JPH03275684A - Benzothiazine compound - Google Patents
Benzothiazine compoundInfo
- Publication number
- JPH03275684A JPH03275684A JP7798890A JP7798890A JPH03275684A JP H03275684 A JPH03275684 A JP H03275684A JP 7798890 A JP7798890 A JP 7798890A JP 7798890 A JP7798890 A JP 7798890A JP H03275684 A JPH03275684 A JP H03275684A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- phenylalkyl
- compound
- formula
- hydrogen
- 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
- -1 Benzothiazine compound Chemical class 0.000 title claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 125000003884 phenylalkyl group Chemical group 0.000 claims abstract description 22
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims 6
- 150000001875 compounds Chemical class 0.000 abstract description 49
- 239000012442 inert solvent Substances 0.000 abstract description 10
- 238000001816 cooling Methods 0.000 abstract description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 6
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 abstract description 2
- 241001601725 Sthenias Species 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 210000002784 stomach Anatomy 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 239000013078 crystal Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 230000003474 anti-emetic effect Effects 0.000 description 5
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 208000028017 Psychotic disease Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CZZZABOKJQXEBO-UHFFFAOYSA-N 2,4-dimethylaniline Chemical compound CC1=CC=C(N)C(C)=C1 CZZZABOKJQXEBO-UHFFFAOYSA-N 0.000 description 2
- 102000035037 5-HT3 receptors Human genes 0.000 description 2
- 108091005477 5-HT3 receptors Proteins 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- 150000003936 benzamides Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 2
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000005359 phenoxyalkyl group Chemical group 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 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
- UNRBEYYLYRXYCG-UHFFFAOYSA-N (1-ethylpyrrolidin-2-yl)methanamine Chemical compound CCN1CCCC1CN UNRBEYYLYRXYCG-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical compound CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- DZKRDHLYQRTDBU-UPHRSURJSA-N (z)-but-2-enediperoxoic acid Chemical compound OOC(=O)\C=C/C(=O)OO DZKRDHLYQRTDBU-UPHRSURJSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- IGNPOXGBNFMJHE-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-2-amine Chemical compound C1CN2C(N)CC1CC2 IGNPOXGBNFMJHE-UHFFFAOYSA-N 0.000 description 1
- YUBDLZGUSSWQSS-UHFFFAOYSA-N 1-benzylpiperidin-4-amine Chemical compound C1CC(N)CCN1CC1=CC=CC=C1 YUBDLZGUSSWQSS-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical group CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 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
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000006561 Cluster Headache Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010021518 Impaired gastric emptying Diseases 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 210000003403 autonomic nervous system Anatomy 0.000 description 1
- 229940054066 benzamide antipsychotics Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- TXHWYSOQHNMOOU-UHFFFAOYSA-N chloro(diethoxy)phosphane Chemical compound CCOP(Cl)OCC TXHWYSOQHNMOOU-UHFFFAOYSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 208000018912 cluster headache syndrome Diseases 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- PVCINRPAXRJLEP-UHFFFAOYSA-N dichloro(ethoxy)phosphane Chemical compound CCOP(Cl)Cl PVCINRPAXRJLEP-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical group CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- HTXVBGDRUBBSBH-UHFFFAOYSA-N ethyl 2,5-dichloro-3-nitrobenzoate Chemical compound CCOC(=O)C1=CC(Cl)=CC([N+]([O-])=O)=C1Cl HTXVBGDRUBBSBH-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910000358 iron sulfate Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical group [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
- NYCVSSWORUBFET-UHFFFAOYSA-M sodium;bromite Chemical compound [Na+].[O-]Br=O NYCVSSWORUBFET-UHFFFAOYSA-M 0.000 description 1
- 201000006152 substance dependence Diseases 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 229960004940 sulpiride Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は薬理学上の活性を有し、医薬品として有用であ
る新規なベンゾチアジン化合物、その光学異性体および
医薬上許容される塩類に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel benzothiazine compound having pharmacological activity and useful as a pharmaceutical, its optical isomers and pharmaceutically acceptable salts.
〔従来の技術・発明が解決しようとする課題〕セロトニ
ン（５−ＨＴ）受容体のサブタイプの一つである５
ＨＴ！受容体は知覚神経系、自律神経系などに存在し、
さらに、中枢神経系にも分布していることが確認されて
いる。この５−ＨＴ３受容体の全貌が明らかになるにつ
れて、その拮抗薬の臨床適用は末梢から中枢まで広範に
わたることが示唆されている。ところで、ある種のベン
ズアミド類は精神病治療薬あるいは鎮吐薬として有用で
ある。たとえば、スルピリド〔２−メトキシ−Ｎ−（１
−エチル−２−ピロリジニルメチル）−５−スルファモ
イルベンズアミド〕は精神病の治療に使われている。ま
た、メトクロプラミド〔４−アミノ−５−クロロ−Ｎ−
（２−ジエチルアミノ）エチル−２−メトキシベンズア
ミド〕は制吐作用を有するために鎮吐薬として使用され
ている。しかしながら、これらベンズアミド誘導体はド
パミンＤｚ受容体をも遮断するため、それによる副作用
の出現のために、使用しづらい薬剤である。[Prior art/problems to be solved by the invention] 5, which is one of the subtypes of serotonin (5-HT) receptors.
HT! Receptors exist in the sensory nervous system, autonomic nervous system, etc.
Furthermore, it has been confirmed that it is also distributed in the central nervous system. As the full picture of this 5-HT3 receptor becomes clearer, it has been suggested that the clinical application of its antagonists will be widespread from the periphery to the central nervous system. By the way, certain benzamides are useful as psychotic drugs or antiemetics. For example, sulpiride [2-methoxy-N-(1
-ethyl-2-pyrrolidinylmethyl)-5-sulfamoylbenzamide] is used in the treatment of psychosis. In addition, metoclopramide [4-amino-5-chloro-N-
(2-Diethylamino)ethyl-2-methoxybenzamide] is used as an antiemetic because it has an antiemetic effect. However, since these benzamide derivatives also block dopamine Dz receptors, they are difficult to use due to the appearance of side effects.
したがって、上記のような副作用を示さない有効な選択
的５−ＨＴ、受容体遮断薬を開発することは、制吐作用
のみならず、胃腸運動性亢進作用、鎮痛作用、抗不安作
用等の幅広い薬理活性を有する化合物の開発につながる
。Therefore, it is important to develop an effective selective 5-HT receptor blocker that does not exhibit the side effects mentioned above.It has a wide range of effects, including not only antiemetic effects but also gastrointestinal motility enhancing effects, analgesic effects, and anxiolytic effects. Leading to the development of compounds with pharmacological activity.
本発明者らの一連の研究の結果、ある種のベンゾチアジ
ン化合物が上記目的に合致することを見出し、本発明を
完成した。As a result of a series of studies by the present inventors, it was discovered that a certain type of benzothiazine compound met the above object, and the present invention was completed.
