JPH11279175A - Benzoimidazole derivative - Google Patents
Benzoimidazole derivativeInfo
- Publication number
- JPH11279175A JPH11279175A JP10079187A JP7918798A JPH11279175A JP H11279175 A JPH11279175 A JP H11279175A JP 10079187 A JP10079187 A JP 10079187A JP 7918798 A JP7918798 A JP 7918798A JP H11279175 A JPH11279175 A JP H11279175A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- benzimidazole
- compound
- nmr
- 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
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical class C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 10
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims abstract description 9
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims abstract description 9
- 230000001419 dependent effect Effects 0.000 claims abstract description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 3
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- -1 nitro, ureido Chemical group 0.000 abstract description 67
- 150000001875 compounds Chemical class 0.000 abstract description 46
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 abstract description 3
- 229910052740 iodine Inorganic materials 0.000 abstract description 3
- 210000004556 brain Anatomy 0.000 abstract description 2
- 208000013677 cerebrovascular dementia Diseases 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- JJPYQDDKAOKJIU-UHFFFAOYSA-N methyl 2-(quinolin-2-ylmethylsulfanyl)-3h-benzimidazole-5-carboxylate Chemical compound C1=CC=CC2=NC(CSC3=NC4=CC=C(C=C4N3)C(=O)OC)=CC=C21 JJPYQDDKAOKJIU-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 3
- 150000002367 halogens Chemical class 0.000 abstract 3
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- 208000026106 cerebrovascular disease Diseases 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 239000007810 chemical reaction solvent Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- 230000002490 cerebral effect Effects 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 4
- 150000004703 alkoxides Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 150000004679 hydroxides Chemical class 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- WDETYCRYUBGKCE-UHFFFAOYSA-N 2-(chloromethyl)quinolin-1-ium;chloride Chemical compound Cl.C1=CC=CC2=NC(CCl)=CC=C21 WDETYCRYUBGKCE-UHFFFAOYSA-N 0.000 description 1
- CTYYDYWKCWWQAM-UHFFFAOYSA-N 2-[(6-methoxy-1h-benzimidazol-2-yl)sulfanylmethyl]quinoline Chemical compound C1=CC=CC2=NC(CSC=3NC4=CC=C(C=C4N=3)OC)=CC=C21 CTYYDYWKCWWQAM-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-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
- 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
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- NBLBCGUCPBXKOV-UHFFFAOYSA-N 8-(methoxymethyl)-1-methyl-3-(2-methylpropyl)-7H-purine-2,6-dione Chemical compound CC(C)CN1C(=O)N(C)C(=O)C2=C1N=C(COC)N2 NBLBCGUCPBXKOV-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102000000584 Calmodulin Human genes 0.000 description 1
- 108010041952 Calmodulin Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
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- DDNCQMVWWZOMLN-IRLDBZIGSA-N Vinpocetine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OCC)N5C2=C1 DDNCQMVWWZOMLN-IRLDBZIGSA-N 0.000 description 1
- BAHFQKFLVNHMNQ-UHFFFAOYSA-L [Na].O.O.O.O.O.O.[Ni](Cl)Cl Chemical compound [Na].O.O.O.O.O.O.[Ni](Cl)Cl BAHFQKFLVNHMNQ-UHFFFAOYSA-L 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 150000004645 aluminates Chemical class 0.000 description 1
- REWFUSHVOGNMCQ-UHFFFAOYSA-N azanium;iron;chloride Chemical compound [NH4+].[Cl-].[Fe] REWFUSHVOGNMCQ-UHFFFAOYSA-N 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 210000004720 cerebrum Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000005921 isopentoxy group Chemical group 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 208000021331 vascular occlusion disease Diseases 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229960000744 vinpocetine Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- 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、Ｃａ−カルモジュ
リン依存性ホスホジエステラーゼ（ＰＤＥＩ）阻害作用
を有するベンゾイミダゾール誘導体およびその塩に関す
る。TECHNICAL FIELD The present invention relates to a benzimidazole derivative having a Ca-calmodulin-dependent phosphodiesterase (PDEI) inhibitory activity and a salt thereof.
【０００２】[0002]
【従来の技術】従来、Ｃａ−カルモジュリン依存性ホス
ホジエステラーゼ（ＰＤＥＩ）を選択的に阻害し、細胞
内のｃＡＭＰやｃＧＭＰの濃度を上昇させ、脳血管拡張
作用や中枢機能改善作用を有する化合物としてはビンポ
セチン、８−メトキシメチル−ＩＢＭＸ、ＫＳ−５０５
等の化合物が知られている（Physiol.Rev.,1995,75(4),
725.）。しかしながら、本発明で示すベンゾイミダゾー
ル骨格を有する化合物にＣａ−カルモジュリン依存性ホ
スホジエステラーゼ（ＰＤＥＩ）阻害作用を有すること
の報告は一切ない。2. Description of the Related Art Conventionally, vinpocetine is a compound that selectively inhibits Ca-calmodulin-dependent phosphodiesterase (PDEI), increases intracellular cAMP and cGMP levels, and has a cerebral vasodilator action and a central function improving action. , 8-methoxymethyl-IBMX, KS-505
Are known (Physiol. Rev., 1995, 75 (4),
725.). However, there is no report that the compound having a benzimidazole skeleton shown in the present invention has a Ca-calmodulin-dependent phosphodiesterase (PDEI) inhibitory action.
【０００３】一方、Quant.Struct.-Act.Relact.(1991),
10(2),107-9.にはベンゾイミダゾール誘導体として、２
−（２−キノリルメチルチオ）−１Ｈ−ベンゾイミダゾ
ールが開示されているが、本発明化合物の報告は一切な
い。On the other hand, Quant. Struct.-Act. Relact. (1991),
10 (2), 107-9.
Although-(2-quinolylmethylthio) -1H-benzimidazole is disclosed, there is no report on the compound of the present invention.
【０００４】[0004]
【発明が解決しようとする課題】本発明の目的は、Ｃａ
−カルモジュリン依存性ホスホジエステラーゼ（ＰＤＥ
Ｉ）を選択的に阻害する化合物を提供し、脳血管閉塞後
の中枢機能低下症、脳血管性痴呆症、老人性痴呆症、記
憶・学習機能障害等の疾患に対する脳循環及び中枢機能
改善に役立てることにある。SUMMARY OF THE INVENTION An object of the present invention is to provide a Ca
-Calmodulin-dependent phosphodiesterase (PDE)
Provide compounds that selectively inhibit I) to improve cerebral circulation and central function for diseases such as central dysfunction after cerebral vascular occlusion, cerebrovascular dementia, senile dementia, and memory / learning dysfunction. To help.
【０００５】[0005]
【課題を解決するための手段】本発明者らは、Ｃａ−カ
ルモジュリン依存性ホスホジエステラーゼ（ＰＤＥＩ）
阻害作用を有する化合物を鋭意検討した結果、ある種の
ベンズイミダゾール骨格を有する化合物が当該目的を満
たすことを見いだし、さらにその知見に基づき本発明を
完成した。Means for Solving the Problems The present inventors have proposed Ca-calmodulin-dependent phosphodiesterase (PDEI).
As a result of intensive studies on compounds having an inhibitory action, they have found that a compound having a certain benzimidazole skeleton satisfies the above object, and further completed the present invention based on the findings.
【０００６】すなわち本発明は、式That is, the present invention provides
【０００７】[0007]
【化２】 Embedded image
【０００８】［式中、Ｒ1は水素原子またはアルキル基
を示す。Ｒ2はアルキル基、アルコキシ基、ハロゲン原
子、ヒドロキシ基、ヒドロキシアルキル基、ペルフルオ
ロアルキル基、ニトロ基、アミノ基、カルボキシル基、
アルコキシカルボニル基、ウレイド基、式 ＮＨＣＯ(Ｃ
Ｈ2)mＣＯ2Ｈ（式中、ｍは２〜４の整数を示す。）で表
される基または式 ＣＯＮＲ6Ｒ7｛式中、Ｒ6及びＲ7は
同一または異なって水素原子、アルキル基、シクロアル
キル基若しくは式 (ＣＨ2)nＮＲ8Ｒ9（式中、ｎは１〜
４の整数を示し、Ｒ8及びＲ9は同一または異なって水素
原子、アルキル基、またはＲ8とＲ9が一緒になってアル
キレン基を形成する。）で表される基を示すか、または
Ｒ6及びＲ7は隣接する窒素原子と一緒になって５員若し
くは６員環の複素環（隣接する窒素原子以外の他にさら
に酸素原子または窒素原子を含んでもよい。）を形成す
る。｝で表される基を示し、Ｒ3は水素原子、アルキル
基、アルコキシ基、ハロゲン原子、ペルフルオロアルキ
ル基を示すか、またはＲ2とＲ3は互いに隣接する炭素原
子と結合し、かつそれらの炭素原子と共にベンゼン環を
形成する。Ｒ4は水素原子、アルキル基、アルコキシ基
またはニトロ基を示し、Ｒ5は水素原子またはアルキル
基を示し、ＸはＣＨまたは窒素原子を示す。］で表され
るベンゾイミダゾール誘導体またはその塩である。[In the formula, R 1 represents a hydrogen atom or an alkyl group. R 2 is an alkyl group, an alkoxy group, a halogen atom, a hydroxy group, a hydroxyalkyl group, a perfluoroalkyl group, a nitro group, an amino group, a carboxyl group,
Alkoxycarbonyl group, ureido group, formula NHCO (C
H 2 ) m CO 2 H (wherein m is an integer of 2 to 4) or a group represented by the formula CONR 6 R 7 , wherein R 6 and R 7 are the same or different and are a hydrogen atom, Alkyl group, cycloalkyl group or formula (CH 2 ) n NR 8 R 9 (where n is 1 to
And R 8 and R 9 are the same or different and each represents a hydrogen atom, an alkyl group, or R 8 and R 9 taken together to form an alkylene group. ) Or R 6 and R 7 are taken together with an adjacent nitrogen atom to form a 5- or 6-membered heterocyclic ring (in addition to the adjacent nitrogen atom, further an oxygen atom or a nitrogen atom May be included.). And R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, a perfluoroalkyl group, or R 2 and R 3 are bonded to adjacent carbon atoms, and Form a benzene ring with carbon atoms. R 4 represents a hydrogen atom, an alkyl group, an alkoxy group or a nitro group, R 5 represents a hydrogen atom or an alkyl group, and X represents CH or a nitrogen atom. ] Or a salt thereof.
【０００９】本発明においてアルキル基とは炭素数１〜
６の直鎖または分枝状のアルキル基を意味し、例えばメ
チル基、エチル基、プロピル基、イソプロピル基、ブチ
ル基、イソブチル基、sec-ブチル基、tert-ブチル基、
ペンチル基、イソペンチル基、ヘキシル基等が挙げられ
る。In the present invention, the alkyl group is one having 1 to carbon atoms.
6 means a linear or branched alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group,
Examples include a pentyl group, an isopentyl group, and a hexyl group.
【００１０】アルコキシ基とは炭素数１〜６の直鎖また
は分枝状のアルコキシ基を意味し、例えばメトキシ基、
エトキシ基、プロポキシ基、イソプロポキシ基、ブトキ
シ基、イソブトキシ基、sec-ブトキシ基、tert-ブトキ
シ基、ペンチルオキシ基、イソペンチルオキシ基、ヘキ
シルオキシ基等が挙げられる。The alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, a methoxy group,
Examples include an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, and a hexyloxy group.
【００１１】ハロゲン原子としては塩素原子、臭素原
子、ヨウ素原子、フッ素原子が挙げられる。[0011] Examples of the halogen atom include a chlorine atom, a bromine atom, an iodine atom and a fluorine atom.
【００１２】ヒドロキシアルキル基とは、炭素数１〜６
の直鎖または分枝状のヒドロキシアルキルを意味し、例
えばヒドロキシメチル基、１−ヒドロキシエチル基、２
−ヒドロキシエチル基、１−ヒドロキシプロピル基、２
−ヒドロキシプロピル基、３−ヒドロキシプロピル基、
１−ヒドロキシ−１−メチルエチル基等を挙げることが
できる。A hydroxyalkyl group is one having 1 to 6 carbon atoms.
