JPH05255302A - New chromanyloxyalkylamine derivative - Google Patents
New chromanyloxyalkylamine derivativeInfo
- Publication number
- JPH05255302A JPH05255302A JP4086016A JP8601692A JPH05255302A JP H05255302 A JPH05255302 A JP H05255302A JP 4086016 A JP4086016 A JP 4086016A JP 8601692 A JP8601692 A JP 8601692A JP H05255302 A JPH05255302 A JP H05255302A
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- acid
- formula
- fluoro
- 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
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は，医薬，特に５−ＨＴ
１Ａ受容体に対して選択的な親和性を有する新規なクロ
マニルオキシアルキルアミン誘導体又はその塩に関す
る。FIELD OF THE INVENTION The present invention relates to pharmaceuticals, especially 5-HT.
The present invention relates to a novel chromanyloxyalkylamine derivative having a selective affinity for a 1A receptor or a salt thereof.
【０００２】[0002]
【従来の技術】最近，数年の間に，神経伝達物質セロト
ニン（５−ヒドロキシトリプタミン：以下５−ＨＴと略
記する。）が，食欲，記憶，体温調節，睡眠，性的行
動，不安，うつ病および幻覚行動を含む多くの生理学的
現象と直接的または間接的に関連していることが明らか
にされてきた〔Glennon,R．A., J, Med. Chem. 30,1(19
87)〕。2. Description of the Related Art In recent years, a neurotransmitter serotonin (5-hydroxytryptamine: hereinafter abbreviated as 5-HT) has been shown to have appetite, memory, thermoregulation, sleep, sexual behavior, anxiety, depression. It has been shown to be directly or indirectly associated with many physiological phenomena including disease and hallucinatory behavior [Glennon, R. et al. A., J, Med. Chem. 30,1 (19
87)].
【０００３】５−ＨＴ受容体には，複数のタイプが存在
することが認識されている。これらの受容体は，５−Ｈ
Ｔ１，５−ＨＴ２および５−ＨＴ３受容体として分類さ
れており，最初の５−ＨＴ１はさらにサブクラスとして
５−ＨＴ１Ａ，５−ＨＴ１Ｂ，５−ＨＴ１Ｃおよび５−
ＨＴ１Ｄに分類されている。上記５−ＨＴ１のサブクラ
スの中で，５−ＨＴ１Ａ受容体は不安，うつなどの中枢
神経の疾病に関与していると考えられており，従って，
５ＨＴ１Ａ受容体に対して親和性を有する化合物は，中
枢神経形が関与する種々の疾病の治療又は予防に有効で
あると考えられる。It is recognized that there are multiple types of 5-HT receptors. These receptors are 5-H
Classified as T 1 , 5-HT 2 and 5-HT 3 receptors, the first 5-HT 1 is further subclassed as 5-HT 1A , 5-HT 1B , 5-HT 1C and 5-
It is classified as HT 1D . Among the above-mentioned 5-HT 1 subclasses, 5-HT 1A receptors are considered to be involved in central nervous system diseases such as anxiety and depression.
Compounds having an affinity for the 5HT 1A receptor are considered to be effective in treating or preventing various diseases involving the central nervous system.
【０００４】従来，５−ＨＴ１Ａ受容体に対し選択的な
親和性を有する化合物の代表的なものとしては，ブスピ
ロン（Buspirone;メルクインデックス 11版 229頁に記
載の化合物）や，ビノスピロン (Br.J.Pharmacol,93,2
(1988) にＭＤＬ７３００５ＥＦとして，及び特願昭６
１−２４６１８０号広報に実施例９として記載された化
合物）等が知られている。このような化合物は，不安，
うつ，精神***病，食餌摂取の障害，学習および認識の
障害，アルツハイマ−病，あるいは高血圧や偏頭痛など
の治療薬となる可能性があると考えられており，中でも
ブスピロンは既に抗不安薬として上市されている。Conventionally, as typical compounds having a selective affinity for the 5-HT 1A receptor, buspirone (Buspirone; compound described in Merck Index, 11th edition, page 229) and binospirone (Br. J.Pharmacol, 93,2
(1988) as MDL 73005EF and Japanese Patent Application No. 6
Compounds described as Example 9 in JP-A No. 1-246180) and the like are known. Such compounds are
Depression, schizophrenia, disorders of food intake, learning and cognitive disorders, Alzheimer's disease, and hypertension and migraine are considered to be potential therapeutic agents. Among them, buspirone is already an anxiolytic drug. It is on the market.
【０００５】[0005]
【発明が解決しようとする課題】本発明者は，５−ＨＴ
１Ａ受容体に関する研究を重ね，種々の化合物を創製し
てスクリ−ニングを進めてきた結果，新規なクロマニル
オキシアルキルアン誘導体が５−ＨＴ１Ａ受容体に対し
て格段に優れた選択的親和性を有することを知見して，
本発明を完成させるに至った。DISCLOSURE OF THE INVENTION The present inventors have found that 5-HT
As a result of repeated research on the 1A receptor and development of various compounds to promote screening, the novel chromanyloxyalkylan derivative has a remarkably excellent selective affinity for the 5-HT 1A receptor. Is found to have
The present invention has been completed.
【０００６】なおアリールオキシアルキルアミン誘導体
に関しては，特表平１−５０１３９３号広報に報告され
ているが，本発明の化合物はアリ−ルオキシ基における
置換基の種類を異にする新規化合物である。また，同広
報は，殺真菌剤としての作用を説明しているだけで５−
ＨＴ受容体に対する親和性については全く記載していな
い。Regarding the aryloxyalkylamine derivative, it has been reported in Japanese Patent Publication No. 1-501393, that is, the compound of the present invention is a novel compound having different kinds of substituents in the aryloxy group. In addition, the public information only explains the action as a fungicide.
There is no mention of affinity for the HT receptor.
【０００７】[0007]
【課題を解決するための手段】すなわち，本発明は，下
記一般式（Ｉ）で示される新規なクロマニルオキシアル
キルアミン誘導体又はその製薬学的に許容される塩を提
供するものである。That is, the present invention provides a novel chromanyloxyalkylamine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
【０００８】[0008]
【化２】 [Chemical 2]
【０００９】（式中の記号は，以下の意味を示す。 Ｒ１：水素原子又は低級アルキル基。 Ｒ２：低級アルコキシ基。 Ｙ ：低級アルキレン基。）(The symbols in the formulas have the following meanings: R 1 : hydrogen atom or lower alkyl group; R 2 : lower alkoxy group; Y: lower alkylene group.)
【００１０】本発明化合物（Ｉ）をさらに説明すると，
次の通りである。本明細書中，『低級』なる語は，炭素
数１乃至６個の直鎖状または分枝状の炭化水素鎖を意味
する。従って，『低級アルキル基』としては，具体的に
は例えばメチル基，エチル基，プロピル基，イソプロピ
ル基，ブチル基，イソブチル基，ｓｅｃ−ブチル基，ｔ
ｅｒｔ−ブチル基，ペンチル基，イソペンチル基，ネオ
ペンチル基，ｔｅｒｔ−ペンチル基，１−メチルブチル
基，２−メチルブチル基，１，２−ジメチルプロピル
基，ヘキシル基，イソヘキシル基，１−メチルペンチル
基，２−メチルペンチル基，３−メチルペンチル基，
１，１−ジメチルブチル基，１，２−ジメチルブチル
基，２，２−ジメチルブチル基，１，３−ジメチルブチ
ル基，２，３−ジメチルブチル基，３，３−ジメチルブ
チル基，１−エチルブチル基，２−エチルブチル基，
１，１，２−トリメチルプロピル基，１，２，２−トリ
メチルプロピル基，１−エチル−１−メチルプロピル
基，１−エチル−２−メチルプロピル基等が挙げられ
る。The compound (I) of the present invention will be further described below.
It is as follows. In the present specification, the term "lower" means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms. Therefore, as the "lower alkyl group", specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t
ert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2 -Methylpentyl group, 3-methylpentyl group,
1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1- Ethylbutyl group, 2-ethylbutyl group,
Examples include 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like.
【００１１】又，『低級アルコキシ基』としては，メト
キシ基，エトキシ基，プロポキシ基，イソプロポキシ
基，ブトキシ基，イソブトキシ基，ｓｅｃ−ブトキシ
基，ｔｅｒｔ−ブトキシ基，ペンチルオキシ（アミルオ
キシ）基，イソペンチルオキシ基，ｔｅｒｔ−ペンチル
オキシ基，ネオペンチルオキシ基，２−メチルブトキシ
基，１，２−ジメチルプロポキシ基，１−エチルプロポ
キシ基，ヘキシルオキシ基等が挙げられる。The "lower alkoxy group" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy), iso- Examples thereof include a pentyloxy group, a tert-pentyloxy group, a neopentyloxy group, a 2-methylbutoxy group, a 1,2-dimethylpropoxy group, a 1-ethylpropoxy group and a hexyloxy group.
【００１２】『低級アルキレン基』としては，メチレン
基，エチレン基，プロピレン基，ブチレン基，ペンチレ
ン基，ヘキシレン基，メチルメチレン基，メチルエチレ
ン基，メチルプロピレン基，１，１−ジメチルブチレン
基，１，２−ジメチルブチレン基等が挙げられる。The "lower alkylene group" includes methylene group, ethylene group, propylene group, butylene group, pentylene group, hexylene group, methylmethylene group, methylethylene group, methylpropylene group, 1,1-dimethylbutylene group, 1 , 2-dimethylbutylene group and the like.
