JPH0560463B2 - - Google Patents
Info
- Publication number
- JPH0560463B2 JPH0560463B2 JP11288385A JP11288385A JPH0560463B2 JP H0560463 B2 JPH0560463 B2 JP H0560463B2 JP 11288385 A JP11288385 A JP 11288385A JP 11288385 A JP11288385 A JP 11288385A JP H0560463 B2 JPH0560463 B2 JP H0560463B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- present
- group
- isoindolinone
- 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 - Lifetime
Links
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical class C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000203 mixture Substances 0.000 description 5
- -1 nicotinoyl group Chemical group 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 230000002785 anti-thrombosis Effects 0.000 description 4
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 230000001754 anti-pyretic effect Effects 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229960004909 aminosalicylic acid Drugs 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229940054441 o-phthalaldehyde Drugs 0.000 description 2
- JKNKNWJNCOJPLI-UHFFFAOYSA-N o-phthalaldehydic acid Chemical compound C1=CC=C2C(O)OC(=O)C2=C1 JKNKNWJNCOJPLI-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229940058287 salicylic acid derivative anticestodals Drugs 0.000 description 2
- 150000003872 salicylic acid derivatives Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WVAUWNBCPCZJSU-UHFFFAOYSA-N 2-(2,3-dihydro-1H-isoindol-1-yl)-2-methyl-3-oxo-3-phenylpropanoic acid Chemical class C1(NCC2=CC=CC=C12)C(C(=O)O)(C)C(=O)C1=CC=CC=C1 WVAUWNBCPCZJSU-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-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
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- RJMIEHBSYVWVIN-UHFFFAOYSA-N indoprofen Chemical class C1=CC(C(C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-UHFFFAOYSA-N 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical class C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Description
(イ) 産業上の利用分野
本発明は、新規なイソインドリノン誘導体に関
するものであり、特に抗炎症作用及び抗血栓作用
を有し、医薬品として有用なイソインドリノン誘
導体に関するものである。
(ロ) 従来の技術
従来、イソインドリノン誘導体としては、２−
〔４−（１−オキソ−２−イソインドリニル）フエ
ニル〕プロピオン酸誘導体（特公昭51−11627号
公報、特公昭54−29492号公報、特開昭53−50156
号公報等）又はイソインドリニルフエニルカルボ
ニルプロピオン酸誘導体（特開昭53−12852号公
報等）が知られている。
しかし、イソインドリノンを母核としたサリチ
ル酸誘導体に関する記載は全くなく、又それを示
唆刷するものもない。
(ハ) 発明が解決しようとする問題点
本発明はイソインドリノンを母核としたサリチ
ル酸誘導体を合成することを目的とするものであ
る。
又、本発明は抗炎症作用、抗血栓作用、鎮痛作
用、解熱作用等の優れた薬理作用を有するイソイ
ンドリノン誘導体の開発を目的とするものであ
る。
(ニ) 問題を解決するための手段
本発明は下記に示す一般式（）
（式中、R1は水素原子又は低級アルキル基を、
R2は水素原子、低級アルキル基又はアシル基を
意味する）で表わされる新規なイソインドリノン
誘導体に関するものである。
前記一般式（）において、R1は水素原子又
はメチル、エチル、ｎ−プロピル、イソプロピ
ル、ｎ−ブチル、イソブチル等の低級アルキル基
を、R2は水素原子又はメチル、エチル、ｎ−プ
ロピル、イソプロピル、ｎ−ブチル、イソブチ
ル、ｎ−ペンチル、イソペンチル、ｎ−ヘキシ
ル、イソヘキシル等の低級アルキル基、又はアセ
チル、ベンゾイル、置換ベンゾイル（例えば、ハ
ロゲン原子、低級アルキル基、低級アルコキシ
基、ニトロ基、トリフルオロメチル基等で１〜３
個置換したベンゾイル基）又はニコチノイル基等
のアシル基を意味する。
又、一般式（）中記載の−COOR1及び−
OR2の置換位置は特に限定されることなく任意に
置換されるものである。
次に本発明のイソインドリノン誘導体の製造法
について述べる。
製造法
（式中、R1は水素原子又は低級アルキル基を、
R2及びＲは前記と同じ意味を有する）
当該方法を更に詳しく説明すると、一般式
（）で示されるＯ−フタルアルデヒド酸又はエ
ステル体と一般式（）の芳香族アミン誘導体と
を有機溶媒（例えば、ベンゼン、トルエン、キシ
レン、ジオキサン、クロロホルム、塩化メチレ
ン、テトラヒドロフラン、ジメチルホルムアミ
ド、ジメチルスルホキシド、メタノール、エタノ
ール、プロパノール等）中、室温又は加熱下に反
応させると一般式（）で表わされるベンジリデ
ン誘導体が得られる。
次に、単離した一般式（）のベンジリデン誘
導体をアルコール中に懸濁させ氷冷する。その中
に還元剤である水素化ホウ素ナトリウム又は水素
化ホウ素カリウムを一般式（）に対して１〜３
倍モル添加する。添加終了後、室温状態に戻し、
0.5〜10時間余り反応させることにより、一般式
（）で示される目的化合物を収率よく得ること
ができる。
又、一般式（）のＯ−フタルアルデヒド酸又
はエステル体と一般式（）の芳香族アミン誘導
