JPH0641123A - Amonocoumaran derivative - Google Patents
Amonocoumaran derivativeInfo
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- JPH0641123A JPH0641123A JP32952692A JP32952692A JPH0641123A JP H0641123 A JPH0641123 A JP H0641123A JP 32952692 A JP32952692 A JP 32952692A JP 32952692 A JP32952692 A JP 32952692A JP H0641123 A JPH0641123 A JP H0641123A
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- amino
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Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、新規アミノクマラン誘
導体またはその塩およびこれを有効成分とする医薬組成
物に関する。さらに詳しくは、動脈硬化、肝疾患、脳血
管障害等の種々の疾患の予防・治療剤として有用な新規
過酸化脂質生成抑制作用を有する新規アミノクマラン誘
導体またはその塩およびそれを有効成分とする過酸化脂
質生成抑制剤に関する。TECHNICAL FIELD The present invention relates to a novel aminocoumarane derivative or a salt thereof and a pharmaceutical composition containing the same as an active ingredient. More specifically, a novel aminocoumaran derivative or its salt having a novel lipid peroxide production-inhibitory effect useful as a prophylactic / therapeutic agent for various diseases such as arteriosclerosis, liver disease, cerebrovascular disorder, and peroxidation containing the same as an active ingredient The present invention relates to a lipogenesis inhibitor.
【０００２】[0002]
【従来の技術および発明が解決しようとする課題】体内
での過酸化脂質の生成およびそれに付随したラジカル反
応が、膜障害や酵素障害等を介して生体に種々の悪影響
を及ぼすことが明らかになるにつれて、抗酸化・過酸化
脂質生成抑制剤の医薬への応用が種々試みられる様にな
ってきた。現在、医薬分野で用いられる過酸化脂質生成
抑制剤は、主として、ビタミンＣやビタミンＥ等の天然
抗酸化剤の誘導体およびフェノール誘導体である（福沢
健治著、日本臨床４６巻、２２６９〜２２７６頁（１９
８８））が、作用が弱かったり、副作用があったり、実
用的に必ずしも満足できるものではない。また、アミノ
クマラン誘導体としては従来、特開昭６０−１３２９７
７号（用途：冠状脈管系の疾患の予防・治療剤として有
用な２，２′−イミノビスエタノール誘導体の中間
体）、特開昭６０−１６９４７３号（用途：鎮吐剤、抗
精神病剤）、特開昭６２−２３４０８３号（用途：鎮吐
剤、抗精神病剤）、特開昭６４−３８０９０号（用途：
糖尿病およびその合併症ならびに高脂血症の治療薬）、
特表平１−５０１２２６号（用途：鎮吐剤）および米国
特許第４，７７２，７３０号（用途：ピラゾリン殺虫
剤）が知られている。本発明者らは、アミノクマランの
ベンゼン環に特定の置換基を４つ（アミノ基を含む）有
し、かつアミノクマランの２位に置換基を有していても
よい脂肪族基を２つ有し、そのうち少なくとも１つはα
位がメチレン基であるアミノクマラン誘導体の合成に成
功し、それらが過酸化脂質生成抑制作用として有用であ
ることを見出した（ＥＰ−Ａ−０４８３７７２）。しか
し、アミノクマランの２位に置換フェニルピペリジノメ
チルを有するアミノクマラン誘導体は従来全く合成され
ていなかった。本発明の主たる目的は、優れた過酸化脂
質生成抑制作用を有する新規化合物およびそれを有効成
分とする過酸化脂質生成抑制剤を提供することにある。2. Description of the Related Art It has been clarified that the production of lipid peroxide and its associated radical reaction in the body have various adverse effects on the living body through membrane disorders and enzyme disorders. Along with this, various attempts have been made to apply antioxidant / lipid peroxide production inhibitors to pharmaceuticals. Currently, lipid peroxide production inhibitors used in the pharmaceutical field are mainly derivatives of natural antioxidants such as vitamin C and vitamin E and phenol derivatives (Kenji Fukuzawa, Japan Clinical Vol. 46, 2269-2276 ( 19
88)) has a weak action or has side effects and is not always practically satisfactory. Further, as an aminocoumarane derivative, conventionally, JP-A-60-13297 has been used.
No. 7 (use: intermediate of 2,2'-iminobisethanol derivative useful as a prophylactic / therapeutic agent for coronary vascular disease), JP-A-60-169473 (use: antiemetic, antipsychotic) JP-A-62-234083 (use: antiemetic agent, antipsychotic agent), JP-A-64-38090 (use:
Drugs for diabetes and its complications and hyperlipidemia),
JP-A-1-501226 (use: antiemetic) and U.S. Pat. No. 4,772,730 (use: pyrazoline insecticide) are known. The present inventors have four specific substituents (including an amino group) on the benzene ring of aminocoumarane, and two aliphatic groups which may have a substituent at the 2-position of aminocoumarane. , At least one of them is α
We have succeeded in synthesizing aminocoumaran derivatives in which the position is a methylene group, and have found that they are useful as a lipid peroxide production inhibitory action (EP-A-0483772). However, no aminocoumarane derivative having a substituted phenylpiperidinomethyl at the 2-position of aminocoumarane has been synthesized so far. It is a main object of the present invention to provide a novel compound having an excellent lipid peroxide production inhibitory action and a lipid peroxide production inhibitor containing the compound as an active ingredient.
