JPS62221679A - Benzothazoline derivative - Google Patents
Benzothazoline derivativeInfo
- Publication number
- JPS62221679A JPS62221679A JP61063189A JP6318986A JPS62221679A JP S62221679 A JPS62221679 A JP S62221679A JP 61063189 A JP61063189 A JP 61063189A JP 6318986 A JP6318986 A JP 6318986A JP S62221679 A JPS62221679 A JP S62221679A
- Authority
- JP
- Japan
- Prior art keywords
- group
- lower alkyl
- formula
- hydroxy
- phenyl
- 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
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 31
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- -1 phenylcarbamoyl Chemical group 0.000 claims abstract description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 14
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims abstract description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 10
- 125000004423 acyloxy group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 4
- PUMTTZYYKPFOTK-UHFFFAOYSA-N 1-[6-chloro-2-(2-hydroxy-5-methoxyphenyl)-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound COC1=CC=C(O)C(C2N(C3=CC=C(Cl)C=C3S2)C(C)=O)=C1 PUMTTZYYKPFOTK-UHFFFAOYSA-N 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- WOHLSTOWRAOMSG-UHFFFAOYSA-N 2,3-dihydro-1,3-benzothiazole Chemical compound C1=CC=C2SCNC2=C1 WOHLSTOWRAOMSG-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- FZHSPPYCNDYIKD-UHFFFAOYSA-N 5-methoxysalicylaldehyde Chemical compound COC1=CC=C(O)C(C=O)=C1 FZHSPPYCNDYIKD-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000002213 calciumantagonistic effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- XOCGJJLRMWWZSC-UHFFFAOYSA-N 2-(fluoromethyl)-1,3-benzothiazole Chemical class C1=CC=C2SC(CF)=NC2=C1 XOCGJJLRMWWZSC-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
- TYRZAGMAVZESQX-UHFFFAOYSA-N 2-amino-5-chlorobenzenethiol Chemical compound NC1=CC=C(Cl)C=C1S TYRZAGMAVZESQX-UHFFFAOYSA-N 0.000 description 1
- LJQNMDZRCXJETK-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine;hydron;chloride Chemical compound Cl.CN(C)CCCCl LJQNMDZRCXJETK-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- VIHYIVKEECZGOU-UHFFFAOYSA-N N-acetylimidazole Chemical compound CC(=O)N1C=CN=C1 VIHYIVKEECZGOU-UHFFFAOYSA-N 0.000 description 1
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008187 granular material Substances 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
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000000144 pharmacologic effect Effects 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
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Abstract
Description
【発明の詳細な説明】
「産業上の利用分野」
本発明化合物はカルシウム拮抗作用、血小板凝集阻害作
用等を有し、循環器系疾患の治療剤として有用である。DETAILED DESCRIPTION OF THE INVENTION "Industrial Application Field" The compound of the present invention has calcium antagonistic activity, platelet aggregation inhibiting activity, etc., and is useful as a therapeutic agent for cardiovascular diseases.
「従来の技術および発明が解決しようとする問題点」
循環器系疾患の治療剤として有用なベンゾチアゾリン化
合物に関する先行文献として、本発明者等の研究に係る
特開昭５８−４６０７９号、特開昭５９−６７２７６号
および特開昭６０−１３９６７９号がある。これらは種
々のベンゾチアゾリン誘導体を開示しているが、ベンゾ
チアゾリン環のフェニル環に置換基を有する化合物は開
示しておらず、それらのベンゾチアゾリン誘導体の合成
ならびに効果を検討する必要があった。"Prior art and problems to be solved by the invention" Prior documents regarding benzothiazoline compounds useful as therapeutic agents for cardiovascular diseases include JP-A No. 58-46079 and JP-A-58-46079, which are related to research by the present inventors. There are No. 59-67276 and JP-A No. 60-139679. Although these disclose various benzothiazoline derivatives, they do not disclose compounds having a substituent on the phenyl ring of the benzothiazoline ring, and it was necessary to study the synthesis and effects of these benzothiazoline derivatives.
「問題を解決するための手段および作用」本発明者等は
一般式〔■〕で表わされる文献未知の種々のベンゾチア
ゾリン誘導体を合成し、その薬理作用を検討したところ
、優れたカルシウム拮抗作用を有す・ることを見い出し
た。本発明化合物の特徴はベンゾチアゾリンのフェニル
環に置換基を有することである。"Means and Actions for Solving the Problem" The present inventors synthesized various benzothiazoline derivatives represented by the general formula [■] that were unknown in the literature, and investigated their pharmacological actions. I discovered what I have. The compound of the present invention is characterized by having a substituent on the phenyl ring of benzothiazoline.
一般式ＣＩ）で表わされる化合物およびその塩類に関す
る。The present invention relates to a compound represented by the general formula CI) and salts thereof.
〔式中、Ｒ１は低級アルキル基、低級アルコキシ基、ヒ
ドロキシ基、ハロゲン原子、シアノ基、ニトロ基、ハロ
ゲノ低級アルキル基および低級アルカノイルオキシ基か
ら選択てれる１個又は複数の基を示す。[In the formula, R1 represents one or more groups selected from a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen atom, a cyano group, a nitro group, a halogeno lower alkyl group, and a lower alkanoyloxy group.
Ｒ２は低級アルカノイル基、低級アルキルカルバモイル
基、フェニルカルバモイル基又はメタンスルホニル基を
示す。R2 represents a lower alkanoyl group, a lower alkylcarbamoyl group, a phenylcarbamoyl group or a methanesulfonyl group.
