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JP4596792B2 - Drugs having both 5-HT1A agonistic action and 5-HT3 antagonistic action - Google Patents

Drugs having both 5-HT1A agonistic action and 5-HT3 antagonistic action Download PDF

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JP4596792B2
JP4596792B2 JP2004048344A JP2004048344A JP4596792B2 JP 4596792 B2 JP4596792 B2 JP 4596792B2 JP 2004048344 A JP2004048344 A JP 2004048344A JP 2004048344 A JP2004048344 A JP 2004048344A JP 4596792 B2 JP4596792 B2 JP 4596792B2
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通隆 佐藤
照明 松井
章 朝烏
博之 林
誠一 荒木
賢 玉置
伸行 高橋
淑子 山本
則夫 山本
ちさと 小川
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Aska Pharmaceutical Co Ltd
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Description

本発明は、後記式(I)で示されるピペラジニルピリジン誘導体の、セロトニン受容体サブタイプ1A(5−HT1A)作動作用とセロトニン受容体サブタイプ3(5−HT)拮抗作用を併有する薬剤としての利用、殊に、該ピペラジニルピリジン誘導体を有効成分として含有する過敏性腸症候群(Irritable Bowel Syndrome;以下、「IBS」という)等の処置剤に関する。 The present invention combines a serotonin receptor subtype 1A (5-HT 1A ) agonistic action and a serotonin receptor subtype 3 (5-HT 3 ) antagonistic action of a piperazinylpyridine derivative represented by the following formula (I). In particular, the present invention relates to a therapeutic agent such as irritable bowel syndrome (hereinafter referred to as “IBS”) containing the piperazinylpyridine derivative as an active ingredient.

IBSは下痢や便秘等の便通異常や腹痛を主症状とする疾患で、腸管の器質的病変を認めない機能的疾患である。IBSは、腸管運動異常、内臓知覚過敏及び心理・社会的因子が相互に関連し合って成立している。   IBS is a disease mainly having stool abnormalities such as diarrhea and constipation and abdominal pain, and is a functional disease in which no organic lesions of the intestine are recognized. IBS is formed by intestinal motility abnormalities, visceral hypersensitivity, and psychological and social factors interrelated.

腸管には種々のセロトニン受容体サブタイプが存在するが、このうち、5−HTは腸管収縮、腸液分泌、蠕動運動、内容物輸送等に関与している。したがって、IBSによる下痢症状が5−HT拮抗薬によって改善されることがあり、実際に米国において、5−HT拮抗薬であるアロセトロン(alosetron)がIBS治療薬として承認されている。 Although the intestinal There are various serotonin receptor subtypes, of which, 5-HT 3 intestinal contraction, intestinal fluid secretion, peristalsis, are involved in the contents such as transportation. Therefore, diarrhea symptoms caused by IBS may be ameliorated by 5-HT 3 antagonists. In fact, 5-HT 3 antagonist alosetron has been approved as an IBS therapeutic agent in the United States.

特許文献1及び特許文献2には、オンダンセトロン(ondansetron)、アロセトロン(alosetron)、トロピセトロン(tropisetron)あるいはグラニセトロン(granisetron)などの種々の5−HT拮抗薬がIBS治療剤として有用であることが記載されている。 In Patent Document 1 and Patent Document 2, various 5-HT 3 antagonists such as ondansetron, allosetron, tropisetron, or granisetron are useful as IBS therapeutic agents. It is described.

非特許文献1には、5−HT受容体に対して選択的に親和性を有するピペラジニルピラジン誘導体が記載されているが、非特許文献1に記載されているピペラジニルピリジン誘導体の5−HT受容体に対する作用は作動作用である。 Non-Patent Document 1 describes a piperazinyl pyrazine derivative having selective affinity for the 5-HT 3 receptor, but the piperazinyl pyridine derivative described in Non-Patent Document 1 The action on the 5-HT 3 receptor is an agonistic action.

一方、IBSには心理的・社会的因子も関与していることから、抗不安薬がIBSの治療において何らかの有用性を示す可能性もあり、この可能性を拠り所にして、ベンゾジアゼピン系の抗不安薬がIBSの治療の目的にて用いられる場合もある。最近、より副作用の少ない非ベンゾジアゼピン系化合物を含むセロトニン作動性の抗不安薬が開発され、それらの化合物のIBS治療における有用性が期待されている。   On the other hand, since psychological and social factors are involved in IBS, anxiolytic drugs may show some usefulness in the treatment of IBS. Based on this possibility, benzodiazepine anxiolytic In some cases, the drug is used for the purpose of treating IBS. Recently, serotonergic anxiolytic drugs including non-benzodiazepine compounds with fewer side effects have been developed, and their usefulness in the treatment of IBS is expected.

我が国においては、5−HT1A作動薬であるタンドスピロン(tandospirone)がストレス性消化性潰瘍等を適応症として上市されている。しかしながら、当該化合物はIBSの適応症を有していない。 In Japan, the 5-HT 1A agonist tandospirone is marketed for the indication of stress peptic ulcer and the like. However, the compound has no indication for IBS.

非特許文献2には、5−HT1A受容体に対して選択的に親和性を有するピリミジノン誘導体が開示されている。この文献においては、5−HT1A受容体への選択性がα受容体に対する選択性との比較において検討されている。 Non-Patent Document 2 discloses a pyrimidinone derivative having selective affinity for the 5-HT 1A receptor. In this document, the selectivity for the 5-HT 1A receptor is examined in comparison with the selectivity for the α 1 receptor.

特許文献3及び4には、5−HT1A受容体に対する親和性を有するアリールピペラジン誘導体が開示されている。これらの文献においては、アリールピペラジンの5−HT1A受容体に対する作用に基づく精神的作用が検討されている。 Patent Documents 3 and 4 disclose aryl piperazine derivatives having affinity for the 5-HT 1A receptor. In these documents, a mental action based on the action of arylpiperazines on 5-HT 1A receptors is examined.

上記のように、これまで、種々の5−HT拮抗薬又は5−HT1A作動薬が提案されているが、それらの化合物が5−HT1A作動作用及び5−HT拮抗作用の両作用を併せ持つかどうかについては検討されていない。また、これまでに開発又は上市されている5−HT拮抗薬又は5−HT1A作動薬はいずれも、その作用が一方向性であるため、複数の成因を有するIBSに対して十分な治療効果を発揮するまでには至っていない。 As described above, various 5-HT 3 antagonists or 5-HT 1A agonists have been proposed so far, and these compounds have both 5-HT 1A agonistic action and 5-HT 3 antagonistic action. Whether or not to have both is not considered. In addition, since 5-HT 3 antagonists or 5-HT 1A agonists that have been developed or marketed so far are unidirectional in their action, sufficient treatment for IBS having multiple causes is possible. It has not yet reached its effect.

非特許文献3には、5−HT1A及び5−HTの両受容体に対して親和性を有するベンズイミダゾール−アリルピペラジン誘導体が開示されている。しかしながら、この文献には、当該誘導体の神経系に対する作用について記載されているのみで、5−HT拮抗作用及び5−HT1A作動作用の両作用をIBSに対して作用させることについては記載されていない。
PCT国際公開WO 99/17755パンフレット 米国特許第6,284,770号明細書 欧州特許公開第343050号明細書 特開2001−97978号公報 J.Med.Chem.,42,4362−4379(1999) J.Med.Chem.,40,574−585(1997) Bioorg.Med.Chem.Lett.,13,3177−3180(2003)
Non-Patent Document 3 discloses a benzimidazole-allyl piperazine derivative having affinity for both 5-HT 1A and 5-HT 3 receptors. However, this document only describes the action of the derivative on the nervous system, and describes that both 5-HT 3 antagonistic action and 5-HT 1A acting action are exerted on IBS. Not.
PCT International Publication WO 99/17755 Pamphlet US Pat. No. 6,284,770 European Patent Publication No. 343050 JP 2001-97978 A J. et al. Med. Chem. , 42, 4362-4379 (1999) J. et al. Med. Chem. , 40, 574-585 (1997) Bioorg. Med. Chem. Lett. , 13, 3177-3180 (2003)

本発明の主たる目的は、5−HT1A作動作用と5−HT拮抗作用を併有する薬剤を提供することである。 The main object of the present invention is to provide a drug having both 5-HT 1A agonistic action and 5-HT 3 antagonistic action.

本発明の別の目的は、また、当該拮抗剤を有効成分とするIBS等の処置剤を提供することである。   Another object of the present invention is to provide a therapeutic agent such as IBS containing the antagonist as an active ingredient.

本発明によれば、式(I)

Figure 0004596792
According to the invention, the formula (I)
Figure 0004596792

式中、
A環は場合によりハロゲン原子、低級アルキル基、フェニル基、ヒドロキシ基、低級アルコキシ基、フェニル低級アルコキシ基(この基のフェニル部分は場合によりハロゲン原子で置換されていてもよい)アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、低級アルキルチオ基、低級アルキルスルフィニル基又はアミノスルホニルオキシ基で置換されていてもよいベンゼン環、又は場合によりハロゲン原子もしくは低級アルキル基で置換されていてもよいピリジン、フラン及びチオフェンから選ばれる複素環を表し、
は水素原子、ハロゲン原子又は低級アルキル基を表し、
は水素原子、低級アルキル基、フェニル低級アルキル基(この基のフェニル部分は場合によりハロゲン原子、低級アルキル基もしくは低級アルコキシ基で置換されていてもよい)、アミノ低級アルキル基(この基のアミノ部分は場合により低級アルキル基でモノ−もしくはジ−置換されているか又は環状イミド基を形成していてもよい)又はフェニルシクロアルキル基(この基のフェニル部分は場合によりハロゲン原子、低級アルキル基もしくは低級アルコキシ基で置換されていてもよい)を表し、そして
は水素原子又は低級アルキル基を表すか、或いは
及びRは一緒になって場合によりヒドロキシ基、低級アルコキシ基又はフェニル低級アルコキシ基で置換されていてもよいピロリジン環又はピペリジン環の残員を形成していてもよく、
は水素原子又は低級アルキル基を表す、
で示されるピペラジニルピリジン誘導体又はその製薬学的に許容されうる塩を有効成分として含むことを特徴とする、5−HT1A作動作用と5−HT拮抗作用を併有する薬剤が提供される。
Where
A ring is optionally a halogen atom, a lower alkyl group, a phenyl group, a hydroxy group, a lower alkoxy group, a phenyl lower alkoxy group (the phenyl portion of this group may be optionally substituted with a halogen atom) an amino group, a lower alkyl group A benzene ring optionally substituted with an amino group, a di-lower alkylamino group, a lower alkylthio group, a lower alkylsulfinyl group or an aminosulfonyloxy group, or optionally a pyridine optionally substituted with a halogen atom or a lower alkyl group, Represents a heterocyclic ring selected from furan and thiophene,
R 1 represents a hydrogen atom, a halogen atom or a lower alkyl group,
R 2 represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group (the phenyl portion of this group may be optionally substituted with a halogen atom, a lower alkyl group or a lower alkoxy group), an amino lower alkyl group (of this group The amino moiety is optionally mono- or di-substituted with a lower alkyl group or may form a cyclic imide group) or a phenylcycloalkyl group (the phenyl portion of this group is optionally a halogen atom, lower alkyl group) Or R 3 may be substituted with a lower alkoxy group, and R 3 represents a hydrogen atom or a lower alkyl group, or R 2 and R 3 together may optionally be a hydroxy group, a lower alkoxy group or a phenyl group. Forming a residue of a pyrrolidine ring or piperidine ring optionally substituted with a lower alkoxy group; You may,
R 4 represents a hydrogen atom or a lower alkyl group,
A drug having both 5-HT 1A agonistic activity and 5-HT 3 antagonistic activity, comprising a piperazinylpyridine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient is provided: .

本発明によれば、また、上記薬剤を有効成分とするIBS等の処置剤が提供される。
本明細書において、「低級」なる語は、この語が付された基の炭素原子数が6個以下、好ましくは4個以下であることを意味する。
According to the present invention, there is also provided a treatment agent such as IBS containing the above drug as an active ingredient.
In the present specification, the term “lower” means that the group to which the word is attached has 6 or less carbon atoms, preferably 4 or less.

したがって、「低級アルキル基」としては、例えば、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、n−ヘキシル基等を挙げることができ、中でも、メチル、エチル、n−プロピル及びイソプロピル基が好ましい。また、「低級アルコキシ基」としては、例えば、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、イソブチルオキシ、sec−ブチルオキシ、tert−ブチルオキシ、n−ペンチルオキシ、n−ヘキシルオキシ基等を挙げることができ、中でも、メトキシ、エトキシ、n−プロポキシ及びイソプロポキシ基が好ましい。   Accordingly, examples of the “lower alkyl group” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl group and the like. Of these, methyl, ethyl, n-propyl and isopropyl groups are preferred. Examples of the “lower alkoxy group” include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, n-hexyloxy group and the like. Among them, methoxy, ethoxy, n-propoxy and isopropoxy groups are preferable.

本明細書において、「フェニル低級アルコキシ基(この基のフェニル部分は場合によりハロゲン原子で置換されていてもよい)」は、未置換の又はハロゲン原子で置換されたフェニル基で置換された低級アルコキシ基を意味し、例えば、ベンジルオキシ、フェニルエトキシ、フェニルプロピルオキシ、フェニルブトキシ、2−クロロベンジルオキシ、2−ブロモベンジルオキシ、2−フルオロベンジルオキシ、3−ブロモベンジルオキシ、4−フルオロベンジルオキシ、2,4−ジクロロベンジルオキシ、1−(4−フルオロフェニルメチル)エトキシ基等を挙げることができる。この中でも特に、未置換の又は1個のハロゲン原子で置換されたベンジルオキシ基が好適である。   In the present specification, “phenyl lower alkoxy group (the phenyl portion of this group may be optionally substituted with a halogen atom)” refers to a lower alkoxy substituted with an unsubstituted or substituted phenyl group. Means a group such as benzyloxy, phenylethoxy, phenylpropyloxy, phenylbutoxy, 2-chlorobenzyloxy, 2-bromobenzyloxy, 2-fluorobenzyloxy, 3-bromobenzyloxy, 4-fluorobenzyloxy, 2,4-dichlorobenzyloxy, 1- (4-fluorophenylmethyl) ethoxy group and the like can be mentioned. Among these, a benzyloxy group which is unsubstituted or substituted with one halogen atom is particularly preferable.

前記式(I)において、A環の定義における「低級アルキルアミノ基」は、1個の低級アルキル基で置換されたアミノ基であり、例えば、N−メチルアミノ、N−エチルアミノ、N−n−プロピルアミノ、N−sec−ブチルアミノ基等を挙げることができ、特に、N−メチルアミノ及びN−エチルアミノ基が好ましい。また、A環の定義における「ジ低級アルキルアミノ基」は、同一のもしくは異なった2個の低級アルキル基で置換されたアミノ基であり、例えば、N,N−ジメチルアミノ、N,N−ジエチルアミノ、N,N−ジイソプロピルアミノ、N−メチル−N−エチルアミノ、N−メチル−N−tert−ブチルアミノ基等を挙げることができ、特に、N,N−ジメチルアミノ及びN,N−ジエチルアミノ基が好ましい。   In the formula (I), the “lower alkylamino group” in the definition of the A ring is an amino group substituted with one lower alkyl group, and examples thereof include N-methylamino, N-ethylamino, Nn. -Propylamino, N-sec-butylamino group and the like can be mentioned, and N-methylamino and N-ethylamino groups are particularly preferable. The “di-lower alkylamino group” in the definition of the A ring is an amino group substituted with two identical or different lower alkyl groups, and examples thereof include N, N-dimethylamino, N, N-diethylamino. , N, N-diisopropylamino, N-methyl-N-ethylamino, N-methyl-N-tert-butylamino group, etc., particularly N, N-dimethylamino and N, N-diethylamino groups Is preferred.

また、前記式(I)のA環の定義における「低級アルキルチオ基」は、低級アルキル基で置換されたチオ基であり、例えば、メチルチオ、エチルチオ、イソブチルチオ基等を挙げることができる。この中でも特に、メチルチオ基が好適である。また、A環の定義における「低級アルキルスルフィニル基」は、低級アルキル基で置換されたスルフィニル基であり、例えば、メチルスルフィニル、エチルスルフィニル、イソプロピルスルフィニル基等を挙げることができ、この中でも特に、メチルスルフィニル基が好適である。   Further, the “lower alkylthio group” in the definition of the A ring in the formula (I) is a thio group substituted with a lower alkyl group, and examples thereof include methylthio, ethylthio, isobutylthio group and the like. Of these, a methylthio group is particularly preferred. Further, the “lower alkylsulfinyl group” in the definition of the A ring is a sulfinyl group substituted with a lower alkyl group, and examples thereof include methylsulfinyl, ethylsulfinyl, isopropylsulfinyl groups and the like. A sulfinyl group is preferred.

前記式(I)において、A環が「ベンゼン環」を表す場合の式(I)の化合物は、下記式(III)

Figure 0004596792
In the formula (I), when the A ring represents a “benzene ring”, the compound of the formula (I) is represented by the following formula (III)
Figure 0004596792

式中、
、R、R及びRは前記の意味を有し、
は水素原子、ハロゲン原子、低級アルキル基、フェニル基、ヒドロキシ基、低級アルコキシ基、フェニル低級アルコキシ基(この基のフェニル部分は場合によりハロゲン原子で置換されていてもよい)、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、低級アルキルチオ基、低級アルキルスルフィニル基又はアミノスルホニルオキシ基を表す、
で表すことができる。
Where
R 1 , R 2 , R 3 and R 4 have the meanings given above,
R 5 represents a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group, a hydroxy group, a lower alkoxy group, a phenyl lower alkoxy group (the phenyl portion of this group may be optionally substituted with a halogen atom), an amino group, A lower alkylamino group, a di-lower alkylamino group, a lower alkylthio group, a lower alkylsulfinyl group or an aminosulfonyloxy group;
Can be expressed as

またさらに、前記式(I)において、A環が「ピリジン、フラン及びチオフェンから選ばれる複素環」を表す場合に、それが式(I)中のピリジン環と縮合して形成される複素環としては、例えば、1,6−ナフチリジン、2,6−ナフチリジン、2,7−ナフチリジン、1,7−ナフチリジン、フロ[3,2−c]ピリジン、フロ[3,4−c]ピリジン、フロ[2,3−c]ピリジン、チエノ[3,2−c]ピリジン、チエノ[3,4−c]ピリジン、チエノ[2,3−c]ピリジンを挙げることができる。この中、1,6−ナフチリジン、2,6−ナフチリジン、2,7−ナフチリジン、1,7−ナフチリジン、フロ[3,2−c]ピリジン、フロ[2,3−c]ピリジン、チエノ[3,2−c]ピリジン及びチエノ[2,3−c]ピリジンが好ましく、特に、1,6−ナフチリジン、1,7−ナフチリジン、フロ[2,3−c]ピリジン及びチエノ[2,3−c]ピリジンが好適である。   Furthermore, in the formula (I), when the A ring represents a “heterocycle selected from pyridine, furan and thiophene”, it is a heterocycle formed by condensation with the pyridine ring in the formula (I). Are, for example, 1,6-naphthyridine, 2,6-naphthyridine, 2,7-naphthyridine, 1,7-naphthyridine, furo [3,2-c] pyridine, furo [3,4-c] pyridine, furo [ Examples include 2,3-c] pyridine, thieno [3,2-c] pyridine, thieno [3,4-c] pyridine, and thieno [2,3-c] pyridine. Among them, 1,6-naphthyridine, 2,6-naphthyridine, 2,7-naphthyridine, 1,7-naphthyridine, furo [3,2-c] pyridine, furo [2,3-c] pyridine, thieno [3] , 2-c] pyridine and thieno [2,3-c] pyridine are preferred, especially 1,6-naphthyridine, 1,7-naphthyridine, furo [2,3-c] pyridine and thieno [2,3-c. Pyridine is preferred.

の定義において用いられる「フェニル低級アルキル基(この基のフェニル部分は場合によりハロゲン原子、低級アルキル基もしくは低級アルコキシ基で置換されていてもよい)」は、置換もしくは未置換のフェニル基で置換された低級アルキル基であり、ここで、フェニル基上の置換基としては、例えば、2−フルオロ、3−フルオロ、4−フルオロ、2−クロロ、4−クロロ、3−ブロモ、4−ブロモ、4−ヨード、2−メチル、3−メチル、4−メチル、2−エチル、3−エチル、3−n−プロピル、4−イソプロピル、2−メトキシ、3−メトキシ、4−メトキシ、3−エトキシ、4−イソプロピルオキシ、3,4−メチレンジオキシ基等を挙げることができ、中でも、4−フルオロ、4−クロロ、4−ブロモ、3−メチル、3−エチル、3−メトキシ、3−エトキシ及び3,4−メチレンジオキシ基が好ましい。また、上記低級アルキル基としては、例えば、メチル、エチル、n−プロピル及びn−ブチル基が好適である。かくして、「フェニル低級アルキル基」の好適具体例としては、ベンジル、4−フルオロベンジル、2−(4−クロロフェニル)エチル、3−(4−ブロモフェニル)−n−プロピル、3−メチルベンジル、3−(3−エチルフェニル)−n−ブチル、3−メトキシベンジル、4−(3−メトキシフェニル)−n−ブチル及び(3,4−メチレンジオキシフェニル)メチル基を挙げることができる。 “Phenyl lower alkyl group (the phenyl portion of this group may be optionally substituted with a halogen atom, lower alkyl group or lower alkoxy group)” used in the definition of R 2 is a substituted or unsubstituted phenyl group. A substituted lower alkyl group, and examples of the substituent on the phenyl group include 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 4-chloro, 3-bromo, 4-bromo. 4-iodo, 2-methyl, 3-methyl, 4-methyl, 2-ethyl, 3-ethyl, 3-n-propyl, 4-isopropyl, 2-methoxy, 3-methoxy, 4-methoxy, 3-ethoxy , 4-isopropyloxy, 3,4-methylenedioxy group and the like, among which 4-fluoro, 4-chloro, 4-bromo, 3-methyl, 3- Ethyl, 3-methoxy, 3-ethoxy and 3,4-methylenedioxy groups are preferred. Moreover, as said lower alkyl group, a methyl, ethyl, n-propyl, and n-butyl group is suitable, for example. Thus, preferred specific examples of the “phenyl lower alkyl group” include benzyl, 4-fluorobenzyl, 2- (4-chlorophenyl) ethyl, 3- (4-bromophenyl) -n-propyl, 3-methylbenzyl, 3 Mention may be made of-(3-ethylphenyl) -n-butyl, 3-methoxybenzyl, 4- (3-methoxyphenyl) -n-butyl and (3,4-methylenedioxyphenyl) methyl groups.

の定義において用いられる「アミノ低級アルキル基(この基のアミノ部分は場合により低級アルキル基でモノ−もしくはジ−置換されているか又は環状イミド基を形成していてもよい)」は、アミノ基で置換された低級アルキル基であり、ここで、「アミノ」は、未置換のアミノ基のみならず1もしくは2個の低級アルキル基で置換されたアミノ基及び環状イミド基を形成したアミノ基を包含する。また、該アミノ基に置換していてもよい低級アルキル基としては、好適には、メチル、エチル、n−プロピル及びn−ブチル基が挙げられる。かくして、「アミノ低級アルキル基(この基のアミノ部分は場合により低級アルキル基でモノ−もしくはジ−置換されているか又は環状イミド基を形成していてもよい)」の好適具体例としては、アミノメチル、2−アミノエチル、3−アミノ−n−プロピル、4−アミノ−n−ブチル、2−(N−メチルアミノ)エチル、3−(N,N−ジメチルアミノ)−n−プロピル及び3−フタルイミノ−n−プロピル基を挙げることができる。 As used in the definition of R 2 , “amino lower alkyl group (the amino portion of this group may optionally be mono- or di-substituted with a lower alkyl group or form a cyclic imido group)” A lower alkyl group substituted with a group, wherein “amino” means not only an unsubstituted amino group but also an amino group substituted with one or two lower alkyl groups and an amino group forming a cyclic imido group Is included. The lower alkyl group which may be substituted on the amino group preferably includes methyl, ethyl, n-propyl and n-butyl groups. Thus, preferred specific examples of “amino lower alkyl group (the amino portion of this group may optionally be mono- or di-substituted with a lower alkyl group or form a cyclic imide group)” include amino Methyl, 2-aminoethyl, 3-amino-n-propyl, 4-amino-n-butyl, 2- (N-methylamino) ethyl, 3- (N, N-dimethylamino) -n-propyl and 3- Mention may be made of the phthalimino-n-propyl group.

の定義において用いられる「フェニルシクロアルキル基(この基のフェニル部分は場合によりハロゲン原子、低級アルキル基もしくは低級アルコキシ基で置換されていてもよい)」は、場合によりハロゲン原子、低級アルキル基もしくは低級アルコキシ基で置換されていてもよいフェニル基が置換したシクロアルキル基であり、ここで、フェニル基上の置換基は、上記Rの定義における「フェニル低級アルキル基」のフェニル基上の置換基において述べたと同様の置換基を挙げることができる。また、該シクロアルキル基としては、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル基等を挙げることができ、中でも、シクロヘキシル基が好ましい。さらに、「フェニルシクロアルキル基」におけるフェニル基の置換位置は、シクロペンチル基の場合は3位、シクロヘキシル基及びシクロヘプチル基の場合は4位、シクロオクチル基の場合は5位が好ましい。かくして、「フェニルシクロアルキル基(この基のフェニル部分は場合によりハロゲン原子、低級アルキル基もしくは低級アルコキシ基で置換されていてもよい)」の好適具体例としては、4−(4−フルオロフェニル)シクロヘキシル、4−(4−クロロフェニル)シクロヘキシル、4−(4−ブロモフェニル)シクロヘキシル、4−(3−メチルフェニル)シクロヘキシル、4−(3−エチルフェニル)シクロヘキシル、4−(3−メトキシフェニル)シクロヘキシル、4−(3−エトキシフェニル)シクロヘキシル及び4−(3,4−メチレンジオキシフェニル)シクロヘキシル基を挙げることができる。 As used in the definition of R 2 , “phenylcycloalkyl group (the phenyl portion of this group may be optionally substituted with a halogen atom, lower alkyl group or lower alkoxy group)” is optionally a halogen atom, lower alkyl group Or a cycloalkyl group substituted by a phenyl group which may be substituted with a lower alkoxy group, wherein the substituent on the phenyl group is the phenyl group of the “phenyl lower alkyl group” in the definition of R 2 above. The same substituents as described in the substituent can be given. Examples of the cycloalkyl group include cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Among them, a cyclohexyl group is preferable. Furthermore, the substitution position of the phenyl group in the “phenylcycloalkyl group” is preferably the 3-position for the cyclopentyl group, the 4-position for the cyclohexyl group and the cycloheptyl group, and the 5-position for the cyclooctyl group. Thus, preferred examples of “phenylcycloalkyl group (the phenyl portion of this group may be optionally substituted with a halogen atom, a lower alkyl group or a lower alkoxy group)” include 4- (4-fluorophenyl) Cyclohexyl, 4- (4-chlorophenyl) cyclohexyl, 4- (4-bromophenyl) cyclohexyl, 4- (3-methylphenyl) cyclohexyl, 4- (3-ethylphenyl) cyclohexyl, 4- (3-methoxyphenyl) cyclohexyl , 4- (3-ethoxyphenyl) cyclohexyl and 4- (3,4-methylenedioxyphenyl) cyclohexyl groups.

本明細書において、A環がベンゼン環を表す場合に形成されるイソキノリン環における該ベンゼン環上の置換基、すなわち、前記式(III)におけるRで表される基としては、例えば、5−クロロ、6−クロロ、7−クロロ、8−クロロ、5−フルオロ、7−フルオロ、5−ブロモ、7−ブロモ、5−ヨード、5−メチル、6−メチル、7−メチル、8−メチル、5−エチル、5−n−プロピル、5−sec−ブチル、5−フェニル、6−フェニル、7−フェニル、8−フェニル、5−ヒドロキシ、6−ヒドロキシ、7−ヒドロキシ、8−ヒドロキシ、5−メトキシ、6−メトキシ、7−メトキシ、8−メトキシ、5−エトキシ、7−エトキシ、5−イソプロピルオキシ、5−tert−ブチルオキシ、5−ベンジルオキシ、7−ベンジルオキシ、5−(2−フェニル)エチルオキシ、5−(4−フルオロフェニル)メトキシ、7−(4−フルオロフェニル)メトキシ、5−(2−クロロフェニル)メトキシ、5−(3−ブロモフェニル)メトキシ、5−(2−フルオロ−4−クロロフェニル)メトキシ、6−(2,4−ジクロロフェニル)エトキシ、5−アミノ、6−アミノ、7−アミノ、8−アミノ、5−(N−メチルアミノ)、7−(N−メチルアミノ)、5−(N−エチルアミノ)、5−(N−イソブチルアミノ)、6−(N−tert−ブチルアミノ)、5−(N,N−ジメチルアミノ)、7−(N,N−ジメチルアミノ)、5−(N,N−ジイソプロピルアミノ)、6−(N−メチル−N−n−ブチルアミノ)、5−メチルチオ、6−メチルチオ、7−メチルチオ、8−メチルチオ、5−エチルチオ、5−n−プロピルチオ、5−イソブチルチオ、6−イソプロピルチオ、5−メチルスルフィニル、6−メチルスルフィニル、7−メチルスルフィニル、8−メチルスルフィニル、5−エチルスルフィニル、6−イソプロピルスルフィニル、7−tert−ブチルスルフィニル、8−n−ペンチルスルフィニル、5−アミノスルホニルオキシ、6−アミノスルホニルオキシ、7−アミノスルホニルオキシ、8−アミノスルホニルオキシ基等が挙げられ、中でも、5−クロロ、6−クロロ、7−クロロ、7−フルオロ、7−ブロモ、7−メチル、7−フェニル、7−ヒドロキシ、5−メトキシ、6−メトキシ、7−メトキシ、7−エトキシ、7−ベンジルオキシ、7−(4−フルオロフェニル)メトキシ、7−(N−メチルアミノ)、7−(N,N−ジメチルアミノ)、7−メチルチオ、7−メチルスルフィニル、7−アミノスルホニルオキシ基が好ましく、特に、6−クロロ、7−クロロ、7−フルオロ、7−ブロモ、7−メチル、7−ヒドロキシ、7−メトキシ、7−エトキシ、7−ベンジルオキシ、7−(4−フルオロフェニル)メトキシ、7−(N,N−ジメチルアミノ)、7−メチルチオ基が好適である。 In the present specification, examples of the substituent on the benzene ring in the isoquinoline ring formed when the A ring represents a benzene ring, that is, the group represented by R 5 in the formula (III) include 5- Chloro, 6-chloro, 7-chloro, 8-chloro, 5-fluoro, 7-fluoro, 5-bromo, 7-bromo, 5-iodo, 5-methyl, 6-methyl, 7-methyl, 8-methyl, 5-ethyl, 5-n-propyl, 5-sec-butyl, 5-phenyl, 6-phenyl, 7-phenyl, 8-phenyl, 5-hydroxy, 6-hydroxy, 7-hydroxy, 8-hydroxy, 5- Methoxy, 6-methoxy, 7-methoxy, 8-methoxy, 5-ethoxy, 7-ethoxy, 5-isopropyloxy, 5-tert-butyloxy, 5-benzyloxy, 7-benzyl Ruoxy, 5- (2-phenyl) ethyloxy, 5- (4-fluorophenyl) methoxy, 7- (4-fluorophenyl) methoxy, 5- (2-chlorophenyl) methoxy, 5- (3-bromophenyl) methoxy, 5- (2-fluoro-4-chlorophenyl) methoxy, 6- (2,4-dichlorophenyl) ethoxy, 5-amino, 6-amino, 7-amino, 8-amino, 5- (N-methylamino), 7 -(N-methylamino), 5- (N-ethylamino), 5- (N-isobutylamino), 6- (N-tert-butylamino), 5- (N, N-dimethylamino), 7- (N, N-dimethylamino), 5- (N, N-diisopropylamino), 6- (N-methyl-Nn-butylamino), 5-methylthio, 6-methylthio, 7-methylthio 8-methylthio, 5-ethylthio, 5-n-propylthio, 5-isobutylthio, 6-isopropylthio, 5-methylsulfinyl, 6-methylsulfinyl, 7-methylsulfinyl, 8-methylsulfinyl, 5-ethylsulfinyl, 6 -Isopropylsulfinyl, 7-tert-butylsulfinyl, 8-n-pentylsulfinyl, 5-aminosulfonyloxy, 6-aminosulfonyloxy, 7-aminosulfonyloxy, 8-aminosulfonyloxy group, etc. -Chloro, 6-chloro, 7-chloro, 7-fluoro, 7-bromo, 7-methyl, 7-phenyl, 7-hydroxy, 5-methoxy, 6-methoxy, 7-methoxy, 7-ethoxy, 7-benzyl Oxy, 7- (4-fluorophenyl) methoxy, 7 (N-methylamino), 7- (N, N-dimethylamino), 7-methylthio, 7-methylsulfinyl and 7-aminosulfonyloxy groups are preferred, especially 6-chloro, 7-chloro, 7-fluoro, 7-bromo, 7-methyl, 7-hydroxy, 7-methoxy, 7-ethoxy, 7-benzyloxy, 7- (4-fluorophenyl) methoxy, 7- (N, N-dimethylamino), 7-methylthio group Is preferred.

