JPH03184963A - Dibenzoxazepine derivative - Google Patents
Dibenzoxazepine derivativeInfo
- Publication number
- JPH03184963A JPH03184963A JP32156489A JP32156489A JPH03184963A JP H03184963 A JPH03184963 A JP H03184963A JP 32156489 A JP32156489 A JP 32156489A JP 32156489 A JP32156489 A JP 32156489A JP H03184963 A JPH03184963 A JP H03184963A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- formula
- solvent
- chlorodibenz
- oxazepin
- 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
- RVSGRNKUJJUAPV-UHFFFAOYSA-N benzo[d][1,2]benzoxazepine Chemical class O1N=CC2=CC=CC=C2C2=CC=CC=C12 RVSGRNKUJJUAPV-UHFFFAOYSA-N 0.000 title abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 239000002904 solvent Substances 0.000 abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 9
- 239000002253 acid Substances 0.000 abstract description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 abstract description 8
- 229960002519 amoxapine Drugs 0.000 abstract description 5
- QWGDMFLQWFTERH-UHFFFAOYSA-N amoxapine Chemical compound C12=CC(Cl)=CC=C2OC2=CC=CC=C2N=C1N1CCNCC1 QWGDMFLQWFTERH-UHFFFAOYSA-N 0.000 abstract description 5
- -1 analgesic Substances 0.000 abstract description 5
- 230000001430 anti-depressive effect Effects 0.000 abstract description 5
- 239000000935 antidepressant agent Substances 0.000 abstract description 5
- 229940005513 antidepressants Drugs 0.000 abstract description 5
- 230000000202 analgesic effect Effects 0.000 abstract description 4
- 230000003288 anthiarrhythmic effect Effects 0.000 abstract description 4
- 230000003266 anti-allergic effect Effects 0.000 abstract description 4
- 230000003474 anti-emetic effect Effects 0.000 abstract description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 abstract description 4
- 230000000049 anti-anxiety effect Effects 0.000 abstract description 3
- 239000002111 antiemetic agent Substances 0.000 abstract description 3
- 239000002249 anxiolytic agent Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 2
- 150000002366 halogen compounds Chemical class 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 208000001953 Hypotension Diseases 0.000 abstract 1
- 239000003416 antiarrhythmic agent Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 125000004494 ethyl ester group Chemical group 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 208000021822 hypotensive Diseases 0.000 abstract 1
- 230000001077 hypotensive effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000001737 promoting effect Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000013078 crystal Substances 0.000 description 10
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000003276 anti-hypertensive effect Effects 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
- 238000002329 infrared spectrum Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- WXLCDTBTIVJDCE-UHFFFAOYSA-N 1,4-oxazepine Chemical compound O1C=CC=NC=C1 WXLCDTBTIVJDCE-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000005176 gastrointestinal motility Effects 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-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
- 229910000029 sodium carbonate Inorganic materials 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
- 229940086542 triethylamine Drugs 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- PMNSFJGEIMTFJA-UHFFFAOYSA-N 3-[4-(8-chlorobenzo[b][1,4]benzoxazepin-6-yl)piperazin-1-yl]propanoic acid Chemical compound C1CN(CCC(=O)O)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 PMNSFJGEIMTFJA-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
- PNVMETHNPLIUGC-UHFFFAOYSA-N 4-[4-(8-chlorobenzo[b][1,4]benzoxazepin-6-yl)piperazin-1-yl]butanoic acid Chemical compound C1CN(CCCC(=O)O)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 PNVMETHNPLIUGC-UHFFFAOYSA-N 0.000 description 1
- UFCWTMHULGCDRJ-UHFFFAOYSA-N 5-[4-(8-chlorobenzo[b][1,4]benzoxazepin-6-yl)piperazin-1-yl]pentanoic acid Chemical compound C1CN(CCCCC(=O)O)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 UFCWTMHULGCDRJ-UHFFFAOYSA-N 0.000 description 1
- 208000028048 Accommodation disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010012218 Delirium Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 206010052402 Gastrointestinal hypermotility Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-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
- 206010044565 Tremor Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- OMOKMRLPUJILEE-UHFFFAOYSA-N ethyl 6-[4-(8-chlorobenzo[b][1,4]benzoxazepin-6-yl)piperazin-1-yl]hexanoate Chemical compound C1CN(CCCCCC(=O)OCC)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 OMOKMRLPUJILEE-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000004410 intraocular pressure Effects 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
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
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Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は抗うつ、抗不安、鎮痛、鎮吐、胃腸管運動冗進
、抗不整脈、降圧あるいは抗アレルギー作用を有し、医
薬品として有用な一般式（Ｉ） −
１
（式中、Ｒは水素原子又は低級アルキル基を、ｎは１か
ら５の整数を表す。）
で示される新規なジベンズオキサゼピン誘導体、及びそ
の薬理学的に許容しつる塩に関するものである。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention has antidepressant, antianxiety, analgesic, antiemetic, gastrointestinal hypermotility, antiarrhythmia, antihypertensive or antiallergic effects, and is useful as a pharmaceutical. I) A novel dibenzoxazepine derivative represented by -1 (wherein R represents a hydrogen atom or a lower alkyl group, and n represents an integer from 1 to 5), and its pharmacologically acceptable derivatives. It's about salt.
