JP2007015928A - New olefin derivative - Google Patents
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- JP2007015928A JP2007015928A JP2003354946A JP2003354946A JP2007015928A JP 2007015928 A JP2007015928 A JP 2007015928A JP 2003354946 A JP2003354946 A JP 2003354946A JP 2003354946 A JP2003354946 A JP 2003354946A JP 2007015928 A JP2007015928 A JP 2007015928A
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- 0 *[n]1c2nccc(I)c2cc1 Chemical compound *[n]1c2nccc(I)c2cc1 0.000 description 1
- JCVQZVBWNFFVBT-RVDMUPIBSA-N CC(C)(c(cc1)ccc1/C(/CO)=C/c1ccnc2c1cc[nH]2)N Chemical compound CC(C)(c(cc1)ccc1/C(/CO)=C/c1ccnc2c1cc[nH]2)N JCVQZVBWNFFVBT-RVDMUPIBSA-N 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
Description
本発明は、医薬として有用な新規オレフィン誘導体またはその塩に関する。本発明に係るオレフィン誘導体は、Rhoキナーゼ阻害作用を有し、Rhoキナーゼが関与する疾患、例えば、緑内障等の眼疾患治療剤として有用である。 The present invention relates to a novel olefin derivative or a salt thereof useful as a medicine. The olefin derivative according to the present invention has a Rho kinase inhibitory action, and is useful as a therapeutic agent for diseases involving Rho kinase, for example, eye diseases such as glaucoma.
低分子量GTP結合タンパク質であるRhoは種々の細胞膜受容体からのシグナルにより活性化される。活性化されたRhoは、Rhoキナーゼ情報伝達系およびアクトミオシン情報伝達系を介して、平滑筋収縮、細胞の形態変化、細胞運動、細胞***、細胞間接着、血小板凝集、白血球凝集、癌細胞の浸潤・亢進等、種々の細胞現象の分子スイッチとして機能する。 Rho, a low molecular weight GTP-binding protein, is activated by signals from various cell membrane receptors. The activated Rho, via the Rho kinase signal transduction system and actomyosin signal transduction system, smooth muscle contraction, cell shape change, cell movement, cell division, cell-cell adhesion, platelet aggregation, leukocyte aggregation, cancer cell It functions as a molecular switch for various cellular phenomena such as invasion and enhancement.
また、これらの細胞現象が、高血圧症、狭心症、喘息、抹消循環障害、早産、動脈硬化症、癌、炎症性疾患、自己免疫疾患、AIDS、受精および受精卵の着床、骨粗鬆症、脳機能障害、細菌の消化管障害、緑内障、網膜症等の疾患に深く関与していることが知られている。 In addition, these cellular phenomena include hypertension, angina pectoris, asthma, peripheral circulatory disorder, premature birth, arteriosclerosis, cancer, inflammatory disease, autoimmune disease, AIDS, fertilization and implantation of fertilized eggs, osteoporosis, brain It is known to be deeply involved in diseases such as dysfunction, bacterial digestive tract disorders, glaucoma and retinopathy.
したがって、Rhoを阻害することで、前記のRhoが関与する疾患の予防および/または治療が可能になると考えられている。 Therefore, inhibition of Rho is considered to enable prevention and / or treatment of the aforementioned diseases involving Rho.
一方、Rhoを介する情報伝達系の下流に存在するRhoキナーゼを阻害することによっても、Rhoによる種々の細胞現象を抑制できることが知られている。 On the other hand, it is known that various cellular phenomena caused by Rho can also be suppressed by inhibiting Rho kinase existing downstream of the information transmission system via Rho.
すなわち、Rhoキナーゼを阻害する化合物は、前記のRhoが関与する疾患、例えば、高血圧症、狭心症、喘息、抹消循環障害、早産、動脈硬化症、癌、炎症性疾患、自己免疫疾患、AIDS、受精および受精卵の着床、骨粗鬆症、脳機能障害、細菌の消化管障害、緑内障、網膜症等の有効な予防および/または治療剤となると考えられている(特許文献1)。 That is, a compound that inhibits Rho kinase is a disease involving Rho, such as hypertension, angina pectoris, asthma, peripheral circulation disorder, premature birth, arteriosclerosis, cancer, inflammatory disease, autoimmune disease, AIDS Fertilization and implantation of fertilized eggs, osteoporosis, brain dysfunction, bacterial gastrointestinal dysfunction, glaucoma, retinopathy and the like are considered to be effective preventive and / or therapeutic agents (Patent Document 1).
Rhoキナーゼ阻害剤は、一般的にRhoの活性化に伴い活性化されるセリン/スレオニンキナーゼの阻害剤として定義されている。そのRhoキナーゼ阻害剤には、ROCKα(ROCK−II)、p160ROCK(ROKβ、ROCK−I)、その他のセリン/スレオニン活性を有するタンパク質を阻害する化合物が含まれる。 Rho kinase inhibitors are generally defined as inhibitors of serine / threonine kinases that are activated with Rho activation. The Rho kinase inhibitors include ROCKα (ROCK-II), p160ROCK (ROKβ, ROCK-I), and other compounds that inhibit serine / threonine activity.
公知のRhoキナーゼ阻害剤としては、特許文献1に開示されているアミド誘導体、特許文献2、非特許文献1および特許文献3に開示されているイソキノリンスルホニル誘導体、特許文献4に開示されているヘテロサイクルアミノ誘導体、特許文献5に開示されているインダゾール誘導体、特許文献6および特許文献7に開示されているキナゾリン誘導体等が挙げられる。
Known Rho kinase inhibitors include amide derivatives disclosed in
また、Rhoキナーゼ阻害剤が緑内障の治療剤として有用であることが特許文献8および特許文献9に開示されている。 Patent Document 8 and Patent Document 9 disclose that Rho kinase inhibitors are useful as therapeutic agents for glaucoma.
しかしながら、上記いずれの文献にも本発明に係る化合物についての具体的な開示はない。
医薬として有用な新規オレフィン誘導体を創製すること、また、その誘導体の新たな薬理作用を見出すことは非常に興味のある課題である。 Creating a novel olefin derivative useful as a medicine and finding a new pharmacological action of the derivative are very interesting subjects.
本発明者等は、上記の課題を解決するために新規オレフィン誘導体の合成研究を行い、数多くの新規化合物を創製することに成功した。 In order to solve the above-mentioned problems, the present inventors have conducted synthetic studies on novel olefin derivatives and succeeded in creating many new compounds.
また、本発明に係るオレフィン誘導体(以下、特記なき限り、これを「本オレフィン誘導体」とする)の医薬としての有用性を種々検討したところ、本オレフィン誘導体はRhoキナーゼ阻害作用を有し、Rhoキナーゼが関与する疾患の治療剤として有用であることを見出した。 Further, various studies have been made on the usefulness of the olefin derivative according to the present invention (hereinafter referred to as “the present olefin derivative” unless otherwise specified) as a pharmaceutical. The olefin derivative has a Rho kinase inhibitory action, and Rho. It was found useful as a therapeutic agent for diseases involving kinases.
さらに、本オレフィン誘導体のRhoキナーゼが関与する具体的な疾患への適用を検証するために、本オレフィン誘導体の眼圧下降作用についても検討した。その結果、本オレフィン誘導体は優れた眼圧下降作用を有しており、緑内障等の眼疾患治療剤としても有用であることを併せて見出し、本発明を完成させた。 Furthermore, in order to verify the application of this olefin derivative to a specific disease involving Rho kinase, the effect of lowering intraocular pressure of this olefin derivative was also examined. As a result, the present olefin derivative was found to have an excellent intraocular pressure lowering action and useful as a therapeutic agent for eye diseases such as glaucoma, and the present invention was completed.
すなわち、本発明は、下記一般式[I]で表される化合物またはその塩(以下、特記なき限り、これを「本発明化合物」とする)および本発明化合物を含有する医薬に関し、より詳しくは、本発明化合物を有効成分とするRhoキナーゼ阻害剤に関するものであり、例えば、緑内障等の眼疾患治療剤に関するものである。 That is, the present invention relates to a compound represented by the following general formula [I] or a salt thereof (hereinafter referred to as “the compound of the present invention” unless otherwise specified) and a pharmaceutical containing the compound of the present invention. The present invention relates to a Rho kinase inhibitor comprising the compound of the present invention as an active ingredient, for example, a therapeutic agent for eye diseases such as glaucoma.
本発明化合物は、以下1〜3)に示す化学構造的特徴を有する:
1)エチレン基を主骨格とする。
The compound of the present invention has the chemical structural characteristics shown in the following 1-3):
1) The main skeleton is an ethylene group.
2)環Xとピリジン環がエチレン基に直接結合している。 2) Ring X and the pyridine ring are directly bonded to the ethylene group.
3)環Xがアミノ基で置換されたアルキル基を有する。 3) Ring X has an alkyl group substituted with an amino group.
また、それら1〜3)の各構造的特徴および/またはそれらの組み合わせが、本発明化合物のRhoキナーゼ阻害作用の発現に非常に重要である。
環Yはピリジン環または1H−ピロロ[2,3−b]ピリジン環を示し;
R1とR2は同一または異なって、水素原子またはアルキル基を示し;
R3とR4は同一または異なって、ハロゲン原子、水素原子、ヒドロキシ基、アルコキシ基、アリールオキシ基、アルキル基、アリール基、アミノ基、アルキルアミノ基またはアリールアミノ基を示し;
R3とR5は結合して、シクロアルケン環を形成してもよく;
R5およびR6は同一または異なって、ハロゲン原子、水素原子、ヒドロキシ基、アルコキシ基、アリールオキシ基、アルキル基、アリール基、カルボキシ基、そのエステル若しくはそのアミド、ニトロ基またはシアノ基を示し;
上記で規定した各アルキル基がヒドロキシ基、アルコキシ基、アリールオキシ基、ヒドロキシイミノ基およびアルコキシイミノ基からなる群より選択される1または複数の基で置換されていてもよい。以下、同じ。]
In addition, each structural feature of 1 to 3) and / or a combination thereof is very important for the expression of the Rho kinase inhibitory action of the compound of the present invention.
Ring Y represents a pyridine ring or a 1H-pyrrolo [2,3-b] pyridine ring;
R 1 and R 2 are the same or different and each represents a hydrogen atom or an alkyl group;
R 3 and R 4 are the same or different and each represents a halogen atom, hydrogen atom, hydroxy group, alkoxy group, aryloxy group, alkyl group, aryl group, amino group, alkylamino group or arylamino group;
R 3 and R 5 may combine to form a cycloalkene ring;
R 5 and R 6 are the same or different and each represents a halogen atom, hydrogen atom, hydroxy group, alkoxy group, aryloxy group, alkyl group, aryl group, carboxy group, ester or amide thereof, nitro group or cyano group;
Each alkyl group defined above may be substituted with one or more groups selected from the group consisting of a hydroxy group, an alkoxy group, an aryloxy group, a hydroxyimino group and an alkoxyimino group. same as below. ]
本発明は、医薬として有用な新規オレフィン誘導体またはその塩を提供する。特に本発明に係るオレフィン誘導体は、優れたRhoキナーゼ阻害作用を有し、Rhoキナーゼが関与する疾患、例えば、緑内障等の眼疾患治療剤として有用である。 The present invention provides a novel olefin derivative or a salt thereof useful as a medicine. In particular, the olefin derivative according to the present invention has an excellent Rho kinase inhibitory action, and is useful as a therapeutic agent for diseases involving Rho kinase, for example, eye diseases such as glaucoma.
前記で規定した各基について以下に詳しく説明する。 Each group defined above will be described in detail below.
ハロゲン原子とは、フッ素、塩素、臭素またはヨウ素を示す。 The halogen atom represents fluorine, chlorine, bromine or iodine.
アルキル基とは、炭素原子数1〜6個の直鎖または分枝のアルキルを示す。具体例として、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、sec−ブチル、tert−ブチル、n−ペンチル、イソペンチル、n−ヘキシル等が挙げられる。 The alkyl group represents a straight-chain or branched alkyl having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and the like.
アルコキシ基とは、炭素原子数1〜6個の直鎖または分枝のアルコキシを示す。具体例として、メトキシ、エトキシ、n−プロポキシ、イソプロポキシ、n−ブトキシ、イソブトキシ、sec−ブトキシ、tert−ブトキシ、n−ペントキシ、イソペントキシ、n−ヘキシルオキシ等が挙げられる。 An alkoxy group refers to a straight or branched alkoxy having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, n-hexyloxy and the like.
アリール基とは、炭素数が6〜14個の単環式または縮合多環式芳香族炭化水素を示す。具体例として、フェニル、ナフチル、アントリル、フェナントリル等が挙げられる。 The aryl group refers to a monocyclic or condensed polycyclic aromatic hydrocarbon having 6 to 14 carbon atoms. Specific examples include phenyl, naphthyl, anthryl, phenanthryl and the like.
シクロアルカン環とは、炭素数が3〜8個のシクロアルカンを示す。具体例としては、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロペプタン、シクロオクタン等が挙げられる。 The cycloalkane ring refers to a cycloalkane having 3 to 8 carbon atoms. Specific examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopeptane, cyclooctane and the like.
シクロアルケン環とは、炭素数が3〜8個のシクロアルケンを示す。具体例として、シクロプロペン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、シクロオクテン等が挙げられる。 The cycloalkene ring refers to a cycloalkene having 3 to 8 carbon atoms. Specific examples include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and the like.
1若しくは複数の窒素原子を環内に有する芳香族複素環とは、1または2個の窒素原子を環内に含む単環式の芳香族複素環を示す。具体例として、ピリジン、ピリミジン、ピロール、イミダゾール、オキサゾール、チアゾール等の1または2個の窒素原子を環内に有する単環式芳香族複素環が挙げられる。 The aromatic heterocycle having one or more nitrogen atoms in the ring refers to a monocyclic aromatic heterocycle having 1 or 2 nitrogen atoms in the ring. Specific examples include monocyclic aromatic heterocycles having 1 or 2 nitrogen atoms in the ring, such as pyridine, pyrimidine, pyrrole, imidazole, oxazole and thiazole.
カルボキシ基のエステルとは、アルキルアルコール、アリールアルコール等とのエステルを示す。アルキルアルコールの具体例として、メタノール、エタノール、プロパノール、ブタノール等が挙げられ、アリールアルコールの具体例として、フェノール、ナフトール等が挙げられる。 The ester of a carboxy group refers to an ester with an alkyl alcohol, aryl alcohol or the like. Specific examples of the alkyl alcohol include methanol, ethanol, propanol, butanol and the like, and specific examples of the aryl alcohol include phenol, naphthol and the like.
カルボキシ基のアミドとは、アンモニアまたは1級若しくは2級のアミン等とのアミドを示す。アミンはアルキルアミンまたはアリールアミンであってよく、アルキルアミンの具体例として、メチルアミン、エチルアミン、エチルメチルアミン、ジメチルアミン、ジエチルアミン等が挙げられ、アリールアミンの具体例として、アニリン、メチルフェニルアミン、エチルフェニルアミン、ジフェニルアミン等を挙げられる。 The amide of carboxy group refers to an amide with ammonia or a primary or secondary amine. The amine may be an alkylamine or an arylamine, and specific examples of the alkylamine include methylamine, ethylamine, ethylmethylamine, dimethylamine, diethylamine and the like, and specific examples of the arylamine include aniline, methylphenylamine, Examples include ethylphenylamine and diphenylamine.
本発明化合物が、ヒドロキシ基、アミノ基、アルキルアミノ基またはアリールアミノ基を置換基として有する場合、それらの基は保護基で保護されていてもよい。 When the compound of the present invention has a hydroxy group, an amino group, an alkylamino group or an arylamino group as a substituent, these groups may be protected with a protecting group.
ヒドロキシ基の保護基とは、ベンジルオキシメチル基、アリル基、ベンジル基、p−メトキシベンジル基、トリチル基、テトラヒドロピラニル基、テトラヒドロフラニル基等の置換または無置換アルキル基;メトキシカルボニル基、エトキシカルボニル基、イソブトキシカルボニル基、tert−ブトキシカルボニル基、ビニルオキシカルボニル基、アリルオキシカルボニル基、ベンジルオキシカルボニル基、p−メトキシベンジルオキシカルボニル等のエステル;トリメチルシリル基、トリエチルシリル基、トリイソプロピルシリル基、tert−ブチルジメチルシリル基、tert−ブチルジフェニルシリル基等の置換または無置換シリル基等のヒドロキシ基の保護基として汎用されるものを示す。 Protecting groups for hydroxy groups are substituted or unsubstituted alkyl groups such as benzyloxymethyl group, allyl group, benzyl group, p-methoxybenzyl group, trityl group, tetrahydropyranyl group, tetrahydrofuranyl group; methoxycarbonyl group, ethoxy Esters such as carbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl; trimethylsilyl group, triethylsilyl group, triisopropylsilyl group , Tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group and the like, and those commonly used as protective groups for hydroxy groups such as substituted or unsubstituted silyl groups.