すなわち、本発明は一般式
〔式中、Ｒ１，Ｒ１は同一または異なって水素、アルキ
ルを、Ｒ３は水素、アルキル、フェニルアルキル、置換
フェニルアルキルを、Ｒ４，Ｒ５は同一または異なって
水素、ハロゲン、アルキル、アルコキシ、アξ）、アシ
ルアミノ、モノまたはジアルキル置換アミノ、水酸基、
ニトロを、Ｘは酸素またはＮＨを、Ｒ６は
（ｍは０．１を示す、）、
一以下余白一
一以下余白一
Ｒ１
（Ｒ″はアルキル、フェニルアルキル、置換フェニルア
ルキル、フェノキシアルキル、置換フェノキシアルキル
を、ＲＩ′は水素、アルコキシを、ｎは０、ｌを示す。That is, the present invention relates to the general formula [wherein R1 and R1 are the same or different and represent hydrogen or alkyl, R3 is hydrogen, alkyl, phenylalkyl, or substituted phenylalkyl, and R4 and R5 are the same or different and represent hydrogen, halogen, alkyl, alkoxy, aξ), acylamino, mono- or dialkyl-substituted amino, hydroxyl group,
nitro; RI' represents hydrogen or alkoxy; n represents 0 or 1;
）、
キル、フェニルアルキル、置換フェニルアルキルを示す
か、またはＲＩＯとＲ１１は結合して隣接する窒素原子
とともに複素環を形成する基を示し、Ｖは１〜８の整数
を示す。）
または
（Ｒ’はアルキル、フェニルアルキル、置換フェニルア
ルキルを、ｐ、ｑはそれぞれ０または１を示す。〉、
（Ｒ１１１、Ｒ１１は同一または異なって水素、アｌし
〔環Ａは環中に酸素、硫黄またはＮ Ｒｌｍ（ＲＩ３
は水素、アルキルを示す。）を含む縮合または非縮合の
窒素含有複素環基を、Ｒ′２は水素、アルキル、フェニ
ルアルキル、置換フェニルアルキル、アミノ、モノまた
はジアルキル置換アミノ、アシルアミノを、Ｗは１．２
．３．４を示す、〕により表わされる基を示す。〕
により表わされるベンゾチアジン化合物、その光学異性
体および医薬上許容される塩類に関する。), kyl, phenylalkyl, substituted phenylalkyl, or RIO and R11 combine to form a heterocycle with adjacent nitrogen atoms, and V represents an integer of 1 to 8. ) or (R' represents alkyl, phenylalkyl, substituted phenylalkyl, p and q each represent 0 or 1)>, (R111 and R11 are the same or different and are hydrogen, Al [Ring A is Oxygen, sulfur or N Rlm (RI3
represents hydrogen or alkyl. ), R'2 is hydrogen, alkyl, phenylalkyl, substituted phenylalkyl, amino, mono- or dialkyl-substituted amino, acylamino, W is 1.2
．． 3.4, ] represents a group. ] The present invention relates to a benzothiazine compound represented by the following, its optical isomers, and pharmaceutically acceptable salts.
上記の定義をより一層詳しく説明すると、ノ＼ロゲンと
はフン素、塩素、臭素、ヨウ素を、アルキルとはメチル
、エチル、プロピル、イソプロピル、ブチル、イソブチ
ル、第三級ブチル、ペンチル、ヘキシル、ヘプチル、オ
クチルなどの炭素数１〜８個のアルキルを、アルコキシ
とはメトキシ、エトキシ、プロポキシ、イソプロポキシ
、ブトキシ、イソブトキシ、第三級ブトキシ、ペンチル
オキシ、ヘキシルオキシ、ヘプチルオキシ、オクチルオ
キシなどの炭素数１〜８個のアルコキシを、アジルア逅
ノとはアセチルア逅ノ、プロピオニルアミノ、ブチリル
アミノ、ピバロイルアミノなどの炭素数２〜５個のアル
カノイルアくノを、モノまたはジアルキル置換アミノと
はアルキル部が１〜８個の炭素数を有しており、たとえ
ばメチルアミノ、エチルアミノ、プロピルアミノ、イソ
プロピルアミノ、ブチルアくノ、ヘキシルアミノ、オク
チルオキシ、ジメチルアミノ、ジエチルアミノ、ジプロ
ビルア逅ノ、ジイソプロピルアミノ、ジブチルアミノ、
ジヘキシル了ξノ、ジオクチル７ミノを示す。フェニル
アルキルの例としてはベンジル、１−マタは２−フェニ
ルエチル、３−フェニルプロピル、４−フェニルブチル
などが、フェノキシアルキルの例としてはフェノキシメ
チル、２−フェノキシエチル、３−フェノキシプロピル
、４−フェノキシブチルなどがあげられる。隣接する窒
素原子とともに複素環を形成する基としては、該窒素原
子のほかに窒素、酸素、硫黄などのへテロ原子を有して
いてもよい環状ア壽ノ基があげられ、たとえばピロリジ
ニル、モルホリノ、チオモルホリノ、ピペリジノ、ピペ
ラジニル、ホモピペラジニルなどの５〜７１１１飽和環
状ア果ノ基が含まれる。該環状アミノ基は置換可能な位
置に直換基を有していてもよく、かかる置換基としては
アルキル、フェニル、置換フェニル、フェニルアルキル
、置換フェニルアルキル、アルカノイル（アセチル、プ
ロピオニル、ブチリル、イソブチリルなど）などがあげ
られる、環中に酸素、硫黄またはＨ−Ｒｔｓ（ＲＩ３は
水素、アルキルを示す。）を含む縮合または非縮合の窒
素含有複素環基とは、２−または３−ピロリジニル、モ
ルホリニル、チオモルホリニル、ピペリジル、チアゾリ
ル、イソチアゾリル、オキサシリル、イソオキサシリル
、ピラゾリル、イミダゾリル、１−メチル−２−イミダ
ゾリル、ピリダジニル、ピリミジニル、ＬＨ−イミダゾ
リル、プリニル、キノキサリニル、フタラジニル、キナ
ゾリニル、シンノリニル、ブテリジニル、ベンゾチアゾ
リル、１，２−ベンズイソチアゾリル、ベンズオキサシ
リル、１，２−ベンズイソキサゾリル、ベンズイミダゾ
リル、１−メチル−２−ベンズイミダゾリルなどを示す
。置換フェニル、置換フェニルアルキルまたはＩ換フェ
ノキシアルキルの置換基としてはハロゲン、アルコキシ
、アルキル、ニトロ、アもノ、トリフルオロメチル、カ
ルボキシ、アルコキシカルボニルから選ばれる１〜３個
の置換基（ハロゲン、アルキル、アルコキシは前記の定
義と同じである。）を示す。To explain the above definition in more detail, \logen means fluorine, chlorine, bromine, and iodine, and alkyl means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and heptyl. , octyl, etc., and alkoxy refers to carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, etc. 1 to 8 alkoxy atoms, azila-amino refers to alkanoyl atoms having 2 to 5 carbon atoms such as acetylamino, propionylamino, butyrylamino, pivaloylamino, etc., and mono- or dialkyl-substituted amino refers to an alkyl group having 1 to 8 carbon atoms. It has 8 carbon atoms, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamino, octyloxy, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino,
Shows dihexyl and dioctyl. Examples of phenylalkyl are benzyl, 1-mata is 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, etc. Examples of phenoxyalkyl are phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl, 4-phenylbutyl, etc. Examples include phenoxybutyl. Groups that form a heterocycle together with adjacent nitrogen atoms include cyclic ajuno groups which may have a heteroatom such as nitrogen, oxygen, or sulfur in addition to the nitrogen atom, such as pyrrolidinyl, morpholino, etc. , thiomorpholino, piperidino, piperazinyl, homopiperazinyl, and the like. The cyclic amino group may have a direct substituent at a substitutable position, and such substituents include alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, alkanoyl (acetyl, propionyl, butyryl, isobutyryl, etc.). ), fused or non-fused nitrogen-containing heterocyclic groups containing oxygen, sulfur or H-Rts (RI3 represents hydrogen or alkyl) in the ring include 2- or 3-pyrrolidinyl, morpholinyl, Thiomorpholinyl, piperidyl, thiazolyl, isothiazolyl, oxasilyl, isoxasyl, pyrazolyl, imidazolyl, 1-methyl-2-imidazolyl, pyridazinyl, pyrimidinyl, LH-imidazolyl, purinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, buteridinyl, benzothiazolyl, 1, 2-benzisothiazolyl, benzoxasilyl, 1,2-benzisoxazolyl, benzimidazolyl, 1-methyl-2-benzimidazolyl, etc. Substituted phenyl, substituted phenylalkyl, or I-substituted phenoxyalkyl has 1 to 3 substituents selected from halogen, alkoxy, alkyl, nitro, ammono, trifluoromethyl, carboxy, alkoxycarbonyl (halogen, alkyl , alkoxy is the same as defined above).
