JP3884476B2 - Pyridine derivatives - Google Patents

Pyridine derivatives Download PDF

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JP3884476B2
JP3884476B2 JP50301196A JP50301196A JP3884476B2 JP 3884476 B2 JP3884476 B2 JP 3884476B2 JP 50301196 A JP50301196 A JP 50301196A JP 50301196 A JP50301196 A JP 50301196A JP 3884476 B2 JP3884476 B2 JP 3884476B2
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pyridine
phenyl
salt
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汪芳 白井
謙二 英
雄樹 高橋
文夫 溝部
和紀 花田
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Taisho Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C—CHEMISTRY; METALLURGY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Description

技術分野
本発明は神経成長因子（以下、ＮＧＦと称する。）産生促進作用あるいは神経栄養因子作用を有するピリジン誘導体及びその塩、並びにそれらの薬学的用途に関する。
背景技術
近年増えつつあるアルツハイマー型老年痴呆においては、大脳基底核神経細胞であるアセチルコリン作動性神経の変性、脱落が、記憶障害、知的活動低下に深く係わっていることが示唆されている〔Witehorseら、Science、第２１５巻、第１２３７頁（１９８２年）〕。
ＮＧＦは、繊維切断による中枢性アセチルコリン作動性神経の変性、脱落を抑制すること〔Korsingら、Neuroscience Lett.、第６６巻、第１７５頁（１９８６年）］及び老齢ラットの迷路学習障害を改善すると共にアセチルコリン作動性神経細胞の萎縮を抑制することが報告されている〔茂野 卓ら、医学のあゆみ、第１４５巻、第５７９頁（１９８６年）〕。これらのことはＮＧＦがアルツハイマー型老年痴呆の治療薬となりうることを示している。
さらには、ＮＧＦは、脳虚血スナネズミの海馬神経細胞死を防ぐことも確かめられており、脳卒中後遺症治療薬としても有用であると考えられる。
一方、ＮＧＦは、末梢神経損傷の回復を早める作用を持っており、末梢神経障害治療薬としても有用であることが明らかにされている。
ＮＧＦの他にも、神経細胞の生存・機能維持作用あるいは変性修復活性を示す生体成分が数多く見つかっており、神経栄養因子と呼ばれている。従って、これら神経栄養因子は、神経細胞変性に伴う中枢性神経障害及び末梢神経障害の治療剤として有用であると考えられる。
神経栄養因子と呼ばれる生体成分は、ＮＧＦも含めそのいずれもがタンパク質である。タンパク質は中枢性神経障害治療薬として用いる際、その物状から判断して、直接脳室内投与が必要となることが予想され、実用上問題が多い。従って、より簡単な投与方法が可能な神経栄養因子作用自身あるいは神経栄養因子の産生促進作用を持つ低分子化合物の治療薬が望まれている。
本発明の目的は、ＮＧＦ産生促進作用及び神経栄養因子作用の一方あるいは両方を有し、神経変性疾患の改善もしくは治療に有用な新規化合物を提供することにある。
発明の開示
本発明者らは、前記目的の達成のために多数の化合物について種々検討した結果、ある種のピリジン誘導体が、ＮＧＦ産生促進作用及び神経栄養因子作用の一方あるいは両方を有し、神経変性疾患の改善もしくは治療に有用な化合物であることを見いだし本発明を完成するに至った。
本発明の目的は、式（１）

