JPH08325234A - Benzoic acid derivative or its salt - Google Patents
Benzoic acid derivative or its saltInfo
- Publication number
- JPH08325234A JPH08325234A JP7131264A JP13126495A JPH08325234A JP H08325234 A JPH08325234 A JP H08325234A JP 7131264 A JP7131264 A JP 7131264A JP 13126495 A JP13126495 A JP 13126495A JP H08325234 A JPH08325234 A JP H08325234A
- Authority
- JP
- Japan
- Prior art keywords
- group
- ring
- acid
- compound
- imidazole
- 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.)
- Withdrawn
Links
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 150000003839 salts Chemical class 0.000 title claims description 14
- 239000000126 substance Substances 0.000 claims abstract description 15
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 239000000018 receptor agonist Substances 0.000 claims abstract description 7
- 229940044601 receptor agonist Drugs 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 150000002460 imidazoles Chemical class 0.000 claims 1
- -1 4-amino-5- chloro-2-methoxy-N-(4,5,6,7-tetrahydro-5-benzimidazolyl)-benzamide Chemical compound 0.000 abstract description 81
- 150000001875 compounds Chemical class 0.000 abstract description 63
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 8
- 201000000980 schizophrenia Diseases 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- 108091005482 5-HT4 receptors Proteins 0.000 abstract 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 41
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 28
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 28
- 239000002904 solvent Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- 239000002994 raw material Substances 0.000 description 13
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 235000011114 ammonium hydroxide Nutrition 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 238000000921 elemental analysis Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 235000011181 potassium carbonates Nutrition 0.000 description 8
- 150000008065 acid anhydrides Chemical class 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 6
- 238000012937 correction Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-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
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000001270 agonistic effect Effects 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 210000003169 central nervous system Anatomy 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
- 238000001816 cooling Methods 0.000 description 3
- 210000002249 digestive system Anatomy 0.000 description 3
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- IUWQKKXSWXHIBQ-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-benzimidazol-4-amine Chemical compound NC1CCCC2=C1N=CN2 IUWQKKXSWXHIBQ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- JTEJPPKMYBDEMY-UHFFFAOYSA-N 5-methoxytryptamine Chemical compound COC1=CC=C2NC=C(CCN)C2=C1 JTEJPPKMYBDEMY-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 210000000748 cardiovascular system Anatomy 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000012156 elution solvent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 230000005176 gastrointestinal motility Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000012280 lithium aluminium hydride 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
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 210000001428 peripheral nervous system Anatomy 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 238000006462 rearrangement reaction Methods 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- 201000002327 urinary tract obstruction Diseases 0.000 description 2
- 239000000080 wetting agent Substances 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
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- 125000005927 1,2,2-trimethylpropyloxy group Chemical group 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
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- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000004866 oxadiazoles Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229960003540 oxyquinoline Drugs 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 210000003903 pelvic floor Anatomy 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
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 201000007847 postgastrectomy syndrome Diseases 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 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
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 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
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 125000005922 tert-pentoxy group Chemical group 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、医薬として有用な、特
に５−ＨＴ4 受容体作動薬として有用な安息香酸誘導体
及びその中間体に関する。TECHNICAL FIELD The present invention relates to a benzoic acid derivative useful as a medicine, especially as a 5-HT 4 receptor agonist, and an intermediate thereof.
【０００２】[0002]
【従来の技術】セロトニン（５−ＨＴ）受容体には、複
数のサブタイプが存在し、５−ＨＴ1，５−ＨＴ2 ，５
−ＨＴ3 及び５−ＨＴ4 受容体等に分類されている。５
−ＨＴ4 受容体は、中枢及び末梢神経系、消化器系、心
血管系、泌尿器系など生体に広く分布する。BACKGROUND OF THE INVENTION There are multiple subtypes of serotonin (5-HT) receptors, and 5-HT 1 , 5-HT 2 , 5
-HT 3 and 5-HT 4 receptors are classified. 5
-HT 4 receptors are widely distributed in the living body such as central and peripheral nervous system, digestive system, cardiovascular system and urinary system.
【０００３】５−ＨＴ4 受容体作動薬としては、シサプ
リドが非選択的な作動薬であることが知られている。ま
た、本発明者らは、特開平６−１５７８１８号公報に開
示されているオキサジアゾール誘導体が選択的な作動活
性があることを報告している。As a 5-HT 4 receptor agonist, cisapride is known to be a non-selective agonist. The present inventors have also reported that the oxadiazole derivative disclosed in JP-A-6-157818 has selective agonistic activity.
【０００４】４−アミノ−２−アルコキシ−５−ハロゲ
ノベンゼン誘導体は、ＷＯ９２／１５５９０号、特開平
６−３０６０７５号公報、特表平６−５１０７６４号公
報及び特開平６−１５７８１８号公報に記載されてい
る。The 4-amino-2-alkoxy-5-halogenobenzene derivative is described in WO92 / 15590, JP-A-6-306075, JP-A-6-510764 and JP-A-6-157818. ing.
【０００５】国際公開ＷＯ９２／１５５９０号は、５−
ＨＴ3受容体拮抗作用を有する４−アミノ−２−アルコ
キシ−５−ハロゲノ安息香酸アミドを記載する。また、
特開平６−３０６０７５号公報は、消化管運動機能を改
善する４−アミノ−２−アルコキシ−５−ハロゲノ安息
香酸アミドを記載する。更に、特表平６−５１０７６４
号公報は、５−ＨＴ4受容体拮抗作用を示す４−アミノ
−２−アルコキシ−５−ハロゲノ安息香酸エステルを記
載する。International Publication WO92 / 15590 describes 5-
Described are 4-amino-2-alkoxy-5-halogenobenzoic acid amides that have HT 3 receptor antagonism. Also,
JP-A-6-306075 describes 4-amino-2-alkoxy-5-halogenobenzoic acid amides that improve gastrointestinal motility. Furthermore, the special table flat 6-510764
The publication describes 4-amino-2-alkoxy-5-halogenobenzoate which exhibits 5-HT 4 receptor antagonism.
【０００６】[0006]
【発明が解決しようとする課題】本発明者らは、５−Ｈ
Ｔ4 受容体に対する選択的な作動活性を有する化合物に
ついて、鋭意研究を進めた結果、特定の安息香酸誘導体
に５−ＨＴ4 受容体の選択的な作動活性があることを突
きとめ、本発明を完成させた。本発明化合物は、５−Ｈ
Ｔ4 受容体に対する有効かつ選択的な作動薬として作用
する。本発明化合物は、直接的又は遠心性神経終末より
アセチルコリンを遊離させることにより間接的にその作
用を発現する。従って、５−ＨＴ4 受容体作動薬は、中
枢神経系、消化器系、循環器系などの障害に対して有用
であろうと考えられる。DISCLOSURE OF THE INVENTION The present inventors
As a result of intensive studies on a compound having a selective agonistic activity on the T 4 receptor, it was found that a specific benzoic acid derivative has a selective agonistic activity on the 5-HT 4 receptor. Completed The compound of the present invention is 5-H
It acts as an effective and selective agonist for the T 4 receptor. The compound of the present invention exerts its action directly or indirectly by releasing acetylcholine from the efferent nerve endings. Therefore, it is considered that the 5-HT 4 receptor agonist may be useful for disorders of the central nervous system, digestive system, circulatory system and the like.
【０００７】[0007]
【課題を解決するための手段】すなわち、本発明によれ
ば、下記一般式（Ｉ）で示される新規な安息香酸誘導体
又はその塩が提供される。That is, according to the present invention, a novel benzoic acid derivative represented by the following general formula (I) or a salt thereof is provided.
【０００８】[0008]
【化７】 [Chemical 7]
【０００９】（ただし、式中の記号は以下の意味を示
す。(However, the symbols in the formulas have the following meanings.
【００１０】[0010]
【化８】 Embedded image
【００１１】Ａ環：イミダゾール環と縮合し、かつ、イ
ミダゾール環中の窒素原子を含んでいてもよい４〜８員
のシクロアルキル環 ｎ：０、１又は２ Ｒ2：水素原子又は低級アルキル基Ring A: 4- to 8-membered cycloalkyl ring which is condensed with an imidazole ring and may contain a nitrogen atom in the imidazole ring n: 0, 1 or 2 R 2 : hydrogen atom or lower alkyl group
【００１２】[0012]
【化９】 [Chemical 9]
【００１３】Ｂ環：イミダゾール環と縮合する窒素原子
１〜２個含む４〜８員含窒素飽和へテロ環 Ｒ3：ハロゲン原子 Ｒ4：低級アルコキシ基 Ｒ5、Ｒ6、Ｒ7、Ｒ8：同一又は異なって、水素原子又は
低級アルキル基） また、本発明によれば、上記安息香酸誘導体又はその薬
学的に許容される塩を有効成分とする５−ＨＴ4受容体
作動薬が提供される。Ring B: 4- to 8-membered nitrogen-containing saturated hetero ring containing 1 to 2 nitrogen atoms condensed with an imidazole ring R 3 : halogen atom R 4 : lower alkoxy group R 5 , R 6 , R 7 , R 8 A hydrogen atom or a lower alkyl group, which may be the same or different) Further, according to the present invention, there is provided a 5-HT 4 receptor agonist comprising the above benzoic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It
【００１４】更に、本発明によれば、下記一般式（Ｉ
Ｉ）で示されるイミダゾール誘導体又はその塩が提供さ
れる。Furthermore, according to the present invention, the following general formula (I
There is provided an imidazole derivative represented by I) or a salt thereof.
【００１５】[0015]
【化１０】 [Chemical 10]
【００１６】（ただし、式中の記号は以下の意味を示
す。(However, the symbols in the formulas have the following meanings.
【００１７】Ｉｍ環：イミダゾール環Im ring: imidazole ring
【００１８】[0018]
【化１１】 [Chemical 11]
【００１９】Ａ環：イミダゾール環と縮合し、かつ、イ
ミダゾール環中の窒素原子を含んでいてもよい４〜８員
のシクロアルキル環 Ｒ7：水素原子又は低級アルキル基 ｎ：０、１又は２ Ｒ9：アミノ基又はカルボキシル基Ring A: 4- to 8-membered cycloalkyl ring which is condensed with an imidazole ring and may contain a nitrogen atom in the imidazole ring R 7 : hydrogen atom or lower alkyl group n: 0, 1 or 2 R 9 : amino group or carboxyl group
【００２０】[0020]
【化１２】 [Chemical 12]
【００２１】本発明化合物（Ｉ）は、Ｒ1及びＲ2によ
り、下記一般式（Ｉａ）で示される化合物及び下記一般
式（Ｉｂ）で示される化合物に分けられる。The compound (I) of the present invention is classified into a compound represented by the following general formula (Ia) and a compound represented by the following general formula (Ib) by R 1 and R 2 .
【００２２】[0022]
【化１３】 [Chemical 13]
【００２３】（式中、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、ｎ、
Ｉｍ環、Ａ環及びＢ環は、前記の意味を有する。） 一般式（Ｉａ）で示される化合物は、下記一般式（Ｉ
ｃ）、（Ｉｄ）及び（Ｉｅ）に示される化合物を包含す
る。(Wherein R 2 , R 3 , R 4 , R 5 , R 6 , n,
The Im ring, A ring and B ring have the above-mentioned meanings. ) The compound represented by the general formula (Ia) has the following general formula (I
c), (Id) and (Ie) are included.
【００２４】[0024]
【化１４】 Embedded image
【００２５】（式中、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7、
Ｒ8、ｎ及びＡ環環は、前記の意味を有する。）(Wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 ,
R 8 , n and ring A have the meanings given above. )
【００２６】[0026]
【表１】 [Table 1]
【００２７】一般式（Ｉｂ）で示される化合物は、下記
一般式（Ｉｆ）、（Ｉｇ）及び（Ｉｈ）に示される化合
物を包含する。The compound represented by the general formula (Ib) includes the compounds represented by the following general formulas (If), (Ig) and (Ih).
【００２８】[0028]
【化１５】 [Chemical 15]
【００２９】（式中、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7、Ｒ8及
びＢ環は、前記の意味を有する。）(In the formulae, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and the B ring have the above meanings.)
【００３０】[0030]
【表２】 [Table 2]
【００３１】以下、上記一般式（Ｉ）及び（ＩＩ）につ
いて詳述する。本明細書の一般式の定義において、特に
断わらない限り「低級」なる用語は炭素数が１乃至６個
の直鎖又は分枝上の炭素鎖を意味する。The above general formulas (I) and (II) will be described in detail below. In the definition of general formulas herein, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified.
【００３２】従って低級アルキル基とは、炭素数１〜６
個の直鎖状又は分枝状のアルキル基を意味し、具体的に
は例えば、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、ネ
オペンチル基、ｔｅｒｔ−ペンチル基、１−メチルブチ
ル基、２−メチルブチル基、１，２−ジメチルプロピル
基、ヘキシル基、イソヘキシル基、１−メチルペンチル
基、２−メチルペンチル基、３−メチルペンチル基、
１，１−ジメチルブチル基、１，２−ジメチルブチル
基、２，２−ジメチルブチル基、１，３−ジメチルブチ
ル基、２，３−ジメチルブチル基、３，３−ジメチルブ
チル基、１−エチルブチル基、２−エチルブチル基、
１，１，２−トリメチルプロピル基、１，２，２−トリ
メチルプロピル基、１−エチル−１−メチルプロピル
基、１−エチル−２−メチルプロピル基等が挙げられ、
特に好ましいのはメチル基、エチル基、プロピル基、イ
ソプロピル基等であり、メチル基が更に好ましい。Therefore, a lower alkyl group has 1 to 6 carbon atoms.
Means a straight-chain or branched alkyl group, specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group,
tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2 -Methylpentyl group, 3-methylpentyl group,
1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1- Ethylbutyl group, 2-ethylbutyl group,
1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like,
Particularly preferred are a methyl group, an ethyl group, a propyl group, an isopropyl group and the like, and a methyl group is more preferred.
【００３３】また、低級アルコキシ基とは、炭素数１〜
６個の直鎖状又は分枝状のアルコキシ基を意味し、具体
的には例えば、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、ネオペンチルオキシ
基、ｔｅｒｔ−ペンチルオキシ基、１−メチルブトキシ
基、２−メチルブトキシ基、１，２−ジメチルプロポキ
シ基、ヘキシルオキシ基、イソヘキシルオキシ基、１−
メチルペンチルオキシ基、２−メチルペンチルオキシ
基、３−メチルペンチルオキシ基、１，１−ジメチルブ
トキシ基、１，２−ジメチルブトキシ基、２，２−ジメ
チルブトキシ基、１，３−ジメチルブトキシ基、２，３
−ジメチルブトキシ基、３，３−ジメチルブトキシ基、
１−エチルブトキシ基、２−エチルブトキシ基、１，
１，２−トリメチルプロポキシ基、１，２，２−トリメ
チルプロポキシ基、１−エチル−１−メチルプロポキシ
基、１−エチル−２−メチルプロポキシ基等が挙げられ
る。メトキシ基、エトキシ基、プロポキシ基、イソプロ
ポキシ基等が特に好ましく、メトキシ基が更に好まし
い。ハロゲン原子とは、フッ素原子、塩素原子、臭素原
子又はヨウ素原子を意味し、塩素原子が好ましい。The lower alkoxy group has 1 to 1 carbon atoms.
