JPH1017564A - New thiophene derivative - Google Patents
New thiophene derivativeInfo
- Publication number
- JPH1017564A JPH1017564A JP17207896A JP17207896A JPH1017564A JP H1017564 A JPH1017564 A JP H1017564A JP 17207896 A JP17207896 A JP 17207896A JP 17207896 A JP17207896 A JP 17207896A JP H1017564 A JPH1017564 A JP H1017564A
- Authority
- JP
- Japan
- Prior art keywords
- group
- hexahydro
- methyl
- azepinyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000003577 thiophenes Chemical class 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- -1 hexahydro-1-azepinyl Chemical group 0.000 abstract description 91
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 8
- 150000007530 organic bases Chemical class 0.000 abstract description 4
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract description 2
- 150000001718 carbodiimides Chemical class 0.000 abstract description 2
- 239000012024 dehydrating agents Substances 0.000 abstract 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 31
- 238000000034 method Methods 0.000 description 29
- 238000002844 melting Methods 0.000 description 28
- 230000008018 melting Effects 0.000 description 28
- 230000009435 amidation Effects 0.000 description 26
- 238000007112 amidation reaction Methods 0.000 description 26
- 229910052739 hydrogen Inorganic materials 0.000 description 23
- 239000000243 solution Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 8
- BMWZMDDFCPGUSM-UHFFFAOYSA-N thiophene-2-carboxylic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=CS1 BMWZMDDFCPGUSM-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- HKTIGNLOQJHHEO-UHFFFAOYSA-N 5-(azepan-1-ylmethyl)thiophene-2-carboxylic acid;hydrochloride Chemical compound Cl.S1C(C(=O)O)=CC=C1CN1CCCCCC1 HKTIGNLOQJHHEO-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 201000000980 schizophrenia Diseases 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 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
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- MRNPEODSSIKDBF-UHFFFAOYSA-N 2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid Chemical compound CC1(C)OCCN1C(O)=O MRNPEODSSIKDBF-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 2
- 206010000117 Abnormal behaviour Diseases 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- 206010012218 Delirium Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 2
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 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
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229960001413 acetanilide Drugs 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000005236 alkanoylamino group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 2
- CJYXCQLOZNIMFP-UHFFFAOYSA-N azocan-2-one Chemical compound O=C1CCCCCCN1 CJYXCQLOZNIMFP-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000021824 exploration behavior Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- HELPELRZZBKHLM-UHFFFAOYSA-N methyl thiophene-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)C1=CC=CS1 HELPELRZZBKHLM-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229950010883 phencyclidine Drugs 0.000 description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 1
- AWNXKUKDGIDDBE-UHFFFAOYSA-N (4-methoxyphenyl)-piperazin-1-ylmethanone Chemical compound C1=CC(OC)=CC=C1C(=O)N1CCNCC1 AWNXKUKDGIDDBE-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000004815 1,2-dimethylethylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([*:2])C([H])([H])[H] 0.000 description 1
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 description 1
- FAAWECNSILPHMQ-UHFFFAOYSA-N 1,3-oxazolidine-2,2-dicarboxylic acid Chemical compound O1C(NCC1)(C(=O)O)C(=O)O FAAWECNSILPHMQ-UHFFFAOYSA-N 0.000 description 1
- MRBFGEHILMYPTF-UHFFFAOYSA-N 1-(2-Pyrimidyl)piperazine Chemical compound C1CNCCN1C1=NC=CC=N1 MRBFGEHILMYPTF-UHFFFAOYSA-N 0.000 description 1
- BNPCRHWMJSUKDM-UHFFFAOYSA-N 1-benzylpiperazin-2-one Chemical compound O=C1CNCCN1CC1=CC=CC=C1 BNPCRHWMJSUKDM-UHFFFAOYSA-N 0.000 description 1
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 description 1
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N 4-Piperidine carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 description 1
- NPBDHWVEOIEDJX-UHFFFAOYSA-N 4-[5-(piperidin-1-ylmethyl)thiophen-2-yl]-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2SC(CN3CCCCC3)=CC=2)=C1 NPBDHWVEOIEDJX-UHFFFAOYSA-N 0.000 description 1
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- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 208000027776 Extrapyramidal disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は，抗ＰＣＰ（フェン
サイクリジン）作用を有する新規チオフェン誘導体に関
する。TECHNICAL FIELD The present invention relates to a novel thiophene derivative having an anti-PCP (phencyclidine) action.
【０００２】[0002]
【従来の技術】ＰＣＰは，陰性症状を含む精神分裂病の
諸症状に酷似した精神症状を誘発することが知られてい
る［Ａｍ．Ｊ．Ｐｓｙｃｈｉａｔ．，１３５，１０８１
（１９８７）］。一方，ＰＣＰを動物に投与すると種々
の異常行動が誘発される。このことから動物のＰＣＰ誘
発異常行動を特異的に抑制する（抗ＰＣＰ作用）薬物
は，人間における精神分裂病の治療薬として有用である
と考えられる。またＰＣＰがＮＭＤＡ受容体阻害作用を
有することから，これら抗ＰＣＰ作用を有する薬物は，
ＮＭＤＡ受容体の機能低下に起因すると考えられる疾
患，すなわち老年痴呆における記憶・認知障害やせん妄
などの問題行動の治療薬としても有用であると考えられ
る。従来，精神分裂病の治療薬としては主としてドパミ
ン受容体の遮断薬が用いられてきた。しかしながら，こ
れらドパミン遮断薬は陰性症状に対して効果が少ないば
かりでなく，錐体外路症状などの副作用を発現するとい
う問題がある［Ｔ．Ｉ．Ｐ．Ｓ．，１３，１１６（１９
９２）］。これに対して，特異的な抗ＰＣＰ薬は，ドパ
ミン遮断薬が奏功しない精神分裂病の陰性症状をも改善
し，一方でドパミン遮断薬のような副作用を有さないと
いう点で優れている。先に本発明者等は，含窒素シクロ
アルキル低級アルキル基を有する新規なチオフェン誘導
体に抗ＰＣＰ作用を有することを見い出し，ＷＯ９４／
２２５４５０及びＷＯ９５／２９９１０で報告してい
る。一方，含窒素シクロアルキル低級アルキル基を有す
るチオフェン誘導体としては，２−アミノ−４−（５−
ピペリジノメチル−２−チエニル）チアゾール（特開昭
６２−１９２３７９）が知られているが，抗ＰＣＰ作用
については何ら開示されていない。2. Description of the Related Art It is known that PCP induces psychiatric symptoms very similar to those of schizophrenia including negative symptoms [Am. J. Psychiat. , 135,1081
(1987)]. On the other hand, administration of PCP to animals induces various abnormal behaviors. This suggests that drugs that specifically suppress PCP-induced abnormal behavior in animals (anti-PCP action) are useful as therapeutic agents for schizophrenia in humans. Further, since PCP has an NMDA receptor inhibitory action, these drugs having an anti-PCP action are:
It is also considered to be useful as a therapeutic drug for diseases considered to be caused by decreased NMDA receptor function, ie, memory / cognitive impairment in senile dementia and problematic behaviors such as delirium. Conventionally, dopamine receptor blockers have been mainly used as therapeutic agents for schizophrenia. However, these dopamine blockers are not only ineffective against negative symptoms, but also cause side effects such as extrapyramidal symptoms [T. I. P. S. , 13, 116 (19
92)]. On the other hand, specific anti-PCP drugs are also excellent in that they also improve the negative symptoms of schizophrenia in which dopamine blockers do not work, and do not have side effects like dopamine blockers. First, the present inventors have found that a novel thiophene derivative having a nitrogen-containing cycloalkyl lower alkyl group has an anti-PCP effect, and
225450 and WO 95/29910. On the other hand, thiophene derivatives having a nitrogen-containing cycloalkyl lower alkyl group include 2-amino-4- (5-
Piperidinomethyl-2-thienyl) thiazole (Japanese Patent Application Laid-Open No. 62-192379) is known, but it does not disclose any anti-PCP activity.
【０００３】[0003]
【発明が解決しようとする課題】本発明の目的は，抗Ｐ
ＣＰ（フェンサイクリジン）作用を有する新規チオフェ
ン誘導体又はその塩を提供することである。SUMMARY OF THE INVENTION An object of the present invention is to provide an anti-P
An object of the present invention is to provide a novel thiophene derivative having a CP (phencyclidine) action or a salt thereof.
【０００４】[0004]
【課題を解決するための手段】本発明者らは，優れた特
異的な抗ＰＣＰ作用を有する化合物を鋭意研究した結
果，従来の化合物とは化学構造を全く異にする含窒素シ
クロアルキル基及びカルバモイル基を有するチオフェン
誘導体又はその塩を創製し本発明を完成した。即ち，本
発明は一般式（Ｉ）で示されるチオフェン誘導体又はそ
の塩，及び化合物（Ｉ）又は製薬学的に許容されるその
塩を有効成分とする医薬組成物に関する。Means for Solving the Problems The present inventors have conducted intensive studies on compounds having an excellent specific anti-PCP activity, and as a result, have found that nitrogen-containing cycloalkyl groups and chemical compounds whose chemical structures are completely different from those of conventional compounds. The present invention was completed by creating a thiophene derivative having a carbamoyl group or a salt thereof. That is, the present invention relates to a thiophene derivative represented by the general formula (I) or a salt thereof, and a pharmaceutical composition containing the compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
【０００５】[0005]
【化２】 （式中の記号は，以下の意味を示す。 Ｂ環：４乃至１０員含窒素シクロアルキル環 Ａ：結合又は低級アルキレン基 Ｒ3，Ｒ4，Ｒ6及びＲ7：同一又は異なって水素原子又は
置換基をそれぞれ有していても良い低級アルキル基若し
くはアラルキル基 ｎ及びｍ：同一又は異なって０又は１乃至６の整数 Ｒ5，Ｒ8及びＲ9：同一又は異なって水素原子又は置換
基をそれぞれ有していても良い低級アルキル基，シクロ
アルキル基，アラルキル基，アリール基若しくは窒素原
子を１又は２個含む５又は６員ヘテロアリール基 Ｄ環：カルボニル基を有していても良く窒素原子を１又
は２個含む５乃至７員シクロアルキル環 Ｒ10，Ｒ11及びＲ12：同一又は異なって水素原子，低級
アルキル基又はＲ3若しくはＲ6と一体となって５乃至８
員環を形成しても良い。）Embedded image (The symbols in the formula have the following meanings. Ring B: 4- to 10-membered nitrogen-containing cycloalkyl ring A: bond or lower alkylene group R 3 , R 4 , R 6 and R 7 are the same or different and are each a hydrogen atom or a lower alkyl group or an aralkyl group which may have a substituent n and m: the same or different and an integer of 0 or 1 to 6 R 5 , R 8 and R 9 are the same or different and each include a hydrogen atom or a lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group or one or two nitrogen atoms which may have a substituent, or 5 or 6-membered heteroaryl group D-ring: a 5- to 7-membered cycloalkyl ring which may have a carbonyl group and contains 1 or 2 nitrogen atoms R 10 , R 11 and R 12 are the same or different and are combined with a hydrogen atom, a lower alkyl group or R 3 or R 6 to form 5 to 8
A member ring may be formed. )
【０００６】[0006]
【発明の実施の形態】以下，本発明化合物（Ｉ）につい
て詳細に説明する。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個の直鎖又は分岐状の炭素鎖を意味する。「低級アル
キル基」としては，具体的に例えばメチル基，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，ヘキシル基又はイソヘキ
シル基等が挙げられ，好ましくは炭素数が１乃至４個の
直鎖又は分岐状のアルキル基である。「低級アルキレン
基」とは炭素数が１乃至６個の直鎖又は分枝状のアルキ
レン基であり，具体的にはメチレン基，エチレン基，エ
チリデン基，プロピリデン基，イソプロピリデン基，プ
ロピレン基，トリメチレン基，テトラメチレン基，１，
１−ジメチルエチレン基，１，２−ジメチルエチレン
基，エチルエチレン基，ペンタメチレン基，ヘキサメチ
レン基等が挙げられ，好ましくは炭素数が１乃至３個の
直鎖状のアルキレン基である。BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the compound (I) of the present invention will be described in detail. In the definition of the general formula in this specification,
Unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms. As the "lower alkyl group", specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert group -Pentyl group, 1-methylbutyl group, 2-methylbutyl group,
Examples thereof include a 1,2-dimethylpropyl group, a hexyl group, and an isohexyl group, and are preferably a linear or branched alkyl group having 1 to 4 carbon atoms. The “lower alkylene group” is a linear or branched alkylene group having 1 to 6 carbon atoms, specifically, a methylene group, an ethylene group, an ethylidene group, a propylidene group, an isopropylidene group, a propylene group, Trimethylene group, tetramethylene group, 1,
Examples thereof include a 1-dimethylethylene group, a 1,2-dimethylethylene group, an ethylethylene group, a pentamethylene group, and a hexamethylene group, and are preferably a linear alkylene group having 1 to 3 carbon atoms.