また、本明細書において、A環がベンゼン環を表す場合に形成されるイソキノリン環におけるピリジン環上の置換基、すなわち、前記式(I)においてRで表される基としては、例えば、3−フルオロ、4−フルオロ、3−クロロ、4−クロロ、3−ブロモ、4−ブロモ、3−ヨード、4−ヨード、3−メチル、4−メチル、3−エチル、4−エチル、3−n−プロピル、4−イソプロピル、3−tert−ブチル、4−n−ブチル、3−イソペンチル、4−(1,2−ジメチル−n−ブチル)基等が挙げられ、中でも、3−クロロ、4−クロロ、3−メチル、4−メチル基が好適である。かくして、A環がベンゼン環を表す場合に形成されるイソキノリン環上の好ましい置換基としては、5−クロロ、6−クロロ、7−クロロ、7−フルオロ、7−ブロモ、7−メチル、7−フェニル、7−ヒドロキシ、5−メトキシ、6−メトキシ、7−メトキシ、7−エトキシ、7−ベンジルオキシ、7−(4−フルオロフェニル)メトキシ、7−(N−メチルアミノ)、7−(N,N−ジメチルアミノ)、7−メチルチオ、7−メチルスルフィニル、7−アミノスルホニルオキシ、3−メチル−5−クロロ、4−メチル−6−クロロ、3−メチル−7−クロロ、3−メチル−7−フルオロ、3,7−ジメチル、3−メチル−7−ヒドロキシ、4−クロロ−7−メトキシ、4−メチル−7−ベンジルオキシ、3−クロロ−7−(4−フルオロフェニル)メトキシ、3−クロロ−7−(N−メチルアミノ)、4−クロロ−7−(N,N−ジメチルアミノ)、3−メチル−7−メトキシ、4−メチル−7−メトキシ及び3−クロロ−7−メチル基を挙げることができる。 In the present specification, examples of the substituent on the pyridine ring in the isoquinoline ring formed when the A ring represents a benzene ring, that is, the group represented by R 1 in the formula (I) include 3 -Fluoro, 4-fluoro, 3-chloro, 4-chloro, 3-bromo, 4-bromo, 3-iodo, 4-iodo, 3-methyl, 4-methyl, 3-ethyl, 4-ethyl, 3-n -Propyl, 4-isopropyl, 3-tert-butyl, 4-n-butyl, 3-isopentyl, 4- (1,2-dimethyl-n-butyl) group and the like, among which 3-chloro, 4- Chloro, 3-methyl and 4-methyl groups are preferred. Thus, preferred substituents on the isoquinoline ring formed when the A ring represents a benzene ring include 5-chloro, 6-chloro, 7-chloro, 7-fluoro, 7-bromo, 7-methyl, 7- Phenyl, 7-hydroxy, 5-methoxy, 6-methoxy, 7-methoxy, 7-ethoxy, 7-benzyloxy, 7- (4-fluorophenyl) methoxy, 7- (N-methylamino), 7- (N , N-dimethylamino), 7-methylthio, 7-methylsulfinyl, 7-aminosulfonyloxy, 3-methyl-5-chloro, 4-methyl-6-chloro, 3-methyl-7-chloro, 3-methyl- 7-fluoro, 3,7-dimethyl, 3-methyl-7-hydroxy, 4-chloro-7-methoxy, 4-methyl-7-benzyloxy, 3-chloro-7- (4-fluoro Enyl) methoxy, 3-chloro-7- (N-methylamino), 4-chloro-7- (N, N-dimethylamino), 3-methyl-7-methoxy, 4-methyl-7-methoxy and 3- Mention may be made of the chloro-7-methyl group.

また、本明細書において、A環がピリジン環を表す場合において形成される複素環が1,6−ナフチリジン環である場合に、この1,6−ナフチリジン環上の置換基としては、例えば、2−クロロ、3−クロロ、4−クロロ、2−フルオロ、3−フルオロ、2−ブロモ、3−ブロモ、2−ヨード、2−メチル、3−メチル、4−メチル、2−エチル、2−n−プロピル、2−sec−ブチル、2,7−ジクロロ、2,8−ジクロロ、3,7−ジクロロ、3,8−ジクロロ、4,7−ジクロロ、4,8−ジクロロ、8−クロロ−4−フルオロ、2,7−ジメチル、2,8−ジメチル、3,7−ジメチル、3,8−ジメチル、4,7−ジメチル、4,8−ジメチル、2−メチル−7−エチル、2−クロロ−7−メチル、3−クロロ−7−メチル、7−クロロ−2−メチル、7−クロロ−3−メチル基等を挙げることができ、中でも、2−クロロ、3−クロロ、3−フルオロ、3−ブロモ、3−メチル及び3クロロ−7−メチル基が好適である。   In this specification, when the heterocyclic ring formed when the A ring represents a pyridine ring is a 1,6-naphthyridine ring, examples of the substituent on the 1,6-naphthyridine ring include 2 -Chloro, 3-chloro, 4-chloro, 2-fluoro, 3-fluoro, 2-bromo, 3-bromo, 2-iodo, 2-methyl, 3-methyl, 4-methyl, 2-ethyl, 2-n -Propyl, 2-sec-butyl, 2,7-dichloro, 2,8-dichloro, 3,7-dichloro, 3,8-dichloro, 4,7-dichloro, 4,8-dichloro, 8-chloro-4 -Fluoro, 2,7-dimethyl, 2,8-dimethyl, 3,7-dimethyl, 3,8-dimethyl, 4,7-dimethyl, 4,8-dimethyl, 2-methyl-7-ethyl, 2-chloro -7-methyl, 3-chloro-7-methyl, -Chloro-2-methyl, 7-chloro-3-methyl and the like can be mentioned, among which 2-chloro, 3-chloro, 3-fluoro, 3-bromo, 3-methyl and 3chloro-7-methyl A group is preferred.

さらに、本明細書において、A環がピリジン環を表す場合において形成される複素環が2,6−ナフチリジン環である場合に、この2,6−ナフチリジン環上の置換基としては、例えば、5−クロロ、7−クロロ、8−クロロ、5−フルオロ、7−フルオロ、5−ブロモ、7−ブロモ、5−ヨード、5−メチル、7−メチル、8−メチル、5−エチル、7−n−プロピル、8−sec−ブチル、3,5−ジクロロ、3,7−ジクロロ、3,8−ジクロロ、4,5−ジクロロ、4,7−ジクロロ、4,8−ジクロロ、4−クロロ−8−フルオロ、3,5−ジメチル、3,7−ジメチル、3,8−ジメチル、4,5−ジメチル、4,7−ジメチル、4,8−ジメチル、3−クロロ−5−メチル、3−クロロ−7−メチル、3−クロロ−8−メチル、4−クロロ−5−メチル、4−クロロ−7−メチル、4−クロロ−8−メチル、5−クロロ−3−メチル、5−クロロ−4−メチル、7−クロロ−3−メチル、7−クロロ−4−メチル、8−クロロ−3−メチル、8−クロロ−4−メチル基等を挙げることができ、中でも、5−クロロ、7−クロロ、7−フルオロ、7−ブロモ、7−メチル及び3,7−ジクロロ基が好適である。   Furthermore, in this specification, when the heterocyclic ring formed when the A ring represents a pyridine ring is a 2,6-naphthyridine ring, examples of the substituent on the 2,6-naphthyridine ring include 5 -Chloro, 7-chloro, 8-chloro, 5-fluoro, 7-fluoro, 5-bromo, 7-bromo, 5-iodo, 5-methyl, 7-methyl, 8-methyl, 5-ethyl, 7-n -Propyl, 8-sec-butyl, 3,5-dichloro, 3,7-dichloro, 3,8-dichloro, 4,5-dichloro, 4,7-dichloro, 4,8-dichloro, 4-chloro-8 -Fluoro, 3,5-dimethyl, 3,7-dimethyl, 3,8-dimethyl, 4,5-dimethyl, 4,7-dimethyl, 4,8-dimethyl, 3-chloro-5-methyl, 3-chloro -7-methyl, 3-chloro-8-methyl 4-chloro-5-methyl, 4-chloro-7-methyl, 4-chloro-8-methyl, 5-chloro-3-methyl, 5-chloro-4-methyl, 7-chloro-3-methyl, 7- Chloro-4-methyl, 8-chloro-3-methyl, 8-chloro-4-methyl group and the like can be mentioned, among which 5-chloro, 7-chloro, 7-fluoro, 7-bromo, 7-methyl And 3,7-dichloro groups are preferred.

さらに、本明細書において、A環がピリジン環を表す場合において形成される複素環が2,7−ナフチリジン環である場合に、この2,7−ナフチリジン環上の置換基としては、例えば、5−クロロ、6−クロロ、8−クロロ、5−フルオロ、6−フルオロ、5−ブロモ、6−ブロモ、5−ヨード、5−メチル、6−メチル、8−メチル、5−エチル、6−n−プロピル、8−sec−ブチル、3,5−ジクロロ、3,6−ジクロロ、3,8−ジクロロ、4,5−ジクロロ、4,6−ジクロロ、4,8−ジクロロ、4−クロロ−8−フルオロ、3,5−ジメチル、3,6−ジメチル、3,8−ジメチル、4,5−ジメチル、4,6−ジメチル、4,8−ジメチル、5−クロロ−3−メチル、5−クロロ−4−メチル、6−クロロ−3−メチル、6−クロロ−4−メチル、8−クロロ−3−メチル、8−クロロ−4−メチル、3−クロロ−5−メチル、3−クロロ−6−メチル、3−クロロ−8−メチル、4−クロロ−5−メチル、4−クロロ−6−メチル、4−クロロ−8−メチル基等を挙げることができ、中でも、5−クロロ、6−クロロ、6−フルオロ、6−ブロモ、6−メチル、3,6−ジクロロ及び3,6−ジメチル基が好適である。   Furthermore, in this specification, when the heterocyclic ring formed when the A ring represents a pyridine ring is a 2,7-naphthyridine ring, examples of the substituent on the 2,7-naphthyridine ring include 5 -Chloro, 6-chloro, 8-chloro, 5-fluoro, 6-fluoro, 5-bromo, 6-bromo, 5-iodo, 5-methyl, 6-methyl, 8-methyl, 5-ethyl, 6-n -Propyl, 8-sec-butyl, 3,5-dichloro, 3,6-dichloro, 3,8-dichloro, 4,5-dichloro, 4,6-dichloro, 4,8-dichloro, 4-chloro-8 -Fluoro, 3,5-dimethyl, 3,6-dimethyl, 3,8-dimethyl, 4,5-dimethyl, 4,6-dimethyl, 4,8-dimethyl, 5-chloro-3-methyl, 5-chloro -4-methyl, 6-chloro-3-methyl 6-chloro-4-methyl, 8-chloro-3-methyl, 8-chloro-4-methyl, 3-chloro-5-methyl, 3-chloro-6-methyl, 3-chloro-8-methyl, 4- Chloro-5-methyl, 4-chloro-6-methyl, 4-chloro-8-methyl group and the like can be mentioned, among which 5-chloro, 6-chloro, 6-fluoro, 6-bromo, 6-methyl 3,6-dichloro and 3,6-dimethyl groups are preferred.

さらに、本明細書において、A環がピリジン環を表す場合において形成される複素環が1,7−ナフチリジン環である場合に、この1,7−ナフチリジン環上の置換基としては、例えば、2−クロロ、3−クロロ、4−クロロ、2−フルオロ、4−フルオロ、2−ブロモ、4−ブロモ、4−ヨード、2−メチル、3−メチル、4−メチル、4−エチル、3−n−プロピル、2−sec−ブチル、2,5−ジクロロ、2,6−ジクロロ、3,5−ジクロロ、3,6−ジクロロ、4,5−ジクロロ、4,6−ジクロロ、5−クロロ−2−フルオロ、2,5−ジメチル、2,6−ジメチル、3,5−ジメチル、3,6−ジメチル、4,5−ジメチル、4,6−ジメチル、2−クロロ−5−メチル、2−クロロ−6−メチル、3−クロロ−5−メチル、3−クロロ−6−メチル、4−クロロ−5−メチル、4−クロロ−6−メチル、5−クロロ−2−メチル、6−クロロ−2−メチル、5−クロロ−3−メチル、6−クロロ−3−メチル、5−クロロ−4−メチル、6−クロロ−4−メチル基等を挙げることができ、中でも、2−クロロ、4−クロロ、2−フルオロ、2−ブロモ、2−メチル及び2,6−ジクロロ基が好適である。   Furthermore, in this specification, when the heterocyclic ring formed when the A ring represents a pyridine ring is a 1,7-naphthyridine ring, examples of the substituent on the 1,7-naphthyridine ring include 2 -Chloro, 3-chloro, 4-chloro, 2-fluoro, 4-fluoro, 2-bromo, 4-bromo, 4-iodo, 2-methyl, 3-methyl, 4-methyl, 4-ethyl, 3-n -Propyl, 2-sec-butyl, 2,5-dichloro, 2,6-dichloro, 3,5-dichloro, 3,6-dichloro, 4,5-dichloro, 4,6-dichloro, 5-chloro-2 -Fluoro, 2,5-dimethyl, 2,6-dimethyl, 3,5-dimethyl, 3,6-dimethyl, 4,5-dimethyl, 4,6-dimethyl, 2-chloro-5-methyl, 2-chloro -6-methyl, 3-chloro-5-methyl 3-chloro-6-methyl, 4-chloro-5-methyl, 4-chloro-6-methyl, 5-chloro-2-methyl, 6-chloro-2-methyl, 5-chloro-3-methyl, 6- Examples include chloro-3-methyl, 5-chloro-4-methyl, 6-chloro-4-methyl group, among which 2-chloro, 4-chloro, 2-fluoro, 2-bromo, 2-methyl And 2,6-dichloro groups are preferred.

またさらに、本明細書において、A環がフラン環を表す場合において形成される複素環がフロ[3,2−c]ピリジンである場合に、このフロ[3,2−c]ピリジン上の置換基としては、上記「Aがベンゼン環を表す場合のイソキノリン環におけるピリジン環上の置換基」において述べたと同様の置換基のほかに、例えば、2−クロロ、3−クロロ、2−フルオロ、2−ブロモ、2−ヨード、2−メチル、3−メチル、2−エチル、3−n−プロピル、2,6−ジクロロ、2,7−ジクロロ、3,6−ジクロロ、3,7−ジクロロ、2,6−ジメチル、2,7−ジメチル、3,6−ジメチル、3,7−ジメチル、7−クロロ−3−フルオロ、2−クロロ−6−メチル、3−クロロ−6−メチル、2−クロロ−7−メチル、3−クロロ−7−メチル、6−クロロ−2−メチル、6−クロロ−3−メチル、7−クロロ−2−メチル、7−クロロ−3−メチル基等を挙げることができ、中でも、2−クロロ、3−クロロ、2−ブロモ、2−メチル、3−メチル、6−クロロ−2−メチル、6−クロロ−3−メチル、2,6−ジメチル、3,6−ジメチル及び7−クロロ−3−メチル基が好適である。   Furthermore, in the present specification, when the heterocyclic ring formed when the A ring represents a furan ring is furo [3,2-c] pyridine, the substitution on the furo [3,2-c] pyridine is performed. Examples of the group include the same substituents as described in the above-mentioned “substituents on the pyridine ring in the isoquinoline ring when A represents a benzene ring”, for example, 2-chloro, 3-chloro, 2-fluoro, 2 -Bromo, 2-iodo, 2-methyl, 3-methyl, 2-ethyl, 3-n-propyl, 2,6-dichloro, 2,7-dichloro, 3,6-dichloro, 3,7-dichloro, 2 , 6-dimethyl, 2,7-dimethyl, 3,6-dimethyl, 3,7-dimethyl, 7-chloro-3-fluoro, 2-chloro-6-methyl, 3-chloro-6-methyl, 2-chloro -7-methyl, 3-chloro-7- Til, 6-chloro-2-methyl, 6-chloro-3-methyl, 7-chloro-2-methyl, 7-chloro-3-methyl and the like can be mentioned, among which 2-chloro, 3-chloro 2-bromo, 2-methyl, 3-methyl, 6-chloro-2-methyl, 6-chloro-3-methyl, 2,6-dimethyl, 3,6-dimethyl and 7-chloro-3-methyl groups Is preferred.

またさらに、本明細書において、A環がフラン環を表す場合において形成される複素環がフロ[3,4−c]ピリジンである場合に、このフロ[3,4−c]ピリジン上の置換基としては、例えば、1−クロロ、3−クロロ、1−フルオロ、1−ブロモ、1−ヨード、1−メチル、3−メチル、1−エチル、3−n−プロピル、1,6−ジクロロ、3,6−ジクロロ、1,7−ジクロロ、3,7−ジクロロ、7−クロロ−3−フルオロ、1,6−ジメチル、1,7−ジメチル、3,6−ジメチル、3,7−ジメチル、1−クロロ−6−メチル、1−クロロ−7−メチル、3−クロロ−6−メチル、3−クロロ−7−メチル、6−クロロ−1−メチル、6−クロロ−3−メチル、7−クロロ−1−メチル、7−クロロ−3−メチル基等を挙げることができ、中でも、1−クロロ、3−クロロ、1−ブロモ、1−メチル、3−メチル、6−クロロ−1−メチル、3−クロロ−6−メチル及び6−クロロ−3−メチル基が好適である。   Furthermore, in this specification, when the heterocyclic ring formed when the A ring represents a furan ring is furo [3,4-c] pyridine, the substitution on the furo [3,4-c] pyridine is performed. Examples of the group include 1-chloro, 3-chloro, 1-fluoro, 1-bromo, 1-iodo, 1-methyl, 3-methyl, 1-ethyl, 3-n-propyl, 1,6-dichloro, 3,6-dichloro, 1,7-dichloro, 3,7-dichloro, 7-chloro-3-fluoro, 1,6-dimethyl, 1,7-dimethyl, 3,6-dimethyl, 3,7-dimethyl, 1-chloro-6-methyl, 1-chloro-7-methyl, 3-chloro-6-methyl, 3-chloro-7-methyl, 6-chloro-1-methyl, 6-chloro-3-methyl, 7- Examples include chloro-1-methyl, 7-chloro-3-methyl group, etc. 1-chloro, 3-chloro, 1-bromo, 1-methyl, 3-methyl, 6-chloro-1-methyl, 3-chloro-6-methyl and 6-chloro-3-methyl groups Is preferred.

またさらに、本明細書において、A環がフラン環を表す場合において形成される複素環がフロ[2,3−c]ピリジンである場合に、このフロ[2,3−c]ピリジン上の置換基としては、例えば、2−クロロ、3−クロロ、3−フルオロ、3−ブロモ、3−ヨード、2−メチル、3−メチル、3−エチル、2−n−プロピル、2,4−ジクロロ、2,5−ジクロロ、3,4−ジクロロ、3,5−ジクロロ、4−クロロ−2−フルオロ、2,4−ジメチル、2,5−ジメチル、3,4−ジメチル、3,5−ジメチル、2−クロロ−4−メチル、2−クロロ−5−メチル、3−クロロ−4−メチル、3−クロロ−5−メチル、4−クロロ−2−メチル、4−クロロ−3−メチル、5−クロロ−2−メチル、5−クロロ−3−メチル基等を挙げることができ、中でも、2−クロロ、3−クロロ、3−ブロモ、3−メチル、2−メチル、2−クロロ−5−メチル、5−クロロ−2−メチル及び5−クロロ−3−メチル基が好適である。   Furthermore, in this specification, when the heterocyclic ring formed when the A ring represents a furan ring is furo [2,3-c] pyridine, the substitution on the furo [2,3-c] pyridine Examples of the group include 2-chloro, 3-chloro, 3-fluoro, 3-bromo, 3-iodo, 2-methyl, 3-methyl, 3-ethyl, 2-n-propyl, 2,4-dichloro, 2,5-dichloro, 3,4-dichloro, 3,5-dichloro, 4-chloro-2-fluoro, 2,4-dimethyl, 2,5-dimethyl, 3,4-dimethyl, 3,5-dimethyl, 2-chloro-4-methyl, 2-chloro-5-methyl, 3-chloro-4-methyl, 3-chloro-5-methyl, 4-chloro-2-methyl, 4-chloro-3-methyl, 5- Listed are chloro-2-methyl, 5-chloro-3-methyl, etc. Among them, 2-chloro, 3-chloro, 3-bromo, 3-methyl, 2-methyl, 2-chloro-5-methyl, 5-chloro-2-methyl and 5-chloro-3-methyl groups Is preferred.

さらに、本明細書において、A環がチオフェン環を表す場合において形成される複素環がチエノ[3,2−c]ピリジンである場合に、このチエノ[3,2−c]ピリジン上の置換基としては、例えば、2−クロロ、3−クロロ、2−フルオロ、2−ブロモ、2−ヨード、2−メチル、3−メチル、2−エチル、3−n−プロピル、2,6−ジクロロ、2,7−ジクロロ、3,6−ジクロロ、3,7−ジクロロ、2,6−ジメチル、2,7−ジメチル、3,6−ジメチル、3,7−ジメチル、7−クロロ−3−フルオロ、2−クロロ−6−メチル、3−クロロ−6−メチル、2−クロロ−7−メチル、3−クロロ−7−メチル、6−クロロ−2−メチル、6−クロロ−3−メチル、7−クロロ−2−メチル、7−クロロ−3−メチル基等を挙げることができ、中でも、2−クロロ、3−クロロ、2−ブロモ、2−メチル、3−メチル、6−クロロ−2−メチル、6−クロロ−3−メチル、2,6−ジメチル、3,6−ジメチル及び7−クロロ−3−メチル基が好適である。   Furthermore, in the present specification, when the heterocyclic ring formed when the A ring represents a thiophene ring is thieno [3,2-c] pyridine, the substituent on the thieno [3,2-c] pyridine As, for example, 2-chloro, 3-chloro, 2-fluoro, 2-bromo, 2-iodo, 2-methyl, 3-methyl, 2-ethyl, 3-n-propyl, 2,6-dichloro, , 7-dichloro, 3,6-dichloro, 3,7-dichloro, 2,6-dimethyl, 2,7-dimethyl, 3,6-dimethyl, 3,7-dimethyl, 7-chloro-3-fluoro, 2 -Chloro-6-methyl, 3-chloro-6-methyl, 2-chloro-7-methyl, 3-chloro-7-methyl, 6-chloro-2-methyl, 6-chloro-3-methyl, 7-chloro -2-methyl, 7-chloro-3-methyl group, etc. Among them, 2-chloro, 3-chloro, 2-bromo, 2-methyl, 3-methyl, 6-chloro-2-methyl, 6-chloro-3-methyl, 2,6-dimethyl, 3 , 6-Dimethyl and 7-chloro-3-methyl groups are preferred.

さらに、本明細書において、A環がチオフェン環を表す場合において形成される複素環がチエノ[3,4−c]ピリジンである場合に、このチエノ[3,4−c]ピリジン上の置換基としては、例えば、1−クロロ、3−クロロ、1−フルオロ、1−ブロモ、1−ヨード、1−メチル、3−メチル、1−エチル、3−n−プロピル、1,6−ジクロロ、3,6−ジクロロ、1,7−ジクロロ、3,7−ジクロロ、7−クロロ−3−フルオロ、1,6−ジメチル、1,7−ジメチル、3,6−ジメチル、3,7−ジメチル、1−クロロ−6−メチル、1−クロロ−7−メチル、3−クロロ−6−メチル、3−クロロ−7−メチル、6−クロロ−1−メチル、6−クロロ−3−メチル、7−クロロ−1−メチル、7−クロロ−3−メチル基等を挙げることができ、中でも、1−クロロ、3−クロロ、1−ブロモ、1−メチル、3−メチル、6−クロロ−1−メチル、3−クロロ−6−メチル及び6−クロロ−3−メチル基が好適である。   Further, in the present specification, when the heterocyclic ring formed when the A ring represents a thiophene ring is thieno [3,4-c] pyridine, the substituent on the thieno [3,4-c] pyridine. As, for example, 1-chloro, 3-chloro, 1-fluoro, 1-bromo, 1-iodo, 1-methyl, 3-methyl, 1-ethyl, 3-n-propyl, 1,6-dichloro, 3 , 6-dichloro, 1,7-dichloro, 3,7-dichloro, 7-chloro-3-fluoro, 1,6-dimethyl, 1,7-dimethyl, 3,6-dimethyl, 3,7-dimethyl, -Chloro-6-methyl, 1-chloro-7-methyl, 3-chloro-6-methyl, 3-chloro-7-methyl, 6-chloro-1-methyl, 6-chloro-3-methyl, 7-chloro -1-methyl, 7-chloro-3-methyl group, etc. 1-chloro, 3-chloro, 1-bromo, 1-methyl, 3-methyl, 6-chloro-1-methyl, 3-chloro-6-methyl and 6-chloro-3-methyl, among others A group is preferred.

さらに、本明細書において、A環がチオフェン環を表す場合において形成される複素環がチエノ[2,3−c]ピリジンである場合に、このチエノ[2,3−c]ピリジン上の置換基としては、例えば、2−クロロ、3−クロロ、3−フルオロ、3−ブロモ、3−ヨード、2−メチル、3−メチル、3−エチル、2−n−プロピル、2,4−ジクロロ、2,5−ジクロロ、3,4−ジクロロ、3,5−ジクロロ、4−クロロ−2−フルオロ、2,4−ジメチル、2,5−ジメチル、3,4−ジメチル、3,5−ジメチル、2−クロロ−4−メチル、2−クロロ−5−メチル、3−クロロ−4−メチル、3−クロロ−5−メチル、4−クロロ−2−メチル、4−クロロ−3−メチル、5−クロロ−2−メチル、5−クロロ−3−メチル基等を挙げることができ、中でも、2−クロロ、3−クロロ、3−ブロモ、3−メチル、2−メチル、2−クロロ−5−メチル、5−クロロ−2−メチル及び5−クロロ−3−メチル基が好適である。   Furthermore, in the present specification, when the heterocyclic ring formed when the A ring represents a thiophene ring is thieno [2,3-c] pyridine, the substituent on the thieno [2,3-c] pyridine As, for example, 2-chloro, 3-chloro, 3-fluoro, 3-bromo, 3-iodo, 2-methyl, 3-methyl, 3-ethyl, 2-n-propyl, 2,4-dichloro, 2 , 5-dichloro, 3,4-dichloro, 3,5-dichloro, 4-chloro-2-fluoro, 2,4-dimethyl, 2,5-dimethyl, 3,4-dimethyl, 3,5-dimethyl, 2 -Chloro-4-methyl, 2-chloro-5-methyl, 3-chloro-4-methyl, 3-chloro-5-methyl, 4-chloro-2-methyl, 4-chloro-3-methyl, 5-chloro -2-methyl, 5-chloro-3-methyl group, etc. Among others, 2-chloro, 3-chloro, 3-bromo, 3-methyl, 2-methyl, 2-chloro-5-methyl, 5-chloro-2-methyl and 5-chloro-3-methyl A group is preferred.

本明細書において、R及びRが「一緒になって場合によりヒドロキシ基、低級アルコキシ基又はフェニル低級アルコキシ基で置換されていてもよいピロリジン環又はピペリジン環を形成して」いる場合における好適な環としては、ピロリジン環を挙げることができ、また、該ピロリジン環又はピペリジン環上の置換基としては、例えば、ヒドロキシ、メトキシ、エトキシ、n−プロポキシ、ベンジルオキシ、(2−フェニル)エトキシ基等を挙げることができ、中でも、ヒドロキシ、メトキシ及びベンジルオキシ基が好適である。 In the present specification, it is preferable that R 2 and R 3 “form together a pyrrolidine ring or a piperidine ring optionally substituted with a hydroxy group, a lower alkoxy group or a phenyl lower alkoxy group”. Examples of such a ring include a pyrrolidine ring, and examples of the substituent on the pyrrolidine ring or piperidine ring include a hydroxy group, a methoxy group, an ethoxy group, an n-propoxy group, a benzyloxy group, and a (2-phenyl) ethoxy group. Among them, hydroxy, methoxy and benzyloxy groups are preferable.

さらに、「ハロゲン原子」にはフッ素、塩素、臭素及びヨウ素原子が包含され、この中でも好ましいものとしてフッ素、塩素及び臭素原子を挙げることができる。   Furthermore, the “halogen atom” includes fluorine, chlorine, bromine and iodine atoms. Among them, preferred are fluorine, chlorine and bromine atoms.