【００１３】本発明化合物は，不斉炭素原子を有するこ
とがあり，該不斉炭素原子に基づく異性体が存在する。
本発明目的化合物には，光学異性体の混合物や単離され
たものが含まれる。The compound of the present invention may have an asymmetric carbon atom, and isomers based on the asymmetric carbon atom exist.
The object compound of the present invention includes a mixture of optical isomers and an isolated one.
【００１４】さらに，本発明化合物は，酸付加塩を形成
する場合がある。塩としては，具体的に塩酸臭化水素
酸，ヨウ化水素酸，硫酸，硝酸，リン酸等の鉱酸，ギ
酸，酢酸，プロピオン酸，シュウ酸，マロン酸，コハク
酸，フマ−ル酸，マレイン酸，乳酸，リンゴ酸，酒石
酸，クエン酸，メタンスルホン酸，エタンスルホン酸等
の有機酸，アスパラギン酸，グルタミン酸等の酸性アミ
ノ酸との酸付加塩等が挙げられる。Further, the compound of the present invention may form an acid addition salt. Specific examples of salts include hydrochloric acid hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and other mineral acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Examples thereof include organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamic acid.
【００１５】（製造法）本発明化合物及びその塩は，そ
の基本骨格あるいは置換基の種類に基づく特徴を利用
し，種々の合成を適用して製造することができる。以下
にその代表的な製造法を例示する。 第１製法(Production Method) The compound of the present invention and a salt thereof can be produced by utilizing various characteristics based on the basic skeleton or the type of substituent. The typical manufacturing method is illustrated below. First manufacturing method
【００１６】[0016]
【化３】 [Chemical 3]
【００１７】（式中，Ｒ１，Ｒ２及びＹは前記の意味を
有し，Ｘはハロゲン原子，またはメチルスルホニルオキ
シ基，トリフルオロメチルスルホニルオキシ基，パラト
ルエンスルホニルオキシ基等のアルキル基の活性化基を
意味し，Ｚは水素原子，またはベンジル基，アシル基な
どのアミノ基の保護基を意味する。）本製法は，上式中
（II）及び（III） で示される化合物を適当な溶媒中
で反応させ（Ｎ−アルキル化工程），Ｚがアミノ基の保
護基であるときは，これを除去して（脱保護工程），上
式中の（Ｉ）で示される本発明化合物を得る方法であ
る。(Wherein R 1 , R 2 and Y have the above-mentioned meanings, X is a halogen atom or an alkyl group such as a methylsulfonyloxy group, a trifluoromethylsulfonyloxy group or a paratoluenesulfonyloxy group. Means an activating group, Z means a hydrogen atom, or a protecting group for an amino group such as a benzyl group or an acyl group.) In this production method, the compounds represented by the above formulas (II) and (III) are suitable. In a different solvent (N-alkylation step), and when Z is a protecting group for an amino group, this is removed (deprotection step), and the compound of the present invention represented by (I) in the above formula Is a way to get.
【００１８】Ｎ−アルキル化工程は化合物（II）とその
反応対応量ないし過剰量の（III）とを使用し，適当な
溶媒中で冷却下ないし加熱下，好ましくは室温ないし加
熱下（還流下）に行われる。この際反応対応量ないし過
剰量の塩基を添加することが反応を円滑に進行させる上
で有利な場合がある。溶媒としてはメタノ−ル，エタノ
−ル等のアルコ−ル類，ベンゼン，トルエン等の炭化水
素類，あるいはテトラヒドロフラン，ジオキサン，アセ
トニトリル，ジメチルホルムアミド，ジメチルスルホキ
シド等，この反応に不活性な溶媒が適宜用いられるほ
か，無溶媒で反応を行うこともある。In the N-alkylation step, compound (II) and the amount corresponding to the reaction or excess amount of (III) are used, and the mixture is cooled or heated in a suitable solvent, preferably at room temperature or under heating (under reflux). ) Is done. At this time, it may be advantageous to add an amount of the base corresponding to the reaction or an excess amount thereof in order to allow the reaction to proceed smoothly. As the solvent, alcohols such as methanol and ethanol, hydrocarbons such as benzene and toluene, or tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide and the like, and an inert solvent for this reaction is appropriately used. In addition, the reaction may be performed without solvent.
【００１９】また，この反応に用いる塩基としては，ト
リエチルアミン，ピリジン等の有機塩基類，炭酸ナトリ
ウム，炭酸カリウム，水酸化ナトリウム等の無機塩基
類，水素化ナトリウム等が挙げられる。さらに塩基が液
体である場合には，その塩基が溶媒を兼ねてもよい。脱
保護工程は，保護基の種類に応じて適宜に方法が採用さ
れる。保護基がベンジル基である場合には通常パラジウ
ム炭素等の貴金属触媒を用いて加水素分解を行えばよ
く，また保護基がアセチル基である場合には酸又はアル
カリによる加水分解等の処理が用いられる。Examples of the base used in this reaction include organic bases such as triethylamine and pyridine, inorganic bases such as sodium carbonate, potassium carbonate and sodium hydroxide, and sodium hydride. Further, when the base is a liquid, the base may also serve as a solvent. For the deprotection step, a method is appropriately adopted depending on the type of protecting group. When the protecting group is a benzyl group, hydrogenolysis may be usually carried out using a noble metal catalyst such as palladium carbon, and when the protecting group is an acetyl group, treatment such as hydrolysis with an acid or alkali is used. Be done.
【００２０】[0020]
【化４】 [Chemical 4]
【００２１】（式中，Ｒ１，Ｒ２，Ｙ，ＸおよびＺは前
記の意味を有する。）本製法は，上式中（IV）および
（Ｖ）で示される化合物を適当な溶媒中で反応させ（Ｎ
−アルキル化工程），Ｚがアミノ基の保護基であるとき
はこれを除去して（脱保護工程），上式中の（Ｉ）で示
される本発明化合物を得る方法である。本製法における
Ｎ−アルキル化工程及び脱保護工程は前記（１）と同様
に行うことができる。 第２製法(In the formula, R 1 , R 2 , Y, X and Z have the above-mentioned meanings.) In this production method, the compounds represented by the above formulas (IV) and (V) are added in a suitable solvent. React (N
-Alkylation step), when Z is a protecting group for amino group, it is removed (deprotection step) to obtain the compound of the present invention represented by (I) in the above formula. The N-alkylation step and the deprotection step in this production method can be performed in the same manner as in the above (1). Second manufacturing method
【００２２】[0022]
【化５】 [Chemical 5]
【００２３】（式中，Ｒ１，Ｒ２およびＹは前記の意味
を有する。），本製法は 上式中（VI）で示されるアル
デヒド化合物と（VII）で示されるアミン化合物を脱水
縮合させ（縮合工程），次いで還元する（還元工程），
いわゆる還元的アミノ化として知られる反応にて処理す
ることにより，上式中の（Ｉ）で示される本発明化合物
を得る方法である。(In the formula, R 1 , R 2 and Y have the above-mentioned meanings.) In this production method, the aldehyde compound represented by the formula (VI) and the amine compound represented by the formula (VII) are dehydrated and condensed. (Condensation step), then reduction (reduction step),
This is a method for obtaining the compound of the present invention represented by (I) in the above formula by treating by a reaction known as so-called reductive amination.
【００２４】縮合工程は化合物（VI）とその反応対応量
の（VII）とを利用して適当な溶媒中で冷却下ないし加
熱下，好ましくは室温ないし加熱下（還流下）に行わ
れ，その際共沸脱水装置あるいは分子ふるい等の脱水剤
を用いて脱水しながら反応を行ってもよい。また溶媒と
して酢酸，ｐ−トルエンスルホン酸等を加えることが好
ましい。溶媒としてメタノ−ル，エタノ−ル等のアルコ
−ル類，ベンゼン，トルエン等の炭化水素類，クロロホ
ルム，１，２−ジクロロエタン等のハロゲン化炭化水素
類，あるいはテトラヒドロフラン，ジオキサン，アセト
ニトリル等，この反応に不活性な溶媒が適宜用いられ
る。The condensation step is carried out by utilizing the compound (VI) and a corresponding amount of the compound (VII) in a suitable solvent under cooling or heating, preferably at room temperature or under heating (reflux). At this time, the reaction may be carried out while dehydrating using an azeotropic dehydrator or a dehydrating agent such as a molecular sieve. It is also preferable to add acetic acid, p-toluenesulfonic acid or the like as a solvent. Solvents such as alcohols such as methanol and ethanol, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and 1,2-dichloroethane, or tetrahydrofuran, dioxane, acetonitrile, etc. An inert solvent is used as appropriate.