A straight-chain or branched hydroxyalkyl, for example, a hydroxymethyl group, a 1-hydroxyethyl group,
-Hydroxyethyl group, 1-hydroxypropyl group, 2
-Hydroxypropyl group, 3-hydroxypropyl group,
Examples thereof include a 1-hydroxy-1-methylethyl group.
【００１３】ペルフルオロアルキル基とは、炭素数１〜
３のペルフルオロアルキル基を意味し、例えばトリフル
オロメチル基、ペンタフルオロエチル基、ヘプタフルオ
ロプロピル基等が挙げられる。A perfluoroalkyl group is a compound having 1 to 1 carbon atoms.
3, which means a trifluoromethyl group, a pentafluoroethyl group, a heptafluoropropyl group, or the like.
【００１４】アルコキシカルボニル基とは、炭素数２〜
７の直鎖または分枝状のアルコキシカルボニル基を意味
し、例えばメトキシカルボニル基、エトキシカルボニル
基、プロポキシカルボニル基、イソプロポキシカルボニ
ル基、ブトキシカルボニル基、イソブトキシカルボニル
基、１−メチルプロポキシカルボニル基、tert-ブトキ
シカルボニル基等が挙げられる。An alkoxycarbonyl group is a compound having 2 to 2 carbon atoms.
7 means a straight-chain or branched alkoxycarbonyl group, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, 1-methylpropoxycarbonyl group, and a tert-butoxycarbonyl group.
【００１５】シクロアルキル基とは、炭素数３〜８のシ
クロアルキル基を意味し、例えばシクロプロピル基、シ
クロブチル基、シクロペンチル基、シクロヘキシル基、
シクロヘプチル基、シクロオクチル基等が挙げられる。The cycloalkyl group means a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Examples include a cycloheptyl group and a cyclooctyl group.
【００１６】アルキレン基とは炭素数４〜１０の直鎖ま
たは分枝状のアルキレン基を意味し、例えばテトラメチ
レン基、ペンタメチレン基、ヘキサメチレン基、ヘプタ
メチレン基、及びこれらに１〜４個のメチル基、エチル
基、及びその両方が導入されたものが挙げられる。The alkylene group means a linear or branched alkylene group having 4 to 10 carbon atoms, such as a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, and 1 to 4 carbon atoms. In which a methyl group, an ethyl group, or both are introduced.
【００１７】Ｒ6及びＲ7が隣接する窒素原子と一緒にな
って形成する５員または６員環の複素環とは、２種また
はそれ以上の元素から構成されている環式化合物を意味
し、隣接する窒素原子以外の他にさらに酸素原子または
窒素原子を含んでもよい。具体的には、例えばピロリジ
ン、ピペリジン、ピペラジン、ヘキサメチレンイミン、
モルホリン等が挙げられる。A 5- or 6-membered heterocyclic ring formed by R 6 and R 7 together with an adjacent nitrogen atom means a cyclic compound composed of two or more elements. And may further contain an oxygen atom or a nitrogen atom in addition to the adjacent nitrogen atom. Specifically, for example, pyrrolidine, piperidine, piperazine, hexamethylene imine,
Morpholine and the like.
【００１８】塩としては、塩酸塩、臭化水素酸塩、硫酸
塩、硝酸塩、リン酸塩等の鉱酸塩、メタンスルホン酸
塩、ベンゼンスルホン酸塩、ｐ−トルエンスルホン酸
塩、酢酸塩、プロピオン酸塩、コハク酸塩、酒石酸塩、
クエン酸塩、安息香酸塩、マンデル酸塩、乳酸塩、トリ
フルオロ酢酸塩等の有機酸塩等、薬学的に許容される塩
が挙げられる。The salts include mineral salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, and the like. Propionate, succinate, tartrate,
Pharmaceutically acceptable salts such as organic acid salts such as citrate, benzoate, mandelate, lactate, and trifluoroacetate are exemplified.
【００１９】本発明の化合物は、例えば下記の製造スキ
ームにより製造することができる。The compound of the present invention can be produced, for example, by the following production scheme.
【００２０】[0020]
【化３】 Embedded image
【００２１】（式中、Ｒ1、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7及
びＸは前記と同義である。Ｒ10はアルキル基、アルコキ
シ基、ハロゲン原子、ヒドロキシ基、ペルフルオロアル
キル基、ニトロ基、アルコキシカルボニル基を示す。Ｒ
11はアルキル基を示す。Ｚ及びＷはヨウ素原子、臭素原
子、塩素原子を示す。）。すなわち、式（２）で表され
る化合物を塩基存在下、式（３）で表される化合物と反
応させ、本発明化合物（１ａ）を得ることが出来る。(Wherein, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and X are as defined above. R 10 is an alkyl group, an alkoxy group, a halogen atom, a hydroxy group, a perfluoroalkyl R, nitro group and alkoxycarbonyl group.
11 represents an alkyl group. Z and W represent an iodine atom, a bromine atom and a chlorine atom. ). That is, the compound of the present invention (1a) can be obtained by reacting the compound of the formula (2) with the compound of the formula (3) in the presence of a base.
【００２２】ここで、塩基としては、炭酸カリウム等の
炭酸塩、水酸化カリウム、水酸化ナトリウム等の水酸化
物、カリウムtert−ブトキシド、ナトリウムメトキシド
等のアルコキシド類、水素化ナトリウム等の塩基などを
用いることができる。反応溶媒としては、メタノール、
エタノール等のアルコール類、ジオキサン、テトラヒド
ロフラン等のエーテル類、Ｎ，Ｎ−ジメチルホルムアミ
ド、塩化メチレン、クロロホルム等の溶媒を用いること
ができる。反応温度は氷温から還流温度である。 次
に、式（１ａ）で表される本発明化合物と、式（４）で
表される化合物とを塩基存在下反応させ、本発明化合物
（１ｂ）を得ることが出来る。Here, examples of the base include carbonates such as potassium carbonate, hydroxides such as potassium hydroxide and sodium hydroxide, alkoxides such as potassium tert-butoxide and sodium methoxide, and bases such as sodium hydride. Can be used. As a reaction solvent, methanol,
Alcohols such as ethanol, ethers such as dioxane and tetrahydrofuran, and solvents such as N, N-dimethylformamide, methylene chloride and chloroform can be used. The reaction temperature is from ice temperature to reflux temperature. Next, the compound of the present invention (1b) can be obtained by reacting the compound of the present invention represented by the formula (1a) with the compound of the formula (4) in the presence of a base.
【００２３】ここで、塩基としては、炭酸カリウム等の
炭酸塩、水酸化カリウム、水酸化ナトリウム等の水酸化
物、カリウムtert−ブトキシド、ナトリウムメトキシド
等のアルコキシド類、水素化ナトリウム等の塩基などを
用いることができる。また、必要に応じてヨウ化カリウ
ム、ヨウ化ナトリウム等を添加することが出来る。反応
溶媒としては、メタノール、エタノール等のアルコール
類、ジオキサン、テトラヒドロフラン等のエーテル類、
Ｎ，Ｎ−ジメチルホルムアミド、塩化メチレン、クロロ
ホルム等の溶媒を用いることができる。反応温度は氷温
から還流温度である。Here, examples of the base include carbonates such as potassium carbonate, hydroxides such as potassium hydroxide and sodium hydroxide, alkoxides such as potassium tert-butoxide and sodium methoxide, and bases such as sodium hydride. Can be used. Further, potassium iodide, sodium iodide and the like can be added as needed. As the reaction solvent, methanol, alcohols such as ethanol, dioxane, ethers such as tetrahydrofuran,
Solvents such as N, N-dimethylformamide, methylene chloride and chloroform can be used. The reaction temperature is from ice temperature to reflux temperature.
【００２４】また、式（１ｃ）で表される化合物は、式
（１ａ）または（１ｂ）においてＲ10がアルコキシカル
ボニル基である化合物を加水分解して得ることが出来
る。The compound represented by the formula (1c) can be obtained by hydrolyzing a compound of the formula (1a) or (1b) wherein R 10 is an alkoxycarbonyl group.
【００２５】ここで、加水分解の試薬としては、水酸化
カリウム、水酸化ナトリウム、水酸化バリウム等の水酸
化物、カリウムtert−ブトキシド、ナトリウムメトキシ
ド等のアルコキシド類等の塩基、又は、濃塩酸、濃硫
酸、臭化水素酸、トリフルオロ酢酸、ｐ−トルエンスル
ホン酸等の酸を用いることができる。反応溶媒として
は、水、メタノール、エタノール等のアルコール類、
Ｎ，Ｎ−ジメチルホルムアミド、酢酸等の溶媒を単独ま
たは混合して用いることができる。Here, the hydrolysis reagent may be a hydroxide such as potassium hydroxide, sodium hydroxide or barium hydroxide, a base such as alkoxides such as potassium tert-butoxide or sodium methoxide, or concentrated hydrochloric acid. , Concentrated sulfuric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid and the like. As a reaction solvent, water, alcohols such as methanol and ethanol,
Solvents such as N, N-dimethylformamide and acetic acid can be used alone or as a mixture.
【００２６】また、式（１ｄ）で表される化合物は、式
（１ｃ）で表される化合物と式（５）で表される化合物
を反応させることにより得ることが出来る。The compound represented by the formula (1d) can be obtained by reacting the compound represented by the formula (1c) with the compound represented by the formula (5).
【００２７】ここで、縮合剤としては、ジシクロヘキシ
ルカルボジイミド、１−エチル−３−（３−ジメチルア
ミノプロピル）カルボジイミド等の縮合剤を用いること
ができる。また、必要に応じて１−ヒドロキシベンゾト
リアゾール、又は４−（ジメチルアミノ）ピリジン等を
添加することが出来る。反応溶媒としては、ジオキサ
ン、テトラヒドロフラン等のエーテル類、Ｎ，Ｎ−ジメ
チルホルムアミド、塩化メチレン、クロロホルム等の溶
媒を用いることができる。反応温度は氷温から室温であ
る。Here, as the condensing agent, a condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide can be used. Further, 1-hydroxybenzotriazole, 4- (dimethylamino) pyridine, or the like can be added as needed. As the reaction solvent, ethers such as dioxane and tetrahydrofuran, and solvents such as N, N-dimethylformamide, methylene chloride and chloroform can be used. The reaction temperature is from ice temperature to room temperature.
【００２８】また、式（１ｅ）で表される化合物は、式
（１ａ）または（１ｂ）においてＲ10がニトロ基である
化合物を還元して得られる。Further, the compound represented by the formula (1e) is obtained by reducing a compound in which R 10 is a nitro group in the formula (1a) or (1b).
【００２９】ここで、還元剤としては水素−パラジウム
カーボン、鉄−塩化アンモニウム、塩化ニッケル・６水
和物−水素化ホウ素ナトリウム等を用いることができ、
反応溶媒としてはメタノール、エタノール等のアルコー
ル類、ジオキサン、テトラヒドロフラン等のエーテル類
等の溶媒を用いることができる。反応温度としては室温
から還流温度である。Here, as the reducing agent, hydrogen-palladium carbon, iron-ammonium chloride, nickel chloride hexahydrate-sodium borohydride and the like can be used.
As the reaction solvent, solvents such as alcohols such as methanol and ethanol, and ethers such as dioxane and tetrahydrofuran can be used. The reaction temperature is from room temperature to reflux temperature.
【００３０】また、式（１）においてＲ2がウレイド基
である化合物は、Ｒ10がアミノ基である式（１ｅ）で表
される化合物をシアン酸塩と反応させることにより得ら
れる。The compound of the formula (1) wherein R 2 is a ureido group is obtained by reacting a compound of the formula (1e) wherein R 10 is an amino group with a cyanate.
【００３１】ここで、シアン酸塩としては、シアン酸カ
リウム、又はシアン酸ナトリウム等を用いることができ
る。反応溶媒としては、ギ酸、酢酸、プロピオン酸等と
水との混合溶媒を用いることができる。Here, potassium cyanate, sodium cyanate or the like can be used as the cyanate. As a reaction solvent, a mixed solvent of formic acid, acetic acid, propionic acid or the like and water can be used.