本発明において好ましい一群の化合物は、A環がハロゲン原子、ヒドロキシ基又は低級アルコキシ基で置換されていてもよいベンゼン環を表す場合の式(I)の化合物、すなわち、Rがハロゲン原子、ヒドロキシ基又は低級アルコキシ基を表す場合の式(III)の化合物である。 A preferred group of compounds in the present invention is a compound of the formula (I) when the A ring represents a benzene ring optionally substituted with a halogen atom, a hydroxy group or a lower alkoxy group, that is, R 5 is a halogen atom, a hydroxy A compound of formula (III) in the case of a group or a lower alkoxy group

本発明において好ましい別の一群の化合物は、Rが水素原子を表す場合の式(I)の化合物である。 Another group of compounds preferred in the present invention are the compounds of formula (I) when R 1 represents a hydrogen atom.

本発明において好ましいさらに別の一群の化合物は、Rが水素原子又は低級アルキル基を表す場合の式(I)の化合物である。 Yet another group of compounds preferred in the present invention are compounds of formula (I) when R 2 represents a hydrogen atom or a lower alkyl group.

本発明において好ましいさらに別の一群の化合物は、R及びRがともに水素原子を表す場合の式(I)の化合物である。 Yet another group of compounds preferred in the present invention are compounds of formula (I) when R 3 and R 4 both represent a hydrogen atom.

本発明により提供される薬剤を構成する前記式(I)の化合物の代表例としては、次のものを挙げることができる。   Typical examples of the compound of the formula (I) constituting the drug provided by the present invention include the following.

7−ピペラジン−1−イルフロ[2,3−c]ピリジン、
6−メチル−7−ピペラジン−1−イルフロ[2,3−c]ピリジン、
7−(3−メチルピペラジン−1−イル)フロ[2,3−c]ピリジン、
7−(4−メチルピペラジン−1−イル)フロ[2,3−c]ピリジン、
4−ピペラジン−1−イルフロ[3,2−c]ピリジン、
4−(3−メチルピペラジン−1−イル)フロ[3,2−c]ピリジン、
3−クロロ−4−(3−メチルピペラジン−1−イル)フロ[3,2−c]ピリジン、
4−(4−メチルピペラジン−1−イル)フロ[3,2−c]ピリジン、
4−ピペラジン−1−イルフロ[3,4−c]ピリジン、
7−ピペラジン−1−イルチエノ[2,3−c]ピリジン、
7−(3−メチルピペラジン−1−イル)チエノ[2,3−c]ピリジン、
3−クロロ−7−(3−メチルピペラジン−1−イル)チエノ[2,3−c]ピリジン、
7−(4−メチルピペラジン−1−イル)チエノ[2,3−c]ピリジン、
4−ピペラジン−1−イルチエノ[3,2−c]ピリジン、
4−ピペラジン−1−イルチエノ[3,4−c]ピリジン、
4−(3−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジン、
6−クロロ−4−(3−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジン、
4−(4−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジン、
2−ブロモ−4−ピペラジン−1−イルチエノ[3,2−c]ピリジン 2塩酸塩、
2−ブロモ−4−(3−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジン、
2−ブロモ−6−メチル−4−(3−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジン、
2−ブロモ−4−(4−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジン、
2−メチル−4−ピペラジン−1−イルチエノ[3,2−c]ピリジン 2塩酸塩、
2−メチル−4−(3−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジン 2塩酸塩、
2−メチル−4−(4−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジン 2塩酸塩、
3−ブロモ−4−ピペラジン−1−イルチエノ[3,2−c]ピリジン 2塩酸塩、
3−ブロモ−4−(3−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジン、
3−ブロモ−4−(4−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジン、
3−クロロ−1−ピペラジン−1−イルイソキノリン 2塩酸塩、
3−クロロ−7−メトキシ−1−ピペラジン−1−イルイソキノリン、
3−クロロ−1−(4−メチルピペラジン−1−イル)イソキノリン 2塩酸塩、
7−(4−エチルピペラジン−1−イル)チエノ[2,3−c]ピリジン、
4−(4−エチルピペラジン−1−イル)チエノ[3,2−c]ピリジン、
5−ピペラジン−1−イル−1,6−ナフチリジン、
7−クロロ−5−ピペラジン−1−イル−1,6−ナフチリジン、
5−(4−エチルピペラジン−1−イル)−1,6−ナフチリジン、
8−ピペラジン−1−イル−1,7−ナフチリジン、
8−(4−エチルピペラジン−1−イル)−1,7−ナフチリジン、
1−ピペラジン−1−イル−2,6−ナフチリジン、
1−ピペラジン−1−イル−2,7−ナフチリジン、
2−メチル−ピペラジン−1−イルフロ[3,2−c]ピリジン、
7−メトキシ−3−メチル−1−ピペラジン−1−イルイソキノリン、
7−メトキシ−3,4−ジメチル−1−(4−メチルピペラジン−1−イル)イソキノリン、
7−メトキシ−4−メチル−1−ピペラジン−1−イルイソキノリン、
7−メトキシ−4−メチル−1−(4−メチルピペラジン−1−イル)イソキノリン、
7−ブロモ−1−ピペラジン−1−イルイソキノリン、
7−ブロモ−1−(4−メチルピペラジン−1−イル)イソキノリン、
7−メトキシ−1−(4−メチルピペラジン−1−イル)イソキノリン、
1−(4−エチルピペラジン−1−イル)−7−メトキシイソキノリン、
7−メトキシ−1−ピペラジン−1−イルイソキノリン、
1−ピペラジン−1−イルイソキノリン、
1−(4−メチルピペラジン−1−イル)イソキノリン、
1−(4−エチルピペラジン−1−イル)イソキノリン、
7−メトキシ−1−(3−メチルピペラジン−1−イル)イソキノリン、
1−(3,5−ジメチルピペラジン−1−イル)−7−メトキシ−イソキノリン、
6−メトキシ−1−ピペラジン−1−イルイソキノリン、
6−メトキシ−1−(4−メチルピペラジン−1−イル)イソキノリン、
1−(4−エチルピペラジン−1−イル)−6−メトキシイソキノリン、
5−メトキシ−1−ピペラジン−1−イルイソキノリン、
5−メトキシ−1−(4−メチルピペラジン−1−イル)イソキノリン、
1−(4−エチルピペラジン−1−イル)−5−メトキシイソキノリン、
7−メチル−1−ピペラジン−1−イルイソキノリン、
7−メチル−1−(4−メチルピペラジン−1−イル)イソキノリン、
1−(4−エチルピペラジン−1−イル)−7−メチルイソキノリン、
7−クロロ−1−ピペラジン−1−イルイソキノリン、
7−クロロ−1−(4−メチルピペラジン−1−イル)イソキノリン、
7−クロロ−1−(4−エチルピペラジン−1−イル)イソキノリン、
7−フルオロ−1−(4−メチルピペラジン−1−イル)イソキノリン、
1−(4−エチルピペラジン−1−イル)−7−フルオロイソキノリン、
1−(4−メチルピペラジン−1−イル)−7−フェニルイソキノリン、
1−(4−エチルピペラジン−1−イル)−7−フェニルイソキノリン、
7−フェニル−1−ピペラジン−1−イルイソキノリン、
6−クロロ−1−ピペラジン−1−イルイソキノリン、
6−クロロ−1−(4−メチルピペラジン−1−イル)イソキノリン、
6−クロロ−1−(4−エチルピペラジン−1−イル)イソキノリン、
5−クロロ−1−ピペラジン−1−イルイソキノリン、
5−クロロ−1−(4−メチルピペラジン−1−イル)イソキノリン、
5−クロロ−1−(4−エチルピペラジン−1−イル)イソキノリン、
7−フルオロ−1−ピペラジン−1−イルイソキノリン、
7−クロロ−1−[4−[4−(3−メトキシフェニル)ブチル]ピペラジン−1−イル]イソキノリン、
7−メトキシ−1−[4−[4−(3−メトキシフェニル)ブチル]ピペラジン−1−イル]イソキノリン、
7−クロロ−1−[4−[トランス−4−(3−メトキシフェニル)シクロヘキサン−1−イル]ピペラジン−1−イル]イソキノリン、
7−メトキシ−1−[4−[トランス−4−(3−メトキシフェニル)シクロヘキサン−1−イル]ピペラジン−1−イル]イソキノリン、
1−((8aS)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)−7−メトキシイソキノリン、
7−クロロ−1−((8aS)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)イソキノリン、
8−((8aS)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)−1,7−ナフチリジン、
5−((8aS)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)−1,6−ナフチリジン、
7−クロロ−1−((8aR)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)イソキノリン、
1−((8aR)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)−7−メトキシイソキノリン、
3−クロロ−1−((8aS)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)イソキノリン、
3−クロロ−1−((8aS)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)−7−メチルイソキノリン、
7−クロロ−1−オクタヒドロピリド[1,2−a]ピラジン−2−イルイソキノリン、
7−メトキシ−1−オクタヒドロピリド[1,2−a]ピラジン−2−イルイソキノリン、
7−メチルチオ−1−(S)−オクタヒドロピリド[1,2−a]ピラン−2−イルイソキノリン、
7−メチルスルフィニル−1−(S)−オクタヒドロピリド[1,2−a]ピラン−2−イルイソキノリン、
7−ヒドロキシ−1−オクタヒドロピリド[1,2−a]ピラジン−2−イルイソキノリン、
1−(S)−オクタヒドロピリド[1,2−a]ピラン−2−イル−7−ヒドロキシイソキノリン、
1−オクタヒドロピリド[1,2−a]ピラジン−2−イル−7−スルファモイルオキシイソキノリン、
1−(S)−オクタヒドロピリド[1,2−a]ピラン−2−イル−7−スルファモイルオキシイソキノリン、
1−(4−ベンジルピペラジン−1−イル)−7−クロロイソキノリン、
1−(4−ベンジルピペラジン−1−イル)−7−ジメチルアミノイソキノリン、
7−メチルアミノ−1−ピペラジン−1−イルイソキノリン、
7−エチルアミノ−1−ピペラジン−1−イルイソキノリン、
7−ジメチルアミノ−1−ピペラジン−1−イルイソキノリン、
7−ジメチルアミノ−1−(4−メチルピペラジン−1−イル)イソキノリン、
7−メチルアミノ−1−(4−メチルピペラジン−1−イル)イソキノリン、
1−[4−(4−フルオロベンジル)ピペラジン−1−イル]−7−メトキシイソキノリン、
1−[4−(4−フルオロベンジル)ピペラジン−1−イル]イソキノリン、
7−ヒドロキシ−1−ピペラジン−1−イルイソキノリン 塩酸塩、
7−ヒドロキシ−1−(4−メチルピペラジン−1−イル)イソキノリン、
7−エトキシ−1−ピペラジン−1−イルイソキノリン、
7−(4−フルオロベンジルオキシ)−1−ピペラジン−1−イルイソキノリン、
7−ベンジルオキシ−1−ピペラジン−1−イルイソキノリン、
7−スルファモイルオキシ−1−ピペラジン−1−イルイソキノリン 塩酸塩、など。
7-piperazin-1-ylfuro [2,3-c] pyridine,
6-methyl-7-piperazin-1-ylfuro [2,3-c] pyridine,
7- (3-methylpiperazin-1-yl) furo [2,3-c] pyridine,
7- (4-methylpiperazin-1-yl) furo [2,3-c] pyridine,
4-piperazin-1-ylfuro [3,2-c] pyridine,
4- (3-methylpiperazin-1-yl) furo [3,2-c] pyridine,
3-chloro-4- (3-methylpiperazin-1-yl) furo [3,2-c] pyridine,
4- (4-methylpiperazin-1-yl) furo [3,2-c] pyridine,
4-piperazin-1-ylfuro [3,4-c] pyridine,
7-piperazine-1-ylthieno [2,3-c] pyridine,
7- (3-methylpiperazin-1-yl) thieno [2,3-c] pyridine,
3-chloro-7- (3-methylpiperazin-1-yl) thieno [2,3-c] pyridine,
7- (4-methylpiperazin-1-yl) thieno [2,3-c] pyridine,
4-piperazin-1-ylthieno [3,2-c] pyridine,
4-piperazin-1-ylthieno [3,4-c] pyridine,
4- (3-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
6-chloro-4- (3-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
2-bromo-4-piperazin-1-ylthieno [3,2-c] pyridine dihydrochloride,
2-bromo-4- (3-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
2-bromo-6-methyl-4- (3-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
2-bromo-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
2-methyl-4-piperazin-1-ylthieno [3,2-c] pyridine dihydrochloride,
2-methyl-4- (3-methylpiperazin-1-yl) thieno [3,2-c] pyridine dihydrochloride,
2-methyl-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine dihydrochloride,
3-bromo-4-piperazin-1-ylthieno [3,2-c] pyridine dihydrochloride,
3-bromo-4- (3-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
3-bromo-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine,
3-chloro-1-piperazin-1-ylisoquinoline dihydrochloride,
3-chloro-7-methoxy-1-piperazin-1-ylisoquinoline,
3-chloro-1- (4-methylpiperazin-1-yl) isoquinoline dihydrochloride,
7- (4-ethylpiperazin-1-yl) thieno [2,3-c] pyridine,
4- (4-ethylpiperazin-1-yl) thieno [3,2-c] pyridine,
5-piperazin-1-yl-1,6-naphthyridine,
7-chloro-5-piperazin-1-yl-1,6-naphthyridine,
5- (4-ethylpiperazin-1-yl) -1,6-naphthyridine,
8-piperazin-1-yl-1,7-naphthyridine,
8- (4-ethylpiperazin-1-yl) -1,7-naphthyridine,
1-piperazin-1-yl-2,6-naphthyridine,
1-piperazin-1-yl-2,7-naphthyridine,
2-methyl-piperazin-1-ylfuro [3,2-c] pyridine,
7-methoxy-3-methyl-1-piperazin-1-ylisoquinoline,
7-methoxy-3,4-dimethyl-1- (4-methylpiperazin-1-yl) isoquinoline,
7-methoxy-4-methyl-1-piperazin-1-ylisoquinoline,
7-methoxy-4-methyl-1- (4-methylpiperazin-1-yl) isoquinoline,
7-bromo-1-piperazin-1-ylisoquinoline,
7-bromo-1- (4-methylpiperazin-1-yl) isoquinoline,
7-methoxy-1- (4-methylpiperazin-1-yl) isoquinoline,
1- (4-ethylpiperazin-1-yl) -7-methoxyisoquinoline,
7-methoxy-1-piperazin-1-ylisoquinoline,
1-piperazin-1-ylisoquinoline,
1- (4-methylpiperazin-1-yl) isoquinoline,
1- (4-ethylpiperazin-1-yl) isoquinoline,
7-methoxy-1- (3-methylpiperazin-1-yl) isoquinoline,
1- (3,5-dimethylpiperazin-1-yl) -7-methoxy-isoquinoline,
6-methoxy-1-piperazin-1-ylisoquinoline,
6-methoxy-1- (4-methylpiperazin-1-yl) isoquinoline,
1- (4-ethylpiperazin-1-yl) -6-methoxyisoquinoline,
5-methoxy-1-piperazin-1-ylisoquinoline,
5-methoxy-1- (4-methylpiperazin-1-yl) isoquinoline,
1- (4-ethylpiperazin-1-yl) -5-methoxyisoquinoline,
7-methyl-1-piperazin-1-ylisoquinoline,
7-methyl-1- (4-methylpiperazin-1-yl) isoquinoline,
1- (4-ethylpiperazin-1-yl) -7-methylisoquinoline,
7-chloro-1-piperazin-1-ylisoquinoline,
7-chloro-1- (4-methylpiperazin-1-yl) isoquinoline,
7-chloro-1- (4-ethylpiperazin-1-yl) isoquinoline,
7-fluoro-1- (4-methylpiperazin-1-yl) isoquinoline,
1- (4-ethylpiperazin-1-yl) -7-fluoroisoquinoline,
1- (4-methylpiperazin-1-yl) -7-phenylisoquinoline,
1- (4-ethylpiperazin-1-yl) -7-phenylisoquinoline,
7-phenyl-1-piperazin-1-ylisoquinoline,
6-chloro-1-piperazin-1-ylisoquinoline,
6-chloro-1- (4-methylpiperazin-1-yl) isoquinoline,
6-chloro-1- (4-ethylpiperazin-1-yl) isoquinoline,
5-chloro-1-piperazin-1-ylisoquinoline,
5-chloro-1- (4-methylpiperazin-1-yl) isoquinoline,
5-chloro-1- (4-ethylpiperazin-1-yl) isoquinoline,
7-fluoro-1-piperazin-1-ylisoquinoline,
7-chloro-1- [4- [4- (3-methoxyphenyl) butyl] piperazin-1-yl] isoquinoline,
7-methoxy-1- [4- [4- (3-methoxyphenyl) butyl] piperazin-1-yl] isoquinoline,
7-chloro-1- [4- [trans-4- (3-methoxyphenyl) cyclohexane-1-yl] piperazin-1-yl] isoquinoline,
7-methoxy-1- [4- [trans-4- (3-methoxyphenyl) cyclohexane-1-yl] piperazin-1-yl] isoquinoline,
1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -7-methoxyisoquinoline,
7-chloro-1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) isoquinoline,
8-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -1,7-naphthyridine,
5-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -1,6-naphthyridine,
7-chloro-1-((8aR) -octahydropyrrolo [1,2-a] pyrazin-2-yl) isoquinoline,
1-((8aR) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -7-methoxyisoquinoline,
3-chloro-1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) isoquinoline,
3-chloro-1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -7-methylisoquinoline,
7-chloro-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline,
7-methoxy-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline,
7-methylthio-1- (S) -octahydropyrido [1,2-a] pyran-2-ylisoquinoline,
7-methylsulfinyl-1- (S) -octahydropyrido [1,2-a] pyran-2-ylisoquinoline,
7-hydroxy-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline,
1- (S) -octahydropyrido [1,2-a] pyran-2-yl-7-hydroxyisoquinoline,
1-octahydropyrido [1,2-a] pyrazin-2-yl-7-sulfamoyloxyisoquinoline,
1- (S) -octahydropyrido [1,2-a] pyran-2-yl-7-sulfamoyloxyisoquinoline,
1- (4-benzylpiperazin-1-yl) -7-chloroisoquinoline,
1- (4-benzylpiperazin-1-yl) -7-dimethylaminoisoquinoline,
7-methylamino-1-piperazin-1-ylisoquinoline,
7-ethylamino-1-piperazin-1-ylisoquinoline,
7-dimethylamino-1-piperazin-1-ylisoquinoline,
7-dimethylamino-1- (4-methylpiperazin-1-yl) isoquinoline,
7-methylamino-1- (4-methylpiperazin-1-yl) isoquinoline,
1- [4- (4-fluorobenzyl) piperazin-1-yl] -7-methoxyisoquinoline,
1- [4- (4-fluorobenzyl) piperazin-1-yl] isoquinoline,
7-hydroxy-1-piperazin-1-ylisoquinoline hydrochloride,
7-hydroxy-1- (4-methylpiperazin-1-yl) isoquinoline,
7-ethoxy-1-piperazin-1-ylisoquinoline,
7- (4-fluorobenzyloxy) -1-piperazin-1-ylisoquinoline,
7-benzyloxy-1-piperazin-1-ylisoquinoline,
7-sulfamoyloxy-1-piperazin-1-ylisoquinoline hydrochloride, etc.

本明細書における前記式(I)の化合物は、そのほとんどが文献(例えば、J.Med.Chem.,42,4362−4379(1999)など)に記載された既知の化合物であり、たとえ未知の化合物であったとしても、文献等に記載の合成方法又は後記製造例に従って容易に合成することができる。   Most of the compounds of the formula (I) in the present specification are known compounds described in the literature (for example, J. Med. Chem., 42, 4362-4379 (1999), etc.). Even if it is a compound, it can be easily synthesized according to the synthesis method described in the literature or the like or the production examples described later.

本発明の式(I)の化合物は、また、塩を形成することができ、その塩の例としては、例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸等の無機酸との塩;酢酸、蓚酸、クエン酸、乳酸、酒石酸、p−トルエンスルホン酸等の有機酸との塩;ナトリウム塩、カリウム塩、リチウム塩等のアルカリ金属塩;カルシウム塩、マグネシウム塩等のアルカリ土類金属塩;トリエチルアミン、ジシクロヘキシルアミン、ピロリジン、モルホリン、ピリジン等の有機塩基との塩;アンモニウム塩等が挙げられ、中でも製薬学的に許容しうる塩が好ましい。   The compounds of formula (I) according to the invention can also form salts, examples of which include salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid. A salt with an organic acid such as acetic acid, succinic acid, citric acid, lactic acid, tartaric acid or p-toluenesulfonic acid; an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal such as calcium salt or magnesium salt; Salts; salts with organic bases such as triethylamine, dicyclohexylamine, pyrrolidine, morpholine, pyridine; ammonium salts, and the like. Among them, pharmaceutically acceptable salts are preferable.

本発明の薬剤は、5−HT1A及び5−HTの両者が関連する疾患の治療、処置のため、例えば、ヒト、その他の哺乳動物の過敏性腸症候群、不安、腹圧性尿失禁、切迫性尿失禁、うつ病、前立腺癌、総合失調症、頻尿、精神分裂病、過活動性膀胱症候群、精神病、下部尿路症、老人性痴呆症、前立腺肥大症に伴う排尿障害、アルツハイマー病、間質性膀胱炎、嗜癖/禁断症状、慢性前立腺炎、認知障害、急性脳卒中から生じる虚血、ハンチントン病、一過性脳虚血発作、パーキンソン病、頭部もしくは脊髄の外傷、筋萎縮性側索硬化症、胎仔低酸素症、AIDS痴呆症、非潰瘍性消化不良、網膜疾患などの慢性神経変性疾患、逆流性食道炎、アルコール又はコカインに対する嗜癖、刺激反応性腸症候群、錐体外路障害、無呼吸もしくは無呼吸症、パニック症候群、振戦、短期記憶障害、悪心もしくは嘔吐、アルコール中毒症、癲癇、ニコチン依存症、睡眠障害、薬物嗜癖、疼痛、摂食障害、性的機能不全、外傷性ストレス症、肥満、幼少期自閉症、せき、神経の圧迫による症候群、筋膜症候群、ニューロパシー、テンドミオシス(tendomyosis)、疼痛性ジストロフィー、テンディノーシス(tendinosis)、興奮症状(agitation)、挿入テンドバシー(tendopathy)、攻撃性(hostility)、滑液包疾患、強迫性障害、関節周囲症(periarthropathy)、知能促進(cognition enhancement)、筋内の過負荷症候群、性的機能不全、月経前緊張症候群、自律神経失調症、本態性高血圧症、心身症、痙攣、消化性潰瘍、躁病、胃炎、片頭痛、半月損傷、慢性多発性関節炎、関節症外傷、傍腫瘍性症状、局所離断性骨軟骨炎、腫瘍誘導性炎症性疾患、骨壊死、白濁性滲出、関節軟骨腫症、膠原病、慢性閉塞性肺疾患(COPD)、感染後関節炎、成人呼吸困難症候群(ARDS)、血清反応陰性脊髄関節炎、気管支炎、脈管炎、じん肺、サルコイドーシス関節症、喉頭痙攣、肺脈管炎、肺肉芽腫、外因性アレルギー性肺胞炎、慢性疲労症候群又は緑内障の治療、処置等のために有用である。 The agent of the present invention is used for the treatment and treatment of diseases associated with both 5-HT 1A and 5-HT 3 , such as irritable bowel syndrome, anxiety, stress urinary incontinence, urgency in humans and other mammals. Urinary incontinence, depression, prostate cancer, schizophrenia, frequent urination, schizophrenia, overactive bladder syndrome, psychosis, lower urinary tract disease, senile dementia, dysuria associated with benign prostatic hyperplasia, Alzheimer's disease, Interstitial cystitis, addiction / withdrawal symptoms, chronic prostatitis, cognitive impairment, ischemia resulting from acute stroke, Huntington's disease, transient ischemic attack, Parkinson's disease, head or spinal cord trauma, muscle atrophic side Cord sclerosis, fetal hypoxia, AIDS dementia, non-ulcer dyspepsia, chronic neurodegenerative diseases such as retinal disease, reflux esophagitis, addiction to alcohol or cocaine, stimulus-responsive bowel syndrome, extrapyramidal disorders, Apnea or Respiratory disease, panic syndrome, tremor, short-term memory impairment, nausea or vomiting, alcoholism, epilepsy, nicotine dependence, sleep disorder, drug addiction, pain, eating disorders, sexual dysfunction, traumatic stress disorder, obesity Childhood autism, cough, nerve compression syndrome, fascia syndrome, neuropathy, tendomyosis, painful dystrophy, tendinosis, agitation, insertion tendonpathy, attack Hostility, bursal disease, obsessive compulsive disorder, periarthropathy, cognitive enhancement, intramuscular overload syndrome, sexual dysfunction, premenstrual tension syndrome, autonomic ataxia, Essential hypertension, Physical disease, convulsions, peptic ulcer, gonorrhea, gastritis, migraine, half-moon injury, chronic polyarthritis, arthritic trauma, paraneoplastic symptoms, locally severe osteochondritis, tumor-induced inflammatory disease, osteonecrosis , Cloudy exudation, articular chondromatosis, collagen disease, chronic obstructive pulmonary disease (COPD), post-infection arthritis, adult respiratory distress syndrome (ARDS), seronegative spinal arthritis, bronchitis, vasculitis, pneumoconiosis, sarcoidosis It is useful for the treatment and treatment of arthropathy, laryngeal spasm, pulmonary vasculitis, pulmonary granuloma, exogenous allergic alveolitis, chronic fatigue syndrome or glaucoma.

本発明の薬剤における5−HT1A作動作用及び5−HT拮抗作用は、以下に述べる実験によって示すことができる。
(1)ヒト5−HT 1A 受容体に対する化合物の親和性の測定(インビトロ):
ヒト5−HT1A受容体を発現させたCHO細胞膜標本(パッカードバイオサイエンシーズ社(Packard Bioscience)より購入)0.25mL(約50ユニット)を24.75mLのインキュベーションバッファーA液(50mmol/LのTris−塩酸、10mmol/Lの硫酸マグネシウム、0.5mmol/LのEDTA及び0.1%アスコルビン酸の混合物の水溶液を、1N−水酸化ナトリウム水溶液を用いて27℃においてpH7.4に調整したもの)に加え、膜標本懸濁液A液とした。また、各被検化合物を270μmol/LのDMSO溶液とした後、インキュベーションバッファーA液を用いて所定の濃度まで希釈し、化合物溶液とした。
The 5-HT 1A agonistic action and 5-HT 3 antagonism of the drug of the present invention can be shown by the experiments described below.
(1) Determination of the affinity of a compound for human 5-HT 1A receptor (in vitro):
CHO cell membrane specimen expressing human 5-HT 1A receptor (purchased from Packard Bioscience) 0.25 mL (about 50 units) 24.75 mL incubation buffer A solution (50 mmol / L Tris) -An aqueous solution of a mixture of hydrochloric acid, 10 mmol / L magnesium sulfate, 0.5 mmol / L EDTA and 0.1% ascorbic acid, adjusted to pH 7.4 at 27 ° C with 1N aqueous sodium hydroxide) In addition, a membrane specimen suspension A solution was obtained. Each test compound was made into a 270 μmol / L DMSO solution, and then diluted to a predetermined concentration using incubation buffer A solution to obtain a compound solution.

ポリプロピレン製チューブに、[H]8−OH−DPAT(8−ハイドロキシ−2−(ジ−N−プロピルアミノ)テトラリン;第一化学薬品株式会社より購入)のインキュベーションバッファーA溶液20μL(ただし、反応混合物中の[H]8−OH−DPATの濃度が0.25nmol/Lとなるように、[H]8−OH−DPATの濃度を調整)及び20μLの化合物溶液を入れ、さらに膜標本懸濁液A液500μLを加えて、27℃で60分間インキュベーションした。Brandel cell harvesterを用いて、インキュベーションバッファーA液に0.3%濃度となるようにポリエチレンイミンを加えた溶液に前もって浸しておいたGF/Cフィルターで急速にフィルトレーションすることにより反応を停止させた後、4℃に冷却した50mmol/LのTris−塩酸約5mLを用いてフィルターを洗浄し、再度、同様の操作によりフィルターを洗浄した。 In a polypropylene tube, 20 μL of incubation buffer A solution of [ 3 H] 8-OH-DPAT (8-hydroxy-2- (di-N-propylamino) tetralin; purchased from Daiichi Chemical Co., Ltd.) The concentration of [ 3 H] 8-OH-DPAT is adjusted so that the concentration of [ 3 H] 8-OH-DPAT in the mixture is 0.25 nmol / L) and 20 μL of the compound solution are added. 500 μL of suspension A solution was added and incubated at 27 ° C. for 60 minutes. Using a Brandel cell harvester, the reaction was stopped by rapidly filtering with a GF / C filter that had been pre-soaked in a solution of polyethyleneimine to a concentration of 0.3% in incubation buffer A solution. After that, the filter was washed with about 5 mL of 50 mmol / L Tris-hydrochloric acid cooled to 4 ° C., and the filter was washed again by the same operation.

フィルターに残存する放射活性を液体シンチレーションカウンター(Aloka社製、LSC−5100)で測定した。0.25nmol/Lの濃度における[H]8−OH−DPATの5−HT1A受容体への結合に対する各被検化合物の抑制率(%)、すなわち、5−HT1A受容体に対する各被検化合物の親和性は以下の式により算出することができる。なお、非特異結合の割合は10μmol/Lの濃度の8−OH−DPATを用いた場合の放射活性を測定することにより算出し、それをもって各被検化合物の測定値を修正した。 The radioactivity remaining on the filter was measured with a liquid scintillation counter (manufactured by Aloka, LSC-5100). Inhibition rate (%) of each test compound with respect to the binding of [ 3 H] 8-OH-DPAT to 5-HT 1A receptor at a concentration of 0.25 nmol / L, that is, each test target for 5-HT 1A receptor. The affinity of the test compound can be calculated by the following formula. The ratio of non-specific binding was calculated by measuring the radioactivity when 8-OH-DPAT having a concentration of 10 μmol / L was used, and the measured value of each test compound was corrected accordingly.