【００２５】還元工程は適当な溶媒中金属水素化物等の
還元剤を用いるか，あるいは貴金属触媒の存在下接触還
元により行うことができる。還元剤としては水素化ホウ
素ナトリウム，シアノ水素化ホウ素ナトリウム等が適宜
用いられ，冷却下ないし加熱下に縮合工程と同様の溶媒
を用いて行なわれる。接触還元の場合はパラジウム炭
素，酸化白金などの貴金属触媒の存在下，メタノ−ル，
エタノ−ル，酢酸エチル等，通常接触還元に使用される
溶媒中で常圧ないし加圧下に行われる。なお本製法にお
いては，縮合工程後脱水縮合体を単離してから還元工程
を行なってもよいし，脱水縮合と還元の二つの反応を連
続的もしくは同時に行なってもよい。The reduction step can be carried out by using a reducing agent such as a metal hydride in a suitable solvent or by catalytic reduction in the presence of a noble metal catalyst. As the reducing agent, sodium borohydride, sodium cyanoborohydride, etc. are appropriately used, and the same solvent as in the condensation step is used under cooling or heating. In the case of catalytic reduction, in the presence of a noble metal catalyst such as palladium carbon or platinum oxide, methanol,
The reaction is carried out in a solvent usually used for catalytic reduction, such as ethanol or ethyl acetate, under normal pressure or increased pressure. In this production method, the reduction step may be carried out after the dehydration condensation product is isolated after the condensation step, or the two reactions of dehydration condensation and reduction may be carried out continuously or simultaneously.
【００２６】[0026]
【化６】 [Chemical 6]
【００２７】（式中，Ｒ１およびＲ２は前記の意味を有
し，Ａは水素原子または低級アルキル基を示し，Ｙ′は
低級アルキレン基を示し，ここにＡ−ＣＨ−Ｙ′は前記
Ｙに等しい。）本発明化合物（Ｉ）中，上式中（Ｉａ）
で示される化合物は，上式中（VIII）で示されるアミン
化合物と（IX）で示されるアルデヒド（またはケトン）
化合物を脱水縮合させ（縮合工程），次いで還元する
（還元工程），いわゆる還元的アミノ化として知られる
反応にて処理することにより得られる。本製法における
縮合工程と還元工程は前記（１）と同様に行なうことが
できる。 第３製法(Wherein R 1 and R 2 have the above-mentioned meanings, A represents a hydrogen atom or a lower alkyl group, Y ′ represents a lower alkylene group, and A—CH—Y ′ represents the above. Equal to Y.) In the compound (I) of the present invention, in the above formula (Ia)
The compound represented by is an amine compound represented by (VIII) and an aldehyde (or ketone) represented by (IX) in the above formula.
It is obtained by subjecting a compound to dehydration condensation (condensation step), followed by reduction (reduction step), and treatment in a reaction known as so-called reductive amination. The condensation step and the reduction step in this production method can be performed in the same manner as in the above (1). Third method
【００２８】[0028]
【化７】 [Chemical 7]
【００２９】（式中，Ｒ１，Ｒ２及びＹは前記の意味を
有する。）本製法は，上式中（Ｘ）で示されるカルボン
酸またはその反応性誘導体と（XI）で示されるアミン化
合物をカップリングさせ（アシル化工程），次いで生成
した酸アミド（XII）を還元する（還元工程）ことによ
り，上式中の（Ｉ）で示される本発明化合物を得る方法
である。(In the formula, R 1 , R 2 and Y have the above-mentioned meanings.) In the present production method, the carboxylic acid represented by the formula (X) or the reactive derivative thereof and the amine represented by the formula (XI) are used. This is a method for obtaining the compound of the present invention represented by (I) in the above formula by coupling the compound (acylation step) and then reducing the generated acid amide (XII) (reduction step).
【００３０】アシル化工程は，化合物（Ｘ）またはその
反応性誘導体と化合物（XI）とを反応対応量，あるいは
一方を過剰量として用い，ベンゼン，トルエン等の炭化
水素類，ジクロロメタン，クロロホルム等のハロゲン化
炭化水素類，あるいはエ−テル，テトラヒドロフラン，
ジオキサン，アセトニトリル，ジメチルホルムアミド，
水等，この反応に不活性な溶媒中に行われる。反応性誘
導体の種類によっては塩基の存在下に反応を行うのが有
利な場合が有り，そのような塩基としては，トリエチル
アミン，ピリジン，４−ジメチルアミノピリジン等の有
機塩基類，炭酸ナトリウム，炭酸カリウム，水酸化ナト
リウム等の無機塩基類等が挙げられる。さらにピリジン
等液体の塩基の場合，その塩基を溶媒として用いてもよ
い。In the acylation step, the compound (X) or its reactive derivative and the compound (XI) are used in an amount corresponding to the reaction, or one of them is used in an excess amount, and hydrocarbons such as benzene and toluene, dichloromethane, chloroform and the like are used. Halogenated hydrocarbons, ether, tetrahydrofuran,
Dioxane, acetonitrile, dimethylformamide,
It is carried out in a solvent inert to this reaction, such as water. Depending on the type of reactive derivative, it may be advantageous to carry out the reaction in the presence of a base. Examples of such a base include organic bases such as triethylamine, pyridine and 4-dimethylaminopyridine, sodium carbonate, potassium carbonate. , Inorganic bases such as sodium hydroxide, and the like. Further, in the case of a liquid base such as pyridine, the base may be used as a solvent.
【００３１】反応温度は反応性誘導体の種類によって異
なり，特に限定されない。還元工程エーテル，テトラヒ
ドロフラン，ジメトキシエタン，あるいはヘキサン，ベ
ンゼン，トルエン等，反応に不活性な溶媒中で，冷却下
ないし加熱下，好ましくは０℃ないし加熱下（還流下）
に適当な還元利用を用いて行われる。還元剤としてはボ
ラン，水素化アルミニウム，水素化リチウムアルミニウ
ム，水素化ビス（２−メトキシエトキシ）アルミニウム
ナトリウム等が適宜用いられる。なお還元工程は，アシ
ル工程に続けて行ってもよいし，アシル化工程で得た酸
アミドを単離してから行ってもよい。The reaction temperature depends on the kind of the reactive derivative and is not particularly limited. Reduction step In a solvent inert to the reaction, such as ether, tetrahydrofuran, dimethoxyethane, or hexane, benzene, toluene, etc., under cooling or heating, preferably at 0 ° C or under heating (under reflux).
Is carried out using the appropriate reduction utilization. As the reducing agent, borane, aluminum hydride, lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride or the like is appropriately used. The reduction step may be carried out after the acylation step or after isolation of the acid amide obtained in the acylation step.
【００３２】[0032]
【化８】 [Chemical 8]
【００３３】（式中，Ｒ１およびＲ２は前記の意味を有
し，Ｙ″は低級アルキレン基を示し，このＣＨ２−Ｙ″
は前記Ｙに等しい。）本発明化合物（Ｉ）中，上式中
（Ib）で示される化合物は，上式中（XIII）示されるア
ミン化合物と（XIV）で示されるカルボン酸またはその
反応性誘導体とをカップリング（アシル化工程），次い
で生成した酸アミド（XV）を還元する（還元工程）こと
により得られる。本製法におけるアシル化工程と還元工
程は前記（１）と同様に行うことができる。(Wherein R 1 and R 2 have the above-mentioned meanings, Y ″ represents a lower alkylene group, and CH 2 —Y ″
Is equal to Y above. ) In the compound (I) of the present invention, the compound represented by the formula (Ib) is obtained by coupling the amine compound represented by the formula (XIII) with the carboxylic acid represented by the formula (XIV) or a reactive derivative thereof. Acylation step), and then the resulting acid amide (XV) is reduced (reduction step). The acylation step and reduction step in this production method can be performed in the same manner as in the above (1).
【００３４】[0034]
【発明の効果】本発明の化合物は５−ＨＴ受容体に対し
て親和性を有し，とりわけ，５−ＨＴ受容体のサブタイ
プである５−ＨＴ１Ａ受容体に対して非常に高い親和性
を示す。このため本発明の化合物は５−ＨＴ神経系が関
与する種々の疾患の処置に用いることができる。このよ
うな疾患としては例えば不安，緊張およびうつ，精神分
裂病などの精神神経疾患，性的機能障害，食餌摂取の障
害，睡眠障害，動揺病および薬物依存等があげられる。
さらにこれらは脳卒中，脳虚血，認識障害，学習・記憶
障害，アルツハイマ−病などの処置のために用いること
ができる。さらにまた，これらは偏頭痛や高血圧などの
循環器系の障害に対して用いることができる。さらに本
発明の包含する化合物の一部はアドレナリンα受容体に
親和性を持つことから，当該化合物は排尿障害，高血圧
症の治療剤および脳循環改善剤として用いることができ
る。INDUSTRIAL APPLICABILITY The compounds of the present invention have an affinity for 5-HT receptors, and in particular, a very high affinity for 5-HT 1A receptors which is a subtype of 5-HT receptors. Indicates. Therefore, the compounds of the present invention can be used in the treatment of various diseases involving the 5-HT nervous system. Such disorders include, for example, anxiety, tension and depression, neuropsychiatric disorders such as schizophrenia, sexual dysfunction, disorders in food intake, sleep disorders, motion sickness and drug dependence.
Further, they can be used for treatment of stroke, cerebral ischemia, cognitive impairment, learning / memory impairment, Alzheimer's disease and the like. Furthermore, they can be used for cardiovascular disorders such as migraine and hypertension. Furthermore, since some of the compounds included in the present invention have an affinity for the adrenergic α receptor, the compounds can be used as therapeutic agents for dysuria and hypertension and cerebral circulation improving agents.