アミノ基、アルキルアミノ基またはアリールアミノ基の保護基とは、アリル基、ベンジル基、トリチル基、(4−メトキシフェニル)ジフェニルメチル基、ジフェニルメチル基等の置換または無置換のアルキル基;ホルミル基、アセチル基、トリクロロアセチル基、トリフルオロアセチル基、ピコリノイル基、ベンゾイル基等のアシル基;メトキシカルボニル基、イソブトキシカルボニル基、tert−ブトキシカルボニル基、2,2,2−トリクロロエトキシカルボニル基、ベンジルオキシカルボニル基、ジフェニルメトキシカルボニル基、フェノキシカルボニル基等のエステル基;メタンスルホニル基、ベンゼンスルホニル基、トルエンスルホニル基、2,4,6−トリメチルベンゼンスルホニル基等の置換または無置換のスルホニル基等のアミノ基、アルキルアミノ基またはアリールアミノ基の保護基として汎用されるものを示す。 Protecting group for amino group, alkylamino group or arylamino group is a substituted or unsubstituted alkyl group such as allyl group, benzyl group, trityl group, (4-methoxyphenyl) diphenylmethyl group, diphenylmethyl group; formyl group , Acyl groups such as acetyl group, trichloroacetyl group, trifluoroacetyl group, picolinoyl group, benzoyl group; methoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyl Ester groups such as oxycarbonyl group, diphenylmethoxycarbonyl group, phenoxycarbonyl group; substituted or unsubstituted sulfonyl groups such as methanesulfonyl group, benzenesulfonyl group, toluenesulfonyl group, 2,4,6-trimethylbenzenesulfonyl group, etc. Amino group, a what is commonly used as a protective group of an alkyl group or an arylamino group.
また、一般式Iで表される本発明化合物のY環が、1H−ピロロ[2,3−b]ピリジン環である場合、その1H−ピロロ[2,3−b]ピリジン環の窒素原子は保護基で保護されていてもよい。 When the Y ring of the compound of the present invention represented by the general formula I is a 1H-pyrrolo [2,3-b] pyridine ring, the nitrogen atom of the 1H-pyrrolo [2,3-b] pyridine ring is It may be protected with a protecting group.
1H−ピロロ[2,3−b]ピリジン環の窒素原子の保護基としては、2−(トリメチルシリル)エトキシメチル基、アリル基、ベンジル基、トリチル基、(4−メトキシフェニル)ジフェニルメチル基、ジフェニルメチル基等の置換または無置換のアルキル基;ホルミル基、アセチル基、トリクロロアセチル基、トリフルオロアセチル基、ピコリノイル基、ベンゾイル基等のアシル基;メトキシカルボニル基、イソブトキシカルボニル基、tert−ブトキシカルボニル基、2,2,2−トリクロロエトキシカルボニル基、ベンジルオキシカルボニル基、ジフェニルメトキシカルボニル基、フェノキシカルボニル基等のエステル基;メタンスルホニル基、ベンゼンスルホニル基、トルエンスルホニル基、2,4,6−トリメチルベンゼンスルホニル基等の置換または無置換のスルホニル基等のピロール環の窒素原子の保護基として汎用されるものを示す。 As protecting groups for nitrogen atoms of 1H-pyrrolo [2,3-b] pyridine ring, 2- (trimethylsilyl) ethoxymethyl group, allyl group, benzyl group, trityl group, (4-methoxyphenyl) diphenylmethyl group, diphenyl Substituted or unsubstituted alkyl group such as methyl group; acyl group such as formyl group, acetyl group, trichloroacetyl group, trifluoroacetyl group, picolinoyl group, benzoyl group; methoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl Group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, diphenylmethoxycarbonyl group, phenoxycarbonyl group and the like; methanesulfonyl group, benzenesulfonyl group, toluenesulfonyl group, 2,4,6-trimethyl Benzenesulfur It shows what is commonly used as a substituted or unsubstituted protecting group for the nitrogen atom of the pyrrole ring, such as a sulfonyl group such as a group.
本発明化合物における『塩』とは、医薬として許容される塩であれば、特に制限はなく、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等の無機酸との塩、酢酸、フマル酸、マレイン酸、コハク酸、クエン酸、酒石酸、アジピン酸、乳酸、メタンスルホン酸、トリフルオロメタンスルホン酸、p−トルエンスルホン酸、トリフルオロ酢酸等の有機酸との塩、リチウム、ナトリウム、カリウム等のアルカリ金属との塩、カルシウム、マグネシウム等のアルカリ土類金属との塩、アンモニア、ヨウ化メチル等との四級塩等が挙げられる。 The “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or the like. , Salts with organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, lactic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, lithium, Examples thereof include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and quaternary salts with ammonia and methyl iodide.
本発明化合物に幾何異性体、例えばシン−アンチ(syn-anti)異性体、または光学異性体が存在する場合は、それらの異性体も本発明の範囲に含まれる。 When a geometric isomer, for example, a syn-anti isomer or an optical isomer is present in the compound of the present invention, these isomers are also included in the scope of the present invention.
本発明化合物における好ましい例としては、一般式[I]で規定された各基が以下の基から選択され、またはそれらの組み合わせからなる化合物またはその塩が挙げられる:
環X:ベンゼン環、シクロアルカン環または1若しくは複数の窒素原子を環内に有する芳香族複素環を示し;
環Y:ピリジン環または1H−ピロロ[2,3−b]ピリジン環を示し;
R1とR2:同一または異なって、水素原子またはアルキル基を示し;
R3:ハロゲン原子、水素原子またはアルキル基を示し;
R3とR5:結合して、シクロアルケン環を形成してもよく;
R4:水素原子またはアミノ基を示し;
R5:水素原子またはアルキル基を示し;
R6:水素原子、アルキル基、カルボキシ基、そのエステルまたはシアノ基を示し;
R6で規定したアルキル基:ヒドロキシ基、アルコキシ基、アリールオキシ基またはヒドロキシイミノ基から選択される1または複数の基で置換されていてもよい。
Preferable examples of the compound of the present invention include a compound or a salt thereof in which each group defined by the general formula [I] is selected from the following groups or a combination thereof:
Ring X: a benzene ring, a cycloalkane ring or an aromatic heterocycle having one or more nitrogen atoms in the ring;
Ring Y: represents a pyridine ring or a 1H-pyrrolo [2,3-b] pyridine ring;
R 1 and R 2 are the same or different and each represents a hydrogen atom or an alkyl group;
R 3 represents a halogen atom, a hydrogen atom or an alkyl group;
R 3 and R 5 may combine to form a cycloalkene ring;
R 4 represents a hydrogen atom or an amino group;
R 5 represents a hydrogen atom or an alkyl group;
R 6 represents a hydrogen atom, an alkyl group, a carboxy group, an ester or a cyano group thereof;
The alkyl group defined by R 6 may be substituted with one or more groups selected from a hydroxy group, an alkoxy group, an aryloxy group or a hydroxyimino group.
より好ましい例としては、一般式[I]で規定された各基が以下の基から選択され、またはそれらの組み合わせからなる化合物またはその塩が挙げられる:
環X:ベンゼン環、シクロヘキサン環またはピリジン環を示し;
環Y:ピリジン環または1H−ピロロ[2,3−b]ピリジン環を示し;
R1とR2:同一または異なって、水素原子またはアルキル基を示し;
R3:塩素原子、水素原子またはメチル基を示し;
R3とR5:結合してシクロヘキセン環を形成してもよく;
R4:水素原子またはアミノ基を示し;
R5:水素原子またはメチル基を示し;
R6:水素原子、メチル基、エチル基、ヒドロキシメチル基、1−ヒドロキシエチル基、メトキシメチル基、フェノキシメチル基、ヒドロキシイミノメチル基、カルボキシ基、メトキシカルボニル基またはシアノ基を示す。
More preferred examples include a compound or a salt thereof in which each group defined by the general formula [I] is selected from the following groups, or a combination thereof:
Ring X: represents a benzene ring, a cyclohexane ring or a pyridine ring;
Ring Y: represents a pyridine ring or a 1H-pyrrolo [2,3-b] pyridine ring;
R 1 and R 2 are the same or different and each represents a hydrogen atom or an alkyl group;
R 3 represents a chlorine atom, a hydrogen atom or a methyl group;
R 3 and R 5 may combine to form a cyclohexene ring;
R 4 represents a hydrogen atom or an amino group;
R 5 represents a hydrogen atom or a methyl group;
R 6 represents a hydrogen atom, methyl group, ethyl group, hydroxymethyl group, 1-hydroxyethyl group, methoxymethyl group, phenoxymethyl group, hydroxyiminomethyl group, carboxy group, methoxycarbonyl group or cyano group.
本発明化合物における別の好ましい例としては、一般式[I]で規定された各基が以下の基から選択され、またはそれらの組み合わせからなる化合物またはその塩が挙げられる:
環X:ベンゼン環を示し;
環Y:ピリジン環または1H−ピロロ[2,3−b]ピリジン環を示し;
R1とR2:水素原子またはアルキル基を示し;
R3:水素原子を示し;
R4:水素原子またはアミノ基を示し;
R5:水素原子またはアルキル基を示し;
R6:水素原子、アルキル基、カルボキシ基、そのエステルまたはシアノ基を示し;
R6で規定したアルキル基:ヒドロキシ基またはヒドロキシイミノ基から選択される1または複数の基で置換されていてもよい。
Another preferred example of the compound of the present invention includes a compound or a salt thereof in which each group defined by the general formula [I] is selected from the following groups or a combination thereof:
Ring X represents a benzene ring;
Ring Y: represents a pyridine ring or a 1H-pyrrolo [2,3-b] pyridine ring;
R 1 and R 2 represent a hydrogen atom or an alkyl group;
R 3 represents a hydrogen atom;
R 4 represents a hydrogen atom or an amino group;
R 5 represents a hydrogen atom or an alkyl group;
R 6 represents a hydrogen atom, an alkyl group, a carboxy group, an ester or a cyano group thereof;
The alkyl group defined by R 6 may be substituted with one or more groups selected from a hydroxy group or a hydroxyimino group.
別のより好ましい例としては、一般式[I]で規定された各基が以下の基から選択され、またはそれらの組み合わせからなる化合物またはその塩が挙げられる:
環X:ベンゼン環を示し;
環Y:ピリジン環または1H−ピロロ[2,3−b]ピリジン環を示し;
R1とR2:水素原子またはアルキル基を示し;
R3:水素原子を示し;
R4:水素原子またはアミノ基を示し;
R5:水素原子またはメチル基を示し;
R6:水素原子、メチル基、エチル基、ヒドロキシメチル基、ヒドロキシイミノメチル基、カルボキシ基、メトキシカルボニル基またはシアノ基を示す。
Another more preferable example includes a compound or a salt thereof in which each group defined by the general formula [I] is selected from the following groups or a combination thereof:
Ring X represents a benzene ring;
Ring Y: represents a pyridine ring or a 1H-pyrrolo [2,3-b] pyridine ring;
R 1 and R 2 represent a hydrogen atom or an alkyl group;
R 3 represents a hydrogen atom;
R 4 represents a hydrogen atom or an amino group;
R 5 represents a hydrogen atom or a methyl group;
R 6 represents a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a hydroxyiminomethyl group, a carboxy group, a methoxycarbonyl group or a cyano group.
本発明化合物は前述したとおり、以下1〜3)に示す化学構造的特徴を有し、また、それら1〜3)の各構造的特徴および/またはそれらの組み合わせが、本発明化合物のRhoキナーゼ阻害作用の発現に非常に重要である。 As described above, the compound of the present invention has the chemical structural characteristics shown in the following 1 to 3), and each of the structural characteristics of 1 to 3) and / or a combination thereof can inhibit Rho kinase inhibition of the compound of the present invention. Very important for the onset of action.
1)エチレン基を主骨格とする。 1) The main skeleton is an ethylene group.
2)環Xとピリジン環がエチレン基に直接結合している。 2) Ring X and the pyridine ring are directly bonded to the ethylene group.
3)環Xがアミノ基で置換されたアルキル基を有する。 3) Ring X has an alkyl group substituted with an amino group.
特に、環Xと環Yの位置関係がエチレン基に対して、トランス位に直接結合している本発明化合物が、優れたRhoキナーゼ阻害作用を示し、この位置に環Xと環Yが置換された本発明化合物がより好ましい。 In particular, the compound of the present invention in which the positional relationship between ring X and ring Y is directly bonded to the trans position with respect to the ethylene group exhibits an excellent Rho kinase inhibitory action, and ring X and ring Y are substituted at this position. The compounds of the present invention are more preferred.
本発明化合物における特に好ましい具体例として、以下に示す化合物またはその塩が挙げられる。 Particularly preferred specific examples of the compound of the present invention include the following compounds or salts thereof.
・E−1−[4−(1−アミノ−1−メチルエチル)フェニル]−2−(4−ピリジル)エチレン
合成経路2:化合物Aと化合物Cとを有機溶媒中、塩基存在下、求核反応させることにより化合物Dを得る。この化合物Dを有機溶媒中、塩基存在下、脱離基を導入した後、さらなる塩基を加え、脱離反応させることにより本発明化合物を得ることもできる。 Synthesis route 2: Compound D is obtained by subjecting Compound A and Compound C to a nucleophilic reaction in an organic solvent in the presence of a base. The compound of the present invention can also be obtained by introducing a leaving group into this compound D in an organic solvent in the presence of a base and then adding a further base to cause a leaving reaction.
合成経路3:化合物Eと化合物Fとを有機溶媒中、金属触媒および塩基存在下、カップリング反応させることにより本発明化合物を得ることもできる。 Synthesis route 3: The compound of the present invention can also be obtained by subjecting compound E and compound F to a coupling reaction in an organic solvent in the presence of a metal catalyst and a base.
上記の製造方法において、製造の便宜上、保護基を使用した場合には、その保護基を汎用される方法にて除去することができる。 In the above production method, when a protective group is used for the convenience of production, the protective group can be removed by a widely used method.
本発明化合物の環X、ピリジン環およびオレフィンの置換基は、当初から所望の置換基を導入しておいてもよく、また、上記の方法により基本骨格を製造した後に、酸化、還元、アルキル化、アミド化、オキシム化、脱水反応、脱保護反応および/またはそれらの反応を組み合わせた汎用される合成方法を使用して、基本骨格に所望の置換基を導入してもよい。 The substituent of the ring X, pyridine ring and olefin of the compound of the present invention may be introduced with desired substituents from the beginning, and after the basic skeleton is produced by the above method, oxidation, reduction, alkylation , Amidation, oximation, dehydration reaction, deprotection reaction and / or a commonly used synthetic method combining those reactions may be used to introduce a desired substituent to the basic skeleton.
本発明化合物の合成中間体の製造方法については、後述の実施例[製造例の項]で詳述する。 The method for producing the synthetic intermediate of the compound of the present invention will be described in detail in the below-mentioned Examples [Production Examples].
本発明化合物の有用性を見出すため、本発明化合物のRhoキナーゼ阻害活性について評価検討した。その詳細は後述の実施例[薬理試験の項(Rhoキナーゼ阻害活性評価試験)]で説明するが、ジャーナル・オブ・バイオロジカル・ケミストリー,274巻,32418頁,1999年発行[J.Biol.Chem.,274,32418(1999)]に記載の貝淵等の方法および市販の活性型ROCKII[アップステイツ バイオテクノロジー,カタログ 番号14−338,(5Unit/50μl)[upstate biotechnology,Catalog No.14-338,(5Unit/50μl)]]付属の説明書記載の方法に準じて、本発明化合物のRhoキナーゼ阻害活性を評価検討した。その結果、本発明化合物は優れたRhoキナーゼ阻害作用を有しており、Rhoキナーゼが関与する疾患の治療剤として非常に有用であることを見出した。 In order to find out the usefulness of the compound of the present invention, the Rho kinase inhibitory activity of the compound of the present invention was evaluated and examined. Details thereof will be described in the following [Example of Pharmacological Test (Rho Kinase Inhibitory Activity Evaluation Test)]. Journal of Biological Chemistry, 274, 32418, published in 1999 [J. Biol. Chem. , 274, 32418 (1999)] and commercially available activated ROCKII [Upstate Biotechnology, Catalog No. 14-338, (5Unit / 50 μl) [upstate biotechnology, Catalog No. 14-338, (5 Unit / 50 μl)]] The Rho kinase inhibitory activity of the compounds of the present invention was evaluated according to the method described in the attached instruction manual. As a result, it has been found that the compound of the present invention has an excellent Rho kinase inhibitory action and is very useful as a therapeutic agent for diseases involving Rho kinase.
さらに本発明化合物のRhoキナーゼが関与する具体的な疾患への適用を検証するために、本発明化合物の眼圧下降作用についても検討した。その詳細は後述の実施例[薬理試験の項(眼圧下降作用測定試験)]で説明するが、カニクイザル(性別:雄性、一群6匹)に本発明化合物を点眼投与したところ、本発明化合物は優れた眼圧下降作用を有しており、緑内障等の眼疾患の治療剤としても有用であることも併せて見出した。 Furthermore, in order to verify the application of the compounds of the present invention to specific diseases involving Rho kinase, the intraocular pressure lowering action of the compounds of the present invention was also examined. The details thereof will be described in the following [Example of pharmacological test (measurement test for lowering intraocular pressure)]. When the compound of the present invention was administered to cynomolgus monkeys (sex: male, 6 per group), the compound of the present invention was The present inventors also found that it has an excellent intraocular pressure lowering effect and is useful as a therapeutic agent for eye diseases such as glaucoma.