It means 6 linear or branched alkoxy groups, specifically, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group,
sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, Hexyloxy group, isohexyloxy group, 1-
Methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,3-dimethylbutoxy group , 2, 3
-Dimethylbutoxy group, 3,3-dimethylbutoxy group,
1-ethylbutoxy group, 2-ethylbutoxy group, 1,
Examples thereof include a 1,2-trimethylpropoxy group, a 1,2,2-trimethylpropoxy group, a 1-ethyl-1-methylpropoxy group, a 1-ethyl-2-methylpropoxy group and the like. A methoxy group, an ethoxy group, a propoxy group, an isopropoxy group and the like are particularly preferable, and a methoxy group is further preferable. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and a chlorine atom is preferable.
【００３４】Ａ環とは、イミダゾール環と縮合し、か
つ、イミダゾール環中の窒素原子を含んでいてもよい４
〜８員のシクロアルキル環を意味する。ここで、４〜８
員のシクロアルキル環としては、例えば、シクロブタ
ン、シクロペンタン、シクロヘキサン、シクロヘプタ
ン、シクロオクタン等が挙げられる。イミダゾール環中
の窒素原子を含んでいる４〜８員のシクロアルキル環と
は、窒素原子を１個含む４〜８員不飽和ヘテロ環を意味
し、アゼチジン、ピロリジン、ピペリジン、ヘキサヒド
ロアゼピン、オクタヒドロアゾシン等が挙げられる。The ring A is condensed with the imidazole ring and may contain a nitrogen atom in the imidazole ring 4.
~ 8 membered cycloalkyl ring. Where 4 to 8
Examples of the membered cycloalkyl ring include cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like. The 4- to 8-membered cycloalkyl ring containing a nitrogen atom in the imidazole ring means a 4- to 8-membered unsaturated heterocyclic ring containing one nitrogen atom, and is azetidine, pyrrolidine, piperidine, hexahydroazepine, octahedine. Hydroazocine etc. are mentioned.
【００３５】Ｂ環とは、イミダゾール環と縮合する窒素
原子１〜２個含む４〜８員含窒素飽和へテロ環を意味す
る。ここで、窒素原子１〜２個含む４〜８員含窒素飽和
へテロ環としては、アゼチジン、ピロリジン、イミダゾ
リジン、ピラゾリジン、ピペリジン、ピペラジン、ヘキ
サヒドロアゼピン、オクタヒドロアゾシン等が挙げられ
る。Ａ環及びＢ環は、５又は６員環であることが好まし
い。The ring B means a 4- to 8-membered nitrogen-containing saturated hetero ring containing 1 to 2 nitrogen atoms which is condensed with the imidazole ring. Examples of the 4- to 8-membered nitrogen-containing saturated heterocyclic ring containing 1 to 2 nitrogen atoms include azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, hexahydroazepine, octahydroazocine and the like. Rings A and B are preferably 5- or 6-membered rings.
【００３６】本発明化合物（Ｉ）は、酸付加塩を形成す
る。かかる塩としては、具体的には塩酸、臭化水素酸、
ヨウ化水素酸、硫酸、硝酸、リン酸等の鉱酸、ギ酸、酢
酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フ
マール酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエ
ン酸、メタンスルホン酸、エタンスルホン酸等の有機
酸、アスパラギン酸、グルタミン酸などの酸性アミノ酸
との酸付加塩等が挙げられる。The compound (I) of the present invention forms an acid addition salt. Specific examples of such salts include hydrochloric acid, hydrobromic acid,
Mineral acids such as hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfone Examples thereof include acids, organic acids such as ethanesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamic acid.
【００３７】さらに、本発明には、本発明化合物（Ｉ）
の水和物、各種の溶媒和物や結晶多形の物質も含まれ
る。Further, the present invention provides the compound (I) of the present invention.
Hydrates, various solvates and polymorphic substances are also included.
【００３８】一般式（Ｉ）で示される化合物は、不斉炭
素原子を有する場合があるため、光学異性体が存在する
場合がある。本発明化合物は、これらの光学異性体、そ
れらの混合物、ラセミ体を包含する。Since the compound represented by the general formula (I) may have an asymmetric carbon atom, an optical isomer may exist. The compound of the present invention includes these optical isomers, a mixture thereof, and a racemate.
【００３９】（製造法）本発明化合物は、その基本骨格
又は置換基の種類に基づく特徴を利用し、種々の合成法
を適用して製造することができる。以下にその代表的な
製法を示す。(Production Method) The compound of the present invention can be produced by utilizing various characteristics of the basic skeleton or the type of the substituent, and applying various synthetic methods. The typical manufacturing method is shown below.
【００４０】[0040]
【化１６】 Embedded image
【００４１】（式中、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、ｎ、
Ｉｍ環、Ａ環及びＢ環は、前記の意味を有する。） 本発明化合物（Ｉ）は一般式（Ｉａ）又は（Ｉｂ）で示
され、一般式（Ｉａ）又は（Ｉｂ）で示される化合物
は、一般式（ＩＩＩ）で示されるカルボン酸若しくはそ
の反応性誘導体又はそれらの塩と、一般式（ＩＶａ）又
は（ＩＶｂ）で示される化合物とを反応させることによ
り製造できる。(Wherein R 2 , R 3 , R 4 , R 5 , R 6 , n,
The Im ring, A ring and B ring have the above-mentioned meanings. The compound (I) of the present invention is represented by the general formula (Ia) or (Ib), and the compound represented by the general formula (Ia) or (Ib) is a carboxylic acid represented by the general formula (III) or its reactivity. It can be produced by reacting a derivative or a salt thereof with a compound represented by the general formula (IVa) or (IVb).
【００４２】ここに、カルボン酸の反応性誘導体として
は、低級アルキルエステル、活性エステル、酸無水物、
酸ハライド、酸アジド等が挙げられる。Here, as the reactive derivative of carboxylic acid, lower alkyl ester, active ester, acid anhydride,
Examples thereof include acid halides and acid azides.
【００４３】活性エステルとしては、ｐ―ニトロフェニ
ルエステル、２，４，５―トリクロロフェニルエステ
ル、ペンタクロロフェニルエステル、シアノメチルエス
テル、Ｎ―ヒドロキシコハク酸イミドエステル、Ｎ―ヒ
ドロキシフタルイミドエステル、Ｎ―ヒドロキシ―５―
ノルボルネン―２，３―ジカルボキシイミドエステル、
Ｎ―ヒドロキシピペリジンエステル、８―ヒドロキシキ
ノリンエステル、２―ヒドロキシフェニルエステル、２
―ヒドロキシ―４，５―ジクロロフェニルエステル、２
―ヒドロキシピリジンエステル、２―ピリジルチオール
エステル、１−ベンズトリアゾリルエステル等が挙げら
れる。Examples of the active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester and N-hydroxy-ester. 5-
Norbornene-2,3-dicarboximide ester,
N-hydroxypiperidine ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester, 2
-Hydroxy-4,5-dichlorophenyl ester, 2
-Hydroxypyridine ester, 2-pyridyl thiol ester, 1-benztriazolyl ester and the like can be mentioned.
【００４４】酸無水物としては、対称酸無水物又は混合
酸無水物が用いられ、混合酸無水物の具体例としてはク
ロロ炭酸エチル、クロロ炭酸イソブチルのようなクロロ
炭酸アルキルエステルとの混合酸無水物、クロロ炭酸ベ
ンジルのようなクロロ炭酸アラルキルエステルとの混合
酸無水物、クロロ炭酸フェニルのようなクロロ炭酸アリ
ールエステルとの混合酸無水物、イソ吉草酸、ピバリン
酸のようなアルカン酸との混合酸無水物等が挙げられ
る。As the acid anhydride, a symmetrical acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include a mixed acid anhydride with a chlorocarbonic acid alkyl ester such as ethyl chlorocarbonate and isobutyl chlorocarbonate. , Mixed anhydride with chlorocarbonic acid aralkyl ester such as benzyl chlorocarbonate, mixed anhydride with chlorocarbonic acid aryl ester such as phenyl chlorocarbonate, mixed with alkanoic acid such as isovaleric acid, pivalic acid Examples thereof include acid anhydrides.
【００４５】一般式（ＩＩＩ）の化合物を用いる場合に
は、縮合剤の存在下に反応させることができ、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
塩酸塩、Ｎ，Ｎ′―カルボニルジイミダゾール、１―エ
トキシカルボニル―２―エトキシ―１，２―ジヒドロキ
ノリン等が挙げられる。縮合剤としてジシクロヘキシル
カルボジイミド又は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を用いる場合に
は、Ｎ―ヒドロキシコハク酸イミド、１―ヒドロキシベ
ンゾトリアゾール、３―ヒドロキシ―４―オキソ―３，
４―ジヒドロ―１，２，３―ベンゾトリアジン、Ｎ―ヒ
ドロキシ―５―ノルボルネン―２，３―ジカルボキシイ
ミド等を添加して反応させてもよい。When the compound of the general formula (III) is used, the reaction can be carried out in the presence of a condensing agent, and as the condensing agent, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide can be used. Hydrochloride, N, N'-carbonyldiimidazole, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and the like can be mentioned. When dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as the condensing agent, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3 is used. ，
4-dihydro-1,2,3-benzotriazine, N-hydroxy-5-norbornene-2,3-dicarboximide and the like may be added and reacted.
【００４６】一般式（ＩＩＩ）の化合物又はその反応性
誘導体と一般式（ＩＶａ）又は（ＩＶｂ）の化合物との
反応は、溶媒中又は無溶媒下で行われる。溶媒はベンゼ
ン、トルエン、キシレン等の芳香族炭化水素類、ジエチ
ルエーテル、テトラヒドロフラン、ジオキサン等のエー
テル類、塩化メチレン、クロロホルム等のハロゲン化炭
化水素類、酢酸エチル、アセトニトリル、ジメチルホル
ムアミド、ジメチルスルホキシド、エチレングリコー
ル、水等が挙げられる。これらの溶媒は単独で、又は２
種以上混合して用いられる。溶媒は原料化合物の種類等
に従い適宜選択されるべきである。本反応は必要に応じ
て塩基の存在下に行われ、塩基としては重炭酸ナトリウ
ム、重炭酸カリウム等の重炭酸アルカリ、炭酸ナトリウ
ム、炭酸カリウム等の炭酸アルカリ又はトリエチルアミ
ン、トリブチルアミン、ジイソプロピルエチルアミン、
Ｎ―メチルモルホリン、４−ジメチルアミノピリジン等
の有機塩基が挙げられるが、一般式（ＩＶａ）又は（Ｉ
Ｖｂ）の化合物の過剰量で兼ねることもできる。反応温
度は用いる原料化合物の種類により異なるが、通常は冷
却下乃至加熱還流下である。The reaction of the compound of the general formula (III) or its reactive derivative with the compound of the general formula (IVa) or (IVb) is carried out in a solvent or without a solvent. Solvents include aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, halogenated hydrocarbons such as methylene chloride, chloroform, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, ethylene. Examples thereof include glycol and water. These solvents may be used alone or in 2
Used as a mixture of two or more species. The solvent should be appropriately selected according to the type of raw material compound. This reaction is carried out in the presence of a base as necessary, and as the base, sodium bicarbonate, an alkali bicarbonate such as potassium bicarbonate, sodium carbonate, an alkali carbonate such as potassium carbonate or triethylamine, tributylamine, diisopropylethylamine,
Examples thereof include organic bases such as N-methylmorpholine and 4-dimethylaminopyridine, which are represented by general formula (IVa) or (I
It is also possible to serve as an excess amount of the compound of Vb). The reaction temperature varies depending on the kind of the raw material compound used, but is usually under cooling or under heating under reflux.
【００４７】（製造法２）(Manufacturing method 2)
【００４８】[0048]
【化１７】 [Chemical 17]
【００４９】（式中、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、ｎ、
Ｉｍ環、Ａ環及びＢ環は、前記の意味を有する。Ｘは、
ハロゲン原子等の脱離基である。ｌ及びｍは、同一又は
異なって、０〜５の整数である。ただし、ｌ及びｍの和
は１〜５の整数である。）本発明化合物のうち、一般式
（Ｉｉ）で示される化合物は、一般式（Ｖ）で示される
化合物を塩基性条件下、室温乃至加熱下で分子内環化さ
せることにより製造することができる。(Wherein R 2 , R 3 , R 4 , R 5 , R 6 , n,
The Im ring, A ring and B ring have the above-mentioned meanings. X is
It is a leaving group such as a halogen atom. l and m are the same or different and each is an integer of 0 to 5. However, the sum of l and m is an integer of 1 to 5. ) Of the compounds of the present invention, the compound represented by the general formula (Ii) can be produced by intramolecular cyclization of the compound represented by the general formula (V) under basic conditions at room temperature or under heating. .
【００５０】本発明化合物（Ｉ）の塩は、通常の造塩反
応に付すことにより容易に製造できる。また、本発明化
合物（Ｉ）の単離・精製は、各種クロマトグラフィー、
溶媒留去、再結晶等の通常の化学操作を適宜適用して行
うことが可能である。The salt of the compound (I) of the present invention can be easily produced by subjecting it to an ordinary salt-forming reaction. In addition, the isolation and purification of the compound (I) of the present invention can be carried out by various chromatographies,
It is possible to appropriately apply ordinary chemical operations such as solvent removal and recrystallization.
【００５１】各種の異性体は、異性体間の物理化学的性
質の差を利用して分離することができる。例えば、エキ
ソ−エンド異性の立体異性体は、その異性体間の各種吸
着剤に対する吸着親和性の差を利用して分画クロマトグ
ラフィーに付すことなどにより分離することができる。Various isomers can be separated by utilizing the difference in physicochemical properties between the isomers. For example, exo-endo isomer stereoisomers can be separated by subjecting them to fractionation chromatography utilizing the difference in adsorption affinity between the isomers for various adsorbents.
【００５２】また、光学異性体は、適当な原料化合物を
選択することにより、又はラセミ化合物のラセミ分割法
（例えば、接種法）又は一般的な光学活性な化合物との
縮合によりジアステレオマー化合物に導き分離しうる。
また、光学活性な酸と塩を形成させ、光学分割する方法
等により立体化学的に純粋な異性体に導くことができ
る。The optical isomers are converted into diastereomeric compounds by selecting an appropriate starting compound or by a racemic resolution method of a racemic compound (for example, an inoculation method) or a condensation with a general optically active compound. Can be guided and separated.
In addition, a stereochemically pure isomer can be obtained by a method of forming a salt with an optically active acid and performing optical resolution.
【００５３】（中間体の製法）次に、一般式（ＩＶａ）
で示される化合物の代表的な製造方法について説明す
る。アミン（ＩＶａ）は、本発明化合物（Ｉａ）の原料
である 一般式（ＩＶａ）で示される化合物の内、ｎが０のアミ
ン（ＩＶｃ）は、１）ケトン（Ｖ）の還元的アミノ化、
２）カルボン酸又はその誘導体（ＶＩ）の転位反応、又
は、３）イミダゾリルアルキルハライド（ＶＩＩ）の環
化反応により得られる。(Production Method of Intermediate) Next, the compound represented by the general formula (IVa)
A typical method for producing the compound represented by will be described. The amine (IVa) is a raw material of the compound (Ia) of the present invention. Among the compounds represented by the general formula (IVa), the amine (IVc) in which n is 0 is 1) a reductive amination of a ketone (V),
It is obtained by 2) rearrangement reaction of carboxylic acid or its derivative (VI), or 3) cyclization reaction of imidazolylalkyl halide (VII).