一般式（１）の本発明化合物は、次の方法により製造す
ることができる。The compound of the present invention represented by general formula (1) can be produced by the following method.
ｆｉｌ 一般式（１）の化合物中、ｍ、ｎ、ｐがＯの
化合物は、一般式
（式中、各記号は前記と同義である。）により表わされ
るカルボン酸またはその反応性誘導体と一般式
％式％（）
（式中、各記号は前記と同義である。）により表わされ
る化合物とを反応させることにより製造される。fil Among the compounds of the general formula (1), the compound in which m, n, and p are O is a carboxylic acid represented by the general formula (in the formula, each symbol has the same meaning as above) or a reactive derivative thereof and the general formula It is produced by reacting a compound represented by the formula %() (in the formula, each symbol has the same meaning as above).
（ａ） 一般式（ＩＩ）の化合物が遊離のカルボン酸
である場合、反応は、ジシクロへキシルカルボジイミド
、四塩化チタン、ハロゲン化リン（三塩化リン、オキシ
塩化リンなど）、ジエチルクロロホスファイト、０−フ
ェニレンクロロホスファイト、エチルジクロロホスファ
イトなどの縮合剤の存在下に不活性溶媒中、冷却下、室
温下または加温下に行なわれる。なお、化合物（Ｉ［［
）にあらかしめハロゲン化リンを不活性溶媒中で作用さ
せた後、化合物（ＩＩ）と縮合させることもできる。た
とえば、ハロゲン化リンが三塩化リンである場合には、
化合物（Ｉ［［）にあらかじめ約〃モルの三塩化リンを
不活性溶媒中、トリエチルアミン、ピリジン、Ｎ、Ｎ−
ジメチルアニリンなどの三級塩基の存在下に冷却または
室温下で作用させた後、不活性溶媒中で化合物（ＩＩ）
と室温または加温下、好ましくは加熱還流下に反応させ
る。(a) When the compound of general formula (II) is a free carboxylic acid, the reaction may include dicyclohexylcarbodiimide, titanium tetrachloride, phosphorus halides (such as phosphorus trichloride and phosphorus oxychloride), diethylchlorophosphite, The reaction is carried out in the presence of a condensing agent such as 0-phenylenechlorophosphite or ethyldichlorophosphite in an inert solvent under cooling, at room temperature, or under heating. In addition, the compound (I[[
) can be reacted with phosphorus halide in an inert solvent and then condensed with compound (II). For example, if the phosphorus halide is phosphorus trichloride,
About mol of phosphorus trichloride was added to compound (I [
After reacting in the presence of a tertiary base such as dimethylaniline at cooling or room temperature, compound (II) is prepared in an inert solvent.
The reaction is carried out at room temperature or under heating, preferably under heating and reflux.
（ｂ） 一般式（ｎ）のカルボン酸の反応性誘導体と
して、酸クロリド、酸プロミドなどの酸ノ＼ライドを用
いる場合、反応は不活性溶媒中でトリエチルアくン、ピ
リジン、Ｎ、Ｎ−ジメチルアニリンなどの三級塩基の存
在下に冷却下または室温下で行なわれるか、または水酸
化ナトリウム、水酸化カリウムなどのアルカリの存在下
、水中で冷却下あるいは室温下に行なわれる。(b) When an acid salt such as acid chloride or acid bromide is used as the reactive derivative of the carboxylic acid of general formula (n), the reaction is carried out in an inert solvent with triethylamine, pyridine, N,N-dimethyl The reaction is carried out in the presence of a tertiary base such as aniline under cooling or at room temperature, or in the presence of an alkali such as sodium hydroxide or potassium hydroxide in water under cooling or at room temperature.
（Ｃ） 化合物（ＩＩ）の反応性誘導体として対称型
酸無水物またはアルキル炭酸混合＃ＩｔＩＡ水物、アル
キルリン酸混合酸無水物、アルキル亜リン酸混合酸無水
物、硫酸混合酸無水物などの混合酸無水物を用いる場合
、反応は不活性溶媒中でトリエチルアくン、ピリジン、
Ｎ、Ｎ−ジメチルアニリンなどの三級塩基の存在下、冷
却下、室温または加温下に行なわれる。(C) As a reactive derivative of compound (II), symmetrical acid anhydrides or alkyl carbonic acid mixed #ItIA hydrate, alkyl phosphoric acid mixed acid anhydride, alkyl phosphorous acid mixed acid anhydride, sulfuric acid mixed acid anhydride, etc. When using mixed acid anhydrides, the reaction is carried out in an inert solvent with triethylamine, pyridine,
The reaction is carried out in the presence of a tertiary base such as N,N-dimethylaniline, under cooling, at room temperature, or under heating.
