JPH08333368A - New imide derivatives - Google Patents
New imide derivativesInfo
- Publication number
- JPH08333368A JPH08333368A JP16826195A JP16826195A JPH08333368A JP H08333368 A JPH08333368 A JP H08333368A JP 16826195 A JP16826195 A JP 16826195A JP 16826195 A JP16826195 A JP 16826195A JP H08333368 A JPH08333368 A JP H08333368A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- substituted
- hydroxyl group
- hydrocarbon ring
- 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.)
- Granted
Links
- 150000003949 imides Chemical class 0.000 title claims abstract description 14
- -1 phenoxy, phenylthio Chemical group 0.000 claims description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 15
- 125000002947 alkylene group Chemical group 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 10
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 8
- 239000000126 substance Substances 0.000 abstract description 22
- 230000000694 effects Effects 0.000 abstract description 8
- 230000000506 psychotropic effect Effects 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 description 100
- 239000002585 base Substances 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 150000002430 hydrocarbons Chemical group 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- HUXSAESWQBPYHL-UHFFFAOYSA-N azecane-2,10-dione Chemical compound O=C1CCCCCCCC(=O)N1 HUXSAESWQBPYHL-UHFFFAOYSA-N 0.000 description 12
- 239000007810 chemical reaction solvent Substances 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 238000009835 boiling Methods 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000000561 anti-psychotic effect Effects 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 6
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- ILPBINAXDRFYPL-UHFFFAOYSA-N 2-octene Chemical compound CCCCCC=CC ILPBINAXDRFYPL-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 150000002923 oximes Chemical class 0.000 description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 3
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 229910010082 LiAlH Inorganic materials 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 3
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 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
- 238000004440 column chromatography Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000001924 cycloalkanes Chemical class 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 125000005956 isoquinolyl group Chemical group 0.000 description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 208000009132 Catalepsy Diseases 0.000 description 2
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KRDOFMHJLWKXIU-UHFFFAOYSA-N ID11614 Chemical compound C1CNCCN1C1=NSC2=CC=CC=C12 KRDOFMHJLWKXIU-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 206010047853 Waxy flexibility Diseases 0.000 description 2
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 150000001925 cycloalkenes Chemical class 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 229960001270 d- tartaric acid Drugs 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229960001252 methamphetamine Drugs 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 238000003797 solvolysis reaction Methods 0.000 description 2
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 2
- DIORMHZUUKOISG-UHFFFAOYSA-N sulfoformic acid Chemical compound OC(=O)S(O)(=O)=O DIORMHZUUKOISG-UHFFFAOYSA-N 0.000 description 2
- 125000004434 sulfur atom Chemical group 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
- 238000005406 washing Methods 0.000 description 2
- AAWZDTNXLSGCEK-WYWMIBKRSA-N (-)-quinic acid Chemical compound O[C@@H]1C[C@](O)(C(O)=O)C[C@@H](O)[C@H]1O AAWZDTNXLSGCEK-WYWMIBKRSA-N 0.000 description 1
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- LSPHULWDVZXLIL-LDWIPMOCSA-N (?)-Camphoric acid Chemical compound CC1(C)[C@@H](C(O)=O)CC[C@@]1(C)C(O)=O LSPHULWDVZXLIL-LDWIPMOCSA-N 0.000 description 1
- YCTDZYMMFQCTEO-FNORWQNLSA-N (E)-3-octene Chemical compound CCCC\C=C\CC YCTDZYMMFQCTEO-FNORWQNLSA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- SSBQOSIEGFXXEQ-UHFFFAOYSA-N 1-hydroxycyclohexane-1,2-dicarboxylic acid Chemical compound OC(=O)C1CCCCC1(O)C(O)=O SSBQOSIEGFXXEQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- YCNYCBYHUAGZIZ-UHFFFAOYSA-N 7-oxabicyclo[2.2.1]hept-2-ene Chemical compound O1C2CCC1C=C2 YCNYCBYHUAGZIZ-UHFFFAOYSA-N 0.000 description 1
- YPWFNLSXQIGJCK-UHFFFAOYSA-N 7-oxabicyclo[2.2.1]heptane Chemical compound C1CC2CCC1O2 YPWFNLSXQIGJCK-UHFFFAOYSA-N 0.000 description 1
- RORKRCKNZOWREF-UHFFFAOYSA-N 7-oxabicyclo[4.1.1]oct-3-ene Chemical compound C1C=CCC2CC1O2 RORKRCKNZOWREF-UHFFFAOYSA-N 0.000 description 1
- FQUMQEFEWGUVRR-UHFFFAOYSA-N 7-oxabicyclo[4.1.1]octane Chemical compound C1CCCC2CC1O2 FQUMQEFEWGUVRR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- AWEGTPPFDJUPRI-UHFFFAOYSA-N 8-oxabicyclo[3.2.1]octane Chemical compound C1CCC2CCC1O2 AWEGTPPFDJUPRI-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010029333 Neurosis Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-ZDFGOMNRSA-N [2,2,3,3,4,5,5-heptadeuterio-7-methyl-6-oxo-7-(trideuteriomethyl)-1-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C12(C(=O)C(C(C(C1([2H])[2H])([2H])[2H])(C2(C([2H])([2H])[2H])C)[2H])([2H])[2H])CS(=O)(=O)O MIOPJNTWMNEORI-ZDFGOMNRSA-N 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
- 230000003354 anti-apomorphinic effect Effects 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- PWHCIQQGOQTFAE-UHFFFAOYSA-L barium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ba+2] PWHCIQQGOQTFAE-UHFFFAOYSA-L 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- MKCBRYIXFFGIKN-UHFFFAOYSA-N bicyclo[1.1.1]pentane Chemical compound C1C2CC1C2 MKCBRYIXFFGIKN-UHFFFAOYSA-N 0.000 description 1
- YWDBHFZUBPOPRQ-UHFFFAOYSA-N bicyclo[2.1.1]hex-2-ene Chemical compound C1C2CC1C=C2 YWDBHFZUBPOPRQ-UHFFFAOYSA-N 0.000 description 1
- JSMRMEYFZHIPJV-UHFFFAOYSA-N bicyclo[2.1.1]hexane Chemical compound C1C2CC1CC2 JSMRMEYFZHIPJV-UHFFFAOYSA-N 0.000 description 1
- VIQRCOQXIHFJND-UHFFFAOYSA-N bicyclo[2.2.2]oct-2-ene Chemical compound C1CC2CCC1C=C2 VIQRCOQXIHFJND-UHFFFAOYSA-N 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- YEHSTKKZWWSIMD-UHFFFAOYSA-N bicyclo[3.2.1]oct-3-ene Chemical compound C1C2CCC1C=CC2 YEHSTKKZWWSIMD-UHFFFAOYSA-N 0.000 description 1
- GVDVAKABGZRLLQ-UHFFFAOYSA-N bicyclo[3.2.1]oct-6-ene Chemical compound C1CCC2C=CC1C2 GVDVAKABGZRLLQ-UHFFFAOYSA-N 0.000 description 1
- LPCWKMYWISGVSK-UHFFFAOYSA-N bicyclo[3.2.1]octane Chemical compound C1C2CCC1CCC2 LPCWKMYWISGVSK-UHFFFAOYSA-N 0.000 description 1
- BCCQOAANWUKEPI-UHFFFAOYSA-N bicyclo[3.2.2]non-3-ene Chemical compound C1CC2CCC1C=CC2 BCCQOAANWUKEPI-UHFFFAOYSA-N 0.000 description 1
- JBAWYNWUHODEAV-UHFFFAOYSA-N bicyclo[3.2.2]non-6-ene Chemical compound C1CCC2CCC1C=C2 JBAWYNWUHODEAV-UHFFFAOYSA-N 0.000 description 1
- GNTFBMAGLFYMMZ-UHFFFAOYSA-N bicyclo[3.2.2]nonane Chemical compound C1CC2CCC1CCC2 GNTFBMAGLFYMMZ-UHFFFAOYSA-N 0.000 description 1
- IBJMNXAEDQNPFI-UHFFFAOYSA-N bicyclo[4.1.1]oct-3-ene Chemical compound C1C2CC1CC=CC2 IBJMNXAEDQNPFI-UHFFFAOYSA-N 0.000 description 1
- JVCSOJVVTVMKAE-UHFFFAOYSA-N bicyclo[4.1.1]oct-4-ene Chemical compound C1C2CC1CCC=C2 JVCSOJVVTVMKAE-UHFFFAOYSA-N 0.000 description 1
- QVAUSBVLMVBCPN-UHFFFAOYSA-N bicyclo[4.1.1]octane Chemical compound C1C2CC1CCCC2 QVAUSBVLMVBCPN-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- ZCDOYSPFYFSLEW-UHFFFAOYSA-N chromate(2-) Chemical class [O-][Cr]([O-])(=O)=O ZCDOYSPFYFSLEW-UHFFFAOYSA-N 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 description 1
- YSSSPARMOAYJTE-UHFFFAOYSA-N dibenzo-18-crown-6 Chemical compound O1CCOCCOC2=CC=CC=C2OCCOCCOC2=CC=CC=C21 YSSSPARMOAYJTE-UHFFFAOYSA-N 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- CMMUKUYEPRGBFB-UHFFFAOYSA-L dichromic acid Chemical compound O[Cr](=O)(=O)O[Cr](O)(=O)=O CMMUKUYEPRGBFB-UHFFFAOYSA-L 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 208000015238 neurotic disease Diseases 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- IICQZTQZQSBHBY-UHFFFAOYSA-N non-2-ene Chemical compound CCCCCCC=CC IICQZTQZQSBHBY-UHFFFAOYSA-N 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- JFNLZVQOOSMTJK-UHFFFAOYSA-N norbornene Chemical compound C1C2CCC1C=C2 JFNLZVQOOSMTJK-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
(57)【要約】
【目的】 副作用の少ない向精神性物質の提供。
【構成】 例えば式
【化１】
（式中、くさび形の実線および破線は絶対配置を表し、
太線の実線および破線は相対配置を表す）で表される新
規なイミド誘導体。(57) [Summary] [Purpose] To provide psychotropic substances with few side effects. [Structure] For example, the formula (In the formula, the wedge-shaped solid line and the broken line represent the absolute configuration,
The bold solid line and the broken line represent the relative configuration), which is a novel imide derivative.
Description
【０００１】[0001]
【産業上の利用分野】本発明は向精神性物質として有用
な新規イミド誘導体およびその酸付加塩に関する。詳し
くいえば、本発明の向精神性物質｛抗精神性作用および
（または）不安解消作用を持つ物質｝は、精神分裂病、
老年性精神疾患、そううつ病、神経症等の治療薬として
有用である。FIELD OF THE INVENTION The present invention relates to a novel imide derivative useful as a psychotropic substance and an acid addition salt thereof. More specifically, the psychotropic substance of the present invention {a substance having an antipsychotic action and / or anxiolytic action} is schizophrenia,
It is useful as a remedy for senile psychiatric disorders, depression, neurosis, etc.
【０００２】[0002]
【従来の技術】向精神性作用を持つイミド誘導体は例え
ば表１、表２に示されるものが知られている。2. Description of the Related Art As imide derivatives having a psychotropic effect, those shown in Tables 1 and 2 are known.
【０００３】[0003]
【表１】 [Table 1]
【表２】 [Table 2]
【０００４】しかし、これらの誘導体はイミド部分とピ
ペラジンまたはピペリジンとの間が直鎖のアルキレン鎖
であることが特徴となっている。ここに炭化水素環を含
むアルキレン鎖を持つ化合物は唯一、特開平５−１７４
４０号公報に報告された化合物以外には知られていな
い。しかしながら、前記公報中にはイミド部分が水酸基
によって置換された化合物は記載されていない。However, these derivatives are characterized by a linear alkylene chain between the imide moiety and piperazine or piperidine. The only compound having an alkylene chain containing a hydrocarbon ring here is disclosed in JP-A 5-174.
It is not known other than the compound reported in JP-A-40. However, the above publication does not describe a compound in which an imide moiety is substituted with a hydroxyl group.
【０００５】従来の不安解消作用および（または）抗精
神病性作用を有する向精神性物質には、中枢性副作用、
血圧降下等の末梢性副作用が付随しており、臨床上大き
な問題点〔ザ・ファーマコロジカル・ベイシス・オブ・
セラピューティクス The Pharmacological basis of t
herapeutics,A.Goodman Gilman,L.S.Goodman et al,New
York (1985) P387, 現代医療, 22,P22,(1990) 〕とな
っていた。Conventional psychotropic substances having anxiolytic action and / or antipsychotic action have central side effects,
Peripheral side effects such as hypotension are accompanied, and clinically significant problems [The Pharmacologic Basis of
Therapeutics The Pharmacological basis of t
herapeutics, A.Goodman Gilman, LSGoodman et al, New
York (1985) P387, Contemporary Medicine, 22 , P22, (1990)].
