JPS631311B2 - - Google Patents
Info
- Publication number
- JPS631311B2 JPS631311B2 JP6459679A JP6459679A JPS631311B2 JP S631311 B2 JPS631311 B2 JP S631311B2 JP 6459679 A JP6459679 A JP 6459679A JP 6459679 A JP6459679 A JP 6459679A JP S631311 B2 JPS631311 B2 JP S631311B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- dibenzothiepine
- thiepin
- dihydro
- derivative
- 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.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 16
- FKKFMCSXGHRBON-UHFFFAOYSA-N benzo[d][1]benzothiepine Chemical class S1C=CC2=CC=CC=C2C2=CC=CC=C12 FKKFMCSXGHRBON-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004325 thiepin-2-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C(*)S1 0.000 description 17
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- -1 dibenzothiepine propionamide derivative Chemical class 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 235000019260 propionic acid Nutrition 0.000 description 7
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 229940080818 propionamide Drugs 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- PAWXCZWQIASDOH-UHFFFAOYSA-N 2-[2-[4-(1-cyanoethyl)phenyl]sulfanylphenyl]acetic acid Chemical class C1=CC(C(C#N)C)=CC=C1SC1=CC=CC=C1CC(O)=O PAWXCZWQIASDOH-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000679 carrageenan Substances 0.000 description 3
- 229920001525 carrageenan Polymers 0.000 description 3
- 235000010418 carrageenan Nutrition 0.000 description 3
- 229940113118 carrageenan Drugs 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- IPBVNPXQWQGGJP-UHFFFAOYSA-N phenyl acetate Chemical class CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WUKHOVCMWXMOOA-UHFFFAOYSA-N 2-(3-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC([N+]([O-])=O)=C1 WUKHOVCMWXMOOA-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229940111131 antiinflammatory and antirheumatic product propionic acid derivative Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 244000240602 cacao Species 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
- 239000003054 catalyst Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- KPUNOVLMCQQCSK-UHFFFAOYSA-N diazomethane;ethoxyethane Chemical compound C=[N+]=[N-].CCOCC KPUNOVLMCQQCSK-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、次の一般式（）
