JP2004107299A - New 1-substituted urasil derivative and therapeutic agent for allergic disease - Google Patents

New 1-substituted urasil derivative and therapeutic agent for allergic disease Download PDF

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JP2004107299A
JP2004107299A JP2002275714A JP2002275714A JP2004107299A JP 2004107299 A JP2004107299 A JP 2004107299A JP 2002275714 A JP2002275714 A JP 2002275714A JP 2002275714 A JP2002275714 A JP 2002275714A JP 2004107299 A JP2004107299 A JP 2004107299A
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2h
ar
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uracil
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Yoshiaki Isobe
Ikuhiro Obara
小原 郁博
磯部 義明
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Japan Energy Corp
株式会社ジャパンエナジー
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound having also antiinflammatory action in addition to antihistamic action. <P>SOLUTION: The present invention provides a salt of a compound represented by general formula (I) which is an urasil derivative having a substituted piperidine or piperazine through a spacer from a phenyl group at first position of 1-phenyl-2, 4(1H, 3H)-pyrimidinedione skeleton and pharmaceutical applications thereof. Concrete one example of the compound represented by general formula (I) is 6-amino-1-[4-[3-[4-(diphenylmethyl)-1-piperazinyl]pyropyl]aminocarbonylphenyl]-3-methyluracyl. <P>COPYRIGHT: (C)2004,JPO

Description

【0001】 [0001]
【発明の属する技術分野】 BACKGROUND OF THE INVENTION
本発明は、優れた抗アレルギー作用、抗ヒスタミン作用、抗炎症作用などを有し、アトピー性皮膚炎、アレルギー鼻炎、気管支喘息、アレルギー性結膜炎、慢性蕁麻疹などの予防・治療剤として有用な新規なウラシル誘導体及びその医薬用途に関する。 The present invention has an excellent antiallergic action, antihistaminic action, having a like anti-inflammatory action, atopic dermatitis, allergic rhinitis, bronchial asthma, allergic conjunctivitis, useful novel as a prophylactic or therapeutic agent for chronic urticaria a related uracil derivatives and their pharmaceutical use.
【0002】 [0002]
【従来の技術】 BACKGROUND OF THE INVENTION
アレルギー性結膜炎、アレルギー性鼻炎、慢性蕁麻疹、アトピー性皮膚炎などのアレルギー性疾患は主にはI型アレルギーにより引き起こされる疾患であるが、慢性的に経過すると好酸球を主体とする炎症性細胞が患部に浸潤し、炎症像を呈するようになる。 Allergic conjunctivitis, allergic rhinitis, chronic urticaria, inflammatory but mainly allergic diseases such as atopic dermatitis is a disease caused by type I allergy, which when chronically course mainly of eosinophils cells infiltrate the affected area, so exhibits inflammation image. これらの疾患に対しては、対症療法剤として抗ヒスタミン剤が汎用されている。 For these diseases, antihistamines are commonly used as symptomatic therapy agent. しかしながら、抗ヒスタミン剤は炎症自体に対しては無効であり、根治療法剤とはなり得ない。 However, antihistamines are ineffective against inflammation itself, it can not become a radical treatment agent. そのため、抗ヒスタミン剤に加えて、抗炎症剤であるステロイド剤を併用する治療が行われている。 Therefore, in addition to antihistamines, therapeutic used in combination steroids is an anti-inflammatory agent has been carried out. しかしながら、ステロイド剤は感染症、副腎萎縮、骨粗鬆症、糖尿病、小児の成長障害等問題となる副作用がある。 However, steroids have side effects that become infectious diseases, adrenal atrophy, osteoporosis, diabetes, children with growth failure or the like problem.
【0003】 [0003]
【発明が解決しようとする課題】 [Problems that the Invention is to Solve
従来の抗ヒスタミン剤は抗炎症作用を持たないため、抗ヒスタミン作用に加えて、抗炎症作用を併せ持ち、安全性などの点でより満足のいく新規化合物の開発が望まれている。 Since conventional antihistamines have no anti-inflammatory effects, in addition to antihistaminic activity, combines an anti-inflammatory effect, it has been desired to develop novel compounds go a more satisfactory in terms of safety and the like.
【0004】 [0004]
【課題を解決するための手段】 In order to solve the problems]
本発明者らは、前記の課題を解決するため、種々鋭意研究を行った結果、1−フェニル−2,4(1H,3H)−ピリミジンジオン骨格の1位のフェニル基からスペーサーを介して置換ピペリジンやピペラジンを有するところに化学構造上の大きな特徴を持つ新規なウラシル誘導体が、抗ヒスタミン作用を示すと共に遅発型の炎症反応をも顕著に抑制することを見いだし、本発明を完成するに至った。 The present inventors have found that in order to solve the above problems, various intensive result of research, 1-phenyl -2,4 (1H, 3H) - via a spacer from 1-position of the phenyl group of pyrimidinedione backbone substituted found that novel uracil derivatives having a major feature of the chemical structure where having a piperidine or piperazine, also significantly inhibited inflammatory reaction of delayed-type with show antihistaminic activity, leading to completion of the present invention It was.
【0005】 [0005]
即ち、本発明は以下の発明を包含する。 That is, the present invention includes the following inventions.
(1)一般式(I): (1) the general formula (I):
【化2】 ## STR2 ##
(式中、R は水素原子、置換又は無置換の炭素数1〜4のアルキル基あるいは置換又は無置換の炭素数7〜10のアラルキル基を表し、R 、R はそれぞれ水素原子又は炭素数1〜4のアルキル基を表し、Ar 、Ar はそれぞれ置換又は無置換のフェニル基あるいは置換又は無置換の単環芳香族複素環基を表すが、Ar 及びAr の双方に結合する基によって第3の環を形成してもよく、WはO、NH、COO、OCO、CONH、NHCO、CH NH、又はCH NHCOを表し、Wはウラシル骨格1位のフェニル基上のオルト、メタ、パラいずれの位置に置換していてもよく、Xはメチン基(CH)又は窒素原子を表し、Yは、Xがメチン基の時、単結合又は酸素原子を表し、Xが窒素原子の時、単結合を表し、Z (Wherein, R 1 represents a hydrogen atom, a substituted or unsubstituted alkyl group or a substituted or unsubstituted aralkyl group having 7 to 10 carbon atoms having 1 to 4 carbon atoms, R 2, R 3 are each a hydrogen atom or represents an alkyl group having 1 to 4 carbon atoms, Ar 1, Ar 2 each represents independently a substituted or unsubstituted phenyl group or a substituted or unsubstituted monocyclic aromatic heterocyclic group, both of Ar 1 and Ar 2 by binding to group may form a third ring, W is O, NH, COO, OCO, CONH, NHCO, CH 2 NH, or an CH 2 NHCO, W is on the phenyl group of the uracil skeleton 1 of ortho, meta, may be substituted on the para any position, X represents a a methine group (CH) and an nitrogen atom, Y when X is a methine group, represents a single bond or an oxygen atom, X is when the nitrogen atom, represents a single bond, Z は、Xがメチン基でYが単結合の時、水素原子又は水酸基を表し、Xがメチン基でYが酸素原子の時及びXが窒素原子(Yは単結合)の時、水素原子を表し、mは2〜6を表す。) When X is methine group Y is a single bond, represents a hydrogen atom or a hydroxyl group, X is when Y methine group when and X is a nitrogen atom an oxygen atom (Y is a single bond), represents a hydrogen atom , m represents 2-6.)
で表されるウラシル誘導体又はその薬学的に許容される塩。 In uracil derivative or a pharmaceutically acceptable salt thereof.
【0006】 [0006]
(2)一般式(I)において、Ar 、Ar がそれぞれ置換又は無置換のフェニル基である前記(1)に記載のウラシル誘導体又はその薬学的に許容される塩。 (2) In the general formula (I), Ar 1, Ar 2 is uracil derivative or a pharmaceutically acceptable salt thereof according to the respectively substituted or unsubstituted phenyl group (1).
(3)一般式(I)において、Ar 、Ar がそれぞれ(1)ハロゲン原子もしくは炭素数1〜4のアルキル基で置換されていてもよいフェニル基又は(2)炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれる1ないし4個のヘテロ原子を含む5ないし8員の芳香族複素環基である前記(1)に記載のウラシル誘導体又はその薬学的に許容される塩。 (3) In the general formula (I), Ar 1, Ar 2 are each (1) a halogen atom or a phenyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms or (2) a nitrogen atom in addition to carbon atoms uracil derivative or a pharmaceutically acceptable salt thereof according to 5 to the aromatic heterocyclic group having 8 membered (1) contains 1 to 4 heteroatoms selected from sulfur and oxygen atoms.
(4)一般式(I)において、WがCONH又はNHCOである前記(1)〜(3)のいずれかに記載のウラシル誘導体又はその薬学的に許容される塩。 (4) In the general formula (I), W is uracil derivative or a pharmaceutically acceptable salt thereof according to any one of the is CONH or NHCO (1) ~ (3).
(5)一般式(I)において、Xがメチン基である前記(1)〜(4)のいずれかに記載のウラシル誘導体又はその薬学的に許容される塩。 (5) In the general formula (I), X is uracil derivative or a pharmaceutically acceptable salt thereof according to any one of the a methine group (1) to (4).
(6)一般式(I)において、Xが窒素原子である前記(1)〜(4)のいずれかに記載のウラシル誘導体又はその薬学的に許容される塩。 (6) In the formula (I), uracil derivative or a pharmaceutically acceptable salt thereof according to any one of the X is a nitrogen atom (1) to (4).
(7)前記(1)〜(6)のいずれかに記載のウラシル誘導体又はその薬学的に許容される塩を有効成分として含有する抗ヒスタミン剤。 (7) the (1) to antihistamines containing as uracil derivative or active ingredients a pharmaceutically acceptable salt thereof according to any one of (6).
(8)前記(1)〜(6)のいずれかに記載のウラシル誘導体又はその薬学的に許容される塩を有効成分として含有する抗アレルギー剤。 (8) wherein (1) - antiallergic agent comprising as an active ingredient the uracil derivative or a pharmaceutically acceptable salt thereof according to any one of (6).
(9)前記(1)〜(6)のいずれかに記載のウラシル誘導体又はその薬学的に許容される塩を有効成分として含有するアレルギー性結膜炎、アレルギー性鼻炎、慢性蕁麻疹、アトピー性皮膚炎、喘息又は慢性気管支炎の予防・治療剤。 (9) the (1) to allergic conjunctivitis comprising as an active ingredient the uracil derivative or a pharmaceutically acceptable salt thereof according to any one of (6), allergic rhinitis, chronic urticaria, atopic dermatitis , an agent for preventing or treating asthma or chronic bronchitis.
