JP2000109463A - New 1,2,3,4-tetrahydroisoquinoline derivative - Google Patents
New 1,2,3,4-tetrahydroisoquinoline derivativeInfo
- Publication number
- JP2000109463A JP2000109463A JP10296132A JP29613298A JP2000109463A JP 2000109463 A JP2000109463 A JP 2000109463A JP 10296132 A JP10296132 A JP 10296132A JP 29613298 A JP29613298 A JP 29613298A JP 2000109463 A JP2000109463 A JP 2000109463A
- Authority
- JP
- Japan
- Prior art keywords
- benzo
- imidazole
- mmol
- tetrahydro
- isoquinolylsulfonyl
- 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
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical class C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 title claims abstract description 14
- -1 nitro, amino Chemical group 0.000 claims abstract description 79
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 21
- 125000003118 aryl group Chemical group 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 239000000460 chlorine Chemical group 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 35
- 230000006907 apoptotic process Effects 0.000 abstract description 13
- 230000030833 cell death Effects 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 abstract description 4
- 125000004434 sulfur atom Chemical group 0.000 abstract description 4
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 abstract description 2
- 241001601725 Sthenias Species 0.000 abstract 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 96
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 70
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 39
- 238000000862 absorption spectrum Methods 0.000 description 36
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 36
- 238000004949 mass spectrometry Methods 0.000 description 35
- 235000011054 acetic acid Nutrition 0.000 description 32
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 31
- 238000002844 melting Methods 0.000 description 26
- 230000008018 melting Effects 0.000 description 26
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 14
- 230000016273 neuron death Effects 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 229960001338 colchicine Drugs 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 6
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 210000000653 nervous system Anatomy 0.000 description 6
- 210000002569 neuron Anatomy 0.000 description 6
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 5
- 150000002537 isoquinolines Chemical class 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 229910052987 metal hydride Inorganic materials 0.000 description 4
- 150000004681 metal hydrides Chemical class 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- JIHVGOLTABHOBF-UHFFFAOYSA-N 2-cyclopentyl-1h-benzimidazole Chemical compound C1CCCC1C1=NC2=CC=CC=C2N1 JIHVGOLTABHOBF-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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 230000001640 apoptogenic effect Effects 0.000 description 3
- 230000002490 cerebral effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000000302 ischemic effect Effects 0.000 description 3
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 208000015122 neurodegenerative disease Diseases 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- FBLJZPQLNMVEMR-UHFFFAOYSA-N 2-propyl-1h-benzimidazole Chemical compound C1=CC=C2NC(CCC)=NC2=C1 FBLJZPQLNMVEMR-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- OHBVLSXPJWACEV-UHFFFAOYSA-N 5-(benzimidazol-1-ylsulfonyl)isoquinoline Chemical compound C1=NC=CC2=C(C=CC=C12)S(=O)(=O)N1C=NC2=C1C=CC=C2 OHBVLSXPJWACEV-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
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- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 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
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 229930002330 retinoic acid Natural products 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 229910052718 tin Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229960001727 tretinoin Drugs 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- WNRWEBKEQARBKV-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine Chemical compound ClCCN1CCCCC1 WNRWEBKEQARBKV-UHFFFAOYSA-N 0.000 description 1
- IMIUCCHPLSVTKZ-UHFFFAOYSA-N 1-nitrobenzimidazole Chemical compound C1=CC=C2N([N+](=O)[O-])C=NC2=C1 IMIUCCHPLSVTKZ-UHFFFAOYSA-N 0.000 description 1
- NMGLVHXJOMBIJW-UHFFFAOYSA-N 1h-benzimidazole;dihydrochloride Chemical compound Cl.Cl.C1=CC=C2NC=NC2=C1 NMGLVHXJOMBIJW-UHFFFAOYSA-N 0.000 description 1
- MVHOAOSHABGEFL-UHFFFAOYSA-N 2,6-dimethyl-1h-benzimidazole Chemical compound C1=C(C)C=C2NC(C)=NC2=C1 MVHOAOSHABGEFL-UHFFFAOYSA-N 0.000 description 1
- HDDPXVRMDRQLOQ-UHFFFAOYSA-N 2-cycloheptyl-1h-benzimidazole Chemical compound C1CCCCCC1C1=NC2=CC=CC=C2N1 HDDPXVRMDRQLOQ-UHFFFAOYSA-N 0.000 description 1
- ZUKYCLYMFNPDCT-UHFFFAOYSA-N 2-cyclohexyl-1h-benzimidazole Chemical compound C1CCCCC1C1=NC2=CC=CC=C2N1 ZUKYCLYMFNPDCT-UHFFFAOYSA-N 0.000 description 1
- PLKPKIIZGCWKSF-UHFFFAOYSA-N 2-cyclohexyl-6-nitro-1h-benzimidazole Chemical compound N1C2=CC([N+](=O)[O-])=CC=C2N=C1C1CCCCC1 PLKPKIIZGCWKSF-UHFFFAOYSA-N 0.000 description 1
- QEFBQPKNYBYOIS-UHFFFAOYSA-N 2-cyclopentyl-6-nitro-1H-benzimidazole Chemical compound C1(CCCC1)C1=NC2=C(N1)C=C(C=C2)[N+](=O)[O-] QEFBQPKNYBYOIS-UHFFFAOYSA-N 0.000 description 1
- QHCCOYAKYCWDOJ-UHFFFAOYSA-N 2-ethyl-1h-benzimidazole Chemical compound C1=CC=C2NC(CC)=NC2=C1 QHCCOYAKYCWDOJ-UHFFFAOYSA-N 0.000 description 1
- RBMSXLGNJDFTIO-UHFFFAOYSA-N 2-ethyl-4-nitro-1h-benzimidazole Chemical compound C1=CC=C2NC(CC)=NC2=C1[N+]([O-])=O RBMSXLGNJDFTIO-UHFFFAOYSA-N 0.000 description 1
- AAJAEEPAUQTYFB-UHFFFAOYSA-N 2-ethyl-6-nitro-1h-benzimidazole Chemical compound C1=C([N+]([O-])=O)C=C2NC(CC)=NC2=C1 AAJAEEPAUQTYFB-UHFFFAOYSA-N 0.000 description 1
- LDZYRENCLPUXAX-UHFFFAOYSA-N 2-methyl-1h-benzimidazole Chemical compound C1=CC=C2NC(C)=NC2=C1 LDZYRENCLPUXAX-UHFFFAOYSA-N 0.000 description 1
- NPNUZBBMRYRAPF-UHFFFAOYSA-N 2-methyl-4-nitro-1h-benzimidazole Chemical compound C1=CC=C2NC(C)=NC2=C1[N+]([O-])=O NPNUZBBMRYRAPF-UHFFFAOYSA-N 0.000 description 1
- RKRXTVLCZDPERO-UHFFFAOYSA-N 2-methyl-6-nitro-1h-benzimidazole Chemical compound C1=C([N+]([O-])=O)C=C2NC(C)=NC2=C1 RKRXTVLCZDPERO-UHFFFAOYSA-N 0.000 description 1
- DPJCXCZTLWNFOH-UHFFFAOYSA-N 2-nitroaniline Chemical compound NC1=CC=CC=C1[N+]([O-])=O DPJCXCZTLWNFOH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LJQNMDZRCXJETK-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine;hydron;chloride Chemical compound Cl.CN(C)CCCCl LJQNMDZRCXJETK-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- XJCVRTZCHMZPBD-UHFFFAOYSA-N 3-nitroaniline Chemical compound NC1=CC=CC([N+]([O-])=O)=C1 XJCVRTZCHMZPBD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- BXIXXXYDDJVHDL-UHFFFAOYSA-N 4-Chloro-ortho-phenylenediamine Chemical compound NC1=CC=C(Cl)C=C1N BXIXXXYDDJVHDL-UHFFFAOYSA-N 0.000 description 1
- NBTIYXCWOONOBX-UHFFFAOYSA-N 4-chloro-5-isoquinolin-5-ylsulfanylbenzene-1,2-diamine Chemical compound C1=C(N)C(N)=CC(Cl)=C1SC1=CC=CC2=CN=CC=C12 NBTIYXCWOONOBX-UHFFFAOYSA-N 0.000 description 1
- FRBQEWKGFIFQJB-UHFFFAOYSA-N 4-isoquinolin-5-ylsulfanyl-3-nitroaniline Chemical compound [O-][N+](=O)C1=CC(N)=CC=C1SC1=CC=CC2=CN=CC=C12 FRBQEWKGFIFQJB-UHFFFAOYSA-N 0.000 description 1
- VRDKTAKYWNNTMK-UHFFFAOYSA-N 4-isoquinolin-5-ylsulfonylbenzene-1,2-diamine Chemical compound C1=C(N)C(N)=CC=C1S(=O)(=O)C1=CC=CC2=CN=CC=C12 VRDKTAKYWNNTMK-UHFFFAOYSA-N 0.000 description 1
- FYWPFRMXRKQLHO-UHFFFAOYSA-N 4-nitro-2-propyl-1h-benzimidazole Chemical compound C1=CC=C2NC(CCC)=NC2=C1[N+]([O-])=O FYWPFRMXRKQLHO-UHFFFAOYSA-N 0.000 description 1
- MNHCOZPGIVBARO-UHFFFAOYSA-N 5-(4-nitrophenyl)sulfonylisoquinoline Chemical compound C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)C1=CC=CC2=CN=CC=C12 MNHCOZPGIVBARO-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、新規な1, 2, 3, 4
−テトラヒドロイソキノリン誘導体及びその薬学的に許
容される酸付加塩に関する。本発明の化合物は、神経系
でのアポトーシス亢進で生じる神経細胞死（アポトーシ
ス型神経細胞死）の抑制活性を有し、アルツハイマー
病、パーキンソン病、ハンチントン舞踏病、筋萎縮性側
索硬化症等の神経変性疾患、脳卒中等の脳虚血性障害、
及び糖尿病等で観察される末梢性神経障害等の予防及び
／又は治療剤として有用である。TECHNICAL FIELD The present invention relates to a novel 1, 2, 3, 4
-Tetrahydroisoquinoline derivatives and pharmaceutically acceptable acid addition salts thereof. The compound of the present invention has an inhibitory activity on neuronal cell death (apoptotic neuronal cell death) caused by enhanced apoptosis in the nervous system, and has activities such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis Neurodegenerative diseases, cerebral ischemic disorders such as stroke,
And useful as a preventive and / or therapeutic agent for peripheral neuropathy and the like observed in diabetes and the like.
【０００２】[0002]
【従来の技術】細胞死は形態学的変化から、細胞膜の変
性により細胞全体が膨化して死滅するネクローシスと、
核構造の変化・ＤＮＡのはしご状断片化を伴い、細胞全
体のサイズが縮小して死滅するアポトーシスとに分類さ
れる（Kerr and Harrnon, Apoptosis: The Molecular B
asis of Cell Death, Tomei and Cope (Eds), pp5-29(1
991), Cold Spring Harbor Laboratory Press)。アポト
ーシスは、近年になり多くの疾患の発症病理に深く関与
していることが明らかとなり、アポトーシス異常の制御
による新しい治療の可能性が出てきている（Thompson,
Science, Vol.267, pp1456-1462(1995))。2. Description of the Related Art Cell death is caused by morphological changes, necrosis in which the entire cell swells and dies due to degeneration of the cell membrane,
Apoptosis involves changes in nuclear structure and ladder-like fragmentation of DNA, resulting in a reduction in the size of the entire cell and death (Kerr and Harrnon, Apoptosis: The Molecular B)
asis of Cell Death, Tomei and Cope (Eds), pp5-29 (1
991), Cold Spring Harbor Laboratory Press). Apoptosis has recently been shown to be deeply involved in the pathogenesis of many diseases, and new therapeutic possibilities by controlling apoptotic abnormalities have emerged (Thompson,
Science, Vol.267, pp1456-1462 (1995)).
【０００３】神経系においては、神経変性疾患（アルツ
ハイマー病、パーキンソン病、ハンチントン舞踏病、筋
萎縮性側索硬化症等）に認められる神経細胞死に、アポ
トーシスの関与を示唆する報告がなされている（Su et
al., NeuroReport, Vol.5, pp2529-2533(1994); Yoshiy
ama et al., Acta Neuropathologica, Vol.88, pp207-2
11(1994); Lassmann et al., Acta Neuropathologica,
Vol.89, pp35-41(1995); Smale et al., Experimental
Neurology, Vol.133, pp225-230(1995); Dragunow et a
l., NeuroReport, Vol.6, pp1053-1057(1995); Portera
-Cailliau et al., Journal of Neuroscience, Vol.15,
pp3775-3787(1995); Cotman and Anderson, Molecular
Neurobiology, Vol.10, pp19-45(1995); Bredesen, An
nals ofNeurology, Vol.38, pp839-851(1995)) 。さら
に、脳虚血に伴う神経細胞死も同様にアポトーシスであ
ることが、一過性脳虚血砂ネズミで証明されている（Ni
tatori et al., Journal of Neuroscience, Vol.15, pp
1001-1011(1995))。神経系のアポトーシスを抑制するも
のとしては、蛋白質合成阻害剤やＲＮＡ合成阻害剤が挙
げられるが、それらについてはいずれもその作用の特異
性が問題となる。また、Bcl-2 遺伝子産物やニューロト
ロフィック因子等の蛋白性因子は生体内に安定的かつ効
率的に投与することに問題点が多く、まだ実用には至っ
ていない。従って、現在までにこれらの神経細胞死を伴
う疾患の有効な治療法は確立されていない。[0003] In the nervous system, there have been reports suggesting that apoptosis is involved in neuronal cell death observed in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, etc.) ( Su et
al., NeuroReport, Vol.5, pp2529-2533 (1994); Yoshiy
ama et al., Acta Neuropathologica, Vol.88, pp207-2
11 (1994); Lassmann et al., Acta Neuropathologica,
Vol.89, pp35-41 (1995); Smale et al., Experimental
Neurology, Vol. 133, pp225-230 (1995); Dragunow et a
l., NeuroReport, Vol. 6, pp1053-1057 (1995); Portera
-Cailliau et al., Journal of Neuroscience, Vol. 15,
pp3775-3787 (1995); Cotman and Anderson, Molecular
Neurobiology, Vol. 10, pp19-45 (1995); Bredesen, An
nals of Neurology, Vol. 38, pp839-851 (1995)). Furthermore, it has been shown in transient cerebral ischemic sand rats that nerve cell death associated with cerebral ischemia is also apoptosis (Ni
tatori et al., Journal of Neuroscience, Vol. 15, pp
1001-1011 (1995)). Examples of inhibitors of apoptosis of the nervous system include protein synthesis inhibitors and RNA synthesis inhibitors, but the specificity of their action poses a problem. In addition, protein factors such as Bcl-2 gene products and neurotrophic factors have many problems in stable and efficient administration into living organisms, and have not yet been put to practical use. Therefore, to date, no effective treatment for these diseases involving neuronal death has been established.
【０００４】これまでにイソキノリンの誘導体は様々な
ものが知られており、その中でイソキノリンの５位にイ
オウ原子を介してアルキル基や芳香環が結合した化合物
は、数例 (Euerby, Mervin R. and Waigh, Roger D.,
J. Chem. Soc. Chem. Commun., Vol.2, 127-128(198
4)、特開平10-87629号公報、特開平10-101650 号公報
等）報告されているが、1, 2, 3, 4−テトラヒドロイソ
キノリンの５位にイオウ原子を介して芳香環が結合した
化合物は、まだ知られていない。A variety of isoquinoline derivatives have been known so far. Among them, a compound in which an alkyl group or an aromatic ring is bonded to the 5-position of isoquinoline via a sulfur atom (Euerby, Mervin R.) . and Waigh, Roger D.,
J. Chem. Soc. Chem. Commun., Vol. 2, 127-128 (198
4), JP-A-10-87629, JP-A-10-101650, etc.) reported that an aromatic ring was bonded to the 5-position of 1,2,3,4-tetrahydroisoquinoline via a sulfur atom. The compound is not yet known.
【０００５】[0005]
【発明が解決しようとする課題】本発明者らは、上述の
状況に鑑み1, 2, 3, 4−テトラヒドロイソキノリンの５
位にイオウ原子を介して芳香環が結合した種々の化合物
を合成し、その有用性について検討したところ、神経系
でのアポトーシス亢進で生じる神経細胞死の抑制に優れ
た効果を示す新規な化合物を見出すに至った。従って本
発明は、神経系でのアポトーシス亢進で生じる神経細胞
死に対して抑制活性を有する、新規な1, 2, 3, 4−テト
ラヒドロイソキノリン誘導体を提供することを課題とす
る。SUMMARY OF THE INVENTION In view of the above-mentioned situation, the present inventors have studied the 1,2,3,4-tetrahydroisoquinoline
Of various compounds in which an aromatic ring is bonded via a sulfur atom at the 1-position, and the usefulness of the compounds was examined.A new compound showing an excellent effect on suppressing neuronal cell death caused by apoptosis in the nervous system was investigated. I came to find it. Therefore, an object of the present invention is to provide a novel 1,2,3,4-tetrahydroisoquinoline derivative having an inhibitory activity on nerve cell death caused by enhanced apoptosis in the nervous system.
【０００６】[0006]
【課題を解決するための手段】本発明は、新規な1, 2,
3, 4−テトラヒドロイソキノリン誘導体及びその薬学的
に許容される酸付加塩に関する。本発明の新規1, 2, 3,
4−テトラヒドロイソキノリン誘導体及びその薬学的に
許容される酸付加塩は、一般式(I) で表される。SUMMARY OF THE INVENTION The present invention provides a novel 1, 2,
The present invention relates to a 3,4-tetrahydroisoquinoline derivative and a pharmaceutically acceptable acid addition salt thereof. New 1,2,3 of the present invention
The 4-tetrahydroisoquinoline derivative and a pharmaceutically acceptable acid addition salt thereof are represented by the general formula (I).
【０００７】[0007]
【化３】 （式中、Arは置換されていてもよい芳香環または複素
環、ｎは０、１または２、R1は水素、低級アルキル、低
級アルキルカルボニル、アリールカルボニル、アリール
スルホニル、アラルキル及び-A-NR2R3より選択される置
換基を示す。-A-NR2R3においてＡは低級アルキレンを、
R2、R3は同一または異なる低級アルキルであり、R2, R3
は一緒になって環を形成していてもよい置換基を示す。
また、低級アルキルは直鎖または分枝状の炭素数が１か
ら６個のアルキルを、アリールは置換されていてもよい
フェニル基を、アラルキルは置換されていてもよいフェ
ニル低級アルキル基を、低級アルキレンは直鎖または分
枝状の炭素数が１から６個のアルキレンを示す）Embedded image (Wherein, Ar is an optionally substituted aromatic or heterocyclic ring, n is 0, 1 or 2, R 1 is hydrogen, lower alkyl, lower alkylcarbonyl, arylcarbonyl, arylsulfonyl, aralkyl and -A-NR 2 R 3 represents a substituent selected from the group consisting of -A-NR 2 R 3 wherein A represents lower alkylene;
R 2 and R 3 are the same or different lower alkyl, and R 2 and R 3
Represents a substituent which may form a ring together.