前述したようにRhoキナーゼは、高血圧症、狭心症、喘息、抹消循環障害、早産、動脈硬化症、癌、炎症性疾患、自己免疫疾患、AIDS、受精および受精卵の着床、骨粗鬆症、脳機能障害、細菌の消化管障害、緑内障、網膜症等の疾患と深く関係していることが知られている。したがって、本発明化合物はRhoキナーゼの関与するそれら疾患の治療剤として非常に期待されるものである。 As described above, Rho kinase is used for hypertension, angina pectoris, asthma, peripheral circulatory disorder, premature birth, arteriosclerosis, cancer, inflammatory disease, autoimmune disease, AIDS, fertilization and implantation of fertilized eggs, osteoporosis, brain It is known to be deeply related to diseases such as dysfunction, bacterial digestive tract disorder, glaucoma, and retinopathy. Therefore, the compound of the present invention is highly expected as a therapeutic agent for those diseases in which Rho kinase is involved.
また、本発明におけるRhoキナーゼ阻害剤とはRhoの活性化に伴い活性化されるセリン/スレオニンキナーゼを阻害する化合物を意味する。 In addition, the Rho kinase inhibitor in the present invention means a compound that inhibits serine / threonine kinase activated with the activation of Rho.
さらに本発明における緑内障としては、原発性開放隅角緑内障、正常眼圧緑内障、房水産生過多緑内障、高眼圧症、急性閉塞隅角緑内障、慢性閉塞隅角緑内障、混合型緑内障、ステロイド緑内障、アミロイド緑内障、血管新生緑内障、悪性緑内障、水晶体の嚢性緑内障、台地状虹彩シンドローム(plateau iris syndrom)等が例示される。 Further, glaucoma in the present invention includes primary open-angle glaucoma, normal-tension glaucoma, aqueous humor production hyperglaucoma, ocular hypertension, acute closed-angle glaucoma, chronic closed-angle glaucoma, mixed glaucoma, steroid glaucoma, amyloid Examples include glaucoma, neovascular glaucoma, malignant glaucoma, capsular glaucoma of the lens, plateau iris syndrom and the like.
本発明化合物は経口でも、非経口でも投与することができる。投与剤型として、錠剤、カプセル剤、顆粒剤、散剤、注射剤、点眼剤等が挙げられ、それらは汎用される技術を組合わせて使用することで製剤化することができる。 The compound of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, granules, powders, injections, eye drops and the like, which can be formulated by using a combination of commonly used techniques.
例えば、錠剤、カプセル剤、顆粒剤、散剤等の経口剤は、例えば、乳糖、マンニトール、デンプン、結晶セルロース、軽質無水ケイ酸、炭酸カルシウム、リン酸水素カルシウム等の賦形剤、ステアリン酸、ステアリン酸マグネシウム、タルク等の滑沢剤、デンプン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン等の結合剤、カルボキシメチルセルロース、低置換度ヒドロキシプロピルメチルセルロース、クエン酸カルシウム等の崩壊剤、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコーン樹脂等のコーティング剤、パラオキシ安息香酸エチル、ベンジルアルコール等の安定化剤、甘味料、酸味料、香料等の矯味矯臭剤等を必要に応じて本発明化合物に組合わせて調製することができる。 For example, oral preparations such as tablets, capsules, granules, powders and the like include excipients such as lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, calcium hydrogen phosphate, stearic acid, stearin Lubricants such as magnesium acid and talc, binders such as starch, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose and calcium citrate, hydroxypropylmethylcellulose, macro Preparations such as coating agents such as gall, silicone resin, stabilizers such as ethyl paraoxybenzoate and benzyl alcohol, and flavoring agents such as sweeteners, acidulants and fragrances may be prepared in combination with the compounds of the present invention as necessary. It can be.
また、注射剤、点眼剤等の非経口剤は、グリセリン、プロピレングリコール、塩化ナトリウム、塩化カリウム、ソルビトール、マンニトール等の等張化剤、リン酸、リン酸塩、クエン酸、酢酸、ε-アミノカプロン酸、トロメタモール等の緩衝剤、塩酸、クエン酸、リン酸、酢酸、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等のpH調節剤、ポリソルベート80、ポリオキシエチレン硬化ヒマシ油60、マクロゴール4000、精製大豆レシチン、ポリオキシエチレン(160)ポリオキシプロピレン(30)グリコール等の可溶化または分散剤、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース等のセルロース系高分子、ポリビニルアルコール、ポリビニルピロリドン等の増粘剤、エデト酸、エデト酸ナトリウム等の安定化剤、汎用のソルビン酸、ソルビン酸カリウム、塩化ベンザルコニウム、塩化ベンゼトニウム、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、クロロブタノール等の保存または防腐剤、クロロブタノール、ベンジルアルコール、リドカイン等の無痛化剤を必要に応じて本発明名化合物に組合わせて調製することができる。 In addition, parenterals such as injections and eye drops include isotonic agents such as glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol, phosphoric acid, phosphate, citric acid, acetic acid, and ε-aminocaprone. Buffers such as acid and trometamol, pH adjusters such as hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macro Gol 4000, refined soybean lecithin, solubilizing or dispersing agents such as polyoxyethylene (160) polyoxypropylene (30) glycol, cellulose polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc. Sticky, Eddy Stabilizers such as acid and sodium edetate, general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, preservatives such as chlorobutanol, chlorobutanol, A soothing agent such as benzyl alcohol or lidocaine can be prepared in combination with the compound of the present invention as necessary.
尚、注射剤または点眼剤の場合、pHは4.0〜8.0に設定することが望ましく、また、浸透圧比は1.0付近に設定することが望ましい。 In the case of injections or eye drops, the pH is preferably set to 4.0 to 8.0, and the osmotic pressure ratio is preferably set to around 1.0.
本発明化合物の投与量は、症状、年齢、剤型等により適宜選択して使用することができる。例えば、経口剤であれば通常1日当たり0.01〜1000mg、好ましくは1〜100mgを1回または数回に分けて投与することができる。 The dose of the compound of the present invention can be appropriately selected and used depending on symptoms, age, dosage form and the like. For example, in the case of an oral preparation, 0.01 to 1000 mg, preferably 1 to 100 mg per day can be administered once or divided into several times.
また、点眼剤であれば通常0.0001%〜10%(w/v)、好ましくは0.01%〜5%(w/v)の濃度のものを1回または数回に分けて投与することができる。 In the case of eye drops, those having a concentration of usually 0.0001% to 10% (w / v), preferably 0.01% to 5% (w / v) are administered once or divided into several times. be able to.
以下に本発明化合物(実施例1〜13)および合成中間体(参考例1〜9)の製造例、製剤例ならびに薬理試験の結果を示す。尚、これらの例示は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。なお、実施例の物性におけるRf値は、薄層クロマトグラフィー(メルク社製、TLCプレートシリカゲル60F254(商品名))を用いて測定した値である。 The production examples, formulation examples, and pharmacological test results of the compounds of the present invention (Examples 1 to 13) and synthetic intermediates (Reference Examples 1 to 9) are shown below. In addition, these illustrations are for understanding this invention better, and do not limit the scope of the present invention. Incidentally, Rf value in the physical properties of the examples, thin layer chromatography is a value measured using a (Merck, TLC plate silica gel 60F 254 (trade name)).
[製造例]
(参考例1)
1−ブロモ−4−(1−シアノ−1−メチルエチル)ベンゼン(参考化合物1−1)の合成
(Reference Example 1)
Synthesis of 1-bromo-4- (1-cyano-1-methylethyl) benzene (reference compound 1-1)
反応終了後、反応溶液を飽和塩化アンモニウム水溶液900gにゆっくり注加し、水500mlを加えた後、酢酸エチル2000mlで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄、無水硫酸ナトリウムで乾燥した後、減圧濃縮することにより標記の化合物110gを茶褐色油状物として得た。(収率96%)
Rf値:0.78(n−ヘキサン:酢酸エチル=1:1(V/V))。
After completion of the reaction, the reaction solution was slowly poured into 900 g of a saturated aqueous ammonium chloride solution, 500 ml of water was added, and the mixture was extracted with 2000 ml of ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 110 g of the title compound as a brown oil. (Yield 96%)
Rf value: 0.78 (n-hexane: ethyl acetate = 1: 1 (V / V)).
マススペクトル(CI,m/z):224,226(M++1)。 Mass spectrum (CI, m / z): 224,226 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.71(s,6H),7.32-7.38(m,2H),7.49-7.54(m,2H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.71 (s, 6H), 7.32-7.38 (m, 2H), 7.49-7.54 (m, 2H).
以下、参考化合物1−1の製造方法に準じて、参考化合物1−2を製造した。 Hereinafter, Reference Compound 1-2 was produced according to the production method of Reference Compound 1-1.
4−(1−シアノ−1−メチルエチル)−1−ヨードベンゼン(参考化合物1−2)
1H−NMRスペクトル(CDCl3,δppm):1.70(s,6H),7.20-7.24(m,2H), 7.70-7.74(m,2H)。
4- (1-cyano-1-methylethyl) -1-iodobenzene (reference compound 1-2)
1 H-NMR spectrum (CDCl 3 , δ ppm): 1.70 (s, 6H), 7.20-7.24 (m, 2H), 7.70-7.74 (m, 2H).
(参考例2)
4−(1−アミノカルボニル−1−メチルエチル)−1−ブロモベンゼン(参考化合物2−1)の合成
Synthesis of 4- (1-aminocarbonyl-1-methylethyl) -1-bromobenzene (reference compound 2-1)
反応終了後、室温まで冷却し水500mlを滴下した。次いで室温で25分間撹拌後、生成した固体を濾取し、水400mlで洗浄、乾燥することにより標記の化合物99gを白色粉末として得た。(収率92%)
融点:139-141℃。
After completion of the reaction, the reaction mixture was cooled to room temperature and 500 ml of water was added dropwise. Then, after stirring at room temperature for 25 minutes, the produced solid was collected by filtration, washed with 400 ml of water and dried to obtain 99 g of the title compound as a white powder. (Yield 92%)
Melting point: 139-141 ° C.
Rf値:0.23(n−ヘキサン:酢酸エチル=1:1(V/V))。 Rf value: 0.23 (n-hexane: ethyl acetate = 1: 1 (V / V)).
マススペクトル(CI,m/z):242,244(M++1)。 Mass spectrum (CI, m / z): 242,244 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.56(s,6H),5.18(brs,1H),5.52(brs,1H),7.25-7.30(m,2H),7.46-7.51(m,2H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.56 (s, 6H), 5.18 (brs, 1H), 5.52 (brs, 1H), 7.25-7.30 (m, 2H), 7.46-7.51 (m, 2H) .
以下、参考化合物2−1の製造方法に準じて、参考化合物2−2〜3を製造した。 Hereinafter, Reference Compounds 2-2 to 3 were produced according to the production method of Reference Compound 2-1.
4−(1−アミノカルボニル−1−メチルエチル)−1−ヨードベンゼン(参考化合物2−2)
Rf値:0.25(n-ヘキサン:酢酸エチル=4:1(V/V))
マススペクトル(CI,m/z):290(M++1)。
4- (1-aminocarbonyl-1-methylethyl) -1-iodobenzene (reference compound 2-2)
Rf value: 0.25 (n-hexane: ethyl acetate = 4: 1 (V / V))
Mass spectrum (CI, m / z): 290 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.56(s,6H),5.00-5.50(m,2H),
7.13-7.17(m,2H),7.66-7.71(m,2H)。
1 H-NMR spectrum (CDCl 3 , δ ppm): 1.56 (s, 6H), 5.00-5.50 (m, 2H),
7.13-7.17 (m, 2H), 7.66-7.71 (m, 2H).
4−アミノカルボニルメチル−1−ヨードベンゼン(参考化合物2−3)
Rf値:0.30(n−ヘキサン:酢酸エチル=1:1(V/V))。
4-Aminocarbonylmethyl-1-iodobenzene (Reference compound 2-3)
Rf value: 0.30 (n-hexane: ethyl acetate = 1: 1 (V / V)).
マススペクトル(CI,m/z):262(M++1)。 Mass spectrum (CI, m / z): 262 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):3.53(s,2H),5.36(brs,2H),7.04(d,J=8.4Hz,2H),7.69(d,J=8.4Hz,2H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 3.53 (s, 2H), 5.36 (brs, 2H), 7.04 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H).
(参考例3)
1−ブロモ−4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)ベンゼン(参考化合物3−1)の合成
Synthesis of 1-bromo-4- (1-tert-butoxycarbonylamino-1-methylethyl) benzene (reference compound 3-1)
反応終了後、反応溶液を減圧濃縮して、得られた残渣に10重量%クエン酸水溶液500gを加え、トルエン2000mlで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液で順次洗浄、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残渣にn−ヘキサン200mlを加えて生成した固体を濾取し、冷n−ヘキサン400mlで洗浄、乾燥することにより標記の化合物77gを薄茶色粉末として得た。(収率60%)
融点:92-93℃。
After completion of the reaction, the reaction solution was concentrated under reduced pressure, 500 g of a 10 wt% aqueous citric acid solution was added to the resulting residue, and the mixture was extracted with 2000 ml of toluene. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 200 ml of n-hexane was added to the resulting residue, and the resulting solid was collected by filtration, washed with 400 ml of cold n-hexane and dried to obtain 77 g of the title compound as a light brown powder. (Yield 60%)
Melting point: 92-93 ° C.
Rf値:0.56(n−ヘキサン:酢酸エチル=4:1(V/V))。 Rf value: 0.56 (n-hexane: ethyl acetate = 4: 1 (V / V)).
マススペクトル(CI,m/z):314,316(M++1)。 Mass spectrum (CI, m / z): 314,316 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.36(brs,9H),1.59(s,6H),4.90(brs,1H),7.24-7.29(m,2H),7.39-7.45(m,2H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.36 (brs, 9H), 1.59 (s, 6H), 4.90 (brs, 1H), 7.24-7.29 (m, 2H), 7.39-7.45 (m, 2H) .
以下、参考化合物3−1の製造方法に準じて、参考化合物3−2〜3を製造した。 Hereinafter, reference compounds 3-2 to 3 were produced according to the production method of reference compound 3-1.
4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)−1−ヨードベンゼン(参考化合物3−2)
Rf値:0.50(n-ヘキサン:酢酸エチル=4:1(V/V))
マススペクトル(EI,m/z):361(M+)。
4- (1-tert-butoxycarbonylamino-1-methylethyl) -1-iodobenzene (reference compound 3-2)
Rf value: 0.50 (n-hexane: ethyl acetate = 4: 1 (V / V))
Mass spectrum (EI, m / z): 361 (M + ).
1H−NMRスペクトル(CDCl3,δppm):1.37(brs,9H),1.58(s,6H),
4.90(brs,1H),7.12-7.16(m,2H),7.60-7.65(m,2H)。
1 H-NMR spectrum (CDCl 3 , δ ppm): 1.37 (brs, 9H), 1.58 (s, 6H),
4.90 (brs, 1H), 7.12-7.16 (m, 2H), 7.60-7.65 (m, 2H).
4−(tert−ブトキシカルボニルアミノメチル)−1−ヨードベンゼン(参考化合物3−3)
Rf値:0.40(n-ヘキサン:酢酸エチル=4:1(V/V))
マススペクトル(EI,m/z):334(M+)。
4- (tert-Butoxycarbonylaminomethyl) -1-iodobenzene (Reference compound 3-3)
Rf value: 0.40 (n-hexane: ethyl acetate = 4: 1 (V / V))
Mass spectrum (EI, m / z): 334 (M + ).
1H−NMRスペクトル(CDCl3,δppm):1.45(s,9H),4.23-4.26(m,2H),4.78-4.93(m,1H),7.03(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.45 (s, 9H), 4.23-4.26 (m, 2H), 4.78-4.93 (m, 1H), 7.03 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H).
(参考例4)
1−アセチル−4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)ベンゼン(参考化合物4−1)の合成
Synthesis of 1-acetyl-4- (1-tert-butoxycarbonylamino-1-methylethyl) benzene (reference compound 4-1)
反応終了後、反応溶液に飽和塩化アンモニウム水溶液300mlを添加し、酢酸エチル300mlで抽出した。有機層を水、次いで飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;n−ヘキサン:酢酸エチル=4:1(V/V))に付し、目的物を含む画分を減圧濃縮して標記の化合物2.9gを白色粉末として得た。(収率35%)
Rf値:0.50(n−ヘキサン:酢酸エチル=1:1(V/V))。
After completion of the reaction, 300 ml of a saturated aqueous ammonium chloride solution was added to the reaction solution, and extracted with 300 ml of ethyl acetate. The organic layer was washed successively with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 2.9 g of the title compound. Was obtained as a white powder. (Yield 35%)
Rf value: 0.50 (n-hexane: ethyl acetate = 1: 1 (V / V)).