Figure 0004596792
Figure 0004596792

(2)ヒト5−HT 受容体に対する化合物の親和性の測定(インビトロ):
ヒト5−HT受容体を発現させたHEK−293細胞膜標本(バイオリンクス株式会社より購入)0.05mL(約50マイクロアッセイ)を24.95mLのインキュベーションバッファーB液(50mmol/LのTris−塩酸、5mmol/Lの塩化マグネシウム及び1mmol/LのEDTAの混合物の水溶液を1N−水酸化ナトリウム水溶液を用いて25℃においてpH7.5に調整したもの)に加えてホモジナイズし、膜標本懸濁液B液とした。また、各被検化合物を270μmol/LのDMSO溶液とした後、インキュベーションバッファーB液を用いて所定の濃度まで希釈し、化合物溶液とした。
ポリプロピレン製チューブに、[H]BRL−43694(第一化学薬品株式会社より購入)のインキュベーションバッファーB溶液20μL(ただし、反応混合物中の[H]BRL−43694の濃度が0.5nmol/Lとなるように、[H]BRL−43694の濃度をあらかじめ調整)及び20μLの化合物溶液を入れ、さらに膜標本懸濁液B液500μLを加えて、25℃で60分間インキュベーションした。Brandel cell harvesterを用いて、インキュベーションバッファーB液に0.5%濃度となるようにポリエチレンイミンを加えた溶液に前もって浸しておいたGF/Bフィルターで急速にフィルトレーションすることにより反応を停止させた後、4℃に冷却した50mmol/LのTris−塩酸約5mLを用いてフィルターを洗浄し、再度、同様の操作によりフィルターを洗浄した。
フィルターに残存する放射活性を液体シンチレーションカウンター(Aloka社製、LSC−5100)で測定した。0.5nmol/Lの濃度における[H]BRL−43694の5−HT受容体への結合に対する各被検化合物の抑制率(%)、すなわち、5−HT受容体に対する各被検化合物の親和性は以下の式により算出することができる。なお、非特異結合の割合は10μmol/Lの濃度のトロピセトロン(tropisetron:ICS205−930)を用いた場合の放射活性を測定することにより算出し、それをもって各被検化合物の測定値を修正した。
(2) Measuring the affinity of a compound for human 5-HT 3 receptor (in vitro):
Human 5-HT 3 (purchased from Bio Links Ltd) receptor was expressed HEK-293 cell membranes sample 0.05 mL (about 50 microassay) the 24.95mL incubation buffer B solution (50 mmol / L of Tris- hydrochloric acid Membrane sample suspension B was added to an aqueous solution of a mixture of 5 mmol / L magnesium chloride and 1 mmol / L EDTA, adjusted to pH 7.5 at 25 ° C. using a 1N-sodium hydroxide aqueous solution). A liquid was used. Each test compound was made into a 270 μmol / L DMSO solution, and then diluted to a predetermined concentration using incubation buffer B solution to obtain a compound solution.
In a polypropylene tube, 20 μL of an incubation buffer B solution of [ 3 H] BRL-43694 (purchased from Daiichi Chemical Co., Ltd.) (however, the concentration of [ 3 H] BRL-43694 in the reaction mixture is 0.5 nmol / L). Then, the concentration of [ 3 H] BRL-43694 was adjusted in advance) and 20 μL of the compound solution were added, and 500 μL of the membrane sample suspension B solution was further added, followed by incubation at 25 ° C. for 60 minutes. Using a Brandel cell harvester, the reaction was stopped by rapid filtration with a GF / B filter pre-soaked in a solution of polyethyleneimine to 0.5% concentration in incubation buffer B. After that, the filter was washed with about 5 mL of 50 mmol / L Tris-hydrochloric acid cooled to 4 ° C., and the filter was washed again by the same operation.
The radioactivity remaining on the filter was measured with a liquid scintillation counter (manufactured by Aloka, LSC-5100). Inhibition rate (%) of each test compound for binding of [ 3 H] BRL-43694 to 5-HT 3 receptor at a concentration of 0.5 nmol / L, ie, each test compound against 5-HT 3 receptor The affinity can be calculated by the following equation. The ratio of non-specific binding was calculated by measuring the radioactivity when tropisetron (ICS205-930) at a concentration of 10 μmol / L was used, and the measured value of each test compound was corrected accordingly. .

Figure 0004596792
Figure 0004596792

5−HT1A受容体及び5−HT受容体に対する、100nmol/Lの濃度における各被検化合物の親和性を下記表Aに示す。なお、5−HT受容体に対する化合物の親和性の測定に用いるBRL−43694及びtropisetron(ICS205−930)は以下の構造式で示される。

Figure 0004596792
Table A below shows the affinity of each test compound at a concentration of 100 nmol / L for the 5-HT 1A receptor and 5-HT 3 receptor. BRL-43694 and tropistron (ICS205-930) used for measuring the affinity of a compound for 5-HT 3 receptor are represented by the following structural formulas.
Figure 0004596792

Figure 0004596792
Figure 0004596792

(3)ラットに対する5−HT 1A 受容体作動作用の測定(インビボ):
7週齢のSD系雄性ラットを1群あたり4〜5匹に分けた。これを実験環境に2度馴化させ、2度目の馴化の1週間後に透明なプラスチックケースに入れ、被検化合物10mg/kg(1N−塩酸に溶解した後、適量の生理食塩液にて希釈したもの)を腹腔内投与した。化合物の投与直前並びに投与後5、10、20及び30分後に、lower lip retraction(LLR)及びflat body posture(FBP)についての行動観察を行い、これを4段階(0:無反応、1:微反応、2:中程度反応、3:最大反応)で評価した。そして、各測定ポイントにおける各群の評価の最大値を求めた。その結果を下記表Bに示す。
(3) Measurement of 5-HT 1A receptor agonist effect on rats (in vivo):
Seven-week-old SD male rats were divided into 4-5 animals per group. This was acclimated twice to the experimental environment, placed in a transparent plastic case one week after the second acclimation, and 10 mg / kg of the test compound (dissolved in 1N hydrochloric acid and then diluted with an appropriate amount of physiological saline) ) Was administered intraperitoneally. Immediately before the administration of the compound and 5, 10, 20 and 30 minutes after the administration, behavioral observations were made on lower lip retraction (LLR) and flat body posture (FBP), which were classified into four stages (0: no response, 1: slight). Reaction, 2: moderate reaction, 3: maximum reaction). And the maximum value of evaluation of each group in each measurement point was calculated | required. The results are shown in Table B below.

Figure 0004596792
Figure 0004596792

(4)ラットに対する5−HT 受容体拮抗作用の測定(インビボ):
270〜410gのSD系雄性ラットの腹腔内にウレタン1.25g/kg(蒸留水に溶解したもの)を投与して麻酔した後、左頚動脈に血圧測定及び心拍数測定用、右頚静脈に化合物投与用のカテーテルをそれぞれ挿入した。血圧及び心拍数が安定した後、5−ヒドロキシトリプタミン クレアチニン サルフェート(以下、セロトニンという。)300μg/kgを静脈内に急速に投与し、一過性に発現する徐脈反応(BC1)を観察した。次に、セロトニン投与後に再び血圧及び心拍数が安定したところで、被検化合物を静脈内に投与し、投与10分後に再びセロトニン300μg/kgを急速静脈内投与した際に発現する一過性の徐脈(BC2)を観察した。各被検化合物の徐脈発現抑制率、すなわち、BJ反射抑制率は以下の式により算出することができる。
(4) Measurement of 5-HT 3 receptor antagonism on rats (in vivo):
270-410 g SD male rats were intranasally injected with urethane 1.25 g / kg (dissolved in distilled water) and anesthetized, then the left carotid artery was used for blood pressure and heart rate measurement, and the right jugular vein was compounded Each administration catheter was inserted. After stabilization of blood pressure and heart rate, 300 μg / kg of 5-hydroxytryptamine creatinine sulfate (hereinafter referred to as serotonin) was rapidly administered intravenously, and a bradycardia reaction (BC1) that was transiently expressed was observed. Next, when the blood pressure and heart rate are stabilized again after serotonin administration, a test compound is administered intravenously, and 10 minutes after administration, a transient gradual expression that occurs when serotonin 300 μg / kg is rapidly intravenously administered again. A pulse (BC2) was observed. The bradycardia suppression rate of each test compound, that is, the BJ reflection suppression rate can be calculated by the following equation.

Figure 0004596792
Figure 0004596792

各被検化合物の徐脈発現抑制率を下記表Cに示す。   Table C below shows the rate of suppression of bradycardia for each test compound.

Figure 0004596792
Figure 0004596792

かくして、本発明の式(I)で示されるピペラジニルピリジン誘導体又はその製薬学的に許容されうる塩を含むことを特徴とする5−HT1A作動作用及び5−HT拮抗作用を併有する薬剤は、ヒト、その他の哺乳動物の治療、処置のため、経口投与又は非経口投与(例えば、筋注、静注、直腸投与、経皮投与など)することができる。 Thus, it has both 5-HT 1A agonistic action and 5-HT 3 antagonistic action characterized by including the piperazinylpyridine derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof. The drug can be administered orally or parenterally (for example, intramuscular injection, intravenous injection, rectal administration, transdermal administration, etc.) for the treatment and treatment of humans and other mammals.

本発明の薬剤は、その用途に応じて、無毒性の添加剤とともに、固体形態(例えば、錠剤、硬カプセル剤、軟カプセル剤、顆粒剤、散剤、細粒剤、丸剤、トローチ錠など)、半固体形態(例えば、坐剤、軟膏など)又は液体形態(例えば、注射剤、乳剤、懸濁液、ローション、スプレーなど)のいずれかの製剤形態に調製して用いることができる。しかして、上記製剤に使用しうる無毒性の添加剤としては、例えば、でん粉、ゼラチン、ブドウ糖、乳糖、果糖、マルトース、炭酸マグネシウム、タルク、ステアリン酸マグネシウム、メチルセルロース、カルボキシメチルセルロース又はその塩、アラビアゴム、ポリエチレングリコール、p−ヒドロキシ安息香酸アルキルエステル、シロップ、エタノール、プロピレングリコール、ワセリン、カーボワックス、グリセリン、塩化ナトリウム、亜硫酸ナトリウム、リン酸ナトリウム、クエン酸等が挙げられる。該製剤はまた、治療学的に有用な他の薬剤を含有することもできる。   The drug of the present invention is in a solid form (for example, tablet, hard capsule, soft capsule, granule, powder, fine granule, pill, troche tablet, etc.) with non-toxic additives depending on its use. It can be prepared and used in any pharmaceutical form in a semi-solid form (eg, suppository, ointment, etc.) or liquid form (eg, injection, emulsion, suspension, lotion, spray, etc.). Examples of non-toxic additives that can be used in the above preparation include starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, and gum arabic. , Polyethylene glycol, p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol, petrolatum, carbowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid and the like. The formulation can also contain other therapeutically useful agents.

該製剤中における本発明の式(I)で示されるピペラジニルピリジン誘導体又はその製薬学的に許容されうる塩の含有量は、その剤形などに応じて異なるが、一般に、固体及び半固体形態の場合には0.1〜50重量%の濃度で、そして液体形態の場合には0.05〜10重量%の濃度で含有していることが望ましい。   The content of the piperazinyl pyridine derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof in the preparation varies depending on the dosage form and the like, but is generally solid and semi-solid. In the case of the form, it is desirable to contain it at a concentration of 0.1 to 50% by weight, and in the case of the liquid form, it is contained at a concentration of 0.05 to 10% by weight.

本発明の薬剤の投与量は、対象とするヒトをはじめとする温血動物の種類、投与経路、症状の軽重、医師の診断等により広範に変えることができるが、一般には、1日当たり0.01〜5mg/kg、好適には0.02〜2mg/kgの範囲内とすることができる。しかし、上記の如く患者の症状の軽重、医師の診断等に応じて、上記範囲の下限よりも少ない量又は上限よりも多い量を投与することはもちろん可能である。上記投与量は1日1回又は数回に分けて投与することができる。   The dose of the drug of the present invention can vary widely depending on the type of warm-blooded animals including human beings, administration route, severity of symptoms, doctor's diagnosis, etc. It can be in the range of 01-5 mg / kg, preferably 0.02-2 mg / kg. However, as described above, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit depending on the severity of the patient's symptoms, the diagnosis of the doctor, and the like. The above dose can be administered once a day or divided into several times.

以下、製剤例及び製造例により本発明をさらに具体的に説明する。
製剤例1
錠剤:
mg/錠
活性成分 5.0
でん粉 10.0
乳糖 73.0
カルボキシメチルセルロースカルシウム 10.0
タルク 1.0
ステアリン酸マグネシウム 1.0
100.0
活性成分を70μm以下の粒度に粉砕し、それにでん粉、乳糖及びカルボキシメチルセルロースカルシウムを加えてよく混合する。10%のでん粉のりを上記混合粉体に加えて攪拌混合し、顆粒を製造する。乾燥後粒径を1000μm前後に整粒し、これにタルク及びステアリン酸マグネシウムを混合し、打錠する。
Hereinafter, the present invention will be described in more detail with reference to formulation examples and production examples.
Formulation Example 1
tablet:
mg / tablet
Active ingredient 5.0
Starch 10.0
Lactose 73.0
Carboxymethylcellulose calcium 10.0
Talc 1.0
Magnesium stearate 1.0
100.0
The active ingredient is ground to a particle size of 70 μm or less, starch, lactose and carboxymethylcellulose calcium are added and mixed well. 10% starch paste is added to the above mixed powder and mixed by stirring to produce granules. After drying, the particle size is adjusted to about 1000 μm, and talc and magnesium stearate are mixed therein and tableted.

製造例Production example

製造例1Production Example 1

Figure 0004596792
Figure 0004596792

無水ピペラジン8.6gをエチレングリコール100mlに溶解し、7−クロロフロ[2,3−c]ピリジンを加え、140℃で一晩撹拌した。冷後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出し、有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、7−ピペラジン−1−イルフロ[2,3−c]ピリジン1.52g(75%)を得た。
H−NMR(CDCl)δ:7.96(d,J=5.5Hz,1H),7.63(d,J=2.3Hz,1H),6.97(d,J=5.4Hz,1H),6.72(d,J=1.9Hz,1H),3.83〜3.80(m,4H),3.06(t,J=5.0Hz,4H)
Mass,m/e:203(M),135(base)
製造例2
製造例1と同様にして、7−(4−メチルピペラジン−1−イル)フロ[2,3−c]ピリジンを得た。

Figure 0004596792
8.6 g of anhydrous piperazine was dissolved in 100 ml of ethylene glycol, 7-chlorofuro [2,3-c] pyridine was added, and the mixture was stirred at 140 ° C. overnight. After cooling, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.52 g (75%) of 7-piperazin-1-ylfuro [2,3-c] pyridine.
1 H-NMR (CDCl 3 ) δ: 7.96 (d, J = 5.5 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.97 (d, J = 5. 4 Hz, 1 H), 6.72 (d, J = 1.9 Hz, 1 H), 3.83 to 3.80 (m, 4 H), 3.06 (t, J = 5.0 Hz, 4 H)
Mass, m / e: 203 (M + ), 135 (base)
Production Example 2
In the same manner as in Production Example 1, 7- (4-methylpiperazin-1-yl) furo [2,3-c] pyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:7.95(d,J=5.3Hz,1H),7.62(d,J=1.9Hz,1H),6.96(d,J=5.4Hz,1H),6.72(d,J=1.9Hz,1H),3.88(t,J=5.0Hz,4H),2.59(t,J=5.0Hz,4H),2.38(s,3H)
Mass,m/e:217(M),147(base)
製造例3
製造例1と同様にして、4−ピペラジン−1−イルフロ[3,2−c]ピリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 7.95 (d, J = 5.3 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 6.96 (d, J = 5. 4 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 3.88 (t, J = 5.0 Hz, 4H), 2.59 (t, J = 5.0 Hz, 4H), 2.38 (s, 3H)
Mass, m / e: 217 (M + ), 147 (base)
Production Example 3
In the same manner as in Production Example 1, 4-piperazin-1-ylfuro [3,2-c] pyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.05(d,J=5.8Hz,1H),7.53(d,J=2.0Hz,1H),6.94(dd,J=0.8Hz,5.8Hz,1H),6.81(dd,J=1.2Hz,2.3Hz,1H),3.67(t,J=5.0Hz,4H),3.05(t,J=5.0Hz,4H)
Mass,m/e:203(M),135(base)
製造例4
製造例1と同様にして、4−(4−メチルピペラジン−1−イル)フロ[2,3−c]ピリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.05 (d, J = 5.8 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 0. 8 Hz, 5.8 Hz, 1 H), 6.81 (dd, J = 1.2 Hz, 2.3 Hz, 1 H), 3.67 (t, J = 5.0 Hz, 4 H), 3.05 (t, J = 5.0Hz, 4H)
Mass, m / e: 203 (M + ), 135 (base)
Production Example 4
In the same manner as in Production Example 1, 4- (4-methylpiperazin-1-yl) furo [2,3-c] pyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.05(d,J=5.8Hz,1H),7.53(d,J=2.3Hz,1H),6.94(dd,J=1.2Hz,5.8Hz,1H),6.81(dd,J=1.2Hz,2.3Hz,1H),3.74(t,J=5.0Hz,4H),2.59(t,J=5.0Hz,4H),2.37(s,3H)
Mass,m/e:217(M),147(base)
製造例5
製造例1と同様にして、7−ピペラジン−1−イルチエノ[2,3−c]ピリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.05 (d, J = 5.8 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 1. 2 Hz, 5.8 Hz, 1 H), 6.81 (dd, J = 1.2 Hz, 2.3 Hz, 1 H), 3.74 (t, J = 5.0 Hz, 4 H), 2.59 (t, J = 5.0 Hz, 4H), 2.37 (s, 3H)
Mass, m / e: 217 (M + ), 147 (base)
Production Example 5
In the same manner as in Production Example 1, 7-piperazin-1-ylthieno [2,3-c] pyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.14(d,J=5.8Hz,1H),7.58(d,J=5.4Hz,1H),7.32(d,J=5.4Hz,1H),7.25(d,J=5.4Hz,1H),3.64(t,J=5.0Hz,4H),3.09(t,J=5.0Hz,4H)
Mass,m/e:219(M),151(base)
製造例6
製造例1と同様にして、7−(4−メチルピペラジン−1−イル)チエノ[2,3−c]ピリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.14 (d, J = 5.8 Hz, 1H), 7.58 (d, J = 5.4 Hz, 1H), 7.32 (d, J = 5. 4Hz, 1H), 7.25 (d, J = 5.4Hz, 1H), 3.64 (t, J = 5.0Hz, 4H), 3.09 (t, J = 5.0Hz, 4H)
Mass, m / e: 219 (M + ), 151 (base)
Production Example 6
In the same manner as in Production Example 1, 7- (4-methylpiperazin-1-yl) thieno [2,3-c] pyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.13(d,J=5.8Hz,1H),7.57(d,J=5.4Hz,1H),7.31(d,J=5.4Hz,1H),7.24(d,J=5.4Hz,1H),3.71(t,J=5.0Hz,4H),2.63(t,J=5.0Hz,4H),2.38(s,3H)
Mass,m/e:233(M),163(base)
製造例7
製造例1と同様にして、4−ピペラジン−1−イルチエノ[3,2−c]ピリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.13 (d, J = 5.8 Hz, 1H), 7.57 (d, J = 5.4 Hz, 1H), 7.31 (d, J = 5. 4 Hz, 1H), 7.24 (d, J = 5.4 Hz, 1H), 3.71 (t, J = 5.0 Hz, 4H), 2.63 (t, J = 5.0 Hz, 4H), 2.38 (s, 3H)
Mass, m / e: 233 (M + ), 163 (base)
Production Example 7
In the same manner as in Production Example 1, 4-piperazin-1-ylthieno [3,2-c] pyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.09(d,J=5.8Hz,1H),7.42〜7.35(m,3H),3.50(t,J=5.0Hz,4H),3.11(t,J=5.0Hz,4H)
Mass,m/e:219(M),151(base)
製造例8
製造例1と同様にして、4−(4−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.09 (d, J = 5.8 Hz, 1H), 7.42-7.35 (m, 3H), 3.50 (t, J = 5.0 Hz, 4H), 3.11 (t, J = 5.0 Hz, 4H)
Mass, m / e: 219 (M + ), 151 (base)
Production Example 8
In the same manner as in Production Example 1, 4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.08(d,J=5.8Hz,1H),7.41〜7.33(m,3H),3.57(t,J=5.0Hz,4H),2.64(t,J=5.0Hz,4H),2.39(s,3H)
Mass,m/e:233(M),163(base)
製造例9
製造例1と同様にして、2−ブロモ−4−ピペラジン−1−イルチエノ[3,2−c]ピリジン 2塩酸塩を得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.08 (d, J = 5.8 Hz, 1H), 7.41-7.33 (m, 3H), 3.57 (t, J = 5.0 Hz, 4H), 2.64 (t, J = 5.0 Hz, 4H), 2.39 (s, 3H)
Mass, m / e: 233 (M + ), 163 (base)
Production Example 9
In the same manner as in Production Example 1, 2-bromo-4-piperazin-1-ylthieno [3,2-c] pyridine dihydrochloride was obtained.
Figure 0004596792

H−NMR(DMSO−d)δ:8.03(d,J=5.8Hz,1H),7.90(s,1H),7.67(d,J=5.8Hz,1H),3.72(br s,4H),2.59(br s,4H)
Mass,m/e:297(M),229(base)
製造例10
製造例1と同様にして、2−ブロモ−4−(4−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジンを得た。

Figure 0004596792
1 H-NMR (DMSO-d 6 ) δ: 8.03 (d, J = 5.8 Hz, 1H), 7.90 (s, 1H), 7.67 (d, J = 5.8 Hz, 1H) , 3.72 (br s, 4H), 2.59 (br s, 4H)
Mass, m / e: 297 (M + ), 229 (base)
Production Example 10
In the same manner as in Production Example 1, 2-bromo-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.05(d,J=5.4Hz,1H),7.36(d,J=0.8Hz,1H),7.19(dd,J=0.8Hz,5.8Hz,1H),3.53(t,J=5.0Hz,4H),2.63(t,J=5.0Hz,4H),2.39(s,3H)
Mass,m/e:311(M),83(base)
製造例11
製造例1と同様にして、2−メチル−4−ピペラジン−1−イルチエノ[3,2−c]ピリジン 2塩酸塩を得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.05 (d, J = 5.4 Hz, 1H), 7.36 (d, J = 0.8 Hz, 1H), 7.19 (dd, J = 0. 8Hz, 5.8Hz, 1H), 3.53 (t, J = 5.0Hz, 4H), 2.63 (t, J = 5.0Hz, 4H), 2.39 (s, 3H)
Mass, m / e: 311 (M + ), 83 (base)
Production Example 11
In the same manner as in Production Example 1, 2-methyl-4-piperazin-1-ylthieno [3,2-c] pyridine dihydrochloride was obtained.
Figure 0004596792

H−NMR(DMSO−d)δ:7.94(d,J=6.2Hz,1H),7.76(d,J=6.2Hz,1H),7.55(s,1H),3.91(br s,4H),2.59(br s,4H),2.64(s,3H)
Mass,m/e:233(M),177(base)
製造例12
製造例1と同様にして、2−メチル−4−(4−メチルピペラジン−1−イルチエノ[3,2−c]ピリジン 2塩酸塩を得た。

Figure 0004596792
1 H-NMR (DMSO-d 6 ) δ: 7.94 (d, J = 6.2 Hz, 1H), 7.76 (d, J = 6.2 Hz, 1H), 7.55 (s, 1H) , 3.91 (br s, 4H), 2.59 (br s, 4H), 2.64 (s, 3H)
Mass, m / e: 233 (M + ), 177 (base)
Production Example 12
In the same manner as in Production Example 1, 2-methyl-4- (4-methylpiperazin-1-ylthieno [3,2-c] pyridine dihydrochloride was obtained.
Figure 0004596792

H−NMR(DMSO−d)δ:7.96(d,J=6.2Hz,1H),7.73(d,J=5.8Hz,1H),7.50(s,1H),4.20(d,J=5.9Hz,3H),3.57(br s,4H),3.30〜3.27(m,4H),2.84(d,J=4.3Hz,3H)
Mass,m/e:247(M),177(base)
製造例13
製造例1と同様にして、3−ブロモ−4−ピペラジン−1−イルチエノ[3,2−c]ピリジン 2塩酸塩を得た。

Figure 0004596792
1 H-NMR (DMSO-d 6 ) δ: 7.96 (d, J = 6.2 Hz, 1H), 7.73 (d, J = 5.8 Hz, 1H), 7.50 (s, 1H) , 4.20 (d, J = 5.9 Hz, 3H), 3.57 (brs, 4H), 3.30-3.27 (m, 4H), 2.84 (d, J = 4.3 Hz) , 3H)
Mass, m / e: 247 (M + ), 177 (base)
Production Example 13
In the same manner as in Production Example 1, 3-bromo-4-piperazin-1-ylthieno [3,2-c] pyridine dihydrochloride was obtained.
Figure 0004596792

H−NMR(DMSO−d)δ:8.17(d,J=5.4Hz,1H),8.02(s,1H),7.83(d,J=5.8Hz,1H),3.56〜3.32(m,8H)
Mass,m/e:297(M),229(base)
製造例14
製造例1と同様にして、3−ブロモ−4−(4−メチルピペラジン−1−イル)チエノ[3,2−c]ピリジンを得た。

Figure 0004596792
1 H-NMR (DMSO-d 6 ) δ: 8.17 (d, J = 5.4 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J = 5.8 Hz, 1H) 3.56 to 3.32 (m, 8H)
Mass, m / e: 297 (M + ), 229 (base)
Production Example 14
In the same manner as in Production Example 1, 3-bromo-4- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine was obtained.
Figure 0004596792

H−NMR(DMSO−d)δ:8.17(d,J=5.4Hz,1H),8.03(s,1H),7.84(d,J=5.4Hz,1H),3.59〜3.51(m,4H),3.37〜3.27(m,4H),2.87(m,3H)
Mass,m/e:311(M),83(base)
製造例15
製造例1と同様にして、3−クロロ−1−ピペラジン−1−イルイソキノリン 2塩酸塩を得た。

Figure 0004596792
1 H-NMR (DMSO-d 6 ) δ: 8.17 (d, J = 5.4 Hz, 1H), 8.03 (s, 1H), 7.84 (d, J = 5.4 Hz, 1H) 3.59 to 3.51 (m, 4H), 3.37 to 3.27 (m, 4H), 2.87 (m, 3H)
Mass, m / e: 311 (M + ), 83 (base)
Production Example 15
In the same manner as in Production Example 1, 3-chloro-1-piperazin-1-ylisoquinoline dihydrochloride was obtained.
Figure 0004596792

H−NMR(DMSO−d)δ:8.08(d,J=8.5Hz,1H),7.90(d,J=8.1Hz,1H),7.78〜7.75(m,1H),7.64〜7.62(m,1H),7.60(s,1H),3.60〜3.57(m,4H),3.29(br s,4H)
Mass,m/e:247(M),179(base)
製造例16
製造例1と同様にして、3−クロロ−1−(4−メチルピペラジン−1−イル)イソキノリン 2塩酸塩を得た。