【0007】 [0007]
【発明の実施の形態】 DETAILED DESCRIPTION OF THE INVENTION
本発明の化合物を更に詳細に説明すると、R で示される無置換の炭素数1〜4のアルキル基としては、メチル基、エチル基、プロピル基(1−プロピル基)、イソプロピル基(2−プロピル基)、ブチル基(1−ブチル基)、sec−ブチル基(2−ブチル基)、イソブチル基(2−メチル−1−プロピル基)、t−ブチル基(2−メチル−2−プロピル基)を挙げることができる。 When the compound described in further detail of the present invention, the unsubstituted alkyl group having 1 to 4 carbon atoms represented by R 1, a methyl group, an ethyl group, a propyl group (1-propyl), isopropyl (2- propyl), butyl (1-butyl group), sec-butyl group (2-butyl group), an isobutyl group (2-methyl-1-propyl group), t-butyl group (2-methyl-2-propyl group ) can be mentioned. で示される炭素数1〜4のアルキル基上に許容される置換基としては、フッ素原子、塩素原子のようなハロゲン原子、水酸基、炭素数1〜4のアルコキシ基、炭素数1〜5のアシルオキシ基、カルボキシル基、炭素数2〜5のアルコキシカルボニル基を挙げることができ、具体的なR で示される置換の炭素数1〜4のアルキル基として、トリフルオロメチル基、2−クロロエチル基、2−ヒドロキシエチル基、3−ヒドロキシプロピル基、2−メトキシエチル基、2−エトキシエチル基、3−メトキシプロピル基、2−アセトキシエチル基、カルボキシメチル基、メトキシカルボニルメチル基、エトキシカルボニルメチル基などを挙げることができる。 The permissible substituents on the alkyl group having 1 to 4 carbon atoms represented by R 1, a fluorine atom, a halogen atom such as chlorine atom, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, carbon atoms 1-5 an acyloxy group, a carboxyl group, and a alkoxycarbonyl group having 2 to 5 carbon atoms, the alkyl group having 1 to 4 carbon atoms substituted represented by specific R 1, trifluoromethyl group, 2-chloroethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 3-methoxypropyl group, 2-acetoxyethyl group, a carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl or the like can be given to the group. またR で示される無置換の炭素数7〜10のアラルキル基としては、ベンジル基、1−フェニルエチル基、2−フェニルエチル基(フェネチル基)、1−フェニルプロピル基、2−フェニルプロピル基、2−フェニル−2−プロピル基、3−フェニルプロピル基、2−メチルベンジル基、3−メチルベンジル基、4−メチルベンジル基、4−メチルフェネチル基などを挙げることができる。 As the unsubstituted aralkyl group having 7 to 10 carbon atoms represented by R 1, benzyl, 1-phenylethyl, 2-phenylethyl group (phenethyl group), 1-phenylpropyl group, 2-phenylpropyl group , 2-phenyl-2-propyl group, 3-phenylpropyl, 2-methylbenzyl group, 3-methylbenzyl, 4-methylbenzyl group, and the like 4-methylphenethyl group. で示される炭素数7〜10のアラルキル基上に許容される置換基としては、フッ素原子、塩素原子のようなハロゲン原子、水酸基、炭素数1〜4のアルコキシ基、炭素数1〜5のアシルオキシ基、カルボキシル基、炭素数2〜5のアルコキシカルボニル基を挙げることができ、具体的なR で示される置換の炭素数7〜10のアラルキル基として、4−フルオロベンジル基、3−クロロベンジル基、4−ヒドロキシベンジル基、3−メトキシベンジル基、4−メトキシベンジル基、4−エトキシベンジル基、4−アセトキシベンジル基、4−カルボキシベンジル基、4−メトキシカルボニルベンジル基などを挙げることができる。 The permissible substituents on aralkyl group having 7 to 10 carbon atoms represented by R 1, a fluorine atom, a halogen atom such as chlorine atom, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, carbon atoms 1-5 an acyloxy group, a carboxyl group, and a alkoxycarbonyl group having 2 to 5 carbon atoms, aralkyl group having 7 to 10 carbon atoms substituted represented by specific R 1, 4-fluorobenzyl group, 3- chlorobenzyl group, 4-hydroxybenzyl, 3-methoxybenzyl group, 4-methoxybenzyl group, 4-ethoxy benzyl group, 4-acetoxybenzyl group, 4-carboxy benzyl group, and the like 4-methoxycarbonyl benzyl group can. 以上の中で好ましいR として水素原子、メチル基、エチル基、プロピル基、ブチル基、ベンジル基、2−フェニルエチル基を挙げることができ、中でも水素原子、メチル基、エチル基が特に好ましい。 More preferably R 1 as a hydrogen atom in a methyl group, an ethyl group, a propyl group, a butyl group, a benzyl group, and a 2-phenylethyl group, among them a hydrogen atom, a methyl group, an ethyl group are particularly preferred.
【0008】 [0008]
、R で示される炭素数1〜4のアルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、sec−ブチル基、イソブチル基、t−ブチル基を挙げることができる。 The alkyl group having 1 to 4 carbon atoms represented by R 2, R 3, methyl, ethyl, propyl, isopropyl, butyl, sec- butyl group, an isobutyl group, and the like t- butyl group it can. 好ましいR 、R として水素原子、メチル基、エチル基、プロピル基、ブチル基を挙げることができ、中でも水素原子、メチル基、エチル基が特に好ましい。 Preferred R 2, R 3 as hydrogen atom, a methyl group, an ethyl group, a propyl group, and a butyl group, among them a hydrogen atom, a methyl group, an ethyl group are particularly preferred.
【0009】 [0009]
Ar 、Ar で示されるフェニル基上に有していてもよい置換基として、ハロゲン原子、炭素数1〜4のアルキル基、水酸基、炭素数1〜4のアルコキシ基、炭素数1〜5のアシルオキシ基、カルボキシル基、炭素数2〜5のアルコキシカルボニル基、シアノ基、テトラゾリル基、ニトロ基を挙げることができ、具体的なAr 、Ar で示される置換のフェニル基として、2−フルオロフェニル基、3−フルオロフェニル基、4−フルオロフェニル基、2−クロロフェニル基、3−クロロフェニル基、4−クロロフェニル基、2−メチルフェニル基、3−メチルフェニル基、4−メチルフェニル基、2−エチルフェニル基、3−エチルフェニル基、2,3−ジメチルフェニル基、2,4−ジメチルフェニル基、2,5−ジメチルフェ Ar 1, as the substituent which may have, on the phenyl group represented by Ar 2, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, 1 to 5 carbon atoms acyloxy group, a carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, a cyano group, a tetrazolyl group, and a nitro group, a substituted phenyl group represented by specific Ar 1, Ar 2, 2- fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2 - ethylphenyl group, 3-ethylphenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethyl-Fe ル基、2,6−ジメチルフェニル基、3,4−ジメチルフェニル基、3,5−ジメチルフェニル基、4−エチルフェニル基、2−ヒドロキシフェニル基、3−ヒドロキシフェニル基、4−ヒドロキシフェニル基、2−メトキシフェニル基、3−メトキシフェニル基、4−メトキシフェニル基、2−エトキシフェニル基、3−エトキシフェニル基、4−エトキシフェニル基、2−アセトキシフェニル基、3−アセトキシフェニル基、4−アセトキシフェニル基、2−カルボキシフェニル基、3−カルボキシフェニル基、4−カルボキシフェニル基、2−メトキシカルボニルフェニル基、3−メトキシカルボニルフェニル基、4−メトキシカルボニルフェニル基、2−シアノフェニル基、3−シアノフェニル基、4−シアノフェニル基、2−テ Group, 2,6-dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 4-ethylphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group , 2-methoxyphenyl group, 3-methoxyphenyl group, a 4-methoxyphenyl group, 2-ethoxyphenyl group, 3-ethoxyphenyl group, 4-ethoxyphenyl group, 2-acetoxyphenyl group, 3-acetoxyphenyl group, 4 - acetoxyphenyl group, 2-carboxyphenyl group, 3-carboxyphenyl group, 4-carboxyphenyl group, 2-methoxycarbonylphenyl group, 3-methoxycarbonylphenyl group, 4-methoxycarbonylphenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2-te ラゾリルフェニル基、3−テトラゾリルフェニル基、4−テトラゾリルフェニル基、2−ニトロフェニル基、3−ニトロフェニル基、4−ニトロフェニル基などを挙げることができる。 Razorirufeniru group, 3-tetrazolyl-phenyl group, 4-tetrazolyl-phenyl group, 2-nitrophenyl group, 3-nitrophenyl group, a 4-nitrophenyl group can be exemplified. またAr 、Ar で示される無置換の芳香族複素環基としては、フリル基、チエニル基、ピロリル基、オキサゾリル基、チアゾリル基、ピラゾリル基、イミダゾリル基、テトラゾリル基、ピリジル基、ピリダジニル基、ピリミジニル基、ピラジニル基などを挙げることができる。 As the unsubstituted aromatic heterocyclic groups represented by Ar 1, Ar 2, a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, a pyrazolyl group, an imidazolyl group, a tetrazolyl group, a pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group and the like. 前記芳香族複素環基上に有していてもよい置換基として、ハロゲン原子、炭素数1〜4のアルキル基、水酸基、炭素数1〜4のアルコキシ基、炭素数1〜5のアシルオキシ基、カルボキシル基、炭素数2〜5のアルコキシカルボニル基、シアノ基、ニトロ基を挙げることができ、具体的なAr 、Ar で示される置換の芳香族複素環基として、3−メチル−2−フリル基、4−メチル−2−フリル基、5−メチル−2−フリル基、2−メチル−3−フリル基、4−メチル−3−フリル基、5−メチル−3−フリル基、3−メトキシ−2−フリル基、4−メトキシ−2−フリル基、5−メトキシ−2−フリル基、2−メトキシ−3−フリル基、4−メトキシ−3−フリル基、5−メトキシ−3−フリル基、3−クロロ−2−フリル基、4− As the substituent which may have on the aromatic heterocyclic group, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, an acyloxy group having 1 to 5 carbon atoms, carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, a cyano group, and a nitro group, a substituted aromatic heterocyclic group represented by specific Ar 1, Ar 2, 3- methyl-2- furyl group, 4-methyl-2-furyl group, 5-methyl-2-furyl group, 2-methyl-3-furyl group, 4-methyl-3-furyl group, 5-methyl-3-furyl group, 3- methoxy-2-furyl group, 4-methoxy-2-furyl group, 5-methoxy-2-furyl group, 2-methoxy-3-furyl group, 4-methoxy-3-furyl group, 5-methoxy-3-furyl group, 3-chloro-2-furyl group, 4- ロロ−2−フリル基、5−クロロ−2−フリル基、2−クロロ−3−フリル基、4−クロロ−3−フリル基、5−クロロ−3−フリル基、3−フルオロ−2−フリル基、4−フルオロ−2−フリル基、5−フルオロ−2−フリル基、2−フルオロ−3−フリル基、4−フルオロ−3−フリル基、5−フルオロ−3−フリル基、3−メチル−2−チエニル基、4−メチル−2−チエニル基、5−メチル−2−チエニル基、2−メチル−3−チエニル基、4−メチル−3−チエニル基、5−メチル−3−チエニル基、3−メトキシ−2−チエニル基、4−メトキシ−2−チエニル基、5−メトキシ−2−チエニル基、2−メトキシ−3−チエニル基、4−メトキシ−3−チエニル基、5−メトキシ−3−チエニル基、3−クロロ−2−チエニル Lolo-2-furyl group, 5-chloro-2-furyl group, 2-chloro-3-furyl group, 4-chloro-3-furyl group, 5-chloro-3-furyl group, 3-fluoro-2-furyl group, 4-fluoro-2-furyl group, 5-fluoro-2-furyl group, 2-fluoro-3-furyl group, 4-fluoro-3-furyl group, 5-fluoro-3-furyl group, 3-methyl 2-thienyl group, 4-methyl-2-thienyl group, 5-methyl-2-thienyl group, 2-methyl-3-thienyl, 4-methyl-3-thienyl group, 5-methyl-3-thienyl group 3-methoxy-2-thienyl group, 4-methoxy-2-thienyl group, 5-methoxy-2-thienyl group, 2-methoxy-3-thienyl, 4-methoxy-3-thienyl group, 5-methoxy - 3-thienyl group, 3-chloro-2-thienyl 、4−クロロ−2−チエニル基、5−クロロ−2−チエニル基、2−クロロ−3−チエニル基、4−クロロ−3−チエニル基、5−クロロ−3−チエニル基、3−フルオロ−2−チエニル基、4−フルオロ−2−チエニル基、5−フルオロ−2−チエニル基、2−フルオロ−3−チエニル基、4−フルオロ−3−チエニル基、5−フルオロ−3−チエニル基、2−メチル−3−ピリジル基、4−メチル−3−ピリジル基、5−メチル−3−ピリジル基、6−メチル−3−ピリジル基、3−メチル−2−ピリジル基、4−メチル−2−ピリジル基、5−メチル−2−ピリジル基、6−メチル−2−ピリジル基、2−メチル−4−ピリジル基、3−メチル−4−ピリジル基、5−メチル−4−ピリジル基、6−メチル−4−ピリジル基、2−メト , 4-chloro-2-thienyl group, 5-chloro-2-thienyl group, 2-chloro-3-thienyl, 4-chloro-3-thienyl, 5-chloro-3-thienyl group, 3-fluoro - 2-thienyl, 4-fluoro-2-thienyl group, 5-fluoro-2-thienyl group, 2-fluoro-3-thienyl, 4-fluoro-3-thienyl group, 5-fluoro-3-thienyl group, 2-methyl-3-pyridyl group, 4-methyl-3-pyridyl group, 5-methyl-3-pyridyl, 6-methyl-3-pyridyl group, 3-methyl-2-pyridyl group, 4-methyl-2 - a pyridyl group, 5-methyl-2-pyridyl group, 6-methyl-2-pyridyl group, 2-methyl-4-pyridyl group, 3-methyl-4-pyridyl group, 5-methyl-4-pyridyl group, 6 - methyl-4-pyridyl group, 2-meth キシ−3−ピリジル基、4−メトキシ−3−ピリジル基、5−メトキシ−3−ピリジル基、6−メトキシ−3−ピリジル基、3−メトキシ−2−ピリジル基、4−メトキシ−2−ピリジル基、5−メトキシ−2−ピリジル基、6−メトキシ−2−ピリジル基、2−メトキシ−4−ピリジル基、3−メトキシ−4−ピリジル基、5−メトキシ−4−ピリジル基、6−メトキシ−4−ピリジル基、2−エトキシ−3−ピリジル基、4−エトキシ−3−ピリジル基、3−エトキシ−2−ピリジル基、4−エトキシ−2−ピリジル基、3−エトキシ−4−ピリジル基、2−ヒドロキシ−3−ピリジル基、4−ヒドロキシ−3−ピリジル基、3−ヒドロキシ−2−ピリジル基、3−ヒドロキシ−4−ピリジル基、2−クロロ−3−ピリジル基、4−クロ Carboxymethyl-3-pyridyl, 4-methoxy-3-pyridyl group, 5-methoxy-3-pyridyl group, 6-methoxy-3-pyridyl group, 3-methoxy-2-pyridyl group, 4-methoxy-2-pyridyl group, 5-methoxy-2-pyridyl group, 6-methoxy-2-pyridyl group, 2-methoxy-4-pyridyl group, 3-methoxy-4-pyridyl group, 5-methoxy-4-pyridyl group, 6-methoxy 4-pyridyl, 2-ethoxy-3-pyridyl, 4-ethoxy-3-pyridyl group, 3-ethoxy-2-pyridyl group, 4-ethoxy-2-pyridyl group, 3-ethoxy-4-pyridyl group , 2-hydroxy-3-pyridyl, 4-hydroxy-3-pyridyl group, 3-hydroxy-2-pyridyl group, 3-hydroxy-4-pyridyl group, 2-chloro-3-pyridyl group, 4-black −3−ピリジル基、3−クロロ−2−ピリジル基、4−クロロ−2−ピリジル基、3−クロロ−4−ピリジル基、5−メチル−2−ピラジル基、6−メチル−2−ピラジル基、5−メトキシ−2−ピラジル基、6−メトキシ−2−ピラジル基、5−エトキシ−2−ピラジル基、6−エトキシ−2−ピラジル基、5−クロロ−2−ピラジル基、6−クロロ−2−ピラジル基などを挙げることができる。 3-pyridyl group, 3-chloro-2-pyridyl group, 4-chloro-2-pyridyl group, 3-chloro-4-pyridyl group, 5-methyl-2-pyrazinyl group, 6-methyl-2-pyrazinyl group 5-methoxy-2-pyrazinyl group, 6-methoxy-2-pyrazinyl group, 5-ethoxy-2-pyrazinyl group, 6-ethoxy-2-pyrazinyl group, 5-chloro-2-pyrazinyl group, 6-chloro - and 2-pyrazinyl group, and the like. 好ましいAr 、Ar として、フェニル基、4−フルオロフェニル基、4−クロロフェニル基、4−メチルフェニル基、4−メトキシフェニル基、4−シアノフェニル基、3−ピリジル基、4−ピリジル基を挙げることができ、中でも特にフェニル基、4−フルオロフェニル基、4−メチルフェニル基、4−メトキシフェニル基、4−シアノフェニル基、3−ピリジル基、4−ピリジル基が好ましい。 Preferred Ar 1, Ar 2, a phenyl group, a 4-fluorophenyl group, chlorophenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, 4-cyanophenyl group, 3-pyridyl group, a 4-pyridyl group It can be cited, among others a phenyl group, a 4-fluorophenyl group, 4-methylphenyl group, a 4-methoxyphenyl group, 4-cyanophenyl group, 3-pyridyl, 4-pyridyl are preferred.