【００３２】また、式（１）においてＲ2が式 ＮＨＣＯ
(ＣＨ2)mＣＯ2Ｈ基である化合物は、式（１ｅ）で表さ
れる化合物と式（６）Further, in the formula (1), R 2 is represented by the formula NHCO
(CH 2) a compound which is m CO 2 H group, the compound represented by formula (1e) and the formula (6)
【００３３】[0033]
【化４】 Embedded image
【００３４】（式中、ｍは前記と同義である。）で表さ
れる化合物を反応させることにより得られる。ここで、
必要に応じて、炭酸カリウム等の炭酸塩、水酸化カリウ
ム、水酸化ナトリウム等の水酸化物、カリウムtert−ブ
トキシド、ナトリウムメトキシド等のアルコキシド類、
水素化ナトリウム等の塩基を添加することができる。反
応溶媒としては、ジオキサン、テトラヒドロフラン等の
エーテル類、Ｎ，Ｎ−ジメチルホルムアミド、塩化メチ
レン、クロロホルム等の溶媒を用いることができる。反
応温度は氷温から還流温度である。(Wherein m has the same meaning as described above). here,
If necessary, carbonates such as potassium carbonate, potassium hydroxide, hydroxides such as sodium hydroxide, potassium tert-butoxide, alkoxides such as sodium methoxide,
A base such as sodium hydride can be added. As the reaction solvent, ethers such as dioxane and tetrahydrofuran, and solvents such as N, N-dimethylformamide, methylene chloride and chloroform can be used. The reaction temperature is from ice temperature to reflux temperature.
【００３５】また、式（１ｆ）で表される化合物は、式
（１ａ）または（１ｂ）においてＲ10がアルコキシカル
ボニル基である化合物を還元して得られる。The compound represented by the formula (1f) can be obtained by reducing a compound of the formula (1a) or (1b) wherein R 10 is an alkoxycarbonyl group.
【００３６】ここで、還元剤としては、水素化リチウム
アルミニウム、水素化ホウ素ナトリウム、水素化ジイソ
ブチルアルミニウム、ジヒドロビス（２−メトキシエト
キシ）アルミン酸ナトリウム等の還元剤を用いることが
できる。反応溶媒としては、ジオキサン、テトラヒドロ
フラン等のエーテル類、Ｎ，Ｎ−ジメチルホルムアミ
ド、塩化メチレン、クロロホルム等の溶媒を用いること
ができる。Here, as the reducing agent, a reducing agent such as lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride, sodium dihydrobis (2-methoxyethoxy) aluminate can be used. As the reaction solvent, ethers such as dioxane and tetrahydrofuran, and solvents such as N, N-dimethylformamide, methylene chloride and chloroform can be used.
【００３７】反応温度としては氷温から室温である。The reaction temperature is from ice temperature to room temperature.
【００３８】[0038]
【発明の効果】本発明の化合物は、Ｃａ−カルモジュリ
ン依存性ホスホジエステラーゼ（ＰＤＥＩ）阻害作用を
有し、細胞内のｃＡＭＰやｃＧＭＰの濃度を上昇させる
ことにより、薬理作用を発現する。ＰＤＥＩは血管平滑
筋、脳に多く存在し、ＰＤＥＩ阻害剤が脳血管拡張作用
や中枢機能改善作用を有することから、脳血管閉塞後の
中枢機能低下症、脳血管性痴呆症、老人性痴呆症、記憶
・学習機能障害等の疾患に対する脳循環及び中枢機能改
善に有用である。Industrial Applicability The compound of the present invention has a Ca-calmodulin-dependent phosphodiesterase (PDEI) inhibitory effect, and exerts a pharmacological effect by increasing intracellular cAMP and cGMP concentrations. PDEI is abundant in vascular smooth muscle and brain, and PDEI inhibitors have a cerebral vasodilatory effect and a central function improving effect. It is useful for improving cerebral circulation and central function for diseases such as memory and learning dysfunction.
【００３９】[0039]
【実施例】以下、実施例及び試験例を挙げて本発明を更
に詳細に説明する。The present invention will be described below in more detail with reference to examples and test examples.
【００４０】また、実施例１〜５０により製造した化合
物の構造式を表１に示す。Table 1 shows the structural formulas of the compounds prepared in Examples 1 to 50.
【００４１】[0041]
【表１】 [Table 1]
【００４２】[0042]
【表２】 [Table 2]
【００４３】実施例１ ２−（２−キノリルメチルチオ）−５−メチル−１Ｈ−
ベンゾイミダゾール２−メルカプト−５−メチル−１Ｈ
−ベンゾイミダゾール(1.00g,6.10mmol)のＮ，Ｎ−ジメ
チルホルムアミド(70ml)溶液に炭酸カリウム(0.843g,6.
10mmol)と２−クロロメチルキノリン塩酸塩(2.61g,12.2
mmol)を加え、室温で一晩攪拌した。水を加えろ取、乾
燥後、少量の酢酸エチル溶液で洗浄し、表題化合物(1.7
2g)を得た。Example 1 2- (2-quinolylmethylthio) -5-methyl-1H-
Benzimidazole 2-mercapto-5-methyl-1H
To a solution of -benzimidazole (1.00 g, 6.10 mmol) in N, N-dimethylformamide (70 ml) was added potassium carbonate (0.843 g, 6.
10 mmol) and 2-chloromethylquinoline hydrochloride (2.61 g, 12.2 g)
mmol) and stirred at room temperature overnight. Water was added to the mixture, which was collected by filtration, dried and washed with a small amount of ethyl acetate solution to give the title compound (1.7
2g) was obtained.
【００４４】1Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);2.48
(s,3H),4.54(s,2H),7.05(d,J=8Hz,1H),7.38(s,1H),7.48
(d,J=8Hz,1H),7.51(d,J=8Hz,1H),7.61(t,J=8Hz,1H),7.8
3(t,J=8Hz,1H),7.87(d,J=8Hz,1H),8.15(d,J=8Hz,1H),8.
26(d,J=8Hz,1H)。ＭＡＳＳ(m/e);306(M++1)。 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 2.48
(s, 3H), 4.54 (s, 2H), 7.05 (d, J = 8Hz, 1H), 7.38 (s, 1H), 7.48
(d, J = 8Hz, 1H), 7.51 (d, J = 8Hz, 1H), 7.61 (t, J = 8Hz, 1H), 7.8
3 (t, J = 8Hz, 1H), 7.87 (d, J = 8Hz, 1H), 8.15 (d, J = 8Hz, 1H), 8.
26 (d, J = 8Hz, 1H). MASS (m / e); 306 (M ++ 1).
【００４５】実施例１と同様にして実施例２〜３２の化
合物を得た。The compounds of Examples 2 to 32 were obtained in the same manner as in Example 1.
【００４６】実施例２ ２−（２−キノリルメチルチオ）−５−（メトキシカル
ボニル）−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);3.95(s,3H),4.63
(s,2H),7.55-7.68(m,3H),7.82-7.98(m,3H),8.18(d,J=8H
z,1H),8.31(d,J=8Hz,1H),8.33(s,1H)。Example 2 2- (2-quinolylmethylthio) -5- (methoxycarbonyl) -1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 3.95 (s, 3H), 4.63
(s, 2H), 7.55-7.68 (m, 3H), 7.82-7.98 (m, 3H), 8.18 (d, J = 8H
z, 1H), 8.31 (d, J = 8Hz, 1H), 8.33 (s, 1H).
【００４７】実施例３ ２−（２−キノリルメチルチオ）−５−ニトロ−１Ｈ−
ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);4.97(s,2H),7.58
-8.12(m,7H),8.37(s,1H),8.39(d,J=8Hz,1H)。Example 3 2- (2-quinolylmethylthio) -5-nitro-1H-
Benzimidazole 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 4.97 (s, 2H), 7.58
-8.12 (m, 7H), 8.37 (s, 1H), 8.39 (d, J = 8Hz, 1H).
【００４８】実施例４ ２−（２−キノリルメチルチオ）−５−メトキシ−１Ｈ
−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);3.87(s,3H),4.53
(s,2H),6.87(dd,J=2,8Hz,1H),7.10(d,J=2Hz,1H),7.47
(d,J=8Hz,1H),7.51(d,J=8Hz,1H),7.61(t,J=8Hz,1H),7.8
0(d,J=8Hz,1H),7.87(d,J=8Hz,1H),8.12(d,J=8Hz,1H),8.
25(d,J=8Hz,1H)。 ＭＡＳＳ(m/e);322(M++1)。Example 4 2- (2-quinolylmethylthio) -5-methoxy-1H
-Benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 3.87 (s, 3H), 4.53
(s, 2H), 6.87 (dd, J = 2,8Hz, 1H), 7.10 (d, J = 2Hz, 1H), 7.47
(d, J = 8Hz, 1H), 7.51 (d, J = 8Hz, 1H), 7.61 (t, J = 8Hz, 1H), 7.8
0 (d, J = 8Hz, 1H), 7.87 (d, J = 8Hz, 1H), 8.12 (d, J = 8Hz, 1H), 8.
25 (d, J = 8Hz, 1H). MASS (m / e); 322 (M ++ 1).
【００４９】実施例５ ２−（キノリルメチルチオ）−５−フルオロ−１Ｈ−ベ
ンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);4.52(s,2H),6.97(d
dd,J=2,9,10Hz,1H),7.31(d,J=2Hz,1H),7.50(d,J=9Hz,1
H),7.52(d,J=8Hz,1H),7.62(t,J=7Hz,1H),7.78-7.92(m,2
H),8.11(d,J=7Hz,1H),8.28(d,J=8Hz,1H)。 ＭＡＳＳ(m/e);309(M+)。Example 5 2- (quinolylmethylthio) -5-fluoro-1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 4.52 (s, 2H), 6.97 (d)
dd, J = 2,9,10Hz, 1H), 7.31 (d, J = 2Hz, 1H), 7.50 (d, J = 9Hz, 1
H), 7.52 (d, J = 8Hz, 1H), 7.62 (t, J = 7Hz, 1H), 7.78-7.92 (m, 2
H), 8.11 (d, J = 7 Hz, 1H), 8.28 (d, J = 8 Hz, 1H). MASS (m / e); 309 (M + ).
【００５０】実施例６ ２−（２−キノリルメチルチオ）−５−（エトキシカル
ボニル）−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);1,33(t,J=7Hz,3
H),4.32(q,J=7Hz,2H),4.93(s,2H),7.53-7.82(m,5H),7.9
3-8.07(m,3H),8.35(d,J=9Hz,1H),13.03(bs,1H)。Example 6 2- (2-quinolylmethylthio) -5- (ethoxycarbonyl) -1H-benzimidazole 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 1,33 (t, J = 7Hz, 3
H), 4.32 (q, J = 7Hz, 2H), 4.93 (s, 2H), 7.53-7.82 (m, 5H), 7.9
3-8.07 (m, 3H), 8.35 (d, J = 9 Hz, 1H), 13.03 (bs, 1H).
【００５１】実施例７ ２−（２−キノリルメチルチオ）−５，６−ジクロロ−
１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);4.51(s,2H),7.52
(d,J=8Hz,1H),7.60-7.73(m,3H),7.82-7.94(m,2H),8.11
(d,J=8Hz,1H),8.30(d,J=8Hz,1H),13.62(s,1H)。 ＭＡＳＳ(m/e);359(M+),361(M++2),363(M++4)。Example 7 2- (2-quinolylmethylthio) -5,6-dichloro-
1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 4.51 (s, 2H), 7.52
(d, J = 8Hz, 1H), 7.60-7.73 (m, 3H), 7.82-7.94 (m, 2H), 8.11
(d, J = 8 Hz, 1H), 8.30 (d, J = 8 Hz, 1H), 13.62 (s, 1H). MASS (m / e); 359 (M + ), 361 (M ++ 2), 363 (M ++ 4).
