 7.62 (1H, d,
J=8.7 Hz), 8.20 (1H, d, J=2.6 Hz), 8.23 (1H, dd,
J=2.6, 8.7 Hz)。
(実施例328)4−(2−クロロ−5−ニトロベンゾ
イル)−1−ピペリジンカルボン酸 tert−ブチル
エステル
N−tert−ブトキシカルボニルピペリジン(5.6
5g、30.3mmol)、2−クロロ−5−ニトロ安
息香酸クロリド(8.01g、36.4mmol)、ト
リエチルアミン(6.5mL)及びTHF(100m
L)を使用して、実施例1に記載した方法に従い反応し
た。反応溶液を濃縮し、過剰の重曹水及びジイソプロピ
ルエーテルを加え攪拌した。生じた結晶を濾取し、水及
びジイソプロピルエーテルで洗浄し、減圧乾燥して、標
記目的化合物(10.7g、収率95%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.40 (9H, s), 3.
08-3.22 (2H, m), 3.25-3.35 (2H, m), 3.38-3.52 (2H,
m), 3.55-3.73 (2H, m), 7.85 (1H, d, J=8.8 Hz), 8.
28 (1H, d, J=2.7, 8.8 Hz), 8.33 (1H, d, J=2.7 H
z)。
(実施例329)1−(2−クロロ−5−ニトロベンゾ
イル)ピペラジン・1塩酸塩
実施例328で製造した4−(2−クロロ−5−ニトロ
ベンゾイル)−1−ピペリジンカルボン酸 tert−
ブチルエステル(10.2g、27.5mmol)を
1,4−ジオキサン(100mL)に懸濁させ、4N塩
化水素−1,4−ジオキサン溶液(20mL)を加え
て、室温で3日間、60℃で20時間攪拌した。反応溶
液をジエチルエーテルで希釈して、生じた固体を濾取
し、減圧乾燥して、標記目的化合物(7.68g、収率
91%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.97-3.05 (2H,
m), 3.10-3.30 (4H, m),3.41 (2H, t, J=5.4 Hz), 3.65
-3.72 (1H, m), 4.04-4.10 (1H, m), 7.87 (1H,d, J=8.
8 Hz), 8.30 (1H, dd, J=2.8, 8.8 Hz), 8.46 (1H, d,
J=2.8 Hz), 9.32-9.35 (1H, m);
MS(FAB) m/z: 270 ((M-HCl) + H)+;
Anal.calcd for C11H13Cl2N3O3: C,43.16; H,4.28; N,1
3.73; Cl,23.16. FoundC,42.73; H,3.99; N,13.56; Cl,
22.65。
(実施例330)1−(2−クロロ−5−ニトロベンゾ
イル)−4−メチルピペラジン
N−メチルピペラジン(0.27g、2.74mmo
l)、2−クロロ−5−ニトロ安息香酸クロリド(0.
72g、3.29mmol)、トリエチルアミン(0.
8mL)及びTHF(5mL)を使用して、実施例1に
記載した方法に従い反応した。反応溶液を濃縮し、酢酸
エチルで希釈し、飽和重曹水及び飽和食塩水で洗浄し
た。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮
し、減圧乾燥した。残渣をジイソプロピルエーテルで固
化させ、標記目的化合物(0.70g、収率90%)を
得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 2.31-2.46 (2H, m),
2.34 (3H, s), 2.48-2.56 (2H, m), 3.20-3.33 (2H,
m), 3.85 (2H, t, J=5.1 Hz), 7.60 (1H, d, J=8.0 H
z), 8.18-8.22 (2H, m)。
(実施例331)1−ベンジル−4−(2−クロロ−5
−ニトロベンゾイル)ピペラジン
N−ベンジルピペラジン(0.22g、1.26mmo
l)、2−クロロ−5−ニトロ安息香酸クロリド(0.
33g、1.51mmol)、トリエチルアミン(0.
8mL)及びTHF(5mL)を使用して、実施例1に
記載した方法に従い反応した。反応溶液を濃縮し、酢酸
エチルで希釈し、飽和重曹水及び飽和食塩水で洗浄し
た。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮
し、減圧乾燥した。残渣をジエチルエーテルで固化さ
せ、標記目的化合物(0.31g、収率68%)を得
た。1
H-NMR (400MHz, CDCl3): δ(ppm) 2.34-2.40 (1H, m),
2.45-2.60 (3H, m), 3.18-3.31 (2H, m), 3.55 (2H,
m), 3.79-3.87 (2H, m), 7.26-7.35 (5H, m), 7.59 (1
H, d), 8.17-8.20 (2H, m)。
(実施例332)1−(2−クロロ−5−ニトロベンゾ
イル)−4−フェニルピペラジン
N−フェニルピペラジン(0.38g、2.34mmo
l)、2−クロロ−5−ニトロ安息香酸クロリド(0.
62g、2.81mmol)、トリエチルアミン(0.
80mL)及びTHF(5mL)を使用して、実施例1
に記載した方法に従い反応した。反応溶液を濃縮し、酢
酸エチルで希釈し、飽和重曹水及び飽和食塩水で洗浄し
た。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮
し、減圧乾燥した。残渣をジイソプロピルエーテルで固
化させ、標記目的化合物(0.76g、収率93%)を
得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 3.11-3.23 (2H, m),
3.31 (2H, t, J=5.2 Hz), 3.37-3.47 (2H, m), 3.93-
4.70 (2H, m), 6.92 - 6.95 (3H, m), 7.30 (2H,t, J=
8.0 Hz), 7.63 (1H, d, J=9.5 Hz), 8.20-8.24 (2H,
m)。
(実施例333)1−(2−クロロ−5−ニトロベンゾ
イル)−4−[4−(N,N−ジメチルアミノ)フェニ
ル]ピペラジン
(333a)4−[4−(N,N−ジメチルアミノ)フ
ェニル]ピペラジン−1−カルボン酸 tert−ブチ
ルエステル
4−(4−アミノフェニル)ピペラジン−1−カルボン
酸 tert−ブチルエステル(Tetrahedron Lett.,2
000年,第41巻,p.385)(0.970g、3.5mmo
l)をエタノール(40mL)に溶解させ、氷冷下、3
5%ホルムアルデヒド水溶液(1.39mL、17.5
mmol)、1N塩酸(3.68mL、3.68mmo
l)及びシアノ水素化ホウ素ナトリウム(0.549
g、8.75mmol)を加えて、0℃で2時間、室温
で16時間攪拌した。反応溶液を減圧下濃縮して、酢酸
エチルで希釈し、飽和重曹水及び飽和食塩水で洗浄し
た。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮
して、標記目的化合物(1.07g、収率100%)を
得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.48 (9H, s), 2.88
(6H, s), 2.99 (4H, m), 3.57 (4H, m), 6.75 (2H, d,
J=8.9 Hz), 6.91 (2H, d, J=8.9 Hz)。
(333b)4−[4−(N,N−ジメチルアミノ)フ
ェニル]ピペラジン
実施例333aで製造した4−[4−(N,Nジメチル
アミノ)フェニル]ピペラジン−1−カルボン酸 te
rt−ブチルエステル(1.07g、3.5mmo
l)、p−アニソール、トリフルオロ酢酸(2mL)及
び塩化メチレン(20mL)を使用して、実施例292
に記載した方法に従い、標記目的化合物(0.552
g、収率77%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 2.87 (6H, s), 3.03
(8H, m), 6.75 (2H, d,J=9.1 Hz), 6.91 (2H, d, J=9.
1 Hz)。
(333c)1−(2−クロロ−5−ニトロベンゾイ
ル)−4−[4−(N,N−ジメチルアミノ)フェニ
ル]ピペラジン
実施例333bで製造した4−[4−(N,N−ジメチ
ルアミノ)フェニル]ピペラジン(0.355g、1.
72mmol)、2−クロロ−5−ニトロ安息香酸クロ
リド(0.570g、2.59mmol)及びDMA
(10mL)を使用して、実施例1に記載した方法に従
い、標記目的化合物(0.557g、収率83%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.78 (6H, s),2.8
0-3.20 (6H, m), 3.80 (2H, m), 6.68 (2H, d, J=9.1 H
z), 6.86 (2H, d, J=9.1 Hz), 7.86 (1H, d, J=8.8 H
z), 8.28 (1H, dd, J=2.7, 8.8 Hz), 8.33 (1H, d, J=
2.7 Hz);
MS(FAB) m/z: 388 M+。
(実施例334)N−[4−[4−[(2−クロロ−5
−ニトロフェニル)カルボニル]ピペラジン−1−イ
ル]フェニル]メトキシカルボキサミド
(334a)4−[4−(メトキシカルボニルアミノ)
フェニル]ピペラジン−1−カルボン酸 tert−ブ
チルエステル
4−(4−アミノフェニル)ピペラジン−1−カルボン
酸 tert−ブチルエステル(Tetrahedron Lett.,2
000年,第41巻,p.385)(0.970g、3.5mmo
l)をTHF(10mL)に溶解させ、クロロ蟻酸 メ
チルエステル(0.297mL、3.85mmol)を
加えて、室温で45分間攪拌した。反応溶液に飽和重曹
水を加えて、酢酸エチルで抽出した。有機層を飽和食塩
水で洗浄し、減圧下濃縮して、標記目的化合物(1.1
7g、収率100%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.48 (9H, s), 3.06
(4H, m), 3.57 (4H, m), 3.76 (3H, s), 6.44 (1H, b
s), 6.89 (2H, d, J=8.9 Hz), 7.28 (2H, m)。
(334b)4−(1−ピペラジニル)フェニルカルバ
ミン酸 メチルエステル実施例334aで製造した4−
[4−(メトキシカルボニルアミノ)フェニル]ピペラ
ジン−1−カルボン酸 tert−ブチルエステル
(1.17g、3.49mmol)、p−アニソール、
トリフルオロ酢酸(2mL)及び塩化メチレン(20m
L)を使用して、実施例292に記載した方法に従い、
標記目的化合物(0.819g、収率99%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.93 (4H, dd, J=
7.0, 7.0 Hz), 3.30 (3H, s), 3.58 (4H, dd, J=7.0, 1
2.8 Hz), 6.25 (2H, t, J=2.2 Hz), 7.35 (2H, t, J=2.
2 Hz), 7.79 (1H, d, J=8.8 Hz), 8.13 (1H, d, J=2.8
Hz), 8.25 (1H, dd, J=2.8, 8.8 Hz), 8.78 (1H, m)。
(334c)N−[4−[4−[(2−クロロ−5−ニ
トロフェニル)カルボニル]ピペラジン−1−イル]フ
ェニル]メトキシカルボキサミド
実施例334bで製造した4−(1−ピペラジニル)フ
ェニルカルバミン酸メチルエステル(0.235g、
1.0mmol)、2−クロロ−5−ニトロ安息香酸ク
ロリド(0.264g、1.2mmol)及びDMA
(5mL)を使用して、実施例1に記載した方法に従
い、標記目的化合物(0.287g、収率69%)を得
た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.51-3.70 (6H,
m), 3.63 (3H, s), 3.80(2H, m), 6.90 (2H, d, J=9.1
Hz), 7.31 (2H, m), 7.87 (1H, d, J=8.9 Hz), 8.28 (1
H, dd, J=2.8, 8.9 Hz), 8.34 (1H, d, J=2.8 Hz), 9.3
8 (1H, m);
MS(FAB) m/z: 419 (M + H)+。
(実施例335)N−[4−[4−[(2−クロロ−5
−ニトロフェニル)カルボニル]ピペリジン−1−イ
ル]フェニル]アセトアミド
(335a)4−[4−(アセチルアミノ)フェニル]
ピペラジン−1−カルボン酸 tert−ブチルエステ
ル
4−(4−アミノフェニル)ピペラジン−1−カルボン
酸 tert−ブチルエステル(Tetrahedron Lett.,2
000年,第41巻,p.385)(0.970g、3.5mmo
l)、アセチルクロリド(0.273mL、3.85m
mol)及びDMA(10mL)を使用して、実施例1
に記載した方法に従い、標記目的化合物(1.02g、
収率92%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.48 (9H, s), 2.15
(3H, s), 3.08 (4H, m), 3.57 (4H, m), 6.89 (2H, d,
J=9.0 Hz), 7.05 (1H, bs), 7.37 (2H, d, J=9.0 H
z)。
(335b)N−[4−[4−[(2−クロロ−5−ニ
トロフェニル)カルボニル]ピペラジン−1−イル]フ
ェニル]アセトアミド
実施例335aで製造した4−[4−(アセチルアミ
ノ)フェニル]ピペラジン−1−カルボン酸 tert
−ブチルエステル(1.02g、3.20mmol)、
p−アニソール、トリフルオロ酢酸(2mL)及び塩化
メチレン(20mL)を使用して、実施例292に記載
した方法に従い、粗製のN−アセチル−4−(1−ピペ
ラジニル)アニリン(1.51g)を得た。The crude compound obtained was treated with 1,4-dioxa
Solution (10 mL), and under ice cooling, 4N hydrogen chloride-1,
4-Dioxane solution (1 mL) was added. The reaction solution
Ethyl ether (20 mL) was added and the resulting white solid was
It is collected by filtration and dried under reduced pressure to give the title object compound (0.491
g, yield 15%).1
H-NMR (400MHz, DMSO-d6): δ (ppm) 1.40 (9H, s), 3.
19 (4H, m), 6.90 (2H, d, J = 8.8 Hz), 7.06 (2H, m),
7.63 (2H, m), 7.89 (1H, d, J = 8.8 Hz), 8.33 (1H, d
d, J = 2.9, 8.8 Hz), 8.43 (1H, d, J = 2.9 Hz), 10.66
(1H, bs);
MS (FAB) m / z: 435 ((M-HCl) + H)+.
(Example 317) N- [4-[(2-aminoethyl) a]
Mino] phenyl]-(2-chloro-5-nitrophenyl
Le) carboxamide dihydrochloride
N- [4-[[2- (tert
-Butoxycarbonylamino) ethyl] amino] phenyl
]-(2-Chloro-5-nitrophenyl) carboxa
Mido monohydrochloride (0.300g, 0.636mmo
l) 4N hydrogen chloride-1,4-dioxane solution (3 m
L) and 1,4-dioxane (3 mL),
According to the method described in Example 288, the title object compound was obtained.
(0.221 g, yield 85%) was obtained.1
H-NMR (400MHz, DMSO-d6): δ (ppm) 3.05 (2H, m), 3.
37 (2H, m), 6.88 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J =
8.8 Hz), 7.88 (1H, d, J = 8.8 Hz), 8.19 (2H, bs), 8.3
2 (1H, dd, J = 2.9, 8.8 Hz), 8.41 (1H, d, J = 2.9 Hz),
10.56 (1H, bs);
MS (FAB) m / z: 335 ((M-2HCl) + H)+.
(Example 318) N- [4-[[(2-dimethylamido
No) ethyl] (methyl) amino] phenyl]-(2-q
Lolo-5-nitrophenyl) carboxamide
(318a) 4-[[(2-dimethylamino) ethyl]
(Methyl) amino] nitrobenzene
4-Fluoronitrobenzene (1.00 mL, 9.43
mmol) and N, N, N'-trimethylethylenedia
Min (2.89 g, 28.3 mmol) in ethanol
It was dissolved in (20 mL) and heated under reflux for 9 hours. Reaction melting
The solution was allowed to cool to room temperature and then concentrated under reduced pressure. Obtained residue
The residue is subjected to silica gel column chromatography (hexane:
Ethyl acetate = 1: 1 (v / v)), and
The product (2.04 g, yield 97%) was obtained.1
H-NMR (400MHz, CDCl3): δ (ppm) 2.30 (6H, s), 2.50
(2H, t, J = 7.0 Hz), 3.10 (3H, s), 3.56 (2H, t, J =
7.0 Hz), 6.11 (2H, d, J = 8.8 Hz), 8.11 (2H, d, J = 8.8
Hz).
(318b) 4-[[2- (dimethylamino) ethyl]
(Methyl) amino] aniline
4-[[(2-dimethylamido) prepared in Example 318a
No) ethyl] (methyl) amino] nitrobenzene (2.
04 g, 9.14 mmol), 10% palladium-carbon
(0.20 g) and ethanol (40 mL)
According to the method described in Example 296b.
A compound (1.73 g, yield 98%) was obtained. 1
H-NMR (400MHz, CDCl3): δ (ppm) 2.27 (6H, s), 2.44
(2H, t, J = 7.0 Hz), 2.84 (3H, s), 3.31 (2H, t, J =
7.0 Hz), 6.66 (4H, s).
(318c) N- [4-[[(2-dimethylamino) e
Cyl] (methyl) amino] phenyl]-(2-chloro-
5-nitrophenyl) carboxamide
4-[[2- (dimethylamido) prepared in Example 318b
No) ethyl] (methyl) amino] aniline (1.72)
g, 8.90 mmol) in DMA (17 mL)
2-chloro-5-nitrobenzoic acid chloride (2.3
5 g, 10.7 mmol) and stirred at room temperature for 24 hours.
I stirred. To the reaction solution, add saturated aqueous sodium hydrogen carbonate and water and add acetic acid.
Extracted with chill. Dry the organic layer over anhydrous sodium sulfate
, Concentrate under reduced pressure, and dry under reduced pressure to give the title object compound.
(3.12 g, yield 92%) was obtained.1
H-NMR (400MHz, DMSO-d6): δ (ppm) 2.18 (6H, s), 2.
36 (2H, t, J = 7.0 Hz), 2.89 (3H, s), 3.40 (2H, t, J =
7.0 Hz), 6.69 (2H, d, J = 8.8 Hz), 7.49 (2H, d, J = 8.8
Hz), 7.87 (1H, d, J = 8.8 Hz), 8.31 (1H, dd, J = 2.9,
8.8 Hz), 8.39 (1H, d, J = 2.9 Hz), 10.36 (1H, bs);
MS (FAB) m / z: 377 (M + H)+.
(Example 319) N- [4-[[3- (tert-but
Xycarbonylamino) propyl] amino] phenyl]
-(2-chloro-5-nitrophenyl) carboxamide
・ Monohydrochloride
In a manner similar to Examples 316a, 316b and 316c.
4-[[3- (tert-butoxycarbo
Nylamino) propyl] amino] aniline (1.45
g, 5.46 mmol), 2-chloro-5-nitrobenzoate
Perfume chloride (1.44 g, 6.58 mmol) and D
MA (20 mL) was used and described in Example 316.
According to the method, the title object compound (0.346 g, yield 13
%) Was obtained.1
H-NMR (400MHz, DMSO-d6): δ (ppm) 1.38 (9H, s), 1.
77 (2H, m), 3.02 (2H, m), 3.21 (2H, m), 6.97 (1H,
m), 7.41 (2H, m), 7.78 (2H, d, J = 8.8 Hz), 7.90 (1
H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 2.9, 8.8 Hz), 8.4
7 (1H, d, J = 2.9 Hz), 10.90 (1H, bs);
MS (FAB) m / z: 449 ((M-HCl) + H)+.
(Example 320) N- [4-[(3-aminopropyl)
Amino] phenyl]-(2-chloro-5-nitrophenyl
Le) carboxamide dihydrochloride
N- [4-[[3- (tert
-Butoxycarbonylamino) propyl] amino] phen
Nyl]-(2-chloro-5-nitrophenyl) carboxy
Samide monohydrochloride (0.150 g, 0.309 mmo
1) 4N hydrogen chloride-1,4-dioxane solution (1.5
mL) and 1,4-dioxane (1.5 mL)
According to the method described in Example 288.
The product (0.108 g, yield 83%) was obtained.1
H-NMR (400MHz, DMSO-d6): δ (ppm) 1.93 (2H, m), 2.
90 (2H, m), 3.27 (2H, m), 7.66 (2H, m), 7.89 (1H,
d, J = 8.8 Hz), 7.97 (2H, m), 8.34 (1H, dd, J = 2.9,
8.8 Hz), 8.44 (1H, d, J = 2.9 Hz), 10.71 (1H, bs);
MS (FAB) m / z: 349 ((M-2HCl) + H)+.
(Example 321) N- [4-[[(3-dimethylamido
No) propyl] (methyl) amino] phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide
Prepared according to a method similar to Examples 318a and 318b
4-[[3- (dimethylamino) propyl] (meth
Lu) amino] aniline (1.82 g, 8.78 mmo
1) was dissolved in DMA (20 mL) and 2-chloro-5
-Nitrobenzoyl chloride (2.32 g, 10.5 mm)
ol) was added and the mixture was stirred at room temperature for 24 hours. In the reaction solution
Saturated aqueous sodium hydrogen carbonate and water were added, and the mixture was extracted with ethyl acetate. Existence
The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography.