【０００３】[0003]
【課題を解決するための手段】本発明者らは前記課題を
解決するために、数多くの新規化合物を合成し、それぞ
れについて抗酸化活性・過酸化脂質生成抑制作用を調べ
た。その結果、一般式〔I〕[Means for Solving the Problems] In order to solve the above problems, the present inventors synthesized a large number of novel compounds, and investigated the antioxidant activity and lipid peroxide production inhibitory effect of each of them. As a result, the general formula [I]
【化３】 とも１つで置換されたベンゼン環を示す。〕で表わされ
る新規構造のアミノクマラン誘導体あるいはその塩の創
製に成功するとともに、これらの新規化合物が強力な過
酸化脂質生成抑制作用等医薬として有用な作用を有する
ことを見出し、さらに検討を重ねて本発明を完成した。
すなわち、本発明は前記一般式〔I〕で表わされる新規
アミノクマラン誘導体、その塩およびそれを有効成分と
する医薬組成物を提供するものである。[Chemical 3] Both represent a benzene ring substituted with one. ], And succeeded in creating an aminocoumarane derivative having a novel structure represented by or a salt thereof, and found that these novel compounds have a useful action as a drug such as a strong inhibitory action on lipid peroxide production, and after further study, Completed the invention.
That is, the present invention provides a novel aminocoumaran derivative represented by the above general formula [I], a salt thereof and a pharmaceutical composition containing the same as an active ingredient.
【０００４】一般式〔I〕中、Ｒ1，Ｒ2，Ｒ3およびＲ4
で表わされる低級アルキル基およびIn the general formula [I], R 1 , R 2 , R 3 and R 4
A lower alkyl group represented by
【化４】 低級アルキル基としては、炭素数１〜６程度の直鎖状、
分枝状または環状アルキル基、例えば、メチル，エチ
ル，プロピル，ｉ−プロピル，ブチル，ｉ−ブチル，ｔ
−ブチル，ペンチル，ヘキシル，シクロプロピル，シク
ロブチル，シクロペンチル等が用いられるが、炭素数１
〜３のアルキル基が好ましい。 Ｒ1，Ｒ2，Ｒ3およびＲ4
はそれぞれメチル基が特に好ましい。[Chemical 4] The lower alkyl group is a straight chain having about 1 to 6 carbon atoms,
Branched or cyclic alkyl groups such as methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t
-Butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, etc. are used, but the number of carbon atoms is 1
Alkyl groups of 3 are preferred. R 1 , R 2 , R 3 and R 4
Is particularly preferably a methyl group.
【化５】 低級アルコキシ基としては、炭素数１〜３の直鎖または
分枝状アルコキシ基、例えば、メトキシ，エトキシ，ｎ
−プロポキシ，ｉ−プロポキシ等が用いられる。[Chemical 5] As the lower alkoxy group, a linear or branched alkoxy group having 1 to 3 carbon atoms, for example, methoxy, ethoxy, n
-Propoxy, i-propoxy and the like are used.
【化６】 ハロゲン原子としては、塩素，臭素，弗素が用いられ
る。[Chemical 6] As the halogen atom, chlorine, bromine or fluorine is used.
【化７】 環が好ましい。尚、一般式〔I〕で表わされる化合物に
は光学異性体が存在するが、これら異性体単独のみなら
ず、それらの混合物も本発明に含まれる。[Chemical 7] Rings are preferred. Incidentally, the compound represented by the general formula [I] has optical isomers, but the present invention includes not only these isomers but also a mixture thereof.
【０００５】一般式〔I〕で表わされる化合物の塩とし
ては、好ましくは、医薬上許容される塩であり、医薬上
許容される塩の例としては、ハロゲン化水素酸（例、塩
酸、臭化水素酸）、リン酸、硫酸などの無機酸との塩や
有機カルボン酸（例、シュウ酸、フタル酸、フマル酸、
マレイン酸）、スルホン酸（例、メタンスルホン酸、ベ
ンゼンスルホン酸）などの有機酸との塩が用いられる。
以下、一般式〔I〕で表わされる化合物およびその塩を
化合物〔I〕と総称する。The salt of the compound represented by the general formula [I] is preferably a pharmaceutically acceptable salt, and examples of the pharmaceutically acceptable salt include hydrohalic acid (eg, hydrochloric acid, odor). Hydrofluoric acid), phosphoric acid, salts with inorganic acids such as sulfuric acid, and organic carboxylic acids (eg, oxalic acid, phthalic acid, fumaric acid,
Salts with organic acids such as maleic acid) and sulfonic acids (eg, methanesulfonic acid, benzenesulfonic acid) are used.
Hereinafter, the compound represented by the general formula [I] and salts thereof are collectively referred to as the compound [I].
【０００６】本発明の化合物〔I〕は、例えば、反応式
−１の方法により製造することができる。 反応式〔I〕The compound [I] of the present invention can be produced, for example, by the method of reaction formula-1. Reaction formula [I]
【化８】 化合物〔II〕をハロゲン分子を用いて、さらに所望によ
り塩基の存在下で閉環した時には、化合物〔III〕にお
いて、Ｘがハロゲンの化合物が、また化合物〔II〕を過
酸を用いて、さらに所望により塩基の存在下で閉環させ
た場合には、Ｘが水酸基である化合物〔III〕が得られ
る。[Chemical 8] When the compound [II] is cyclized in the presence of a base using a halogen molecule, and optionally in the presence of a base, a compound in which X is a halogen in the compound [III] and a compound [II] using a peracid are further desired. When the ring is closed in the presence of a base, a compound [III] in which X is a hydroxyl group is obtained.