Lower alkyl is a straight-chain or branched alkyl having 1 to 6 carbon atoms, aryl is an optionally substituted phenyl group, and aralkyl is an optionally substituted phenyl lower alkyl group. Alkylene represents a straight-chain or branched alkylene having 1 to 6 carbon atoms)
【０００８】本発明の一般式(I) のArの芳香環として
は、ニトロベンゼン、クロロベンゼン、アニリン、2-ニ
トロアニリン、3-ニトロアニリン、3-クロロアニリン、
1,2-ジアミノベンゼン、4-クロロ-1,2- ジアミノベンゼ
ン等を、また複素環としては、ピリジン、キノリン、イ
ソキノリン、ベンゾイミダゾール、2-メチルベンゾイミ
ダゾール、2-エチルベンゾイミダゾール、2-プロピルベ
ンゾイミダゾール、2-シクロベンゾイミダゾール、2-シ
クロペンチルベンゾイミダゾール、2-シクロヘキシルベ
ンゾイミダゾール、2-シクロヘプチルベンゾイミダゾー
ル、2-メチル-6-ニトロベンゾイミダゾール、2-エチル-
6- ニトロベンゾイミダゾール、2-プロピル-6- ニトロ
ベンゾイミダゾール、2-イソプロピル-6- ニトロベンゾ
イミダゾール、2-シクロペンチル-6- ニトロベンゾイミ
ダゾール、2-シクロヘキシル-6- ニトロベンゾイミダゾ
ール、2-メチル-7- ニトロベンゾイミダゾール、2-エチ
ル-7- ニトロベンゾイミダゾール、2-プロピル-7- ニト
ロベンゾイミダゾール、2-シクロペンチル-7- ニトロベ
ンゾイミダゾール、6-クロロ-2- エチルベンゾイミダゾ
ール、6-クロロ-2- プロピルベンゾイミダゾール、6-ク
ロロ-2- シクロペンチルベンゾイミダゾール、2,6-ジメ
チルベンゾイミダゾール等を例示することができる。R1
の低級アルキルは、直鎖又は分枝状の炭素数が１から６
個のアルキルで、このようなアルキルとしては、メチ
ル、エチル、プロピル、ブチル、ペンチル、ヘキシル
基、あるいはそれらの異性体等を例示することができ
る。また、低級アルキルカルボニルには、メチルカルボ
ニル、エチルカルボニル、ブチルカルボニル、ペンチル
カルボニル、ヘキシルカルボニル、あるいはそれらの異
性体等を、アリールカルボニルのアリールは、前記のよ
うに置換されてもよいフェニルカルボニル基であって、
置換基としては、フェニルカルボニル、トルオイル等を
例示することができる。アリールスルホニルは、同様に
置換されてもよいフェニルスルホニル基であって、置換
基としてはフェニルスルホニル、トルエンスルホニル等
が例示される。アラルキルには、置換されてもよいフェ
ニル低級アルキル基であって、置換基としては、フェニ
ルメチル、フェニルエチル、フェニルプロピル、フェニ
ルブチル、フェニルペンチル、フェニルヘキシル、トル
エンメチル、トルエンエチル、トルエンプロピル、トル
エンブチル、トルエンペンチル、トルエンヘキシル、ク
ロロフェニルメチル、クロロフェニルエチル、クロロフ
ェニルプロピル、クロロフェニルブチル、クロロフェニ
ルペンチル、クロロフェニルヘキシル、ブロモフェニル
メチル、ブロモフェニルエチル、ブロモフェニルプロピ
ル、ブロモフェニルブチル、ブロモフェニルペンチル、
ブロモフェニルヘキシル、あるいはそれらの異性体等が
例示され、また低級アルキル基は上記と同様のものが用
いられる。また、一般式-A-NR2R3- のＡは炭素数１〜６
個のアルキレン基を示すが、このようなものとしては、
メチレン、エチレン、プロピレン、ブチレン、ペンチレ
ン、ヘキシレン基、あるいはその異性体を例示すること
ができる。さらに、R2及びR3の低級アルキルはR1と同様
の低級アルキルを示し、これらが一緒になって環を形成
したものとして、アジリジン、アゼチジン、ピロリジ
ン、ピペリジン等を例示することができる。The aromatic ring of Ar in the general formula (I) of the present invention includes nitrobenzene, chlorobenzene, aniline, 2-nitroaniline, 3-nitroaniline, 3-chloroaniline,
1,2-diaminobenzene, 4-chloro-1,2-diaminobenzene, etc., and as a heterocycle, pyridine, quinoline, isoquinoline, benzimidazole, 2-methylbenzimidazole, 2-ethylbenzimidazole, 2-propyl Benzimidazole, 2-cyclobenzimidazole, 2-cyclopentylbenzimidazole, 2-cyclohexylbenzimidazole, 2-cycloheptylbenzimidazole, 2-methyl-6-nitrobenzimidazole, 2-ethyl-
6-nitrobenzimidazole, 2-propyl-6-nitrobenzimidazole, 2-isopropyl-6-nitrobenzimidazole, 2-cyclopentyl-6-nitrobenzimidazole, 2-cyclohexyl-6-nitrobenzimidazole, 2-methyl- 7-nitrobenzimidazole, 2-ethyl-7-nitrobenzimidazole, 2-propyl-7-nitrobenzimidazole, 2-cyclopentyl-7-nitrobenzimidazole, 6-chloro-2-ethylbenzimidazole, 6-chloro- Examples thereof include 2-propylbenzimidazole, 6-chloro-2-cyclopentylbenzimidazole, and 2,6-dimethylbenzimidazole. R 1
Is a straight or branched chain having 1 to 6 carbon atoms.
The alkyl may be a methyl, ethyl, propyl, butyl, pentyl, hexyl group or an isomer thereof. In addition, lower alkylcarbonyl includes methylcarbonyl, ethylcarbonyl, butylcarbonyl, pentylcarbonyl, hexylcarbonyl, and isomers thereof, and the like.The aryl of arylcarbonyl is a phenylcarbonyl group which may be substituted as described above. So,
Examples of the substituent include phenylcarbonyl and toluoyl. Arylsulfonyl is a phenylsulfonyl group which may be similarly substituted, and examples of the substituent include phenylsulfonyl and toluenesulfonyl. Aralkyl is a phenyl lower alkyl group which may be substituted, and the substituent is phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, toluenemethyl, tolueneethyl, toluenepropyl, toluene Butyl, toluenepentyl, toluenehexyl, chlorophenylmethyl, chlorophenylethyl, chlorophenylpropyl, chlorophenylbutyl, chlorophenylpentyl, chlorophenylhexyl, bromophenylmethyl, bromophenylethyl, bromophenylpropyl, bromophenylbutyl, bromophenylpentyl,
Bromophenylhexyl and their isomers are exemplified, and the same lower alkyl group as described above is used. A in the general formula -A-NR 2 R 3- has 1 to 6 carbon atoms.
Shows alkylene groups, such as,
Examples include a methylene, ethylene, propylene, butylene, pentylene, hexylene group, and isomers thereof. Further, the lower alkyls of R 2 and R 3 represent the same lower alkyls as R 1, and examples of the lower alkyls formed together to form a ring include aziridine, azetidine, pyrrolidine, piperidine and the like.
【０００９】本発明の1, 2, 3, 4−テトラヒドロイソキ
ノリン誘導体において、好ましくは、Arが置換されてい
てもよい式(II)〜(IV)の芳香環または複素環のいずれか
から選択される基をもつ1, 2, 3, 4−テトラヒドロイソ
キノリン誘導体及びその薬学的に許容される酸付加塩で
ある。In the 1,2,3,4-tetrahydroisoquinoline derivative of the present invention, Ar is preferably selected from any of the aromatic or heterocyclic rings of the formulas (II) to (IV) which may be substituted. A 1,2,3,4-tetrahydroisoquinoline derivative having the following groups: and a pharmaceutically acceptable acid addition salt thereof.
【００１０】[0010]
【化４】 （式中、R4-R16は水素、ニトロ、アミノ、ハロゲン、低
級アルキル及びシクロアルキルより選択される同一また
は異なる置換基を示す。ハロゲンはフッ素、塩素、臭素
またはヨウ素を、シクロアルキルは炭素数が３から７個
のシクロアルキルを示す）Embedded image Wherein R 4 -R 16 represent the same or different substituents selected from hydrogen, nitro, amino, halogen, lower alkyl and cycloalkyl. Halogen represents fluorine, chlorine, bromine or iodine, cycloalkyl represents carbon The number represents 3 to 7 cycloalkyl)
【００１１】[0011]
【発明の実施の形態】一般式(I) で示される本発明のイ
ソキノリン誘導体の具体例として、以下の化合物を挙げ
ることができる。 (1) 5-[(4-ニトロフェニル) スルファニル]-1,2,3,4-
テトラヒドロイソキノリン (2) 4-(1,2,3,4- テトラヒドロ-5- イソキノリルスル
ファニル) アニリン (3) 3-ニトロ-4-(1,2,3,4-テトラヒドロ-5- イソキノ
リルスルファニル) アニリン (4) 4-クロロ-5-(1,2,3,4-テトラヒドロ-5- イソキノ
リルスルファニル)-1,2-ベンゼンジアミン (5) 5(6)-(1,2,3,4-テトラヒドロ-5- イソキノリルス
ルファニル)-1H- ベンゾ[d] イミダゾール (6) 2-メチル-5(6)-(1,2,3,4- テトラヒドロ-5- イソ
キノリルスルファニル)-1H- ベンゾ[d] イミダゾール (7) 2-メチル-6(5)-ニトロ-5(6)-(1,2,3,4- テトラヒ
ドロ-5- イソキノリルスルファニル)-1H- ベンゾ[d] イ
ミダゾール (8) 2-プロピル-5(6)-(1,2,3,4- テトラヒドロ-5- イ
ソキノリルスルファニル)-1H- ベンゾ[d] イミダゾール (9) 5-[(4-ニトロフェニル) スルホニル]-1,2,3,4-テ
トラヒドロイソキノリン (10) 4-(1,2,3,4- テトラヒドロ-5- イソキノリルスル
ホニル)-1,2-ベンゼンジアミンBEST MODE FOR CARRYING OUT THE INVENTION As specific examples of the isoquinoline derivative of the present invention represented by the general formula (I), the following compounds can be mentioned. (1) 5-[(4-nitrophenyl) sulfanyl] -1,2,3,4-
Tetrahydroisoquinoline (2) 4- (1,2,3,4-tetrahydro-5-isoquinolylsulfanyl) aniline (3) 3-nitro-4- (1,2,3,4-tetrahydro-5-isoquino Rylsulfanyl) aniline (4) 4-chloro-5- (1,2,3,4-tetrahydro-5-isoquinolylsulfanyl) -1,2-benzenediamine (5) 5 (6)-(1,2 , 3,4-tetrahydro-5-isoquinolylsulfanyl) -1H-benzo [d] imidazole (6) 2-methyl-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolyl Sulfanyl) -1H-benzo [d] imidazole (7) 2-Methyl-6 (5) -nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfanyl) -1H- Benzo [d] imidazole (8) 2-propyl-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfanyl) -1H-benzo [d] imidazole (9) 5-[( 4-nitrophenyl) sulfonyl] -1,2,3,4-tetrahydroisoquinoline (10) 4- (1,2,3,4-tetrahydro-5-isoquinoline Rirusuruhoniru) -1,2-benzenediamine
【００１２】(11) 4-クロロ-5-(1,2,3,4-テトラヒドロ-
5- イソキノリルスルホニル)-1,2-ベンゼンジアミン (12) 2-メチル-5(6)-(1,2,3,4- テトラヒドロ-5- イソ
キノリルスルホニル)-1H- ベンゾ[d] イミダゾール (13) 2-エチル-5(6)-(1,2,3,4- テトラヒドロ-5- イソ
キノリルスルホニル)-1H- ベンゾ[d] イミダゾール (14) 2-プロピル-5(6)-(1,2,3,4- テトラヒドロ-5- イ
ソキノリルスルホニル)-1H- ベンゾ[d] イミダゾール (15) 2-シクロブチル-5(6)-(1,2,3,4- テトラヒドロ-5-
イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾー
ル (16) 2-シクロペンチル-5(6)-(1,2,3,4- テトラヒドロ-
5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾ
ール (17) 2-シクロヘキシル-5(6)-(1,2,3,4- テトラヒドロ-
5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾ
ール (18) 2-シクロヘプチル-5(6)-(1,2,3,4- テトラヒドロ-
5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾ
ール (19) 2-メチル-6(5)-ニトロ-5(6)-(1,2,3,4- テトラヒ
ドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d] イミ
ダゾール (20) 2-エチル-6(5)-ニトロ-5(6)-(1,2,3,4- テトラヒ
ドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d] イミ
ダゾール(11) 4-chloro-5- (1,2,3,4-tetrahydro-
5-isoquinolylsulfonyl) -1,2-benzenediamine (12) 2-methyl-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d ] Imidazole (13) 2-ethyl-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole (14) 2-propyl-5 (6 )-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole (15) 2-cyclobutyl-5 (6)-(1,2,3,4-tetrahydro -Five-
Isoquinolylsulfonyl) -1H-benzo [d] imidazole (16) 2-cyclopentyl-5 (6)-(1,2,3,4-tetrahydro-
5-isoquinolylsulfonyl) -1H-benzo [d] imidazole (17) 2-cyclohexyl-5 (6)-(1,2,3,4-tetrahydro-
5-isoquinolylsulfonyl) -1H-benzo [d] imidazole (18) 2-cycloheptyl-5 (6)-(1,2,3,4-tetrahydro-
5-isoquinolylsulfonyl) -1H-benzo [d] imidazole (19) 2-methyl-6 (5) -nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolyl (Sulfonyl) -1H-benzo [d] imidazole (20) 2-ethyl-6 (5) -nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H- Benzo [d] imidazole
【００１３】(21) 6(5)- ニトロ-2- プロピル-5(6)-(1,
2,3,4- テトラヒドロ-5- イソキノリルスルホニル)-1H-
ベンゾ[d] イミダゾール (22) 2-イソプロピル-6(5)-ニトロ-5(6)-(1,2,3,4- テ
トラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール (23) 2-シクロペンチル-6(5)-ニトロ-5(6)-(1,2,3,4-
テトラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール (24) 2-シクロヘキシル-6(5)-ニトロ-5(6)-(1,2,3,4-
テトラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール (25) 2-メチル-7(4)-ニトロ-5(6)-(1,2,3,4- テトラヒ
ドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d] イミ
ダゾール (26) 2-エチル-7(4)-ニトロ-5(6)-(1,2,3,4- テトラヒ
ドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d] イミ
ダゾール (27) 7(4)- ニトロ -2-プロピル-5(6)-(1,2,3,4- テト
ラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d]
イミダゾール (28) 2-シクロペンチル-7(4)-ニトロ-5(6)-(1,2,3,4-
テトラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール (29) 6(5)- クロロ-2- エチル-5(6)-(1,2,3,4- テトラ
ヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d] イ
ミダゾール (30) 6(5)- クロロ-2- プロピル-5(6)-(1,2,3,4- テト
ラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d]
イミダゾール(21) 6 (5) -Nitro-2-propyl-5 (6)-(1,
2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-
Benzo [d] imidazole (22) 2-isopropyl-6 (5) -nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo
[d] Imidazole (23) 2-cyclopentyl-6 (5) -nitro-5 (6)-(1,2,3,4-
(Tetrahydro-5-isoquinolylsulfonyl) -1H-benzo
[d] Imidazole (24) 2-cyclohexyl-6 (5) -nitro-5 (6)-(1,2,3,4-
(Tetrahydro-5-isoquinolylsulfonyl) -1H-benzo
[d] Imidazole (25) 2-methyl-7 (4) -nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole ( 26) 2-Ethyl-7 (4) -nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole (27) 7 (4 ) -Nitro-2-propyl-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d]
Imidazole (28) 2-cyclopentyl-7 (4) -nitro-5 (6)-(1,2,3,4-
(Tetrahydro-5-isoquinolylsulfonyl) -1H-benzo
[d] Imidazole (29) 6 (5) -Chloro-2-ethyl-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole ( 30) 6 (5) -Chloro-2-propyl-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d]
Imidazole
【００１４】(31) 6(5)- クロロ-2- シクロペンチル-5
(6)-(1,2,3,4- テトラヒドロ-5- イソキノリルスルホニ
ル)-1H- ベンゾ[d] イミダゾール (32) 2,6(5)- ジメチル-5(6)-(1,2,3,4- テトラヒドロ-
5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾ
ール (33) 5(6)-[(2- アセチル-1,2,3,4- テトラヒドロ-5-
イソキノリル) スルホニル]-2-シクロペンチル-1H-ベン
ゾ[d] イミダゾール (34) 5(6)-[(2- ベンゾイル-1,2,3,4- テトラヒドロ-5-
イソキノリル) スルホニル]-2-シクロペンチル-6(5)-
ニトロ-1H-ベンゾ[d] イミダゾール (35) 2-シクロペンチル-6(5)-ニトロ-5(6)-[(2-トシル-
1,2,3,4- テトラヒドロ-5- イソキノリル) スルホニル]
-1H- ベンゾ[d] イミダゾール (36) 2-シクロペンチル-5(6)-[(2-メチル-1,2,3,4- テ
トラヒドロ-5- イソキノリル) スルホニル]-6(5)- ニト
ロ-1H-ベンゾ[d] イミダゾール (37) 5(6)-[(2- ベンジル-1,2,3,4- テトラヒドロ-5-
イソキノリル) スルホニル]-2-シクロペンチル-6(5)-ニ
トロ-1H-ベンゾ[d] イミダゾール (38) 2-シクロペンチル-5(6)-｛[2-(N,N-ジメチルアミ
ノプロピル)-1,2,3,4-テトラヒドロ-5- イソキノリル]
スルホニル｝-6(5)-ニトロ-1H-ベンゾ[d] イミダゾール (39) 2-シクロペンチル-6(5)-ニトロ-5(6)-｛[2-(2-ピ
ペリジノエチル)-1,2,3,4-テトラヒドロ-5- イソキノリ
ル] スルホニル｝-1H-ベンゾ[d] イミダゾール(31) 6 (5) -Chloro-2-cyclopentyl-5
(6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole (32) 2,6 (5) -dimethyl-5 (6)-(1, 2,3,4-tetrahydro-
5-isoquinolylsulfonyl) -1H-benzo [d] imidazole (33) 5 (6)-[(2-acetyl-1,2,3,4-tetrahydro-5-
Isoquinolyl) sulfonyl] -2-cyclopentyl-1H-benzo [d] imidazole (34) 5 (6)-[(2-benzoyl-1,2,3,4-tetrahydro-5-
Isoquinolyl) sulfonyl] -2-cyclopentyl-6 (5)-
Nitro-1H-benzo [d] imidazole (35) 2-cyclopentyl-6 (5) -nitro-5 (6)-[(2-tosyl-
1,2,3,4-tetrahydro-5-isoquinolyl) sulfonyl]
-1H-benzo [d] imidazole (36) 2-cyclopentyl-5 (6)-[(2-methyl-1,2,3,4-tetrahydro-5-isoquinolyl) sulfonyl] -6 (5) -nitro- 1H-benzo [d] imidazole (37) 5 (6)-[(2-benzyl-1,2,3,4-tetrahydro-5-
Isoquinolyl) sulfonyl] -2-cyclopentyl-6 (5) -nitro-1H-benzo [d] imidazole (38) 2-cyclopentyl-5 (6)-｛[2- (N, N-dimethylaminopropyl) -1 , 2,3,4-Tetrahydro-5-isoquinolyl]
Sulfonyl｝ -6 (5) -nitro-1H-benzo [d] imidazole (39) 2-cyclopentyl-6 (5) -nitro-5 (6)-｛[2- (2-piperidinoethyl) -1,2, 3,4-tetrahydro-5-isoquinolyl] sulfonyl｝ -1H-benzo [d] imidazole
【００１５】これらの化合物はいずれも、下記実施例40
及び41に記載される神経細胞のアポトーシスを抑制する
活性を有しており、特に好ましい化合物として前記
(2)、(18)、(20)、(21)、(22)、(23)、(24)、(31)、(3
6)及び(37)の化合物が挙げられる。All of these compounds are described in Example 40 below.
