JP2860688B2 - Indole derivatives - Google Patents
Indole derivativesInfo
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- JP2860688B2 JP2860688B2 JP6390990A JP6390990A JP2860688B2 JP 2860688 B2 JP2860688 B2 JP 2860688B2 JP 6390990 A JP6390990 A JP 6390990A JP 6390990 A JP6390990 A JP 6390990A JP 2860688 B2 JP2860688 B2 JP 2860688B2
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Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、強いセロトニン２受容体拮抗作用を有し、
セロトニン２受容体に関する各種疾患の予防や治療、例
えば虚血性心疾患、脳血管障害等の循環器系疾患の予防
または治療、うつ病、精神***症等の精神病の治療等に
用いられる医薬品として有用な新規インドール誘導体ま
たはその塩に関する。The present invention has a strong serotonin 2 receptor antagonism,
Useful as pharmaceuticals used in the prevention and treatment of various diseases related to serotonin 2 receptor, for example, the prevention or treatment of circulatory system diseases such as ischemic heart disease and cerebrovascular disease, and the treatment of mental illness such as depression and schizophrenia. Novel indole derivatives or salts thereof.
セロトニンは血液成分である血小板に多く含まれてお
り、トロンボキサンA2やADP、コラーゲンなどにより血
小板の刺激に際して放出され、これらの血小板凝集物質
や血管収縮物質と協力的に働いて強い血小板凝集や血管
収縮を引き起こす。とりわけセロトニンの血管収縮作用
は強力である。セロトニンは血管及び血小板等にあるセ
ロトニン受容体を介して作用することが知られている。
セロトニン受容体にはセロトニン１受容体とセロトニン
２受容体等が存在するが、心筋梗塞のように冠血管の内
皮細胞が損傷を受けた場合などには、セロトニンはセロ
トニン２受容体を介して血管の収縮や血栓形成の促進を
引き起こし、心筋や脳などの器官に対して血液の供給を
減少、または途絶させる１つの要因となる。また、動脈
硬化などの病変がある場合にはセロトニンの血管収縮作
用がより強く働くことも知られている。現在、このよう
な点に注目し、セロトニン２受容体拮抗薬を心臓や脳の
虚血性疾患用薬とする試みが進みつつある。Serotonin are abundant in platelets is blood components, thromboxane A 2 and ADP, is released upon such a platelet stimulation collagen, stronger platelet aggregation Ya working cooperatively with these platelet aggregation agent and vasoconstrictor Causes vasoconstriction. In particular, vasoconstrictor action of serotonin is strong. Serotonin is known to act via serotonin receptors on blood vessels, platelets and the like.
Serotonin receptors include serotonin 1 receptor and serotonin 2 receptor, but when endothelial cells of coronary vessels are damaged such as in myocardial infarction, serotonin is mediated by serotonin 2 receptors. It causes contraction of blood vessels and promotes thrombus formation, which is one factor that reduces or interrupts blood supply to organs such as the myocardium and the brain. It is also known that serotonin exerts a stronger vasoconstrictive action when there is a lesion such as arteriosclerosis. Attention has been paid to such points at present, and attempts are being made to use serotonin 2 receptor antagonists as drugs for ischemic diseases of the heart and brain.
既知のセロトニン２受容体拮抗作用を有する化合物と
しては、医療に使われているものとしてケタンセリン
が、また、まだ実際に医療に使われてはいないものとし
てリタンセリン、イリンダロンなどが知られている。Known compounds having a serotonin 2 receptor antagonism include ketanserin, which is used in medicine, and ritanserin, irinderone, etc., which are not actually used in medicine.
本発明はセロトニン２受容体に対し強力な拮抗作用を
有する新規化合物を提供することを目的とする。An object of the present invention is to provide a novel compound having a strong antagonistic action on serotonin 2 receptor.
このような実情において、本発明者らは鋭意研究を行
なった結果、下記新規インドール誘導体が経口投与にお
いても強いセロトニン２受容体拮抗作用を有することを
見いだし、本発明を完成した。Under such circumstances, the present inventors have conducted intensive studies, and as a result, have found that the following novel indole derivatives have a strong serotonin 2 receptor antagonistic activity even when administered orally, and have completed the present invention.