Ｒ３は水素原子、ヒドロキシ基、低級アルキル基、低級
アルコキシ基、ニトロ基、）・ロゲン原子および低級ア
ルカノイルオキシ基から選択される１個Ｒ６、Ｒ７は同
一か又は異なって水素原子、低級アルキル基、（０３〜
Ｃ６）シクロアルキル基、フェニル基、ピリジル基ま几
は置換低級アルキル基を示し、置換低級アルキル基の置
換基はヒドロキシ基、フェニル基、ピリジル基およびフ
ェニルカルボニル基から選択される１個又は複数の基を
示し、上記フェニル基およびフェニルカルボニル基のフ
ェニル環ならびにピリジル基は低級アルキル基、ヒドロ
キシ基、ノーロゲン原子、低級アルコキシ基、ニトロ基
、シアノ基、低級アルキレンジオキシ基および低級アル
カノイルオキシ基から選択される１個又は複数の基で置
換されていてもよい。又、Ｒ８は水素原子、低級アルキ
ル基、低級アルカノイル基、低級アルコキシカルボニル
基、カルボキシ基、フェニル基、フェニルカルボニルｉ
、置換低級アルキル基又は置換低級アルカノイル基を示
し、置換低級アルキル基の置換基はヒドロキシ基、低級
アルコキシ基、フェニル基、フェニルカルボニル基、カ
ルボキシ基および低級アルコキシカルボニル基から選択
される１個又は複数の基を示し、上記フェニル基および
フェニルカルボニル基のフェニル環は低級アルキル基、
ヒドロキシ基、低級アルコキシ基、ハロゲン原子、ニト
ロ基、シアン基、低級アルキレンジオキシ基および低級
アルカノイルオキシ基から選択される１個又は複数の基
で置換されていてもよい。R3 is one selected from a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a nitro group, a rogene atom, and a lower alkanoyloxy group. R6 and R7 are the same or different and are a hydrogen atom, a lower alkyl group, (03~
C6) Cycloalkyl group, phenyl group, pyridyl group represents a substituted lower alkyl group, and the substituent of the substituted lower alkyl group is one or more selected from hydroxy group, phenyl group, pyridyl group, and phenylcarbonyl group. The phenyl ring and pyridyl group of the above phenyl group and phenylcarbonyl group are selected from a lower alkyl group, a hydroxy group, a norogen atom, a lower alkoxy group, a nitro group, a cyano group, a lower alkylenedioxy group, and a lower alkanoyloxy group. may be substituted with one or more groups. Moreover, R8 is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a carboxy group, a phenyl group, a phenylcarbonyl i
, represents a substituted lower alkyl group or a substituted lower alkanoyl group, and the substituent of the substituted lower alkyl group is one or more selected from a hydroxy group, a lower alkoxy group, a phenyl group, a phenylcarbonyl group, a carboxyl group, and a lower alkoxycarbonyl group. The phenyl ring of the above phenyl group and phenylcarbonyl group is a lower alkyl group,
It may be substituted with one or more groups selected from a hydroxy group, a lower alkoxy group, a halogen atom, a nitro group, a cyan group, a lower alkylenedioxy group, and a lower alkanoyloxy group.
Ｘはハロゲン原子゛を示す。X represents a halogen atom.
Ａは１〜５個の炭素原子を有する低級アルキレン基？示
す。Is A a lower alkylene group having 1 to 5 carbon atoms? show.
ｌは２又は３を示す。l represents 2 or 3.
ｍはＯ又は】を示す。m represents O or ].
ｎは０又は１を示す。n represents 0 or 1.
ｐは４又は５を示す。p represents 4 or 5.
但し、Ｒ４が水素原子の場合、ｍは０を示す。以下同じ
。〕
上記の基についてさらに詳しく説明すると、低級アルキ
ル基とはメチル基、エチル基、プロピル基、ヘキシル基
等の１〜６個の炭素原子を有するアルキル基を示し、低
級アルコキシ基とはメトキシ基、エトキシ基、プロポキ
シ基、ヘキシルオキシ基等の１〜６個の炭素原子を有す
るアルコキシ基を示し、ハロゲン原子とはフッ素、塩素
、臭素等を示し、ハロゲノ低級アルキル基とはトリフル
オロメチル基等のハロゲン原子で置換された１〜６個の
炭素原子を有するアルキル基を示し、低級アルカノイル
オキシ基とはアセチルオキシ基、プロピオニルオキシ基
、ヘキサノイルオキシ基等の１〜６個の炭素原子を有す
るアルカノイルオキシ基を示し、低級アルキルカルバモ
イル基とはメチルカルバモイル基、エチルカルバモイル
基、ヘキシルカルバモイル基等の炭素原子１〜６個の炭
素原子を有するアルキルで置換されたカルバモイル基を
示し、低級アルキレンジオキシ基とはメチレンジオキシ
基、エチレンジオキシ基等の２個の酸素原子の間に１〜
６個の炭素原子を有するアルキレン基が存在する基を示
し、（Ｃ３〜ｃ６）シクロアルキル基トは、シクロプロ
ピル基、シクロヘキシル基等の３〜６個の炭素原子を有
するシクロアルキル基を示し、低級アルコキシカルボニ
ル基とはメトキシカルボニル基、エトキシ刀ルポニル基
、へ°キシルオキシカルボニル基等ヲ示す。However, when R4 is a hydrogen atom, m represents 0. same as below. ] To explain the above groups in more detail, a lower alkyl group refers to an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, a hexyl group, and a lower alkoxy group refers to a methoxy group, An alkoxy group having 1 to 6 carbon atoms such as an ethoxy group, a propoxy group, a hexyloxy group, etc., a halogen atom refers to fluorine, chlorine, bromine, etc., and a halogeno-lower alkyl group refers to a trifluoromethyl group, etc. It refers to an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, and a lower alkanoyloxy group refers to an alkanoyl group having 1 to 6 carbon atoms such as an acetyloxy group, a propionyloxy group, a hexanoyloxy group, etc. represents an oxy group, and a lower alkylcarbamoyl group represents a carbamoyl group substituted with an alkyl having 1 to 6 carbon atoms, such as a methylcarbamoyl group, an ethylcarbamoyl group, a hexylcarbamoyl group, and a lower alkylenedioxy group. means 1 to 1 between two oxygen atoms such as methylenedioxy group, ethylenedioxy group, etc.