従来の技術
ジベンズオキサゼピン骨格を有する医薬品としては、例
えば、次式（Ｉ［）
１
で示されるアモキサピン〔メルクインデックス（Ｔｈｅ
Ｍｅｒｃｋ Ｉｎｄｅｘ ） 、１１版、６
０９〕が、
う
つ病あるいはうつ状態の治療剤として広く臨床に供され
ている。Conventional technology As a pharmaceutical having a dibenzoxazepine skeleton, for example, amoxapine represented by the following formula (I[) 1 [Merck Index (The
Merck Index), 11th edition, 6
09] is widely used clinically as a therapeutic agent for depression or depressive state.
発明が解決しようとする課題
アモキサピン辱の抗うつ剤の主な欠点は、しばしば、副
作用として振戦、幻覚、せん妄等の精神神経系作用ある
いは口渇、排尿困難、眼内圧冗進。The main disadvantage of amoxapine as an antidepressant is that it often causes side effects such as tremors, hallucinations, delirium, or other neuropsychiatric effects such as dry mouth, difficulty urinating, and increased intraocular pressure.
視調節障害等の抗コリン作用等を引き起こすことである
。従って、臨床の場ではこれら副作用の発現の少ない新
しい薬剤の開発が強く望まれている。It causes anticholinergic effects such as visual accommodation disorder. Therefore, in the clinical setting, there is a strong desire to develop new drugs with fewer side effects.
課題を解決するための手段
本発明者らは、前述の事情を鑑み鋭意研究した結果、本
発明に係わる新規なジベンズオキサゼピン誘導体が、抗
うっ、抗不安作用のみならず、鎮痛、鎮吐、胃腸管運動
冗進、抗不整脈、降圧あるいは抗アレルギー作用を有す
ることを見出し、本発明を完成させた。Means for Solving the Problems The present inventors conducted intensive research in view of the above-mentioned circumstances and found that the novel dibenzoxazepine derivative of the present invention not only has antidepressant and anxiolytic effects, but also has analgesic and antiemetic effects. The present inventors have completed the present invention by discovering that they have gastrointestinal motility hyperactivity, antiarrhythmia, antihypertensive, and antiallergic effects.
即ち、本発明は前記一般式（１）で示される新規なジベ
ンズオキサゼピン誘導体、及びその薬理学的に許容しつ
る塩に関するものである。That is, the present invention relates to a novel dibenzoxazepine derivative represented by the general formula (1) and a pharmacologically acceptable salt thereof.
本発明の前記一般式（Ｉ）中、Ｒで示される低級アルキ
ル基としては、メチル、エチル、ｎ−プロピル、イソプ
ロピル、ｎ−ブチル、イソブチル基等が挙げられる。In the general formula (I) of the present invention, examples of the lower alkyl group represented by R include methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl groups.
本発明の前記一般式（Ｉ）で示される化合物は、所望に
応じて薬理学的に許容しつる塩に変換することも、又は
生成した塩から塩基又は酸を遊離させることもできる。The compound represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt, or a base or acid can be liberated from the generated salt, as desired.