【００５４】[0054]
【化１８】 Embedded image
【００５５】（式中、Ｉｍ環及びＡ環環は、前記の意味
を有する。） １）アミン（ＩＶｃ）は、ケトン（ＶＩ）を還元的アミ
ノ化して得られる。例えば、アンモニア、ヒドロキシル
アミン等の塩基存在下ラネーニッケル等を触媒とした接
触還元、シアノボロヒドリド等を用いた直接的な還元又
は中間体としてオキシム等に変換した後還元剤に付すこ
と等により得られる。(In the formula, the Im ring and the A ring have the above-mentioned meanings.) 1) The amine (IVc) is obtained by reductive amination of the ketone (VI). For example, it can be obtained by catalytic reduction using Raney nickel or the like as a catalyst in the presence of a base such as ammonia or hydroxylamine, direct reduction using cyanoborohydride or the like, or conversion to an oxime or the like as an intermediate and then applying it to a reducing agent. .
【００５６】[0056]
【化１９】 [Chemical 19]
【００５７】（式中、Ｉｍ環及びＡ環環は、前記の意味
を有する。Ｘ1は、ヒドロキシ基、アルコキシ基等を意
味する。） ２）アミン（ＩＶｃ）はカルボン酸又はその誘導体（Ｖ
ＩＩ）の転位反応によっても得られる。例えばＣｕｒｔ
ｉｕｓ転位の場合、カルボン酸（ＶＩＩ）をジフェニル
ホスホリルアジド等に反応させて酸アジドを形成させ、
ｔ−ブタノール中５０〜８０℃程度に加温することで転
位をおこさせて、Ｂｏｃアミノ基とし、次いで、酸で脱
保護させて得られる。(In the formula, the Im ring and the A ring have the above-mentioned meanings. X 1 means a hydroxy group, an alkoxy group, etc.) 2) The amine (IVc) is a carboxylic acid or its derivative (V
It can also be obtained by the rearrangement reaction of II). Curt, for example
In the case of ius rearrangement, carboxylic acid (VII) is reacted with diphenylphosphoryl azide or the like to form an acid azide,
It is obtained by causing rearrangement by heating in t-butanol at about 50 to 80 ° C. to form a Boc amino group, and then deprotecting with an acid.
【００５８】[0058]
【化２０】 Embedded image
【００５９】（式中、Ｘ、Ｉｍ環及びＡ環環は、前記の
意味を有し、Ｙはアミノ基の保護基、ｐは１〜５の整数
を意味する。） ３）アミン（ＩＶｃ）の内、一般式（ＩＶｄ）で示され
る化合物は、保護されたアミノ基を有するイミダゾリル
アルキルハライド（ＶＩＩＩ）（又は他の脱離基）を塩
基性条件下に付し分子内環化させた後、脱保護すること
で得られる。アミノ基の保護基としては、例えば、ｔ−
ブトキシカルボニル基、ベンジルオキシカルボニル基、
９−フルオレニルメチルオキシカルボニル基、アセチル
基、ホルミル基等が挙げられる。(In the formula, X, Im ring and A ring have the above-mentioned meanings, Y is a protecting group for amino group, and p is an integer of 1 to 5.) 3) Amine (IVc) Among them, the compound represented by the general formula (IVd) is prepared by subjecting an imidazolylalkyl halide (VIII) (or another leaving group) having a protected amino group to basic conditions to undergo intramolecular cyclization. , Obtained by deprotection. Examples of the amino-protecting group include t-
Butoxycarbonyl group, benzyloxycarbonyl group,
Examples thereof include 9-fluorenylmethyloxycarbonyl group, acetyl group, and formyl group.
【００６０】[0060]
【化２１】 [Chemical 21]
【００６１】（式中、Ｉｍ環及びＡ環環は、前記の意味
を有する。Ｘ2は、ヒドロキシ基、アルコキシ基、アル
キルカルボニルオキシ基等を意味する。） また、一般式（ＩＶａ）で示される化合物の内、ｎ＝１
のもの（ＩＶｅ）は、カルボン酸又はエステル等のその
誘導体（ＩＸ）とアンモニアとを縮合させてアミドにし
て、このアミドをボラン、水素化リチウムアルミニウム
等の還元剤で還元することにより得られる。(In the formula, the Im ring and the A ring have the above-mentioned meanings. X 2 means a hydroxy group, an alkoxy group, an alkylcarbonyloxy group or the like.) Further, it is represented by the general formula (IVa). N = 1 of the compounds
The compound (IVe) is obtained by condensing a carboxylic acid or its derivative (IX) such as an ester with ammonia to form an amide, and reducing the amide with a reducing agent such as borane or lithium aluminum hydride.
【００６２】[0062]
【発明の効果】本発明化合物若しくはその塩、溶媒和物
又は水和物は、中枢及び末梢神経系、消化器系、心血管
系、泌尿器系などに存在する５−ＨＴ4 受容体に特異的
に作用することにより、精神分裂病、鬱病、不安、記憶
障害、痴呆などの中枢神経系障害、また逆流性食道炎、
嚢胞性繊維症に伴う胃食道逆流等の胃食道逆流疾患、バ
レット症候群、非潰瘍性消化不良、腹部不定愁訴、胃内
容うっ滞、鼓脹、食欲不振・悪心・嘔吐、偽性腸閉塞、
弛緩性便秘、慢性便秘、過敏性腸症候群、麻酔手術後の
消化管機能不全、胃切除後症候群、若しくは、急・慢性
胃炎、胃・十二指腸潰瘍、胃神経症、胃下垂、糖尿病な
どの疾患に伴う消化管運動障害の治療及び予防において
有用である。また、シスプラチンのような抗癌剤投与時
及び放射線治療時の悪心、嘔吐及び消化管運動不全の治
療、及び予防に有用である。さらに、本発明化合物は、
心不全、心筋虚血など心機能不全に伴う疾患や、尿路閉
塞、尿管結石若しくは前立腺肥大などに伴う排尿困難な
ど泌尿器系の疾患、さらには脊髄損傷、骨盤底不全症等
による排便及び排尿困難の治療に用いることができる。
又、本発明化合物は抗侵害作用を有することにより、疼
痛の閾値を増加させる鎮痛用の抗侵害剤としても有用で
ある。INDUSTRIAL APPLICABILITY The compound of the present invention or a salt, solvate or hydrate thereof is specific to 5-HT 4 receptor existing in central and peripheral nervous system, digestive system, cardiovascular system, urinary system and the like. , Schizophrenia, depression, anxiety, memory disorders, central nervous system disorders such as dementia, and reflux esophagitis,
Gastroesophageal reflux disease such as gastroesophageal reflux associated with cystic fibrosis, Barrett's syndrome, non-ulcer dyspepsia, abdominal indefinite complaint, gastric stasis, bloating, anorexia / nausea / vomiting, pseudoileus,
Flaccid constipation, chronic constipation, irritable bowel syndrome, gastrointestinal dysfunction after anesthesia surgery, post gastrectomy syndrome, or associated with diseases such as acute / chronic gastritis, gastric / duodenal ulcer, gastric neuropathy, gastric ptosis, diabetes It is useful in the treatment and prevention of gastrointestinal motility disorders. Further, it is useful for treating and preventing nausea, vomiting and gastrointestinal motility dysfunction during administration of an anticancer drug such as cisplatin and during radiotherapy. Furthermore, the compound of the present invention is
Diseases associated with cardiac dysfunction such as heart failure and myocardial ischemia, urinary system diseases such as urinary obstruction due to urinary tract obstruction, ureteral stones, or enlarged prostate, and defecation and urination due to spinal cord injury, pelvic floor insufficiency, etc. Can be used to treat
In addition, the compound of the present invention has an anti-nociceptive action, and thus is also useful as an anti-nociceptive agent for analgesia that increases the threshold of pain.
【００６３】本発明化合物の薬理活性は、以下の実験方
法により確認されたものである。The pharmacological activity of the compound of the present invention was confirmed by the following experimental method.
【００６４】１）本発明化合物は、Ｃｒａｉｇ，Ｄ．
Ａ．らの方法（Craig,D.A.and Clarke,D.E. :J.Pharmac
ol. Exp.Ther.,252, 1378-1386(1990)）に準じて実験し
た結果、ニューロン性の５−ＨＴ4 受容体を介するモル
モット摘出回腸縦走筋標本において、濃度依存的な電気
刺激収縮増強作用を示した。1) The compounds of the present invention are described in Craig, D .;
A. (Craig, DA and Clarke, DE: J.Pharmac
ol. Exp.Ther., 252, 1378-1386 (1990)), and as a result, concentration-dependent electrical stimulation contraction enhancement was observed in guinea pig isolated ileum longitudinal muscle samples mediated by neuronal 5-HT 4 receptors. Showed action.
【００６５】２）本発明化合物によるモルモット摘出回
腸縦走筋電気刺激収縮増強作用は、Ｃｒａｉｇらの方法
（Craig,D.A.et al :Naunyn-Schmied. Arch. Pharmaco
l., 342, 9-16(1990)）に準じて実験した結果、５−Ｈ
Ｔ4受容体作動薬である５−メトキシトリプタミン１０
μＭによる脱感作用により消失した。2) The action of enhancing the electrical stimulation contraction of longitudinally isolated guinea pig longitudinal ileum by the compound of the present invention is determined by the method of Craig et al. (Craig, DA et al: Naunyn-Schmied. Arch. Pharmaco
l., 342, 9-16 (1990)), the result was 5-H
5-methoxytryptamine 10 which is a T 4 receptor agonist
It disappeared due to the desensitizing effect of μM.
【００６６】以上の結果から、本発明化合物は、強力か
つ選択的な５−ＨＴ4 受容体作動薬であることが示され
た。From the above results, it was shown that the compound of the present invention is a potent and selective 5-HT 4 receptor agonist.
【００６７】本発明化合物（Ｉ）又はその塩を主成分と
して含有する薬剤組成物は、当分野において通常用いら
れている薬剤用担体、賦形剤等を用いて通常使用されて
いる方法によって調製することができる。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、又は、静注、筋注等の注射剤、坐剤等による非経口
投与のいずれの形態であってもよい。１日の投与量は、
体重当たり約０．００１から１０ｍｇ／ｋｇが適当であ
るが、１日に１回から４回、約０．０１から１ｍｇ／ｋ
ｇの投与を行うことが好ましい。投与量は症状、投与対
象の年令、性別等を考慮して個々の場合に応じて適宜決
定される。A pharmaceutical composition containing the compound (I) of the present invention or a salt thereof as a main component is prepared by a commonly used method using a pharmaceutical carrier, an excipient and the like which are commonly used in this field. can do. Administration is tablets,
It may be in any form of oral administration such as pills, capsules, granules, powders and liquids, or parenteral administration such as injections such as intravenous injection and intramuscular injection, and suppositories. The daily dose is
About 0.001 to 10 mg / kg of body weight is suitable, but about 1 to 4 times a day, about 0.01 to 1 mg / k
It is preferred to administer g. The dose is appropriately determined depending on the individual case in consideration of symptoms, age of the subject, sex and the like.
【００６８】本発明による経口投与のための固体組成物
としては、錠剤、散剤、顆粒剤等が用いられる。このよ
うな固体組成物においては、ひとつ又はそれ以上の活性
物質が、少なくともひとつの不活性な希釈剤、例えば乳
糖、マンニトール、ブドウ糖、ヒドロキシプロピルセル
ロース、微結晶セルロース、デンプン、ポリビニルピロ
リドン、メタケイ酸アルミン酸マグネシウムと混合され
る。組成物は、常法に従って、不活性な希釈剤以外の添
加剤、例えばステアリン酸マグネシウムのような潤滑剤
や繊維素グリコール酸カルシウムのような崩壊剤、ラク
トースのような安定化剤、グルタミン酸又はアスパラギ
ン酸のような溶解補助剤を含有していてもよい。錠剤又
は丸剤は必要によりショ糖、ゼラチン、ヒドロキシプロ
ピルセルロース、ヒドロキシプロピルメチルセルロース
フタレートなどの胃溶性又は腸溶性物質のフィルムで被
膜してもよい。As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances are at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminometasilicate. Mixed with magnesium acid. According to a conventional method, the composition comprises an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or asparagine. It may contain a solubilizing agent such as an acid. If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate.
【００６９】経口投与のための液体組成物は、薬剤的に
許容される乳濁剤、溶液剤、懸濁剤、シロップ剤、エリ
キシル剤等を含み、一般的に用いられる不活性な希釈
剤、例えば精製水、エタノールを含む。この組成物は不
活性な希釈剤以外に湿潤剤、懸濁剤のような補助剤、甘
味剤、風味剤、芳香剤、防腐剤を含有していてもよい。Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert diluents. For example, it contains purified water and ethanol. This composition may contain, in addition to an inert diluent, auxiliary agents such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative.
【００７０】非経口投与のための注射剤としては、無菌
の水性又は非水性の溶液剤、懸濁剤、乳濁剤を含有す
る。水性の溶液剤、懸濁剤としては、例えば注射用蒸留
水及び生理食塩液が含まれる。非水溶性の溶液剤、懸濁
剤としては、例えばプロピレングリコール、ポリエチレ
ングリコール、オリーブ油のような植物油、エタノール
のようなアルコール類、ポリソルベート８０等がある。
このような組成物は、さらに防腐剤、湿潤剤、乳化剤、
分散剤、安定化剤（例えば、ラクトース）、溶解補助剤
（例えば、グルタミン酸、アスパラギン酸）のような補
助剤を含んでもよい。これらは例えばバクテリア保留フ
ィルターを通す濾過、殺菌剤の配合又は照射によって無
菌化される。これらはまた無菌の固体組成物を製造し、
使用前に無菌水又は無菌の注射用溶媒に溶解して使用す
ることもできる。Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of the non-aqueous solution and suspension include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, polysorbate 80 and the like.
Such compositions further include preservatives, wetting agents, emulsifiers,
Adjuvants such as dispersants, stabilizers (eg lactose), solubilizers (eg glutamic acid, aspartic acid) may also be included. These are sterilized by, for example, filtration through a bacteria-retaining filter, addition of a bactericide, or irradiation. These also produce sterile solid compositions,
It can also be used by dissolving it in sterile water or a sterile solvent for injection before use.
【００７１】[0071]
【実施例】以下、本発明を実施例により詳細に説明す
る。ただし、本発明は下記実施例により制限されるもの
ではない。EXAMPLES The present invention will be described in detail below with reference to examples. However, the present invention is not limited to the following examples.
【００７２】（参考例１）５，６，７，８−テトラヒド
ロイミダゾ［１，２−ａ］ピリジン−６−カルボン酸・
塩酸塩０．６１ｇ、ジフェニルホスホリルアジド０．９
１ｇ、トリエチルアミン０．６６ｇのｔ−ブタノール溶
液を室温で１時間撹拌後、終夜加熱還流した。反応液を
減圧下濃縮後、残渣に酢酸エチルを加え、これを飽和炭
酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無
水硫酸マグネシウムで乾燥後再び濃縮した。残渣をシリ
カゲルカラムクロマトグラフィー（２５ｇ）に付し、ク
ロロホルム−メタノール（１００：５）で溶出して、６
−（ｔｅｒｔ−ブトキシカルボニルアミノ）−５，６，
７，８−テトラヒドロイミダゾ［１，２−ａ］ピリジン
０．５６ｇ（８０％）を得た。Reference Example 1 5,6,7,8-Tetrahydroimidazo [1,2-a] pyridine-6-carboxylic acid
Hydrochloride 0.61 g, diphenylphosphoryl azide 0.9
A solution of 1 g and triethylamine 0.66 g in t-butanol was stirred at room temperature for 1 hour and then heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated again. The residue was subjected to silica gel column chromatography (25 g) and eluted with chloroform-methanol (100: 5) to give 6
-(Tert-Butoxycarbonylamino) -5,6
There was obtained 0.56 g (80%) of 7,8-tetrahydroimidazo [1,2-a] pyridine.