【００３５】以下に本発明化合物の５−ＨＴ１Ａ受容体
に対する親和性および不安寛解作用について，実験例を
掲記して説明する。 ５−ＨＴ１Ａに受容体に対する親和性試験 １）実験方法 ５−ＨＴ１Ａに対する親和性は，Peroutka の方法 (J.
Neurochem. 47, 529(1986)) に従い，ラット海馬の標本
を用いてトリチウム標識した８−ＯＨ−ＤＰＡＴの置換
を測定することにより求め，Ｋｉ値として表わした。本
発明化合物及び５−ＨＴ１Ａ受容体に対し，選択的な親
和性を有するブスピロン（本試験の対照化合物）のＫｉ
値を下記表に示す。The affinity and anxiolytic action of the compound of the present invention for the 5-HT 1A receptor will be described below by posting experimental examples. Affinity test for 5-HT 1A receptor 1) Experimental method Affinity for 5-HT 1A was determined by the method of Peroutka (J.
According to Neurochem. 47, 529 (1986)), it was determined by measuring the displacement of tritiated 8-OH-DPAT using a rat hippocampal specimen and expressed as a Ki value. Ki of buspirone (control compound of this test) having a selective affinity for the compound of the present invention and 5-HT 1A receptor
The values are shown in the table below.
【００３６】[0036]
【表１】 [Table 1]
【００３７】この結果，本発明化合物は，対照化合物で
あるブスピロンと比較して，５−ＨＴ１Ａ受容体に対す
る親和性が著しく強力であることが知見された。このた
め本発明化合物は，５−ＨＴ神経系に関与する種々の疾
患の予防又は治療において，より優れた効果を有するこ
とが期待できる。As a result, it was found that the compound of the present invention has remarkably strong affinity for the 5-HT 1A receptor as compared with the control compound buspirone. Therefore, the compound of the present invention can be expected to have a more excellent effect in the prevention or treatment of various diseases related to the 5-HT nervous system.
【００３８】不安寛解作用試験 １）実験方法 本発明化合物の不安寛解作用を，マウスの明暗箱での実
験により調べた (CRAWLEY et al,Pharmacol. Biochem.
Behav., 13, 167(1980))。不安寛解作用は明暗箱の明領
域におけるマウスの滞在時間率の増加として示される。
試験に先立ち３週間以上昼夜逆転飼育した雄性ＩＣＲマ
ウス（８−１０週齢）に薬物を腹腔内投与し，３０分後
マウスを明暗箱に入れ，５分間の行動を観察した。その
間，マウスが明領域に滞在した時間の合計を求め，明領
域と暗領域の滞在時間の合計に対する百分率％として表
した。本発明化合物の投与群では対照群に対して明領域
での滞在時間率の有意な増加が認められた。Anxiolytic effect test 1) Experimental method The anxiolytic effect of the compound of the present invention was examined by an experiment in a light-dark box of mice (CRAWLEY et al, Pharmacol. Biochem.
Behav., 13 , 167 (1980)). Anxiolytic activity is shown as an increase in the residence time rate of mice in the light area of the light-dark box.
Prior to the test, the drug was intraperitoneally administered to male ICR mice (8-10 weeks old) that had been reared upside down for at least 3 weeks, and after 30 minutes, the mice were placed in a light-dark box and observed for 5 minutes of behavior. During that time, the total time spent by the mice in the light area was calculated and expressed as a percentage of the total time spent in the light area and the dark area. In the group to which the compound of the present invention was administered, a significant increase in the residence time rate in the bright region was observed as compared with the control group.
【００３９】一般式（Ｉ）で示された化合物又はその塩
の１種又は２種以上を有効成分として含有する製薬組成
物は，通常製剤化に用いられる担体や賦形剤，その他添
加剤を用いて調製される。製剤用の担体や賦形剤として
は，固体又は液体状の非毒性医薬用物質が挙げられる。
これらの例としては，たとえば乳糖，ステアリン酸マグ
ネシウム，スタ−チ，タルク，ゼラチン，寒天，ペクチ
ン，アラビアゴム，オリ−ブ油，ゴマ油，カカオバタ
−，エチレングリコ−ル等やその他常用のものが例示さ
れる。A pharmaceutical composition containing, as an active ingredient, one or two or more of the compound represented by the general formula (I) or a salt thereof contains a carrier, an excipient, and other additives usually used for formulation. Is prepared using. Carriers and excipients for formulation include solid or liquid non-toxic pharmaceutical substances.
Examples of these include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and others commonly used. To be done.
【００４０】投与は錠剤，丸剤，カプセル剤，顆粒剤，
散剤，液剤等による経口投与，あるいは静注，筋注等の
注射剤，坐剤，経皮等による非経口投与のいずれの形態
であってもよい。投与量は症状，投与対象の年令，性別
等を考慮して個々の場合に応じて適宜決定されるが，通
常経口投与の場合成人１日当たり０．１〜１０００ｍ
ｇ，好ましくは１〜５００ｍｇ程度であり，これを１回
で，あるいは２〜４回に分けて投与する。For administration, tablets, pills, capsules, granules,
It may be in any form of oral administration such as powder and liquid preparation, or parenteral administration such as injection such as intravenous injection and intramuscular injection, suppository and transdermal injection. The dose is appropriately determined according to the individual case in consideration of symptoms, age of the subject, sex, etc., but usually 0.1 to 1000 m per day for an adult in the case of oral administration.
g, preferably about 1 to 500 mg, which is administered once or in 2 to 4 divided doses.
【００４１】[0041]
【実施例】以下に実施例を掲記して本発明を更に詳細に
説明する。なお，本発明原料化合物には新規な物質も含
まれており実施例で使用した原料化合物は新規であるか
ら，その製法を参考例に示す。 参考例 １EXAMPLES The present invention will be described in more detail with reference to the following examples. Since the raw material compounds of the present invention also include novel substances and the raw material compounds used in the examples are novel, the production method thereof will be shown in Reference Examples. Reference example 1
【００４２】[0042]
【化９】 [Chemical 9]
【００４３】（１）６−フルオロ−２−メチル−４−ク
ロマノン５．０ｇを氷酢酸２５ｍｌに溶解し，１０％パ
ラジウム炭素０．５ｇを加え，常圧水素下一夜撹拌し
た。パラジウム炭素を濾去し，濾液を濃縮後残渣にエ−
テルを加え，炭酸水素ナトリウム水溶液および飽和食塩
水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後
溶媒を留去し，６−フルオロ−２−メチルクロマン４．
３ｇを得た。(1) 5.0 g of 6-fluoro-2-methyl-4-chromanone was dissolved in 25 ml of glacial acetic acid, 0.5 g of 10% palladium carbon was added, and the mixture was stirred overnight under hydrogen at atmospheric pressure. Palladium carbon was removed by filtration, the filtrate was concentrated, and the residue was evaporated.
Tellurium was added, and the mixture was washed with an aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to give 6-fluoro-2-methylchroman.
3 g was obtained.
【００４４】理化学的性状 質量分析値（ＥＩ，ｍ／ｚ）：１６６（Ｍ＋） 核磁気共鳴スペクトル（ＣＤＣｌ３ ，ＴＭＳ内部標
準） δ：１．３７（３Ｈ，ｄ，２−ＣＨ３），１．５−２．
１（２Ｈ，ｍ，Ｃ３−Ｈ２），２．７−３．０（２Ｈ，
ｍ，Ｃ４−Ｈ２），３．９−４．３（１Ｈ，ｍ，Ｃ２−
Ｈ），６．６−６．９（３Ｈ，ｍ）Physicochemical properties Mass spectrometric value (EI, m / z): 166 (M + ) Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.37 (3H, d, 2-CH 3 ), 1.5-2.
1 (2H, m, C3- H 2), 2.7-3.0 (2H,
m, C4-H 2), 3.9-4.3 (1H, m, C2-
H), 6.6-6.9 (3H, m)
【００４５】（２）塩化アルミニウム１．５６ｇを１，
２−ジクロロエタン１５ｍｌに溶解し，−５℃に冷却し
た。ここに塩化アセチル１．８４ｇの１，２−ジクロロ
エタン溶液（３ｍｌ）を滴下し，次いで，（１）の６−
フルオロ−２−メチルクロマン３．２４ｇの１，２−ジ
クロロエタン溶液（５ｍｌ）を滴下した。−１０〜−５
℃を保って２時間撹拌した後，反応混合物を氷水に注
ぎ，エ−テルで抽出した。有機層を濃縮後残渣をカラム
クロマトグラフィ−に付し，ヘキサン−酢酸エチル（９
７：３）の混合溶媒で溶出することにより，第一分画と
して未反応の原料１．１３ｇを回収し，第二分画として
目的の８−アセチル−６−フルオロ−２−メチルクロマ
ン２．２２ｇを白色結晶として得た。(2) 1.56 g of aluminum chloride was added to 1,
It was dissolved in 2-dichloroethane (15 ml) and cooled to -5 ° C. A solution of acetyl chloride (1.84 g) in 1,2-dichloroethane (3 ml) was added dropwise thereto, and then 6-of (1) was added.