（式中、R1はニトロ基またはアミノ基を、R2は
アミノ基、ヒドロキシ基または低級アルコキシ基
を示す）
で表わされるジベンゾチエピン誘導体およびその
製法に関する。
本発明者らは多くのジベンゾチエピン系化合物
を合成し、その薬理作用を検討していたところ、
上記一般式（）で表わされる化合物が優れた抗
炎症作用を有し医薬として有用であることを見出
し、本発明を完成した。
従つて、本発明の目的は優れた薬理作用を有す
る一般式（）で表わされる新規な化合物を提供
せんとするにある。
他の目的は一般式（）の化合物を製造する方
法を提供せんとするにある。
本発明の一般式（）の化合物は次に示すいず
れかの方法によつて製造される。
方法１：
すなわち、一般式（）の２−〔４−（１−シア
ノエチル）−フエニルチオ〕フエニル酢酸誘導体
を閉環せしめることにより、一般式（）のジベ
ンゾチエピンプロピオンアミド誘導体が製造され
る。
閉環反応には、ポリリン酸、ポリリン酸エステ
ルなどの縮合剤を使用するのが好ましい。反応は
溶媒なしでも行われるがベンゼン、トルエン、キ
シレンなどの溶媒中で行うこともできる。
反応温度は70〜200℃で反応時間は0.5〜４時間
が好ましい。
尚、原料の一般式（）の２−〔４−（１−シア
ノエチル）−フエニルチオ〕フエニル酢酸誘導体
は次の如くして製造される。
（式中、ＡおよびＢの何れか一方はハロゲン原子
で、他方はメルカプト基を、Ｘはハロゲン原子
を、R4はエステル残基を示す）
すなわち、一般式（）の２−〔４−（１−シアノ
エチル）−フエニルチオ〕フエニル酢酸誘導体は、
２−ハロゲノ（またはメルカプト）フエニル酢酸
エステル誘導体と４−メルカプト（またはハロゲ
ノ）アセトフエノンを縮合させて２−（４−アセ
チルフエニルチオ）フエニル酢酸エステル誘導体
となし、これを還元して、２−〔４−（１−ヒドロ
キシエチル）フエニルチオ〕フエニル酢酸エステ
ル誘導体となし、次いでハロゲン化後、シアノ化
し、さらに加水分解により脱エステル化すること
により製造される。
方法２：
（式中、R1は前記と同じ、R5はアミノ基または
低級アルコキシ基を示す）
すなわち、一般式（）のジベンゾチエピン誘導
体を加水分解せしめることにより、一般式（）
のジベンゾチエピンプロピオン酸誘導体が製造さ
れる。
反応は通常の加水分解すなわち、水または含水
有機溶媒中、塩酸、硫酸、酢酸等の酸または水酸
化ナトリウム、水酸化カリウム等の塩基の存在下
に２〜５時間反応させることにより行われる。
方法３：
（式中、R3は低級アルキル基を示す）
すなわち、一般式（）のジベンゾチエピンプロ
ピオン酸誘導体またはその反応性誘導体に低級ア
ルコールまたはその反応性誘導体を反応させるこ
とにより、一般式（）のジベンゾチエピンプロ
ピオン酸エステル誘導体が製造される。
一般式（）の化合物の反応性誘導体として
は、酸ハライド、混合酸無水物、活性エステル等
があげられる。また、低級アルコールの反応性誘
導体としてはジアゾアルカンがあげられる。
反応は反応に関与しない有機溶媒中で、冷却下
から高められた温度で10分間〜３時間反応させる
ことにより行われる。
一般式（）の化合物と低級アルコールを直接
反応させる場合には、ジシクロヘキシルカルボジ
イミド等の縮合剤を用いるのが好ましい。
方法４：
（式中、R3は前記と同じ）
すなわち、一般式（）のジベンゾチエピンプロ
ピオン酸エステル誘導体を接触還元に付すことに
より、一般式（）のアミノジベンゾチエピンプ
ロピオン酸エステル誘導体が製造される。
反応は、反応に関与しない溶媒例えばアセトン
中で、パラジウム、白金などの触媒の存在下に５
〜10時間接触還元を行うのが好ましい。
一般式（）で表わされる本発明化合物は、優
れた抗炎症作用を有する。以下に本発明化合物を
カラゲニン浮腫法を用いて検討した薬理結果を示
す。
すなわち、１群５〜７匹からなる体重約100ｇ
のWister系雄性ラツトに本発明化合物を経口投
与し、１時間後に１％カラゲニン生理食塩水0.1
ml／ラツトを後肢足蹠皮下に注射し、足蹠容積を
Volume differential meterを用いて経時的に測
定した。カラゲニンを注射してから３時間目の抑
制率を表１に示す。
The present invention is based on the following general formula () (wherein, R 1 represents a nitro group or an amino group, and R 2 represents an amino group, a hydroxy group, or a lower alkoxy group) and a method for producing the same. The present inventors synthesized many dibenzothiepine compounds and investigated their pharmacological effects.