（ｄ） 化合物（ＩＩ）の反応性誘導体として酸イミ
ダゾリド、酸ピロリシト、２．４−ジメチルアニリンな
どの活性アミドを用いる場合、反応は不活性溶媒中で室
温または加温下に行なわれる。(d) When using an active amide such as acid imidazolide, acid pyrrolisito, or 2,4-dimethylaniline as the reactive derivative of compound (II), the reaction is carried out in an inert solvent at room temperature or under heating.
−以下余白一
（ｅ） 式（Ｉ［［）の化合物中、ＸがＮＨである化
合物は、さらに化合物（■）の反応性誘導体としてメチ
ルエステル、エチルエステル、ｐ−ニトロフェニルエス
テル、ｐ−クロロフェニルエステルなどのエステルと反
応させることもでき、その反応は不活性溶媒（化合物（
ＩＩ）を過剰に用いて溶媒を兼ねさせることができる）
中、室温または加温下に、好ましくは加熱還流下に行な
われる。- Below margin 1 (e) Among the compounds of the formula (I[[), the compound in which It can also be reacted with esters such as esters, and the reaction is carried out in an inert solvent (compound (
II) can be used in excess to serve as a solvent)
The reaction is carried out at room temperature or under heating, preferably under heating and reflux.
前記の各縮合反応で使用される不活性溶媒としては、ベ
ンゼン、トルエン、キシレン、メタノール、エタノール
、イソプロピルアルコール、ジエチルエーテル、ジオキ
サン、テトラヒドロフラン、クロロホルム、ジクロロメ
タン、ジクロロエタン、ヘキサメチルホスホリックトリ
ア５ド、ジエチレンゲルコール、ジメチルホルムアミド
、酢酸エチルなどまたはこれらの混合溶媒であり、化合
物（■）が反応性誘導体である場合、その種類により適
当に選択される。Inert solvents used in each of the above condensation reactions include benzene, toluene, xylene, methanol, ethanol, isopropyl alcohol, diethyl ether, dioxane, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, hexamethylphosphoric trioxide, and diethylene. The solvent is gelcol, dimethylformamide, ethyl acetate, etc., or a mixed solvent thereof, and when the compound (■) is a reactive derivative, it is appropriately selected depending on the type thereof.
一般式（ＩＩ）の化合物は、たとえば以下の反応経路に
従って製造することができる。The compound of general formula (II) can be produced, for example, according to the following reaction route.
（１）
（２）
一以下余白
（上記経路において、ＲＬはＲ３から水素を除いた基を
、Ｒ１４はエステル残基を、Ｙは塩素、臭素、ヨウ素、
メタンスルホニルオキシ、ｐ−トルエンスルホニルオキ
シなどの脱離基を示し、他の記号は前記と同義である。(1) (2) One or less margins (In the above route, RL is a group obtained by removing hydrogen from R3, R14 is an ester residue, Y is chlorine, bromine, iodine,
It represents a leaving group such as methanesulfonyloxy and p-toluenesulfonyloxy, and other symbols have the same meanings as above.
）
すなわち、化合物（１）を水−アルコール系溶媒中、適
当な脱酸剤、たとえば炭酸水素ナトリウムの存在下、チ
オグリコール＃１誘導体と反応させて化合物（２）が得
られる。化合物（２）を還元剤、たとえば還元鉄で還元
すると、還元と同時に閉環して化合物（３）が得られる
。化合物（３）をアルカリ金属、たとえばカリウム−第
三級ブトキシドの存在下、ＲＨ−ｙと反応させて化合物
（４〉が得られる。化合物（４）をアルカリで加水分解
して化合物（Ｉ［）を製造することができる。) That is, compound (2) is obtained by reacting compound (1) with thioglycol #1 derivative in a water-alcoholic solvent in the presence of a suitable deoxidizing agent, such as sodium hydrogen carbonate. When compound (2) is reduced with a reducing agent such as reduced iron, compound (3) is obtained through ring closure at the same time as the reduction. Compound (4) is obtained by reacting compound (3) with RH-y in the presence of an alkali metal such as potassium-tert-butoxide. Compound (4) is hydrolyzed with an alkali to obtain compound (I[) can be manufactured.
また、Ｒ８がニトロである化合物（Ｉ［）は、ＲＳが水
素である化合物（ＩＩ）を、たとえば硝酸−硫酸の混液
でニトロ化することにより、またＲ５がアミノである化
合物（ＩＩ）はこのようにして得たＲ５がニトロである
化合物（ｎ）を鉄、硫酸第一鉄などの還元剤により還元
することにより、さらに、Ｒ５がハロゲンである化合物
はＲ５がアミノである化合物（ＩＩ）をジアゾ化し、つ
いで、ハロゲン化第−銅（塩化第一銅、臭化第一銅、ヨ
ウ化第−銅など）を用いるザンドマイヤー反応に付すこ
とによりそれぞれ得られる。Compound (I[) in which R8 is nitro can be obtained by nitrating compound (II) in which RS is hydrogen, for example, by nitration of compound (II) in which R5 is amino. By reducing the thus obtained compound (n) in which R5 is nitro with a reducing agent such as iron or ferrous sulfate, the compound (n) in which R5 is halogen can be further reduced to the compound (II) in which R5 is amino. They are obtained by diazotization and then subjecting to Sandmeyer reaction using cupric halides (cuprous chloride, cuprous bromide, cuprous iodide, etc.).
ＲＳが水酸基である化合物（ＩＩ）はＲ５がアミノであ
る化合物（Ｉｔ）をジアゾ化し、コーエンらの方法（Ｊ
、Ｏｒｇ、Ｃｈｅｍ、 第４２巻、第２０５３頁、１
９７７年）に準して、酸化第一銅および硝酸銅で処理す
ることにより得られる。Ｒ５がアルコキシである化合物
（ＩＩ）はＲｓが水酸基である化合ＩＦＩ （ｎ）とア
ルキルハライドまたは硫酸ジアルキルとを脱酸剤の存在
下に反応させることにより得られる。Compound (II) in which RS is a hydroxyl group is obtained by diazotizing the compound (It) in which R5 is amino, and the method of Cohen et al. (J
, Org, Chem, Volume 42, Page 2053, 1
977) by treatment with cuprous oxide and copper nitrate. Compound (II) in which R5 is alkoxy can be obtained by reacting compound IFI (n) in which Rs is hydroxyl and an alkyl halide or dialkyl sulfate in the presence of a deoxidizing agent.
（２）一般式（１）の化合物において、ｍ、ｎ、ｐが１
である化合物は、方法＋１１により得られる一般式（１
）の化合物においてｍ、ｎ、ｐが０である化合物を酸化
反応に付すことにより製造できる。(2) In the compound of general formula (1), m, n, p are 1
A compound having the general formula (1) obtained by method +11 is
) can be produced by subjecting a compound in which m, n, and p are 0 to an oxidation reaction.