Purify with (hexane: ethyl acetate = 1: 1 (v / v)),
The title object compound (2.26 g, yield 66%) was obtained.1
H-NMR (400MHz, CDCl3): δ (ppm) 1.74 (2H, tt, J = 7.
3 Hz), 2.24 (6H, s), 2.29 (2H, t, J = 7.3 Hz), 2.94
(3H, s), 3.38 (2H, t, J = 7.3 Hz), 6.71 (2H, d, J = 8.
8 Hz), 7.44 (2H, d, J = 8.8 Hz), 7.63 (1H, d, J = 8.8
Hz), 7.73 (1H, bs), 8.23 (1H, dd, J = 2.9, 8.8 Hz),
8.59 (1H, d, J = 2.9 Hz);
MS (FAB) m / z: 391 (M + H)+.
(Example 322) N- [4-[[(3-dimethylamido
No) propyl] (methyl) amino] phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide dihydrochloride
salt
N- [4-[[(3-dimethyl
Amino) propyl] (methyl) amino] phenyl]-
(2-chloro-5-nitrophenyl) carboxamide
(0.50 g, 1.28 mmol) in diethyl ether
(5 mL) and suspended in 1N hydrogen chloride-diethyl ether
Solution (3.84 mL) was added and the mixture was stirred for 3 hours. reaction
The solution was concentrated under reduced pressure and dried under reduced pressure to give the title object compound.
(0.545 g, 92%) was obtained.1
H-NMR (400MHz, DMSO-d6): δ (ppm) 1.91 (2H, m), 2.7
3 (6H, s), 2.99 (3H, bs), 3.10 (2H, m), 3.47 (2H,
m), 7.68 (4H, m), 7.89 (1H, d, J = 8.8 Hz), 8.34 (1
H, dd, J = 2.9, 8.8 Hz), 8.43 (1H, d, J = 2.9 Hz), 10.
38 (1H, bs); MS (FAB) m / z: 391 ((M-2HCl) + H)+.
(Example 323) N- [4-[[4- (tert-but
Xycarbonylamino) butoxy] amino] phenyl]
-(2-chloro-5-nitrophenyl) carboxamide
・ Monohydrochloride
Prepared according to a method similar to Examples 318a and 318b
4-[[4- (tert-butoxycarbonylamido
No) butyl] amino] aniline (0.450 g, 1.6
1 mmol), 2-chloro-5-nitrobenzoic acid chloride
De (0.354 g, 1.61 mmol) and DMA (5
mL) using the method described in Example 316.
The title compound (0.160 g, yield 20%) was obtained.
It was1
H-NMR (400MHz, DMSO-d6): δ (ppm) 1.38 (9H, s), 1.
45 (2H, m), 1.61 (2H, m), 2.92 (2H, m), 3.21 (2H,
m), 6.85 (1H, m), 7.41 (2H, m), 7.78 (2H, d, J = 8.0
Hz), 7.90 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 2.9,
8.8 Hz), 8.47 (1H, d, J = 2.9 Hz), 10.90 (1H, bs);
MS (FAB) m / z: 463 ((M-HCl) + H)+.
(Example 324) N- [4-[(4-aminobutoxy)
Amino] phenyl]-(2-chloro-5-nitrophenyl
Le) carboxamide dihydrochloride
N- [4-[[4- (tert
-Butoxycarbonylamino) butyl] amino] phenyl
]-(2-Chloro-5-nitrophenyl) carboxa
Mido monohydrochloride (0.100g, 0.200mmo
l), 4N hydrogen chloride-1,4-dioxane solution (1 m
L) and 1,4-dioxane (1 mL),
According to the method described in Example 288, the title object compound was obtained.
(0.084 g, yield 96%) was obtained.1
H-NMR (400MHz, DMSO-d6): δ (ppm) 1.70 (4H, m), 2.
81 (2H, m), 3.24 (2H, m), 7.37 (2H, m), 7.90 (1H,
d, J = 8.8 Hz), 7.98 (2H, m), 8.35 (1H, dd, J = 2.2,
8.8 Hz), 8.46 (1H, d, J = 2.2 Hz), 10.86 (1H, bs);
MS (FAB) m / z: 363 ((M-2HCl) + H)+.
(Example 325) N- [4- (4-methanesulfonyl-
1-Piperazinyl) phenyl]-(2-chloro-5-di
Trophenyl) carboxamide
N- [4- (1-piperazinyl) phenyl]-(2-q
Lolo-5-nitrophenyl) carboxamide (0.20
0 g, 0.461 mmol) in pyridine (2 mL)
And methanesulfonyl chloride (0.054 mL,
0.692 mmol) was added and the mixture was stirred for 4 hours. Reaction melting
Saturated sodium hydrogen carbonate solution (6 mL) and water (20 mL) were added to the solution,
The solid formed is filtered off and washed with water and diisopropyl ether.
Wash and dry under reduced pressure to give the title compound (0.144
g, yield 72%) was obtained.1
H-NMR (400MHz, DMSO-d6): δ (ppm) 2.84 (3H, s), 3.
29 (4H, m), 3.41 (4H, m), 6.97 (2H, d, J = 8.8 Hz),
7.56 (2H, d, J = 8.8 Hz), 7.66 (1H, d, J = 8.8 Hz), 7.
72 (1H, bs), 8.27 (1H, dd, J = 2.9, 8.8 Hz), 8.63 (1
H, d, J = 2.9 Hz); MS (FAB) m / z: 439 (M + H)+.
(Example 326) N- [4- (4-phenylsulfonyl)
-1-Piperazinyl) phenyl]-(2-chloro-5-
Nitrophenyl) carboxamide
N- [4- (piperazine-1-) prepared in Example 133
Iyl) phenyl]-(2-chloro-5-nitrophenyl
Le) carboxamide (0.200 g, 0.461 mmo
l), benzenesulfonyl chloride (0.088 mL,
0.692 mmol) and pyridine (2 mL)
According to the method described in Example 325.
The product (0.194 g, yield 84%) was obtained.1
H-NMR (400MHz, DMSO-d6): δ (ppm) 3.19 (4H, m), 3.
25 (4H, m), 6.90 (2H, d, J = 9.2 Hz), 7.50-7.66 (5H,
m), 7.70 (1H, bs), 7.81 (2H, d, J = 9.2 Hz), 8.26 (1
H, dd, J = 2.9, 8.8 Hz), 8.61 (1H, d, J = 2.9 Hz);
MS (FAB) m / z: 501 (M + H)+.
(Example 327) 4- (2-chloro-5-nitrobenzo
Yl) -1-piperidinecarboxylic acid ethyl ester
N-ethoxycarbonylpiperidine (10.97 g, 6
9.3 mmol), 2-chloro-5-nitrobenzoic acid
Lolid (18.31 g, 83.2 mmol), triechi
Use luamine (15 mL) and THF (100 mL)
Then, the reaction was performed according to the method described in Example 1. Reaction melting
The solution was concentrated, diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate and saturated solution.
Washed with brine. Dry the organic layer over anhydrous sodium sulfate
, Concentrated under reduced pressure, and dried under reduced pressure. Diisopropyi residue
It was solidified with ether to give the title compound (19.94).
g, yield 85%).1
H-NMR (400MHz, CDCl3): δ (ppm) 1.26 (3H, t, J = 7.1
Hz), 3.17-3.29 (2H, m), 3.45-3.67 (4H, m), 3.74-
3.90 (2H, m), 4.17 (2H, q, J = 7.1 Hz), 7.62 (1H, d,
J = 8.7 Hz), 8.20 (1H, d, J = 2.6 Hz), 8.23 (1H, dd,
J = 2.6, 8.7 Hz).
(Example 328) 4- (2-chloro-5-nitrobenzo
Yl) -1-piperidinecarboxylic acid tert-butyl ester
ester
N-tert-butoxycarbonylpiperidine (5.6
5 g, 30.3 mmol), 2-chloro-5-nitro ammonium
Benzoic acid chloride (8.01 g, 36.4 mmol)
Liethylamine (6.5 mL) and THF (100 m
L) was reacted according to the method described in Example 1.
It was The reaction solution was concentrated, and excess sodium hydrogen carbonate solution and diisopropylpropionate were added.
Ruether was added and stirred. The crystals formed were collected by filtration and washed with water.
And diisopropyl ether, dried under reduced pressure, and
The target compound (10.7 g, yield 95%) was obtained.1
H-NMR (400MHz, DMSO-d6): δ (ppm) 1.40 (9H, s), 3.
08-3.22 (2H, m), 3.25-3.35 (2H, m), 3.38-3.52 (2H, m
m), 3.55-3.73 (2H, m), 7.85 (1H, d, J = 8.8 Hz), 8.
28 (1H, d, J = 2.7, 8.8 Hz), 8.33 (1H, d, J = 2.7 H
z).
(Example 329) 1- (2-chloro-5-nitrobenzo
Il) Piperazine monohydrochloride
4- (2-chloro-5-nitro prepared in Example 328
Benzoyl) -1-piperidinecarboxylic acid tert-
Butyl ester (10.2 g, 27.5 mmol)
Suspended in 1,4-dioxane (100 mL), 4N salt
Hydrogen chloride-1,4-dioxane solution (20 mL) was added.
Then, the mixture was stirred at room temperature for 3 days and at 60 ° C. for 20 hours. Reaction melting
Dilute the solution with diethyl ether and collect the resulting solid by filtration.
And dried under reduced pressure to give the title object compound (7.68 g, yield
91%).1
H-NMR (400MHz, DMSO-d6): δ (ppm) 2.97-3.05 (2H,
m), 3.10-3.30 (4H, m), 3.41 (2H, t, J = 5.4 Hz), 3.65
-3.72 (1H, m), 4.04-4.10 (1H, m), 7.87 (1H, d, J = 8.
8 Hz), 8.30 (1H, dd, J = 2.8, 8.8 Hz), 8.46 (1H, d,
J = 2.8 Hz), 9.32-9.35 (1H, m);
MS (FAB) m / z: 270 ((M-HCl) + H)+;
Anal.calcd for C11H13Cl2N3O3: C, 43.16; H, 4.28; N, 1
3.73; Cl, 23.16.FoundC, 42.73; H, 3.99; N, 13.56; Cl,
22.65.
(Example 330) 1- (2-chloro-5-nitrobenzo
Yl) -4-methylpiperazine
N-methylpiperazine (0.27 g, 2.74 mmo
l), 2-chloro-5-nitrobenzoic acid chloride (0.
72 g, 3.29 mmol), triethylamine (0.
8 mL) and THF (5 mL) to Example 1.
The reaction was performed according to the method described. The reaction solution is concentrated and
Dilute with ethyl and wash with saturated aqueous sodium hydrogen carbonate and saturated brine.
It was The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure.
And dried under reduced pressure. The residue was solidified with diisopropyl ether.
To give the title object compound (0.70 g, yield 90%)
Obtained.1
H-NMR (400MHz, CDCl3): δ (ppm) 2.31-2.46 (2H, m),
2.34 (3H, s), 2.48-2.56 (2H, m), 3.20-3.33 (2H,
m), 3.85 (2H, t, J = 5.1 Hz), 7.60 (1H, d, J = 8.0 H
z), 8.18-8.22 (2H, m).
(Example 331) 1-benzyl-4- (2-chloro-5)
-Nitrobenzoyl) piperazine
N-benzylpiperazine (0.22 g, 1.26 mmo
l), 2-chloro-5-nitrobenzoic acid chloride (0.
33 g, 1.51 mmol), triethylamine (0.
8 mL) and THF (5 mL) to Example 1.
The reaction was performed according to the method described. The reaction solution is concentrated and
Dilute with ethyl and wash with saturated aqueous sodium hydrogen carbonate and saturated brine.
It was The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure.
And dried under reduced pressure. The residue was solidified with diethyl ether
To give the title object compound (0.31 g, yield 68%).
It was1
H-NMR (400MHz, CDCl3): δ (ppm) 2.34-2.40 (1H, m),
2.45-2.60 (3H, m), 3.18-3.31 (2H, m), 3.55 (2H, m
m), 3.79-3.87 (2H, m), 7.26-7.35 (5H, m), 7.59 (1
H, d), 8.17-8.20 (2H, m).
(Example 332) 1- (2-chloro-5-nitrobenzo
Yl) -4-phenylpiperazine
N-phenylpiperazine (0.38 g, 2.34 mmo
l), 2-chloro-5-nitrobenzoic acid chloride (0.
62 g, 2.81 mmol), triethylamine (0.
Example 1 using 80 mL) and THF (5 mL)
The reaction was performed according to the method described in 1. Concentrate the reaction solution and add vinegar.
Dilute with ethyl acetate and wash with saturated aqueous sodium hydrogen carbonate and saturated brine.
It was The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure.
And dried under reduced pressure. The residue was solidified with diisopropyl ether.
To give the title compound (0.76 g, yield 93%)
Obtained.1
H-NMR (400MHz, CDCl3): δ (ppm) 3.11-3.23 (2H, m),
3.31 (2H, t, J = 5.2 Hz), 3.37-3.47 (2H, m), 3.93-
4.70 (2H, m), 6.92-6.95 (3H, m), 7.30 (2H, t, J =
8.0 Hz), 7.63 (1H, d, J = 9.5 Hz), 8.20-8.24 (2H,
m).
(Example 333) 1- (2-chloro-5-nitrobenzo
Yl) -4- [4- (N, N-dimethylamino) phenyl
Lu] piperazine
(333a) 4- [4- (N, N-dimethylamino) phenyl
Phenyl] piperazine-1-carboxylic acid tert-butyl
Luster
4- (4-aminophenyl) piperazine-1-carvone
Acid tert-butyl ester (Tetrahedron Lett., 2
000 years, 41st volume, p.385) (0.970g, 3.5mmo
l) was dissolved in ethanol (40 mL) and cooled under ice for 3
5% formaldehyde aqueous solution (1.39 mL, 17.5
mmol), 1N hydrochloric acid (3.68 mL, 3.68 mmo)
l) and sodium cyanoborohydride (0.549
g, 8.75 mmol) and added at 0 ° C. for 2 hours at room temperature.
It was stirred for 16 hours. The reaction solution was concentrated under reduced pressure and
Dilute with ethyl and wash with saturated aqueous sodium hydrogen carbonate and saturated brine.
It was The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure.
To give the title object compound (1.07 g, yield 100%)
Obtained.1
H-NMR (400MHz, CDCl3): δ (ppm) 1.48 (9H, s), 2.88
(6H, s), 2.99 (4H, m), 3.57 (4H, m), 6.75 (2H, d,
J = 8.9 Hz), 6.91 (2H, d, J = 8.9 Hz).
(333b) 4- [4- (N, N-dimethylamino) fu
[Phenyl] piperazine
4- [4- (N, Ndimethyl) prepared in Example 333a
Amino) phenyl] piperazine-1-carboxylic acid te
rt-butyl ester (1.07 g, 3.5 mmo
l), p-anisole, trifluoroacetic acid (2 mL) and
Example 292 using methylene chloride and methylene chloride (20 mL).
According to the method described in 1.
g, yield 77%) was obtained.1
H-NMR (400MHz, CDCl3): δ (ppm) 2.87 (6H, s), 3.03
(8H, m), 6.75 (2H, d, J = 9.1 Hz), 6.91 (2H, d, J = 9.
1 Hz).
(333c) 1- (2-chloro-5-nitrobenzoi
) -4- [4- (N, N-Dimethylamino) phenyl
Lu] piperazine
4- [4- (N, N-dimethyl) prepared in Example 333b
Lumino) phenyl] piperazine (0.355 g, 1.
72 mmol), 2-chloro-5-nitrobenzoic acid chloride
Lido (0.570 g, 2.59 mmol) and DMA
(10 mL) using the method described in Example 1.
The title compound (0.557 g, yield 83%) was obtained.
It was1
H-NMR (400MHz, DMSO-d6): δ (ppm) 2.78 (6H, s), 2.8
0-3.20 (6H, m), 3.80 (2H, m), 6.68 (2H, d, J = 9.1 H
z), 6.86 (2H, d, J = 9.1 Hz), 7.86 (1H, d, J = 8.8 H
z), 8.28 (1H, dd, J = 2.7, 8.8 Hz), 8.33 (1H, d, J =
2.7 Hz);
MS (FAB) m / z: 388 M+.
(Example 334) N- [4- [4-[(2-chloro-5
-Nitrophenyl) carbonyl] piperazine-1-i
] Phenyl] methoxycarboxamide
(334a) 4- [4- (methoxycarbonylamino)
Phenyl] piperazine-1-carboxylic acid tert-bu
Chill ester
4- (4-aminophenyl) piperazine-1-carvone
Acid tert-butyl ester (Tetrahedron Lett., 2
000 years, 41st volume, p.385) (0.970g, 3.5mmo
l) was dissolved in THF (10 mL), and chloroformate
Chill ester (0.297 mL, 3.85 mmol)
In addition, the mixture was stirred at room temperature for 45 minutes. Saturated baking soda in the reaction solution
Water was added and the mixture was extracted with ethyl acetate. Saturated salt in the organic layer
Wash with water and concentrate under reduced pressure to give the title compound (1.1
7 g, yield 100%) was obtained.1
H-NMR (400MHz, CDCl3): δ (ppm) 1.48 (9H, s), 3.06
(4H, m), 3.57 (4H, m), 3.76 (3H, s), 6.44 (1H, b
s), 6.89 (2H, d, J = 8.9 Hz), 7.28 (2H, m).
(334b) 4- (1-piperazinyl) phenylcarba
Mic acid methyl ester 4-prepared in Example 334a
[4- (methoxycarbonylamino) phenyl] pipera
Gin-1-carboxylic acid tert-butyl ester
(1.17 g, 3.49 mmol), p-anisole,
Trifluoroacetic acid (2 mL) and methylene chloride (20 m
L), according to the method described in Example 292,
The title object compound (0.819 g, yield 99%) was obtained.1
H-NMR (400MHz, DMSO-d6): δ (ppm) 2.93 (4H, dd, J =
7.0, 7.0 Hz), 3.30 (3H, s), 3.58 (4H, dd, J = 7.0, 1
2.8 Hz), 6.25 (2H, t, J = 2.2 Hz), 7.35 (2H, t, J = 2.
2 Hz), 7.79 (1H, d, J = 8.8 Hz), 8.13 (1H, d, J = 2.8
Hz), 8.25 (1H, dd, J = 2.8, 8.8 Hz), 8.78 (1H, m).
(334c) N- [4- [4-[(2-chloro-5-ni
Trophenyl) carbonyl] piperazin-1-yl] f
[Ethyl] methoxycarboxamide
4- (1-Piperazinyl) furan prepared in Example 334b
Methyl phenylcarbamic acid (0.235 g,
1.0 mmol), 2-chloro-5-nitrobenzoic acid
Lolid (0.264g, 1.2mmol) and DMA
(5 mL) using the method described in Example 1.
The title compound (0.287 g, yield 69%) was obtained.
It was1
H-NMR (400MHz, DMSO-d6): δ (ppm) 2.51-3.70 (6H,
m), 3.63 (3H, s), 3.80 (2H, m), 6.90 (2H, d, J = 9.1
Hz), 7.31 (2H, m), 7.87 (1H, d, J = 8.9 Hz), 8.28 (1
H, dd, J = 2.8, 8.9 Hz), 8.34 (1H, d, J = 2.8 Hz), 9.3
8 (1H, m);
MS (FAB) m / z: 419 (M + H)+.
(Example 335) N- [4- [4-[(2-chloro-5
-Nitrophenyl) carbonyl] piperidine-1-i
Lu] phenyl] acetamide
(335a) 4- [4- (acetylamino) phenyl]
Piperazine-1-carboxylic acid tert-butyl ester
Le
4- (4-aminophenyl) piperazine-1-carvone
Acid tert-butyl ester (Tetrahedron Lett., 2
000 years, 41st volume, p.385) (0.970g, 3.5mmo
l), acetyl chloride (0.273 mL, 3.85 m)
mol) and DMA (10 mL), Example 1
According to the method described in 1, the title object compound (1.02 g,
Yield 92%) was obtained.1
H-NMR (400MHz, CDCl3): δ (ppm) 1.48 (9H, s), 2.15
(3H, s), 3.08 (4H, m), 3.57 (4H, m), 6.89 (2H, d,
J = 9.0 Hz), 7.05 (1H, bs), 7.37 (2H, d, J = 9.0 H
z).