And 41 has the activity of suppressing apoptosis of nerve cells described in 41, as a particularly preferred compound
(2), (18), (20), (21), (22), (23), (24), (31), (3
6) and (37).
【００１６】本発明化合物は、酸または塩基と塩を形成
する。酸との塩としては塩酸、臭化水素酸、ヨウ化水素
酸、硫酸、硝酸、リン酸等の鉱酸や、ぎ酸、酢酸、プロ
ピオン酸、しゅう酸、マロン酸、こはく酸、フマル酸、
マレイン酸、乳酸、りんご酸、クエン酸、酒石酸、炭
酸、ピクリン酸、メタンスルホン酸、グルタミン酸等の
有機酸との塩を挙げることができる。塩基との塩として
はナトリウム、カリウム、マグネシウム、カルシウム、
アルミニウム等の無機塩基、メチルアミン、エチルアミ
ン、エタノールアミン等の有機塩基またはリジン、アル
ギニン、オルニチン等の塩基性アミノ酸との塩やアンモ
ニウム塩が挙げられる。さらに、本発明化合物は水和
物、エタノール等との溶媒和物や結晶多形を形成する場
合もある。The compound of the present invention forms a salt with an acid or a base. Examples of salts with acids include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
Examples thereof include salts with organic acids such as maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, and glutamic acid. As salts with bases, sodium, potassium, magnesium, calcium,
Examples thereof include salts with inorganic bases such as aluminum, organic bases such as methylamine, ethylamine and ethanolamine, and basic amino acids such as lysine, arginine and ornithine, and ammonium salts. Further, the compound of the present invention may form a hydrate, a solvate with ethanol or the like, or a crystalline polymorph.
【００１７】本発明の化合物は、下記の反応式に従っ
て、各種イソキノリン誘導体を還元することにより製造
することができる。The compound of the present invention can be produced by reducing various isoquinoline derivatives according to the following reaction formula.
【００１８】[0018]
【化５】 Embedded image
【００１９】本発明の化合物（式VI) は、上記の反応式
で示されるようにイソキノリン誘導体 (式V)を還元する
ことによって得ることができる。還元は、通常、金属お
よび金属塩による還元や金属水素化物による還元、金属
水素錯化合物による還元、接触水素添加反応などの還元
反応が用いられる。金属および金属塩としてはアルカリ
金属とアルカリ土類金属、亜鉛、アルミニウム、スズ、
鉄、銅など、金属水素化物としてはホウ素、アルミニウ
ム、ケイ素、スズなどの水素化物を、又、金属水素錯化
合物としては、水素化アルミニウム、水素化ホウ素とア
ルカリ金属等の水素化物との錯化合物が挙げられる。The compound of the present invention (formula VI) can be obtained by reducing an isoquinoline derivative (formula V) as shown in the above reaction formula. For the reduction, reduction reactions such as reduction with a metal and a metal salt, reduction with a metal hydride, reduction with a metal hydride complex compound, catalytic hydrogenation reaction and the like are usually used. Metals and metal salts include alkali and alkaline earth metals, zinc, aluminum, tin,
Examples of metal hydrides such as iron and copper include hydrides such as boron, aluminum, silicon, and tin, and examples of metal hydride complex compounds include aluminum hydride and complex compounds of borohydride and hydrides such as alkali metals. Is mentioned.
【００２０】又、本発明の化合物は上記の製造方法で得
られた化合物に通常の方法により新たな置換基を導入、
または置換することによっても製造することができる。
例えば、一般式（Ｉ）のｎ＝２、Arが2-シクロペンチル
ベンズイミダゾール、R1がアセチルである化合物（式VI
II) は、以下の反応式で示されるように2-シクロペンチ
ル- 5-[5-(1,2,3,4-テトラヒドロイソキノリル) スルホ
ニル]-1H- ベンゾ[d]イミダゾール (式VII)をアセチル
化して製造することができる。Further, the compound of the present invention may be obtained by introducing a new substituent into the compound obtained by the above-mentioned production method by an ordinary method,
Alternatively, it can also be produced by substitution.
For example, a compound of the formula (I) wherein n = 2, Ar is 2-cyclopentylbenzimidazole, and R 1 is acetyl (formula VI
II) is 2-cyclopentyl-5- [5- (1,2,3,4-tetrahydroisoquinolyl) sulfonyl] -1H-benzo [d] imidazole (formula VII) as shown in the following reaction formula. Can be produced by acetylation.
【００２１】[0021]
【化６】 Embedded image
【００２２】このようにして得られた本発明化合物は、
遊離のまま、あるいはその塩として単離・精製される。
単離・精製は、抽出、濃縮、留去、結晶化、濾過、再結
晶、各種クロマトグラフィー等の常法により行なうこと
ができる。The compound of the present invention thus obtained is
It is isolated and purified as it is or as its salt.
Isolation and purification can be performed by a conventional method such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.
【００２３】本発明化合物は、ヒト及び動物に対し医薬
として安全に投与される。本発明化合物またはその塩の
１種または２種以上を有効成分として含有する製剤は、
通常製剤化に用いられる担体や賦形剤、その他の添加剤
を用いて調製される。製剤用の担体や賦形剤としては、
固体または液体いずれでもよく、例えば乳糖、ステアリ
ン酸マグネシウム、スターチ、タルク、ゼラチン、寒
天、ペクチン、アラビアゴム、オリーブ油、ゴマ油、カ
カオバター、エチレングリコール等やその他常用のもの
が挙げられる。投与は錠剤、丸剤、カプセル剤、顆粒
剤、散剤、液剤等による経口投与、あるいは静注、筋注
等の注射剤、座剤、経皮等による非経口投与のいずれの
形態であってもよい。投与量は症状、投与対象の年齢、
性別等を考慮して個々の場合に応じて適宜決定される
が、通常成人１人当たり、経口投与の時には１日につき
１〜1000mg、好ましくは10〜200mg の範囲で１日１回か
ら数回に分けて投与し、また静脈内投与の時には１日に
つき１〜500mg の範囲で１日１回から数回、あるいは１
日１時間〜24時間の範囲で持続的に投与される。The compound of the present invention can be safely administered to humans and animals as a medicament. A preparation containing one or more of the compound of the present invention or a salt thereof as an active ingredient,
It is prepared using carriers, excipients and other additives that are usually used for formulation. As carriers and excipients for pharmaceuticals,
Either solid or liquid may be used, and examples thereof include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol and the like and other commonly used ones. Administration may be in the form of tablets, pills, capsules, granules, powders, liquids, etc., or oral administration, intravenous injection, intramuscular injection, parenteral administration, suppositories, transdermal, etc. Good. The dosage depends on the symptoms, age of the subject,
It is appropriately determined according to the individual case in consideration of gender and the like, but it is usually 1 to 1000 mg, preferably 10 to 200 mg per day for an adult, orally when administered orally, once to several times a day. It is administered in divided doses, and in the case of intravenous administration, in the range of 1 to 500 mg per day, once to several times a day, or
It is administered continuously for 1 hour to 24 hours a day.
【００２４】[0024]
【実施例】以下の実施例をもって本発明をよりに詳細に
説明するが、これらは単に例示するのみであり、これら
によって本発明は何ら限定されるものではない。尚、以
下の実施例において用いた原料化合物は、特開平 10-10
1650号公報に記載の方法で得られたものである。The present invention will be described in more detail with reference to the following examples, which are merely illustrative and do not limit the present invention in any way. The starting compounds used in the following examples are described in
It was obtained by the method described in Japanese Patent Publication No. 1650.
【００２５】[0025]
【実施例１】5-[(4-ニトロフェニル) スルファニル]-1,
2,3,4-テトラヒドロイソキノリン 5-(4- ニトロフェニルスルファニル) イソキノリン780m
g(2.8mmol)を酢酸(7ml) に溶解し、シアノ水素化ほう素
ナトリウム500mg(8.0mmol)を加え１時間室温で攪拌し
た。反応液に水、水酸化ナトリウム水溶液を加え、液性
をアルカリ性とした後、酢酸エチルで抽出した。有機層
を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減
圧濃縮して、5-[(4-ニトロフェニル) スルファニル]-1,
2,3,4-テトラヒドロイソキノリン600mg(2.1mmol,76.2%)
を得た。 融点:238〜241 ℃ 質量分析値(m/z):287(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:9.97(1H,brs),8.10(2H,d),7.56(1H,d),7.46(1H,d),
7.40(1H,dd),7.22(2H,d),4.29(2H,s),3.30(2H,t),2.98
(2H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 1580, 1500, 13
40Example 1 5-[(4-nitrophenyl) sulfanyl] -1,
2,3,4-tetrahydroisoquinoline 5- (4-nitrophenylsulfanyl) isoquinoline780m
g (2.8 mmol) was dissolved in acetic acid (7 ml), 500 mg (8.0 mmol) of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 1 hour. Water and an aqueous sodium hydroxide solution were added to the reaction solution to make the solution alkaline, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-[(4-nitrophenyl) sulfanyl] -1,
2,3,4-tetrahydroisoquinoline 600 mg (2.1 mmol, 76.2%)
I got Melting point: 238-241 ° C Mass spec (m / z): 287 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 9.97 (1H, brs), 8.10 (2H, d), 7.56 (1H, d), 7.46 (1H, d),
7.40 (1H, dd), 7.22 (2H, d), 4.29 (2H, s), 3.30 (2H, t), 2.98
(2H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 1580, 1500, 13
40
【００２６】[0026]
【実施例２】4-(1,2,3,4- テトラヒドロ-5- イソキノリ
ルスルファニル) アニリン 実施例１と同様の方法により、4-(5- イソキノリルスル
ファニル) アニリン590mg(2.3mmol)、酢酸(5ml) 、シア
ノ水素化ほう素ナトリウム400mg(6.4mmol)を用いて、4-
(1,2,3,4- テトラヒドロ-5- イソキノリルスルファニ
ル) アニリン260mg(1.0mmol,43.7%)を得た。 融点:138〜140 ℃ 質量分析値(m/z):257(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:7.10(2H,d),6.93(1H,dd),6.76(1H,d),6.61(2H,d),6.
57(1H,d),5.47(2H,s),3.79(2H,s),2.97(2H,t),2.55(2H,
t). 赤外吸収スペクトルνmax (KBr) cm-1: 3440, 3300, 16
00, 1500 Example 2 4- (1,2,3,4-tetrahydro-5-isoquinolyl
Rusulfanyl) aniline In the same manner as in Example 1, 590 mg (2.3 mmol) of 4- (5-isoquinolylsulfanyl) aniline, acetic acid (5 ml), and 400 mg (6.4 mmol) of sodium cyanoborohydride were used. Four-
(1,2,3,4-tetrahydro-5-isoquinolylsulfanyl) 260 mg (1.0 mmol, 43.7%) of aniline was obtained. Melting point: 138-140 ° C Mass spec (m / z): 257 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.10 (2H, d), 6.93 (1H, dd), 6.76 (1H, d), 6.61 (2H, d), 6.
57 (1H, d), 5.47 (2H, s), 3.79 (2H, s), 2.97 (2H, t), 2.55 (2H, s
t). Infrared absorption spectrum νmax (KBr) cm -1 : 3440, 3300, 16
00, 1500
【００２７】[0027]
【実施例３】3-ニトロ-4-(1,2,3,4-テトラヒドロ-5- イ
ソキノリルスルファニル) アニリン 実施例１と同様の方法により、3-ニトロ-4-(5-イソキノ
リルスルファニル) アニリン450mg(1.5mmol)、酢酸(5m
l) 、シアノ水素化ほう素ナトリウム300mg(4.8mmol)を
用いて、3-ニトロ-4-(1,2,3,4-テトラヒドロ-5- イソキ
ノリルスルファニル) アニリン350mg(1.2mmol,76.9%)を
得た。 融点:180〜185 ℃ 質量分析値(m/z):302(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:7.25(1H,d),7.13(1H,dd),7.00(1H,d),7.04(1H,dd),
6.79(1H,dd),6.73(1H,d),5.89(2H,s),3.83(2H,s),2.89
(2H,t),2.50(2H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 1620, 1510, 13
20 Example 3 3-nitro-4- (1,2,3,4-tetrahydro-5-i
Soquinolylsulfanyl ) aniline 450 mg (1.5 mmol) of 3-nitro-4- (5- isoquinolylsulfanyl) aniline , acetic acid (5 m
l), using sodium cyanoborohydride 300 mg (4.8 mmol), 3-nitro-4- (1,2,3,4-tetrahydro-5-isoquinolylsulfanyl) aniline 350 mg (1.2 mmol, 76.9% ). Melting point: 180-185 ° C Mass spectrometry (m / z): 302 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.25 (1H, d), 7.13 (1H, dd), 7.00 (1H, d), 7.04 (1H, dd),
6.79 (1H, dd), 6.73 (1H, d), 5.89 (2H, s), 3.83 (2H, s), 2.89
(2H, t), 2.50 (2H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 1620, 1510, 13
20
【００２８】[0028]
【実施例４】4-クロロ-5-(1,2,3,4-テトラヒドロ-5- イ
ソキノリルスルファニル)-1,2-ベンゼンジアミン 実施例１と同様の方法により、4-クロロ-5-(5-イソキノ
リルスルファニル)-1,2-ベンゼンジアミン790mg(2.3mmo
l)、酢酸(7ml) 、シアノ水素化ほう素ナトリウム500mg
(8.0mmol)を用いて、4-クロロ-5-(1,2,3,4-テトラヒド
ロ-5- イソキノリルスルファニル)-1,2-ベンゼンジアミ
ン510mg(1.7mmol,71.9%)を得た。 融点:253〜255 ℃ 質量分析値(m/z):306(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:9.42(1H,brs),7.12(1H,dd),6.19(1H,d),6.71(1H,d),
6.68(1H,d),6.60(1H,d),5.21(2H,s),4.81(2H,s),4.23(2
H,s),3.40(2H,t),2.90(2H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 1570，1490Example 4 4-chloro-5- (1,2,3,4-tetrahydro-5-i
Soquinolylsulfanyl) -1,2-benzenediamine In the same manner as in Example 1, 790 mg of 4-chloro-5- (5-isoquinolylsulfanyl) -1,2-benzenediamine (2.3 mmo
l), acetic acid (7ml), sodium cyanoborohydride 500mg
(8.0 mmol) to obtain 510 mg (1.7 mmol, 71.9%) of 4-chloro-5- (1,2,3,4-tetrahydro-5-isoquinolylsulfanyl) -1,2-benzenediamine. . Melting point: 253-255 ° C Mass spectrometry (m / z): 306 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 9.42 (1H, brs), 7.12 (1H, dd), 6.19 (1H, d), 6.71 (1H, d),
6.68 (1H, d), 6.60 (1H, d), 5.21 (2H, s), 4.81 (2H, s), 4.23 (2
H, s), 3.40 (2H, t), 2.90 (2H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 1570,1490
【００２９】[0029]
【実施例５】5(6)-(1,2,3,4-テトラヒドロ-5- イソキノ
リルスルファニル)-1H- ベンゾ[d]イミダゾール 実施例１と同様の方法により、5(6)-(5-イソキノリルス
ルファニル)-1H- ベンゾ[d] イミダゾール 60mg(0.2mmo
l)、酢酸(1ml) 、シアノ水素化ほう素ナトリウム 50mg
(0.8mmol)を用いて、5(6)-(1,2,3,4-テトラヒドロ-5-
イソキノリルスルファニル)-1H- ベンゾ[d] イミダゾー
ル 30mg(0.1mmol,48.6%)を得た。 融点:169〜175 ℃ 質量分析値(m/z):282(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.24(1H,s),7.61(1H,d),7.54(1H,s),7.18(1H,d),7.0
1(1H,dd),6.90(1H,d),6.78(1H,d),3.82(2H,s),2.95(2H,
t),2.62(2H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 1450, 1285Example 5 5 (6)-(1,2,3,4-tetrahydro-5-isoquino
Rylsulfanyl) -1H-benzo [d] imidazole In the same manner as in Example 1, 5 (6)-(5-isoquinolylsulfanyl) -1H-benzo [d] imidazole 60 mg (0.2 mmo
l), acetic acid (1ml), sodium cyanoborohydride 50mg
(0.8 mmol) using 5 (6)-(1,2,3,4-tetrahydro-5-
30 mg (0.1 mmol, 48.6%) of isoquinolylsulfanyl) -1H-benzo [d] imidazole were obtained. Melting point: 169-175 ° C Mass spec (m / z): 282 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.24 (1H, s), 7.61 (1H, d), 7.54 (1H, s), 7.18 (1H, d), 7.0
1 (1H, dd), 6.90 (1H, d), 6.78 (1H, d), 3.82 (2H, s), 2.95 (2H,
t), 2.62 (2H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 1450, 1285
【００３０】[0030]
【実施例６】2-メチル-5(6)-(1,2,3,4- テトラヒドロ-5
- イソキノリルスルファニル)-1H-ベンゾ[d] イミダゾ
ール 実施例１と同様の方法により、2-メチル-5(6)-(5- イソ
キノリルスルファニル)-1H- ベンゾ[d] イミダゾール15
0mg(0.5mmol)、酢酸(2ml) 、シアノ水素化ほう素ナトリ
ウム100mg(1.6mmol)を用いて、2-メチル-5(6)-(1,2,3,4
- テトラヒドロ-5- イソキノリルスルファニル)-1H- ベ
ンゾ[d] イミダゾール 50mg(0.2mmol,33.2%)を得た。 質量分析値(m/z):296(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:7.40-7.55(2H,m),7.11(1H,d),7.01(1H,dd),6.89(1H,
d),6.78(1H,brs),3.85(2H,s),2.98(2H,t),2.65(2H,t),
2.49(3H,s). 赤外吸収スペクトルνmax (KBr) cm-1: 1450, 1400 Example 6 2-methyl-5 (6)-(1,2,3,4-tetrahydro-5
-Isoquinolylsulfanyl) -1H-benzo [d] imidazo
In the same manner as in Example 1, 2-methyl-5 (6)-(5-isoquinolylsulfanyl) -1H-benzo [d] imidazole 15
Using 0 mg (0.5 mmol), acetic acid (2 ml) and sodium cyanoborohydride (100 mg, 1.6 mmol), 2-methyl-5 (6)-(1,2,3,4
-Tetrahydro-5-isoquinolylsulfanyl) -1H-benzo [d] imidazole 50 mg (0.2 mmol, 33.2%) was obtained. Mass spectrometry (m / z): 296 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.40-7.55 (2H, m), 7.11 (1H, d), 7.01 (1H, dd), 6.89 (1H,
d), 6.78 (1H, brs), 3.85 (2H, s), 2.98 (2H, t), 2.65 (2H, t),
2.49 (3H, s). Infrared absorption spectrum νmax (KBr) cm -1 : 1450, 1400
【００３１】[0031]
【実施例７】2-メチル-6(5)-ニトロ-5(6)-(1,2,3,4- テ
トラヒドロ-5- イソキノリルスルファニル)-1H- ベンゾ
[d] イミダゾール 実施例１と同様の方法により、2-メチル-6(5)-ニトロ-5
(6)-(5- イソキノリルスルファニル)-1H- ベンゾ[d] イ
ミダゾール 60mg(0.2mmol)、酢酸(1ml) 、シアノ水素化
ほう素ナトリウム 50mg(0.8mmol)を用いて、2-メチル-6
(5)-ニトロ-5(6)-(1,2,3,4- テトラヒドロ-5- イソキノ
リルスルファニル)-1H- ベンゾ[d] イミダゾール 40mg
(0.1mmol,65.3%)を得た。 質量分析値(m/z):341(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.38(1H,s),7.42(1H,d),7.28(1H,dd),7.24(1H,d),6.