体とをアルコール溶媒（例えば、メタノール、エ
タノール、プロパノール等）中、室温又は加熱下
に反応させると一般式（）で表わされるベンジ
リデン誘導体がすみやかに生成される。次にベン
ジリデン誘導体を単離精製することなく、前記の
反応混合溶液を氷浴上で冷却しながら、還元剤で
ある水素化ホウ素ナトリウム又は水素化ホウ素カ
リウムを１〜３倍モル添加する。添加終了後、室
温状態に戻し0.5〜10時間余り反応させることに
より、一般式（）で示される目的化合物を経済
的な方法で収率よく得ることができる。
又、これらの製造法は一例にすぎず、他の公知
の方法によつても製造し得るものである。
尚、本発明の化合物の中で−COOH基又は−
OH基を有する化合物は必要に応じ無機塩又は有
機塩となすことができる。つまり、これらが薬理
学的に許容される塩を包含するものであり、かか
る塩としては、ナトリウム、カリウム等の金属
塩、カルシウム等のアルカリ土類金属塩、アルミ
ニウム塩等の無機塩基との塩、又はアンモニウム
塩、トリメチルアミン、トリエチルアミン、アル
ギニン、リジン等の有機塩基等が挙げられる。
又、本発明の化合物は種々の医薬用不活性担体
と処方することにより、錠剤、カプセル、軟膏、
クリーム、ゲル、ローシヨン、坐薬、噴霧剤、シ
ロツプ、注射剤等の各種医薬製剤形態となすこと
ができる。
(ホ) 作用
本発明のイソインドリン誘導体はラツト又はマ
ウスを用いた動物実験において、抗炎症作用並び
に抗血栓作用を有することを示し、更に鎮痛作
用、解熱作用等を有することも示した。
(ヘ) 実施例
以下に実施例を示し、本発明を更に具体的に説
明するが、勿論、本発明はこれらの実施例にのみ
限定されるものではない。
実施例 １
Ｏ−フタルアルデヒド酸1.5ｇと４−アミノサ
リチル酸1.5ｇをメタノール30ml中に加え、室温
状態で30分間余り攪拌すると結晶が析出する。こ
の反応溶液を氷浴上で冷却攪拌しながら還元剤で
ある水素化ホウ素ナトリウム0.5ｇを徐々に添加
する。添加終了後、室温状態に戻し３時間余り攪
拌後、析出の結晶を濾取、乾燥後、ジメチルホル
ムアミドより再結晶すると、無色プリズム晶の下
記の構造を有するＮ−４−（イソインドリール−
２−オン）−サリチル酸2.4ｇを得た。
構造式
融点278〜280℃（分解）
赤外線吸収スペクトル νc＝ｏ 1680cm-1
マススペクトル M+269
実施例 ２
Ｏ−フタルアルデヒド酸1.5ｇと４−アミノサ
リチル酸1.5ｇをメタノール30ml中に加え、室温
状態で30分間余り攪拌すると白色結晶のベンジリ
デン化合物を生成する。次に、得られたベンジリ
デン化合物2.7ｇをエタノール30mlに懸濁し、氷
浴で冷却攪拌下水素化ホウ素カリウム0.6ｇを
徐々に添加する。添加終了後、室温状態に戻し５
時間余り攪拌後、析出の結晶を濾取、乾燥後、ジ
メチルホルムアミドより再結晶すると無色プリズ
ム晶の実施例１に示される化合物2.4ｇを得た。
融点 278〜280℃（分解）
赤外線吸収スペクトル νc＝ｏ 1680cm1
マススペクトル M+269
実施例 ３〜６
実施例１〜２の方法により次表の化合物を合成
した。
(a) Industrial Application Field The present invention relates to a novel isoindolinone derivative, and particularly to an isoindolinone derivative that has anti-inflammatory and antithrombotic effects and is useful as a pharmaceutical. (b) Conventional technology Conventionally, as isoindolinone derivatives, 2-
[4-(1-oxo-2-isoindolinyl)phenyl]propionic acid derivatives (Japanese Patent Publication No. 11627/1983, Japanese Patent Publication No. 29492/1983, 50156/1983)
JP-A-53-12852, etc.) and isoindolinyl phenylcarbonylpropionic acid derivatives (JP-A-53-12852, etc.) are known. However, there is no description of salicylic acid derivatives having isoindolinone as the core, nor is there anything that suggests this. (c) Problems to be Solved by the Invention The purpose of the present invention is to synthesize salicylic acid derivatives using isoindolinone as a core. Another object of the present invention is to develop isoindolinone derivatives having excellent pharmacological effects such as anti-inflammatory, antithrombotic, analgesic, and antipyretic effects. (d) Means for solving the problem The present invention is based on the general formula () shown below. (In the formula, R 1 is a hydrogen atom or a lower alkyl group,
The present invention relates to a novel isoindolinone derivative represented by R 2 (representing a hydrogen atom, a lower alkyl group, or an acyl group). In the general formula (), R 1 is a hydrogen atom or a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc., and R 2 is a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl group. , n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, lower alkyl groups such as isohexyl, or acetyl, benzoyl, substituted benzoyl (e.g., halogen atom, lower alkyl group, lower alkoxy group, nitro group, trifluoro 1 to 3 with methyl group, etc.
It means an acyl group such as a substituted benzoyl group) or a nicotinoyl group. In addition, -COOR 1 and - described in general formula ()