【００５２】実施例８ ２−（２−キノリルメチルチオ）−５−クロロ−６−フ
ルオロ−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);4.51(s,2H),7.37(d
d,J=8,10Hz,1H),7.51(d,J=8Hz,1H),7.57(d,J=6Hz,1H),
7.62(t,J=6Hz,1H),7.80-7.93(m,2H),8.10(dd,J=2,8Hz,1
H),8.29(d,J=8Hz,1H),13.55(s,1H)。 ＭＡＳＳ(m/e);343(M+)。Example 8 2- (2-quinolylmethylthio) -5-chloro-6-fluoro-1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 4.51 (s, 2H), 7.37 (d
d, J = 8,10Hz, 1H), 7.51 (d, J = 8Hz, 1H), 7.57 (d, J = 6Hz, 1H),
7.62 (t, J = 6Hz, 1H), 7.80-7.93 (m, 2H), 8.10 (dd, J = 2,8Hz, 1
H), 8.29 (d, J = 8 Hz, 1H), 13.55 (s, 1H). MASS (m / e); 343 (M + ).
【００５３】実施例９ ２−（２−キノリルメチルチオ）−４−ブロモ−６−
（トリフルオロメチル）−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);4.56(s,2H),7.51
(d,J=8Hz,1H),7.61-7.70(m,2H),7.77-7.94(m,3H),8.31
(d,J=8Hz,1H),8.51(d,J=8Hz,1H),13.79(s,1H)。 ＭＡＳＳ(m/e);437(M+),439(M++2)。Example 9 2- (2-quinolylmethylthio) -4-bromo-6-
(Trifluoromethyl) -1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 4.56 (s, 2H), 7.51
(d, J = 8Hz, 1H), 7.61-7.70 (m, 2H), 7.77-7.94 (m, 3H), 8.31
(d, J = 8 Hz, 1H), 8.51 (d, J = 8 Hz, 1H), 13.79 (s, 1H). MASS (m / e); 437 (M + ), 439 (M ++ 2).
【００５４】実施例１０ ２−（２−キノリルメチルチオ）−４−クロロ−６−
（トリフルオロメチル）−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);4.55(s,2H),7.48-
7.69(m,3H),7.79-7.95(m,3H),8.31(d,J=8Hz,1H),8.40
(d,J=8Hz,1H),14.15(s,1H)。 ＭＡＳＳ(m/e);393(M+),395(M++2)。Example 10 2- (2-quinolylmethylthio) -4-chloro-6
(Trifluoromethyl) -1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 4.55 (s, 2H), 7.48-
7.69 (m, 3H), 7.79-7.95 (m, 3H), 8.31 (d, J = 8Hz, 1H), 8.40
(d, J = 8 Hz, 1H), 14.15 (s, 1H). MASS (m / e); 393 (M + ), 395 (M ++ 2).
【００５５】実施例１１ ２−（２−キノリルメチルチオ）−１Ｈ−ナフト［２，
３−ｄ］イミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);4.62(s,2H),7.38
(t,J=8Hz,1H),7.43(t,J=8Hz,1H),7.55(d,J=8Hz,1H),7.6
4(d,J=8Hz,1H),7.81-8.00(m,5H),8.08(s,1H),8.21(d,J=
8Hz,1H),8.28(d,J=8Hz,1H),12.97(s,1H)。 ＭＡＳＳ(m/e);342(M++1)。Example 11 2- (2-quinolylmethylthio) -1H-naphtho [2,
3-d] Imidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 4.62 (s, 2H), 7.38
(t, J = 8Hz, 1H), 7.43 (t, J = 8Hz, 1H), 7.55 (d, J = 8Hz, 1H), 7.6
4 (d, J = 8Hz, 1H), 7.81-8.00 (m, 5H), 8.08 (s, 1H), 8.21 (d, J =
8 Hz, 1 H), 8.28 (d, J = 8 Hz, 1 H), 12.97 (s, 1 H). MASS (m / e); 342 (M ++ l).
【００５６】実施例１２ ２−（２−キノリルメチルチオ）−５−クロロ−１Ｈ−
ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);4.53(s,2H),7.14-
7.22(m,1H),7.42-7.68(m,4H),7.78-7.93(m,2H),8.12(d,
J=8Hz,1H),8.29(d,J=8Hz,1H),13.36(s,1H)。 ＭＡＳＳ(m/e);325(M+),327(M++2)。Example 12 2- (2-quinolylmethylthio) -5-chloro-1H-
Benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 4.53 (s, 2H), 7.14-
7.22 (m, 1H), 7.42-7.68 (m, 4H), 7.78-7.93 (m, 2H), 8.12 (d,
J = 8Hz, 1H), 8.29 (d, J = 8Hz, 1H), 13.36 (s, 1H). MASS (m / e); 325 (M + ), 327 (M ++ 2).
【００５７】実施例１３ ２−（２−キノリルメチルチオ）−５−（トリフルオロ
メチル）−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);4.56(s,2H),7.43-
7.58(m,2H),7.59-7.71(m,2H),7.80-7.85(m,1H),7.90(d,
J=7Hz,2H),8,14(dd,J=2,8Hz,1H),8.31(d,J=7Hz,1H),13.
65(bs,1H)。 ＭＡＳＳ(m/e);359(M+)。Example 13 2- (2-quinolylmethylthio) -5- (trifluoromethyl) -1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 4.56 (s, 2H), 7.43-
7.58 (m, 2H), 7.59-7.71 (m, 2H), 7.80-7.85 (m, 1H), 7.90 (d,
J = 7Hz, 2H), 8,14 (dd, J = 2,8Hz, 1H), 8.31 (d, J = 7Hz, 1H), 13.
65 (bs, 1H). MASS (m / e); 359 (M + ).
【００５８】実施例１４ ２−（２−キノリルメチルチオ）−４−ニトロ−１Ｈ−
ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);4.61(s,2H),7.32
(t,J=8Hz,1H),7.51(d,J=8Hz,1H),7.60(t,J=8Hz,1H),7.7
7-7.89(m,2H),7.95(d,J=8Hz,1H),8.14(d,J=8Hz,1H),8.2
8(d,J=8Hz,1H),8.57(d,J=8Hz,1H),13.58(s,1H)。 ＭＡＳＳ(m/e);336(M+)。Example 14 2- (2-quinolylmethylthio) -4-nitro-1H-
Benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 4.61 (s, 2H), 7.32
(t, J = 8Hz, 1H), 7.51 (d, J = 8Hz, 1H), 7.60 (t, J = 8Hz, 1H), 7.7
7-7.89 (m, 2H), 7.95 (d, J = 8Hz, 1H), 8.14 (d, J = 8Hz, 1H), 8.2
8 (d, J = 8 Hz, 1H), 8.57 (d, J = 8 Hz, 1H), 13.58 (s, 1H). MASS (m / e); 336 (M + ).
【００５９】実施例１５ ２−（２−キノリルメチルチオ）−４−メチル−１Ｈ−
ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);2.70(s,3H),4.52
(s,2H),7.01(d,J=8Hz,1H),7.12(t,J=8Hz,1H),7.44(d,J=
8Hz,1H),7.52(d,J=8Hz,1H),7.61(t,J=8Hz,1H),7.77-7.9
1(m,2H),8.16(d,J=8Hz,1H),8.27(d,J=8Hz,1H)。 ＭＡＳＳ(m/e);305(M+)。Example 15 2- (2-quinolylmethylthio) -4-methyl-1H-
Benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 2.70 (s, 3H), 4.52
(s, 2H), 7.01 (d, J = 8Hz, 1H), 7.12 (t, J = 8Hz, 1H), 7.44 (d, J =
8Hz, 1H), 7.52 (d, J = 8Hz, 1H), 7.61 (t, J = 8Hz, 1H), 7.77-7.9
1 (m, 2H), 8.16 (d, J = 8Hz, 1H), 8.27 (d, J = 8Hz, 1H). MASS (m / e); 305 (M + ).
【００６０】実施例１６ ２−（２−キノリルメチルチオ）−５，６−ジメチル−
１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);2.37(s,6H),4.52
(s,2H),7.30(s,1H),7.41(s,1H),7.50(d,J=8Hz,1H),7.60
(t,J=8Hz,1H),7.82(t,J=8Hz,1H),7.87(d,J=8Hz,1H),8.1
4(d,J=8Hz,1H),8.23(d,J=8Hz,1H),12.58(s,1H)。 ＭＡＳＳ(m/e);319(M+)。Example 16 2- (2-quinolylmethylthio) -5,6-dimethyl-
1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 2.37 (s, 6H), 4.52
(s, 2H), 7.30 (s, 1H), 7.41 (s, 1H), 7.50 (d, J = 8Hz, 1H), 7.60
(t, J = 8Hz, 1H), 7.82 (t, J = 8Hz, 1H), 7.87 (d, J = 8Hz, 1H), 8.1
4 (d, J = 8Hz, 1H), 8.23 (d, J = 8Hz, 1H), 12.58 (s, 1H). MASS (m / e); 319 (M + ).
【００６１】実施例１７ ２−（２−キノリルメチルチオ）−４，５−ジメチル−
１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);2.39(s,3H),2.61
(s,3H),4.52(s,2H),7.03(d,J=8Hz,1H),7.20-7.43(s,1
H),7.52(d,J=8Hz,1H),7.60(t,J=8Hz,1H),7.77-7.91(m,2
H),8.16(d,J=8Hz,1H),8.25(d,J=8Hz,1H),12.40(s,1H),1
2.84(s,1H)。 ＭＡＳＳ(m/e);319(M+)。Example 17 2- (2-quinolylmethylthio) -4,5-dimethyl-
1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 2.39 (s, 3H), 2.61
(s, 3H), 4.52 (s, 2H), 7.03 (d, J = 8Hz, 1H), 7.20-7.43 (s, 1
H), 7.52 (d, J = 8Hz, 1H), 7.60 (t, J = 8Hz, 1H), 7.77-7.91 (m, 2
H), 8.16 (d, J = 8Hz, 1H), 8.25 (d, J = 8Hz, 1H), 12.40 (s, 1H), 1
2.84 (s, 1H). MASS (m / e); 319 (M + ).
【００６２】実施例１８ ２−（２−キノリルメチルチオ）−４−ヒドロキシ−１
Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);4.84(s,2H),6.48
-6.59(m,1H),6.78-7.02(m,2H),7.53-7.82(m,3H),7.92-
8.03(m,2H),8.33(dd,J=2,8Hz,1H),9.62,9.65(each s,1
H),12.53,12.71(each s,1H)。 ＭＡＳＳ(m/e);307(M+)。Example 18 2- (2-quinolylmethylthio) -4-hydroxy-1
H-benzimidazole 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 4.84 (s, 2H), 6.48
-6.59 (m, 1H), 6.78-7.02 (m, 2H), 7.53-7.82 (m, 3H), 7.92-
8.03 (m, 2H), 8.33 (dd, J = 2,8Hz, 1H), 9.62,9.65 (each s, 1
H), 12.53, 12.71 (each s, 1H). MASS (m / e); 307 (M + ).
【００６３】実施例１９ ２−（２−キノリルメチルチオ）−５−ｔｅｒｔ−ブチ
ル−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);1.39(s,9H),4.54
(s,2H),7.29(d,J=8Hz,1H),7.46-7.66(m,4H),7.78-7.91
(m,2H),8.14(d,J=8Hz,1H),8.24(d,J=8Hz,1H),12.63(s,1
H)。 ＭＡＳＳ(m/e);347(M+)。Example 19 2- (2-quinolylmethylthio) -5-tert-butyl-1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 1.39 (s, 9H), 4.54
(s, 2H), 7.29 (d, J = 8Hz, 1H), 7.46-7.66 (m, 4H), 7.78-7.91
(m, 2H), 8.14 (d, J = 8Hz, 1H), 8.24 (d, J = 8Hz, 1H), 12.63 (s, 1
H). MASS (m / e); 347 (M + ).
【００６４】実施例２０ ２−（２−キノリルメチルチオ）−５−エトキシ−１Ｈ
−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);1.44(t,J=7Hz,3H),
4.10(q,J=7Hz,2H),4.52(s,2H),6.86(dd,J=2,8Hz,1H),7.