71(1H,s),3.89(2H,s),2.86(2H,t),2.55(2H,t),2.46(3H,
s) 赤外吸収スペクトルνmax (KBr) cm-1: 3320, 1510, 14
60, 1320 Example 7 2-Methyl-6 (5) -nitro-5 (6)-(1,2,3,4-te
Trahydro-5-isoquinolylsulfanyl) -1H-benzo
[d] Imidazole In the same manner as in Example 1, 2-methyl-6 (5) -nitro-5
(6)-(5-Isoquinolylsulfanyl) -1H-benzo [d] imidazole 60 mg (0.2 mmol), acetic acid (1 ml), sodium cyanoborohydride 50 mg (0.8 mmol) were used to prepare 2-methyl- 6
(5) -Nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfanyl) -1H-benzo [d] imidazole 40mg
(0.1 mmol, 65.3%). Mass spectrometry (m / z): 341 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.38 (1H, s), 7.42 (1H, d), 7.28 (1H, dd), 7.24 (1H , d), 6.
71 (1H, s), 3.89 (2H, s), 2.86 (2H, t), 2.55 (2H, t), 2.46 (3H,
s) Infrared absorption spectrum νmax (KBr) cm -1 : 3320, 1510, 14
60, 1320
【００３２】[0032]
【実施例８】2-プロピル-5(6)-(1,2,3,4- テトラヒドロ
-5- イソキノリルスルファニル)-1H- ベンゾ[d] イミダ
ゾール 実施例１と同様の方法により、2-プロピル-5(6)-(5- イ
ソキノリルスルファニル)-1H- ベンゾ[d] イミダゾール
60mg(0.2mmol)、酢酸(1ml) 、シアノ水素化ほう素ナト
リウム 50mg(0.8mmol)を用いて、2-プロピル-5(6)-(1,
2,3,4- テトラヒドロ-5- イソキノリルスルファニル)-1
H- ベンゾ[d] イミダゾール 40mg(0.1mmol,77.3%)を得
た。 質量分析値(m/z):324(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:7.35-7.55(2H,m),7.13(1H,d),6.99(1H,dd),6.88(1H,
d),6.72(1H,brs),3.82(2H,s),2.96(2H,t),2.77(2H,t),
2.62(2H,t),1.74-1.79(2H,m),0.93(3H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 3300, 1440Example 8 2-propyl-5 (6)-(1,2,3,4-tetrahydro
-5-isoquinolylsulfanyl) -1H-benzo [d] imida
Zole 2-Propyl-5 (6)-(5-isoquinolylsulfanyl) -1H-benzo [d] imidazole was prepared in the same manner as in Example 1.
Using 60 mg (0.2 mmol), acetic acid (1 ml) and sodium cyanoborohydride 50 mg (0.8 mmol), 2-propyl-5 (6)-(1,
2,3,4-tetrahydro-5-isoquinolylsulfanyl) -1
40 mg (0.1 mmol, 77.3%) of H-benzo [d] imidazole were obtained. Mass spectrometry value (m / z): 324 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.35-7.55 (2H, m), 7.13 (1H, d), 6.99 (1H, dd), 6.88 (1H,
d), 6.72 (1H, brs), 3.82 (2H, s), 2.96 (2H, t), 2.77 (2H, t),
2.62 (2H, t), 1.74-1.79 (2H, m), 0.93 (3H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 3300, 1440
【００３３】[0033]
【実施例９】5-[(4-ニトロフェニル) スルホニル]-1,2,
3,4-テトラヒドロイソキノリン 実施例１と同様の方法により、5-(4- ニトロフェニルス
ルホニル) イソキノリン220mg(0.7mmol)、酢酸(2ml) 、
シアノ水素化ほう素ナトリウム150mg(2.4mmol)を用い
て、5-[(4-ニトロフェニル) スルホニル]-1,2,3,4-テト
ラヒドロイソキノリン160mg(0.5mmol,71.8%)を得た。 融点:181〜188 ℃ 質量分析値(m/z):319(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.40(2H,d),8.08(2H,d),8.03(1H,d),7.47(1H,dd),7.
43(1H,d),3.85(1H,s),2.82(2H,t),2.69(2H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 1530, 1350, 13
00, 1140 Example 9 5-[(4-nitrophenyl) sulfonyl] -1,2,
3,4-Tetrahydroisoquinoline In the same manner as in Example 1, 5- (4-nitrophenylsulfonyl) isoquinoline 220 mg (0.7 mmol), acetic acid (2 ml),
Using 150 mg (2.4 mmol) of sodium cyanoborohydride, 160 mg (0.5 mmol, 71.8%) of 5-[(4-nitrophenyl) sulfonyl] -1,2,3,4-tetrahydroisoquinoline was obtained. Melting point: 181 to 188 ° C Mass spectrometry value (m / z): 319 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.40 (2H, d), 8.08 (2H, d), 8.03 (1H, d), 7.47 (1H, dd), 7.
43 (1H, d), 3.85 (1H, s), 2.82 (2H, t), 2.69 (2H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 1530, 1350, 13
00, 1140
【００３４】[0034]
【実施例１０】4-(1,2,3,4- テトラヒドロ-5- イソキノ
リルスルホニル)-1,2-ベンゼンジアミン 実施例１と同様の方法により、4-(5- イソキノリルスル
ホニル)-1,2-ベンゼンジアミン500mg(1.7mmol)、酢酸(5
ml) 、シアノ水素化ほう素ナトリウム400mg(6.4mmol)を
用いて、4-(1,2,3,4- テトラヒドロ-5- イソキノリルス
ルホニル)-1,2-ベンゼンジアミン330mg(1.1mmol,65.1%)
を得た。 融点:165〜172 ℃ 質量分析値(m/z):304(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:7.78(1H,d),7.32(1H,dd),6.89(1H,dd),6.85(1H,d),
6.56(1H,dd),5.41(2H,s),4.88(2H,s),3.83(2H,s),2.83
(2H,t),2.79(2H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 3350, 1510, 12
90, 1135, 1120 Example 10 4- (1,2,3,4-tetrahydro-5-isoquino
Rylsulfonyl) -1,2 -benzenediamine 500 mg (1.7 mmol) of 4- (5-isoquinolylsulfonyl) -1,2-benzenediamine and acetic acid (5
400 mg (6.4 mmol) of sodium cyanoborohydride, 330 mg of 4- (1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1,2-benzenediamine (1.1 mmol, (65.1%)
I got Melting point: 165-172 ° C Mass spectrometry (m / z): 304 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.78 (1H, d), 7.32 (1H, dd), 6.89 (1H, dd), 6.85 (1H, d),
6.56 (1H, dd), 5.41 (2H, s), 4.88 (2H, s), 3.83 (2H, s), 2.83
(2H, t), 2.79 (2H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 3350, 1510, 12
90, 1135, 1120
【００３５】[0035]
【実施例１１】4-クロロ-5-(1,2,3,4-テトラヒドロ-5-
イソキノリルスルホニル)-1,2-ベンゼンジアミン 実施例１と同様の方法により、4-クロロ-5-(5-イソキノ
リルスルホニル)-1,2-ベンゼンジアミン150mg(0.5mmo
l)、酢酸(2ml) 、シアノ水素化ほう素ナトリウム100mg
(1.6mmol)を用いて、4-クロロ-5-(1,2,3,4-テトラヒド
ロ-5- イソキノリルスルホニル)-1,2-ベンゼンジアミン
120mg(0.4mmol,78.9%)を得た。 融点:231〜237 ℃ 質量分析値(m/z):338(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:7.86(1H,dd),7.35(1H,s),7.32(1H,d),7.28(1H,d),6.
52(1H,s),5.69(2H,s),5.08(2H,s),3.84(2H,s),2.81(2H,
t),2.65(2H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 3450, 3375, 15
00, 1310, 1290, 1140 Example 11 4-chloro-5- (1,2,3,4-tetrahydro-5-
In a similar manner to that Isoquinolylmethyl) -1,2-benzenediamine Example 1, 4-chloro-5- (5-isoquinolyloxy) -1,2-benzenediamine 150 mg (0.5Mmo
l), acetic acid (2ml), sodium cyanoborohydride 100mg
(1.6 mmol), using 4-chloro-5- (1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1,2-benzenediamine
120 mg (0.4 mmol, 78.9%) were obtained. Melting point: 231-237 ° C Mass spectrometry (m / z): 338 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.86 (1H, dd), 7.35 (1H, s), 7.32 (1H, d), 7.28 (1H, d), 6.
52 (1H, s), 5.69 (2H, s), 5.08 (2H, s), 3.84 (2H, s), 2.81 (2H, s
t), 2.65 (2H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 3450, 3375, 15
00, 1310, 1290, 1140
【００３６】[0036]
【実施例１２】2-メチル-5(6)-(1,2,3,4- テトラヒドロ
-5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾ
ール 実施例１と同様の方法により、2-メチル-5(6)-(5- イソ
キノリルスルホニル)-1H- ベンゾ[d] イミダゾール430m
g(1.3mmol)、酢酸(5ml) 、シアノ水素化ほう素ナトリウ
ム300mg(4.8mmol)を用いて、2-メチル-5(6)-(1,2,3,4-
テトラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール200mg(0.6mmol,46.0%)を得た。 融点: ＞270 ℃ 質量分析値(m/z):328(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:7.92(1H,d),7.89(1H,s),7.59(1H,d),7.48(1H,d),7.3
6(1H,dd),7.29(1H,d),3.78(2H,s),2.76(2H,t),2.70(2H,
t),2.49(3H,s). 赤外吸収スペクトルνmax (KBr) cm-1: 3300, 1620, 14
25, 1300 Example 12 2-Methyl-5 (6)-(1,2,3,4-tetrahydro
-5-isoquinolylsulfonyl) -1H-benzo [d] imidazo
In the same manner as in Example 1, 2-methyl-5 (6)-(5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 430 m
g (1.3 mmol), acetic acid (5 ml), and sodium cyanoborohydride (300 mg, 4.8 mmol) to give 2-methyl-5 (6)-(1,2,3,4-
(Tetrahydro-5-isoquinolylsulfonyl) -1H-benzo
[d] 200 mg (0.6 mmol, 46.0%) of imidazole was obtained. Melting point:> 270 ° C Mass spec (m / z): 328 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.92 (1H, d), 7.89 (1H, s), 7.59 (1H, d ), 7.48 (1H, d), 7.3
6 (1H, dd), 7.29 (1H, d), 3.78 (2H, s), 2.76 (2H, t), 2.70 (2H,
t), 2.49 (3H, s). Infrared absorption spectrum νmax (KBr) cm -1 : 3300, 1620, 14
25, 1300
【００３７】[0037]
【実施例１３】2-エチル-5(6)-(1,2,3,4- テトラヒドロ
-5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾ
ール 実施例１と同様の方法により、2-エチル-5(6)-(5- イソ
キノリルスルホニル)-1H- ベンゾ[d] イミダゾール 90m
g(0.3mmol)、酢酸(2ml) 、シアノ水素化ほう素ナトリウ
ム 80mg(1.3mmol)を用いて、2-エチル-5(6)-(1,2,3,4-
テトラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール 80mg(0.2mmol,86.9%)を得た。 質量分析値(m/z):342(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:7.94-7.97(2H,m),7.63(1H,d),7.52(1H,dd),7.39(1H,
dd),7.33(1H,d),3.82(2H,s),2.87(2H,q),2.80(2H,t),2.
75(2H,t),1.31(3H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 1460, 1420, 13
00, 1160, 1120 Example 13 2-Ethyl-5 (6)-(1,2,3,4-tetrahydro
-5-isoquinolylsulfonyl) -1H-benzo [d] imidazo
In the same manner as in Example 1, 2-ethyl-5 (6)-(5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 90m
g (0.3 mmol), acetic acid (2 ml), and sodium cyanoborohydride 80 mg (1.3 mmol) to give 2-ethyl-5 (6)-(1,2,3,4-
(Tetrahydro-5-isoquinolylsulfonyl) -1H-benzo
[d] 80 mg (0.2 mmol, 86.9%) of imidazole was obtained. Mass spec (m / z): 342 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.94-7.97 (2H, m), 7.63 (1H, d), 7.52 (1H, dd), 7.39 (1H,
dd), 7.33 (1H, d), 3.82 (2H, s), 2.87 (2H, q), 2.80 (2H, t), 2.
75 (2H, t), 1.31 (3H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 1460, 1420, 13
00, 1160, 1120
【００３８】[0038]
【実施例１４】2-プロピル-5(6)-(1, 2, 3, 4-テトラヒ
ドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d] イミ
ダゾール 実施例１と同様の方法により、2-プロピル-5(6)-(5- イ
ソキノリルスルホニル)-1H- ベンゾ[d] イミダゾール26
0mg(0.7mmol)、酢酸(3ml) 、シアノ水素化ほう素ナトリ
ウム200mg(3.2mmol)を用いて、2-プロピル-5(6)-(1, 2,
3, 4-テトラヒドロ-5- イソキノリルスルホニル)-1H-
ベンゾ[d] イミダゾール100mg(0.3mmol,37.9%)を得た。 質量分析値(m/z):401(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:7.96(1H,d),7.94(1H,brs),7.63(1H,brs),7.53(1H,
d),7.40(1H,dd),7.33(1H,d),3.83(2H,s),2.76-2.83(6H,
m),1.74-1.80(2H,m),0.93(3H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 2980, 1460, 14
20, 1300, 1120 Example 14 2-propyl-5 (6)-(1,2,3,4-tetrahi
Dro-5-isoquinolylsulfonyl) -1H-benzo [d] imi
Dazole By the same method as in Example 1, 2-propyl-5 (6)-(5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 26
Using 0 mg (0.7 mmol), acetic acid (3 ml) and 200 mg (3.2 mmol) of sodium cyanoborohydride, 2-propyl-5 (6)-(1, 2,
3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-
100 mg (0.3 mmol, 37.9%) of benzo [d] imidazole were obtained. Mass spectrometry (m / z): 401 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.96 (1H, d), 7.94 (1H, brs), 7.63 (1H, brs), 7.53 (1H ,
d), 7.40 (1H, dd), 7.33 (1H, d), 3.83 (2H, s), 2.76-2.83 (6H,
m), 1.74-1.80 (2H, m), 0.93 (3H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 2980, 1460, 14
20, 1300, 1120
【００３９】[0039]
【実施例１５】2-シクロブチル-5(6)-(1,2,3,4- テトラ
ヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d] イ
ミダゾール 実施例１と同様の方法により、2-シクロブチル-5(6)-(5
- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾー
ル100mg(0.3mmol)、酢酸(2ml) 、シアノ水素化ほう素ナ
トリウム 80mg(1.3mmol)を用いて、2-シクロブチル-5
(6)-(1, 2, 3, 4-テトラヒドロ-5- イソキノリルスルホ
ニル)-1H- ベンゾ[d] イミダゾール 60mg(0.2mmol,58.4
%)を得た。 質量分析値(m/z):368(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:7.95-7.96(2H,m),7.55-7.65(2H,m),7.53(1H,dd),7.4
0(1H,dd),7.33(1H,d),3.82(2H,s),3.73(1H,tt),2.80(2
H,t),2.74(2H,t),2.36-2.40(4H,m),2.04(1H,tt). 赤外吸収スペクトルνmax (KBr) cm-1: 2950, 1620, 15
40, 1450, 1420, 1300,1160, 1120Example 15 2-cyclobutyl-5 (6)-(1,2,3,4-tetra
Hydro-5-isoquinolylsulfonyl) -1H-benzo [d] a
Midazole In the same manner as in Example 1, 2-cyclobutyl-5 (6)-(5
-Isoquinolylsulfonyl) -1H-benzo [d] imidazole (100 mg, 0.3 mmol), acetic acid (2 ml), sodium cyanoborohydride (80 mg, 1.3 mmol) to give 2-cyclobutyl-5
(6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 60 mg (0.2 mmol, 58.4
%). Mass spec (m / z): 368 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.95-7.96 (2H, m), 7.55-7.65 (2H, m), 7.53 (1H, dd) , 7.4
0 (1H, dd), 7.33 (1H, d), 3.82 (2H, s), 3.73 (1H, tt), 2.80 (2
H, t), 2.74 (2H, t), 2.36-2.40 (4H, m), 2.04 (1H, tt) .Infrared absorption spectrum νmax (KBr) cm -1 : 2950, 1620, 15
40, 1450, 1420, 1300,1160, 1120
【００４０】[0040]
【実施例１６】2-シクロペンチル-5(6)-(1,2,3,4- テト
ラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d]
イミダゾール 2-シクロペンチル-5(6)-(5- イソキノリルスルホニル)-
1H- ベンゾ[d] イミダゾール 10.00g(26.5mmol) を酢酸
(200ml) に懸濁し、白金ブラック１g を加え、水素気流
下60℃に加温し一夜攪拌した。反応混合物を室温まで冷
却後、不溶物を濾別し濾液を減圧濃縮した。次に飽和炭
酸水素ナトリウム溶液を加えた後、メチルエチルケトン
で抽出した。有機層を無水硫酸マグネシウムで乾燥し減
圧濃縮した。残渣をシリカゲルクロマトグラフィー(NH-
シリカゲル、2%メタノール- 酢酸エチル) で精製して、
2-シクロペンチル-5(6)-(1,2,3,4- テトラヒドロ-5- イ
ソキノリルスルホニル)-1H- ベンゾ[d] イミダゾール7.