【００７３】核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭ
Ｓ内部標準） δ：１．４５（９Ｈ，ｓ），１．７５〜２．４５（２
Ｈ，ｍ），２．９７（２Ｈ，ｔ，Ｊ＝７Ｈｚ），３．６
０〜４．４０（３Ｈ，ｍ），６．７７（１Ｈ，ｄ，Ｊ＝
１Ｈｚ），７．００（１Ｈ，ｄ，Ｊ＝１Ｈｚ）。Nuclear magnetic resonance spectrum (CDCl 3 , TM
S internal standard) δ: 1.45 (9H, s), 1.75 to 2.45 (2
H, m), 2.97 (2H, t, J = 7 Hz), 3.6
0 to 4.40 (3H, m), 6.77 (1H, d, J =
1 Hz), 7.00 (1H, d, J = 1 Hz).
【００７４】（参考例２）ベンズイミダゾール−４−カ
ルボン酸メチル・硫酸塩５．６５ｇを酢酸（１００ｍ
ｌ）溶液中、１０％パラジウム−炭素１．９ｇを触媒と
して８０℃、６０気圧水素雰囲気下で終夜接触還元し
た。反応液を濾過後減圧下濃縮し、残渣に酢酸エチルを
加えた後、これを希塩酸で抽出した。水層を炭酸カリウ
ムでアルカリ性とした後酢酸エチルで抽出した。酢酸エ
チル層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥
後、減圧下濃縮し残渣をシリカゲルカラムクロマトグラ
フィー（４０ｇ）に付した。クロロホルム−メタノール
（１００：１５）で溶出して、４，５，６，７−テトラ
ヒドロベンズイミダゾール−４−カルボン酸メチル３．
２０ｇ（８６％）を得た。(Reference Example 2) 5.65 g of methyl benzimidazole-4-carboxylate / sulfate was added to acetic acid (100 m).
l) In the solution, catalytic reduction was carried out overnight at 80 ° C. under a hydrogen atmosphere of 60 atm using 1.9 g of 10% palladium-carbon as a catalyst. The reaction solution was filtered and concentrated under reduced pressure, ethyl acetate was added to the residue, and this was extracted with diluted hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (40 g). Methyl 4,5,6,7-tetrahydrobenzimidazole-4-carboxylate, 3. eluting with chloroform-methanol (100: 15).
20 g (86%) was obtained.
【００７５】核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭ
Ｓ内部標準） δ：１．６０〜２．２５（４Ｈ，ｍ），２．５０〜２．
７５（２Ｈ，ｍ），３．６０〜３．８５（１Ｈ，ｍ），
３．７１（３Ｈ，ｓ），７．４９（１Ｈ，ｓ）。Nuclear magnetic resonance spectrum (CDCl 3 , TM
S internal standard) δ: 1.60 to 2.25 (4H, m), 2.50 to 2.
75 (2H, m), 3.60 to 3.85 (1H, m),
3.71 (3H, s), 7.49 (1H, s).
【００７６】（参考例３）４，５，６，７−テトラヒド
ロベンズイミダゾール−４−カルボン酸メチル０．５０
ｇの飽和アンモニア−メタノール（３０ｍｌ）溶液を封
管容器中４０℃で２０時間撹拌した。反応液を減圧下濃
縮後、ジクロロメタンより結晶化し、４，５，６，７−
テトラヒドロベンズイミダゾール−４−ベンズアミド
０．３８ｇ（８３％）を得た。Reference Example 3 Methyl 4,5,6,7-tetrahydrobenzimidazole-4-carboxylate 0.50
g of a saturated ammonia-methanol (30 ml) solution was stirred at 40 ° C. for 20 hours in a sealed tube container. The reaction solution was concentrated under reduced pressure and crystallized from dichloromethane to give 4,5,6,7-
0.38 g (83%) of tetrahydrobenzimidazole-4-benzamide was obtained.
【００７７】核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、
ＴＭＳ内部標準） δ：１．４５〜２．１０（４Ｈ，ｍ），２．３０〜２．
６５（２Ｈ，ｍ），３．２５〜３．５０（１Ｈ，ｍ），
６．９３（１Ｈ，ｂｒｓ），７．３５（１Ｈ，ｂｒ
ｓ），７．４６（１Ｈ，ｓ）。Nuclear magnetic resonance spectrum (DMSO-d 6 ,
TMS internal standard) δ: 1.45 to 2.10 (4H, m), 2.30 to 2.
65 (2H, m), 3.25 to 3.50 (1H, m),
6.93 (1H, brs), 7.35 (1H, br)
s), 7.46 (1H, s).
【００７８】（参考例４）４，５，６，７−テトラヒド
ロベンズイミダゾール−４−カルボン酸メチル２．０５
ｇ、トリエチルアミン１．７３ｇ、クロロトリフェニル
メタン４．１３ｇのジメチルホルムアミド（３０ｍｌ）
溶液を室温で終夜撹拌した。反応液を減圧下濃縮後残渣
に酢酸エチルを加え、これを水で洗浄した。酢酸エチル
層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、
減圧下濃縮し、ヘキサン−酢酸エチル（５：１）よりト
リチル体３．９０ｇを得た。これを１０％水酸化ナトリ
ウムのメタノール−水（１：１）５０ｍｌ混合溶液中で
加水分解した。反応液を濃塩酸でｐＨ５とし、析出した
１−トリフェニルメチル−４，５，６，７−テトラヒド
ロカルボン酸０．９２ｇを得た。(Reference Example 4) Methyl 4,5,6,7-tetrahydrobenzimidazole-4-carboxylate 2.05
g, 1.73 g of triethylamine, 4.13 g of chlorotriphenylmethane, dimethylformamide (30 ml)
The solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and this was washed with water. The ethyl acetate layer was washed with saturated brine and dried over magnesium sulfate,
The mixture was concentrated under reduced pressure, and 3.90 g of a trityl compound was obtained from hexane-ethyl acetate (5: 1). This was hydrolyzed in a mixed solution of 10% sodium hydroxide in 50 ml of methanol-water (1: 1). The reaction solution was adjusted to pH 5 with concentrated hydrochloric acid to obtain 0.92 g of precipitated 1-triphenylmethyl-4,5,6,7-tetrahydrocarboxylic acid.
【００７９】核磁気共鳴スペクトル（ＣＤ3ＯＤ−ＣＤ
Ｃｌ3（１：１）、ＴＭＳ内部標準） δ：１．１５〜２．１０（６Ｈ，ｍ），３．６１（１
Ｈ，ｂｒｔ，Ｊ＝７Ｈｚ），７．０５〜７．６５（１６
Ｈ，ｍ）。Nuclear magnetic resonance spectrum (CD 3 OD-CD
Cl 3 (1: 1), TMS internal standard δ: 1.15 to 2.10 (6H, m), 3.61 (1
H, brt, J = 7 Hz), 7.05 to 7.65 (16
H, m).
【００８０】（参考例５）イミダゾ［１，２−ａ］ピリ
ジン−８−カルボン酸メチル・硫酸塩１．３８ｇを酢酸
２５ｍｌに溶解し、パラジウム−炭素を加え、７０ｋｇ
／ｃｍ2の水素雰囲気下、８０℃で６３．５時間撹拌し
た。不溶物をセライトを用いて濾去しメタノールで洗浄
した。濾液と洗液を合わせ溶媒を留去して得た残渣をシ
リカゲルカラムクロマトグラフィー（溶出溶媒：クロロ
ホルム／メタノール／２９％アンモニア水）で精製し
て、０．４０ｇの５，６，７，８−テトラヒドロイミダ
ゾ［１，２−ａ］ピリジン−８−カルボン酸メチルを得
た。Reference Example 5 1.38 g of imidazo [1,2-a] pyridine-8-carboxylic acid methyl sulfate was dissolved in 25 ml of acetic acid, and palladium-carbon was added to 70 kg.
The mixture was stirred at 80 ° C. for 63.5 hours in a hydrogen atmosphere of / cm 2 . The insoluble matter was filtered off using Celite and washed with methanol. The residue obtained by combining the filtrate and the washing solution and distilling off the solvent was purified by silica gel column chromatography (eluting solvent: chloroform / methanol / 29% aqueous ammonia) to give 0.40 g of 5,6,7,8-. Methyl tetrahydroimidazo [1,2-a] pyridine-8-carboxylate was obtained.
【００８１】核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭ
Ｓ内部標準） δ：１．８５〜２．３２（４Ｈ，ｍ），３．４１〜４．
１０（６Ｈ，ｍ），６．８２（１Ｈ，ｄ，Ｊ＝１Ｈ
ｚ），７．０１（１Ｈ，ｄ，Ｊ＝１Ｈｚ）。Nuclear magnetic resonance spectrum (CDCl 3 , TM
S internal standard) δ: 1.85 to 2.32 (4H, m), 3.41 to 4.
10 (6H, m), 6.82 (1H, d, J = 1H
z), 7.01 (1H, d, J = 1 Hz).
【００８２】（参考例６）５，６，７，８−テトラヒド
ロイミダゾ［１，２−ａ］ピリジン−８−カルボン酸メ
チル０．４０ｇに２９％アンモニア水１５ｍｌを加え、
３０分間加熱還流した。さらに２９％アンモニア水１５
ｍｌを加えて、３０分間加熱還流した。溶媒を減圧留去
して得た残渣をシリカゲルカラムクロマトグラフィー
（溶出溶媒：クロロホルム／メタノール／２９％アンモ
ニア水）で精製して０．０８ｇの５，６，７，８−テト
ラヒドロイミダゾ［１，２−ａ］ピリジン−８−カルボ
キサミドを得た。Reference Example 6 To 0.40 g of methyl 5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-8-carboxylate was added 15 ml of 29% aqueous ammonia.
The mixture was heated under reflux for 30 minutes. Further 29% ammonia water 15
ml was added and the mixture was heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluting solvent: chloroform / methanol / 29% aqueous ammonia) to obtain 0.08 g of 5,6,7,8-tetrahydroimidazo [1,2]. -A] Pyridine-8-carboxamide was obtained.
【００８３】核磁気共鳴スペクトル（ＣＤ3ＯＤ、ＴＭ
Ｓ内部標準） δ：１．８８〜２．３２（４Ｈ，ｍ），３．７７（１
Ｈ，ｔ，Ｊ＝５．３Ｈｚ），３．９５〜４．０７（２
Ｈ，ｍ），６．９１（１Ｈ，ｄ，Ｊ＝１Ｈｚ），６．９
８（１Ｈ，ｄ，Ｊ＝１Ｈｚ）。Nuclear magnetic resonance spectrum (CD 3 OD, TM
S internal standard) δ: 1.88 to 2.32 (4H, m), 3.77 (1
H, t, J = 5.3 Hz), 3.95 to 4.07 (2
H, m), 6.91 (1H, d, J = 1 Hz), 6.9
8 (1H, d, J = 1 Hz).
【００８４】（参考例７）水素化リチウムアルミニウム
０．１８ｇのテトラヒドロフラン（１０ｍｌ）懸濁液に
氷冷下４−アミノ−５−クロロ−Ｎ−［２−（４−イミ
ダゾリル）−１−（エトキシカルボニル）エチル］−２
−メトキシベンズアミド０．７０ｇを加え、同温で３０
分間攪袢した。反応液に硫酸ナトリウム１０水和物を氷
冷下２ｇ加え、これを濾過後減圧下濃縮し、残渣をシリ
カゲルカラムクロマトグラフィー（２０ｇ）に付した。
クロロホルム−メタノール（１００：１５）で溶出し、
４−アミノ−５−クロロ−Ｎ−［２−（４−イミダゾリ
ル）−１−（ヒドロキシメチル）エチル］−２−メトキ
シベンズアミド０．４０ｇ（６５％）を得た。Reference Example 7 A suspension of 0.18 g of lithium aluminum hydride in tetrahydrofuran (10 ml) was cooled with ice while 4-amino-5-chloro-N- [2- (4-imidazolyl) -1- (ethoxy) was used. Carbonyl) ethyl] -2
-0.70 g of methoxybenzamide was added, and the mixture was heated to
I stirred for a minute. 2 g of sodium sulfate decahydrate was added to the reaction solution under ice cooling, this was filtered and then concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (20 g).
Elute with chloroform-methanol (100: 15),
0.40 g (65%) of 4-amino-5-chloro-N- [2- (4-imidazolyl) -1- (hydroxymethyl) ethyl] -2-methoxybenzamide was obtained.
【００８５】核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、
ＴＭＳ内部標準） δ：２．８０（２Ｈ，ｄ，Ｊ＝６Ｈｚ），３．１０〜
３．６０（２Ｈ，ｍ），３．８１（３Ｈ，ｓ），３．９
５〜４．３５（１Ｈ，ｍ），５．９２（２Ｈ，ｂｒ
ｓ），６．４８（１Ｈ，ｓ），６．８４（１Ｈ，ｄ，Ｊ
＝１Ｈｚ），７．５９（１Ｈ，ｄ，Ｊ＝１Ｈｚ），７．
７３（１Ｈ，ｓ），８．１４（１Ｈ，ｂｒｄ，Ｊ＝７Ｈ
ｚ）。Nuclear magnetic resonance spectrum (DMSO-d 6 ,
TMS internal standard) δ: 2.80 (2H, d, J = 6Hz), 3.10
3.60 (2H, m), 3.81 (3H, s), 3.9
5 to 4.35 (1H, m), 5.92 (2H, br
s), 6.48 (1H, s), 6.84 (1H, d, J
= 1 Hz), 7.59 (1H, d, J = 1 Hz), 7.
73 (1H, s), 8.14 (1H, brd, J = 7H
z).
【００８６】（参考例８）トリエチルホスホノアセテー
ト１．８４ｇのジオキサン３０ｍｌ溶液を１０℃に冷却
し、水素化ナトリウム（６０％）０．３２８ｇを添加
し、１０〜１５℃で１５分間攪袢した。同温で６，７−
ジヒドロ−７−オキソ−５Ｈ−ピロロ［１，２−ａ］イ
ミダゾール１．０ｇのジオキサン４０ｍｌ溶液を加え、
１．５時間攪袢した。溶媒を留去した残渣に水を加えク
ロロホルムで抽出し、飽和塩化ナトリウム水溶液で洗浄
後、無水炭酸カリウムで乾燥した。溶媒を留去して得た
残渣をシリカゲルカラムクロマトグラフィー（溶出溶
媒：クロロホルム／メタノール／２９％アンモニア水）
で精製して、０．８６ｇの７−（エトキシカルボニルメ
チレン）−６，７−ジヒドロ−５Ｈ−ピロロ［１，２−
ａ］イミダゾールを得た。Reference Example 8 A solution of 1.84 g of triethylphosphonoacetate in 30 ml of dioxane was cooled to 10 ° C., 0.328 g of sodium hydride (60%) was added, and the mixture was stirred at 10 to 15 ° C. for 15 minutes. . 6,7- at the same temperature
A solution of 1.0 g of dihydro-7-oxo-5H-pyrrolo [1,2-a] imidazole in 40 ml of dioxane was added,
Stirred for 1.5 hours. Water was added to the residue obtained by distilling the solvent off, the mixture was extracted with chloroform, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous potassium carbonate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (eluting solvent: chloroform / methanol / 29% aqueous ammonia).