(335b) N- [4- [4-[(2-chloro-5-ni
Trophenyl) carbonyl] piperazin-1-yl] f
]] Acetamide
4- [4- (acetylamido) prepared in Example 335a
No) phenyl] piperazine-1-carboxylic acid tert
-Butyl ester (1.02 g, 3.20 mmol),
p-anisole, trifluoroacetic acid (2 mL) and chloride
Described in Example 292 using methylene (20 mL)
The crude N-acetyl-4- (1-pipet
Razinyl) aniline (1.51 g) was obtained.
【0274】得られた粗製のN−アセチル−4−(1−
ピペラジニル)アニリン(1.30g)、2−クロロ−
5−ニトロ安息香酸クロリド(1.56g、7.09m
mol)及びピリジン(10mL)を使用して、実施例
1に記載した方法に従い、標記目的化合物(0.335
g、収率30%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.99 (3H, s), 3.
00-3.30 (6H, m), 3.80(2H, m), 6.90 (2H, d, J=9.0 H
z), 7.43 (2H, d, J=9.0 Hz), 7.87 (1H, d, J=8.8 H
z), 8.28 (1H, dd, J=2.7, 8.8 Hz), 8.34 (1H, d, J=
2.7 Hz), 9.72 (1H,bs);
MS(FAB) m/z: 403 (M + H)+。
(実施例336)N−[4−[4−[(2−クロロ−5
−ニトロフェニル)カルボニル]ピペラジン−1−イ
ル]フェニル]メタンスルホンアミド
(336a)4−(4−メタンスルホニルアミノフェニ
ル)ピペラジン−1−カルボン酸 tert−ブチルエ
ステル
4−(4−アミノフェニル)ピペラジン−1−カルボン
酸 tert−ブチルエステル(Tetrahedron Lett.,2
000年,第41巻,p.385)(0.970g、3.50mm
ol)、メタンスルホニルクロリド(0.298mL、
3.85mmol)及びピリジン(10mL)を使用し
て、実施例325に記載した方法に従い、標記目的化合
物(1.24g、収率100%)を得た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.49 (9H, s), 2.95
(3H, s), 3.12 (4H, m), 3.58 (4H, m), 6.61 (1H, b
s), 6.90 (2H, d, J=8.9 Hz), 7,18 (2H, d, J=8.9 H
z)。
(336b)N−[4−(1−ピペラジニル)フェニ
ル]メタンスルホンアミド・2塩酸塩
実施例336aで製造した4−(4−メタンスルホニル
アミノフェニル)ピペラジン−1−カルボン酸 ter
t−ブチルエステル(1.24g、3.49mmo
l)、p−アニソール、トリフルオロ酢酸(2mL)及
び塩化メチレン(20mL)を使用して、実施例292
に記載した方法に従い、N−[4−(1−ピペラジニ
ル)フェニル]メタンスルホンアミド・2トリフルオロ
酢酸塩(1.28g)を得た。The resulting crude N-acetyl-4- (1-
Piperazinyl) aniline (1.30 g), 2-chloro-
5-Nitrobenzoyl chloride (1.56g, 7.09m
mol) and pyridine (10 mL) according to the method described in Example 1 to give the title compound (0.335)
g, yield 30%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.99 (3H, s), 3.
00-3.30 (6H, m), 3.80 (2H, m), 6.90 (2H, d, J = 9.0 H
z), 7.43 (2H, d, J = 9.0 Hz), 7.87 (1H, d, J = 8.8 H
z), 8.28 (1H, dd, J = 2.7, 8.8 Hz), 8.34 (1H, d, J =
2.7 Hz), 9.72 (1H, bs); MS (FAB) m / z: 403 (M + H) + . (Example 336) N- [4- [4-[(2-chloro-5
-Nitrophenyl) carbonyl] piperazin-1-yl] phenyl] methanesulfonamide (336a) 4- (4-methanesulfonylaminophenyl) piperazine-1-carboxylic acid tert-butyl ester 4- (4-aminophenyl) piperazine- 1-Carboxylic acid tert-butyl ester (Tetrahedron Lett., 2
000 years, 41st volume, p.385) (0.970g, 3.50mm
ol), methanesulfonyl chloride (0.298 mL,
The title compound (1.24 g, yield 100%) was obtained according to the method described in Example 325 using 3.85 mmol) and pyridine (10 mL). 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.49 (9H, s), 2.95
(3H, s), 3.12 (4H, m), 3.58 (4H, m), 6.61 (1H, b
s), 6.90 (2H, d, J = 8.9 Hz), 7,18 (2H, d, J = 8.9 H
z). (336b) N- [4- (1-Piperazinyl) phenyl] methanesulfonamide dihydrochloride 4- (4-methanesulfonylaminophenyl) piperazine-1-carboxylic acid ter prepared in Example 336a
t-Butyl ester (1.24 g, 3.49 mmo
Example 292 using 1), p-anisole, trifluoroacetic acid (2 mL) and methylene chloride (20 mL).
According to the method described in 1., N- [4- (1-piperazinyl) phenyl] methanesulfonamide.2 trifluoroacetate salt (1.28 g) was obtained.
【0275】得られたトリフルオロ酢酸塩(1.28
g)を2N塩化水素−1,4−ジオキサン溶液(4m
L)に懸濁させ、室温で1時間攪拌した。反応溶液を減
圧下濃縮し、標記目的化合物(1.09g、収率95
%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.88 (3H, s), 3.
21 (4H, m), 3.31 (4H,m), 6.98 (2H, d, J=8.9 Hz),
7,13 (2H, d, J=8.9 Hz), 9.11 (1H, bs), 9.37(1H, b
s)。
(336c)N−[4−[4−[(2−クロロ−5−ニ
トロフェニル)カルボニル]ピペラジン−1−イル]フ
ェニル]メタンスルホンアミド
実施例336bで製造したN−[4−(1−ピペラジニ
ル)フェニル]メタンスルホンアミド・2塩酸塩(1.
09g、3.31mmol)、2−クロロ−5−ニトロ
安息香酸クロリド(0.874g、3.97mmol)
及びピリジン(15mL)を使用して、実施例325に
記載した方法に従い、粗製の標記目的化合物(0.62
3g、収率43%)を得た。得られた粗製の標記目的化
合物をシリカゲルカラムクロマトグラフィー(塩化メチ
レン:メタノール=10:1(v/v))にて精製し、標記
目的化合物(0.413g、収率28%)を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 2.86 (3H, s), 3.
00-3.30 (6H, m), 3.80(2H, m), 6.94 (2H, d, J=8.9 H
z), 7.10 (2H, d, J=8.9 Hz), 7.87 (1H, d, J=8.8 H
z), 8.28 (1H, dd, J=2.8, 8.8 Hz), 8.34 (1H, d, J=
2.8 Hz), 8.29 (1H,bs);
MS(FAB) m/z: 439 (M + H)+。
(実施例337)1−[(2−クロロ−5−ニトロフェ
ニル)カルボニル]−4−フェニルピペリジン
4−フェニルピペリジン(0.25g、1.52mmo
l)、2−クロロ−5−ニトロ安息香酸クロリド(0.
40g、1.82mmol)、ピリジン(2mL)及び
THF(10mL)を使用して、実施例1に記載した方
法に従い、標記目的化合物(0.45g、収率86%)
を得た。1
H-NMR (400MHz, DMSO-d6): δ(ppm) 1.55-1.97 (4H,
m), 2.78-2.98 (2H, m),3.14-3.26 (1H, m), 3.35-3.39
(1H, m), 4.62-4.72 (1H, m), 7.18-7.37 (5H,m), 7.8
3-7.88 (1H, m), 7.25-7.28 (2H, m), 8.42 (1H, d, J=
2.7 Hz);
MS(FAB) m/z: 345 (M + H)+。
(実施例338)N−(1−ベンジル−3−ピロリジニ
ル)−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド
1−ベンジル−3−アミノピロリジン(0.52g、
2.97mmol)、2−クロロ−5−ニトロ安息香酸
クロリド(0.79g、3.57mmol)及びピリジ
ン(10mL)を使用して、実施例1に記載した方法に
従い、標記目的化合物(0.83g、収率77%)を得
た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.74-1.82 (1H, m),
2.27-2.44 (2H, m), 2.58 (1H, dd, J=5.9, 10.0 Hz),
2.78 (1H, bd J=10.0 Hz), 2.94-3.00 (1H, m),
3.65 (2H, dd, J=12.8, 22.4 Hz), 4.65-4.70 (1H, m),
6.65 (1H, bd, J=7.9Hz), 7.23-7.38 (5H, m), 7.59
(1H, d, J=8.8 Hz), 8.20 (1H, dd, J=2.8, 8.8Hz), 8.
47 (1H, d, J=2.8 Hz)。
(実施例339)N−(1−ベンゾイルピロリジン−3
−イル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド
1−ベンゾイル−3−アミノピロリジン・1塩酸塩
(0.23g、1.00mmol)、2−クロロ−5−
ニトロ安息香酸クロリド(0.26g、1.20mmo
l)及びピリジン(5mL)を使用して、実施例1に記
載した方法に従い反応した。反応溶液を濃縮し、酢酸エ
チルで希釈し、飽和重曹水及び飽和食塩水で洗浄した。
有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮し、
減圧乾燥した。残渣をジイソプロピルエーテルで固化さ
せ、標記目的化合物(0.33g、収率88%)を得
た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.89-2.05 (1H, m),
2.10-2.25 (1H, m), 3.13-3.36及び3.14- 3.42 (計1H,
各m), 3.53-3.61及び3.64-3.71 (計2H, 各m), 3.72-3.
89 (1H, m), 4.34-4.40及び4.49-4.55 (計1H, 各m), 7.
41-7.55 (5H, m),7.80及び7.84 (計1H, 各d, 各J=8.7 H
z), 8.23-8.33 (2H, m), 8.96及び9.02 (計1H, 各d, J=
6.3及び7.0 Hz);
MS(FAB) m/z: 374 (M + H)+。
(実施例340)3−(N−tert−ブトキシカルボ
ニル)アミノ−1−(2−クロロ−5−ニトロベンゾイ
ル)ピロリジン
3−(N−tert−ブトキシカルボニル)アミノピロ
リジン(3.00g、16.11mmol)、2−クロ
ロ−5−ニトロ安息香酸クロリド(3.90g、17.
73mmol)、トリエチルアミン(4.5mL)及び
THF(30mL)を使用して、実施例1に記載した方
法に従い反応した。反応溶液を濃縮し、酢酸エチルで希
釈し、飽和重曹水及び飽和食塩水で洗浄した。有機層を
無水硫酸ナトリウムで乾燥し、減圧下濃縮し、減圧乾燥
して、標記目的化合物(5.66g、収率95%)を得
た。1
H-NMR (400MHz, CDCl3): δ(ppm) 1.35及び1.41 (計9
H, 各s), 1.71-1.90 (1H,m), 1.99-2.10 (1H, m), 3.11
-3.18及び2.95-3.00 (計1H, 各m), 3.20-3.30 (1H, m),
3.47-3.55及び3.58-3.70 (計2H, 各m), 3.94-4.00及び
4.06-4.14 (計1H,各m), 7.83及び7.86 (計1H, 各d, 各J
=2.7 Hz), 8.25-8.28及び8.34 (計2H, m及びd, J=2.7 H
z);
MS(FAB) m/z: 370 (M + H)+。
(参考例1)2−アミノ−4−(3,5−ジ−tert
−ブチル−4−ヒドロキシフェニル)チアゾール
3,5−ジ−tert−ブチル−4−ヒドロキシフェナ
シルブロミド9.81gをアセトン50mLに溶解し、
チオウレア4.56gを加え、室温で一晩攪拌した。反
応溶液を濃縮し、飽和重曹水を加え、酢酸エチルで抽出
した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウ
ムで乾燥し、減圧下濃縮した。残渣をジイソプロピルエ
ーテル及びヘキサンで固化させ、濾取し、乾燥して、標
記目的化合物8.92gを得た。1
H-NMR (400MHz, DMSO-d6,TMS): δ(ppm) 1.44 (9H,
s), 6.71 (1H, s), 7.26 (1H, s), 6.96 (2H, s), 6.97
(1H, s), 7.52 (1H, s)。
(参考例2)2−アミノ−4−(3−ピリジル)チアゾ
ール
3−アセチルピリジン4.37g、チオウレア5.49
g及びヨウ素9.16gを105℃で30時間攪拌し
た。反応混合物を冷却した後、水及びジエチルエ−テル
を加えて攪拌し、固形物を濾取した。得られた固形物を
飽和重曹水及び酢酸エチルに懸濁させ(水層のpHを8
以下に調整した)、1時間攪拌した。生じた固形物を濾
取し、乾燥して、標記目的化合物3.69gを得た。The obtained trifluoroacetic acid salt (1.28
g) in 2N hydrogen chloride-1,4-dioxane solution (4 m
L) and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the title object compound (1.09 g, yield 95
%) Was obtained. 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.88 (3H, s), 3.
21 (4H, m), 3.31 (4H, m), 6.98 (2H, d, J = 8.9 Hz),
7,13 (2H, d, J = 8.9 Hz), 9.11 (1H, bs), 9.37 (1H, b
s). (336c) N- [4- [4-[(2-chloro-5-nitrophenyl) carbonyl] piperazin-1-yl] phenyl] methanesulfonamide N- [4- (1-piperazinyl) prepared in Example 336b. ) Phenyl] methanesulfonamide dihydrochloride (1.
09 g, 3.31 mmol), 2-chloro-5-nitrobenzoic acid chloride (0.874 g, 3.97 mmol).
And pyridine (15 mL) according to the method described in Example 325 to give the crude title compound (0.62
3 g, yield 43%) was obtained. The obtained crude title compound was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1 (v / v)) to obtain the title compound (0.413 g, yield 28%). 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 2.86 (3H, s), 3.
00-3.30 (6H, m), 3.80 (2H, m), 6.94 (2H, d, J = 8.9 H
z), 7.10 (2H, d, J = 8.9 Hz), 7.87 (1H, d, J = 8.8 H
z), 8.28 (1H, dd, J = 2.8, 8.8 Hz), 8.34 (1H, d, J =
2.8 Hz), 8.29 (1H, bs); MS (FAB) m / z: 439 (M + H) + . (Example 337) 1-[(2-chloro-5-nitrophenyl) carbonyl] -4-phenylpiperidine 4-phenylpiperidine (0.25 g, 1.52 mmo
l), 2-chloro-5-nitrobenzoic acid chloride (0.
40 g, 1.82 mmol), pyridine (2 mL) and THF (10 mL) according to the method described in Example 1 (0.45 g, 86% yield).
Got 1 H-NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.55-1.97 (4H,
m), 2.78-2.98 (2H, m), 3.14-3.26 (1H, m), 3.35-3.39
(1H, m), 4.62-4.72 (1H, m), 7.18-7.37 (5H, m), 7.8
3-7.88 (1H, m), 7.25-7.28 (2H, m), 8.42 (1H, d, J =
2.7 Hz); MS (FAB) m / z: 345 (M + H) + . (Example 338) N- (1-benzyl-3-pyrrolidinyl)-(2-chloro-5-nitrophenyl) carboxamide 1-benzyl-3-aminopyrrolidine (0.52 g,
2.97 mmol), 2-chloro-5-nitrobenzoic acid chloride (0.79 g, 3.57 mmol) and pyridine (10 mL) according to the method described in Example 1 to give the title compound (0.83 g). , 77%) was obtained. 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.74-1.82 (1H, m),
2.27-2.44 (2H, m), 2.58 (1H, dd, J = 5.9, 10.0 Hz),
2.78 (1H, bd J = 10.0 Hz), 2.94-3.00 (1H, m), 3.65 (2H, dd, J = 12.8, 22.4 Hz), 4.65-4.70 (1H, m),
6.65 (1H, bd, J = 7.9Hz), 7.23-7.38 (5H, m), 7.59
(1H, d, J = 8.8 Hz), 8.20 (1H, dd, J = 2.8, 8.8 Hz), 8.
47 (1H, d, J = 2.8 Hz). (Example 339) N- (1-benzoylpyrrolidine-3)
-Yl)-(2-chloro-5-nitrophenyl) carboxamide 1-benzoyl-3-aminopyrrolidine monohydrochloride (0.23 g, 1.00 mmol), 2-chloro-5-
Nitrobenzoyl chloride (0.26g, 1.20mmo
The reaction was performed according to the method described in Example 1 using 1) and pyridine (5 mL). The reaction solution was concentrated, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine.
The organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure,
It was dried under reduced pressure. The residue was solidified with diisopropyl ether to give the title object compound (0.33 g, yield 88%). 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.89-2.05 (1H, m),
2.10-2.25 (1H, m), 3.13-3.36 and 3.14-3.42 (total 1H,
M), 3.53-3.61 and 3.64-3.71 (total 2H, m), 3.72-3.
89 (1H, m), 4.34-4.40 and 4.49-4.55 (total 1H, each m), 7.
41-7.55 (5H, m), 7.80 and 7.84 (total 1H, each d, each J = 8.7H
z), 8.23-8.33 (2H, m), 8.96 and 9.02 (total 1H, each d, J =
6.3 and 7.0 Hz); MS (FAB) m / z: 374 (M + H) + . (Example 340) 3- (N-tert-butoxycarbonyl) amino-1- (2-chloro-5-nitrobenzoyl) pyrrolidine 3- (N-tert-butoxycarbonyl) aminopyrrolidine (3.00 g, 16.11 mmol) ), 2-chloro-5-nitrobenzoic acid chloride (3.90 g, 17.
73 mmol), triethylamine (4.5 mL) and THF (30 mL) and reacted according to the method described in Example 1. The reaction solution was concentrated, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under reduced pressure to give the title object compound (5.66 g, yield 95%). 1 H-NMR (400MHz, CDCl 3 ): δ (ppm) 1.35 and 1.41 (total 9
H, each s), 1.71-1.90 (1H, m), 1.99-2.10 (1H, m), 3.11
-3.18 and 2.95-3.00 (total 1H, each m), 3.20-3.30 (1H, m),
3.47-3.55 and 3.58-3.70 (total 2H, each m), 3.94-4.00 and
4.06-4.14 (total 1H, each m), 7.83 and 7.86 (total 1H, each d, each J
= 2.7 Hz), 8.25-8.28 and 8.34 (total 2H, m and d, J = 2.7H)
z); MS (FAB) m / z: 370 (M + H) + . Reference Example 1 2-Amino-4- (3,5-di-tert)
-Butyl-4-hydroxyphenyl) thiazole 3,5-di-tert-butyl-4-hydroxyphenacyl bromide 9.81 g was dissolved in acetone 50 mL,
4.56 g of thiourea was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was solidified with diisopropyl ether and hexane, collected by filtration, and dried to obtain 8.92 g of the title object compound. 1 H-NMR (400MHz, DMSO-d 6 , TMS): δ (ppm) 1.44 (9H,
s), 6.71 (1H, s), 7.26 (1H, s), 6.96 (2H, s), 6.97
(1H, s), 7.52 (1H, s). (Reference Example 2) 2-amino-4- (3-pyridyl) thiazole 3-acetylpyridine 4.37 g, thiourea 5.49
g and 9.16 g of iodine were stirred at 105 ° C. for 30 hours. After cooling the reaction mixture, water and diethyl ether were added and stirred, and the solid substance was collected by filtration. The obtained solid was suspended in saturated aqueous sodium hydrogen carbonate and ethyl acetate (the pH of the aqueous layer was adjusted to 8
(Adjusted below), and stirred for 1 hour. The resulting solid matter was collected by filtration and dried to obtain 3.69 g of the title object compound.
【0276】1H-NMR (400MHz, DMSO-d6,TMS): δ(ppm)
7.16 (2H, s), 7.19 (1H, s), 7.39(1H, dd, J=8.0, 4.