【０００７】「４乃至１０員含窒素シクロアルキル環」
としては，具体的に例えばアゼチジン，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，オクタヒドロアゾニン又はデカヒドロキシアゼシン
等が挙げられ，好ましくはヘキサヒドロアゼピンであ
る。「カルボニル基を有していても良く窒素原子を１又
は２個含む５乃至７員シクロアルキル」としては，具体
的に例えばピロリジン，ピペリジン，ピペラジン，ピペ
ラジンジオン，ヘキサヒドロアゼピン，２−ピロリジノ
ン，２−ピペリジノン，ε−カプロラクタム又は７−ヘ
プタンラクタム等が挙げられ，好ましくは２−ピペリジ
ノンである。「Ｒ3若しくはＲ6と一体になって環を形成
しても良い」とは５乃至８員ラクタム環若しくは環状イ
ミドを意味し，具体的に例えば２−ピロリジノン，２−
ピペリジノン，２，６−ピペリジンジオン，ε−カプロ
ラクタム又は７−ヘプタンラクタム等が挙げられ，好ま
しくはε−カプロラクタムである。"4- to 10-membered nitrogen-containing cycloalkyl ring"
Specific examples thereof include, for example, azetidine, pyrrolidine, piperidine, hexahydroazepine, octahydroazosin, octahydroazonin, and decahydroxyazecin, and hexahexaazepine is preferred. As the “5- to 7-membered cycloalkyl optionally having a carbonyl group and containing 1 or 2 nitrogen atoms”, specifically, for example, pyrrolidine, piperidine, piperazine, piperazinedione, hexahydroazepine, 2-pyrrolidinone, 2-pyrrolidinone -Piperidinone, ε-caprolactam or 7-heptane lactam, and the like, preferably 2-piperidinone. The phrase “may form a ring together with R 3 or R 6 ” means a 5- to 8-membered lactam ring or cyclic imide, specifically, for example, 2-pyrrolidinone, 2-pyrrolidinone,
Examples thereof include piperidinone, 2,6-piperidinedione, ε-caprolactam and 7-heptane lactam, and ε-caprolactam is preferred.
【０００８】「シクロアルキル基」とは環原子３乃至８
個の単環系炭化水素環基であり具体的に例えば，シクロ
プロピル基，シクロブチル基，シクロペンチル基，シク
ロヘキシル基，シクロヘプチル基又はシクロオクチル基
等が挙げられ，好ましくはシクロヘキシル基である。
「アラルキル基」としては前記「低級アルキル基」の任
意の水素原子がフェニル基やナフチル基などで置換され
た基であり，具体的に例えばベンジル基，フェネチル
基，フェニルプロピル基，メチルフェニルエチル基，フ
ェニルブチル基，メチルフェニルプロピル基，エチルフ
ェニルエチル基，ジメチルフェニルエチル基，フェニル
ペンチル基，メチルフェニルブチル基，フェニルヘキシ
ル基，メチルフェニルペンチル基，ナフチルメチル基，
ナフチルエチル基，ナフチルプロピル基，ナフチルブチ
ル基，ナフチルペンチル基又はナフチルヘキシル基等が
挙げられ，好ましくはベンジル基である。「アリール
基」とは，炭素環アリールを意味し，具体的に例えばフ
ェニル基，トリル基，キシリル基，ビフェニル基，ナフ
チル基，アントリル基又はフェナントリル基等が挙げら
れ，好ましくはフェニル基である。「ヘテロアリール
基」とは窒素原子を１乃至２含む５乃至６員ヘテロ芳香
環であり，具体的に例えばピロール，イミダゾール，ピ
リジン，ピリダジン，ピリミジン又はピラジン等が挙げ
られ，好ましくはピリジン又はピリミジンである。The "cycloalkyl group" is a ring atom having 3 to 8 ring atoms.
And monocyclic hydrocarbon ring groups, specifically, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group, and a cyclohexyl group is preferable.
The “aralkyl group” is a group in which an arbitrary hydrogen atom of the above “lower alkyl group” is substituted with a phenyl group, a naphthyl group or the like, and specifically, for example, a benzyl group, a phenethyl group, a phenylpropyl group, a methylphenylethyl group , Phenylbutyl, methylphenylpropyl, ethylphenylethyl, dimethylphenylethyl, phenylpentyl, methylphenylbutyl, phenylhexyl, methylphenylpentyl, naphthylmethyl,
Examples thereof include a naphthylethyl group, a naphthylpropyl group, a naphthylbutyl group, a naphthylpentyl group and a naphthylhexyl group, and a benzyl group is preferable. The “aryl group” means a carbocyclic aryl, and specifically includes, for example, a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group or a phenanthryl group, and is preferably a phenyl group. The "heteroaryl group" is a 5- or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms, and specifically includes, for example, pyrrole, imidazole, pyridine, pyridazine, pyrimidine or pyrazine, and preferably pyridine or pyrimidine. is there.
【０００９】「置換基をそれぞれ有していても良い低級
アルキル基若しくはアラルキル基」及び「置換基をそれ
ぞれ有していても良い低級アルキル基，シクロアルキル
基，アラルキル基，アリール基若しくはヘテロアリール
基」の「置換基」としては，水酸基，低級アルコキシ
基，アミノ基，モノ若しくはジ低級アルキルアミノ基，
低級アルカノイルアミノ基，カルボキシル基，低級アル
コキシカルボニル基，シアノ基，ハロゲン原子又はニト
ロ基等が挙げられる。「低級アルコキシ基」とは，炭素
数が１乃至６個の直鎖又は分岐状のアルコキシ基であ
り，具体的に例えば，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−ペンチルオキシ基等が挙げられ，好
ましくはメトキシ基である。「モノ若しくはジ低級アル
キルアミノ基」とは，低級アルキル基を１乃至２個有す
るアミノ基であり，具体的に例えば，メチルアミノ基，
エチルアミノ基，プロピルアミノ基，イソプロピルアミ
ノ基，ジメチルアミノ基，ジエチルアミノ基，ジプロピ
ルアミノ基，ジイソプロピルアミノ基等が挙げられる。
「低級アルカノイルアミノ基」とは低級アルカノイル基
を有するアミノ基であり，具体的に例えばホルミルアミ
ノ基，アセチルアミノ基，プロピオニルアミノ基，ブチ
リルアミノ基，イソブチリルアミノ基等が挙げられ，好
ましくはアセチルアミノ基である。「低級アルコキシカ
ルボニル基」とは，炭素数が１乃至６個の直鎖又は分岐
状のアルコキシカルボニル基であり，具体的に例えば，
メトキシカルボニル基，エトキシカルボニル基，プロポ
キシカルボニル基，イソプロポキシカルボニル基，ブト
キシカルボニル基，イソブトキシカルボニル基，ｓｅｃ
−ブトキシカルボニル基，ｔｅｒｔ−ブトキシカルボニ
ル基，ペンチルオキシカルボニル基，イソペンチルオキ
シカルボニル基，ネオペンチルオキシカルボニル基，ｔ
ｅｒｔ−ペンチルオキシカルボニル基等が挙げられる。"Lower alkyl group or aralkyl group optionally having substituents" and "Lower alkyl group, cycloalkyl group, aralkyl group, aryl group or heteroaryl group optionally having substituents""Asa" substituent "includes a hydroxyl group, a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group,
Examples thereof include a lower alkanoylamino group, a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a halogen atom and a nitro group. The "lower alkoxy group" is a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group and an isobutoxy group. , Sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group and the like, and preferably a methoxy group. The “mono- or di-lower alkylamino group” is an amino group having one or two lower alkyl groups, specifically, for example, a methylamino group,
Examples include an ethylamino group, a propylamino group, an isopropylamino group, a dimethylamino group, a diethylamino group, a dipropylamino group, and a diisopropylamino group.
The “lower alkanoylamino group” is an amino group having a lower alkanoyl group, and specific examples include a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, an isobutyrylamino group, and the like. It is an amino group. The “lower alkoxycarbonyl group” is a straight-chain or branched alkoxycarbonyl group having 1 to 6 carbon atoms.
Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec
-Butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, t
ert-pentyloxycarbonyl group and the like.
【００１０】「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，好ましくはフ
ッ素原子である。本発明化合物は酸又は塩基と塩を形成
する場合もある。かかる酸との塩としては，塩酸，臭化
水素酸，硫酸，硝酸又はリン酸等の鉱酸やギ酸，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，クエン酸，酒石
酸，炭酸，ピクリン酸，メタンスルホン酸，エタンスル
ホン酸又はグルタミン酸等の有機酸との酸付加塩を挙げ
ることができる。また塩基との塩としては例えばリチウ
ム，ナトリウム，カリウム，マグネシウム，カルシウム
又はアルミニウム等の無機塩基と，メチルアミン，エチ
ルアミン，エタノールアミン等の有機塩基との付加塩
や，リジン又はオルニチン等の塩基性アミノ酸との塩や
アンモニウム塩が挙げられる。"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom. The compound of the present invention may form a salt with an acid or a base in some cases. Salts with such acids include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, formic acid, acetic acid,
Acid addition with organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid or glutamic acid Salts may be mentioned. Examples of salts with bases include addition salts of inorganic bases such as lithium, sodium, potassium, magnesium, calcium and aluminum with organic bases such as methylamine, ethylamine and ethanolamine, and basic amino acids such as lysine and ornithine. And ammonium salts.
【００１１】また，本発明化合物は，不斉炭素原子を含
有する場合もあるので，これに基づく光学異性体が存在
する。更に，２以上の不斉炭素原子を有するときは，ジ
アステレオ異性体が存在する。本発明にはこれらの異性
体の混合物や単離されたものが含まれる。さらに，本発
明化合物は水和物又はメタノールもしくはエタノール等
の溶媒和物又はそれらの結晶多形も含む。以上，本発明
化合物について詳述したがこれらはすべて本発明化合物
に包含される。Further, the compound of the present invention may contain an asymmetric carbon atom, and there are optical isomers based on this. In addition, when it has more than one asymmetric carbon atom, diastereoisomers are present. The present invention includes a mixture of these isomers and an isolated one. Furthermore, the compound of the present invention also includes a hydrate or a solvate such as methanol or ethanol or a polymorph thereof. As described above, the compounds of the present invention have been described in detail, but all of them are included in the compounds of the present invention.
【００１２】（製造法）本発明化合物は，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
製造法を例示する。(Production method) The compound of the present invention can be produced by applying various synthetic methods. The typical production method is illustrated below.
【００１３】（第一製法）(First manufacturing method)
【化３】 （式中，Ｂ環，Ａ，Ｒ1及びＲ2は前述のとおりであ
る。） 本発明化合物（Ｉ）は一般式（ＩＩ）で示されるカルボ
ン酸化合物を常法によりアミド化する事で製造できる。
本反応は，塩化メチレン，ＤＭＦ，テトラヒドロフラ
ン，エーテル，ジオキサン等の有機溶媒中，トリエチル
アミン，ジイソプロピエチルアミン等の有機塩基存在
下，ジシクロヘキシルカルボジイミド等のカルボジイミ
ド，ジフェニルフォスフォリルアジド，Ｎ，Ｎ’−ジス
クシンイミジニルカーボネート等の脱水縮合剤を用い氷
冷乃至加熱寒流下行うか，又は常法により（ＩＩ）を酸
ハライド又は酸無水物とした後種々のアミン化合物と塩
化メチレン，ＤＭＦ，テトラヒドロフラン，エーテル，
ジオキサン等の有機溶媒中，トリエチルアミン，ジイソ
プロピエチルアミン等の有機塩基存在下，氷冷乃至加熱
還流下反応させる。Embedded image (In the formula, ring B, A, R 1 and R 2 are as described above.) The compound (I) of the present invention is produced by amidating a carboxylic acid compound represented by the general formula (II) by a conventional method. it can.