The present invention was completed based on the discovery that the compound represented by the above general formula () has an excellent anti-inflammatory effect and is useful as a medicine. Therefore, an object of the present invention is to provide a novel compound represented by the general formula () having excellent pharmacological action. Another object is to provide a method for producing compounds of general formula (). The compound of general formula () of the present invention can be produced by any of the following methods. Method 1: That is, the dibenzothiepine propionamide derivative of the general formula () is produced by ring-closing the 2-[4-(1-cyanoethyl)-phenylthio]phenylacetic acid derivative of the general formula (). It is preferable to use a condensing agent such as polyphosphoric acid or polyphosphoric acid ester in the ring-closing reaction. The reaction can be carried out without a solvent, but it can also be carried out in a solvent such as benzene, toluene, or xylene. The reaction temperature is preferably 70 to 200°C and the reaction time is preferably 0.5 to 4 hours. The raw material 2-[4-(1-cyanoethyl)-phenylthio]phenylacetic acid derivative of general formula () is produced as follows. (In the formula, either A or B is a halogen atom, the other is a mercapto group, X is a halogen atom, and R 4 is an ester residue.) That is, 2-[4-( 1-cyanoethyl)-phenylthio]phenyl acetic acid derivative is
A 2-halogeno (or mercapto) phenyl acetate derivative and a 4-mercapto (or halogeno) acetophenone are condensed to form a 2-(4-acetylphenylthio) phenyl acetate derivative, which is reduced to form a 2-[ It is produced by forming a 4-(1-hydroxyethyl)phenylthio]phenyl acetate derivative, followed by halogenation, cyanation, and deesterification by hydrolysis. Method 2: (In the formula, R 1 is the same as above, R 5 represents an amino group or a lower alkoxy group) That is, by hydrolyzing the dibenzothiepine derivative of the general formula (),
dibenzothiepine propionic acid derivatives are produced. The reaction is carried out in conventional hydrolysis, that is, by reacting in water or a water-containing organic solvent for 2 to 5 hours in the presence of an acid such as hydrochloric acid, sulfuric acid, or acetic acid or a base such as sodium hydroxide or potassium hydroxide. Method 3: (In the formula, R 3 represents a lower alkyl group) That is, by reacting the dibenzothiepine propionic acid derivative of the general formula () or its reactive derivative with a lower alcohol or its reactive derivative, the A dibenzothiepine propionate derivative is produced. Examples of reactive derivatives of the compound of general formula () include acid halides, mixed acid anhydrides, and active esters. Furthermore, examples of reactive derivatives of lower alcohols include diazoalkanes. The reaction is carried out in an organic solvent that does not participate in the reaction at an elevated temperature from cooling for 10 minutes to 3 hours. When directly reacting the compound of general formula () with a lower alcohol, it is preferable to use a condensing agent such as dicyclohexylcarbodiimide. Method 4: (In the formula, R 3 is the same as above.) That is, by subjecting the dibenzothiepine propionate derivative of the general formula () to catalytic reduction, the aminodibenzothiepine propionate derivative of the general formula () is produced. . The reaction is carried out in a solvent that does not participate in the reaction, such as acetone, in the presence of a catalyst such as palladium or platinum.
Preferably, the catalytic reduction is carried out for ~10 hours. The compound of the present invention represented by the general formula () has an excellent anti-inflammatory effect. The pharmacological results of the compound of the present invention examined using the carrageenan edema method are shown below. In other words, each group consists of 5 to 7 animals, weighing approximately 100g.
The compound of the present invention was orally administered to male Wistar rats, and 1 hour later, 0.1% carrageenan saline was administered.
ml/rat was injected subcutaneously into the hind footpad, and the footpad volume was determined.
It was measured over time using a volume differential meter. Table 1 shows the inhibition rate 3 hours after carrageenan injection.