8Hz), 8.12 (1H, dt, J=8.0, 2.0Hz), 8.45 (1H, dd, J
=4.8, 1.6Hz), 9.00 (1H, m)。
(試験例)下記試験例において、各操作は特に記載がな
い限り、文献(Sambrook, J., Fritsch, E.F.及びMani
atis, T.著,「Molecular Cloning」,Cold Spring Har
bor Laboratory Press,1989年)に記載の方法により行
った。また、市販の試薬やキットは添付の指示書に従っ
て使用した。
(試験例1)PPARγモジュレーター活性の評価
(手順1)ポリメラーゼ連鎖反応プライマーとなるDNA
オリゴマーの化学合成
ポリメラーゼ連鎖反応(以下「PCR」という)プライマ
ーの設計にあたっては、ヒトPPARγ2遺伝子配列(GenBA
NK accession No. D83233)に基づいて行なった。ヒトP
PARγ2タンパク質をコードする遺伝子の上流域及び下流
域には、該遺伝子の発現プラスミドpSG5(Staratagene
社)の制限酵素部位BamHIに挿入せしめるために必要な
制限酵素BglIIによる認識配列を付加し、PCRプライマー
となる後記配列表の配列番号1及び2に示された2種のポ
リヌクレオチド(以下それぞれ「S1」、「AS1」とい
う)を使用した。
(手順2)PPARγ応答遺伝子配列を含むDNAオリゴマー
の化学合成
PPARγを介した転写活性化能を測定する目的で、PPAR応
答配列を有するレポータープラスミドを構築するため
に、以下の後記配列表の配列番号3及び4に示された2種
のポリヌクレオチド(以下「S2」、「AS2」という)を
使用した。挿入するDNA断片の設計は、ラットにおける
アシルCo-Aオキシダーゼのプロモーター領域の遺伝子配
列(J. D. Tugwood, EMBO J, 1992年,第11巻,第2号,
p.433-439)に基づいて行なった。レポータープラスミ
ドpGV-P2(東洋インキ社)に挿入せしめるために、S2に
は制限酵素NheI、AS2にはXhoIによる認識配列を付加し
た。
(手順3)ヒトPPARγ発現プラスミドの構築
図1にPPARγ発現プラスミドの模式図を示す。 1 H-NMR (400 MHz, DMSO-d 6 , TMS): δ (ppm)
7.16 (2H, s), 7.19 (1H, s), 7.39 (1H, dd, J = 8.0, 4.
8Hz), 8.12 (1H, dt, J = 8.0, 2.0Hz), 8.45 (1H, dd, J
= 4.8, 1.6Hz), 9.00 (1H, m). (Test Examples) In the following test examples, each operation is described in the literature (Sambrook, J., Fritsch, EF and Mani unless otherwise specified.
atis, T., "Molecular Cloning", Cold Spring Har
bor Laboratory Press, 1989). In addition, commercially available reagents and kits were used according to the attached instructions. (Test Example 1) Evaluation of PPARγ modulator activity (procedure 1) Polymerase chain reaction primer DNA
Oligomers chemically synthesized Polymerase chain reaction (hereinafter referred to as "PCR") When designing primers, the human PPARγ2 gene sequence (GenBA
NK accession No. D83233). Human P
In the upstream region and downstream region of the gene encoding the PARγ2 protein, the expression plasmid pSG5 (Staratagene
Of the two types of polynucleotides shown in SEQ ID NOS: 1 and 2 in the sequence listing below as PCR primers by adding a recognition sequence by the restriction enzyme BglII necessary for insertion into the restriction enzyme site BamHI of "S1", "AS1") was used. (Procedure 2) Chemical Synthesis of DNA Oligomers Containing PPARγ Response Gene Sequence For the purpose of measuring the PPARγ-mediated transcription activation ability, in order to construct a reporter plasmid having a PPAR response sequence, SEQ ID NO: Two types of polynucleotides shown in 3 and 4 (hereinafter referred to as "S2" and "AS2") were used. The design of the DNA fragment to be inserted is based on the gene sequence of the promoter region of acyl Co-A oxidase in rat (JD Tugwood, EMBO J, 1992, Vol. 11, No. 2,
p.433-439). In order to insert into the reporter plasmid pGV-P2 (Toyo Ink Co., Ltd.), a recognition sequence by restriction enzyme NheI was added to S2 and a recognition sequence by XhoI was added to AS2. (Procedure 3) Construction of human PPARγ expression plasmid Figure 1 shows a schematic diagram of the PPARγ expression plasmid.
【0277】ヒト脂肪組織由来のcDNAライブラリー(Cl
ontech社)を鋳型として、手順1で得られるPCRプライ
マーとなるDNAオリゴマーS1、AS1を用いて、PCRを耐熱
性DNAポリメラーゼEx-Taq(宝酒造社)を用いて行な
い、約1500塩基対(以下bpという)のDNA断片が増幅さ
れた。各サイクルは、94℃で1分、55℃で30秒及び72℃
で30秒のインキュベーションの30サイクルからなる。得
られた約1500bpのDNA断片を制限酵素BglIIで部分的に切
断し、pSG5の制限酵素部位BamHIに挿入し、ヒトPPARγ
発現プラスミドpSG5-hPPARgを得た。挿入されたDNA断片
はジデオキシヌクレオチド鎖終結法により、そのDNAの
塩基配列がヒトPPARγ2であることを確認した。
(手順4)レポータープラスミドの構築
図2にPPREレポータープラスミドの模式図を示す。CDNA library derived from human adipose tissue (Cl
ontech) as a template and PCR using the DNA oligomers S1 and AS1 as PCR primers obtained in step 1, PCR was performed using a thermostable DNA polymerase Ex-Taq (Takara Shuzo), and about 1500 base pairs (hereinafter bp DNA fragment) was amplified. Each cycle consists of 94 ° C for 1 minute, 55 ° C for 30 seconds and 72 ° C.
It consists of 30 cycles of 30 seconds incubation. The obtained DNA fragment of about 1500 bp was partially cleaved with the restriction enzyme BglII and inserted into the restriction enzyme site BamHI of pSG5 to obtain human PPARγ.
The expression plasmid pSG5-hPPARg was obtained. By the dideoxynucleotide chain termination method, it was confirmed that the DNA sequence of the inserted DNA fragment was human PPARγ2. (Procedure 4) Construction of Reporter Plasmid FIG. 2 shows a schematic diagram of the PPRE reporter plasmid.
【0278】制限酵素NheI、XhoIにより消化され、1.0%
アガロースゲル電気泳動により精製されたベクターpGV-
P2消化物を調製した。手順2で得られたDNAオリゴマーS
2、AS2を混合し、94℃の湯浴中1分間インキュベートし
た後、25℃で1時間インキュベートしてS2とAS2がアニー
リングした2本鎖DNAを形成させた。その後、DNAポリヌ
クレオチドキナーゼ(東洋紡績社)を用いて末端をリン
酸化した後、先に調製したpGV-P2消化物と制限酵素部位
NheI、XhoIを用いて連結し、PPAR応答配列を有するレポ
ータープラスミドpGV-P2-PPREを得た。
(手順5)動物細胞への遺伝子導入
手順3、手順4で得られたプラスミド用いて、大腸菌HB
-101株を常法により、形質転換した。プラスミドを有す
るHB-101株をアンピシリン100μg/mlを含むL-broth培地
(10g トリプトン(Difco)、5g イーストエクストラク
ト(Difco)、5g 塩化ナトリウムをそれぞれ1Lの水溶液
に含む)にて、37℃で17時間培養を行なった。その後、
アルカリSDS法により、各々のプラスミドを精製し、動
物細胞への遺伝子導入に用いた。LipofectAMINE試薬の
添付のマニュアルに準じて、pSG5-hPPARg、pGV-P2-PPR
E、LipofectAMINE試薬(Invitrogen Cat.No.18324-02
0)を混合し、ヒト骨肉腫細胞株MG63に一過性に遺伝子
導入したのち、細胞を回収した。回収された細胞は10%
牛胎児血清(MOREGATE BATCH:474030)10%(v/v)、Peni
cillin−Streptomycin,Liquid(GIBCO BRL Cat.No.1514
0-122)を1%(v/v)となるように混合したα-MEM培地(GI
BCO BRL Cat.No.12571-048)(以下10% α-MEMと略
す)を用いて、96穴プレート(COSTAR 3917)に30000乃
至40000 cells/wellになるように各ウェルに播種し、CO
2インキュベータ(NAPCO)を用いて37℃、5%CO2、95%
-RHの条件で24時間培養した。
(手順6)転写活性化促進作用評価のための試薬添加法
手順5で調整した培養プレートから培地を取り除いた。
コントロール群には10%α-MEMを95μl/wellずつ加え
た。ポジティブコントロール群には10μM DMSO溶液に調
製した下記の化合物A(一例として化合物Aを示すがPPAR
γアゴニストであれば、これに限らない)を10%α-MEM
で千分の一になるよう希釈し、これを95μl/wellずつ加
えた。その後、DMSOを10%α-MEMで20倍希釈したものを
5μl/wellずつコントロール群及びポジティブコントロ
ール群へ添加した。被験化合物添加群には10%α-MEMを
95μl/wellずつ加えた。その後、DMSOにより種々の濃度
に希釈した被験化合物を10%α-MEMで20倍希釈し、これ
を5μl/well添加した。
(化合物A及びその製造方法)
化合物A:N-[4-[2-[4-(2,4-ジオキソチアゾリジン-5-イ
ルメチル)フェノキシメチル]-1-メチル-1H-ベンズイミ
ダゾール-6-イルオキシ]フェニル]ベンズアミド
5-[4-[6-(4-アミノフェノキシ)-1-メチル-1H-ベンズイ
ミダゾール-2-イルメトキシ]ベンジル]チアゾリジン-2,
4-ジオン・二塩酸塩400mgの無水N,N-ジメチルホルム
アミド8mlの溶液に、トリエチルアミン0.36ml及び
ベンゾイルクロリド0.10mlを滴下した。この反応溶液
を室温で1時間撹拌した後、減圧下、溶媒を留去し、残
査に水を加え、酢酸エチルで抽出した。有機層を飽和食
塩水で洗浄し、無水硫酸ナトリウムで乾燥した。酢酸エ
チルを留去し、残査をシリカゲルカラムクロマトグラフ
ィ−(酢酸エチル:n−ヘキサン=1:1→2:1→3:1→
4:1)により精製して、白色粉末の目的化合物247mgを
得た。Digested with restriction enzymes NheI and XhoI, 1.0%
Vector pGV- purified by agarose gel electrophoresis
A P2 digest was prepared. DNA oligomer S obtained in step 2
2. AS2 was mixed and incubated in a 94 ° C water bath for 1 minute and then at 25 ° C for 1 hour to form double-stranded DNA in which S2 and AS2 annealed. Then, after phosphorylating the ends using DNA polynucleotide kinase (Toyobo Co., Ltd.), the pGV-P2 digest and the restriction enzyme site prepared above were used.
Ligation was performed using NheI and XhoI to obtain a reporter plasmid pGV-P2-PPRE having a PPAR response element. (Procedure 5) Escherichia coli HB was prepared using the plasmids obtained in Procedure 3 and Procedure 4 for gene transfer into animal cells.
The -101 strain was transformed by a conventional method. Plasmid-containing HB-101 strain in L-broth medium containing 100 μg / ml ampicillin (10 g tryptone (Difco), 5 g yeast extract (Difco), 5 g sodium chloride in 1 L aqueous solution at 37 ° C) The culture was performed for 17 hours. afterwards,
Each plasmid was purified by the alkaline SDS method and used for gene transfer into animal cells. According to the attached manual of LipofectAMINE reagent, pSG5-hPPARg, pGV-P2-PPR
E, LipofectAMINE Reagent (Invitrogen Cat.No.18324-02
0) was mixed and the gene was transiently introduced into the human osteosarcoma cell line MG63, and then the cells were collected. 10% of recovered cells
Fetal bovine serum (MOREGATE BATCH: 474030) 10% (v / v), Peni
cillin-Streptomycin, Liquid (GIBCO BRL Cat.No.1514
0-122) was mixed at 1% (v / v) in α-MEM medium (GI
BCO BRL Cat.No.12571-048) (hereinafter abbreviated as 10% α-MEM) is used to inoculate each well into a 96-well plate (COSTAR 3917) at 30,000 to 40,000 cells / well, and CO
37 ° C, 5% CO 2 , 95% using 2 incubator (NAPCO)
-The cells were cultured under RH conditions for 24 hours. (Procedure 6) Reagent addition method for evaluating transcription activation promoting action The medium was removed from the culture plate prepared in Procedure 5.
95% / well of 10% α-MEM was added to the control group. For the positive control group, the following compound A prepared in a 10 μM DMSO solution (compound A is shown as an example
If it is a γ agonist, it is not limited to this) 10% α-MEM
It was diluted to 1 / 1,000, and this was added at 95 μl / well. Then, dilute DMSO 20 times with 10% α-MEM.
5 μl / well was added to each of the control group and the positive control group. 10% α-MEM was added to the test compound-added group
95 μl / well was added. Then, the test compound diluted to various concentrations with DMSO was diluted 20-fold with 10% α-MEM, and 5 μl / well was added thereto. (Compound A and production method thereof) Compound A: N- [4- [2- [4- (2,4-dioxothiazolidine-5-y
Lumethyl) phenoxymethyl] -1-methyl-1H-benzimi
Dazol-6-yloxy] phenyl] benzamide 5- [4- [6- (4-aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,
To a solution of 400 mg of 4-dione dihydrochloride in 8 ml of anhydrous N, N-dimethylformamide, 0.36 ml of triethylamine and 0.10 ml of benzoyl chloride were added dropwise. The reaction solution was stirred at room temperature for 1 hour, the solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1 → 2: 1 → 3: 1 →
Purification by 4: 1) yielded 247 mg of the target compound as a white powder.
【0279】融点:200-204℃。
(手順7)転写活性化抑制作用評価のための試薬添加法
手順5で調整した培養プレートから培地を取り除いた。
コントロール群には10%α-MEMを95μl/wellずつ加え
た。ポジティブコントロール群には10μM DMSO溶液に調
製した上記の化合物Aを10%α-MEMで千分の一になるよ
う希釈し、これを95μl/wellずつ加えた。その後、DMSO
を10%α-MEMで20倍希釈し、これを5μl/wellずつコン
トロール群及びポジティブコントロール群へ添加した。
被験化合物添加群には、10μM DMSO溶液に調製した化合
物Aを10%α-MEMで千分の一になるよう希釈したものを9
5μl/wellずつ加えた。その後、DMSOにより種々の濃度
に希釈した被験化合物を10%α-MEMで20倍希釈し、これ
を5μl/well添加した。
(手順8)ルシフェラーゼ活性の測定法
手順6及び手順7で調製した細胞を24時間培養後、培地
を取り除き、ルシフェラーゼ発光基質LT2.0(和光純薬
工業 Cat.No.309-05884)に等量のDulbecco's Phosphat
e-Buffered Saline(GIBCO BRL Cat.No.14040-117また
はSIGMA CHEMICALCO. Cat.No.D8662)を加えたものを50
μl/wellずつ加え、室温で約10分間放置後、マイクロミ
キサー(TAITEC E-36)で攪拌した。ルミノメーターARG
US50(浜松ホトニクス社)又はAnalyst(LjL社)を用い
て、ルシフェラーゼ活性を測定し、用量依存曲線を描い
た。
(手順9)IC50及びEC50の算出方法
被験化合物のIC50、Imax、EC50及びEmaxを定めるにあた
り、これらの値を次のように定義する。図3に概念図を
示す。ポジティブコントロール群のルシフェラーゼ活性
値を100%、コントロール群のルシフェラーゼ活性値を0
%とするとき、被験化合物単独で示すルシフェラーゼ活
性の最大値をEmax(%)、化合物A存在時に被験化合物に
よって抑制されたルシフェラーゼ活性の最大抑制値をIm
ax(%)とする。そのとき、Emax/2の値を示す被験化合
物の濃度をEC50として算出する。また、(100-Imax)/2の
値を示す被験化合物の濃度をIC50として算出する。この
ようにして算出されたIC50及びEC50をPPARγモジュレー
ター活性の評価に用いた。Melting point: 200-204 ° C. (Procedure 7) Reagent Addition Method for Evaluation of Transcriptional Activation Inhibition The medium was removed from the culture plate prepared in Step 5.
95% / well of 10% α-MEM was added to the control group. For the positive control group, the above compound A prepared in a 10 μM DMSO solution was diluted with 10% α-MEM to a thousandth, and this was added at 95 μl / well. Then DMSO
Was diluted 20-fold with 10% α-MEM, and 5 μl / well of this was added to the control group and the positive control group.
For the test compound-added group, compound A prepared in a 10 μM DMSO solution was diluted with 10% α-MEM to 1/1000, and
5 μl / well was added. Then, the test compound diluted to various concentrations with DMSO was diluted 20-fold with 10% α-MEM, and 5 μl / well was added thereto. (Procedure 8) Method for measuring luciferase activity After culturing the cells prepared in Procedure 6 and Procedure 7 for 24 hours, the medium was removed and an equal amount was added to the luciferase luminescent substrate LT2.0 (Wako Pure Chemical Industries Cat. No. 309-05884). Dulbecco's Phosphat
50 with e-Buffered Saline (GIBCO BRL Cat.No.14040-117 or SIGMA CHEMICALCO.Cat.No.D8662) added
Each μl / well was added, and the mixture was left at room temperature for about 10 minutes and then stirred with a micromixer (TAITEC E-36). Luminometer ARG
Luciferase activity was measured using US50 (Hamamatsu Photonics) or Analyst (LjL), and a dose-dependent curve was drawn. (Procedure 9) Calculation method of IC 50 and EC 50 In determining IC 50 , Imax, EC 50 and Emax of the test compound, these values are defined as follows. Figure 3 shows a conceptual diagram. The luciferase activity value of the positive control group is 100%, and the luciferase activity value of the control group is 0.
%, The maximum value of luciferase activity shown by the test compound alone is Emax (%), and the maximum value of luciferase activity suppressed by the test compound in the presence of Compound A is Im.
Let it be ax (%). At that time, the concentration of the test compound showing the value of Emax / 2 is calculated as EC 50 . Further, the concentration of the test compound showing a value of (100-Imax) / 2 is calculated as IC 50 . The IC 50 and EC 50 calculated in this way were used for evaluation of PPARγ modulator activity.
【0280】測定結果を表1に示す。The measurement results are shown in Table 1.
【0281】[0281]
【表1】
表1に示されるように、本発明の化合物は、PPARγ
モジュレーター活性を有し、脂質代謝異常に基づく疾
患、動脈硬化症、高脂血症、糖尿病、退行期骨粗鬆症、
肥満若しくはガン等の治療薬又は予防薬として有用であ
る。
(試験例2)骨芽細胞分化試験
本試験において、マウス骨髄初代培養細胞の培養には、
非働化した牛胎児血清(Hyclone社、FBS, Lot.AHM941
9)を15%(v/v)、Penicillin − Streptomycin,Liquid
(GIBCO BRL Cat.No.15140-122)を1%(v/v)となるよう
に混合したα-MEM培地(GIBCO BRL Cat.No.11900-024)
(以下15%-FBS-αMEMと略す)を用いた。本試験での培
養はすべてCO2インキュベータ内(37℃、95%湿度、5%
CO2)で行った。[Table 1] As shown in Table 1, the compounds of the present invention have PPARγ
It has a modulator activity and is caused by abnormal lipid metabolism, arteriosclerosis, hyperlipidemia, diabetes, regressive osteoporosis,
It is useful as a therapeutic or preventive drug for obesity or cancer. (Test Example 2) Osteoblast Differentiation Test In this test, for culturing mouse bone marrow primary culture cells,
Inactivated fetal bovine serum (Hyclone, FBS, Lot.AHM941
9) 15% (v / v), Penicillin-Streptomycin, Liquid
(GIBCO BRL Cat.No.15140-122) mixed at 1% (v / v) α-MEM medium (GIBCO BRL Cat.No.11900-024)
(Hereinafter, abbreviated as 15% -FBS-αMEM) was used. All cultures in this test were performed in a CO 2 incubator (37 ℃, 95% humidity, 5%
CO 2 ).
【0282】7週齢雄性BDF1マウスを日本チャ−ルスリ
バーより購入し、以下の実験に供した。マウスをエーテ
ル麻酔下で頚動脈切断により放血死させ、左右大腿骨及
び脛骨を摘出した。摘出した大腿骨及び脛骨の周囲の組
織を除去した後、両端を切断した。調整した大腿骨及び
脛骨に対し、15%-FBS-αMEM 1mLを入れた注射器の針を
骨端部から挿入して、骨髄を押し出して採取した。セル
ストレーナー(BectonDickinson社)で濾過して採取し
た骨髄細胞を25cm2培養用プレート(SUMITOMOBAKELITE
社 Cat.No.MS-22050)に播種し、15%-FBS-αMEM 5mLで
コンフルエントになるまで7日間培養した。Seven-week-old male BDF1 mice were purchased from Japan Charles River and used for the following experiments. The mice were exsanguinated to death by carotid artery cutting under ether anesthesia, and the left and right femurs and tibias were excised. After removing the tissue around the extracted femur and tibia, both ends were cut. For the adjusted femur and tibia, a needle of a syringe containing 1 mL of 15% -FBS-αMEM was inserted from the epiphyseal part, and bone marrow was extruded and collected. Bone marrow cells collected by filtration with a cell strainer (Becton Dickinson) are used for 25 cm 2 culture plate (SUMITOMOBAKELITE
Cat. No. MS-22050) of the same company, and cultured for 7 days until it became confluent with 5 mL of 15% -FBS-αMEM.