This reaction is carried out in an organic solvent such as methylene chloride, DMF, tetrahydrofuran, ether or dioxane, in the presence of an organic base such as triethylamine, diisopropylethylamine or the like, in a carbodiimide such as dicyclohexylcarbodiimide, diphenylphosphoryl azide, N, N'-disc. Using a dehydrating condensing agent such as cinimidinyl carbonate or the like under ice-cooling or heating under cooling, or by converting (II) into an acid halide or an acid anhydride by a conventional method, various amine compounds and methylene chloride, DMF, tetrahydrofuran, ether,
The reaction is carried out in an organic solvent such as dioxane in the presence of an organic base such as triethylamine and diisopropylethylamine under ice cooling or heating to reflux.
【００１４】（第二製法）(Second production method)
【化４】 （式中，Ｂ環，Ａ，Ｒ1及びＲ2は前述のとおりであり，
Ｒ13は低級アルキル基を，ＤＩＢＡＬはジイソブチルア
ルミニウムヒドリドを意味する。） 本発明化合物（Ｉ）は一般式（ＩＩＩ）で示されるエス
テル化合物とアミン化合物をＤＩＢＡＬ存在下反応させ
る事で製造できる。本反応はトルエン，ベンゼン，テト
ラヒドロフラン，エーテル，ジオキサン等の有機溶媒
中，氷冷乃至加熱条件下で行うことができる。このよう
にして製造された本発明化合物は，遊離のまま，その
塩，その水和物，その溶媒和物，あるいは結晶多形の物
質として単離精製される。化合物（Ｉ）の塩は，常法の
造塩反応に付すことにより製造することもできる。単離
精製は，抽出，濃縮，留去，結晶化，濾過，再結晶，各
種クロマトグラフィー等の通常の化学操作を適用して行
われる。各種の異性体は，適当な原料化合物を選択する
ことにより，あるいは異性体間の物理的性質の差を利用
して分離することができる。例えば，光学異性体は，適
当な原料を選択することにより，あるいはラセミ化合物
のラセミ分割法（例えば，一般的な光学活性な塩基との
ジアステレオマー塩に導き，光学分割する方法等）によ
り立体科学的に純粋な異性体に導くことができる。以
下，実施例に記載されているものの他に，前述の製造
法，実施例の製造法及び通常の当業者によって公知のそ
れらの変法を用いて合成することができ，特別の実験を
必要とせずに次の化合物を得ることができる。Embedded image (Wherein B ring, A, R 1 and R 2 are as described above,
R 13 represents a lower alkyl group, and DIBAL represents diisobutylaluminum hydride. The compound (I) of the present invention can be produced by reacting an ester compound represented by the general formula (III) with an amine compound in the presence of DIBAL. This reaction can be carried out in an organic solvent such as toluene, benzene, tetrahydrofuran, ether or dioxane under ice-cooling or heating conditions. The compound of the present invention thus produced is isolated and purified as a salt, a hydrate, a solvate or a polymorphic substance as it is free. The salt of compound (I) can also be produced by subjecting the salt to a conventional salt formation reaction. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography. Various isomers can be separated by selecting an appropriate starting compound or by utilizing a difference in physical properties between the isomers. For example, optical isomers can be obtained by selecting appropriate raw materials or by a racemic resolution method of a racemic compound (for example, a method of optically resolving a diastereomer salt with a general optically active base). It can lead to scientifically pure isomers. Hereinafter, in addition to those described in the examples, the compounds can be synthesized using the above-mentioned production methods, the production methods of the examples, and modifications thereof which are known to those skilled in the art, and require special experiments. The following compound can be obtained without using:
【００１５】Ｎ−エチル ４−［５−［（ヘキサヒドロ
−１−アゼピニル）メチル］−２−テノイル］−１−ピ
ペラジンカルボキサミド Ｎ−（４−ニトロフェニル） ４−［５−［（ヘキサヒ
ドロ−１−アゼピニル）メチル］−２−テノイル］−１
−ピペラジンカルボキサミド Ｎ−（４−メチルベンジル） ４−［５−［（ヘキサヒ
ドロ−１−アゼピニル）メチル］−２−テノイル］−１
−ピペラジンカルボキサミド ４−ベンゾイル−１−［５−［（ヘキサヒドロ−１−ア
ゼピニル）メチル］−２−テノイル］−［１，４］−ジ
アゼパン Ｎ−ベンジル ４−［５−［（ヘキサヒドロ−１−アゼ
ピニル）メチル］−２−テノイル］−［１，４］−ジア
ゼパン−１−カルボキサミド ２−［５−［（ヘキサヒドロ−１−アゼピニル）メチ
ル］−２−テノイル］−３，４−ジヒドロ−１Ｈ−イソ
キノリン Ｎ−［１−［５−［（ヘキサヒドロ−１−アゼピニル）
メチル］−２−テノイル］ピペリジン−４−イル ベン
ズアミド Ｎ−（２−ピリジル） ５−［（ヘキサヒドロアゼピニ
ル）メチル］−２−チオフェンカルボキサミド Ｎ−（３−ピリジル） ５−［（ヘキサヒドロアゼピニ
ル）メチル］−２−チオフェンカルボキサミド Ｎ−（４−ピリジル） ５−［（ヘキサヒドロアゼピニ
ル）メチル］−２−チオフェンカルボキサミド ４−ベンジリデン−１−［５−［（ヘキサヒドロ−１−
アゼピニル）メチル］−２−テノイル］ピペリジン Ｎ−ベンジル−３−［１−［５−［（ヘキサヒドロ−１
−アゼピニル）メチル］−２−テノイル］ピロリジン−
３−イル］ウレア Ｎ−（２−オキソ−２−フェニル） ５−［（ヘキサヒ
ドロ−１−アゼピニル）メチル］−２−チオフェンカル
ボキサミド １−［５−［（ヘキサヒドロ−１−アゼピニル）メチ
ル］−２−テノイル］ピペリジン−４−オン ４−［５−［（ヘキサヒドロ−１−アゼピニル）メチ
ル］−２−テノイル］モルホリン １−［５−［（ヘキサヒドロ−１−アゼピニル）メチ
ル］−２−テノイル］−４−フェノキシピペリジン １−ベンゼンスルフォニル−４−［５−［（ヘキサヒド
ロ−１−アゼピニル）メチル］−２−テノイル］ピペラ
ジン １−［５−［（ヘキサヒドロ−１−アゼピニル）メチ
ル］−２−テノイル］−４−（ｐ−トルイル）ピペラジ
ン Ｎ−ベンジル ４−［４−［（ヘキサヒドロ−１−アゼ
ピニル）メチル］−２−テノイル］−１−ピペラジンカ
ルボキサミド Ｎ−ベンジル ３−［４−［（ヘキサヒドロ−１−アゼ
ピニル）メチル］−２−テノイル］−１−ピペラジンカ
ルボキサミド Ｎ−ベンジル ４−［５−［（１−ピロリジル）メチ
ル］−２−テノイル］−１−ピペラジンカルボキサミドN-ethyl 4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -1-piperazinecarboxamide N- (4-nitrophenyl) 4- [5-[(hexahydro-1- Azepinyl) methyl] -2-thenoyl] -1
-Piperazinecarboxamide N- (4-methylbenzyl) 4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -1
-Piperazinecarboxamido 4-benzoyl-1- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl]-[1,4] -diazepane N-benzyl 4- [5-[(hexahydro-1-azepinyl) ) Methyl] -2-thenoyl]-[1,4] -diazepan-1-carboxamide 2- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -3,4-dihydro-1H-isoquinoline N- [1- [5-[(hexahydro-1-azepinyl)
Methyl] -2-thenoyl] piperidin-4-yl benzamide N- (2-pyridyl) 5-[(hexahydroazepinyl) methyl] -2-thiophenecarboxamide N- (3-pyridyl) 5-[(hexahydro Azepinyl) methyl] -2-thiophenecarboxamide N- (4-pyridyl) 5-[(hexahydroazepinyl) methyl] -2-thiophenecarboxamide 4-benzylidene-1- [5-[(hexahydro-1-
Azepinyl) methyl] -2-thenoyl] piperidine N-benzyl-3- [1- [5-[(hexahydro-1
-Azepinyl) methyl] -2-thenoyl] pyrrolidine-
3-yl] urea N- (2-oxo-2-phenyl) 5-[(hexahydro-1-azepinyl) methyl] -2-thiophencarboxamide 1- [5-[(hexahydro-1-azepinyl) methyl] -2 -Thenoyl] piperidin-4-one 4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] morpholine 1- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl]- 4-phenoxypiperidine 1-benzenesulfonyl-4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] piperazine 1- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -4- (p-toluyl) piperazine N-benzyl 4- [4-[(hexahydro-1-azepinyl) methyl] -2-te Yl] -1-piperazinecarboxamide N-benzyl 3- [4-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -1-piperazinecarboxamide N-benzyl 4- [5-[(1-pyrrolidyl) methyl ] -2-Thenoyl] -1-piperazinecarboxamide
【００１６】[0016]
【実施例】以下，実施例により本発明をさらに詳細に説
明するが，本発明はこれらの実施例に限定されるもので
はない。The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.
【００１７】実施例１ ４−［５−［（ヘキサヒドロ−１−アゼピニル）メチ
ル］−２−テノイル］−１−ピペラジンカルボキサルデ
ヒド １−ピペラジンカルボキサルデヒド６００ｍｇのＮ，Ｎ
−ジメチルホルムアルデヒド溶液３０ｍｌに５−［（ヘ
キサヒドロ−１−アゼピニル）メチル］−２−チオフェ
ンカルボン酸塩酸塩１．５ｇ，トリエチルアミン３．７
ｍｌを加え，氷冷下ジフェニルフォスフォリルアジド
１．２ｍｌを加えた後室温で一晩攪拌した。反応液に飽
和重曹水１００ｍｌを加え析出した結晶を濾過し，イソ
プロパノール−ジイソプロピルエーテルで再結晶して標
題化合物７８１ｍｇを得た。 融点：８６−８７℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．５０−１．７０（８Ｈ，ｍ），２．６５−２．
７０（４Ｈ，ｍ），３．４５（２Ｈ，ｔ），３．６２
（２Ｈ，ｔ），３．７５（２Ｈ，ｔ），３．７９（２
Ｈ，ｔ），３．８３（２Ｈ，ｓ），６．８５（１Ｈ，
ｄ），７．１９（１Ｈ，ｄ），８．１２（１Ｈ，ｓ）Example 1 4- [5-[(Hexahydro-1-azepinyl) methyl] -2-thenoyl] -1-piperazinecarboxaldehyde 1-piperazinecarboxaldehyde 600 mg of N, N
1.5 g of 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate in 30 ml of -dimethylformaldehyde solution, 3.7 g of triethylamine.
After adding 1.2 ml of diphenylphosphoryl azide under ice cooling, the mixture was stirred at room temperature overnight. To the reaction solution was added 100 ml of saturated aqueous sodium hydrogen carbonate, and the precipitated crystals were filtered and recrystallized from isopropanol-diisopropyl ether to obtain 781 mg of the title compound. Melting point: 86-87 ° C. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.50-1.70 (8H, m), 2.65-2.