【０００６】[0006]
【発明が解決しようとする問題点】本発明の目的は副作
用の少ない優れた向精神性物質を提供することにある。DISCLOSURE OF THE INVENTION The object of the present invention is to provide an excellent psychotropic substance with few side effects.
【０００７】[0007]
【問題を解決するための手段】本発明者らは、鋭意検討
を重ねた結果、イミド部分が水酸基によって置換され、
炭化水素環を含むアルキレン鎖を持つことを特徴とする
新規イミド誘導体が目的とした薬理的諸作用を有するこ
とを見出し本発明を完成するに至った。As a result of intensive studies, the present inventors have found that the imide moiety is substituted with a hydroxyl group,
The inventors have found that a novel imide derivative having an alkylene chain containing a hydrocarbon ring has desired pharmacological actions, and completed the present invention.
【０００８】本発明は、一般式〔Ｉ〕The present invention has the general formula [I]
【化８】 ｛式中、Ｚ−は式Embedded image {In the formula, Z- is a formula
【化９】 （式中、Ｂはカルボニルまたはスルホニルを表す。
Ｒ1 、Ｒ2 およびＲ3 は、Ｒ 1 とＲ2 が一緒になって、
少なくとも１つの水酸基で置換された炭化水素環を表
し、Ｒ3 が水素原子もしくは水酸基を表すか、またはＲ
1 とＲ3 が一緒になって、少なくとも１つの水酸基で置
換された炭化水素環を表し、Ｒ2 が水素原子もしくは水
酸基を表す。当該炭化水素環は少なくとも１つの水酸基
で置換されていてもよい低級アルキレンまたは酸素原子
で架橋されていてもよい。当該炭化水素環および低級ア
ルキレンは少なくとも１つのアルキルで置換されていて
もよい。Ｒ4 は水素原子または低級アルキルを表す。ｎ
は０または１を表す。）を表す。Ａは炭化水素環を表
し、当該炭化水素環は低級アルキレンまたは酸素原子で
架橋されていてもよい。また、当該低級アルキレンおよ
び炭化水素環は少なくとも１つのアルキルで置換されて
いてもよい。ｌ、ｍは各々０、１または２を表す。Ｇは
Ｎ、ＣＨもしくはＣＯＨを、Ａｒは芳香族複素環基、芳
香族炭化水素基、ベンゾイル、フェノキシもしくはフェ
ニルチオを表すか、またはＧは炭素原子を、Ａｒはビフ
ェニルメチリデンを表す。当該芳香族複素環基、芳香族
炭化水素基、ベンゾイル、フェノキシ、フェニルチオお
よびビフェニルメチリデンは少なくとも１つの低級アル
キル、低級アルコキシまたはハロゲン原子で置換されて
いてもよい。｝で表されるイミド誘導体またはその酸付
加塩に関する。[Chemical 9](In the formula, B represents carbonyl or sulfonyl.
R1, R2And R3Is R 1And R2Together,
Represents a hydrocarbon ring substituted with at least one hydroxyl group
Then R3Represents a hydrogen atom or a hydroxyl group, or R
1And R3Together with at least one hydroxyl group
Represents a substituted hydrocarbon ring, R2Is hydrogen atom or water
Represents an acid group. The hydrocarbon ring has at least one hydroxyl group
Lower alkylene optionally substituted with or an oxygen atom
May be cross-linked. The hydrocarbon ring and lower
Rukilen is substituted with at least one alkyl
Good. RFourRepresents a hydrogen atom or lower alkyl. n
Represents 0 or 1. ) Represents. A represents a hydrocarbon ring
And the hydrocarbon ring is a lower alkylene or an oxygen atom.
It may be crosslinked. In addition, the lower alkylene and
And the hydrocarbon ring is substituted with at least one alkyl
May be. l and m each represent 0, 1 or 2. G is
N, CH or COH, Ar is an aromatic heterocyclic group,
Aromatic hydrocarbon groups, benzoyl, phenoxy or phenoxy
Represents Nylthio or G is a carbon atom and Ar is a bif
Represents methylenylidene. The aromatic heterocyclic group, aromatic
Hydrocarbon groups, benzoyl, phenoxy, phenylthio,
And biphenylmethylidene are at least one lower
Substituted with a kill, lower alkoxy or halogen atom
May be. } The imide derivative represented by
Regarding salting.
【０００９】以下に本発明で使われている基について詳
しく説明する。The groups used in the present invention will be described in detail below.
【００１０】ＺおよびＡに於ける低級アルキレンとして
は、例えば炭素数３個以下の基が挙げられ、具体的には
メチレン、エチレン、トリメチレン等が挙げられる。Examples of the lower alkylene in Z and A include groups having 3 or less carbon atoms, and specific examples thereof include methylene, ethylene and trimethylene.
【００１１】ＺおよびＡに於ける炭化水素環としては、
例えば炭素数７個以下のシクロアルカン、シクロアルケ
ンが挙げられる。炭素数７個以下のシクロアルカンとし
ては例えばシクロプロパン、シクロブタン、シクロペン
タン、シクロヘキサン、シクロヘプタン等が挙げられ
る。炭素数７個以下のシクロアルケンとしては例えばシ
クロペンテン、シクロヘキセン、シクロヘプテン等が挙
げられる。As the hydrocarbon ring in Z and A,
Examples thereof include cycloalkanes and cycloalkenes having 7 or less carbon atoms. Examples of the cycloalkane having 7 or less carbon atoms include cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. Examples of the cycloalkene having 7 or less carbon atoms include cyclopentene, cyclohexene, cycloheptene and the like.
【００１２】ＺおよびＡに於ける低級アルキレンまたは
酸素原子で架橋された炭化水素環としては、例えば炭素
数１０個以下の環が挙げられ、具体的にはビシクロ
〔１．１．１〕ペンタン、ビシクロ〔２．１．１〕ヘキ
サン、ビシクロ〔２．１．１〕ヘキサ−２−エン、ビシ
クロ〔２．２．１〕ヘプタン、ビシクロ〔２．２．１〕
ヘプタ−２−エン、ビシクロ〔２．２．２〕オクタン、
ビシクロ〔２．２．２〕オクタ−２−エン、ビシクロ
〔４．１．１〕オクタン、ビシクロ〔４．１．１〕オク
タ−２−エン、ビシクロ〔４．１．１〕オクタ−３−エ
ン、ビシクロ〔３．２．１〕オクタン、ビシクロ〔３．
２．１〕オクタ−２−エン、ビシクロ〔３．２．１〕オ
クタ−３−エン、ビシクロ〔３．２．１〕オクタ−６−
エン、ビシクロ〔３．２．２〕ノナン、ビシクロ〔３．
２．２〕ノナ−２−エン、ビシクロ〔３．２．２〕ノナ
−３−エン、ビシクロ〔３．２．２〕ノナ−６−エン、
７−オキサビシクロ〔２．２．１〕ヘプタン、７−オキ
サビシクロ〔２．２．１〕ヘプタ−２−エン、７−オキ
サビシクロ〔４．１．１〕オクタン、７−オキサビシク
ロ〔４．１．１〕オクタ−２−エン、７−オキサビシク
ロ〔４．１．１〕オクタ−３−エン、８−オキサビシク
ロ〔３．２．１〕オクタン、８−オキサビシクロ〔３．
２．１〕オクタ−２−エン、８−オキサビシクロ〔３．
２．１〕オクタ−３−エン、８−オキサビシクロ〔３．
２．１〕オクタ−６−エン等が挙げられる。Examples of the hydrocarbon ring bridged with a lower alkylene or oxygen atom in Z and A include a ring having 10 or less carbon atoms, specifically bicyclo [1.1.1] pentane, Bicyclo [2.1.1] hexane, bicyclo [2.1.1] hex-2-ene, bicyclo [2.2.1] heptane, bicyclo [2.2.1]
Hepta-2-ene, bicyclo [2.2.2] octane,
Bicyclo [2.2.2] oct-2-ene, Bicyclo [4.1.1] octane, Bicyclo [4.1.1] oct-2-ene, Bicyclo [4.1.1] oct-3- Ene, bicyclo [3.2.1] octane, bicyclo [3.
2.1] oct-2-ene, bicyclo [3.2.1] oct-3-ene, bicyclo [3.2.1] oct-6-
Ene, bicyclo [3.2.2] nonane, bicyclo [3.
2.2] nona-2-ene, bicyclo [3.2.2] non-3-ene, bicyclo [3.2.2] non-6-ene,
7-oxabicyclo [2.2.1] heptane, 7-oxabicyclo [2.2.1] hept-2-ene, 7-oxabicyclo [4.1.1] octane, 7-oxabicyclo [4. 1.1] oct-2-ene, 7-oxabicyclo [4.1.1] oct-3-ene, 8-oxabicyclo [3.2.1] octane, 8-oxabicyclo [3.
2.1] Oct-2-ene, 8-oxabicyclo [3.
2.1] oct-3-ene, 8-oxabicyclo [3.
2.1] Oct-6-ene and the like can be mentioned.
【００１３】Ａに於ける炭化水素環の結合位置としては
例えば−１，１−、−１，２−、−１，３−、−１，４
−等が挙げられる。The bonding position of the hydrocarbon ring in A is, for example, -1,1-, -1,2-, -1,3-, -1,4.
-And the like.
【００１４】Ａｒに於ける芳香族炭化水素基としては例
えば炭素数１０個以下の基が挙げられ、具体的にはフェ
ニル、ナフチル等が挙げられる。Ａｒに於ける芳香族複
素環基としては例えば単環の芳香族複素環基、二環性の
芳香族複素環基が挙げられる。Examples of the aromatic hydrocarbon group in Ar include groups having 10 or less carbon atoms, and specific examples thereof include phenyl and naphthyl. Examples of the aromatic heterocyclic group in Ar include a monocyclic aromatic heterocyclic group and a bicyclic aromatic heterocyclic group.
【００１５】単環の芳香族複素環基としては例えば炭素
数６個以下の、ヘテロ原子として窒素原子、酸素原子も
しくは硫黄原子を１〜４個、同一または相異って含む基
が挙げられ、具体的にはピリジル、ピリミジニル、チア
ゾリル、オキサゾリル、イソオキサゾリル、イソチアゾ
リル、フリル、イミダゾリル等が挙げられる。Examples of the monocyclic aromatic heterocyclic group include groups having 6 or less carbon atoms, containing 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms as hetero atoms, the same or different, Specific examples thereof include pyridyl, pyrimidinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, furyl and imidazolyl.
【００１６】二環性の芳香族複素環基としては例えば炭
素数１０個以下のヘテロ原子として窒素原子、酸素原子
もしくは硫黄原子を１〜５個同一または相異って含む基
が挙げられ、具体的にはベンズイソチアゾリル、ベンズ
イソオキサゾリル、ベンズフリル、キノリル、イソキノ
リル、インドリル、インダゾリル、ベンズイミダゾリ
ル、ベンズオキサゾリル等のベンゼン環と縮合した芳香
族複素環基、ナフチリジニル、プテリジニル、チエノフ
ラニル、イミダゾチオフェン−イル、イミダゾフラニル
等が挙げられる。Examples of the bicyclic aromatic heterocyclic group include groups containing 1 to 5 nitrogen atoms, oxygen atoms or sulfur atoms as hetero atoms having 10 or less carbon atoms, which are the same or different. Specifically, benzisothiazolyl, benzisoxazolyl, benzfuryl, quinolyl, isoquinolyl, indolyl, indazolyl, benzimidazolyl, aromatic heterocyclic group condensed with benzene ring such as benzoxazolyl, naphthyridinyl, pteridinyl, thienofuranyl, Examples thereof include imidazothiophen-yl and imidazofuranyl.
【００１７】アルキルとしては例えば炭素数６個以下の
基が挙げられ、好ましくは炭素数４個以下の低級アルキ
ルが挙げられ、具体的にはメチル、エチル、プロピル、
２−プロピル、ブチル等が挙げられる。低級アルキルと
しては例えば炭素数４個以下の基が挙げられ、具体的に
はメチル、エチル、プロピル、２−プロピル、ブチル等
が挙げられる。The alkyl includes, for example, groups having 6 or less carbon atoms, preferably lower alkyl having 4 or less carbon atoms, specifically methyl, ethyl, propyl,
2-propyl, butyl and the like can be mentioned. Examples of the lower alkyl include groups having 4 or less carbon atoms, and specific examples thereof include methyl, ethyl, propyl, 2-propyl and butyl.