Indicates a group in which an alkylene group having 6 carbon atoms is present, (C3-C6) cycloalkyl group represents a cycloalkyl group having 3 to 6 carbon atoms such as a cyclopropyl group and a cyclohexyl group, The lower alkoxycarbonyl group includes a methoxycarbonyl group, an ethoxycarbonyl group, a hexyloxycarbonyl group, and the like.
本発明化合物は例えば下記の方法によって製造すること
ができる。The compound of the present invention can be produced, for example, by the method described below.
Ｊ）一般式〔口〕で表わされる化合物と一般式〔■〕で
表わされる化合物を反応させた後、Ｒ２導入活性体（Ｒ
２のＮ−アシルイミダゾール、酸無水物、酸クロリド、
インシアネートなどを示す。）を反応させる方法。J) After reacting the compound represented by the general formula [■] with the compound represented by the general formula [■], the R2-introduced activated form (R
2 N-acylimidazole, acid anhydride, acid chloride,
Indicates incyanate, etc. ) how to react.
［１１’：） Ｏｎ）［ＩＤ
２）一般式〔ｌＤで表わされる化合物と一般式〔ｖ〕で
表わし九化合物とを反応させる方法。[11':) On) [ID 2) A method of reacting a compound represented by the general formula [ID] with a compound represented by the general formula [v].
３）一般式〔■〕で表わされる化合物と一般式ｒＶＩ）
で表わ嘔れる化合物とを反応式せ一般式〔■〕を得、こ
れにさらに一般式〔■〕を反応式せる方法。3) Compound represented by general formula [■] and general formula rVI)
A method in which the general formula [■] is obtained by reacting with the compound represented by the formula [■], and then the general formula [■] is further reacted with the general formula [■].
ＣＡＬＫはヒドロキシ基で置換されていてもよい低級ア
ルキレン基を示す。以下同じ。〕４）一般式［ｒｆｆ、
ｌで表わされる化合物と一般式〔ｘ〕で表わされる化合
物とを反応させる方法。CALK represents a lower alkylene group which may be substituted with a hydroxy group. same as below. ]4) General formula [rff,
A method of reacting a compound represented by l with a compound represented by general formula [x].
さらに一般式〔Ｉで表わされる化合物と反応させてもよ
い。Furthermore, it may be reacted with a compound represented by the general formula [I].
上記に示した反応は、通常塩基性条件下で行なわれる。The reactions shown above are usually carried out under basic conditions.
好ましい塩基の例としては、水素化ナトリウム、炭酸カ
リウム、炭酸ナトリウム、水酸化ナトリウム、ナトリウ
ムアルコラード、トリエチルアミン、ピリジン、Ｎ、Ｎ
−ジメチルアニリン等の無機又は有機塩基が挙げられる
。又、上記反応は特に塩基を用いなくとも反応に関与す
るアミン成分を過剰に用いる事によっても行うことがで
きる０
上記反応に用いられる溶媒、反応温度等の諸条件には特
に制限はなく、塩基の種類、反応成分の溶解度等に応じ
て適宜選択することができる。Examples of preferred bases include sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, sodium alcoholade, triethylamine, pyridine, N,N
- Inorganic or organic bases such as dimethylaniline. In addition, the above reaction can be carried out by using an excess amount of the amine component involved in the reaction without using a base. There are no particular restrictions on the conditions such as the solvent and reaction temperature used in the above reaction. It can be appropriately selected depending on the type of the reaction component, the solubility of the reaction component, etc.
本発明化合物は医薬として許容される塩の形態にするこ
とができる。塩の例として、塩酸塩、硫酸塩、リン酸塩
、乳酸塩、マレイン酸塩、フマル酸塩、シュウ酸塩、メ
タンスルホン酸塩、パラトルエンスルホン酸塩等がある
。The compounds of the present invention can be in the form of pharmaceutically acceptable salts. Examples of salts include hydrochloride, sulfate, phosphate, lactate, maleate, fumarate, oxalate, methanesulfonate, paratoluenesulfonate, and the like.
本発明化合物には立体異性体が存在するが、それらはい
ずれも本発明に包含される。Although the compounds of the present invention have stereoisomers, all of them are included in the present invention.
本発明化合物は経口でも非経口でも投与することができ
る。剤型としては、錠剤、カプセル、顆粒、散剤、坐剤
、注射剤等があげられる。投与量は症状、剤型等により
決められるが、通常、１日１〜５，０ＯＯＷ好ましくは
ｌ Ｏ〜１．０００”Ｐを１回又は数回に分は投与する
。The compounds of the present invention can be administered orally or parenterally. Examples of dosage forms include tablets, capsules, granules, powders, suppositories, and injections. The dosage is determined depending on symptoms, dosage form, etc., but usually 1 to 5.0 OOW, preferably 1 O to 1.000''P, is administered once or in several doses per day.
「実施例」 実施例］。"Example" Example].
３−アセチル−６・−クロロ−２−（２−ヒドロキシ−
５−メトキシフェニル）ベンゾチアゾリンの製造
２−アミノ−５−クロロチオフェノール（２０ｙ）のト
ルエン（２０ｍｅ）−メタノール（４，４ｍｔ’）溶液
に２−ヒドロキシ−５−メトキシベンズアルデヒド（１
９，２ｙ）のトルエン（２０ｒｎり溶液を窒素気流下加
え、４０℃で１時間加熱撹拌する。3-acetyl-6・-chloro-2-(2-hydroxy-
Preparation of 2-hydroxy-5-methoxybenzaldehyde (1) to a solution of 2-amino-5-chlorothiophenol (20y) in toluene (20me)-methanol (4,4mt').