【表】
化合物Ａ：２−（10・11−ジヒドロ−８−ニトロ
−11−オキソベンゾ〔ｂ・ｆ〕チエピン−２−
イル）プロピオンアミド
化合物Ｂ：２−（10・11−ジヒドロ−８−ニトロ
−11−オキソベンゾ〔ｂ・ｆ〕チエピン−２−
イル）プロピオン酸
化合物Ｃ：２−（８−アミノ−10・11−ジヒドロ
−11−オキソジベンゾ〔ｂ・ｆ〕チエピン−２
−イル）プロピオン酸
本発明の化合物は医薬として用いる場合には、
それ自体あるいはその塩の形で使用できる。塩と
しては、ナトリウム、カリウム、カルシウム、ア
ルミニウムのような無毒性塩とするのが好まし
い。
本発明の化合物は、経口投与、非経口投与のい
ずれにおいても作用を発揮し、経口、注射、経直
腸、局所投与用の剤型にすることができる。
経口投与用の固体剤型としてはカプセル、錠
剤、丸剤、粉末剤、顆粒剤がある。これらの剤型
の場合の添加剤としては、白糖、乳糖、澱粉等の
賦形剤の他にステアリン酸マグネシウムのような
滑沢剤を使用することもできる。また腸溶性、徐
放性を持つた剤型にすることもできる。
経口投与用の液体剤型としては、乳化剤、溶液
剤、懸濁剤、シロツプ剤、エリキシル剤等があ
る。これらの剤型の場合の添加剤としては、糖製
水、アルコール等の溶剤の他に湿潤剤、乳化剤、
懸濁剤等の補助剤を加えることができる。
本発明化合物の非経口投与用製剤としては注射
剤、座剤等がある。注射剤の場合には、殺菌した
水性または非水性溶液にすることができる。溶剤
の例としては、プロピレングリコール、ポリエチ
レングリコール、植物油、有機酸エステル等が挙
げられる。また、粉末充填の形にして使用前に溶
剤に溶かすことのできる剤型にしてもよい。座剤
の場合には、ココア、バターあるいは座薬用ワツ
クスのような賦形剤を加える。
本発明の化合物の投与量は症状、投与経路、投
与期間等によつて異なるが、一般的には人間の場
合、１日15〜1000mgが好適である。
次に実施例をあげて本発明を詳細に説明する。
実施例 １
２−（10・11−ジヒドロ−８−ニトロ−11−オ
キソジベンゾ〔ｂ・ｆ〕チエピン−２−イル）
プロピオンアミド：
２−〔４−（α−シアノエチル）−フエニルチオ〕
−５−ニトロフエニル酢酸1.7ｇにポリリン酸34
ｇを加えて90℃にて２時間撹拌した。氷水を加え
て酢酸エチルにて抽出し、１％水酸化ナトリウム
水溶液及び飽和食塩水にて洗浄後、無水硫酸ナト
リウムにて乾燥した。溶媒を留去して黄色結晶を
得、メタノールから再結晶して、融点207〜209℃
の２−（10・11−ジヒドロ−８−ニトロ−11−オ
キソベンゾ〔ｂ・ｆ〕チエピン−２−イル）プロ
ピオンアミドの淡黄色粉末0.5ｇ（収率30％）を
得た。
IRνKBr naxcm-1：3380、3190（NH2）、1670、1650（Ｃ
＝０）
NMR（CDCl3
DMSO−d6）δ：1.37（3H、ｄ、Ｊ＝７
Hz、＝CHCH3 ）
3.67（1H、ｑ、Ｊ＝７Hz、＝ＣＨCH3）
4.44（2H、ｓ、−ＣH2 CO−）
6.50、7.26（2H、broad、ｓ、−CONH2 ）
7.53〜8.27（6H、ｍ、芳香族プロトン）
実施例 ２
２−（10・11−ジヒドロ−８−ニトロ−11−オ
キソジベンゾ〔ｂ・ｆ〕チエピン−２−イル）
プロピオン酸：
濃塩酸３mlおよび酢酸３mlの混液中に２−
（10・11−ジヒドロ−８−ニトロ−11−オキソジ
ベンゾ〔ｂ・ｆ〕チエピン−２−イル）プロピオ
ンアミド0.33ｇを加え、撹拌下に3.5時間加熱環
流した。反応液を濃縮して水を加えて、酢酸エチ
ルにて抽出した。さらに飽和炭酸水素ナトリウム
水溶液にて抽出し、塩酸酸性として酢酸エチルに
て抽出した。さらに飽和食塩水にて洗浄後、無水
硫酸ナトリウムにて乾燥した。溶媒を留去して褐
色固体を得、シリカゲル６ｇを用いてカラムクロ
マトグラフイーに付し、クロロホルムにて溶出し
て淡黄色固体を得、クロロホルムから再結晶して
融点209.5〜211℃の２−（10・11−ジヒドロ−８
−ニトロ−11−オキソジベンゾ〔ｂ・ｆ〕チエピ
ン−２−イル）プロピオン酸の淡黄色粉末0.14ｇ
（収率43％）を得た。
IRνKBr naxcm-1：1710、1675（Ｃ＝０）
NMR（CDCl3）δ：1.47（3H、ｄ、Ｊ＝７Hz、＝
CHCH3 ）
3.70（1H、ｑ、Ｊ＝７Hz、＝ＣＨCH3）
4.42（2H、ｓ、−CH2CO−）
7.43〜8.23（6H、ｍ、芳香族プロトン）
実施例 ３
メチル２−（10・11−ジヒドロ−８−ニトロ−
11−オキソベンゾ〔ｂ・ｆ〕チエピン−２−イ
ル）プロピオネート：
２−（10・11−ジヒドロ−８−ニトロ−11−オ