本発明の前記一般式（１）で示される化合物の薬理学的
に許容しうる塩としては、酸付加塩もしくはアルカリ付
加塩が提供され、酸付加塩としては、例えば、塩酸、臭
化水素酸、硫酸、硝酸、燐酸等の鉱酸塩、酢酸、マレイ
ン酸、フマル酸、リンゴ酸、クエン酸、シュウ酸、乳酸
、酒石酸等の有機酸塩が、また、アルカリ付加塩として
は、例えば、ナトリウム、カリウム、カルシウム等の金
属塩、アンモニウム塩、メチルアミン、エチルアミン、
ジメチルアミン、トリエチルアミン、エタノールアミン
、ピペリジン、ピペラジン等の有機塩基の塩が挙げられ
る。As the pharmacologically acceptable salt of the compound represented by the general formula (1) of the present invention, an acid addition salt or an alkali addition salt is provided, and examples of the acid addition salt include hydrochloric acid, hydrobromic acid , mineral acid salts such as sulfuric acid, nitric acid, and phosphoric acid; organic acid salts such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, oxalic acid, lactic acid, and tartaric acid; , metal salts such as potassium and calcium, ammonium salts, methylamine, ethylamine,
Examples include salts of organic bases such as dimethylamine, triethylamine, ethanolamine, piperidine, and piperazine.
本発明の前記一般式（Ｉ）で示される新規なジベンズオ
キサゼピン誘導体は、以下の様にして製造することがで
きる。The novel dibenzoxazepine derivative represented by the general formula (I) of the present invention can be produced as follows.
即ち、本発明に係わる化合物の製造方法の第一の様式に
よれば、前記式（Ｉ［）で示されるアモキサピンと、次
の一般式（ｍ）
Ｘ−（ＣＨ２）、−ＣＯＯＲ（Ｉ［）
（式中、Ｒ及びｎは前述と同意義を表し、Ｘはハロゲン
原子を表す。）
で示されるハロゲン化合物とを、無溶媒あるいは溶媒中
、脱酸剤としての塩基の存在下で反応させることにより
製造することができる。That is, according to the first mode of the method for producing a compound according to the present invention, amoxapine represented by the above formula (I[) and the following general formula (m) X-(CH2), -COOR(I[) (In the formula, R and n represent the same meanings as above, and X represents a halogen atom.) Reacting with a halogen compound represented by the following without a solvent or in a solvent in the presence of a base as a deoxidizing agent. It can be manufactured by
本発明において使用される溶媒としては、反応を阻害し
ない限りいかなるものでもよく、例えば、ベンゼン、ト
ルエン、テトラヒドロフラン、ジオキサン、アセトン、
アセトニトリル、メタノール。The solvent used in the present invention may be any solvent as long as it does not inhibit the reaction, such as benzene, toluene, tetrahydrofuran, dioxane, acetone,
Acetonitrile, methanol.
エタノール、イソプロパツール、ｎ−ブタノール。Ethanol, isopropanol, n-butanol.
ジメチルスルホキシド、Ｎ、Ｎ−ジメチルホルムアミド
等が挙げられる。Examples include dimethyl sulfoxide, N,N-dimethylformamide, and the like.
又、使用される塩基としては、例えば、炭酸カリウム、
炭酸ナトリウム、ピリジン、トリエチル −
アミン等が挙げられ、反応は０℃から２００℃の範囲で
行われる。In addition, examples of the base used include potassium carbonate,
Examples include sodium carbonate, pyridine, triethyl-amine, etc., and the reaction is carried out at a temperature ranging from 0°C to 200°C.
本発明に係る化合物の製造方法の第二の様式によれば、
前記一般式（Ｉ）で示される化合物のうち、ｎが２であ
る化合物は、前記式（ＩＩ）で示されるアモキサピンと
、次の一般式（ＩＶ）ＣＨ２＝ＣＨ−ＣＯＯＲ（ＩＶ
）
（式中、Ｒは前述と同意義を表す。）
で示されるアクリル酸誘導体とを、無溶媒あるいは溶媒
中で反応させることにより製造することができる。According to the second mode of the method for producing a compound according to the present invention,
Among the compounds represented by the general formula (I), the compound in which n is 2 is a compound represented by the amoxapine represented by the above formula (II) and the following general formula (IV) CH2=CH-COOR(IV
) (In the formula, R represents the same meaning as above.) It can be produced by reacting the acrylic acid derivative represented by the following without a solvent or in a solvent.