すなわち、本発明は次の一般式（Ｉ） 〔式中、R1は水素原子、ハロゲン原子を示し、R2は水素
原子、低級アルキル基、又はハロゲン原子で置換されて
いてもよいフェニル基を示し、R3は水素原子、低級アル
キル基、又はハロゲン原子で置換されていてもよいフェ
ニル基もしくはアラルキル基を示し、Ｑは炭素数２〜８
の直鎖又は分岐状のアルキレン基を示し、Hetは次の一
般式（II）〜（IV） のいずれかで表わされる置換基を示す。但し、Hetが式
（IV）で示される基のときは、R3は水素原子又は低級ア
ルキル基を示す。〕 で表わされるインドール誘導体及びその塩を提供するも
のである。That is, the present invention provides the following general formula (I) (In the formula, R 1 represents a hydrogen atom, a halogen atom, R 2 represents a hydrogen atom, a lower alkyl group, or a phenyl group which may be substituted with a halogen atom, R 3 is a hydrogen atom, a lower alkyl group, Or a phenyl group or an aralkyl group which may be substituted with a halogen atom;
Represents a linear or branched alkylene group, and Het has the following general formula (II) to (IV) And a substituent represented by any of However, when Het is a group represented by the formula (IV), R 3 represents a hydrogen atom or a lower alkyl group. ] It provides the indole derivative represented by these, and its salt.
本発明において、低級アルキル基は直鎖状、分岐状の
いずれをも意味し、その例としては、メチル基、エチル
基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、
ｔ−ブチル基等の炭素数１〜７のものが挙げられる。ハ
ロゲン原子としてはフッ素原子、塩素原子、臭素原子又
はヨウ素原子が挙げられる。アラルキル基としてはベン
ジル基、フェネチル基、フェニルプロピル基、フェニル
ブチル基、ジフェニルメチル基、ジフェニルエチル基、
ジフェニルプロピル基、トリフェニルメチル基、ナフチ
ルメチル基、ナフチルエチル基等が挙げられる。In the present invention, the lower alkyl group means either linear or branched, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
Those having 1 to 7 carbon atoms such as a t-butyl group are exemplified. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Aralkyl groups include benzyl, phenethyl, phenylpropyl, phenylbutyl, diphenylmethyl, diphenylethyl,
Examples include a diphenylpropyl group, a triphenylmethyl group, a naphthylmethyl group, and a naphthylethyl group.
また、本発明インドール誘導体（Ｉ）の塩としては、
塩酸、硫酸、硝酸、りん酸等の鉱酸；メタンスルホン
酸、ベンゼンスルホン酸、トルエンスルホン酸等の有機
スルホン酸；または酒石酸、マレイン酸、フマール酸、
りんご酸、しゅう酸、乳酸、クエン酸等の有機カルボン
酸による酸付加塩などが挙げられる。The salt of the indole derivative (I) of the present invention includes
Mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; or tartaric acid, maleic acid, fumaric acid,
Acid addition salts with organic carboxylic acids such as malic acid, oxalic acid, lactic acid, citric acid and the like.
本発明のインドール誘導体（Ｉ）は、例えば下記反応
式に従って製造される。The indole derivative (I) of the present invention is produced, for example, according to the following reaction formula.
（式中、R1、R2、R3、Ｑは前記と同じ意味を示し、Ｘは
ハロゲン原子、アルキルスルホニルオキシ基又はアリー
ルスルホニルオキシ基を示す。） すなわち、化合物（VI）と、化合物（VII）〜（IX）
のいずれかとを、塩基の存在下、溶媒中で室温〜溶媒の
沸点の温度にて反応させることにより、本発明インドー
ル誘導体（Ｉ）が製造される。 (Wherein, R 1 , R 2 , R 3 , and Q have the same meanings as described above, and X represents a halogen atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group.) That is, the compound (VI) and the compound ( VII)-(IX)
Is reacted in a solvent at a temperature from room temperature to the boiling point of the solvent in the presence of a base to produce the indole derivative (I) of the present invention.