A solution of 9,2y) in toluene (20 rn) was added under a nitrogen stream, and the mixture was heated and stirred at 40°C for 1 hour.
Ｎ−アセチルイミダゾール（１５，３ｙ）のトルエン（
２０ｍｔ’）−メタノール（２，２ｒＩｄり溶液を加え
６時間室温下撹拌する。反応液ｔクロロホルムに溶解し
、ＩＮ塩酸、飽和重曹水、飽和食塩水の順に洗浄し、無
水硫酸マグネシウムで乾燥する。溶媒を減圧留去し標記
化合物２２．５９ （収率５３．３％）を得る。N-acetylimidazole (15,3y) in toluene (
Add a solution of 20mt')-methanol (2,2rId) and stir at room temperature for 6 hours. The reaction mixture is dissolved in chloroform, washed in this order with IN hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound 22.59 (yield 53.3%).
融点２０１〜２０２°Ｃ（酢酸エチル−メタノール−エ
ーテル）
ＩＲ（ＫＢｒ、ｃｍ−” 、以下同じ）３２９６．１６
３６．１５０２
実施例】と同様の方法で以下の化合物を得ることが出来
る。Melting point: 201-202°C (ethyl acetate-methanol-ether) IR (KBr, cm-”, same hereinafter) 3296.16
36.1502 The following compounds can be obtained in the same manner as in Example.
−２−（２−ヒドロキシ−５−二トロフェニル）−６−
メドキシー３−プロピオニルベンゾチアゾリン
ＩＲ：３２４０，１６２７，１５８９．１３７１・ ３
−ホルミル−５−フルオロ−２−（４−ヒドロキシフェ
ニル）ベンゾチアゾリン
ＩＲ：３２６０，１６４２．１５７８
・ ３−アセチル−２−（４−ヒドロキシ−３−メトキ
シフェニル）−６−ト替フルオロメチルベンゾチアゾリ
ン
ＩＲ：３１８Ｑ、 ］ ６５２． ］ ５］ ８φ ３
−アセチル−４−シアノ−２−（２−ヒドロキシ−３−
クロロフェニル）ペンゾチアゾリン
ＩＲ：３１５０．１６２４．１４６６
・ ３−アセチル−２−（２−ヒドロキシ−５−メトキ
シフェニル）−６−メチルベンゾチアゾリン
ＩＲ：３］ ８０． ｌ ６３４． ］ ５
４３・ ３−アセチル−２−（２−ヒドロキシ−５−メ
トキシフェニル）−５−二トロペンゾチアゾリン
ＩＲ：３２３０． １６２２． １５８６． １３７０
・ ３−アセチル−２−（２−ヒドロキシ−５−メトキ
シフェニル）−６−メチルベンゾチアゾリン
ＩＲ：３１８３．１６５０．１５６３
実施例２゜
３−アセチル−２−Ｃ２−（４−ブロモブトキシ）−５
−メトキシフェニル］−６−／ロロペンゾチアゾリンの
製造
３−アセチル−６−クロロ−２−（２−ヒドロキシ−５
−メトキシフェニル）ベンゾチアゾリン（５，０？ ）
のＤＭＦ （ｌ Ｏｄ）溶液を水冷下、６０チ含有水素
化ナトリウム（０，６６ｙ）のＤＭＦ （１０ｍｅ）懸
濁液に滴下し、１５分間撹拌する。１゜４−ジブロモブ
タン（９，７ｙ）を加え、５０°Ｃで２時間撹拌する。-2-(2-hydroxy-5-nitrophenyl)-6-
Medoxy 3-propionylbenzothiazoline IR: 3240, 1627, 1589.1371/3
-Formyl-5-fluoro-2-(4-hydroxyphenyl)benzothiazoline IR: 3260,1642.1578 ・3-acetyl-2-(4-hydroxy-3-methoxyphenyl)-6-substituted fluoromethylbenzothiazoline IR:318Q, ] 652. ] 5] 8φ 3
-acetyl-4-cyano-2-(2-hydroxy-3-
3-Acetyl-2-(2-hydroxy-5-methoxyphenyl)-6-methylbenzothiazoline IR: 3] 80. l 634. ] 5
43. 3-acetyl-2-(2-hydroxy-5-methoxyphenyl)-5-nitropenzothiazoline IR: 3230. 1622. 1586. 1370
・3-acetyl-2-(2-hydroxy-5-methoxyphenyl)-6-methylbenzothiazoline IR: 3183.1650.1563 Example 2゜3-acetyl-2-C2-(4-bromobutoxy)-5
-methoxyphenyl]-6-/Production of loropenzothiazoline 3-acetyl-6-chloro-2-(2-hydroxy-5
-methoxyphenyl)benzothiazoline (5,0?)
A DMF (l Od) solution of the above was added dropwise to a DMF (10me) suspension of 60% sodium hydride (0,66y) under water cooling, and the mixture was stirred for 15 minutes. Add 1°4-dibromobutane (9,7y) and stir at 50°C for 2 hours.
放冷後、反応液を水に注ぎ、エーテルで抽出し、飽和食
塩水で洗浄後、無水硫酸マグネシウムで乾燥する。溶媒
を減圧留去し、標記化合物を４．８２ｙ（収率６８．３
％）得る。After cooling, the reaction solution is poured into water, extracted with ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.82y (yield 68.3) of the title compound.
%)obtain.
融点１２１〜１２３℃（クロロホルム−メタノール）
ＩＲ：２９］ ６．１６６２．１４５９実施例２と同様
の方法で以下の化合物を得ることが出来る。Melting point: 121-123°C (chloroform-methanol) IR: 29] 6.1662.1459 The following compound can be obtained in the same manner as in Example 2.