マススペクトル(CI,m/z):278(M++1)。 Mass spectrum (CI, m / z): 278 (M ++ 1).
1H−NMRスペクトル(CDCl3,δppm):1.37(brs,9H),1.63(s,6H),2.59(s,3H),4.96(brs,1H),7.46-7.51(m,2H),7.89-7.94(m,2H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.37 (brs, 9H), 1.63 (s, 6H), 2.59 (s, 3H), 4.96 (brs, 1H), 7.46-7.51 (m, 2H), 7.89 -7.94 (m, 2H).
以下、参考化合物4−1の製造方法に準じて、参考化合物4−2を製造した。 Hereinafter, Reference Compound 4-2 was produced according to the production method of Reference Compound 4-1.
1−プロピオニル−4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)ベンゼン(参考化合物4−2)
Rf値:0.55 (n−ヘキサン:酢酸エチル=4:1(V/V))。
1-propionyl-4- (1-tert-butoxycarbonylamino-1-methylethyl) benzene (reference compound 4-2)
Rf value: 0.55 (n-hexane: ethyl acetate = 4: 1 (V / V)).
マススペクトル(CI,m/z):292(M++1)。 Mass spectrum (CI, m / z): 292 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.22(t,J=7.3Hz,3H),1.38(brs,9H),1.62(s,6H),2.99(q,J=7.3Hz,2H),4.97(brs,1H),7.45-7.50(m,2H),7.90-7.94(m,2H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.22 (t, J = 7.3 Hz, 3H), 1.38 (brs, 9H), 1.62 (s, 6H), 2.99 (q, J = 7.3 Hz, 2H), 4.97 (brs, 1H), 7.45-7.50 (m, 2H), 7.90-7.94 (m, 2H).
(参考例5)
4−ヨード−1H−ピロロ[2,3−b]ピリジン(参考化合物5−1)および1−アセチル−4−ヨード−1H−ピロロ[2,3−b]ピリジン(参考化合物5−2)の合成
参考化合物5−1
4-Iodo-1H-pyrrolo [2,3-b] pyridine (reference compound 5-1) and 1-acetyl-4-iodo-1H-pyrrolo [2,3-b] pyridine (reference compound 5-2) Synthesis Reference Compound 5-1
反応終了後、反応懸濁液を濾過し、得られた残渣に酢酸エチル15ml及び10%炭酸ナトリウム水15mlを添加して抽出した。有機層を10%亜硫酸水素ナトリウム水溶液、水、次いで飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;n−ヘキサン:酢酸エチル=49:1(V/V))に付し、4−ヨード−1H−ピロロ[2,3−b]ピリジン(参考化合物5−1)を含む画分を減圧濃縮し、この化合物137mgを白色粉末として得た。(収率22%)
Rf値:0.58(酢酸エチル)。
After completion of the reaction, the reaction suspension was filtered, and the resulting residue was extracted by adding 15 ml of ethyl acetate and 15 ml of 10% aqueous sodium carbonate. The organic layer was washed successively with 10% aqueous sodium bisulfite, water, and then saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 49: 1 (V / V)) to give 4-iodo-1H-pyrrolo [2,3-b] pyridine (reference The fraction containing Compound 5-1) was concentrated under reduced pressure to obtain 137 mg of this compound as a white powder. (Yield 22%)
Rf value: 0.58 (ethyl acetate).
マススペクトル(CI,m/z):245(M++1)。 Mass spectrum (CI, m / z): 245 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):6.42(dd,J1=3.5Hz,J2=1.8Hz,1H),7.38(dd,J1=3.5Hz,J2=1.6Hz,1H),7.51(d,J=5.1Hz,1H),7.94(d,J=5.1Hz,1H),9.30-9.54(m,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 6.42 (dd, J1 = 3.5 Hz, J2 = 1.8 Hz, 1H), 7.38 (dd, J1 = 3.5 Hz, J2 = 1.6 Hz, 1H), 7.51 (d, J = 5.1 Hz, 1H), 7.94 (d, J = 5.1 Hz, 1H), 9.30-9.54 (m, 1H).
また、同時に1−アセチル−4−ヨード−1H−ピロロ[2,3−b]ピリジン(参考化合物5−2)を含む画分を減圧濃縮し、この化合物の272mgを白色粉末として得た。(収率37%)
Rf値:0.37 (n−ヘキサン:酢酸エチル=19:1(V/V))。
At the same time, a fraction containing 1-acetyl-4-iodo-1H-pyrrolo [2,3-b] pyridine (reference compound 5-2) was concentrated under reduced pressure to obtain 272 mg of this compound as a white powder. (Yield 37%)
Rf value: 0.37 (n-hexane: ethyl acetate = 19: 1 (V / V)).
マススペクトル(CI,m/z):287(M++1)。 Mass spectrum (CI, m / z): 287 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):3.04(s,3H),6.53(d,J=4.2Hz,1H),7.61(d,J=5.1Hz,1H),7.99(d,J=5.1Hz,1H),8.06(d,J=4.2Hz,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 3.04 (s, 3H), 6.53 (d, J = 4.2 Hz, 1H), 7.61 (d, J = 5.1 Hz, 1H), 7.99 (d, J = 5.1 Hz, 1H), 8.06 (d, J = 4.2 Hz, 1H).
(参考例6)
4−ヨード−1−[2−(トリメチルシリル)エトキシメチル]−1H−ピロロ[2,3−b]ピリジン(参考化合物6)
4-Iodo-1- [2- (trimethylsilyl) ethoxymethyl] -1H-pyrrolo [2,3-b] pyridine (reference compound 6)
反応終了後、反応溶液に水100mlを添加し、酢酸エチル100mlで抽出した。有機層を水、次いで飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;n−ヘキサン:酢酸エチル=9:1(V/V))に付し、目的物を含む画分を減圧濃縮し、標記の化合物3.1gを白色粉末として得た。(収率84%)
Rf値:0.49(n−ヘキサン:酢酸エチル=4:1(V/V))。
After completion of the reaction, 100 ml of water was added to the reaction solution and extracted with 100 ml of ethyl acetate. The organic layer was washed successively with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 9: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 3.1 g of the title compound. Was obtained as a white powder. (Yield 84%)
Rf value: 0.49 (n-hexane: ethyl acetate = 4: 1 (V / V)).
マススペクトル(CI,m/z):375(M++1)。 Mass spectrum (CI, m / z): 375 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):-0.07(s,9H),0.86-0.94(m,2H),3.49-3.56(m,2H),5.64(s,2H),6.42(d,J=3.7Hz,1H),7.41(d,J=3.7Hz,1H),7.50(d,J=5.1Hz,1H),7.96(d,J=5.1Hz,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): -0.07 (s, 9H), 0.86-0.94 (m, 2H), 3.49-3.56 (m, 2H), 5.64 (s, 2H), 6.42 (d, J = 3.7Hz, 1H), 7.41 (d, J = 3.7Hz, 1H), 7.50 (d, J = 5.1Hz, 1H), 7.96 (d, J = 5.1Hz, 1H).
(参考例7)
4−(3−ヒドロキシプロピン−1−イル)−1−[2−(トリメチルシリル)エトキシメチル]−1H−ピロロ[2,3−b]ピリジン(参考化合物7−1)
4- (3-Hydroxypropyn-1-yl) -1- [2- (trimethylsilyl) ethoxymethyl] -1H-pyrrolo [2,3-b] pyridine (Reference compound 7-1)
反応終了後、反応溶液に水50mlを添加し、酢酸エチル50mlで抽出した。有機層を水、次いで飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;n−ヘキサン:酢酸エチル=4:1(V/V))に付し、目的物を含む画分を減圧濃縮し、標記の化合物0.30gを褐色油状物として得た。(収率67%)
Rf値:0.28(n−ヘキサン:酢酸エチル=3:1(V/V))
マススペクトル(CI,m/z):303(M++1)。
After completion of the reaction, 50 ml of water was added to the reaction solution, and extracted with 50 ml of ethyl acetate. The organic layer was washed successively with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (0.30 g). Was obtained as a brown oil. (Yield 67%)
Rf value: 0.28 (n-hexane: ethyl acetate = 3: 1 (V / V))
Mass spectrum (CI, m / z): 303 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):-0.08(s,9H),0.86-0.94(m,2H),1.80(t,J=6.2Hz,1H),3.49-3.56(m,2H),4.61(d,J=6.2Hz,2H),5.67(s,2H),6.65(d,J=3.7Hz,1H),7.13(d,J=5.1Hz,1H),7.39(d,J=3.7Hz,1H),8.28(d,J=5.1Hz,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): −0.08 (s, 9H), 0.86-0.94 (m, 2H), 1.80 (t, J = 6.2 Hz, 1H), 3.49-3.56 (m, 2H), 4.61 (d, J = 6.2Hz, 2H), 5.67 (s, 2H), 6.65 (d, J = 3.7Hz, 1H), 7.13 (d, J = 5.1Hz, 1H), 7.39 (d, J = 3.7 Hz, 1H), 8.28 (d, J = 5.1 Hz, 1H).
以下、参考化合物7−1の製造方法に準じて、参考化合物7−2〜3を製造した。 Hereinafter, reference compounds 7-2 to 3 were produced according to the production method of reference compound 7-1.
1−アセチル−4−(3−ヒドロキシプロピン−1−イル)−1H−ピロロ[2,3−b]ピリジン(参考化合物7−2)
Rf値:0.31 (n−ヘキサン:酢酸エチル=4:1(V/V))。
1-acetyl-4- (3-hydroxypropin-1-yl) -1H-pyrrolo [2,3-b] pyridine (reference compound 7-2)
Rf value: 0.31 (n-hexane: ethyl acetate = 4: 1 (V / V)).
マススペクトル(CI,m/z):215(M++1)。 Mass spectrum (CI, m / z): 215 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):3.04(s,3H),4.61(s,2H),6.72(d,J=4.2Hz,1H),7.20(d,J=5.0Hz,1H),8.01(d,J=4.2Hz,1H),8.30(d,J=5.0Hz,1H)
1−アセチル−4−(2−メトキシカルボニルエチン−1−イル)−1H−ピロロ[2,3−b]ピリジン(参考化合物7−3)
Rf値:0.40 (クロロホルム)。
1 H-NMR spectrum (CDCl 3 , δ ppm): 3.04 (s, 3H), 4.61 (s, 2H), 6.72 (d, J = 4.2 Hz, 1H), 7.20 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 4.2Hz, 1H), 8.30 (d, J = 5.0Hz, 1H)
1-acetyl-4- (2-methoxycarbonylethyn-1-yl) -1H-pyrrolo [2,3-b] pyridine (reference compound 7-3)
Rf value: 0.40 (chloroform).
マススペクトル(CI,m/z):243(M++1)。 Mass spectrum (CI, m / z): 243 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):3.05(s,3H),3.89(s,3H),6.81(d,J=4.2Hz,1H),7.35(d,J=5.2Hz,1H),8.10(d,J=4.2Hz,1H),8.39(d,J=5.2Hz,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 3.05 (s, 3H), 3.89 (s, 3H), 6.81 (d, J = 4.2 Hz, 1H), 7.35 (d, J = 5.2 Hz, 1H), 8.10 (d, J = 4.2 Hz, 1H), 8.39 (d, J = 5.2 Hz, 1H).
(参考例8)
E−1−(4−シアノフェニル)−2−(4−ピリジル)エチレンの合成(参考化合物8)
Rf値:0.59(クロロホルム:メタノール=9:1(V/V))。
(Reference Example 8)
Synthesis of E-1- (4-cyanophenyl) -2- (4-pyridyl) ethylene (Reference Compound 8)
Rf value: 0.59 (chloroform: methanol = 9: 1 (V / V)).
マススペクトル(CI,m/z):207(M++1)。 Mass spectrum (CI, m / z): 207 (M + +1).
1H−NMRスペクトル(DMSO-d6,δppm):7.46(d,J=16.6Hz,1H),7.60(dd,J1=4.6Hz,J2=1.5Hz,2H),7.63(d,J=16.6Hz,1H),7.84(d,J=8.6Hz,2H),7.89(d,J=8.6Hz,2H),8.58(dd,J1=4.6Hz,J2=1.5Hz,2H)。 1 H-NMR spectrum (DMSO-d 6 , δ ppm): 7.46 (d, J = 16.6 Hz, 1H), 7.60 (dd, J1 = 4.6 Hz, J2 = 1.5 Hz, 2H), 7.63 (d, J = 16.6) Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.6 Hz, 2H), 8.58 (dd, J1 = 4.6 Hz, J2 = 1.5 Hz, 2H).
(参考例9)
1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−2−(2−tert−ブトキシカルボニルアミノピリジン−4−イル)−1−ヒドロキシ−1−メチルエタン(参考化合物9)の合成
1- [4- (1-tert-Butoxycarbonylamino-1-methylethyl) phenyl] -2- (2-tert-butoxycarbonylaminopyridin-4-yl) -1-hydroxy-1-methylethane (Reference Compound 9) ) Synthesis
反応終了後、反応溶液に飽和塩化アンモニウム水溶液30mlを添加し、酢酸エチル30mlで抽出した。有機層を水、次いで飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;n−ヘキサン:酢酸エチル=3:1(V/V))に付し、目的物を含む画分を減圧濃縮して標記の化合物110mgを白色粉末として得た。(収率56%)
Rf値:0.55 (n−ヘキサン:酢酸エチル=1:1(V/V))。
After completion of the reaction, 30 ml of a saturated aqueous ammonium chloride solution was added to the reaction solution, and extracted with 30 ml of ethyl acetate. The organic layer was washed successively with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 110 mg of the title compound as white. Obtained as a powder. (Yield 56%)
Rf value: 0.55 (n-hexane: ethyl acetate = 1: 1 (V / V)).
マススペクトル(CI,m/z):486(M++1)。 Mass spectrum (CI, m / z): 486 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.38(brs,9H),1.52(s,9H),1.55(s,3H),1.62(s,6H),1.80(s,1H),2.98(d,J=13.2Hz,1H),3.07(d,J=13.2Hz,1H),4.91(brs,1H),6.59-6.62(m,1H),7.25(brs,1H),7.36(s,4H),7.68-7.71(m,1H),8.03(d,J=5.4Hz,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.38 (brs, 9H), 1.52 (s, 9H), 1.55 (s, 3H), 1.62 (s, 6H), 1.80 (s, 1H), 2.98 (d , J = 13.2Hz, 1H), 3.07 (d, J = 13.2Hz, 1H), 4.91 (brs, 1H), 6.59-6.62 (m, 1H), 7.25 (brs, 1H), 7.36 (s, 4H) 7.68-7.71 (m, 1H), 8.03 (d, J = 5.4Hz, 1H).
(実施例1)
E−1−[4−(1−アミノ−1−メチルエチル)フェニル]−2−(4−ピリジル)エチレン 2塩酸塩(化合物1)の合成
Synthesis of E-1- [4- (1-amino-1-methylethyl) phenyl] -2- (4-pyridyl) ethylene dihydrochloride (Compound 1)
反応終了後、反応溶液を−30℃まで昇温し、水20mlを添加し、酢酸エチル50mlで抽出した。次いで水層を酢酸エチルで2回抽出し、合わせた有機層を無水硫酸マグネシウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;クロロホルム:メタノール=49:1(V/V))に付し、目的物を含む画分を減圧濃縮した。次いで得られた残渣を薄層クロマトグラフィー(溶出溶媒;クロロホルム:メタノール=9:1(V/V))に付し、目的物を含む画分を減圧濃縮して微黄色粉末52mgを得た。 After completion of the reaction, the reaction solution was heated to −30 ° C., 20 ml of water was added, and the mixture was extracted with 50 ml of ethyl acetate. The aqueous layer was then extracted twice with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; chloroform: methanol = 49: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. Subsequently, the obtained residue was subjected to thin layer chromatography (elution solvent; chloroform: methanol = 9: 1 (V / V)), and the fraction containing the target product was concentrated under reduced pressure to obtain 52 mg of a slightly yellow powder.
得られた粉末21mgのエタノール3ml溶液に0.1N塩酸3.4mlを添加し、室温で20分間撹拌した。反応溶液を減圧濃縮して標記の化合物25mgを淡黄色粉末として得た。(収率4%)
融点:247-249℃ (分解)
Rf値:0.31(クロロホルム:メタノール:28%アンモニア水=9:1:0.01(V/V/V))
マススペクトル(CI,m/z):239(M++1)。
To a solution of 21 mg of the obtained powder in 3 ml of ethanol, 3.4 ml of 0.1N hydrochloric acid was added and stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure to obtain 25 mg of the title compound as a pale yellow powder. (
Melting point: 247-249 ° C (decomposition)
Rf value: 0.31 (chloroform: methanol: 28% aqueous ammonia = 9: 1: 0.01 (V / V / V))
Mass spectrum (CI, m / z): 239 (M + +1).