01g(18.4mmol,69.4%) を得た。 融点:122〜123 ℃ 質量分析値(m/z):382(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:7.95(1H,d),7.92(1H,brs),7.62(1H,brs),7.52(1H,
d),7.40(1H,dd),7.32(1H,d),3.81(2H,s),3.27-3.33(1H,
m),2.80(1H,t),2.74(1H,t),2.03-2.09(2H,m),1.83-1.91
(2H,m),1.71-1.76(2H,m),1.63-1.68(2H,m). 赤外吸収スペクトルνmax (KBr) cm-1: 2950, 1440, 13
00, 1110 Example 16 2-Cyclopentyl-5 (6)-(1,2,3,4-tetra
Lahydro-5-isoquinolylsulfonyl) -1H-benzo [d]
Imidazole 2-cyclopentyl-5 (6)-(5-isoquinolylsulfonyl)-
1H-benzo [d] imidazole 10.00g (26.5mmol)
(200 ml), 1 g of platinum black was added, the mixture was heated to 60 ° C. under a hydrogen stream and stirred overnight. After cooling the reaction mixture to room temperature, insolubles were filtered off and the filtrate was concentrated under reduced pressure. Next, a saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with methyl ethyl ketone. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (NH-
(Silica gel, 2% methanol-ethyl acetate)
2-cyclopentyl-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 7.
01 g (18.4 mmol, 69.4%) was obtained. Melting point: 122-123 ° C Mass spectrometry value (m / z): 382 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.95 (1H, d), 7.92 (1H, brs), 7.62 (1H, brs), 7.52 (1H,
d), 7.40 (1H, dd), 7.32 (1H, d), 3.81 (2H, s), 3.27-3.33 (1H,
m), 2.80 (1H, t), 2.74 (1H, t), 2.03-2.09 (2H, m), 1.83-1.91
(2H, m), 1.71-1.76 (2H, m), 1.63-1.68 (2H, m). Infrared absorption spectrum νmax (KBr) cm -1 : 2950, 1440, 13
00, 1110
【００４１】[0041]
【実施例１７】2-シクロヘキシル-5(6)-(1,2,3,4- テト
ラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d]
イミダゾール 実施例１と同様の方法により、2-シクロヘキシル-5(6)-
(5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾ
ール400mg(1.0mmol)、酢酸(5ml) 、シアノ水素化ほう素
ナトリウム350mg(5.6mmol)を用いて、2-シクロヘキシル
-5(6)-(1,2,3,4- テトラヒドロ-5- イソキノリルスルホ
ニル)-1H- ベンゾ[d] イミダゾール220mg(0.6mmol,54.5
%)を得た。 融点:147〜149 ℃ 質量分析値(m/z):396(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:7.95(1H,d),7.92(1H,s),7.63(1H,d),7.53(1H,dd),7.
39(1H,dd),7.33(1H,d),3.81(2H,s),2.86-2.90(1H,m),2.
80(1H,t),2.74(1H,t),1.99-2.02(2H,m),1.70-1.79(2H,
m),1.67-1.70(1H,m),1.55-1.62(1H,m),1.34-1.42(2H,
m),1.23-1.28(1H,m). 赤外吸収スペクトルνmax (KBr) cm-1: 2950, 1460, 13
00, 1120 Example 17 2-cyclohexyl-5 (6)-(1,2,3,4-tetra
Lahydro-5-isoquinolylsulfonyl) -1H-benzo [d]
Imidazole By a method similar to that in Example 1, 2-cyclohexyl-5 (6)-
Using (5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 400 mg (1.0 mmol), acetic acid (5 ml) and sodium cyanoborohydride 350 mg (5.6 mmol), give 2-cyclohexyl
-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 220 mg (0.6 mmol, 54.5
%). Melting point: 147-149 ° C Mass spectrometry value (m / z): 396 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.95 (1H, d), 7.92 (1H, s), 7.63 (1H, d), 7.53 (1H, dd), 7.
39 (1H, dd), 7.33 (1H, d), 3.81 (2H, s), 2.86-2.90 (1H, m), 2.
80 (1H, t), 2.74 (1H, t), 1.99-2.02 (2H, m), 1.70-1.79 (2H,
m), 1.67-1.70 (1H, m), 1.55-1.62 (1H, m), 1.34-1.42 (2H,
m), 1.23-1.28 (1H, m). Infrared absorption spectrum νmax (KBr) cm -1 : 2950, 1460, 13
00, 1120
【００４２】[0042]
【実施例１８】2-シクロヘプチル-5(6)-(1,2,3,4- テト
ラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d]
イミダゾール 実施例１と同様の方法により、2-シクロヘプチル-5(6)-
(5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾ
ール 60mg(0.2mmol)、酢酸(2ml) 、シアノ水素化ほう素
ナトリウム 40mg(0.6mmol)を用いて、2-シクロヘプチル
-5(6)-(1,2,3,4- テトラヒドロ-5- イソキノリルスルホ
ニル)-1H- ベンゾ[d] イミダゾール 30mg(0.1mmol,48.8
%)を得た。 質量分析値(m/z):410(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:12.61(1H,brs),7.90-7.96(2H,m),7.45-7.65(2H,m),
7.39(1H,dd),7.33(1H,d),3.82(2H,s),3.06-3.10(1H,m),
2.80(2H,t),2.76(2H,t),2.01-2.04(2H,m),1.73-1.85(4
H,m),1.53-1.63(6H,m). 赤外吸収スペクトルνmax (KBr) cm-1: 2930, 1460, 13
00, 1160, 1120Example 18 2-cycloheptyl-5 (6)-(1,2,3,4-tetra
Lahydro-5-isoquinolylsulfonyl) -1H-benzo [d]
Imidazole By a method similar to that in Example 1, 2-cycloheptyl-5 (6)-
Using (5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 60 mg (0.2 mmol), acetic acid (2 ml) and sodium cyanoborohydride 40 mg (0.6 mmol), give 2-cycloheptyl
-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 30 mg (0.1 mmol, 48.8
%). Mass spectrometry (m / z): 410 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 12.61 (1H, brs), 7.90-7.96 (2H, m), 7.45-7.65 (2H, m) ,
7.39 (1H, dd), 7.33 (1H, d), 3.82 (2H, s), 3.06-3.10 (1H, m),
2.80 (2H, t), 2.76 (2H, t), 2.01-2.04 (2H, m), 1.73-1.85 (4
H, m), 1.53-1.63 (6H, m). Infrared absorption spectrum νmax (KBr) cm -1 : 2930, 1460, 13
00, 1160, 1120
【００４３】[0043]
【実施例１９】2-メチル-6(5)-ニトロ-5(6)-(1,2,3,4-
テトラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール 実施例１と同様の方法により、2-メチル-6(5)-ニトロ-5
(6)-(5- イソキノリルスルホニル)-1H- ベンゾ[d] イミ
ダゾール600mg(1.6mmol)、酢酸(20ml)、シアノ水素化ほ
う素ナトリウム500mg(8.0mmol)を用いて、2-メチル-6
(5)-ニトロ-5(6)-(1,2,3,4- テトラヒドロ-5- イソキノ
リルスルホニル)-1H- ベンゾ[d] イミダゾール400mg(1.
1mmol,65.9%)を得た。 質量分析値(m/z):373(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.26(1H,s),8.24(1H,s),7.70(1H,dd),7.37-7.40(2H,
m),3.91(2H,s),2.89(2H,t),2.81(2H,t),2.61(3H,s). 赤外吸収スペクトルνmax (KBr) cm-1: 1540, 1350, 13
10 Example 19 2-Methyl-6 (5) -nitro-5 (6)-(1,2,3,4-
(Tetrahydro-5-isoquinolylsulfonyl) -1H-benzo
[d] Imidazole In the same manner as in Example 1, 2-methyl-6 (5) -nitro-5
(6)-(5-Isoquinolylsulfonyl) -1H-benzo [d] imidazole 600 mg (1.6 mmol), acetic acid (20 ml), sodium cyanoborohydride 500 mg (8.0 mmol) were used to give 2-methyl- 6
(5) -Nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 400 mg (1.
1 mmol, 65.9%). Mass spectrum (m / z): 373 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.26 (1H, s), 8.24 (1H, s), 7.70 (1H, dd), 7.37-7.40 (2H,
m), 3.91 (2H, s), 2.89 (2H, t), 2.81 (2H, t), 2.61 (3H, s). Infrared absorption spectrum νmax (KBr) cm -1 : 1540, 1350, 13
Ten
【００４４】[0044]
【実施例２０】2-エチル-6(5)-ニトロ-5(6)-(1,2,3,4-
テトラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール 実施例１と同様の方法により、2-エチル-6(5)-ニトロ-5
(6)-(5- イソキノリルスルホニル)-1H- ベンゾ[d] イミ
ダゾール1.00g(2.6mmol)、酢酸(20ml)、シアノ水素化ほ
う素ナトリウム540mg(8.6mmol)で還元し、得られた油状
物を塩化水素飽和酢酸エチルに溶解した。溶媒を減圧濃
縮し、アセトンで結晶化させ、2-エチル-6(5)-ニトロ-5
(6)-(1,2,3,4- テトラヒドロ-5- イソキノリルスルホニ
ル)-1H-ベンゾ[d] イミダゾール二塩酸塩630mg(1.4mmo
l,52.5%)を得た。 融点:211〜220 ℃ 質量分析値(m/z):387(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.37(1H,s),8.36(1H,s),7.78(1H,d),7.58(1H,d),7.5
2(1H,t),4.33(2H,s),3.32(2H,t),3.22(2H,t),3.02(2H,
q),1.38(3H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 1550, 1360, 13
20, 1130 Example 20 2-Ethyl-6 (5) -nitro-5 (6)-(1,2,3,4-
(Tetrahydro-5-isoquinolylsulfonyl) -1H-benzo
[d] Imidazole In the same manner as in Example 1, 2-ethyl-6 (5) -nitro-5
(6)-(5-Isoquinolylsulfonyl) -1H-benzo [d] imidazole was obtained by reduction with 1.00 g (2.6 mmol), acetic acid (20 ml), and 540 mg (8.6 mmol) of sodium cyanoborohydride. The oil was dissolved in hydrogen chloride saturated ethyl acetate. The solvent was concentrated under reduced pressure, crystallized with acetone, and 2-ethyl-6 (5) -nitro-5
(6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole dihydrochloride 630 mg (1.4 mmo
1,52.5%). Melting point: 211-220 ° C Mass spec (m / z): 387 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.37 (1H, s), 8.36 (1H, s), 7.78 (1H, d), 7.58 (1H, d), 7.5
2 (1H, t), 4.33 (2H, s), 3.32 (2H, t), 3.22 (2H, t), 3.02 (2H, t
q), 1.38 (3H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 1550, 1360, 13
20, 1130
【００４５】[0045]
【実施例２１】6(5)- ニトロ-2- プロピル-5(6)-(1,2,
3,4- テトラヒドロ-5- イソキノリルスルホニル)-1H-
ベンゾ[d] イミダゾール 実施例１と同様の方法により、6(5)- ニトロ-2- プロピ
ル-5(6)-(5- イソキノリルスルホニル)-1H- ベンゾ[d]
イミダゾール410mg(1.0mmol)、酢酸(20ml)、シアノ水素
化ほう素ナトリウム260mg(4.1mmol)を用いて、6(5)- ニ
トロ-2- プロピル-5(6)-(1,2,3,4- テトラヒドロ-5- イ
ソキノリルスルホニル)-1H- ベンゾ[d]イミダゾール200
mg(0.5mmol,48.5%)を得た。 融点:232〜234 ℃ 質量分析値(m/z):401(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.27(1H,S),8.25(1H,s),7.70(1H,dd),7.36-7.40(2H,
m),3.91(2H,s),2.83-2.92(6H,m),1.78-1.86(2H,m),0.95
(3H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 1540, 1360, 13
00, 1130 Example 21 6 (5) -Nitro-2-propyl-5 (6)-(1,2,
3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-
Benzo [d] imidazole By a method similar to that of Example 1, 6 (5) -nitro-2-propyl-5 (6)-(5-isoquinolylsulfonyl) -1H-benzo [d]
Using 410 mg (1.0 mmol) of imidazole, 20 ml of acetic acid, 260 mg (4.1 mmol) of sodium cyanoborohydride, 6 (5) -nitro-2-propyl-5 (6)-(1,2,3, 4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 200
mg (0.5 mmol, 48.5%). Melting point: 232-234 ° C Mass spec (m / z): 401 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.27 (1H, S), 8.25 (1H, s), 7.70 (1H, dd), 7.36-7.40 (2H,
m), 3.91 (2H, s), 2.83-2.92 (6H, m), 1.78-1.86 (2H, m), 0.95
(3H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 1540, 1360, 13
00, 1130
【００４６】[0046]
【実施例２２】2-イソプロピル-6(5)-ニトロ-5(6)-(1,
2,3,4- テトラヒドロ-5- イソキノリルスルホニル)-1H-
ベンゾ[d] イミダゾール 実施例１と同様の方法により、2-イソプロピル-6(5)-ニ
トロ-5(6)-(5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール 70mg(0.2mmol)、酢酸(2ml) 、シアノ
水素化ほう素ナトリウム 70mg(1.1mmol)を用いて、2-イ
ソプロピル-6(5)-ニトロ-5(6)-(1,2,3,4- テトラヒドロ
-5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾ
ール 50mg(0.1mmol,69.4%)を得た。 融点:160〜172 ℃ 質量分析値(m/z):401(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.25-8.26(2H,m),7.70(1H,d),7.37-7.38(2H,m),3.91
(2H,s),3.27(1H,m),2.89(2H,t),2.83(2H,t),1.38(6H,
d). 赤外吸収スペクトルνmax (KBr) cm-1: 2980, 1540, 13
40, 1310, 1130 Example 22 2-Isopropyl-6 (5) -nitro-5 (6)-(1,
2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-
Benzo [d] imidazole In the same manner as in Example 1, 2-isopropyl-6 (5) -nitro-5 (6)-(5-isoquinolylsulfonyl) -1H-benzo
[d] 70 mg (0.2 mmol) of imidazole, 2 ml of acetic acid, 70 mg (1.1 mmol) of sodium cyanoborohydride were used to give 2-isopropyl-6 (5) -nitro-5 (6)-(1,2 , 3,4-tetrahydro
-5-Isoquinolylsulfonyl) -1H-benzo [d] imidazole (50 mg, 0.1 mmol, 69.4%) was obtained. Melting point: 160-172 ° C Mass spectrometry (m / z): 401 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.25-8.26 (2H, m), 7.70 (1H, d), 7.37- 7.38 (2H, m), 3.91
(2H, s), 3.27 (1H, m), 2.89 (2H, t), 2.83 (2H, t), 1.38 (6H,
d). Infrared absorption spectrum νmax (KBr) cm -1 : 2980, 1540, 13
40, 1310, 1130
【００４７】[0047]
【実施例２３】2-シクロペンチル-6(5)-ニトロ-5(6)-
(1,2,3,4- テトラヒドロ-5- イソキノリルスルホニル)-
1H- ベンゾ[d] イミダゾール 実施例１と同様の方法により、2-シクロペンチル-6(5)-
ニトロ-5(6)-(5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール3.00g(7.1mmol)、酢酸(60ml)、シアノ
水素化ほう素ナトリウム2.00g(31.8mmol) から、2-シク
ロペンチル-6(5)-ニトロ-5(6)-(1,2,3,4- テトラヒドロ
-5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾ
ール1.80g(4.2mmol,59.4%)を得た。 融点:200〜203 ℃ 質量分析値(m/z):427(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.25(1H,s),8.24(1H,s),7.70(1H,dd),7.35-7.39(2H,
m),3.90(2H,s),3.37-3.40(1H,m),2.89(2H,t),2.83(2H,
t),2.09-2.10(2H,m),1.89-1.92(2H,m),1.75-1.77(2H,
m),1.64-1.66(2H,m). 赤外吸収スペクトルνmax (KBr) cm-1: 1540, 1350, 13
10, 1140 Example 23 2-Cyclopentyl-6 (5) -nitro-5 (6)-
(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl)-
1H-benzo [d] imidazole By a method similar to that in Example 1, 2-cyclopentyl-6 (5)-
Nitro-5 (6)-(5-isoquinolylsulfonyl) -1H-benzo
[d] From 3.00 g (7.1 mmol) of imidazole, acetic acid (60 ml), and 2.00 g (31.8 mmol) of sodium cyanoborohydride, 2-cyclopentyl-6 (5) -nitro-5 (6)-(1,2 , 3,4-tetrahydro
This gave 1.80 g (4.2 mmol, 59.4%) of -5-isoquinolylsulfonyl) -1H-benzo [d] imidazole. Melting point: 200-203 ° C Mass spectrometry value (m / z): 427 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.25 (1H, s), 8.24 (1H, s), 7.70 (1H, dd), 7.35-7.39 (2H,
m), 3.90 (2H, s), 3.37-3.40 (1H, m), 2.89 (2H, t), 2.83 (2H,
t), 2.09-2.10 (2H, m), 1.89-1.92 (2H, m), 1.75-1.77 (2H, m
m), 1.64-1.66 (2H, m). Infrared absorption spectrum νmax (KBr) cm -1 : 1540, 1350, 13
10, 1140
【００４８】[0048]
【実施例２４】2-シクロヘキシル-6(5)-ニトロ-5(6)-
(1,2,3,4- テトラヒドロ-5- イソキノリルスルホニル)-
1H- ベンゾ[d] イミダゾール 実施例１と同様の方法により、2-シクロヘキシル-6(5)-
ニトロ-5(6)-(5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール120mg(0.3mmol)、酢酸(2ml)、シアノ
水素化ほう素ナトリウム100mg(1.6mmol)を用いて、2-シ
クロヘキシル-6(5)-ニトロ-5(6)-(1,2,3,4- テトラヒド
ロ-5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダ
ゾール 80mg(0.2mmol,67.3%)を得た。 融点:170〜171 ℃ 質量分析値(m/z):441(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.25-8.26(1H,m),7.69(1H,dd),7.36-7.39(2H,m),3.9
1(2H,s),2.95-2.99(1H,m),2.89(2H,t),2.83(2H,t),2.04
-2.06(2H,m),1.58-1.98(5H,m),1.25-1.44(3H,m). 赤外吸収スペクトルνmax (KBr) cm-1: 2950, 2850, 15
20, 1470, 1300, 1130 Example 24 2-Cyclohexyl-6 (5) -nitro-5 (6)-
(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl)-
1H-benzo [d] imidazole By a method similar to that in Example 1, 2-cyclohexyl-6 (5)-
Nitro-5 (6)-(5-isoquinolylsulfonyl) -1H-benzo
[d] 2-cyclohexyl-6 (5) -nitro-5 (6)-(1,2) using 120 mg (0.3 mmol) of imidazole, 2 ml of acetic acid, and 100 mg (1.6 mmol) of sodium cyanoborohydride. 80 mg (0.2 mmol, 67.3%) of 3,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole were obtained. Melting point: 170-171 ° C Mass spectrometry value (m / z): 441 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.25-8.26 (1H, m), 7.69 (1H, dd), 7.36 7.39 (2H, m), 3.9
1 (2H, s), 2.95-2.99 (1H, m), 2.89 (2H, t), 2.83 (2H, t), 2.04
-2.06 (2H, m), 1.58-1.98 (5H, m), 1.25-1.44 (3H, m). Infrared absorption spectrum νmax (KBr) cm -1 : 2950, 2850, 15
20, 1470, 1300, 1130
【００４９】[0049]
【実施例２５】2-メチル-7(4)-ニトロ-5(6)-(1,2,3,4-
テトラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール 実施例１と同様の方法により、2-メチル-7(4)-ニトロ-5
(6)-(5- イソキノリルスルホニル)-1H- ベンゾ[d] イミ
ダゾール820mg(2.2mmol)、酢酸(16ml)、シアノ水素化ほ
う素ナトリウム800mg(12.7mmol) から、2-メチル-7(4)-
ニトロ-5(6)-(1,2,3,4- テトラヒドロ-5- イソキノリル
スルホニル)-1H- ベンゾ[d] イミダゾール430mg(1.1mmo
l,51.8%)を得た。 融点:243〜245 ℃ 質量分析値(m/z):373(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.30(1H,d),8.29(1H,d),8.04(1H,d),7.44(1H,dd),7.