Purified with 0.86 g of 7- (ethoxycarbonylmethylene) -6,7-dihydro-5H-pyrrolo [1,2-
a] Imidazole was obtained.
【００８７】質量分析値（ｍ／ｚ）：１９２（ＥＩ、Ｍ
+） 核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭＳ内部標準） δ：１．３１（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），３．６５
〜３．８１（２Ｈ，ｍ），４．１０〜４．３４（４Ｈ，
ｍ），６．４８（１Ｈ，ｔ，Ｊ＝２．７Ｈｚ），７．１
０（１Ｈ，ｓ），７．３２（１Ｈ，ｓ）。Mass spectrum (m / z): 192 (EI, M
+ ) Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.31 (3H, t, J = 7.3 Hz), 3.65
~ 3.81 (2H, m), 4.10 to 4.34 (4H,
m), 6.48 (1H, t, J = 2.7Hz), 7.1
0 (1H, s), 7.32 (1H, s).
【００８８】（参考例９）７−（エトキシカルボニルメ
チレン）−６，７−ジヒドロ−５Ｈ−ピロロ［１，２−
ａ］イミダゾール０．８５ｇのメタノール溶液にパラジ
ウム−炭素を加え、１気圧の水素雰囲気下室温で６時間
攪袢した。不溶物をセライトを用いて濾去し、溶媒を留
去して、０．８２ｇの（６，７−ジヒドロ−５Ｈ−ピロ
ロ［１，２−ａ］イミダゾール−７−イル）酢酸エチル
を得た。Reference Example 9 7- (Ethoxycarbonylmethylene) -6,7-dihydro-5H-pyrrolo [1,2-
a] Palladium-carbon was added to a methanol solution of 0.85 g of imidazole, and the mixture was stirred at room temperature under a hydrogen atmosphere of 1 atm for 6 hours. The insoluble material was filtered off using Celite, and the solvent was distilled off to obtain 0.82 g of (6,7-dihydro-5H-pyrrolo [1,2-a] imidazol-7-yl) ethyl acetate. .
【００８９】核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭ
Ｓ内部標準） δ：１．２６（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．１８
〜３．１６（４Ｈ，ｍ），３．３６〜３．７５（１Ｈ，
ｍ），３．８７〜４．２９（４Ｈ，ｍ），６．８５（１
Ｈ，ｄ，Ｊ＝１Ｈｚ），７．０５（１Ｈ，ｄ，Ｊ＝１Ｈ
ｚ）。Nuclear magnetic resonance spectrum (CDCl 3 , TM
S internal standard) δ: 1.26 (3H, t, J = 7.3Hz), 2.18
Up to 3.16 (4H, m), 3.36 to 3.75 (1H,
m), 3.87 to 4.29 (4H, m), 6.85 (1
H, d, J = 1Hz), 7.05 (1H, d, J = 1H
z).
【００９０】（実施例１）６−（ｔｅｒｔ−ブトキシカ
ルボニルアミノ）−５，６，７，８−テトラヒドロイミ
ダゾ［１，２−ａ］ピリジン０．５５ｇを１Ｎ塩酸５ｍ
ｌに加え、これを６０℃で２０分間攪袢した。反応液を
減圧下濃縮後、飽和炭酸水素ナトリウム水溶液を加えて
中和し再び濃縮した。残渣のクロロホルム−メタノール
（１０：１）可溶部分をアルミナカラムクロマトグラフ
ィー（５ｇ）に付した。クロロホルム−メタノール−２
９％アンモニア水（１００：１５：２）で溶出して、６
−アミノ−５，６，７，８−テトラヒドロイミダゾ
［１，２−ａ］ピリジン０．２９ｇ（９１％）を得た。Example 1 0.55 g of 6- (tert-butoxycarbonylamino) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine was added to 5 m of 1N hydrochloric acid.
1 and this was stirred at 60 ° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to neutralize, and the mixture was concentrated again. The chloroform-methanol (10: 1) soluble portion of the residue was subjected to alumina column chromatography (5 g). Chloroform-methanol-2
Elute with 9% aqueous ammonia (100: 15: 2) to give 6
0.29 g (91%) of -amino-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine was obtained.
【００９１】核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭ
Ｓ内部標準） δ：１．６０〜２．３０（２Ｈ，ｍ），２．６０〜３．
２５（２Ｈ，ｍ），３．２５〜３．８０（２Ｈ，ｍ），
３．９５〜４．２５（１Ｈ，ｍ），６．７５（１Ｈ，
ｄ，Ｊ＝１Ｈｚ），６．９８（１Ｈ，ｄ，Ｊ＝１Ｈ
ｚ）。Nuclear magnetic resonance spectrum (CDCl 3 , TM
S internal standard) δ: 1.60 to 2.30 (2H, m), 2.60 to 3.
25 (2H, m), 3.25 to 3.80 (2H, m),
3.95-4.25 (1H, m), 6.75 (1H,
d, J = 1 Hz), 6.98 (1H, d, J = 1H
z).
【００９２】実施例１と同様にして実施例２〜３の化合
物を得た。The compounds of Examples 2 and 3 were obtained in the same manner as in Example 1.
【００９３】（実施例２） ７−アミノ−１−メチル−５，６，７，８−テトラヒド
ロイミダゾ［１，５−ａ］ピリジン 原料化合物：１−メチル−５，６，７，８−テトラヒド
ロイミダゾ［１，５−ａ］ピリジン−７−カルボン酸・
塩酸塩 核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭＳ内部標準） δ：１．５５〜２．５５（３Ｈ，ｍ），２．１１（３
Ｈ，ｓ），２．７５〜３．５０（２Ｈ，ｍ），３．６５
〜４．３０（２Ｈ，ｍ），７．２９（１Ｈ，ｓ）。Example 2 7-Amino-1-methyl-5,6,7,8-tetrahydroimidazo [1,5-a] pyridine Raw material compound: 1-methyl-5,6,7,8-tetrahydro Imidazo [1,5-a] pyridine-7-carboxylic acid
Hydrochloride Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.55 to 2.55 (3H, m), 2.11 (3
H, s), 2.75 to 3.50 (2H, m), 3.65.
˜4.30 (2H, m), 7.29 (1H, s).
【００９４】（実施例３） ６−アミノ−５，６，７，８−テトラヒドロイミダゾ
［１，５−ａ］ピリジン 原料化合物：５，６，７，８−テトラヒドロイミダゾ
［１，５−ａ］ピリジン−６−カルボン酸 核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭＳ内部標準） δ：１．５０〜２．２５（２Ｈ，ｍ），２．５０〜３．
０５（２Ｈ，ｍ），３．０５〜３．８０（２Ｈ，ｍ），
４．００〜４．３０（１Ｈ，ｍ），６．７４（１Ｈ，
ｓ），７．３３（１Ｈ，ｓ）。Example 3 6-Amino-5,6,7,8-tetrahydroimidazo [1,5-a] pyridine Raw material compound: 5,6,7,8-tetrahydroimidazo [1,5-a] Pyridine-6-carboxylic acid Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.50 to 2.25 (2H, m), 2.50 to 3.
05 (2H, m), 3.05 to 3.80 (2H, m),
4.00 to 4.30 (1H, m), 6.74 (1H,
s), 7.33 (1H, s).
【００９５】（実施例４）ヒドロキシルアミン塩酸塩
０．４７ｇと酢酸ナトリウム０．５５ｇにメタノール５
ｍｌを加え、室温で３０分攪袢した。不溶物を濾去しメ
タノール５ｍｌで洗浄した。濾液と洗液を合わせ、これ
に６，７−ジヒドロ−７−オキソ−５Ｈ−ピロロ［１，
２−ａ］イミダゾール０．２５ｇを加え室温で６時間攪
袢した。溶媒を留去した後、クロロホルムを加え不溶物
を濾去後クロロホルムで洗浄した。濾液と洗液を合わ
せ、溶媒を留去して残渣を得た。この残渣をアンモニア
を飽和したエタノール２０ｍｌに溶解し、ラネーニッケ
ル約２ｇを加え、１気圧の水素雰囲気下室温で３時間攪
袢した。不溶物をセライトを用いて濾去し、溶媒を留去
した。得られた残渣をシリカゲルカラムクロマトグラフ
ィー（溶出溶媒：クロロホルム／メタノール／２９％ア
ンモニア水）で精製して、０．１０ｇの７−アミノ−
６，７−ジヒドロ−５Ｈ−ピロロ［１，２−ａ］イミダ
ゾールを得た。Example 4 Hydroxylamine hydrochloride (0.47 g), sodium acetate (0.55 g) and methanol (5)
ml was added, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was filtered off and washed with 5 ml of methanol. The filtrate and the washing liquid were combined, and to this, 6,7-dihydro-7-oxo-5H-pyrrolo [1,
2-a] Imidazole (0.25 g) was added, and the mixture was stirred at room temperature for 6 hours. After the solvent was distilled off, chloroform was added and the insoluble material was filtered off and washed with chloroform. The filtrate and the washing solution were combined and the solvent was distilled off to obtain a residue. This residue was dissolved in 20 ml of ethanol saturated with ammonia, about 2 g of Raney nickel was added, and the mixture was stirred at room temperature under a hydrogen atmosphere of 1 atm for 3 hours. The insoluble matter was filtered off using Celite, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: chloroform / methanol / 29% aqueous ammonia) to give 0.10 g of 7-amino-.
6,7-Dihydro-5H-pyrrolo [1,2-a] imidazole was obtained.
【００９６】核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭ
Ｓ内部標準） δ：２．１５〜２．４４（１Ｈ，ｍ），２．７２〜３．
１０（１Ｈ，ｍ），３．７０〜４．２１（２Ｈ，ｍ），
４．３２（１Ｈ，ｄｄ，Ｊ＝５．８Ｈｚ，７．７Ｈ
ｚ），６．８３（１Ｈ，ｄ，Ｊ＝１Ｈｚ），７．０３
（１Ｈ，ｓ）。Nuclear magnetic resonance spectrum (CDCl 3 , TM
S internal standard) δ: 2.15 to 2.44 (1H, m), 2.72 to 3.
10 (1H, m), 3.70 to 4.21 (2H, m),
4.32 (1H, dd, J = 5.8Hz, 7.7H
z), 6.83 (1H, d, J = 1 Hz), 7.03
(1H, s).
【００９７】（実施例５）４，５，６，７−テトラヒド
ロベンズイミダゾール−４−ベンズアミド０．３８ｇの
テトラヒドロフラン（５ｍｌ）溶液に１Ｎボラン−ＴＨ
Ｆ溶液（１５ｍｌ）を加え３時間加熱還流した。反応液
に濃塩酸２ｍｌを加えた後、６０℃で１時間加熱した。
反応液を減圧下濃縮後、残渣を飽和炭酸水素ナトリウム
水溶液で中和し再び濃縮した。残渣のクロロホルム−メ
タノール（１０：１）可溶部分をアルミナカラムクロマ
トグラフィー（１０ｇ）に付した。クロロホルム−メタ
ノール−２９％アンモニア水（１００：１５：２）で溶
出し、（４，５，６，７−テトラヒドロベンズイミダゾ
ール−４−イル）メチルアミン０．２４ｇを得た。Example 5 A solution of 4,5,6,7-tetrahydrobenzimidazole-4-benzamide (0.38 g) in tetrahydrofuran (5 ml) was dissolved in 1N borane-TH.
The F solution (15 ml) was added and the mixture was heated under reflux for 3 hours. After adding 2 ml of concentrated hydrochloric acid to the reaction solution, it was heated at 60 ° C. for 1 hour.
The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium hydrogen carbonate solution and concentrated again. The chloroform-methanol (10: 1) soluble portion of the residue was subjected to alumina column chromatography (10 g). Chloroform-methanol-29% aqueous ammonia (100: 15: 2) was used for elution to obtain (4,5,6,7-tetrahydrobenzimidazol-4-yl) methylamine (0.24 g).
【００９８】核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭ
Ｓ内部標準） δ：１．２０〜２．１５（６Ｈ，ｍ），２．３０〜３．
１０（５Ｈ，ｍ），７．４２（１Ｈ，ｓ）。Nuclear magnetic resonance spectrum (CDCl 3 , TM
S internal standard) δ: 1.20 to 2.15 (6H, m), 2.30 to 3.
10 (5H, m), 7.42 (1H, s).
【００９９】実施例１と同様にして実施例６の化合物を
得た。The compound of Example 6 was obtained in the same manner as in Example 1.
【０１００】（実施例６） ４−アミノ−４，５，６，７−テトラヒドロベンズイミ
ダゾール 原料化合物：１−トリフェニルメチル−４，５，６，７
−テトラヒドロベンズイミダゾール−４−カルボン酸 核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭＳ内部標準） δ：１．２５〜２．２５（４Ｈ，ｍ），２．３５〜２．
７０（２Ｈ，ｍ），３．９９（１Ｈ，ｂｒｔ，Ｊ＝５Ｈ
ｚ），７．４１（１Ｈ，ｓ）。Example 6 4-Amino-4,5,6,7-tetrahydrobenzimidazole Raw material compound: 1-triphenylmethyl-4,5,6,7
- tetrahydrobenz-imidazole-4-carboxylic acid Nuclear magnetic resonance spectrum (CDCl 3, TMS internal standard) δ: 1.25~2.25 (4H, m ), 2.35~2.
70 (2H, m), 3.99 (1H, brt, J = 5H
z), 7.41 (1H, s).
【０１０１】（実施例７）５，６，７，８，テトラヒド
ロイミダゾ［１，２−ａ］ピリジン−８−カルボキサミ
ド０．０８ｇにテトラヒドロフラン４ｍｌと１．０Ｍボ
ラン−テトラヒドロフランコンプレックス テトラヒド
ロフラン溶液２ｍｌを加え、１時間加熱還流した。反応
液を冷却後、濃塩酸１ｍｌとメタノール２ｍｌを加え、
１５分間加熱還流した。溶媒を留去して得た残渣をクロ
ロホルム／メタノール（２：１）濃液に溶かし、ナトリ
ウムメトキシド１．０ｇを添加後、アルミナカラムクロ
マトグラフィー（溶出溶媒：クロロホルム／メタノー
ル）を通じて、溶出液から０．０５ｇの（５，６，７，
８，テトラヒドロイミダゾ［１，２−ａ］ピリジン−８
−イル）メチルアミンを得た。Example 7 To 0.08 g of 5,6,7,8, tetrahydroimidazo [1,2-a] pyridine-8-carboxamide were added 4 ml of tetrahydrofuran and 2 ml of 1.0 M borane-tetrahydrofuran complex tetrahydrofuran solution, The mixture was heated under reflux for 1 hour. After cooling the reaction solution, 1 ml of concentrated hydrochloric acid and 2 ml of methanol were added,
Heated to reflux for 15 minutes. The residue obtained by distilling off the solvent was dissolved in a concentrated solution of chloroform / methanol (2: 1), and after adding 1.0 g of sodium methoxide, it was passed through an alumina column chromatography (elution solvent: chloroform / methanol) to remove the eluate. 0.05 g of (5, 6, 7,
8, tetrahydroimidazo [1,2-a] pyridine-8
-Yl) methylamine was obtained.
【０１０２】核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭ
Ｓ内部標準） δ：１．５８〜２．１６（４Ｈ，ｍ），２．８７〜３．
１０（２Ｈ，ｍ），３．５５〜４．００（３Ｈ，ｍ），
６．７８（１Ｈ，ｄ，Ｊ＝１Ｈｚ），６．９６（１Ｈ，
ｄ，Ｊ＝１Ｈｚ）。Nuclear magnetic resonance spectrum (CDCl 3 , TM
S internal standard) δ: 1.58 to 2.16 (4H, m), 2.87 to 3.