キソジベンゾ〔ｂ・ｆ〕チエピン−２−イル）プ
ロピオン酸72mgにジアゾメタン−エーテル溶液10
mlおよびメタノール１mlを加えて室温にて30分間
撹拌した。酢酸を加えた後、飽和炭酸水素ナトリ
ウム水溶液にてアルカリ性とし、ベンゼンにて抽
出した。飽和食塩水にて洗浄後、無水硫酸ナトリ
ウムにて乾燥した。溶媒を留去して黄色油状物を
得、シリカゲル２ｇを用いてカラムクロマトグラ
フイーに付し、クロロホルムにて溶出して、メチ
ル２−（10・11−ジヒドロ−８−ニトロ−11−オ
キソジベンゾ〔ｂ・ｆ〕チエピン−２−イル）プ
ロピオネートの黄色油状物44mg（収率57％）を得
た。
IRνCHCl3 naxcm-1：1735、1680（Ｃ＝０）
NMR（CDCl3）δ：1.50（3H、ｄ、Ｊ＝７Hz、＝
CHCH3 ）
3.65（3H、ｓ、−COOCH3 ）
3.75（1H、ｑ、Ｊ＝７Hz、＝ＣＨCH3）
4.45（2H、ｓ、−CH2CO−）
7.37〜8.27（6H、ｍ、芳香族プロトン）
実施例 ４
メチル２−（８−アミノ−10・11−ジヒドロ−
11−オキソジベンゾ〔ｂ・ｆ〕チエピン−２−
イル）プロピオネート：
メチル２−（10・11−ジヒドロ−８−ニトロ−
11−オキソジベンゾ〔ｂ・ｆ〕チエピン−２−イ
ル）プロピオネート40mgをアセトン３mlに溶解
し、10％パラジウム活性炭少量を加えて９時間接
触還元した。反応液をセライトを用いて吸引過
し、溶媒を留去して黄色油状物を得、シリカゲル
９ｇを用いてカラムクロマトグラフイーに付し、
クロロホルムにて溶出して、メチル２−（８−ア
ミノ−10・11−ジヒドロ−11−オキソジベンゾ
〔ｂ・ｆ〕チエピン−２−イル）プロピオネート
の黄色油状物13mg（収率36％）を得た。
IRνCHCI3 naxcm-1：3400（NH2）、1730、1670（Ｃ＝０
）
NMR（CDCl3）δ：1.46（3H、ｄ＝、Ｊ＝７Hz、
＝CHCH3 ）
3.58（3H、ｓ、−COOCH3 ）
3.70（1H、ｑ、Ｊ＝７Hz、＝ＣＨCH3）
4.22（2H、ｓ、−ＣH2 CO−）
実施例 ５
２−（８−アミノ−10・11−ジヒドロ−11−オ
キソジベンゾ〔ｂ・ｆ〕チエピン−２−イル）
プロピオン酸：
メチル２−（８−アミノ−10・11−ジヒドロ−
11−オキソジベンゾ〔ｂ・ｆ〕チエピン−２−イ
ル）プロピオネート78mgをメタノール３mlに懸濁
し、氷冷下に水酸化カリウム200mgを水３mlに溶
解して加え、室温にて６時間撹拌した。反応液を
過し、塩酸で弱酸性として酢酸エチルにて抽出
し、飽和食塩水にて洗浄後、無水硫酸ナトリウム
にて乾燥した。溶媒を留去して黄色固体を得、シ
リカゲル２ｇを用いてカラムクロマトグラフイー
に付し、クロロホルム：メタノール＝50：１にて
溶出し、さらにクロロホルム−メタノールから再
結晶して、融点189〜191℃の２−（８−アミノ−
10・11−ジヒドロ−11−オキソジベンゾ〔ｂ・
ｆ〕チエピン−２−イル）プロピオン酸の淡黄色
結晶49mg（収率75％）を得た。
IRνKBr naxcm-1：3360、3280（NH2）、1710、1650（Ｃ
＝０）
NMR（アセトン−d6）δ：1.43（3H、ｄ、Ｊ＝７
Hz、＝CHCH3 ）
3.80（1H、ｑ、Ｊ＝７Hz、＝ＣＨCH3）
4.20（2H、ｓ、−ＣH2 CO−）
6.52（1H、dd、Ｊ＝９、３Hz、C7 Ｈ）
6.78（1H、ｄ、Ｊ＝３Hz、C9 Ｈ）
7.28〜7.83（3H、ｍ、芳香族プロトン）
8.09（1H、ｄ、Ｊ＝３Hz、C1 Ｈ）[Table] Compound A: 2-(10・11-dihydro-8-nitro-11-oxobenzo[b・f]thiepin-2-
yl) propionamide compound B: 2-(10·11-dihydro-8-nitro-11-oxobenzo[b·f]thiepin-2-
yl) propionic acid compound C: 2-(8-amino-10,11-dihydro-11-oxodibenzo[b/f]thiepin-2
-yl)propionic acid When the compound of the present invention is used as a medicine,