【０００７】ハロゲンによる閉環反応は、臭素などを用
い、ハロゲン化炭素（例、クロロホルム、塩化メチレン
など）または酢酸などの有機溶媒中、所望により酢酸ナ
トリウムあるいはトリエチルアミンなどの塩基の存在
下、−５℃〜１００℃で反応させることにより行う。過
酸による閉環反応はｍ−クロロ過安息香酸などの過酸を
用い、塩化メチレンなどの有機溶媒中、所望によりトリ
エチルアミンなどの塩基の存在下、−１０〜５０℃で行
う。かくして得られた化合物〔III〕は化合物〔IV〕と
反応させることにより、化合物〔I〕へ導くことができ
る。例えば、ハロゲンによって閉環した２−ハロメチル
−２，３−ジヒドロベンゾフラン誘導体を化合物〔IV〕
と反応させる場合、無溶媒あるいはジメチルホルムアミ
ドやトルエン，トリエチルアミンなどの有機溶媒中で必
要に応じて、水酸化ナトリウム等の塩基を用いて、２０
℃〜２００℃で反応させることにより行う。反応容器と
しては、必要によりオートクレーブを用いる。またＸが
水酸基である化合物〔III〕は水酸基の活性エステル体
（例えばメタンスルホネイト，トルエンスルホネイト）
や水酸基を自体公知の方法によりハロゲンに導いた後、
化合物〔IV〕と反応させることにより化合物〔I〕を得
ることができる。The ring-closing reaction with halogen uses bromine or the like, and at −5 ° C. in an organic solvent such as carbon halide (eg, chloroform, methylene chloride) or acetic acid, if desired, in the presence of a base such as sodium acetate or triethylamine. It is carried out by reacting at -100 ° C. The ring closure reaction with a peracid is carried out using a peracid such as m-chloroperbenzoic acid and the like in an organic solvent such as methylene chloride, optionally in the presence of a base such as triethylamine, at -10 to 50 ° C. The compound [III] thus obtained can be converted to the compound [I] by reacting with the compound [IV]. For example, a 2-halomethyl-2,3-dihydrobenzofuran derivative ring-closed with a halogen compound (IV)
In the case of reacting with a solvent such as dimethylformamide, toluene or triethylamine, a base such as sodium hydroxide may be used, if necessary, to
It is carried out by reacting at a temperature of 200 to 200 ° C. If necessary, an autoclave is used as the reaction vessel. The compound [III] in which X is a hydroxyl group is an active ester of a hydroxyl group (eg, methane sulfonate, toluene sulfonate).
After introducing a hydroxyl group to a halogen by a method known per se,
Compound [I] can be obtained by reacting with compound [IV].
【０００８】本発明の原料化合物〔II〕は、特表昭６２
−５０２３３３号公報記載の方法に、化合物〔IV〕は特
開昭６０−１４６８７２号公報記載の方法に従って合成
することができる。かくして得られる化合物〔I〕は、
通常の分離・精製手段（例、抽出、クロマトグラフィ
ー、再結晶など）により単離することができる。なお、
化合物〔I〕がジアステレオマーとして存在する場合
は、所望により、前記分離・精製手段によりそれぞれを
単離することができる。また、化合物〔I〕は、通常の
光学分割手段により、ｄ体、ｌ体に分離することができ
る。具体的には次のような方法によって光学分割でき
る。The starting material compound [II] of the present invention has
Compound [IV] can be synthesized according to the method described in JP-A No. 502333/1982 and according to the method described in JP-A No. 60-146872. The compound [I] thus obtained is
It can be isolated by usual separation / purification means (eg, extraction, chromatography, recrystallization, etc.). In addition,
When compound [I] exists as a diastereomer, each can be isolated by the above-mentioned separation / purification means, if desired. The compound [I] can be separated into a d-form and an l-form by a usual optical resolution means. Specifically, it can be optically divided by the following method.
【０００９】本発明の化合物〔I〕は、多価不飽和脂肪
酸（リノール酸、γ−リノレン酸、α−リノレン酸、ア
ラキドン酸、ジホモ−γ−リノレン酸、エイコサペンタ
エン酸）の代謝改善、特に、過酸化脂質生成反応を抑制
する作用（抗酸化作用）、５−リポキシゲナーゼ系代謝
産物〔例、ロイコトリエン類、５−ヒドロペルオキシエ
イコサテトラエン酸（ＨＰＥＴＥ）、５−ヒドロキシエ
イコサテトラエン酸（ＨＥＴＥ）、リポキシン類、ロイ
コトキシン類など〕の生成抑制作用、トロンボキサンＡ
2合成酵素の阻害作用、プロスタグランジンＩ2合成酵素
保持促進作用、ＬＴＤ4受容体拮抗作用、活性酸素種の
消去作用などの循環系改善作用や抗アレルギー作用を有
する。前記のこれらの作用のうち、とりわけ、本発明の
化合物〔I〕は、過酸化脂質生成反応抑制作用（抗酸化
作用）を顕著に示す傾向にある。また、化合物〔I〕の
毒性、副作用は低い。The compound [I] of the present invention improves the metabolism of polyunsaturated fatty acids (linoleic acid, γ-linolenic acid, α-linolenic acid, arachidonic acid, dihomo-γ-linolenic acid, eicosapentaenoic acid), especially , An action of suppressing lipid peroxide formation reaction (antioxidant action), 5-lipoxygenase metabolites [eg, leukotrienes, 5-hydroperoxyeicosatetraenoic acid (HPETE), 5-hydroxyeicosatetraenoic acid ( HETE), lipoxins, leukotoxins, etc.], and thromboxane A
It has a circulatory system improving action such as an inhibitory action of 2 synthase, a prostaglandin I 2 synthase retention promoting action, an LTD 4 receptor antagonizing action, a scavenging action of reactive oxygen species and an antiallergic action. Among the above-mentioned actions, the compound [I] of the present invention, in particular, tends to remarkably exhibit a lipid peroxide production reaction inhibitory action (antioxidant action). In addition, the toxicity and side effects of compound [I] are low.