【0010】 [0010]
また、Ar 及びAr の双方に結合する基によって第3の環を形成する場合、式(I)中の次式: In the case of forming the third ring by a group attached to both of Ar 1 and Ar 2, the following equation in of formula (I):
【化3】 [Formula 3]
で表される構造として次式: Following formula in a structure represented:
【化4】 [Of 4]
で表される構造などを挙げることができ、これらもまた好ましいものである。 Etc. can be mentioned structure represented by the, but these are also preferred.
WはO、NH、COO、OCO、CONH、NHCO、CH NH、又はCH NHCOを表し、これらのうち、O、NH、CONH、NHCO、CH NH、又はCH NHCOが好ましく、中でもCONH、又はNHCOが特に好ましい。 W represents O, NH, COO, OCO, CONH, NHCO, CH 2 NH, or CH 2 NHCO, among these, O, NH, CONH, NHCO , CH 2 NH, or CH 2 NHCO is preferred, CONH , or NHCO it is particularly preferred.
【0011】 [0011]
Xはメチン基(CH)又は窒素原子を表し、YはXがメチン基の時、単結合又は酸素原子を表し、Xが窒素原子の時、単結合を表し、Zは、Xがメチン基でYが単結合の時、水素原子又は水酸基を表し、Xがメチン基でYが酸素原子の時及びXが窒素原子(Yは単結合)の時、水素原子を表すが、式(I)中の次式: X represents a methine group (CH) and an nitrogen atom, when Y is X is a methine group, represents a single bond or an oxygen atom, when X is a nitrogen atom, represents a single bond, Z is, X is methine group when Y is a single bond, represents a hydrogen atom or a hydroxyl group, when Y is when and X is a nitrogen atom an oxygen atom (Y is a single bond) X is methine group, it represents a hydrogen atom, in the formula (I) the following formula:
【化5】 [Of 5]
で表される構造の好ましいものとして次式: The following equation in a preferred structure represented:
【化6】 [Omitted]
で表される構造を挙げることができ、これらのうち、次式: Structure represented by the can be cited, among these, the following formula:
【化7】 [Omitted]
で表される構造が特に好ましい。 Structure represented by the particularly preferred.
mは2〜6を表すが、好ましくは3〜5、特に好ましくは3〜4である。 m represents an 2-6, preferably 3-5, particularly preferably 3-4.
【0012】 [0012]
本発明の好ましいウラシル誘導体を具体的に表1及び表2に示す。 Preferred uracil derivatives of the present invention will be specifically shown in Table 1 and Table 2.
【表1】 [Table 1]
【0013】 [0013]
【表2】 [Table 2]
【0014】 [0014]
一般式(I)で示されるウラシル誘導体は、下記の式に従って合成できる。 Uracil derivative represented by the general formula (I) can be synthesized according to the following equation.
【化8】 [Of 8]
(式中、A及びBは、互いに反応してWを形成を形成しうる官能基を表し、R 、R 、R 、Ar 、Ar 、X、Y、Z及びmは前記と同義である。) (Wherein, A and B represents a functional group capable of forming a form W react with each other, R 1, R 2, R 3, Ar 1, Ar 2, X, Y, Z and m are as above They are synonymous.)
【0015】 [0015]
即ち、目的とする結合基Wを形成するのに必要な置換基Aを有する1−アリール−2,4(1H,3H)−ピリミジンジオン(II)と、目的とする結合基Wを形成するのに必要な置換基Bを有するアミン(III)を反応させることにより合成できる。 That is, the 1-aryl-2,4 (IH, 3H) having a substituent group A required to form a bond group W of interest - to form the pyrimidine-dione (II), the linking group W of interest It can be synthesized by reacting the amine (III) having a substituent group B required. 具体的にはWがOの場合、AはOH基、Bはハロゲン原子やスルホン酸エステルのような脱離基である化合物を原料に用い、一般的なWilliamsonのエーテル合成条件で所望の化合物を得ることができる。 If specifically W is O, A is OH group, B is used a compound which is a leaving group such as halogen atom or a sulfonic acid ester as a raw material, a typical desired compound with ether synthesis conditions of Williamson it is possible to obtain. WがCOO又はOCOの場合、A、BをCOOHとOHとしてエステル化条件で反応させて合成することができる。 W is the case of the COO or OCO, it can be synthesized by reacting the esterification conditions A, B as COOH and OH. また、WがCONH又はNHCOの場合、A、BをCOOHとNH としてアミド化条件で反応させて合成することができる。 Further, W is the case of CONH or NHCO, it may be synthesized by reacting an amide of conditions A, B as COOH and NH 2. WがCH NHCOの場合、A、BをCH NH とCOOHとしてアミド化条件で反応させて合成することができる。 W is the case of CH 2 NHCO, A, B can be synthesized by reacting an amide conditions as CH 2 NH 2 and COOH. WがCH NH又はNHの場合は前記CONH又はNHCOの化合物をボランで還元することにより合成することができる。 W is the case of CH 2 NH or NH can be synthesized by reduction with borane compound of the CONH or NHCO. 置換基Aを有する1−アリール−2,4(1H,3H)−ピリミジンジオン(II)は、例えば特開平8−109171号公報の記載に準じた方法により合成できる。 Having substituents A 1-aryl -2,4 (1H, 3H) - pyrimidinedione (II) can be synthesized, for example, by a method analogous to that described in JP-A 8-109171 JP. 置換基Bを有するアミン(III)は、例えば特開平11−310581号公報に記載の方法又は当該公報に準じた方法により合成できる。 Amines having a substituent B (III) can be synthesized, for example, by a method according to the method or the publication described in JP-A-11-310581.
【0016】 [0016]
一般式(I)で示されるウラシル誘導体は塩基性の3級アミノ基を有していることから、各種の酸と塩を形成しうる。 Uracil derivative represented by the general formula (I) from to have a basic tertiary amino group, can form a variety of acid and salt. 薬学的に許容される塩としては、塩酸塩、硫酸塩、酢酸塩、メタンスルホン酸、マレイン酸、フマル酸、コハク酸塩などを挙げることができる。 Pharmaceutically acceptable salts include hydrochloride, sulfate, acetate, methanesulfonic acid, maleic acid, fumaric acid, and succinic acid salts. また、ウラシル誘導体が酸性を示す置換基を有している場合、各種の塩基とも塩を形成しうる。 Also, if the uracil derivative has a substituent exhibiting acidity, with various bases may form salts. この場合の薬学的に許容される塩としては、ナトリウム塩、カリウム塩、カルシウム塩、アンモニウム塩などが挙げられる。 Pharmaceutically acceptable salts of this case, sodium salts, potassium salts, calcium salts, and ammonium salts. これらの塩はウラシル誘導体と酸又は塩基を混合した後、再結晶などの常法により得ることができる。 These salts were mixed uracil derivative with an acid or a base can be obtained by a conventional method such as recrystallization.
【0017】 [0017]
本発明のウラシル誘導体は、錠剤、カプセル剤、散剤などの経口剤をはじめ、注射剤、外用剤など種々の剤形で使用することができる。 Uracil derivatives of the present invention, initially tablets, capsules, oral agents such as powder, injection, can be used in a variety of dosage forms such as external preparations. 例えば、本発明のウラシル誘導体又は薬学的に許容される塩をワセリンなどの軟膏基剤に混和させ、軟膏剤とすることができる。 For example, a uracil derivative or a pharmaceutically acceptable salt of the present invention is incorporated into an ointment base such as petrolatum, it can be ointments. また、本発明のウラシル誘導体又は薬学的に許容される塩と乳糖、澱粉などの賦形剤、ステアリン酸マグネシウム、タルクなどの滑沢剤、その他常用の添加剤を混合し、錠剤とすることもできる。 Furthermore, excipients such as uracil derivative or a pharmaceutically acceptable salt thereof and lactose, starches of this invention, lubricating agents such as magnesium stearate, talc, and mixed additives other customary be a tablet it can.
【0018】 [0018]
本発明のウラシル誘導体の用量は、患者の性別、年齢、体重、疾患の種類、症状などに応じて適宜定めるものであるが、例えば、アトピー性皮膚炎、接触性皮膚炎、乾癬等の皮膚疾患においては、有効成分0.01〜10%含有の軟膏剤を1日1回から数回、患部に塗布することができる。 Dose of the uracil derivative of the present invention, the patient's sex, age, weight, type of disease, but in which appropriately determined depending on the symptoms, such as atopic dermatitis, contact dermatitis, skin diseases such as psoriasis in can be applied with active ingredients 0.01% to 10% content of ointment from once a day several times, to the affected area. アレルギー性結膜炎などの眼疾患に対しては、有効成分0.001〜1%含有の点眼剤を1日1回から数回点眼することができる。 For ocular diseases such as allergic conjunctivitis can be instilled several times eye drops containing 0.001 to 1% active ingredient from once a day. アレルギー性鼻炎などの疾患に対しては、有効成分0.001〜1%含有の点鼻剤を1日1回から数回点鼻することができる。 For diseases such as allergic rhinitis, it can be several times nasal from once daily nasal agent containing 0.001 to 1% active ingredient. また、錠剤、カプセル剤、散剤などの経口剤としては一般に、1日当たり0.01〜100 mg/kgの範囲で、単回又は数回に分けて投与することもできる。 Moreover, tablets, capsules, generally as an oral agent such as powders, in the range of 1 day 0.01 to 100 mg / kg, may be administered in single or several times.