1H−NMRスペクトル(DMSO-d6,δppm):1.65(s,6H),7.49(d,J=16.4Hz,1H),7.63(d,J=8.5Hz,2H),7.79(d,J=8.5Hz,2H),7.86(d,J=16.4Hz,1H),7.98(d,J=6.2Hz,2H),8.44-8.66(m,3H),8.76(d,J=6,2Hz,2H)。 1 H-NMR spectrum (DMSO-d 6 , δppm): 1.65 (s, 6H), 7.49 (d, J = 16.4 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.5Hz, 2H), 7.86 (d, J = 16.4Hz, 1H), 7.98 (d, J = 6.2Hz, 2H), 8.44-8.66 (m, 3H), 8.76 (d, J = 6,2Hz, 2H).
(実施例2)
E−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−メチル−2−(4−ピリジル)エチレン(化合物2−1)およびZ−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−メチル−2−(4−ピリジル)エチレン(化合物2−2)の合成
化合物2−1
E-1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -1-methyl-2- (4-pyridyl) ethylene (Compound 2-1) and Z-1- [4- Synthesis of (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -1-methyl-2- (4-pyridyl) ethylene (Compound 2-2) Compound 2-1
反応終了後、反応溶液に水5mlを添加し、トルエン5mlで抽出した。有機層を水、次いで飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;n−ヘキサン:酢酸エチル=4:1(V/V))に付し、標記の化合物E−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−メチル−2−(4−ピリジル)エチレン(化合物2−1)及びZ−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−メチル−2−(4−ピリジル)エチレン(化合物2−2)の混合物(55:45)62mgを白色粉末として得た。 After completion of the reaction, 5 ml of water was added to the reaction solution and extracted with 5 ml of toluene. The organic layer was washed successively with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1 (V / V)) to give the title compound E-1- [4- (1-tert-butoxycarbonyl). Amino-1-methylethyl) phenyl] -1-methyl-2- (4-pyridyl) ethylene (compound 2-1) and Z-1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) 62 mg of a mixture (55:45) of phenyl] -1-methyl-2- (4-pyridyl) ethylene (compound 2-2) was obtained as a white powder.
この混合物62mgを高速液体クロマトグラフィー(溶出溶媒;アセトニトリル:水=13:7(V/V))に付し、E−2−[4−(1−t−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−(4−ピリジル)プロペン(化合物2−1)32mgを白色粉末として得た。(収率23%)
Rf値:0.34(n−ヘキサン:エタノール=4:1(V/V))。
62 mg of this mixture was subjected to high performance liquid chromatography (elution solvent; acetonitrile: water = 13: 7 (V / V)) to give E-2- [4- (1-t-butoxycarbonylamino-1-methylethyl). 32 mg of phenyl] -1- (4-pyridyl) propene (compound 2-1) was obtained as a white powder. (Yield 23%)
Rf value: 0.34 (n-hexane: ethanol = 4: 1 (V / V)).
マススペクトル(CI,m/z):353(M++1)。 Mass spectrum (CI, m / z): 353 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.39(brs,9H),1.64(s,6H),2.30(s,3H),4.94(brs,1H),6.72(s,1H),7.24(dd,J1=6.0Hz,J2=1.6Hz,2H),7.39-7.43(m,2H),7.45-7.49(m,2H),8.59(dd,J1=6.0Hz,J2=1.6Hz,2H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.39 (brs, 9H), 1.64 (s, 6H), 2.30 (s, 3H), 4.94 (brs, 1H), 6.72 (s, 1H), 7.24 (dd , J1 = 6.0 Hz, J2 = 1.6 Hz, 2H), 7.39-7.43 (m, 2H), 7.45-7.49 (m, 2H), 8.59 (dd, J1 = 6.0 Hz, J2 = 1.6 Hz, 2H).
また、同時にZ−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−メチル−2−(4−ピリジル)エチレン(化合物2−2)21mgを白色粉末として得た。(収率15%)
Rf値:0.38(n−ヘキサン:エタノール=4:1(V/V))。
At the same time, 21 mg of Z-1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -1-methyl-2- (4-pyridyl) ethylene (compound 2-2) was used as a white powder. Obtained. (Yield 15%)
Rf value: 0.38 (n-hexane: ethanol = 4: 1 (V / V)).
マススペクトル(CI,m/z):353(M++1)。 Mass spectrum (CI, m / z): 353 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.37(brs,9H),1.62(s,6H),2.22(d,J=1.7Hz,3H),4.91(brs,1H),6.37(d,J=1.7Hz,1H),6.75-6.85(m,2H),7.08-7.12(m,2H),7.28-7.35(m,2H),8.29(dd,J1=6.3Hz,J2=1.7Hz,2H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.37 (brs, 9H), 1.62 (s, 6H), 2.22 (d, J = 1.7 Hz, 3H), 4.91 (brs, 1H), 6.37 (d, J = 1.7Hz, 1H), 6.75-6.85 (m, 2H), 7.08-7.12 (m, 2H), 7.28-7.35 (m, 2H), 8.29 (dd, J1 = 6.3Hz, J2 = 1.7Hz, 2H) .
以下、化合物2−1及び2−2の製造方法に準じて、化合物2−3および化合物2−4の混合物を製造した。 Hereafter, according to the manufacturing method of compound 2-1 and 2-2, the mixture of compound 2-3 and compound 2-4 was manufactured.
E−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−エチル−2−(4−ピリジル)エチレン(化合物2−3)およびZ−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−エチル−2−(4−ピリジル)エチレン(化合物2−4)
Rf値:0.23(n−ヘキサン:酢酸エチル=4:1(V/V))。
E-1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -1-ethyl-2- (4-pyridyl) ethylene (compound 2-3) and Z-1- [4- (1-tert-Butoxycarbonylamino-1-methylethyl) phenyl] -1-ethyl-2- (4-pyridyl) ethylene (Compound 2-4)
Rf value: 0.23 (n-hexane: ethyl acetate = 4: 1 (V / V)).
マススペクトル(CI,m/z):367(M++1)。 Mass spectrum (CI, m / z): 367 (M + +1).
(実施例3)
E−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−メチル−2−(4−ピリジル)エチレン 2塩酸塩(化合物3−1)の合成
Synthesis of E-1- [4- (1-amino-1-methylethyl) phenyl] -1-methyl-2- (4-pyridyl) ethylene dihydrochloride (Compound 3-1)
反応終了後、反応液を減圧濃縮し、残渣をジエチルエーテルで洗浄することにより、標記の化合物18mgを淡黄色粉末として得た。(収率67%)
融点:160-163℃ (分解)
Rf値:0.31(クロロホルム:メタノール:28%アンモニア水=9:1:0.01(V/V/V))
マススペクトル(CI,m/z):253(M++1)。
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether to obtain 18 mg of the title compound as a pale yellow powder. (Yield 67%)
Melting point: 160-163 ℃ (decomposition)
Rf value: 0.31 (chloroform: methanol: 28% aqueous ammonia = 9: 1: 0.01 (V / V / V))
Mass spectrum (CI, m / z): 253 (M ++ 1).
1H−NMRスペクトル(DMSO-d6,δppm):1.66(s,6H),2.37(d,J=1.2Hz,3H),7.08(d,J=1.2Hz,1H),7.62(d,J=8.5Hz,2H),7.73(d,J=8.5Hz,2H),7.85(d,J=6.6Hz,2H),8.56-8.71(m,3H),8.78(d,J=6.6Hz,2H)
以下、化合物3−1の製造方法に準じて、化合物3−2〜11を製造した。
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 1.66 (s, 6H), 2.37 (d, J = 1.2 Hz, 3H), 7.08 (d, J = 1.2 Hz, 1H), 7.62 (d, J = 8.5Hz, 2H), 7.73 (d, J = 8.5Hz, 2H), 7.85 (d, J = 6.6Hz, 2H), 8.56-8.71 (m, 3H), 8.78 (d, J = 6.6Hz, 2H )
Hereinafter, compounds 3-2 to 11 were produced according to the production method of compound 3-1.
ただし、化合物3−3、3−6、3−10及び3−11の合成では、分離、精製するために高速液体クロマトグラフィー(溶出溶媒;0.03容量%トリフルオロ酢酸水溶液:アセトニトリル=1:1(V/V)及び9:1(V/V))を用いた。その際、塩酸塩からトリフルオロ酢酸塩へ交換された。 However, in the synthesis of compounds 3-3, 3-6, 3-10 and 3-11, high performance liquid chromatography (elution solvent; 0.03% by volume trifluoroacetic acid aqueous solution: acetonitrile = 1: 1 (V / V) and 9: 1 (V / V)) were used. At that time, the hydrochloride salt was changed to trifluoroacetate salt.
Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−メチル−2−(4−ピリジル)エチレン 2塩酸塩(化合物3−2)
融点:171-175℃ (分解)
Rf値:0.31(クロロホルム:メタノール:28%アンモニア水=9:1:0.01(V/V/V))
マススペクトル(CI,m/z):253(M++1)。
Z-1- [4- (1-Amino-1-methylethyl) phenyl] -1-methyl-2- (4-pyridyl) ethylene dihydrochloride (Compound 3-2)
Melting point: 171-175 ° C (decomposition)
Rf value: 0.31 (chloroform: methanol: 28% aqueous ammonia = 9: 1: 0.01 (V / V / V))
Mass spectrum (CI, m / z): 253 (M ++ 1).
1H−NMRスペクトル(DMSO-d6,δppm):1.64(s,6H),2.26(s,3H),6.70(s,1H),7.13(d,J=5.5Hz,2H),7.29(d,J=8.5Hz,2H),7.54(d,J=8.5Hz,2H),8.47(d,J=5.5Hz,2H),8.54(brs,3H)。 1 H-NMR spectrum (DMSO-d 6 , δ ppm): 1.64 (s, 6H), 2.26 (s, 3H), 6.70 (s, 1H), 7.13 (d, J = 5.5 Hz, 2H), 7.29 (d , J = 8.5Hz, 2H), 7.54 (d, J = 8.5Hz, 2H), 8.47 (d, J = 5.5Hz, 2H), 8.54 (brs, 3H).
E−1−[4−(1−アミノ−1−メチルエチル)フェニル]−2−(2−アミノピリジン−4−イル)−1−メチルエチレン 2トリフルオロ酢酸塩(化合物3−3)
融点:214-217℃ (分解)
マススペクトル(CI,m/z):268(M++1)。
E-1- [4- (1-Amino-1-methylethyl) phenyl] -2- (2-aminopyridin-4-yl) -1-methylethylene 2-trifluoroacetate (Compound 3-3)
Melting point: 214-217 ° C (decomposition)
Mass spectrum (CI, m / z): 268 (M + +1).
1H−NMRスペクトル(DMSO-d6,δppm):1.64(s,6H),2.25(s,3H),6.29(brs,2H),6.54(s,1H),6.58(d,J=5.4Hz,1H),6.75(s,1H),7.55(d,J=8.5Hz,2H),7.65(d,J=8.5Hz,2H),7.91(d,J=5.4Hz,1H),8.49(brs,3H)。 1 H-NMR spectrum (DMSO-d 6 , δ ppm): 1.64 (s, 6H), 2.25 (s, 3H), 6.29 (brs, 2H), 6.54 (s, 1H), 6.58 (d, J = 5.4Hz , 1H), 6.75 (s, 1H), 7.55 (d, J = 8.5Hz, 2H), 7.65 (d, J = 8.5Hz, 2H), 7.91 (d, J = 5.4Hz, 1H), 8.49 (brs , 3H).
E−1−[4−(1−アミノ−1−メチルエチル)フェニル]−2−メチル−2−(4−ピリジル)エチレン 2塩酸塩(化合物3−4)
融点:181-183℃ (分解)
マススペクトル(CI,m/z):253(M++1)。
E-1- [4- (1-Amino-1-methylethyl) phenyl] -2-methyl-2- (4-pyridyl) ethylene dihydrochloride (Compound 3-4)
Melting point: 181-183 ° C (decomposition)
Mass spectrum (CI, m / z): 253 (M ++ 1).
1H−NMRスペクトル(DMSO-d6,δppm):1.66(s,6H),2.29(d,J=1.2Hz,3H),7.40-7.42(m,1H),7.56(d,J=8.6Hz,2H),7.63(d,J=8.6Hz,2H),7.95(d,J=6.4Hz,2H),8.56-8.68(m,3H),8.75(d,J=6.4Hz,2H)。 1 H-NMR spectrum (DMSO-d 6 , δ ppm): 1.66 (s, 6H), 2.29 (d, J = 1.2 Hz, 3H), 7.40-7.42 (m, 1H), 7.56 (d, J = 8.6 Hz) , 2H), 7.63 (d, J = 8.6 Hz, 2H), 7.95 (d, J = 6.4 Hz, 2H), 8.56-8.68 (m, 3H), 8.75 (d, J = 6.4 Hz, 2H).
Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−ヒドロキシメチル−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン 2塩酸塩(化合物3−5)
融点:214-216℃ (分解)
Rf値:0.17(クロロホルム:メタノール:28%アンモニア水=9:1:0.01(V/V/V))
マススペクトル(CI,m/z):308(M++1)。
Z-1- [4- (1-Amino-1-methylethyl) phenyl] -1-hydroxymethyl-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene dihydrochloride (compound 3-5)
Melting point: 214-216 ° C (decomposition)
Rf value: 0.17 (chloroform: methanol: 28% aqueous ammonia = 9: 1: 0.01 (V / V / V))
Mass spectrum (CI, m / z): 308 (M + +1).
1H−NMRスペクトル(DMSO-d6,δppm):1.67(s,6H),4.55(s,2H),6.79(dd,J1=3.4Hz,J2=1.7Hz,1H),7.28(s,1H),7.41(d,J=5.3Hz,1H),7.59-7.62(m,3H),7.82(d,J=8.8Hz,2H),8.34(d,J=5.3Hz,2H),8.63(brs,3H),12.10-12.30(m,1H)。 1 H-NMR spectrum (DMSO-d 6 , δ ppm): 1.67 (s, 6H), 4.55 (s, 2H), 6.79 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H), 7.28 (s, 1H ), 7.41 (d, J = 5.3Hz, 1H), 7.59-7.62 (m, 3H), 7.82 (d, J = 8.8Hz, 2H), 8.34 (d, J = 5.3Hz, 2H), 8.63 (brs , 3H), 12.10-12.30 (m, 1H).
Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−(ヒドロキシイミノメチル)−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン 2トリフルオロ酢酸塩(化合物3−6)
融点:164-166℃ (分解)
Rf値:0.16(クロロホルム:メタノール:28%アンモニア水=9:1:0.01(V/V/V))。
Z-1- [4- (1-amino-1-methylethyl) phenyl] -1- (hydroxyiminomethyl) -2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene 2tri Fluoroacetate (Compound 3-6)
Melting point: 164-166 ° C (decomposition)
Rf value: 0.16 (chloroform: methanol: 28% aqueous ammonia = 9: 1: 0.01 (V / V / V)).
マススペクトル(CI,m/z):321(M++1)。 Mass spectrum (CI, m / z): 321 (M + +1).
1H−NMRスペクトル(DMSO-d6,δppm):1.64(s,6H),6.24(d,J=5.1Hz,1H),6.63(dd,J1=3.4Hz,J2=2.0Hz,1H),7.27(d,J=8.3Hz,2H),7.38(s,1H),7.46-7.54(m,3H),7.81(d,J=5.1Hz,1H),8.28(s,1H),8.40(brs,3H),11.23(s,1H),11.62-11.68(m,1H)。 1 H-NMR spectrum (DMSO-d 6 , δ ppm): 1.64 (s, 6H), 6.24 (d, J = 5.1 Hz, 1H), 6.63 (dd, J1 = 3.4 Hz, J2 = 2.0 Hz, 1H), 7.27 (d, J = 8.3Hz, 2H), 7.38 (s, 1H), 7.46-7.54 (m, 3H), 7.81 (d, J = 5.1Hz, 1H), 8.28 (s, 1H), 8.40 (brs , 3H), 11.23 (s, 1H), 11.62-11.68 (m, 1H).
Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−シアノ−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン 2塩酸塩(化合物3−7)
融点:255-256℃ (分解)
Rf値:0.38(クロロホルム:メタノール:28%アンモニア水=9:1:0.01(V/V/V))
マススペクトル(CI,m/z):303(M++1)。
Z-1- [4- (1-Amino-1-methylethyl) phenyl] -1-cyano-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene dihydrochloride (Compound 3 -7)
Melting point: 255-256 ° C (decomposition)
Rf value: 0.38 (chloroform: methanol: 28% aqueous ammonia = 9: 1: 0.01 (V / V / V))
Mass spectrum (CI, m / z): 303 (M + +1).
1H−NMRスペクトル(DMSO-d6,δppm):1.69(s,6H),6.95(dd,J1=3.4Hz,J2=1.7Hz,1H),7.67-7.70(m,1H),7.76(d,J=8.6Hz,2H),7.78(d,J=5.0Hz,1H),7.96(d,J=8.6Hz,2H),8.41(d,J=5.0Hz,1H),8.42(s,1H),8.85(brs,3H),12.09-12.22(m,1H)。 1 H-NMR spectrum (DMSO-d 6 , δ ppm): 1.69 (s, 6H), 6.95 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H), 7.67-7.70 (m, 1H), 7.76 (d , J = 8.6Hz, 2H), 7.78 (d, J = 5.0Hz, 1H), 7.96 (d, J = 8.6Hz, 2H), 8.41 (d, J = 5.0Hz, 1H), 8.42 (s, 1H ), 8.85 (brs, 3H), 12.09-12.22 (m, 1H).