【００１０】従って、本発明の化合物〔I〕は哺乳動物
（マウス、ラット、ウサギ、イヌ、サル、ヒトなど）に
おける血小板凝集による血栓症、心、肺、脳、腎におけ
る動脈血管平滑筋の収縮あるいは血管れん縮による虚血
性疾患（例えば、心筋梗塞、脳卒中）、神経変性疾患
（例、パーキンソン病、アルツハイマー病、ルー・ゲー
リッヒ氏病、筋ジストロフィ）、頭部外傷、脊髄外傷な
ど中枢損傷にともなう機能障害、記憶障害や情動障害
（酸欠、脳損傷、脳卒中、脳梗塞、脳血栓等により惹起
される神経細胞壊死などにともなう障害）、脳卒中、脳
梗塞後や脳外科手術、頭部外傷後に起こるけいれんおよ
びてんかん、腎炎、肺不全、気管支喘息、炎症、動脈硬
化、アテローム変性動脈硬化、肝炎、急性肺炎、肝硬
変、過敏症肝臓炎、免疫不全症、活性酸素種（スーパー
オキサイド、水酸化ラジカルなど）による酵素、生体組
織、細胞などの障害によって引き起こされる循環器系疾
患（心筋梗塞、脳卒中、脳浮腫、腎炎など）、組織繊維
化現象や発癌などの諸疾患に対して治療および予防効果
を有し、例えば、抗血栓剤、抗血管れん縮剤、抗喘息
剤、抗アレルギー剤、心、脳の循環器系改善剤、腎炎治
療剤、肝炎治療剤、組織繊維化阻止剤、活性酸素種消去
剤、アラキドン酸カスケード物質調節改善剤などの医薬
として有用である。化合物〔I〕は、そのままもしくは
自体公知の薬学的に許容される担体、賦形剤など（例、
乳糖、結晶セルロース、トウモロコシデンプン、ステア
リン酸マグネシウム、ポリエチレングリコール４００、
グリセリン）と混合した医薬組成物（例、錠剤、カプセ
ル剤、液剤、注射剤、坐剤）として経口的もしくは非経
口的に安全に投与することができる。投与量は投与対
象、投与ルート、症状などによっても異なるが、例え
ば、成人の循環器系疾患の患者に対して経口投与すると
きは、通常１回量として約０．１mg／kg〜２０mg／kg体
重程度、好ましくは０．２mg／kg〜１０mg／kg体重程度
を１日１〜３回程度投与するのが好都合である。Therefore, the compound [I] of the present invention is a thrombosis due to platelet aggregation in mammals (mouse, rat, rabbit, dog, monkey, human, etc.), and contraction of arterial vascular smooth muscle in heart, lung, brain and kidney. Or ischemic diseases due to vasospasm (eg myocardial infarction, stroke), neurodegenerative diseases (eg Parkinson's disease, Alzheimer's disease, Lu Gehrig's disease, muscular dystrophy), head injury, spinal cord injury, etc. Functional disorders, memory disorders and affective disorders (disorders associated with nerve cell necrosis caused by oxygen deficiency, brain injury, stroke, cerebral infarction, cerebral thrombosis, etc.), convulsion that occurs after stroke, cerebral infarction, brain surgery, head injury And epilepsy, nephritis, pulmonary failure, bronchial asthma, inflammation, arteriosclerosis, atherosclerotic arteriosclerosis, hepatitis, acute pneumonia, cirrhosis, hypersensitivity liver disease, immunodeficiency All diseases, cardiovascular diseases (myocardial infarction, stroke, cerebral edema, nephritis, etc.) caused by disorders of enzymes, living tissues, cells, etc. due to reactive oxygen species (superoxide, hydroxyl radical, etc.), tissue fibrosis phenomenon, Having a therapeutic and preventive effect against various diseases such as carcinogenesis, for example, antithrombotic agent, antivasoconstrictor, antiasthma agent, antiallergic agent, heart and brain circulatory system improving agent, nephritis therapeutic agent, It is useful as a medicine such as a hepatitis therapeutic agent, a tissue fibrosis inhibitor, an active oxygen species eliminator, and an arachidonic acid cascade substance regulation-improving agent. The compound [I] may be a pharmaceutically acceptable carrier, an excipient, etc. (eg, as it is known per se) (eg,
Lactose, crystalline cellulose, corn starch, magnesium stearate, polyethylene glycol 400,
It can be safely administered orally or parenterally as a pharmaceutical composition (eg, tablet, capsule, solution, injection, suppository) mixed with glycerin). Although the dose varies depending on the administration subject, administration route, symptoms, etc., for example, when it is orally administered to an adult patient with cardiovascular disease, a single dose is usually about 0.1 mg / kg to 20 mg / kg. It is convenient to administer about body weight, preferably about 0.2 mg / kg to 10 mg / kg body weight about 1 to 3 times a day.