【0283】上記の細胞を0.05 %トリプシン-EDTA溶液
(GIBCO BRL Cat.No.25200-056)1mLで剥離させ、15%-
FBS-αMEM 5mLを加え細胞を分散させた後、遠心分離に
より(25℃, 800 rpm, 4分間)細胞を回収した。回収し
た細胞を15%-FBS-αMEMを用いて、80,000 cells/mLの
細胞懸濁液を調製した。細胞懸濁液を96穴マイクロプレ
ート(SUMITOMO BAKELITE社)に、8,000個/wellになる
ように100μLずつ各ウェルに分注し、24時間培養した。
下記のコントロール群Iを除くウェルには、化合物Aを
終濃度10nMになるように調製した15%-FBS-αMEMを96μ
Lずつ分注した。コントロール群Iのウェルには化合物A
を含まない15%-FBS-αMEMを分注した。ウェルに対し
て、1)被験化合物1mM、100μM及び10μMのDMSO溶液
を15%-FBS-αMEMで20倍希釈したものを、4μL/well
(最終濃度1μM、100nMおよび10nM)、2)DMSOを15%-
FBS-αMEMで20倍希釈したものを4μL/well(最終濃度0.
1%(v/v))(コントロール群I)、3)DMSOを15%-FBS-
αMEMで20倍希釈したものを4μL/well(最終濃度0.1%
(v/v))(コントロール群II)各々添加した。1週間培養
後、各群に対してアルカリホスファターゼ(ALP)活性
の測定を行った。The above cells were detached with 1 mL of 0.05% trypsin-EDTA solution (GIBCO BRL Cat.No.25200-056), and 15%-
After adding 5 mL of FBS-αMEM to disperse the cells, the cells were collected by centrifugation (25 ° C, 800 rpm, 4 minutes). A cell suspension of 80,000 cells / mL was prepared from the recovered cells using 15% -FBS-αMEM. 100 μL of the cell suspension was dispensed into a 96-well microplate (SUMITOMO BAKELITE) at 100 μL / well and cultured for 24 hours.
96 μl of 15% -FBS-αMEM prepared so that the final concentration of Compound A was 10 nM was added to the wells except the control group I below.
L was dispensed. Compound A in control group I wells
15% -FBS-αMEM that did not contain was dispensed. 4 μL / well of 1) DMSO solution of 1 mM, 100 μM and 10 μM of test compound diluted 20-fold with 15% -FBS-αMEM for each well
(Final concentration 1 μM, 100 nM and 10 nM), 2) DMSO 15%-
Dilute 20 times with FBS-αMEM to 4 μL / well (final concentration of 0.
1% (v / v)) (control group I), 3) DMSO 15% -FBS-
4μL / well (final concentration 0.1%)
(v / v)) (control group II). After culturing for 1 week, alkaline phosphatase (ALP) activity was measured for each group.
【0284】ALP活性の測定は、以下のように行った。
即ち、培養プレートの各ウェルの培地を全量除去した
後、Dulbecco'sリン酸バッファー(GIBCO BRL Cat.No.1
4190-144)100μLで分注し除去することにより、各ウェ
ルを2回ずつ洗浄した。0.67Mジエタノールアミン(和光
純薬 Cat.No.099-03112)、0.67mM MgCl2、0.1%(v/v)T
riton X-100(Sigma社)を含む細胞溶解液を作製し、細
胞溶解液を50 μL/wellで分注し室温で5分、撹拌した。
最終濃度20%(v/v)SapphireII(登録商標:TROPIX社)、
最終濃度6.7%(v/v)CDP-Star(TROPIX社)になるように
細胞溶解液と混合してALP基質溶液を作成し、ALP基質溶
液を50 μL/well分注し、室温で10分間撹拌後、マイク
ロプレートマルチリーダーAnalyst(LjL社)を用いて発
光強度を測定した。各プレートのコントロール群Iの測
定値を100 %、コントロール群IIの測定値を0%とした際
の、被験化合物添加群のアルカリフォスファターゼ回復
率(%)を算出し、骨芽細胞の分化度を評価した。The ALP activity was measured as follows.
That is, after completely removing the medium from each well of the culture plate, Dulbecco's phosphate buffer (GIBCO BRL Cat. No. 1
4190-144) Each well was washed twice by pipetting 100 μL and removing. 0.67M Diethanolamine (Wako Pure Chemical Industries Cat.No.099-03112), 0.67mM MgCl 2 , 0.1% (v / v) T
A cell lysate containing riton X-100 (Sigma) was prepared, the cell lysate was dispensed at 50 μL / well, and the mixture was stirred at room temperature for 5 minutes.
Final concentration 20% (v / v) SapphireII (registered trademark: TROPIX),
ALP substrate solution was prepared by mixing with cell lysate so that the final concentration was 6.7% (v / v) CDP-Star (TROPIX), and the ALP substrate solution was dispensed at 50 μL / well for 10 minutes at room temperature. After stirring, the luminescence intensity was measured using a microplate multi-reader Analyst (LjL). Calculate the alkaline phosphatase recovery rate (%) of the test compound-added group when the measured value of the control group I of each plate was 100% and the measured value of the control group II was 0%, and the degree of osteoblast differentiation was calculated. evaluated.
【0285】脂肪細胞分化抑制の指標として、脂肪細胞
染色を以下のように行った。培地を全量除去し、10%(v
/v)ホルムアルデヒド水溶液(固定液)を各ウェルに60
μLを加えて、細胞を20分間室温で静置した。固定液を
全量除去し、0.2%(v/v) Triton X-100(Sigma社)水溶
液を60μL各ウェルに分注し5分間室温で静置した。Trit
on X-100水溶液を全量除去し、60%(v/v)イソプロパノー
ル水溶液にOil Red O(Sigma社)を0.3%(w/v)になるよ
うに溶解した脂肪染色液を各ウェルに60μLずつ分注
し、室温で10分間静置した。脂肪染色液を全量除去した
後、60%(v/v)イソプロパノール水溶液60μLを分注し除
去することにより、各ウェルを2回ずつ洗浄した。プレ
ートを顕鏡して、コントロール群IIと被験化合物添加群
で染色された細胞の割合を比較し、被験化合物添加群
は、コントロール群と比較して、脂肪細胞分化度が少な
い事を確認した。Adipocyte staining was performed as follows as an index for suppressing adipocyte differentiation. Remove all the medium and
/ v) 60% formaldehyde solution (fixed solution) in each well
μL was added and the cells were left at room temperature for 20 minutes. The fixing solution was completely removed, and a 0.2% (v / v) Triton X-100 (Sigma) aqueous solution was dispensed into each well in an amount of 60 μL, and left still at room temperature for 5 minutes. Trit
on X-100 aqueous solution was completely removed, and 60 μL of lipid staining solution was prepared by dissolving Oil Red O (Sigma) in 60% (v / v) isopropanol aqueous solution to 0.3% (w / v). It dispensed and left still at room temperature for 10 minutes. After completely removing the fat staining liquid, 60 μL of a 60% (v / v) isopropanol aqueous solution was dispensed and removed to wash each well twice. The plate was observed under a microscope to compare the proportions of cells stained in the control group II and the test compound-added group, and it was confirmed that the test compound-added group had a lesser degree of adipocyte differentiation than the control group.
【0286】アルカリフォスファターゼ回復率を表2に
示す。The alkaline phosphatase recovery rate is shown in Table 2.
【0287】[0287]
【表2】
表2に示されるように、本発明の化合物は骨芽細胞の脂
肪細胞化を抑制し、骨粗鬆症の治療薬又は予防薬として
有用である。
(試験例3)脂肪細胞分化抑制試験
ラット白色脂肪細胞は、ホクドー社より購入した白色脂
肪細胞培養キットに含まれる細胞を実験に供した。増殖
用メディウム、分化誘導用メディウムは、ホクドー社よ
り購入した白色脂肪細胞培養キットに含まれるメディウ
ムを用いた。本実験の細胞培養は、全てCO2インキュベ
ーター(37℃、95%湿度、5%CO2)で培養を行った。[Table 2] As shown in Table 2, the compound of the present invention suppresses adipogenesis of osteoblasts and is useful as a therapeutic or preventive agent for osteoporosis. Test Example 3 Adipocyte Differentiation Inhibition Test As rat white adipocytes, the cells contained in the white adipocyte culture kit purchased from Hokudo Co., Ltd. were used for the experiment. As the medium for proliferation and the medium for differentiation induction, the medium contained in the white adipocyte culture kit purchased from Hokudo Co., Ltd. was used. All cell cultures in this experiment were carried out in a CO 2 incubator (37 ° C, 95% humidity, 5% CO 2 ).
【0288】購入した細胞は到着後直ちに輸送用培地を
全量抜き取り、増殖用メディウム5ml(/25cm2-フラス
コ)を加えて、1日培養した。その後、増殖用メディウ
ムを用いて83,000cells/mLの細胞懸濁液を調整し、96穴
I型コラーゲンコートマイクロプレート(SUMITOMO BAK
ELITE社)に5,000cells/well(60μL/well)になるよう
に細胞懸濁液を分注した。ブランク群として、細胞を含
まない増殖用メディウムのみを分注したウェル(ブラン
クウェル)を各プレートに設けた。Immediately after arrival of the purchased cells, the entire amount of the transport medium was extracted, 5 ml of a growth medium (/ 25 cm 2 -flask) was added, and the cells were cultured for 1 day. After that, a cell suspension of 83,000 cells / mL was prepared using a growth medium, and a 96-well type I collagen-coated microplate (SUMITOMO BAK
The cell suspension was dispensed at 5,000 cells / well (60 μL / well) in ELITE. As a blank group, each plate was provided with wells (blank wells) into which only cells-free growth medium was dispensed.
【0289】翌日、増殖用メディウムを全量除去し、分
化誘導用メディウムを147μL/wellずつ加えた。更に
1)被験化合物添加群には、被験化合物の100μM DMSO
溶液を分化誘導用メディウムで20倍希釈したものを3μL
/well(被験化合物最終濃度:100nM、DMSO最終濃度:0.
1%(v/v))及び前記化合物Aを最終濃度3.3nM(この際
のDMSOは最終濃度0.01%となるので無視できる量とす
る)、2)ポジティブ対照群には、DMSOを分化誘導用メ
ディウムで20倍希釈したものを3μL/well(DMSO最終濃
度:0.1%(v/v))及び化合物Aを最終濃度3.3nM、3)
ネガティブ対照群には、DMSOを分化誘導用メディウムで
20倍希釈したものを3μL/well(DMSO最終濃度:0.1%
(v/v))、細胞を撒いたウェルに加えた。On the next day, the entire amount of the proliferation medium was removed, and the differentiation-inducing medium was added at 147 μL / well. 1) The test compound added group contained 100 μM DMSO of the test compound.
3 μL of 20-fold diluted solution with differentiation-inducing medium
/ well (final concentration of test compound: 100 nM, final concentration of DMSO: 0.
1% (v / v)) and the compound A at a final concentration of 3.3 nM (DMSO at this time is 0.01% so the concentration is negligible). 2) DMSO is used for differentiation induction in the positive control group. 3μL / well (DMSO final concentration: 0.1% (v / v)) diluted 20 times with medium and Compound A final concentration 3.3nM, 3)
DMSO was used as a medium for differentiation induction in the negative control group.
20μ diluted to 3μL / well (DMSO final concentration: 0.1%
(V / v)), and the cells were added to the wells.
【0290】5日間培養した後、各ウェルの分化誘導用
メディウムを全量除去し、10%(v/v)ホルムアルデヒ
ド水溶液(固定液)60μLを各ウェルに加えて、細胞を2
0分間室温で静置した。固定液を全量除去し、0.2%(v/
v) Triton X-100(Sigma社)水溶液を60μL各ウエルに
分注し5分間室温で静置した。Triton X-100水溶液を全
量除去し、60%(v/v)イソプロパノール水溶液にOil Re
d O(Sigma社)を0.3%(w/v)になるように溶解した脂
肪染色液60μLを各ウエルに分注し、室温で10分間静置
した。脂肪染色液を全量除去した後、60%(v/v)イソプ
ロパノール水溶液60μLを分注し除去することにより、
各ウエルを2回ずつ洗浄した。その後、DMSOを各ウエル
に100μLずつ添加し、室温で5分間攪拌した。マルチプ
レートリーダー(BIO-TEK INSTRUMENTS INC.)を用い
て、550nmの吸光度(ABS550)を測定し、Oil Red Oによ
り染色された量を測定した。ポジティブ対照群のABS550
測定値を100%、ネガティブ対照群のABS550測定値を0
として、被験化合物添加群の脂肪細胞分化度(%)を算
出した。After culturing for 5 days, the total amount of the differentiation-inducing medium in each well was removed, and 60 μL of 10% (v / v) formaldehyde aqueous solution (fixation solution) was added to each well to add 2 cells.
Let stand for 0 minutes at room temperature. Remove all the fixative solution to 0.2% (v /
v) An aqueous solution of Triton X-100 (Sigma) was dispensed into each well in an amount of 60 μL and allowed to stand at room temperature for 5 minutes. Remove all Triton X-100 aqueous solution and add Oil Re to 60% (v / v) isopropanol aqueous solution.
60 μL of a fat staining solution containing 0.3% (w / v) of d 2 O (Sigma) was dispensed into each well, and the mixture was allowed to stand at room temperature for 10 minutes. After completely removing the fat staining solution, by dispensing and removing 60 μL of 60% (v / v) isopropanol aqueous solution,
Each well was washed twice. Then, DMSO was added to each well in an amount of 100 μL, and the mixture was stirred at room temperature for 5 minutes. The absorbance at 550 nm (ABS550) was measured using a multi-plate reader (BIO-TEK INSTRUMENTS INC.), And the amount stained with Oil Red O was measured. ABS 550 in positive control
Measured value is 100%, ABS550 measured value of negative control group is 0
As, the adipocyte differentiation degree (%) of the test compound-added group was calculated.
【0291】結果を表3に示す。The results are shown in Table 3.
【0292】[0292]
【表3】
表3に示されるように、本発明の化合物は、脂肪細胞へ
の分化を抑制し、抗肥満剤として有用である。
(試験例4) レプチン産生促進能測定
脂肪採取にはHanks液を用いた。Hanks液は120mM NaCl、
4.8mM KCl、0.74mM MgSO4、0.30mM Na2HPO4、0.40mM KH
2PO4、20mM HEPES、0.05%(w/v) Glucose、2%(w/v) BSA
(SIGMA社 Cat.No.A7888)、0.95mM CaCl2、4.17mM NaHCO
3、1%(v/v) Penicillin − Streptomycin,Liquid(GIBC
O BRL Cat.No.15140-122)の混合液(pH7.5)を濾過
し、調整した。脂肪細胞は、Dulbecco's modified Eagl
e's 培地(GIBCO BRL Cat.No.11995-040)とDMEM/F-12
(GIBCO BRL Cat.No.11320-033)を1:1(v/v)で混合
し、0.2%(v/v) Hanks液、0.2μg/L Sodium Selenite
(GIBCO BRL Cat.No.13012-018)、0.002%(v/v) Ethanol
amine、25mM HEPESおよび1%(v/v)Penicillin − Strept
omycin,Liquid(GIBCO BRL Cat.No.15140-122)を添加
して調整した培養用培地を用いて培養した。他の試薬は
可能な限り特級試薬を用いた。本実験では、全てCO2イ
ンキュベーター(37℃、95%湿度、5%CO2)で培養を行
った。[Table 3] As shown in Table 3, the compound of the present invention suppresses differentiation into adipocytes and is useful as an antiobesity agent. (Test Example 4) Hanks liquid was used for measuring leptin production promoting fat. Hanks solution is 120 mM NaCl,
4.8 mM KCl, 0.74 mM MgSO 4 , 0.30 mM Na 2 HPO 4 , 0.40 mM KH
2 PO 4 , 20 mM HEPES, 0.05% (w / v) Glucose, 2% (w / v) BSA
(SIGMA Cat.No.A7888), 0.95mM CaCl 2 , 4.17mM NaHCO
3 , 1% (v / v) Penicillin − Streptomycin, Liquid (GIBC
O BRL Cat. No. 15140-122) mixed solution (pH 7.5) was filtered and adjusted. Adipocytes are Dulbecco's modified Eagl
e's medium (GIBCO BRL Cat.No.11995-040) and DMEM / F-12
(GIBCO BRL Cat.No.11320-033) was mixed at 1: 1 (v / v), 0.2% (v / v) Hanks solution, 0.2 μg / L Sodium Selenite
(GIBCO BRL Cat.No.13012-018), 0.002% (v / v) Ethanol
amine, 25 mM HEPES and 1% (v / v) Penicillin-Strept
Culture was performed using a culture medium prepared by adding omycin, Liquid (GIBCO BRL Cat. No. 15140-122). Other reagents used were special grade reagents as much as possible. In this experiment, all cultures were performed in a CO 2 incubator (37 ° C, 95% humidity, 5% CO 2 ).
【0293】Wister Imamichiラット雄、6週齢を断頭
により屠殺し脱血後、副睾丸脂肪組織を摘出し、37℃に
保温したHanks液中で血管を除去し秤量後、鋏で細断し
た。調整後の脂肪組織に10mg collagenase(和光純薬、
034-10533)を含むHanks液1mLを添加、50mLチューブに
移し、37℃、90rpm、50分間緩やかに振蕩しつつインキ
ュベートし細胞を均一に分散させる。20mL Hanks液を添
加して、200μmナイロン・メッシュで濾過し、未消化の
組織片を除去した。1000rpm、1分間、室温で遠心するこ
とにより、浮遊している脂肪細胞を沈殿物及び下層と分
離した。沈殿物及び下層22mLをゾンデで吸い取り、浮遊
している脂肪細胞を回収した。同様の操作をHanks液で2
回、培養用培地で4回行った。操作後の脂肪細胞に予め
秤量した脂肪組織1gに対し、60mLの割合で培養用培地を
加え、脂肪細胞を懸濁した。懸濁液を96穴マイクロプレ
ート(旭テクノガラス社)に培養用培地100μLずつ分注
した。被験化合物添加群には、200μM、20μM、2μM及
び0.2μMのDMSO溶液を1μL/well(最終濃度1μM、100n
m、10nM及び1nM)ずつ添加した。対照群としてDMSOを1
μL/well(最終濃度0.1%(v/v))ずつ添加した。プレー
トはCO2インキュベーターで1時間以上静置し、37℃に平
衡化した。平衡化後、プレートに対して、水浴中でマグ
ネティックスターラーで攪拌し37℃を保った懸濁液を10
0μL/wellずつ分注した。24時間培養後、マイクロプレ
ート用濾過装置MultiScreen(MILLIPORE社 MADV-N65)
で濾液を回収し、Rat Leptin測定キット-IBL(免疫生物
研究所 Cat.No.17195)を用いてLeptin濃度をELISA法に
て測定した。Leptin産生促進作用は定量した培養液中の
Leptin濃度から以下に示す計算式により求めた。
Leptin産生促進活性 (%) = (A/B) x 100
A: 被験化合物添加群のLeptin濃度
B: 対照群のLeptin濃度
Leptin産生促進作用の測定結果を表4に示す。[0293] Wister Imamichi male rats, 6 weeks old, were sacrificed by decapitation, and after blood removal, epididymal adipose tissue was removed, blood vessels were removed in Hanks solution kept at 37 ° C, weighed, and shredded with scissors. 10mg collagenase (Wako Pure Chemical,
Add 1 mL of Hanks solution containing 034-10533), transfer to a 50 mL tube, and incubate at 37 ° C, 90 rpm for 50 minutes with gentle shaking to uniformly disperse the cells. 20 mL Hanks' solution was added and filtered through a 200 μm nylon mesh to remove undigested tissue pieces. The floating adipocytes were separated from the precipitate and the lower layer by centrifugation at 1000 rpm for 1 minute at room temperature. The sediment and the lower layer (22 mL) were sucked up with a sonde to collect floating adipocytes. Do the same operation with Hanks liquid 2
And 4 times with the culture medium. The culture medium was added at a rate of 60 mL to 1 g of preliminarily weighed adipose tissue in the adipocytes after the operation to suspend the adipocytes. The suspension was dispensed into 96-well microplates (Asahi Techno Glass Co., Ltd.) in 100 μL aliquots of culture medium. The test compound added group, 200μM, 20μM, 2μM and 0.2μM DMSO solution 1μL / well (final concentration 1μM, 100n
m, 10 nM and 1 nM) each. DMSO 1 as a control group
μL / well (final concentration 0.1% (v / v)) was added. The plate was left to stand for 1 hour or more in a CO 2 incubator and equilibrated at 37 ° C. After equilibration, stir the suspension on the plate with a magnetic stirrer in a water bath and keep it at 37 ℃.