A solution of 3.24 g of fluoro-2-methylchroman in 1,2-dichloroethane (5 ml) was added dropwise. -10 to -5
After stirring at 2 ° C for 2 hours, the reaction mixture was poured into ice water and extracted with ether. After concentrating the organic layer, the residue was subjected to column chromatography, and hexane-ethyl acetate (9
By elution with a mixed solvent of 7: 3), 1.13 g of unreacted raw material was recovered as the first fraction, and the target 8-acetyl-6-fluoro-2-methylchroman was obtained as the second fraction. 22 g was obtained as white crystals.
【００４６】理化学的性状 質量分析値（ＥＩ，ｍ／ｚ）：２０８（Ｍ＋） 核磁気共鳴スペクトル（ＣＤＣｌ３ ，ＴＭＳ内部標
準） δ：１．４５（３Ｈ，ｄ，２−ＣＨ３），１．５−２．
２（２Ｈ，ｍ，Ｃ３−Ｈ２），２．６１（３Ｈ，ｓ，Ｃ
ＯＣＨ３），２．７−３．０（２Ｈ，ｍ，Ｃ４−
Ｈ２），４．０−４．５（１Ｈ，ｍ，Ｃ２−Ｈ），６．
９０（１Ｈ，ｄｄ），７．２３（１Ｈ，ｄｄ）Physicochemical properties Mass spectrometric value (EI, m / z): 208 (M + ) Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.45 (3H, d, 2-CH 3 ), 1.5-2.
2 (2H, m, C3- H 2), 2.61 (3H, s, C
OCH 3), 2.7-3.0 (2H, m, C4-
H 2), 4.0-4.5 (1H, m, C2-H), 6.
90 (1H, dd), 7.23 (1H, dd)
【００４７】（３）８−アセチル−６−フルオロ−２−
メチルクロマン２．１５ｇをトルエン２５ｍｌに溶解
し，氷冷下トリフルオロ酢酸３．５４ｇ，続いてｍ−ク
ロロ過安息香酸３．３４ｇを徐々に加えた。５℃で１８
時間撹拌後希アンモニア水を加え，エ−テルで抽出し
た。溶媒を留去後，残渣にメタノ−ル２５ｍｌおよび１
規定水酸化ナトリウム２３ｍｌを加え，室温で１時間撹
拌した。反応混合物からメタノ−ルの大半を留去後，氷
冷下に希塩酸を加えて中和し，析出する結晶を濾取し
た。減圧乾燥し，６−フルオロ−２−メチル−８−クロ
マノ−ル１．０ｇを得た(3) 8-acetyl-6-fluoro-2-
Methylchroman (2.15 g) was dissolved in toluene (25 ml), and trifluoroacetic acid (3.54 g) and m-chloroperbenzoic acid (3.34 g) were gradually added under ice cooling. 18 at 5 ° C
After stirring for a period of time, dilute aqueous ammonia was added and the mixture was extracted with ether. After distilling off the solvent, 25 ml of methanol and 1 were added to the residue.
23 ml of normal sodium hydroxide was added, and the mixture was stirred at room temperature for 1 hour. After most of the methanol was distilled off from the reaction mixture, dilute hydrochloric acid was added under ice cooling to neutralize, and the precipitated crystals were collected by filtration. After drying under reduced pressure, 1.0 g of 6-fluoro-2-methyl-8-chromanol was obtained.
【００４８】理化学的性状 質量分析値（ＥＩ，ｍ／ｚ）：１８２（Ｍ＋） 核磁気共鳴スペクトル（ＣＤＣｌ３ ，ＴＭＳ内部標
準） δ：１．４０（３Ｈ，ｄ，２−ＣＨ３），１．６−２．
２（２Ｈ，ｍ，Ｃ３−Ｈ２），２．６−２．９（２Ｈ，
ｍ，Ｃ４−Ｈ２），４．０−４．３（１Ｈ，ｍ，Ｃ２−
Ｈ），４．９（１Ｈ，ｂｒ ｓ，ＯＨ），６．３１（１
Ｈ，ｄｄ），６．４８（１Ｈ，ｄｄ）Physicochemical properties Mass spectrometric value (EI, m / z): 182 (M + ) Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.40 (3H, d, 2-CH 3 ), 1.6-2.
2 (2H, m, C3- H 2), 2.6-2.9 (2H,
m, C4-H 2), 4.0-4.3 (1H, m, C2-
H), 4.9 (1H, br s, OH), 6.31 (1
H, dd), 6.48 (1H, dd)
【００４９】（４）（３）で得た６−フルオロ−２−メ
チル−８−クロマノール１．５８ｇを１，２−ジブロム
エタン７．５ｍｌに溶解し，３規定水酸化ナトリウム水
溶液１０ｍｌおよび硫酸水素テトラブチルアンモニウム
（ＴＢＡＨＳ）１５０ｍｇを加え，７０℃で２時間撹拌
した。冷後反応混合物をジクロロメタンで抽出し，有機
層を飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥し
た。溶媒を留去後残渣をカラムクロマトグラフィーに付
し，ヘキサン−酢酸エチル（９５：５）の混合溶媒で溶
出することにより，８−（ブロモエトキシ）−６−フル
オロ−２−メチルクロマンの白色結晶２．２９ｇを得
た。(4) 1.58 g of 6-fluoro-2-methyl-8-chromanol obtained in (3) was dissolved in 7.5 ml of 1,2-dibromoethane, 10 ml of 3N aqueous sodium hydroxide solution and tetrahydrogen sulfate were added. Butyl ammonium (TBAHS) 150 mg was added and stirred at 70 ° C. for 2 hours. After cooling, the reaction mixture was extracted with dichloromethane, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was subjected to column chromatography and eluted with a mixed solvent of hexane-ethyl acetate (95: 5) to give 8- (bromoethoxy) -6-fluoro-2-methylchroman white crystals. 2.29 g was obtained.
【００５０】理化学的性状 質料分析値（ＥＩ，ｍ／ｚ）：２８８（Ｍ＋），２９０
（Ｍ＋＋２） 核磁気共鳴スペクトル（ＣＤＣｌ３，ＴＭＳ内部標準） δ：１．４３（３Ｈ，ｄ，２−ＣＨ３），１．６−２．
２（２Ｈ，ｍ，Ｃ３−Ｈ２），２．７−３．０（２Ｈ，
ｍ，Ｃ４−Ｈ２），３．６３（２Ｈ，ｔ，ＣＨ２Ｂ
ｒ），４．０−４．３（１Ｈ，ｍ，Ｃ２−Ｈ），４．２
９（２Ｈ，ｔ，ＯＣＨ２），６．４２（１Ｈ，ｄｄ），
６．５２（１Ｈ，ｄｄ） 参考例２Physicochemical properties Analytical value of material (EI, m / z): 288 (M + ), 290
(M + +2) Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.43 (3H, d, 2-CH 3 ), 1.6-2.
2 (2H, m, C3- H 2), 2.7-3.0 (2H,
m, C4-H 2), 3.63 (2H, t, CH 2 B
r), 4.0-4.3 (1H, m, C2-H), 4.2
9 (2H, t, OCH 2 ), 6.42 (1H, dd),
6.52 (1H, dd) Reference example 2
【００５１】[0051]
【化１０】 [Chemical 10]
【００５２】参考例１で得た８−（２−ブロモエトキ
シ）−６−フルオロ−２−メチルクロマン０．６０ｇ，
ベンジルアミン１．０７ｇをアセトニトリル６ｍｌに溶
解し，炭酸カリウム０．２９ｇを加え，３時間加熱還流
した。冷後エーテルを加えて不溶物を濾去し，濾液を減
圧濃縮して粗製のＮ−［２−（６−フルオロ−２−メチ
ル−８−クロマニルオキシ）エチル］ベンジルアミン
０．７８ｇを得た。次にこの粗製のアミンをメタノール
１０ｍｌに溶解し，１０％パラジウム炭素０．４ｇ，ギ
酸１．５ｍｌを加え，室温で２日間放置した。パラジウ
ム炭素を濾去し，溶媒を留去後残渣に水酸化ナトリウム
水溶液を加え，ジクロロメタンで抽出した。無水硫酸マ
グネシウムで乾燥後溶媒を留去し，２−（６−フルオロ
−２−メチル−８−クロマニルオキシ）エチルアミンの
固体 ０．４３ｇを得た。理化学的性状 質量分析値（ＥＩ，ｍ／ｚ）：２２５（Ｍ＋） 核磁気共鳴スペクトル（ＣＤＣｌ３， ＴＭＳ内部標
準） δ：１．４２（３Ｈ，ｄ，２’−ＣＨ３），１．５５
（２Ｈ，ｂｒ ｓ，ＮＨ２），１．６−２．２（２Ｈ，
ｍ，Ｃ３’−Ｈ２），２．７−３．０（２Ｈ，ｍ，Ｃ
４’−Ｈ２），３．０７（２Ｈ，ｔ，ＣＨ２Ｎ），４．
００（２Ｈ，ｔ，ＯＣＨ２），４．０−４．３（１Ｈ，
ｍ，Ｃ２−Ｈ），６．３−６．６（２Ｈ，ｍ） 実施例１0.60 g of 8- (2-bromoethoxy) -6-fluoro-2-methylchroman obtained in Reference Example 1,
1.07 g of benzylamine was dissolved in 6 ml of acetonitrile, 0.29 g of potassium carbonate was added, and the mixture was heated under reflux for 3 hours. After cooling, ether was added, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure to obtain 0.78 g of crude N- [2- (6-fluoro-2-methyl-8-chromanyloxy) ethyl] benzylamine. It was Next, this crude amine was dissolved in 10 ml of methanol, 0.4 g of 10% palladium carbon and 1.5 ml of formic acid were added, and the mixture was allowed to stand at room temperature for 2 days. Palladium carbon was filtered off, the solvent was distilled off, an aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 0.43 g of 2- (6-fluoro-2-methyl-8-chromanyloxy) ethylamine solid. Physicochemical properties Mass spectrometry value (EI, m / z): 225 (M + ) Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.42 (3H, d, 2′-CH 3 ), 1. 55
(2H, br s, NH 2 ), 1.6-2.2 (2H,
m, C3'-H 2), 2.7-3.0 (2H, m, C
4'-H 2), 3.07 ( 2H, t, CH 2 N), 4.