【００１１】[0011]
実施例１ ５−アミノ−２−〔４−（３，４−ジメトキシフェニ
ル）ピペリジノ〕メチル−２，４，６，７−テトラメチ
ル−２，３−ジヒドロベンゾフラン ５−アミノ−２−ブロモメチル−２，４，６，７−テト
ラメチル−２，３−ジヒドロベンゾフラン（１．５０
ｇ、５．２７mmol）、４−（３，４−ジメトキシフェニ
ル）ピペリジン（１．４０ｇ、６．３２mmol）およびト
リエチルアミン（２．２０ml、１５．８mmol）の混合物
を、封管中アルゴン雰囲気下、１８０℃で１７時間撹拌
した。反応液を冷却した後、重曹水で中和し、これをク
ロロホルムで抽出した。抽出液を飽和食塩水で洗浄した
後、無水硫酸マグネシウム乾燥し、減圧下で濃縮した。
残渣をフラッシュカラムクロマトグラフィー（クロロホ
ルム−メタノール、９８：２）で精製した後、酢酸エチ
ル−ヘキサンから再結晶し、目的物１．７５ｇ（収率７
８．２％）を得た。融点１２９−１３１℃。 ＮＭＲ（ＣＤＣl3）δ：1.46(3H,s),1.65-1.82(4H,m),
2.08(6H,s),2.11(3H,s),2.14-2.43(3H,m),2.52(1H,d,J=
15.0Hz),2.60(1H,d,J=15.0Hz),2.83(1H,d,J=15.6Hz),2.
96-3.25(5H,m),3.85(3H,s),3.88(3H,s),6.73-6.82(3H,
m)。Example 1 5-amino-2- [4- (3,4-dimethoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran 5-amino-2-bromomethyl-2 , 4,6,7-Tetramethyl-2,3-dihydrobenzofuran (1.50
g, 5.27 mmol), 4- (3,4-dimethoxyphenyl) piperidine (1.40 g, 6.32 mmol) and triethylamine (2.20 ml, 15.8 mmol) in a sealed tube under argon atmosphere at 180. The mixture was stirred at C for 17 hours. After cooling the reaction solution, it was neutralized with aqueous sodium hydrogen carbonate and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by flash column chromatography (chloroform-methanol, 98: 2) and then recrystallized from ethyl acetate-hexane to give 1.75 g of the desired product (yield 7
8.2%) was obtained. Melting point 129-131 [deg.] C. NMR (CDCl 3 ) δ: 1.46 (3H, s), 1.65-1.82 (4H, m),
2.08 (6H, s), 2.11 (3H, s), 2.14-2.43 (3H, m), 2.52 (1H, d, J =
15.0Hz), 2.60 (1H, d, J = 15.0Hz), 2.83 (1H, d, J = 15.6Hz), 2.
96-3.25 (5H, m), 3.85 (3H, s), 3.88 (3H, s), 6.73-6.82 (3H,
m).
【００１２】実施例２ ５−アミノ−２−〔４−（２，４−ジメトキシフェニ
ル）ピペリジノ〕メチル−２，４，６，７−テトラメチ
ル−２，３−ジヒドロベンゾフラン 上記の方法に従って合成した。収率６８．４％。融点
１６３−１６５℃（酢酸エチル−イソプロピルエーテ
ル）。 ＮＭＲ（ＣＤＣl3）δ：1.45(3H,s),1.61-1.78(4H,m),
2.08(6H,s),2.11(3H,s),2.18-2.36(3H,m),2.52(1H,d,J=
14.0Hz),2.61(1H,d,J=14.0Hz),2.74-3.23(8H,m),3.79(6
H,s),6.40-6.48(2H,m),7.09(1H,d,J=9.2Hz)。Example 2 5-Amino-2- [4- (2,4-dimethoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran Synthesized according to the above method. . Yield 68.4%. Melting point
163-165 ° C (ethyl acetate-isopropyl ether). NMR (CDCl 3 ) δ: 1.45 (3H, s), 1.61-1.78 (4H, m),
2.08 (6H, s), 2.11 (3H, s), 2.18-2.36 (3H, m), 2.52 (1H, d, J =
14.0Hz), 2.61 (1H, d, J = 14.0Hz), 2.74-3.23 (8H, m), 3.79 (6
H, s), 6.40-6.48 (2H, m), 7.09 (1H, d, J = 9.2Hz).