Figure 0004596792
1 H-NMR (DMSO-d 6 ) δ: 8.08 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.78-7.75 ( m, 1H), 7.64 to 7.62 (m, 1H), 7.60 (s, 1H), 3.60 to 3.57 (m, 4H), 3.29 (brs, 4H)
Mass, m / e: 247 (M + ), 179 (base)
Production Example 16
In the same manner as in Production Example 1, 3-chloro-1- (4-methylpiperazin-1-yl) isoquinoline dihydrochloride was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.02(d,J=8.1Hz,1H),7.90(d,J=8.1Hz,1H),7.79〜7.75(m,1H),7.64(d,J=7.3Hz,1H),7.61(s,1H),3.98〜3.52(m,4H),3.52〜3.32(m,4H),2.86(m,3H)
Mass,m/e:261(M),83(base)
製造例17
製造例1と同様にして、7−(4−エチルピペラジン−1−イル)−チエノ[2,3−c]ピリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.02 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.79-7.75 (m, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.61 (s, 1H), 3.98 to 3.52 (m, 4H), 3.52 to 3.32 (m, 4H), 2.86 (m, 3H)
Mass, m / e: 261 (M + ), 83 (base)
Production Example 17
In the same manner as in Production Example 1, 7- (4-ethylpiperazin-1-yl) -thieno [2,3-c] pyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.12(d,J=5.8Hz,1H),7.57(d,J=5.4Hz,1H),7.31(d,J=5.4Hz,1H),7.23(d,J=5.8Hz,1H),3.73(t,J=5.0Hz,4H),2.67(t,J=5.0Hz,4H),2.52(q,J=7.3Hz,2H),1.53(t,J=7.3Hz,3H)
Mass,m/e:247(M),163(base)
製造例18
製造例1と同様にして、4−(4−エチルピペラジン−1−イル)−チエノ[3,2−c]ピリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.12 (d, J = 5.8 Hz, 1H), 7.57 (d, J = 5.4 Hz, 1H), 7.31 (d, J = 5. 4 Hz, 1H), 7.23 (d, J = 5.8 Hz, 1H), 3.73 (t, J = 5.0 Hz, 4H), 2.67 (t, J = 5.0 Hz, 4H), 2.52 (q, J = 7.3 Hz, 2H), 1.53 (t, J = 7.3 Hz, 3H)
Mass, m / e: 247 (M + ), 163 (base)
Production Example 18
In the same manner as in Production Example 1, 4- (4-ethylpiperazin-1-yl) -thieno [3,2-c] pyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.08(d,J=5.8Hz,1H),7.41〜7.33(m,3H),3.59(t,J=5.0Hz,4H),2.68(t,J=5.0Hz,4H),2.52(q,J=7.3Hz,2H),1.15(t,J=7.3Hz,3H)
Mass,m/e:247(M),163(base)
製造例19
製造例1と同様にして、5−ピペラジン−1−イル−[1,6]ナフチリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.08 (d, J = 5.8 Hz, 1H), 7.41-7.33 (m, 3H), 3.59 (t, J = 5.0 Hz, 4H), 2.68 (t, J = 5.0 Hz, 4H), 2.52 (q, J = 7.3 Hz, 2H), 1.15 (t, J = 7.3 Hz, 3H)
Mass, m / e: 247 (M + ), 163 (base)
Production Example 19
In the same manner as in Production Example 1, 5-piperazin-1-yl- [1,6] naphthyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.99(dd,J=1.9Hz,4.2Hz,1H),8.39(dd,J=1.2Hz,8.5Hz,1H),8.34(d,J=6.2Hz,1H),7.48(d,J=6.2Hz,1H),7.42(dd,J=4.2Hz,8.5Hz,1H),3.42〜3.39(m,4H),3.16〜3.14(m,4H)
Mass,m/e:214(M),146(base)
製造例20
製造例1と同様にして、5−(4−メチルピペラジン−1−イル)−[1,6]ナフチリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.9 (dd, J = 1.9 Hz, 4.2 Hz, 1H), 8.39 (dd, J = 1.2 Hz, 8.5 Hz, 1H), 8. 34 (d, J = 6.2 Hz, 1H), 7.48 (d, J = 6.2 Hz, 1H), 7.42 (dd, J = 4.2 Hz, 8.5 Hz, 1H), 3.42 To 3.39 (m, 4H), 3.16 to 3.14 (m, 4H)
Mass, m / e: 214 (M + ), 146 (base)
Production Example 20
In the same manner as in Production Example 1, 5- (4-methylpiperazin-1-yl)-[1,6] naphthyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.98(dd,J=1.9Hz,4.2Hz,1H),8.39〜8.36(m,1H),8.33(d,J=6.2Hz,1H),7.48(dd,J=0.8Hz,5.8Hz,1H),7.41(dd,J=4.3Hz,5.8Hz,1H),3.49(t,J=5.0Hz,4H),2.69(t,J=5.0Hz,4H),2.41(s,3H)
Mass,m/e:228(M),158(base)
製造例21
製造例1と同様にして、5−(4−エチルピペラジン−1−イル)−[1,6]ナフチリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.98 (dd, J = 1.9 Hz, 4.2 Hz, 1H), 8.39-8.36 (m, 1H), 8.33 (d, J = 6.2 Hz, 1H), 7.48 (dd, J = 0.8 Hz, 5.8 Hz, 1H), 7.41 (dd, J = 4.3 Hz, 5.8 Hz, 1H), 3.49 (t , J = 5.0 Hz, 4H), 2.69 (t, J = 5.0 Hz, 4H), 2.41 (s, 3H)
Mass, m / e: 228 (M + ), 158 (base)
Production Example 21
In the same manner as in Production Example 1, 5- (4-ethylpiperazin-1-yl)-[1,6] naphthyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.97(dd,J=1.9Hz,4.2Hz,1H),8.38〜8.35(m,1H),8.32(d,J=5.8Hz,1H),7.46〜7.45(m,1H),7.40(dd,J=4.2Hz,8.5Hz,1H),3.49(t,J=5.0Hz,4H),2.71(t,J=5.0Hz,4H),2.54(q,J=7.3Hz,2H),1.15(t,J=7.3Hz,3H)
Mass,m/e:242(M),158(base)
製造例22
製造例1と同様にして、8−ピペラジン−1−イル−[1,7]ナフチリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.97 (dd, J = 1.9 Hz, 4.2 Hz, 1H), 8.38 to 8.35 (m, 1H), 8.32 (d, J = 5.8 Hz, 1H), 7.46-7.45 (m, 1H), 7.40 (dd, J = 4.2 Hz, 8.5 Hz, 1H), 3.49 (t, J = 5.0 Hz) 4H), 2.71 (t, J = 5.0 Hz, 4H), 2.54 (q, J = 7.3 Hz, 2H), 1.15 (t, J = 7.3 Hz, 3H)
Mass, m / e: 242 (M + ), 158 (base)
Production Example 22
In the same manner as in Production Example 1, 8-piperazin-1-yl- [1,7] naphthyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.82(dd,J=1.9Hz,4.3Hz,1H),8.13(d,J=5.4Hz,1H),8.00(dd,J=1.9Hz,8.5Hz,1H),7.47(dd,J=4.2Hz,8.5Hz,1H),7.04(d,J=5.8Hz,1H),3.93(t,J=5.0Hz,4H),3.13(t,J=5.0Hz,4H)
Mass,m/e:214(M),146(base)
製造例23
製造例1と同様にして、8−(4−メチルピペラジン−1−イル)−[1,7]ナフチリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.82 (dd, J = 1.9 Hz, 4.3 Hz, 1H), 8.13 (d, J = 5.4 Hz, 1H), 8.00 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.47 (dd, J = 4.2 Hz, 8.5 Hz, 1H), 7.04 (d, J = 5.8 Hz, 1H), 3.93. (T, J = 5.0 Hz, 4H), 3.13 (t, J = 5.0 Hz, 4H)
Mass, m / e: 214 (M + ), 146 (base)
Production Example 23
In the same manner as in Production Example 1, 8- (4-methylpiperazin-1-yl)-[1,7] naphthyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.82(dd,J=1.9Hz,4.3Hz,1H),8.12(d,J=5.8Hz,1H),7.80(dd,J=1.9Hz,8.5Hz,1H),7.47(dd,J=4.2Hz,8.5Hz,1H),7.04(d,J=5.4Hz,1H),4.01(br s,4H),2.67(t,J=5.0Hz,4H),2.38(s,3H)
Mass,m/e:228(M),158(base)
製造例24
製造例1と同様にして、8−(4−エチルピペラジン−1−イル)−[1,7]ナフチリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.82 (dd, J = 1.9 Hz, 4.3 Hz, 1H), 8.12 (d, J = 5.8 Hz, 1H), 7.80 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.47 (dd, J = 4.2 Hz, 8.5 Hz, 1H), 7.04 (d, J = 5.4 Hz, 1H), 4.01 (Br s, 4H), 2.67 (t, J = 5.0 Hz, 4H), 2.38 (s, 3H)
Mass, m / e: 228 (M + ), 158 (base)
Production Example 24
In the same manner as in Production Example 1, 8- (4-ethylpiperazin-1-yl)-[1,7] naphthyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.81(dd,J=1.9Hz,4.2Hz,1H),8.16(d,J=5.4Hz,1H),7.99(dd,J=1.9Hz,8.5Hz,1H),7.47(dd,J=4.2Hz,8.5Hz,1H),7.03(d,J=5.4Hz,1H),4.03(t,J=4.6Hz,4H),2.71(t,J=4.6Hz,4H),2.51(q,J=7.3Hz,2H),1.15(t,J=7.3Hz,3H)
Mass,m/e:242(M),158(base)
製造例25
製造例1と同様にして、2−メチル−ピペラジン−1−イルフロ[3,2−c]ピリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.81 (dd, J = 1.9 Hz, 4.2 Hz, 1H), 8.16 (d, J = 5.4 Hz, 1H), 7.99 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.47 (dd, J = 4.2 Hz, 8.5 Hz, 1H), 7.03 (d, J = 5.4 Hz, 1H), 4.03 (T, J = 4.6 Hz, 4H), 2.71 (t, J = 4.6 Hz, 4H), 2.51 (q, J = 7.3 Hz, 2H), 1.15 (t, J = 7.3Hz, 3H)
Mass, m / e: 242 (M + ), 158 (base)
Production Example 25
In the same manner as in Production Example 1, 2-methyl-piperazin-1-ylfuro [3,2-c] pyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:7.93(d,J=5.8Hz,1H),6.86(dd,J=1.2Hz,5.8Hz,1H),6.38(s,1H),3.60(t,J=5.0Hz,4H),3.03(t,J=5.0Hz,4H),2.43(d,J=1.2Hz,3H)
Mass,m/e:217(M),161(base)
製造例26
製造例1と同様にして、7−メトキシ−3−メチル−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 7.93 (d, J = 5.8 Hz, 1H), 6.86 (dd, J = 1.2 Hz, 5.8 Hz, 1H), 6.38 (s, 1H), 3.60 (t, J = 5.0 Hz, 4H), 3.03 (t, J = 5.0 Hz, 4H), 2.43 (d, J = 1.2 Hz, 3H)
Mass, m / e: 217 (M + ), 161 (base)
Production Example 26
In the same manner as in Production Example 1, 7-methoxy-3-methyl-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:7.58(d,J=8.9Hz,1H),7.36(d,J=2.3Hz,1H),7.23(dd,J=2.3Hz,8.9Hz,1H),7.05(s,1H),3.92(s,3H),3.36〜3.32(m,4H),3.18〜3.14(m,4H),2.54(s,3H)
Mass,m/e:257(M),188(Base)
製造例27
製造例1と同様にして、7−メトキシ−3,4−ジメチル−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 7.58 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 2. 3 Hz, 8.9 Hz, 1 H), 7.05 (s, 1 H), 3.92 (s, 3 H), 3.36 to 3.32 (m, 4 H), 3.18 to 3.14 (m, 4H), 2.54 (s, 3H)
Mass, m / e: 257 (M + ), 188 (Base)
Production Example 27
In the same manner as in Production Example 1, 7-methoxy-3,4-dimethyl-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:7.82(d,J=9.2Hz,1H),7.41(d,J=2.7Hz,1H),7.27(dd,J=2.7Hz,9.2Hz,1H),3.93(s,3H),3.41〜3.34(m,4H),2.73〜2.68(m,4H),2.56(s,3H),2.46(s,3H),2.41(s,3H)
Mass,m/e:285(M),215(base),202
製造例28
製造例1と同様にして、7−メトキシ−4−メチル−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 7.82 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H), 7.27 (dd, J = 2. 7Hz, 9.2Hz, 1H), 3.93 (s, 3H), 3.41 to 3.34 (m, 4H), 2.73 to 2.68 (m, 4H), 2.56 (s, 3H), 2.46 (s, 3H), 2.41 (s, 3H)
Mass, m / e: 285 (M + ), 215 (base), 202
Production Example 28
In the same manner as in Production Example 1, 7-methoxy-4-methyl-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:7.92(d,J=0.7Hz,1H),7.81(d,J=9.2Hz,1H),7.49(d,J=2.7Hz,1H),7.40(dd,J=2.7Hz,9.2Hz,1H),3.95(s,3H),3.31〜3.26(m,4H),3.18〜3.14(m,4H),2.49(d,J=0.7Hz,3H)
Mass,m/e:257(M),201,188(base)
製造例29
製造例1と同様にして、7−メトキシ−4−メチル−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 7.92 (d, J = 0.7 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.49 (d, J = 2. 7 Hz, 1H), 7.40 (dd, J = 2.7 Hz, 9.2 Hz, 1H), 3.95 (s, 3H), 3.31 to 3.26 (m, 4H), 3.18- 3.14 (m, 4H), 2.49 (d, J = 0.7 Hz, 3H)
Mass, m / e: 257 (M + ), 201, 188 (base)
Production Example 29
In the same manner as in Production Example 1, 7-methoxy-4-methyl-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:7.90(s,1H),7.80(d,J=9.3Hz,1H),7.45(d,J=2.7Hz,1H),7.33(dd,J=2.7Hz,9.3Hz,1H),3.95,(s,3H),3.48〜3.39(m,4H),2.75〜2.66(m,4H),2.49(s,3H),2.41(s,3H)
Mass,m/e: 305(M),235,83(base)
製造例30
製造例1と同様にして、7−ブロモ−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 7.90 (s, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7 .33 (dd, J = 2.7 Hz, 9.3 Hz, 1H), 3.95, (s, 3H), 3.48 to 3.39 (m, 4H), 2.75 to 2.66 (m , 4H), 2.49 (s, 3H), 2.41 (s, 3H)
Mass, m / e: 305 (M + ), 235, 83 (base)
Production Example 30
In the same manner as in Production Example 1, 7-bromo-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.24〜8.22(m,1H),8.16(d,J=5.8Hz,1H),7.67(dd,J=1.9Hz,8.5Hz,1H),7.61(d,J=8.9Hz,1H),7.26〜7.19(m,1H),3.36〜3.32(m,4H),3.16〜3.12(m,4H)
Mass,m/e:292(M),235,223(base)
製造例31
製造例1と同様にして、7−ブロモ−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.24-8.22 (m, 1H), 8.16 (d, J = 5.8 Hz, 1H), 7.67 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.26-7.19 (m, 1H), 3.36-3.32 (m, 4H), 3. 16-3.12 (m, 4H)
Mass, m / e: 292 (M + ), 235, 223 (base)
Production Example 31
In the same manner as in Production Example 1, 7-bromo-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.23〜8.21(m,1H),8.16(d,J=5.8Hz,1H),7.67(dd,J=1.9Hz,8.5Hz,1H),7.61(d,J=8.5Hz,1H),7.20(dd,J=0.8Hz,5.8Hz),3.47〜3.39(m,4H),2.76〜2.26(m,4H),2.41(s,3H)
Mass,m/e:305(M),235,83(base)
製造例32
製造例1と同様にして、7−メトキシ−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.23 to 8.21 (m, 1H), 8.16 (d, J = 5.8 Hz, 1H), 7.67 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.20 (dd, J = 0.8 Hz, 5.8 Hz), 3.47-3.39 (m, 4H) ), 2.76-2.26 (m, 4H), 2.41 (s, 3H)
Mass, m / e: 305 (M + ), 235, 83 (base)
Production Example 32
In the same manner as in Production Example 1, 7-methoxy-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.07(d,J=5.8Hz,1H),7.68(d,J=8.9Hz,1H),7.39(d,J=2.7Hz,1H),7.29(dd,J=2.7Hz,8.9Hz,1H),7.22(d,J=5.8Hz,1H),3.94(s,3H),3.48〜3.40(m,4H),2.77〜2.69(m,4H)
Mass,m/e:257(M),187(base)
製造例33
製造例1と同様にして、1−(4−エチルピペラジン−1−イル)−7−メトキシイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.07 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 2. 7 Hz, 1H), 7.29 (dd, J = 2.7 Hz, 8.9 Hz, 1H), 7.22 (d, J = 5.8 Hz, 1H), 3.94 (s, 3H), 3. 48-3.40 (m, 4H), 2.77-2.69 (m, 4H)
Mass, m / e: 257 (M + ), 187 (base)
Production Example 33
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) -7-methoxyisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.07(d,J=5.8Hz,1H),7.68(d,J=8.7Hz,1H),7.40(d,J=2.5Hz,1H),7.31〜7.25(m,1H),7.21(d,J=5.8Hz,1H),3.48〜3.39(m,4H),2.79〜2.69(m,4H),2.55(q,J=7.2Hz,2H),1.17(t,J=7.2Hz,3H)
Mass,m/e:271(M),187(base)
製造例34
製造例1と同様にして、7−メトキシ−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.07 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 2. 5 Hz, 1H), 7.31-7.25 (m, 1H), 7.21 (d, J = 5.8 Hz, 1H), 3.48-3.39 (m, 4H), 2.79- 2.69 (m, 4H), 2.55 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H)
Mass, m / e: 271 (M + ), 187 (base)
Production Example 34
In the same manner as in Production Example 1, 7-methoxy-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.08(d,J=5.5Hz,1H),7.68(d,J=9.2Hz,1H),7.42(d,J=2.6Hz,1H),7.29(dd,J=2.6Hz,9.2Hz,1H),7.23(d,J=5.5Hz,1H),3.94(s,3H),3.37〜3.30(m,4H),3.20〜3.13(m,4H)
Mass,m/e:243(M),174(base)
製造例35
製造例1と同様にして、1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.08 (d, J = 5.5 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 2. 6 Hz, 1 H), 7.29 (dd, J = 2.6 Hz, 9.2 Hz, 1 H), 7.23 (d, J = 5.5 Hz, 1 H), 3.94 (s, 3 H), 3. 37-3.30 (m, 4H), 3.20-3.13 (m, 4H)
Mass, m / e: 243 (M + ), 174 (base)
Production Example 35
In the same manner as in Production Example 1, 1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.15(d,J=5.9Hz,1H),8.11(d,J=8.4Hz,1H),7.75(d,J=8.1Hz,1H),7.61(ddd,J=1.1Hz,7.0Hz,8.1Hz,1H),7.51(ddd,1.1Hz,7.0Hz,8.4Hz,1H),7.25(d,J=5.9Hz,1H),3.41〜3.34(m,4H),3.18〜3.13(m,4H)
Mass,m/e:213(M),145(base)
製造例36
製造例1と同様にして、1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.15 (d, J = 5.9 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8. 1 Hz, 1 H), 7.61 (ddd, J = 1.1 Hz, 7.0 Hz, 8.1 Hz, 1 H), 7.51 (ddd, 1.1 Hz, 7.0 Hz, 8.4 Hz, 1 H), 7 .25 (d, J = 5.9 Hz, 1H), 3.41-3.34 (m, 4H), 3.18-3.13 (m, 4H)
Mass, m / e: 213 (M + ), 145 (base)
Production Example 36
In the same manner as in Production Example 1, 1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.15(d,J=5.9Hz,1H),8.09(d,J=8.4Hz,1H),7.75(d,J=8.1Hz,1H),7.60(ddd,J=1.1Hz,7.0Hz,8.1Hz,1H),7.50(ddd,1.1Hz,7.0Hz,8.4Hz,1H),7.24(d,J=5.9Hz,1H),3.51〜3.41(m,4H),2.74〜2.66(m,4H),2.42(s,3H)
Mass,m/e:227(M),157(base)
製造例37
製造例1と同様にして、1−(4−エチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.15 (d, J = 5.9 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8. 1 Hz, 1 H), 7.60 (ddd, J = 1.1 Hz, 7.0 Hz, 8.1 Hz, 1 H), 7.50 (ddd, 1.1 Hz, 7.0 Hz, 8.4 Hz, 1 H), 7 .24 (d, J = 5.9 Hz, 1H), 3.51 to 3.41 (m, 4H), 2.74 to 2.66 (m, 4H), 2.42 (s, 3H)
Mass, m / e: 227 (M + ), 157 (base)
Production Example 37
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.14(d,J=5.9Hz,1H),8.09(d,J=8.4Hz,1H),7.74(d,J=8.1Hz,1H),7.60(ddd,J=1.1Hz,7.0Hz,8.1Hz,1H),7.50(ddd,1.1Hz,7.0Hz,8.4Hz,1H),7.23(d,J=5.9Hz,1H),3.51〜3.44(m,4H),2.77〜2.69(m,4H),2.55(q,J=7.3Hz,2H),1.17(t,J=7.3Hz,3H)
Mass,m/e:241(M),157(base)
製造例38
製造例1と同様にして、7−メトキシ−1−(3−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.14 (d, J = 5.9 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8. 1 Hz, 1 H), 7.60 (ddd, J = 1.1 Hz, 7.0 Hz, 8.1 Hz, 1 H), 7.50 (ddd, 1.1 Hz, 7.0 Hz, 8.4 Hz, 1 H), 7 .23 (d, J = 5.9 Hz, 1H), 3.51-3.44 (m, 4H), 2.77-2.69 (m, 4H), 2.55 (q, J = 7. 3Hz, 2H), 1.17 (t, J = 7.3Hz, 3H)
Mass, m / e: 241 (M + ), 157 (base)
Production Example 38
In the same manner as in Production Example 1, 7-methoxy-1- (3-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.07(d,J=5.8Hz,1H),7.68(d,J=8.9Hz,1H),7.40(d,J=2.7Hz,1H),7.29(dd,J=2.7Hz,8.9Hz,1H),7.23(d,J=5.8Hz,1H),3.94(s,3H),3.70〜3.62(m,2H),3.30〜3.17(m,3H),3.08〜2.99(m,1H),2.80〜2.71(m,1H),1.20(d,J=6.6Hz,3H)
Mass,m/e:257(M),175(base)
製造例39
製造例1と同様にして、1−(3,5−ジメチルピペラジン−1−イル)−7−メトキシ−イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.07 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2. 7 Hz, 1H), 7.29 (dd, J = 2.7 Hz, 8.9 Hz, 1H), 7.23 (d, J = 5.8 Hz, 1H), 3.94 (s, 3H), 3. 70 to 3.62 (m, 2H), 3.30 to 3.17 (m, 3H), 3.08 to 2.99 (m, 1H), 2.80 to 2.71 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H)
Mass, m / e: 257 (M + ), 175 (base)
Production Example 39
In the same manner as in Production Example 1, 1- (3,5-dimethylpiperazin-1-yl) -7-methoxy-isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.07(d,J=5.8Hz,1H),7.68(d,J=8.9Hz,1H),7.40(d,J=2.7Hz,1H),7.29(dd,J=2.7Hz,8.9Hz,1H),7.21(d,J=5.8Hz,1H),3.93(s,3H),3.70〜3.62(m,2H),3.33〜3.23(m,2H),2.66〜2.57(m,2H),1.17(d,J=6.6Hz,6H)
Mass,m/e:271(M),187(base)
製造例40
製造例1と同様にして、6−メトキシ−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.07 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2. 7 Hz, 1H), 7.29 (dd, J = 2.7 Hz, 8.9 Hz, 1H), 7.21 (d, J = 5.8 Hz, 1H), 3.93 (s, 3H), 3. 70 to 3.62 (m, 2H), 3.33 to 3.23 (m, 2H), 2.66 to 2.57 (m, 2H), 1.17 (d, J = 6.6 Hz, 6H) )
Mass, m / e: 271 (M + ), 187 (base)
Production Example 40
In the same manner as in Production Example 1, 6-methoxy-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.10(d,J=5.9Hz,1H),8.01(d,J=9.2Hz,1H),7.16(d,J=5.9Hz,1H),7.13(dd,J=2.6Hz,9.2Hz,1H),7.02(d,J=2.6Hz,1H),3.93(s,3H),3.38〜3.32(m,4H),3.18〜3.12(m,4H)
Mass,m/e:243(M),187(base)
製造例41
製造例1と同様にして、6−メトキシ−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.10 (d, J = 5.9 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 5. 9 Hz, 1 H), 7.13 (dd, J = 2.6 Hz, 9.2 Hz, 1 H), 7.02 (d, J = 2.6 Hz, 1 H), 3.93 (s, 3 H), 3. 38 to 3.32 (m, 4H), 3.18 to 3.12 (m, 4H)
Mass, m / e: 243 (M + ), 187 (base)
Production Example 41
In the same manner as in Production Example 1, 6-methoxy-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.09(d,J=5.9Hz,1H),7.99(d,J=9.2Hz,1H),7.15(d,J=5.9Hz,1H),7.12(dd,J=2.6Hz,9.2Hz,1H),7.02(d,J=2.6Hz,1H),3.93(s,3H),3.48〜3.38(m,4H),2.74〜2.64(m,4H),2.41(s,3H)
Mass,m/e:257(M),187(base)
製造例42
製造例1と同様にして、1−(4−エチルピペラジン−1−イル)−6−メトキシイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.09 (d, J = 5.9 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.15 (d, J = 5. 9 Hz, 1H), 7.12 (dd, J = 2.6 Hz, 9.2 Hz, 1H), 7.02 (d, J = 2.6 Hz, 1H), 3.93 (s, 3H), 3. 48-3.38 (m, 4H), 2.74-2.64 (m, 4H), 2.41 (s, 3H)
Mass, m / e: 257 (M + ), 187 (base)
Production Example 42
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) -6-methoxyisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.09(d,J=5.9Hz,1H),7.99(d,J=9.2Hz,1H),7.14(d,J=5.9Hz,1H),7.11(dd,J=2.6Hz,9.2Hz,1H),7.01(d,J=2.6Hz,1H),3.93(s,3H),3.48〜3.38(m,4H),2.76〜2.67(m,4H),2.55(q,J=7.3Hz,2H),1.16(t,J=7.3Hz,3H)
Mass,m/e:271(M),187(base)
製造例43
製造例1と同様にして、5−メトキシ−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.09 (d, J = 5.9 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.14 (d, J = 5. 9 Hz, 1H), 7.11 (dd, J = 2.6 Hz, 9.2 Hz, 1H), 7.01 (d, J = 2.6 Hz, 1H), 3.93 (s, 3H), 3. 48-3.38 (m, 4H), 2.76-2.67 (m, 4H), 2.55 (q, J = 7.3 Hz, 2H), 1.16 (t, J = 7.3 Hz) , 3H)
Mass, m / e: 271 (M + ), 187 (base)
Production Example 43
In the same manner as in Production Example 1, 5-methoxy-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.16(d,J=6.2Hz,1H),7.67(d,J=8.5Hz,1H),7.63(dd,J=0.8Hz,5.8Hz,1H),7.41(t,J=7.7Hz,1H),6.94(d,J=7.7Hz,1H),3.99(s,3H),3.39〜3.31(m,4H),3.18〜3.11(m,4H)
Mass,m/e:243(M),174(base)
製造例44
製造例1と同様にして、5−メトキシ−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.16 (d, J = 6.2 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.63 (dd, J = 0. 8 Hz, 5.8 Hz, 1 H), 7.41 (t, J = 7.7 Hz, 1 H), 6.94 (d, J = 7.7 Hz, 1 H), 3.99 (s, 3 H), 3. 39 to 3.31 (m, 4H), 3.18 to 3.11 (m, 4H)
Mass, m / e: 243 (M + ), 174 (base)
Production Example 44
In the same manner as in Production Example 1, 5-methoxy-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.16(d,J=5.8Hz,1H),7.65(dd,J=0.8Hz,8.5Hz,1H),7.62(dd,J=0.8Hz,5.8Hz,1H),7.41(t,J=7.7Hz,1H),6.94(d,J=7.7Hz,1H),3.98(s,3H),3.50〜3.38(m,4H),2.74〜2.63(m,4H),2.41(s,3H)
Mass,m/e:257(M),187(base)
製造例45
製造例1と同様にして、1−(4−エチルピペラジン−1−イル)−5−メトキシイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.16 (d, J = 5.8 Hz, 1H), 7.65 (dd, J = 0.8 Hz, 8.5 Hz, 1H), 7.62 (dd, J = 0.8 Hz, 5.8 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 3.98 (s, 3H) ), 3.50 to 3.38 (m, 4H), 2.74 to 2.63 (m, 4H), 2.41 (s, 3H)
Mass, m / e: 257 (M + ), 187 (base)
Production Example 45
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) -5-methoxyisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.15(d,J=5.8Hz,1H),7.65(d,J=8.5Hz,1H),7.62(d,J=5.8Hz,1H),7.40(t,J=7.7Hz,1H),6.93(d,J=7.7Hz,1H),3.98(s,3H),3.50〜3.40(m,4H),2.77〜2.68(m,4H),2.55(q,J=7.3Hz,2H),1.16(t,J=7.3Hz,3H)
Mass,m/e:271(M),187(base)
製造例46
製造例1と同様にして、7−メチル−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.15 (d, J = 5.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 5. 8 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 3.98 (s, 3H), 3.50-3. 40 (m, 4H), 2.77 to 2.68 (m, 4H), 2.55 (q, J = 7.3 Hz, 2H), 1.16 (t, J = 7.3 Hz, 3H)
Mass, m / e: 271 (M + ), 187 (base)
Production Example 46
In the same manner as in Production Example 1, 7-methyl-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.10(d,J=5.8Hz,1H),7.88(s,1H),7.66(d,J=8.1Hz,1H),7.45(dd,J=1.5Hz,8.1Hz,1H),7.22(d,J=5.8Hz,1H),3.39〜3.32(m,4H),3.20〜3.13(m,4H)
Mass,m/e:227(M),159(base)
製造例47
製造例1と同様にして、7−メチル−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.10 (d, J = 5.8 Hz, 1H), 7.88 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7 .45 (dd, J = 1.5 Hz, 8.1 Hz, 1H), 7.22 (d, J = 5.8 Hz, 1H), 3.39 to 3.32 (m, 4H), 3.20 to 3.13 (m, 4H)
Mass, m / e: 227 (M + ), 159 (base)
Production Example 47
In the same manner as in Production Example 1, 7-methyl-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.09(d,J=5.8Hz,1H),7.85(s,1H),7.65(d,J=8.5Hz,1H),7.44(dd,J=1.5Hz,8.5Hz,1H),7.21(d,J=5.8Hz,1H),3.51〜3.38(m,4H),2.77〜2.64(m,4H),2.54(s,3H),2.42(s,3H)
Mass,m/e:241(M),171(base)
製造例48
製造例1と同様にして、1−(4−エチルピペラジン−1−イル)−7−メチルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.09 (d, J = 5.8 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7 .44 (dd, J = 1.5 Hz, 8.5 Hz, 1H), 7.21 (d, J = 5.8 Hz, 1H), 3.51 to 3.38 (m, 4H), 2.77 to 2.64 (m, 4H), 2.54 (s, 3H), 2.42 (s, 3H)
Mass, m / e: 241 (M + ), 171 (base)
Production Example 48
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) -7-methylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.09(d,J=5.8Hz,1H),7.85(s,1H),7.65(d,J=8.5Hz,1H),7.44(dd,J=1.5Hz,8.5Hz,1H),7.20(d,J=5.8Hz,1H),3.50〜3.40(m,4H),2.80〜2.69(m,4H),2.59〜2.52(m,5H),1.17(t,J=7.3Hz,3H)
Mass,m/e:255(M),171(base)
製造例49
製造例1と同様にして、7−クロロ−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.09 (d, J = 5.8 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7 .44 (dd, J = 1.5 Hz, 8.5 Hz, 1H), 7.20 (d, J = 5.8 Hz, 1H), 3.50 to 3.40 (m, 4H), 2.80 to 2.69 (m, 4H), 2.59 to 2.52 (m, 5H), 1.17 (t, J = 7.3 Hz, 3H)
Mass, m / e: 255 (M + ), 171 (base)
Production Example 49
In the same manner as in Production Example 1, 7-chloro-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.16(d,J=5.8Hz,1H),8.07(d,J=1.9Hz,1H),7.70(d,J=8.5Hz,1H),7.55(dd,J=1.9Hz,8.5Hz,1H),7.23(d,J=5.8Hz,1H),3.41〜3.33(m,4H),3.20〜3.14(m,4H)
Mass,m/e:247(M),179(base)
製造例50
製造例1と同様にして、7−クロロ−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.16 (d, J = 5.8 Hz, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 8. 5 Hz, 1H), 7.55 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.23 (d, J = 5.8 Hz, 1H), 3.41 to 3.33 (m, 4H) ), 3.20-3.14 (m, 4H)
Mass, m / e: 247 (M + ), 179 (base)
Production Example 50
In the same manner as in Production Example 1, 7-chloro-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.15(d,J=5.8Hz,1H),8.05(d,J=1.9Hz,1H),7.70(d,J=8.5Hz,1H),7.55(dd,J=1.9Hz,8.5Hz,1H),7.22(d,J=5.8Hz,1H),3.48〜3.40(m,4H),2.77〜2.70(m,4H),2.42(s,3H)
Mass,m/e:261(M),83(base)
製造例51
製造例1と同様にして、7−クロロ−1−(4−エチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 8. 5 Hz, 1H), 7.55 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.22 (d, J = 5.8 Hz, 1H), 3.48-3.40 (m, 4H) ), 2.77-2.70 (m, 4H), 2.42 (s, 3H)
Mass, m / e: 261 (M + ), 83 (base)
Production Example 51
In the same manner as in Production Example 1, 7-chloro-1- (4-ethylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.15(d,J=5.8Hz,1H),8.05(d,J=1.9Hz,1H),7.70(d,J=8.5Hz,1H),7.55(dd,J=1.9Hz,8.5Hz,1H),7.21(d,J=5.8Hz,1H),3.49〜3.40(m,4H),2.79〜2.69(m,4H),2.56(q,J=7.3Hz,2H),1.17(t,J=7.3Hz,3H)
Mass,m/e:275(M),97(base)
製造例52
製造例1と同様にして、7−フルオロ−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 8. 5 Hz, 1H), 7.55 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.21 (d, J = 5.8 Hz, 1H), 3.49-3.40 (m, 4H) ), 2.79-2.69 (m, 4H), 2.56 (q, J = 7.3 Hz, 2H), 1.17 (t, J = 7.3 Hz, 3H)
Mass, m / e: 275 (M + ), 97 (base)
Production Example 52
In the same manner as in Production Example 1, 7-fluoro-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.14(d,J=5.8Hz,1H),7.78〜7.73(m,1H),7.73〜7.66(m,1H),7.42〜7.35(m,1H),7.24(d,J=5.8Hz,1H),3.48〜3.37(m,4H),2.76〜2.64(m,4H),2.42(s,3H)
Mass,m/e:245(M),175(base)
製造例53
製造例1と同様にして、1−(4−エチルピペラジン−1−イル)−7−フルオロイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.14 (d, J = 5.8 Hz, 1H), 7.78-7.73 (m, 1H), 7.73-7.66 (m, 1H) , 7.42 to 7.35 (m, 1H), 7.24 (d, J = 5.8 Hz, 1H), 3.48 to 3.37 (m, 4H), 2.76 to 2.64 ( m, 4H), 2.42 (s, 3H)
Mass, m / e: 245 (M + ), 175 (base)
Production Example 53
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) -7-fluoroisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.14(d,J=5.8Hz,1H),7.78〜7.73(m,1H),7.73〜7.67(m,1H),7.42〜7.36(m,1H),7.24(d,J=5.8Hz,1H),3.49〜3.39(m,4H),2.79〜2.70(m,4H),2.56(q,J=7.3Hz,2H),1.17(t,J=7.3Hz,3H)
Mass,m/e:259(M),175(base)
製造例54
製造例1と同様にして、1−(4−メチルピペラジン−1−イル)−7−フェニルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.14 (d, J = 5.8 Hz, 1H), 7.78-7.73 (m, 1H), 7.73-7.67 (m, 1H) , 7.42 to 7.36 (m, 1H), 7.24 (d, J = 5.8 Hz, 1H), 3.49 to 3.39 (m, 4H), 2.79 to 2.70 ( m, 4H), 2.56 (q, J = 7.3 Hz, 2H), 1.17 (t, J = 7.3 Hz, 3H)
Mass, m / e: 259 (M + ), 175 (base)
Production Example 54
In the same manner as in Production Example 1, 1- (4-methylpiperazin-1-yl) -7-phenylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.30〜8.27(m,1H),8.16(d,J=5.8Hz,1H),7.90〜7.80(m,2H),7.72〜7.67(m,2H),7.55〜7.48(m,2H),7.44〜7.39(m,1H),7.29〜7.25(m,1H),3.55〜3.49(m,4H),2.76〜2.66(m,4H),2.42(s,3H)
Mass,m/e:303(M),233(base)
製造例55
製造例1と同様にして、1−(4−エチルピペラジン−1−イル)−7−フェニルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.30-8.27 (m, 1H), 8.16 (d, J = 5.8 Hz, 1H), 7.90-7.80 (m, 2H) , 7.72-7.67 (m, 2H), 7.55-7.48 (m, 2H), 7.44-7.39 (m, 1H), 7.29-7.25 (m, 1H), 3.55 to 3.49 (m, 4H), 2.76 to 2.66 (m, 4H), 2.42 (s, 3H)
Mass, m / e: 303 (M + ), 233 (base)
Production Example 55
In the same manner as in Production Example 1, 1- (4-ethylpiperazin-1-yl) -7-phenylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.30〜8.27(m,1H),8.16(d,J=5.8Hz,1H),7.89〜7.80(m,2H),7.72〜7.67(m,2H),7.55〜7.49(m,2H),7.44〜7.39(m,1H),7.28〜7.24(m,1H),3.58〜3.48(m,4H),2.81〜2.72(m,4H),2.56(q,J=7.3Hz,2H),1.17(t,J=7.3Hz,3H)
Mass,m/e:317(M),233(base)
製造例56
製造例1と同様にして、7−フェニル−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.30-8.27 (m, 1H), 8.16 (d, J = 5.8 Hz, 1H), 7.89-7.80 (m, 2H) , 7.72-7.67 (m, 2H), 7.55-7.49 (m, 2H), 7.44-7.39 (m, 1H), 7.28-7.24 (m, 1H), 3.58 to 3.48 (m, 4H), 2.81 to 2.72 (m, 4H), 2.56 (q, J = 7.3 Hz, 2H), 1.17 (t, J = 7.3Hz, 3H)
Mass, m / e: 317 (M + ), 233 (base)
Production Example 56
In the same manner as in Production Example 1, 7-phenyl-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.30(s,1H),8.16(d,J=5.8Hz,1H),7.90〜7.80(m,2H),7.72〜7.67(m,2H),7.54〜7.48(m,2H),7.44〜7.39(m,1H),7.28(d,J=5.8Hz,1H),3.47〜3.38(m,4H),3.21〜3.14(m,4H)
Mass,m/e:289(M),220(base)
製造例57
製造例1と同様にして、6−クロロ−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.30 (s, 1H), 8.16 (d, J = 5.8 Hz, 1H), 7.90-7.80 (m, 2H), 7.72 ˜7.67 (m, 2H), 7.54 to 7.48 (m, 2H), 7.44 to 7.39 (m, 1H), 7.28 (d, J = 5.8 Hz, 1H) 3.47-3.38 (m, 4H), 3.21-3.14 (m, 4H)
Mass, m / e: 289 (M + ), 220 (base)
Production Example 57
In the same manner as in Production Example 1, 6-chloro-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.16(d,J=5.8Hz,1H),8.03(d,J=8.9Hz,1H),7.73(d,J=1.9Hz,1H),7.44(dd,J=1.9Hz,8.9Hz,1H),7.16(d,J=5.8Hz,1H),3.40〜3.34(m,4H),3.17〜3.12(m,4H)
Mass,m/e:247(M),179(base)
製造例58
製造例1と同様にして、6−クロロ−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.16 (d, J = 5.8 Hz, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 1. 9 Hz, 1H), 7.44 (dd, J = 1.9 Hz, 8.9 Hz, 1H), 7.16 (d, J = 5.8 Hz, 1H), 3.40 to 3.34 (m, 4H) ), 3.17-3.12 (m, 4H)
Mass, m / e: 247 (M + ), 179 (base)
Production Example 58
In the same manner as in Production Example 1, 6-chloro-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.15(d,J=5.8Hz,1H),8.01(d,J=8.9Hz,1H),7.72(d,J=1.9Hz,1H),7.43(dd,J=1.9Hz,8.9Hz,1H),7.14(d,J=5.8Hz,1H),3.45(t,J=4.6Hz,4H),2.69(t,J=4.6Hz,4H),2.41(s,3H)
Mass,m/e:261(M),83(base)
製造例59
製造例1と同様にして、6−クロロ−1−(4−エチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.01 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 1. 9 Hz, 1 H), 7.43 (dd, J = 1.9 Hz, 8.9 Hz, 1 H), 7.14 (d, J = 5.8 Hz, 1 H), 3.45 (t, J = 4.6 Hz) , 4H), 2.69 (t, J = 4.6 Hz, 4H), 2.41 (s, 3H)
Mass, m / e: 261 (M + ), 83 (base)
Production Example 59
In the same manner as in Production Example 1, 6-chloro-1- (4-ethylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.15(d,J=5.8Hz,1H),8.01(d,J=8.9Hz,1H),7.72(d,J=1.9Hz,1H),7.42(dd,J=1.9Hz,8.9Hz,1H),7.14(d,J=5.8Hz,1H),3.46(t,J=4.6Hz,4H),2.72(t,J=4.6Hz,4H),2.55(q,J=7.3Hz,2H),1.16(t,J=7.3Hz,3H)
Mass,m/e:275(M),83(base)
製造例60
製造例1と同様にして、5−クロロ−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.01 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 1. 9 Hz, 1H), 7.42 (dd, J = 1.9 Hz, 8.9 Hz, 1H), 7.14 (d, J = 5.8 Hz, 1H), 3.46 (t, J = 4.6 Hz) , 4H), 2.72 (t, J = 4.6 Hz, 4H), 2.55 (q, J = 7.3 Hz, 2H), 1.16 (t, J = 7.3 Hz, 3H)
Mass, m / e: 275 (M + ), 83 (base)
Production Example 60
In the same manner as in Production Example 1, 5-chloro-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.25(d,J=5.8Hz,1H),8.04(td,J=1.2Hz,8.5Hz,1H),7.69(dd,J=1.2Hz,7.3Hz,1H),7.64(dd,J=1.2Hz,5.8Hz,1H),7.42(dd,J=7.3Hz,8.5Hz,1H),3.41〜3.35(m,4H),3.18〜3.13(m,4H)
Mass,m/e:247(M),179(base)
製造例61
製造例1と同様にして、5−クロロ−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.25 (d, J = 5.8 Hz, 1H), 8.04 (td, J = 1.2 Hz, 8.5 Hz, 1H), 7.69 (dd, J = 1.2 Hz, 7.3 Hz, 1H), 7.64 (dd, J = 1.2 Hz, 5.8 Hz, 1H), 7.42 (dd, J = 7.3 Hz, 8.5 Hz, 1H) , 3.41-3.35 (m, 4H), 3.18-3.13 (m, 4H)
Mass, m / e: 247 (M + ), 179 (base)
Production Example 61
In the same manner as in Production Example 1, 5-chloro-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.24(d,J=5.8Hz,1H),8.02(d,J=8.5Hz,1H),7.68(dd,J=1.2Hz,7.3Hz,1H),7.62(dd,J=1.2Hz,5.8Hz,1H),7.41(dd,J=7.3Hz,8.5Hz,1H),3.45(t,J=4.6Hz,4H),2.69(t,J=4.6Hz,4H),2.41(s,3H)
Mass,m/e:261(M),83(base)
製造例62
製造例1と同様にして、5−クロロ−1−(4−エチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.24 (d, J = 5.8 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.68 (dd, J = 1. 2 Hz, 7.3 Hz, 1 H), 7.62 (dd, J = 1.2 Hz, 5.8 Hz, 1 H), 7.41 (dd, J = 7.3 Hz, 8.5 Hz, 1 H), 3.45 (T, J = 4.6 Hz, 4H), 2.69 (t, J = 4.6 Hz, 4H), 2.41 (s, 3H)
Mass, m / e: 261 (M + ), 83 (base)
Production Example 62
In the same manner as in Production Example 1, 5-chloro-1- (4-ethylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.24(d,J=5.8Hz,1H),8.02(d,J=8.5Hz,1H),7.68(dd,J=0.8Hz,7.3Hz,1H),7.61(d,J=6.2Hz,1H),7.40(t,J=8.1Hz,1H),3.47(t,J=4.6Hz,4H),2.73(t,J=4.6Hz,4H),2.55(q,J=7.3Hz,2H),1.16(t,J=7.3Hz,3H)
Mass,m/e:275(M),97(base)
製造例63
製造例1と同様にして、7−フルオロ−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.24 (d, J = 5.8 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.68 (dd, J = 0. 8 Hz, 7.3 Hz, 1 H), 7.61 (d, J = 6.2 Hz, 1 H), 7.40 (t, J = 8.1 Hz, 1 H), 3.47 (t, J = 4.6 Hz) , 4H), 2.73 (t, J = 4.6 Hz, 4H), 2.55 (q, J = 7.3 Hz, 2H), 1.16 (t, J = 7.3 Hz, 3H)
Mass, m / e: 275 (M + ), 97 (base)
Production Example 63
In the same manner as in Production Example 1, 7-fluoro-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.14(d,J=5.8Hz,1H),7.79〜7.69(m,2H),7.43〜7.37(m,1H),7.27〜7.24(m,1H),3.38〜3.32(m,4H),3.19〜3.14(m,4H)
Mass,m/e:231(M),163(base)
製造例64
製造例1と同様にして、1−(2,5−ジアザビシクロ[2.2.2]オクタン−1−イル)−7−メトキシイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.14 (d, J = 5.8 Hz, 1H), 7.79-7.69 (m, 2H), 7.43-7.37 (m, 1H) 7.27-7.24 (m, 1H), 3.38-3.32 (m, 4H), 3.19-3.14 (m, 4H)
Mass, m / e: 231 (M + ), 163 (base)
Production Example 64
In the same manner as in Production Example 1, 1- (2,5-diazabicyclo [2.2.2] octan-1-yl) -7-methoxyisoquinoline was obtained.
Figure 0004596792