Dispense by 0 μL / well. After culturing for 24 hours, MicroScreen filtration device MultiScreen (MILLIPORE MADV-N65)
The filtrate was collected by and the Leptin concentration was measured by the ELISA method using Rat Leptin measurement kit-IBL (Institute for Immunological Biology Cat. No. 17195). Leptin production promoting action in quantified culture solution
It was calculated from the Leptin concentration by the following formula. Leptin production promoting activity (%) = (A / B) x 100 A: Leptin concentration in test compound-added group B: Leptin concentration in control group Table 4 shows the measurement results of the Leptin production promoting action.
【0294】[0294]
【表4】
 ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄
表4に示されるように、本発明の化合物は顕著なレプチ
ン産生促進能を有し、食欲抑制作用による抗肥満剤とし
て有用である。
(試験例5)脂肪細胞分化促進試験
ラット白色脂肪細胞は、ホクドー社より購入した白色脂
肪細胞培養キットに含まれる細胞を実験に供した。増殖
用メディウム、分化誘導用メディウムは、ホクドー社よ
り購入した白色脂肪細胞培養キットに含まれるメディウ
ムを用いた。本実験の細胞培養は、全てCO2インキュベ
ーター(37℃、95%湿度、5%CO2)で培養を行った。[Table 4]  ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄
As shown in Table 4, the compound of the present invention has a remarkable ability to promote leptin production, and is useful as an antiobesity agent with an appetite suppressing effect. (Test Example 5) Adipocyte Differentiation Promotion Test As rat white adipocytes, the cells contained in the white adipocyte culture kit purchased from Hokudo Co., Ltd. were used for the experiment. As the medium for proliferation and the medium for differentiation induction, the medium contained in the white adipocyte culture kit purchased from Hokudo Co., Ltd. was used. All cell cultures in this experiment were carried out in a CO 2 incubator (37 ° C, 95% humidity, 5% CO 2 ).
【0295】購入した細胞は到着後直ちに輸送用培地を
全量抜き取り、増殖用メディウム5ml(/25cm2-フラス
コ)を加えて、1日培養した。その後、増殖用メディウ
ムを用いて83,000cells/mLの細胞懸濁液を調整し、96穴
I型コラーゲンコートマイクロプレート(SUMITOMO BAK
ELITE社)に5,000cells/well(60μL/well)になるよう
に細胞懸濁液を分注した。ブランク群として、細胞を含
まない増殖用メディウムのみを分注したウェル(ブラン
クウェル)を各プレートに設けた。Immediately after arrival of the purchased cells, the entire amount of the transport medium was extracted, 5 ml (/ 25 cm 2 -flask) of growth medium was added, and the cells were cultured for 1 day. After that, a cell suspension of 83,000 cells / mL was prepared using a growth medium, and a 96-well type I collagen-coated microplate (SUMITOMO BAK
The cell suspension was dispensed at 5,000 cells / well (60 μL / well) in ELITE. As a blank group, each plate was provided with wells (blank wells) into which only cells-free growth medium was dispensed.
【0296】翌日、増殖用メディウムを全量除去し、分
化誘導用メディウムを147μL/wellずつ加えた。更に
1)被験化合物添加群には、被験化合物の100μM DMSO
溶液を分化誘導用メディウムで20倍希釈したものを3μL
/well(被験化合物最終濃度:100nM、DMSO最終濃度:0.
1%(v/v))、2)ポジティブ対照群には、DMSOを分化
誘導用メディウムで20倍希釈したものを3μL/well(DMS
O最終濃度:0.1%(v/v))及び化合物Aを最終濃度3.3n
M(この際のDMSOは最終濃度0.01%となるので無視でき
る量とする)、3)ネガティブ対照群には、DMSOを分化
誘導用メディウムで20倍希釈したものを3μL/well(DMS
O最終濃度:0.1%(v/v))、細胞を撒いたウェルに加
えた。On the next day, the whole amount of the proliferation medium was removed, and the differentiation-inducing medium was added at 147 μL / well. 1) The test compound added group contained 100 μM DMSO of the test compound.
3 μL of 20-fold diluted solution with differentiation-inducing medium
/ well (final concentration of test compound: 100 nM, final concentration of DMSO: 0.
1% (v / v)), 2) For the positive control group, DMSO diluted 20-fold with differentiation-inducing medium was added at 3 μL / well (DMS).
O final concentration: 0.1% (v / v)) and compound A at final concentration 3.3n
M (DMSO at this time is a negligible amount because the final concentration is 0.01%), 3) For the negative control group, DMSO diluted 20-fold with differentiation-inducing medium was added at 3 μL / well (DMS).
O final concentration: 0.1% (v / v)) was added to the wells seeded with cells.
【0297】5日間培養した後、各ウェルの分化誘導用
メディウムを全量除去し、10%(v/v)ホルムアルデヒ
ド水溶液(固定液)60μLを各ウェルに加えて、細胞を2
0分間室温で静置した。固定液を全量除去し、0.2%(v/
v) Triton X-100(Sigma社)水溶液を60μL各ウェルに
分注し5分間室温で静置した。Triton X-100水溶液を全
量除去し、60%(v/v)イソプロパノール水溶液にOil Re
d O(Sigma社)を0.3%(w/v)になるように溶解した脂
肪染色液60μLを各ウェルに分注し、室温で10分間静置
した。脂肪染色液を全量除去した後、60%(v/v)イソプ
ロパノール水溶液60μLを分注し除去することにより、
各ウェルを2回ずつ洗浄した。その後、DMSOを各ウェル
に100μLずつ添加し、室温で5分間攪拌した。マルチプ
レートリーダー(BIO-TEK INSTRUMENTS INC.)を用い
て、550nmの吸光度(ABS550)を測定し、Oil Red Oによ
り染色された量を測定した。ポジティブ対照群ABS550測
定値を100%、ネガティブ対照群のABS550測定値を0とし
て、被験化合物添加群の脂肪細胞分化度(%)を算出し
た。After culturing for 5 days, the total amount of the differentiation-inducing medium in each well was removed, and 60 μL of a 10% (v / v) formaldehyde aqueous solution (fixation solution) was added to each well to add 2 cells.
Let stand for 0 minutes at room temperature. Remove all the fixative solution to 0.2% (v /
v) 60 μL of Triton X-100 (Sigma) aqueous solution was dispensed into each well, and the mixture was allowed to stand at room temperature for 5 minutes. Remove all Triton X-100 aqueous solution and add Oil Re to 60% (v / v) isopropanol aqueous solution.
60 μL of a fat staining solution in which d O (Sigma) was dissolved to 0.3% (w / v) was dispensed into each well, and left still at room temperature for 10 minutes. After completely removing the fat staining solution, by dispensing and removing 60 μL of 60% (v / v) isopropanol aqueous solution,
Each well was washed twice. Then, DMSO was added to each well in an amount of 100 μL and stirred at room temperature for 5 minutes. The absorbance at 550 nm (ABS550) was measured using a multi-plate reader (BIO-TEK INSTRUMENTS INC.), And the amount stained with Oil Red O was measured. The degree of adipocyte differentiation (%) in the test compound-added group was calculated by setting the ABS550 measured value of the positive control group to 100% and the ABS550 measured value of the negative control group to 0.
【0298】結果を表5に示す。The results are shown in Table 5.
【0299】[0299]
【表5】
 ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄表5に
示されるように、本発明の化合物は、脂肪の取込を促進
し、抗糖尿病薬として有用である。
(試験例6)ヒト全血IL−1β,TNFα産生に対す
る抑制試験
実験はHartmanらの方法(D.A.Hartman, S.J.Ochalski,
R.P.Carlson, The effects of antiinflammatory and a
ntiallergic drugs on cytokine release after stimul
ation of human whole blood by lipopolysaccharide a
nd zymosan A,Inflamm. Res., 1995年,第44巻,p.26
9)に準じて行なった。[Table 5]  ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ As shown in Table 5, the compounds of the present invention are useful as antidiabetic agents. is there. (Test Example 6) Inhibition test on human whole blood IL-1β and TNFα production The method of Hartman et al. (DA Hartman, SJOchalski,
RP Carlson, The effects of antiinflammatory and a
ntiallergic drugs on cytokine release after stimul
ation of human whole blood by lipopolysaccharide a
nd zymosan A, Inflamm. Res., 1995, Volume 44, p.26
It carried out according to 9).
【0300】健常人のボランティアよりヘパリン存在下
末梢血を採取した。全血1000μlを、被検化合物のジメ
チルスルホキシド溶液2μlを予め添加したエッペンド
ルフチューブに加え、更に刺激剤としてリポ多糖(LP
S)(E.coli 026:B6由来、Difco社)(終濃度10μg/m
l)10μlを添加後よく混和し、37℃、5%CO2の条件下で
6時間培養を行なった。培養終了後、4℃に冷却して反応
を止め、直ちに14,000rpmの条件で5分間遠心し、上清の
血漿を分離回収した。血漿中に産生、放出されたIL-1β
およびTNFαは酵素免疫測定(ELISA)キット(Biosourc
e社)で測定した。被験化合物100nM存在下および非存在
下のサイトカイン産生量より抑制率を求めた。Peripheral blood was collected in the presence of heparin from healthy volunteers. 1000 μl of whole blood was added to an Eppendorf tube to which 2 μl of a dimethylsulfoxide solution of the test compound had been added in advance, and lipopolysaccharide (LP
S) (from E. coli 026: B6, Difco) (final concentration 10 μg / m
l) Add 10 μl and mix well, and at 37 ° C, 5% CO 2
Culture was performed for 6 hours. After completion of the culture, the reaction was stopped by cooling to 4 ° C., and immediately centrifuged at 14,000 rpm for 5 minutes to separate and collect the plasma of the supernatant. IL-1β produced and released in plasma
And TNFα are enzyme-linked immunosorbent assay (ELISA) kits (Biosourc
e company). The inhibition rate was determined from the amount of cytokine production in the presence and absence of 100 nM of the test compound.
【0301】結果を表6に示す。The results are shown in Table 6.
【0302】[0302]
【表6】
 ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄表6に
示されるように、本発明の化合物は優れたサイトカイン
産生抑制作用を示した。
(試験例7)脂質調整作用試験
1.動物
雄性7週齢のシリアンゴールデンハムスターを日本SLC
より購入し、水および通常飼育飼料(FR-2、株式会社船
橋農場)は自由摂取とし、7日間以上予備飼育した動物
を実験に供した。
2.試験群の構成
8週齢の体重測定を行い、各試験において体重を測定し
た全ての個体のうち極端な外れ値を示した個体を除外し
た。特に前述の項目に該当する個体が存在しない場合に
は、体重により順位付けし、上位および下位から均等に
除外した。この時、除外すべき個体数が奇数の場合は、
上位の除外を優先した。除外後の動物の体重がほぼ均等
になるように、5匹ずつに分けた。
3. 被験化合物の投与
被験化合物の投与は混餌投与または経口投与で行った。
(1)混餌投与の場合
被験化合物が粉餌(FR-2、株式会社船橋農場)に0.3%(w
/w)若しくは0.03%(w/w)含有されるように調製し、金属
飼育ケージに1週間給餌した。
(2)経口投与の場合
被験化合物を投与基質(プロピレングリコール/Tween 8
0=4/1)に混合し、1日1回、午後、30mg/2ml/kgで、3日
間強制経口投与した。
4.実験期間、採血、および薬効の判定
投与開始日をDay 0とし、混餌投与の場合はDay 7に、経
口投与の場合はDay 3に、非絶食下において採血し、血
清生化学的検査を行った。血清をHDL分画用試薬(HDL-
コレステロール沈殿試液セット、和光純薬工業)を用い
て、HDL画分を分離後、本画分の総コレステロール(T
C)および遊離コレステロール(FC)を日立7250形自動
分析装置により、酵素法にて測定した。各群のHDL-TCお
よびHDL-FC値は各実験毎の対照群に対する変化率に換算
して、混餌投与の場合の結果を表7に、経口投与の場合
の結果を表8に示した。[Table 6]  ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ (Test Example 7) Lipid-regulating action test 1. Animal male 7-week-old Syrian golden hamster was treated with Japan SLC
Water and normal feed (FR-2, Funabashi Farm Co., Ltd.) were purchased freely, and animals preliminarily bred for 7 days or longer were used for the experiment. 2. Composition of test group Body weight was measured at 8 weeks of age, and individuals showing extreme outliers were excluded from all the individuals whose weight was measured in each test. In particular, when there was no individual corresponding to the above items, the animals were ranked according to body weight and excluded from the top and bottom equally. At this time, if the number of individuals to be excluded is odd,
Prioritized higher exclusions. The animals were divided into 5 groups so that the weights of the animals after the exclusion were almost equal. 3. Administration of test compound The administration of the test compound was performed by dietary administration or oral administration. (1) In case of mixed diet administration: 0.3% (w) of the test compound in the diet (FR-2, Funabashi Farm Co., Ltd.)
/ w) or 0.03% (w / w) was prepared and fed to a metal breeding cage for 1 week. (2) Oral administration Test compound is administered as a substrate (propylene glycol / Tween 8
0 = 4/1), and was orally administered once a day in the afternoon at 30 mg / 2 ml / kg for 3 days. 4.Experimental period, blood sampling, and determination of drug efficacy The administration start date is set to Day 0. Day 7 for dietary administration, Day 3 for oral administration, blood sampling under non-fasting conditions, and serum biochemical examination. went. Reagent for serum HDL fractionation (HDL-
After separating the HDL fraction using a cholesterol precipitation reagent set, Wako Pure Chemical Industries, Ltd., total cholesterol (T
C) and free cholesterol (FC) were measured by an enzymatic method using a Hitachi 7250 type automatic analyzer. The HDL-TC and HDL-FC values of each group were converted into the change rate with respect to the control group in each experiment, and the results in the case of dietary administration are shown in Table 7 and the results in the case of oral administration are shown in Table 8.
【0303】[0303]
【表7】  ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄[Table 7]  ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄
【0304】[0304]
【表8】
 ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄表7
及び表8に示されるように、PPARγモジュレーター活性
を有する本発明の化合物は、顕著なHDLコレステロール
の上昇作用を有することが明らかとなり、脂質代謝異常
に基づく疾患の治療薬または予防薬(脂質調整薬)およ
び高脂血症もしくは動脈硬化性疾患の治療薬または予防
薬として有用である。[Table 8]  ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ Table 7
Further, as shown in Table 8, it was revealed that the compound of the present invention having PPARγ modulator activity has a remarkable HDL cholesterol-elevating action, and thus it is a therapeutic or prophylactic agent for a disease caused by abnormal lipid metabolism (lipid regulator). ) And hyperlipidemia or arteriosclerotic diseases.
【0305】[0305]
【発明の効果】本発明の前記一般式(I)を有する化合
物及びその薬理上許容される塩は、ペルオキシソームプ
ロリフェレータ活性化受容体γ(PPARγ)に対するアゴ
ニスト、部分的アゴニスト、アンタゴニストまたは部分
的アンタゴニスト活性を有する。INDUSTRIAL APPLICABILITY The compound of the present invention represented by the general formula (I) and its pharmacologically acceptable salt are an agonist, a partial agonist, an antagonist or a partial agonist for peroxisome proliferator activated receptor γ (PPARγ). Has antagonistic activity.
【0306】したがって、本発明の前記一般式(I)を
有する化合物及びその薬理上許容される塩は、優れた、
老人性骨粗鬆症、閉経後骨粗鬆症、廃用性骨粗鬆症、ス
テロイド投与による骨粗鬆症、骨折、骨形成不全、クル
病、老年性骨関節疾患、肥満、るい痩、I型糖尿病、I
I型糖尿病、動脈硬化症、脂質代謝異常、膵炎、自己免
疫疾患、糖代謝異常、糖尿病性神経障害、糖尿病合併
症、高尿酸血症、白血病、レチノイド関連受容体機能異
常、肝機能異常、貧血、癌、炎症、バセドウ氏病、心疾
患、アルツハイマー病、摂食障害、高血圧、腎臓病の、
治療薬または予防薬として有用である。Therefore, the compound of the present invention represented by the general formula (I) and its pharmaceutically acceptable salt are excellent in
Senile osteoporosis, postmenopausal osteoporosis, disuse osteoporosis, osteoporosis due to steroid administration, bone fracture, osteogenesis imperfecta, rickets, senile osteoarthropathy, obesity, leanness, type I diabetes, I
Type I diabetes, arteriosclerosis, lipid metabolism disorder, pancreatitis, autoimmune disease, glucose metabolism disorder, diabetic neuropathy, diabetic complication, hyperuricemia, leukemia, retinoid-related receptor dysfunction, liver dysfunction, anemia , Cancer, inflammation, Graves' disease, heart disease, Alzheimer's disease, eating disorders, hypertension, kidney disease,
It is useful as a therapeutic or prophylactic agent.
【0307】[0307]
配列番号1:PCRプライマーS1 配列番号2:PCRプライマーAS1 配列番号3:PCRプライマーS2 配列番号4:PCRプライマーAS2 SEQ ID NO: 1 PCR primer S1 SEQ ID NO: 2 PCR primer AS1 SEQ ID NO: 3: PCR primer S2 Sequence No. 4: PCR primer AS2
【0308】[0308]
【配列表】 SEQUENCE LISTING <110> Sankyo Company, Limited <120> Benzamide derivative <130> 2001168SL <140> <141> <160> 10 <170> PatentIn Ver. 2.0 <210> 1 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer S1 <400> 1 cccagatctc caccatgggt gaaactctgg gagattctcc t 41 <210> 2 <211> 42 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer AS1 <400> 2 cccagatctg gatccctagt acaagtcctt gtagatctcc tg 42 <210> 3 <211> 59 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer S2 <400> 3 ctagagggga ccaggacaaa ggtcacgttc ggggaccagg acaaaagtca cgttcggga 59 <210> 4 <211> 59 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer AS2 <400> 4 tcgatcccga acgtgacctt tgtcctggtc cccgaacgtg acctttgtcc tggtcccct 59[Sequence list] SEQUENCE LISTING <110> Sankyo Company, Limited <120> Benzamide derivative <130> 2001168SL <140> <141> <160> 10 <170> PatentIn Ver. 2.0 <210> 1 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer S1 <400> 1 cccagatctc caccatgggt gaaactctgg gagattctcc t 41 <210> 2 <211> 42 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer AS1 <400> 2 cccagatctg gatccctagt acaagtcctt gtagatctcc tg 42 <210> 3 <211> 59 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer S2 <400> 3 ctagagggga ccaggacaaa ggtcacgttc ggggaccagg acaaaagtca cgttcggga 59 <210> 4 <211> 59 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer AS2 <400> 4 tcgatcccga acgtgacctt tgtcctggtc cccgaacgtg acctttgtcc tggtcccct 59
【図1】試験例1で引用され、PPARγ発現プラスミドの
模式図を示す。FIG. 1 shows a schematic diagram of a PPARγ expression plasmid cited in Test Example 1.
【図2】試験例1で引用され、PPREレポータープラスミ
ドの模式図を示す。FIG. 2 shows a schematic diagram of the PPRE reporter plasmid cited in Test Example 1.
【図3】試験例1で引用され、用量依存曲線概念図を示
す。図3において、ポジティブコントロール群のルシフ
ェラーゼ活性値を100%、コントロール群のルシフェラ
ーゼ活性値を0%とする。被験化合物単独で示すルシフ
ェラーゼ活性の最大値をEmax(%)、化合物A存在時の
被験化合物のルシフェラーゼ活性抑制の最大値をImax
(%)とする。また、Emax/2の値を示す部分的アゴニス
トの薬剤濃度をEC50、(100−Imax)/2の値を示す部分的
アンタゴニストの薬剤濃度をIC50とする。FIG. 3 is a schematic diagram of a dose-dependent curve cited in Test Example 1. In FIG. 3, the luciferase activity value of the positive control group is 100%, and the luciferase activity value of the control group is 0%. The maximum luciferase activity of the test compound alone is Emax (%), and the maximum luciferase activity inhibition of the test compound in the presence of Compound A is Imax.
(%). Further, the drug concentration of the partial agonist showing the value of Emax / 2 is taken as EC 50 , and the drug concentration of the partial antagonist showing the value of (100-Imax) / 2 is taken as IC 50 .
【手続補正書】[Procedure amendment]
【提出日】平成14年10月28日(2002.10.