09(d,J=2Hz,1H),7.47(d,J=8Hz,1H),7.50(d,J=8Hz,1H),
7.60(t,J=8Hz,1H),7.79(d,J=8Hz,1H),7.84(d,J=8Hz,1
H),8.12(d,J=8Hz,1H),8.24(d,J=8Hz,1H),12.84(bs,1
H)。Example 20 2- (2-quinolylmethylthio) -5-ethoxy-1H
-Benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 1.44 (t, J = 7 Hz, 3H),
4.10 (q, J = 7Hz, 2H), 4.52 (s, 2H), 6.86 (dd, J = 2,8Hz, 1H), 7.
09 (d, J = 2Hz, 1H), 7.47 (d, J = 8Hz, 1H), 7.50 (d, J = 8Hz, 1H),
7.60 (t, J = 8Hz, 1H), 7.79 (d, J = 8Hz, 1H), 7.84 (d, J = 8Hz, 1H
H), 8.12 (d, J = 8Hz, 1H), 8.24 (d, J = 8Hz, 1H), 12.84 (bs, 1H
H).
【００６５】実施例２１ ２−（２−キノリルメチルチオ）−４，６−ジクロロ−
１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);4.53(s,2H),7.22-
7.28(m,1H),7.47-7.56(m,2H),7.59-7.69(m,1H),7.78-7.
94(m,2H),8.31(d,J=8Hz,1H),8.38(d,J=8Hz,1H),13.93
(s,1H)。 ＭＡＳＳ(m/e);359(M+),361(M++2)。Example 21 2- (2-quinolylmethylthio) -4,6-dichloro-
1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 4.53 (s, 2H), 7.22-
7.28 (m, 1H), 7.47-7.56 (m, 2H), 7.59-7.69 (m, 1H), 7.78-7.
94 (m, 2H), 8.31 (d, J = 8Hz, 1H), 8.38 (d, J = 8Hz, 1H), 13.93
(s, 1H). MASS (m / e); 359 (M + ), 361 (M ++ 2).
【００６６】実施例２２ ２−（２−キノリルメチルチオ）−５，６−ジメトキシ
−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);3.96(s,6H),4.52
(s,2H),7.02-7.20(m,2H,),7.50(d,J=8Hz,1H),7.62(t,J=
8Hz,1H),7.81(d,J=8Hz,1H),7.87(t,J=8Hz,1H),8.13(d,J
=8Hz,1H),8.26(d,J=8Hz,1H),12.63(s,1H)。 ＭＡＳＳ(m/e);351(M+)。Example 22 2- (2-quinolylmethylthio) -5,6-dimethoxy-1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 3.96 (s, 6H), 4.52
(s, 2H), 7.02-7.20 (m, 2H,), 7.50 (d, J = 8Hz, 1H), 7.62 (t, J =
8Hz, 1H), 7.81 (d, J = 8Hz, 1H), 7.87 (t, J = 8Hz, 1H), 8.13 (d, J
= 8Hz, 1H), 8.26 (d, J = 8Hz, 1H), 12.63 (s, 1H). MASS (m / e); 351 (M + ).
【００６７】実施例２３ ２−（２−キノリルメチルチオ）−４，６−ジメチル−
１Ｈ−ベンゾイミダゾール ｍｐ．99〜102℃1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);2.44(s,3H),2.63
(s,3H),4.51(s,2H),6.85(s,1H),7.17-7.32(m,1H),7.52
(d,J=8Hz,1H),7.60(t,J=8Hz,1H),7.77-7.92(m,2H),8.16
(d,J=8Hz,1H),8.25(d,J=8Hz,1H)。 ＭＡＳＳ(m/e);319(M+)。Example 23 2- (2-quinolylmethylthio) -4,6-dimethyl-
1H-benzimidazole mp. 99-102 ° C 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 2.44 (s, 3H), 2.63
(s, 3H), 4.51 (s, 2H), 6.85 (s, 1H), 7.17-7.32 (m, 1H), 7.52
(d, J = 8Hz, 1H), 7.60 (t, J = 8Hz, 1H), 7.77-7.92 (m, 2H), 8.16
(d, J = 8 Hz, 1H), 8.25 (d, J = 8 Hz, 1H). MASS (m / e); 319 (M + ).
【００６８】実施例２４ ２−［（３−メチル−２−キノキサリル）メチルチオ］
−５−（メトキシカルボニル）−１Ｈ−ベンゾイミダゾ
ール ｍｐ．145〜147℃1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);2.89(s,3H),3.96
(s,3H),4.72(s,2H),7.64(d,J=9Hz,1H),7.73-8.12(m,5
H),8.20(s,1H),12.18(s,1H)。Example 24 2-[(3-methyl-2-quinoxalyl) methylthio]
-5- (methoxycarbonyl) -1H-benzimidazole mp. 145-147 ° C 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 2.89 (s, 3H), 3.96
(s, 3H), 4.72 (s, 2H), 7.64 (d, J = 9Hz, 1H), 7.73-8.12 (m, 5
H), 8.20 (s, 1H), 12.18 (s, 1H).
【００６９】実施例２５ ２−［（８−ニトロ−２−キノリル）メチルチオ］−５
−（メトキシカルボニル）−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);3.94(s,3H),4.54
(s,2H),7.66-7.74(m,2H),7.90-8.00(m,2H),8.14(d,J=9H
z,1H),8.31(d,J=9Hz,2H),8.40(d,J=9Hz,1H),12.03(bs,1
H)。Example 25 2-[(8-Nitro-2-quinolyl) methylthio] -5
-(Methoxycarbonyl) -1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 3.94 (s, 3H), 4.54
(s, 2H), 7.66-7.74 (m, 2H), 7.90-8.00 (m, 2H), 8.14 (d, J = 9H
z, 1H), 8.31 (d, J = 9Hz, 2H), 8.40 (d, J = 9Hz, 1H), 12.03 (bs, 1
H).
【００７０】実施例２６ ２−［（６−メトキシ−２−キノリル）メチルチオ］−
５，６−ジメトキシ−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);3.95(s,9H),4.48
(s,2H),7.11(m,2H),7.44(d,J=9Hz,1H),7.47(dd,J=3,9H
z,1H),8.01(d,J=9Hz,1H),8.12(d,J=9Hz,1H)。 ＭＡＳＳ(m/e);381(M+)。Example 26 2-[(6-methoxy-2-quinolyl) methylthio]-
5,6-dimethoxy-1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 3.95 (s, 9H), 4.48
(s, 2H), 7.11 (m, 2H), 7.44 (d, J = 9Hz, 1H), 7.47 (dd, J = 3,9H
z, 1H), 8.01 (d, J = 9 Hz, 1H), 8.12 (d, J = 9 Hz, 1H). MASS (m / e); 381 (M + ).
【００７１】実施例２７ ２−［（８−ニトロ−２−キノリル）メチルチオ］−
５，６−ジメトキシ−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);3.95(s,6H),4.49
(s,2H),7.20-7.40(m,2H),7.67(d,J=9Hz,1H),7.70(dd,J=
8,9Hz,1H),8.13(d,J=9Hz,1H),8.28(d,J=8Hz,1H),8.38
(d,J=9Hz,1H)。 ＭＡＳＳ(m/e);396(M+)。Example 27 2-[(8-Nitro-2-quinolyl) methylthio]-
5,6-dimethoxy-1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 3.95 (s, 6H), 4.49
(s, 2H), 7.20-7.40 (m, 2H), 7.67 (d, J = 9Hz, 1H), 7.70 (dd, J =
8,9Hz, 1H), 8.13 (d, J = 9Hz, 1H), 8.28 (d, J = 8Hz, 1H), 8.38
(d, J = 9 Hz, 1H). MASS (m / e); 396 (M + ).
【００７２】実施例２８ ２−［（３−メチル−２−キノキサリル）メチルチオ］
−５，６−ジメトキシ−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);2.88(s,3H),3.93
(s,6H),4.66(s,2H),7.06(m,2H),7.76(dd,J=3,6Hz,2H),
8.05(dd,J=3,6Hz,2H)。 ＭＡＳＳ(m/e);323(M+)。Example 28 2-[(3-methyl-2-quinoxalyl) methylthio]
-5,6-dimethoxy-1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 2.88 (s, 3H), 3.93
(s, 6H), 4.66 (s, 2H), 7.06 (m, 2H), 7.76 (dd, J = 3,6Hz, 2H),
8.05 (dd, J = 3,6Hz, 2H). MASS (m / e); 323 (M + ).
【００７３】実施例２９ ２−（２−キノキサリルメチルチオ）−５，６−ジメト
キシ−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);3.93(s,3H),4.67
(s,2H),7.06(m,2H),7.82(m,2H),8.10(m,2H),9.00(s,1
H)。 ＭＡＳＳ(m/e);352(M+)。Example 29 2- (2-quinoxalylmethylthio) -5,6-dimethoxy-1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 3.93 (s, 3H), 4.67
(s, 2H), 7.06 (m, 2H), 7.82 (m, 2H), 8.10 (m, 2H), 9.00 (s, 1
H). MASS (m / e); 352 (M + ).
【００７４】実施例３０ ２−［（３−メチル−２−キノキサリル）メチルチオ］
−４，５−ジメチル−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);2.35(s,3H),2.51
(s,3H),2.85(s,3H),4.65(s,2H),7.99(d,J=8Hz,1H),7.28
(d,J=8Hz,1H),7.73(m,2H),8.03(m,2H)。 ＭＡＳＳ(m/e);334(M+)。Example 30 2-[(3-methyl-2-quinoxalyl) methylthio]
-4,5-dimethyl-1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 2.35 (s, 3H), 2.51
(s, 3H), 2.85 (s, 3H), 4.65 (s, 2H), 7.99 (d, J = 8Hz, 1H), 7.28
(d, J = 8Hz, 1H), 7.73 (m, 2H), 8.03 (m, 2H). MASS (m / e); 334 (M + ).
【００７５】実施例３１ ２−（２−キノキサリルメチルチオ）−４，５−ジメチ
ル−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);2.37(s,3H),2.54
(s,3H),4.68(s,2H),7.01(d,J=8Hz,1H),7.29(d,J=8Hz,1
H),7.81(m,2H),8.11(m,2H),9.02(s,1H)。 ＭＡＳＳ(m/e);320(M+)。Example 31 2- (2-quinoxalylmethylthio) -4,5-dimethyl-1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 2.37 (s, 3H), 2.54
(s, 3H), 4.68 (s, 2H), 7.01 (d, J = 8Hz, 1H), 7.29 (d, J = 8Hz, 1
H), 7.81 (m, 2H), 8.11 (m, 2H), 9.02 (s, 1H). MASS (m / e); 320 (M + ).
【００７６】実施例３２ ２−（８−ニトロ−２−キノリルメチルチオ）−４，５
−ジメチル−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);2.36(s,3H),2.51
(s,3H),4.53(s,2H),7.04(d,J=8Hz,1H),7.68(d,J=9Hz,1
H),7.70(d,J=8Hz,1H),8.11(d,J=8Hz,1H),8.95(d,J=9Hz,
1H)。 ＭＡＳＳ(m/e);364(M+)。Example 32 2- (8-Nitro-2-quinolylmethylthio) -4,5
-Dimethyl-1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 2.36 (s, 3H), 2.51
(s, 3H), 4.53 (s, 2H), 7.04 (d, J = 8Hz, 1H), 7.68 (d, J = 9Hz, 1
H), 7.70 (d, J = 8Hz, 1H), 8.11 (d, J = 8Hz, 1H), 8.95 (d, J = 9Hz,
1H). MASS (m / e); 364 (M + ).
【００７７】実施例３３ ２−（２−キノリルメチルチオ）−１−ｎ−プロピル−
６−メチル−１Ｈ−ベンゾイミダゾール ２−（２−キノリルメチルチオ）−５−メチル−１Ｈ−
ベンゾイミダゾール(1.01g,3.31mmol)のＮ，Ｎ−ジメチ
ルホルムアミド(50ml)溶液に炭酸カリウム(0.501g,3.63
mmol)と１−ヨードプロパン(0.4ml,4.10mmol)を加え、
室温で一晩攪拌した。水を加え、酢酸エチルで抽出し、
有機層を水、飽和食塩水の順で洗浄した後、無水硫酸マ
グネシウムで乾燥し、溶媒を減圧留去した。残留物を少
量のジエチルエーテルで洗浄後、表題化合物(0.689g)を
得た。Example 33 2- (2-quinolylmethylthio) -1-n-propyl-
6-methyl-1H-benzimidazole 2- (2-quinolylmethylthio) -5-methyl-1H-
Potassium carbonate (0.501 g, 3.63 g) was added to a solution of benzimidazole (1.01 g, 3.31 mmol) in N, N-dimethylformamide (50 ml).
mmol) and 1-iodopropane (0.4 ml, 4.10 mmol),
Stirred overnight at room temperature. Add water, extract with ethyl acetate,
The organic layer was washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with a small amount of diethyl ether to give the title compound (0.689 g).