【0019】 [0019]
【実施例】 【Example】
以下、実施例により本発明を具体的に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, a detailed explanation of the present invention through examples, the scope of the present invention is not limited thereto.
(参考例1)4−(4−(ジフェニルメチル)−1−ピペラジニル)ブタン酸1−(ジフェニルメチル)ピペラジン 2.0 g(7.9 mmol)をアセトニトリル 80 mlに溶解し、4−ブロモ酪酸エチル 1.2 g(8.7 mmol)、トリエチルアミン 1.2 ml(8.7 mmol)を加え80 ℃で2時間撹拌した。 (Reference Example 1) 4- (4- (diphenylmethyl) -1-piperazinyl) butanoic acid 1 (diphenylmethyl) piperazine 2.0 g (7.9 mmol) were dissolved in 80 ml of acetonitrile, 4-bromobutyrate ethyl 1.2 g (8.7 mmol), and stirred for 2 hours at 80 ° C. was added triethylamine 1.2 ml (8.7 mmol). アセトニトリルを留去し、ジクロロメタンと5 %クエン酸水溶液で分配し、有機層を10 % 塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。 Acetonitrile was distilled off, and partitioned between dichloromethane and 5% aqueous citric acid solution, the organic layer was washed with 10% aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. ジクロロメタンを留去して残渣をメタノール 30 mlに溶解し、5N 水酸化ナトリウム水溶液7.9 mlを加え30分撹拌した。 The residue was dissolved in methanol 30 ml dichloromethane was distilled off, was added and stirred for 30 minutes 7.9 ml 5N aqueous solution of sodium hydroxide. 中和後メタノールを留去し、ジクロロメタンと10 % 塩化ナトリウム水溶液で分配し、有機層を無水硫酸ナトリウムで乾燥した。 Was distilled off after neutralization of methanol, and partitioned between dichloromethane and 10% aqueous sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate. 溶媒を留去することにより標記化合物を得た(2.0 g(5.9 mmol)、収率75 %)。 By distilling off the solvent to give the title compound (2.0 g (5.9 mmol), 75% yield).
【0020】 [0020]
(参考例2)5−(4−(ジフェニルメチル)−1−ピペラジニル)ペンタン酸4−ブロモ酪酸エチルの代わりに5−ブロモ吉草酸エチルを用い参考例1と同様の操作により標記化合物を得た。 It was obtained (Reference Example 2) 5- (4- (diphenylmethyl) -1-piperazinyl) of the title compound in the same manner as in Reference Example 1 using 5-bromo valeric acid ethyl instead of pentanoic acid ethyl 4-bromobutyrate .
【0021】 [0021]
(参考例3)4−(4−(ヒドロキシジフェニルメチル)−1−ピペリジニル)ブタン酸1−(ジフェニルメチル)ピペラジンの代わりにα,α−ジフェニル−4−ピペリジニルメタノールを用い参考例1と同様の操作により標記化合物を得た。 (Reference Example 3) 4- (4- (hydroxydiphenylmethyl) -1-piperidinyl) butanoic acid 1 (diphenylmethyl) instead of piperazine alpha, as in Reference Example 1 using α- diphenyl-4-piperidinylmethyl methanol to give the title compound by a similar operation.
【0022】 [0022]
(参考例4)4−(4−(ジフェニルメトキシ)−1−ピペリジニル)ブタン酸1−(ジフェニルメチル)ピペラジンの代わりに4−(ジフェニルメトキシ)ピペリジンを用い参考例1と同様の操作により標記化合物を得た。 (Reference Example 4) 4- (4- (diphenyl-methoxy) -1-piperidinyl) butanoic acid 1 (diphenylmethyl) The title compound in the same manner as in Reference Example 1 using 4- (diphenyl-methoxy) piperidine in place of piperazine It was obtained.
【0023】 [0023]
(参考例5)4−(4−(ビス(4−フルオロフェニル)メチル)−1−ピペラジニル)ブタン酸1−(ジフェニルメチル)ピペラジンの代わりに1−(ビス(4−フルオロフェニル)メチル)ピペラジンを用い参考例1と同様の操作により標記化合物を得た。 (Reference Example 5) 4- (4- (bis (4-fluorophenyl) methyl) -1-piperazinyl) substituting 1- (bis (4-fluorophenyl) methyl) butanoic acid 1 (diphenylmethyl) piperazine piperazine to give the title compound in the same manner as in reference example 1 using.
【0024】 [0024]
(参考例6)4−(4−(ビス(4−フルオロフェニル)メトキシ)−1−ピペリジニル)ブタン酸1−(ジフェニルメチル)ピペラジンの代わりに4−(ビス(4−フルオロフェニル)メトキシ)ピペリジンを用い参考例1と同様の操作により標記化合物を得た。 (Reference Example 6) 4- (4- (bis (4-fluorophenyl) methoxy) -1-piperidinyl) instead of 4- (bis (4-fluorophenyl) methoxy) butanoic acid 1 (diphenylmethyl) piperazine piperidine to give the title compound in the same manner as in reference example 1 using.
【0025】 [0025]
(参考例7)4−(4−(10,11−ジヒドロ−5H−ジベンゾ[a,d]シクロヘプテン−5−イル)−1−ピペラジニル)ブタン酸1−(ジフェニルメチル)ピペラジンの代わりに4−(10,11−ジヒドロ−5H−ジベンゾ[a,d]シクロヘプテン−5−イル)−1−ピペラジンを用い参考例1と同様の操作により標記化合物を得た。 (Reference Example 7) 4- (4- (10,11-dihydro -5H- dibenzo [a, d] cyclohepten-5-yl) -1-piperazinyl) instead of butanoic acid 1- (diphenylmethyl) piperazine 4- (10,11-dihydro -5H- dibenzo [a, d] cyclohepten-5-yl) -1-piperazine the title compound was obtained in the same manner as in reference example 1 using.
【0026】 [0026]
(実施例1)6−アミノ−1−[4−[3−[4−(ジフェニルメチル)−1−ピペラジニル]プロピル]アミノカルボニルフェニル]−3−メチルウラシル(化合物647) (Example 1) 6-Amino-1- [4- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] amino carbonyl phenyl] -3-methyl-uracil (Compound 647)
6−アミノ−1−(4−カルボキシフェニル)−3−メチルウラシル 600 mg(2.31 mmol)と3−(4−(ジフェニルメチル)−1−ピペラジニル)プロピルアミン 786 mg (2.54 mmol)をジメチルホルムアミド 23 mlに溶解し、1−ヒドロキシベンゾトリアゾール 374 mg(2.77 mmol)と1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩 531 mg(2.77mmol)を加え、2時間30分撹拌した。 6-amino-1- (4-carboxyphenyl) -3-methyl uracil 600 mg (2.31 mmol) and 3- (4- (diphenylmethyl) -1-piperazinyl) propylamine 786 mg (2.54 mmol) was dissolved in dimethylformamide 23 ml, 1-hydroxybenzotriazole 374 mg (2.77 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 531 mg (2.77 mmol) was added, 2 and the mixture was stirred for 30 minutes. 溶媒を留去し、酢酸エチルと5 % 炭酸水素ナトリウム水溶液で分配し、有機層を10 % 塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。 The solvent was evaporated, partitioned between ethyl acetate and 5% aqueous sodium hydrogen carbonate solution, the organic layer was washed with 10% aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. 溶媒を留去後、シリカゲルカラムクロマトグラフィーで精製(ジクロロメタン:メタノール=30:1〜10:1)することにより標記化合物を得た(950mg(1.72 mmol)、収率74 %)。 After distilling off the solvent, purified by silica gel column chromatography (dichloromethane: methanol = 30: 1 to 10: 1) to afford the title compound by (950 mg (1.72 mmol), 74% yield).
H−NMR (DMSO−d , δppm): 8.62 (1H, br.t, J = 5.4 Hz), 7.95 (2H, d, J = 8.4 Hz), 7.14−7.43 (12H, m), 6.19 (2H, br.s), 4.82 (1H, s), 4.26 (1H, s),3.28 (2H, m), 3.28 (3H, s), 2.31−2.49 (10H, m), 1.67 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 8.62 (1H, br.t, J = 5.4 Hz), 7.95 (2H, d, J = 8.4 Hz), 7.14 -7.43 (12H, m), 6.19 (2H, br.s), 4.82 (1H, s), 4.26 (1H, s), 3.28 (2H, m), 3. 28 (3H, s), 2.31-2.49 (10H, m), 1.67 (2H, m)
飛行時間型質量分析計TOF−mass:553 (M+H) Time-of-flight mass spectrometer TOF-mass: 553 (M + H)
【0027】 [0027]
(実施例2)6−アミノ−1−[3−[3−[4−(ジフェニルメチル)−1−ピペラジニル]プロピル]アミノカルボニルフェニル]−3−メチルウラシル(化合物557) (Example 2) 6-Amino-1- [3- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] amino carbonyl phenyl] -3-methyl-uracil (Compound 557)
6−アミノ−1−(4−カルボキシフェニル)−3−メチルウラシルの代わりに、6−アミノ−1−(3−カルボキシフェニル)−3−メチルウラシルを用い実施例1と同様の操作により標記化合物を得た。 Instead of 6-amino-1- (4-carboxyphenyl) -3-methyl uracil, 6-amino-1- (3-carboxyphenyl) -3-title compound in the same manner as in Example 1 using methyl uracil It was obtained.
H−NMR (DMSO−d , δppm): 8.55 (1H, br.t, J = 5.1 Hz), 7.97 (2H, d, J = 8.4 Hz), 7.77 (1H, br.s), 7.14−7.63 (12H, m), 6.22 (2H, br.s), 4.84 (1H, s), 4.23 (1H, s), 3.31 (2H, m), 3.09 (3H, s), 2.30−2.49 (10H, m), 1.66 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 8.55 (1H, br.t, J = 5.1 Hz), 7.97 (2H, d, J = 8.4 Hz), 7.77 (1H, br.s), 7.14-7.63 (12H, m), 6.22 (2H, br.s), 4.84 (1H, s), 4.23 (1H, s), 3.31 (2H, m), 3.09 (3H, s), 2.30-2.49 (10H, m), 1.66 (2H, m)
飛行時間型質量分析計TOF−mass:553 (M+H) Time-of-flight mass spectrometer TOF-mass: 553 (M + H)
【0028】 [0028]
(実施例3)6−アミノ−1−[4−[3−[4−[(4−メチルフェニル)フェニルメチル]−1−ピペラジニル]プロピル]アミノカルボニルフェニル]−3−メチルウラシル(化合物611) (Example 3) 6-Amino-1- [4- [3- [4 - [(4-methylphenyl) phenylmethyl] -1-piperazinyl] propyl] amino carbonyl phenyl] -3-methyl-uracil (Compound 611)
3−(4−(ジフェニルメチル)−1−ピペラジニル)プロピルアミンの代わりに、3−(4−((4−メチルフェニル)フェニルメチル)−1−ピペラジニル)プロピルアミンを用い実施例1と同様の操作により標記化合物を得た。 Instead of 3- (4- (diphenylmethyl) -1-piperazinyl) propylamine, 3- (4 - ((4-methylphenyl) phenylmethyl) -1-piperazinyl) propylamine as in Example 1 using to give the title compound operation.