28)[Submission date] October 28, 2002 (2002.10.
28)
【手続補正1】[Procedure Amendment 1]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】0308[Correction target item name] 0308
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【0308】[0308]
【配列表】 SEQUENCE LISTING <110> Sankyo Company, Limited <120> Lipid modulator <130> 2002114SB <140> <141> <150> JP2001-327189 <151> 2001-10-25 <160> 10 <170> PatentIn Ver. 2.0 <210> 1 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> Inventor: Amemiya, Yoshiya; Wakabayashi, Kenji; Takaishi, Sachiko; Inventor: Kitayama, Ken <220> <223> Description of Artificial Sequence: PCR primer S1 <400> 1 cccagatctc caccatgggt gaaactctgg gagattctcc t 41 <210> 2 <211> 42 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer AS1 <400> 2 cccagatctg gatccctagt acaagtcctt gtagatctcc tg 42 <210> 3 <211> 59 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer S2 <400> 3 ctagagggga ccaggacaaa ggtcacgttc ggggaccagg acaaaagtca cgttcggga 59 <210> 4 <211> 59 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer AS2 <400> 4 tcgatcccga acgtgacctt tgtcctggtc cccgaacgtg acctttgtcc tggtcccct 59 [Sequence list] SEQUENCE LISTING <110> Sankyo Company, Limited <120> Lipid modulator <130> 2002114SB <140> <141> <150> JP2001-327189 <151> 2001-10-25 <160> 10 <170> PatentIn Ver. 2.0 <210> 1 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> Inventor: Amemiya, Yoshiya; Wakabayashi, Kenji; Takaishi, Sachiko; Inventor: Kitayama, Ken <220> <223> Description of Artificial Sequence: PCR primer S1 <400> 1 cccagatctc caccatgggt gaaactctgg gagattctcc t 41 <210> 2 <211> 42 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer AS1 <400> 2 cccagatctg gatccctagt acaagtcctt gtagatctcc tg 42 <210> 3 <211> 59 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer S2 <400> 3 ctagagggga ccaggacaaa ggtcacgttc ggggaccagg acaaaagtca cgttcggga 59 <210> 4 <211> 59 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: PCR primer AS2 <400> 4 tcgatcccga acgtgacctt tgtcctggtc cccgaacgtg acctttgtcc tggtcccct 59
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 FI テーマコート゛(参考) A61K 31/352 A61K 31/352 4C055 31/381 31/381 4C056 31/40 31/40 4C062 31/4035 31/4035 4C063 31/415 31/415 4C069 31/416 31/416 4C086 31/4164 31/4164 4C204 31/423 31/423 4C206 31/426 31/426 4H006 31/427 31/427 31/428 31/428 31/433 31/433 31/44 31/44 31/4402 31/4402 31/4453 31/4453 31/47 31/47 31/472 31/472 31/495 31/495 31/4965 31/4965 31/505 31/505 31/5375 31/5375 A61P 3/00 A61P 3/00 3/04 3/04 3/06 3/06 3/10 3/10 9/10 101 9/10 101 19/10 19/10 25/28 25/28 29/00 29/00 35/00 35/00 37/02 37/02 43/00 111 43/00 111 C07C 233/66 C07C 233/66 233/75 233/75 233/76 233/76 233/80 233/80 233/87 233/87 255/60 255/60 311/08 311/08 311/18 311/18 311/21 311/21 311/50 311/50 311/60 311/60 C07D 207/325 C07D 207/325 209/48 213/40 213/40 213/75 213/75 215/38 215/38 217/22 217/22 231/40 231/40 231/44 231/44 231/54 231/54 233/61 101 233/61 101 239/42 239/42 241/28 241/28 263/58 263/58 277/46 277/46 277/82 277/82 295/12 A 285/135 Z 295/12 311/22 333/36 311/22 333/40 333/36 417/04 333/40 285/12 F 417/04 209/48 (72)発明者 高石 祥子 東京都品川区広町1丁目2番58号 三共株 式会社内 (72)発明者 北山 健 東京都品川区広町1丁目2番58号 三共株 式会社内 Fターム(参考) 4C023 HA03 4C031 JA07 4C033 AD13 AD17 AD20 AE14 AE17 AE20 4C034 AL03 4C036 AD08 4C055 AA01 BA02 BA39 BA53 BB17 CA01 CA02 CA03 CA39 CA51 DA01 DA53 DB17 4C056 AA01 AB01 AC02 AD03 AE03 CA24 4C062 EE56 4C063 AA01 BB01 CC62 CC92 DD12 DD62 EE01 4C069 AC05 4C086 AA01 AA02 AA03 BA08 BB03 BC05 BC07 BC11 BC17 BC21 BC28 BC30 BC36 BC37 BC38 BC42 BC48 BC50 BC70 BC73 BC82 BC84 BC85 GA04 GA08 GA10 MA01 MA04 NA14 ZA16 ZA45 ZA70 ZA97 ZB07 ZB11 ZB26 ZC02 ZC33 ZC35 4C204 BB01 CB04 DB30 EB03 FB17 GB01 4C206 AA01 AA02 AA03 GA08 GA31 GA34 HA14 JA11 JA16 MA01 MA04 NA14 ZA16 ZA45 ZA70 ZA97 ZB07 ZB11 ZB26 ZC02 ZC33 ZC35 4H006 AA01 AA03 AB23 BJ50 BM30 BM72 BN30 BP30 BR30 BS10 BU26 BU32 ─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 7 Identification code FI theme code (reference) A61K 31/352 A61K 31/352 4C055 31/381 31/381 4C056 31/40 31/40 4C062 31/4035 31 / 4035 4C063 31/415 31/415 4C069 31/416 31/416 4C086 31/4164 31/4164 4C204 31/423 31/423 4C206 31/426 31/426 4H006 31/427 31/427 31/428 31/428 31/433 31/433 31/44 31/44 31/4402 31/4402 31/4453 31/4453 31/47 31/47 31/472 31/472 31/495 31/495 31/4965 31/4965 31 / 505 31/505 31/5375 31/5375 A61P 3/00 A61P 3/00 3/04 3/04 3/06 3/06 3/10 3/10 9/10 101 9/10 101 19/10 19/10 25/28 25/28 29/00 29/00 35/00 35/00 37/02 37/02 43/00 111 43/00 111 C07C 233/66 C07C 233/66 233/75 233/75 233/76 233 / 76 233/80 233/80 233 / 87 233/87 255/60 255/60 311/08 311/08 311/18 311/18 311/21 311/21 311/50 311/50 311/60 311/60 C07D 207/325 C07D 207/325 209 / 48 213/40 213/40 213/75 213/75 215/38 215/38 217/22 217/22 231/40 231/40 231/44 231/44 231/54 231/54 233/61 101 101 233/61 101 239/42 239/42 241/28 241/28 263/58 263/58 277/46 277/46 277/82 277/82 295/12 A 285/135 Z 295/12 311/22 333/36 311 / 22 333/40 333/36 417/04 333/40 285/12 F 417/04 209/48 (72) Inventor Shoko Takaishi 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company (72) Inventor Ken Kitayama 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. F-term in company (reference) 4C023 HA03 4C031 JA07 4C033 AD13 AD17 AD20 AE14 AE17 AE20 4C034 AL03 4C036 AD08 4C055 AA01 BA02 BA39 BA53 BB17 CA01 CA02 CA03 CA03 CA39 CA51 DA01 DA53 DB17 4C056 AA01 AB01 AC02 AD03 AE03 CA24 4C062 EE56 4C063 AA01 BB01 CC62 CC92 DD12 DD62 EE01 4C069 AC05 4C086 AA01 AA02 AA03 BA08 BB03 BC05 BC07 BC11 BC17 BC21 BC28 BC30 BC36 BC36 BC50 BC70 BC73 BC82 BC84 BC85 GA04 GA08 GA10 MA01 MA04 NA14 ZA16 ZA45 ZA70 ZA97 ZB07 ZB11 ZB26 ZC02 ZC33 ZC35 4C204 BB01 CB04 DB30 EB03 FB17 GB01 4C206 AA01 A14 02 ZC33 ZC35 4H006 AA01 AA03 AB23 BJ50 BM30 BM72 BN30 BP30 BR30 BS10 BU26 BU32
Claims (9)
ル基、ピリジル基、キノリル基、イソキノリル基、ピリ
ミジニル基、フリル基、ベンゾフリル基、ピラニル基、
クロメニル基、チエニル基、ベンゾチエニル基、ピロリ
ル基、インドリル基、イソインドリル基、イミダゾリル
基、ピラゾリル基、ピリダジニル基、ピラジニル基、オ
キサゾリル基、ピロリジニル基、ピペリジル基、ピペラ
ジニル基、イソオキサゾリル基、ベンゾオキサゾリル
基、ベンゾイソオキサゾリル基、チアゾリル基、イソチ
アゾリル基、ベンゾチアゾリル基、ベンゾイソチアゾリ
ル基又はビフェニル基(当該Aは、下記置換基群αから
選ばれる1個乃至2個以上の同一又は異なった置換基に
より置換されていても良い)を示し、Bは、アリール
基、シクロアルキル基又は複素環基(当該Bは、下記置
換基群α及び置換基群βから選ばれる1個乃至2個以上
の同一又は異なった置換基により置換されていても良
い)を示し、Raは水素原子又はC1−C6アルキル基を
示し、Xは、結合手、酸素原子、硫黄原子、CH2基、
CO基、NH基、SO2NH基、NHSO2基、CONH
基、NHCO基又はOCH2基を示し、nは0又は1を
示す。 [置換基群α]C1−C20アルキル基、ニトロ基、シア
ノ基、カルボキシ基、カルボキシC2−C 7アルキル基、
C2−C7アルキルオキシカルボニル基、C3−C15アル
キルオキシカルボニルアルキル基、アミノ基(当該アミ
ノ基は、1個又は2個の同一又は異なったC1−C6アル
キル基若しくは1個のC3−C6アルケニル基により置換
されていても良い)、C1−C12アルキルアミノ基(当
該アルキルアミノ基は、アミノ基、C1−C12アルキル
アミノ基、C2−C6アルキルオキシカルボニル基、イミ
ド基又は置換カルバモイル基により置換されていても良
い)、水酸基(当該水酸基は、1個のC1−C6アルキル
基又は1個のC1−C6ハロアルキル基により置換されて
いても良い)、C1−C6アルコキシ基(当該アルコキシ
基は、アミノ基、C1−C12アルキルアミノ基、C2−C
6アルキルオキシカルボニル基、イミド基又は置換カル
バモイル基により置換されていても良い)、メルカプト
基(当該メルカプト基は、1個のC1−C6アルキル基に
より置換されていても良い)、及び、C1−C6アルキル
チオ基(当該アルキルチオ基は、アミノ基、C1−C12
アルキルアミノ基、C2−C6アルキルオキシカルボニル
基、イミド基又は置換カルバモイル基により置換されて
いても良い)。 [置換基群β]ハロゲン原子、スルホンアミド基、C1
−C6アルキルスルホンアミド基、アミジノアミノスル
ホニル基及びフェニル基]で表される化合物又はその薬
理上許容される塩。1. The following general formula (I): [Chemical 1] [In the formula, A is a phenyl group, a naphthyl group, an acenaphthenic group.
Group, pyridyl group, quinolyl group, isoquinolyl group, pyri group
Midinyl group, furyl group, benzofuryl group, pyranyl group,
Chromenyl group, thienyl group, benzothienyl group, pyrrolyl
Group, indolyl group, isoindolyl group, imidazolyl group
Group, pyrazolyl group, pyridazinyl group, pyrazinyl group, o
Xazolyl group, pyrrolidinyl group, piperidyl group, pipera
Dinyl group, isoxazolyl group, benzoxazolyl
Group, benzisoxazolyl group, thiazolyl group, isothiyl group
Azolyl group, benzothiazolyl group, benzisothiazol
Group or biphenyl group (the A is from the following substituent group α)
1 to 2 or more same or different substituents selected
May be further substituted), and B is aryl
Group, cycloalkyl group or heterocyclic group (the B is
1 to 2 or more selected from the substituent group α and the substituent group β
May be substituted with the same or different substituents of
R)aIs a hydrogen atom or C1-C6Alkyl group
X is a bond, oxygen atom, sulfur atom, CH2Base,
CO group, NH group, SO2NH group, NHSO2Group, CONH
Group, NHCO group or OCH2Represents a group, and n is 0 or 1.
Show. [Substituent group α] C1-C20Alkyl group, nitro group, shear
Group, carboxy group, carboxy C2-C 7An alkyl group,
C2-C7Alkyloxycarbonyl group, C3-C15Al
Killoxycarbonylalkyl group, amino group
Group is 1 or 2 identical or different C1-C6Al
Kill group or 1 C3-C6Substitute with alkenyl group
C)1-C12Alkylamino group (this
The alkylamino group is an amino group, C1-C12Alkyl
Amino group, C2-C6Alkyloxycarbonyl group, imimi
May be substituted with a substituted group or a substituted carbamoyl group.
A hydroxyl group (the hydroxyl group is one C1-C6Alkyl
Group or 1 C1-C6Substituted by a haloalkyl group
C)1-C6Alkoxy group (the alkoxy
The group is an amino group, C1-C12Alkylamino group, C2-C
6Alkyloxycarbonyl group, imide group or substituted calcium
Which may be substituted by a vamoyl group), mercapto
A group (the mercapto group is one C1-C6On an alkyl group
May be further substituted), and C1-C6Alkyl
Thio group (the alkylthio group is an amino group, C1-C12
Alkylamino group, C2-C6Alkyloxycarbonyl
Substituted by groups, imido groups or substituted carbamoyl groups
You may stay). [Substituent group β] halogen atom, sulfonamide group, C1
-C6Alkylsulfonamide group, amidinoaminosul
[Fonyl group and phenyl group] or its drug
Salt that is theoretically acceptable.
チアゾリル基である化合物又はその薬理上許容される
塩。2. The compound according to claim 1, wherein A is a phenyl group or a thiazolyl group, or a pharmaceutically acceptable salt thereof.
が結合手である化合物又はその薬理上許容される塩。3. The X according to any one of claims 1 and 2.
Is a bond or a pharmacologically acceptable salt thereof.
が1である化合物又はその薬理上許容される塩。4. The method according to claim 1, wherein n
Wherein the compound is 1, or a pharmaceutically acceptable salt thereof.
ボニルアミノフェニル)]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド、N−(3−カルボエトキシ
−4,5,6,7−テトラヒドロベンゾ[b]チオフェ
ン−2−イル)−(2−クロロ−5−ニトロフェニル)
カルボキサミド、N−(1−メチルベンズイミダゾール
−2−イル)−(2−クロロ−5−ニトロフェニル)カ
ルボキサミド、N−[4−[4−(tert−ブトキシ
カルボニルアミノ)フェニル]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド、N−[4−
(6−アセトキシ−2,5,7,8−テトラメチル−4
−オキソクロマン−2−イルメトキシ)フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド、
N−[4−(6−ヒドロキシ−2,5,7,8−テトラ
メチル−4−オキソクロマン−2−イルメトキシ)フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキ
サミド、N−[4−(アミジノアミノスルホニル)フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド、N−[4−(ブチルアミノカルボニルアミノスル
ホニル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド、N−(5−フェニル−[1,3,
4]チアジアゾール−2−イル)−(2−クロロ−5−
ニトロフェニル)カルボキサミド、N−(4−アセチル
アミノフェニル)−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド、N−[4−(4−アセチルアミノ
フェニル)フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド、N−(4−エタンスルホニルア
ミノフェニル)−(2−クロロ−5−ニトロフェニル)
カルボキサミド、N−[4−(4−アセトキシフェニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド、N−(4−メタンスルホニルアミノフ
ェニル)−(2−クロロ−5−ニトロフェニル)カルボ
キサミド、N−[4−(ピロリジニルスルホニル)フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキ
サミド、N−[4−(モルホリン−4−イルスルホニ
ル)フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド、N−[3−(ピロリジルスルホニル)
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド、N−(4−アセチルフェニル)−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド、N−(3
−アセチルフェニル)−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド、N−[4−(2−tert−ブ
トキシカルボニルアミノエチル)フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド、N−[4
−(2−アミノエチル)フェニル]−(2−クロロ−5
−ニトロフェニル)カルボキサミド・塩酸塩 0.2水
和物、N−[4−[4−(モルホリン−4−イル)フェ
ニル]アミノスルホニル]フェニル−(2−クロロ−5
−ニトロフェニル)カルボキサミド、N−[4−(4−
アセチルピペラジン−1−イル)フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド、N−[4
−(4−ベンゾイルピペラジン−1−イル)フェニル]
−(2−クロロ−5−ニトロフェニル)カルボキサミ
ド、N−[[4−[4−(イミダゾール−1−イル)フ
ェニル]アミノスルホニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド、N−[4−
(4−tert−ブトキシカルボニルアミノフェニル)
チアゾール−2−イル]−(2−クロロ−5−ニトロフ
ェニル)カルボキサミド、N−[4−[4−(ピリジン
−3−イルカルボニル)ピペラジン−1−イル]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド、N−[4−(2−ヒドロキシエチル)フェニル]
−(2−クロロ−5−ニトロフェニル)カルボキサミ
ド、N−[[3−[4−(イミダゾール−1−イル)フ
ェニル]アミノカルボニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド、N−[4−
(3−tert−ブトキシカルボニルアミノフェニル)
チアゾール−2−イル]−(2−クロロ−5−ニトロフ
ェニル)カルボキサミド、N−[4−[4−(メチルア
ミノチオカルボニルアミノ)フェニル]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド、
N−[4−(2,2,2−トリフルオロ−1−ヒドロキ
シ−1−トリフルオロメチルエチル)フェニル]−(2
−クロロ−5−ニトロフェニル)カルボキサミド、N−
[4−(1−ヒドロキシエチル)フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド、N−[3
−(1−ヒドロキシエチル)フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド、N−[4−
[4−(フェニルアミノカルボニルアミノ)フェニル]
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド、N−[4−[4−(アミノカルボニルアミ
ノ)フェニル]フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド、N−[4−[4−(エトキ
シカルボニルアミノカルボニルアミノ)フェニル]フェ
ニル]−(2−クロロ−5−ニトロフェニル)カルボキ
サミド、N−[4−[4−[(3−フルオロフェニル)
アミノチオカルボニルアミノ]フェニル]フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド、
N−[4−[4−[(3−メトキシフェニル)アミノカ
ルボニルアミノ]フェニル]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド、N−[4−
[4−(ベンジルアミノカルボニルアミノ)フェニル]
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド、N−[4−[4−[(2,4−ジフルオロ
フェニル)アミノカルボニルアミノ]フェニル]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド、N−[4−[4−(ベンゾイルアミノチオカルボ
ニルアミノ)フェニル]フェニル]−(2−クロロ−5
−ニトロフェニル)カルボキサミド、N−[4−[4−
(エトキシカルボニルアミノチオカルボニルアミノ)フ
ェニル]フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド、N−[4−[4−(フェニルアミ
ノチオカルボニルアミノ)フェニル]フェニル]−(2
−クロロ−5−ニトロフェニル)カルボキサミド、N−
[4−[4−(2−ニトロフェニルアミノカルボニルア
ミノ)フェニル]フェニル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド、N−[4−[4−[(ピ
リジン−3−イル)アミノチオカルボニルアミノ]フェ
ニル]フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド、N−[4−[(ピリジン−3−イ
ル)アミノチオカルボニルアミノ]フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド、N−
[4−[4−[(ピリジン−4−イル)アミノチオカル
ボニルアミノ]フェニル]フェニル]−(2−クロロ−
5−ニトロフェニル)カルボキサミド、N−[4−
[(ピリジン−4−イル)アミノチオカルボニルアミ
ノ]フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド、N−[(6−tert−ブトキシカル
ボニルアミノ)ベンゾチアゾール−2−イル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド、N−
[4−(4−アセチルアミノフェニル)チアゾール−2
−イル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド、N−[4−[(4−アミノカルボニル)ピペ
ラジン−1−イル]フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド、N−[4−(2−アセ
チルアミノチアゾール−4−イル)フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド、N−
[3−(2−アセチルアミノチアゾール−4−イル)フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド、N−[4−(2−アミノエチル)フェニル]
−(2−クロロ−5−ニトロフェニル)カルボキサミ
ド、N−[4−(2−フェニルアミノカルボニルアミノ
エチル)フェニル]−(2−クロロ−5−ニトロフェニ
ル)カルボキサミド、N−[4−(2−フェニルアミノ
チオカルボニルアミノエチル)フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド、N−[4−
(2−アミノカルボニルアミノエチル)フェニル]−
(2−クロロ−5−ニトロフェニル)カルボキサミド、
N−[4−(2−フェニルカルボニルアミノチオカルボ
ニルアミノエチル)フェニル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド、N−[4−(2−エト
キシカルボニルアミノチオカルボニルアミノエチル)フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド、N−[4−[2−(ピリジン−3−イル)ア
ミノチオカルボニルアミノエチル]フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド、N−
[3−(2−ヒドロキシエチル)フェニル]−(2−ク
ロロ−5−ニトロフェニル)カルボキサミド、N−[4
−[4−(N、N−ジエタンスルホニルアミノ)フェニ
ル]フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド、N−[4−(3−アセチルアミノフェ
ニル)チアゾール−2−イル]−(2−クロロ−5−ニ
トロフェニル)カルボキサミド、N−[4−[4−
(2,5−ジメチルピロール−1−イル)フェニル]フ
ェニル]−(2−クロロ−5−ニトロフェニル)カルボ
キサミド、N−(6−アセチルアミノベンゾチアゾール