・ ３−アセチル−６−クロロ−２−Ｃ２−（３−クロ
ロプロポキシ）−５−メトキシフェニル〕ベンゾチアゾ
リン
ＩＲ：２９１２，１６７６、］４５８
・ ２−Ｃ２−（４−ブロモブトキシ）−５−二トロフ
ェニル〕−６−メドキシー３−プロピオニルベンゾチア
ゾリン
ＩＲ：２９１７，１６５７．１５８３
・ ３−アセチル−２−Ｃ２−（５−ブロモペンチルオ
キシ）−５−メトキシフェニル）−６−クロロベンゾチ
アゾリン
ＩＲ：２９２０，１６８０．１４９１
・ ２−Ｃ２−（３−ブロモプロポキシ）−５−二トロ
フェニル］−６−メドキシー３−７”ロピオニルペンゾ
チアゾリン
ＩＲ：２９１６，１６５９．１５８６
・ ２−Ｃ４−（５−７’ロモペンチルオキシ）フェニ
ル）−３−ホルミル−５−フルオロベンゾチアゾリン
ＩＲ：２９１９，１６７２．１４６３
・ ３−アセチル−２−Ｃ４−（３−クロロプロポキシ
）−３−メトキシフェニル］−６−ドリフルオロメチル
ペンゾチアゾリン
ＩＲ：２９１４．１６７５．１４５９
・ ３−アセチル−２−［２−、（４−ブロモブトキシ
）−３−クロロフェニルヨー４−シアノペ／ゾチアゾリ
ン
ＩＲ：２９１７．１６７９．１４８３
・ ３−アセチル−２−Ｃ２−（４−ブロモブトキシ）
−５−メトキシフェニル）−６−メチルベンゾチアゾリ
ン
ＩＲ：２９２２，１６７２．１４９０
・ ３−アセチル−２−Ｃ２−（４−ブロモブトキシ）
−５−メトキシフェニルシー５−二トロペンゾチアゾリ
ン
ＩＲ：２９２１．１６８０．１５８４
・ ３−アセチル−２−Ｃ２−（３−ブロモプロポキシ
）−５−メトキシフェニル〕−６−メドキシペンゾチア
ゾリン
ＩＲ：２９１６．１６７８．１４９２
実施例３゜
３−アセチル−６−クロロ−２−Ｃ２−［３−（ジメチ
ルアミノ）プロポキシシー５−メトキシフエニル〕ベン
ゾチアゾリン マレインａ塩ｏｇ造
３−アセチル−６−クロロ−２−（２−ヒドロキシ−５
−メトキシフェニル）ベンゾチアゾリン＜ ２．Ｏｙ
）のＤＭＦ （７ｍｅ ）溶液を６０％含有水素化ナト
リウム（０，２８ｙ）のＤＭＦ （３ｍｌ ） ！ｆ！
！。・3-acetyl-6-chloro-2-C2-(3-chloropropoxy)-5-methoxyphenyl]benzothiazoline IR:2912,1676, ]458 ・2-C2-(4-bromobutoxy)-5-di trophenyl]-6-medoxy 3-propionylbenzothiazoline IR: 2917,1657.1583 ・3-acetyl-2-C2-(5-bromopentyloxy)-5-methoxyphenyl)-6-chlorobenzothiazoline IR: 2920 , 1680.1491 ・2-C2-(3-bromopropoxy)-5-nitrophenyl]-6-medoxy 3-7" ropionylpenzothiazoline IR: 2916,1659.1586 ・2-C4-(5- 7'romopentyloxy)phenyl)-3-formyl-5-fluorobenzothiazoline IR: 2919,1672.1463 ・3-acetyl-2-C4-(3-chloropropoxy)-3-methoxyphenyl]-6-doly Fluoromethylpenzothiazoline IR: 2914.1675.1459 ・3-acetyl-2-[2-,(4-bromobutoxy)-3-chlorophenyl-4-cyanope/zothiazoline IR: 2917.1679.1483 ・3-acetyl -2-C2-(4-bromobutoxy)
-5-methoxyphenyl)-6-methylbenzothiazoline IR: 2922,1672.1490 ・3-acetyl-2-C2-(4-bromobutoxy)
-5-methoxyphenyl-5-nitropenzothiazoline IR: 2921.1680.1584 ・3-acetyl-2-C2-(3-bromopropoxy)-5-methoxyphenyl]-6-medoxypenzothiazoline IR :2916.1678.1492 Example 3゜3-acetyl-6-chloro-2-C2-[3-(dimethylamino)propoxy-5-methoxyphenyl]benzothiazoline maleic a salt og preparation 3-acetyl-6- Chloro-2-(2-hydroxy-5
-methoxyphenyl)benzothiazoline<2. Oy
) of DMF (7me) solution containing 60% sodium hydride (0,28y) in DMF (3 ml)! f!
! .
濁液に水冷下加え、室温下１５分間撹拌する。３−ジメ
チルアミノプロピルクロリド塩酸塩（２，０ｙ）のＤＭ
Ｆ （６ｍｅ ）懸濁溶液にトリエチルアミン（１，８
ｍ＋’）を加え室温下５分間撹拌後、析出物？戸数し、
得られたＰ液を上で調製した溶液中に水冷下漬下し、８
０’Ｃで２時間撹拌する。反応液を水に加えた後、酢酸
エチルで抽出し飽和食塩水で洗浄する。無水硫駿マグネ
シウムで乾燥後、マレイン酸（０，５？ ）の酢酸エチ
ル（５ｒＩｄり溶液を加え、標記化合物を１．５ｙ（収
率５５％）得る。Add to the cloudy solution while cooling with water, and stir at room temperature for 15 minutes. DM of 3-dimethylaminopropyl chloride hydrochloride (2,0y)
Triethylamine (1,8
m+') and stirred at room temperature for 5 minutes, precipitate? number of houses,
The obtained P solution was soaked in the solution prepared above under water cooling, and
Stir at 0'C for 2 hours. After adding the reaction solution to water, it is extracted with ethyl acetate and washed with saturated brine. After drying over anhydrous magnesium sulfate, a solution of maleic acid (0,5?) in ethyl acetate (5rId) was added to obtain 1.5y (yield 55%) of the title compound.