70 (4H, m), 3.45 (2H, t), 3.62
(2H, t), 3.75 (2H, t), 3.79 (2
H, t), 3.83 (2H, s), 6.85 (1H,
d), 7.19 (1H, d), 8.12 (1H, s)
【００１８】実施例２ エチル ２−［［５−［（ヘキサヒドロ−１−アゼピニ
ル）メチル］−２−テノイル］アミノ］アセテート ５−［（ヘキサヒドロ−１−アゼピニル）メチル］チオ
フェン−２−カルボン酸塩酸塩９００ｍｇのアセトニト
リル懸濁液２０ｍｌにトリエチルアミン２．５ｍｌを加
え１０分間攪拌後，Ｎ，Ｎ’−ジスクシンイミジルカー
ボネート８３５ｍｇを加え室温で２時間攪拌した。次に
グリシンエチルエステル塩酸塩４５５ｍｇを加え室温で
一晩攪拌後，減圧濃縮し，残渣に飽和重曹水５０ｍｌを
加えクロロホルム５０ｍｌで３回抽出した。有機層を合
わせてブラインで洗浄し，無水硫酸ナトリウムにて乾燥
後，減圧濃縮して得られた残渣をシリカゲルカラムクロ
マトグラフィーにて精製して標題化合物４００ｍｇを得
た。 融点：６３−６４℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．２９（３Ｈ，ｔ），１．５５（８Ｈ，ｓ），
１．６０−１．７０（４Ｈ，ｍ），２．６０−２．６７
（２Ｈ，ｍ），３．８２（２Ｈ，ｓ），４．２０（２
Ｈ，ｄ），４．２５（２Ｈ，ｑ），６．３８（１Ｈ，ｂ
ｒ），６．８６（１Ｈ，ｄ），６．４４（１Ｈ，ｄ）EXAMPLE 2 Ethyl 2-[[5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] amino] acetate 5-[(hexahydro-1-azepinyl) methyl] thiophen-2-carboxylate 2.5 ml of triethylamine was added to 20 ml of a suspension of 900 mg of salt in acetonitrile, stirred for 10 minutes, 835 mg of N, N'-disuccinimidyl carbonate was added, and the mixture was stirred at room temperature for 2 hours. Next, 455 mg of glycine ethyl ester hydrochloride was added, the mixture was stirred at room temperature overnight, concentrated under reduced pressure, 50 ml of saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted three times with 50 ml of chloroform. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 400 mg of the title compound. Melting point: 63-64 ° C. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.29 (3H, t), 1.55 (8H, s),
1.60-1.70 (4H, m), 2.60-2.67
(2H, m), 3.82 (2H, s), 4.20 (2
H, d), 4.25 (2H, q), 6.38 (1H, b
r), 6.86 (1H, d), 6.44 (1H, d)
【００１９】実施例３ Ｎ−ベンジル−２−［［５［（ヘキサヒドロ−１−アゼ
ピニル）メチル］−２−テノイル］アミノ］アセタミド Ｎ−ベンジル−２−アミノアセタミド塩酸塩５３４ｍ
ｇ，５−［１−［（ヘキサヒドロ−１−アゼピニル）メ
チル］−２−チオフェンカルボン酸塩酸塩８００ｍｇを
用い，実施例１の方法によりアミド化し，標題化合物６
００ｍｇを得た。 融点：１５７−１５８℃ 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6，ＴＭＳ内部標
準） δ：１．５６（８Ｈ，ｓ），２．５５−２．６０（４
Ｈ，ｍ），３．７９（２Ｈ，ｓ），３．８６（２Ｈ，
ｄ），４．２９（２Ｈ，ｄ），６．９５（１Ｈ，ｄ），
７．２０−７．３５（５Ｈ，ｍ），７．６１（１Ｈ，
ｄ），８．４０（１Ｈ，ｔ），８．６７（１Ｈ，ｔ）Example 3 N-benzyl-2-[[5 [(hexahydro-1-azepinyl) methyl] -2-thenoyl] amino] acetamide N-benzyl-2-aminoacetamide hydrochloride 534m
g, amidation was conducted using 800 mg of 5- [1-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate hydrochloride according to the method of Example 1 to give the title compound 6
00 mg was obtained. Melting point: 157-158 ° C Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.56 (8H, s), 2.55-2.60 (4
H, m), 3.79 (2H, s), 3.86 (2H,
d), 4.29 (2H, d), 6.95 (1H, d),
7.20-7.35 (5H, m), 7.61 (1H,
d), 8.40 (1H, t), 8.67 (1H, t)
【００２０】実施例４ Ｎ−ベンジル−３−［［５−［（ヘキサヒドロ−１−ア
ゼピニル）メチル］−２−テノイル］アミノ］プロピオ
ナミド Ｎ−ベンジル−３−アミノプロピオナミド塩酸塩８５６
ｍｇ，５−［（ヘキサヒドロ−１−アゼピニル）メチ
ル］−２−チオフェンカルボン酸塩酸塩１．０ｇを用
い，実施例１の方法によりアミド化して標題化合物８０
０ｍｇを得た。 融点：１５２−１５３℃ 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6，ＴＭＳ内部標
準） δ：１．５６（８Ｈ，ｓ），２．５９（４Ｈ，ｓ），
３．１０−３．２０（２Ｈ，ｍ），３．２５−３．４０
（２Ｈ，ｍ），３．７８（２Ｈ，ｓ），４．２１（２
Ｈ，ｄ），６．９４（１Ｈ，ｄ），７．１５−７．３０
（５Ｈ，ｍ），７．５５（１Ｈ，ｄ），８．４３（１
Ｈ，ｔ），８．５１（１Ｈ，ｔ）Example 4 N-benzyl-3-[[5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] amino] propionamide N-benzyl-3-aminopropionamide hydrochloride 856
mg, 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate hydrochloride (1.0 g) was amidated by the method of Example 1 to give the title compound 80
0 mg was obtained. Melting point: 152-153 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.56 (8H, s), 2.59 (4H, s),
3.10-3.20 (2H, m), 3.25-3.40
(2H, m), 3.78 (2H, s), 4.21 (2
H, d), 6.94 (1H, d), 7.15-7.30.
(5H, m), 7.55 (1H, d), 8.43 (1
H, t), 8.51 (1H, t)
【００２１】実施例５ Ｎ−［３−（Ｎ−ベンジルカルバモイル）プロピル］−
５−［（ヘキサヒドロ−１−アゼピニル）メチル］−２
−チオフェンカルボキサミド Ｎ−ベンジル−４−アミノブチラミド塩酸塩１．２ｇ，
５−［（ヘキサヒドロ−１−アゼピニル）メチル］−２
−チオフェンカルボン酸塩酸塩１．０ｇを用い，実施例
１の方法によりアミド化して標題化合物７２０ｍｇを得
た。 融点：１３７−１３８℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．５６（８Ｈ，ｓ），１．９０−２．００（２
Ｈ，ｍ），２．３５（２Ｈ，ｄｄ），２．６５（４Ｈ，
ｄｄ），３．４０−３．５０（２Ｈ，ｍ），３．８１
（２Ｈ，ｓ），４．４２（２Ｈ，ｄ），６．２２（１
Ｈ，ｂｒ），６．７０（１Ｈ，ｂｒ），６．８４（１
Ｈ，ｄ），７．３１（５Ｈ，ｓ），７．３８（１Ｈ，
ｄ）Example 5 N- [3- (N-benzylcarbamoyl) propyl]-
5-[(hexahydro-1-azepinyl) methyl] -2
-Thiophenecarboxamide N-benzyl-4-aminobutyramide hydrochloride 1.2 g,
5-[(hexahydro-1-azepinyl) methyl] -2
Using 1.0 g of -thiophenecarboxylic acid hydrochloride, amidation was carried out by the method of Example 1 to obtain 720 mg of the title compound. Melting point: 137-138 ° C. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.56 (8H, s), 1.90-2.00 (2
H, m), 2.35 (2H, dd), 2.65 (4H,
dd), 3.40-3.50 (2H, m), 3.81
(2H, s), 4.42 (2H, d), 6.22 (1
H, br), 6.70 (1H, br), 6.84 (1
H, d), 7.31 (5H, s), 7.38 (1H,
d)
【００２２】実施例６ １）ｔ−ブチル（Ｓ）−４−ベンジルカルバモイル−
２，２−ジメチル−３−オキサゾリジンカルボキシレー
ト １Ｎ ジイソブチルアルミニウムヒドリド−トルエン溶
液１０ｍｌにベンジルアミン１．２ｍｌを加え発熱した
反応液が室温に戻るまで約１時間攪拌し，３−ｔ−ブチ
ル，４−メチル，（Ｓ）−２，２−ジメチル−３，４−
オキサゾリジンジカルボキシレート２．６ｇのトルエン
溶液１０ｍｌを加え，６０℃で３時間攪拌した。次に反
応液を氷冷し，水１０ｍｌを加え３０分間攪拌後セライ
ト濾過し，ブライン１００ｍｌを加えトルエン１００ｍ
ｌで２回分液した。有機層を合わせて無水硫酸ナトリウ
ムにて乾燥後減圧濃縮し，シリカゲルカラムクロマトグ
ラフィーにて精製して標題化合物２．５ｇを得た。 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．４１（９Ｈ，ｓ），１．５２（３Ｈ，ｓ），
１．６１（３Ｈ，ｓ），３．９０−４．６０（５Ｈ，
ｍ），７．３２（５Ｈ，ｓ）Example 6 1) t-Butyl (S) -4-benzylcarbamoyl-
To the solution of 2,2-dimethyl-3-oxazolidinecarboxylate 1N diisobutylaluminum hydride-toluene (10 ml) was added benzylamine (1.2 ml), and the mixture was stirred for about 1 hour until the exothermic reaction solution returned to room temperature. Methyl, (S) -2,2-dimethyl-3,4-
10 ml of a toluene solution of 2.6 g of oxazolidine dicarboxylate was added, and the mixture was stirred at 60 ° C. for 3 hours. Next, the reaction solution was ice-cooled, 10 ml of water was added, and the mixture was stirred for 30 minutes, filtered through celite, 100 ml of brine was added, and 100 ml of toluene was added.
1 was separated twice. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2.5 g of the title compound. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.41 (9H, s), 1.52 (3H, s),
1.61 (3H, s), 3.90-4.60 (5H,
m), 7.32 (5H, s)
【００２３】２）（Ｓ）−Ｎ−ベンジル−２−アミノ−
３−ヒドロキシプロピオナミド塩酸塩 ｔ−ブチル（Ｓ）−４−ベンジルアミノカルボニル−
２，２−ジメチル−３−オキサゾリジンカルボキシレー
ト２．５ｇに４Ｎ塩−酢酸エチル溶液を加え室温で攪拌
後，析出した結晶を濾過して標題化合物８００ｍｇを得
た。 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6，ＴＭＳ内部標
準） δ：３．３４（１Ｈ，ｓ），３．６０−４．００（２
Ｈ，ｍ），４．３５（２Ｈ，ｄ），５．５３（１Ｈ，
ｔ），７．３１（５Ｈ，ｓ），８．９１（１Ｈ，ｔ）2) (S) -N-benzyl-2-amino-
3-hydroxypropionamide hydrochloride t-butyl (S) -4-benzylaminocarbonyl-
A 4N salt-ethyl acetate solution was added to 2.5 g of 2,2-dimethyl-3-oxazolidinecarboxylate, and the mixture was stirred at room temperature. The precipitated crystals were filtered to obtain 800 mg of the title compound. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 3.34 (1H, s), 3.60-4.00 (2
H, m), 4.35 (2H, d), 5.53 (1H,
t), 7.31 (5H, s), 8.91 (1H, t)
【００２４】３）（Ｓ）−Ｎ−［１−［（Ｎ−ベンジル
カルバモイル）−２−ヒドロキシエチル］−５−［（ヘ
キサヒドロ−１−アゼピニル）メチル］−２−チオフェ
ンカルボキサミド （Ｓ）−Ｎ−ベンジル−２−アミノ−３−ヒドロキシプ
ロピオナミド塩酸塩３６７ｍｇ，５−［（ヘキサヒドロ
−１−アゼピニル）メチル］−２−チオフェンカルボン
酸塩酸塩２４３ｍｇを用い，実施例２の方法によりアミ
ド化して標題化合物４３８ｍｇを得た。 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．６５（８Ｈ，ｓ），２．５０−２．７０（４
Ｈ，ｍ），３．６０−３．７０（１Ｈ，ｍ），３．８１
（２Ｈ，ｓ），４．２２（１Ｈ，ｄ），４．４０−４．
６０（２Ｈ，ｍ），４．６３（１Ｈ，ｂｒ），６．８５
（１Ｈ，ｄ），７．２０−７．４０（５Ｈ，ｍ），７．
４１（１Ｈ，ｄ）3) (S) -N- [1-[(N-benzylcarbamoyl) -2-hydroxyethyl] -5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxamide (S) -N Using 367 mg of -benzyl-2-amino-3-hydroxypropionamide hydrochloride and 243 mg of 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate hydrochloride, amidation was carried out by the method of Example 2. 438 mg of the title compound were obtained. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.65 (8H, s), 2.50-2.70 (4
H, m), 3.60-3.70 (1H, m), 3.81
(2H, s), 4.22 (1H, d), 4.40-4.
60 (2H, m), 4.63 (1H, br), 6.85
(1H, d), 7.20-7.40 (5H, m), 7.