【００１８】低級アルコキシとしては例えば炭素数４個
以下の基が挙げられ、具体的にはメトキシ、エトキシ、
プロポキシ、２−プロポキシ、ブトキシ等が挙げられ
る。Examples of the lower alkoxy include groups having 4 or less carbon atoms, such as methoxy, ethoxy,
Propoxy, 2-propoxy, butoxy and the like can be mentioned.
【００１９】ハロゲン原子としては例えばフッ素、塩
素、臭素、ヨウ素が挙げられる。Examples of the halogen atom include fluorine, chlorine, bromine and iodine.
【００２０】酸付加塩としては薬学上許される無機酸、
有機酸との付加塩が挙げられる。無機酸としては例えば
塩酸、臭化水素酸、ヨウ化水素酸、硫酸等が挙げられ
る。有機酸としては例えば酢酸、シュウ酸、クエン酸、
リンゴ酸、酒石酸、マレイン酸、フマール酸等が挙げら
れる。The acid addition salt is a pharmaceutically acceptable inorganic acid,
Examples thereof include addition salts with organic acids. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and the like. Examples of organic acids include acetic acid, oxalic acid, citric acid,
Examples thereof include malic acid, tartaric acid, maleic acid, fumaric acid and the like.
【００２１】本発明化合物〔Ｉ〕には立体異性体および
（または）光学異性体が存在する。本発明においては、
これらの異性体の混合物および単離された異性体を含
む。The compound [I] of the present invention has stereoisomers and / or optical isomers. In the present invention,
Includes mixtures of these isomers and isolated isomers.
【００２２】Ａｒで表される好ましい基としては、二環
性の芳香族複素環基であるか、ナフチル、ベンゾイル、
フェノキシもしくはフェニルチオ（この際、ＧはＮ、Ｃ
ＨもしくはＣＯＨを表す。）またはビフェニルメチリデ
ン（この際Ｇは炭素原子を表す。）（当該、二環性の芳
香族複素環基、ナフチル、ベンゾイル、フェノキシ、フ
ェニルチオおよびビフェニルメチリデンは少なくとも１
つの低級アルキル、低級アルコキシまたはハロゲン原子
で置換されていてもよい。）が挙げられる。The preferred group represented by Ar is a bicyclic aromatic heterocyclic group, naphthyl, benzoyl,
Phenoxy or phenylthio (where G is N, C
Represents H or COH. ) Or biphenylmethylidene (wherein G represents a carbon atom) (wherein the bicyclic aromatic heterocyclic group, naphthyl, benzoyl, phenoxy, phenylthio and biphenylmethylidene are at least 1).
It may be substituted with one lower alkyl, lower alkoxy or halogen atom. ) Is mentioned.
【００２３】Ａｒで表される更に好ましい基としてはベ
ンゼン環と縮合した芳香族複素環基、ナフチル、ベンゾ
イル、フェノキシまたはフェニルチオ（当該ベンゼン環
と縮合した芳香族複素環基、ナフチル、ベンゾイル、フ
ェノキシおよびフェニルチオは少なくとも１つの低級ア
ルキル、低級アルコキシまたはハロゲン原子で置換され
ていてもよい。）が挙げられる。この際ＧはＮ、ＣＨま
たはＣＯＨを表す。More preferred groups represented by Ar are aromatic heterocyclic groups fused with a benzene ring, naphthyl, benzoyl, phenoxy or phenylthio (aromatic heterocyclic groups fused with the benzene ring, naphthyl, benzoyl, phenoxy and Phenylthio may be substituted with at least one lower alkyl, lower alkoxy or halogen atom). At this time, G represents N, CH or COH.
【００２４】Ａｒで表される更に好ましい基としては、
具体的にはベンズイソチアゾリル、ベンズイソオキサゾ
リル、イソキノリル、ベンズフラニル、インダゾリルま
たはインドリル（当該ベンズイソチアゾリル、ベンズイ
ソオキサゾリル、イソキノリル、ベンズフラニル、イン
ダゾリルおよびインドリルは少なくとも１つの低級アル
キル、低級アルコキシまたはハロゲン原子で置換されて
いてもよい。）が挙げられる。この際ＧはＮ、ＣＨまた
はＣＯＨを表す。Ａｒで表される最も好ましい基として
は、３−ベンズイソチアゾリル、３−ベンズイソオキサ
ゾリル、３−インダゾリルまたは３−インドリル（当該
３−ベンズイソチアゾリル、３−ベンズイソオキサゾリ
ル、３−インダゾリルおよび３−インドリルは少なくと
も１つの低級アルキル、低級アルコキシまたはハロゲン
原子で置換されていてもよい。）が挙げられる。この際
ＧはＮ、ＣＨまたはＣＯＨを表す。More preferable groups represented by Ar include:
Specifically, benzisothiazolyl, benzisoxazolyl, isoquinolyl, benzfuranyl, indazolyl or indolyl (the benzisothiazolyl, benzisoxazolyl, isoquinolyl, benzfuranyl, indazolyl and indolyl are at least one lower alkyl, lower Optionally substituted with an alkoxy or halogen atom). At this time, G represents N, CH or COH. The most preferable group represented by Ar is 3-benzisothiazolyl, 3-benzisoxazolyl, 3-indazolyl or 3-indolyl (the 3-benzisothiazolyl, 3-benzisoxazolyl, 3-indazolyl and 3-indolyl may be substituted with at least one lower alkyl, lower alkoxy or halogen atom). At this time, G represents N, CH or COH.
【００２５】Ｚ−で表される好ましい基としては式A preferred group represented by Z-is the formula
【化１０】 （式中、Ｌは単結合または二重結合を表す。Ｅは水酸基
もしくは低級アルキルで置換されていてもよい低級アル
キレンまたは酸素原子を表す。Ｒ5 は水酸基を表し、Ｒ
6 は水素原子または低級アルキルを表す。Ｂは前記の意
味を表す。）、式[Chemical 10] (In the formula, L represents a single bond or a double bond. E represents a hydroxyl group or lower alkylene optionally substituted by lower alkyl or an oxygen atom. R 5 represents a hydroxyl group, R 5
6 represents a hydrogen atom or lower alkyl. B represents the above meaning. ),formula
【化１１】 （式中、Ｌ、Ｅ、Ｒ5 、Ｒ6 およびＢは前記の意味を表
す。）、式[Chemical 11] (In the formula, L, E, R 5 , R 6 and B have the above-mentioned meanings), Formula
【化１２】 （式中、Ｒ7 、Ｒ8 、Ｒ9 、Ｒ10、Ｒ11、Ｒ12は各々水
素原子、水酸基または低級アルキルを表すか、またはＲ
7 、Ｒ8 、Ｒ9 、Ｒ10、Ｒ11、Ｒ12で隣接するふたつが
結合して二重結合を表す。但し、Ｒ7 、Ｒ8 、Ｒ9 、Ｒ
10、Ｒ11、Ｒ12のうち少なくとも１つは水酸基を表す。
Ｂは前記の意味を表す。）または式[Chemical 12] (In the formula, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 each represent a hydrogen atom, a hydroxyl group or a lower alkyl, or
Two adjacent to each other at 7 , R 8 , R 9 , R 10 , R 11 and R 12 are bonded to each other to represent a double bond. However, R 7 , R 8 , R 9 , R
At least one of 10 , R 11 and R 12 represents a hydroxyl group.
B represents the above meaning. ) Or expression
【化１３】 （式中、Ｒ13、Ｒ14は各々独立して水素原子もしくは少
なくとも１つの水酸基で置換されていてもよい低級アル
キルを表すか、またはＲ13とＲ14は一緒になって少なく
とも１つの水酸基で置換されていてもよい飽和炭化水素
環を表す。Ｒ5 、Ｒ6 およびＢは前記の意味を表す。）
で表される基等が挙げられる。[Chemical 13] (In the formula, R 13 and R 14 each independently represent a hydrogen atom or a lower alkyl which may be substituted with at least one hydroxyl group, or R 13 and R 14 together represent at least one hydroxyl group. Represents a saturated hydrocarbon ring which may be substituted, and R 5 , R 6 and B have the above-mentioned meanings.)
And the like.
【００２６】ここでＲ13とＲ14が一緒になって形成する
飽和炭化水素環としては、例えば炭素数７個以下のシク
ロアルカンが挙げられ、具体的にはシクロプロパン、シ
クロブタン、シクロペンタン、シクロヘキサン、シクロ
ヘプタン等が挙げられる。Examples of the saturated hydrocarbon ring formed by R 13 and R 14 together include a cycloalkane having 7 or less carbon atoms, specifically, cyclopropane, cyclobutane, cyclopentane, cyclohexane. , Cycloheptane and the like.
【００２７】Ｚ−で表される更に好ましい基としては、
式More preferred groups represented by Z- are:
formula
【化１４】 （式中、Ｂ、Ｅ、Ｒ5 およびＲ6 は前記の意味を表
す。）、式Embedded image (In the formula, B, E, R 5 and R 6 have the above meanings.)
【化１５】 （式中、Ｅ、Ｒ5 、Ｒ6 およびＢは前記の意味を表
す。）、式[Chemical 15] (In the formula, E, R 5 , R 6 and B have the above-mentioned meanings), Formula
【化１６】 （式中、Ｒ7'、Ｒ8'、Ｒ9'、Ｒ10' 、Ｒ11' 、Ｒ12' は
各々水素原子、水酸基または低級アルキルを表すが、Ｒ
7'、Ｒ8'、Ｒ9'、Ｒ10' 、Ｒ11' 、Ｒ12' のうち少なく
とも１つは水酸基を表す。Ｂは前記の意味を表す。）ま
たは式 式Embedded image (In the formula, R 7 ′ , R 8 ′ , R 9 ′ , R 10 ′ , R 11 ′ and R 12 ′ each represent a hydrogen atom, a hydroxyl group or a lower alkyl,
At least one of 7 ' , R8 ' , R9 ' , R10 ' , R11 ' and R12 ' represents a hydroxyl group. B represents the above meaning. ) Or expression
【化１７】 （式中、Ｂ、Ｒ5 、Ｒ6 、Ｒ13およびＲ14は前記の意味
を表す。）で表される基が挙げられる。[Chemical 17] (In the formula, B, R 5 , R 6 , R 13 and R 14 have the above-mentioned meanings).
【００２８】本発明化合物〔Ｉ〕は、例えば、以下の反
応式で表される方法により製造することができる。The compound [I] of the present invention can be produced, for example, by the method represented by the following reaction formula.
【００２９】製造法 ａ）Manufacturing method a)
【化１８】 Embedded image
【００３０】製造法 ｂ）Manufacturing method b)
【化１９】 [Chemical 19]
【００３１】製造法 ｃ）Manufacturing method c)
【化２０】 Embedded image
【００３２】製造法 ｄ）Manufacturing method d)
【化２１】 [Chemical 21]
【００３３】〔反応式中、Ｒ15、Ｒ16はヒドロキシ、ア
ルコキシまたは一緒になって酸素原子を表す。Ｒ17はヒ
ドロキシの保護基を表す。ｐ、ｑは各々０または１を表
す。Ｘは脱離基を表す。脱離基としては例えばハロゲン
原子、アルキルスルホニルオキシ、アリールスルホニル
オキシが挙げられる。アルキルスルホニルオキシとして
は、例えば、メタンスルホニルオキシ等が挙げられる。
アリールスルホニルオキシとしては例えば、ｐ−トルエ
ンスルホニルオキシ、ベンゼンスルホニルオキシ等が挙
げられる。ヒドロキシの保護基としては例えば、ベンジ
ル、置換ベンジル、メトキシメチル、メトキシエトキシ
メチル、テトラヒドロフラニル等が挙げられる。置換ベ
ンジルの置換基としては、ハロゲン原子、メトキシ、ニ
トロ等が挙げられる。Ｒ5'はＲ5 に対して立体配置の反
転した水酸基を表し、Ｚ、Ａ、ｌ、ｍ、Ｇ、Ａｒ、Ｂ、
Ｅ、Ｒ5 およびＲ6 は前記の意味を表す。〕[In the reaction formula, R 15 and R 16 together represent hydroxy, alkoxy or, together, represent an oxygen atom. R 17 represents a hydroxy protecting group. p and q each represent 0 or 1. X represents a leaving group. Examples of the leaving group include a halogen atom, alkylsulfonyloxy and arylsulfonyloxy. Examples of alkylsulfonyloxy include methanesulfonyloxy and the like.