Z−1−[4−(アミノメチル)フェニル]−1−ヒドロキシメチル−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン 2塩酸塩(化合物3−8)
融点:189-192℃ (分解)
Rf値:0.08(クロロホルム:メタノール:28%アンモニア水=9:1:0.01(V/V/V))
マススペクトル(CI,m/z):280(M++1)。
Z-1- [4- (Aminomethyl) phenyl] -1-hydroxymethyl-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene dihydrochloride (Compound 3-8)
Melting point: 189-192 ℃ (decomposition)
Rf value: 0.08 (chloroform: methanol: 28% aqueous ammonia = 9: 1: 0.01 (V / V / V))
Mass spectrum (CI, m / z): 280 (M + +1).
1H−NMRスペクトル(DMSO-d6,δppm):4.05(d,J=5.7Hz,1H),4.09(d,J=5.7Hz,1H),4.55(s,2H),6.83-6.85(m,1H),7.30(s,1H),7.46(d,J=5.4Hz,1H),7.55(d,J=8.5Hz,2H),7.61-7.64(m,1H),7.82(d,J=8.5Hz,2H),8.36(d,J=5.4Hz,2H),8.41(brs,3H),12.20-12.40(m,1H)。 1 H-NMR spectrum (DMSO-d 6 , δ ppm): 4.05 (d, J = 5.7 Hz, 1H), 4.09 (d, J = 5.7 Hz, 1H), 4.55 (s, 2H), 6.83 to 6.85 (m , 1H), 7.30 (s, 1H), 7.46 (d, J = 5.4Hz, 1H), 7.55 (d, J = 8.5Hz, 2H), 7.61-7.64 (m, 1H), 7.82 (d, J = 8.5Hz, 2H), 8.36 (d, J = 5.4Hz, 2H), 8.41 (brs, 3H), 12.20-12.40 (m, 1H).
Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−メトキシカルボニル−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン 2塩酸塩(化合物3−9)
融点:192-194℃ (分解)
Rf値:0.28(クロロホルム:メタノール:28%アンモニア水=9:1:0.01(V/V/V))
マススペクトル(CI,m/z):336(M++1)。
Z-1- [4- (1-Amino-1-methylethyl) phenyl] -1-methoxycarbonyl-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene dihydrochloride (compound 3-9)
Melting point: 192-194 ℃ (decomposition)
Rf value: 0.28 (chloroform: methanol: 28% aqueous ammonia = 9: 1: 0.01 (V / V / V))
Mass spectrum (CI, m / z): 336 (M + +1).
1H−NMRスペクトル(DMSO-d6,δppm):1.66(s,6H),3.73(s,3H),6.71(dd,J1=3.4Hz,J2=1.7Hz,1H),6.97(d,J=5.2Hz,1H),7.55-7.58(m,1H),7.61(d,J=8.9Hz,2H),7.62(s,1H),7.66(d,J=8.9Hz,2H),8.23(d,J=5.2Hz,1H),8.42-8.64(m,3H),11.70-11.90(m,1H)。 1 H-NMR spectrum (DMSO-d 6 , δ ppm): 1.66 (s, 6H), 3.73 (s, 3H), 6.71 (dd, J1 = 3.4 Hz, J2 = 1.7 Hz, 1H), 6.97 (d, J = 5.2Hz, 1H), 7.55-7.58 (m, 1H), 7.61 (d, J = 8.9Hz, 2H), 7.62 (s, 1H), 7.66 (d, J = 8.9Hz, 2H), 8.23 (d , J = 5.2 Hz, 1H), 8.42-8.64 (m, 3H), 11.70-11.90 (m, 1H).
E−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−エチル−2−(4−ピリジル)エチレン 2トリフルオロ酢酸塩(化合物3−10)
Rf値:0.31(クロロホルム:メタノール:28%アンモニア水=9:1:0.01(V/V/V))
マススペクトル(CI,m/z):267(M++1)。
E-1- [4- (1-Amino-1-methylethyl) phenyl] -1-ethyl-2- (4-pyridyl) ethylene 2trifluoroacetate (Compound 3-10)
Rf value: 0.31 (chloroform: methanol: 28% aqueous ammonia = 9: 1: 0.01 (V / V / V))
Mass spectrum (CI, m / z): 267 (M + +1).
1H−NMRスペクトル(CD3OD,δppm):1.10(t,J=7.3Hz,3H),1.78(s,6H),2.89(q,J=7.3Hz,2H),6.87(s,1H),7.58-7.61(m,2H),7.67-7.70(m,2H),7.81-7.88(m,2H),8.60-8.80(m,2H)。 1 H-NMR spectrum (CD 3 OD, δ ppm): 1.10 (t, J = 7.3 Hz, 3H), 1.78 (s, 6H), 2.89 (q, J = 7.3 Hz, 2H), 6.87 (s, 1H) 7.58-7.61 (m, 2H), 7.67-7.70 (m, 2H), 7.81-7.88 (m, 2H), 8.60-8.80 (m, 2H).
Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−エチル−2−(4−ピリジル)エチレン 2トリフルオロ酢酸塩(化合物3−11)
マススペクトル(CI,m/z):267(M++1)。
Z-1- [4- (1-Amino-1-methylethyl) phenyl] -1-ethyl-2- (4-pyridyl) ethylene 2trifluoroacetate (Compound 3-11)
Mass spectrum (CI, m / z): 267 (M + +1).
1H−NMRスペクトル(CD3OD,δppm):1.10(t,J=7.3Hz,3H),1.78(s,6H),2.66(q,J=7.3Hz,2H),6.73(s,1H),7.31(d,J=8.3Hz,2H),7.34-7.44(m,2H),7.57(d,J=8.3Hz,2H),8.20-8.55(m,2H)。 1 H-NMR spectrum (CD 3 OD, δ ppm): 1.10 (t, J = 7.3 Hz, 3H), 1.78 (s, 6H), 2.66 (q, J = 7.3 Hz, 2H), 6.73 (s, 1H) 7.31 (d, J = 8.3 Hz, 2H), 7.34-7.44 (m, 2H), 7.57 (d, J = 8.3 Hz, 2H), 8.20-8.55 (m, 2H).
(実施例4)
E−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−2−(2−tert−ブトキシカルボニルアミノピリジン−4−イル)−1−メチルエチレン(化合物4)
E-1- [4- (1-tert-Butoxycarbonylamino-1-methylethyl) phenyl] -2- (2-tert-butoxycarbonylaminopyridin-4-yl) -1-methylethylene (Compound 4)
反応終了後、反応溶液に水15mlを添加し、塩化メチレン15mlで抽出した。有機層を水、次いで飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;n−ヘキサン:酢酸エチル=2:1(V/V))に付し、目的物を含む画分を減圧濃縮した。得られた残渣を高速液体クロマトグラフィー(溶出溶媒;アセトニトリル:水=4:1(V/V))に付し、標記の化合物11mgを白色粉末として得た。(収率14%)
Rf値:0.54 (n−ヘキサン:酢酸エチル=1:1(V/V))
マススペクトル(CI,m/z):468(M++1)。
After completion of the reaction, 15 ml of water was added to the reaction solution and extracted with 15 ml of methylene chloride. The organic layer was washed successively with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 2: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained residue was subjected to high performance liquid chromatography (eluent: acetonitrile: water = 4: 1 (V / V)) to give 11 mg of the title compound as a white powder. (14% yield)
Rf value: 0.54 (n-hexane: ethyl acetate = 1: 1 (V / V))
Mass spectrum (CI, m / z): 468 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.39(brs,9H),1.64(s,6H),2.31(d,J=1.2Hz,3H),4.94(brs,1H),6.71-6.74(m,1H),6.93(dd,J1=5.4Hz,J2=1.1Hz,1H),7.24(brs,1H),7.37-7.41(m,2H),7.44-7.48(m,2H),7.91-7.92(m,1H),8.19(d,J=5.4Hz,2H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.39 (brs, 9H), 1.64 (s, 6H), 2.31 (d, J = 1.2 Hz, 3H), 4.94 (brs, 1H), 6.71-6.74 (m , 1H), 6.93 (dd, J1 = 5.4Hz, J2 = 1.1Hz, 1H), 7.24 (brs, 1H), 7.37-7.41 (m, 2H), 7.44-7.48 (m, 2H), 7.91-7.92 ( m, 1H), 8.19 (d, J = 5.4 Hz, 2H).
(実施例5)
E−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−2−メチル−2−(4−ピリジル)エチレン(化合物5)の合成
Synthesis of E-1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -2-methyl-2- (4-pyridyl) ethylene (Compound 5)
反応終了後、反応溶液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;n−ヘキサン:酢酸エチル=2:1(V/V))に付し、目的物を含む画分を減圧濃縮した。得られた粗精製物を高速液体クロマトグラフィー(溶出溶媒;アセトニトリル:水=7:3(V/V))に付し、標記の化合物220mgを白色粉末として得た。(収率21%)
Rf値:0.49 (n−ヘキサン:酢酸エチル=1:1(V/V))。
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 2: 1 (V / V)) to obtain a fraction containing the desired product. Was concentrated under reduced pressure. The resulting crude product was subjected to high performance liquid chromatography (elution solvent; acetonitrile: water = 7: 3 (V / V)) to obtain 220 mg of the title compound as a white powder. (Yield 21%)
Rf value: 0.49 (n-hexane: ethyl acetate = 1: 1 (V / V)).
マススペクトル(CI,m/z):353(M++1)。 Mass spectrum (CI, m / z): 353 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.39(brs,9H),1.65(s,6H),2.28(d,J=1.5Hz,3H),4.94(brs,1H),6.98-7.01(m,1H),7.33(d,J=8.3Hz,2H),7.38-7.44(m,4H),8.58(dd,J1=4.6Hz,J2=1.7Hz,2H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.39 (brs, 9H), 1.65 (s, 6H), 2.28 (d, J = 1.5 Hz, 3H), 4.94 (brs, 1H), 6.98-7.01 (m , 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.38-7.44 (m, 4H), 8.58 (dd, J1 = 4.6 Hz, J2 = 1.7 Hz, 2H).
(実施例6)
Z−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−ヒドロキシメチル−2−{1−[2−(トリメチルシリル)エトキシメチル]−1H−ピロロ[2,3−b]ピリジン−4−イル}エチレン(化合物6−1)の合成
Z-1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -1-hydroxymethyl-2- {1- [2- (trimethylsilyl) ethoxymethyl] -1H-pyrrolo [2, Synthesis of 3-b] pyridin-4-yl} ethylene (Compound 6-1)
反応終了後、反応溶液に水100mlに添加し、酢酸エチル100mlで抽出した。有機層を水、次いで飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;n−ヘキサン:酢酸エチル=2:1(V/V))に付し、標記の化合物5.8gを微褐色泡状物として得た。(収率36%)
Rf値:0.22(n−ヘキサン:酢酸エチル=2:1(V/V))
マススペクトル(CI,m/z):538(M++1)。
After completion of the reaction, the reaction solution was added to 100 ml of water and extracted with 100 ml of ethyl acetate. The organic layer was washed successively with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 2: 1 (V / V)) to obtain 5.8 g of the title compound as a fine brown foam. (Yield 36%)
Rf value: 0.22 (n-hexane: ethyl acetate = 2: 1 (V / V))
Mass spectrum (CI, m / z): 538 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):-0.06(s,9H),0.89-0.95(m,2H),1.40(brs,9H),1.66(s,6H),3.53-3.59(m,2H),4.72(s,2H),4.98(brs,1H),5.70(s,2H),6.59(d,J=3.7Hz,1H),7.15-7.19(m,2H),7.37(d,J=3.7Hz,1H),7.44-7.49(m,2H),7.59-7.64(m,2H),8.34(d,J=4.9Hz,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): -0.06 (s, 9H), 0.89-0.95 (m, 2H), 1.40 (brs, 9H), 1.66 (s, 6H), 3.53-3.59 (m, 2H ), 4.72 (s, 2H), 4.98 (brs, 1H), 5.70 (s, 2H), 6.59 (d, J = 3.7Hz, 1H), 7.15-7.19 (m, 2H), 7.37 (d, J = 3.7Hz, 1H), 7.44-7.49 (m, 2H), 7.59-7.64 (m, 2H), 8.34 (d, J = 4.9Hz, 1H).
以下、化合物6−1の製造方法に準じて、化合物6−2〜3を製造した。 Hereinafter, compounds 6-2 to 3 were produced according to the production method of compound 6-1.
Z−1−[4−(tert−ブトキシカルボニルアミノメチル)フェニル]−1−ヒドロキシメチル−2−(1−アセチル−1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン(化合物6−2)
Rf値:0.74(n−ヘキサン:酢酸エチル=1:1(V/V))。
Z-1- [4- (tert-Butoxycarbonylaminomethyl) phenyl] -1-hydroxymethyl-2- (1-acetyl-1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene (Compound 6) -2)
Rf value: 0.74 (n-hexane: ethyl acetate = 1: 1 (V / V)).
マススペクトル(CI,m/z):422(M++1)。 Mass spectrum (CI, m / z): 422 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.48(s,9H),3.09(s,3H),4.35-4.38(m,2H),4.68(s,2H),4.70-4.97(m,1H),6.69(d,J=4.2Hz,1H),7.07(s,1H),7.28(d,J=4.9Hz,1H),7.37(d,J=8.5Hz,2H),7.61(d,J=8.5Hz,2H),8.01(d,J=4.2Hz,1H),8.38(d,J=4.9Hz,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.48 (s, 9H), 3.09 (s, 3H), 4.35-4.38 (m, 2H), 4.68 (s, 2H), 4.70-4.97 (m, 1H) , 6.69 (d, J = 4.2Hz, 1H), 7.07 (s, 1H), 7.28 (d, J = 4.9Hz, 1H), 7.37 (d, J = 8.5Hz, 2H), 7.61 (d, J = 8.5Hz, 2H), 8.01 (d, J = 4.2Hz, 1H), 8.38 (d, J = 4.9Hz, 1H).
Z−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−メトキシカルボニル−2−(1−アセチル−1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン(化合物6−3)
マススペクトル(CI,m/z):436(M++1)。
Z-1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -1-methoxycarbonyl-2- (1-acetyl-1H-pyrrolo [2,3-b] pyridine-4- Yl) ethylene (compound 6-3)
Mass spectrum (CI, m / z): 436 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.40(brs,9H),1.65(s,6H),3.72(s,3H),4.97(brs,1H),6.60(dd,J1=3.7Hz,J2=1.7Hz,1H),7.07(d,J=5.1Hz,1H),7.33-7.35(m,2H),7.44(d,J=8.8Hz,2H),7.49(d,J=8.8Hz,2H),8.28(d,J=5.1Hz,1H),8.74-8.84(m,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.40 (brs, 9H), 1.65 (s, 6H), 3.72 (s, 3H), 4.97 (brs, 1H), 6.60 (dd, J1 = 3.7 Hz, J2 = 1.7Hz, 1H), 7.07 (d, J = 5.1Hz, 1H), 7.33-7.35 (m, 2H), 7.44 (d, J = 8.8Hz, 2H), 7.49 (d, J = 8.8Hz, 2H ), 8.28 (d, J = 5.1 Hz, 1H), 8.74-8.84 (m, 1H).
(実施例7)
Z−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−ヒドロキシメチル−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン(化合物7)の合成
Z-1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -1-hydroxymethyl-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene ( Synthesis of compound 7)
反応終了後、反応溶液に水100mlに添加し、酢酸エチル100mlで抽出した。有機層を水、次いで飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;酢酸エチル)に付し、目的物を含む画分を減圧濃縮し、標記の化合物0.65gを白色粉末として得た。(収率80%)
Rf値:0.17(n−ヘキサン:酢酸エチル=1:1(V/V))
マススペクトル(CI,m/z):408(M++1)。
After completion of the reaction, the reaction solution was added to 100 ml of water and extracted with 100 ml of ethyl acetate. The organic layer was washed successively with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound (0.65 g) as a white powder. (Yield 80%)
Rf value: 0.17 (n-hexane: ethyl acetate = 1: 1 (V / V))
Mass spectrum (CI, m / z): 408 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.40(brs,9H),1.67(s,6H),4.73(s,2H),5.01(brs,1H),6.58(dd,J1=3.4Hz,J2=2.0Hz,1H),7.16-7.18(m,2H),7.34(dd,J1=3.4Hz,J2=2.2Hz,1H),7.44-7.50(m,2H),7.59-7.65(m,2H),8.32(d,J=5.1Hz,1H),9.56-9.34(m,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.40 (brs, 9H), 1.67 (s, 6H), 4.73 (s, 2H), 5.01 (brs, 1H), 6.58 (dd, J1 = 3.4Hz, J2 = 2.0Hz, 1H), 7.16-7.18 (m, 2H), 7.34 (dd, J1 = 3.4Hz, J2 = 2.2Hz, 1H), 7.44-7.50 (m, 2H), 7.59-7.65 (m, 2H) 8.32 (d, J = 5.1 Hz, 1H), 9.56-9.34 (m, 1H).