融点】７１〜１７２°Ｃ（メタノール）ＩＲ：２９２４
．２５９６．１６７７
実施例３と同様の方法で以下の化合物を得ることが出来
る。Melting point] 71-172°C (methanol) IR: 2924
．． 2596.1677 The following compound can be obtained in the same manner as in Example 3.
・ ３−アセチル−６−クロロ−２−Ｃ２−Ｃ４−Ｃ４
−（３，４−ジメトキシフェネチル） −１−ピペラジ
ニル〕ブトキシ〕−５−メトキシフェニル〕ベンゾチア
ゾリン フマル酸塩ＩＲ：３４２０，２４２０，１７０
８．１６６８・ ３−アセチル−６−クロロ−２−Ｃ２
−Ｃ５−（４−ベンゾイルピペリジノ）ペンチルオキシ
）’−５−メトキシフェニル〕ベンゾチアゾリン シュ
ウ酸塩
ＩＲ：３４５０．１７２０．］６７１
・ ６−メドキシー２−〔５−ニトロ−２−〔３−〔Ｎ
−エチル−Ｎ−（２，３，４−トリットキシフェネチル
）アミノ〕プロポキシ〕フェニル〕−３−プロピオニル
ベンゾチアゾリン 塩酸塩ＩＲ：３４４０，１６６５．
１５８０
・ ３−ホルミル−５−フルオロ−２−Ｃ４−Ｃ５−Ｃ
Ｃ３−ピリジル）メチルアミノ〕ペンチルオキシ〕フェ
ニル〕ベンゾチアゾリン シュウ酸塩
ＩＲ：３４］２．１７］９，１６７３
・ ３−アセチル−２−〔３−クロロ−２−（４−モル
ホリノ）ブトキシフェニルシー４−シアノベンゾチアゾ
リン マレイン酸塩
ＩＲ：３４１２，１７］９．］６３６
実６３６実
施−アセチル−６−クロロ−２−Ｃ２−Ｃ５−〔（Ｎ−
シクロヘキシル−Ｎ−メチル）アミノ〕ペンチルオキシ
〕−５−メトキシフェニル〕ベンゾチアゾリン フマル
酸塩の製造
３−アセチル−２−Ｃ２−（５−ブロモペンチルオキシ
）−５−メトキシフェニル］−６−／ロロベンゾチアゾ
リン（０，９７ｙ）のＤＭＦ（４ｍｅ）溶液にＮ−メチ
ルシクロヘキシルアミン（０，６８））を加え、６０℃
で３時間撹拌する。反応液を水に注ぎ酢酸エチルで抽出
し、飽和食塩水で洗浄する。無水硫酸マグネシウムで乾
燥後、フマル酸（０，１９ｙ）のメタノール（２ｒｎｌ
）溶液を加え、標記化合物を０．８１ ｙ（収率６４．
０％）得る。・3-acetyl-6-chloro-2-C2-C4-C4
-(3,4-dimethoxyphenethyl) -1-piperazinyl]butoxy]-5-methoxyphenyl]benzothiazoline fumarate IR: 3420,2420,170
8.1668・3-acetyl-6-chloro-2-C2
-C5-(4-benzoylpiperidino)pentyloxy)'-5-methoxyphenyl]benzothiazoline oxalate IR: 3450.1720. ]671 ・6-Medoxy 2-[5-nitro-2-[3-[N
-Ethyl-N-(2,3,4-tritoxyphenethyl)amino]propoxy]phenyl]-3-propionylbenzothiazoline hydrochloride IR: 3440,1665.
1580 ・3-formyl-5-fluoro-2-C4-C5-C
C3-Pyridyl)methylamino]pentyloxy]phenyl]benzothiazoline oxalate IR:34]2.17]9,1673 ・3-acetyl-2-[3-chloro-2-(4-morpholino)butoxyphenylcy 4-cyanobenzothiazoline maleate IR: 3412,17]9. ]636 Example 636 - Acetyl-6-chloro-2-C2-C5-[(N-
Preparation of cyclohexyl-N-methyl)amino[pentyloxy]-5-methoxyphenyl]benzothiazoline fumarate 3-acetyl-2-C2-(5-bromopentyloxy)-5-methoxyphenyl]-6-/Rolo Add N-methylcyclohexylamine (0,68) to a DMF (4me) solution of benzothiazoline (0,97y) and heat at 60°C.
Stir for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, and washed with saturated brine. After drying with anhydrous magnesium sulfate, fumaric acid (0,19y) in methanol (2rnl
) solution to obtain the title compound in 0.81 y (yield 64.
0%).
融点１４２〜１４３°Ｃ（酢酸エチル）ＩＲ：２９１６
．２６００−２３００．１７０１．１６５８実施例４と
同様の方法で以下の化合物を得ることが出来る。Melting point 142-143°C (ethyl acetate) IR: 2916
．． 2600-2300.1701.1658 The following compound can be obtained in the same manner as in Example 4.