10 (2H, m), 3.55 to 4.00 (3H, m),
6.78 (1H, d, J = 1 Hz), 6.96 (1H,
d, J = 1 Hz).
【０１０３】（実施例８） （６，７−ジヒドロ−５Ｈ−ピロロ［１，２−ａ］イミ
ダゾール−７−イル）酢酸メチル０．８１ｇを３Ｎ塩酸
水に溶解し、２時間加熱還流した。溶媒を留去して得た
残渣を減圧乾燥して、０．８３ｇの（６，７−ジヒドロ
−５Ｈ−ピロロ［１，２−ａ］イミダゾール−７−イ
ル）酢酸・塩酸塩を得た。Example 8 0.81 g of methyl (6,7-dihydro-5H-pyrrolo [1,2-a] imidazol-7-yl) acetate was dissolved in 3N aqueous hydrochloric acid and heated under reflux for 2 hours. The solvent was distilled off and the obtained residue was dried under reduced pressure to obtain 0.83 g of (6,7-dihydro-5H-pyrrolo [1,2-a] imidazol-7-yl) acetic acid hydrochloride.
【０１０４】質量分析値（ｍ／ｚ）：１６６（ＥＩ、Ｍ
+） 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、ＴＭＳ内部標
準） δ：２．１８〜３．１９（４Ｈ、ｍ），３．６４〜４．
２７（３Ｈ，ｍ），７．５６〜７．６２（２Ｈ，ｍ）。Mass spectrum (m / z): 166 (EI, M
+) Nuclear magnetic resonance spectrum (DMSO-d 6, TMS internal standard) δ: 2.18~3.19 (4H, m ), 3.64~4.
27 (3H, m), 7.56 to 7.62 (2H, m).
【０１０５】（実施例９）４−アミノ−５−クロロ−２
−メトキシ安息香酸１−ベンズトリアゾリルエステル
（以下、活性エステルと略す）０．３２ｇのジメチルホ
ルムアミド（３ｍｌ）溶液に５−アミノ−４，５，６，
７−テトロヒドロベンズイミダゾール０．１５ｇを室温
下加えた。反応液を室温で１時間撹拌し、濾過後減圧下
濃縮した。残渣をクロロホルムに溶解後、希塩酸で抽出
した。水層を炭酸カリウムでアルカリ性とした後、クロ
ロホルム−メタノール（１０：１）で抽出した。クロロ
ホルム層を飽和食塩水で洗浄し、無水硫酸ナトリウムで
乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロ
マトグラフィー（１０ｇ）に付し、クロロホルム−メタ
ノール−２９％アンモニア水（１００：１０：１）で溶
出して、４−アミノ−５−クロロ−２−メトキシ−Ｎ−
（４，５，６，７−テトラヒドロ−５−ベンズイミダゾ
リル）ベンズアミド０．１５ｇを得た。これを当量のフ
マル酸とともに、メタノール−アセトニトリル液中撹拌
し、モノフマル酸塩に導いた。(Example 9) 4-amino-5-chloro-2
-Methoxybenzoic acid 1-benztriazolyl ester (hereinafter referred to as active ester) 0.32 g of dimethylformamide (3 ml) in 5-amino-4,5,6,6.
0.15 g of 7-tetrohydrobenzimidazole was added at room temperature. The reaction solution was stirred at room temperature for 1 hour, filtered and concentrated under reduced pressure. The residue was dissolved in chloroform and then extracted with diluted hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and then extracted with chloroform-methanol (10: 1). The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (10 g), and eluted with chloroform-methanol-29% aqueous ammonia (100: 10: 1) to give 4-amino-5-chloro-2-methoxy-N-.
0.15 g of (4,5,6,7-tetrahydro-5-benzimidazolyl) benzamide was obtained. This was stirred with an equivalent amount of fumaric acid in a methanol-acetonitrile solution to give a monofumaric acid salt.
【０１０６】融点 １７３−１７５℃（ＭｅＯＨ−ＣＨ
3ＣＮ） 元素分析値（Ｃ15Ｈ17Ｎ4Ｏ2Ｃｌ・Ｃ4Ｈ4Ｏ4・０．４Ｈ2Ｏとして） Ｃ（％） Ｈ（％） Ｎ（％） Ｃｌ（％） 理論値 ５１．３９ ４．９５ １２．６２ ７．９８ 実験値 ５１．２２ ４．８３ １２．９７ ７．８５ 質量分析値（ｍ／ｚ）：３２０，３２２（ＥＩ、Ｍ+） 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、ＴＭＳ内部標
準） δ：１．６０〜２．１５（２Ｈ，ｍ），２．３５〜３．
１０（４Ｈ，ｍ），３．７６（３Ｈ，ｓ），４．０５〜
４．４５（１Ｈ，ｍ），５．９５（２Ｈ，ｂｒｓ），
６．４６（１Ｈ，ｓ），６．６０（２Ｈ，ｓ），７．６
９（１Ｈ，ｓ），７．７２（１Ｈ，ｓ），７．８８（１
Ｈ，ｂｒｄ，Ｊ＝７Ｈｚ）。Melting point 173-175 ° C. (MeOH-CH
3 CN) Elemental analysis value (as C 15 H 17 N 4 O 2 Cl.C 4 H 4 O 4 .0.4H 2 O) C (%) H (%) N (%) Cl (%) theoretical value 51 .39 4.95 12.62 7.98 Experimental value 51.22 4.83 12.97 7.85 Mass spectrum (m / z): 320,322 (EI, M + ) Nuclear magnetic resonance spectrum (DMSO-) d 6 , TMS internal standard) δ: 1.60 to 2.15 (2H, m), 2.35 to 3.
10 (4H, m), 3.76 (3H, s), 4.05
4.45 (1H, m), 5.95 (2H, brs),
6.46 (1H, s), 6.60 (2H, s), 7.6
9 (1H, s), 7.72 (1H, s), 7.88 (1
H, brd, J = 7 Hz).
【０１０７】実施例９と同様にして実施例１０〜１７の
化合物を得た。The compounds of Examples 10 to 17 were obtained in the same manner as in Example 9.
【０１０８】（実施例１０） ５−［（４−アミノ−５−クロロ−２−メトキシフェニ
ル）カルボニル］−４，５，６，７−テトラヒドロイミ
ダゾ［４，５−ｃ］ピリジン・フマル酸塩 原料化合物：４，５，６，７−テトラヒドロイミダゾ
［４，５−ｃ］ピリジン 融点 １５０−１５８℃（ＭｅＯＨ−ＣＨ3ＣＮ） 元素分析値（Ｃ14Ｈ15Ｎ4Ｏ2Ｃｌ・Ｃ4Ｈ4Ｏ4・Ｈ2Ｏとして） Ｃ（％） Ｈ（％） Ｎ（％） Ｃｌ（％） 理論値 ４９．０４ ４．８０ １２．７１ ８．０４ 実験値 ４９．２２ ４．６０ １２．９２ ７．８４ 質量分析値（ｍ／ｚ）：３０６（ＥＩ、Ｍ+） 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、ＴＭＳ内部標
準） δ：２．１〜２．４（２Ｈ，ｍ），３．３〜３．９（２
Ｈ，ｍ），３．７１（３Ｈ，ｓ），４．０〜４．４（１
Ｈ，ｍ），４．５３（１Ｈ，ｓ），５．４〜５．９（２
Ｈ，ｂｒｓ），６．５０（１Ｈ，ｓ），６．６４（２
Ｈ，ｓ），７．０２（１Ｈ，ｓ），７，４５〜７．７
（１Ｈ、ｍ）。Example 10 5-[(4-amino-5-chloro-2-methoxyphenyl) carbonyl] -4,5,6,7-tetrahydroimidazo [4,5-c] pyridine fumarate starting compound: 4,5,6,7-imidazo [4,5-c] pyridine mp 150-158 ℃ (MeOH-CH 3 CN ) elemental analysis (C 14 H 15 N 4 O 2 Cl · C 4 H 4 O as 4 · H 2 O) C ( %) H (%) N (%) Cl (%) theoretical values 49.04 4.80 12.71 8.04 Found 49.22 4.60 12.92 7.84 Mass spectrum (m / z): 306 (EI, M + ) Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 2.1 to 2.4 (2H, m), 3. 3 to 3.9 (2
H, m), 3.71 (3H, s), 4.0 to 4.4 (1
H, m), 4.53 (1H, s), 5.4 to 5.9 (2
H, brs), 6.50 (1H, s), 6.64 (2
H, s), 7.02 (1H, s), 7, 45 to 7.7.
(1H, m).
【０１０９】（実施例１１） ４−アミノ−５−クロロ−２−メトキシ−Ｎ−（５，
６，７，８−テトラヒドロイミダゾ［１，２−ａ］ピリ
ジン−６−イル）ベンズアミド・０．５フマル酸塩 原料化合物：６−アミノ−５，６，７，８−テトラヒド
ロイミダゾ［１，２−ａ］ピリジン 融点 １９９−２０１℃（エタノール−酢酸エチル） 元素分析値（Ｃ15Ｈ17Ｎ4Ｏ2Ｃｌ・０．５Ｃ4Ｈ4Ｏ4・０．５Ｈ2Ｏとして） Ｃ（％） Ｈ（％） Ｎ（％） Ｃｌ 理論値 ５２．６５ ５．２０ １４．４５ ９．１４ 実験値 ５２．５５ ５．０７ １４．６１ ８．８３ 質量分析値（ｍ／ｚ）：３２０，３２２（ＥＩ、Ｍ+） 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、ＴＭＳ内部標
準） δ：１．８５〜２．２５（２Ｈ，ｍ），２．７０〜３．
１０（２Ｈ，ｍ），３．７６（３Ｈ，ｓ），３．８５〜
４．６５（３Ｈ，ｍ），６．４７（１Ｈ，ｓ），６．６
１（１Ｈ，ｓ），６．９４（１Ｈ，ｄ，Ｊ＝１Ｈｚ），
７．０６（１Ｈ，ｄ，Ｊ＝１Ｈｚ），７．６７（１Ｈ，
ｓ），７．９３（１Ｈ，ｂｒｄ，Ｊ＝７Ｈｚ）。Example 11 4-amino-5-chloro-2-methoxy-N- (5,
6,7,8-Tetrahydroimidazo [1,2-a] pyridin-6-yl) benzamide 0.5 fumarate Raw material compound: 6-amino-5,6,7,8-tetrahydroimidazo [1,2] -a] pyridine mp 199-201 ° C. (ethanol - ethyl acetate) elemental analysis (C 15 H 17 N 4 O 2 Cl · 0.5C 4 H 4 O 4 · 0.5H as 2 O) C (%) H (%) N (%) Cl Theoretical value 52.65 5.20 14.45 9.14 Experimental value 52.55 5.07 14.61 8.83 Mass spectrometry value (m / z): 320,322 (EI) , M + ) Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.85 to 2.25 (2H, m), 2.70 to 3.
10 (2H, m), 3.76 (3H, s), 3.85
4.65 (3H, m), 6.47 (1H, s), 6.6
1 (1H, s), 6.94 (1H, d, J = 1Hz),
7.06 (1H, d, J = 1 Hz), 7.67 (1H,
s), 7.93 (1H, brd, J = 7Hz).
【０１１０】（実施例１２） ４−アミノ−５−クロロ−２−メトキシ−Ｎ−（１−メ
チル−５，６，７，８−テトラヒドロイミダゾ［１，５
−ａ］ピリジン−７−イル）ベンズアミド・フマル酸塩 原料化合物：７−アミノ−１−メチル−５，６，７，８
−テトラヒドロイミダゾ［１，５−ａ］ピリジン 融点 １８７−１８９℃（エタノール−酢酸エチル） 質量分析値（ｍ／ｚ）：３３４，３３６（ＥＩ、Ｍ+） 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、ＴＭＳ内部標
準） δ：１．６５〜２．２５（２Ｈ，ｍ），２．０３（３
Ｈ，ｓ），２．６０（１Ｈ，ｄｄ，Ｊ＝９Ｈｚ，１５Ｈ
ｚ），３．０１（１Ｈ，ｄｄ，Ｊ＝６Ｈｚ，１５Ｈ
ｚ），３．７８（３Ｈ，ｓ），３．８５〜４．４０（３
Ｈ，ｍ），６．４８（１Ｈ，ｓ），６．６１（２Ｈ，
ｓ），７．６２（１Ｈ，ｓ），７．６７（１Ｈ，ｓ），
７．８９（１Ｈ，ｂｒｄ，Ｊ＝７Ｈｚ）。Example 12 4-amino-5-chloro-2-methoxy-N- (1-methyl-5,6,7,8-tetrahydroimidazo [1,5
-A] Pyridin-7-yl) benzamide fumarate raw material compound: 7-amino-1-methyl-5,6,7,8
- tetrahydroimidazo [1,5-a] pyridine mp 187-189 ° C. (ethanol - ethyl acetate) Mass spectrometry value (m / z): 334,336 ( EI, M +) Nuclear magnetic resonance spectrum (DMSO-d 6, TMS internal standard) δ: 1.65 to 2.25 (2H, m), 2.03 (3
H, s), 2.60 (1H, dd, J = 9Hz, 15H
z), 3.01 (1H, dd, J = 6Hz, 15H
z), 3.78 (3H, s), 3.85 to 4.40 (3
H, m), 6.48 (1H, s), 6.61 (2H,
s), 7.62 (1H, s), 7.67 (1H, s),
7.89 (1H, brd, J = 7Hz).
【０１１１】（実施例１３） ４−アミノ−５−クロロ−２−メトキシ−Ｎ−（５，
６，７，８−テトラヒドロイミダゾ［１，５−ａ］ピリ
ジン−６−イル）ベンズアミド・フマル酸塩 原料化合物：６−アミノ−５，６，７，８−テトラヒド
ロイミダゾ［１，５−ａ］ピリジン 融点 １８４−１８５℃（エタノール−酢酸エチル） 元素分析値（Ｃ15Ｈ17Ｎ4Ｏ2Ｃｌ・Ｃ4Ｈ4Ｏ4として） Ｃ（％） Ｈ（％） Ｎ（％） Ｃｌ（％） 理論値 ５２．２４ ４．８５ １２．８３ ８．１２ 実験値 ５１．９２ ４．８８ １２．７７ ８．０５ 質量分析値（ｍ／ｚ）：３２０，３２２（ＥＩ、Ｍ+） 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、ＴＭＳ内部標
準） δ：１．８０〜２．１５（２Ｈ，ｍ），２．７０〜２．
９５（２Ｈ，ｍ），３．７５（３Ｈ，ｓ），３．８０〜
４．５０（３Ｈ，ｍ），５．９６（２Ｈ，ｂｒｓ），
６．４６（１Ｈ，ｓ），６．６２（２Ｈ，ｓ），６．７
４（１Ｈ，ｓ），７．６２（１Ｈ，ｓ），７．６７（１
Ｈ，ｓ），７．９１（１Ｈ，ｄ，Ｊ＝７Ｈｚ）。(Example 13) 4-amino-5-chloro-2-methoxy-N- (5,
6,7,8-Tetrahydroimidazo [1,5-a] pyridin-6-yl) benzamide fumarate Raw material compound: 6-amino-5,6,7,8-tetrahydroimidazo [1,5-a] pyridine mp 184-185 ° C. (ethanol - ethyl acetate) elemental analysis (as C 15 H 17 N 4 O 2 Cl · C 4 H 4 O 4) C (%) H (%) N (%) Cl (%) Theoretical value 52.24 4.85 12.83 8.12 Experimental value 51.92 4.88 12.77 8.05 Mass spectrum (m / z): 320,322 (EI, M + ) Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.80 to 2.15 (2H, m), 2.70 to 2.