H−NMR (DMSO−d , δppm): 8.62 (1H, m), 7.95 (2H, d, J = 8.6 Hz), 7.07−7.43 (11H, m), 6.20 (2H, br.s), 4.81 (1H, s), 4.21 (1H, s), 3.29 (2H, m), 3.09 (3H, s), 2.30−2.49 (10H, m), 2.22 (3H, s), 1.66 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 8.62 (1H, m), 7.95 (2H, d, J = 8.6 Hz), 7.07-7.43 (11H, m) , 6.20 (2H, br.s), 4.81 (1H, s), 4.21 (1H, s), 3.29 (2H, m), 3.09 (3H, s), 2. 30-2.49 (10H, m), 2.22 (3H, s), 1.66 (2H, m)
TOF−mass:567 (M+H) TOF-mass: 567 (M + H)
【0029】 [0029]
(実施例4)6−アミノ−1−[4−[3−[4−[ビス(4−フルオロフェニル)メチル]−1−ピペラジニル]プロピル]アミノカルボニルフェニル]−3−メチルウラシル(化合物622) (Example 4) 6-Amino-1- [4- [3- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] propyl] amino carbonyl phenyl] -3-methyl-uracil (Compound 622)
3−(4−(ジフェニルメチル)−1−ピペラジニル)プロピルアミンの代わりに、3−(4−(ビス(4−フルオロフェニル)メチル)−1−ピペラジニル)プロピルアミンを用い実施例1と同様の操作により標記化合物を得た。 Instead of 3- (4- (diphenylmethyl) -1-piperazinyl) propylamine, 3- (4- (bis (4-fluorophenyl) methyl) -1-piperazinyl) propylamine as in Example 1 using to give the title compound operation.
H−NMR (DMSO−d , δppm): 8.63 (1H, m), 7.96 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.04−7.45 (8H, m), 6.20 (2H, br.s), 4.81 (1H, s), 4.01 (1H, s), 3.31 (2H, m), 3.09 (3H, s), 2.22−2.32 (10H, m), 1.65 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 8.63 (1H, m), 7.96 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8. 6 Hz), 7.04-7.45 (8H, m), 6.20 (2H, br.s), 4.81 (1H, s), 4.01 (1H, s), 3.31 ( 2H, m), 3.09 (3H, s), 2.22-2.32 (10H, m), 1.65 (2H, m)
TOF−mass:589 (M+H) TOF-mass: 589 (M + H)
【0030】 [0030]
(実施例5)6−アミノ−1−[4−[3−[4−[ビス(4−フルオロフェニル)メトキシ]−1−ピペリジニル]プロピル]アミノカルボニルフェニル]−3−メチルウラシル(化合物625) (Example 5) 6-amino-1- [4- [3- [4- [bis (4-fluorophenyl) methoxy] -1-piperidinyl] propyl] amino carbonyl phenyl] -3-methyl-uracil (Compound 625)
3−(4−(ジフェニルメチル)−1−ピペラジニル)プロピルアミンの代わりに、3−(4−(ビス(4−フルオロフェニル)メトキシ)−1−ピペリジニル)プロピルアミンを用い実施例1と同様の操作により標記化合物を得た。 Instead of 3- (4- (diphenylmethyl) -1-piperazinyl) propylamine, 3- (4- (bis (4-fluorophenyl) methoxy) -1-piperidinyl) propylamine as in Example 1 using to give the title compound operation.
H−NMR (DMSO−d , δppm): 8.61 (1H, m), 7.96 (2H, t, J = 8.6 Hz), 7.35−7.44 (6H, m), 7.15 (2H, t, J = 8.6 Hz), 6.19 (2H, br.s), 5.67 (1H, s), 4.81 (1H, s), 3.33 (1H, m), 3.08 (3H, s), 2.66 (2H, m), 2.27−2.34 (4H, m), 2.02 (2H, m), 1.72−1.80 (4H,m) 1.55−1.54 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 8.61 (1H, m), 7.96 (2H, t, J = 8.6 Hz), 7.35-7.44 (6H, m) , 7.15 (2H, t, J = 8.6 Hz), 6.19 (2H, br.s), 5.67 (1H, s), 4.81 (1H, s), 3.33 ( 1H, m), 3.08 (3H, s), 2.66 (2H, m), 2.27-2.34 (4H, m), 2.02 (2H, m), 1.72-1 .80 (4H, m) 1.55-1.54 (2H, m)
TOF−mass:605 (M+H) TOF-mass: 605 (M + H)
【0031】 [0031]
(実施例6)6−アミノ−1−[4−[3−[4−(ジフェニルメチル)−1−ピペラジニル]プロピル]アミノカルボニルフェニル]ウラシル(化合物632) (Example 6) 6-Amino-1- [4- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] amino carbonyl phenyl] uracil (Compound 632)
6−アミノ−1−(4−カルボキシフェニル)−3−メチルウラシルの代わりに、6−アミノ−1−(4−カルボキシフェニル)ウラシルを用い実施例1と同様の操作により標記化合物を得た。 Instead of 6-amino-1- (4-carboxyphenyl) -3-methyl uracil to give the title compound 6-amino-1- (4-carboxyphenyl) same operation as in Example 1 using uracil.
H−NMR (DMSO−d , δppm): 10.50 (1H, br.s), 8.61 (1H, brt J = 5.4 Hz), 7.94 (2H, d, J = 8.4 Hz), 7.14−7.43 (12H, m), 6.18 (2H, br.s), 4.67 (1H, s), 4.26 (1H s), 3.31 (2H, m), 2.31−2.50 (10H, m), 1.66 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 10.50 (1H, br.s), 8.61 (1H, brt J = 5.4 Hz), 7.94 (2H, d, J = 8 .4 Hz), 7.14-7.43 (12H, m), 6.18 (2H, br.s), 4.67 (1H, s), 4.26 (1H s), 3.31 ( 2H, m), 2.31-2.50 (10H, m), 1.66 (2H, m)
TOF−mass:540 (M+H) TOF-mass: 540 (M + H)
【0032】 [0032]
(実施例7)6−アミノ−1−[4−[2−[4−(ジフェニルメチル)−1−ピペラジニル]エチル]アミノカルボニルフェニル]−3−メチルウラシル(化合物646) (Example 7) 6-Amino-1- [4- [2- [4- (diphenylmethyl) -1-piperazinyl] ethyl] aminocarbonyl phenyl] -3-methyl-uracil (Compound 646)
3−(4−(ジフェニルメチル)−1−ピペラジニル)プロピルアミンの代わりに、2−(4−(ジフェニルメチル)−1−ピペラジニル)エチルアミンを用い実施例1と同様の操作により標記化合物を得た。 Instead of 3- (4- (diphenylmethyl) -1-piperazinyl) propylamine to give 2- (4- (diphenylmethyl) -1-piperazinyl) of the title compound in the same manner as in Example 1 using ethylamine .
H−NMR (DMSO−d , δppm): 8.51 (1H, br.t, J = 5.1 Hz), 7.95 (2H, d, J = 8.6 Hz), 7.14−7.44 (12H, m), 6.20 (2H, br.s), 4.81 (1H, s), 4.26 (1H, s),3.39 (2H, m), 3.09 (3H, s), 2.31−2.52 (10H, m) 1 H-NMR (DMSO-d 6, δppm): 8.51 (1H, br.t, J = 5.1 Hz), 7.95 (2H, d, J = 8.6 Hz), 7.14 -7.44 (12H, m), 6.20 (2H, br.s), 4.81 (1H, s), 4.26 (1H, s), 3.39 (2H, m), 3. 09 (3H, s), 2.31-2.52 (10H, m)
TOF−mass:539 (M+H) TOF-mass: 539 (M + H)
【0033】 [0033]
(実施例8)6−アミノ−1−[4−[4−[4−(ジフェニルメチル)−1−ピペラジニル]ブチル]アミノカルボニルフェニル]−3−メチルウラシル(化合物648) (Example 8) 6-amino-1- [4- [4- [4- (diphenylmethyl) -1-piperazinyl] butyl] aminocarbonyl phenyl] -3-methyl-uracil (Compound 648)
3−(4−(ジフェニルメチル)−1−ピペラジニル)プロピルアミンの代わりに、4−(4−(ジフェニルメチル)−1−ピペラジニル)ブチルアミンを用い実施例1と同様の操作により標記化合物を得た。 Instead of 3- (4- (diphenylmethyl) -1-piperazinyl) propylamine to give 4- (4- (diphenylmethyl) -1-piperazinyl) of the title compound in the same manner as in Example 1 using butylamine .
H−NMR (DMSO−d , δppm): 8.57 (1H, br.t, J = 5.3 Hz), 7.91 (2H, d, J = 8.6 Hz), 7.14−7.43 (12H, m), 6.19 (2H, br.s), 4.81 (1H, s), 4.24 (1H, s),3.53 (2H, m), 3.08 (3H, s), 2.28−2.50 (10H, m), 3.53 (4H, m) 1 H-NMR (DMSO-d 6, δppm): 8.57 (1H, br.t, J = 5.3 Hz), 7.91 (2H, d, J = 8.6 Hz), 7.14 -7.43 (12H, m), 6.19 (2H, br.s), 4.81 (1H, s), 4.24 (1H, s), 3.53 (2H, m), 3. 08 (3H, s), 2.28-2.50 (10H, m), 3.53 (4H, m)
TOF−mass:567 (M+H) TOF-mass: 567 (M + H)
【0034】 [0034]
(実施例9)6−アミノ−1−[4−[3−[4−(ジフェニルメトキシ)−1−ピペリジニル]プロピル]アミノカルボニルフェニル]−3−メチルウラシル(化合物657) (Example 9) 6-amino-1- [4- [3- [4- (diphenyl-methoxy) -1-piperidinyl] propyl] amino carbonyl phenyl] -3-methyl-uracil (Compound 657)
3−(4−(ジフェニルメチル)−1−ピペラジニル)プロピルアミンの代わりに、3−(4−(ジフェニルメトキシ)−1−ピペリジニル)プロピルアミンを用い実施例1と同様の操作により標記化合物を得た。 3- obtained instead of (4- (diphenylmethyl) -1-piperazinyl) propylamine, 3- (4- (diphenyl-methoxy) -1-piperidinyl) the title compound in the same manner as in Example 1 using propylamine It was.
H−NMR (DMSO−d , δppm): 8.62 (1H, br.t, J = 5.4 Hz), 7.96 (2H, d, J = 8.6 Hz), 7.14−7.43 (12H, m), 6.19 (2H, br.s), 4.01 (1H, s), 4.24 (1H, s),3.33 (1H, s), 3.26 (2H, m), 3.08 (3H, s), 2.67 (2H, m), 2.51 (2H, m), 2.29 (2H, m), 2.01 (2H, m), 1.85 (2H, m), 1.49−1.71 (4H, m) 1 H-NMR (DMSO-d 6, δppm): 8.62 (1H, br.t, J = 5.4 Hz), 7.96 (2H, d, J = 8.6 Hz), 7.14 -7.43 (12H, m), 6.19 (2H, br.s), 4.01 (1H, s), 4.24 (1H, s), 3.33 (1H, s), 3. 26 (2H, m), 3.08 (3H, s), 2.67 (2H, m), 2.51 (2H, m), 2.29 (2H, m), 2.01 (2H, m ), 1.85 (2H, m), 1.49-1.71 (4H, m)
TOF−mass:568 (M+H) TOF-mass: 568 (M + H)
【0035】 [0035]
(実施例10)6−アミノ−1−[4−[3−[4−[ビス(4−フルオロフェニル)メチル]−1−ピペラジニル]プロピル]アミノカルボニルフェニル]ウラシル(化合物711) (Example 10) 6-amino-1- [4- [3- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] propyl] amino carbonyl phenyl] uracil (Compound 711)
6−アミノ−1−(4−カルボキシフェニル)−3−メチルウラシルの代わりに6−アミノ−1−(4−カルボキシフェニル)ウラシルを用い、3−(4−(ジフェニルメチル)−1−ピペラジニル)プロピルアミンの代わりに、3−(4−(ビス(4−フルオロフェニル)メチル)−1−ピペラジニル)プロピルアミンを用い実施例1と同様の操作により標記化合物を得た。 Using 6-amino-1- (4-carboxyphenyl) -3 instead of 6-amino-methyl uracil-1- (4-carboxyphenyl) uracil, 3- (4- (diphenylmethyl) -1-piperazinyl) instead of propylamine to give 3- (4- (bis (4-fluorophenyl) methyl) -1-piperazinyl) of the title compound in the same manner as in example 1 using propylamine.