The substitution position of OR 2 is not particularly limited and may be substituted arbitrarily. Next, the method for producing the isoindolinone derivative of the present invention will be described. Manufacturing method (In the formula, R 1 is a hydrogen atom or a lower alkyl group,
R 2 and R have the same meanings as above) To explain the method in more detail, the O-phthalaldehyde acid or ester represented by the general formula () and the aromatic amine derivative of the general formula () are mixed in an organic solvent ( For example, when reacted at room temperature or under heating in benzene, toluene, xylene, dioxane, chloroform, methylene chloride, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, propanol, etc., the benzylidene derivative represented by the general formula () is produced. can get. Next, the isolated benzylidene derivative of general formula () is suspended in alcohol and cooled on ice. Therein, sodium borohydride or potassium borohydride, which is a reducing agent, is added to the general formula () by 1 to 3
Add twice the mole. After the addition is complete, return to room temperature,
By reacting for about 0.5 to 10 hours, the target compound represented by the general formula () can be obtained in good yield. In addition, when O-phthalaldehyde acid or ester of general formula () is reacted with aromatic amine derivative of general formula () in an alcohol solvent (e.g., methanol, ethanol, propanol, etc.) at room temperature or under heating, a general reaction can be obtained. A benzylidene derivative represented by the formula () is immediately produced. Next, without isolating and purifying the benzylidene derivative, while cooling the reaction mixture solution on an ice bath, 1 to 3 times the mole of sodium borohydride or potassium borohydride as a reducing agent is added. After the addition is complete, the mixture is returned to room temperature and allowed to react for about 0.5 to 10 hours, thereby making it possible to obtain the target compound represented by the general formula () in an economical manner and in good yield. In addition, these manufacturing methods are only examples, and it can also be manufactured by other known methods. In addition, in the compound of the present invention, -COOH group or -
The compound having an OH group can be made into an inorganic salt or an organic salt, if necessary. In other words, these include pharmacologically acceptable salts, such as metal salts such as sodium and potassium, alkaline earth metal salts such as calcium, and salts with inorganic bases such as aluminum salts. , or organic bases such as ammonium salts, trimethylamine, triethylamine, arginine, and lysine. The compounds of the present invention can also be formulated with various pharmaceutical inert carriers to form tablets, capsules, ointments,
It can be made into various pharmaceutical preparation forms such as creams, gels, lotions, suppositories, sprays, syrups, and injections. (e) Effect The isoindoline derivative of the present invention was shown to have anti-inflammatory and antithrombotic effects in animal experiments using rats and mice, and was also shown to have analgesic and antipyretic effects. (f) Examples The present invention will be explained in more detail by way of Examples below, but of course the present invention is not limited only to these Examples. Example 1 1.5 g of