【００１３】実施例３ ５−アミノ−２−〔４−（４−メトキシフェニル）ピペ
リジノ〕メチル−２，４，６，７−テトラメチル−２，
３−ジヒドロベンゾフラン 上記の方法に従って合成した。収率７６．８％。融点１
０８−１０９℃（ヘキサン）。 ＮＭＲ（ＣＤＣl3）δ：1.47(3H,s),1.67-1.83(4H,m),
2.09(6H,s),2.11(3H,s),2.20-2.48(3H,m),2.51-2.68(2
H,m),2.84(1H,d,J=15.6Hz),2.96-3.08(1H,m),3.15(1H,
d,J=15.6Hz),3.16(2H,broad s),3.28(1H,broad s),3.79
(3H,s),6.85(2H,d,J=8.8Hz),7.15(2H,d,J=8.8Hz)。Example 3 5-amino-2- [4- (4-methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,
3-Dihydrobenzofuran Synthesized according to the above method. Yield 76.8%. Melting point 1
08-109 ° C (hexane). NMR (CDCl 3 ) δ: 1.47 (3H, s), 1.67-1.83 (4H, m),
2.09 (6H, s), 2.11 (3H, s), 2.20-2.48 (3H, m), 2.51-2.68 (2
H, m), 2.84 (1H, d, J = 15.6Hz), 2.96-3.08 (1H, m), 3.15 (1H,
d, J = 15.6Hz), 3.16 (2H, broad s), 3.28 (1H, broad s), 3.79
(3H, s), 6.85 (2H, d, J = 8.8Hz), 7.15 (2H, d, J = 8.8Hz).
【００１４】実施例４ ５−アミノ−２−〔４−（３−メトキシフェニル）ピペ
リジノ〕メチル−２，４，６，７−テトラメチル−２，
３−ジヒドロベンゾフラン 上記の方法に従って合成した。収率７５．７％。 融点 ９４−９５℃（ヘキサン）。 ＮＭＲ（ＣＤＣl3）δ：1.47(3H,s),1.76(4H,broad s),
2.08(6H,s),2.11(3H,s),2.18-2.68(5H,m),2.84(1H,d,J=
15.4Hz),2.95-3.30(5H,m),3.80(3H,s),6.71-6.85(3H,
m),7.22(1H,t,J=8.2Hz)。Example 4 5-amino-2- [4- (3-methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,
3-Dihydrobenzofuran Synthesized according to the above method. Yield 75.7%. Melting point 94-95 [deg.] C (hexane). NMR (CDCl 3 ) δ: 1.47 (3H, s), 1.76 (4H, broad s),
2.08 (6H, s), 2.11 (3H, s), 2.18-2.68 (5H, m), 2.84 (1H, d, J =
15.4Hz), 2.95-3.30 (5H, m), 3.80 (3H, s), 6.71-6.85 (3H,
m), 7.22 (1H, t, J = 8.2Hz).
【００１５】実施例５ （Ｓ）−（＋）−５−アミノ−２−〔４−（４−メトキ
シフェニル）ピペリジノ〕メチル−２，４，６，７−テ
トラメチル−２，３−ジヒドロベンゾフラン・（Ｓ）−
（＋）−マンデル酸塩 （±）−５−アミノ−２−〔４−（４−メトキシフェニ
ル）ピペリジノ〕メチル−２，４，６，７−テトラメチ
ル−２，３−ジヒドロベンゾフラン１２．５７ｇのクロ
ロホルム２００ｍｌ溶液に、（Ｓ）−（＋）−マンデル
酸５ｇのメタノール１００ｍｌ溶液を加えて濃縮した。
残渣にエーテルを加え、生じた沈殿を濾過してエーテル
で洗浄した。得られた粗結晶１４ｇをメタノール−アセ
トニトリル−エーテルからの再結晶に４回供して、
（Ｓ）−（＋）−５−アミノ−２−〔４−（４−メトキ
シフェニル）ピペリジノ〕メチル−２，４，６，７−テ
トラメチル−２，３−ジヒドロベンゾフラン・（Ｓ）−
（＋）−マンデル酸塩３．５５ｇを得た。 融点 １６０−１６１℃ 〔α〕26 ＋５８．５゜（ｃ＝１．０９５，メタノー
ル） 元素分析値 Ｃ25Ｈ34Ｎ2Ｏ2・Ｃ8Ｈ8Ｏ3 として 計算値： Ｃ：７２．５０ Ｈ：７．７４ Ｎ：５．１２ 実験値： Ｃ：７２．３７ Ｈ：７．８５ Ｎ：５．２１Example 5 (S)-(+)-5-amino-2- [4- (4-methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran・ (S)-
(+)-Mandelate salt (±) -5-amino-2- [4- (4-methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran 12.57 g To 200 ml of chloroform in 100 ml of (S)-(+)-mandelic acid was added 100 ml of methanol for concentration.