反応は通常不活性な溶媒（クロロホルム、ジクロロメタ
ン、テトラヒドロフラン、ジオキサン、ジメチルホルム
アミド、酢酸、水など、またはそれらの混合溶媒）中、
−５０℃から室温下、好ましくは一２０℃から０℃で、
５分から２４時間、好ましくは５分から６時間で進行す
る。用いられる酸化剤としては、メタクロロ過安息香酸
、過安息香酸、過酢酸、トリフルオロ過酢酸、過マレイ
ン酸、亜臭素酸ナトリウム、次亜塩素酸ナトリウム、過
酸化水素などがあげられ、通常１〜ｌＯ当量、好ましく
は１当量からやや過剰量用いる。この酸化反応はタング
ステン酸ナトリウムなどの触媒の存在下に進行させるこ
とができる。The reaction is usually carried out in an inert solvent (chloroform, dichloromethane, tetrahydrofuran, dioxane, dimethylformamide, acetic acid, water, etc., or a mixed solvent thereof).
-50°C to room temperature, preferably -20°C to 0°C,
The process proceeds from 5 minutes to 24 hours, preferably from 5 minutes to 6 hours. Examples of the oxidizing agent used include metachloroperbenzoic acid, perbenzoic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, sodium bromite, sodium hypochlorite, and hydrogen peroxide. The amount used is 1 O equivalent, preferably 1 equivalent to a slight excess. This oxidation reaction can proceed in the presence of a catalyst such as sodium tungstate.
本発明化合物のうち、Ｒ１，Ｒ２が異なっている場合お
よび／または記号Ｒ’ −Ｘ−で表わされる基中にキラ
ルな炭素を有する群は、ジアステレオマーまたはラセミ
化合物として得られるが、本発明には、それぞれのジア
ステレオマーまたは光学異性体も包含される。ジアステ
レオマーは所望により再結晶またはカラムクロマトグラ
フィーなどの常法により分離することができる。また、
ラセミ化合物は所望により、その塩基性を利用して光学
活性な＃（酒石酸、ジベンゾイル酒石酸、マンデル酸、
１０−カンファースルホン酸など）を用いて常法により
光学分割することができる。また、ラセミ体（■）（た
だしＲ＋、Ｒ２は同一でない）を光学活性な塩基（シン
コニン、シンコニジン、プルシン、キニーネ、α−メチ
ルベンジルアミンなど）を用いて光学分割して得た光学
活性カルボン酸またはその反応性誘導体と、別途に、光
学活性な酸（酒石酸、ジベンゾイル酒石酸、マンデル酸
、１０−カンファースルホン酸など）で分割して調製し
た光学活性な化合物（Ｉ［［）とを、前述の縮合反応に
付すことにより、所望する立体配置を有する目的化合物
（１）を立体選択的に製造することができる。Among the compounds of the present invention, a group in which R1 and R2 are different and/or a group having a chiral carbon in the group represented by the symbol R' -X- can be obtained as a diastereomer or a racemic compound; Also includes the respective diastereomers or optical isomers. Diastereomers can be separated, if desired, by conventional methods such as recrystallization or column chromatography. Also,
If desired, the racemic compound can be prepared using its basicity to create an optically active # (tartaric acid, dibenzoyltartaric acid, mandelic acid,
(10-camphorsulfonic acid, etc.) by a conventional method. In addition, an optically active carboxylic acid obtained by optically resolving a racemate (■) (however, R+ and R2 are not the same) using an optically active base (cinchonine, cinchonidine, purusin, quinine, α-methylbenzylamine, etc.) or its reactive derivative, and an optically active compound (I [ By subjecting it to a condensation reaction, the target compound (1) having a desired stereoconfiguration can be stereoselectively produced.
また、本発明はシス−トランス異性体も含む。The invention also includes cis-trans isomers.
一般式（１）の化合物は、塩酸塩、臭化水素酸塩、リン
酸塩、硫酸塩、ｐ−）ルエンスルホン酸塩、クエン酸塩
、乳酸塩、マレイン酸塩、フマール酸塩、酒石酸塩など
の医薬上許容しうる酸付加塩とすることができる。また
、カルボキシル基を有する化合物はナトリウム塩、カリ
ウム塩、カルシウム塩、マグネシウム塩、亜鉛塩、アル
ミニウム塩などの金属塩、トリエチルアミンなどのアえ
ンとの塩、リジン、オルニチンなどのアミノ酸との塩と
することができる。Compounds of general formula (1) include hydrochloride, hydrobromide, phosphate, sulfate, p-)luenesulfonate, citrate, lactate, maleate, fumarate, and tartrate. It can be made into a pharmaceutically acceptable acid addition salt such as. In addition, compounds with carboxyl groups include metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, and aluminum salts, salts with aene such as triethylamine, and salts with amino acids such as lysine and ornithine. can do.
本発明の化合物を医薬として用いる場合、通常医薬とし
て許容しうる担体、賦形剤、希釈剤などの添加剤と混合
して錠剤（糖衣綻、フィルムコート錠も含む）、顆粒、
散剤、注射剤などの剤型として患者に安全に投与される
。投与量は患者の症状、体重、年齢などにより変わりう
るが、通常経口投与の場合、成人１臼当たり０．１〜１
００ｗ／瞼程度であり、これを１回または数回に分けて
投与するのが好ましい。When the compound of the present invention is used as a medicine, it is usually mixed with pharmaceutically acceptable carriers, excipients, diluents, and other additives to form tablets (including sugar-coated and film-coated tablets), granules, etc.
It is safely administered to patients in dosage forms such as powders and injections. The dosage may vary depending on the patient's symptoms, weight, age, etc., but in the case of oral administration, it is usually 0.1 to 1 per adult molar.
00w/eyelid, and it is preferable to administer this once or in divided doses.
本発明の化合物は、胃の運動性亢進作用、抗嘔吐活性お
よび／または５−ＨＴ３受容体遮断活性を有し、消化不
良、遅延性胃内容排出、消化性潰瘍などの消化器系諸疾
患の予防、治療などおよび／または片頭痛、群発性頭痛
、不整脈、またはシスプラチンなどの制癌剤投与により
誘発される嘔吐、放射線治療により誘発される悪心もし
くは嘔吐、あるいは不安、精神病などの中枢神経系の障
害、痴呆症、認識障害、薬物乱用および物質依存症など
の治療に有用である。The compound of the present invention has gastric motility-promoting action, anti-emetic activity and/or 5-HT3 receptor blocking activity, and is effective in treating various gastrointestinal diseases such as indigestion, delayed gastric emptying, and peptic ulcers. Prevention, treatment, etc. and/or central nervous system disorders such as migraine, cluster headache, arrhythmia, or emesis induced by the administration of anticancer drugs such as cisplatin, nausea or vomiting induced by radiation therapy, or anxiety, psychosis, etc. It is useful in treating conditions such as dementia, cognitive impairment, drug abuse and substance dependence.
以下、参考例および実施例により本発明を具体的に説明
するが、本発明はこれらに限定されるものではない。Hereinafter, the present invention will be specifically explained with reference to Reference Examples and Examples, but the present invention is not limited thereto.