本発明において使用される溶媒としては、反応を阻害し
ない限りいかなるものでもよく、例えば、ベンゼン、ト
ルエン、テトラヒドロフラン、ジオキサン、アセトン、
アセトニトリル、メタノールエタノール、イソプロパツ
ール、ｎ−ブタノール。The solvent used in the present invention may be any solvent as long as it does not inhibit the reaction, such as benzene, toluene, tetrahydrofuran, dioxane, acetone,
Acetonitrile, methanol ethanol, isopropanol, n-butanol.
ジメチルスルホキシド、Ｎ、Ｎ−ジメチルホルムアミド
等が挙げられ、反応は０℃から１００℃の範囲で行われ
る。Examples include dimethyl sulfoxide, N,N-dimethylformamide, etc., and the reaction is carried out at a temperature ranging from 0°C to 100°C.
本発明に係る化合物の製造方法の第三の様式に −
よれば、前記一般式（Ｉ）で示される化合物のうちＲが
水素原子である化合物は、Ｒが低級アルキル基である化
合物を、溶媒中、酸又は塩基で加水分解することにより
製造することができる。According to the third mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) in which R is a hydrogen atom, the compound in which R is a lower alkyl group, It can be produced by hydrolysis with medium, acid or base.
本発明において使用される酸としては塩酸、硫酸等が、
又、塩基としては水酸化ナトリウム、水酸化カリウム、
炭酸カリウム、炭酸ナトリウム。Acids used in the present invention include hydrochloric acid, sulfuric acid, etc.
In addition, as a base, sodium hydroxide, potassium hydroxide,
Potassium carbonate, sodium carbonate.
炭酸水素ナトリウム等が、反応溶媒としては水。Sodium hydrogen carbonate, etc., but water is used as the reaction solvent.
メタノール、エタノール、アセトン、テトラヒドロフラ
ン等が挙げられ、反応は０°Ｃから１００℃の範囲で行
われる。Examples include methanol, ethanol, acetone, tetrahydrofuran, etc., and the reaction is carried out at a temperature ranging from 0°C to 100°C.
この様にして製造される前記一般式（Ｉ）で示される新
規なジベンズオキサゼピン誘導体、及びその薬理学的に
許容しつる塩は、常法により錠剤。The novel dibenzoxazepine derivative represented by the general formula (I) and its pharmacologically acceptable salts produced in this manner are prepared into tablets by a conventional method.
散剤、カプセル剤、注射剤１点眼剤１点鼻剤、吸入剤又
は外用剤等の製剤とすることができ、経口又は非経口投
与により臨床に供される。投与量は治療すべき症状及び
投与方法により左右されるが、成人に経口投与する場合
で、通常１日１〜５００■である。It can be formulated into powders, capsules, injections, eye drops, nasal drops, inhalants, or external preparations, and is clinically administered orally or parenterally. The dosage depends on the symptoms to be treated and the administration method, but when administered orally to adults, it is usually 1 to 500 ml per day.
実施例
以下、本発明を実施例によって説明するが、本発明はこ
の実施例の特定の細部に限定されるものではない。EXAMPLES The present invention will be explained below by way of examples, but the present invention is not limited to the specific details of these examples.
実施例１
４−（２−クロロジベンズ（ｂ、ｆ）（１，’４）オキ
サゼピン−１１−イル）−１−ピペラジンプロピオン酸
エチル
２−クロロ−１１−（１−ピペラジニル）ジベンズ（ｂ
、ｆ）（１，４）オキサゼピン３．１４ｇ、アクリル酸
エチル１．２０ｇ及びエタノール１６−の混合物を２時
間加熱還流する。溶媒を留去し、残渣をシリカゲルカラ
ムクロマトグラフィー （ｎ−ヘキサン：酢酸エチル（
２；１〜１ ： １） ）にて精製して、黄色結晶３．
６８ｇを得る。イソプロピルエムチルとｎ−ペンタンの
混液より再結晶して、融点７３〜７５°Ｃの黄色プリズ
ム晶を得る。Example 1 Ethyl 4-(2-chlorodibenz(b,f)(1,'4)oxazepin-11-yl)-1-piperazinepropionate 2-chloro-11-(1-piperazinyl)dibenz(b
, f) A mixture of 3.14 g of (1,4)oxazepine, 1.20 g of ethyl acrylate and 16-g of ethanol is heated under reflux for 2 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate (
2;1 to 1:1)) to give yellow crystals3.