本反応において、アルキルスルホニルオキシ基として
は例えばメタンスルホニルオキシ基等が、アリールスル
ホニルオキシ基としては例えばトルエンスルホニルオキ
シ基等が使用される。また、塩基としては例えば炭酸ナ
トリウム、炭酸カリウム、トリエチルアミン等が、溶媒
としてはジメチルホルムアミド、ジメチルスルホキシ
ド、アセトニトリル、ジメチルアセトアミド、Ｎ−メチ
ルピロリドン、ベンゼン等が使用される。また、必要に
応じてヨウ化ナトリウム、ヨウ化カリウム等のヨウ化ア
ルカリを存在せしめて反応を行ってもよい。In this reaction, for example, a methanesulfonyloxy group or the like is used as the alkylsulfonyloxy group, and a toluenesulfonyloxy group or the like is used as the arylsulfonyloxy group. Further, as the base, for example, sodium carbonate, potassium carbonate, triethylamine and the like are used, and as the solvent, dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidone, benzene and the like are used. If necessary, the reaction may be carried out in the presence of an alkali iodide such as sodium iodide or potassium iodide.
また、本発明のインドール誘導体（Ｉ）は、下記反応
式に従って製造することもできる。Further, the indole derivative (I) of the present invention can also be produced according to the following reaction formula.
（式中、R1、R2、R3、Ｑは前記と同じ意味を示す。） すなわち、（化合物（Ｘ）と、化合物（XI）〜（XII
I）のいずれかとを、トリフェニルホスフィン及びアゾ
ジカルボン酸アルキルエステルの存在下、溶媒中で０℃
〜溶媒の沸点までの温度にて反応させることにより、本
発明インドール誘導体（Ｉ）が製造される。 (In the formula, R 1 , R 2 , R 3 , and Q have the same meanings as described above.) That is, (Compound (X) and compounds (XI) to (XII)
Any one of the above I) is subjected to 0 ° C. in a solvent in the presence of triphenylphosphine and an alkyl azodicarboxylate.
By reacting at a temperature up to the boiling point of the solvent, the indole derivative (I) of the present invention is produced.
本反応において、溶媒としては例えばテトラヒドロフ
ラン、ジメチルホルムアミド、ジオキサン、Ｎ−メチル
ピロリドン等が使用される。In this reaction, for example, tetrahydrofuran, dimethylformamide, dioxane, N-methylpyrrolidone and the like are used as a solvent.
かくして得られたインドール誘導体（Ｉ）は、必要に
応じて常法により酸付加塩に変換させ、自体公知の手
段、例えば再結晶、カラムクロマトグラフィー等により
単離することができる。The thus obtained indole derivative (I) can be converted into an acid addition salt by a conventional method, if necessary, and can be isolated by a means known per se, for example, recrystallization, column chromatography and the like.
試験例1.セロトニン２受容体拮抗活性の測定（インビト
ロ試験） SD−SLC雄性ラットから頸動脈放血致死後胸部大動脈
を摘出し、幅5mmのリング標本としてマグヌス装置に懸
垂（張力1g）した。張力はFD−ピックアップを介し、ポ
リグラフを用いて記録した。栄養液にはクレブス−ヘン
セライト（Krebs−Henselite）栄養液を用い、95％酸素
ガスと５％炭酸ガスの混合ガスを通気し、37℃に保温し
た。90分間の標本安定化後に塩化カリウム60mMで血管を
収縮させた。塩化カリウムを洗浄した60分後にセロトニ
ンを累積的に添加してその収縮高を測定した。さらに標
本の洗浄安定化後に後記実施例で得られた本発明化合物
の0.01〜10μＭを添加し、セロトニンに対する血管の収
縮高を測定し、その値からpA2値を算出した。Test Example 1. Measurement of Serotonin 2 Receptor Antagonistic Activity (In Vitro Test) The thoracic aorta was extirpated from a male SD-SLC rat after exsanguination by carotid artery exsanguination, and suspended in a Magnus apparatus (1 g tension) as a 5 mm wide ring specimen. Tension was recorded using a polygraph via an FD-pickup. A Krebs-Henselite nutrient solution was used as the nutrient solution, and a mixture of 95% oxygen gas and 5% carbon dioxide gas was passed through the nutrient solution, and the temperature was maintained at 37 ° C. After 90 minutes of sample stabilization, vessels were contracted with 60 mM potassium chloride. Sixty minutes after washing the potassium chloride, serotonin was added cumulatively and the shrinkage height was measured. Furthermore, after washing and stabilizing the sample, 0.01 to 10 μM of the compound of the present invention obtained in Examples described later was added, and the blood vessel contraction height against serotonin was measured, and the pA2 value was calculated from the value.