【００７８】ｍｐ．118〜119℃1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);1.84-1.96(m,3H),
1.79(sextet,J=7Hz,2H),2.48(s,3H),4.00(t,J=7Hz,2H),
4.96(s,2H),7.01-7.08(m,2H),7.46-7.62(m,3H),7.67-7.
81(m,2H),8.07(d,J=8Hz,2H)。 ＭＡＳＳ(m/e);347(M+)。Mp. 118-119 ° C 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 1.84-1.96 (m, 3H),
1.79 (sextet, J = 7Hz, 2H), 2.48 (s, 3H), 4.00 (t, J = 7Hz, 2H),
4.96 (s, 2H), 7.01-7.08 (m, 2H), 7.46-7.62 (m, 3H), 7.67-7.
81 (m, 2H), 8.07 (d, J = 8 Hz, 2H). MASS (m / e); 347 (M + ).
【００７９】実施例３３と同様にして実施例３４〜３７
の化合物を得た。Examples 34 to 37 were carried out in the same manner as in Example 33.
Was obtained.
【００８０】実施例３４ ２−（２−キノリルメチルチオ）−１−エチル−６−メ
チル−１Ｈ−ベンゾイミダゾール ｍｐ．126〜130℃1 Ｈ−ＮＭＲ(300MHz,DMSO-d6)δ(ppm);1.25(t,J=7Hz,3
H),2.42(s,3H),4.16(q,J=7Hz,2H),4.91(s,2H),7.00(d,J
=8Hz,1H),7.32(s,1H),7.45(d,J=8Hz,1H),7.59(t,J=8Hz,
1H),7.68(d,J=8Hz,1H),7.77(t,J=8Hz,1H),7.96(d,J=8H
z,1H),7.98(d,J=8Hz,1H),8.33(d,J=8Hz,1H)。 ＭＡＳＳ(m/e);333(M+)。Example 34 2- (2-quinolylmethylthio) -1-ethyl-6-methyl-1H-benzimidazole mp. 126-130 ° C 1 H-NMR (300 MHz, DMSO-d 6 ) δ (ppm); 1.25 (t, J = 7 Hz, 3
H), 2.42 (s, 3H), 4.16 (q, J = 7Hz, 2H), 4.91 (s, 2H), 7.00 (d, J
= 8Hz, 1H), 7.32 (s, 1H), 7.45 (d, J = 8Hz, 1H), 7.59 (t, J = 8Hz,
1H), 7.68 (d, J = 8Hz, 1H), 7.77 (t, J = 8Hz, 1H), 7.96 (d, J = 8H
z, 1H), 7.98 (d, J = 8 Hz, 1H), 8.33 (d, J = 8 Hz, 1H). MASS (m / e); 333 (M + ).
【００８１】実施例３５ ２−（２−キノリルメチルチオ）−１−ブチル−６−メ
チル−１Ｈ−ベンゾイミダゾール ｍｐ．91〜93℃1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);0.87(dt,J=2,7Hz,3
H),1.19-1.42(m,2H),1.71(quintet,J=7Hz,2H),2.48(s,3
H),4.03(t,J=7Hz,2H),4.95(s,2H),7.00-7.08(m,2H),7.4
7-7.62(m,3H),7.66-7.82(m,2H),8.07(d,J=8Hz,2H)。 ＭＡＳＳ(m/e);361(M+)。Example 35 2- (2-quinolylmethylthio) -1-butyl-6-methyl-1H-benzimidazole mp. 91-93 ° C. 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 0.87 (dt, J = 2.7 Hz, 3
H), 1.19-1.42 (m, 2H), 1.71 (quintet, J = 7Hz, 2H), 2.48 (s, 3
H), 4.03 (t, J = 7Hz, 2H), 4.95 (s, 2H), 7.00-7.08 (m, 2H), 7.4
7-7.62 (m, 3H), 7.66-7.82 (m, 2H), 8.07 (d, J = 8Hz, 2H). MASS (m / e); 361 (M + ).
【００８２】実施例３６ ２−（２−キノリルメチルチオ）−１−プロピル−６−
（メトキシカルボニル）−１Ｈ−ベンゾイミダゾール ｍｐ．103〜106℃1 Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);0.83(t,J=7Hz,3
H),1.75(sextet,J=7Hz,2H),3.87(s,3H),4.16(t,J=7Hz,2
H),4.98(s,2H),7.54-7.87(m,5H),7.93-8.02(m,2H),8.15
(d,J=2Hz,1H),8.34(d,J=8Hz,1H)。 ＭＡＳＳ(m/e);392(M++1)。Example 36 2- (2-quinolylmethylthio) -1-propyl-6-
(Methoxycarbonyl) -1H-benzimidazole mp. 103-106 ° C 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 0.83 (t, J = 7 Hz, 3
H), 1.75 (sextet, J = 7 Hz, 2H), 3.87 (s, 3H), 4.16 (t, J = 7 Hz, 2
H), 4.98 (s, 2H), 7.54-7.87 (m, 5H), 7.93-8.02 (m, 2H), 8.15
(d, J = 2 Hz, 1H), 8.34 (d, J = 8 Hz, 1H). MASS (m / e); 392 (M ++ l).
【００８３】実施例３７ ２−（２−キノリルメチルチオ）−１−ブチル−６−
（メトキシカルボニル）−１Ｈ−ベンゾイミダゾール ｍｐ．80〜81℃1 Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);0.83(t,J=7Hz,3
H),1.28(sextet,J=7Hz,2H),1.66(quitet,J=7Hz,2H),3.8
8(s,3H),4.24(t,J=7Hz,2H),5.00(s,2H),7.60(t,J=8Hz,1
H),7.65(d,J=8Hz,1H),7.72(d,J=8Hz,1H),7.77(t,J=8Hz,
1H),7.82(d,J=8Hz,1H),7.96(d,J=8Hz,1H),7.98(d,J=8H
z,1H),8.13(s,1H),8.35(d,J=8Hz,1H)。 ＭＡＳＳ(m/e);405(M+)。Example 37 2- (2-quinolylmethylthio) -1-butyl-6
(Methoxycarbonyl) -1H-benzimidazole mp. 80-81 ° C 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 0.83 (t, J = 7 Hz, 3
H), 1.28 (sextet, J = 7Hz, 2H), 1.66 (quitet, J = 7Hz, 2H), 3.8
8 (s, 3H), 4.24 (t, J = 7Hz, 2H), 5.00 (s, 2H), 7.60 (t, J = 8Hz, 1
H), 7.65 (d, J = 8Hz, 1H), 7.72 (d, J = 8Hz, 1H), 7.77 (t, J = 8Hz,
1H), 7.82 (d, J = 8Hz, 1H), 7.96 (d, J = 8Hz, 1H), 7.98 (d, J = 8H
z, 1H), 8.13 (s, 1H), 8.35 (d, J = 8 Hz, 1H). MASS (m / e); 405 (M + ).
【００８４】実施例３８２−（２−キノリルメチルチオ）−５−カルボキシ−１
Ｈ−ベンゾイミダゾール ２−（２−キノリルメチルチオ）−５−（メトキシカル
ボニル）−１Ｈ−ベンゾイミダゾール(3.29g,9.43mmol)
のメタノール(50ml)溶液に水酸化ナトリウム(0.75g,18.
9mmol)の水溶液(50ml)を加え、１００℃で１０時間攪拌
した。溶媒を減圧留去し、１Ｎ塩酸で中和した後、析出
してきた結晶を濾取、乾燥し、表題化合物(2.38g)を得
た。Example 38 2- (2-quinolylmethylthio) -5-carboxy-1
H-benzimidazole 2- (2-quinolylmethylthio) -5- (methoxycarbonyl) -1H-benzimidazole (3.29 g, 9.43 mmol)
Sodium hydroxide (0.75 g, 18.
An aqueous solution (50 ml) was added thereto, followed by stirring at 100 ° C. for 10 hours. After evaporating the solvent under reduced pressure and neutralizing with 1N hydrochloric acid, the precipitated crystals were collected by filtration and dried to give the title compound (2.38 g).
【００８５】1Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);4.9
3(s,2H),7.51-7.72(m,5H),7.93-8.04(m,3H),8.35(d,J=9
Hz,1H)。 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 4.9
3 (s, 2H), 7.51-7.72 (m, 5H), 7.93-8.04 (m, 3H), 8.35 (d, J = 9
Hz, 1H).
【００８６】実施例３８と同様にして実施例３９〜４１
の化合物を得た。In the same manner as in Embodiment 38, Embodiments 39 to 41
Was obtained.
【００８７】実施例３９ ２−［（３−メチル−２−キノキサリル）メチルチオ］
−５−カルボキシ−１Ｈ−ベンゾイミダゾール ｍｐ．252℃ (decomp.)1 Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);2.86(s,3H),5.06
(s,2H),7.53(d,J=8Hz,1H),7.72-7.84(m,3H),7.95-8.07
(m,3H)。Example 39 2-[(3-methyl-2-quinoxalyl) methylthio]
-5-carboxy-1H-benzimidazole mp. 252 ° C (decomp.) 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 2.86 (s, 3H), 5.06
(s, 2H), 7.53 (d, J = 8Hz, 1H), 7.72-7.84 (m, 3H), 7.95-8.07
(m, 3H).
【００８８】実施例４０ ２−（２−キノキサリルメチルチオ）−５−カルボキシ
−１Ｈ−ベンゾイミダゾール ｍｐ．156〜157℃1 Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);4.98(s,2H),7.51
(d,J=9Hz,1H),7.74-7.90(m,3H),7.98-8.12(m,3H),9.16
(s,1H),12.92(bs,1H)。Example 40 2- (2-quinoxalylmethylthio) -5-carboxy-1H-benzimidazole mp. 156-157 ° C 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 4.98 (s, 2H), 7.51
(d, J = 9Hz, 1H), 7.74-7.90 (m, 3H), 7.98-8.12 (m, 3H), 9.16
(s, 1H), 12.92 (bs, 1H).
【００８９】実施例４１ ２−［（８−ニトロ−２−キノリル）メチルチオ］−５
−カルボキシ−１Ｈ−ベンゾイミダゾール ｍｐ．211〜213℃1 Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);4.93(s,2H),7.51
(d,J=9Hz,1H),7.70-7.82(m,2H),7.91(d,J=9Hz,1H),8.04
(s,1H),8.27(d,J=9Hz,2H),8.57(d,J=9Hz,1H),12.87(bs,
1H)。Example 41 2-[(8-nitro-2-quinolyl) methylthio] -5
-Carboxy-1H-benzimidazole mp. 211-213 ° C 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 4.93 (s, 2H), 7.51
(d, J = 9Hz, 1H), 7.70-7.82 (m, 2H), 7.91 (d, J = 9Hz, 1H), 8.04
(s, 1H), 8.27 (d, J = 9Hz, 2H), 8.57 (d, J = 9Hz, 1H), 12.87 (bs,
1H).