41 (1H, d)
【００２５】実施例７ Ｎ，Ｎ−ビス［（Ｎ−ベンジルカルバモイル）メチル］
−５−［（ヘキサヒドロ−１−アゼピニル）メチル］−
２−チオフェンカルボキサミド Ｎ，Ｎ−ビス［Ｎ−ベンジルカルバモイル）メチル］ア
ミン１．７ｇ，５−［（ヘキサヒドロ−１−アゼピニ
ル）メチル］−２−チオフェンカルボン酸塩酸塩１．５
ｇを用い，実施例１の方法によりアミド化して標題化合
物２．０ｇを得た。 融点：１４７−１４８℃ 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6，ＴＭＳ内部標
準） δ：１．５６（８Ｈ，ｓ），２．５０−２．６５（４
Ｈ，ｍ），３．３１（４Ｈ，ｓ），３．７９（２Ｈ，
ｓ），６．８８（１Ｈ，ｄ），７．１３（１Ｈ，ｄ），
７．２０−７．４０（１０Ｈ，ｍ），８．７８（１Ｈ，
ｂｒ），９．２６（１Ｈ，ｂｒ）Example 7 N, N-bis [(N-benzylcarbamoyl) methyl]
-5-[(hexahydro-1-azepinyl) methyl]-
2-thiophenecarboxamide N, N-bis [N-benzylcarbamoyl) methyl] amine 1.7 g, 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate 1.5
Using g, amidation was carried out by the method of Example 1 to obtain 2.0 g of the title compound. Melting point: 147-148 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.56 (8H, s), 2.50-2.65 (4
H, m), 3.31 (4H, s), 3.79 (2H,
s), 6.88 (1H, d), 7.13 (1H, d),
7.20-7.40 (10H, m), 8.78 (1H,
br), 9.26 (1H, br)
【００２６】実施例８ Ｎ−ベンジル−２−［Ｎ−［５−［（ヘキサヒドロ−１
−アゼピニル）メチル］−２−テノイル］−Ｎ−メチル
アミノ］アセタミド エチル ２−［Ｎ−［５−［（ヘキサヒドロ−１−アゼ
ピニル）メチル］−Ｎ−メチルアミノ］アセテート１．
５ｇ，ベンジルアミン０．６ｍｌを用い，実施例６−
１）の方法によりアミド化して標題化合物１．０ｇを得
た。 融点：１０５−１０６℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．５６（８Ｈ，ｓ），２．６６（４Ｈ，ｄｄ），
３．３２（３Ｈ，ｓ），３．８２（２Ｈ，ｓ），４．１
８（２Ｈ，ｓ），４．４８（２Ｈ，ｄ），６．８３（１
Ｈ，ｄ），７．２７（５Ｈ，ｓ），７．３２（１Ｈ，
ｄ）Example 8 N-benzyl-2- [N- [5-[(hexahydro-1
-Azepinyl) methyl] -2-thenoyl] -N-methylamino] acetamidoethyl 2- [N- [5-[(hexahydro-1-azepinyl) methyl] -N-methylamino] acetate
Example 6 using 5 g and 0.6 ml of benzylamine
Amidation was carried out by the method of 1) to obtain 1.0 g of the title compound. Melting point: 105-106 ° C Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.56 (8H, s), 2.66 (4H, dd),
3.32 (3H, s), 3.82 (2H, s), 4.1
8 (2H, s), 4.48 (2H, d), 6.83 (1
H, d), 7.27 (5H, s), 7.32 (1H,
d)
【００２７】実施例９ Ｎ−ベンジル−２−［Ｎ−ベンジル−Ｎ−［５−［（ヘ
キサヒドロ−１−アゼピニル）メチル］−２−テノイル
アミノ］アセタミド エチル ２−［Ｎ−ベンジル−Ｎ−［５−［（ヘキサヒ
ドロ−１−アゼピニル）メチル］−２−テノイルアミ
ノ］アセテート１．５ｇ，ベンジルアミン０．５ｍｌを
用い実施例６−１）の方法によりアミド化して標題化合
物１．０ｇを得た。 融点：１１９−１２０℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．５７（８Ｈ，ｓ），１．６０−１．７０（４
Ｈ，ｍ），２．６０−２．７０（４Ｈ，ｍ），３．８１
（２Ｈ，ｓ），４．６１（２Ｈ，ｄ），６．１４（１
Ｈ，ｂｒ），６．８４（１Ｈ，ｄ），７．２０−７．４
０（６Ｈ，ｍ）Example 9 N-benzyl-2- [N-benzyl-N- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoylamino] acetamidoethyl 2- [N-benzyl-N- [5 Amidation was carried out by the method of Example 6-1) using 1.5 g of-[(hexahydro-1-azepinyl) methyl] -2-thenoylamino] acetate and 0.5 ml of benzylamine to obtain 1.0 g of the title compound. Melting point: 119-120 ° C Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.57 (8H, s), 1.60-1.70 (4
H, m), 2.60-2.70 (4H, m), 3.81
(2H, s), 4.61 (2H, d), 6.14 (1
H, br), 6.84 (1H, d), 7.20-7.4.
0 (6H, m)
【００２８】実施例１０ Ｎ−（２−ベンジルオキシエチル）−５−［（ヘキサヒ
ドロ−１−アゼピニル）メチル］−２−チオフェンカル
ボキサミド （２−ベンジルオキシエチル）アミン４３９ｍｇ，５−
［（ヘキサヒドロ−１−アゼピニル）メチル］−２−チ
オフェンカルボン酸塩酸塩８００ｍｇを用い，実施例２
の方法によりアミド化して標題化合物８００ｍｇを得
た。 融点：５６−５７℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．６０−１．７０（８Ｈ，ｍ），２．６０−２．
７０（４Ｈ，ｍ），３．６４（４Ｈ，ｓ），３．８０
（２Ｈ，ｓ），４．５５（２Ｈ，ｓ），６．３０（１
Ｈ，ｂｒ），６．８４（１Ｈ，ｄ），７．２０−７．４
０（６Ｈ，ｍ）Example 10 N- (2-benzyloxyethyl) -5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxamide (2-benzyloxyethyl) amine 439 mg, 5-
Example 2 using 800 mg of [(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate hydrochloride
The title compound was obtained by amidation according to the procedure described above in 800 mg. Melting point: 56-57 ° C. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.60-1.70 (8H, m), 2.60-2.
70 (4H, m), 3.64 (4H, s), 3.80
(2H, s), 4.55 (2H, s), 6.30 (1
H, br), 6.84 (1H, d), 7.20-7.4.
0 (6H, m)
【００２９】実施例１１ Ｎ−ベンジル−４−［５−［（ヘキサヒドロ−１−アゼ
ピニル）メチル］−２−テノイル］−１−ピペラジンカ
ルボキサミド Ｎ−ベンジル−１−ピペラジンカルボキサミド６９０ｍ
ｇ，５−［ヘキサヒドロ−１−アゼピニル）メチル］−
２−チオフェンカルボン酸塩酸塩８７５ｍｇを用い実施
例１の方法によりアミド化して標題化合物７００ｍｇを
得た。 融点：８６−８８℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．５６（８Ｈ，ｓ），２．６６（４Ｈ，ｄｄ），
３．４０−３．５０（４Ｈ，ｍ），３．７０−３．８０
（４Ｈ，ｍ），３．８１（２Ｈ，ｓ），４．４５（２
Ｈ，ｄ），４．７２（１Ｈ，ｔ），６．８４（１Ｈ，ｂ
ｒ），７．２５−７．５２（６Ｈ，ｍ）Example 11 N-benzyl-4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -1-piperazinecarboxamide N-benzyl-1-piperazinecarboxamide 690 m
g, 5- [Hexahydro-1-azepinyl) methyl]-
Amidation was carried out using 875 mg of 2-thiophenecarboxylic acid hydrochloride according to the method of Example 1 to obtain 700 mg of the title compound. Melting point: 86-88 ° C. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.56 (8H, s), 2.66 (4H, dd),
3.40-3.50 (4H, m), 3.70-3.80
(4H, m), 3.81 (2H, s), 4.45 (2
H, d), 4.72 (1H, t), 6.84 (1H, b
r), 7.25-7.52 (6H, m)
【００３０】実施例１２ １−ベンゾイル−４−［５−［（ヘキサヒドロ−１−ア
ゼピニル）メチル］−２−テノイル］ピペラジン １−ベンゾイルピペラジン塩酸塩７４０ｍｇ，５−
［（ヘキサヒドロ−１−アゼピニル）メチル］−２−チ
オフェンカルボン酸塩酸塩９００ｍｇを用い実施例１の
方法によりアミド化して標題化合物８００ｍｇを得た。 融点：１０３−１０５℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．５０−１．７０（８Ｈ，ｍ），２．６０−２．
７０（４Ｈ，ｍ），３．３０−４．００（１０Ｈ，
ｍ），６．８３（１Ｈ，ｄ），７．１８（１Ｈ，ｄ），
７．４０−７．５０（４Ｈ，ｍ）Example 12 1-benzoyl-4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] piperazine 740 mg of 1-benzoylpiperazine hydrochloride, 5-
Amidation was carried out using 900 mg of [(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate according to the method of Example 1 to obtain 800 mg of the title compound. Melting point: 103-105 ° C Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.50-1.70 (8H, m), 2.60-2.
70 (4H, m), 3.30-4.00 (10H,
m), 6.83 (1H, d), 7.18 (1H, d),
7.40-7.50 (4H, m)
【００３１】実施例１３ １−［５−［［４−（２−ピリミジニル）−１−ピペラ
ジニル］カルボニル］−２−テニル］ヘキサヒドロ−１
−アゼピン １−（２−ピリミジニル）ピペラジン８９３ｍｇ，５−
［（ヘキサヒドロ−１−アゼピニル）メチル］−２−チ
オフェンカルボン酸塩酸塩１．５ｇを用い，実施例１の
方法によりアミド化して標題化合物１．２ｇを得た。 融点：１０８−１０９℃ 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6，ＴＭＳ内部標
準） δ：１．５７（８Ｈ，ｓ），２．６２（４Ｈ，ｄｄ），
３．７３（４Ｈ，ｓ），３．７５−３．８５（６Ｈ，
ｍ），６．６７（１Ｈ，ｔ），６．９５（１Ｈ，ｄ），
７．３０（１Ｈ，ｄ），８．３９（２Ｈ，ｄ）Example 13 1- [5-[[4- (2-Pyrimidinyl) -1-piperazinyl] carbonyl] -2-thenyl] hexahydro-1
-Azepine 1- (2-pyrimidinyl) piperazine 893 mg, 5-
Amidation was performed by the method of Example 1 using 1.5 g of [(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate to obtain 1.2 g of the title compound. Melting point: 108-109 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.57 (8H, s), 2.62 (4H, dd),
3.73 (4H, s), 3.75-3.85 (6H,
m), 6.67 (1H, t), 6.95 (1H, d),
7.30 (1H, d), 8.39 (2H, d)
【００３２】実施例１４ １−［５−［［４−（２−ピリジニル）−１−ピペラジ
ニル］カルボニル］−２−テニル］ヘキサヒドロ−１−
アゼピン １−（２−ピリジニル）ピペラジン１．０ｍｌ，５−
［（ヘキサヒドロ−１−アゼピニル）メチル］−２−チ
オフェンカルボン酸塩１．５ｇを用い実施例１の方法に
よりアミド化して標題化合物１．０ｇを得た。 融点：８４−８５℃ 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6，ＴＭＳ内部標
準） δ：１．５７（８Ｈ，ｓ），２．６２（４Ｈ，ｄｄ），
３．５０−３．６０（４Ｈ，ｍ），３．７０−３．８０
（４Ｈ，ｍ），３．８１（２Ｈ，ｓ），６．６７（１
Ｈ，ｄｄ），６．８４（１Ｈ，ｄ），６．９５（１Ｈ，
ｄ），７．３０（１Ｈ，ｄ），７．５７（１Ｈ，ｄ
ｄ），８．１３（１Ｈ，ｄ）Example 14 1- [5-[[4- (2-pyridinyl) -1-piperazinyl] carbonyl] -2-thenyl] hexahydro-1-
Azepine 1- (2-pyridinyl) piperazine 1.0 ml, 5-
Amidation was conducted by the method of Example 1 using 1.5 g of [(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate to obtain 1.0 g of the title compound. Melting point: 84-85 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.57 (8H, s), 2.62 (4H, dd),
3.50-3.60 (4H, m), 3.70-3.80
(4H, m), 3.81 (2H, s), 6.67 (1
H, dd), 6.84 (1H, d), 6.95 (1H,
d), 7.30 (1H, d), 7.57 (1H, d
d), 8.13 (1H, d)
【００３３】実施例１５ １−［５−［（４−フェニル−１−ピペラジニル）カル
ボニル］−２−テニル］−ヘキサヒドロアゼピン １−フェニルピペラジン０．８ｍｌ，５−［（ヘキサヒ
ドロ−１−アゼピニル）メチル］−２−チオフェンカル
ボン酸塩酸塩１．５ｇを用い，実施例１の方法によりア
ミド化して標題化合物８００ｍｇを得た。 融点：８３−８４℃ 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6，ＴＭＳ内部標
準） δ：１．５７（８Ｈ，ｓ），２．６２（４Ｈ，ｄｄ），
３．２０（４Ｈ，ｔ），３．７８（４Ｈ，ｔ），３．８
１（２Ｈ，ｓ），６．８２（１Ｈ，ｄ），６．４０−
７．００（３Ｈ，ｍ），７．２０−７．３０（３Ｈ，
ｍ）Example 15 1- [5-[(4-Phenyl-1-piperazinyl) carbonyl] -2-thenyl] -hexahydroazepine 0.8 ml of 1-phenylpiperazine, 5-[(hexahydro-1-azepinyl) Using 1.5 g of [methyl] -2-thiophenecarboxylate hydrochloride, amidation was carried out by the method of Example 1 to obtain 800 mg of the title compound. Melting point: 83-84 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.57 (8H, s), 2.62 (4H, dd),
3.20 (4H, t), 3.78 (4H, t), 3.8
1 (2H, s), 6.82 (1H, d), 6.40 −
7.00 (3H, m), 7.20-7.30 (3H,
m)
【００３４】実施例１６ １−［５−［（４−ベンジル−１−ピペラジニル）カル
ボニル］−２−テニル］ヘキサヒドロ−１−アゼピン １−ベンジルピペラジン９６０ｍｇ，５−［（ヘキサヒ
ドロ−１−アゼピニル）メチル］−２−チオフェンカル
ボン酸塩酸塩１．５ｇを用い，実施例１の方法によりア
ミド化して標題化合物１．９ｇを得た。 融点：８８−８９℃ 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6，ＴＭＳ内部標
準） δ：１．５６（８Ｈ，ｓ），２．４０（４Ｈ，ｄｄ），
２．６０（４Ｈ，ｔ），３．５１（２Ｈ，ｓ），３．６
３（４Ｈ，ｔ），３．７９（２Ｈ，ｓ），６．９１（１
Ｈ，ｄ），７．２１（１Ｈ，ｄ），７．２５−７．４０
（５Ｈ，ｍ）Example 16 1- [5-[(4-benzyl-1-piperazinyl) carbonyl] -2-thenyl] hexahydro-1-azepine 960 mg of 1-benzylpiperazine, 5-[(hexahydro-1-azepinyl) methyl Amidation was carried out according to the method of Example 1 using 1.5 g of 2-thiophenecarboxylic acid hydrochloride to obtain 1.9 g of the title compound. Melting point: 88-89 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.56 (8H, s), 2.40 (4H, dd),
2.60 (4H, t), 3.51 (2H, s), 3.6
3 (4H, t), 3.79 (2H, s), 6.91 (1
H, d), 7.21 (1H, d), 7.25-7.40.