O-phthalaldehydic acid and 1.5 g of 4-aminosalicylic acid were added to 30 ml of methanol, and the mixture was stirred at room temperature for about 30 minutes to precipitate crystals. While cooling the reaction solution on an ice bath and stirring, 0.5 g of sodium borohydride, which is a reducing agent, is gradually added. After the addition was completed, the temperature was returned to room temperature and the mixture was stirred for about 3 hours. The precipitated crystals were collected by filtration, dried, and recrystallized from dimethylformamide to produce N-4-(isoindolyl-
2.4 g of 2-one)-salicylic acid were obtained. Structural formula Melting point 278-280℃ (decomposed) Infrared absorption spectrum νc=o 1680cm -1 Mass spectrum M + 269 Example 2 1.5g of O-phthalaldehydic acid and 1.5g of 4-aminosalicylic acid were added to 30ml of methanol, and the mixture was heated to 30% at room temperature. If the mixture is stirred for more than a minute, a white crystalline benzylidene compound is produced. Next, 2.7 g of the obtained benzylidene compound is suspended in 30 ml of ethanol, and 0.6 g of potassium borohydride is gradually added while stirring and cooling in an ice bath. After the addition is complete, return to room temperature 5
After stirring for more than an hour, the precipitated crystals were collected by filtration, dried, and recrystallized from dimethylformamide to obtain 2.4 g of the compound shown in Example 1 as colorless prism crystals. Melting point 278-280°C (decomposed) Infrared absorption spectrum νc=o 1680cm 1 mass spectrum M + 269 Examples 3-6 The compounds shown in the following table were synthesized by the methods of Examples 1-2.
【表】【table】
【表】
(ト) 発明の効果
本発明は文献未載の新規イソインドリノン誘導
体を提供するものである。
又、本発明の化合物は顕著な抗炎症作用、抗血
栓作用、鎮痛作用又は解熱作用等の薬理効果を有
し、医薬品として産業上有用である。[Table] (g) Effects of the invention The present invention provides novel isoindolinone derivatives that have not been described in any literature. Furthermore, the compounds of the present invention have significant pharmacological effects such as anti-inflammatory action, antithrombotic action, analgesic action, and antipyretic action, and are industrially useful as pharmaceuticals.
Claims (1)
R2は水素原子、低級アルキル基又はアシル基を
意味する）で表わされるイソインドリノン誘導
体。[Claims] 1. General formula (In the formula, R 1 is a hydrogen atom or a lower alkyl group,
R2 means a hydrogen atom, a lower alkyl group, or an acyl group).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11288385A JPS61271273A (en) | 1985-05-24 | 1985-05-24 | Isoindolinone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11288385A JPS61271273A (en) | 1985-05-24 | 1985-05-24 | Isoindolinone derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61271273A JPS61271273A (en) | 1986-12-01 |
| JPH0560463B2 true JPH0560463B2 (en) | 1993-09-02 |
Family
ID=14597907
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11288385A Granted JPS61271273A (en) | 1985-05-24 | 1985-05-24 | Isoindolinone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61271273A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1308108C (en) * | 1987-10-27 | 1992-09-29 | Dominick A. Quagliato | Antihypertensive benzopyran derivatives |
-
1985
- 1985-05-24 JP JP11288385A patent/JPS61271273A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61271273A (en) | 1986-12-01 |
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