Obtain 68g. Recrystallization from a mixture of isopropylethyl and n-pentane yields yellow prismatic crystals with a melting point of 73-75°C.
元素分析値 Ｃ！！Ｈ２４ＣＩＮ ｓｏ ｍ理論値 Ｃ
，６３，８４； Ｈ，５，８４； Ｎ、ｌＯ，１５実験
値 Ｃ，６３，９５，Ｈ，５，８６，Ｎ、１０．１６実
施例２
４−（２−クロロジベンズ（ｂ、ｆ）（１，４）オキサ
ゼピン−１１−イル）−１−ピペラジン酢酸エチル
２−クロロ−１１−（１−ピペラジニル）ジベンズＣｂ
、ｆ〕 （１，４）オキサゼピン３．１４ｇ、ブロモ酢
酸エチル２．ＯＯｇ、炭酸カリウム１．３８ｇ及びＮ、
Ｎ−ジメチルホルムアミド１６艷の混合物を６０〜７０
℃にて３時間攪拌する。Elemental analysis value C! ! H24CIN so m theoretical value C
,63,84; H,5,84; N, 1O,15 Experimental value C,63,95,H,5,86,N,10.16 Example 2 4-(2-chlorodibenz(b,f)( 1,4) Oxazepin-11-yl)-1-piperazineethyl acetate 2-chloro-11-(1-piperazinyl)dibenzCb
, f] (1,4)oxazepine 3.14 g, ethyl bromoacetate 2. OOg, potassium carbonate 1.38g and N,
A mixture of 16 N-dimethylformamides at 60 to 70
Stir at ℃ for 3 hours.
反応液に水を加え、エーテルにて抽出する。エーテル層
は、水洗、乾燥後、溶媒を留去し、残渣をシリカゲルカ
ラムクロマトグラフィー〔ｎ−ヘキサン：酢酸エチル（
２：１〜１：１）〕にて精製して、黄色結晶３．’１２
ｇを得る。ｎ−ヘキサンより再結晶して、融点１２３〜
１’２３．５℃の黄色プリズム品を得る。Add water to the reaction solution and extract with ether. After washing the ether layer with water and drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [n-hexane:ethyl acetate (
2:1 to 1:1)] to give yellow crystals 3. '12
get g. Recrystallized from n-hexane, melting point 123~
A yellow prism product with a temperature of 1'23.5°C is obtained.
元素分析値 Ｃ１１Ｈ２２ＣＩＮ ｓｏ ｓ理論値 Ｃ
，６３，０７； Ｈ，５，５５，Ｎ、１０．−５１実験
値
Ｃ，６３，２６゜
Ｈｌ
５．５６゜
Ｎ 、１０．６０
実施例２の方法に準拠して、実施例３〜５の化合物を得
る。Elemental analysis value C11H22CIN so sTheoretical value C
,63,07; H,5,55,N,10. -51 Experimental value C, 63,26°Hl 5.56°N, 10.60 According to the method of Example 2, the compounds of Examples 3 to 5 are obtained.
実施例３
４−（２−クロロジベンズ（ｂ、ｆ）（１，４）オキサ
ゼピン−１１−イル）−１−ピペラジン酪酸エチル
性状 黄色プリズム晶 （ｎ−ｈｅｘａｎｅ）融点 ８
６〜８７℃
元素分析値 Ｃ２３Ｈｔａｃ ＩＮ ｓｏ ｓ理論値
Ｃ，６４，５６； Ｈ，６，１２，Ｎ、 ９．８２実験
値 Ｃ，６４，５８； Ｈ，６，２０，Ｎ、 ９．８２
実施例４
４−（２
オキサゼピン
草酸エチル
性状 黄色プリズム晶
クロロジベンズ（ｂ、ｆ）［１，４’）１１−イル）−
１−ピペラジン吉
（ｉｓ。Example 3 4-(2-chlorodibenz(b,f)(1,4)oxazepin-11-yl)-1-piperazine ethyl butyrate Properties Yellow prismatic crystals (n-hexane) Melting point 8
6～87℃ Elemental analysis value C23Htac IN so s Theoretical value
C, 64, 56; H, 6, 12, N, 9.82 Experimental value C, 64, 58; H, 6, 20, N, 9.82
Example 4 4-(2 Oxazepine Ethyl Grassate Properties Yellow prismatic chlorodibenz(b,f)[1,4')11-yl)-
1-Piperazine Kichi (is.