Examples of arylsulfonyloxy include p-toluenesulfonyloxy and benzenesulfonyloxy. Examples of the hydroxy protecting group include benzyl, substituted benzyl, methoxymethyl, methoxyethoxymethyl, and tetrahydrofuranyl. Examples of the substituent of the substituted benzyl include a halogen atom, methoxy, nitro and the like. R 5 'represents an inverted hydroxyl configurations with respect to R 5, Z, A, l , m, G, Ar, B,
E, R 5 and R 6 have the above-mentioned meanings. ]
【００３４】製造法ａ〜ｃにおいて使用される原料化合
物〔II〕、〔III 〕、〔IV〕、〔Ｖ〕、〔VI〕、〔VII
I〕、〔IX〕、〔XI〕、〔XII 〕、〔XIII〕、〔XIV
〕、〔XV〕および〔XVI 〕は公知化合物であるか、特
開平５−１７４４０号公報に記載の方法で合成すること
ができる。また、原料化合物〔VII 〕は対応するジカル
ボン酸またはカルボキシスルホン酸を尿素と反応させる
ことにより得られる。ジカルボン酸またはカルボキシス
ルホン酸は、例えば文献（アナーレン・デル・ヘミーAn
nalen der Chemie, 514, 91 (1935)、ケミッシェ・ベリ
ヒテ Chemische Berichte, 67, 1811 (1934) 等）記載
の方法に従って得ることができる。Starting compounds [II], [III], [IV], [V], [VI], [VII] used in the production methods a to c
I], [IX], [XI], [XII], [XIII], [XIV
], [XV] and [XVI] are known compounds, or can be synthesized by the method described in JP-A-5-17440. The starting compound [VII] can be obtained by reacting the corresponding dicarboxylic acid or carboxysulfonic acid with urea. Dicarboxylic acids or carboxysulfonic acids are described, for example, in the literature (Anallen del Chemie An.
nalen der Chemie, 514, 91 (1935), Chemische Berichte, 67, 1811 (1934), etc.).
【００３５】製造法 ａ） 式〔III 〕の化合物は、不活性溶媒中、式〔II〕の化合
物と還元剤を反応させることにより得られる。反応温度
は０℃〜溶媒の沸点の範囲である。還元剤の量は、式
〔II〕の化合物に対し、１〜１０倍モルの範囲である。
ここで不活性溶媒としては、エーテル系の溶媒例えば、
ジエチルエーテル、テトラヒドロフラン等が挙げられ
る。還元剤としては、例えば、 LiAlH4 、NaBH4 、 Ca
(BH4 ）2 、 LiAlH2 （OCH 2 CH2 OCH 3 ）2 等が挙げ
られる。Production Method a) The compound of the formula [III] can be obtained by reacting the compound of the formula [II] with a reducing agent in an inert solvent. The reaction temperature is in the range of 0 ° C to the boiling point of the solvent. The amount of reducing agent is in the range of 1 to 10 times by mole with respect to the compound of the formula [II].
Here, as the inert solvent, an ether solvent, for example,
Examples include diethyl ether and tetrahydrofuran. Examples of the reducing agent include LiAlH 4 , NaBH 4 , and Ca.
(BH 4 ) 2 , LiAlH 2 (OCH 2 CH 2 OCH 3 ) 2 and the like.
【００３６】式〔IV〕の化合物は、式〔III 〕の化合物
に脱離基を導入することにより得られる。 ・脱離基がハロゲン原子の場合（例えば塩素原子の場
合） 式〔IV〕の化合物は、式〔III 〕の化合物と塩化チオニ
ルを必要に応じて塩基存在下反応させることにより得ら
れる。反応溶媒としては例えばピリジン、テトラヒドロ
フラン、塩化メチレン等が挙げられる。塩基としては例
えば、ピリジン等が挙げられる。反応温度としては０℃
〜３０℃の範囲が挙げられる。塩化チオニルの量として
は式〔III 〕の化合物に対して２〜４倍モルの範囲が挙
げられる。The compound of the formula [IV] can be obtained by introducing a leaving group into the compound of the formula [III]. When the leaving group is a halogen atom (for example, when it is a chlorine atom) The compound of the formula [IV] can be obtained by reacting the compound of the formula [III] with thionyl chloride in the presence of a base, if necessary. Examples of the reaction solvent include pyridine, tetrahydrofuran, methylene chloride and the like. Examples of the base include pyridine and the like. 0 ℃ as the reaction temperature
The range of -30 degreeC is mentioned. The amount of thionyl chloride is in the range of 2 to 4 times by mole with respect to the compound of the formula [III].
【００３７】・脱離基が、スルホニルオキシの場合 式〔IV〕の化合物は式〔III 〕の化合物とスルホニルク
ロライドを必要に応じて塩基存在下反応させることによ
り得られる。反応溶媒としては、例えばピリジン、テト
ラヒドロフラン、塩化メチレン、クロロホルム等が挙げ
られる。塩基としては例えばトリエチルアミン等が挙げ
られる。反応温度としては０℃〜３０℃の範囲が挙げら
れる。スルホニルクロライドとしては例えば、塩化メタ
ンスルホニル等のアルキルスルホニルクロライド、トシ
ルクロライド、ベンゼンスルホニルクロライド等のアリ
ールスルホニルクロライドが挙げられる。スルホニルク
ロライドの量としては式〔III 〕の化合物に対して２〜
４倍モルの範囲が挙げられる。When the leaving group is sulfonyloxy: The compound of formula [IV] can be obtained by reacting the compound of formula [III] with a sulfonyl chloride in the presence of a base, if necessary. Examples of the reaction solvent include pyridine, tetrahydrofuran, methylene chloride, chloroform and the like. Examples of the base include triethylamine and the like. The reaction temperature may be in the range of 0 ° C to 30 ° C. Examples of the sulfonyl chloride include alkylsulfonyl chloride such as methanesulfonyl chloride, arylsulfonyl chloride such as tosyl chloride, benzenesulfonyl chloride and the like. The amount of sulfonyl chloride is 2 to the compound of the formula [III].
A 4-fold molar range can be mentioned.
【００３８】式〔VI〕の化合物は、式〔IV〕の化合物と
式〔Ｖ〕の化合物を塩基存在下反応させることにより得
られる。反応溶媒としては例えば、アルコール、アセト
ニトリル、ジメチルホルムアミド等が挙げられる。反応
温度としては溶媒の沸点付近の範囲が挙げられる。塩基
としては例えば炭酸カリウム、炭酸ナトリウム等が挙げ
られる。塩基の量としては式〔IV〕の化合物に対して0.
５〜２倍モルの範囲が挙げられる。式〔Ｖ〕の化合物の
量としては式〔IV〕の化合物に対して１〜1.５倍モルの
範囲が挙げられる。アルコールとしては例えばメタノー
ル、エタノール、プロパノール、２−プロパノール、ブ
タノール等が挙げられる。The compound of formula [VI] can be obtained by reacting the compound of formula [IV] with the compound of formula [V] in the presence of a base. Examples of the reaction solvent include alcohol, acetonitrile, dimethylformamide and the like. Examples of the reaction temperature include a range around the boiling point of the solvent. Examples of the base include potassium carbonate, sodium carbonate and the like. The amount of base is 0 with respect to the compound of formula (IV).
The range of 5 to 2 times mol is mentioned. The amount of the compound of the formula [V] is in the range of 1 to 1.5 times the mol of the compound of the formula [IV]. Examples of alcohols include methanol, ethanol, propanol, 2-propanol, butanol and the like.
【００３９】式〔Ｉ−ａ〕の化合物は、式〔VI〕の化合
物と式〔VII 〕の化合物を塩基および必要に応じて触媒
存在下、反応させることにより得られる。反応溶媒とし
ては例えばトルエン、キシレン、クロロベンゼン等の芳
香族溶媒が挙げられる。反応温度としては溶媒の沸点付
近の範囲が挙げられる。塩基としては例えば炭酸カリウ
ム、炭酸ナトリウム等が挙げられる。塩基の量としては
式〔VII 〕の化合物に対して１〜１．５倍モルの範囲が
挙げられる。触媒としては例えばジベンゾ−１８−クラ
ウン−６−エーテル等のクラウンエーテルが挙げられ
る。触媒の量としては、式〔VI〕の化合物に対して0.１
〜１０重量％の範囲が挙げられる。式〔VII 〕の化合物
の量としては式〔VI〕の化合物に対して１〜1.５倍モル
の範囲が挙げられる。The compound of the formula [Ia] is obtained by reacting the compound of the formula [VI] with the compound of the formula [VII] in the presence of a base and optionally a catalyst. Examples of the reaction solvent include aromatic solvents such as toluene, xylene and chlorobenzene. Examples of the reaction temperature include a range around the boiling point of the solvent. Examples of the base include potassium carbonate, sodium carbonate and the like. The amount of the base is in the range of 1- to 1.5-fold the molar amount of the compound of the formula [VII]. Examples of the catalyst include crown ethers such as dibenzo-18-crown-6-ether. The amount of the catalyst is 0.1 with respect to the compound of the formula [VI].
The range is from 10 to 10% by weight. The amount of the compound of the formula [VII] is in the range of 1 to 1.5 times mol with respect to the compound of the formula [VI].
【００４０】製造法 ｂ） 式〔IX〕の化合物は、式〔III 〕の化合物から式〔IV〕
の化合物を得る方法と同様にして、式〔VIII〕の化合物
に脱離基を導入することにより得られる。式〔X 〕の化
合物は式〔IX〕の化合物と式〔VII 〕の化合物を塩基お
よび必要に応じて反応助剤存在下反応させることにより
得られる。反応溶媒としては例えばアルコール、ジメチ
ルホルムアミド、アセトニトリル等が挙げられる。反応
温度としては溶媒の沸点付近の範囲が挙げられる。塩基
としては例えば炭酸カリウム、炭酸ナトリウム等の無機
塩基が挙げられる。反応助剤としては例えばヨウ化カリ
ウム、ヨウ化ナトリウム等のヨウ化アルカリ金属塩が挙
げられる。塩基の量としては、式〔IX〕の化合物に対し
て１〜２倍モルの範囲が挙げられる。反応助剤の量とし
ては式〔IX〕の化合物に対して0.１〜１倍モルの範囲が
挙げられる。式〔VII 〕の化合物の量は式〔IX〕の化合
物に対して0.１〜１倍モルの範囲が挙げられる。Production Method b) The compound of the formula [IX] is prepared by converting the compound of the formula [III] into the compound of the formula [IV]
The compound can be obtained by introducing a leaving group into the compound of the formula [VIII] in the same manner as the method of obtaining the compound of. The compound of the formula [X] can be obtained by reacting the compound of the formula [IX] with the compound of the formula [VII] in the presence of a base and optionally a reaction aid. Examples of the reaction solvent include alcohol, dimethylformamide, acetonitrile and the like. Examples of the reaction temperature include a range around the boiling point of the solvent. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate. Examples of the reaction aid include alkali metal iodides such as potassium iodide and sodium iodide. The amount of the base may be in the range of 1 to 2 times the mol of the compound of the formula [IX]. The amount of the reaction aid may be in the range of 0.1 to 1 mol per mol of the compound of the formula [IX]. The amount of the compound of the formula [VII] is in the range of 0.1 to 1 mol per mol of the compound of the formula [IX].
【００４１】式〔Ｉ〕の化合物は式〔X 〕の化合物と式
〔Ｖ〕の化合物を塩基および必要に応じて反応助剤存在
下反応させることにより得られる。反応溶媒としては例
えばアルコール、ジメチルホルムアミド、アセトニトリ
ル等が挙げられる。反応温度としては溶媒の沸点付近の
範囲が挙げられる。塩基としては例えば炭酸カリウム、
炭酸ナトリウム等の無機塩基が挙げられる。反応助剤と
しては例えば、ヨウ化カリウム、ヨウ化ナトリウム等の
ヨウ化アルカリ金属塩が挙げられる。塩基の量として
は、式〔X 〕の化合物に対して１〜２倍モルの範囲が挙
げられる。反応助剤の量としては式〔X 〕の化合物に対
して0.１〜１倍モルの範囲が挙げられる。式〔Ｖ〕の化
合物の量は式〔X 〕の化合物に対して１〜1.５倍モルの
範囲が挙げられる。The compound of the formula [I] can be obtained by reacting the compound of the formula [X] with the compound of the formula [V] in the presence of a base and optionally a reaction aid. Examples of the reaction solvent include alcohol, dimethylformamide, acetonitrile and the like. Examples of the reaction temperature include a range around the boiling point of the solvent. Examples of the base include potassium carbonate,
An inorganic base such as sodium carbonate can be used. Examples of the reaction aid include alkali metal iodides such as potassium iodide and sodium iodide. The amount of the base may be in the range of 1 to 2 times the mol of the compound of the formula [X]. The amount of the reaction aid is in the range of 0.1 to 1 mol per mol of the compound of the formula [X]. The amount of the compound of the formula [V] is in the range of 1 to 1.5 times the mol of the compound of the formula [X].