参考例１
２．５−ジクロロ−３−ニトロ安息香酸エチル１００ｇ
をエタノール１１に溶解し、チオグリコール酸３５．０
ｇを加え、室温で攪拌しながら、炭酸水素ナトリウム
６３．８ ｇ、水５００ｍ１の溶液を加えた。希塩酸水
でｐＨ１に調整したのち、酢酸エチルで抽出し、有機層
を水洗し、無水硫酸マグネシウムで乾燥した。濃縮後、
残金をシリカゲルカラムクロマトに付し、クロロホルム
で溶出して、油状の２−（４−クロロ−２−エトキシカ
ルボニル−６−二トロフエニルチオ）酢酸を得た。Reference example 1 100 g of ethyl 2.5-dichloro-3-nitrobenzoate
was dissolved in ethanol 11, thioglycolic acid 35.0
A solution of 63.8 g of sodium hydrogen carbonate and 500 ml of water was added while stirring at room temperature. After adjusting the pH to 1 with diluted hydrochloric acid, extraction was performed with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. After concentration,
The residue was subjected to silica gel column chromatography and eluted with chloroform to obtain oily 2-(4-chloro-2-ethoxycarbonyl-6-nitrophenylthio)acetic acid.
参考例２
アンモニウムクロライド４．４ｇ、水１１５ｓＬジメチ
ルホルムアミド５７−１の溶液に鉄粉４１．３ｇを加え
、８０℃で攪拌しなから２−（４−クロロ−２−エトキ
シカルボニル−６−二トロフエニルチオ）酢酸６６ｇ、
ジメチルホルムアミド１７０ｍ１の溶液を滴下したのち
、９０℃で３時間攪拌した。反応液を熱時セライト濾過
し、濾液に水を加え、析出した結晶を濾取し、メタノー
ルから再結晶して、褐色結晶の６−クロロ−３，４−ジ
ヒドロ３−オキソ−２Ｈ−１，４−ベンゾチアジン−８
−カルボン酸エチルを得た。融点２２３〜２２５℃（分
解）
参考例３
６−クロロ−３，４−ジヒドロ−３−オキソ２Ｈ−１，
４−ベンゾチアジン−８−カルボン酸エチル２０．０ｇ
をジメチルホルムアミドに溶解し、カリウム−第三級ブ
トキシド９．９１ｇを加え、６０℃で１５分間攪拌した
。水冷下でヨウ化メチル１ ２． ５ ｇを滴下し、室
温で１５分間、次いで６０℃で１時間攪拌した。反応液
に水を加え、酢酸エチルで抽出し、水洗後、無水硫酸マ
グネシウムで乾燥し、濃縮した。残金をシリカゲルカラ
ムクロマトに付し、クロロホルムで溶出し、油状の６−
クロロ−３．４−ジヒドロ−４−メチル−３−オキソ−
２Ｈ−１．４−ベンゾチアジン−８−カルボン酸エチル
を得た。Reference Example 2 41.3 g of iron powder was added to a solution of 4.4 g of ammonium chloride and 115 sL of water and 57-1 dimethylformamide, and while stirring at 80°C, 2-(4-chloro-2-ethoxycarbonyl-6-nitrophenylthio) was added. ) 66g of acetic acid,
After dropping a solution of 170 ml of dimethylformamide, the mixture was stirred at 90°C for 3 hours. The reaction solution was filtered through Celite while hot, water was added to the filtrate, the precipitated crystals were collected by filtration, and recrystallized from methanol to give brown crystals of 6-chloro-3,4-dihydro-3-oxo-2H-1, 4-benzothiazine-8
- Ethyl carboxylate was obtained. Melting point 223-225°C (decomposition) Reference example 3 6-chloro-3,4-dihydro-3-oxo2H-1,
Ethyl 4-benzothiazine-8-carboxylate 20.0g
was dissolved in dimethylformamide, 9.91 g of potassium tert-butoxide was added, and the mixture was stirred at 60°C for 15 minutes. Methyl iodide 1 under water cooling 2. 5 g was added dropwise, and the mixture was stirred at room temperature for 15 minutes and then at 60°C for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, eluted with chloroform, and the oily 6-
Chloro-3,4-dihydro-4-methyl-3-oxo-
Ethyl 2H-1,4-benzothiazine-8-carboxylate was obtained.
参考例４
６−クロロ−３．４−ジヒドロ−４−メチル−３−オキ
ソ−２Ｈ−１．４−ベンゾチアジン−８−カルボン酸エ
チル１ ９． ０ ｇをメタノール２００ｍｌに溶解し
、水酸化ナトリウム３． ２ ９ ｇ、水４０ｍｌの溶
液を加え、３０分間還流した。反応液を濃縮し、残金に
水を加え、希塩酸水でｐＨ３に調整した。析出する結晶
を濾取後、エタノールから再結晶して淡黄色結晶の６−
クロロ−３．４−ジヒドロ−４−メチル−３−オキソ−
２Ｈ−１．４ヘンゾチアジン−８−カルボン酸を得た。Reference Example 4 Ethyl 6-chloro-3.4-dihydro-4-methyl-3-oxo-2H-1.4-benzothiazine-8-carboxylate 1 9. Dissolve 0 g in 200 ml of methanol and add 3.0 g of sodium hydroxide. A solution of 29 g and 40 ml of water was added, and the mixture was refluxed for 30 minutes. The reaction solution was concentrated, water was added to the residue, and the pH was adjusted to 3 with diluted hydrochloric acid. After filtering the precipitated crystals, they were recrystallized from ethanol to give pale yellow crystals of 6-
Chloro-3,4-dihydro-4-methyl-3-oxo-
2H-1.4henzothiazine-8-carboxylic acid was obtained.