Ｐｒ、０
ｐｅｎｔａｎｅ）
１ 〇 −
融点 ８２．５〜８４℃
元素分析値 Ｃ２４Ｈ２＃ＣＩＮ ３０ ｓ理論値 Ｃ
，６５，２２，Ｈ，６，３９，Ｎ、 ９．５１実験値
Ｃ，６５，１８； Ｈ，６，４８，Ｎ、 ９．３６実施
例５
４−（２−クロロジベンズ（ｂ、ｆ）（１，４）オキサ
ゼピン−１１−イル）−１−ピペラジンカプロン酸エチ
ル
性状 淡黄色粘稠性液体
ＩＲスペクトル ｖ （Ｉｉｑ） ａｎ−’ ：１
７３８ （Ｃｏｏ）
ＮＭＲスペクトル δ（ＣＤＣＩｓ） Ｉ）ＤＩ ：
１、１０−２．８０（１４Ｈ，ｍ）、 １．２８（３Ｈ
，ｔ＋ Ｊ＝７．０）ｌｚ）。Pr, 0 pentane) 1 〇 - Melting point 82.5~84℃ Elemental analysis value C24H2#CIN 30 s Theoretical value C
,65,22,H,6,39,N, 9.51 experimental value
C,65,18; H,6,48,N, 9.36 Example 5 Ethyl 4-(2-chlorodibenz(b,f)(1,4)oxazepin-11-yl)-1-piperazinecaproate Properties Pale yellow viscous liquid IR spectrum v (Iiq) an-': 1
738 (Coo) NMR spectrum δ (CDCIs) I) DI:
1, 10-2.80 (14H, m), 1.28 (3H
,t+J=7.0)lz).
３、４０−３．７５（４８，ｌ）、 ４．１９（２Ｈ，
ｑ、 Ｊ＝７．０Ｈｚ）。3, 40-3.75 (48, l), 4.19 (2H,
q, J=7.0Hz).
７、００−７．６５（７Ｈ，ｍ）
高分解能マススペクトル： Ｃ！ｓＨｓａｃ ＩＮ ｓ
ｏ ｓ理論値 ｍ／ｚ ： ４５５．１９７６実験
値 ｍ／ｚ ： ４５５．１９９４１１
実施例６
４−（２−クロロジベンズ（ｂ、ｆ）Ｎ、４）オキサゼ
ピン−１１−イル）−１−ピペラジン酢酸
４−（２−クロロジベンズ（ｂ、ｆ）（ｌ、４）オキサ
ゼピン−１１−イル）−１−ピペラジン酢酸エチル２．
ＯＯｇのメタノール２０ｄ溶液に、２Ｎ水酸化ナトリウ
ム水溶液５−を加え、３０分間加熱還流する。溶媒を留
去し、残渣を温水に溶解後、０，５Ｎ塩酸で中和する。7, 00-7.65 (7H, m) High resolution mass spectrum: C! sHsac IN s
o s Theoretical value m/z: 455.1976 Experimental value m/z: 455.199411 Example 6 4-(2-chlorodibenz(b,f)N,4)oxazepin-11-yl)-1-piperazineacetic acid 4 -(2-chlorodibenz(b,f)(l,4)oxazepin-11-yl)-1-piperazineethyl acetate2.
A 2N aqueous sodium hydroxide solution 5- is added to a methanol 20d solution of OOg, and the mixture is heated under reflux for 30 minutes. The solvent was distilled off, the residue was dissolved in warm water, and then neutralized with 0.5N hydrochloric acid.
析出結晶を濾取して、無色結晶１．６７ｇを得る。含水
エタノールより再結晶し、融点２１０〜２１２℃の無色
結晶を得る。The precipitated crystals were collected by filtration to obtain 1.67 g of colorless crystals. Recrystallization from aqueous ethanol gives colorless crystals with a melting point of 210-212°C.