【００４２】製造法 ｃ） 式〔XI〕の化合物は、式〔VIII〕の化合物より通常の方
法、例えば、「プロテクテブ・グループ・イン・オーガ
ニック・シンセシス Protective group in Organic Sy
nthesis,Theodora W.Greene, John Wiley & Sone, 10〜
39頁」記載の保護基の導入方法により得られる。Production Method c) The compound of the formula [XI] can be prepared from the compound of the formula [VIII] by a conventional method, for example, “Protective Group in Organic Synthesis Protective group in Organic Sy”.
nthesis, Theodora W. Greene, John Wiley & Sone, 10 ~
It can be obtained by the method for introducing a protecting group described on page 39.
【００４３】式〔XII 〕の化合物は式〔XI〕の化合物を
酸化し、オキシム化し、さらに還元することにより得ら
れる。酸化剤として例えば、無水クロム酸、重クロム酸
等のクロム酸塩が挙げられる。オキシム化剤としてはヒ
ドロキシアミンが挙げられる。オキシム化の溶媒として
は例えばアルコール等が挙げられる。オキシム化の温度
としては０〜３０℃の範囲が挙げられる。オキシム化剤
の量としては式〔XI〕の化合物に対して１〜２倍の範囲
が挙げられる。還元剤としては例えば LiAlH4 等が挙げ
られる。還元の温度としては溶媒の沸点付近の範囲が挙
げられる。還元剤の量としては式〔XI〕の化合物に対し
て１〜２倍モルの範囲が挙げられる。The compound of the formula [XII] can be obtained by oxidizing the compound of the formula [XI], forming an oxime, and further reducing the compound. Examples of the oxidizing agent include chromates such as chromic anhydride and dichromic acid. Hydroxylamine is mentioned as an oxime agent. Examples of the oxime forming solvent include alcohol. The oxime formation temperature may be in the range of 0 to 30 ° C. The amount of the oxime-forming agent is in the range of 1 to 2 times that of the compound of the formula [XI]. Examples of the reducing agent include LiAlH 4 and the like. Examples of the reduction temperature include a range around the boiling point of the solvent. The amount of the reducing agent is in the range of 1 to 2 moles based on the compound of the formula [XI].
【００４４】式〔XIV 〕の化合物は式〔XII 〕の化合物
と式〔XIII〕の化合物を塩基存在下反応して得られる。
反応溶媒としては例えばアルコール、ジグライム、トル
エン、クロロベンゼン等が挙げられる。反応温度として
は溶媒の沸点付近の範囲が挙げられる。塩基としては例
えば炭酸カリウム、炭酸ナトリウム等の無機塩基が挙げ
られる。塩基の量としては、式〔XII 〕の化合物に対し
て１〜２倍モルの範囲が挙げられる。式〔XIII〕の化合
物の量は式〔XII 〕の化合物に対して１〜1.５倍モルの
範囲が挙げられる。The compound of formula [XIV] is obtained by reacting the compound of formula [XII] with the compound of formula [XIII] in the presence of a base.
Examples of the reaction solvent include alcohol, diglyme, toluene, chlorobenzene and the like. Examples of the reaction temperature include a range around the boiling point of the solvent. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate. The amount of the base may be in the range of 1 to 2 times the mol of the compound of the formula [XII]. The amount of the compound of the formula [XIII] is in the range of 1 to 1.5 times mol with respect to the compound of the formula [XII].
【００４５】式〔XV〕の化合物は、式〔XIV 〕の化合物
より通常の方法例えば、「プロテクテブ・グループ・イ
ン・オーガニック・シンセシス Protective group in
Organic Synthesis,Theodora W.Greene, John Wiley &
Sons, 10〜39頁」記載の脱保護の方法により得ることが
できる。The compound of the formula [XV] can be prepared from the compound of the formula [XIV] by a conventional method, for example, “Protective group in organic synthesis Protective group in
Organic Synthesis, Theodora W. Greene, John Wiley &
Sons, pages 10 to 39 ”.
【００４６】式〔XVI 〕の化合物は式〔XV〕の化合物に
脱離基を導入して得られる。 ・脱離基がハロゲン原子の場合（例えば塩素原子の場
合） 式〔XVI 〕の化合物は、式〔XV〕の化合物と塩化チオニ
ルを必要に応じて塩基存在下反応して得られる。反応溶
媒としては例えばピリジン、テトラヒドロフラン、塩化
メチレン等が挙げられる。塩基としては例えば、ピリジ
ン等が挙げられる。反応温度としては０℃〜３０℃の範
囲が挙げられる。塩化チオニルの量としては式〔XV〕の
化合物に対して２〜４倍モルの範囲が挙げられる。The compound of the formula [XVI] can be obtained by introducing a leaving group into the compound of the formula [XV]. -When the leaving group is a halogen atom (for example, when it is a chlorine atom) The compound of the formula [XVI] is obtained by reacting the compound of the formula [XV] with thionyl chloride in the presence of a base, if necessary. Examples of the reaction solvent include pyridine, tetrahydrofuran, methylene chloride and the like. Examples of the base include pyridine and the like. The reaction temperature may be in the range of 0 ° C to 30 ° C. The amount of thionyl chloride is in the range of 2 to 4 times by mole with respect to the compound of the formula [XV].
【００４７】・脱離基がスルホニルオキシ基の場合 式〔XVI 〕の化合物は、式〔XV〕の化合物とスルホニル
クロライドを必要に応じて塩基存在下反応して得られ
る。反応溶媒としては例えばピリジン、テトラヒドロフ
ラン、塩化メチレン、クロロホルム等が挙げられる。塩
基としては例えばトリエチルアミン等が挙げられる。反
応温度としては０℃〜３０℃の範囲が挙げられる。スル
ホニルクロライドとしては例えば、塩化メタンスルホニ
ル等のアルキルスルホニルクロライド、トシルクロライ
ド、ベンゼンスルホニルクロライド等のアリールスルホ
ニルクロラドが挙げられる。スルホニルクロライドの量
として式〔XV〕の化合物に対して２〜４倍モルの範囲が
挙げられる。When the leaving group is a sulfonyloxy group: The compound of the formula [XVI] can be obtained by reacting the compound of the formula [XV] with a sulfonyl chloride in the presence of a base, if necessary. Examples of the reaction solvent include pyridine, tetrahydrofuran, methylene chloride, chloroform and the like. Examples of the base include triethylamine and the like. The reaction temperature may be in the range of 0 ° C to 30 ° C. Examples of the sulfonyl chloride include alkylsulfonyl chlorides such as methanesulfonyl chloride and arylsulfonyl chlorides such as tosyl chloride and benzenesulfonyl chloride. The amount of the sulfonyl chloride may be in the range of 2 to 4 times the mol of the compound of the formula [XV].
【００４８】式〔Ｉ〕の化合物は式〔XVI 〕の化合物と
式〔VII 〕の化合物を塩基存在下反応して得られる。反
応溶媒としては例えば、アルコール、アセトニトリル、
ジメチルホルムアミド等が挙げられる。反応温度として
は溶媒の沸点付近の範囲が挙げられる。塩基としては例
えば炭酸カリウム、炭酸ナトリウム等が挙げられる。塩
基の量として式〔XVI 〕の化合物に対して0.５〜２倍モ
ルの範囲が挙げられる。式〔VII 〕の化合物の量として
は式〔XVI 〕の化合物に対して１〜1.５倍モルの範囲が
挙げられる。The compound of formula [I] is obtained by reacting the compound of formula [XVI] with the compound of formula [VII] in the presence of a base. Examples of the reaction solvent include alcohol, acetonitrile,
Examples thereof include dimethylformamide. Examples of the reaction temperature include a range around the boiling point of the solvent. Examples of the base include potassium carbonate, sodium carbonate and the like. The amount of the base is in the range of 0.5 to 2 times by mole with respect to the compound of the formula [XVI]. The amount of the compound of the formula [VII] is in the range of 1 to 1.5 times the mol of the compound of the formula [XVI].
【００４９】製造法 ｄ） 式〔Ｉ−ｃ〕の化合物は、式〔Ｉ−ｂ〕の化合物より通
常の方法、例えば、「ビュレタン・オブ・ザ・ケミカル
・ソサエティ・オブ・ジャパン Bull. Chem.Soc. Ja
p., 40, 2380 (1967)」記載の方法に準じて得られる。Production Method d) The compound of the formula [Ic] can be prepared from the compound of the formula [Ib] by a conventional method, for example, “Buretan of the Chemical Society of Japan Bull. Chem. Soc. Ja
p., 40, 2380 (1967) ”.
【００５０】式〔Ｉ−ｃ〕の化合物は、式〔Ｉ−ｂ〕の
化合物をトリフェニルフォスフィンおよびジエチル ア
ゾジカルボキシレートの存在下、蟻酸と反応させて得ら
れた蟻酸エステル誘導体を、塩基の存在下、加溶媒分解
することにより得られる。蟻酸エステル誘導体製造の際
の反応溶媒としては例えば、ジエチルエーテル、テトラ
ヒドロフラン等のエーテル系溶媒が望ましい。反応温度
としては氷冷から溶媒の沸点付近の範囲が挙げられる。
トリフェニルフォスフィンの量としては式〔Ｉ−ｂ〕の
化合物に対して１〜１．５倍モルの範囲が挙げられる。
ジエチルアゾジカルボキシレートの量としては式〔Ｉ−
ｂ〕の化合物に対して１〜1.５倍モルの範囲が挙げられ
る。蟻酸の量としては式〔Ｉ−ｂ〕の化合物に対して１
〜１０倍モルの範囲が挙げられる。加溶媒分解の際の塩
基としては、例えば炭酸カリウム、炭酸ナトリウム、水
酸化ナトリウム等が挙げられる。塩基の量としては、蟻
酸エステル誘導体に対して１〜1.５倍モルの範囲が挙げ
られる。反応溶媒としては例えば、メタノール、エタノ
ール等のアルコール系溶媒およびそれらと水との混合溶
媒が挙げられる。The compound of the formula [Ic] is obtained by reacting the compound of the formula [Ib] with formic acid in the presence of triphenylphosphine and diethyl azodicarboxylate to give a base of an formic acid ester derivative. It is obtained by solvolysis in the presence of. As a reaction solvent for producing the formic acid ester derivative, for example, an ether solvent such as diethyl ether or tetrahydrofuran is desirable. The reaction temperature may be in the range of ice cooling to around the boiling point of the solvent.
The amount of triphenylphosphine may be in the range of 1 to 1.5 times the mol of the compound of the formula [Ib].
The amount of diethyl azodicarboxylate may be represented by the formula [I-
The range of 1-1.5 times the molar amount of the compound [b] is included. The amount of formic acid is 1 with respect to the compound of the formula [Ib].
The range of 10 to 10 times by mole is included. Examples of the base for the solvolysis include potassium carbonate, sodium carbonate, sodium hydroxide and the like. The amount of the base may be in the range of 1 to 1.5 times the molar amount of the formic acid ester derivative. Examples of the reaction solvent include alcohol solvents such as methanol and ethanol, and mixed solvents thereof with water.
【００５１】製造法ａ）〜ｄ）で得られる化合物〔Ｉ−
ａ〕、〔Ｉ−ｃ〕および〔Ｉ〕は、結晶化溶媒中（例え
ば、アルコール、ジエチルエーテル、酢酸エチル、ヘキ
サンまたはこれらの混合溶媒等）で再結晶、またはシリ
カゲルクロマトグラフィーにより精製できる。また化合
物〔Ｉ−ａ〕、〔Ｉ−ｃ〕および〔Ｉ〕は、酸付加塩と
した後、結晶化溶媒中（例えば、アセトン、ジエチルエ
ーテル、アルコール等）にて再結晶することによっても
精製できる。Compounds [I-obtained by the production methods a) to d)
a], [Ic] and [I] can be purified by recrystallization in a crystallization solvent (for example, alcohol, diethyl ether, ethyl acetate, hexane or a mixed solvent thereof) or silica gel chromatography. The compounds [Ia], [Ic] and [I] are also purified by recrystallizing them in the crystallization solvent (eg acetone, diethyl ether, alcohol, etc.) after forming acid addition salts. it can.