融点２６３〜２６４℃（分解）
実施例１
６−クロロ−３．４−ジヒドロ−４−メチル−３−オキ
ソ−２Ｈ−１．４−ベンゾチアジン−８カルボンｆｌｌ
２． Ｏ ｇを酢酸エチル４０ｍｌに溶解し、トリエ
チルアミン１． １ ｇを加え、−１０〜−５℃で撹拌
しながらピバロイルクロライド
を滴下したのち、同温度で１５分間攪拌した。次に３−
アミノキヌクリジン１．１８ｇ、酢酸エチル２０−１の
溶液を、−１０〜−５℃で加え、室温で１時間攪拌した
。反応液を水洗後、無水硫酸マグネシウムで乾燥し、濃
縮し、残金をエタノールに熔解した。エタノール性塩酸
を加え、析出する結晶を濾取した後、エタノール−メタ
ノール混合溶媒から再結晶して無色結晶の６−クロロ−
３，４ジヒドロ−４−メチル−３−オキソ−Ｎ−（３キ
ヌクリジニル）−２Ｈ−１．４−ベンゾチアジン−８−
カルボキサミド・塩酸塩を得た。融点２９２〜２９５℃
（分解）
実施例２
６−クロロ−３．４−ジヒドロ−４−メチル−３−オキ
ソ−２Ｈ−１．４−ベンゾチアジン−８カルボン酸２．
０ｇを酢酸エチル４０ｍｌに溶解し、トリエチルアミン
１．１ｇを加え、−１０〜−５℃で攪拌しながらピバロ
イルクロライド０．９３６ ｇを滴下した後、同温度で
１５分間攪拌した。次にＮ，Ｎジエチルエチレンジアミ
ン１．０８ｇを一ｌＯ〜−５℃で加え、室温で１時間攪
拌した．反応液を水洗後、無水硫酸マグネシウムで乾燥
し、濃縮した．残金の結晶を酢酸エチルから再結晶して
無色結晶の６−クロロ−Ｎ−（２−ジエチルアミノエチ
ル）−３，４−ジヒドロ−４−メチル−３−オキソ−２
Ｈ−１，４−ヘンジチアジン−８−カルボキサくドを得
た。融点１７９〜１８０℃実施例３
６−クロロ−３，４−ジヒドロ−４−メチル−３−オキ
ソ−２Ｈ−１，４−ベンゾチアジン−８＝カルボン酸２
．０ｇを酢酸エチル４（ｌｓｌに溶解し、トリエチルア
くン１．１ｇを加え、−１０〜−５℃で攪拌しながらピ
バロイルクロライド０．９３６ ｇを滴下した後、同温
度で１５分間攪拌した。次に２−アミノメチル−１−エ
チルピロリジン１．１９ｇを一１Ｏ〜−５℃で加え、室
温で１時間攪拌した０反応液を水洗後、無水硫酸マグネ
シウムで乾燥し、濃縮した。残金をイソプロピルエーテ
ルで結晶化させ、濾取した結晶を酢酸エチルから再結晶
して淡黄色結晶の６−クロロ−Ｎ−（１−エチル−２−
ピロリジニル〉メチル−３，４−ジヒドロ−４−メチル
−３−オキソ−２Ｈ−１，４−ベンゾチアジン−８−カ
ルボキサミドを得た。融点１８４〜１８５℃
実施例４
６−クロロ−３，４−ジヒドロ−４−メチル３−オキソ
−２Ｈ−１，４−ヘンジチアジン−８−カルボン酸２．
０ｇを酢酸エチル４０ｍ１に溶解し、トリエチルアミン
１．１ｇを加え、−１０〜−５℃で攪拌しながら、ピバ
ロイルクロライド０．９３６を滴下した後、同温度で１
５分間攪拌した。次に４−アミノ−１−ベンジルピペリ
ジン１．７７ｇ。Melting point 263-264°C (decomposition) Example 1 6-chloro-3.4-dihydro-4-methyl-3-oxo-2H-1.4-benzothiazine-8carvone full
2. Dissolve 1.0 g of triethylamine in 40 ml of ethyl acetate. After adding 1 g of pivaloyl chloride dropwise while stirring at -10 to -5°C, the mixture was stirred at the same temperature for 15 minutes. Next 3-
A solution of 1.18 g of aminoquinuclidine and 20-1 of ethyl acetate was added at -10 to -5°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, concentrated, and the residue was dissolved in ethanol. After adding ethanolic hydrochloric acid and collecting the precipitated crystals by filtration, recrystallization from an ethanol-methanol mixed solvent yields colorless crystals of 6-chloro-
3,4dihydro-4-methyl-3-oxo-N-(3quinuclidinyl)-2H-1,4-benzothiazine-8-
Carboxamide hydrochloride was obtained. Melting point 292-295℃
(Decomposition) Example 2 6-chloro-3.4-dihydro-4-methyl-3-oxo-2H-1.4-benzothiazine-8carboxylic acid 2.
0 g was dissolved in 40 ml of ethyl acetate, 1.1 g of triethylamine was added, and 0.936 g of pivaloyl chloride was added dropwise with stirring at -10 to -5°C, followed by stirring at the same temperature for 15 minutes. Next, 1.08 g of N,N diethylethylenediamine was added at 10 to -5°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The remaining crystals were recrystallized from ethyl acetate to give colorless crystals of 6-chloro-N-(2-diethylaminoethyl)-3,4-dihydro-4-methyl-3-oxo-2.
H-1,4-hendithiazine-8-carboxamide was obtained. Melting point 179-180°C Example 3 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine-8=carboxylic acid 2
．． 0 g was dissolved in ethyl acetate 4 (lsl), 1.1 g of triethyl acetate was added, and 0.936 g of pivaloyl chloride was added dropwise with stirring at -10 to -5°C, followed by stirring at the same temperature for 15 minutes. Next, 1.19 g of 2-aminomethyl-1-ethylpyrrolidine was added at -10 to -5°C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Crystallization was performed from isopropyl ether, and the crystals collected by filtration were recrystallized from ethyl acetate to give pale yellow crystals of 6-chloro-N-(1-ethyl-2-
Pyrrolidinyl>Methyl-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine-8-carboxamide was obtained. Melting point 184-185°C Example 4 6-chloro-3,4-dihydro-4-methyl 3-oxo-2H-1,4-hendithiazine-8-carboxylic acid 2.
0 g was dissolved in 40 ml of ethyl acetate, 1.1 g of triethylamine was added, and 0.936 g of pivaloyl chloride was added dropwise while stirring at -10 to -5°C.
Stir for 5 minutes. Next, 1.77 g of 4-amino-1-benzylpiperidine.