00 (2H, t, OCH 2 ), 4.0-4.3 (1H,
m, C2-H), 6.3-6.6 (2H, m) Example 1
【００５３】[0053]
【化１１】 [Chemical 11]
【００５４】８−（２−ブロモエトキシ）−６−フルオ
ロ−２−メチルクロマン（参考例１の化合物）３５０ｍ
ｇ，ｐ−メトキシフェネチルアミン３７０ｍｇをアセト
ニトリル５ｍｌに溶解し，炭酸カリウム１９０ｍｇを加
え，２時間加熱還流した。溶媒を留去し，残渣をシリカ
ゲルカラムクロマトグラフィーに付し，クロロホルム−
メタノール（９９：１）の混合溶媒で溶出することによ
り，無色油状の遊離塩基３７０ｍｇを得た。これを酢酸
エチル中塩化水素で処理することにより粗製の結晶を
得，さらに酢酸エチル−エーテルより再結晶して，Ｎ−
［２−（６−フルオロ−２−メチル−８−クロマニルオ
キシ）エチル］−ｐ−メチルフェネチルアミン 塩酸塩
０．２５水和物 ３７０ｍｇを得た。8- (2-Bromoethoxy) -6-fluoro-2-methylchroman (Compound of Reference Example 1) 350 m
370 mg of g, p-methoxyphenethylamine was dissolved in 5 ml of acetonitrile, 190 mg of potassium carbonate was added, and the mixture was heated under reflux for 2 hours. The solvent was evaporated, the residue was subjected to silica gel column chromatography, and chloroform-
By elution with a mixed solvent of methanol (99: 1), 370 mg of a colorless oily free base was obtained. This was treated with hydrogen chloride in ethyl acetate to give crude crystals, which were recrystallized from ethyl acetate-ether to give N-
370 mg of [2- (6-fluoro-2-methyl-8-chromanyloxy) ethyl] -p-methylphenethylamine hydrochloride 0.25 hydrate were obtained.
【００５５】理化学的性状 融点 １３８−１４０℃ 元素分析値 （Ｃ２１Ｈ２６ＮＯ３Ｆ・ＨＣｌ・０．２
５Ｈ２Ｏとして） C(%) H(%) N(%) Cl(%) F(%) 理論値 62.99 6.92 3.50 8.85 4.75 実験値 63.05 6.81 3.55 8.75 4.49Physicochemical properties Melting point 138-140 ° C. Elemental analysis value (C 21 H 26 NO 3 F.HCl.0.2
5H 2 O) C (%) H (%) N (%) Cl (%) F (%) Theoretical value 62.99 6.92 3.50 8.85 4.75 Experimental value 63.05 6.81 3.55 8.75 4.49
【００５６】理化学的性状 質量分析値（ＥＩ，ｍ／ｚ）：３６０（Ｍ＋＋１）（遊
離塩基基準） 核磁気共鳴スペクトル（ＣＤ３ＯＤ，ＴＭＳ内部標準） δ：１．３４（３Ｈ，ｄ，２’−ＣＨ３），１．６−
２．２（２Ｈ，ｍ，Ｃ３’−Ｈ２），２．７−３．０
（２Ｈ，ｍ，Ｃ４’−Ｈ２），２．９９（２Ｈ，ｔ，Ｎ
ＣＨ２ＣＨ ２Ａｒ），３．３７（２Ｈ，ｔ，ＮＣＨ ２Ｃ
Ｈ２Ａｒ），３．３７（２Ｈ，ｔ，ＯＣＨ２ＣＨ
２Ｎ），４．０−４．２（１Ｈ，ｍ，Ｃ２’−Ｈ），
４．２７（２Ｈ，ｔ，ＯＣＨ ２ＣＨ２Ｎ），６．５１
（１Ｈ，ｄｄ），６．６５（１Ｈ，ｄｄ），６．９０
（２Ｈ，ｄ），７．２２（２Ｈ，ｄ） 実施例２Physicochemical properties Mass spectrometric value (EI, m / z): 360 (M++1) (Yu
Base separation) Nuclear magnetic resonance spectrum (CDThreeOD, TMS internal standard) δ: 1.34 (3H, d, 2'-CHThree), 1.6-
2.2 (2H, m, C3'-HTwo), 2.7-3.0
(2H, m, C4'-HTwo), 2.99 (2H, t, N
CHTwoCH TwoAr), 3.37 (2H, t, NCH TwoC
HTwoAr), 3.37 (2H, t, OCHTwoCH
TwoN), 4.0-4.2 (1H, m, C2'-H),
4.27 (2H, t, OCH TwoCHTwoN), 6.51
(1H, dd), 6.65 (1H, dd), 6.90
(2H, d), 7.22 (2H, d) Example 2
【００５７】[0057]
【化１２】 [Chemical 12]
【００５８】（１）３−（ｐ−メトキシフェニル）プロ
ピオン酸１９０ｍｇをジクロロメタン２．５ｍｌに溶解
し，オキザリルクロリド１５０ｍｇおよびジメチルホル
ムアミド１滴を加え，室温で１時間撹拌した後，反応液
を濃縮して，対応する酸クロリドを得た。別に，２−
（６−フルオロ−２−メチル−８−クロマニルオキシ）
エチルアミン（参考例２の化合物）２００ｍｇおよびト
リエチルアミン１３０ｍｇをジクロロメタン３ｍｌに溶
解し，さきに調製した酸クロリドの塩化メチレン溶液
（２ｍｌ）を滴下後，室温で２時間撹拌した。(1) 190 mg of 3- (p-methoxyphenyl) propionic acid was dissolved in 2.5 ml of dichloromethane, 150 mg of oxalyl chloride and 1 drop of dimethylformamide were added, and the mixture was stirred at room temperature for 1 hour, and then the reaction solution was concentrated. The corresponding acid chloride was obtained. Separately, 2-
(6-Fluoro-2-methyl-8-chromanyloxy)
200 mg of ethylamine (the compound of Reference Example 2) and 130 mg of triethylamine were dissolved in 3 ml of dichloromethane, and the methylene chloride solution (2 ml) of the acid chloride prepared above was added dropwise, followed by stirring at room temperature for 2 hours.
【００５９】反応液を希塩酸，炭酸水素ナトリウム水溶
液，飽和食塩水の順で洗い，無水硫酸マグネシウムで乾
燥後溶媒を留去し，得られた固体をエーテルで洗浄し
て，Ｎ−［２−（６−フルオロ−２−メチル−８−クロ
マニルオキシ）エチル］−３−（ｐ−メトキトフェニ
ル）プロピオンアミド２８０ｍｇを得た。The reaction solution was washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and saturated saline in this order, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the obtained solid was washed with ether to obtain N- [2- ( 280 mg of 6-fluoro-2-methyl-8-chromanyloxy) ethyl] -3- (p-methotophenyl) propionamide were obtained.