(5H, m)
【００３５】実施例１７ １−ベンジル−４−［５−［ヘキサヒドロ−１−アゼピ
ニル）メチル］−２−テノイル］−２−ピペラジノン １−ベンジル−２−ピペラジノン４１５ｍｇ，５−
［（ヘキサヒドロ−１−アゼピニル）メチル］−２−チ
オフェンカルボン酸６０１ｍｇを用い，実施例１の方法
によりアミド化して標題化合物６００ｍｇを得た。 融点：９８−９９℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．５０−１．７０（８Ｈ，ｍ），２．６６（４
Ｈ，ｄｄ），３．３５（２Ｈ，ｔ），３．８２（２Ｈ，
ｓ），３．９１（２Ｈ，ｔ），４．５２（２Ｈ，ｓ），
４．６４（２Ｈ，ｓ），６．８４（１Ｈ，ｄ），７．２
２（１Ｈ，ｄ），７．３０−７．４０（５Ｈ，ｍ）Example 17 1-benzyl-4- [5- [hexahydro-1-azepinyl) methyl] -2-thenoyl] -2-piperazinone 1-benzyl-2-piperazinone 415 mg, 5-
Amidation was carried out according to the method of Example 1 using 601 mg of [(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylic acid to obtain 600 mg of the title compound. Melting point: 98-99 ° C. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.50-1.70 (8H, m), 2.66 (4
H, dd), 3.35 (2H, t), 3.82 (2H,
s), 3.91 (2H, t), 4.52 (2H, s),
4.64 (2H, s), 6.84 (1H, d), 7.2
2 (1H, d), 7.30-7.40 (5H, m)
【００３６】実施例１８ エチル ４［４−［５−［（ヘキサヒドロ−１−アゼピ
ニル）メチル］−２−テノイルピペラジン−１−カルボ
キシレート塩酸塩 エチル １−ピペラジンカルボキシレート０．８ｍｌ，
５−［（ヘキサヒドロ−１−アゼピニルメチル］−２−
チオフェンカルボン酸塩酸塩１．５ｇを用い，実施例１
の方法によりアミド化し，得られた化合物に４Ｎ塩酸−
酢酸エチル溶液を加え析出した結晶を濾過して標題化合
物１．１ｇを得た。 融点：２０７−２０９℃ 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6，ＴＭＳ内部標
準） δ：１．２０（３Ｈ，ｔ），１．５０−１．９０（８
Ｈ，ｍ），３．００−３．１０（２Ｈ，ｍ），３．３０
−３．４０（２Ｈ，ｍ），３．４６（４Ｈ，ｔ），３．
６４（４Ｈ，ｔ），４．０７（２Ｈ，ｑ），４．５６
（２Ｈ，ｄ），７．４２（１Ｈ，ｄ），７．４４（１
Ｈ，ｄ），１０．８０（１Ｈ，ｂｒ）Example 18 Ethyl 4 [4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoylpiperazine-1-carboxylate hydrochloride 0.8 ml of ethyl 1-piperazinecarboxylate,
5-[(hexahydro-1-azepinylmethyl) -2-
Example 1 Using 1.5 g of thiophenecarboxylate hydrochloride
Amidation was carried out by the method of 4
An ethyl acetate solution was added, and the precipitated crystals were filtered to obtain 1.1 g of the title compound. Melting point: 207-209 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.20 (3H, t), 1.50-1.90 (8
H, m), 3.00-3.10 (2H, m), 3.30
-3.40 (2H, m), 3.46 (4H, t), 3.
64 (4H, t), 4.07 (2H, q), 4.56
(2H, d), 7.42 (1H, d), 7.44 (1
H, d), 10.80 (1H, br)
【００３７】実施例１９ １−［５−［（ヘキサヒドロ−１−アゼピニル）メチ
ル］−２−テノイル］−４−（４−メトキシベンゾイ
ル］ピペラジン塩酸塩 １−（４−メトキシベンゾイル）ピペラジン２．２ｇ，
５−［（ヘキサヒドロ−１−アゼピニル）メチル］−２
−チオフェンカルボン酸塩酸塩２．８ｇを用い，実施例
１の方法によりアミド化して得られた化合物に４Ｎ塩酸
−酢酸エチル溶液を加え析出した結晶を濾過し，メタノ
ール−イソプロパノールより再結晶して標題化合物２．
７ｇを得た。 融点：２０５−２０７℃ 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6，ＴＭＳ内部標
準） δ：１．３０−１．９０（８Ｈ，ｍ），３．００−３．
１５（２Ｈ，ｍ），３．３０−３．４０（２Ｈ，ｍ），
３．５０−３．７５（８Ｈ，ｍ），３．８０（３Ｈ，
ｓ），４．５９（２Ｈ，ｄ），７．００（２Ｈ，ｄ），
７．３８（１Ｈ，ｄ），７．４１（２Ｈ，ｄ），７．４
４（１Ｈ，ｄ），１０．１０（１Ｈ，ｂｒ）Example 19 1- [5-[(Hexahydro-1-azepinyl) methyl] -2-thenoyl] -4- (4-methoxybenzoyl] piperazine hydrochloride 2.2 g of 1- (4-methoxybenzoyl) piperazine ,
5-[(hexahydro-1-azepinyl) methyl] -2
Using 2.8 g of thiophenecarboxylate hydrochloride, a 4N hydrochloric acid-ethyl acetate solution was added to the compound obtained by amidation according to the method of Example 1, and the precipitated crystals were filtered and recrystallized from methanol-isopropanol to give the title. Compound 2.
7 g were obtained. Melting point: 205-207 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.30-1.90 (8H, m), 3.00-3.
15 (2H, m), 3.30-3.40 (2H, m),
3.50-3.75 (8H, m), 3.80 (3H,
s), 4.59 (2H, d), 7.00 (2H, d),
7.38 (1H, d), 7.41 (2H, d), 7.4
4 (1H, d), 10.10 (1H, br)
【００３８】実施例２０ ｔ−ブチル ４−［５−［（ヘキサヒドロ−１−アゼピ
ニル）メチル］−２−テノイル］−１−ピペラジンカル
ボキシレート ｔ−ブチル １−ピペラジンカルボキシレート９８０ｍ
ｇ，５−［（ヘキサヒドロ−１−アゼピニル）メチル］
−２−チオフェンカルボン酸塩酸塩１．５ｇを用い，実
施例１の方法によりアミド化して標題化合物１．１ｇを
得た。 融点：１１５−１１６℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．４８（９Ｈ，ｓ），１．６２（８Ｈ，ｂｒ），
２．６７（４Ｈ，ｄｄ），３．４９（４Ｈ，ｔ），３．
７２（４Ｈ，ｔ），３．８２（２Ｈ，ｓ），６．８３
（１Ｈ，ｄ），７．１６（１Ｈ，ｄ）Example 20 t-butyl 4- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -1-piperazinecarboxylate 980 m of t-butyl 1-piperazinecarboxylate
g, 5-[(hexahydro-1-azepinyl) methyl]
Using 1.5 g of -2-thiophenecarboxylate hydrochloride, amidation was carried out by the method of Example 1 to obtain 1.1 g of the title compound. Melting point: 115-116 ° C. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.48 (9H, s), 1.62 (8H, br),
2.67 (4H, dd), 3.49 (4H, t), 3.
72 (4H, t), 3.82 (2H, s), 6.83
(1H, d), 7.16 (1H, d)
【００３９】実施例２１ ４−（４−フルオロベンゾイル）−１−［５−［（ヘキ
サヒドロ−１−アゼピニル）メチル］−２−テノイル］
ピペラジン １−（４−フルオロペンゾイル）ピペラジン塩酸塩１．
３ｇ，５−［（ヘキサヒドロ−１−アゼピニル）メチ
ル］−２−チオフェンカルボン酸塩酸塩１．５ｇを用
い，実施例１の方法によりアミド化して標題化合物１．
６ｇを得た。 融点：１０７−１０８℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．５０−１．７０（８Ｈ，ｍ），２．６７（４
Ｈ，ｔ），３．４０−３．８０（８Ｈ，ｂｒ），３．８
２（２Ｈ，ｓ），６．８３（１Ｈ，ｄ），７．１０−
７．３０（４Ｈ，ｍ），７．４５（１Ｈ，ｄ）Example 21 4- (4-Fluorobenzoyl) -1- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl]
Piperazine 1- (4-Fluoropenzoyl) piperazine hydrochloride
Using 3 g of 1.5 g of 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate hydrochloride, the title compound was obtained by amidation according to the method of Example 1.
6 g were obtained. Melting point: 107-108 ° C Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.50-1.70 (8H, m), 2.67 (4
H, t), 3.40-3.80 (8H, br), 3.8
2 (2H, s), 6.83 (1H, d), 7.10-
7.30 (4H, m), 7.45 (1H, d)
【００４０】実施例２２ １−［５−［（ヘキサヒドロアゼピニル）メチル］−２
−テノイル］−４−（４−ニトロベンゾイル）ピペラジ
ン １−（４−ニトロベンゾイル）ピペラジン塩酸塩１．４
ｇ，５−［（ヘキサヒドロ−１−アゼピニル）メチル］
−２−チオフェンカルボン酸１．５ｇを用い，実施例１
の方法によりアミド化し，標題化合物９６０ｍｇを得
た。 融点：１２１−１２２℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．５０−１．７０（８Ｈ，ｍ），２．６７（４
Ｈ，ｔ），３．４６（２Ｈ，ｂｒ），３．７４（２Ｈ，
ｂｒ），３．８２（２Ｈ，ｓ），３．８７（４Ｈ，ｂ
ｒ），６．８４（１Ｈ，ｄ），７．１９（１Ｈ，ｄ），
７．６０（２Ｈ，ｄ），８．３１（２Ｈ，ｄ）Example 22 1- [5-[(Hexahydroazepinyl) methyl] -2
-Thenoyl] -4- (4-nitrobenzoyl) piperazine 1- (4-nitrobenzoyl) piperazine hydrochloride 1.4
g, 5-[(hexahydro-1-azepinyl) methyl]
Example 1 using 1.5 g of -2-thiophenecarboxylic acid
Amidation was carried out by the method described above to obtain 960 mg of the title compound. Melting point: 121-122 ° C Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.50-1.70 (8H, m), 2.67 (4
H, t), 3.46 (2H, br), 3.74 (2H,
br), 3.82 (2H, s), 3.87 (4H, b
r), 6.84 (1H, d), 7.19 (1H, d),
7.60 (2H, d), 8.31 (2H, d)
【００４１】実施例２３ ４−シクロヘキシルカルボニル−１−［５−［（ヘキサ
ヒドロ−１−アゼピニル）メチル］−２−テノイル］ピ
ペラジン １−シクロヘキサンカルボニルピペラジン１．１ｇ，５
−［（ヘキサヒドロ−１−アゼピニル）メチル］−２−
チオフェンカルボン酸塩酸塩１．４ｇを用い，実施例１
の方法によりアミド化して標題化合物１．０ｇを得た。 融点：９６−９７℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．２０−１．３０（２Ｈ，ｍ），１．５０−１．
９０（１６Ｈ，ｍ），２．４０−２．５０（１Ｈ，
ｍ），２．６７（４Ｈ，ｄｄ），３．５０〜３．８０
（８Ｈ，ｍ），３．８２（２Ｈ，ｓ），６．８３（１
Ｈ，ｄ），７．１７（１Ｈ，ｄ）Example 23 4-cyclohexylcarbonyl-1- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] piperazine 1.1 g, 5 of 1-cyclohexanecarbonylpiperazine
-[(Hexahydro-1-azepinyl) methyl] -2-
Example 1 Using 1.4 g of thiophenecarboxylate hydrochloride
Amidation was carried out by the method of to give 1.0 g of the title compound. Melting point: 96-97 ° C. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.20-1.30 (2H, m), 1.50-1.