H−NMR (DMSO−d , δppm): 10.50 (1H, br.s), 8.59 (1H, m), 7.94 (2H, d, J = 8.6 Hz), 7.38−7.45 (6H, m), 7.11 (4H, t, J = 8.6 Hz), 6.17 (2H, br.s),4.67 (1H, s), 4.36 (1H s), 3.30 (2H, m), 3.07 (3H, s), 2.31−2.52 (10H, m), 1.66 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 10.50 (1H, br.s), 8.59 (1H, m), 7.94 (2H, d, J = 8.6 Hz), 7 .38-7.45 (6H, m), 7.11 (4H, t, J = 8.6 Hz), 6.17 (2H, br.s), 4.67 (1H, s), 4. 36 (1H s), 3.30 (2H, m), 3.07 (3H, s), 2.31-2.52 (10H, m), 1.66 (2H, m)
TOF−mass:576 (M+H) TOF-mass: 576 (M + H)
【0036】 [0036]
(実施例11)6−アミノ−1−[4−[3−[4−(10,11−ジヒドロ−5H−ジベンゾ[a,d]シクロヘプテン−5−イル)−1−ピペラジニル]プロピル]アミノカルボニルフェニル]−3−メチルウラシル(化合物1234) (Example 11) 6-amino-1- [4- [3- [4- (10,11-dihydro -5H- dibenzo [a, d] cyclohepten-5-yl) -1-piperazinyl] propyl] aminocarbonyl phenyl] -3-methyl-uracil (compound 1234)
3−(4−(ジフェニルメチル)−1−ピペラジニル)プロピルアミンの代わりに、3−(4−(10,11−ジヒドロ−5H−ジベンゾ[a,d]シクロヘプテン−5−イル)−1−ピペラジニル)プロピルアミンを用い実施例1と同様の操作により標記化合物を得た。 3- (4- (diphenylmethyl) -1-piperazinyl) in place of propylamine, 3- (4- (10,11-dihydro -5H- dibenzo [a, d] cyclohepten-5-yl) -1-piperazinyl ) to give the title compound in the same manner as in example 1 using propylamine.
H−NMR (DMSO−d , δppm): 8.62 (1H, br.t, J = 5.1 Hz), 7.95 (2H, d, J = 8.6 Hz), 7.44 (6H, m), 7.12 (4H, t, J = 8.6 Hz), 6.20 (2H, br.s), 5.63 (1H, s), 4.81 (1H, s), 4.34 (2H, m), 3.28 (2H, m), 3.09 (3H, s), 2.25−2.49(14H, m), 1.66 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 8.62 (1H, br.t, J = 5.1 Hz), 7.95 (2H, d, J = 8.6 Hz), 7.44 (6H, m), 7.12 (4H, t, J = 8.6 Hz), 6.20 (2H, br.s), 5.63 (1H, s), 4.81 (1H, s) , 4.34 (2H, m), 3.28 (2H, m), 3.09 (3H, s), 2.25-2.49 (14H, m), 1.66 (2H, m)
TOF−mass:579 (M+H) TOF-mass: 579 (M + H)
【0037】 [0037]
(実施例12)6−アミノ−1−[4−[4−[4−(ジフェニルメチル)−1−ピペラジニル]ブタノイルアミノ]フェニル]−3−メチルウラシル(化合物827) (Example 12) 6-amino-1- [4- [4- [4- (diphenylmethyl) -1-piperazinyl] butanoylamino] phenyl] -3-methyl-uracil (Compound 827)
6−アミノ−1−(4−アミノフェニル)−3−メチルウラシル 478 mg(2.06 mmol)と4−(4−(ジフェニルメチル)−1−ピペラジニル)ブタン酸 768mg(2.27 mmol)をN,N−ジメチルホルムアミド 25 mlに溶解し、1−ヒドロキシ−7−アザ−ベンゾトリアゾール 370 mg(2.72 mmol)と1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩 521 mg(2.72mmol)を加え2時間半撹拌した。 6-amino-1- (4-aminophenyl) -3-methyl uracil 478 mg (2.06 mmol) and 4- (4- (diphenylmethyl) -1-piperazinyl) 768 mg butanoic acid (2.27 mmol) N, N- dimethylformamide were dissolved in 25 ml, 1-hydroxy-7-aza - benzotriazole 370 mg (2.72 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 521 mg ( 2.72 mmol) was stirred for 2 hours added. 溶媒を留去し、酢酸エチルと5 % 炭酸水素ナトリウム水溶液で分配した。 The solvent was evaporated and partitioned between ethyl acetate and 5% aqueous sodium hydrogen carbonate solution. 有機層を10 % 塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。 The organic layer was washed with 10% aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. 溶媒を留去後、シリカゲルカラムクロマトグラフィーで精製することにより標記化合物を得た(110 mg(0.20 mmol)、収率13 %)。 After distilling off the solvent, purified by silica gel column chromatography to give the title compound (110 mg (0.20 mmol), 13% yield).
H−NMR (DMSO−d , δppm): 10.08 (1H, s), 7.71 (2H, d, J = 8.6 Hz), 7.14−7.42 (12H, m), 6.14 (2H, br.s), 4.78 (1H, s), 4.23 (1H, s), 3.08 (3H, s),2.25−2.50 (12H, m), 1.72 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 10.08 (1H, s), 7.71 (2H, d, J = 8.6 Hz), 7.14-7.42 (12H, m) , 6.14 (2H, br.s), 4.78 (1H, s), 4.23 (1H, s), 3.08 (3H, s), 2.25-2.50 (12H, m ), 1.72 (2H, m)
TOF−mass:553 (M+H) TOF-mass: 553 (M + H)
【0038】 [0038]
(実施例13)6−アミノ−1−[4−[5−[4−(ジフェニルメチル)−1−ピペラジニル]ペンタノイルアミノ]フェニル]−3−メチルウラシル(化合物828) (Example 13) 6-amino-1- [4- [5- [4- (diphenylmethyl) -1-piperazinyl] pentanoylamino] phenyl] -3-methyl-uracil (Compound 828)
4−(4−(ジフェニルメチル)−1−ピペラジニル)ブタン酸の代わりに、5−(4−(ジフェニルメチル)−1−ピペラジニル)ペンタン酸を用い実施例12と同様の操作により標記化合物を得た。 4 obtained instead of (4- (diphenylmethyl) -1-piperazinyl) butanoic acid, 5- (4- (diphenylmethyl) -1-piperazinyl) of the title compound in the same manner as in Example 12 using pentanoic acid It was.
H−NMR (DMSO−d , δppm): 10.08 (1H, s), 7.71 (2H, d, J = 8.6 Hz), 7.14−7.42 (12H, m), 6.14 (2H, br.s), 4.78 (1H, s), 4.25 (1H, s), 3.08 (3H, s),2.25−2.50 (12H, m), 1.58 (2H, m), 1.44 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 10.08 (1H, s), 7.71 (2H, d, J = 8.6 Hz), 7.14-7.42 (12H, m) , 6.14 (2H, br.s), 4.78 (1H, s), 4.25 (1H, s), 3.08 (3H, s), 2.25-2.50 (12H, m ), 1.58 (2H, m), 1.44 (2H, m)
TOF−mass:567 (M+H) TOF-mass: 567 (M + H)
【0039】 [0039]
(実施例14)6−アミノ−1−[4−[4−[4−(ヒドロキシジフェニルメチル)−1−ピペリジニル]ブタノイルアミノ]フェニル]−3−メチルウラシル(化合物834) (Example 14) 6-amino-1- [4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] butanoylamino] phenyl] -3-methyl-uracil (Compound 834)
4−(4−(ジフェニルメチル)−1−ピペラジニル)ブタン酸の代わりに、4−(4−(ヒドロキシジフェニルメチル)−1−ピペリジニル)ブタン酸を用い実施例12と同様の操作により標記化合物を得た。 4 instead of (4- (diphenylmethyl) -1-piperazinyl) butanoic acid, 4- (4- (hydroxydiphenylmethyl) -1-piperidinyl) the title compound in the same manner as in Example 12 using the butanoic acid and Obtained.
H−NMR (DMSO−d , δppm): 8.63 (1H, br.t, J = 5.4 Hz), 7.96 (2H, t, J = 8.6 Hz), 7.43−7.17 (12H, m), 5.79 (2H, br.s), 4.71 (1H, s), 4.26 (1H, s),3.29 (2H, m), 3.11 (3H, s), 2.31−2.40 (10H, m), 1.66 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 8.63 (1H, br.t, J = 5.4 Hz), 7.96 (2H, t, J = 8.6 Hz), 7.43 -7.17 (12H, m), 5.79 (2H, br.s), 4.71 (1H, s), 4.26 (1H, s), 3.29 (2H, m), 3. 11 (3H, s), 2.31-2.40 (10H, m), 1.66 (2H, m)
TOF−mass:568 (M+H) TOF-mass: 568 (M + H)
【0040】 [0040]
(実施例15)6−アミノ−1−[4−[4−[4−(ジフェニルメトキシ)−1−ピペリジニル]ブタノイルアミノ]フェニル]−3−メチルウラシル(化合物837) (Example 15) 6-amino-1- [4- [4- [4- (diphenylmethoxy) -1-piperidinyl] butanoylamino] phenyl] -3-methyl-uracil (Compound 837)
4−(4−(ジフェニルメチル)−1−ピペラジニル)ブタン酸の代わりに、4−(4−(ジフェニルメトキシ)−1−ピペリジニル)ブタン酸を用い実施例12と同様の操作により標記化合物を得た。 4 obtained instead of (4- (diphenylmethyl) -1-piperazinyl) butanoic acid, 4- (4- (diphenyl-methoxy) -1-piperidinyl) the title compound in the same manner as in Example 12 using the butanoic acid It was.
H−NMR (DMSO−d , δppm): 10.08 (1H, s), 7.71 (2H, t, J = 8.6 Hz), 7.20−7.38 (12H, m), 6.14 (2H, br.s), 5.63 (1H, s), 4.78 (1H, s), 3.34 (1H, m),3.07 (3H, s), 2.66 (2H, m), 2.23−2.37 (4H, m), 2.00 (2H, m), 1.69−1.74 (4H, m), 1.55 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 10.08 (1H, s), 7.71 (2H, t, J = 8.6 Hz), 7.20-7.38 (12H, m) , 6.14 (2H, br.s), 5.63 (1H, s), 4.78 (1H, s), 3.34 (1H, m), 3.07 (3H, s), 2. 66 (2H, m), 2.23-2.37 (4H, m), 2.00 (2H, m), 1.69-1.74 (4H, m), 1.55 (2H, m)
TOF−mass:568 (M+H) TOF-mass: 568 (M + H)
【0041】 [0041]
(実施例16)6−アミノ−1−[4−[4−[4−[ビス(4−フルオロフェニル)メチル]−1−ピペラジニル]ブタノイルアミノ]フェニル]−3−メチルウラシル(化合物892) (Example 16) 6-amino-1- [4- [4- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] butanoylamino] phenyl] -3-methyl-uracil (Compound 892)
4−(4−(ジフェニルメチル)−1−ピペラジニル)ブタン酸の代わりに、4−(4−(ビス(4−フルオロフェニル)メチル)−1−ピペラジニル)ブタン酸を用い実施例12と同様の操作により標記化合物を得た。 4 instead of (4- (diphenylmethyl) -1-piperazinyl) butanoic acid, 4- (4- (bis (4-fluorophenyl) methyl) -1-piperazinyl) as in Example 12 using the butanoic acid to give the title compound operation.
H−NMR (CDCl , δppm): 10.07 (1H, s), 7.71 (2H, d, J = 8.9 Hz), 7.42 (4H, m), 7.42 (4H, m), 7.22 (2H, d, J = 8.9 Hz), 7.12 (4H, d, J = 8.9 Hz), 6.13 (2H, br.s), 4.79 (1H, s), 4.31 (1H, s), 3.08 (3H, s), 2.31−2.51 (12H, m), 1.72 (2H, m) 1 H-NMR (CDCl 3, δppm): 10.07 (1H, s), 7.71 (2H, d, J = 8.9 Hz), 7.42 (4H, m), 7.42 (4H , m), 7.22 (2H, d, J = 8.9 Hz), 7.12 (4H, d, J = 8.9 Hz), 6.13 (2H, br.s), 4.79 (1H, s), 4.31 (1H, s), 3.08 (3H, s), 2.31-2.51 (12H, m), 1.72 (2H, m)
TOF−mass:590 (M+H) TOF-mass: 590 (M + H)
【0042】 [0042]
(実施例17)6−アミノ−1−[4−[4−[4−[ビス(4−フルオロフェニル)メトキシ]−1−ピペリジニル]ブタノイルアミノ]フェニル]−3−メチルウラシル(化合物895) (Example 17) 6-amino-1- [4- [4- [4- [bis (4-fluorophenyl) methoxy] -1-piperidinyl] butanoylamino] phenyl] -3-methyl-uracil (Compound 895)
4−(4−(ジフェニルメチル)−1−ピペラジニル)ブタン酸の代わりに、4−(4−(ビス(4−フルオロフェニル)メトキシ)−1−ピペリジニル)ブタン酸を用い実施例12と同様の操作により標記化合物を得た。 4 instead of (4- (diphenylmethyl) -1-piperazinyl) butanoic acid, 4- (4- (bis (4-fluorophenyl) methoxy) -1-piperidinyl) as in Example 12 using the butanoic acid to give the title compound operation.