It can be used by itself or in the form of its salts. The salt is preferably a non-toxic salt such as sodium, potassium, calcium or aluminum. The compound of the present invention exerts its action in both oral and parenteral administration, and can be formulated into dosage forms for oral, injection, rectal, and topical administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. As additives for these dosage forms, in addition to excipients such as white sugar, lactose, and starch, a lubricant such as magnesium stearate can also be used. It can also be made into enteric-coated and sustained-release dosage forms. Liquid dosage forms for oral administration include emulsions, solutions, suspensions, syrups, elixirs, and the like. Additives for these dosage forms include wetting agents, emulsifiers, and solvents such as sugar water and alcohol.
Auxiliary agents such as suspending agents can be added. Preparations for parenteral administration of the compound of the present invention include injections, suppositories, and the like. In the case of injections, it can be a sterile aqueous or non-aqueous solution. Examples of the solvent include propylene glycol, polyethylene glycol, vegetable oil, organic acid ester, and the like. It may also be in the form of a powder filling which can be dissolved in a solvent before use. In the case of suppositories, excipients such as cocoa, butter or suppository wax are added. The dosage of the compound of the present invention varies depending on the symptoms, administration route, administration period, etc., but in general, 15 to 1000 mg per day is suitable for humans. Next, the present invention will be explained in detail with reference to Examples. Example 1 2-(10·11-dihydro-8-nitro-11-oxodibenzo[b·f]thiepin-2-yl)
Propionamide: 2-[4-(α-cyanoethyl)-phenylthio]
-1.7g of 5-nitrophenyl acetic acid to 34g of polyphosphoric acid
g was added thereto, and the mixture was stirred at 90°C for 2 hours. Ice water was added and extracted with ethyl acetate, washed with a 1% aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain yellow crystals, which were recrystallized from methanol to give a melting point of 207-209°C.