H−NMR(DMSO−d)δ:7.97(d,J=8.9Hz,1H),7.79(d,J=6.2Hz,1H),7.59(d,J=8.9Hz,1H),7.48(s,1H),7.42(d,J=6.2Hz,1H),4.63(br s,1H),4.42〜4.31(m,1H),4.10〜3.98(m,1H),3.96(s,3H),3.96〜3.27(m,3H),2.48〜2.37(m,1H),2.28〜2.13(m,1H),2.08〜1.92(m,2H)
Mass,m/e:269(M),175(base)
製造例65
製造例1と同様にして、7−クロロ−1−[4−[4−(3−メトキシフェニル)ブチル]ピペラジン−1−イル]イソキノリンを得た。

Figure 0004596792
1 H-NMR (DMSO-d 6 ) δ: 7.97 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 6.2 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1 H), 7.48 (s, 1 H), 7.42 (d, J = 6.2 Hz, 1 H), 4.63 (br s, 1 H), 4.42 to 4.31 (m) , 1H), 4.10 to 3.98 (m, 1H), 3.96 (s, 3H), 3.96 to 3.27 (m, 3H), 2.48 to 2.37 (m, 1H) ), 2.28 to 2.13 (m, 1H), 2.08 to 1.92 (m, 2H)
Mass, m / e: 269 (M + ), 175 (base)
Production Example 65
In the same manner as in Production Example 1, 7-chloro-1- [4- [4- (3-methoxyphenyl) butyl] piperazin-1-yl] isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.15(d,J=5.8Hz,1H),8.06(m,1H),7.67(d,J=8.9Hz,1H),7.56(d,J=1.9Hz,1H),7.52(d,J=2.3Hz,1H),7.26(t,J=3.9Hz,1H),6.82(d,J=7.7Hz,1H),6.75〜6.69(m,2H),3.86(s,3H),3.39(t,J=5.0Hz,4H),2.69(t,J=4.8Hz,4H),2.59(t,J=7.0Hz,2H),2.41(t,J=7.5Hz,2H),1.75〜1.50(m,4H)
Mass,m/e:409(M),191(base),121,107
製造例66
製造例1と同様にして、7−メトキシ−1−[4−[4−(3−メトキシフェニル)ブチル]ピペラジン−1−イル]イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.06 (m, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7 .56 (d, J = 1.9 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.26 (t, J = 3.9 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.75-6.69 (m, 2H), 3.86 (s, 3H), 3.39 (t, J = 5.0 Hz, 4H), 2.69 ( t, J = 4.8 Hz, 4H), 2.59 (t, J = 7.0 Hz, 2H), 2.41 (t, J = 7.5 Hz, 2H), 1.75 to 1.50 (m , 4H)
Mass, m / e: 409 (M + ), 191 (base), 121, 107
Production Example 66
In the same manner as in Production Example 1, 7-methoxy-1- [4- [4- (3-methoxyphenyl) butyl] piperazin-1-yl] isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.17(d,J=5.9Hz,1H),8.08(s,1H),7.20(d,J=8.9Hz,1H),7.13(d,J=1.9Hz,1H),7.10(d,J=2.3Hz,1H),7.04(t,J=3.9Hz,1H),6.80(d,J=7.6Hz,1H),6.79〜6.65(m,2H)3.96(s,3H),3.89(s,3H),3.42(t,J=4.8Hz,4H),2.73(t,J=4.8Hz,4H),2.63(t,J=6.9Hz,2H),2.43(t,J=7.5Hz,2H),1.78〜1.47(m,4H)
Mass,m/e:405(M),187(base),121,107
製造例67
製造例1と同様にして、7−クロロ−1−[4−[トランス−4−(3−メトキシフェニル)シクロヘキサン−1−イル]ピペラジン−1−イル]イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.17 (d, J = 5.9 Hz, 1H), 8.08 (s, 1H), 7.20 (d, J = 8.9 Hz, 1H), 7 .13 (d, J = 1.9 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 7.04 (t, J = 3.9 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.79-6.65 (m, 2H) 3.96 (s, 3H), 3.89 (s, 3H), 3.42 (t, J = 4.8 Hz) 4H), 2.73 (t, J = 4.8 Hz, 4H), 2.63 (t, J = 6.9 Hz, 2H), 2.43 (t, J = 7.5 Hz, 2H), 1 .78 to 1.47 (m, 4H)
Mass, m / e: 405 (M + ), 187 (base), 121, 107
Production Example 67
In the same manner as in Production Example 1, 7-chloro-1- [4- [trans-4- (3-methoxyphenyl) cyclohexane-1-yl] piperazin-1-yl] isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.14(d,J=5.8Hz,1H),8.03(m,1H),7.69(d,J=8.9Hz,1H),7.55(d,J=1.9Hz,1H),7.53(d,J=1.9Hz,1H),7.22(d,J=5.9Hz,1H),6.81(d,J=7.7Hz,1H),6.76〜6.72(m,2H),3.80(s,3H),3.59(t,J=5.0Hz,4H),2.97(t,J=4.8Hz,4H),2.53〜2.47(m,2H),2.21〜2.10(m,4H),2.09〜2.00(m,4H)
Mass,m/e:435(M),420,191(base),121,107
製造例68
製造例1と同様にして、7−メトキシ−1−[4−[トランス−4−(3−メトキシフェニル)シクロヘキサン−1−イル]ピペラジン−1−イル]イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.14 (d, J = 5.8 Hz, 1H), 8.03 (m, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7 .55 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.22 (d, J = 5.9 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.76 to 6.72 (m, 2H), 3.80 (s, 3H), 3.59 (t, J = 5.0 Hz, 4H), 2.97 ( t, J = 4.8 Hz, 4H), 2.53 to 2.47 (m, 2H), 2.21 to 2.10 (m, 4H), 2.09 to 2.00 (m, 4H)
Mass, m / e: 435 (M + ), 420, 191 (base), 121, 107
Production Example 68
In the same manner as in Production Example 1, 7-methoxy-1- [4- [trans-4- (3-methoxyphenyl) cyclohexane-1-yl] piperazin-1-yl] isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.08(d,J=5.7Hz,1H),8.00(d,J=9.3Hz,1H),7.20(d,J=5.7Hz,1H),7.14(d,J=5.7Hz,1H),7.11(dd,J=2.7Hz,9.3Hz,1H),7.01(d,J=2.7Hz,1H),6.82(d,J=7.3Hz,1H),6.78〜6.72(m,2H),3.92(s,3H),3.80(s,3H),3.43(m,4H),2.87(t,J=4.4Hz,4H),2.50〜2.47(m,2H),2.16〜2.10(m,4H),2.06〜1.98(m,4H)
Mass,m/e:431(M),416,187(base),121
製造例69
製造例1と同様にして、1−[4−(2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−2−イルメチル)−ピペラジン−1−イル]−7−メトキシイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.08 (d, J = 5.7 Hz, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.20 (d, J = 5. 7 Hz, 1 H), 7.14 (d, J = 5.7 Hz, 1 H), 7.11 (dd, J = 2.7 Hz, 9.3 Hz, 1 H), 7.01 (d, J = 2.7 Hz) , 1H), 6.82 (d, J = 7.3 Hz, 1H), 6.78 to 6.72 (m, 2H), 3.92 (s, 3H), 3.80 (s, 3H), 3.43 (m, 4H), 2.87 (t, J = 4.4 Hz, 4H), 2.50 to 2.47 (m, 2H), 2.16 to 2.10 (m, 4H), 2.06-1.98 (m, 4H)
Mass, m / e: 431 (M + ), 416, 187 (base), 121
Production Example 69
In the same manner as in Production Example 1, 1- [4- (2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -piperazin-1-yl] -7-methoxyisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.06(d,J=5.7Hz,1H),7.66(d,J=9.0Hz,1H),7.39(d,J=2.3Hz,1H),7.22(d,J=5.4Hz,1H),7.28(dd,J=2.3Hz,8.8Hz,1H),6.89(dd,J=4.6Hz,9.6Hz,1H),6.84(dd,J=3.4Hz,5.8Hz,1H),4.41〜4.35(m,2H),4.05(dd,J=7.4Hz,11.2Hz,1H),3.94(s,3H),3.41(t,J=4.5Hz,4H),2.92〜2.85(m,2H),2.83〜2.73(m,4H)
Mass,m/e:391(M),376,282,187(base),174
製造例70
製造例1と同様にして、1−[1,4]ジアゼパン−1−イル−7−メトキシイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.06 (d, J = 5.7 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 2. 3 Hz, 1 H), 7.22 (d, J = 5.4 Hz, 1 H), 7.28 (dd, J = 2.3 Hz, 8.8 Hz, 1 H), 6.89 (dd, J = 4.6 Hz) , 9.6 Hz, 1H), 6.84 (dd, J = 3.4 Hz, 5.8 Hz, 1H), 4.41 to 4.35 (m, 2H), 4.05 (dd, J = 7. 4 Hz, 11.2 Hz, 1 H), 3.94 (s, 3 H), 3.41 (t, J = 4.5 Hz, 4 H), 2.92 to 2.85 (m, 2 H), 2.83 2.73 (m, 4H)
Mass, m / e: 391 (M + ), 376, 282, 187 (base), 174
Production Example 70
In the same manner as in Production Example 1, 1- [1,4] diazepan-1-yl-7-methoxyisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.02〜7.99(m,2H),7.11〜7.09(m,2H),7.00(d,J=2.3Hz,1H),3.92(s,3H),3.76(t,J=5.4Hz,2H),3.72(t,J=5.8Hz,2H),3.27(t,J=5.4Hz,2H),3.16(t,J=5.7Hz,2H),2.75(br s,1H),2.00〜1.95(m,2H)
Mass,m/e:257(M),242,201,187(base)
製造例71
製造例1と同様にして、1−(4−ベンゾ[1,3]ジオキソール−5−イルメチルピペラジン−1−イル)−7−メトキシイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.02 to 7.99 (m, 2H), 7.11 to 7.09 (m, 2H), 7.00 (d, J = 2.3 Hz, 1H) , 3.92 (s, 3H), 3.76 (t, J = 5.4 Hz, 2H), 3.72 (t, J = 5.8 Hz, 2H), 3.27 (t, J = 5. 4 Hz, 2H), 3.16 (t, J = 5.7 Hz, 2H), 2.75 (brs, 1H), 2.00 to 1.95 (m, 2H)
Mass, m / e: 257 (M + ), 242, 201, 187 (base)
Production Example 71
In the same manner as in Production Example 1, 1- (4-benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -7-methoxyisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.07(d,J=5.8Hz,1H),7.97(d,J=9.3Hz,1H),7.13(d,J=5.8Hz,1H),7.09(dd,J=2.7Hz,9.3Hz,1H),7.00(d,J=2.7Hz,1H),6.91(s,1H),6.77(t,J=7.2Hz,2H),5.94(s,2H),3.91(s,3H),3.53(s,2H),3.39(m,4H),2.69(t,J=4.5Hz,4H)
Mass,m/e:377(M),187(base),174,135
製造例72
製造例1と同様にして、1−((8aS)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)−7−メトキシイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.07 (d, J = 5.8 Hz, 1H), 7.97 (d, J = 9.3 Hz, 1H), 7.13 (d, J = 5. 8 Hz, 1 H), 7.09 (dd, J = 2.7 Hz, 9.3 Hz, 1 H), 7.00 (d, J = 2.7 Hz, 1 H), 6.91 (s, 1 H), 6. 77 (t, J = 7.2 Hz, 2H), 5.94 (s, 2H), 3.91 (s, 3H), 3.53 (s, 2H), 3.39 (m, 4H), 2 .69 (t, J = 4.5Hz, 4H)
Mass, m / e: 377 (M + ), 187 (base), 174, 135
Production Example 72
In the same manner as in Production Example 1, 1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -7-methoxyisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.07(d,J=5.4Hz,1H),7.68(d,J=8.9Hz,1H),7.40(d,J=2.7Hz,1H),7.29(dd,J=2.3Hz,8.9Hz,1H),7.21(d,J=5.4Hz,1H),3.94(s,3H),3.87〜3.84(m,1H),3.79〜3.75(m,2H),3.22〜3.16(m,2H),2.93〜2.88(m,1H),2.64〜2.58(m,1H),2.40〜2.38(m,1H),2.29(q,J=8.5Hz,1H),1.94〜1.76(m,3H),1.65〜1.52(m,1H)
Mass,m/e:283(M),96(base)
製造例73
製造例1と同様にして、7−クロロ−1−((8aS)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.07 (d, J = 5.4 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2. 7 Hz, 1 H), 7.29 (dd, J = 2.3 Hz, 8.9 Hz, 1 H), 7.21 (d, J = 5.4 Hz, 1 H), 3.94 (s, 3 H), 3. 87-3.84 (m, 1H), 3.79-3.75 (m, 2H), 3.22-3.16 (m, 2H), 2.93-2.88 (m, 1H), 2.64 to 2.58 (m, 1H), 2.40 to 2.38 (m, 1H), 2.29 (q, J = 8.5 Hz, 1H), 1.94 to 1.76 (m , 3H), 1.65 to 1.52 (m, 1H)
Mass, m / e: 283 (M + ), 96 (base)
Production Example 73
In the same manner as in Production Example 1, 7-chloro-1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.14(d,J=5.8Hz,1H),8.04(d,J=2.3Hz,1H),7.68(d,J=8.9Hz,1H),7.55〜7.52(m,1H),7.19(d,J=5.4Hz,1H),3.87〜3.83(m,1H),3.78〜3.73(m,1H),3.24〜3.16(m,3H),2.93〜2.87(m,1H),2.63〜2.60(m,1H),2.38〜2.25(m,2H),1.93〜1.83(m,3H),1.63〜1.51(m,1H)
Mass,m/e:287(M),96(base)
製造例74
製造例1と同様にして、8−((8aS)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)−1,7−ナフチリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.14 (d, J = 5.8 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.68 (d, J = 8. 9 Hz, 1H), 7.55 to 7.52 (m, 1H), 7.19 (d, J = 5.4 Hz, 1H), 3.87 to 3.83 (m, 1H), 3.78 to 3.73 (m, 1H), 3.24 to 3.16 (m, 3H), 2.93 to 2.87 (m, 1H), 2.63 to 2.60 (m, 1H), 2. 38 to 2.25 (m, 2H), 1.93 to 1.83 (m, 3H), 1.63 to 1.51 (m, 1H)
Mass, m / e: 287 (M + ), 96 (base)
Production Example 74
In the same manner as in Production Example 1, 8-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -1,7-naphthyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.83(dd,J=1.9Hz,4.2Hz,1H),8.13(d,J=5.4Hz,1H),8.01(dd,J=1.9Hz,8.5Hz,1H),7.48(dd,J=4.3Hz,8.5Hz,1H),7.04(d,J=5.4Hz,1H),4.96〜4.90(m,2H),3.32〜3.25(m,1H),3.19〜3.15(m,2H),2.97〜2.92(m,1H),2.62〜2.56(m,1H),2.34〜2.33(m,1H),2.25(q,J=8.9Hz,1H),1.96〜1.85(m,2H),1.82〜1.75(m、1H),1.56〜1.50(m,1H)
Mass,m/e:254(M),96(base)
製造例75
製造例1と同様にして、5−((8aS)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)−1,6−ナフチリジンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.83 (dd, J = 1.9 Hz, 4.2 Hz, 1H), 8.13 (d, J = 5.4 Hz, 1H), 8.01 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.48 (dd, J = 4.3 Hz, 8.5 Hz, 1H), 7.04 (d, J = 5.4 Hz, 1H), 4.96. ˜4.90 (m, 2H), 3.32 to 3.25 (m, 1H), 3.19 to 3.15 (m, 2H), 2.97 to 2.92 (m, 1H), 2 .62 to 2.56 (m, 1H), 2.34 to 2.33 (m, 1H), 2.25 (q, J = 8.9 Hz, 1H), 1.96 to 1.85 (m, 2H), 1.82-1.75 (m, 1H), 1.56-1.50 (m, 1H)
Mass, m / e: 254 (M + ), 96 (base)
Production Example 75
In the same manner as in Production Example 1, 5-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -1,6-naphthyridine was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.98(dd,J=1.9Hz,4.2Hz,1H),8.40〜8.37(m,1H),8.33(d,J=5.8Hz,1H),7.47〜7.40(m,2H),3.93(td,J=2.3Hz,8.3Hz,1H),3.82(dd,J=2.7Hz,11.8Hz,1H),3.32〜3.25(m,1H),3.21〜3.16(m,2H),2.97〜2.93(m,1H),2.59(dt,J=2.7Hz,11.2Hz,1H),2.37〜2.25(m,2H),1.94〜1.75(m,3H),1.55〜1.50(m,1H)
Mass,m/e:254(M),96(base)
製造例76
製造例1と同様にして、7−クロロ−1−((8aR)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.98 (dd, J = 1.9 Hz, 4.2 Hz, 1H), 8.40-8.37 (m, 1H), 8.33 (d, J = 5.8 Hz, 1H), 7.47-7.40 (m, 2H), 3.93 (td, J = 2.3 Hz, 8.3 Hz, 1H), 3.82 (dd, J = 2.7 Hz) , 11.8 Hz, 1H), 3.32 to 3.25 (m, 1H), 3.21 to 3.16 (m, 2H), 2.97 to 2.93 (m, 1H), 2.59. (Dt, J = 2.7 Hz, 11.2 Hz, 1H), 2.37 to 2.25 (m, 2H), 1.94 to 1.75 (m, 3H), 1.55 to 1.50 ( m, 1H)
Mass, m / e: 254 (M + ), 96 (base)
Production Example 76
In the same manner as in Production Example 1, 7-chloro-1-((8aR) -octahydropyrrolo [1,2-a] pyrazin-2-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.15(d,J=5.8Hz,1H),8.06(d,J=1.9Hz,1H),7.69(d,J=8.9Hz,1H),7.55(dd,J=1.9Hz,8.9Hz,1H),7.21(d,J=5.8Hz,1H),3.86(td,J=2.3Hz,11.6Hz,1H),3.80〜3.75(m,1H),3.25〜3.17(m,3H),2.94〜2.88(m,1H),2.65〜2.59(m,1H),2.39〜2.34(m,1H),2.28(t,J=8.9Hz,1H),1.95〜1.84(m,2H),1.84〜1.75(m,1H),1.55〜1.48(m,1H)
Mass,m/e:287(M),96(base)
製造例77
製造例1と同様にして、1−((8aR)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)−7−メトキシイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 8. 9 Hz, 1H), 7.55 (dd, J = 1.9 Hz, 8.9 Hz, 1H), 7.21 (d, J = 5.8 Hz, 1H), 3.86 (td, J = 2.3 Hz) , 11.6 Hz, 1H), 3.80 to 3.75 (m, 1H), 3.25 to 3.17 (m, 3H), 2.94 to 2.88 (m, 1H), 2.65. ˜2.59 (m, 1H), 2.39 to 2.34 (m, 1H), 2.28 (t, J = 8.9 Hz, 1H), 1.95 to 1.84 (m, 2H) , 1.84 to 1.75 (m, 1H), 1.55 to 1.48 (m, 1H)
Mass, m / e: 287 (M + ), 96 (base)
Production Example 77
In the same manner as in Production Example 1, 1-((8aR) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -7-methoxyisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.06(d,J=5.8Hz,1H),7.66(dd,J=3.4Hz,8.9Hz,1H),7.39(d,J=2.3Hz,1H),7.27(dd,J=2.3Hz,8.9Hz,1H),7.19(d,J=5.4Hz,1H),3.93(s,3H),3.85(td,J=2.3Hz,12.0Hz,1H),3.77〜3.74(m,1H),3.20〜3.15(m,3H),2.89(t,J=10.8Hz,1H),2.60(t,J=11.2Hz,1H),2.39〜2.37(m,1H),2.32〜2.25(m,1H),1.93〜1.83(m,2H),1.80〜1.76(m,1H),1.59〜1.51(m,1H)
Mass,m/e:283(M),96(base)
製造例78
製造例1と同様にして、3−クロロ−1−((8aS)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.06 (d, J = 5.8 Hz, 1H), 7.66 (dd, J = 3.4 Hz, 8.9 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = 2.3 Hz, 8.9 Hz, 1H), 7.19 (d, J = 5.4 Hz, 1H), 3.93 (s, 3H) ), 3.85 (td, J = 2.3 Hz, 12.0 Hz, 1H), 3.77-3.74 (m, 1H), 3.20-3.15 (m, 3H), 2.89 (T, J = 10.8 Hz, 1H), 2.60 (t, J = 11.2 Hz, 1H), 2.39 to 2.37 (m, 1H), 2.32 to 2.25 (m, 1H), 1.93 to 1.83 (m, 2H), 1.80 to 1.76 (m, 1H), 1.59 to 1.51 (m, 1H)
Mass, m / e: 283 (M + ), 96 (base)
Production Example 78
In the same manner as in Production Example 1, 3-chloro-1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.00(d,J=8.5Hz,1H),7.64(d,J=7.7Hz,1H),7.60〜7.56(m,1H),7.46〜7.42(m,1H),7.22(s,1H),3.99(td,J=2.3Hz,12.3Hz,1H),3.93〜3.89(m,1H),3.24(dt,J=2.7Hz,12.0Hz,1H),3.18〜3.13(m,2H),2.95〜2.90(m,1H),2.61〜2.23(m,2H),1.93〜1.83(m,1H),1.81〜1.74(m,2H),1.53〜1.47(m,1H)
Mass,m/e:287(M),96(base)
製造例79
製造例1と同様にして、3−クロロ−1−((8aS)−オクタヒドロピロロ[1,2−a]ピラジン−2−イル)−7−メチルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.00 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.60-7.56 (m, 1H), 7.46-7.42 (m, 1H), 7.22 (s, 1H), 3.99 (td, J = 2.3 Hz, 12.3 Hz, 1H), 3.93-3. 89 (m, 1H), 3.24 (dt, J = 2.7 Hz, 12.0 Hz, 1H), 3.18 to 3.13 (m, 2H), 2.95 to 2.90 (m, 1H) ), 2.61-1.23 (m, 2H), 1.93-1.83 (m, 1H), 1.81-1.74 (m, 2H), 1.53-1.47 (m) , 1H)
Mass, m / e: 287 (M + ), 96 (base)
Production Example 79
In the same manner as in Production Example 1, 3-chloro-1-((8aS) -octahydropyrrolo [1,2-a] pyrazin-2-yl) -7-methylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:7.55(d,J=8.5Hz,1H),7.42(dd,J=1.5Hz,8.5Hz,1H),7.19(s,1H),3.95(td,J=2.3Hz,12.3Hz,1H),3.90〜3.86(m,1H),3.25〜3.13(m,2H),2.95〜2.89(m,1H),2.62〜2.57(m,1H),2.51(s,3H),2.35〜2.24(m,2H),1.91〜1.83(m,2H),1.79〜1.76(m,1H),1.56〜1.51(m,1H)
Mass,m/e:301(M),96(base)
製造例80
製造例1と同様にして、7−クロロ−1−オクタヒドロピリド[1,2−a]ピラジン−2−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 7.55 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 1.5 Hz, 8.5 Hz, 1H), 7.19 (s, 1H), 3.95 (td, J = 2.3 Hz, 12.3 Hz, 1H), 3.90 to 3.86 (m, 1H), 3.25 to 3.13 (m, 2H), 2. 95-2.89 (m, 1H), 2.62-2.57 (m, 1H), 2.51 (s, 3H), 2.35-2.24 (m, 2H), 1.91- 1.83 (m, 2H), 1.79 to 1.76 (m, 1H), 1.56 to 1.51 (m, 1H)
Mass, m / e: 301 (M + ), 96 (base)
Production Example 80
In the same manner as in Production Example 1, 7-chloro-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.15(d,J=5.8Hz,1H),8.05(d,J=1.9Hz,1H),7.69(d,J=8.9Hz,1H),7.55(dd,J=1.9Hz,8.9Hz,1H),7.21(d,J=5.8Hz,1H),3.72(qd,J=2.7Hz,12.3Hz,1H),3.56(td,J=2.7Hz,12.3Hz,1H),3.23(dt,J=2.7Hz,12.3Hz,1H),2.97〜2.84(m,3H),2.63(dt,J=2.7Hz,11.6Hz,1H),2.33〜2.16(m,2H),1.87〜1.78(m,1H),1.75〜1.57(m,3H),1.45〜1.28(m,2H)
Mass,m/e:301(M),110(base)
製造例81
製造例1と同様にして、7−メトキシ−1−オクタヒドロピリド[1,2−a]ピラジン−2−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.15 (d, J = 5.8 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 8. 9 Hz, 1H), 7.55 (dd, J = 1.9 Hz, 8.9 Hz, 1H), 7.21 (d, J = 5.8 Hz, 1H), 3.72 (qd, J = 2.7 Hz) , 12.3 Hz, 1H), 3.56 (td, J = 2.7 Hz, 12.3 Hz, 1H), 3.23 (dt, J = 2.7 Hz, 12.3 Hz, 1H), 2.97- 2.84 (m, 3H), 2.63 (dt, J = 2.7 Hz, 11.6 Hz, 1H), 2.33 to 2.16 (m, 2H), 1.87 to 1.78 (m , 1H), 1.75 to 1.57 (m, 3H), 1.45 to 1.28 (m, 2H)
Mass, m / e: 301 (M + ), 110 (base)
Production Example 81
In the same manner as in Production Example 1, 7-methoxy-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.07(d,J=5.4Hz,1H),7.67(d,J=8.9Hz,1H),7.40(d,J=2.7Hz,1H),7.28(dd,J=2.7Hz,8.9Hz,1H),7.20(d,J=5.8Hz,1H),3.94(s,3H),3.72(qd,J=2.7Hz,12.3Hz,1H),3.57(td,J=2.7Hz,12.3Hz,1H),3.26〜3.16(m,1H),2.98〜2.84(m,3H),2.63(dt,J=2.7Hz,11.6Hz,1H),2.35〜2.25(m,1H),2.25〜2.15(m,1H),1.84〜1.54(m,4H),1.42〜1.32(m,2H)
Mass,m/e:297(M),110(base)
製造例82
製造例1と同様にして、7−メチルスルファニル−1−(S)−オクタヒドロピリド[1,2−a]ピラン−2−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.07 (d, J = 5.4 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2. 7 Hz, 1H), 7.28 (dd, J = 2.7 Hz, 8.9 Hz, 1H), 7.20 (d, J = 5.8 Hz, 1H), 3.94 (s, 3H), 3. 72 (qd, J = 2.7 Hz, 12.3 Hz, 1H), 3.57 (td, J = 2.7 Hz, 12.3 Hz, 1H), 3.26 to 3.16 (m, 1H), 2 .98 to 2.84 (m, 3H), 2.63 (dt, J = 2.7 Hz, 11.6 Hz, 1H), 2.35 to 2.25 (m, 1H), 2.25 to 2. 15 (m, 1H), 1.84 to 1.54 (m, 4H), 1.42 to 1.32 (m, 2H)
Mass, m / e: 297 (M + ), 110 (base)
Production Example 82
In the same manner as in Production Example 1, 7-methylsulfanyl-1- (S) -octahydropyrido [1,2-a] pyran-2-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.10(d,J=5.8Hz,1H),7.85(d,J=1.9Hz,1H),7.65(d,J=8.5Hz,1H),7.50(dd,J=1.9Hz,8.5Hz,1H),7.18(d,J=5.8Hz,1H),3.91〜3.84(m,1H),3.82〜3.75(m,1H),3.25〜3.15(m,3H),2.94〜2.85(m,1H),2.59(s,3H),2.43〜2.24(m,2H),1.97〜1.73(m,3H),1.66〜1.47(m,2H)
Mass,m/e:299(M),96(base)
製造例83