H−NMR (DMSO−d , δppm): 10.08 (1H, s), 7.71 (2H, d, J = 8.9 Hz), 7.38 (4H, m), 7.12−7.23 (6H, m), 6.13 (2H, br.s), 5.67 (1H, s), 4.79 (1H s), 3.33 (1H, m), 3.31 (2H, m), 3.09 (3H, s), 2.30 (2H, m), 2.02 (2H, m), 1.81 (2H, m), 1.55−1.66 (4H, m) 1 H-NMR (DMSO-d 6, δppm): 10.08 (1H, s), 7.71 (2H, d, J = 8.9 Hz), 7.38 (4H, m), 7.12 -7.23 (6H, m), 6.13 (2H, br.s), 5.67 (1H, s), 4.79 (1H s), 3.33 (1H, m), 3.31 (2H, m), 3.09 (3H, s), 2.30 (2H, m), 2.02 (2H, m), 1.81 (2H, m), 1.55-1.66 ( 4H, m)
TOF−mass:605 (M+H) TOF-mass: 605 (M + H)
【0043】 [0043]
(実施例18)6−アミノ−1−[4−[4−[4−(ジフェニルメチル)−1−ピペラジニル]ブタノイルアミノメチル]フェニル]−3−メチルウラシル(化合物1007) (Example 18) 6-amino-1- [4- [4- [4- (diphenylmethyl) -1-piperazinyl] butanoylamino methyl] phenyl] -3-methyl-uracil (Compound 1007)
6−アミノ−1−(4−アミノフェニル)−3−メチルウラシルの代わりに、6−アミノ−1−(4−アミノメチルフェニル)−3−メチルウラシルを用い実施例12と同様の操作により標記化合物を得た。 Instead of 6-amino-1- (4-aminophenyl) -3-methyl uracil, 6-amino-1- (4-aminomethyl phenyl) -3- title in the same manner as in Example 12 with methyl uracil to give compound.
H−NMR (DMSO−d , δppm): 8.40 (1H, br.t J = 5.9 Hz), 7.14−7.42 (14H, m),6.09 (2H, br.s), 4.80 (1H, s), 4.32 (2H, d, J = 5.9 Hz), 4.25 (1H, s), 3.07 (3H, s), 2.14−2.37 (12H, m), 1.67 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 8.40 (1H, br.t J = 5.9 Hz), 7.14-7.42 (14H, m), 6.09 (2H, br .s), 4.80 (1H, s), 4.32 (2H, d, J = 5.9 Hz), 4.25 (1H, s), 3.07 (3H, s), 2.14 -2.37 (12H, m), 1.67 (2H, m)
TOF−mass:568 (M+H) TOF-mass: 568 (M + H)
【0044】 [0044]
(実施例19)6−アミノ−1−[4−[3−[4−(ジフェニルメトキシ)−1−ピペリジニル]ブタノイルアミノメチル]フェニル]−3−メチルウラシル(化合物1017) (Example 19) 6-amino-1- [4- [3- [4- (diphenyl-methoxy) -1-piperidinyl] butanoylamino methyl] phenyl] -3-methyl-uracil (Compound 1017)
6−アミノ−1−(4−アミノフェニル)−3−メチルウラシルの代わりに、6−アミノ−1−(4−アミノメチルフェニル)−3−メチルウラシルを用い、4−(4−(ジフェニルメチル)−1−ピペラジニル)ブタン酸の代わりに、4−(4−(ジフェニルメトキシ)−1−ピペリジニル)ブタン酸を用い実施例12と同様の操作により標記化合物を得た。 Instead of 6-amino-1- (4-aminophenyl) -3-methyl uracil, using 6-amino-1- (4-aminomethyl-phenyl) -3-methyl-uracil, 4- (4- (diphenylmethyl ) -1-piperazinyl) instead of butanoic acid to give 4- (4- (diphenyl-methoxy) -1-piperidinyl) the title compound in the same manner as in example 12 using the butanoic acid.
H−NMR (DMSO−d , δppm): 8.40 (1H, br.t J = 5.9 Hz), 7.18−7.38 (14H, m),6.09 (2H, br.s), 5.63 (1H, s), 4.80 (1H, s), 4.33 (2H, d, J = 5.9 Hz), 3.33 (1H, m), 3.07 (3H, s), 2.65 (2H, m), 2.14−2.23 (4H, m), 1.99 (2H, m), 1.82 (2H, m), 1.52−1.69 (4H, m) 1 H-NMR (DMSO-d 6, δppm): 8.40 (1H, br.t J = 5.9 Hz), 7.18-7.38 (14H, m), 6.09 (2H, br .s), 5.63 (1H, s), 4.80 (1H, s), 4.33 (2H, d, J = 5.9 Hz), 3.33 (1H, m), 3.07 (3H, s), 2.65 (2H, m), 2.14-2.23 (4H, m), 1.99 (2H, m), 1.82 (2H, m), 1.52- 1.69 (4H, m)
TOF−mass:583 (M+H) TOF-mass: 583 (M + H)
【0045】 [0045]
(実施例20)6−アミノ−1−[4−[4−[4−(10,11−ジヒドロ−5H−ジベンゾ[a,d]シクロヘプテン−5−イル)−1−ピペラジニル]ブタノイルアミノ]フェニル]−3−メチルウラシル(化合物1306) (Example 20) 6-amino-1- [4- [4- [4- (10,11-dihydro -5H- dibenzo [a, d] cyclohepten-5-yl) -1-piperazinyl] butanoylamino] phenyl] -3-methyl-uracil (compound 1306)
4−(4−(ジフェニルメチル)−1−ピペラジニル)ブタン酸の代わりに、4−(4−(10,11−ジヒドロ−5H−ジベンゾ[a,d]シクロヘプテン−5−イル)−1−ピペラジニル)ブタン酸を用い実施例12と同様の操作により標記化合物を得た。 4- (4- (diphenylmethyl) -1-piperazinyl) instead of butanoic acid, 4- (4- (10,11-dihydro -5H- dibenzo [a, d] cyclohepten-5-yl) -1-piperazinyl ) to give the title compound in the same manner as in example 12 using the butanoic acid.
H−NMR (DMSO−d , δppm): 10.09 (1H, s), 7.71 (2H, t, J = 8.6 Hz), 7.06−7.24 (12H, m), 6.13 (2H, br.s), 4.79 (1H, s), 3.86−4.00 (3H, m), 3.07 (3H, s), 2.74 (2H, m), 2.22−2.37 (14H, m), 1.73 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 10.09 (1H, s), 7.71 (2H, t, J = 8.6 Hz), 7.06-7.24 (12H, m) , 6.13 (2H, br.s), 4.79 (1H, s), 3.86-4.00 (3H, m), 3.07 (3H, s), 2.74 (2H, m ), 2.22-2.37 (14H, m), 1.73 (2H, m)
TOF−mass:579 (M+H) TOF-mass: 579 (M + H)
【0046】 [0046]
(実施例21)6−アミノ−1−[4−[3−[4−(ジフェニルメチル)−1−ピペラジニル]プロピルオキシ]フェニル]−3−メチルウラシル(化合物107) (Example 21) 6-amino-1- [4- [3- [4- (diphenylmethyl) -1-piperazinyl] propyloxy] phenyl] -3-methyl-uracil (Compound 107)
6−アミノ−1−(4−ヒドロキシフェニル)−3−メチルウラシル 800 mg(3.43 mmol)をN,N−ジメチルホルムアミド 30 mlに溶解し、3−ブロモプロパノール 931μl(10.3 mmol)と炭酸カリウム 948 mg(6.86 mmol)を加え50 ℃で2時間半撹拌した。 6-amino-1- (4-hydroxyphenyl) -3-methyl uracil 800 mg of (3.43 mmol) N, was dissolved in N- dimethylformamide 30 ml, 3- bromo propanol 931μl and (10.3 mmol) added potassium carbonate 948 mg (6.86 mmol) was stirred for 2 hours at 50 ° C.. 放冷後、溶媒を留去し、ジクロロメタンと5 %クエン酸水溶液で分配した。 After cooling, the solvent was distilled off, and partitioned between dichloromethane and 5% aqueous citric acid. 水層を中和して生じた固体を濾取した。 The aqueous layer was neutralized and filtered the resulting solid. 固体にジクロロメタン30 mlを加え、氷冷下メシルクロライド 288μl(3.72 mmol)、トリエチルアミン 519μl(3.72 mmol)、ジメチルアミノピリジン 175 mg(1.43 mmol)を加え5時間撹拌した。 Solids dichloromethane 30 ml was added, under ice-cooling mesyl chloride 288μl (3.72 mmol), triethylamine 519μl (3.72 mmol), dimethylaminopyridine 175 mg (1.43 mmol) was stirred for 5 hours added. 5 % クエン酸水溶液を加え、ジクロロメタンで3回抽出した。 5% citric acid aqueous solution was added, and the mixture was extracted three times with dichloromethane. 有機層を10 % 塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。 The organic layer was washed with 10% aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. 溶媒を留去後、アセトニトリル 20 mlに溶解し、1−(ジフェニルメチル)ピペラジン 686 mg(2.72 mmol)とトリエチルアミン 379 μl(2.72 mmol)を加え80 ℃で2時間撹拌した。 After distilling off the solvent was dissolved in 20 ml of acetonitrile, 1-was stirred for 2 hours at 80 ° C. was added a (diphenylmethyl) piperazine 686 mg (2.72 mmol) and triethylamine 379 [mu] l (2.72 mmol). 放冷後、溶媒を留去し、5 % 炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。 After cooling, the solvent was distilled off, adding 5% aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. 有機層を10 % 塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。 The organic layer was washed with 10% aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. 溶媒を留去して生じた固体を、エーテル、ヘキサン混合溶媒に懸濁して精製することにより標記化合物を得た(50 mg、0.10 mmol、収率3 %)。 And evaporated resulting solid and the solvent, ether to give the title compound by purification suspended in hexane mixed solvent (50 mg, 0.10 mmol, 3% yield).
H−NMR (DMSO−d , δppm): 7.00−7.43 (14H, m), 6.11 (2H, br.s), 4.78 (1H, s), 4.26 (1H, s), 4.02 (2H, t, J = 6.2 Hz), 3.07 (3H, s), 2.32−2.51 (10H, m), 1.87 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 7.00-7.43 (14H, m), 6.11 (2H, br.s), 4.78 (1H, s), 4.26 ( 1H, s), 4.02 (2H, t, J = 6.2 Hz), 3.07 (3H, s), 2.32-2.51 (10H, m), 1.87 (2H, m )
TOF−mass:526 (M+H) TOF-mass: 526 (M + H)
【0047】 [0047]
(実施例22)6−アミノ−1−[4−[4−[4−(ジフェニルメチル)−1−ピペラジニル]ブチルアミノ]フェニル]−3−メチルウラシル(化合物288) (Example 22) 6-amino-1- [4- [4- [4- (diphenylmethyl) -1-piperazinyl] butyl] phenyl] -3-methyl-uracil (Compound 288)
化合物827 249 mg (0.45 mmol)をテトラヒドロフラン 5 mlに溶解し、氷冷下ボランジメチルスルフィドコンプレックス108μl を加え、1時間半加熱還流した。 Compound 827 249 mg of (0.45 mmol) was dissolved in tetrahydrofuran 5 ml, under ice-cooling borane dimethylsulfide complex 108μl and the mixture was heated under reflux for 1.5 hours. 放冷後、氷冷下1N 塩酸 1.0 mlを加え、2時間加熱還流した。 After cooling, 1N hydrochloric acid 1.0 ml under ice-cooling and the mixture was heated under reflux for 2 hours. 放冷後、溶媒を留去し、1N 水酸化ナトリウムを加え、ジクロロメタンで2回抽出した。 After cooling, the solvent was evaporated, 1N sodium hydroxide was added, and the mixture was extracted twice with dichloromethane. 有機層を10 % 塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。 The organic layer was washed with 10% aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. ジクロロメタンを留去後、シリカゲルクロマトグラフィーで精製(ジクロロメタン:メタノール=20:1〜10:1)することにより標記合物を得た(27 mg(0.05 mmol)、収率11 %)。 After distilling off the dichloromethane, purified by silica gel chromatography (dichloromethane: methanol = 20: 1 to 10: 1) to give the title compound by (27 mg (0.05 mmol), 11% yield).