−2−イル)−(2−クロロ−5−ニトロフェニル)カ
ルボキサミドおよびN−(6−アミノカルボニルアミノ
ベンゾチアゾール−2−イル)−(2−クロロ−5−ニ
トロフェニル)カルボキサミドからなる群より選択され
る化合物又はその薬理上許容される塩。5. N- [4- (tert-Butyloxycarbonylaminophenyl)]-(2-chloro-5-nitrophenyl) carboxamide, N- (3-carbethoxy-4,5,6,7-tetrahydro. Benzo [b] thiophen-2-yl)-(2-chloro-5-nitrophenyl)
Carboxamide, N- (1-methylbenzimidazol-2-yl)-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [4- (tert-butoxycarbonylamino) phenyl] phenyl]-(2 -Chloro-5-nitrophenyl) carboxamide, N- [4-
(6-acetoxy-2,5,7,8-tetramethyl-4
-Oxochroman-2-ylmethoxy) phenyl]-
(2-chloro-5-nitrophenyl) carboxamide,
N- [4- (6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy) phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- ( Amidinoaminosulfonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- (butylaminocarbonylaminosulfonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- (5 -Phenyl- [1,3
4] thiadiazol-2-yl)-(2-chloro-5-
Nitrophenyl) carboxamide, N- (4-acetylaminophenyl)-(2-chloro-5-nitrophenyl) carboxamide, N- [4- (4-acetylaminophenyl) phenyl]-(2-chloro-5-nitro Phenyl) carboxamide, N- (4-ethanesulfonylaminophenyl)-(2-chloro-5-nitrophenyl)
Carboxamide, N- [4- (4-acetoxyphenyl) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide, N- (4-methanesulfonylaminophenyl)-(2-chloro-5-nitrophenyl) carboxamide, N- [4- (pyrrolidinylsulfonyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide , N- [4- (morpholin-4-ylsulfonyl) phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide, N- [3- (pyrrolidylsulfonyl)
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- (4-acetylphenyl)-(2-chloro-5-nitrophenyl) carboxamide, N- (3
-Acetylphenyl)-(2-chloro-5-nitrophenyl) carboxamide, N- [4- (2-tert-butoxycarbonylaminoethyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [ Four
-(2-Aminoethyl) phenyl]-(2-chloro-5
-Nitrophenyl) carboxamide hydrochloride 0.2 hydrate, N- [4- [4- (morpholin-4-yl) phenyl] aminosulfonyl] phenyl- (2-chloro-5
-Nitrophenyl) carboxamide, N- [4- (4-
Acetylpiperazin-1-yl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4
-(4-benzoylpiperazin-1-yl) phenyl]
-(2-chloro-5-nitrophenyl) carboxamide, N-[[4- [4- (imidazol-1-yl) phenyl] aminosulfonyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N -[4-
(4-tert-butoxycarbonylaminophenyl)
Thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [4- (pyridin-3-ylcarbonyl) piperazin-1-yl] phenyl]-(2-chloro-5 -Nitrophenyl) carboxamide, N- [4- (2-hydroxyethyl) phenyl]
-(2-chloro-5-nitrophenyl) carboxamide, N-[[3- [4- (imidazol-1-yl) phenyl] aminocarbonyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N -[4-
(3-tert-butoxycarbonylaminophenyl)
Thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [4- (methylaminothiocarbonylamino) phenyl] phenyl]-
(2-chloro-5-nitrophenyl) carboxamide,
N- [4- (2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl) phenyl]-(2
-Chloro-5-nitrophenyl) carboxamide, N-
[4- (1-hydroxyethyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [3
-(1-hydroxyethyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4-
[4- (phenylaminocarbonylamino) phenyl]
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [4- (aminocarbonylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [4- (Ethoxycarbonylaminocarbonylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [4-[(3-fluorophenyl)]
Aminothiocarbonylamino] phenyl] phenyl]-
(2-chloro-5-nitrophenyl) carboxamide,
N- [4- [4-[(3-methoxyphenyl) aminocarbonylamino] phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4-
[4- (benzylaminocarbonylamino) phenyl]
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [4-[(2,4-difluorophenyl) aminocarbonylamino] phenyl] phenyl]-(2-chloro-5-nitrophenyl ) Carboxamide, N- [4- [4- (benzoylaminothiocarbonylamino) phenyl] phenyl]-(2-chloro-5
-Nitrophenyl) carboxamide, N- [4- [4-
(Ethoxycarbonylaminothiocarbonylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [4- (phenylaminothiocarbonylamino) phenyl] phenyl]-(2
-Chloro-5-nitrophenyl) carboxamide, N-
[4- [4- (2-Nitrophenylaminocarbonylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [4-[(pyridin-3-yl) aminothio] Carbonylamino] phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4-[(pyridin-3-yl) aminothiocarbonylamino] phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide, N-
[4- [4-[(Pyridin-4-yl) aminothiocarbonylamino] phenyl] phenyl]-(2-chloro-
5-nitrophenyl) carboxamide, N- [4-
[(Pyridin-4-yl) aminothiocarbonylamino] phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide, N-[(6-tert-butoxycarbonylamino) benzothiazol-2-yl]-(2-
Chloro-5-nitrophenyl) carboxamide, N-
[4- (4-acetylaminophenyl) thiazole-2
-Yl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4-[(4-aminocarbonyl) piperazin-1-yl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N -[4- (2-Acetylaminothiazol-4-yl) phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide, N-
[3- (2-Acetylaminothiazol-4-yl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- (2-aminoethyl) phenyl]
-(2-chloro-5-nitrophenyl) carboxamide, N- [4- (2-phenylaminocarbonylaminoethyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- (2- Phenylaminothiocarbonylaminoethyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4-
(2-Aminocarbonylaminoethyl) phenyl]-
(2-chloro-5-nitrophenyl) carboxamide,
N- [4- (2-phenylcarbonylaminothiocarbonylaminoethyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- (2-ethoxycarbonylaminothiocarbonylaminoethyl) phenyl]- (2-chloro-5-nitrophenyl) carboxamide, N- [4- [2- (pyridin-3-yl) aminothiocarbonylaminoethyl] phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide, N-
[3- (2-hydroxyethyl) phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4
-[4- (N, N-Diethanesulfonylamino) phenyl] phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide, N- [4- (3-acetylaminophenyl) thiazol-2-yl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [4-
(2,5-Dimethylpyrrol-1-yl) phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- (6-acetylaminobenzothiazol-2-yl)-(2-chloro-5 -Nitrophenyl) carboxamide and N- (6-aminocarbonylaminobenzothiazol-2-yl)-(2-chloro-5-nitrophenyl) carboxamide, or a pharmacologically acceptable salt thereof.
オカルボニル]アミノ]フェニル]フェニル]−(2−
クロロ−5−ニトロフェニル)カルボキサミド、N−
[4−[[4−[(tert−ブトキシカルボニル)ア
ミノ]フェニル]メチル]フェニル]−(2−クロロ−
5−ニトロフェニル)カルボキサミド、N−[4−[2
−[[(3−メトキシフェニルアミノ)カルボニル]ア
ミノ]エチル]フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド、N−[3−[4−[(te
rt−ブトキシカルボニル)アミノ]フェニル]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド、N−[4−[2−(tert−ブトキシカルボニ
ルアミノ)エトキシ]フェニル]−(2−クロロ−5−
ニトロフェニル)カルボキサミド、N−[4−[2−
(ジメチルアミノ)エトキシ]フェニル]−(2−クロ
ロ−5−ニトロフェニル)カルボキサミド、N−[4−
[2−(ジエチルアミノ)エトキシ]フェニル]−(2
−クロロ−5−ニトロフェニル)カルボキサミド、N−
[4−[3−(ジメチルアミノ)プロポキシ]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド、N−[4−[2−(tert−ブトキシカルボニ
ルアミノ)エチルチオ]フェニル]−(2−クロロ−5
−ニトロフェニル)カルボキサミド、N−[4−[[2
−(tert−ブトキシカルボニルアミノ)エチル]ス
ルホニル]フェニル]−(2−クロロ−5−ニトロフェ
ニル)カルボキサミド、N−[4−[(2−アミノエチ
ル)スルホニル]フェニル]−(2−クロロ−5−ニト
ロフェニル)カルボキサミド・1塩酸塩、N−[4−
[[4−(1,3−ジオキソイソインドール−2−イ
ル)ブチル]スルホニル]フェニル]−(2−クロロ−
5−ニトロフェニル)カルボキサミド、N−[4−
[[2−(tert−ブトキシカルボニルアミノ)エチ
ル]アミノ]フェニル]−(2−クロロ−5−ニトロフ
ェニル)カルボキサミド・1塩酸塩、N−[4−
[[(2−ジメチルアミノ)エチル](メチル)アミ
ノ]フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド、N−[4−[[3−(tert−ブト
キシカルボニルアミノ)プロピル]アミノ]フェニル]
−(2−クロロ−5−ニトロフェニル)カルボキサミド
・1塩酸塩、N−[4−[[(3−ジメチルアミノ)プ
ロピル](メチル)アミノ]フェニル]−(2−クロロ
−5−ニトロフェニル)カルボキサミド、N−[4−
[[(3−ジメチルアミノ)プロピル](メチル)アミ
ノ]フェニル]−(2−クロロ−5−ニトロフェニル)
カルボキサミド・2塩酸塩、N−[4−[[4−(te
rt−ブトキシカルボニルアミノ)ブトキシ]アミノ]
フェニル]−(2−クロロ−5−ニトロフェニル)カル
ボキサミド・1塩酸塩、N−[4−[(4−アミノブト
キシ)アミノ]フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド・2塩酸塩、N−[4−[4
−(メタンスルホニル)−1−ピペラジニル]フェニ
ル]−(2−クロロ−5−ニトロフェニル)カルボキサ
ミド、N−[4−[4−(フェニルスルホニル)−1−
ピペラジニル]フェニル]−(2−クロロ−5−ニトロ
フェニル)カルボキサミド、4−(2−クロロ−5−ニ
トロベンゾイル)−1−ピペリジンカルボン酸 エチル
エステル、4−(2−クロロ−5−ニトロベンゾイル)
−1−ピペリジンカルボン酸 tert−ブチルエステ
ル、1−(2−クロロ−5−ニトロベンゾイル)ピペラ
ジン・1塩酸塩、1−(2−クロロ−5−ニトロベンゾ
イル)−4−メチルピペラジン、1−ベンジル−4−
(2−クロロ−5−ニトロベンゾイル)ピペラジン、1
−(2−クロロ−5−ニトロベンゾイル)−4−フェニ
ルピペラジン、1−(2−クロロ−5−ニトロベンゾイ
ル)−4−[4−(N,N−ジメチルアミノ)フェニ
ル]ピペラジン、N−[4−[4−[(2−クロロ−5
−ニトロフェニル)カルボニル]ピペラジン−1−イ
ル]フェニル]メトキシカルボキサミド、N−[4−
[4−[(2−クロロ−5−ニトロフェニル)カルボニ
ル]ピペリジン−1−イル]フェニル]アセトアミド、
N−[4−[4−[(2−クロロ−5−ニトロフェニ
ル)カルボニル]ピペラジン−1−イル]フェニル]メ
タンスルホンアミド、1−[(2−クロロ−5−ニトロ
フェニル)カルボニル]−4−フェニルピペリジンおよ
び3−(N−tert−ブトキシカルボニル)アミノ−
1−(2−クロロ−5−ニトロベンゾイル)ピロリジン
からなる群より選択される化合物又はその薬理上許容さ
れる塩。6. N- [4- [4-[[(butylamino) thiocarbonyl] amino] phenyl] phenyl]-(2-
Chloro-5-nitrophenyl) carboxamide, N-
[4-[[4-[(tert-Butoxycarbonyl) amino] phenyl] methyl] phenyl]-(2-chloro-
5-nitrophenyl) carboxamide, N- [4- [2
-[[(3-Methoxyphenylamino) carbonyl] amino] ethyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [3- [4-[(te
rt-Butoxycarbonyl) amino] phenyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [2- (tert-butoxycarbonylamino) ethoxy] phenyl]-(2-chloro-5 −
Nitrophenyl) carboxamide, N- [4- [2-
(Dimethylamino) ethoxy] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4-
[2- (diethylamino) ethoxy] phenyl]-(2
-Chloro-5-nitrophenyl) carboxamide, N-
[4- [3- (Dimethylamino) propoxy] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [2- (tert-butoxycarbonylamino) ethylthio] phenyl]-(2- Chloro-5
-Nitrophenyl) carboxamide, N- [4-[[2
-(Tert-Butoxycarbonylamino) ethyl] sulfonyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4-[(2-aminoethyl) sulfonyl] phenyl]-(2-chloro-5 -Nitrophenyl) carboxamide monohydrochloride, N- [4-
[[4- (1,3-Dioxoisoindol-2-yl) butyl] sulfonyl] phenyl]-(2-chloro-
5-nitrophenyl) carboxamide, N- [4-
[[2- (tert-Butoxycarbonylamino) ethyl] amino] phenyl]-(2-chloro-5-nitrophenyl) carboxamide monohydrochloride, N- [4-
[[(2-Dimethylamino) ethyl] (methyl) amino] phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide, N- [4-[[3- (tert-butoxycarbonylamino) propyl] amino] phenyl]
-(2-chloro-5-nitrophenyl) carboxamide monohydrochloride, N- [4-[[(3-dimethylamino) propyl] (methyl) amino] phenyl]-(2-chloro-5-nitrophenyl) Carboxamide, N- [4-
[[(3-Dimethylamino) propyl] (methyl) amino] phenyl]-(2-chloro-5-nitrophenyl)
Carboxamide dihydrochloride, N- [4-[[4- (te
rt-Butoxycarbonylamino) butoxy] amino]
Phenyl]-(2-chloro-5-nitrophenyl) carboxamide monohydrochloride, N- [4-[(4-aminobutoxy) amino] phenyl]-(2-chloro-5-nitrophenyl) carboxamide dihydrochloride Salt, N- [4- [4
-(Methanesulfonyl) -1-piperazinyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, N- [4- [4- (phenylsulfonyl) -1-
Piperazinyl] phenyl]-(2-chloro-5-nitrophenyl) carboxamide, 4- (2-chloro-5-nitrobenzoyl) -1-piperidinecarboxylic acid ethyl ester, 4- (2-chloro-5-nitrobenzoyl)
-1-Piperidinecarboxylic acid tert-butyl ester, 1- (2-chloro-5-nitrobenzoyl) piperazine monohydrochloride, 1- (2-chloro-5-nitrobenzoyl) -4-methylpiperazine, 1-benzyl -4-
(2-chloro-5-nitrobenzoyl) piperazine, 1
-(2-chloro-5-nitrobenzoyl) -4-phenylpiperazine, 1- (2-chloro-5-nitrobenzoyl) -4- [4- (N, N-dimethylamino) phenyl] piperazine, N- [ 4- [4-[(2-chloro-5
-Nitrophenyl) carbonyl] piperazin-1-yl] phenyl] methoxycarboxamide, N- [4-
[4-[(2-chloro-5-nitrophenyl) carbonyl] piperidin-1-yl] phenyl] acetamide,
N- [4- [4-[(2-chloro-5-nitrophenyl) carbonyl] piperazin-1-yl] phenyl] methanesulfonamide, 1-[(2-chloro-5-nitrophenyl) carbonyl] -4 -Phenylpiperidine and 3- (N-tert-butoxycarbonyl) amino-
A compound selected from the group consisting of 1- (2-chloro-5-nitrobenzoyl) pyrrolidine or a pharmaceutically acceptable salt thereof.
物又はその薬理上許容される塩を含有する、脂質調整
薬。7. A lipid regulating agent containing the compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof.
物又はその薬理上許容される塩を含有する、動脈硬化症
治療薬。8. A therapeutic agent for arteriosclerosis, which comprises the compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof.
物又はその薬理上許容される塩を含有する、高脂血症治
療薬。9. A therapeutic agent for hyperlipidemia, which comprises the compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002310549A JP2003201271A (en) | 2001-10-25 | 2002-10-25 | Lipid modulator |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001-327189 | 2001-10-25 | ||
JP2001327189 | 2001-10-25 | ||
JP2002310549A JP2003201271A (en) | 2001-10-25 | 2002-10-25 | Lipid modulator |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2003201271A true JP2003201271A (en) | 2003-07-18 |
Family
ID=27666474
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2002310549A Pending JP2003201271A (en) | 2001-10-25 | 2002-10-25 | Lipid modulator |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP2003201271A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009521427A (en) * | 2005-12-23 | 2009-06-04 | アストラゼネカ・アクチエボラーグ | Pyrazole for the treatment of gastroesophageal reflux disease and irritable bowel syndrome |
JP2013525448A (en) * | 2010-04-27 | 2013-06-20 | カルシメディカ,インク. | Compounds that regulate intracellular calcium |
WO2017115914A1 (en) * | 2015-12-29 | 2017-07-06 | 서울대학교산학협력단 | PPARγ PHOSPHORYLATION INHIBITOR AND PHARMACEUTICAL COMPOSITION COMPRISING SAME |
-
2002
- 2002-10-25 JP JP2002310549A patent/JP2003201271A/en active Pending
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009521427A (en) * | 2005-12-23 | 2009-06-04 | アストラゼネカ・アクチエボラーグ | Pyrazole for the treatment of gastroesophageal reflux disease and irritable bowel syndrome |
JP2013525448A (en) * | 2010-04-27 | 2013-06-20 | カルシメディカ,インク. | Compounds that regulate intracellular calcium |
US9353099B2 (en) | 2010-04-27 | 2016-05-31 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2017115914A1 (en) * | 2015-12-29 | 2017-07-06 | 서울대학교산학협력단 | PPARγ PHOSPHORYLATION INHIBITOR AND PHARMACEUTICAL COMPOSITION COMPRISING SAME |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1277729A1 (en) | Ppar (gamma) modulators | |
AU2006331656B2 (en) | Calcium channel antagonists | |
JP2011502984A (en) | Amide derivatives as sirtuin modulators | |
US20070197523A1 (en) | Calcium channel antagonists | |
MX2012003778A (en) | Novel compounds. | |
PL211096B1 (en) | New compounds | |
TWI434834B (en) | Pyrazole compounds and thiazole compounds as protein kinases inhibitors, pharmaceutical composition and the use thereof | |
JP5769326B2 (en) | Rho kinase inhibitor | |
CN1918118A (en) | Thioamide compound or its salt and cytokine production inhibitor containing the same | |
CA3101255A1 (en) | Compounds | |
EP1669070A2 (en) | 2-imino-thiazolidine and -oxazolidine derivatives for use as antiinflammatory agents | |
CN100363362C (en) | Thiazole derivatives as NPY receptor antagonists | |
CA2553443C (en) | Thiadiazole derivatives and compositions thereof as lxr modulators | |
EP0979823B1 (en) | Novel amide compounds and drugs containing the same | |
US6288061B1 (en) | Imidazole derivatives | |
NZ576197A (en) | 3 -amino- pyridine derivatives for the treatment of metabolic disorders | |
JP2003201271A (en) | Lipid modulator | |
JP2003128639A (en) | Benzamide derivative | |
HU190669B (en) | Process for preparing 3,4-disubstituted 1,2,5-thiadiazole-1-oxides and -1,1-dioxides | |
US6849647B1 (en) | Amide compounds and medications containing the same technical field | |
AU2003253195A1 (en) | 2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20040816 |