試験例2.セロトニン２受容体拮抗活性の測定（インビボ
試験） SD−SLC雄性ラットに、後記実施例で得られた本発明
化合物10mg/kgを精製水に溶解して経口投与した。30分
後にウレタン（1g/kg,腹腔内投与）とα−クロラロース
（80mg/kg,腹腔内投与）を用いて麻酔した。頸動脈にポ
リエチレンカニューレを挿入し、圧トランスジューサー
を介してポリグラフレコーダーに血圧を記録した。被検
化合物を投与した60分後にセロトニン（300μg/kg）を
静注して昇圧反応を観察した。精製水を投与した対照群
の昇圧反応と被検化合物の投与群の昇圧反応より抑制率
を算出した。Test Example 2. Measurement of Serotonin 2 Receptor Antagonistic Activity (In Vivo Test) To SD-SLC male rats, 10 mg / kg of the compound of the present invention obtained in Examples described later was dissolved in purified water and orally administered. Thirty minutes later, anesthesia was performed using urethane (1 g / kg, intraperitoneal administration) and α-chloralose (80 mg / kg, intraperitoneal administration). A polyethylene cannula was inserted into the carotid artery and blood pressure was recorded on a polygraph recorder via a pressure transducer. Sixty minutes after the administration of the test compound, serotonin (300 μg / kg) was intravenously injected and the pressor response was observed. The inhibition rate was calculated from the pressor response of the control group to which purified water was administered and the pressor response of the test compound administration group.
試験例１及び２の結果を表１に示す。 Table 1 shows the results of Test Examples 1 and 2.
その結果、本発明のインドール誘導体は非常に強力な
セロトニン２受容体拮抗作用を有し、その強さは既知の
セロトニン拮抗薬のケタンセリンよりも優れていること
が分かる。 As a result, it is found that the indole derivative of the present invention has a very strong serotonin 2 receptor antagonism, and its strength is superior to that of the known serotonin antagonist ketanserin.
従って、本発明のインドール誘導体は循環器系疾患、
精神病等に対する医薬品の有効成分として有用である。Therefore, the indole derivative of the present invention is a cardiovascular disease,
It is useful as an active ingredient of medicines for psychosis and the like.
以下、実施例を挙げて更に詳細に説明するが、本発明
はこれらに限定されるものではない。Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
参考例1.2−（２−クロロエチル）−5,6,7,8−テトラヒ
ドロ−1,2,4−トリアゾロ〔4,3−ａ〕ピリジン−３（2
H）−オン 5,6,7,8−テトラヒドロ−1,2,4−トリアゾロ〔4,3−
ａ〕ピリジン−３（2H）−オン61.0g、１−ブロモ−２
−クロロエタン164g及び無水炭酸カリウム90.8gをアセ
トニトリル500ml中で８時間加熱還流した。不溶物をろ
去後、溶媒を減圧留去して残渣をシリカダルカラムクロ
マトグラフィー（200g）に付し、クロロホルムとエタノ
ールの混液（20:1）で溶出した。イソプロピルエーテル
とエーテルの混液で結晶化し、ろ取後、表題化合物の無
色結晶59.8g（収率67.6％）を得た。mp46−49℃。Reference Example 1.2- (2-chloroethyl) -5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyridine-3 (2
H) -one 5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-
a] 61.0 g of pyridin-3 (2H) -one, 1-bromo-2
164 g of chloroethane and 90.8 g of anhydrous potassium carbonate were heated under reflux in 500 ml of acetonitrile for 8 hours. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure, and the residue was subjected to silica column chromatography (200 g), and eluted with a mixed solution of chloroform and ethanol (20: 1). Crystallization was performed with a mixed solution of isopropyl ether and ether, and after filtration, 59.8 g (yield 67.6%) of colorless crystals of the title compound were obtained. mp 46-49 ° C.