【００９０】実施例４２ ５−（シクロプロピルアミノカルボニル）−２−（２−
キノリルメチルチオ）−１Ｈ−ベンゾイミダゾール二塩
酸塩 ２−（２−キノリルメチルチオ）−５−カルボキシ−１
Ｈ−ベンゾイミダゾール(1.00g,2.99mmol)のＮ，Ｎ−ジ
メチルホルムアミド(50ml)溶液にシクロプロピルアミン
(0.23ml,3.32mmol)、１−ヒドロキシベンゾトリアゾー
ル１水和物(0.916g,5.99mmol)及び１−エチル−３−
（３−ジメチルアミノプロピル）カルボジイミド塩酸塩
(0.629g,3.28mmol)を加え、室温で一晩攪拌した。反応
液に水を加え、酢酸エチルで抽出し、有機層を水、飽和
食塩水の順で洗浄した後、無水硫酸マグネシウムで乾燥
し、溶媒を減圧留去した後、シリカゲルカラムクロマト
グラフィー［溶出溶媒；ヘキサン−酢酸エチル（１：
１）］で精製した。残留物を酢酸エチル(1ml)に溶か
し、４Ｎ塩酸酢酸エチル溶液(5ml)を加え、析出してき
た結晶を濾取、乾燥し、表題化合物(0.843g)を得た。Example 42 5- (Cyclopropylaminocarbonyl) -2- (2-
(Quinolylmethylthio) -1H-benzimidazole dihydrochloride 2- (2-quinolylmethylthio) -5-carboxy-1
To a solution of H-benzimidazole (1.00 g, 2.99 mmol) in N, N-dimethylformamide (50 ml) was added cyclopropylamine.
(0.23 ml, 3.32 mmol), 1-hydroxybenzotriazole monohydrate (0.916 g, 5.99 mmol) and 1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide hydrochloride
(0.629 g, 3.28 mmol) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane-ethyl acetate (1:
1)]. The residue was dissolved in ethyl acetate (1 ml), 4N hydrochloric acid in ethyl acetate (5 ml) was added, and the precipitated crystals were collected by filtration and dried to give the title compound (0.843 g).
【００９１】ｍｐ．232〜233℃1 Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);0.54-0.63(m,1
H),0.65-0.77(m,1H),2.40-2.60(m,2H),2.78-2.95(m,1
H),5.12(s,2H),5.60-6.35(m,2H),7.60(d,J=8Hz,1H),7.6
6-7.95(m,4H),8.02-8.13(m,3H),8.55(d,J=3Hz,1H),8.62
(d,J=8Hz,1H)。 ＭＡＳＳ(m/e);374(M+)。Mp. 232 to 233 ° C 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 0.54-0.63 (m, 1
H), 0.65-0.77 (m, 1H), 2.40-2.60 (m, 2H), 2.78-2.95 (m, 1
H), 5.12 (s, 2H), 5.60-6.35 (m, 2H), 7.60 (d, J = 8Hz, 1H), 7.6
6-7.95 (m, 4H), 8.02-8.13 (m, 3H), 8.55 (d, J = 3Hz, 1H), 8.62
(d, J = 8Hz, 1H). MASS (m / e); 374 (M + ).
【００９２】実施例４２と同様にして実施例４３〜４６
の化合物を得た。Embodiments 43 to 46 in the same manner as in Embodiment 42
Was obtained.
【００９３】実施例４３ ２−（２−キノリルメチルチオ）−５−（イソプロピル
アミノカルボニル）−１Ｈ−ベンゾイミダゾール二塩酸
塩 ｍｐ．232〜233℃1 Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);1.19(d,J=6Hz,6
H),4.12(sextet,J=6Hz,1H),5.18(s,2H),7.62(d,J=8Hz,1
H),7.72(t,J=8Hz,1H),7.82-7.94(m,3H),8.03-8.14(m,2
H),8.35(d,J=8Hz,1H),8.64(d,J=8Hz,1H),9.23(bs,2H)。 ＭＡＳＳ(m/e);376(M+)。Example 43 2- (2-quinolylmethylthio) -5- (isopropylaminocarbonyl) -1H-benzimidazole dihydrochloride mp. 232-233 ° C 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 1.19 (d, J = 6 Hz, 6
H), 4.12 (sextet, J = 6Hz, 1H), 5.18 (s, 2H), 7.62 (d, J = 8Hz, 1
H), 7.72 (t, J = 8Hz, 1H), 7.82-7.94 (m, 3H), 8.03-8.14 (m, 2
H), 8.35 (d, J = 8 Hz, 1H), 8.64 (d, J = 8 Hz, 1H), 9.23 (bs, 2H). MASS (m / e); 376 (M + ).
【００９４】実施例４４ ２−（２−キノリルメチルチオ）−５−（２−ピロリジ
ノエチルアミノカルボニル）−１Ｈ−ベンゾイミダゾー
ル三塩酸塩 ｍｐ．191〜194℃1 Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);1.78-2.11(m,4
H),2.91-3.13(m,2H),3.27-3.41(m,2H),3.54-3.75(m,4
H),5.14(s,2H),5.54(bs,2H),7.62(d,J=8Hz,1H),7.73(t,
J=8Hz,1H),7.83-7.97(m,2H),8.05-8.21(m,3H),8.63(d,J
=8Hz,1H),8.92-9.07(m,1H),11.67(bs,1H)。 ＭＡＳＳ(m/e);432(M++1)。Example 44 2- (2-quinolylmethylthio) -5- (2-pyrrolidinoethylaminocarbonyl) -1H-benzimidazole trihydrochloride mp. 191 to 194 ° C 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 1.78-2.11 (m, 4
H), 2.91-3.13 (m, 2H), 3.27-3.41 (m, 2H), 3.54-3.75 (m, 4
H), 5.14 (s, 2H), 5.54 (bs, 2H), 7.62 (d, J = 8Hz, 1H), 7.73 (t,
J = 8Hz, 1H), 7.83-7.97 (m, 2H), 8.05-8.21 (m, 3H), 8.63 (d, J
= 8Hz, 1H), 8.92-9.07 (m, 1H), 11.67 (bs, 1H). MASS (m / e); 432 (M ++ l).
【００９５】実施例４５ ２−（２−キノリルメチルチオ）−５−（１−モルホリ
ノカルボニル）−１Ｈ−ベンゾイミダゾール二塩酸塩 ｍｐ．184〜185℃1 Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);3.35-3.68(m,8
H),5.09(s,2H),7.31(d,J=8Hz,1H),7.38(bs,2H),7.57-7.
63(m,2H),7.70(t,J=8Hz,1H),7.82-7.92(m,2H),8.02-8.1
1(m,2H),8.59(d,J=8Hz,1H)。 ＭＡＳＳ(m/e);404(M+)。Example 45 2- (2-quinolylmethylthio) -5- (1-morpholinocarbonyl) -1H-benzimidazole dihydrochloride mp. 184-185 ° C 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 3.35-3.68 (m, 8
H), 5.09 (s, 2H), 7.31 (d, J = 8Hz, 1H), 7.38 (bs, 2H), 7.57-7.
63 (m, 2H), 7.70 (t, J = 8Hz, 1H), 7.82-7.92 (m, 2H), 8.02-8.1
1 (m, 2H), 8.59 (d, J = 8Hz, 1H). MASS (m / e); 404 (M + ).
【００９６】実施例４６ ２−（２−キノリルメチルチオ）−５−（１−ヘキサメ
チレンイミノカルボニル）−１Ｈ−ベンゾイミダゾール1 Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);1.47-1.98(m,8H),
3.33-3.52(m,2H),3.61-3.70(m,2H),4.56(s,2H),7.20-7.
32(m,1H),7.47-7.70(m,4H),7.75-7.91(m,2H),8.12(d,J=
8Hz,1H),8.27(d,J=8Hz,1H)。 ＭＡＳＳ(m/e);416(M+)。Example 46 2- (2-quinolylmethylthio) -5- (1-hexamethyleneiminocarbonyl) -1H-benzimidazole 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 1.47-1.98 ( m, 8H),
3.33-3.52 (m, 2H), 3.61-3.70 (m, 2H), 4.56 (s, 2H), 7.20-7.
32 (m, 1H), 7.47-7.70 (m, 4H), 7.75-7.91 (m, 2H), 8.12 (d, J =
8Hz, 1H), 8.27 (d, J = 8Hz, 1H). MASS (m / e); 416 (M + ).
【００９７】実施例４７ ５−アミノ−２−（２−キノリルメチルチオ）−１Ｈ−
ベンゾイミダゾール ２−（２−キノリルメチルチオ）−５−ニトロ−１Ｈ−
ベンゾイミダゾール(1.00g,3.0mmol)のメタノール(50m
l)溶液に、鉄粉(0.50g,9.0mg-atom)と酢酸(1.61g,27mmo
l)を加え、６時間還流した。反応溶液を室温まで冷却
し、水にあけ、飽和炭酸水素ナトリウム水溶液で中和し
た。酢酸エチルで抽出し、飽和炭酸水素ナトリウム水溶
液、水、飽和食塩水で洗浄し、乾燥した。溶媒を減圧留
去し、残留物をシリカゲルカラムクロマトグラフィー
［溶出溶媒；酢酸エチル］で精製して表題化合物(0.50
g)を得た。Example 47 5-amino-2- (2-quinolylmethylthio) -1H-
Benzimidazole 2- (2-quinolylmethylthio) -5-nitro-1H-
Benzimidazole (1.00 g, 3.0 mmol) in methanol (50 m
l) In a solution, iron powder (0.50 g, 9.0 mg-atom) and acetic acid (1.61 g, 27 mmo)
l) was added and refluxed for 6 hours. The reaction solution was cooled to room temperature, poured into water, and neutralized with a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: ethyl acetate] to give the title compound (0.50
g) was obtained.
【００９８】1Ｈ−ＮＭＲ(200MHz,DMSO-d6)δ(ppm);4.7
5(s,2H),4.85(bs,2H),6.43-6.60(m,2H),7.16(d,J=8Hz,1
H),7.53-7.77(m,3H),7.90-7.97(m,2H),8.28-8.33(m,1
H),12.09(bs,1H)。 1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm); 4.7
5 (s, 2H), 4.85 (bs, 2H), 6.43-6.60 (m, 2H), 7.16 (d, J = 8Hz, 1
H), 7.53-7.77 (m, 3H), 7.90-7.97 (m, 2H), 8.28-8.33 (m, 1
H), 12.09 (bs, 1H).
【００９９】実施例４８ ２−（２−キノリルメチルチオ）−５−ウレイド−１Ｈ
−ベンゾイミダゾール ５−アミノ−２−（２−キノリルメチルチオ）−１Ｈ−
ベンゾイミダゾール(0.50g,1.6mmol)の酢酸(50ml)溶液
にシアン酸カリウム(1.32g,16mmol)の水(10ml)溶液を加
え、室温で２０時間撹拌した。反応溶液を水にあけ、酢
酸エチルで抽出し、飽和炭酸水素ナトリウム水溶液、
水、飽和食塩水の順で洗浄し、乾燥した。溶媒を減圧留
去した後、残留物をシリカゲルカラムクロマトグラフィ
ー［溶出溶媒；酢酸エチル−メタノール（９：１）］で
精製して表題化合物(0.26g)を得た。Example 48 2- (2-quinolylmethylthio) -5-ureido-1H
-Benzimidazole 5-amino-2- (2-quinolylmethylthio) -1H-
To a solution of benzimidazole (0.50 g, 1.6 mmol) in acetic acid (50 ml) was added a solution of potassium cyanate (1.32 g, 16 mmol) in water (10 ml), and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into water, extracted with ethyl acetate, a saturated aqueous solution of sodium hydrogen carbonate,
The extract was washed with water and saturated saline in that order and dried. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography [eluent: ethyl acetate-methanol (9: 1)] to obtain the title compound (0.26 g).
【０１００】1Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);4.82
(s,2H),5.76(s,2H),6.92(bs,1H),7.26-8.00(m,7H),8.34
(d,J=9Hz,1H),8.45-8.52(m,1H),12.38(bs,1H)。 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 4.82
(s, 2H), 5.76 (s, 2H), 6.92 (bs, 1H), 7.26-8.00 (m, 7H), 8.34
(d, J = 9 Hz, 1H), 8.45-8.52 (m, 1H), 12.38 (bs, 1H).