95 (2H, m), 3.75 (3H, s), 3.80-
4.50 (3H, m), 5.96 (2H, brs),
6.46 (1H, s), 6.62 (2H, s), 6.7
4 (1H, s), 7.62 (1H, s), 7.67 (1
H, s), 7.91 (1H, d, J = 7 Hz).
【０１１２】（実施例１４） ４−アミノ−５−クロロ−Ｎ−（６，７−ジヒドロ−５
Ｈ−ピロロ［１，２−ａ］イミダゾール−７−イル）−
２−メトキシベンズアミド・モノフマル酸塩１水和物 原料化合物：７−アミノ−６，７−ジヒドロ−５Ｈ−ピ
ロロ［１，２−ａ］イミダゾール 融点 １９３−１９４℃（メタノール） 元素分析値（Ｃ14Ｈ15Ｎ4Ｏ2Ｃｌ・Ｃ4Ｈ4Ｏ4・１．２５Ｈ2Ｏとして） Ｃ（％） Ｈ（％） Ｎ（％） Ｃｌ（％） 理論値 ４８．５５ ４．８７ １２．５８ ７．９６ 実験値 ４８．６７ ４．７３ １２．２９ ７．８０ 質量分析値（ｍ／ｚ）：３０６，３０８（ＥＩ、Ｍ+） 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、ＴＭＳ内部標
準） δ：２．２０〜２．６０（１Ｈ，ｍ），２．８３〜３．
１７（１Ｈ，ｍ），３．７９（３Ｈ，ｓ），３．８５〜
４．２０（２Ｈ，ｍ），５．２６（１Ｈ，ｑ，Ｊ＝７Ｈ
ｚ），５．９７（２Ｈ，ｓ），６．４８（１Ｈ，ｓ），
６．６２（２Ｈ，ｓ），６．９７（１Ｈ，ｓ），７．１
３（１Ｈ，ｓ），７．６９（１Ｈ，ｓ），８．２０（１
Ｈ，ｄ，Ｊ＝７Ｈｚ）。 （実施例１５） ４−アミノ−５−クロロ−２−メトキシ−Ｎ−［（４，
５，６，７−テトラヒドロベンズイミダゾール−４−イ
ル）メチル］ベンズアミド・０．５フマル酸塩原料化合
物：（４，５，６，７−テトラヒドロベンズイミダゾー
ル−４−イル）メチルアミン 融点 １８３−１８５℃（エタノール−酢酸エチル） 質量分析値（ｍ／ｚ）：３３４，３３６（ＥＩ、Ｍ+） 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、ＴＭＳ内部標
準） δ：１．３０〜２．１０（４Ｈ，ｍ），２．３５〜２．
６５（２Ｈ，ｍ），２．７０〜３．０５（１Ｈ，ｍ），
３．３０〜３．６５（２Ｈ，ｍ），３．８１（３Ｈ，
ｓ），６．４８（１Ｈ，ｓ），６．６１（１Ｈ，ｓ），
７．６９（１Ｈｓ），７．７３（１Ｈ，ｓ），８．４０
（１Ｈ，ｂｒｔ，Ｊ＝７Ｈｚ）。Example 14 4-Amino-5-chloro-N- (6,7-dihydro-5)
H-pyrrolo [1,2-a] imidazol-7-yl)-
2-Methoxybenzamide monofumarate monohydrate Raw material compound: 7-amino-6,7-dihydro-5H-pyrrolo [1,2-a] imidazole Melting point 193-194 ° C (methanol) Elemental analysis value (C 14 H 15 N 4 O 2 Cl · C 4 H 4 O 4 · 1.25H as 2 O) C (%) H (%) N (%) Cl (%) theoretical values 48.55 4.87 12.58 7 .96 Experimental value 48.67 4.73 12.29 7.80 Mass spectrum (m / z): 306,308 (EI, M + ) Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 2.20-2.60 (1H, m), 2.83-3.
17 (1H, m), 3.79 (3H, s), 3.85
4.20 (2H, m), 5.26 (1H, q, J = 7H
z), 5.97 (2H, s), 6.48 (1H, s),
6.62 (2H, s), 6.97 (1H, s), 7.1
3 (1H, s), 7.69 (1H, s), 8.20 (1
H, d, J = 7 Hz). Example 15 4-amino-5-chloro-2-methoxy-N-[(4
5,6,7-Tetrahydrobenzimidazol-4-yl) methyl] benzamide / 0.5 fumarate raw material compound: (4,5,6,7-tetrahydrobenzimidazol-4-yl) methylamine melting point 183-185 ℃ (Ethanol-ethyl acetate) Mass spectrum (m / z): 334,336 (EI, M + ) Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.30 to 2.10 (4H , M), 2.35-2.
65 (2H, m), 2.70 to 3.05 (1H, m),
3.30 to 3.65 (2H, m), 3.81 (3H,
s), 6.48 (1H, s), 6.61 (1H, s),
7.69 (1Hs), 7.73 (1H, s), 8.40
(1H, brt, J = 7Hz).
【０１１３】（実施例１６） ４−アミノ−５−クロロ−２−メトキシ−Ｎ−（４，
５，６，７−テトラヒドロベンズイミダゾール−４−イ
ル）ベンズアミド 原料化合物：４−アミノ−４，５，６，７−テトラヒド
ロベンズイミダゾール 融点 ２５２−２５５℃（酢酸エチル） 元素分析値（Ｃ15Ｈ17Ｎ4Ｏ2Ｃｌとして） Ｃ（％） Ｈ（％） Ｎ（％） Ｃｌ（％） 理論値 ５６．１６ ５．３４ １７．４７ １１．０５ 実験値 ５５．７９ ５．４１ １７．２０ １０．７１ 質量分析値（ｍ／ｚ）：３２０，３２２（ＥＩ、Ｍ+） 核磁気共鳴スペクトル（ＣＤＣｌ3、ＴＭＳ内部標準） δ：１．５０〜２．２０（４Ｈ，ｍ），２．４０〜２．
６５（２Ｈ，ｍ），３．７６（３Ｈ，ｓ），４．８５〜
５．１０（１Ｈ，ｍ），５．９３（１Ｈ，ｂｒｓ），
６．４８（１Ｈ，ｓ），７．４６（１Ｈ，ｓ），７．７
６（１Ｈ，ｓ），７．８８（１Ｈ，ｂｒｄ，Ｊ＝７Ｈ
ｚ）。Example 16 4-amino-5-chloro-2-methoxy-N- (4,
5,6,7-Tetrahydrobenzimidazol-4-yl) benzamide Raw material compound: 4-amino-4,5,6,7-tetrahydrobenzimidazole Melting point 252-255 ° C (ethyl acetate) Elemental analysis value (C 15 H 17 As N 4 O 2 Cl) C (%) H (%) N (%) Cl (%) Theoretical value 56.16 5.34 17.47 11.05 Experimental value 55.79 5.41 17.20 10. 71 Mass spectrometry value (m / z): 320,322 (EI, M + ) Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.50-2.20 (4H, m), 2.40- 2.
65 (2H, m), 3.76 (3H, s), 4.85
5.10 (1H, m), 5.93 (1H, brs),
6.48 (1H, s), 7.46 (1H, s), 7.7
6 (1H, s), 7.88 (1H, brd, J = 7H
z).
【０１１４】（実施例１７） ４−アミノ−５−クロロ−２−メトキシ−Ｎ−［（５，
６，７，８−テトラヒドロイミダゾ［１，２−ａ］ピリ
ジン−８−イル）メチル］ベンズアミド 原料化合物：（５，６，７，８−テトラヒドロイミダゾ
［１，２−ａ］ピリジン−８−イル）メチルアミン 融点 ２０９−２１１℃（酢酸エチル） 元素分析値（Ｃ16Ｈ19Ｎ4Ｏ2Ｃｌとして） Ｃ（％） Ｈ（％） Ｎ（％） Ｃｌ（％） 理論値 ５７．４０ ５．７２ １６．７３ １０．５９ 実験値 ５７．２９ ５．７２ １６．６２ １０．６２ 質量分析値（ｍ／ｚ）：３３４，３３６（ＥＩ、Ｍ+） 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、ＴＭＳ内部標
準） δ：１．５７〜２．０９（４Ｈ，ｍ），２．８０〜３．
１３（１Ｈ，ｍ），３．２４〜４．０５（７Ｈ，ｍ），
５．９０（２Ｈ，ｂｒｓ），６．４７（１Ｈ，ｓ），
６．９２（１Ｈ，ｄ，Ｊ＝１Ｈｚ），７．０３（１Ｈ，
ｄ，Ｊ＝１Ｈｚ），７．７３（１Ｈ，ｓ），８．８２
（１Ｈ，ｄｄ，Ｊ＝４Ｈｚ，７Ｈｚ）。Example 17 4-amino-5-chloro-2-methoxy-N-[(5
6,7,8-Tetrahydroimidazo [1,2-a] pyridin-8-yl) methyl] benzamide Raw material compound: (5,6,7,8-Tetrahydroimidazo [1,2-a] pyridin-8-yl ) Methylamine Melting point 209-211 ° C (ethyl acetate) Elemental analysis value (as C 16 H 19 N 4 O 2 Cl) C (%) H (%) N (%) Cl (%) Theoretical value 57.40 5. 72 16.73 10.59 Experimental value 57.29 5.72 16.62 10.62 Mass spec (m / z): 334, 336 (EI, M + ) Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS) Internal standard) δ: 1.57 to 2.09 (4H, m), 2.80 to 3.
13 (1H, m), 3.24 to 4.05 (7H, m),
5.90 (2H, brs), 6.47 (1H, s),
6.92 (1H, d, J = 1 Hz), 7.03 (1H,
d, J = 1 Hz), 7.73 (1H, s), 8.82
(1H, dd, J = 4Hz, 7Hz).
【０１１５】（実施例１８）４−アミノ−５−クロロ−
Ｎ−［２−（４−イミダゾリル）−１−（ヒドロキシメ
チル）エチル］−２−メトキシベンズアミド０．７９ｇ
のテトラメチレンスルホン（５ｍｌ）溶液に、塩化チオ
ニル０．５ｍｌを加え５０℃で３０分間撹拌した。反応
液を一部減圧下濃縮した後、これに炭酸カリウム２．０
ｇを加え、５０℃で１時間撹拌した。反応液に酢酸エチ
ルを加え、これを希塩酸で抽出した。水層を炭酸カリウ
ムでアルカリ性とした後、酢酸エチルで抽出した。酢酸
エチル層を飽和食塩水で洗浄し、硫酸マクネシウムで乾
燥後、減圧下濃縮し、残渣をシリカゲルカラムクロマト
グラフィー（２０ｇ）に付した。クロロホルム−メタノ
ール−２９％アンモニア水（１００：１０：２）で溶出
して、４−アミノ−５−クロロ−２−メトキシ−Ｎ−
（６，７−ジヒドロ−５Ｈ−ピロロ［１，２−ｃ］イミ
ダゾール−６−イル）ベンズアミド・フマル酸塩０．１
０ｇを得た。Example 18 4-amino-5-chloro-
0.79 g of N- [2- (4-imidazolyl) -1- (hydroxymethyl) ethyl] -2-methoxybenzamide
0.5 ml of thionyl chloride was added to the tetramethylene sulfone (5 ml) solution of and the mixture was stirred at 50 ° C. for 30 minutes. After partially concentrating the reaction solution under reduced pressure, potassium carbonate 2.0
g was added, and the mixture was stirred at 50 ° C. for 1 hour. Ethyl acetate was added to the reaction solution, and this was extracted with diluted hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (20 g). Chloroform-methanol-29% aqueous ammonia (100: 10: 2) was eluted, and 4-amino-5-chloro-2-methoxy-N- was used.
(6,7-Dihydro-5H-pyrrolo [1,2-c] imidazol-6-yl) benzamide fumarate 0.1
0 g was obtained.
【０１１６】融点 １８７−１８９℃（エタノール−酢
酸エチル） 質量分析値（ｍ／ｚ）：３０６，３０８（ＥＩ、Ｍ+） 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、ＴＭＳ内部標
準） δ：２．８２（１Ｈ，ｄｄ，Ｊ＝８Ｈｚ，１８Ｈｚ），
３．２０（１Ｈ，ｄｄ，Ｊ＝９Ｈｚ，１８Ｈｚ），３．
８０（３Ｈ，ｓ），３．８５〜４．１０（１Ｈ，ｍ），
４．２０〜４．５０（１Ｈ，ｍ），４．９０〜５．３０
（１Ｈ，ｍ），６．４７（１Ｈ，ｓ），６．６１（９
Ｈ，ｓ），６．７３（１Ｈ，ｓ），７．６７（１Ｈ，
ｓ），７．７４（１Ｈ，ｓ），８．２６（１Ｈ，ｂｒ
ｄ，Ｊ＝７Ｈｚ）。Melting point 187-189 ° C. (Ethanol-ethyl acetate) Mass spectrum (m / z): 306,308 (EI, M + ) Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 2. 82 (1H, dd, J = 8Hz, 18Hz),
3.20 (1H, dd, J = 9Hz, 18Hz), 3.
80 (3H, s), 3.85 to 4.10 (1H, m),
4.20-4.50 (1H, m), 4.90-5.30
(1H, m), 6.47 (1H, s), 6.61 (9
H, s), 6.73 (1H, s), 7.67 (1H,
s), 7.74 (1H, s), 8.26 (1H, br)
d, J = 7 Hz).
【０１１７】（実施例１９） （６，７−ジヒドロ−５Ｈ−ピロロ［１，２−ａ］イミ
ダゾール−７−イル）酢酸・塩酸塩０．８２ｇのｔ−ブ
タノール１２．５ｍｌ溶液にジフェニルホスホリルアジ
ド１．２３ｇとトリエチルアミン０．９０ｇを加え、１
６時間加熱還流した。反応液に水を加え、酢酸エチルで
抽出し、有機層を飽和炭酸水素ナトリウム水溶液、飽和
塩化ナトリウム水溶液で順次洗浄後、無水炭酸カリウム
で乾燥した。溶媒を留去して得た残渣をシリカゲルカラ
ムクロマトグラフィー（溶出溶媒：クロロホルム／メタ
ノール／２９％アンモニア水）で精製して、０．３３ｇ
のＮ−（ｔ−ブトキシカルボニル）−（６，７−ジヒド
ロ−５Ｈ−ピロロ［１，２−ａ］イミダゾール−７−イ
ル）メチルアミンを得た。これをエタノール３ｍｌに溶
解し、濃塩酸１．５ｍｌを加え室温で６時間撹拌した。
溶媒を留去して得た残渣をクロロホルム／メタノール
（１０：１）混液に溶解し、ナトリウムメトキシド０．
３ｇを添加後、アルミナカラムクロマトフラフィー（溶
出溶媒：クロロホルム／メタノール）を通じて０．１０
ｇの（６，７−ジヒドロ−５Ｈ−ピロロ［１，２−ａ］
イミダゾール−７−イル）メチルアミンを得た。これの
ジメチルホルムアミド３ｍｌ溶液を４−アミノ−５−ク
ロロ−２−メトキシ安息香酸０．１５ｇと１，３−ジシ
クロヘキシルカルボジイミド０．１７ｇと１−ヒドロキ
シベンゾトリアゾール０．１１ｇのジメチルホルムアミ
ド７ｍｌ溶液を室温で１８時間撹拌した溶液に加え、室
温で１時間撹拌した。不溶物を濾去後、溶媒を留去し、
酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、飽
和塩化ナトリウム水溶液で順次洗浄後、無水炭酸カリウ
ムで乾燥した。溶媒を留去して得た残渣をシリカゲルカ
ラムクロマトグラフィー（溶出溶媒：クロロホルム／メ
タノール／２９％アンモニア水）で精製して得られた粗
結晶を酢酸エチル−アセトニトリルから再結晶して、
０．１０ｇの４−アミノ−５−クロロ−Ｎ−［（６，７
−ジヒドロ−５Ｈ−ピロロ［１，２−ａ］イミダゾール
−７−イル）メチル］−２−メトキシベンズアミドを得
た。Example 19 (6,7-Dihydro-5H-pyrrolo [1,2-a] imidazol-7-yl) acetic acid hydrochloride 0.82 g of a solution of 0.82 g of t-butanol in 12.5 ml of diphenylphosphoryl azide. 1.23 g and triethylamine 0.90 g were added, and 1
The mixture was heated under reflux for 6 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous potassium carbonate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluting solvent: chloroform / methanol / 29% aqueous ammonia) to give 0.33 g.