IR νmax（KBr）cm-1:1700,1580,1495,1435,1410 NMR（DMSO−d6）δ:1.7−2.1（4H,m）,2.68（2H,t）,3.
62（2H,t）,3.77（2H,t）,4.07（2H,t） 参考例2.1−（２−トシルオキシエチル）−２−イミダ
リジノン ２−（２−アミノエチルアミノ）エタノール43.2g、
尿素24.9gを200℃に３時間加熱攪拌した。冷却後、ジク
ロロメタン400mlを加えて反応混合物を溶解し、トリエ
チルアミン75mlを加え、氷冷攪拌下、トシルクロリド9
4.9gを加えて4.5時間攪拌した。反応液に１規定塩酸を
加えて洗浄、水洗、乾燥後、溶媒を減圧留去した。析出
した結晶をろ取し、表題化合物の無色針状晶82.8g（収
率70％）を得た。mp111−112℃。 IR νmax (KBr) cm -1: 1700,1580,1495,1435,1410 NMR (DMSO-d 6) δ: 1.7-2.1 (4H, m), 2.68 (2H, t), 3.
62 (2H, t), 3.77 (2H, t), 4.07 (2H, t) Reference Example 2.1- (2-Tosyloxyethyl) -2-imidaridinone 2- (2-aminoethylamino) ethanol 43.2 g,
24.9 g of urea was heated and stirred at 200 ° C. for 3 hours. After cooling, 400 ml of dichloromethane was added to dissolve the reaction mixture, 75 ml of triethylamine was added, and tosyl chloride 9
4.9 g was added and the mixture was stirred for 4.5 hours. The reaction mixture was washed with 1N hydrochloric acid, washed with water and dried, and the solvent was distilled off under reduced pressure. The precipitated crystals were collected by filtration to obtain 82.8 g (70% yield) of colorless needles of the title compound. mp 111-112 ° C.
IR νmax（KBr）cm-1:3236,3096,1696,1598,1500,1462 NMR（CDCl3）δ:2.44（3H,s）,3.43（6H,m）,3.9（1H,
b）,4.15（2H,t）,7.34（2H,d）,7.79（2H,d） 参考例3.6,7,8,9−テトラヒドロ−2H−ピリド〔1,2−
ａ〕−1,3,5−トリアジン−2,4（3H）−ジオン 金属ナトリウム0.83gと無水エタノール40mlから調製
したソジウム・エトキサイドのエタノール溶液に、氷冷
下２−アミノ−3,4,5,6−テトラヒドロピリジン塩酸塩
4.8gを加えて室温で30分攪拌した。不溶物をろ去後、ろ
液を減圧乾固した。残渣にテトラヒドロフラン30mlを加
えて懸濁し、氷冷攪拌下フェノキシカルボニルイソシア
ナート5.9gを10分間で滴下した。一夜室温に放置して析
出した結晶をろ取後、1.4gを得た。更に、ろ液を減圧乾
固して残渣をシリカゲルカラムクロマトグラフィー（10
0g）に付し、５％メタノール含有クロロホルムで溶出
後、結晶2.04gを得た。先の結晶と合わせ、表題化合物
の無色結晶3.44g（収率57％）を得た。IR νmax (KBr) cm -1 : 3236,3096,1696,1598,1500,1462 NMR (CDCl 3 ) δ: 2.44 (3H, s), 3.43 (6H, m), 3.9 (1H,
b), 4.15 (2H, t), 7.34 (2H, d), 7.79 (2H, d) Reference Example 3.6, 7, 8, 9-tetrahydro-2H-pyrido [1, 2-
a] -1,3,5-Triazine-2,4 (3H) -dione To a solution of sodium ethoxide prepared from 0.83 g of sodium metal and 40 ml of absolute ethanol was added 2-amino-3,4,5 , 6-Tetrahydropyridine hydrochloride
4.8 g was added and the mixture was stirred at room temperature for 30 minutes. After removing the insoluble matter by filtration, the filtrate was dried under reduced pressure. The residue was suspended by adding 30 ml of tetrahydrofuran, and 5.9 g of phenoxycarbonyl isocyanate was added dropwise over 10 minutes while stirring with ice cooling. After leaving overnight at room temperature, the precipitated crystals were collected by filtration to obtain 1.4 g. Further, the filtrate is dried under reduced pressure, and the residue is subjected to silica gel column chromatography (10
0g), and eluted with chloroform containing 5% methanol to obtain 2.04 g of crystals. The crystals were combined with the above crystals to give 3.44 g (57% yield) of colorless crystals of the title compound.