【０１０１】実施例４９ ４−オキソ−４−［２−（２−キノリルメチルチオ）−
１Ｈ−ベンゾイミダゾール−５−イルアミノ］ブタン酸 ５−アミノ−２−（２−キノリルメチルチオ）−１Ｈ−
ベンゾイミダゾール(0.50g,1.6mmol)のテトラヒドロフ
ラン(20ml)溶液に無水コハク酸(0.17g,1.7mmol)を加
え、室温で２時間撹拌した。溶媒を減圧留去し、残留物
をシリカゲルカラムクロマトグラフィー［溶出溶媒；酢
酸エチル］で精製して表題化合物(0.54g)を得た。Example 49 4-oxo-4- [2- (2-quinolylmethylthio)-
1H-benzimidazol-5-ylamino] butanoic acid 5-amino-2- (2-quinolylmethylthio) -1H-
Succinic anhydride (0.17 g, 1.7 mmol) was added to a solution of benzimidazole (0.50 g, 1.6 mmol) in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: ethyl acetate] to obtain the title compound (0.54 g).
【０１０２】1Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);2.55
(s,4H),4.84(s,2H),7.12-7.97(m,8H),8.33(d,J=9Hz,1
H),9.95(s,1H),12.13(bs,1H),12.56(s,1H)。 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 2.55
(s, 4H), 4.84 (s, 2H), 7.12-7.97 (m, 8H), 8.33 (d, J = 9Hz, 1
H), 9.95 (s, 1H), 12.13 (bs, 1H), 12.56 (s, 1H).
【０１０３】実施例５０ ５−ヒドロキシメチル−２−（２−キノリルメチルチ
オ）−１Ｈ−ベンゾイミダゾール ２−（２−キノリルメチルチオ）−５−メトキシカルボ
ニル−１Ｈ−ベンゾイミダゾール(2.01g,5.76mmol)を塩
化メチレン(80ml)に懸濁し、系内を窒素置換した後、−
７８℃まで冷却した。１．５Ｍ水素化ジイソブチルアル
ミニウムトルエン溶液(13ml,19.5mmol)をゆっくり加え
た後３０分間攪拌した。そのまま室温に戻し、２時間攪
拌した。反応液に水酸化ナトリウム水溶液を加え、塩化
メチレンで抽出し、有機層を水、飽和食塩水の順で洗浄
した後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留
去した後、シリカゲルカラムクロマトグラフィー［溶出
溶媒；ヘキサン−酢酸エチル（２：１）］で精製し、表
題化合物(1.10g)を得た。Example 50 5-Hydroxymethyl-2- (2-quinolylmethylthio) -1H-benzimidazole 2- (2-quinolylmethylthio) -5-methoxycarbonyl-1H-benzimidazole (2.01 g, 5.76 mmol) ) Was suspended in methylene chloride (80 ml), and the system was replaced with nitrogen.
Cooled to 78 ° C. A 1.5 M solution of diisobutylaluminum hydride in toluene (13 ml, 19.5 mmol) was slowly added, followed by stirring for 30 minutes. It returned to room temperature as it was and stirred for 2 hours. An aqueous solution of sodium hydroxide was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification with [elution solvent: hexane-ethyl acetate (2: 1)] gave the title compound (1.10 g).
【０１０４】1Ｈ−ＮＭＲ(200MHz,CDCl3)δ(ppm);4.54
(s,2H),4.81(s,2H),7.23(d,J=8Hz,1H),7.52(d,J=8Hz,1
H),7.54-7.67(m,3H),7.81(d,J=8Hz,1H),7.88(d,J=8Hz,1
H),8.14(d,J=8Hz,1H),8.27(d,J=8Hz,1H)。 ＭＡＳＳ(m/e);321(M+)。 1 H-NMR (200 MHz, CDCl 3 ) δ (ppm); 4.54
(s, 2H), 4.81 (s, 2H), 7.23 (d, J = 8Hz, 1H), 7.52 (d, J = 8Hz, 1
H), 7.54-7.67 (m, 3H), 7.81 (d, J = 8Hz, 1H), 7.88 (d, J = 8Hz, 1
H), 8.14 (d, J = 8 Hz, 1H), 8.27 (d, J = 8 Hz, 1H). MASS (m / e); 321 (M + ).
【０１０５】試験例ＰＤＥＩ阻害作用 ＰＤＥＩは牛大脳より調製し、Masuokaらの２段階法（B
iochem.Biophys.Res.Commun.,169,315-322）に準じて測
定した。Test Example PDEI Inhibitory Activity PDEI was prepared from bovine cerebrum and was subjected to a two-step method (B
iochem. Biophys. Res. Commun., 169, 315-322).
【０１０６】50mMＴｒｉｓ−ＨＣｌ(pH8.0)、5mM塩化マ
グネシウム、0.1mg/ml牛血清アルブミン、0.2mM塩化カ
ルシウム、100U/mlカルモジュリンの反応混合液にＰＤ
ＥＩ溶液とＤＭＳＯに溶解した被験化合物を試験管に加
え200μlとした。試験管に基質として5μM［８−3Ｈ］
ｃＡＭＰ(50μl,23.125Kbq/ml)を加え（終濃度1μM、4.
625KBq/ml）最終容量250μlとして、３０℃で１５分間
水浴中にて反応させた。なお、このときの反応混合液の
各物質の濃度は250μlでの最終濃度で、ＤＭＳＯの最終
濃度は１％になるようにした。反応は試験管を沸騰水浴
中に移し５分間加熱することにより停止させ、その後、
氷水中に移し冷却した。PD was added to a reaction mixture of 50 mM Tris-HCl (pH 8.0), 5 mM magnesium chloride, 0.1 mg / ml bovine serum albumin, 0.2 mM calcium chloride, 100 U / ml calmodulin.
An EI solution and a test compound dissolved in DMSO were added to a test tube to make 200 μl. 5μM as a substrate in a test tube [8- 3 H]
cAMP (50 μl, 23.125 Kbq / ml) was added (final concentration 1 μM, 4.
(625 KBq / ml) and reacted in a water bath at 30 ° C. for 15 minutes at a final volume of 250 μl. The concentration of each substance in the reaction mixture at this time was a final concentration at 250 μl, and the final concentration of DMSO was 1%. The reaction was stopped by transferring the test tube into a boiling water bath and heating for 5 minutes, after which time
It was transferred to ice water and cooled.
【０１０７】次に、1mg/ml蛇毒(50μl)を加え、３０℃
で１０分間反応させた後、水(2ml)を加え、陽イオン交
換樹脂カラム［Ｂｉｏ−Ｒａｄ社製、ＡＧ５０Ｗ−Ｘ４
（樹脂容量;0.2ml）］に反応液を通した。水で未反応物
を十分洗浄した後、樹脂に吸着した放射性アデノシンを
１Ｎ-アンモニア水(1ml)で溶出させ放射活性測定用のバ
イアルに受け、液体シンチレーション(7ml)を加え、撹
拌した。［3Ｈ］アデノシンのＤＰＭ値を液体シンチレ
ーションカウンターで測定し、その数値を酵素活性とし
た。Next, 1 mg / ml snake venom (50 μl) was added and the mixture was added at 30 ° C.
, And water (2 ml) was added, and a cation exchange resin column [Bio-Rad AG50W-X4] was added.
(Resin volume: 0.2 ml)]. After sufficiently washing unreacted substances with water, the radioactive adenosine adsorbed on the resin was eluted with 1N-aqueous ammonia (1 ml), placed in a vial for measuring radioactivity, liquid scintillation (7 ml) was added, and the mixture was stirred. The DPM value of [ 3 H] adenosine was measured with a liquid scintillation counter, and the value was used as the enzyme activity.
【０１０８】被験化合物のＰＤＥＩに対する阻害活性
は、溶媒処置群と比較することにより評価した。結果を
表２に示す。The PDEI inhibitory activity of the test compound was evaluated by comparing with the vehicle-treated group. Table 2 shows the results.
【０１０９】[0109]
【表３】 [Table 3]
【０１１０】[0110]
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ Ｃ０７Ｄ 403/12 ２３５ Ｃ０７Ｄ 403/12 ２３５ (72)発明者 冨沢 一雪 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 小堀 武夫 神奈川県厚木市毛利台３−27−14 (72)発明者 松谷 早苗 神奈川県相模原市南台１−９−１−305号──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 6 Identification code FI C07D 403/12 235 C07D 403/12 235 (72) Inventor Kazuki Tomizawa 3-24-1, Takada, Toshima-ku, Tokyo Taisho Seiyaku (72) Inventor Takeo Kobori 3-27-14 Moridai, Atsugi City, Kanagawa Prefecture (72) Inventor Sanae Matsutani 1-9-1-305, Minamidai, Sagamihara City, Kanagawa Prefecture
Claims (2)
アルキル基、アルコキシ基、ハロゲン原子、ヒドロキシ
基、ヒドロキシアルキル基、ペルフルオロアルキル基、
ニトロ基、アミノ基、カルボキシル基、アルコキシカル
ボニル基、ウレイド基、式 ＮＨＣＯ(ＣＨ2)mＣＯ2Ｈ
（式中、ｍは２〜４の整数を示す。）で表される基また
は式 ＣＯＮＲ6Ｒ7｛式中、Ｒ6及びＲ7は同一または異
なって水素原子、アルキル基、シクロアルキル基若しく
は式 (ＣＨ2)nＮＲ8Ｒ9（式中、ｎは１〜４の整数を示
し、Ｒ8及びＲ9は同一または異なって水素原子、アルキ
ル基、またはＲ8とＲ9が一緒になってアルキレン基を形
成する。）で表される基を示すか、またはＲ6及びＲ7は
隣接する窒素原子と一緒になって５員若しくは６員環の
複素環（隣接する窒素原子以外の他にさらに酸素原子ま
たは窒素原子を含んでもよい。）を形成する。｝で表さ
れる基を示し、Ｒ3は水素原子、アルキル基、アルコキ
シ基、ハロゲン原子、ペルフルオロアルキル基を示す
か、またはＲ2とＲ3は互いに隣接する炭素原子と結合
し、かつそれらの炭素原子と共にベンゼン環を形成す
る。Ｒ4は水素原子、アルキル基、アルコキシ基または
ニトロ基を示し、Ｒ5は水素原子またはアルキル基を示
し、ＸはＣＨまたは窒素原子を示す。］で表されるベン
ゾイミダゾール誘導体またはその塩。(1) Formula (1) [In the formula, R 1 represents a hydrogen atom or an alkyl group. R 2 is an alkyl group, an alkoxy group, a halogen atom, a hydroxy group, a hydroxyalkyl group, a perfluoroalkyl group,
Nitro group, amino group, carboxyl group, alkoxycarbonyl group, ureido group, formula NHCO (CH 2 ) m CO 2 H
(Wherein m represents an integer of 2 to 4) or a group represented by the formula: CONR 6 R 7 wherein R 6 and R 7 are the same or different and are a hydrogen atom, an alkyl group, a cycloalkyl group or Formula (CH 2 ) n NR 8 R 9 (In the formula, n represents an integer of 1 to 4, and R 8 and R 9 are the same or different and are a hydrogen atom, an alkyl group, or a combination of R 8 and R 9. R 6 and R 7 are taken together with an adjacent nitrogen atom to form a 5- or 6-membered heterocyclic ring (other than an adjacent nitrogen atom) May further contain an oxygen atom or a nitrogen atom.). And R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, a perfluoroalkyl group, or R 2 and R 3 are bonded to adjacent carbon atoms, and Form a benzene ring with carbon atoms. R 4 represents a hydrogen atom, an alkyl group, an alkoxy group or a nitro group, R 5 represents a hydrogen atom or an alkyl group, and X represents CH or a nitrogen atom. ] Or a salt thereof.
またはその塩を有効成分とする、Ｃａ−カルモジュリン
依存性ホスホジエステラーゼ（ＰＤＥＩ）阻害剤。2. A Ca-calmodulin-dependent phosphodiesterase (PDEI) inhibitor comprising the benzimidazole derivative according to claim 1 or a salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10079187A JPH11279175A (en) | 1998-03-26 | 1998-03-26 | Benzoimidazole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10079187A JPH11279175A (en) | 1998-03-26 | 1998-03-26 | Benzoimidazole derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH11279175A true JPH11279175A (en) | 1999-10-12 |
Family
ID=13682983
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10079187A Pending JPH11279175A (en) | 1998-03-26 | 1998-03-26 | Benzoimidazole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH11279175A (en) |
-
1998
- 1998-03-26 JP JP10079187A patent/JPH11279175A/en active Pending
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