酢酸エチル２０−１の溶液を−１０〜−５℃で加え、室
温で１時間攪拌した。反応液を水洗後、無水硫酸マグネ
シウムで乾燥し、濃縮した。残金の結晶を酢酸エチルか
ら再結晶して無色結晶のＮ−（１−ベンジル−４−ピペ
リジル）−６−クロロ−３，４−ジヒドロ−４−メチル
−３−オキソ−２Ｈ−１，４−ベンゾチアジン−８−カ
ルボキサミドを得た。融点２１４〜２１５℃
◎ ６−クロロ−３，４−ジヒドロ−３−オキソ−Ｎ−
（３−キヌクリジニル）−２Ｈ−１，４−ベンゾチアジ
ン−８−カルボキサミド
◎ ４−ベンジル−６−クロロ−３，４−ジヒドロ−３
−オキソ−Ｎ−（３−キヌクリジニル）２Ｈ−１，４−
ヘンジチアジン−８−カルボキサミド◎ ６−クロロ−
３，４−ジヒドロ−４−メチルＮ−（８−メチル−８−
アザビシクロ（３，２゜１〕オクト−３−イル）−３−
オキソ−２Ｈ−１，４−ベンゾチアジン−８−カルボキ
サミド◎ ６−クロロ−Ｎ−（１−（３−（４−フルオ
ロフェノキシ）プロピル〕−３−メトキシー４ピペリジ
ル） −３，４−ジヒドロ−４−メチル−３−オキソ−
２Ｈ−１，４−ベンゾチアジン−８−カルボキサミド
◎ ６−フルオロ−３，４−ジヒドロ−２，４−ジメチ
ル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ−
１，４−ベンゾチアジン−８−カルボキサミド
◎ ６−クロロ−３，４−ジヒドロ−２，２，４ジニル
）−２Ｈ−１，４−ヘンジチアジン−８カルボキサミド
◎ ６−クロロ−３，４−ジヒドロ−４−メチル７−ニ
トロ−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ
−１，４−ベンゾチアジン−８カルボキサミド
◎ ７−アミノ−６−クロロ−３，４−ジヒドロ４−メ
チル−３−オキソ−Ｎ−（３−キヌクリジニル）−２Ｈ
−１，４−ベンゾチアジン−８−カルボキサミド
◎ ３，４−ジヒドロ−４−メチル−３−オキソＮ−（
３−キヌクリジニル）−２Ｈ−１，４ベンゾチアジン−
８−カルボキサミドA solution of ethyl acetate 20-1 was added at -10 to -5°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The remaining crystals were recrystallized from ethyl acetate to give colorless crystals of N-(1-benzyl-4-piperidyl)-6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4- Benzothiazine-8-carboxamide was obtained. Melting point 214-215°C ◎ 6-chloro-3,4-dihydro-3-oxo-N-
(3-quinuclidinyl)-2H-1,4-benzothiazine-8-carboxamide◎ 4-benzyl-6-chloro-3,4-dihydro-3
-oxo-N-(3-quinuclidinyl)2H-1,4-
Hengethiazine-8-carboxamide ◎ 6-chloro-
3,4-dihydro-4-methyl N-(8-methyl-8-
Azabicyclo(3,2゜1]oct-3-yl)-3-
Oxo-2H-1,4-benzothiazine-8-carboxamide ◎ 6-chloro-N-(1-(3-(4-fluorophenoxy)propyl]-3-methoxy4piperidyl) -3,4-dihydro-4- Methyl-3-oxo-
2H-1,4-benzothiazine-8-carboxamide ◎ 6-fluoro-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-
1,4-Benzothiazine-8-carboxamide◎ 6-chloro-3,4-dihydro-2,2,4dinyl)-2H-1,4-hendithiazine-8carboxamide◎ 6-chloro-3,4-dihydro-4 -Methyl 7-nitro-3-oxo-N-(3-quinuclidinyl)-2H
-1,4-benzothiazine-8carboxamide ◎ 7-amino-6-chloro-3,4-dihydro 4-methyl-3-oxo-N-(3-quinuclidinyl)-2H
-1,4-benzothiazine-8-carboxamide ◎ 3,4-dihydro-4-methyl-3-oxo N-(
3-quinuclidinyl)-2H-1,4benzothiazine-
8-carboxamide
Claims (1)
ルキルを、Ｒ＾３は水素、アルキル、フェニルアルキル
、置換フェニルアルキルを、Ｒ＾４、Ｒ＾５は同一また
は異なって水素、ハロゲン、アルキル、アルコキシ、ア
ミノ、アシルアミノ、モノまたはジアルキル置換アミノ
、水酸基、ニトロを、Ｘは酸素またはＮＨを、Ｒ＾６は ▲数式、化学式、表等があります▼ （ｍは０、１を示す。）、 ▲数式、化学式、表等があります▼ （Ｒ＾７はアルキル、フェニルアルキル、置換フェニル
アルキル、フェノキシアルキル、置換フェノキシアルキ
ルを、Ｒ＾８は水素、アルコキシを、ｎは０、１を示す
。）、 ▲数式、化学式、表等があります▼ （Ｒ＾９はアルキル、フェニルアルキル、置換フェニル
アルキルを、ｐ、ｑはそれぞれ０または１を示す。）、 ▲数式、化学式、表等があります▼ （Ｒ＾１＾０、Ｒ＾１＾１は同一または異なって水素、
アルキル、フェニルアルキル、置換フェニルアルキルを
示すか、またはＲ＾１＾０とＲ＾１＾１は結合して隣接
する窒素原子とともに複素環を形成する基を示し、ｖは
１〜８の整数を示す。） または ▲数式、化学式、表等があります▼ 〔環Ａは環中に酸素、硫黄またはＮ−Ｒ＾１＾３（Ｒ＾
１＾３は水素、アルキルを示す。）を含む縮合または非
縮合の窒素含有複素環基を、Ｒ＾１＾２は水素、アルキ
ル、フェニルアルキル、置換フェニルアルキル、アミノ
、モノまたはジアルキル置換アミノ、アシルアミノを、
ｗは１、２、３、４を示す。〕により表わされる基を示
す。〕 により表わされるベンゾチアジン化合物、その光学異性
体および医薬上許容される塩類。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are the same or different and represent hydrogen or alkyl, and R^3 is hydrogen, alkyl, phenylalkyl, substituted phenylalkyl. , R^4, R^5 are the same or different hydrogen, halogen, alkyl, alkoxy, amino, acylamino, mono- or dialkyl substituted amino, hydroxyl group, nitro, X is oxygen or NH, R^6 is ▲ formula , chemical formulas, tables, etc. ▼ (m indicates 0, 1), ▲ Numerical formulas, chemical formulas, tables, etc. , R^8 represents hydrogen or alkoxy, n represents 0 or 1), ▲Mathematical formulas, chemical formulas, tables, etc.▼ (R^9 represents alkyl, phenylalkyl, substituted phenylalkyl, p and q respectively 0 or 1), ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^1^0 and R^1^1 are the same or different and represent hydrogen,
represents alkyl, phenylalkyl, substituted phenylalkyl, or represents a group in which R^1^0 and R^1^1 combine to form a heterocycle with adjacent nitrogen atoms, and v is an integer from 1 to 8. show. ) or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Ring A has oxygen, sulfur, or N-R^1^3(R^
1^3 represents hydrogen or alkyl. ), R^1^2 is hydrogen, alkyl, phenylalkyl, substituted phenylalkyl, amino, mono- or dialkyl substituted amino, acylamino,
w indicates 1, 2, 3, 4. ] represents a group. ] A benzothiazine compound represented by, its optical isomer and pharmaceutically acceptable salts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7798890A JPH03275684A (en) | 1990-03-26 | 1990-03-26 | Benzothiazine compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7798890A JPH03275684A (en) | 1990-03-26 | 1990-03-26 | Benzothiazine compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03275684A true JPH03275684A (en) | 1991-12-06 |
Family
ID=13649227
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7798890A Pending JPH03275684A (en) | 1990-03-26 | 1990-03-26 | Benzothiazine compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03275684A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5352685A (en) * | 1992-03-12 | 1994-10-04 | Mitsubishi Kasei Corporation | Thieno[3,2-b]pyridine derivatives |
-
1990
- 1990-03-26 JP JP7798890A patent/JPH03275684A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5352685A (en) * | 1992-03-12 | 1994-10-04 | Mitsubishi Kasei Corporation | Thieno[3,2-b]pyridine derivatives |
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