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.10 (d, J = 5.8 Hz, 1H), 7.85 (d, J = 1.9 Hz, 1H), 7.65 (d, J = 8. 5 Hz, 1H), 7.50 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.18 (d, J = 5.8 Hz, 1H), 3.91 to 3.84 (m, 1H) ), 3.82 to 3.75 (m, 1H), 3.25 to 3.15 (m, 3H), 2.94 to 2.85 (m, 1H), 2.59 (s, 3H), 2.43 to 2.24 (m, 2H), 1.97 to 1.73 (m, 3H), 1.66 to 1.47 (m, 2H)
Mass, m / e: 299 (M + ), 96 (base)
Production Example 83
Figure 0004596792

まず、製造例1と同様にして、7−メチルスルファニル−1−(S)−オクタヒドロピリド[1,2−a]ピラン−2−イルイソキノリン285mgを得た。これに、30%過酸化水素水1ml及び酢酸0.5mlを加え、室温で15分攪拌後、アンモニア水でアルカリ性としてジクロロメタンで抽出し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(メタノール:ジクロロメタン=1:4)で精製し、7−メタンスルフィニル−1−(S)−オクタヒドロピリド[1,2−a]ピラン−2−イルイソキノリン235mg(78%)を得た。
H−NMR(CDCl)δ:8.43〜8.40(m,1H),8.23(d,J=5.8Hz,1H),7.89(d,J=8.5Hz,1H),7.77〜7.73(m,1H),7.28〜7.25(m,1H),3.94(d,J=12.0Hz,1H),3.89〜3.81(m,1H),3.33〜3.23(m,1H),3.23〜3.14(m,2H),3.02〜2.91(m,1H),2.79(d,J=1.5Hz,3H),2.70〜2.60(m,1H),2.46〜2.25(m,2H),1.97〜1.75(m,3H),1.62〜1.46(m,1H)
Mass,m/e:315(M),96(base)
製造例84

Figure 0004596792
First, in the same manner as in Production Example 1, 285 mg of 7-methylsulfanyl-1- (S) -octahydropyrido [1,2-a] pyran-2-ylisoquinoline was obtained. To this was added 1 ml of 30% aqueous hydrogen peroxide and 0.5 ml of acetic acid, and the mixture was stirred at room temperature for 15 minutes, made alkaline with aqueous ammonia, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 4) and 235 mg (78 of 7-methanesulfinyl-1- (S) -octahydropyrido [1,2-a] pyran-2-ylisoquinoline (78 %).
1 H-NMR (CDCl 3 ) δ: 8.43-8.40 (m, 1H), 8.23 (d, J = 5.8 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.77-7.73 (m, 1H), 7.28-7.25 (m, 1H), 3.94 (d, J = 12.0 Hz, 1H), 3.89-3. 81 (m, 1H), 3.33 to 3.23 (m, 1H), 3.23 to 3.14 (m, 2H), 3.02 to 2.91 (m, 1H), 2.79 ( d, J = 1.5 Hz, 3H), 2.70-2.60 (m, 1H), 2.46-2.25 (m, 2H), 1.97-1.75 (m, 3H), 1.62-1.46 (m, 1H)
Mass, m / e: 315 (M + ), 96 (base)
Production Example 84
Figure 0004596792

まず、製造例1と同様にして、7−メトキシ−1−オクタヒドロピリド[1,2−a]ピラジン−2−イルイソキノリン610mgを得た。これに、47%臭化水素酸水溶液8mlを加え2時間加熱還流した。冷後、5規定水酸化ナトリウム水溶液を用いて中和し、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥し溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(飽和アンモニア水:メタノール:クロロホルム=0.5:5:45)で精製し7−ヒドロキシ−1−オクタヒドロピリド[1,2−a]ピラジン−2−イルイソキノリン500mg(86%)を得た。
H−NMR(CDCl)δ:8.03(dd,J=1.2Hz,5.8Hz,1H),7.67(d,J=8.9Hz,1H),7.41(d,J=2.3Hz,1H),7.27〜7.21(m,1H),7.20(d,J=5.8Hz,1H),3.71〜3.63(m,1H),3.58〜3.51(m,1H),3.27〜3.17(m,1H),2.95〜2.83(m,3H),2.60〜2.50(m,1H),2.31〜2.07(m,2H),1.82〜1.54(m,4H),1.39〜1.26(m,2H)
Mass,m/e:283(M),110(base)
製造例85
製造例84と同様にして、1−(S)−オクタヒドロピリド[1,2−a]ピラン−2−イル−7−ヒドロキシイソキノリンを得た。

Figure 0004596792
First, in the same manner as in Production Example 1, 610 mg of 7-methoxy-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline was obtained. To this, 8 ml of a 47% hydrobromic acid aqueous solution was added and heated to reflux for 2 hours. After cooling, the mixture was neutralized with 5N aqueous sodium hydroxide solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (saturated aqueous ammonia: methanol: chloroform = 0.5: 5: 45) and 7-hydroxy-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline 500 mg. (86%) was obtained.
1 H-NMR (CDCl 3 ) δ: 8.03 (dd, J = 1.2 Hz, 5.8 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.27 to 7.21 (m, 1H), 7.20 (d, J = 5.8 Hz, 1H), 3.711 to 3.63 (m, 1H), 3.58 to 3.51 (m, 1H), 3.27 to 3.17 (m, 1H), 2.95 to 2.83 (m, 3H), 2.60 to 2.50 (m, 1H) ), 2.31 to 2.07 (m, 2H), 1.82 to 1.54 (m, 4H), 1.39 to 1.26 (m, 2H)
Mass, m / e: 283 (M + ), 110 (base)
Production Example 85
In the same manner as in Production Example 84, 1- (S) -octahydropyrido [1,2-a] pyran-2-yl-7-hydroxyisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.02(d,J=5.4Hz,1H),7.68(d,J=8.9Hz,1H),7.42(d,J=2.3Hz,1H),7.29〜7.25(m,1H),7.23(d,J=5.4Hz,1H),3.71〜3.58(m,2H),3.32〜3.23(m,1H),3.21〜3.13(m,2H),3.01〜2.85(m,3H),2.55〜2.46(m,1H),1.98〜1.79(m,3H),1.59〜1.49(m,1H)
Mass,m/e:269(M),96(base)
製造例86
製造例84において合成した7−ヒドロキシ−1−オクタヒドロピリド[1,2−a]ピラジン−2−イルイソキノリン105mgをN−メチルピロリドン3mlに溶解し、これにスルファモイルクロリド1.00gを加え室温で1時間攪拌した。飽和炭酸水素ナトリウム水溶液で中和し、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(25%アンモニア水:メタノール:クロロホルム=1:10:90)で精製し、1−オクタヒドロピリド[1,2−a]ピラジン−2−イル−7−スルファモイルイソキノリン85mg(75%)を得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.02 (d, J = 5.4 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.42 (d, J = 2. 3 Hz, 1H), 7.29 to 7.25 (m, 1H), 7.23 (d, J = 5.4 Hz, 1H), 3.71 to 3.58 (m, 2H), 3.32 to 3.23 (m, 1H), 3.21 to 3.13 (m, 2H), 3.01 to 2.85 (m, 3H), 2.55 to 2.46 (m, 1H), 1. 98 to 1.79 (m, 3H), 1.59 to 1.49 (m, 1H)
Mass, m / e: 269 (M + ), 96 (base)
Production Example 86
105 mg of 7-hydroxy-1-octahydropyrido [1,2-a] pyrazin-2-ylisoquinoline synthesized in Production Example 84 was dissolved in 3 ml of N-methylpyrrolidone, and 1.00 g of sulfamoyl chloride was added thereto. The mixture was further stirred at room temperature for 1 hour. The mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (25% aqueous ammonia: methanol: chloroform = 1: 10: 90), and 1-octahydropyrido [1,2-a] pyrazin-2-yl-7-sulfamoyl. 85 mg (75%) of isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.05(d,J=5.8Hz,1H),7.97(d,J=2.7Hz,1H),7.75(d,J=8.9Hz,1H),7.57(dd,J=2.7Hz,8.9Hz,1H),7.14(d,J=5.8Hz,1H),3.62〜3.49(m,2H),3.05(dt,J=2.7Hz,12.3Hz,1H),2.94〜2.72(m,3H),2.54(dt,J=3.1Hz,11.6Hz,1H),2.27(t,J=10.8Hz,1H),2.21〜2.12(m,1H),1.83〜1.54(m,4H),1.43〜1.21(m,2H)
Mass,m/e:362(M),110(base)
製造例87
製造例86と同様にして、1−(S)−オクタヒドロピリド[1,2−a]ピラン−2−イル−7−スルファモイルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.05 (d, J = 5.8 Hz, 1H), 7.97 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 8. 9 Hz, 1H), 7.57 (dd, J = 2.7 Hz, 8.9 Hz, 1H), 7.14 (d, J = 5.8 Hz, 1H), 3.62 to 3.49 (m, 2H) ), 3.05 (dt, J = 2.7 Hz, 12.3 Hz, 1H), 2.94 to 2.72 (m, 3H), 2.54 (dt, J = 3.1 Hz, 11.6 Hz, 1H), 2.27 (t, J = 10.8 Hz, 1H), 2.21 to 2.12 (m, 1H), 1.83 to 1.54 (m, 4H), 1.43 to 1. 21 (m, 2H)
Mass, m / e: 362 (M + ), 110 (base)
Production Example 87
In the same manner as in Production Example 86, 1- (S) -octahydropyrido [1,2-a] pyran-2-yl-7-sulfamoylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.08(d,J=5.8Hz,1H),7.98(d,J=2.3Hz,1H),7.77(d,J=8.9Hz,1H),7.57(dd,J=2.3Hz,8.9Hz,1H),7.17(d,J=5.8Hz,1H),3.85〜3.78(m,1H),3.73〜3.65(m,1H),3.18〜3.05(m,3H),2.86〜2.78(m,1H),2.63〜2.54(m,1H),2.43〜2.24(m,2H),1.95〜1.74(m,3H),1.53〜1.41(m,1H)
Mass,m/e:348(M),96(base)
製造例88
ステップ1:1−(4−ベンジルピペラジン−1−イル)−7−クロロイソキノリンの合成。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.08 (d, J = 5.8 Hz, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 8. 9Hz, 1H), 7.57 (dd, J = 2.3Hz, 8.9Hz, 1H), 7.17 (d, J = 5.8Hz, 1H), 3.85 to 3.78 (m, 1H) ), 3.73 to 3.65 (m, 1H), 3.18 to 3.05 (m, 3H), 2.86 to 2.78 (m, 1H), 2.63 to 2.54 (m) , 1H), 2.43 to 2.24 (m, 2H), 1.95 to 1.74 (m, 3H), 1.53 to 1.41 (m, 1H)
Mass, m / e: 348 (M + ), 96 (base)
Production Example 88
Step 1: Synthesis of 1- (4-benzylpiperazin-1-yl) -7-chloroisoquinoline.
Figure 0004596792

1,7−ジクロロイソキノリン3.96g及びベンジルピペラジン10.50gの混合物を150℃で3時間攪拌した。残渣に水を加え、クロロホルムで抽出し、飽和炭酸水素ナトリウム水溶液水素で洗浄し、無水硫酸マグネシウムで乾燥し溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し1−(4−ベンジルピペラジン−1−イル)−7−クロロイソキノリン4.78g(71%)を得た。
H−NMR(CDCl)δ:8.14(d,J=5.4Hz,1H),8.04(d,J=1.9Hz,1H),7.68(d,J=8.5Hz,1H),7.53(dd,J=2.3Hz,8.8Hz,1H),7.39〜7.23(m,5H),7.20(d,J=5.8Hz,1H),3.64(s,2H),3.41(t,J=5.6Hz,4H),2.73(t,J=4.8Hz,4H)
Mass,m/e:337(M),191,159,91(base)
ステップ2:1−(4−ベンジルピペラジン−1−イル)−7−ジメチルアミノイソキノリンの合成。

Figure 0004596792
A mixture of 3.96 g of 1,7-dichloroisoquinoline and 10.50 g of benzylpiperazine was stirred at 150 ° C. for 3 hours. Water was added to the residue, and the mixture was extracted with chloroform, washed with saturated aqueous sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 4.78 g (71%) of 1- (4-benzylpiperazin-1-yl) -7-chloroisoquinoline.
1 H-NMR (CDCl 3 ) δ: 8.14 (d, J = 5.4 Hz, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.68 (d, J = 8. 5 Hz, 1 H), 7.53 (dd, J = 2.3 Hz, 8.8 Hz, 1 H), 7.39 to 7.23 (m, 5 H), 7.20 (d, J = 5.8 Hz, 1 H) ), 3.64 (s, 2H), 3.41 (t, J = 5.6 Hz, 4H), 2.73 (t, J = 4.8 Hz, 4H)
Mass, m / e: 337 (M + ), 191, 159, 91 (base)
Step 2: Synthesis of 1- (4-benzylpiperazin-1-yl) -7-dimethylaminoisoquinoline.
Figure 0004596792

上記ステップ1で合成した1−(4−ベンジルピペラジン−1−イル)−7−クロロイソキノリン1.01gをテトラヒドロフラン30mlに溶解した後、これに酢酸パラジウム20mg、2−(ジ−tert−ブチルホスフィノ)ビフェニル48mg、ナトリウム−tert−ブトキシド450mg及び2.0Mジメチルアミンテトラヒドロフラン溶液5mlを加えて封管し、この混合物を80℃で16時間攪拌した。不溶物を濾別した後、溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー(メタノール:クロロホルム=1:19)で精製して、1−(4−ベンジルピペラジン−1−イル)−7−ジメチルアミノイソキノリン261mg(25%)を得た。
H−NMR(CDCl)δ:7.94(d,J=5.7Hz,1H),7.63(d,J=9.0Hz,1H),7.45〜7.20(m,6H),7.18(d,J=5.4Hz,1H),7.12(d,J=2.3Hz,1H),3.69(s,2H),3.49(t,J=4.8Hz,4H),3.06(s,6H),2.77(t,J=5.0Hz,4H)
Mass,m/e:346(M),330,200(base),187,91
ステップ3:7−ジメチルアミノ−1−ピペラジン−1−イルイソキノリンの合成。

Figure 0004596792
After dissolving 1.01 g of 1- (4-benzylpiperazin-1-yl) -7-chloroisoquinoline synthesized in Step 1 above in 30 ml of tetrahydrofuran, 20 mg of palladium acetate and 2- (di-tert-butylphosphino) were added thereto. ) 48 mg of biphenyl, 450 mg of sodium-tert-butoxide and 5 ml of 2.0 M dimethylamine tetrahydrofuran solution were added and sealed, and the mixture was stirred at 80 ° C. for 16 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: chloroform = 1: 19) to give 1- (4-benzylpiperazin-1-yl) -7- 261 mg (25%) of dimethylaminoisoquinoline was obtained.
1 H-NMR (CDCl 3 ) δ: 7.94 (d, J = 5.7 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.45 to 7.20 (m, 6H), 7.18 (d, J = 5.4 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 3.69 (s, 2H), 3.49 (t, J = 4.8 Hz, 4H), 3.06 (s, 6H), 2.77 (t, J = 5.0 Hz, 4H)
Mass, m / e: 346 (M + ), 330, 200 (base), 187, 91
Step 3: Synthesis of 7-dimethylamino-1-piperazin-1-ylisoquinoline.
Figure 0004596792

上記ステップ2で合成した1−(4−ベンジルピペラジン−1−イル)−7−ジメチルアミノイソキノリン250mgをエタノール20mlに溶解し、これに10%パラジウム炭素50mgを加え、この混合物を水素雰囲気下室温にて16時間攪拌した。不溶物を濾別し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(メタノール:クロロホルム=1:9)で精製し、7−ジメチルアミノ−1−ピペラジン−1−イルイソキノリン46mg(25%)を得た。
H−NMR(CDCl)δ:7.95(d,J=5.4Hz,1H),7.64(d,J=8.9Hz,1H),7.27(dd,J=2.3Hz,8.9Hz,1H),7.16(d,J=5.4Hz,1H),7.12(d,J=2.3Hz,1H),3.39(t,J=5.0Hz,4H),3.19(t,J=5.0Hz,4H),3.07(s,6H)
Mass,m/e:256(M),200,187(base)
製造例89
製造例88で得られた化合物を常法によりメチル化し、7−ジメチルアミノ−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
250 mg of 1- (4-benzylpiperazin-1-yl) -7-dimethylaminoisoquinoline synthesized in Step 2 above was dissolved in 20 ml of ethanol, 50 mg of 10% palladium on carbon was added thereto, and the mixture was brought to room temperature under a hydrogen atmosphere. And stirred for 16 hours. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to obtain 46 mg (25%) of 7-dimethylamino-1-piperazin-1-ylisoquinoline.
1 H-NMR (CDCl 3 ) δ: 7.95 (d, J = 5.4 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.27 (dd, J = 2. 3 Hz, 8.9 Hz, 1 H), 7.16 (d, J = 5.4 Hz, 1 H), 7.12 (d, J = 2.3 Hz, 1 H), 3.39 (t, J = 5.0 Hz) , 4H), 3.19 (t, J = 5.0 Hz, 4H), 3.07 (s, 6H)
Mass, m / e: 256 (M + ), 200, 187 (base)
Production Example 89
The compound obtained in Production Example 88 was methylated by a conventional method to obtain 7-dimethylamino-1- (4-methylpiperazin-1-yl) isoquinoline.
Figure 0004596792

H−NMR(CDCl)δ:7.95(d,J=5.7Hz,1H),7.63(d,J=9.0Hz,1H),7.32(dd,J=2.8Hz,9.0Hz,1H),7.21(d,J=5.4Hz,1H),7.12(d,J=2.8Hz,1H),3.45(t,J=5.0Hz,4H),3.07(s,6H),2.71(t,J=5.0Hz,4H),2.42(s,3H)
Mass,m/e:270(M),200,187(base)
製造例90
製造例88と同様にして、7−メチルアミノ−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 7.95 (d, J = 5.7 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.32 (dd, J = 2. 8 Hz, 9.0 Hz, 1 H), 7.21 (d, J = 5.4 Hz, 1 H), 7.12 (d, J = 2.8 Hz, 1 H), 3.45 (t, J = 5.0 Hz) , 4H), 3.07 (s, 6H), 2.71 (t, J = 5.0 Hz, 4H), 2.42 (s, 3H)
Mass, m / e: 270 (M + ), 200, 187 (base)
Production Example 90
In the same manner as in Production Example 88, 7-methylamino-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:7.93(d,J=5.8Hz,1H),7.57(d,J=8.9Hz,1H),7.17(d,J=5.4Hz,1H),7.01(dd,J=1.3Hz,8.9Hz,1H),6.90(d,J=1.9Hz,1H),3.56(t,J=5.0Hz,4H),3.33(t,J=5.0Hz,4H),2.94(s,3H)
Mass,m/e:242(M),198,186,173(base)
製造例91
製造例89と同様にして、7−メチルアミノ−1−(4−メチルピペラジン−1−イル)イソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 7.93 (d, J = 5.8 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.17 (d, J = 5. 4 Hz, 1 H), 7.01 (dd, J = 1.3 Hz, 8.9 Hz, 1 H), 6.90 (d, J = 1.9 Hz, 1 H), 3.56 (t, J = 5.0 Hz) , 4H), 3.33 (t, J = 5.0 Hz, 4H), 2.94 (s, 3H)
Mass, m / e: 242 (M + ), 198, 186, 173 (base)
Production Example 91
In the same manner as in Production Example 89, 7-methylamino-1- (4-methylpiperazin-1-yl) isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:7.94(d,J=5.7Hz,1H),7.55(d,J=9.5Hz,1H),7.21(d,J=9.2Hz,1H),7.07(dd,J=2.6Hz,5.1Hz,1H),6.97(d,J=2.0Hz,1H),3.44(t,J=4.8Hz,4H),2.95(s,3H),2.72(t,J=5.0Hz,4H),2.42(s,3H)
Mass,m/e:256(M),186(base),173,157
製造例92
ステップ1:2−ベンゾ[1,3]ジオキソール−5−イルメチル−1−tert−ブトキシカルボニル−3−オキソピペラジンの合成。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 7.94 (d, J = 5.7 Hz, 1H), 7.55 (d, J = 9.5 Hz, 1H), 7.21 (d, J = 9. 2 Hz, 1 H), 7.07 (dd, J = 2.6 Hz, 5.1 Hz, 1 H), 6.97 (d, J = 2.0 Hz, 1 H), 3.44 (t, J = 4.8 Hz) , 4H), 2.95 (s, 3H), 2.72 (t, J = 5.0 Hz, 4H), 2.42 (s, 3H)
Mass, m / e: 256 (M + ), 186 (base), 173, 157
Production Example 92
Step 1: Synthesis of 2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonyl-3-oxopiperazine.
Figure 0004596792

アルゴン雰囲気下、テトラヒドロフラン25ml及びジイソプロピルアミン2.78gの混合物に、氷冷下にて、1.58Mのn−ブチルリチウム−n−ヘキサン溶液17.5mlを滴下し、そのまま30分攪拌した。これに、氷冷下にて、1−tert−ブトキシカルボニル−3−オキソピペラジン(Tetrahedron Lett,1980,21,3019−3020を参照して製造したもの)2.50gのテトラヒドロフラン60ml溶液を滴下し、そのまま3時間攪拌した後、5−クロロメチル−ベンゾ[1,3]ジオキソール2.30gのテトラヒドロフラン20ml溶液を氷冷下にて滴下し、そのまま1時間攪拌した。反応液を室温とし、18時間攪拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、2−ベンゾ[1,3]ジオキソール−5−イルメチル−1−tert−ブトキシカルボニル−3−オキソピペラジン2.84g(68%)を得た。
H−NMR(CDCl)δ:6.67(s,1H),6.65(d,J=1.3Hz,2H),5.90(s,2H),4.52〜4.43(m,1H),4.12(d,J=7.2Hz,2H),3.23(t,J=5.1Hz,2H), 2.57(t,J=5.8Hz,2H),1.45(s,9H)
Mass,m/e:334(M),278,144,57(base)
ステップ2:2−ベンゾ[1,3]ジオキソール−5−イルメチル−1−tert−ブトキシカルボニルピペラジンの合成。