mp185−187℃。mp 185-187 ° C.
NMR（DMSO−d6）δ:1.6−1.9（4H,m）,2.65（2H,t）,3.
64（2H,t）,11.39（1H,b） IR νmax（KBr）cm-1:3450,3200,3070,1700,1590,1490,
1440,1390 元素分析 C7H9N3O2として 計算値（％）:C,50.30;H,5.43;N,25.14 実験値（％）:C,50.37;H,5.45;N,24.91 実施例１ ２−〔２−［４−［１−（４−フルオロフェ
ニル）−1H−インドール−３−イル］ピペリジン−１−
イル］エチル〕−5,6,7,8−テトラヒドロ−1,2,4−トリ
アゾロ〔4,3−ａ〕ピリジン−３（2H）−オン 塩酸塩
〔本発明化合物１〕 ４−〔１−（４−フルオロフェニル）−1H−インドー
ル−３−イル〕ピペリジン塩酸塩1.1g、２−（２−クロ
ロエチル）−5,6,7,8−テトラヒドロ−1,2,4−トリアゾ
ロ〔4.3−ａ〕ピリジン−３（2H）−オン0.67g、炭酸カ
リウム1.11g及びヨウ化ナトリウム0.3gをジメチルホル
ムアミド20ml中に混合し、80℃にて21時間加熱攪拌し
た。冷後、減圧濃縮して得られる残渣を酢酸エチルにて
抽出し、抽出液を水洗乾燥後減圧濃縮した。残渣をシリ
カゲルカラムクロマトグラフィーにて精製して得られる
油状物を、エタノールに溶解し、濃塩酸0.2mlを加えて
減圧濃縮した。得られる粉末をアセトンより再結晶して
融点234−237℃の表題化合物の無色結晶0.69gを得た。 NMR (DMSO-d 6) δ : 1.6-1.9 (4H, m), 2.65 (2H, t), 3.
64 (2H, t), 11.39 (1H, b) IR νmax (KBr) cm -1 : 3450,3200,3070,1700,1590,1490,
1440,1390 Elemental analysis As C 7 H 9 N 3 O 2 Calculated value (%): C, 50.30; H, 5.43; N, 25.14 Experimental value (%): C, 50.37; H, 5.45; N, 24.91 12- [2- [4- [1- (4-Fluorophenyl) -1H-indol-3-yl] piperidin-1-
Yl] ethyl] -5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyridin-3 (2H) -one hydrochloride [Compound 1 of the present invention] 4- [1- (4-Fluorophenyl) -1H-indol-3-yl] piperidine hydrochloride 1.1 g, 2- (2-chloroethyl) -5,6,7,8-tetrahydro-1,2,4-triazolo [4.3-a 0.67 g of pyridine-3 (2H) -one, 1.11 g of potassium carbonate and 0.3 g of sodium iodide were mixed in 20 ml of dimethylformamide, and heated and stirred at 80 ° C. for 21 hours. After cooling, the residue obtained by concentration under reduced pressure was extracted with ethyl acetate, and the extract was washed with water, dried and concentrated under reduced pressure. The residue obtained by purifying the residue by silica gel column chromatography was dissolved in ethanol, concentrated hydrochloric acid (0.2 ml) was added, and the mixture was concentrated under reduced pressure. The obtained powder was recrystallized from acetone to obtain 0.69 g of colorless crystals of the title compound having a melting point of 234-237 ° C.