ＩＲスペクトル ｖ （ＫＢｒ） Ｑｌｌ−’ ：
１６０８ （Ｃｏｏ）
Ｍ ａｓｓスペクトルｌ／Ｚ ： ３７１，３７３ （
Ｍ”、３：１）ＮＭＲスペクトルδ（ＤＭＳＯ−ｄｓ）
ｐＨ！ｌ ：２、５０−２．９０（４Ｈ，ｍ）、
３．２４ （２Ｈ，ｓ） 、 ３．３０−３．７０（４
Ｈ，ｍ）、 ７．００−７．８０（７１１，Ｉ）！２一
実施例６の方法に準拠して、実施例７〜ＩＯの化合物を
得る。IR spectrum v (KBr) Qll-':
1608 (Coo) M ass spectrum l/Z: 371,373 (
M”, 3:1) NMR spectrum δ (DMSO-ds)
pH! l: 2, 50-2.90 (4H, m),
3.24 (2H,s), 3.30-3.70 (4
H, m), 7.00-7.80 (711, I)! 21 According to the method of Example 6, the compounds of Examples 7 to IO are obtained.
実施例７
４−（２−クロロジベンズ（ｂ、ｆ）（１，４）オキサ
ゼピン−１１−イル）−１−ピペラジンプロピオン酸
性状 無色結晶 （ＨｘＯ−ＥｔＯＨ）融点 １２２〜
１２４℃
ＩＲスペクトル・ｖ （ＫＢｒ） ａｎ−’ ：１
６０４ （ＣＯＯ）
Ｍ ａｓｓスペクトルｍ／ｚ ： ３８５，３８７ （
Ｍ”、３：１）ＮＭＲスペクトルδ（ＤＭＳＯ−ｄａ）
ｐｐｆｉ ：２．３０−２．８０（８）１．ｍ）、
３．３０−３．７０（４８，鵬）、６．９０−７．８０
（７Ｈ，ｍ）
実施例８
４−（２−クロロジベンズ（ｂ、ｆ）（ｌ、４）オキサ
ゼピン−１１−イル）−１−ピペラジン酪酸
１
性状 淡黄色結晶 （ＨｘＯＥＬＯＨ）融点 １２０〜
１２２℃
！Ｒスペクトル ｖ （ＫＢｒ） ａｎ−’ ：１
６０４ （ＣＯＯ）
Ｍ ａｓｓスペクトルｍ／ｚ ： ３９９．４０１ （
Ｍ”、３：１）ＮＭＲスペクトルδ（ＤＭＳＯ−ｄａ）
ｐＩ）ｌ ：１、５０−２．００（２Ｈ，ｍ） 、
２．１０−２．７０（８Ｈ，ｌ）、 ３．３０−３．
７０（４８，ｍ）、７．００−７．８０（７８，論）実
施例９
４−（２−クロロジベンズ（ｂ、ｆ）（１，４）オキサ
ゼピン−１１−イル）−１−ピペラジン吉草酸
性状 無色結晶 （）ＨｘＯＢｔＯＨ）融点 ２２３〜
２２６℃
元素分析値 ＣｇｔＨ＊４ＣＩＮｓＯｓ理論値 Ｃ，６
３，８４； Ｈ，５，８４；実験値 Ｃ，６３，７２，
Ｈ，５，８９；Ｎ 、１０．１５
Ｎ 、１０．０７
実施例１
１
４−（２−クロロジベンズ［ｂ、ｆ）Ｃ１，４）オキサ
ゼピン−１１−イル）−１−ピペラジンカプロン酸
性状 淡黄色結晶 （Ｈ２Ｏ−ＥｔＯＨ）融点 １７３
〜１７５℃
元素分析値 ＣｇｓＨｓｅｃ ＩＮ ｓｏ ｓ理論値
Ｃ，６４，５６； Ｈ，６，１２，Ｎ、 ９．８２実験
値 Ｃ，６４，５４，Ｈ，６，１１，Ｎ、 ９．８３発
明の効果
本発明の前記−紋穴（Ｉ）で示される新規なジベンズオ
キサゼピン誘導体及びその薬理学的に許容しつる塩は、
抗うつ、抗不安、鎮痛、鎮吐、胃腸管運動冗進、抗不整
脈、降圧あるいは抗アレルギー作用を有し、医薬品とし
て極めて有用である。Example 7 4-(2-chlorodibenz(b,f)(1,4)oxazepin-11-yl)-1-piperazinepropionic acid Properties Colorless crystals (HxO-EtOH) Melting point 122~
124℃ IR spectrum・v (KBr) an-': 1
604 (COO) M ass spectrum m/z: 385,387 (
M'', 3:1) NMR spectrum δ (DMSO-da)
ppfi:2.30-2.80(8)1. m),
3.30-3.70 (48, Peng), 6.90-7.80
(7H, m) Example 8 4-(2-chlorodibenz(b,f)(l,4)oxazepin-11-yl)-1-piperazinebutyric acid 1 Properties Pale yellow crystals (HxOELOH) Melting point 120~
122℃! R spectrum v (KBr) an-' :1
604 (COO) M ass spectrum m/z: 399.401 (
M'', 3:1) NMR spectrum δ (DMSO-da)
pI)l: 1, 50-2.00 (2H, m),
2.10-2.70 (8H, l), 3.30-3.