0.5 g (yield: 30%) of pale yellow powder of 2-(10·11-dihydro-8-nitro-11-oxobenzo[b·f]thiepin-2-yl)propionamide was obtained. IRν KBr nax cm -1 : 3380, 3190 (NH 2 ), 1670, 1650 (C
= 0) NMR (CDCl3 DMSO-d6) δ: 1.37 (3H, d, J = 7
Hz, = CHC H 3 ) 3.67 (1H, q, J = 7Hz, = CH CH 3 ) 4.44 (2H, s, -C H 2 CO-) 6.50, 7.26 (2H, broad, s, -CON H 2 ) 7.53-8.27 (6H, m, aromatic proton) Example 2 2-(10·11-dihydro-8-nitro-11-oxodibenzo[b·f]thiepin-2-yl)
Propionic acid: 2-
0.33 g of (10·11-dihydro-8-nitro-11-oxodibenzo[b·f]thiepin-2-yl)propionamide was added, and the mixture was heated under reflux for 3.5 hours with stirring. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. Further, the mixture was extracted with a saturated aqueous sodium hydrogen carbonate solution, acidified with hydrochloric acid, and extracted with ethyl acetate. After further washing with saturated saline, it was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a brown solid, which was subjected to column chromatography using 6 g of silica gel and eluted with chloroform to obtain a pale yellow solid, which was recrystallized from chloroform to give a 2- (10・11-dihydro-8
-Nitro-11-oxodibenzo[b・f]thiepin-2-yl)propionic acid pale yellow powder 0.14g
(yield 43%). IRν KBr nax cm -1 : 1710, 1675 (C=0) NMR (CDCl 3 ) δ: 1.47 (3H, d, J=7Hz, =
CHC H 3 ) 3.70 (1H, q, J=7Hz, = CH CH 3 ) 4.42 (2H, s, -CH 2 CO-) 7.43-8.23 (6H, m, aromatic proton) Example 3 Methyl 2- (10・11-dihydro-8-nitro-
11-Oxobenzo[b・f]thiepin-2-yl)propionate: 72 mg of 2-(10・11-dihydro-8-nitro-11-oxodibenzo[b・f]thiepin-2-yl)propionic acid and diazomethane- ether solution 10
ml and methanol 1 ml were added, and the mixture was stirred at room temperature for 30 minutes. After adding acetic acid, the mixture was made alkaline with a saturated aqueous sodium bicarbonate solution and extracted with benzene. After washing with saturated brine, it was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a yellow oil, which was subjected to column chromatography using 2 g of silica gel and eluted with chloroform to obtain methyl 2-(10·11-dihydro-8-nitro-11-oxodibenzo 44 mg (yield 57%) of a yellow oil of [b/f]thiepin-2-yl)propionate was obtained. IRν CHCl3 nax cm -1 : 1735, 1680 (C=0) NMR (CDCl 3 ) δ: 1.50 (3H, d, J=7Hz, =
CHC H 3 ) 3.65 (3H, s, −COOC H 3 ) 3.75 (1H, q, J=7Hz, =CH CH 3 ) 4.45 (2H, s, −CH 2 CO−) 7.37 to 8.27 (6H, m , aromatic proton) Example 4 Methyl 2-(8-amino-10·11-dihydro-
11-Oxodibenzo[b・f]thiepin-2-
yl) propionate: Methyl 2-(10,11-dihydro-8-nitro-
40 mg of 11-oxodibenzo[b·f]thiepin-2-yl)propionate was dissolved in 3 ml of acetone, a small amount of 10% palladium on activated carbon was added, and catalytic reduction was carried out for 9 hours. The reaction solution was filtered under suction through Celite, and the solvent was distilled off to obtain a yellow oil, which was subjected to column chromatography using 9 g of silica gel.