実施例２〜17 実施例１と同様にして本発明化合物２〜17を得た。Examples 2 to 17 The compounds of the present invention 2 to 17 were obtained in the same manner as in Example 1.
実施例18 ３−〔２−［４−［１−（４−フルオロフェ
ニル）−1H−インドール−３−イル］ピペリジン−１−
イル］エチル〕−6,7,8,9−テトラヒドロ−2H−ピリド
〔1,2−ａ〕−1,3,5−トリアジン−2,4（3H）−ジオン
二塩酸塩 1/2水和物〔本発明化合物18〕 ジメチルホルムアミド10mlに１−（ヒドロキシエチ
ル）−４−〔１−（４−フルオロフェニル）−1H−イン
ドール−３−イル〕ピペリジン0.86g、6,7,8,9−テトラ
ヒドロ−2H−ピリド〔1,2−ａ〕−1,3,5−トリアジン−
2,4（3H）−ジオン0.43g及びトリフェニルフォスフィン
0.73gを加えて攪拌した。ジエチルアゾジカルボキシレ
ート0.49gとジメチルホルムアミド5mlよりなる溶液を滴
下し、室温にて20分間攪拌した。反応液を減圧濃縮し、
残渣をシリカゲルカラムクロマトグラフィーにて精製し
た。３％メタノール含有クロロホルムにて溶出し、目的
物を含む溶出液を集め、減圧濃縮して表題化合物の遊離
塩基の淡黄色油状物0.81g（収率65％）を得た。Example 18 3- [2- [4- [1- (4-fluorophenyl) -1H-indol-3-yl] piperidin-1-
Yl] ethyl] -6,7,8,9-tetrahydro-2H-pyrido [1,2-a] -1,3,5-triazine-2,4 (3H) -dione dihydrochloride hydrate [Compound 18 of the present invention] 0.86 g of 1- (hydroxyethyl) -4- [1- (4-fluorophenyl) -1H-indol-3-yl] piperidine in 10 ml of dimethylformamide, 6,7,8,9- Tetrahydro-2H-pyrido [1,2-a] -1,3,5-triazine-
0.43 g of 2,4 (3H) -dione and triphenylphosphine
0.73 g was added and stirred. A solution consisting of 0.49 g of diethyl azodicarboxylate and 5 ml of dimethylformamide was added dropwise, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure,
The residue was purified by silica gel column chromatography. The mixture was eluted with chloroform containing 3% methanol, and the eluate containing the target compound was collected and concentrated under reduced pressure to obtain 0.81 g (yield: 65%) of a pale yellow oily substance of the free base of the title compound.
NMR（CDCl3）δ:1.7−2.4（10H,m）,2.6−3.0（5H,m）,
3.1（2H,m）,3.8（2H,m）,4.12（2H,t）,7.0−7.7（9H,
m） 得られた遊離塩基をアセトンとエタノールの混液に溶
解し、濃塩酸0.3mlを加えて減圧濃縮した。残渣をアセ
トン−エタノールの混液より再結晶し、表題化合物の結
晶0.38gを得た。NMR (CDCl 3 ) δ: 1.7-2.4 (10H, m), 2.6-3.0 (5H, m),
3.1 (2H, m), 3.8 (2H, m), 4.12 (2H, t), 7.0-7.7 (9H,
m) The obtained free base was dissolved in a mixture of acetone and ethanol, 0.3 ml of concentrated hydrochloric acid was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixture of acetone and ethanol to obtain 0.38 g of crystals of the title compound.