90 (16H, m), 2.40-2.50 (1H,
m), 2.67 (4H, dd), 3.50-3.80.
(8H, m), 3.82 (2H, s), 6.83 (1
H, d), 7.17 (1H, d)
【００４２】実施例２４ １［５−［（４−アセチル−１−ピペラジニル）カルボ
ニル］−２−テニル］ヘキサヒドロ−１−アゼピン塩酸
塩 １−アセチルピペラジン６５０ｍｇ，５−［（ヘキサヒ
ドロ−１−アゼピニル）メチル］−２−チオフェンカル
ボン酸塩酸塩１．４ｇを用い，実施例１の方法によりア
ミド化して標題化合物９００ｍｇを得た。 融点：１９５−１９７℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．５０−１．７０（４Ｈ，ｂｒ），１．８０−
１．９０（４Ｈ，ｂｒ），２．１２（３Ｈ，ｓ），２．
９６（２Ｈ，ｂｒ），３．５５（４Ｈ，ｔ），３．７０
（４Ｈ，ｔ），３．７９（２Ｈ，ｔ），４．３４（２
Ｈ，ｓ），７．２４（１Ｈ，ｄ），７．６０（１Ｈ，
ｄ），１２．７３（１Ｈ，ｂｒ）Example 24 1 [5-[(4-Acetyl-1-piperazinyl) carbonyl] -2-thenyl] hexahydro-1-azepine hydrochloride 1-acetylpiperazine 650 mg, 5-[(hexahydro-1-azepinyl) Using 1.4 g of [methyl] -2-thiophenecarboxylate hydrochloride, amidation was carried out by the method of Example 1 to obtain 900 mg of the title compound. Melting point: 195-197 ° C Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.50-1.70 (4H, br), 1.80-
1.90 (4H, br), 2.12 (3H, s), 2.
96 (2H, br), 3.55 (4H, t), 3.70
(4H, t), 3.79 (2H, t), 4.34 (2
H, s), 7.24 (1H, d), 7.60 (1H,
d), 12.73 (1H, br)
【００４３】実施例２５ １−ベンジル−３−［［５−［（ヘキサヒドロ−１−ア
ゼピニル）メチル］−２−テノイル］アミノ］−１，
３，４，５，６，７−ヘキサヒドロ−２Ｈ−アゼピン−
２−オンモノオキザレート ２−アミノ−１−ベンジル−１，３，４，５，６，７−
ヘキサヒドロ−２Ｈ−アゼピン−２−オン６６６ｍｇ，
５−［（ヘキサヒドロ−１−アゼピニル）メチル］−２
−チオフェンカルボン酸塩酸塩９００ｍｇを用い，実施
例２の方法によりアミド化して得られた化合物９１０ｍ
ｇにメタノール中シュウ酸１８４ｍｇを加えて溶解した
後減圧濃縮し，アセトニトリルより再結晶して標題化合
物８１０ｍｇを得た。 融点：１２０−１２１℃ 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6，ＴＭＳ内部標
準） δ：１．１５（１Ｈ，ｄｄ），１．５０−１．８０（１
１Ｈ，ｍ），１．８０−１．９０（２Ｈ，ｄｄ），２．
９８（４Ｈ，ｓ），３．２７（１Ｈ，ｄｄ），３．５９
（１Ｈ，ｄｄ），４．２８（２Ｈ，ｓ），４．５０（２
Ｈ，ｄ），４．６３（２Ｈ，ｄ），４．８１（１Ｈ，ｄ
ｄ），７．２０（１Ｈ，ｓ），７．２５−７．３５（５
Ｈ，ｍ），７．８０（１Ｈ，ｄ），８．４７（１Ｈ，
ｄ）Example 25 1-benzyl-3-[[5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] amino] -1,
3,4,5,6,7-hexahydro-2H-azepine-
2-one monooxalate 2-amino-1-benzyl-1,3,4,5,6,7-
666 mg of hexahydro-2H-azepin-2-one,
5-[(hexahydro-1-azepinyl) methyl] -2
Compound 910m obtained by amidation using the method of Example 2 using 900 mg of thiophenecarboxylate hydrochloride
g of oxalic acid in methanol was added to and dissolved in methanol, and the mixture was concentrated under reduced pressure and recrystallized from acetonitrile to obtain 810 mg of the title compound. Melting point: 120-121 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.15 (1H, dd), 1.50-1.80 (1
1H, m), 1.80-1.90 (2H, dd), 2.
98 (4H, s), 3.27 (1H, dd), 3.59
(1H, dd), 4.28 (2H, s), 4.50 (2
H, d), 4.63 (2H, d), 4.81 (1H, d
d), 7.20 (1H, s), 7.25-7.35 (5
H, m), 7.80 (1H, d), 8.47 (1H,
d)
【００４４】実施例２６ Ｎ−（トランス−４−メトキシシクロヘキシル）−５−
［（ヘキサヒドロ−１−アゼピニル）メチル］−２−チ
オフェンカルボキサミド トランス−４−メトキシシクロヘキシルアミン塩酸塩４
８０ｍｇ，５−［（ヘキサヒドロ−１−アゼピニル）メ
チル］−２−チオフェンカルボン酸塩酸塩８００ｍｇを
用い，実施例２の方法によりアミド化して標題化合物６
８０ｍｇを得た。 融点：１３０−１３１℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．２０−１．３０（２Ｈ，ｍ），１．３０−１．
４０（２Ｈ，ｍ），１．５０−１．７０（８Ｈ，ｍ），
２．００−２．２０（４Ｈ，ｍ），２．６６（４Ｈ，ｄ
ｄ），３．１０−３．２０（１Ｈ，ｍ），３．３５（３
Ｈ，ｓ），３．８１（２Ｈ，ｓ），３．９０−４．００
（１Ｈ，ｍ），５．６４（１Ｈ，ｄ），６．８３（１
Ｈ，ｄ），７．３５（１Ｈ，ｄ）Example 26 N- (trans-4-methoxycyclohexyl) -5
[(Hexahydro-1-azepinyl) methyl] -2-thiophenecarboxamide trans-4-methoxycyclohexylamine hydrochloride 4
Using 80 mg, 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate hydrochloride (800 mg) and amidation by the method of Example 2, the title compound 6 was obtained.
80 mg were obtained. Melting point: 130-131 ° C. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.20-1.30 (2H, m), 1.30-1.
40 (2H, m), 1.50-1.70 (8H, m),
2.00-2.20 (4H, m), 2.66 (4H, d
d), 3.10-3.20 (1H, m), 3.35 (3
H, s), 3.81 (2H, s), 3.90-4.00.
(1H, m), 5.64 (1H, d), 6.83 (1
H, d), 7.35 (1H, d)
【００４５】実施例２７ １−［５−［（ヘキサヒドロ−１−アゼピニル）メチ
ル］−２−テノイル］−４−ピペリジンカルボキサミド ４−ピペリジンカルボキサミド０．７ｇ，５−［（ヘキ
サヒドロ−１−アゼピニル）メチル］−２−チオフェン
カルボン酸塩酸塩１．５ｇを用い，実施例１の方法によ
りアミド化して標題化合物１．２ｇを得た。 融点：１２６−１２８℃ 核磁気共鳴スペクトル（ＤＭＳＯ−ｄ6，ＴＭＳ内部標
準） δ：１．４０−１．５０（２Ｈ，ｍ），１．５６（８
Ｈ，ｓ），１．７０−１．８０（２Ｈ，ｍ），２．３５
−２．４５（１Ｈ，ｍ），２．６１（４Ｈ，ｄｄ），
２．９５−３．０５（２Ｈ，ｂｒ），３．２０−３．４
０（２Ｈ，ｂｒ），３．８０（２Ｈ，ｓ），４．２３
（２Ｈ，ｄ），６．９１（１Ｈ，ｄ），７．２０（１
Ｈ，ｄ）Example 27 1- [5-[(Hexahydro-1-azepinyl) methyl] -2-thenoyl] -4-piperidinecarboxamide 0.7 g of 4-piperidinecarboxamide, 5-[(hexahydro-1-azepinyl) methyl Amidation was carried out according to the method of Example 1 using 1.5 g of 2-thiophenecarboxylic acid hydrochloride to obtain 1.2 g of the title compound. Melting point: 126-128 ° C. Nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) δ: 1.40-1.50 (2H, m), 1.56 (8
H, s), 1.70-1.80 (2H, m), 2.35
-2.45 (1H, m), 2.61 (4H, dd),
2.95-3.05 (2H, br), 3.20-3.4
0 (2H, br), 3.80 (2H, s), 4.23
(2H, d), 6.91 (1H, d), 7.20 (1
H, d)
【００４６】実施例２８ ４−［［１−［５−［（ヘキサヒドロ−１−アゼピニ
ル）メチル］−２−テノイル］−４−ピペリジル］オキ
シ］アセトアニリド ４−［（４−ピペリジル）オキシ］アセトアニリド２８
０ｍｇ，５−［（ヘキサヒドロ−１−アゼピニル）メチ
ル］−２−チオフェンカルボン酸塩酸塩３３０ｍｇを用
い，実施例１の方法によりアミド化して標題化合物３４
０ｍｇを得た。 融点：８６−８８℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．５０−１．７０（１２Ｈ，ｍ），１．８５−
１．９０（２Ｈ，ｍ），１．９０−２．０５（２Ｈ，
ｍ），２．１６（３Ｈ，ｓ），２．６６（４Ｈ，ｄ
ｄ），３．７０−３．８０（２Ｈ，ｍ），３．８２（２
Ｈ，ｓ），３．８５−４．００（２Ｈ，ｍ），４．５０
−４．６０（１Ｈ，ｍ），６．８２（１Ｈ，ｄ），６．
８９（２Ｈ，ｄ），７．１２（１Ｈ，ｂｒ），７．１６
（１Ｈ，ｄ），７．４０（２Ｈ，ｄ）Example 28 4-[[1- [5-[(Hexahydro-1-azepinyl) methyl] -2-thenoyl] -4-piperidyl] oxy] acetanilide 4-[(4-piperidyl) oxy] acetanilide 28
Using 0 mg, 330 mg of 5-[(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylate, the title compound 34 was obtained by amidation according to the method of Example 1.
0 mg was obtained. Melting point: 86-88 ° C Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.50-1.70 (12H, m), 1.85-
1.90 (2H, m), 1.90-2.05 (2H,
m), 2.16 (3H, s), 2.66 (4H, d
d), 3.70-3.80 (2H, m), 3.82 (2
H, s), 3.85-4.00 (2H, m), 4.50
-4.60 (1H, m), 6.82 (1H, d), 6.