(実施例8)
Z−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−ホルミル−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン(化合物8)の合成
Z-1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -1-formyl-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene (compound 8) Synthesis
反応終了後、セライトを用いて反応溶液の二酸化マンガンを濾過し、濾液を減圧濃縮することにより、標記の化合物1.36gを黄色粉末として得た。(収率78%)
Rf値:0.40(n−ヘキサン:酢酸エチル=1:1(V/V))。
After completion of the reaction, manganese dioxide of the reaction solution was filtered using celite, and the filtrate was concentrated under reduced pressure to obtain 1.36 g of the title compound as a yellow powder. (Yield 78%)
Rf value: 0.40 (n-hexane: ethyl acetate = 1: 1 (V / V)).
マススペクトル(CI,m/z):406(M++1)。 Mass spectrum (CI, m / z): 406 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.40(brs,9H),1.66(s,6H),4.99(brs,1H),6.57(dd,J1=3.4Hz,J2=1.9Hz,1H),7.08(d,J=4.9Hz,1H),7.42(dd,J1=3.4Hz,J2=2.4Hz,1H),7.48(s,4H),8.07(s,1H),8.38(d,J=4.9Hz,1H),9.25-9.27(m,1H),10.13(s,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.40 (brs, 9H), 1.66 (s, 6H), 4.99 (brs, 1H), 6.57 (dd, J1 = 3.4Hz, J2 = 1.9Hz, 1H), 7.08 (d, J = 4.9Hz, 1H), 7.42 (dd, J1 = 3.4Hz, J2 = 2.4Hz, 1H), 7.48 (s, 4H), 8.07 (s, 1H), 8.38 (d, J = 4.9 Hz, 1H), 9.25-9.27 (m, 1H), 10.13 (s, 1H).
(実施例9)
Z−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−(ヒドロキシイミノメチル)−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン(化合物9)の合成
Z-1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -1- (hydroxyiminomethyl) -2- (1H-pyrrolo [2,3-b] pyridin-4-yl ) Synthesis of ethylene (compound 9)
反応終了後、反応溶液を減圧濃縮して得られた残渣に水100mlを添加し、酢酸エチル150mlで抽出した。有機層を水、次いで飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;n−ヘキサン:酢酸エチル=2/1(V/V))に付し、目的物を含む画分を減圧濃縮し、標記の化合物0.29gを淡黄色粉末として得た。(収率94%)
Rf値:0.40(n−ヘキサン:酢酸エチル=1:1(V/V))。
After completion of the reaction, 100 ml of water was added to the residue obtained by concentrating the reaction solution under reduced pressure, followed by extraction with 150 ml of ethyl acetate. The organic layer was washed successively with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 2/1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 0.29 g of the title compound. Was obtained as a pale yellow powder. (Yield 94%)
Rf value: 0.40 (n-hexane: ethyl acetate = 1: 1 (V / V)).
マススペクトル(CI,m/z):421(M++1)。 Mass spectrum (CI, m / z): 421 (M + +1).
1H−NMRスペクトル(DMSO-d6,δppm):1.36(brs,9H),1.52(s,6H),6.52-6.54(m,1H),6.97(d,J=5.1Hz,1H),7.13-7.24(m,2H),7.34(d,J=8.5Hz,2H),7.46(d,J=8.5Hz,2H),7.49-7.52(m,1H),8.17(s,1H),8.25(d,J=5.1Hz,1H),11.37(s,1H),11.72-11.79(m,1H)。 1 H-NMR spectrum (DMSO-d 6 , δ ppm): 1.36 (brs, 9H), 1.52 (s, 6H), 6.52-6.54 (m, 1H), 6.97 (d, J = 5.1 Hz, 1H), 7.13 -7.24 (m, 2H), 7.34 (d, J = 8.5Hz, 2H), 7.46 (d, J = 8.5Hz, 2H), 7.49-7.52 (m, 1H), 8.17 (s, 1H), 8.25 ( d, J = 5.1 Hz, 1H), 11.37 (s, 1H), 11.72-11.79 (m, 1H).
(実施例10)
Z−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−シアノ−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン(化合物10)の合成
Z-1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -1-cyano-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene (compound 10) Synthesis
反応終了後、反応溶液を減圧濃縮して得られた残渣に水50mlを添加し、酢酸エチル50mlで抽出した。有機層を水、次いで飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;n−ヘキサン:酢酸エチル=2/1(V/V))に付し、目的物を含む画分を減圧濃縮し、標記の化合物0.22gを黄色粉末として得た。(収率70%)
Rf値:0.43(n−ヘキサン:酢酸エチル=1:1(V/V))。
After completion of the reaction, 50 ml of water was added to the residue obtained by concentrating the reaction solution under reduced pressure, followed by extraction with 50 ml of ethyl acetate. The organic layer was washed successively with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: n-hexane: ethyl acetate = 2/1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 0.22 g of the title compound. Was obtained as a yellow powder. (Yield 70%)
Rf value: 0.43 (n-hexane: ethyl acetate = 1: 1 (V / V)).
マススペクトル(CI,m/z):403(M++1)。 Mass spectrum (CI, m / z): 403 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.40(brs,9H),1.66(s,6H),5.01(brs,1H),6.66(dd,J1=3.4Hz,J2=1.8Hz,17.43(dd,J1=3.4Hz,J2=2.2Hz,1H),7.49-7.55(m,2H),7.69-7.73(m,2H),7.89(d,J=5.1Hz,1H),7.91(s,1H),8.44(d,J=5.1Hz,1H),9.20-9.30(m,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.40 (brs, 9H), 1.66 (s, 6H), 5.01 (brs, 1H), 6.66 (dd, J1 = 3.4 Hz, J2 = 1.8 Hz, 17.43 (dd , J1 = 3.4Hz, J2 = 2.2Hz, 1H), 7.49-7.55 (m, 2H), 7.69-7.73 (m, 2H), 7.89 (d, J = 5.1Hz, 1H), 7.91 (s, 1H) 8.44 (d, J = 5.1 Hz, 1H), 9.20-9.30 (m, 1H).
(実施例11)
Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−カルボキシ−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン 2トリフルオロ酢酸塩(化合物11)の合成
Z-1- [4- (1-amino-1-methylethyl) phenyl] -1-carboxy-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene 2trifluoroacetate ( Synthesis of compound 11)
反応終了後、反応溶液を減圧濃縮し、得られた残渣を高速液体クロマトグラフィー(溶出溶媒;0.03容量%トリフルオロ酢酸水溶液:アセトニトリル=85:15(V/V))に付し、目的物を含む画分を減圧濃縮し、標記の化合物16mgを白色粉末として得た。(収率14%)
融点:231-233℃ (分解)
マススペクトル(FAB,m/z):322(M++1)。
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to high performance liquid chromatography (elution solvent; 0.03% by volume trifluoroacetic acid aqueous solution: acetonitrile = 85: 15 (V / V)). The fraction containing the product was concentrated under reduced pressure to obtain 16 mg of the title compound as a white powder. (14% yield)
Melting point: 231-233 ° C (decomposition)
Mass spectrum (FAB, m / z): 322 (M + +1).
1H−NMRスペクトル(DMSO-d6,δppm):1.61(s,6H),6.40(d,J=5.3Hz,1H),6.46-6.48(m,1H),7.26(d,J=8.2Hz,2H),7.46(d,J=8.2Hz,2H),7.49-7.52(m,1H),7.90(d,J=5.3Hz,1H),8.06(s,1H),11.72-11.75(m,1H)
(実施例12)
Z−1−[4−(tert−ブトキシカルボニルアミノメチル)フェニル]−1−ヒドロキシメチル−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン(化合物12)の合成
(Example 12)
Synthesis of Z-1- [4- (tert-butoxycarbonylaminomethyl) phenyl] -1-hydroxymethyl-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene (Compound 12)
反応終了後、反応溶液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒;酢酸エチル)に付し、目的物を含む画分を減圧濃縮し、標記の化合物0.24gを微黄色粉末として得た。(収率91%)
Rf値:0.26 (酢酸エチル)。
After completion of the reaction, the residue obtained by concentrating the reaction solution under reduced pressure was subjected to silica gel column chromatography (elution solvent; ethyl acetate), and the fraction containing the desired product was concentrated under reduced pressure to slightly add 0.24 g of the title compound. Obtained as a yellow powder. (Yield 91%)
Rf value: 0.26 (ethyl acetate).
マススペクトル(CI,m/z):380(M++1)。 Mass spectrum (CI, m / z): 380 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.48(s,9H),4.35-4.38(m,2H),4.73(s,2H),4.81-4.97(m,1H),6.58(dd,J1=3.7Hz,J2=1.7Hz,1H),7.14-7.17(m,2H),7.32-7.40(m,3H),7.63(d,J=8.5Hz,2H),8.32(d,J=5.1Hz,1H),9.16(brs,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.48 (s, 9H), 4.35-4.38 (m, 2H), 4.73 (s, 2H), 4.81-4.97 (m, 1H), 6.58 (dd, J1 = 3.7Hz, J2 = 1.7Hz, 1H), 7.14-7.17 (m, 2H), 7.32-7.40 (m, 3H), 7.63 (d, J = 8.5Hz, 2H), 8.32 (d, J = 5.1Hz, 1H), 9.16 (brs, 1H).
(実施例13)
Z−1−[4−(1−tert−ブトキシカルボニルアミノ−1−メチルエチル)フェニル]−1−メトキシカルボニル−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン(化合物13)の合成
Z-1- [4- (1-tert-butoxycarbonylamino-1-methylethyl) phenyl] -1-methoxycarbonyl-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene ( Synthesis of compound 13)
反応終了後、反応溶液を減圧濃縮し、標記の化合物12mgを淡黄色粉末として得た。(収率 定量的)
マススペクトル(CI,m/z):436(M++1)。
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 12 mg of the title compound as a pale yellow powder. (Yield quantitative)
Mass spectrum (CI, m / z): 436 (M + +1).
1H−NMRスペクトル(CDCl3,δppm):1.40(brs,9H),1.65(s,6H),3.72(s,3H),4.97(brs,1H),6.60(dd,J1=3.7Hz,J2=1.7Hz,1H),7.07(d,J=5.1Hz,1H),7.33-7.35(m,2H),7.44(d,J=8.8Hz,2H),7.49(d,J=8.8Hz,2H),8.28(d,J=5.1Hz,1H),8.74-8.84(m,1H)。 1 H-NMR spectrum (CDCl 3 , δ ppm): 1.40 (brs, 9H), 1.65 (s, 6H), 3.72 (s, 3H), 4.97 (brs, 1H), 6.60 (dd, J1 = 3.7 Hz, J2 = 1.7Hz, 1H), 7.07 (d, J = 5.1Hz, 1H), 7.33-7.35 (m, 2H), 7.44 (d, J = 8.8Hz, 2H), 7.49 (d, J = 8.8Hz, 2H ), 8.28 (d, J = 5.1 Hz, 1H), 8.74-8.84 (m, 1H).
[製剤例]
本発明化合物の一般的な製剤例を以下に示す。
[Formulation example]
Examples of general preparations of the compound of the present invention are shown below.
1)錠剤
処方1 100mg中
本発明化合物 1mg
乳糖 66.4mg
トウモロコシデンプン 20mg
カルボキシメチルセルロースカルシウム 6mg
ヒドロキシプロピルセルロース 4mg
ステアリン酸マグネシウム 0.6mg
上記処方の錠剤に、コーティング剤(例えば、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコーン樹脂等通常のコーティング剤)2mgを用いてコーティングを施し、目的とするコーティング錠を得る(以下の処方の錠剤も同じ)。また、本発明化合物ならびに添加物の種類および量を適宜変更することにより、所望の錠剤を得ることができる。
1)
Lactose 66.4mg
Corn starch 20mg
Carboxymethylcellulose calcium 6mg
Hydroxypropylcellulose 4mg
Magnesium stearate 0.6mg
The tablet with the above formulation is coated with 2 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the desired coated tablet (the same applies to the tablets with the following formulation). . Moreover, a desired tablet can be obtained by changing suitably the kind and quantity of this invention compound and an additive.
2)カプセル剤
処方2 150mg中
本発明化合物 5mg
乳糖 145mg
本発明化合物と乳糖の混合比を適宜変更することにより、所望のカプセル剤を得ることができる。
2)
Lactose 145mg
A desired capsule can be obtained by appropriately changing the mixing ratio of the compound of the present invention and lactose.
3)点眼剤
処方3 100ml中
本発明化合物 100mg
塩化ナトリウム 900mg
ポリソルベート80 200mg
水酸化ナトリウム 適量
塩酸 適量
滅菌精製水 適量
本発明化合物ならびに添加物の種類および量を適宜変更することにより、所望の点眼剤を得ることができる。
3) Eye drops
Sodium chloride 900mg
Polysorbate 80 200mg
Sodium hydroxide Appropriate amount Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount By appropriately changing the type and amount of the compound of the present invention and additives, a desired eye drop can be obtained.
[薬理試験]
A.Rhoキナーゼ阻害活性評価試験
本発明化合物のRhoキナーゼ阻害剤としての有用性を調べるため、ジャーナル・オブ・バイオロジカル・ケミストリー,274巻,32418頁,1999年発行[J.Biol.Chem.,274,32418(1999)]に記載の貝淵等の方法および市販の活性型ROCKII[アップステイツ バイオテクノロジー,カタログ 番号14−338,(5Unit/50μl)[upstate biotechnology,Catalog No.14-338,(5Unit/50μl)]]付属の説明書記載の方法に準じて、本発明化合物のRhoキナーゼ阻害活性を評価検討した。被験化合物としては、化合物3−1、化合物3−2、化合物3−3、化合物3−4、化合物3−5、化合物3−6、化合物3−7、化合物3−8および化合物3−9を使用した。
[Pharmacological test]
A. Rho Kinase Inhibitory Activity Evaluation Test To examine the usefulness of the compounds of the present invention as Rho kinase inhibitors, Journal of Biological Chemistry, 274, 32418, published in 1999 [J. Biol. Chem. , 274, 32418 (1999)] and commercially available activated ROCKII [Upstate Biotechnology, Catalog No. 14-338, (5Unit / 50 μl) [upstate biotechnology, Catalog No. 14-338, (5 Unit / 50 μl)]] The Rho kinase inhibitory activity of the compounds of the present invention was evaluated according to the method described in the attached instruction manual. As test compounds, compound 3-1, compound 3-2, compound 3-3, compound 3-4, compound 3-5, compound 3-6, compound 3-7, compound 3-8 and compound 3-9 were used. used.
(試薬の調製)
1)緩衝溶液の調製
50mM トリスヒドロキシアミノメタン(Tris)(pH7.5)、2mM エチレングリコールビス(β−アミノエチルエーテル)−N,N,N’,N’−四酢酸(EGTA)、1mM エチレンジアミン四酢酸(EDTA)、5mM 塩化マグネシウム(MgCl2)、5mM β−グリセロールホスフェイトおよび2mM ジチオスレイトール(DTT)となるよう混和して緩衝溶液とした。
(Preparation of reagents)
1) Preparation of buffer solution 50 mM Trishydroxyaminomethane (Tris) (pH 7.5), 2 mM ethylene glycol bis (β-aminoethyl ether) -N, N, N ′, N′-tetraacetic acid (EGTA), 1 mM ethylenediamine A buffer solution was prepared by mixing tetraacetic acid (EDTA), 5 mM magnesium chloride (MgCl 2 ), 5 mM β-glycerol phosphate and 2 mM dithiothreitol (DTT).
2)300μM ATP[γ−32P]ATP溶液の調製
緩衝溶液で10mM ATP溶液と市販の[γ−32P]ATP溶液[NEN社 Code No.NEG-002A]を希釈して、300μM ATP[γ−32P]ATP溶液とした。
2) Preparation of 300 μM ATP [γ- 32 P] ATP solution A 10 mM ATP solution and a commercially available [γ- 32 P] ATP solution [NEN Code No. NEG-002A] were diluted with a buffer solution, and 300 μM ATP [γ − 32 P] ATP solution.
3)活性型ROCKII溶液の調製
市販の活性型ROCKII[upstate biotechnology,Catalog No.14-338,(5Unit/50μl)]を緩衝溶液で1/100希釈して、活性型ROCKII溶液とした。
3) Preparation of active ROCKII solution Commercially available active ROCKII [upstate biotechnology, Catalog No. 14-338, (5 Unit / 50 μl)] was diluted 1/100 with a buffer solution to obtain an active ROCKII solution.
4)1mM 基質溶液の調製
S6キナーゼ基質ペプチド(S6 Kinase Substrare Peptide)[アップステイツ バイオテクノロジー,カタログ 番号12−124,(2mg)[upstate biotechnology,Catalog No.12-124,(2mg)]]を蒸留水に溶解して1mM 基質溶液の調製とした。
4) Preparation of 1 mM substrate solution S6 Kinase Substrare Peptide [Upstate Biotechnology, Catalog No. 12-124, (2 mg) [upstate biotechnology, Catalog No.12-124, (2 mg)]] A 1 mM substrate solution was prepared by dissolving in water.