【００６０】理化学的性状 質量分析値（ＦＡＢ，ｍ／ｚ）：３８８（Ｍ＋＋１） 核磁気共鳴スペクトル（ＣＤＣｌ３， ＴＭＳ内部標
準） δ：１．４１（３Ｈ，ｄ，２’−ＣＨ３），１．６−
２．２（２Ｈ，ｍ，Ｃ３’−Ｈ２），２．４７（２Ｈ，
ｔ，ＣＯＣＨ ２ＣＨ２Ａｒ），２．７−３．０（２Ｈ，
ｍ，Ｃ４’−Ｈ２），２．９１（２Ｈ，ｔ，ＣＯＣＨ２
ＣＨ ２Ａｒ），３．６２（２Ｈ，ｑ，ＯＣＨ２ＣＨ
２Ｎ），３．７４（３Ｈ，ｓ，ＯＣＨ３），３．９９
（２Ｈ，ｔ，ＯＣＨ ２ＣＨ２Ｎ），４．０−４．２（１
Ｈ，ｍ，Ｃ２’−Ｈ），６．１７（１Ｈ，ｂｒ ｓ，Ｎ
ＨＣＯ），６．４−６．６（２Ｈ，ｍ），６．７９（２
Ｈ，ｄ），７．１１（２Ｈ，ｄ）Physicochemical properties Mass spectrometric value (FAB, m / z): 388 (M++1) Nuclear magnetic resonance spectrum (CDClThree, TMS internal standard
Quasi) δ: 1.41 (3H, d, 2'-CHThree), 1.6-
2.2 (2H, m, C3'-HTwo), 2.47 (2H,
t, COCH TwoCHTwoAr), 2.7-3.0 (2H,
m, C4'-H2), 2.91 (2H, t, COCHTwo
CH TwoAr), 3.62 (2H, q, OCHTwoCH
TwoN), 3.74 (3H, s, OCHThree), 3.99
(2H, t, OCH TwoCHTwoN), 4.0-4.2 (1
H, m, C2'-H), 6.17 (1H, br s, N
HCO), 6.4-6.6 (2H, m), 6.79 (2
H, d), 7.11 (2H, d)
【００６１】（２）上記（１）で得たＮ−［２−（６−
フルオロ−２−メチル−８−クロマニルオキシ）エチ
ル］−３−（ｐ−メトキシフェニル）プロピオンアミド
２７０ｍｇにボラン−テトラヒドロフラン錯体（１Ｍテ
トラヒドロフラン溶液）２．１ｍｌを加え，２時間加熱
還流した後，メタノール０．２ｍｌおよび濃塩酸０．４
ｍｌを加え，更に１時間加熱還流した。反応混合物に水
酸化ナトリウム水溶液を加え，ジクロロメタンで抽出し
た。(2) N- [2- (6-
To 270 mg of fluoro-2-methyl-8-chromanyloxy) ethyl] -3- (p-methoxyphenyl) propionamide, 2.1 ml of borane-tetrahydrofuran complex (1M tetrahydrofuran solution) was added, and the mixture was heated under reflux for 2 hours and then methanol. 0.2 ml and concentrated hydrochloric acid 0.4
ml was added, and the mixture was heated under reflux for 1 hour. Aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with dichloromethane.
【００６２】溶媒を留去してシリカゲルカラムクロマト
グラフィーに付し，クロロホルム−メタノール（９９：
１）の混合溶媒で溶出することにより，油状の遊離塩基
２００ｍｇを得た。これをフマル酸２９ｍｇで処理して
フマル酸塩とし，エタノールから再結晶することによ
り，Ｎ−［２−（６−フルオロ−２−メチル−８−クロ
マニルオキシ）エチル］−３−（ｐ−メトキトフェニ
ル）プロピルアミン ヘミフマレート ０．２５水和物
２０２ｍｇを得た。The solvent was distilled off and the residue was subjected to silica gel column chromatography, chloroform-methanol (99:
By eluting with the mixed solvent of 1), 200 mg of an oily free base was obtained. This was treated with 29 mg of fumaric acid to give a fumarate and recrystallized from ethanol to give N- [2- (6-fluoro-2-methyl-8-chromanyloxy) ethyl] -3- (p- 202 mg of methokitophenyl) propylamine hemifumarate 0.25 hydrate was obtained.
【００６３】理化学的性状 融点 １２４−１２７℃ 元素分析値（Ｃ２２Ｈ２８ＮＯ３Ｆ・０．５Ｃ４Ｈ４Ｏ
４・０．２５Ｈ２Ｏとして） Ｃ（％） Ｈ（％） Ｎ（％） 理論値 ６６．１１ ７．０５ ３．２１ 実験値 ６６．２８ ７．２５ ３．１１Physicochemical properties Melting point 124-127 ° C. Elemental analysis value (C 22 H 28 NO 3 F.0.5C 4 H 4 O
4 · 0.25H 2 O as) C (%) H (% ) N (%) Theoretical values 66.11 7.05 3.21 Found 66.28 7.25 3.11
【００６４】理化学的性状 質量分析値（ＦＡＢ，ｍ／ｚ）：３７４（Ｍ＋＋１）
（遊離塩基基準） 核磁気共鳴スペクトル（ＣＤ３ＯＤ， ＴＭＳ内部標
準） δ：１．３９（３Ｈ，ｄ，２’−ＣＨ３），１．６−
２．２（４Ｈ，ｍ，Ｃ３’−Ｈ２，ＣＨ２ＣＨ ２ＣＨ２
Ａｒ），２．６６（２Ｈ，ｔ，ＣＨ２ＣＨ２ＣＨ ２Ａ
ｒ），２．７−２．９（２Ｈ，ｍ，Ｃ４’−Ｈ２），
３．０４（２Ｈ，ｔ，ＣＨ ２ＣＨ２ＣＨ２Ａｒ），３．
３４（２Ｈ，ｔ，ＯＣＨ２ＣＨ ２Ｎ），３．７５（３
Ｈ，ｓ，ＯＣＨ３），４．０−４．２（１Ｈ，ｍ，Ｃ
２’−Ｈ），４．１９（２Ｈ，ｔ，ＯＣＨ ２ＣＨ
２Ｎ），６．４９（１Ｈ，ｄｄ），６．６２（１Ｈ，ｄ
ｄ），６．６６（１Ｈ，ｓ，ＣＨ＝ＣＨ），６．８３
（２Ｈ，ｄ），７．１２（２Ｈ，ｄ） 実施例３Physicochemical properties Mass spectrometric value (FAB, m / z): 374 (M + +1)
(Based on free base) Nuclear magnetic resonance spectrum (CD 3 OD, TMS internal standard) δ: 1.39 (3H, d, 2′-CH 3 ), 1.6-
2.2 (4H, m, C3'- H2, CH 2 C H 2 CH 2
Ar), 2.66 (2H, t , CH 2 CH 2 C H 2 A
r), 2.7-2.9 (2H, m , C4'-H 2),
3.04 (2H, t, C H 2 CH 2 CH 2 Ar), 3.
34 (2H, t, OCH 2 C H 2 N), 3.75 (3
H, s, OCH 3), 4.0-4.2 (1H, m, C
2'-H), 4.19 (2H , t, OC H 2 CH
2 N), 6.49 (1H, dd), 6.62 (1H, d
d), 6.66 (1H, s, CH = CH), 6.83
(2H, d), 7.12 (2H, d) Example 3
【００６５】[0065]
【化１３】 [Chemical 13]
【００６６】（１）実施例２と同様の方法により，４−
（ｐ−メトキシフェニル）酪酸と２−（６−フルオロ−
２−メチル−８−クロマニルオキシ）エチルアミンとか
らＮ−［２−（６−フルオロ−２−メチル−８−クロマ
ニルオキシ）エチル］−４−（ｐ−メトキシフェニル）
酪酸アミドを得た。(1) By the same method as in the second embodiment, 4-
(P-Methoxyphenyl) butyric acid and 2- (6-fluoro-)
2-Methyl-8-chromanyloxy) ethylamine and N- [2- (6-fluoro-2-methyl-8-chromanyloxy) ethyl] -4- (p-methoxyphenyl)
Butyric acid amide was obtained.
【００６７】理化学的性状 質量分析値（ＦＡＢ，ｍ／ｚ）：４０２（Ｍ＋＋１） 核磁気共鳴スペクトル（ＣＤＣｌ３， ＴＭＳ内部標
準） δ：１．３９（３Ｈ，ｄ，２’−ＣＨ３），１．６−
２．１（４Ｈ，ｍ，Ｃ３’−Ｈ２，ＣＯＣＨ２ＣＨ ２Ｃ
Ｈ２Ａｒ），２．２０（２Ｈ，ｔ，ＣＯＣＨ ２ＣＨ２Ａ
ｒ），２．５９（２Ｈ，ｔ，ＣＯＣＨ２ＣＨ２ＣＨ ２Ａ
ｒ），２．６−３．０（２Ｈ，ｍ，Ｃ４’−Ｈ２），
３．６３（２Ｈ，ｑ，ＯＣＨ２ＣＨ ２Ｎ），３．７８
（３Ｈ，ｓ，ＯＣＨ３），４．０１（２Ｈ，ｔ，ＯＣＨ
２ＣＨ２Ｎ），４．０−４．２（１Ｈ，ｍ，Ｃ２’−
Ｈ），６．１９（１Ｈ，ｂｒ ｓ，ＮＨＣＯ），６．４
２（１Ｈ，ｄｄ），６．４９（１Ｈ，ｄｄ），６．８２
（２Ｈ，ｄ），７．０７（２Ｈ，ｄ）Physicochemical properties Mass spectrometric value (FAB, m / z): 402 (M + +1) Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.39 (3H, d, 2′-CH 3). ), 1.6-
2.1 (4H, m, C3'- H 2, COCH 2 C H 2 C
H 2 Ar), 2.20 (2H , t, COC H 2 CH 2 A
r), 2.59 (2H, t , COCH 2 CH 2 C H 2 A
r), 2.6-3.0 (2H, m , C4'-H 2),
3.63 (2H, q, OCH 2 C H 2 N), 3.78
(3H, s, OCH 3 ), 4.01 (2H, t, OC H
2 CH 2 N), 4.0-4.2 ( 1H, m, C2'-
H), 6.19 (1H, br s, NHCO), 6.4
2 (1H, dd), 6.49 (1H, dd), 6.82
(2H, d), 7.07 (2H, d)
【００６８】（２）上記（１）で得たＮ−［２−（６−
フルオロ−２−メチル−８−クロマニルオキシ）エチ
ル］−４−（ｐ−メトキトフェニル）酪酸アミドを実施
例２と同様に処理し，エタノール−エーテルから再結晶
して，Ｎ−［２−（６−フルオロ−２−メチル−８−ク
ロマニルオキシ）エチル］−４−（ｐ−メトキシフェニ
ル）ブチルアミン ヘミフマレート ０．２５水和物を
得た。(2) N- [2- (6-
Fluoro-2-methyl-8-chromanyloxy) ethyl] -4- (p-methochitophenyl) butyric acid amide was treated as in Example 2 and recrystallized from ethanol-ether to give N- [2- (6-Fluoro-2-methyl-8-chromanyloxy) ethyl] -4- (p-methoxyphenyl) butylamine hemifumarate 0.25 hydrate was obtained.