Elution with chloroform gave 13 mg (yield 36%) of a yellow oil of methyl 2-(8-amino-10,11-dihydro-11-oxodibenzo[b/f]thiepin-2-yl)propionate. Ta. IRν CHCI3 nax cm -1 : 3400 (NH 2 ), 1730, 1670 (C=0
) NMR (CDCl 3 ) δ: 1.46 (3H, d=, J=7Hz,
=CHC H3 ) 3.58 (3H, s, -COOC H3 ) 3.70 (1H, q, J=7Hz, =CHC H3 ) 4.22 (2H, s, -CH2CO- ) Example 5 2- (8-amino-10,11-dihydro-11-oxodibenzo[b・f]thiepin-2-yl)
Propionic acid: Methyl 2-(8-amino-10,11-dihydro-
78 mg of 11-oxodibenzo[b·f]thiepin-2-yl)propionate was suspended in 3 ml of methanol, 200 mg of potassium hydroxide dissolved in 3 ml of water was added under ice cooling, and the mixture was stirred at room temperature for 6 hours. The reaction solution was filtered, made weakly acidic with hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a yellow solid, which was subjected to column chromatography using 2 g of silica gel, eluted with chloroform:methanol = 50:1, and further recrystallized from chloroform-methanol. 2-(8-amino-
10・11-dihydro-11-oxodibenzo [b・
f] 49 mg (yield 75%) of pale yellow crystals of thiepin-2-yl)propionic acid were obtained. IRν KBr nax cm -1 : 3360, 3280 (NH 2 ), 1710, 1650 (C
= 0) NMR (acetone-d 6 ) δ: 1.43 (3H, d, J = 7
Hz, = CHC H 3 ) 3.80 (1H, q, J = 7Hz, = CH CH 3 ) 4.20 (2H, s, -C H 2 CO-) 6.52 (1H, dd, J = 9, 3Hz, C 7 H ) 6.78 (1H, d, J=3Hz, C9H ) 7.28-7.83 (3H, m, aromatic proton) 8.09 ( 1H, d, J=3Hz, C1H )
Claims (1)
アミノ基、ヒドロキシ基または低級アルコキシ基
を示す） で表わされるジベンゾチエピン誘導体。 ２ 一般式 で表わされる化合物を閉環せしめることを特徴と
する一般式 で表わされるジベンゾチエピン誘導体の製法。 ３ 一般式 で表わされる化合物を加水分解せしめることを特
徴とする一般式 で表わされるジベンゾチエピン誘導体の製法。 ４ 一般式 で表わされる化合物またはその反応性誘導体に低
級アルコールまたはその反応性誘導体を反応させ
ることを特徴とする、一般式 （式中、R3は低級アルキル基を示す） で表わされるジベンゾチエピン誘導体の製法。 ５ 一般式 （式中、R3は低級アルキル基を示す） で表わされる化合物を接触還元に付すことを特徴
とする、一般式 （式中、R3は前記と同じ） で表わされるジベンゾチエピン誘導体の製法。 ６ 一般式 （式中、R3は低級アルキル基を示す） で表わされる化合物を加水分解せしめることを特
徴とする、一般式 で表わされるジベンゾチエピン誘導体の製法。[Claims] 1. General formula A dibenzothiepine derivative represented by (wherein R 1 represents a nitro group or an amino group, and R 2 represents an amino group, a hydroxy group, or a lower alkoxy group). 2 General formula A general formula characterized by ring-closing a compound represented by A method for producing a dibenzothiepine derivative represented by 3 General formula A general formula characterized by hydrolyzing a compound represented by A method for producing a dibenzothiepine derivative represented by 4 General formula A general formula characterized by reacting a compound represented by or a reactive derivative thereof with a lower alcohol or a reactive derivative thereof. (In the formula, R 3 represents a lower alkyl group.) A method for producing a dibenzothiepine derivative represented by the following. 5 General formula (In the formula, R 3 represents a lower alkyl group) (In the formula, R 3 is the same as above.) A method for producing a dibenzothiepine derivative represented by: 6 General formula (In the formula, R 3 represents a lower alkyl group) A method for producing a dibenzothiepine derivative represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6459679A JPS55157582A (en) | 1979-05-26 | 1979-05-26 | Dibenzthiepin derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6459679A JPS55157582A (en) | 1979-05-26 | 1979-05-26 | Dibenzthiepin derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55157582A JPS55157582A (en) | 1980-12-08 |
| JPS631311B2 true JPS631311B2 (en) | 1988-01-12 |
Family
ID=13262785
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6459679A Granted JPS55157582A (en) | 1979-05-26 | 1979-05-26 | Dibenzthiepin derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS55157582A (en) |
-
1979
- 1979-05-26 JP JP6459679A patent/JPS55157582A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55157582A (en) | 1980-12-08 |
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