Ether was added to the residue and the resulting precipitate was filtered and washed with ether. 14 g of the obtained crude crystals were subjected to recrystallization from methanol-acetonitrile-ether four times,
(S)-(+)-5-Amino-2- [4- (4-methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran. (S)-
3.55 g of (+)-mandelate salt was obtained. Melting point 160-161 ° C. [α] 26 + 58.5 ° (c = 1.095, methanol) Elemental analysis value Calculated as C 25 H 34 N 2 O 2 .C 8 H 8 O 3 C: 72.50 H : 7.74 N: 5.12 Experimental value: C: 72.37 H: 7.85 N: 5.21
【００１６】実施例６ （Ｒ）−（−）−５−アミノ−２−〔４−（４−メトキ
シフェニル）ピペリジノ〕メチル−２，４，６，７−テ
トラメチル−２，３−ジヒドロベンゾフラン・（Ｒ）−
（−）−マンデル酸塩 実施例５と同様にして、（±）−５−アミノ−２−〔４
−（４−メトキシフェニル）ピペリジノ〕メチル−２，
４，６，７−テトラメチル−２，３−ジヒドロベンゾフ
ラン１２．５７ｇより（Ｒ）−（−）−５−アミノ−２
−〔４−（４−メトキシフェニル）ピペリジノ〕メチル
−２，４，６，７−テトラメチル−２，３−ジヒドロベ
ンゾフラン・（Ｒ）−（−）−マンデル酸塩４．８０ｇ
を得た。 融点 １６０−１６１℃ 〔α〕26 −６０．６゜（ｃ＝１．０００，メタノー
ル） 元素分析値 Ｃ25Ｈ34Ｎ2Ｏ2・Ｃ8Ｈ8Ｏ3 として 計算値： Ｃ：７２．５０ Ｈ：７．７４ Ｎ：５．１２ 実験値： Ｃ：７２．４７ Ｈ：７．９２ Ｎ：５．１３Example 6 (R)-(-)-5-Amino-2- [4- (4-methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran・ (R)-
(−)-Mandelate salt In the same manner as in Example 5, (±) -5-amino-2- [4
-(4-Methoxyphenyl) piperidino] methyl-2,
From 12,57 g of 4,6,7-tetramethyl-2,3-dihydrobenzofuran, (R)-(-)-5-amino-2
-[4- (4-Methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran. (R)-(-)-mandelate 4.80 g
Got Melting point 160-161 ° C. [α] 26 -60.6 ° (c = 1.000, methanol) Elemental analysis value Calculated as C 25 H 34 N 2 O 2 C 8 H 8 O 3 C: 72.50 H: 7.74 N: 5.12 Experimental value: C: 72.47 H: 7.92 N: 5.13
【００１７】実施例７ （Ｓ）−（＋）−５−アミノ−２−〔４−（４−メトキ
シフェニル）ピペリジノ〕メチル−２，４，６，７−テ
トラメチル−２，３−ジヒドロベンゾフラン・２塩酸塩 （Ｓ）−（＋）−５−アミノ−２−〔４−（４−メトキ
シフェニル）ピペリジノ〕メチル−２，４，６，７−テ
トラメチル−２，３−ジヒドロベンゾフラン・（Ｓ）−
（＋）−マンデル酸塩３．５５ｇを酢酸エチル１００ｍ
ｌと０．５Ｎ水酸化ナトリウム水溶液１００ｍｌに分配
した。有機層を０．５Ｎ水酸化ナトリウム水溶液、飽和
炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、
無水炭酸ナトリウムで乾燥した。濃縮乾固して得られた
残渣２．５ｇをメタノール２５ｍｌに溶解し、４Ｎ塩酸
酢酸エチル溶液４ｍｌを加えた。濃縮乾固して得られた
残渣を、酢酸エチルから結晶化して粗結晶を得た。メタ
ノール−酢酸エチルから再結晶を行い、（Ｓ）−（＋）
−５−アミノ−２−〔４−（４−メトキシフェニル）ピ
ペリジノ〕メチル−２，４，６，７−テトラメチル−
２，３−ジヒドロベンゾフラン・２塩酸塩２．０５ｇを
得た。 融点 ２３１℃（分解） 〔α〕25 ＋３１．２゜（ｃ＝１．０９９，メタノー
ル） 元素分析値 Ｃ25Ｈ34Ｎ2Ｏ2・Ｈ2Ｃｌ2・０．５Ｈ2Ｏとして 計算値： Ｃ：６３．０２ Ｈ：７．８３ Ｎ：５．８８ Ｃｌ：１４．８８ 実験値： Ｃ：６３．１２ Ｈ：７．８０ Ｎ：５．９０ Ｃｌ：１４．８４Example 7 (S)-(+)-5-Amino-2- [4- (4-methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran Dihydrochloride (S)-(+)-5-amino-2- [4- (4-methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran. ( S)-
3.55 g of (+)-mandelate salt was added to 100 m of ethyl acetate.
1 and 0.5N aqueous sodium hydroxide solution (100 ml). The organic layer was washed successively with 0.5N aqueous sodium hydroxide solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine,
It was dried over anhydrous sodium carbonate. 2.5 g of the residue obtained by concentration to dryness was dissolved in 25 ml of methanol, and 4 ml of a 4N hydrochloric acid ethyl acetate solution was added. The residue obtained by concentration to dryness was crystallized from ethyl acetate to give crude crystals. Recrystallization from methanol-ethyl acetate gives (S)-(+)
-5-Amino-2- [4- (4-methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-
2.05 g of 2,3-dihydrobenzofuran dihydrochloride was obtained. Melting point 231 ° C. (decomposition) [α] 25 + 31.2 ° (c = 1.099, methanol) Elemental analysis value C 25 H 34 N 2 O 2 · H 2 Cl 2 · 0.5H 2 O Calculated value: C : 63.02 H: 7.83 N: 5.88 Cl: 14.88 Experimental value: C: 63.12 H: 7.80 N: 5.90 Cl: 14.84
【００１８】実施例８ （Ｒ）−（−）−５−アミノ−２−〔４−（４−メトキ
シフェニル）ピペリジノ〕メチル−２，４，６，７−テ
トラメチル−２，３−ジヒドロベンゾフラン・２塩酸塩 実施例７と同様にして、（Ｒ）−（−）−５−アミノ−
２−〔４−（４−メトキシフェニル）ピペリジノ〕メチ
ル−２，４，６，７−テトラメチル−２，３−ジヒドロ
ベンゾフラン・（Ｒ）−（−）−マンデル酸塩４．０ｇ
より（Ｒ）−（−）−５−アミノ−２−〔４−（４−メ
トキシフェニル）ピペリジノ〕メチル−２，４，６，７
−テトラメチル−２，３−ジヒドロベンゾフラン・２塩
酸塩２．１９ｇを得た。 融点 ２２９℃（分解） 〔α〕28 −３１．３゜（ｃ＝１．３００，メタノー
ル） 元素分析値 Ｃ25Ｈ34Ｎ2Ｏ2・Ｈ2Ｃｌ2・０．５Ｈ2Ｏとして 計算値： Ｃ：６３．０２ Ｈ：７．８３ Ｎ：５．８８ Ｃｌ：１４．８８ 実験値： Ｃ：６３．２０ Ｈ：７．８５ Ｎ：５．９２ Ｃｌ：１５．０３Example 8 (R)-(-)-5-Amino-2- [4- (4-methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran -Dihydrochloride (R)-(-)-5-amino- in the same manner as in Example 7.