H−NMR (DMSO−d , δppm): 7.00−7.43 (14H, m), 5.04 (1H, s), 4.22 (1H, s),4.13 (2H, br.s), 4.04 (2H, t, J = 6.2 Hz), 3.33 (3H, s), 2.50−2.55 (10H, m), 1.97 (2H, m) 1 H-NMR (DMSO-d 6, δppm): 7.00-7.43 (14H, m), 5.04 (1H, s), 4.22 (1H, s), 4.13 (2H, br.s), 4.04 (2H, t, J = 6.2 Hz), 3.33 (3H, s), 2.50-2.55 (10H, m), 1.97 (2H, m )
TOF−mass:526 (M+H) TOF-mass: 526 (M + H)
【0048】 [0048]
(評価例1)OVA誘発マウス2相性皮膚炎抑制作用本発明の抗ヒスタミン作用を併せ持つ新規ウラシル誘導体の炎症抑制作用を検証するため、ヒスタミン関与の強い即時型及び炎症性細胞の浸潤が強い遅発型の両反応を示すOVA誘発マウス2相性皮膚炎モデルにて評価した。 (Evaluation Example 1) To verify the anti-inflammatory effects of the novel uracil derivatives having both antihistaminic effect of OVA-induced mouse biphasic dermatitis inhibition present invention, infiltration strong late strong immediate and inflammatory cells of histamine involved It was evaluated by OVA-induced mouse biphasic dermatitis model shown both reaction types. ICR系雄性マウスに卵白アルブミン(OVA)1μgをAl(OH) 1mgとともに腹腔内投与して感作を誘導した。 To ICR male mice of ovalbumin (OVA) 1 [mu] g induced sensitization was administered intraperitoneally together with Al (OH) 3 1mg. 感作14日目にOVA10μgを耳介内に直接投与してアレルギー反応を惹起した。 It elicited an allergic reaction OVA10μg sensitization day 14 was administered directly into the ear. 被験薬物は0.5% CMC−Na水溶液に懸濁し、惹起の1時間前に経口投与(30 mg/kg)した。 Test drug was suspended in 0.5% CMC-Na aqueous solution was orally administered (30 mg / kg) one hour before inducing. 惹起1時間後及び24時間後に耳介厚を測定し、惹起前の耳介厚との差を指標とし、被験化合物の皮膚炎抑制効果を評価した。 The ear thickness was measured evoked 1 hour after and 24 hours later, the difference between the induced previous ear KaiAtsu an index to assess the dermatitis inhibitory effect of the test compound. 比較例としてオキサトミド(Oxatomide)、フマル酸ケトチフェン(Ketotifen fumarate)を用い、いずれも0.5% CMC−Na水溶液に懸濁し、惹起の1時間前に経口投与した。 Oxatomide as a comparative example (Oxatomide), using ketotifen fumarate (ketotifen fumarate), both suspended in 0.5% CMC-Na solution was administered orally 1 hour prior to elicit. 惹起1時間後の耳介厚の増加はヒスタミンなどの化学伝達物質による浮腫であり、これを即時相と規定した。 Increase in induced one hour after ear KaiAtsu is edema caused by chemical mediators such as histamine, defined this immediate phase. 24時間後のそれは好酸球などの炎症性細胞によるものであり、これを遅発相と規定した。 It after 24 hours is due to inflammatory cells such as eosinophils, was defined as late phase this.
【0049】 [0049]
その結果、表3に示す通り本発明の化合物は即時相及び遅発相の両方を抑制することがわかる。 Consequently, compounds as the invention shown in Table 3 it can be seen that to suppress both immediate phase and late phase. これに対して、既知の抗ヒスタミン薬であるケトチフェンは即時相は強く抑制したが、遅発相に対しては無効であった。 On the other hand, is a known antihistamine ketotifen was immediate phase is strongly suppressed, but was ineffective against the late phase.
【0050】 [0050]
【表3】 [Table 3]
【0051】 [0051]
(評価例2) (Evaluation Example 2)
本発明の新規ウラシル誘導体が抗ヒスタミン作用を有することを検証するためにモルモット回腸を用いたマグヌス法にて評価した。 It was evaluated in Magnus method using guinea pig ileum to verify that the new uracil derivatives of the present invention has anti-histamine effect. モルモットより摘出した回腸をTyrode液中で洗浄し、32℃のTyrode液中で通気しながら保存した。 The excised ileum from guinea pigs is washed with Tyrode solution, and stored with aeration in Tyrode solution of 32 ° C.. 回腸を約2cmの長さで切除し、Tyrode液を満たしたマグヌス管中で一端を固定棒に他端を圧トランスデューサーに固定し、回腸の収縮を記録可能とした。 Ileum was excised with a length of about 2cm and Tyrode solution to fix the other end at one end to the fixing rod to a pressure transducer in Magnus tube filled with, and can be recorded contractions ileum. Tyrode液で満たしたマグヌス管に1.0μMのHistamine水溶液を100μL加えた場合に誘発される回腸の収縮に対する各被験薬物のIC 50を求めた。 It was determined IC 50 of each test drug on the contraction of the ileum induced when the Magnus tube filled with Tyrode solution was added 100μL of Histamine aqueous 1.0 [mu] M. 被験薬物はHistamineを加える2分前にTyrode液中に5μLの容量で加えた。 Test drug was added in a volume of 5μL to Tyrode solution to 2 minutes before the addition of Histamine. 比較例としてジフェンヒドラミン、オキサトミドを用いた。 Diphenhydramine As a comparative example, was used oxatomide.
【0052】 [0052]
表4に示す通り本発明の化合物は既知の抗ヒスタミン薬と同程度の抗ヒスタミン作用を有することが示された。 Compounds as the present invention shown in Table 4 have been shown to have anti-histaminergic comparable to the known antihistamines.
【0053】 [0053]
【表4】 [Table 4]
【0054】 [0054]
(製剤例1)内服用錠剤常法により次の組成からなる内服用錠剤を作成した。 The (Formulation Example 1) in taking tablets conventional manner to create oral tablets having the following composition.
【0055】 [0055]
【0056】 [0056]
【発明の効果】 【Effect of the invention】
本発明のウラシル誘導体は、抗ヒスタミン作用と抗炎症作用を併せ持ち、抗ヒスタミン剤として、及び/又は、抗アレルギー剤として有用である。 Uracil derivatives of the present invention has both the antihistamine and anti-inflammatory action, as antihistamine, and / or are useful as antiallergic agents. 特にアレルギー性炎症に対して、際立った炎症抑制作用を有する。 Particularly for allergic inflammation, it has a pronounced anti-inflammatory action. 本発明のウラシル誘導体は、ヒスタミンによるかゆみを抑制するとともにアレルギー性炎症も効果的に抑制するので、アレルギー性結膜炎、アレルギー性鼻炎、慢性蕁麻疹、アトピー性皮膚炎、喘息又は慢性気管支炎の予防・治療剤として有用であり、従来の抗アレルギー剤、抗ヒスタミン剤、抗炎症剤などと比べて、有効性、安全性などの点でより満足のいく新規化合物である。 Uracil derivatives of the present invention, since also effectively suppress allergic inflammation suppresses itching histamine, allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, prevention of asthma or chronic bronchitis, They are useful as therapeutic agents, the conventional antiallergic agents, antihistamines, as compared with such anti-inflammatory agents, efficacy, are novel compounds go a more satisfactory in terms of safety and the like.

Claims (9)

  1. 一般式(I): The general formula (I):
    (式中、R は水素原子、置換又は無置換の炭素数1〜4のアルキル基あるいは置換又は無置換の炭素数7〜10のアラルキル基を表し、R 、R はそれぞれ水素原子又は炭素数1〜4のアルキル基を表し、Ar 、Ar はそれぞれ置換又は無置換のフェニル基あるいは置換又は無置換の単環芳香族複素環基を表すが、Ar 及びAr の双方に結合する基によって第3の環を形成してもよく、WはO、NH、COO、OCO、CONH、NHCO、CH NH、又はCH NHCOを表し、Wはウラシル骨格1位のフェニル基上のオルト、メタ、パラいずれの位置に置換していてもよく、Xはメチン基(CH)又は窒素原子を表し、Yは、Xがメチン基の時、単結合又は酸素原子を表し、Xが窒素原子の時、単結合を表し、Z (Wherein, R 1 represents a hydrogen atom, a substituted or unsubstituted alkyl group or a substituted or unsubstituted aralkyl group having 7 to 10 carbon atoms having 1 to 4 carbon atoms, R 2, R 3 are each a hydrogen atom or represents an alkyl group having 1 to 4 carbon atoms, Ar 1, Ar 2 each represents independently a substituted or unsubstituted phenyl group or a substituted or unsubstituted monocyclic aromatic heterocyclic group, both of Ar 1 and Ar 2 by binding to group may form a third ring, W is O, NH, COO, OCO, CONH, NHCO, CH 2 NH, or an CH 2 NHCO, W is on the phenyl group of the uracil skeleton 1 of ortho, meta, may be substituted on the para any position, X represents a a methine group (CH) and an nitrogen atom, Y when X is a methine group, represents a single bond or an oxygen atom, X is when the nitrogen atom, represents a single bond, Z は、Xがメチン基でYが単結合の時、水素原子又は水酸基を表し、Xがメチン基でYが酸素原子の時及びXが窒素原子(Yは単結合)の時、水素原子を表し、mは2〜6を表す。) When X is methine group Y is a single bond, represents a hydrogen atom or a hydroxyl group, X is when Y methine group when and X is a nitrogen atom an oxygen atom (Y is a single bond), represents a hydrogen atom , m represents 2-6.)
    で表されるウラシル誘導体又はその薬学的に許容される塩。 In uracil derivative or a pharmaceutically acceptable salt thereof.
  2. 一般式(I)において、Ar 、Ar がそれぞれ置換又は無置換のフェニル基である請求項1記載のウラシル誘導体又はその薬学的に許容される塩。 In the general formula (I), Ar 1, Ar 2 is uracil derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein each substituted or unsubstituted phenyl group.
  3. 一般式(I)において、Ar 、Ar がそれぞれ(1)ハロゲン原子もしくは炭素数1〜4のアルキル基で置換されていてもよいフェニル基又は(2)炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれる1ないし4個のヘテロ原子を含む5ないし8員の芳香族複素環基である請求項1記載のウラシル誘導体又はその薬学的に許容される塩。 In the general formula (I), Ar 1, Ar 2 are each (1) a halogen atom or a phenyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms or (2) a nitrogen atom in addition to carbon atom, a sulfur atom and 1 to 5 to uracil derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the aromatic heterocyclic group having 8 membered containing 4 hetero atoms selected from oxygen atom.
  4. 一般式(I)において、WがCONH又はNHCOである請求項1〜3のいずれか1項に記載のウラシル誘導体又はその薬学的に許容される塩。 In the general formula (I), uracil derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 W is CONH or NHCO.
  5. 一般式(I)において、Xがメチン基である請求項1〜4のいずれか1項に記載のウラシル誘導体又はその薬学的に許容される塩。 In the general formula (I), X is uracil derivative or a pharmaceutically acceptable salt thereof according to claim 1 is a methine group.
  6. 一般式(I)において、Xが窒素原子である請求項1〜4のいずれか1項に記載のウラシル誘導体又はその薬学的に許容される塩。 In the general formula (I), uracil derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 X is a nitrogen atom.
  7. 請求項1〜6のいずれか1項に記載のウラシル誘導体又はその薬学的に許容される塩を有効成分として含有する抗ヒスタミン剤。 Antihistamines containing as uracil derivative or active ingredients a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.
  8. 請求項1〜6のいずれか1項に記載のウラシル誘導体又はその薬学的に許容される塩を有効成分として含有する抗アレルギー剤。 Antiallergic agent comprising as an active ingredient the uracil derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.
  9. 請求項1〜6のいずれか1項に記載のウラシル誘導体又はその薬学的に許容される塩を有効成分として含有するアレルギー性結膜炎、アレルギー性鼻炎、慢性蕁麻疹、アトピー性皮膚炎、喘息又は慢性気管支炎の予防・治療剤。 Allergic conjunctivitis comprising as an active ingredient the uracil derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma or chronic an agent for the prophylaxis or treatment of bronchitis.
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