【００６９】理化学的性状 融点 １０３−１０４℃ 元素分析値（Ｃ２３Ｈ３０ＮＯ３Ｆ・０．５Ｃ４Ｈ４Ｏ
４・０．２５Ｈ２Ｏとして） Ｃ（％） Ｈ（％） Ｎ（％） Ｆ（％） 理論値 ６６．７２ ７．２８ ３．１１ ４．２２ 実験値 ６６．５６ ７．５２ ３．１２ ４．１５Physicochemical properties Melting point 103-104 ° C. Elemental analysis value (C 23 H 30 NO 3 F.0.5C 4 H 4 O
4 · 0.25H 2 as O) C (%) H ( %) N (%) F (%) Theoretical values 66.72 7.28 3.11 4.22 Found 66.56 7.52 3.12 4.15
【００７０】理化学的性状 質量分析値（ＦＡＢ，ｍ／ｚ）：３８８（Ｍ＋＋１）
（遊離塩基基準） 核磁気共鳴スペクトル（ＣＤＣｌ３， ＴＭＳ内部標
準） δ：１．３８（３Ｈ，ｄ，２’−ＣＨ３），１．５−
２．１（６Ｈ，ｍ，Ｃ３’−Ｈ２，ＣＨ２ＣＨ ２ＣＨ ２
ＣＨ２Ａｒ），２．５５（２Ｈ，ｔ，ＣＨ２ＣＨ２ＣＨ
２ＣＨ ２Ａｒ），２．６−２．９（２Ｈ，ｍ，Ｃ４’−
Ｈ２），２．９７（２Ｈ，ｔ，ＣＨ ２ＣＨ２ＣＨ２ＣＨ
２Ａｒ），３．２７（２Ｈ，ｔ，ＯＣＨ２ＣＨ ２Ｎ），
３．７６（３Ｈ，ｓ，ＯＣＨ３），４．０−４．２（１
Ｈ，ｍ，Ｃ２’−Ｈ），４．１８（２Ｈ，ｔ，ＯＣＨ ２
ＣＨ２Ｎ），６．４０（１Ｈ，ｄｄ），６．４６（１
Ｈ，ｄｄ），６．７１（１Ｈ，ｓ，ＣＨ＝ＣＨ），６．
８２（２Ｈ，ｄ），７．０５（２Ｈ，ｄ）Physical and chemical properties Mass spectrometric value (FAB, m / z): 388 (M + +1)
(Based on free base) Nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard) δ: 1.38 (3H, d, 2′-CH 3 ), 1.5-
2.1 (6H, m, C3'- H2, CH 2 C H 2 C H 2
CH 2 Ar), 2.55 (2H, t, CH 2 CH 2 CH
2 C H 2 Ar), 2.6-2.9 (2H, m, C4'-
H 2), 2.97 (2H, t, C H 2 CH 2 CH 2 CH
2 Ar), 3.27 (2H, t, OCH 2 C H 2 N),
3.76 (3H, s, OCH 3 ), 4.0-4.2 (1
H, m, C2'-H) , 4.18 (2H, t, OC H 2
CH 2 N), 6.40 (1H, dd), 6.46 (1
H, dd), 6.71 (1H, s, CH = CH), 6.
82 (2H, d), 7.05 (2H, d)
───────────────────────────────────────────────────── 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 Ａ６１Ｋ 31/35 ＡＥＮ 7252−4Ｃ (72)発明者 山口 時男 埼玉県浦和市領家６−16−３ シティコア 402 (72)発明者 鰐淵 文一 茨城県つくば市春日２−35−２ エトワ− ル春日303─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification number Reference number within the agency FI Technical display location A61K 31/35 AEN 7252-4C (72) Inventor Tokio Yamaguchi 6-16 Ryoke, Urawa City, Saitama Prefecture 3 Citycore 402 (72) Inventor Fumikazu Wanibuchi 2-35-2 Kasuga, Tsukuba, Ibaraki Prefecture Etoile Kasuga 303
Claims (1)
オキシアルキルアミン誘導体又はその塩。 【化１】 （式中の記号は，以下の意味を示す。 Ｒ１：水素原子または低級アルキル基。 Ｒ２：低級アルコキシ基。 Ｙ ：低級アルキレン基。）1. A chromanyloxyalkylamine derivative represented by the following general formula (I) or a salt thereof. [Chemical 1] (The symbols in the formulas have the following meanings: R 1 : hydrogen atom or lower alkyl group; R 2 : lower alkoxy group; Y: lower alkylene group.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4086016A JPH05255302A (en) | 1992-03-09 | 1992-03-09 | New chromanyloxyalkylamine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4086016A JPH05255302A (en) | 1992-03-09 | 1992-03-09 | New chromanyloxyalkylamine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05255302A true JPH05255302A (en) | 1993-10-05 |
Family
ID=13874880
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4086016A Pending JPH05255302A (en) | 1992-03-09 | 1992-03-09 | New chromanyloxyalkylamine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05255302A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994029293A1 (en) * | 1993-06-10 | 1994-12-22 | Yamanouchi Pharmaceutical Co., Ltd. | Novel 8-(2-aminoalkoxy)fluorochroman derivative |
| EP0707007A1 (en) * | 1994-10-14 | 1996-04-17 | MERCK PATENT GmbH | Amino(thio)ether derivatives as CNS active agents |
| WO1999051576A1 (en) * | 1998-04-08 | 1999-10-14 | American Home Products Corporation | N-aryloxyethylamine derivatives for the treatment of depression |
| WO1999051591A3 (en) * | 1998-04-08 | 1999-12-09 | American Home Prod | N-aryloxyethyl-indoly-alkylamines for the treatment of depression |
| US6110956A (en) * | 1998-04-08 | 2000-08-29 | American Home Products Corp. | N-aryloxyethylamine derivatives for the treatment of depression |
| US6121307A (en) * | 1998-04-08 | 2000-09-19 | American Home Products Corp. | N-aryloxyethyl-indoly-alkylamines for the treatment of depression |
| US6150533A (en) * | 1998-04-08 | 2000-11-21 | American Home Products Corp. | N-aryloxyethyl-indoly-alkylamines for the treatment of depression |
| JP2004501148A (en) * | 2000-06-20 | 2004-01-15 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Heterocyclic aminoalkylpyridine derivatives as psychotropic drugs |
| JP2006508080A (en) * | 2002-10-16 | 2006-03-09 | ピエール、ファーブル、メディカマン | 3- (Cyclopenten-1-yl) -benzyl- or 3- (cyclopenten-1-yl) -heteroarylmethylamine derivatives and their use as medicaments for treating schizophrenia |
-
1992
- 1992-03-09 JP JP4086016A patent/JPH05255302A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994029293A1 (en) * | 1993-06-10 | 1994-12-22 | Yamanouchi Pharmaceutical Co., Ltd. | Novel 8-(2-aminoalkoxy)fluorochroman derivative |
| EP0707007A1 (en) * | 1994-10-14 | 1996-04-17 | MERCK PATENT GmbH | Amino(thio)ether derivatives as CNS active agents |
| WO1999051576A1 (en) * | 1998-04-08 | 1999-10-14 | American Home Products Corporation | N-aryloxyethylamine derivatives for the treatment of depression |
| WO1999051591A3 (en) * | 1998-04-08 | 1999-12-09 | American Home Prod | N-aryloxyethyl-indoly-alkylamines for the treatment of depression |
| US6110956A (en) * | 1998-04-08 | 2000-08-29 | American Home Products Corp. | N-aryloxyethylamine derivatives for the treatment of depression |
| US6121307A (en) * | 1998-04-08 | 2000-09-19 | American Home Products Corp. | N-aryloxyethyl-indoly-alkylamines for the treatment of depression |
| US6150533A (en) * | 1998-04-08 | 2000-11-21 | American Home Products Corp. | N-aryloxyethyl-indoly-alkylamines for the treatment of depression |
| US6291683B1 (en) | 1998-04-08 | 2001-09-18 | American Home Products Corp | N-arloxyethyl-alkylamines for the treatment of depression |
| JP2002510676A (en) * | 1998-04-08 | 2002-04-09 | アメリカン・ホーム・プロダクツ・コーポレイション | N-aryloxyethylamine derivatives for treating depression |
| JP2004501148A (en) * | 2000-06-20 | 2004-01-15 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Heterocyclic aminoalkylpyridine derivatives as psychotropic drugs |
| JP2006508080A (en) * | 2002-10-16 | 2006-03-09 | ピエール、ファーブル、メディカマン | 3- (Cyclopenten-1-yl) -benzyl- or 3- (cyclopenten-1-yl) -heteroarylmethylamine derivatives and their use as medicaments for treating schizophrenia |
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