IR νmax（KBr）cm-1:3420,2930,2470,1770,1730,1610,
1580,1515 本発明化合物１〜18の構造式、融点、元素分析及び1H
−NMRスペクトルを表２に示す。IR νmax (KBr) cm -1 : 3420,2930,2470,1770,1730,1610,
1580,1515 Structural formulas, melting points, elemental analysis and 1 H of Compounds 1 to 18 of the present invention
Table 2 shows the -NMR spectrum.
フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ Ａ６１Ｋ 31/53 ＡＢＮ Ａ６１Ｋ 31/53 ＡＢＮ (72)発明者 芝野 俊郎 東京都江戸川区北葛西１丁目16番13号 第一製薬中央研究所内 (56)参考文献 特開 昭61−148175（ＪＰ，Ａ) 特開 昭55−105679（ＪＰ，Ａ) 特開 平２−290872（ＪＰ，Ａ) (58)調査した分野(Int.Cl.6，ＤＢ名) C07D 401/14 C07D 471/04 ＣＡ ＲＥＧＩＳＴＲＹ（ＳＴＮ)Continuation of the front page (51) Int.Cl. 6 Identification code FI A61K 31/53 ABN A61K 31/53 ABN (72) Inventor Toshiro Shibano 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Central Research Laboratory (56) reference Patent Sho 61-148175 (JP, a) JP Akira 55-105679 (JP, a) JP flat 2-290872 (JP, a) (58 ) investigated the field (Int.Cl. 6 , DB name) C07D 401/14 C07D 471/04 CA REGISTRY (STN)
Claims (1)
原子、低級アルキル基、又はハロゲン原子で置換されて
いてもよいフェニル基を示し、R3は水素原子、低級アル
キル基、又はハロゲン原子で置換されていもよいフェニ
ル基もしくはアラルキル基を示し、Ｑは炭素数２〜８の
直鎖又は分岐状のアルキレン基を示し、Hetは次の一般
式（II）〜（IV） のいずれかで表わされる置換基を示す。但し、Hetが式
（IV）で示される基のときは、R3は水素原子又は低級ア
ルキル基を示す。〕 で表わされるインドール誘導体及びその塩。1. The following general formula (I) (In the formula, R 1 represents a hydrogen atom, a halogen atom, R 2 represents a hydrogen atom, a lower alkyl group, or a phenyl group which may be substituted with a halogen atom, R 3 is a hydrogen atom, a lower alkyl group, Or a phenyl group or an aralkyl group which may be substituted with a halogen atom, Q represents a linear or branched alkylene group having 2 to 8 carbon atoms, and Het represents the following general formula (II) to (IV) And a substituent represented by any of However, when Het is a group represented by the formula (IV), R 3 represents a hydrogen atom or a lower alkyl group. ] The indole derivative represented by these, and its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6390990A JP2860688B2 (en) | 1990-03-14 | 1990-03-14 | Indole derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6390990A JP2860688B2 (en) | 1990-03-14 | 1990-03-14 | Indole derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03264581A JPH03264581A (en) | 1991-11-25 |
| JP2860688B2 true JP2860688B2 (en) | 1999-02-24 |
Family
ID=13242933
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6390990A Expired - Fee Related JP2860688B2 (en) | 1990-03-14 | 1990-03-14 | Indole derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2860688B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4414113A1 (en) * | 1994-04-22 | 1995-10-26 | Merck Patent Gmbh | 3-indolylpiperidines |
| DE19500689A1 (en) * | 1995-01-12 | 1996-07-18 | Merck Patent Gmbh | Indole piperidine derivatives |
| GB9718712D0 (en) | 1997-09-03 | 1997-11-12 | Merck Sharp & Dohme | Theraputic Agents |
| GB9810886D0 (en) * | 1998-05-13 | 1998-07-22 | Lilly Industries Ltd | Pharmaceutical compounds |
-
1990
- 1990-03-14 JP JP6390990A patent/JP2860688B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH03264581A (en) | 1991-11-25 |
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