38(1H,d),3.84(2H,s),2.84(2H,t),2.77(2H,t),2.61(3H,
s). 赤外吸収スペクトルνmax (KBr) cm-1: 3330, 1530, 13
40, 1300, 1135 Example 25 2-Methyl-7 (4) -nitro-5 (6)-(1,2,3,4-
(Tetrahydro-5-isoquinolylsulfonyl) -1H-benzo
[d] Imidazole By a method similar to that in Example 1, 2-methyl-7 (4) -nitro-5
(6)-(5-Isoquinolylsulfonyl) -1H-benzo [d] imidazole 820 mg (2.2 mmol), acetic acid (16 ml), sodium cyanoborohydride 800 mg (12.7 mmol) were converted to 2-methyl-7 ( Four)-
Nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 430 mg (1.1 mmo
1,51.8%). Melting point: 243-245 ° C Mass spec (m / z): 373 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.30 (1H, d), 8.29 (1H, d), 8.04 (1H, d), 7.44 (1H, dd), 7.
38 (1H, d), 3.84 (2H, s), 2.84 (2H, t), 2.77 (2H, t), 2.61 (3H,
s). Infrared absorption spectrum νmax (KBr) cm -1 : 3330, 1530, 13
40, 1300, 1135
【００５０】[0050]
【実施例２６】2-エチル-7(4)-ニトロ-5(6)-(1,2,3,4-
テトラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール 実施例１と同様の方法により、2-エチル-7(4)-ニトロ-5
(6)-(5- イソキノリルスルホニル)-1H- ベンゾ[d] イミ
ダゾール260mg(0.7mmol)、酢酸(10ml)、シアノ水素化ほ
う素ナトリウム250mg(4.0mmol)を用いて、2-エチル-7
(4)-ニトロ-5(6)-(1,2,3,4- テトラヒドロ-5- イソキノ
リルスルホニル)-1H- ベンゾ[d] イミダゾール160mg(0.
4mmol,60.8%)を得た。 融点:235〜237 ℃ 質量分析値(m/z):387(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.35(1H,s),8.33(1H,s),8.07(1H,d),7.47(1H,dd),7.
42(1H,d),3.91(2H,s),2.97(2H,q),2.90(2H,t),2.82(2H,
t),1.32(3H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 2930, 1530, 13
10, 1140 Example 26 2-Ethyl-7 (4) -nitro-5 (6)-(1,2,3,4-
(Tetrahydro-5-isoquinolylsulfonyl) -1H-benzo
[d] Imidazole In the same manner as in Example 1, 2-ethyl-7 (4) -nitro-5
(6)-(5-Isoquinolylsulfonyl) -1H-benzo [d] imidazole 260 mg (0.7 mmol), acetic acid (10 ml), sodium cyanoborohydride 250 mg (4.0 mmol) were used to give 2-ethyl- 7
160 mg of (4) -nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole.
4 mmol, 60.8%). Melting point: 235-237 ° C Mass spectrometry value (m / z): 387 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.35 (1H, s), 8.33 (1H, s), 8.07 (1H, d), 7.47 (1H, dd), 7.
42 (1H, d), 3.91 (2H, s), 2.97 (2H, q), 2.90 (2H, t), 2.82 (2H,
t), 1.32 (3H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 2930, 1530, 13
10, 1140
【００５１】[0051]
【実施例２７】7(4)- ニトロ-2- プロピル-5(6)-(1,2,
3,4- テトラヒドロ-5- イソキノリルスルホニル)-1H-
ベンゾ[d] イミダゾール 実施例１と同様の方法により、7(4)- ニトロ-2- プロピ
ル-5(6)-(5- イソキノリルスルホニル)-1H- ベンゾ[d]
イミダゾール 60mg(0.2mmol)、酢酸(6ml) 、シアノ水素
化ほう素ナトリウム 60mg(1.0mmol)を用いて、7(4)- ニ
トロ-2- プロピル-5(6)-(1,2,3,4- テトラヒドロ-5- イ
ソキノリルスルホニル)-1H- ベンゾ[d]イミダゾール 20
mg(0.1mmol,33.3%)を得た。 融点:206〜208 ℃ 質量分析値(m/z):401(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.33(2H,s),8.05(1H,d),7.45(1H,dd),7.39(1H,d),3.
85(2H,s),2.92(2H,t),2.85(2H,t),2.79(2H,t),1.78-1.8
2(2H,m),0.94(3H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 3350, 1520，11
30 Example 27 7 (4) -Nitro-2-propyl-5 (6)-(1,2,
3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-
Benzo [d] imidazole In the same manner as in Example 1, 7 (4) -nitro-2-propyl-5 (6)-(5-isoquinolylsulfonyl) -1H-benzo [d]
Using 60 mg (1.0 mmol) of imidazole 60 mg (0.2 mmol), acetic acid (6 ml) and sodium cyanoborohydride, 7 (4) -nitro-2-propyl-5 (6)-(1,2,3, 4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 20
mg (0.1 mmol, 33.3%). Melting point: 206-208 ° C Mass spectrometry (m / z): 401 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.33 (2H, s), 8.05 (1H, d), 7.45 (1H, dd), 7.39 (1H, d), 3.
85 (2H, s), 2.92 (2H, t), 2.85 (2H, t), 2.79 (2H, t), 1.78-1.8
2 (2H, m), 0.94 (3H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 3350, 1520, 11
30
【００５２】[0052]
【実施例２８】2-シクロペンチル-7(4)-ニトロ-5(6)-
(1,2,3,4- テトラヒドロ-5- イソキノリルスルホニル)-
1H- ベンゾ[d] イミダゾール 実施例１と同様の方法により、2-シクロペンチル-7(4)-
ニトロ-5(6)-(5- イソキノリルスルホニル)-1H- ベンゾ
[d] イミダゾール1.06g(2.5mmol)、酢酸(20ml)、シアノ
水素化ほう素ナトリウム900mg(14.3mmol) から、2-シク
ロペンチル-7(4)-ニトロ-5(6)-(1,2,3,4- テトラヒドロ
-5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾ
ール580mg(1.4mmol,54.5%)を得た。 質量分析値(m/z):427(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.32(1H,d),8.31(1H,s),8.05(1H,d),7.44(1H,dd),7.
39(1H,d),3.85(2H,s),3.45-3.51(1H,m),2.85(2H,t),2.7
8(2H,t),2.05-2.15(2H,m),1.85-1.95(2H,m),1.70-1.80
(2H,m),1.60-1.70(2H,m). 赤外吸収スペクトルνmax (KBr) cm-1: 2980, 1640, 15
20, 1335, 1320 Example 28 2-Cyclopentyl-7 (4) -nitro-5 (6)-
(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl)-
1H-benzo [d] imidazole By a method similar to that in Example 1, 2-cyclopentyl-7 (4)-
Nitro-5 (6)-(5-isoquinolylsulfonyl) -1H-benzo
[d] From 1.06 g (2.5 mmol) of imidazole, acetic acid (20 ml) and 900 mg (14.3 mmol) of sodium cyanoborohydride, 2-cyclopentyl-7 (4) -nitro-5 (6)-(1,2, 3,4-tetrahydro
-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole (580 mg, 1.4 mmol, 54.5%) was obtained. Mass spec (m / z): 427 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.32 (1H, d), 8.31 (1H, s), 8.05 (1H, d), 7.44 (1H , dd), 7.
39 (1H, d), 3.85 (2H, s), 3.45-3.51 (1H, m), 2.85 (2H, t), 2.7
8 (2H, t), 2.05-2.15 (2H, m), 1.85-1.95 (2H, m), 1.70-1.80
(2H, m), 1.60-1.70 (2H, m). Infrared absorption spectrum νmax (KBr) cm -1 : 2980, 1640, 15
20, 1335, 1320
【００５３】[0053]
【実施例２９】6(5)- クロロ-2- エチル-5(6)-(1,2,3,4
- テトラヒドロ-5- イソキノリルスルホニル)-1H- ベン
ゾ[d] イミダゾール 実施例１と同様の方法により、6(5)- クロロ-2- エチル
-5(6)-(5- イソキノリルスルホニル)-1H- ベンゾ[d] イ
ミダゾール 80mg(0.2mmol)、酢酸(2ml) 、シアノ水素化
ほう素ナトリウム 80mg(1.3mmol)を用いて、6(5)- クロ
ロ-2- エチル-5(6)-(1,2,3,4- テトラヒドロ-5- イソキ
ノリルスルホニル)-1H- ベンゾ[d] イミダゾール 50mg
(0.1mmol,60.6%)を得た。 質量分析値(m/z):376(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.36(1H,s),7.99(1H,d),7.67(1H,s),7.40(1H,dd),7.
35(1H,d),3.84(2H,s),2.91(2H,q),2.76(2H,t),2.57(2H,
t),1.33(3H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 1460, 1300, 11
35 Example 29 6 (5) -Chloro-2-ethyl-5 (6)-(1,2,3,4
-Tetrahydro-5-isoquinolylsulfonyl) -1H-ben
Zo [d] imidazole 6 (5) -Chloro-2-ethyl was obtained in the same manner as in Example 1.
Using -5 (6)-(5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 80 mg (0.2 mmol), acetic acid (2 ml), sodium cyanoborohydride 80 mg (1.3 mmol), 6 ( 5) -Chloro-2-ethyl-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 50mg
(0.1 mmol, 60.6%). Mass spec (m / z): 376 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.36 (1H, s), 7.99 (1H, d), 7.67 (1H, s), 7.40 (1H , dd), 7.
35 (1H, d), 3.84 (2H, s), 2.91 (2H, q), 2.76 (2H, t), 2.57 (2H,
t), 1.33 (3H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 1460, 1300, 11
35
【００５４】[0054]
【実施例３０】6(5)- クロロ-2- プロピル-5(6)-(1,2,
3,4- テトラヒドロ-5- イソキノリルス 実施例１と同様の方法により、6(5)- クロロ-2- プロピ
ル-5(6)-(5- イソキノリルスルホニル)-1H- ベンゾ[d]
イミダゾール 40mg(0.1mmol)、酢酸(2ml) 、シアノ水素
化ほう素ナトリウム 40mg(0.6mmol)を用いて、6(5)- ク
ロロ-2- プロピル-5(6)-(1,2,3,4- テトラヒドロ-5- イ
ソキノリルスルホニル)-1H- ベンゾ[d]イミダゾール 30
mg(0.1mmol,77.1%)を得た。 融点:157〜160 ℃ 質量分析値(m/z):390(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.36(1H,s),7.99(1H,dd),7.68(1H,s),7.41(1H,dd),
7.36(1H,d),3.86(2H,s),2.87(2H,dd),2.84(2H,t),2.59
(2H,t),1.77-1.84(2H,m),0.96(3H,t). 赤外吸収スペクトルνmax (KBr) cm-1: 2980, 1460, 13
10, 1160, 1140 Example 30 6 (5) -Chloro-2-propyl-5 (6)-(1,2,
3,4-Tetrahydro-5-isoquinolyls In the same manner as in Example 1, 6 (5) -chloro -2-propyl-5 (6)-(5 -isoquinolylsulfonyl ) -1H-benzo [d]
Using imidazole 40 mg (0.1 mmol), acetic acid (2 ml) and sodium cyanoborohydride 40 mg (0.6 mmol), 6 (5) -chloro-2-propyl-5 (6)-(1,2,3, 4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 30
mg (0.1 mmol, 77.1%). Melting point: 157-160 ° C Mass spec (m / z): 390 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.36 (1H, s), 7.99 (1H, dd), 7.68 (1H, s), 7.41 (1H, dd),
7.36 (1H, d), 3.86 (2H, s), 2.87 (2H, dd), 2.84 (2H, t), 2.59
(2H, t), 1.77-1.84 (2H, m), 0.96 (3H, t). Infrared absorption spectrum νmax (KBr) cm -1 : 2980, 1460, 13
10, 1160, 1140
【００５５】[0055]
【実施例３１】6(5)- クロロ-2- シクロペンチル-5(6)-
(1,2,3,4- テトラヒドロ-5- イソキノリルスルホニル)-
1H- ベンゾ[d] イミダゾール 実施例１６と同様の方法により、6(5)- クロロ-2- シク
ロペンチル-5(6)-(5-イソキノリルスルホニル)-1H- ベ
ンゾ[d] イミダゾール 90mg(0.2mmol)、酢酸(3ml) 、白
金ブラック 90mg から、6(5)- クロロ-2- シクロペンチ
ル-5(6)-(1,2,3,4- テトラヒドロ-5- イソキノリルスル
ホニル)-1H- ベンゾ[d] イミダゾール 45mg(0.1mmol,4
9.6%)を得た。 融点:168〜171 ℃ 質量分析値(m/z):416(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.34(1H,s),7.98(1H,d),7.66(1H,s),7.40(1H,d),7.3
8(1H,dd),3.84(2H,s),2.77(2H,t),2.57(2H,t),2.08(2H,
dd),1.90(2H,dd),1.76(2H,dd),1.66(2H,dd). 赤外吸収スペクトルνmax (KBr) cm-1: 1450, 1300, 11
10 Example 31 6 (5) -Chloro-2-cyclopentyl-5 (6)-
(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl)-
1H-benzo [d] imidazole By a method similar to that in Example 16, 6 (5) -chloro-2-cyclopentyl-5 (6)-(5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 90 mg ( 0.2 mmol), acetic acid (3 ml) and 90 mg of platinum black from 6 (5) -chloro-2-cyclopentyl-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H -Benzo [d] imidazole 45mg (0.1mmol, 4
9.6%). Melting point: 168-171 ° C Mass spec (m / z): 416 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.34 (1H, s), 7.98 (1H, d), 7.66 (1H, s), 7.40 (1H, d), 7.3
8 (1H, dd), 3.84 (2H, s), 2.77 (2H, t), 2.57 (2H, t), 2.08 (2H,
dd), 1.90 (2H, dd), 1.76 (2H, dd), 1.66 (2H, dd). Infrared absorption spectrum νmax (KBr) cm -1 : 1450, 1300, 11
Ten
【００５６】[0056]
【実施例３２】2,6(5)- ジメチル-5(6)-(1,2,3,4- テト
ラヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d]
イミダゾール 実施例１と同様の方法により、2,6(5)- ジメチル-5(6)-
(5- イソキノリルスルホニル)-1H- ベンゾ[d] イミダゾ
ール 80mg(0.2mmol)、酢酸(2ml) 、シアノ水素化ほう素
ナトリウム 60mg(1.0mmol)を用いて、2,6(5)- ジメチル
-5(6)-(1,2,3,4- テトラヒドロ-5- イソキノリルスルホ
ニル)-1H- ベンゾ[d] イミダゾール 70mg(0.2mmol,85.5
%)を得た。 融点:231〜237 ℃ 質量分析値(m/z):342(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.16(1H,s),7.87(1H,d),7.37(1H,dd),7.35(1H,s),7.