N- (t-butoxycarbonyl)-(6,7-dihydro-5H-pyrrolo [1,2-a] imidazol-7-yl) methylamine was obtained. This was dissolved in 3 ml of ethanol, 1.5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 6 hours.
The residue obtained by distilling off the solvent was dissolved in a mixed solution of chloroform / methanol (10: 1), and sodium methoxide (0.1%) was added.
After adding 3 g, 0.10 was applied through alumina column chromatography (elution solvent: chloroform / methanol).
g of (6,7-dihydro-5H-pyrrolo [1,2-a]
Imidazol-7-yl) methylamine was obtained. A solution of this in dimethylformamide (3 ml) was added with 4-amino-5-chloro-2-methoxybenzoic acid (0.15 g), 1,3-dicyclohexylcarbodiimide (0.17 g) and 1-hydroxybenzotriazole (0.11 g) in dimethylformamide (7 ml) at room temperature. The solution was stirred for 18 hours and added at room temperature for 1 hour. After removing the insoluble matter by filtration, the solvent was distilled off,
Ethyl acetate was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous potassium carbonate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (eluting solvent: chloroform / methanol / 29% aqueous ammonia) to obtain crude crystals, which were recrystallized from ethyl acetate-acetonitrile,
0.10 g of 4-amino-5-chloro-N-[(6,7
-Dihydro-5H-pyrrolo [1,2-a] imidazol-7-yl) methyl] -2-methoxybenzamide was obtained.
【０１１８】融点 １９２−１９４℃ 元素分析値（Ｃ15Ｈ17Ｎ4Ｏ2Ｃｌとして） Ｃ（％） Ｈ（％） Ｎ（％） Ｃｌ（％） 理論値 ５６．１６ ５．３４ １７．４７ １１．０５ 実験値 ５５．７８ ５．３３ １７．３２ １１．０６ 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6、ＴＭＳ内部標
準） δ：２．１０〜２．９０（２Ｈ，ｍ），３．１５〜４．
０２（８Ｈ，ｍ），５．９４（２Ｈ，ｂｒｓ），６．４
７（１Ｈ，ｓ），６．９５（１Ｈ，ｄ，Ｊ＝１Ｈｚ），
７．０９（１Ｈ，ｄ，Ｊ＝１Ｈｚ），７．７２（１Ｈ，
ｓ），８．３３（１Ｈ，ｔ，Ｊ＝７Ｈｚ）。Melting point 192-194 ° C. Elemental analysis value (as C 15 H 17 N 4 O 2 Cl) C (%) H (%) N (%) Cl (%) Theoretical value 56.16 5.34 17.47 11.05 Experimental value 55.78 5.33 17.32 11.06 Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 2.10 to 2.90 (2H, m), 3.15 to 4.
02 (8H, m), 5.94 (2H, brs), 6.4
7 (1H, s), 6.95 (1H, d, J = 1Hz),
7.09 (1H, d, J = 1 Hz), 7.72 (1H,
s), 8.33 (1H, t, J = 7Hz).
【０１１９】以下、表３〜５に、実施例１〜１９により
得られた化合物の化学構造式を掲記する。The chemical structural formulas of the compounds obtained in Examples 1 to 19 are listed in Tables 3 to 5 below.
【０１２０】[0120]
【表３】 [Table 3]
【０１２１】[0121]
【表４】 [Table 4]
【０１２２】[0122]
【表５】 [Table 5]
【０１２３】以下に化学構造式を掲記する実施例１−１
〜１−２７の化合物は、前記実施例若しくは製造法に記
載の方法とほぼ同様にして、又は、それらに当業者に自
明の若干の変法を適用して、容易に製造することができ
る。Example 1-1 whose chemical structural formulas are listed below.
The compounds to 1-27 can be easily produced by almost the same method as described in the above-mentioned Examples or the production method or by applying some modifications obvious to those skilled in the art to them.
【０１２４】[0124]
【表６】 [Table 6]
【０１２５】[0125]
【表７】 [Table 7]
【０１２６】[0126]
【表８】 [Table 8]
【０１２７】[0127]
【表９】 [Table 9]
【０１２８】[0128]
【表１０】 [Table 10]
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【手続補正書】[Procedure amendment]
【提出日】平成７年６月８日[Submission date] June 8, 1995
【手続補正１】[Procedure Amendment 1]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】００７８[Correction target item name] 0078
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【００７８】（参考例４）４，５，６，７−テトラヒド
ロベンズイミダゾール−４−カルボン酸メチル２．０５
ｇ、トリエチルアミン１．７３ｇ、クロロトリフェニル
メタン４．１３ｇのジメチルホルムアミド（３０ｍｌ）
溶液を室温で終夜撹拌した。反応液を減圧下濃縮後残渣
に酢酸エチルを加え、これを水で洗浄した。酢酸エチル
層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥し、
減圧下濃縮し、ヘキサン−酢酸エチル（５：１）よりト
リチル体３．９０ｇを得た。これを１０％水酸化ナトリ
ウムのメタノール−水（１：１）５０ｍｌ混合溶液中で
加水分解した。反応液を濃塩酸でｐＨ５とし、析出した
１−トリフェニルメチル−４，５，６，７−テトラヒド
ロベンズイミダゾール−４−カルボン酸０．９２ｇを得
た。(Reference Example 4) Methyl 4,5,6,7-tetrahydrobenzimidazole-4-carboxylate 2.05
g, 1.73 g of triethylamine, 4.13 g of chlorotriphenylmethane, dimethylformamide (30 ml)
The solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and this was washed with water. The ethyl acetate layer was washed with saturated brine and dried over magnesium sulfate,
The mixture was concentrated under reduced pressure, and 3.90 g of a trityl compound was obtained from hexane-ethyl acetate (5: 1). This was hydrolyzed in a mixed solution of 10% sodium hydroxide in 50 ml of methanol-water (1: 1). The reaction solution was adjusted to pH 5 with concentrated hydrochloric acid to obtain 0.92 g of precipitated 1-triphenylmethyl-4,5,6,7-tetrahydrobenzimidazole -4- carboxylic acid.
【手続補正２】[Procedure Amendment 2]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】０１２１[Correction target item name] 0121
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【０１２１】[0121]
【表４】 [Table 4]
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０７Ｄ 471/04 １０８ Ｃ０７Ｄ 471/04 １０８Ｘ １０８Ｅ 487/04 １３８ 9271−4Ｃ 487/04 １３８ (72)発明者 宮田 桂司 茨城県つくば市吾妻４丁目15番地の５ パ ストラルライフ101 (72)発明者 鎌戸 毅 千葉県我孫子市つくし野７−９−５ ペル レシュロ パート２、203号 (72)発明者 太田 光昭 茨城県筑波郡谷和原村絹の台３丁目９番地 11─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification code Internal reference number FI Technical display location C07D 471/04 108 C07D 471/04 108X 108E 487/04 138 9271-4C 487/04 138 (72) Inventor Keiji Miyata 5 Pastoral Life 101, 4-15, Azuma Tsukuba, Ibaraki Prefecture (72) Inventor Takeshi Kamado 7-9-5 Tsukushino, Abiko, Chiba Prefecture Perleschro Part 2, No. 203 (72) Inventor Mitsuaki Ota 3-9-11 Kinindai, Taniwahara Village, Tsukuba-gun, Ibaraki Prefecture
Claims (3)
導体又はその塩。 【化１】 （ただし、式中の記号は以下の意味を示す。 【化２】 Ａ環：イミダゾール環と縮合し、かつ、イミダゾール環
中の窒素原子を含んでいてもよい４〜８員のシクロアル
キル環 ｎ：０、１又は２ Ｒ2：水素原子又は低級アルキル基 【化３】 Ｂ環：イミダゾール環と縮合する窒素原子１〜２個含む
４〜８員含窒素飽和へテロ環 Ｒ3：ハロゲン原子 Ｒ4：低級アルコキシ基 Ｒ5、Ｒ6、Ｒ7、Ｒ8：同一又は異なって、水素原子又は
低級アルキル基）1. A benzoic acid derivative represented by the following general formula (I) or a salt thereof. Embedded image (However, the symbols in the formulas have the following meanings. Ring A: 4- to 8-membered cycloalkyl ring which is condensed with an imidazole ring and may contain a nitrogen atom in the imidazole ring n: 0, 1 or 2 R 2 : hydrogen atom or lower alkyl group ] B ring: an imidazole ring fused to the nitrogen atom 1-2 containing heterocycle R 3 to 4-8 membered nitrogen-containing saturated halogen atom R 4: a lower alkoxy group R 5, R 6, R 7 , R 8: the same or Differently, a hydrogen atom or a lower alkyl group)
その薬学的に許容される塩を有効成分とする５−ＨＴ4
受容体作動薬。2. 5-HT 4 comprising the benzoic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
Receptor agonist.
ール誘導体又はその塩。 【化４】 （ただし、式中の記号は以下の意味を示す。 Ｉｍ環：イミダゾール環 【化５】 Ａ環：イミダゾール環と縮合し、かつ、イミダゾール環
中の窒素原子を含んでいてもよい４〜８員のシクロアル
キル環 Ｒ7：水素原子又は低級アルキル基 ｎ：０、１又は２ Ｒ9：アミノ基又はカルボキシル基 【化６】 3. An imidazole derivative represented by the following general formula (II) or a salt thereof. [Chemical 4] (However, the symbols in the formulas have the following meanings: Im ring: imidazole ring Ring A: 4- to 8-membered cycloalkyl ring which is condensed with an imidazole ring and may contain a nitrogen atom in the imidazole ring R 7 : hydrogen atom or lower alkyl group n: 0, 1 or 2 R 9 : Amino group or carboxyl group
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7131264A JPH08325234A (en) | 1995-05-30 | 1995-05-30 | Benzoic acid derivative or its salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7131264A JPH08325234A (en) | 1995-05-30 | 1995-05-30 | Benzoic acid derivative or its salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH08325234A true JPH08325234A (en) | 1996-12-10 |
Family
ID=15053868
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7131264A Withdrawn JPH08325234A (en) | 1995-05-30 | 1995-05-30 | Benzoic acid derivative or its salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH08325234A (en) |
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| WO2001068651A1 (en) * | 2000-03-17 | 2001-09-20 | Novo Nordisk A/S | Condensed imidazoles as histamine h3 receptor ligands |
| US6610721B2 (en) | 2000-03-17 | 2003-08-26 | Novo Nordisk A/S | Imidazo heterocyclic compounds |
| EP1388342A1 (en) * | 2002-08-07 | 2004-02-11 | Aventis Pharma Deutschland GmbH | Acylated, heteroaryl-condensed cycloalkenylamines and their use as pharmaceuticals |
| WO2006063709A1 (en) * | 2004-12-15 | 2006-06-22 | F.Hoffmann-La Roche Ag | Bi- and tricyclic substituted phenyl methanones as glycine transporter i (glyt-1) inhibitors for the treatment of alzheimer’s disease |
| US7105513B2 (en) | 2002-08-07 | 2006-09-12 | Sanofi-Avertis Deutschland Gmbh | Acylated, heteroaryl-condensed cycloalkenylamines and their use as pharmaceuticals |
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| CN102863447A (en) * | 2008-09-04 | 2013-01-09 | 上海交通大学 | Imidazole chiral organic small molecular compound with dual-loop structure and synthetic method thereof |
| US8859538B2 (en) | 2007-06-21 | 2014-10-14 | Cara Therapeutics, Inc. | Uses of substituted imidazoheterocycles |
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-
1995
- 1995-05-30 JP JP7131264A patent/JPH08325234A/en not_active Withdrawn
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|---|---|---|---|---|
| WO2001068651A1 (en) * | 2000-03-17 | 2001-09-20 | Novo Nordisk A/S | Condensed imidazoles as histamine h3 receptor ligands |
| US6610721B2 (en) | 2000-03-17 | 2003-08-26 | Novo Nordisk A/S | Imidazo heterocyclic compounds |
| EP1388342A1 (en) * | 2002-08-07 | 2004-02-11 | Aventis Pharma Deutschland GmbH | Acylated, heteroaryl-condensed cycloalkenylamines and their use as pharmaceuticals |
| WO2004014372A1 (en) * | 2002-08-07 | 2004-02-19 | Aventis Pharma Deutschland Gmbh | Acylated, heteroaryl-condensed cycloalkenylamines and their use as pharmaceuticals |
| JP2005538124A (en) * | 2002-08-07 | 2005-12-15 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Acylated heteroaryl fused cycloalkenylamines and their use as pharmaceuticals |
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| JP2008523126A (en) * | 2004-12-15 | 2008-07-03 | エフ．ホフマン−ラ ロシュ アーゲー | Bicyclic and tricyclic substituted phenylmethanones as glycine transporter I (GLYT-1) inhibitors for the treatment of Alzheimer's disease |
| US7375226B2 (en) | 2004-12-15 | 2008-05-20 | Hoffman-La Roche Inc. | Bi- and tricyclic substituted phenyl methanones |
| KR100883003B1 (en) * | 2004-12-15 | 2009-02-12 | 에프. 호프만-라 로슈 아게 | Bi- and tricyclic substituted phenyl methanones as glycine transporter 1glyt-1 inhibitors for the treatment of alzheimer's disease |
| WO2006063709A1 (en) * | 2004-12-15 | 2006-06-22 | F.Hoffmann-La Roche Ag | Bi- and tricyclic substituted phenyl methanones as glycine transporter i (glyt-1) inhibitors for the treatment of alzheimer’s disease |
| US7517874B2 (en) | 2007-06-21 | 2009-04-14 | Cara Therapeutics, Inc. | Substituted imidazo[1,5-a][1,4]diazepines and imidazo[1,5-a]pyrazines as cannabinoid receptor agonists for the treatment of pain |
| US8431565B2 (en) | 2007-06-21 | 2013-04-30 | Cara Therapeutics, Inc. | Substituted imidazoheterocycles |
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| CN102863447A (en) * | 2008-09-04 | 2013-01-09 | 上海交通大学 | Imidazole chiral organic small molecular compound with dual-loop structure and synthetic method thereof |
| US11186572B2 (en) * | 2016-12-02 | 2021-11-30 | Fraunhofer-Gesellschaft Zur Forderung Der Angewandten Forschung E.V. | Bacterial glutaminyl cyclases and inhibitors thereof for use in the treatment of periodontitis |
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