Figure 0004596792
Under an argon atmosphere, 17.5 ml of a 1.58M n-butyllithium-n-hexane solution was added dropwise to a mixture of 25 ml of tetrahydrofuran and 2.78 g of diisopropylamine under ice cooling, followed by stirring for 30 minutes. To this, under ice-cooling, a solution of 1-tert-butoxycarbonyl-3-oxopiperazine (produced with reference to Tetrahedron Lett, 1980, 21, 3019-3020) 2.50 g of tetrahydrofuran was added dropwise. After stirring for 3 hours as it was, a solution of 2.30 g of 5-chloromethyl-benzo [1,3] dioxole in 20 ml of tetrahydrofuran was added dropwise under ice cooling, and the mixture was stirred as it was for 1 hour. The reaction solution was allowed to come to room temperature and stirred for 18 hours, a saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 2.84 g (68%) of 2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonyl-3-oxopiperazine.
1 H-NMR (CDCl 3 ) δ: 6.67 (s, 1H), 6.65 (d, J = 1.3 Hz, 2H), 5.90 (s, 2H), 4.52 to 4.43 (M, 1H), 4.12 (d, J = 7.2 Hz, 2H), 3.23 (t, J = 5.1 Hz, 2H), 2.57 (t, J = 5.8 Hz, 2H) , 1.45 (s, 9H)
Mass, m / e: 334 (M + ), 278, 144, 57 (base)
Step 2: Synthesis of 2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazine.
Figure 0004596792

上記ステップで合成した2−ベンゾ[1,3]ジオキソール−5−イルメチル−1−tert−ブトキシカルボニル−3−オキソピペラジン2.00gをテトラヒドロフラン50mlに溶解し、これに水素化リチウムアルミニウム1.00gを加え16時間加熱還流した。反応液に10%水酸化カリウム水溶液を加え、不溶物を濾別し、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(メタノール:クロロホルム=1:19)で精製し、2−ベンゾ[1,3]ジオキソール−5−イルメチル−1−tert−ブトキシカルボニルピペラジン1.27g(66%)を得た。
H−NMR(CDCl)δ:6.68(s,1H),6.65(d,J=0.5Hz,2H),5.90(s,2H),4.02〜3.87(m,3H),3.78〜3.54(m,2H),2.96〜2.77(m,2H),2.65〜2.51(m,2H),1.45(s,9H)
Mass,m/e:320(M),219,57(base)
ステップ3:1−(2−ベンゾ[1,3]ジオキソール−5−イルメチル−1−tert−ブトキシカルボニルピペラジン−4−イル)−7−メトキシイソキノリンの合成。

Figure 0004596792
2.00 g of 2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonyl-3-oxopiperazine synthesized in the above step was dissolved in 50 ml of tetrahydrofuran, and 1.00 g of lithium aluminum hydride was added thereto. The mixture was heated to reflux for 16 hours. A 10% aqueous potassium hydroxide solution was added to the reaction solution, insoluble matter was filtered off, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 19) to obtain 1.27 g (66%) of 2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazine. .
1 H-NMR (CDCl 3 ) δ: 6.68 (s, 1H), 6.65 (d, J = 0.5 Hz, 2H), 5.90 (s, 2H), 4.02 to 3.87 (M, 3H), 3.78 to 3.54 (m, 2H), 2.96 to 2.77 (m, 2H), 2.65 to 2.51 (m, 2H), 1.45 (s , 9H)
Mass, m / e: 320 (M + ), 219, 57 (base)
Step 3: Synthesis of 1- (2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazin-4-yl) -7-methoxyisoquinoline.
Figure 0004596792

上記ステップで合成した2−ベンゾ[1,3]ジオキソール−5−イルメチル−1−tert−ブトキシカルボニルピペラジン320mg、1−クロロ−7−メトキシイソキノリン200mg及びトリエチルアミン110mgの混合物を、エチレングリコール2ml中にて150℃で18時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:n−ヘキサン=1:1)で精製し、1−(2−ベンゾ[1,3]ジオキソール−5−イルメチル−1−tert−ブトキシカルボニルピペラジン−4−イル)−7−メトキシイソキノリン210mg(44%)を得た。
H−NMR(CDCl)δ:8.05(d,J=5.5Hz,1H),7.64(d,J=9.1Hz,1H),7.26(dd,J=2.1Hz,9.1Hz,1H),7.22(d,J=5.4Hz,1H),7.08(d,J=2.1Hz,1H),6.92(s,1H),6.79(d,J=1.3Hz,1H),5.94(s,2H),3.93(s,3H),3.33〜3.26(m,2H),3.21〜3.14(m,2H),2.80〜2.66(m,3H),1.45(s,9H)
Mass,m/e:477(M),342(base),187,135
ステップ4:1−(3−ベンゾ[1,3]ジオキソール−5−イルメチルピペラジン−1−イル)−7−メトキシイソキノリンの合成。

Figure 0004596792
A mixture of 320 mg of 2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazine synthesized in the above step, 200 mg of 1-chloro-7-methoxyisoquinoline and 110 mg of triethylamine was added in 2 ml of ethylene glycol. Stir at 150 ° C. for 18 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1), and 1- (2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazin-4-yl ) -7-methoxyisoquinoline (210 mg, 44%) was obtained.
1 H-NMR (CDCl 3 ) δ: 8.05 (d, J = 5.5 Hz, 1H), 7.64 (d, J = 9.1 Hz, 1H), 7.26 (dd, J = 2. 1 Hz, 9.1 Hz, 1 H), 7.22 (d, J = 5.4 Hz, 1 H), 7.08 (d, J = 2.1 Hz, 1 H), 6.92 (s, 1 H), 6. 79 (d, J = 1.3 Hz, 1H), 5.94 (s, 2H), 3.93 (s, 3H), 3.33 to 3.26 (m, 2H), 3.21 to 3. 14 (m, 2H), 2.80-2.66 (m, 3H), 1.45 (s, 9H)
Mass, m / e: 477 (M + ), 342 (base), 187, 135
Step 4: Synthesis of 1- (3-benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -7-methoxyisoquinoline.
Figure 0004596792

上記ステップで合成した1−(2−ベンゾ[1,3]ジオキソール−5−イルメチル−1−tert−ブトキシカルボニルピペラジン−4−イル)−7−メトキシイソキノリン150mgを4規定塩酸ジオキサン溶液10ml中にて18時間攪拌した。反応液を飽和炭酸水素ナトリウム水溶液で中和し、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(メタノール:クロロホルム=1:9)で精製し、1−(3−ベンゾ[1,3]ジオキソール−5−イルメチルピペラジン−1−イル)−7−メトキシイソキノリン69mg(58%)を得た。
H−NMR(CDCl)δ:8.07(d,J=5.5Hz,1H),7.66(d,J=9.2Hz,1H),7.33〜7.30(m,1H),7.25〜7.18(m,2H),6.74(s,1H),6.72(d,J=0.8Hz,1H),5.93(s,2H),3.84(s,3H),3.66〜3.59(m,2H),3.30〜3.18(m,2H),3.15〜3.10(m,2H),2.80〜2.64(m,3H)
Mass,m/e:377(M),242(base),187,135
製造例93

Figure 0004596792
150 mg of 1- (2-benzo [1,3] dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazin-4-yl) -7-methoxyisoquinoline synthesized in the above step was added to 10 ml of 4N hydrochloric acid dioxane solution. Stir for 18 hours. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9), and 1- (3-benzo [1,3] dioxol-5-ylmethylpiperazin-1-yl) -7-methoxyisoquinoline 69 mg (58 %).
1 H-NMR (CDCl 3 ) δ: 8.07 (d, J = 5.5 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.33 to 7.30 (m, 1H), 7.25 to 7.18 (m, 2H), 6.74 (s, 1H), 6.72 (d, J = 0.8 Hz, 1H), 5.93 (s, 2H), 3 .84 (s, 3H), 3.66 to 3.59 (m, 2H), 3.30 to 3.18 (m, 2H), 3.15 to 3.10 (m, 2H), 2.80 ~ 2.64 (m, 3H)
Mass, m / e: 377 (M + ), 242 (base), 187, 135
Production Example 93
Figure 0004596792

アセトン10ml中に7−メトキシ−1−ピペラジン−1−イルイソキノリン50mg、4−フルオロ臭化ベンジル100mg及びトリエチルアミン100mgを加えて、5時間加熱還流した。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー(メタノール:クロロホルム=1:19)で精製し、1−[4−(4−フルオロベンジル)ピペラジン−1−イル]−7−メトキシイソキノリン52mg(79%)を得た。
H−NMR(CDCl)δ:8.07(d,J=5.5Hz,1H),7.68(d,J=9.2Hz,1H),7.41〜7.32(m,3H),7.30〜7.26(m,1H),7.21(d,J=5.5Hz,1H),7.06〜6.99(m,2H),3.93(s,3H),3.61(s,2H),3.45〜3.35(m,4H),2.77〜2.67(m,4H)
Mass,m/e:351(M),187(base)
製造例94
製造例93と同様にして、1−[4−(4−フルオロベンジル)ピペラジン−1−イル]イソキノリンを得た。

Figure 0004596792
To 10 ml of acetone, 50 mg of 7-methoxy-1-piperazin-1-ylisoquinoline, 100 mg of 4-fluorobenzyl bromide and 100 mg of triethylamine were added and heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: chloroform = 1: 19) to give 52 mg of 1- [4- (4-fluorobenzyl) piperazin-1-yl] -7-methoxyisoquinoline. (79%) was obtained.
1 H-NMR (CDCl 3 ) δ: 8.07 (d, J = 5.5 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.41-7.32 (m, 3H), 7.30-7.26 (m, 1H), 7.21 (d, J = 5.5 Hz, 1H), 7.06-6.99 (m, 2H), 3.93 (s, 3H), 3.61 (s, 2H), 3.45 to 3.35 (m, 4H), 2.77 to 2.67 (m, 4H)
Mass, m / e: 351 (M + ), 187 (base)
Production Example 94
In the same manner as in Production Example 93, 1- [4- (4-fluorobenzyl) piperazin-1-yl] isoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.14(d,J=5.8Hz,1H),8.08(d,J=8.5Hz,1H),7.74(d,J=8.1Hz,1H),7.59(ddd,J=1.2Hz,6.9Hz,8.1Hz,1H),7.49(ddd,1.2Hz,6.9Hz,8.5Hz,1H),7.38〜7.32(m,2H),7.23(d,J=5.8Hz,1H),7.06〜6.99(m,2H),3.61(s,2H),3.47〜3.40(m,4H),2.75〜2.68(m,4H)
Mass,m/e:321(M),157(base)
製造例95
ステップ1:1−(4−tert−ブトキシカルボニルピペラジン−1−イル)−7−ヒドロキシイソキノリンの合成。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.14 (d, J = 5.8 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8. 1 Hz, 1 H), 7.59 (ddd, J = 1.2 Hz, 6.9 Hz, 8.1 Hz, 1 H), 7.49 (ddd, 1.2 Hz, 6.9 Hz, 8.5 Hz, 1 H), 7 .38 to 7.32 (m, 2H), 7.23 (d, J = 5.8 Hz, 1H), 7.06 to 6.99 (m, 2H), 3.61 (s, 2H), 3 .47-3.40 (m, 4H), 2.75-2.68 (m, 4H)
Mass, m / e: 321 (M + ), 157 (base)
Production Example 95
Step 1: Synthesis of 1- (4-tert-butoxycarbonylpiperazin-1-yl) -7-hydroxyisoquinoline.
Figure 0004596792

7−メトキシ−1−ピペラジン−1−イルイソキノリン4.00g及び47%臭化水素酸水溶液40mlの混合物を2時間加熱還流した。冷後、5規定水酸化ナトリウム水溶液を用いてアルカリ性とし、次いで1,4−ジオキサン30ml、ジ−tert−ブチルジカルボネート3.94gを加えて、室温で1時間攪拌した。酢酸エチルで抽出、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(メタノール:クロロホルム=1:19)で精製し、1−(4−tert−ブトキシカルボニルピペラジン−1−イル)7−ヒドロキシイソキノリン4.63g(85%)を得た。
H−NMR(CDCl)δ:8.03(d,J=5.5Hz,1H),7.70(d,J=8.8Hz,1H),7.43(d,J=2.6Hz,1H),7.30〜7.23(m,2H),3.72〜3.64(m,4H),3.34〜3.26(m,4H),1.51(s,9H)
Mass,m/e:329(M),173(base)
ステップ2:7−ヒドロキシ−1−ピペラジン−1−イルイソキノリン 塩酸塩の合成。

Figure 0004596792
A mixture of 4.00 g of 7-methoxy-1-piperazin-1-ylisoquinoline and 40 ml of 47% aqueous hydrobromic acid solution was heated to reflux for 2 hours. After cooling, the mixture was alkalified with 5N aqueous sodium hydroxide solution, 30 ml of 1,4-dioxane and 3.94 g of di-tert-butyl dicarbonate were added, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 19) to obtain 4.63 g (85%) of 1- (4-tert-butoxycarbonylpiperazin-1-yl) 7-hydroxyisoquinoline.
1 H-NMR (CDCl 3 ) δ: 8.03 (d, J = 5.5 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 2. 6 Hz, 1H), 7.30 to 7.23 (m, 2H), 3.72 to 3.64 (m, 4H), 3.34 to 3.26 (m, 4H), 1.51 (s, 9H)
Mass, m / e: 329 (M + ), 173 (base)
Step 2: Synthesis of 7-hydroxy-1-piperazin-1-ylisoquinoline hydrochloride.
Figure 0004596792

上記ステップで合成した1−(4−tert−ブトキシカルボニルピペラジン−1−イル)7−ヒドロキシイソキノリン70mg及び4規定塩酸酢酸エチル溶液3mlの混合物を室温で1時間攪拌した。結晶を濾取して酢酸エチルで洗浄し、7−ヒドロキシ−1−ピペラジン−1−イルイソキノリン 塩酸塩43mg(収率78%)を得た。
H−NMR(CDOD)δ:8.02(d,J=8.5Hz,1H),7.78(d,J=6.6Hz,1H),7.72(d,J=6.6Hz,1H),7.64〜7.56(m,2H),4.06〜3.98(m,4H),3.68〜3.59(m,4H)
Mass,m/e:229(M),173(base)
製造例96

Figure 0004596792
A mixture of 70 mg of 1- (4-tert-butoxycarbonylpiperazin-1-yl) 7-hydroxyisoquinoline synthesized in the above step and 3 ml of 4N ethyl acetate solution was stirred at room temperature for 1 hour. The crystals were collected by filtration and washed with ethyl acetate to obtain 43 mg (yield 78%) of 7-hydroxy-1-piperazin-1-ylisoquinoline hydrochloride.
1 H-NMR (CD 3 OD) δ: 8.02 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 6.6 Hz, 1H), 7.72 (d, J = 6 .6 Hz, 1H), 7.64 to 7.56 (m, 2H), 4.06 to 3.98 (m, 4H), 3.68 to 3.59 (m, 4H)
Mass, m / e: 229 (M + ), 173 (base)
Production Example 96
Figure 0004596792

7−メトキシ−(4−メチルピペラジン−1−イル)イソキノリン795mg及び47%臭化水素酸水溶液8mlの混合物を2.5時間加熱還流した。冷後、20%水酸化ナトリウム水溶液で中和し、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥し溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(飽和アンモニア水:メタノール:クロロホルム=1:10:90)で精製し7−ヒドロキシ−1−(4−メチルピペラジン−1−イル)イソキノリン673mg(80%)を得た。
H−NMR(CDCl)δ:8.01(d,J=5.8Hz,1H),7.66(d,J=8.5Hz,1H),7.36(d,J=2.7Hz,1H),7.26〜7.19(m,2H),3.48〜3.35(m,4H),2.70〜2.55(m,4H),2.33(s,3H)
Mass,m/e:243(M),173(base)
製造例97

Figure 0004596792
A mixture of 795 mg of 7-methoxy- (4-methylpiperazin-1-yl) isoquinoline and 8 ml of 47% aqueous hydrobromic acid solution was heated to reflux for 2.5 hours. After cooling, the mixture was neutralized with 20% aqueous sodium hydroxide solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (saturated aqueous ammonia: methanol: chloroform = 1: 10: 90) to obtain 673 mg (80%) of 7-hydroxy-1- (4-methylpiperazin-1-yl) isoquinoline.
1 H-NMR (CDCl 3 ) δ: 8.01 (d, J = 5.8 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 2. 7 Hz, 1H), 7.26-7.19 (m, 2H), 3.48-3.35 (m, 4H), 2.70-2.55 (m, 4H), 2.33 (s, 3H)
Mass, m / e: 243 (M + ), 173 (base)
Production Example 97
Figure 0004596792

1−(4−tert−ブトキシカルボニルピペラジン−1−イル)−7−ヒドロキシイソキノリン105mgをアセトン10mlに溶解した後、炭酸カリウム93mg及びヨウ化エチル55mgを加え2時間加熱還流した。ヨウ化エチル55mgを追加して2時間還流した後、炭酸カリウム48mg及びヨウ化エチル55mgを追加して、更に、一晩還流した。冷後、水を加えて酢酸エチルで抽出、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下で留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:n−ヘキサン=1:4)で精製し、1−(4−tert−ブトキシカルボニルピペラジン−1−イル)−7−エトキシイソキノリン102mg(90%)を得た。
次にこれを、4規定塩酸ジオキサン溶液3ml中にて、室温で30分攪拌した。10%水酸化ナトリウム水溶液でアルカリ性にし酢酸エチルで抽出、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(メタノール:クロロホルム=1:4)で精製し7−エトキシ−1−ピペラジン−1−イルイソキノリン67mg(93%)を得た。
H−NMR(CDCl)δ:8.07(d,J=5.8Hz,1H),7.67(d,J=8.9Hz,1H),7.40(d,J=2.3Hz,1H),7.28(dd,J=2.3Hz,8.9Hz,1H),7.22(d,J=5.8Hz,1H),4.17(q,J=6.9Hz,2H),3.38〜3.32(m,4H),3.20〜3.14(m,4H),1.51(t,J=6.9Hz,3H)
Mass,m/e:257(M),188(base)
製造例98
製造例97と同様にして、7−(4−フルオロベンジルオキシ)−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
After dissolving 105 mg of 1- (4-tert-butoxycarbonylpiperazin-1-yl) -7-hydroxyisoquinoline in 10 ml of acetone, 93 mg of potassium carbonate and 55 mg of ethyl iodide were added, and the mixture was heated to reflux for 2 hours. After adding 55 mg of ethyl iodide and refluxing for 2 hours, 48 mg of potassium carbonate and 55 mg of ethyl iodide were added, and the mixture was further refluxed overnight. After cooling, water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to obtain 102 mg (90%) of 1- (4-tert-butoxycarbonylpiperazin-1-yl) -7-ethoxyisoquinoline. .
Next, this was stirred in 3 ml of 4N hydrochloric acid dioxane solution at room temperature for 30 minutes. The mixture was made alkaline with a 10% aqueous sodium hydroxide solution, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 4) to obtain 67 mg (93%) of 7-ethoxy-1-piperazin-1-ylisoquinoline.
1 H-NMR (CDCl 3 ) δ: 8.07 (d, J = 5.8 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2. 3 Hz, 1 H), 7.28 (dd, J = 2.3 Hz, 8.9 Hz, 1 H), 7.22 (d, J = 5.8 Hz, 1 H), 4.17 (q, J = 6.9 Hz) , 2H), 3.38 to 3.32 (m, 4H), 3.20 to 3.14 (m, 4H), 1.51 (t, J = 6.9 Hz, 3H)
Mass, m / e: 257 (M + ), 188 (base)
Production Example 98
In the same manner as in Production Example 97, 7- (4-fluorobenzyloxy) -1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.08(d,J=5.8Hz,1H),7.70(d,J=8.8Hz,1H),7.49〜7.42(m,2H),7.41〜7.38(m,1H),7.38〜7.33(m,1H),7.22(d,J=5.8Hz,1H),7.12〜7.06(m,2H),5.20(s,2H),3.29〜3.22(m,4H),3.13〜3.06(m,4H)
Mass,m/e:337(M),109(base)
製造例99
製造例97と同様にして、7−ベンジルオキシ−1−ピペラジン−1−イルイソキノリンを得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.08 (d, J = 5.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.49 to 7.42 (m, 2H), 7.41-7.38 (m, 1H), 7.38-7.33 (m, 1H), 7.22 (d, J = 5.8 Hz, 1H), 7.12-7. 06 (m, 2H), 5.20 (s, 2H), 3.29 to 3.22 (m, 4H), 3.13 to 3.06 (m, 4H)
Mass, m / e: 337 (M + ), 109 (base)
Production Example 99
In the same manner as in Production Example 97, 7-benzyloxy-1-piperazin-1-ylisoquinoline was obtained.
Figure 0004596792

H−NMR(CDCl)δ:8.06(d,J=5.8Hz,1H),7.69(d,J=8.9Hz,1H),7.50〜7.29(m,7H),7.21(d,J=5.8Hz,1H),5.25(s,2H),3.24〜3.18(m,4H),3.08〜3.02(m,4H)
Mass,m/e:319(M),91(base)
製造例100
製造例97と同様にして、7−[4−(1,3−ジオキソ−1,3−ジヒドロイソインドール−2−イル)ブトキシ]−1−ピペラジン−1−イルイソキノリン 塩酸塩を得た。

Figure 0004596792
1 H-NMR (CDCl 3 ) δ: 8.06 (d, J = 5.8 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.50-7.29 (m, 7H), 7.21 (d, J = 5.8 Hz, 1H), 5.25 (s, 2H), 3.24 to 3.18 (m, 4H), 3.08 to 3.02 (m, 4H)
Mass, m / e: 319 (M + ), 91 (base)
Production Example 100
In the same manner as in Production Example 97, 7- [4- (1,3-dioxo-1,3-dihydroisoindol-2-yl) butoxy] -1-piperazin-1-ylisoquinoline hydrochloride was obtained.
Figure 0004596792

H−NMR(DMSO−d)δ:7.97〜7.91(m,2H),7.89〜7.80(m,4H),7.57〜7.48(m,2H),7.38(d,J=2.3Hz,1H),4.25〜4.16(m,4H),3.79〜3.63(m,8H),1.87〜1.77(m,4H)
Mass,m/e:430(M),160(base)
実施例101
実施例97と同様にして、7−スルファモイルオキシ−1−ピペラジン−1−イソキノリン 塩酸塩を得た。

Figure 0004596792
1 H-NMR (DMSO-d 6 ) δ: 7.97 to 7.91 (m, 2H), 7.89 to 7.80 (m, 4H), 7.57 to 7.48 (m, 2H) 7.38 (d, J = 2.3 Hz, 1H), 4.25 to 4.16 (m, 4H), 3.79 to 3.63 (m, 8H), 1.87 to 1.77 ( m, 4H)
Mass, m / e: 430 (M + ), 160 (base)
Example 101
In the same manner as in Example 97, 7-sulfamoyloxy-1-piperazine-1-isoquinoline hydrochloride was obtained.
Figure 0004596792

H−NMR(DMSO−d)δ:8.19〜8.11(m,3H),8.07(d,J=8.9Hz,1H),7.98(d,J=2.3Hz,1H),7.69(dd,J=2.3Hz,8.9Hz,1H),7.57(d,J=5.8Hz,1H),3.65〜3.57(m,4H),3.40〜3.31(m,4H) 1 H-NMR (DMSO-d 6 ) δ: 8.19 to 8.11 (m, 3H), 8.07 (d, J = 8.9 Hz, 1H), 7.98 (d, J = 2. 3Hz, 1H), 7.69 (dd, J = 2.3Hz, 8.9Hz, 1H), 7.57 (d, J = 5.8Hz, 1H), 3.65 to 3.57 (m, 4H) ), 3.40 to 3.31 (m, 4H)

Claims (4)

式(I)
Figure 0004596792

式中、
A環は場合によりハロゲン原子、低級アルキル基、フェニル基、ヒドロキシ基、低級アルコキシ基、フェニル低級アルコキシ基(この基のフェニル部分は場合によりハロゲン原子で置換されていてもよい)、アミノ基、低級アルキルアミノ基、ジ低級アルキルアミノ基、低級アルキルチオ基、低級アルキルスルフィニル基又はアミノスルホニルオキシ基で置換されていてもよいベンゼン環、又は場合によりハロゲン原子もしくは低級アルキル基で置換されていてもよいピリジン環を表し、ここで、A環がピリジン環を表す場合に形成される縮合環は1,7−ナフチリジンであり、
1は水素原子、ハロゲン原子又は低級アルキル基を表し、
2及びR3は一緒になって場合によりヒドロキシ基、低級アルコキシ基又はフェニル低級アルコキシ基で置換されていてもよいピロリジン環又はピペリジン環の残員を形成し、
4は水素原子又は低級アルキル基を表す、
で示されるピペラジニルピリジン誘導体又はその製薬学的に許容されうる塩を有効成分として含むことを特徴とする過敏性腸症候群の処置剤。
Formula (I)
Figure 0004596792

Where
A ring is optionally a halogen atom, a lower alkyl group, a phenyl group, a hydroxy group, a lower alkoxy group, a phenyl lower alkoxy group (the phenyl portion of this group may be optionally substituted with a halogen atom), an amino group, a lower group A benzene ring optionally substituted with an alkylamino group, di-lower alkylamino group, lower alkylthio group, lower alkylsulfinyl group or aminosulfonyloxy group, or optionally a pyridine optionally substituted with a halogen atom or a lower alkyl group Wherein the condensed ring formed when the A ring represents a pyridine ring is 1,7-naphthyridine,
R 1 represents a hydrogen atom, a halogen atom or a lower alkyl group,
R 2 and R 3 together form a residue of a pyrrolidine ring or piperidine ring optionally substituted with a hydroxy group, a lower alkoxy group or a phenyl lower alkoxy group;
R 4 represents a hydrogen atom or a lower alkyl group,
A therapeutic agent for irritable bowel syndrome, comprising as an active ingredient a piperazinylpyridine derivative represented by the formula: or a pharmaceutically acceptable salt thereof.
A環がハロゲン原子、ヒドロキシ基又は低級アルコキシ基で置換されていてもよいベンゼン環を表す請求項1に記載の処置剤。 The treatment agent according to claim 1, wherein the A ring represents a benzene ring which may be substituted with a halogen atom, a hydroxy group or a lower alkoxy group. 1が水素原子を表す請求項1または2に記載の処置剤。 The treatment agent according to claim 1 or 2, wherein R 1 represents a hydrogen atom. 請求項1〜のいずれかに記載のピペラジニルピリジン誘導体又はその製薬学的に許容されうる塩及び製薬学的に許容されうる担体を含む過敏性腸症候群の処置のための医薬組成物。
The pharmaceutical composition for the treatment of irritable bowel syndrome including piperazinyl pyridine derivatives or pharmaceutically acceptable Shio及beauty pharmaceutical acceptable carrier according to any one of claims 1 to 3 .
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WO2005082887A1 (en) * 2004-02-26 2005-09-09 Aska Pharmaceutical Co., Ltd. Pyrimidine derivative
MX2007006387A (en) * 2004-12-03 2007-06-20 Hoffmann La Roche 3-substituted pyridine derivatives as h3 antagonists.
US7887784B2 (en) 2007-03-21 2011-02-15 University Of Montana 1-[(2′-substituted)-piperazin-1′ -yl]-isoquinolines as norepinephrine transporter inhibitor therapeutics and positron emission tomography imaging agents
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US8470828B2 (en) * 2010-07-06 2013-06-25 Hoffmann-La Roche Inc. Anellated pyridine compounds
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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3663559A (en) * 1969-12-03 1972-05-16 Union Carbide Corp Preparation of oxo-furo-pyridines from furylvinyl isocyanates
US3857944A (en) * 1972-04-21 1974-12-31 Sandoz Ag 1-piperazinoisoquinolines as inotropic agents
JPS57500876A (en) * 1980-06-05 1982-05-20
JPH08505381A (en) * 1993-01-06 1996-06-11 ジョン・ワイス・アンド・ブラザー・リミテッド Piperazine derivatives as 5-HT antagonists
FR2761068A1 (en) * 1997-03-20 1998-09-25 Synthelabo Piperazinyl thieno pyridinyl carboxamide derivatives
WO1998042712A1 (en) * 1997-03-20 1998-10-01 Sanofi-Synthelabo Quinoline-2(1h)-one and dihydroquinoline-2(1h)-one derivatives as ligands of 5-ht, 5-ht2 and 5-ht1-like receptors
JP2000053647A (en) * 1997-10-02 2000-02-22 Eisai Co Ltd Condensed pyridine derivative
JP2001500142A (en) * 1996-09-13 2001-01-09 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Piperazine derivatives having D4 receptor selectivity
JP2001097978A (en) * 1999-08-27 2001-04-10 Adir New pyridine compound, method of production therefor and pharmaceutical composition containing the compound
JP2001512491A (en) * 1997-03-04 2001-08-21 ニューロゲン コーポレイション 1- (isoquinolin-1-yl) -4- (1-phenylmethyl) piperazine; a dopamine receptor subtype-specific ligand
JP2005224845A (en) * 2004-02-16 2005-08-25 Hitachi Zosen Corp Method of feeding gas for melt-cutting in metal melt-cutting device

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5001130A (en) * 1988-02-18 1991-03-19 Bristol-Myers Company Psychotropic heterobicycloalkylpiperazine derivatives
WO2003066604A2 (en) * 2002-02-05 2003-08-14 Novo Nordisk A/S Novel aryl- and heteroarylpiperazines

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3663559A (en) * 1969-12-03 1972-05-16 Union Carbide Corp Preparation of oxo-furo-pyridines from furylvinyl isocyanates
US3857944A (en) * 1972-04-21 1974-12-31 Sandoz Ag 1-piperazinoisoquinolines as inotropic agents
JPS57500876A (en) * 1980-06-05 1982-05-20
JPH08505381A (en) * 1993-01-06 1996-06-11 ジョン・ワイス・アンド・ブラザー・リミテッド Piperazine derivatives as 5-HT antagonists
JP2001500142A (en) * 1996-09-13 2001-01-09 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Piperazine derivatives having D4 receptor selectivity
JP2001512491A (en) * 1997-03-04 2001-08-21 ニューロゲン コーポレイション 1- (isoquinolin-1-yl) -4- (1-phenylmethyl) piperazine; a dopamine receptor subtype-specific ligand
FR2761068A1 (en) * 1997-03-20 1998-09-25 Synthelabo Piperazinyl thieno pyridinyl carboxamide derivatives
WO1998042712A1 (en) * 1997-03-20 1998-10-01 Sanofi-Synthelabo Quinoline-2(1h)-one and dihydroquinoline-2(1h)-one derivatives as ligands of 5-ht, 5-ht2 and 5-ht1-like receptors
JP2000053647A (en) * 1997-10-02 2000-02-22 Eisai Co Ltd Condensed pyridine derivative
JP2001097978A (en) * 1999-08-27 2001-04-10 Adir New pyridine compound, method of production therefor and pharmaceutical composition containing the compound
JP2005224845A (en) * 2004-02-16 2005-08-25 Hitachi Zosen Corp Method of feeding gas for melt-cutting in metal melt-cutting device

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