【００５２】保護基導入の通常の方法としては、例え
ば、保護基がベンジル、置換ベンジル、メトキシメチル
の場合は、原料化合物に対して１〜２倍の相当する保護
基のハロゲン化物を塩基（例えば、ＮａＨ、ＫＨ等のア
ルカリ金属ハイドライド、トリエチルアミン、ジメチル
アミノピリジン等の有機塩基）存在下、有機溶媒中（例
えば、テトラヒドロフラン、ジメチルホルムアミド
等）、−１０℃〜３０℃の温度範囲で反応させることに
より保護基が導入される。As a usual method for introducing a protecting group, for example, when the protecting group is benzyl, substituted benzyl or methoxymethyl, one to two times as much halide of the corresponding protecting group as the starting compound is used as a base (eg, , An alkali metal hydride such as NaH and KH, an organic base such as triethylamine and dimethylaminopyridine) in the presence of an organic solvent (for example, tetrahydrofuran and dimethylformamide) at a temperature range of -10 ° C to 30 ° C. A protecting group is introduced.
【００５３】脱保護の通常の方法としては、例えば、保
護基がベンジル、置換ベンジルの場合、触媒（例えば、
Ｐｄ−Ｃ，ＰｔＯ，Ｐｔ−Ｃ等の貴金属触媒）存在下、
水素添加反応（例えば、１〜３気圧の範囲）を行うこと
によって脱保護できる。また、保護基がベンジル、置換
ベンジル、メトキシメチルの場合は、強酸（例えば、CF
3 COOH，HBr ，HBr-CH3 COOH等）を作用させることによ
っても脱保護できる。As a usual method of deprotection, for example, when the protecting group is benzyl or substituted benzyl, a catalyst (eg,
In the presence of a noble metal catalyst such as Pd-C, PtO, Pt-C)
It can be deprotected by carrying out a hydrogenation reaction (for example, in the range of 1 to 3 atm). When the protecting group is benzyl, substituted benzyl or methoxymethyl, a strong acid (for example, CF
3 COOH, HBr, HBr-CH 3 COOH, etc.) can also be used for deprotection.
【００５４】一般式〔Ｉ〕で表される化合物を光学分割
する場合には以下の様にできる。式〔Ｉ〕の化合物を不
活性溶媒（例えばアセトニトリル、アルコール等が挙げ
られる）に溶解し、光学活性な酸（例えばＬ−酒石酸、
Ｄ−酒石酸、Ｄ−カンファー酸、Ｌ−マンデル酸、Ｌ−
ピログルタミン酸、Ｄ−１０−カンファースルホン酸、
Ｄ−キナ酸、Ｌ−リンゴ酸、ジベンゾイル−Ｌ−酒石酸
等が挙げられ、好ましくはＬ−酒石酸、Ｄ−酒石酸が挙
げられる。）を加え塩を形成させる。塩を形成させる際
の温度としては、室温から溶媒の沸点までの範囲で行う
ことができるが、光学純度を向上させるために、一旦溶
媒の沸点近くまで加熱することが望ましい。析出した塩
をろ取する前に必要に応じ冷却し、収率を向上させるこ
とができる。光学活性な酸（分割剤）の使用量は、基質
に対して0.５〜2.０当量、好ましくは１当量前後の範囲
が適当である。必要に応じ、得られた結晶を結晶化溶媒
中（例えば、アルコール等が挙げられる。）で再結晶す
ることにより、高純度の光学活性な塩を得ることもでき
る。必要に応じ、得られた塩を通常の方法で塩基と処理
することによって、一般式〔Ｉ〕で表される化合物の光
学活性体をフリー体として得ることができる。In the case of optically resolving the compound represented by the general formula [I], it can be carried out as follows. The compound of formula [I] is dissolved in an inert solvent (for example, acetonitrile, alcohol and the like), and an optically active acid (for example, L-tartaric acid,
D-tartaric acid, D-camphoric acid, L-mandelic acid, L-
Pyroglutamic acid, D-10-camphorsulfonic acid,
D-quinic acid, L-malic acid, dibenzoyl-L-tartaric acid and the like can be mentioned, preferably L-tartaric acid and D-tartaric acid. ) Is added to form a salt. The temperature at which the salt is formed can be in the range of room temperature to the boiling point of the solvent, but it is desirable to once heat it to near the boiling point of the solvent in order to improve the optical purity. The precipitated salt can be cooled if necessary before being collected by filtration to improve the yield. The amount of the optically active acid (resolving agent) used is appropriately in the range of 0.5 to 2.0 equivalents, preferably about 1 equivalent, relative to the substrate. If necessary, the obtained crystal can be recrystallized in a crystallization solvent (for example, alcohol and the like) to obtain a highly pure optically active salt. If necessary, the obtained salt is treated with a base by a usual method to obtain an optically active form of the compound represented by the general formula [I] as a free form.
【００５５】一般式〔Ｉ〕で表される本発明化合物及び
その酸付加塩は、抗精神病薬として用いる場合、経口的
または非経口的に投与することができる。すなわち通常
用いられる投与形態例えば、錠剤，カプセル剤，シロッ
プ剤、懸濁液等の型で経口的に投与できる。あるいは、
液剤の型にしたものを注射の型で非経口的に投与でき
る。また、坐剤の型で、直腸投与することもできる。ま
た、前記の適当な投与剤型は許容される通常の担体・賦
型剤・結合剤・安定剤等に本発明化合物〔Ｉ〕またはそ
の酸付加塩を配合することにより製造することができ
る。また、注射剤型として用いる場合には、許容される
緩衝剤、溶解補助剤、等張剤等を添加することもでき
る。When used as an antipsychotic, the compound of the present invention represented by the general formula [I] and its acid addition salt can be administered orally or parenterally. That is, it can be orally administered in a commonly used dosage form such as tablets, capsules, syrups, and suspensions. Alternatively,
Solution forms can be administered parenterally in the form of injections. It can also be administered rectally in the form of suppositories. Further, the above-mentioned suitable dosage form can be produced by blending the compound [I] of the present invention or an acid addition salt thereof with an acceptable conventional carrier, excipient, binder, stabilizer and the like. When used as an injection, an acceptable buffering agent, solubilizing agent, isotonic agent, etc. may be added.
【００５６】投与量、投与回数は、症状・年齢・体重・
投与形態等によって異なるが、通常は成人に対し、１日
あたり概ね、経口の場合には１〜５００mg、好ましくは
５〜１００mgを、静注の場合には0.１〜１００mg、好ま
しくは0.３〜５０mgを１回または数回にわけて投与する
ことができる。The dose and frequency of administration are as follows: symptom / age / body weight /
Although it depends on the administration form, etc., it is usually about 1 to 500 mg, preferably 5 to 100 mg in the case of oral administration, and 0.1 to 100 mg, preferably 0.1 in the case of intravenous injection to an adult per day. 3 to 50 mg can be administered once or in several divided doses.
【００５７】実験例１ ＜実験方法＞ （１） 抗精神病作用（抗Ｄ2 作用）（in vitro） 一般に臨床における抗精神病作用とＤ2 受容体遮断作用
との間に相関性が認められている。Ｄ2 受容体作用のイ
ンビトロ試験法であるドーパミンＤ2 受容体に対するバ
インディングアッセイ法を用いた。〔 3Ｈ〕スピロペリ
ドール(spiroperidol)を用い、 Japan J. Pharmacol.,
53, 321〜329 (1990)などの記載の方法により、ラット
線条体膜標品への〔 3Ｈ〕スピロペリドール(spiroperi
dol)結合量を測定し、Ｋｉ値を求めた。その結果を表３
に示した。Experimental Example 1 <Experimental method> (1) Antipsychotic action (anti-D 2 action) (in vitro) Generally, a correlation is observed between clinical antipsychotic action and D 2 receptor blocking action. . A binding assay for the dopamine D 2 receptor, an in vitro test of D 2 receptor action, was used. Using [ 3 H] spiroperidol, Japan J. Pharmacol.,
53, 321-329 (1990), etc., [ 3 H] spiroperidol (spiroperi
The amount of dol) binding was measured to determine the Ki value. The results are shown in Table 3.
It was shown to.
【表３】 [Table 3]
【００５８】（２） 抗精神病作用（in vivo) 臨床における抗精神病作用の代表的なインビボ試験法で
ある抗メタンフェタミン試験を行った。雄性ラットに被
験薬物を静脈内投与し、１０分後にメタンフェタミン
（１mg／kg) を腹腔内投与した。投与後、１０分から９
０分間ラットの運動量をオートメックスを用いて計測
し、５０％抑制有効量・ＥＤ50値を求めた。その結果を
表４に示した。(2) Antipsychotic effect (in vivo) An anti-methamphetamine test, which is a typical in vivo test method for clinical antipsychotic effect, was carried out. The test drug was intravenously administered to male rats, and 10 minutes later, methamphetamine (1 mg / kg) was intraperitoneally administered. 10 minutes to 9 after administration
The locomotor activity of the rat was measured for 0 minutes using Automex, and the 50% inhibitory effective dose / ED 50 value was determined. The results are shown in Table 4.
【表４】 [Table 4]
【００５９】（３） 副作用 臨床における抗精神病薬の代表的な中枢性副作用である
カタレプシー惹起作用を評価した。雄性ラットに被験薬
物を静脈内投与し、１時間後に９ｃｍの高さのところに
水平に渡した直径２．５ｍｍの鉄棒に強制的に３回懸け
させる。背伸びした不自然な状態を３０秒以上、３回の
うち１回でも保持した場合、カタレプシー陽性とした。
その結果を表５に示した。(3) Side Effects The catalepsy-inducing action, which is a typical central side effect of antipsychotic drugs in clinical practice, was evaluated. The test drug is intravenously administered to male rats, and 1 hour later, the test drug is forcibly suspended three times on a horizontal iron bar having a diameter of 2.5 mm at a height of 9 cm. A catalepsy positive was obtained when an unnatural stretched state was held for 30 seconds or longer even once in three times.
The results are shown in Table 5.
【表５】 [Table 5]
【００６０】[0060]
【発明の効果】本発明化合物（Ｉ）およびその酸付加塩
は優れた抗精神病活性を示し、更に抗精神病活性（抗ア
ポモルフィン作用）と副作用の効力比から中枢性副作用
の少ないことが明らかとなった。INDUSTRIAL APPLICABILITY The compound (I) of the present invention and an acid addition salt thereof show excellent antipsychotic activity, and it is clear from the efficacy ratio of antipsychotic activity (anti-apomorphine action) and side effects that there are few central side effects. It was
【００６１】[0061]
参考例１ （１ＲＳ，２ＲＳ，３ＳＲ，４ＲＳ，５Ｓ
Ｒ）−５−ヒドロキシ−２，３−ビシクロ〔２．２．
１．〕ヘプタンジカルボン酸（２）の合成Reference Example 1 (1RS, 2RS, 3SR, 4RS, 5S
R) -5-Hydroxy-2,3-bicyclo [2.2.
1. ] Synthesis of heptane dicarboxylic acid (2)
【化２２】 （式中、太線の実線および破線は相対配置を表す。以下
の構造式も同様。） ビシクロ〔２．２．１．〕ヘプタ−５−エン−２，３−
ジ−エキソ−カルボン酸無水物（１）（５０．０ｇ，
０．３０３ｍｏｌ）を５０％硫酸水溶液（５００ｇ）中
に徐々に加え、８０〜８５℃で３．５時間攪拌した。反
応液を冷却後、反応液を塩化バリウム・２水和物（６２
２ｇ，２．５５ｍｏｌ）と水（１．５ｌ）の混合物中
に、攪拌下滴下した。終夜放置後、析出物を濾別し、濾
液および水洗液を合わせて減圧濃縮したところ、結晶が
析出した。その結晶を濾過、洗浄、乾燥することによ
り、（１ＲＳ，２ＲＳ，３ＳＲ，４ＲＳ，５ＳＲ）−５
−ヒドロキシ−２，３−ビシクロ〔２．２．１．〕ヘプ
タンジカルボン酸（２）（２２．８ｇ）を得た。 融 点 １９６〜１９８℃1 Ｈ−ＮＭＲ（DMSO-d6 ）δ：４．６５（１Ｈ，ｓ），
３．６０（１Ｈ，ｄ，Ｊ＝５Ｈｚ），２．５０（１
Ｈ），２．４３（１Ｈ），２．３５（１Ｈ），２．２０
（１Ｈ），１．１６〜１．８０（４Ｈ）．[Chemical formula 22] (In the formula, thick solid lines and broken lines represent relative arrangements. The same applies to the following structural formulas.) Bicyclo [2.2.1. ] Hepta-5-ene-2,3-
Di-exo-carboxylic acid anhydride (1) (50.0 g,
0.303 mol) was gradually added to a 50% sulfuric acid aqueous solution (500 g), and the mixture was stirred at 80 to 85 ° C for 3.5 hours. After cooling the reaction solution, the reaction solution was barium chloride dihydrate (62
2 g, 2.55 mol) and water (1.5 l) were added dropwise with stirring to the mixture. After standing overnight, the precipitate was separated by filtration, and the filtrate and the washing solution were combined and concentrated under reduced pressure to precipitate crystals. By filtering, washing and drying the crystals, (1RS, 2RS, 3SR, 4RS, 5SR) -5
-Hydroxy-2,3-bicyclo [2.2.1. ] Heptane dicarboxylic acid (2) (22.8g) was obtained. Melting point 196 to 198 ° C. 1 H-NMR (DMSO-d6) δ: 4.65 (1 H, s),
3.60 (1H, d, J = 5Hz), 2.50 (1
H), 2.43 (1H), 2.35 (1H), 2.20.