70 (48, m), 7.00-7.80 (78, theory) Example 9 4-(2-chlorodibenz(b,f)(1,4)oxazepin-11-yl)-1-piperazinevaleric acid Properties Colorless crystals ()HxOBtOH) Melting point 223~
226℃ Elemental analysis value CgtH*4CINsOs theoretical value C,6
3,84; H, 5,84; Experimental value C, 63,72,
H, 5,89; N, 10.15 N, 10.07 Example 1 1 4-(2-chlorodibenz[b,f)C1,4)oxazepin-11-yl)-1-piperazinecaproic acid Properties Pale yellow Crystal (H2O-EtOH) Melting point 173
~175℃ Elemental analysis value CgsHsec IN so s Theoretical value
C, 64, 56; H, 6, 12, N, 9.82 Experimental value C, 64, 54, H, 6, 11, N, 9. 83 Effect of the invention In the above-mentioned hole (I) of the invention The novel dibenzoxazepine derivatives and their pharmacologically acceptable salts are:
It has antidepressant, antianxiety, analgesic, antiemetic, increased gastrointestinal motility, antiarrhythmia, antihypertensive, and antiallergic effects, and is extremely useful as a medicine.
Claims (1)
ら５の整数を表す。） で示されるジベンズオキサゼピン誘導体、及びその薬理
学的に許容しうる塩。[Claims] Dibenzoxase represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R represents a hydrogen atom or a lower alkyl group, and n represents an integer from 1 to 5.) Pin derivatives and pharmacologically acceptable salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32156489A JPH03184963A (en) | 1989-12-13 | 1989-12-13 | Dibenzoxazepine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32156489A JPH03184963A (en) | 1989-12-13 | 1989-12-13 | Dibenzoxazepine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03184963A true JPH03184963A (en) | 1991-08-12 |
Family
ID=18133980
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP32156489A Pending JPH03184963A (en) | 1989-12-13 | 1989-12-13 | Dibenzoxazepine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03184963A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006088786A3 (en) * | 2005-02-14 | 2007-04-19 | Combinatorx Inc | Compounds and uses thereof |
| US7355042B2 (en) | 2001-10-16 | 2008-04-08 | Hypnion, Inc. | Treatment of CNS disorders using CNS target modulators |
| US7538114B2 (en) | 2006-06-28 | 2009-05-26 | Amgen Inc. | Glycine transporter-1 inhibitors |
| US11046651B2 (en) | 2019-10-21 | 2021-06-29 | Alairion, Inc. | Piperazine substituted azapine derivatives and uses thereof |
-
1989
- 1989-12-13 JP JP32156489A patent/JPH03184963A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7355042B2 (en) | 2001-10-16 | 2008-04-08 | Hypnion, Inc. | Treatment of CNS disorders using CNS target modulators |
| WO2006088786A3 (en) * | 2005-02-14 | 2007-04-19 | Combinatorx Inc | Compounds and uses thereof |
| US7538114B2 (en) | 2006-06-28 | 2009-05-26 | Amgen Inc. | Glycine transporter-1 inhibitors |
| US8183244B2 (en) | 2006-06-28 | 2012-05-22 | Amgen Inc. | Glycine transporter-1 inhibitors |
| US8735383B2 (en) | 2006-06-28 | 2014-05-27 | Amgen Inc. | Glycine transporter-1 inhibitors |
| US9663476B2 (en) | 2006-06-28 | 2017-05-30 | Amgen Inc. | Glycine transporter-1 inhibitors |
| US11046651B2 (en) | 2019-10-21 | 2021-06-29 | Alairion, Inc. | Piperazine substituted azapine derivatives and uses thereof |
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