89 (2H, d), 7.12 (1H, br), 7.16
(1H, d), 7.40 (2H, d)
【００４７】実施例２９ Ｎ−ベンジル−Ｎ−アルファ−［５−［（ヘキサヒドロ
−１−アゼピニル）メチル］−２−テノイル］−１−フ
ェニルアラナミド Ｎ−ベンジル−１−フェニルアラナミド１．２ｇ，５−
［（ヘキサヒドロ−１−アゼピニル）メチル］−２−チ
オフェンカルボン酸１．２ｇを用い，実施例１の方法に
よりアミド化して標題化合物６２０ｍｇを得た。 融点：８６−８７℃ 核磁気共鳴スペクトル（ＣＤＣｌ3，ＴＭＳ内部標準） δ：１．５０−１．７０（８Ｈ，ｍ），２．６６（４
Ｈ，ｔ），３．０９（１Ｈ，ｄｄ），３．２６（１Ｈ，
ｄｄ），３．８１（２Ｈ，ｓ），４．２９（１Ｈ，
ｄ），４．３９（１Ｈ，ｄ），４．７８（１Ｈ，ｍ），
５．９９（１Ｈ，ｔ），６．８４（１Ｈ，ｄ），７．０
７（２Ｈ，ｄ），７．２０−７．６０（９Ｈ，ｍ） 以下表に上記実施例１〜２９により得られた化合物の化
学構造式を示した。Example 29 N-benzyl-N-alpha- [5-[(hexahydro-1-azepinyl) methyl] -2-thenoyl] -1-phenylalanamide 1.2 g of N-benzyl-1-phenylalanamide , 5-
Amidation was carried out using 1.2 g of [(hexahydro-1-azepinyl) methyl] -2-thiophenecarboxylic acid according to the method of Example 1 to obtain 620 mg of the title compound. Melting point: 86-87 ° C. Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.50-1.70 (8H, m), 2.66 (4
H, t), 3.09 (1H, dd), 3.26 (1H,
dd), 3.81 (2H, s), 4.29 (1H,
d), 4.39 (1H, d), 4.78 (1H, m),
5.99 (1H, t), 6.84 (1H, d), 7.0
7 (2H, d), 7.20-7.60 (9H, m) The following table shows the chemical structural formulas of the compounds obtained in Examples 1 to 29.
【００４８】[0048]
【表１】 [Table 1]
【００４９】[0049]
【表２】 [Table 2]
【００５０】[0050]
【発明の効果】本発明化合物（Ｉ）は特異的な抗ＰＣＰ
作用を有し，これに基づく向精神薬，抗精神分裂病薬，
アルツハイマー病などの抗痴呆薬，痴呆に伴うせん妄な
どの問題行動改善薬，又は小児期の精神遅滞や自閉症の
治療薬として有用である。本発明化合物（Ｉ）の抗ＰＣ
Ｐ作用は，以下の試験方法によって確認された。The compound (I) of the present invention is a specific anti-PCP
Psychotropic, anti-schizophrenic,
It is useful as an anti-dementia drug such as Alzheimer's disease, a drug for improving behavioral problems such as delirium associated with dementia, or a drug for treating mental retardation and autism in childhood. Anti-PC of compound (I) of the present invention
P action was confirmed by the following test method.
【００５１】抗ＰＣＰ作用試験 実験方法 ウィスター系雄性ラット（ｎ＝８）（体重２００〜３０
０ｇ）にＰＣＰ（３ｍｇ／ｋｇ）を皮下投与し，３０分
後にホールボートアバラータス（ＨＢＡ）に入れた。被
験化合物（１０ｍｇ／ｋｇ）は，ＰＣＰの投与１５分前
に皮下投与した。ＨＢＡは，床に直径４ｃｍの穴１６個
を施し，周囲に高さ２０ｃｍの壁を有する縦横４０ｃｍ
のオープンフィールドである［Ｐｓｙｃｈｏｐｈａｒｍ
ａｃｏｌｏｇｙ，５２，２７１（１９７７）］。ＨＢＡ
におけるラットの運動量（９分割した床の区画を移動す
る回数（Ｌｏｃｏｍｏｔｉｏｎ））及び探索行動（穴に
頭を入れる回数（Ｄｉｐｐｉｎｇ））を５分間にわたり
測定した。また，ＰＣＰ（３ｍｇ／ｋｇ）を皮下投与し
たウィスター系雄性ラット（ｎ＝８）を対照群とした。
この薬理試験において本発明化合物は，ＰＣＰにより誘
発された運動量の増大及び探索行動の低下に対し，統計
学的に有意に（マンホイットニーＵテストによる対照群
との比較）拮抗した。Anti-PCP Action Test Experimental Method Male Wistar rats (n = 8) (body weight 200-30)
0g) was administered subcutaneously with PCP (3 mg / kg) and 30 minutes later, placed in whole boat avalatas (HBA). The test compound (10 mg / kg) was administered subcutaneously 15 minutes before the administration of PCP. HBA has 16 holes of 4cm diameter on the floor and 40cm height and width with 20cm height wall around the floor.
[Psychopharm]
acology, 52, 271 (1977)]. HBA
The locomotor activity (number of times of movement of the floor section divided into 9 (Locommotion)) and exploratory behavior (number of times of putting a head in a hole (Dipping)) were measured over 5 minutes. Male Wistar rats (n = 8) to which PCP (3 mg / kg) was subcutaneously administered were used as a control group.
In this pharmacological test, the compound of the present invention statistically significantly (compared to the control group by the Mann-Whitney U test) antagonized the increase in locomotion and the decrease in exploratory behavior induced by PCP.
【００５２】本発明化合物（Ｉ）又はその塩の一種又は
２種以上を有効成分として含有する製剤は，通常用いら
れる製剤用の担体や賦形剤，その他の添加剤を用いて，
錠剤，バッカル，散剤，細粒剤，顆粒剤，カプセル剤，
丸剤，経口用液剤（シロップ剤を含む），注射剤，吸入
剤，坐剤，経皮用液剤，軟膏，経皮用貼付剤，経粘膜貼
剤（例えば口腔内貼付剤），経粘膜用液剤（例えば経鼻
用液剤）などに調製され，経口的又は非経口的に投与さ
れる。製剤用の担体や賦形剤としては固体又は液体状の
非毒性医薬用が挙げられる。これらの例としては，例え
ば乳糖，ステアリン酸マグネシウム，スターチ，タル
ク，ゼラチン，寒天，ペクチン，アラビアゴム，オリー
ブ油，ゴマ油，カカオバター，エチレングリコール等や
その他常用のものが例示される。A preparation containing one or more of the compound (I) of the present invention or a salt thereof as an active ingredient can be prepared by using carriers, excipients and other additives for preparations which are usually used.
Tablets, buccal, powder, fine granules, granules, capsules,
Pills, oral solutions (including syrups), injections, inhalants, suppositories, transdermal solutions, ointments, transdermal patches, transmucosal patches (for example, oral patches), transmucosal It is prepared as a liquid (for example, a nasal solution) or the like and is orally or parenterally administered. Pharmaceutical carriers and excipients include solid or liquid non-toxic pharmaceuticals. These include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol and the like and other commonly used ones.
【００５３】本発明化合物（Ｉ）のヒトに対する臨床投
与量は適用される患者の症状，体重，年令，性別，投与
ルート等を考慮して個々の場合に応じて適宜決定される
が，通常成人１人当たり，１日につき０．１〜１０００
ｍｇ，好ましくは１〜２００ｍｇの範囲で１日１回から
数回に分け経口投与されるか，又は成人１人当たり，１
日につき０．１〜１０００ｍｇ，好ましくは０．３〜３
０ｍｇの範囲で，１日１回から数回に分け静脈内投与さ
れるか，又は，１日１時間〜２４時間の範囲で静脈内持
続投与される。もちろん前記したように，投与量は種々
の条件で変動するので，上記投与量より少ない量で十分
な場合もある。The clinical dose of the compound (I) of the present invention to humans is appropriately determined depending on the individual case in consideration of the symptoms, body weight, age, sex, administration route and the like of the patient to which the compound (I) is applied. 0.1-1000 per adult per day
mg, preferably in the range of 1 to 200 mg, orally in one to several doses per day, or 1 per adult.
0.1 to 1000 mg per day, preferably 0.3 to 3
It is administered intravenously in the range of 0 mg once to several times a day, or continuously intravenously in the range of 1 hour to 24 hours a day. Of course, as described above, the dose varies under various conditions, so that a smaller dose than the above dose may be sufficient.
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 409/12 ２１３ Ｃ０７Ｄ 409/12 ２１３ ２２３ ２２３ ２３９ ２３９ ２４１ ２４１ 413/12 ３３３ 413/12 ３３３ (72)発明者 森田 琢磨 茨城県つくば市二の宮１−１−１ 二の宮 荒井マンション208号 (72)発明者 塚本 紳一 茨城県つくば市小野川４−14Continued on the front page (51) Int.Cl. 6 Identification code Agency reference number FI Technical display location C07D 409/12 213 C07D 409/12 213 223 223 239 239 241 241 241 413/12 333 413/12 333 (72) Invention Person Takuma Morita 1-1-1 Ninomiya, Tsukuba-shi, Ibaraki Ninomiya Arai Mansion 208 (72) Inventor Shinichi Tsukamoto 4-14 Onogawa, Tsukuba-shi, Ibaraki
Claims (2)
体又はその塩。 【化１】 （式中の記号は，以下の意味を示す。 Ｂ環：４乃至１０員含窒素シクロアルキル環 Ａ：結合又は低級アルキレン基 Ｒ3，Ｒ4，Ｒ6及びＲ7：同一又は異なって水素原子又は
置換基をそれぞれ有していても良い低級アルキル基若し
くはアラルキル基 ｎ及びｍ：同一又は異なって０又は１乃至６の整数 Ｒ5，Ｒ8及びＲ9：同一又は異なって水素原子又は置換
基をそれぞれ有していても良い低級アルキル基，シクロ
アルキル基，アラルキル基，アリール基若しくは窒素原
子を１又は２個含む５又は６員ヘテロアリール基 Ｄ環：カルボニル基を有していても良く窒素原子を１又
は２個含む５乃至７員シクロアルキル環 Ｒ10，Ｒ11及びＲ12：同一又は異なって水素原子，低級
アルキル基又はＲ3若しくはＲ6と一体となって５乃至８
員環を形成しても良い。）1. A thiophene derivative represented by the general formula (I) or a salt thereof. Embedded image (The symbols in the formula have the following meanings. Ring B: 4- to 10-membered nitrogen-containing cycloalkyl ring A: bond or lower alkylene group R 3 , R 4 , R 6 and R 7 are the same or different and are each a hydrogen atom or a lower alkyl group or an aralkyl group which may have a substituent n and m: the same or different and an integer of 0 or 1 to 6 R 5 , R 8 and R 9 are the same or different and each include a hydrogen atom or a lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group or one or two nitrogen atoms which may have a substituent, or 5 or 6-membered heteroaryl group D-ring: a 5- to 7-membered cycloalkyl ring which may have a carbonyl group and contains 1 or 2 nitrogen atoms R 10 , R 11 and R 12 are the same or different and are combined with a hydrogen atom, a lower alkyl group or R 3 or R 6 to form 5 to 8
A member ring may be formed. )
容されるその塩を有効成分とする医薬。2. A medicament comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17207896A JPH1017564A (en) | 1996-07-02 | 1996-07-02 | New thiophene derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17207896A JPH1017564A (en) | 1996-07-02 | 1996-07-02 | New thiophene derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH1017564A true JPH1017564A (en) | 1998-01-20 |
Family
ID=15935136
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17207896A Pending JPH1017564A (en) | 1996-07-02 | 1996-07-02 | New thiophene derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH1017564A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005096734A3 (en) * | 2004-03-31 | 2006-04-20 | Janssen Pharmaceutica Nv | Non-imidazole heterocyclic compounds as histamine h3 receptor modulators |
| WO2011058766A1 (en) * | 2009-11-16 | 2011-05-19 | Raqualia Pharma Inc. | Aryl carboxamide derivatives as ttx-s blockers |
-
1996
- 1996-07-02 JP JP17207896A patent/JPH1017564A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005096734A3 (en) * | 2004-03-31 | 2006-04-20 | Janssen Pharmaceutica Nv | Non-imidazole heterocyclic compounds as histamine h3 receptor modulators |
| JP2007531755A (en) * | 2004-03-31 | 2007-11-08 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Non-imidazole heterocyclic compounds |
| US7429659B2 (en) | 2004-03-31 | 2008-09-30 | Janssen Pharmaceutica N.V. | Furan compounds as histamine H3 modulators |
| WO2011058766A1 (en) * | 2009-11-16 | 2011-05-19 | Raqualia Pharma Inc. | Aryl carboxamide derivatives as ttx-s blockers |
| US9051296B2 (en) | 2009-11-16 | 2015-06-09 | Raqualia Pharma Inc. | Aryl carboxamide derivatives as TTX-S blockers |
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