・ ３−アセチル−６−クロロ−２−Ｃ２−Ｃ４−４Ｎ
−（（３，４−ジメトキシフェネチル） −Ｎ−メチル
〕アミノ〕ブトキシ〕−５−メトキシフェニル〕ベンゾ
チアゾリン 塩酸塩
ＩＲ：３３６４．２９］６，２５７６．１６５６・ ６
−メドキシー２−Ｃ２−〔４−ＣＮ−メチル−Ｎ−（２
，３，４−）リメトキシフエネチル〕アミノ〕ブトキシ
〕−５−ニトロフェニルヨー３−プロピオニルベンゾチ
アゾリン 塩酸塩ＩＲ：３３６０，２９２０．１６６０
・ ２−Ｃ２−Ｃ４−Ｃ４−＜ ４−ヒドロキシフェニ
ルメチル＞−１−ピペラジニル〕フトキシ〕−５−二ト
ロフェニル〕−６−メドキシー３−プロピオニルベンゾ
チアゾリン 塩酸塩ＩＲ：３４３０．２６００，１６６
４．１５８０・ ２−Ｃ４−Ｃ５−Ｃ（４−クロロベン
ジルカルボニル）ピペリジノ〕ペンチルオキシ〕フエ二
ｐｙ ］ −２−ホルミル−５−フルオロベンツチアゾ
リン マレイン酸塩
ＩＲ：３４００，１７０６．１６７２
・ ３−アセチル−２−〔４−Ｃ３−ｒＮ−シクロプロ
ピル−Ｎ−（４−メトキシフェネチル）アミノ〕プロポ
キシ〕−３−メトキシフェニル〕−６−ドリフルオロメ
チルベンゾチアゾリン塩醒塩
ＩＲ：３３Ｂ５，２６２０．］ ６６０・ ３−アセチ
ル−２−〔３−クロロ−２−〔４−Ｃ４−（４−シアノ
ベンジル）−１−ホモピペラジニル〕ブトキシ〕フェニ
ル〕−４−シアノベンゾチアゾリン マレイン酸塩
ＩＲ：３４２０，１７０５．１６５０
「発明の効果」
本発明化合物は優れたカルシウム拮抗作用、血小板凝集
阻害作用等を有し、高血圧、血栓症、狭心症、不整脈等
の循環器系疾患の治療剤として有用である。・3-acetyl-6-chloro-2-C2-C4-4N
-((3,4-dimethoxyphenethyl) -N-methyl]amino]butoxy]-5-methoxyphenyl]benzothiazoline hydrochloride IR:3364.29]6,2576.1656.6
-Medoxy2-C2-[4-CN-methyl-N-(2
,3,4-)rimethoxyphenethyl]amino]butoxy]-5-nitrophenyl-3-propionylbenzothiazoline hydrochloride IR:3360,2920.1660 ・2-C2-C4-C4-< 4-hydroxyphenyl Methyl>-1-piperazinyl]phthoxy]-5-nitrophenyl]-6-medoxy 3-propionylbenzothiazoline hydrochloride IR: 3430.2600,166
4.1580・2-C4-C5-C(4-chlorobenzylcarbonyl)piperidino[pentyloxy]phenipy]-2-formyl-5-fluorobenzthiazoline maleate IR:3400,1706.1672・3- Acetyl-2-[4-C3-rN-cyclopropyl-N-(4-methoxyphenethyl)amino]propoxy]-3-methoxyphenyl]-6-drifluoromethylbenzothiazoline salt IR: 33B5,2620. ] 660. 3-acetyl-2-[3-chloro-2-[4-C4-(4-cyanobenzyl)-1-homopiperazinyl]butoxy]phenyl]-4-cyanobenzothiazoline maleate IR: 3420,1705 .1650 "Effects of the Invention" The compounds of the present invention have excellent calcium antagonistic effects, platelet aggregation inhibitory effects, etc., and are useful as therapeutic agents for cardiovascular diseases such as hypertension, thrombosis, angina pectoris, and arrhythmia.
Claims (1)
ヒドロキシ基、ハロゲン原子、シアノ基、ニトロ基、ハ
ロゲノ低級アルキル基および低級アルカノイルオキシ基
から選択される１個又は複数の基を示す。 Ｒ＾２は低級アルカノイル基、低級アルキルカルバモイ
ル基、フェニルカルバモイル基又はメタンスルホニル基
を示す。 Ｒ＾３は水素原子、ヒドロキシ基、低級アルキル基、低
級アルコキシ基、ニトロ基、ハロゲン原子および低級ア
ルカノイルオキシ基から選択される１個又は複数の基を
示す。 Ｒ＾４は水素原子、▲数式、化学式、表等があります▼
又は▲数式、化学式、表等があります▼を示 す。 Ｒ＾５は▲数式、化学式、表等があります▼又は−ＣＨ
＿２Ｘを示す。 Ｒ＾６、Ｒ＾７は同一か又は異なって水素原子、低級ア
ルキル基、（Ｃ＿３〜Ｃ＿６）シクロアルキル基、フェ
ニル基、ピリジル基または置換低級アルキル基を示し、
置換低級アルキル基の置換基はヒドロキシ基、フェニル
基、ピリジル基およびフェニルカルボニル基から選択さ
れる１個又は複数の基を示し、上記フェニル基およびフ
ェニルカルボニル基のフェニル環ならびにピリジル基は
低級アルキル基、ヒドロキシ基、ハロゲン原子、低級ア
ルコキシ基、ニトロ基、シアノ基、低級アルキレンジオ
キシ基および低級アルカノイルオキシ基から選択される
１個又は複数の基で置換されていてもよい。又、Ｒ＾６
とＲ＾７は夫々一緒になつて▲数式、化学式、表等があ
ります▼、▲数式、化学式、表等があります▼又は▲数
式、化学式、表等があります▼を示してもよい。 Ｒ＾８は水素原子、低級アルキル基、低級アルカノイル
基、低級アルコキシカルボニル基、カルボキシ基、フェ
ニル基、フェニルカルボニル基、置換低級アルキル基又
は置換低級アルカノイル基を示し、置換低級アルキル基
の置換基はヒドロキシ基、低級アルコキシ基、フェニル
基、フェニルカルボニル基、カルボキシ基および低級ア
ルコキシカルボニル基から選択される１個又は複数の基
を示し、上記フェニル基およびフェニルカルボニル基の
フェニル環は低級アルキル基、ヒドロキシ基、低級アル
コキシ基、ハロゲン原子、ニトロ基、シアノ基、低級ア
ルキレンジオキシ基および低級アルカノイルオキシ基か
ら選択される１個又は複数の基で置換されていてもよい
。 Ｘはハロゲン原子を示す。 Ａは１〜５個の炭素原子を有する低級アルキレン基を示
す。 ｌは２又は３を示す。 ｍは０又は１を示す。 ｎは０又は１を示す。 ｐは４又は５を示す。 但し、Ｒ＾４が水素原子の場合、ｍは０を示す。〕[Claims] A compound represented by the general formula [I] and salts thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R^1 is a lower alkyl group, a lower alkoxy group,
It represents one or more groups selected from a hydroxy group, a halogen atom, a cyano group, a nitro group, a halogeno lower alkyl group, and a lower alkanoyloxy group. R^2 represents a lower alkanoyl group, a lower alkylcarbamoyl group, a phenylcarbamoyl group or a methanesulfonyl group. R^3 represents one or more groups selected from a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a nitro group, a halogen atom, and a lower alkanoyloxy group. R^4 is a hydrogen atom, ▲There are mathematical formulas, chemical formulas, tables, etc.▼
Or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. R^5 has ▲mathematical formula, chemical formula, table, etc.▼or -CH
_2X is shown. R^6 and R^7 are the same or different and represent a hydrogen atom, a lower alkyl group, a (C_3 to C_6) cycloalkyl group, a phenyl group, a pyridyl group, or a substituted lower alkyl group,