31(1H,d),3.80(2H,s),2.92(2H,t),2.54(2H,t),2.49(3H,
s),2.25(3H,s). 赤外吸収スペクトルνmax (KBr) cm-1: 1465, 1300, 71
0 Example 32 2,6 (5) -Dimethyl-5 (6)-(1,2,3,4-tetra
Lahydro-5-isoquinolylsulfonyl) -1H-benzo [d]
Imidazole In the same manner as in Example 1, 2,6 (5) -dimethyl-5 (6)-
(5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 80 mg (0.2 mmol), acetic acid (2 ml), sodium cyanoborohydride 60 mg (1.0 mmol), 2,6 (5) -dimethyl
-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 70 mg (0.2 mmol, 85.5
%). Melting point: 231-237 ° C Mass spectrometry (m / z): 342 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.16 (1H, s), 7.87 (1H, d), 7.37 (1H, dd), 7.35 (1H, s), 7.
31 (1H, d), 3.80 (2H, s), 2.92 (2H, t), 2.54 (2H, t), 2.49 (3H,
s), 2.25 (3H, s). Infrared absorption spectrum νmax (KBr) cm -1 : 1465, 1300, 71
0
【００５７】[0057]
【実施例３３】5(6)-[(2- アセチル-1,2,3,4- テトラヒ
ドロ-5- イソキノリル) スルホニル]-2-シクロペンチル
-1H-ベンゾ[d] イミダゾール 2-シクロペンチル-5(6)-(1,2,3,4- テトラヒドロ-5- イ
ソキノリルスルホニル)-1H- ベンゾ[d] イミダゾール2.
00g(5.2mmol)を無水酢酸(7ml) に溶解し、２時間室温で
攪拌した。反応液を氷水に注ぎ、飽和炭酸水素ナトリウ
ム溶液で中和後酢酸エチルで抽出した。有機層を無水硫
酸マグネシウムで乾燥後、減圧濃縮して得られた残渣を
シリカゲルクロマトグラフィー(NH-シリカゲル、2%メタ
ノール-酢酸エチル) で精製して、5(6)-[(2- アセチル-
1,2,3,4- テトラヒドロ-5- イソキノリル) スルホニル]
-2-シクロペンチル-1H-ベンゾ[d] イミダゾール1.68g
(4.0mmol,75.7%)を得た。 融点:128〜129 ℃ 核磁気共鳴スペクトル(DMSO-d6) δ:7.97-8.03(2H,m),7.46-7.63(4H,m),4.64(1H,s),4.58
(1H,s),3.49-3.54(2H,ddd),3.29-3.31(1H,m),3.05(1H,d
d),2.90(1H,dd),2.05-2.06(2H,m),1.99(3H,s),1.84-1.9
0(2H,m),1.72-1.76(2H,m),1.62-1.66(2H,m). Example 33 5 (6)-[(2-acetyl-1,2,3,4-tetrahi
Dro-5-isoquinolyl) sulfonyl] -2-cyclopentyl
-1H-benzo [d] imidazole 2-cyclopentyl-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole 2.
00g (5.2 mmol) was dissolved in acetic anhydride (7 ml) and stirred for 2 hours at room temperature. The reaction solution was poured into ice water, neutralized with a saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue obtained was purified by silica gel chromatography (NH-silica gel, 2% methanol-ethyl acetate) to give 5 (6)-[(2-acetyl-
1,2,3,4-tetrahydro-5-isoquinolyl) sulfonyl]
1.68 g of 2-cyclopentyl-1H-benzo [d] imidazole
(4.0 mmol, 75.7%). Melting point: 128-129 ° C Nuclear magnetic resonance spectrum (DMSO-d6) δ: 7.97-8.03 (2H, m), 7.46-7.63 (4H, m), 4.64 (1H, s), 4.58
(1H, s), 3.49-3.54 (2H, ddd), 3.29-3.31 (1H, m), 3.05 (1H, d
d), 2.90 (1H, dd), 2.05-2.06 (2H, m), 1.99 (3H, s), 1.84-1.9
0 (2H, m), 1.72-1.76 (2H, m), 1.62-1.66 (2H, m).
【００５８】[0058]
【実施例３４】5(6)-[(2- ベンゾイル-1,2,3,4- テトラ
ヒドロ-5- イソキノリル) スルホニル]-2-シクロペンチ
ル-6(5)-ニトロ-1H-ベンゾ[d] イミダゾール 2-シクロペンチル-6(5)-ニトロ-5(6)-(1,2,3,4- テトラ
ヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d] イ
ミダゾール二塩酸塩500mg(1.0mmol)をピリジン(8ml) に
溶解し、塩化ベンゾイル200mg(1.4mmol)を加え室温で２
時間攪拌した。反応液を氷水に注ぎ、酢酸エチルで抽出
した。抽出液を飽和炭酸水素ナトリウム溶液で洗浄し、
無水硫酸マグネシウムで乾燥後減圧濃縮した。得られた
残渣をエタノール−ジエチルエーテルで結晶化して、5
(6)-[(2- ベンゾイル-1,2,3,4- テトラヒドロ-5- イソ
キノリル) スルホニル]-2-シクロペンチル-6(5)-ニトロ
-1H-ベンゾ[d] イミダゾール450mg(0.9mmol,84.7%)を得
た。 融点:167〜172 ℃ 質量分析値(m/z):531(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.25-8.28(2H,m),7.73(1H,d),7.39-7.63(7H,m),4.60
-4.90(2H,m),3.05-3.88(5H,m),2.06-2.16(2H,m),1.85-
1.98(2H,m),1.72-1.81(2H,m),1.61-1.71(2H,m). 赤外吸収スペクトルνmax (KBr) cm-1: 1620, 1540, 14
50, 1340, 1300, 1120 Example 34 5 (6)-[(2-benzoyl-1,2,3,4-tetra
Hydro-5-isoquinolyl) sulfonyl] -2-cyclopentene
-6 (5) -Nitro-1H-benzo [d] imidazole 2-cyclopentyl-6 (5) -nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-Benzo [d] imidazole dihydrochloride (500 mg, 1.0 mmol) was dissolved in pyridine (8 ml), and benzoyl chloride (200 mg, 1.4 mmol) was added.
Stirred for hours. The reaction solution was poured into ice water and extracted with ethyl acetate. Washing the extract with saturated sodium bicarbonate solution,
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The obtained residue was crystallized from ethanol-diethyl ether to give 5
(6)-[(2-Benzoyl-1,2,3,4-tetrahydro-5-isoquinolyl) sulfonyl] -2-cyclopentyl-6 (5) -nitro
450 mg (0.9 mmol, 84.7%) of -1H-benzo [d] imidazole was obtained. Melting point: 167-172 ° C Mass spec (m / z): 531 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.25-8.28 (2H, m), 7.73 (1H, d), 7.39- 7.63 (7H, m), 4.60
-4.90 (2H, m), 3.05-3.88 (5H, m), 2.06-2.16 (2H, m), 1.85-
1.98 (2H, m), 1.72-1.81 (2H, m), 1.61-1.71 (2H, m). Infrared absorption spectrum νmax (KBr) cm -1 : 1620, 1540, 14
50, 1340, 1300, 1120
【００５９】[0059]
【実施例３５】2-シクロペンチル- 5(6)-[(2- トシル-
1,2,3,4- テトラヒドロ-5- イソキノリル) スルホニル]
- 6(5)-ニトロ-1H-ベンゾ[d] イミダゾール 実施例３４と同様の方法により、2-シクロペンチル-6
(5)-ニトロ-5(6)-(1,2,3,4- テトラヒドロ-5- イソキノ
リルスルホニル)-1H- ベンゾ[d] イミダゾール二塩酸塩
530mg(1.1mmol)、ピリジン(12ml)、p-トルエンスルホニ
ニルクロリド250mg(1.3mmol)を用いて、2-シクロペンチ
ル-5(6)-[(2-トシル-1,2,3,4- テトラヒドロ-5- イソキ
ノリル) スルホニル]-6(5)- ニトロ-1H-ベンゾ[d] イミ
ダゾール600mg(1.0mmol,97.4%)を得た。 融点:148〜151 ℃ 質量分析値(m/z):581(M+1) 核磁気共鳴スペクトル(DMSO-d6) δ:8.29(1H,s),8.26(1H,s),7.72(1H,d),7.62(2H,d),7.5
2(1H,d),7.43(1H,dd),7.32(2H,d),4.27(2H,s),3.42(2H,
t),3.25-3.28(1H,m),2.99(2H,t),2.33(3H,s),2.12-2.13
(1H,m),1.91-1.95(2H,m),1.76-1.80(2H,m),1.68-1.70(2
H,m). 赤外吸収スペクトルνmax (KBr) cm-1: 1540, 1340, 13
10, 1160 Example 35 2-Cyclopentyl-5 (6)-[(2-tosyl-
1,2,3,4-tetrahydro-5-isoquinolyl) sulfonyl]
-6 (5) -Nitro-1H-benzo [d] imidazole By a method similar to that in Example 34, 2-cyclopentyl-6
(5) -Nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole dihydrochloride
Using 530 mg (1.1 mmol), pyridine (12 ml) and 250 mg (1.3 mmol) of p-toluenesulfonyl chloride, 2-cyclopentyl-5 (6)-[(2-tosyl-1,2,3,4-tetrahydro -5-Isoquinolyl) sulfonyl] -6 (5) -nitro-1H-benzo [d] imidazole (600 mg, 1.0 mmol, 97.4%) was obtained. Melting point: 148-151 ° C Mass spec (m / z): 581 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 8.29 (1H, s), 8.26 (1H, s), 7.72 (1H, d), 7.62 (2H, d), 7.5
2 (1H, d), 7.43 (1H, dd), 7.32 (2H, d), 4.27 (2H, s), 3.42 (2H,
t), 3.25-3.28 (1H, m), 2.99 (2H, t), 2.33 (3H, s), 2.12-2.13
(1H, m), 1.91-1.95 (2H, m), 1.76-1.80 (2H, m), 1.68-1.70 (2
H, m). Infrared absorption spectrum νmax (KBr) cm -1 : 1540, 1340, 13
10, 1160
【００６０】[0060]
【実施例３６】2-シクロペンチル- 5(6)-[(2- メチル-
1,2,3,4- テトラヒドロ-5- イソキノリル) スルホニル]
- 6(5)-ニトロ-1H-ベンゾ[d] イミダゾール 2-シクロペンチル-6(5)-ニトロ-5(6)-(1,2,3,4- テトラ
ヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d] イ
ミダゾール二塩酸塩500mg(1.0mmol)をメタノール(10ml)
に溶解し、37% ホルムアルデヒド水溶液(0.3ml) とシア
ノ水素化ホウ素ナトリウム100mg(1.6mmol)を加え室温で
３時間攪拌した。実施例１と同様に後処理を行い、残渣
をシリカゲルクロマトグラフィー(NH-シリカゲル、2%メ
タノール- 酢酸エチル) で精製して、2-シクロペンチル
-5(6)-[(2-メチル-1,2,3,4- テトラヒドロ-5- イソキノ
リル) スルホニル]-6(5)- ニトロ-1H-ベンゾ[d] イミダ
ゾール150mg(0.3mmol,34.0%)を得た。 核磁気共鳴スペクトル(CDCl3) δ:8.39(1H,s),7.86(1H,d),7.26-7.31(3H,m),3.61(2H,
s),3.20(1H,m),3.02(2H,t),2.60(2H,t),2.38(3H,s),2.0
4-2.12(2H,m),1.84-1.92(2H,m),1.73-1.81(2H,m),1.62-
1.69(2H,m). Working Example 36 2-Cyclopentyl-5 (6)-[(2-methyl-
1,2,3,4-tetrahydro-5-isoquinolyl) sulfonyl]
-6 (5) -nitro -1H-benzo [d] imidazole 2-cyclopentyl-6 (5) -nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl)- 500 mg (1.0 mmol) of 1H-benzo [d] imidazole dihydrochloride in methanol (10 ml)
Then, a 37% aqueous formaldehyde solution (0.3 ml) and sodium cyanoborohydride (100 mg, 1.6 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Post-treatment was carried out in the same manner as in Example 1, and the residue was purified by silica gel chromatography (NH-silica gel, 2% methanol-ethyl acetate) to give 2-cyclopentyl.
-5 (6)-[(2-methyl-1,2,3,4-tetrahydro-5-isoquinolyl) sulfonyl] -6 (5) -nitro-1H-benzo [d] imidazole 150 mg (0.3 mmol, 34.0% ). Nuclear magnetic resonance spectrum (CDCl 3 ) δ: 8.39 (1H, s), 7.86 (1H, d), 7.26-7.31 (3H, m), 3.61 (2H,
s), 3.20 (1H, m), 3.02 (2H, t), 2.60 (2H, t), 2.38 (3H, s), 2.0
4-2.12 (2H, m), 1.84-1.92 (2H, m), 1.73-1.81 (2H, m), 1.62-
1.69 (2H, m).
【００６１】[0061]
【実施例３７】5(6)-[(2- ベンジル-1,2,3,4- テトラヒ
ドロ-5- イソキノリル) スルホニル]-2-シクロペンチル
-6(5)-ニトロ-1H-ベンゾ[d] イミダゾール 2-シクロペンチル-6(5)-ニトロ-5(6)-(1,2,3,4- テトラ
ヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d] イ
ミダゾール二塩酸塩800mg(1.6mmol)をジメチルホルムア
ミド(12ml)に溶解し、無水炭酸カリウム1100mg(8.0mmo
l) 、塩化べンジル300mg(2.4mmol)を加え室温で５時間
攪拌した。反応液を氷水に注ぎ、酢酸エチルで抽出し
た。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮
して得られた残渣をシリカゲルクロマトグラフィー(NH-
シリカゲル、2%メタノール- 酢酸エチル) で精製して、
5(6)-[(2- ベンジル-1,2,3,4- テトラヒドロ-5- イソキ
ノリル) スルホニル]-2-シクロペンチル-6(5)-ニトロ-1
H-ベンゾ[d] イミダゾール450mg(0.9mmol,54.3%)を得
た。 融点:138〜142 ℃ 質量分析値(m/z):517(M+1) 核磁気共鳴スペクトル(CDCl3) δ:8.45(1H,S),7.87(1H,d),7.17-7.28(8H,m),3.62(2H,
s),3.58(2H,s),3.17-3.23(1H,m),2.96-3.02(2H,m),2.61
-2.68(2H,m),2.04-2.12(2H,m),1.82-1.91(2H,m),1.73-
1.81(2H,m),1.61-1.68(2H,m). 赤外吸収スペクトルνmax (KBr) cm-1: 1540, 1340, 13
20 Example 37 5 (6)-[(2-benzyl-1,2,3,4-tetrahi
Dro-5-isoquinolyl) sulfonyl] -2-cyclopentyl
-6 (5) -Nitro-1H-benzo [d] imidazole 2-cyclopentyl-6 (5) -nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl)- 1H-benzo [d] imidazole dihydrochloride (800 mg, 1.6 mmol) was dissolved in dimethylformamide (12 ml), and anhydrous potassium carbonate (1100 mg, 8.0 mmo) was dissolved.
l), 300 mg (2.4 mmol) of benzyl chloride was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The residue obtained was silica gel chromatography (NH-
(Silica gel, 2% methanol-ethyl acetate)
5 (6)-[(2-benzyl-1,2,3,4-tetrahydro-5-isoquinolyl) sulfonyl] -2-cyclopentyl-6 (5) -nitro-1
450 mg (0.9 mmol, 54.3%) of H-benzo [d] imidazole were obtained. Mp: 138-142 ° C. Mass spectrometry value (m / z): 517 ( M + 1) Nuclear magnetic resonance spectrum (CDCl 3) δ: 8.45 ( 1H, S), 7.87 (1H, d), 7.17-7.28 (8H , m), 3.62 (2H,
s), 3.58 (2H, s), 3.17-3.23 (1H, m), 2.96-3.02 (2H, m), 2.61
-2.68 (2H, m), 2.04-2.12 (2H, m), 1.82-1.91 (2H, m), 1.73-
1.81 (2H, m), 1.61-1.68 (2H, m). Infrared absorption spectrum νmax (KBr) cm -1 : 1540, 1340, 13
20
【００６２】[0062]
【実施例３８】2-シクロペンチル- 5(6)- ｛[2-(N,N-ジ
メチルアミノプロピル)-1,2,3,4-テトラヒドロ-5- イソ
キノリル] スルホニル｝-6(5)-ニトロ-1H-ベンゾ[d] イ
ミダゾール 2-シクロペンチル-6(5)-ニトロ-5(6)-(1,2,3,4- テトラ
ヒドロ-5- イソキノリルスルホニル)-1H- ベンゾ[d] イ
ミダゾール二塩酸塩500mg(1.0mmol)をエタノール(10ml)
に懸濁し、無水炭酸ナトリウム450mg(4.2mmol)、N,N-ジ
メチルアミノプロピルクロリド塩酸塩190mg(1.2mmol)を
加え一夜加熱還流した。反応液を氷水に注ぎ、酢酸エチ
ルで抽出した。有機層を無水硫酸マグネシウムで乾燥
後、減圧濃縮して得られた残渣をシリカゲルクロマトグ
ラフィー(NH-シリカゲル、2%メタノール- 酢酸エチル)
で精製して、2-シクロペンチル-5(6)-｛[2-(N,N-ジメチ
ルアミノプロピル)-1,2,3,4-テトラヒドロ-5- イソキノ
リル)]スルホニル｝-6(5)-ニトロ-1H-ベンゾ[d] イミダ
ゾール150mg(0.3mmol,29.3%)を得た。 核磁気共鳴スペクトル(CDCl3) δ:8.44(1H,s),7.95(1H,s),7.88(1H,d),7.24(1H,dd),7.
20(1H,d),3.61(2H,s),3.23-3.29(1H,m),3.01(2H,t),2.5
9(2H,t),2.45(2H,t),2.32(2H,t),2.20(6H,s),2.09-2.13
(2H,m),1.89-1.94(2H,m),1.78-1.82(2H,m),1.66-1.70(4
H,m).Example 38 2-Cyclopentyl-5 (6)-[2- (N, N-di
Methylaminopropyl) -1,2,3,4-tetrahydro-5-iso
Quinolyl] sulfonyl｝ -6 (5) -nitro-1H-benzo [d]
Midazole 2-cyclopentyl-6 (5) -nitro -5 (6)-(1,2,3,4-tetrahydro-5- isoquinolylsulfonyl ) -1H-benzo [d] imidazole dihydrochloride 500 mg (1.0 mmol ) With ethanol (10ml)
And 450 mg (4.2 mmol) of anhydrous sodium carbonate and 190 mg (1.2 mmol) of N, N-dimethylaminopropyl chloride hydrochloride were added thereto, followed by heating under reflux overnight. The reaction solution was poured into ice water and extracted with ethyl acetate. The residue obtained by drying the organic layer over anhydrous magnesium sulfate and concentrating under reduced pressure is subjected to silica gel chromatography (NH-silica gel, 2% methanol-ethyl acetate).