(1H), 1.16 to 1.80 (4H).
【００６２】参考例２ （１ＲＳ，２ＲＳ，３ＳＲ，４
ＲＳ，５ＳＲ）−５−ヒドロキシ−２，３−ビシクロ
〔２．２．１．〕ヘプタンジカルボキシミド（３）の合
成Reference Example 2 (1RS, 2RS, 3SR, 4
RS, 5SR) -5-Hydroxy-2,3-bicyclo [2.2.1. ] Synthesis of heptane dicarboximide (3)
【化２３】 化合物（２）（２．００ｇ，９．９５ｍｍｏｌ）および
尿素（０．６６ｇ，１０．９ｍｍｏｌ）を混合した後、
油浴温度１７０℃で１時間加熱したところ、目的の（１
ＲＳ，２ＲＳ，３ＳＲ，４ＲＳ，５ＳＲ）−５−ヒドロ
キシ−２，３−ビシクロ〔２．２．１．〕ヘプタンジカ
ルボキシミド（３）（１．９３ｇ）を得た。1 Ｈ−ＮＭＲ（DMSO-d6 ）δ：３．８３（１Ｈ，ｄ，Ｊ
＝６．９Ｈｚ），２．５６（３Ｈ，ｓ），２．４６（１
Ｈ，ｓ），１．７９（１Ｈ，ｄｄｄ，Ｊ＝１３．５，
６．９，２．３Ｈｚ），１．６５（１Ｈ，ｄ，Ｊ＝１
１．２），１．４１（１Ｈ，ｄｄｄ，Ｊ＝１３．５，
４．３，２．３Ｈｚ），１．１８（１Ｈ，ｄ，Ｊ＝１
１．２）． 同様にして、１−ヒドロキシ−１，２−シクロヘキサン
ジカルボン酸から１−ヒドロキシ−１，２−シクロヘキ
サンジカルボキシイミドが得られる。[Chemical formula 23] After mixing the compound (2) (2.00 g, 9.95 mmol) and urea (0.66 g, 10.9 mmol),
When heated at an oil bath temperature of 170 ° C for 1 hour, the desired (1
RS, 2RS, 3SR, 4RS, 5SR) -5-Hydroxy-2,3-bicyclo [2.2.1. ] Heptane dicarboximide (3) (1.93 g) was obtained. 1 H-NMR (DMSO-d6) δ: 3.83 (1 H, d, J
= 6.9 Hz), 2.56 (3H, s), 2.46 (1
H, s), 1.79 (1H, ddd, J = 13.5,
6.9, 2.3 Hz), 1.65 (1H, d, J = 1)
1.2), 1.41 (1H, ddd, J = 13.5,
4.3, 2.3 Hz, 1.18 (1H, d, J = 1)
1.2). Similarly, 1-hydroxy-1,2-cyclohexanedicarboximide is obtained from 1-hydroxy-1,2-cyclohexanedicarboxylic acid.
【００６３】参考例３ 化合物（６）Reference Example 3 Compound (6)
【化２４】 （式中、くさび形の実線および破線は絶対配置を表す。
以下の構造式も同様。） 文献（ジャーナル・オブ・ケミカル・ソサエティ：J. C
hem. Soc., 1953, 389）に従って合成した（−）−（１
Ｒ，２Ｒ）−１，２−ビス（メタンスルホニルオキシメ
チル）シクロヘキサン（４）(32.52 g, 108 mmol) と３
−（１−ピペラジニル）−１，２−ベンズイソチアゾー
ル（５）(18.24 g, 83.3 mmol)と炭酸ナトリウム(17.25
g, 125 mmol) とトルエン(300 ml)の混合物を２１時間
還流加熱した。トルエンを濃縮後、イソプロピルアルコ
ールを加えて還流加熱した後、熱時濾過を行い、濾液を
エバポレートした。残渣にアセトンを加えて熱時溶解
後、冷却することにより、目的の化合物（６）(23.0 g)
を得た。 ＩＲ（nujol)：３４９０，３４５０，１６５５，１５９
０，１５６０，１４９５，１４２５，１２１０，１０４
０ｃｍ-1.1 Ｈ−ＮＭＲ（DMSO-d6 ）δ：７．９６（１Ｈ，ｄ，Ｊ
＝７．９Ｈｚ），７．８２（１Ｈ，ｄ，Ｊ＝８．３Ｈ
ｚ），７．５０（１Ｈ，ｔ，Ｊ＝８．３Ｈｚ），７．４
０（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），４．０８（２Ｈ，ｄ
ｄ，Ｊ＝１１．５，６．５Ｈｚ），３．３９（２Ｈ，
ｔ，Ｊ＝１１．５Ｈｚ），２．１−１．８（８Ｈ，comp
lex-ｍ），１．４−１．２５（４Ｈ，complex-ｍ）．[Chemical formula 24] (In the formula, wedge-shaped solid lines and broken lines represent absolute configurations.
The same applies to the following structural formulas. ) References (Journal of Chemical Society: J. C.
hem. Soc., 1953, 389) (-)-(1
R, 2R) -1,2-bis (methanesulfonyloxymethyl) cyclohexane (4) (32.52 g, 108 mmol) and 3
-(1-Piperazinyl) -1,2-benzisothiazole (5) (18.24 g, 83.3 mmol) and sodium carbonate (17.25
A mixture of g, 125 mmol) and toluene (300 ml) was heated under reflux for 21 hours. After concentrating toluene, isopropyl alcohol was added and the mixture was heated under reflux and then filtered while hot, and the filtrate was evaporated. Acetone was added to the residue, dissolved under heat, and then cooled to give the desired compound (6) (23.0 g)
I got IR (nujol): 3490, 3450, 1655, 159
0,1560,1495,1425,1210,104
. 0cm -1 1 H-NMR ( DMSO-d6) δ: 7.96 (1H, d, J
= 7.9 Hz), 7.82 (1H, d, J = 8.3H)
z), 7.50 (1H, t, J = 8.3 Hz), 7.4
0 (1H, t, J = 7.9 Hz), 4.08 (2H, d
d, J = 11.5, 6.5 Hz), 3.39 (2H,
t, J = 11.5 Hz), 2.1-1.8 (8H, comp
lex-m), 1.4-1.25 (4H, complex-m).
【００６４】実施例１ 化合物（７）の合成Example 1 Synthesis of compound (7)
【化２５】 化合物（３）（０．６４２ｇ，３．５４ｍｍｏｌ）およ
び粉末の無水炭酸カリウム（０．４８９ｇ，３．５４ｍ
ｍｏｌ）を化合物（６）（１．００ｇ，２．３６ｍｍｏ
ｌ）のＤＭＦ（１５ｍｌ）溶液中に加え、油浴温度１２
０℃で１０時間加熱攪拌した。冷却後、反応液を水中に
注ぎ、２度エーテル抽出し、抽出液を水洗し、乾燥し
た。エバポレート後、得られた残渣をカラムクロマト法
により精製することにより、目的の（１ＲＳ，２ＲＳ，
３ＳＲ，４ＲＳ，５ＳＲ）−Ｎ−〔（１Ｒ，２Ｒ）−２
−〔４−（１，２−ベンズイソチアゾール−３−イル）
−１−ピペラジニルメチル〕−１−シクロヘキシルメチ
ル〕−５−ヒドロキシ−２，３−ビシクロ〔２．２．
１〕ヘプタンジカルボキシミド（７）（１．０８ｇ）を
得た。1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ）δ：７．９１（１Ｈ，ｄ，
Ｊ＝７．９Ｈｚ），７．８０（１Ｈ，ｄ，Ｊ＝７．９Ｈ
ｚ），７．４６（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．３
５（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ），３．９６（１Ｈ，
ｄ，Ｊ＝８．９Ｈｚ），３．９ （１Ｈ，ｍ），３．５
２（４Ｈ，ｔ，Ｊ＝５．３Ｈｚ），３．３２（１Ｈ，ｄ
ｄ，Ｊ＝１０．２，１３．２Ｈｚ），２．５５−２．７
５（７Ｈ，complex-ｍ），２．５１（２Ｈ，ｓ），２．
２３（１Ｈ，ｄｄ，Ｊ＝６．６，１２．５Ｈｚ），１．
８−１．９５（２Ｈ，complex-ｍ），１−１．７（１３
Ｈ，complex-ｍ）． 融点 １５５−１６０℃（塩酸塩）[Chemical 25] Compound (3) (0.642 g, 3.54 mmol) and powdery anhydrous potassium carbonate (0.489 g, 3.54 m)
mol) to the compound (6) (1.00 g, 2.36 mmo)
l) in DMF (15 ml) solution, oil bath temperature 12
The mixture was heated and stirred at 0 ° C for 10 hours. After cooling, the reaction solution was poured into water and extracted twice with ether. The extract solution was washed with water and dried. After evaporation, the obtained residue is purified by column chromatography to obtain the desired (1RS, 2RS,
3SR, 4RS, 5SR) -N-[(1R, 2R) -2
-[4- (1,2-benzisothiazol-3-yl)
-1-Piperazinylmethyl] -1-cyclohexylmethyl] -5-hydroxy-2,3-bicyclo [2.2.
1] Heptane dicarboximide (7) (1.08 g) was obtained. 1 H-NMR (CDCl 3 ) δ: 7.91 (1 H, d,
J = 7.9 Hz), 7.80 (1H, d, J = 7.9H)
z), 7.46 (1H, t, J = 7.9 Hz), 7.3
5 (1H, t, J = 7.9 Hz), 3.96 (1H,
d, J = 8.9 Hz), 3.9 (1H, m), 3.5
2 (4H, t, J = 5.3Hz), 3.32 (1H, d
d, J = 10.2, 13.2 Hz), 2.55-2.7
5 (7H, complex-m), 2.51 (2H, s), 2.
23 (1H, dd, J = 6.6, 12.5 Hz), 1.