The substituent of the substituted lower alkyl group represents one or more groups selected from a hydroxy group, a phenyl group, a pyridyl group, and a phenylcarbonyl group, and the phenyl ring and pyridyl group of the above phenyl group and phenylcarbonyl group are lower alkyl groups. , a hydroxy group, a halogen atom, a lower alkoxy group, a nitro group, a cyano group, a lower alkylenedioxy group, and a lower alkanoyloxy group. Also, R^6
and R^7 can be taken together to indicate ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. R^8 represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a carboxy group, a phenyl group, a phenylcarbonyl group, a substituted lower alkyl group, or a substituted lower alkanoyl group, and the substituents of the substituted lower alkyl group are It represents one or more groups selected from a hydroxy group, a lower alkoxy group, a phenyl group, a phenylcarbonyl group, a carboxy group, and a lower alkoxycarbonyl group, and the phenyl ring of the above phenyl group and phenylcarbonyl group is a lower alkyl group, a hydroxy group. , a lower alkoxy group, a halogen atom, a nitro group, a cyano group, a lower alkylenedioxy group, and a lower alkanoyloxy group. X represents a halogen atom. A represents a lower alkylene group having 1 to 5 carbon atoms. l represents 2 or 3. m represents 0 or 1. n represents 0 or 1. p represents 4 or 5. However, when R^4 is a hydrogen atom, m represents 0. ]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61063189A JPS62221679A (en) | 1986-03-19 | 1986-03-19 | Benzothazoline derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61063189A JPS62221679A (en) | 1986-03-19 | 1986-03-19 | Benzothazoline derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62221679A true JPS62221679A (en) | 1987-09-29 |
Family
ID=13222031
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61063189A Pending JPS62221679A (en) | 1986-03-19 | 1986-03-19 | Benzothazoline derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62221679A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003082840A1 (en) | 2002-03-29 | 2003-10-09 | Santen Pharmaceutical Co., Ltd. | κ-OPIOID RECEPTOR AGONIST COMPRISING 2-PHENYLBENZOTHIAZOLINE DERIVATIVE |
| WO2004016600A1 (en) * | 2002-08-14 | 2004-02-26 | Astrazeneca Ab | Novel use of benzothiazole derivatives |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5846079A (en) * | 1981-09-12 | 1983-03-17 | Santen Pharmaceut Co Ltd | Ether having benzothiazoline ring |
| JPS5967276A (en) * | 1982-09-01 | 1984-04-16 | Santen Pharmaceut Co Ltd | Benzothiazoline derivative |
| JPS60139679A (en) * | 1983-12-27 | 1985-07-24 | Santen Pharmaceut Co Ltd | 2-arylbenzothiazoline derivative |
-
1986
- 1986-03-19 JP JP61063189A patent/JPS62221679A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5846079A (en) * | 1981-09-12 | 1983-03-17 | Santen Pharmaceut Co Ltd | Ether having benzothiazoline ring |
| JPS5967276A (en) * | 1982-09-01 | 1984-04-16 | Santen Pharmaceut Co Ltd | Benzothiazoline derivative |
| JPS60139679A (en) * | 1983-12-27 | 1985-07-24 | Santen Pharmaceut Co Ltd | 2-arylbenzothiazoline derivative |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003082840A1 (en) | 2002-03-29 | 2003-10-09 | Santen Pharmaceutical Co., Ltd. | κ-OPIOID RECEPTOR AGONIST COMPRISING 2-PHENYLBENZOTHIAZOLINE DERIVATIVE |
| US7112598B2 (en) | 2002-03-29 | 2006-09-26 | Santen Pharmaceutical Co., Ltd. | κ opioid receptor agonist comprising 2-phenylbenzothiazoline derivative |
| US7410987B2 (en) | 2002-03-29 | 2008-08-12 | Santen Pharmaceutical Co., Ltd. | Method for treating pain or pruritis by administering κ-opioid receptor agonist comprising 2-phenylbenzothiazoline derivative |
| EP2042173A2 (en) | 2002-03-29 | 2009-04-01 | Santen Pharmaceutical Co., Ltd. | Kappa-opioid receptor agonist comprising 2-phenylbenzothiazoline derivative |
| JP2009143940A (en) * | 2002-03-29 | 2009-07-02 | Santen Pharmaceut Co Ltd | Kappa-opioid receptor agonist comprising 2-phenylbenzothiazoline derivative or its salt |
| WO2004016600A1 (en) * | 2002-08-14 | 2004-02-26 | Astrazeneca Ab | Novel use of benzothiazole derivatives |
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