2-cyclopentyl-5 (6)-{[2- (N, N-dimethylaminopropyl) -1,2,3,4-tetrahydro-5-isoquinolyl)] sulfonyl} -6 (5) There was obtained 150 mg (0.3 mmol, 29.3%) of 1-nitro-1H-benzo [d] imidazole. Nuclear magnetic resonance spectrum (CDCl 3 ) δ: 8.44 (1H, s), 7.95 (1H, s), 7.88 (1H, d), 7.24 (1H, dd), 7.
20 (1H, d), 3.61 (2H, s), 3.23-3.29 (1H, m), 3.01 (2H, t), 2.5
9 (2H, t), 2.45 (2H, t), 2.32 (2H, t), 2.20 (6H, s), 2.09-2.13
(2H, m), 1.89-1.94 (2H, m), 1.78-1.82 (2H, m), 1.66-1.70 (4
H, m).
【００６３】[0063]
【実施例３９】2-シクロペンチル-6(5)-ニトロ-5(6)-
｛[2-(2-ピペリジノエチル)-1,2,3,4-テトラヒドロ-5-
イソキノリル] スルホニル｝-1H-ベンゾ[d] イミダゾー
ル 実施例３８と同様の方法により、2-シクロペンチル-6
(5)-ニトロ-5(6)-(1,2,3,4- テトラヒドロ-5- イソキノ
リルスルホニル)-1H- ベンゾ[d] イミダゾール二塩酸塩
500mg(1.0mmol)、エタノール(10ml)、無水炭酸ナトリウ
ム400mg(3.7mmol)、2-ピペリジノエチルクロリド400mg
(2.1mmol)を用いて、2-シクロペンチル-6(5)-ニトロ-5
(6)-｛[2-(2-ピペリジノエチル)-1,2,3,4-テトラヒドロ
-5- イソキノリル] スルホニル｝-1H-ベンゾ[d] イミダ
ゾール300mg(0.6mmol,55.6%)を得た。 核磁気共鳴スペクトル(CDCl3) δ:8.33(1H,s),7.92(1H,s),7.82(1H,d),7.17-7.23(2H,
m),3.63(2H,s), 3.13(1H,dd),2.91(2H,brs),2.59-2.61
(4H,m),2.49-2.51(2H,m),2.39(4H,brs),2.03-2.04(2H,
m),1.83-1.87(2H,m),1.73-1.75(2H,m),1.60-1.61(2H,
m),1.43-1.44(4H,m),1.30-1.35(2H,m).Example 39 2-Cyclopentyl-6 (5) -nitro-5 (6)-
｛[2- (2-piperidinoethyl) -1,2,3,4-tetrahydro-5-
Isoquinolyl] sulfonyl｝ -1H-benzo [d] imidazo
In a similar manner to that Le Example 38, 2-cyclopentyl -6
(5) -Nitro-5 (6)-(1,2,3,4-tetrahydro-5-isoquinolylsulfonyl) -1H-benzo [d] imidazole dihydrochloride
500 mg (1.0 mmol), ethanol (10 ml), anhydrous sodium carbonate 400 mg (3.7 mmol), 2-piperidinoethyl chloride 400 mg
(2.1 mmol) using 2-cyclopentyl-6 (5) -nitro-5
(6)-｛[2- (2-piperidinoethyl) -1,2,3,4-tetrahydro
-5-isoquinolyl] sulfonyl｝ -1H-benzo [d] imidazole (300 mg, 0.6 mmol, 55.6%) was obtained. Nuclear magnetic resonance spectrum (CDCl 3 ) δ: 8.33 (1H, s), 7.92 (1H, s), 7.82 (1H, d), 7.17-7.23 (2H,
m), 3.63 (2H, s), 3.13 (1H, dd), 2.91 (2H, brs), 2.59-2.61
(4H, m), 2.49-2.51 (2H, m), 2.39 (4H, brs), 2.03-2.04 (2H, m
m), 1.83-1.87 (2H, m), 1.73-1.75 (2H, m), 1.60-1.61 (2H, m
m), 1.43-1.44 (4H, m), 1.30-1.35 (2H, m).
【００６４】次に、2-シクロペンチル-6(5)-ニトロ-5
(6)-｛[2-(2-ピペリジノエチル)-1,2,3,4-テトラヒドロ
-5- イソキノリル] スルホニル｝-1H-ベンゾ[d] イミダ
ゾール300mg(0.6mmol)を塩化水素飽和酢酸エチルに溶解
した後減圧濃縮し、2-シクロペンチル-6(5)-ニトロ-5
(6)-｛[2-(2-ピペリジノエチル)-1,2,3,4-テトラヒドロ
-5- イソキノリル] スルホニル｝-1H-ベンゾ[d] イミダ
ゾール三塩酸塩220mg(0.3mmol)を得た。 融点:241〜246 ℃ 質量分析値(m/z):538(M+1) 赤外吸収スペクトルνmax (KBr) cm-1: 1550, 1460, 13
55, 1320 これらの実施例で得られた本発明の化合物の化学式は表
１のとおりである。Next, 2-cyclopentyl-6 (5) -nitro-5
(6)-｛[2- (2-piperidinoethyl) -1,2,3,4-tetrahydro
-5-Isoquinolyl] sulfonyl｝ -1H-benzo [d] imidazole (300 mg, 0.6 mmol) was dissolved in hydrogen chloride saturated ethyl acetate and concentrated under reduced pressure to give 2-cyclopentyl-6 (5) -nitro-5.
(6)-｛[2- (2-piperidinoethyl) -1,2,3,4-tetrahydro
-5-Isoquinolyl] sulfonyl｝ -1H-benzo [d] imidazole trihydrochloride (220 mg, 0.3 mmol) was obtained. Melting point: 241-246 ° C Mass spec (m / z): 538 (M + 1) Infrared absorption spectrum νmax (KBr) cm -1 : 1550, 1460, 13
55, 1320 The chemical formulas of the compounds of the present invention obtained in these examples are as shown in Table 1.
【００６５】[0065]
【表１】 [Table 1]
【００６６】[0066]
【実施例４０】コルヒチン−誘発神経細胞死に対する抑
制効果 ニューロンのアポトーシスに対する効果を検討するた
め、コルヒチン−誘発神経細胞死モデル（Nakagawa-Yag
i 、Biochemical and Biophysical Research Communica
tions, Vol.199, pp807-817(1994))を用いて測定した。
ヒトニューロブラストーマSH-SY5Y 細胞(3x105個／60mm
培養ディシュ) を 10% 牛胎仔血清含有ダルベッコ改変
培地に分注し、翌日レチノイン酸 (10μM)添加を行い５
日間培養した。５日間の培養後、レチノイン酸 (10μM)
を含む10% 牛胎仔血清含有ダルベッコ改変培地に置換し
たディシュに本発明の化合物を添加し、30分間後にコル
ヒチン(1μM)添加し、さらに２日間培養した。細胞死
は、培養液中に漏出したLDH(lactate dehydrogenase)量
で判定した。結果を図１に示す。尚、数値はコルヒチン
によって誘発された漏出LDH 量に対する抑制率を示す。
この結果、本発明化合物を添加することにより、コルヒ
チンによって誘発された漏出LDH 量が顕著に抑制され
た。従って、本発明化合物により、神経細胞死が抑制さ
れることが確認された。Example 40 Inhibition of colchicine-induced neuronal death
To examine the effect of anti- effect neurons on apoptosis, a colchicine-induced neuronal death model (Nakagawa-Yag
i, Biochemical and Biophysical Research Communica
Measurements, Vol.199, pp807-817 (1994)).
Human neuroblastoma SH-SY5Y cells (3x10 5 cells / 60mm
Culture dish) was added to Dulbecco's modified medium containing 10% fetal calf serum, and retinoic acid (10 μM) was added the next day.
Cultured for days. After 5 days of culture, retinoic acid (10 μM)
Was added to a dish replaced with Dulbecco's modified medium containing 10% fetal calf serum, and 30 minutes later, colchicine (1 μM) was added, followed by further culturing for 2 days. Cell death was determined by the amount of LDH (lactate dehydrogenase) leaked into the culture solution. The results are shown in FIG. The numerical values indicate the inhibition rate against the amount of leaked LDH induced by colchicine.
As a result, the amount of leaked LDH induced by colchicine was significantly suppressed by the addition of the compound of the present invention. Therefore, it was confirmed that the compound of the present invention suppressed nerve cell death.
【００６７】[0067]
【実施例４１】6-ヒドロキシドパミン(6-OHDA)−誘発神
経細胞死に対する抑制効果 実施例４０で用いたコルヒチンの代わりに、本発明の化
合物を用いて、6-OHDA(200μM)を添加する実験条件下で
15時間培養した。結果を図２に示す。尚、数値は6-OHDA
によって誘発された漏出LDH 量に対する抑制率を示す。
この結果、本発明化合物を添加することにより、6-OHDA
によって誘発された漏出LDH 量が顕著に抑制された。従
って、本発明化合物により、神経細胞死が抑制されるこ
とが確認された。Example 41 6-Hydroxydopamine (6-OHDA) -Induced God
Inhibitory Effect on Transcellular Death In place of colchicine used in Example 40, using the compound of the present invention, under the experimental conditions of adding 6-OHDA (200 μM)
The cells were cultured for 15 hours. The results are shown in FIG. The numerical value is 6-OHDA
Fig. 4 shows the inhibition rate against the amount of leaked LDH induced by the above.
As a result, by adding the compound of the present invention, 6-OHDA
Induced LDH levels were significantly suppressed. Therefore, it was confirmed that the compound of the present invention suppressed nerve cell death.
【００６８】[0068]
【発明の効果】本発明により、新規な1, 2, 3, 4−テト
ラヒドロイソキノリン誘導体及びその薬学的に許容され
る酸付加塩が提供される。本発明の新規イソキノリン誘
導体及びその薬学的に許容される酸付加塩は、神経系で
のアポトーシス亢進で生じる神経細胞死（アポトーシス
型神経細胞死）の抑制活性を有し、アルツハイマー病、
パーキンソン病、ハンチントン舞踏病、筋萎縮性側索硬
化症等の神経変性疾患、脳卒中等の脳虚血性障害、及び
糖尿病等で観察される末梢性神経障害等の予防及び／又
は治療剤として有用である。According to the present invention, a novel 1,2,3,4-tetrahydroisoquinoline derivative and a pharmaceutically acceptable acid addition salt thereof are provided. The novel isoquinoline derivative of the present invention and a pharmaceutically acceptable acid addition salt thereof have an inhibitory activity on neuronal cell death (apoptotic neuronal cell death) caused by enhanced apoptosis in the nervous system.
It is useful as a preventive and / or therapeutic agent for neurodegenerative diseases such as Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, cerebral ischemic disorder such as stroke, and peripheral neuropathy observed in diabetes and the like. is there.
【図１】実施例４０のコルヒチン−誘発神経細胞死モデ
ルにおける、本発明化合物（実施例２及び２２）の神経
細胞死抑制効果を示す。FIG. 1 shows the inhibitory effect of the compound of the present invention (Examples 2 and 22) on the neuronal cell death in the colchicine-induced neuronal cell death model of Example 40.
【図２】実施例４１の６−ヒドロキシドパミン−誘発神
経細胞死モデルにおける、本発明化合物（実施例１８，
２０〜２４，３１，３６及び３７）の神経細胞死抑制効
果を示す。FIG. 2 shows a compound of the present invention in the 6-hydroxydopamine-induced neuronal death model of Example 41 (Example 18,
20 to 24, 31, 36 and 37).
【化７】 Embedded image
【化８】 Embedded image
【化９】 Embedded image
【化１０】 Embedded image
【化１１】 Embedded image
【化１２】 Embedded image
【化１３】 Embedded image
【化１４】 Embedded image
【化１５】 Embedded image
【化１６】 Embedded image
【化１７】 Embedded image
【化１８】 Embedded image
【化１９】 Embedded image
【化２０】 Embedded image
【化２１】 Embedded image
【化２２】 Embedded image
【化２３】 Embedded image
【化２４】 Embedded image
【化２５】 Embedded image
【化２６】 Embedded image
【化２７】 Embedded image
【化２８】 Embedded image
【化２９】 Embedded image
【化３０】 Embedded image
【化３１】 Embedded image
【化３２】 Embedded image
【化３３】 Embedded image
【化３４】 Embedded image
【化３５】 Embedded image
【化３６】 Embedded image
【化３７】 Embedded image
【化３８】 Embedded image
【化３９】 Embedded image
【化４０】 Embedded image
【化４１】 Embedded image
【化４２】 Embedded image
【化４３】 Embedded image
【化４４】 Embedded image
【化４５】 Embedded image
───────────────────────────────────────────────────── 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） Ａ６１Ｐ 25/14 Ａ６１Ｋ 31/00 ６２６Ｅ 43/00 ６４３ Ａ６１Ｋ 31/472 ６４３Ｄ 31/4725 31/47 ６０４ Ｃ０７Ｄ 217/04 ６０５ 401/12 ２３５ Ｃ０７Ｄ 217/04 401/12 ２３５ (72)発明者 奥江 雅之 栃木県下都賀郡石橋町石橋405 (72)発明者 八木 勇三 栃木県宇都宮市横山３丁目16−17 (72)発明者 大金 信夫 栃木県河内郡南河内町緑６丁目17−３ (72)発明者 斉藤 康成 栃木県下都賀郡壬生町落合３丁目７−34 ラ・セゾン国谷202 Ｆターム(参考） 4C034 AA07 AB10 AB15 AC03 4C063 AA01 AA03 BB08 CC34 DD15 4C086 AA02 AA03 BC30 BC39 GA07 GA08 GA12 NA14 ZA01 ZA02 ZA15 ZA16 ZA36 ZA94 ZB21 ZC35 ZC41 ZC54 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification symbol FI Theme coat ゛ (Reference) A61P 25/14 A61K 31/00 626E 43/00 643 A61K 31/472 643D 31/4725 31/47 604 C07D 217 / 04 605 401/12 235 C07D 217/04 401/12 235 (72) Inventor Masayuki Okue 405 Ishibashi, Ishibashi-cho, Shimotsuga-gun, Tochigi Prefecture (72) Inventor Yuzo Yagi 3- 16-17 Yokoyama, Utsunomiya City, Tochigi Prefecture (72) Inventor Nobuo Ogane 6-17-3 Midori, Kawachi-cho, Kawachi-gun, Tochigi (72) Inventor Yasunari Saito 3-73-34 Ochiai, Mibu-cho, Shimotsuga-gun, Tochigi 202 La Saison Kunitani 202 F term (reference) 4C034 AA07 AB10 AB15 AC03 4C063 AA01 AA03 BB08 CC34 DD15 4C086 AA02 AA03 BC30 BC39 GA07 GA08 GA12 NA14 ZA01 ZA02 ZA15 ZA16 ZA36 ZA94 ZB21 ZC35 ZC41 ZC54
Claims (2)
ラヒドロイソキノリン誘導体及びその薬学的に許容され
る酸付加塩。 【化１】 （式中、Arは置換されていてもよい芳香環または複素
環、ｎは０、１または２、R1は水素、低級アルキル、低
級アルキルカルボニル、アリールカルボニル、アリール
スルホニル、アラルキル及び-A-NR2R3より選択される置
換基を示す。-A-NR2R3において、Ａは低級アルキレン
を、R2、R3は同一または異なる低級アルキルであり、
R2,R3 は一緒になって環を形成していてもよい置換基を
示す。また、低級アルキルは直鎖または分枝状の炭素数
が１から６個のアルキルを、アリールは置換されていて
もよいフェニル基を、アラルキルは置換されていてもよ
いフェニル低級アルキル基を、低級アルキレンは直鎖ま
たは分枝状の炭素数が１から６個のアルキレンを示す）1. A 1,2,3,4-tetrahydroisoquinoline derivative represented by the general formula (I) and a pharmaceutically acceptable acid addition salt thereof. Embedded image (Wherein, Ar is an optionally substituted aromatic or heterocyclic ring, n is 0, 1 or 2, R 1 is hydrogen, lower alkyl, lower alkylcarbonyl, arylcarbonyl, arylsulfonyl, aralkyl and -A-NR A substituent selected from 2 R 3. In -A-NR 2 R 3 , A is lower alkylene, R 2 and R 3 are the same or different lower alkyl,
R 2 and R 3 together represent a substituent which may form a ring. Lower alkyl is a straight-chain or branched alkyl having 1 to 6 carbon atoms, aryl is an optionally substituted phenyl group, and aralkyl is an optionally substituted phenyl lower alkyl group. Alkylene represents a straight-chain or branched alkylene having 1 to 6 carbon atoms)
てもよい式(II)〜(IV) の芳香環及び複素環のいずれか
から選択される基である、請求項１に記載の1, 2, 3, 4
−テトラヒドロイソキノリン誘導体及びその薬学的に許
容される酸付加塩。 【化２】 （式中、R4-R16は水素、ニトロ、アミノ、ハロゲン、低
級アルキル及びシクロアルキルより選択される同一また
は異なる置換基を示す。ハロゲンはフッ素、塩素、臭素
またはヨウ素を、シクロアルキルは炭素数が３から７個
のシクロアルキルを示す）2. The method according to claim 1, wherein in the general formula (I), Ar is a group selected from any of the aromatic rings and heterocyclic rings of the formulas (II) to (IV) which may be substituted. 1, 2, 3, 4
-Tetrahydroisoquinoline derivatives and pharmaceutically acceptable acid addition salts thereof. Embedded image Wherein R 4 -R 16 represent the same or different substituents selected from hydrogen, nitro, amino, halogen, lower alkyl and cycloalkyl. Halogen represents fluorine, chlorine, bromine or iodine, cycloalkyl represents carbon The number represents 3 to 7 cycloalkyl)
Priority Applications (1)
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|---|---|---|---|
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10296132A JP2000109463A (en) | 1998-10-02 | 1998-10-02 | New 1,2,3,4-tetrahydroisoquinoline derivative |
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| Publication Number | Publication Date |
|---|---|
| JP2000109463A true JP2000109463A (en) | 2000-04-18 |
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ID=17829570
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10296132A Pending JP2000109463A (en) | 1998-10-02 | 1998-10-02 | New 1,2,3,4-tetrahydroisoquinoline derivative |
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| Country | Link |
|---|---|
| JP (1) | JP2000109463A (en) |
-
1998
- 1998-10-02 JP JP10296132A patent/JP2000109463A/en active Pending
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