2- [4- (4-methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran. (R)-(-)-mandelate salt 4.0 g
From (R)-(-)-5-amino-2- [4- (4-methoxyphenyl) piperidino] methyl-2,4,6,7
-2.19 g of tetramethyl-2,3-dihydrobenzofuran dihydrochloride were obtained. Mp 229 ° C. (decomposition) [α] 28 -31.3 ° (c = 1.300, methanol) Elemental analysis C 25 H 34 N 2 O 2 · H 2 Cl 2 · 0.5H 2 O Calculated: C: 63.02 H: 7.83 N: 5.88 Cl: 14.88 Experimental value: C: 63.20 H: 7.85 N: 5.92 Cl: 15.03
フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 //(Ｃ０７Ｄ 405/06 211:00 9165−4Ｃ 307:00） 7252−4Ｃ Continuation of front page (51) Int.Cl. 5 Identification number Office reference number FI technical display area // (C07D 405/06 211: 00 9165-4C 307: 00) 7252-4C
Claims (5)
る化合物またはその塩。1. A general formula: Both represent a benzene ring substituted with one. ] The compound or its salt represented by these.
基である請求項１記載の化合物またはその塩。3. The compound according to claim 1 , wherein R 1 , R 2 , R 3 and R 4 are each a methyl group, or a salt thereof.
ェニル）ピペリジノ〕メチル−２，４，６，７−テトラ
メチル−２，３−ジヒドロベンゾフランまたはその塩。4. 5-Amino-2- [4- (4-methoxyphenyl) piperidino] methyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran or a salt thereof.
することを特徴とする過酸化脂質生成抑制剤。5. A lipid peroxide production inhibitor comprising the compound according to claim 1 or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32952692A JP3198395B2 (en) | 1992-05-28 | 1992-12-09 | Amino coumaran derivative |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13702692 | 1992-05-28 | ||
| JP4-137026 | 1992-05-28 | ||
| JP32952692A JP3198395B2 (en) | 1992-05-28 | 1992-12-09 | Amino coumaran derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0641123A true JPH0641123A (en) | 1994-02-15 |
| JP3198395B2 JP3198395B2 (en) | 2001-08-13 |
Family
ID=26470459
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP32952692A Expired - Fee Related JP3198395B2 (en) | 1992-05-28 | 1992-12-09 | Amino coumaran derivative |
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| Country | Link |
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| JP (1) | JP3198395B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5534536A (en) * | 1993-08-24 | 1996-07-09 | Ono Pharmaceuticals Co. Ltd. | Fused phenol derivatives |
| WO1998008842A1 (en) * | 1996-08-29 | 1998-03-05 | Takeda Chemical Industries, Ltd. | Cyclic ether compounds as sodium channel modulators |
| WO2005030198A1 (en) * | 2003-09-26 | 2005-04-07 | Chugai Seiyaku Kabushiki Kaisha | Medicinal composition for treatment for fatty liver or liver disease |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR200493794Y1 (en) * | 2019-05-10 | 2021-06-04 | 이정걸 | Fishing line shift device |
-
1992
- 1992-12-09 JP JP32952692A patent/JP3198395B2/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5534536A (en) * | 1993-08-24 | 1996-07-09 | Ono Pharmaceuticals Co. Ltd. | Fused phenol derivatives |
| US5750544A (en) * | 1993-08-24 | 1998-05-12 | Ono Pharmaceuticals Co., Ltd. | Fused phenol derivatives |
| WO1998008842A1 (en) * | 1996-08-29 | 1998-03-05 | Takeda Chemical Industries, Ltd. | Cyclic ether compounds as sodium channel modulators |
| US6172085B1 (en) * | 1996-08-29 | 2001-01-09 | Takeda Chemical Industries, Ltd. | Cyclic ether compounds as sodium channel modulators |
| WO2005030198A1 (en) * | 2003-09-26 | 2005-04-07 | Chugai Seiyaku Kabushiki Kaisha | Medicinal composition for treatment for fatty liver or liver disease |
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| Publication number | Publication date |
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| JP3198395B2 (en) | 2001-08-13 |
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