5)被験化合物溶液の調製
被験化合物は、10%ジメチルスルホキシド(DMSO)溶液に調製し使用した。
5) Preparation of test compound solution A test compound was prepared and used in a 10% dimethyl sulfoxide (DMSO) solution.
(評価方法)
1)マイクロチューブに被験化合物溶液を入れる。
(Evaluation methods)
1) Put the test compound solution in the microtube.
2)マイクロチューブに300μM ATP[γ−32P]ATP溶液を加えた後、4℃に冷却する。 2) Add 300 μM ATP [γ- 32 P] ATP solution to the microtube and cool to 4 ° C.
3)次いで、各マイクロチューブに活性型ROCKII溶液、1mM基質溶液および緩衝溶液の順で加えて混和し、再度4℃に冷却する。 3) Next, the active ROCKII solution, 1 mM substrate solution and buffer solution are added to each microtube in this order and mixed, and then cooled to 4 ° C. again.
4)マイクロチューブをインキュベーター(30℃)に入れて15分間反応させる。 4) Place the microtube in an incubator (30 ° C.) and let it react for 15 minutes.
5)4℃に冷却した後、各マイクロチューブに250mMリン酸溶液(5μl)を加えて反応を停止する。 5) After cooling to 4 ° C., 250 mM phosphoric acid solution (5 μl) is added to each microtube to stop the reaction.
6)各マイクロチューブから反応溶液30μlを採取した後、濾紙(ワットマンP81)にスポットして、反応生成物(リン酸化された基質)を濾紙に吸着させる。 6) After collecting 30 μl of the reaction solution from each microtube, it is spotted on a filter paper (Whatman P81) to adsorb the reaction product (phosphorylated substrate) on the filter paper.
7)その濾紙を75mMリン酸溶液の入ったビーカーに移し、5分間振盪することで未反応の[γ−32P]ATPを洗い流す。尚、この洗浄操作は4回行う。 7) Transfer the filter paper to a beaker containing 75 mM phosphoric acid solution, and shake for 5 minutes to wash away unreacted [γ- 32 P] ATP. This washing operation is performed four times.
8)次いで、濾紙をエタノールに浸けて脱水処理し、液体シンチレーションカウンターによりろ紙に吸着した反応生成物のエネルギー量(放射活性)を測定する。 8) Next, the filter paper is immersed in ethanol for dehydration treatment, and the amount of energy (radioactivity) of the reaction product adsorbed on the filter paper is measured by a liquid scintillation counter.
(IC50の算出)
IC50値は、XL−fit(IDBS)にて算出した。
(Calculation of IC 50 )
IC 50 value was calculated by XL-fit (IDBS).
(Ki値の算出)
以下の計算式に従って、Ki値を算出する。Sは反応液中に含まれるATP濃度を、Kmはミカエリス−メンテン(Michaelis−Menten)定数を表す。
(Calculation of Ki value)
The Ki value is calculated according to the following calculation formula. S represents the concentration of ATP contained in the reaction solution, and Km represents the Michaelis-Menten constant.
Ki=IC50/(1+S/Km)
(結果および考察)
被験化合物として、化合物3−1、化合物3−2、化合物3−3、化合物3−4、化合物3−5、化合物3−6、化合物3−7、化合物3−8および化合物3−9を使用した時の結果を表1に示す。
(Results and Discussion)
As a test compound, compound 3-1, compound 3-2, compound 3-3, compound 3-4, compound 3-5, compound 3-6, compound 3-7, compound 3-8 and compound 3-9 are used. The results are shown in Table 1.
B.眼圧下降作用測定試験
本発明化合物の緑内症治療剤としての有用性を調べるため、カニクイザル(性別:雄性、一群6匹)に本発明化合物を投与した時の眼圧下降効果を評価検討した。被験化合物としては化合物3−5(以下、被験化合物1とする)および化合物3−8(以下、被験化合物2とする)を使用した。
B. Intraocular pressure lowering action measurement test In order to examine the usefulness of the compound of the present invention as a therapeutic agent for glaucoma, the effect of reducing the intraocular pressure when the compound of the present invention was administered to cynomolgus monkeys (sex: male, 6 per group) was evaluated. . As test compounds, compound 3-5 (hereinafter referred to as test compound 1) and compound 3-8 (hereinafter referred to as test compound 2) were used.
(被験化合物溶液の調製)
被験化合物1または2を5% Tween80(商品名)含有生理食塩液に溶解後、水酸化ナトリウムを加えてpHを調整し(pH4.0〜5.0)、濃度1%の被験化合物1または2溶液を調製した。
(Preparation of test compound solution)
(眼圧下降評価試験方法)
1)0.4%塩酸オキシブプロカイン点眼液をカニクイザルの両眼に一滴点眼し局所麻酔をした。
(Intraocular pressure drop evaluation test method)
1) One drop of 0.4% oxybuprocaine hydrochloride ophthalmic solution was applied to both eyes of cynomolgus monkeys for local anesthesia.
2)被験化合物溶液投与直前に眼圧を測定し初期眼圧とした。 2) The intraocular pressure was measured immediately before administration of the test compound solution to obtain the initial intraocular pressure.
3)被験化合物溶液を実験動物の片眼に点眼した(対側眼は無処置)。 3) The test compound solution was instilled into one eye of an experimental animal (the contralateral eye was untreated).
4)被験化合物溶液点眼の2時間、4時間および6時間後に0.4%塩酸オキシブプロカイン点眼液を一滴両眼に点眼し局所麻酔後、眼圧を測定した。また、各時間の眼圧は3回測定し、その平均値を算出した。
4) A drop of 0.4% oxybuprocaine hydrochloride ophthalmic solution was instilled into both
尚、コントロールには被験化合物溶液に代えて、基剤(5% Tween80含有生理食塩液)のみを投与して、他は上記の1〜4)と同じ方法で試験した。 In addition, instead of the test compound solution, only the base (5% Tween 80-containing physiological saline) was administered as a control, and the others were tested in the same manner as in the above 1 to 4).
(結果および考察)
被験化合物として、被験化合物1を使用した時の結果を図1に、被験化合物2を使用した時の結果を図2に示す。眼圧は初期眼圧からの変化値を示す。
(Results and Discussion)
FIG. 1 shows the results when
図1および図2から明らかなように、本発明化合物は、いずれも優れた眼圧下降作用を示した。上記のことから、本発明化合物は緑内障治療剤として特に有用であることが分かった。 As is clear from FIG. 1 and FIG. 2, the compounds of the present invention exhibited an excellent intraocular pressure lowering action. From the above, it was found that the compound of the present invention is particularly useful as a therapeutic agent for glaucoma.
Claims (10)
環Yはピリジン環または1H−ピロロ[2,3−b]ピリジン環を示し;
R1とR2は同一または異なって、水素原子またはアルキル基を示し;
R3とR4は同一または異なって、ハロゲン原子、水素原子、ヒドロキシ基、アルコキシ基、アリールオキシ基、アルキル基、アリール基、アミノ基、アルキルアミノ基またはアリールアミノ基を示し;
R3とR5は結合して、シクロアルケン環を形成してもよく;
R5およびR6は同一または異なって、ハロゲン原子、水素原子、ヒドロキシ基、アルコキシ基、アリールオキシ基、アルキル基、アリール基、カルボキシ基、そのエステル若しくはそのアミド、ニトロ基またはシアノ基を示し;
上記で規定した各アルキル基がヒドロキシ基、アルコキシ基、アリールオキシ基、ヒドロキシイミノ基およびアルコキシイミノ基からなる群より選択される1または複数の基で置換されていてもよい。] A compound represented by the following general formula [I] or a salt thereof.
Ring Y represents a pyridine ring or a 1H-pyrrolo [2,3-b] pyridine ring;
R 1 and R 2 are the same or different and each represents a hydrogen atom or an alkyl group;
R 3 and R 4 are the same or different and each represents a halogen atom, hydrogen atom, hydroxy group, alkoxy group, aryloxy group, alkyl group, aryl group, amino group, alkylamino group or arylamino group;
R 3 and R 5 may combine to form a cycloalkene ring;
R 5 and R 6 are the same or different and each represents a halogen atom, hydrogen atom, hydroxy group, alkoxy group, aryloxy group, alkyl group, aryl group, carboxy group, ester or amide thereof, nitro group or cyano group;
Each alkyl group defined above may be substituted with one or more groups selected from the group consisting of a hydroxy group, an alkoxy group, an aryloxy group, a hydroxyimino group and an alkoxyimino group. ]
環Xがベンゼン環、シクロアルカン環または1若しくは複数の窒素原子を環内に有する芳香族複素環を示し;
環Yがピリジン環または1H−ピロロ[2,3−b]ピリジン環を示し;
R1とR2は同一または異なって、水素原子またはアルキル基を示し;
R3がハロゲン原子、水素原子またはアルキル基を示し;
R3とR5が結合して、シクロアルケン環を形成してもよく;
R4が水素原子またはアミノ基を示し;
R5が水素原子またはアルキル基を示し;
R6が水素原子、アルキル基、カルボキシ基、そのエステルまたはシアノ基を示し;
R6で規定したアルキル基がヒドロキシ基、アルコキシ基、アリールオキシ基およびヒドロキシイミノ基からなる群より選択される1または複数の基で置換されていてもよい請求項1記載の化合物またはその塩。 In general formula [I],
Ring X represents a benzene ring, a cycloalkane ring or an aromatic heterocycle having one or more nitrogen atoms in the ring;
Ring Y represents a pyridine ring or a 1H-pyrrolo [2,3-b] pyridine ring;
R 1 and R 2 are the same or different and each represents a hydrogen atom or an alkyl group;
R 3 represents a halogen atom, a hydrogen atom or an alkyl group;
R 3 and R 5 may combine to form a cycloalkene ring;
R 4 represents a hydrogen atom or an amino group;
R 5 represents a hydrogen atom or an alkyl group;
R 6 represents a hydrogen atom, an alkyl group, a carboxy group, an ester thereof or a cyano group;
The compound or a salt thereof according to claim 1, wherein the alkyl group defined by R 6 may be substituted with one or more groups selected from the group consisting of a hydroxy group, an alkoxy group, an aryloxy group and a hydroxyimino group.
環Xがベンゼン環、シクロヘキサン環またはピリジン環を示し;
環Yがピリジン環または1H−ピロロ[2,3−b]ピリジン環を示し;
R1とR2は同一または異なって、水素原子またはアルキル基を示し;
R3が塩素原子、水素原子またはメチル基を示し;
R3とR5が結合してシクロヘキセン環を形成してもよく;
R4が水素原子またはアミノ基を示し;
R5が水素原子またはメチル基を示し;
R6が水素原子、メチル基、エチル基、ヒドロキシメチル基、1−ヒドロキシエチル基、メトキシメチル基、フェノキシメチル基、ヒドロキシイミノメチル基、カルボキシ基、メトキシカルボニル基またはシアノ基を示す請求項1記載の化合物またはその塩。 In general formula [I],
Ring X represents a benzene ring, a cyclohexane ring or a pyridine ring;
Ring Y represents a pyridine ring or a 1H-pyrrolo [2,3-b] pyridine ring;
R 1 and R 2 are the same or different and each represents a hydrogen atom or an alkyl group;
R 3 represents a chlorine atom, a hydrogen atom or a methyl group;
R 3 and R 5 may combine to form a cyclohexene ring;
R 4 represents a hydrogen atom or an amino group;
R 5 represents a hydrogen atom or a methyl group;
The R 6 represents a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a methoxymethyl group, a phenoxymethyl group, a hydroxyiminomethyl group, a carboxy group, a methoxycarbonyl group or a cyano group. Or a salt thereof.
環Xがベンゼン環を示し;
環Yがピリジン環または1H−ピロロ[2,3−b]ピリジン環を示し;
R1とR2が水素原子またはアルキル基を示し;
R3が水素原子を示し;
R4が水素原子またはアミノ基を示し;
R5が水素原子またはアルキル基を示し;
R6が水素原子、アルキル基、カルボキシ基、そのエステルまたはシアノ基を示し;
R6で規定したアルキル基が、ヒドロキシ基および/またはヒドロキシイミノ基で置換されていてもよい請求項1記載の化合物またはその塩。 In general formula [I],
Ring X represents a benzene ring;
Ring Y represents a pyridine ring or a 1H-pyrrolo [2,3-b] pyridine ring;
R 1 and R 2 represent a hydrogen atom or an alkyl group;
R 3 represents a hydrogen atom;
R 4 represents a hydrogen atom or an amino group;
R 5 represents a hydrogen atom or an alkyl group;
R 6 represents a hydrogen atom, an alkyl group, a carboxy group, an ester thereof or a cyano group;
The compound or a salt thereof according to claim 1, wherein the alkyl group defined by R 6 may be substituted with a hydroxy group and / or a hydroxyimino group.
環Xがベンゼン環を示し;
環Yがピリジン環または1H−ピロロ[2,3−b]ピリジン環を示し;
R1とR2が水素原子またはアルキル基を示し;
R3が水素原子を示し;
R4が水素原子またはアミノ基を示し;
R5が水素原子またはメチル基を示し;
R6が水素原子、メチル基、エチル基、ヒドロキシメチル基、ヒドロキシイミノメチル基、カルボキシ基、メトキシカルボニル基またはシアノ基を示す請求項1記載の化合物またはその塩。 In general formula [I],
Ring X represents a benzene ring;
Ring Y represents a pyridine ring or a 1H-pyrrolo [2,3-b] pyridine ring;
R 1 and R 2 represent a hydrogen atom or an alkyl group;
R 3 represents a hydrogen atom;
R 4 represents a hydrogen atom or an amino group;
R 5 represents a hydrogen atom or a methyl group;
The compound or a salt thereof according to claim 1, wherein R 6 represents a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a hydroxyiminomethyl group, a carboxy group, a methoxycarbonyl group or a cyano group.
・E−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−メチル−2−(4−ピリジル)エチレン、
・Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−メチル−2−(4−ピリジル)エチレン、
・E−1−[4−(1−アミノ−1−メチルエチル)フェニル]−2−(2−アミノピリジン−4−イル)−1−メチルエチレン、
・E−1−[4−(1−アミノ−1−メチルエチル)フェニル]−2−メチル−2−(4−ピリジル)エチレン、
・Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−ヒドロキシメチル−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン、
・Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−(ヒドロキシイミノメチル)−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン、
・Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−シアノ−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン、
・Z−1−[4−(アミノメチル)フェニル]−1−ヒドロキシメチル−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン、
・Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−メトキシカルボニル−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレン、および、
・Z−1−[4−(1−アミノ−1−メチルエチル)フェニル]−1−カルボキシ−2−(1H−ピロロ[2,3−b]ピリジン−4−イル)エチレンからなる群より選択される化合物またはその塩。 E-1- [4- (1-Amino-1-methylethyl) phenyl] -2- (4-pyridyl) ethylene,
E-1- [4- (1-Amino-1-methylethyl) phenyl] -1-methyl-2- (4-pyridyl) ethylene,
-Z-1- [4- (1-amino-1-methylethyl) phenyl] -1-methyl-2- (4-pyridyl) ethylene,
E-1- [4- (1-Amino-1-methylethyl) phenyl] -2- (2-aminopyridin-4-yl) -1-methylethylene,
E-1- [4- (1-Amino-1-methylethyl) phenyl] -2-methyl-2- (4-pyridyl) ethylene,
-Z-1- [4- (1-amino-1-methylethyl) phenyl] -1-hydroxymethyl-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene,
Z-1- [4- (1-amino-1-methylethyl) phenyl] -1- (hydroxyiminomethyl) -2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene,
-Z-1- [4- (1-amino-1-methylethyl) phenyl] -1-cyano-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene,
Z-1- [4- (aminomethyl) phenyl] -1-hydroxymethyl-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene,
-Z-1- [4- (1-amino-1-methylethyl) phenyl] -1-methoxycarbonyl-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene, and
-Selected from the group consisting of Z-1- [4- (1-amino-1-methylethyl) phenyl] -1-carboxy-2- (1H-pyrrolo [2,3-b] pyridin-4-yl) ethylene Or a salt thereof.
The therapeutic agent for glaucoma which uses the compound or its salt of any one of Claims 1-7 as an active ingredient.
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WO2007007737A1 (en) | 2005-07-12 | 2007-01-18 | Kowa Co., Ltd. | Agent for prevention or treatment of glaucoma |
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WO2018230713A1 (en) | 2017-06-16 | 2018-12-20 | 学校法人同志社 | Compounds having caspase inhibitory activity, pharmaceutical agent containing said compounds and for treating or preventing corneal endothelial symptoms, disorders, or diseases, and application of said pharmaceutical agent |
US11433090B2 (en) | 2017-06-16 | 2022-09-06 | The Doshisha | mTOR-inhibitor-containing medicine for treating or preventing ophthalmic symptoms, disorders, or diseases, and application thereof |
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