8-1.95 (2H, complex-m), 1-1.7 (13
H, complex-m). Melting point 155-160 ° C (hydrochloride)
【００６５】実施例２ 化合物（９）の合成Example 2 Synthesis of compound (9)
【化２６】 ａ）化合物（７）（１．０２ｇ，２．００ｍｍｏｌ）の
ＴＨＦ（２０ｍｌ）中に、トリフェニルホスフィン
（０．７８７ｇ，３．００ｍｍｏｌ）、蟻酸（０．２３
ｇ，５．００ｍｍｏｌ）およびアゾジカルボン酸ジエチ
ルエステル（ＤＥＡＤ）（０．５２２ｇ，３．００ｍｍ
ｏｌ）を加えた後、室温で１日攪拌した。エバポレート
後、残渣にクロロホルムを加えて、そのクロロホルム溶
液を飽和重曹水で洗浄し、乾燥した。クロロホルム溶液
をエバポレートして得られた残渣をカラムクロマト法に
より分離することにより、ホルミルオキシ化合物（８）
を含む分画（１．４９ｇ）を得た。1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ）δ：７．９１（ｄ，Ｊ＝
７．９Ｈｚ），７．８１（ｄ，Ｊ＝７．９Ｈｚ），５．
２（ｍ），３．９８（ｄｄ），３．５２（ｔ），３．３
５（ｄｄ，Ｊ＝１０．２，１３．２Ｈｚ），３．２２
（ｄ，Ｊ＝７．３Ｈｚ），２．９３（ｄ，Ｊ＝４．３Ｈ
ｚ），２．７５（ｄ，Ｊ＝５．１Ｈｚ），２．５５−
２．７（complex-ｍ），２．１５−２．３（complex-
ｍ），０．９−１．９（complex-ｍ）． ｂ）化合物（８）を含む分画（１．４９ｇ）のメタノー
ル（１００ｍｌ）溶液中に粉末の無水炭酸カリウム
（０．４００ｇ）を加え、室温で４時間攪拌した。エバ
ポレート後、残渣に酢酸エチルを加え、水洗、乾燥後エ
バポレートした。その残渣をカラムクロマト法により分
離することにより、目的の（１ＲＳ，２ＲＳ，３ＳＲ，
４ＲＳ，５ＲＳ）−Ｎ−〔（１Ｒ，２Ｒ）−２−〔４−
（１，２−ベンズイソチアゾール−３−イル）−１−ピ
ペラジニルメチル〕−１−シクロヘキシルメチル〕−５
−ヒドロキシ−２，３−ビシクロ〔２．２．１〕ヘプタ
ンジカルボキシミド（９）（０．２５５ｇ）を得た。1 Ｈ−ＮＭＲ（ＣＤＣｌ3 ）δ：７．９１（１Ｈ，ｄ，
Ｊ＝７．９Ｈｚ），７．８１（１Ｈ，ｄ，Ｊ＝７．９Ｈ
ｚ），７．４６（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．３
５（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），４．３９（１Ｈ，
ｍ），３．９６（１Ｈ，ｄｄ，Ｊ＝４．０，１３．５Ｈ
ｚ），３．５２（４Ｈ，ｔ，Ｊ＝４．５Ｈｚ），３．３
−３．４（２Ｈ，ｍ），２．６−２．８（７Ｈ，comple
x-ｍ），２．０５−２．３（２Ｈ，complex-ｍ），１．
８−２．０（１Ｈ，ｍ），０．９５−１．７（１４Ｈ，
complex-ｍ）．[Chemical formula 26] a) triphenylphosphine (0.787 g, 3.00 mmol) and formic acid (0.23) in THF (20 ml) of compound (7) (1.02 g, 2.00 mmol).
g, 5.00 mmol) and azodicarboxylic acid diethyl ester (DEAD) (0.522 g, 3.00 mm
ol) was added, and the mixture was stirred at room temperature for 1 day. After evaporation, chloroform was added to the residue, and the chloroform solution was washed with saturated aqueous sodium hydrogen carbonate and dried. The formyloxy compound (8) was obtained by separating the residue obtained by evaporating the chloroform solution by column chromatography.
A fraction (1.49 g) containing was obtained. 1 H-NMR (CDCl 3 ) δ: 7.91 (d, J =
7.9 Hz), 7.81 (d, J = 7.9 Hz), 5.
2 (m), 3.98 (dd), 3.52 (t), 3.3
5 (dd, J = 10.2, 13.2 Hz), 3.22
(D, J = 7.3 Hz), 2.93 (d, J = 4.3 H)
z), 2.75 (d, J = 5.1 Hz), 2.55-
2.7 (complex-m), 2.15-2.3 (complex-m)
m), 0.9-1.9 (complex-m). b) Powdered anhydrous potassium carbonate (0.400 g) was added to a solution of the fraction (1.49 g) containing the compound (8) in methanol (100 ml), and the mixture was stirred at room temperature for 4 hours. After evaporation, ethyl acetate was added to the residue, washed with water, dried and then evaporated. By separating the residue by column chromatography, the desired (1RS, 2RS, 3SR,
4RS, 5RS) -N-[(1R, 2R) -2- [4-
(1,2-Benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -5
-Hydroxy-2,3-bicyclo [2.2.1] heptanedicarboximide (9) (0.255 g) was obtained. 1 H-NMR (CDCl 3 ) δ: 7.91 (1 H, d,
J = 7.9 Hz), 7.81 (1H, d, J = 7.9H)
z), 7.46 (1H, t, J = 7.3 Hz), 7.3
5 (1H, t, J = 7.3 Hz), 4.39 (1H,
m), 3.96 (1H, dd, J = 4.0, 13.5H
z), 3.52 (4H, t, J = 4.5Hz), 3.3.
-3.4 (2H, m), 2.6-2.8 (7H, comple
x-m), 2.05-2.3 (2H, complex-m), 1.
8-2.0 (1H, m), 0.95-1.7 (14H,
complex-m).
Claims (5)
Ｒ1 、Ｒ2 およびＲ3 は、Ｒ1 とＲ2 が一緒になって、
少なくとも１つの水酸基で置換された炭化水素環を表
し、Ｒ3 が水素原子もしくは水酸基を表すか、またはＲ
1 とＲ3 が一緒になって、少なくとも１つの水酸基で置
換された炭化水素環を表し、Ｒ2 が水素原子もしくは水
酸基を表す。当該炭化水素環は少なくとも１つの水酸基
で置換されていてもよい低級アルキレンまたは酸素原子
で架橋されていてもよい。当該炭化水素環および低級ア
ルキレンは少なくとも１つのアルキルで置換されていて
もよい。Ｒ4 は水素原子または低級アルキルを表す。ｎ
は０または１を表す。）を表す。Ａは炭化水素環を表
し、当該炭化水素環は低級アルキレンまたは酸素原子で
架橋されていてもよい。また、当該低級アルキレンおよ
び炭化水素環は少なくとも１つのアルキルで置換されて
いてもよい。ｌ、ｍは各々０、１または２を表す。Ｇは
Ｎ、ＣＨもしくはＣＯＨを、Ａｒは芳香族複素環基、芳
香族炭化水素基、ベンゾイル、フェノキシもしくはフェ
ニルチオを表すか、またはＧは炭素原子を、Ａｒはビフ
ェニルメチリデンを表す。当該芳香族複素環基、芳香族
炭化水素基、ベンゾイル、フェノキシ、フェニルチオお
よびビフェニルメチリデンは少なくとも１つの低級アル
キル、低級アルコキシまたはハロゲン原子で置換されて
いてもよい。｝で表されるイミド誘導体またはその酸付
加塩。1. A general formula [I]: {In the formula, Z- is the formula: (In the formula, B represents carbonyl or sulfonyl.
R 1 , R 2 and R 3 are the same as R 1 and R 2 together,
Represents a hydrocarbon ring substituted with at least one hydroxyl group, R 3 represents a hydrogen atom or a hydroxyl group, or R 3
1 and R 3 together represent a hydrocarbon ring substituted with at least one hydroxyl group, and R 2 represents a hydrogen atom or a hydroxyl group. The hydrocarbon ring may be bridged with a lower alkylene which may be substituted with at least one hydroxyl group or an oxygen atom. The hydrocarbon ring and lower alkylene may be substituted with at least one alkyl. R 4 represents a hydrogen atom or lower alkyl. n
Represents 0 or 1. ) Represents. A represents a hydrocarbon ring, and the hydrocarbon ring may be bridged with a lower alkylene or an oxygen atom. Further, the lower alkylene and the hydrocarbon ring may be substituted with at least one alkyl. l and m each represent 0, 1 or 2. G represents N, CH or COH, Ar represents an aromatic heterocyclic group, an aromatic hydrocarbon group, benzoyl, phenoxy or phenylthio, or G represents a carbon atom and Ar represents biphenylmethylidene. The aromatic heterocyclic group, aromatic hydrocarbon group, benzoyl, phenoxy, phenylthio and biphenylmethylidene may be substituted with at least one lower alkyl, lower alkoxy or halogen atom. } The imide derivative represented by these or its acid addition salt.
ル、ベンゾイル、フェノキシもしくはフェニルチオを表
し、ＧがＮ、ＣＨもしくはＣＯＨを表すか、またはＡｒ
がビフェニルメチリデンを表し、Ｇが炭素原子を表す
（当該二環性の芳香族複素環基、ナフチル、ベンゾイ
ル、フェノキシ、フェニルチオおよびビフェニルメチリ
デンは少なくとも１つの低級アルキル、低級アルコキシ
またはハロゲン原子で置換されていてもよい。）請求項
１記載のイミド誘導体またはその酸付加塩。2. Ar represents a bicyclic aromatic heterocyclic group, naphthyl, benzoyl, phenoxy or phenylthio, G represents N, CH or COH, or Ar
Represents biphenylmethylidene and G represents a carbon atom (the bicyclic aromatic heterocyclic group, naphthyl, benzoyl, phenoxy, phenylthio and biphenylmethylidene are substituted with at least one lower alkyl, lower alkoxy or halogen atom). The imide derivative according to claim 1 or an acid addition salt thereof.
基を表すか、ナフチル、ベンゾイル、フェノキシまたは
フェニルチオ（当該ベンゼン環と縮環した芳香族複素環
基、ナフチル、ベンゾイル、フェノキシおよびフェニル
チオは少なくとも１つの低級アルキル、低級アルコキシ
またはハロゲン原子により置換されていてもよい。）を
表し、ＧはＮ、ＣＨまたはＣＯＨを表す請求項１記載の
イミド誘導体またはその酸付加塩。3. Ar represents an aromatic heterocyclic group condensed with a benzene ring, or naphthyl, benzoyl, phenoxy or phenylthio (aromatic heterocyclic group condensed with the benzene ring, naphthyl, benzoyl, phenoxy and phenylthio. Is optionally substituted by at least one lower alkyl, lower alkoxy or halogen atom), and G represents N, CH or COH, and the imide derivative or acid addition salt thereof according to claim 1.
もしくは低級アルキルで置換されていてもよい低級アル
キレンまたは酸素原子を表す。Ｒ5 は水酸基を表し、Ｒ
6 は水素原子または低級アルキルを表す。Ｂは請求項１
記載の意味を表す。）、式 【化４】 （式中、Ｌ、Ｅ、Ｒ5 、Ｒ6 およびＢは前記の意味を表
す。）、式 【化５】 （式中、Ｒ7 、Ｒ8 、Ｒ9 、Ｒ10、Ｒ11、Ｒ12は各々水
素原子、水酸基または低級アルキルを表すか、またはＲ
7 、Ｒ8 、Ｒ9 、Ｒ10、Ｒ11、Ｒ12で隣接するふたつが
結合して二重結合を表す。但し、Ｒ7 、Ｒ8 、Ｒ9 、Ｒ
10、Ｒ11、Ｒ12のうち少なくとも１つは水酸基を表す。
Ｂは前記の意味を表す。）または式 【化６】 （式中、Ｒ13、Ｒ14は各々独立して水素原子もしくは少
なくとも１つの水酸基で置換されていてもよい低級アル
キルを表すか、またはＲ13とＲ14は一緒になって少なく
とも１つの水酸基で置換されていてもよい飽和炭化水素
環を表す。Ｒ5 、Ｒ6 およびＢは前記の意味を表す。）
を表す請求項１記載のイミド誘導体またはその酸付加
塩。4. Z- is of the formula: (In the formula, L represents a single bond or a double bond. E represents a hydroxyl group or lower alkylene optionally substituted by lower alkyl or an oxygen atom. R 5 represents a hydroxyl group, R 5
6 represents a hydrogen atom or lower alkyl. B is claim 1
Indicates the meaning of the description. ), The formula: (In the formula, L, E, R 5 , R 6 and B have the above meanings.) (In the formula, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 each represent a hydrogen atom, a hydroxyl group or a lower alkyl, or
Two adjacent to each other at 7 , R 8 , R 9 , R 10 , R 11 and R 12 are bonded to each other to represent a double bond. However, R 7 , R 8 , R 9 , R
At least one of 10 , R 11 and R 12 represents a hydroxyl group.
B represents the above meaning. ) Or the formula: (In the formula, R 13 and R 14 each independently represent a hydrogen atom or a lower alkyl which may be substituted with at least one hydroxyl group, or R 13 and R 14 together represent at least one hydroxyl group. Represents a saturated hydrocarbon ring which may be substituted, and R 5 , R 6 and B have the above-mentioned meanings.)
The imide derivative according to claim 1 or an acid addition salt thereof.
太線の実線および破線は相対配置を表す）で表される請
求項１記載のイミド誘導体またはその酸付加塩。5. The formula: (In the formula, the wedge-shaped solid line and the broken line represent the absolute configuration,
The solid line and the broken line of thick lines represent relative arrangements), The imide derivative or acid addition salt thereof according to claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16826195A JP3775823B2 (en) | 1995-06-09 | 1995-06-09 | Novel imide derivatives |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16826195A JP3775823B2 (en) | 1995-06-09 | 1995-06-09 | Novel imide derivatives |
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| Publication Number | Publication Date |
|---|---|
| JPH08333368A true JPH08333368A (en) | 1996-12-17 |
| JP3775823B2 JP3775823B2 (en) | 2006-05-17 |
Family
ID=15864736
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|---|---|---|---|
| JP16826195A Expired - Lifetime JP3775823B2 (en) | 1995-06-09 | 1995-06-09 | Novel imide derivatives |
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