Figure 0003884476
（式中、Ｒ1はメチル基、ニトロ基、アミノ基及びアセトアミド基からなる群より選ばれた一種または二種以上の置換基で置換されたフェニル基、またはイミダゾリル基を示し、Ｒ2は水素原子、ニトロ基、アミノ基またはジメチルアミノ基を示す。）で表されるピリジン誘導体及びその塩を提供することにある。
本発明の他の目的は、医薬組成物の活性成分としての使用のための上記ピリジン誘導体及びその塩を提供することにある。
更に、本発明の他の目的は、上記ピリジン誘導体またはその塩を活性成分として含有する医薬組成物を提供することにある。
更に、本発明の他の目的は、神経変性疾患の改善もしくは治療用医薬組成物を製造するための上記ピリジン誘導体またはその塩の使用を提供することにある。
更に、本発明の他の目的は、上記ピリジン誘導体またはその塩の有効量をヒトに投与することからなる、神経変性疾患の改善もしくは治療法を提供することにある。
発明を実施するための最良の形態
式（１）のピリジン誘導体におけるＲ1が、メチル基、ニトロ基、アミノ基及びアセトアミド基からなる群より選ばれた一種もしくは二種以上の置換基で置換されたフェニル基である場合、該置換基はフェニル基のオルト、パラ及びメタ位のいずれの位置に置換されていてもよい。
Ｒ1がメチル基で置換されたフェニル基であり、Ｒ2が水素原子、ニトロ基またはアミノ基であるピリジン誘導体、あるいはＲ1がニトロ基、アミノ基もしくはアセトアミド基で置換されたフェニル基、あるいはイミダゾリル基であり、Ｒ2が水素原子であるピリジン誘導体が好ましい。
本発明において、ピリジン誘導体の塩とは、薬理学的により許容されるものを意味し、塩酸、硫酸、リン酸、硝酸などの鉱酸との塩、あるいはクエン酸、コハク酸、酒石酸、メタンスルホン酸などの有機酸との塩があげられる。
本発明の化合物は、例えば以下に示す１）〜３）の方法に従って製造することができる。
１）式（１）において、Ｒ1がメチル基、ニトロ基及びアセトアミド基からなる群より選ばれた一種または二種以上の置換基で置換されたフェニル基、あるいはイミダゾリル基であり、Ｒ2が水素原子、ニトロ基またはジメチルアミノ基である化合物は以下のようにして製造することができる。
すなわち、まず、式（２）
Ｒ3−ＣＨＯ （２）
（式中、Ｒ3はメチル基、ニトロ基及びアセトアミド基からなる群より選ばれた一種または二種以上の置換基で置換されたフェニル基、あるいはイミダゾリル基を示す。）で表される化合物と、式（３）
Figure 0003884476
（式中、Ｒ4は水素原子、ニトロ基またはジメチルアミノ基を示す。）で表される化合物とを、アルカリ化合物の存在下にて縮合させることにより、式（４）
Figure 0003884476
（式中、Ｒ3、Ｒ4は前記と同意義である。）で表される化合物を得ることができる。
ここで、縮合反応で使用するアルカリ化合物としては、水酸化カリウム、水酸化ナトリウム、ナトリウムメトキシド、カリウムｔ−ブトキシド、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸水素カリウムなどがある。反応溶媒は、メタノール、エタノール、ｎ−プロパノール、イソプロパノール、ｔ−ブタノールなどを、単独又は水を添加して用いることができる。反応温度は、０℃から使用する溶媒の沸点までで適宜選択可能である。
次いで、式（４）の化合物と、F.Krohnkeらの方法〔Chemische Berichte、第９２巻、第２２頁（１９５９年）〕により製造され得る、式（５）
Figure 0003884476
で表される化合物とを、酢酸アンモニウムの存在下反応させることにより本発明の化合物を得ることができる。ここで、酢酸アンモニウムは、式（４）の化合物の１〜１０倍モル量を使用し、反応溶媒は、メタノール、エタノール、ｎ−プロパノール、イソプロパノール、ｔ−ブタノール、酢酸などを用いることができる。反応温度は、室温から使用する溶媒の沸点までで適宜選択可能である。
２）式（１）において、アミノ基を持つ化合物、すなわちＲ1がアミノ基で置換されたフェニル基および／またはＲ2がアミノ基である化合物は、前記１）の方法により得た式（１）の化合物のうちニトロ基を持つ化合物、すなわちＲ1がニトロ基で置換されたフェニルおよび基またはＲ2がニトロ基である化合物を、還元することにより得ることができる。
還元方法としては通常の方法を用いることができ、例えば接触水素添加法、エタノール中ヒドラジンとラネーニッケルを用いた還元方法などを用いることができる。
３）式（１）において、Ｒ1がアミノ基で置換されたフェニル基であり、Ｒ2が水素原子、ニトロ基またはジメチルアミノ基である化合物は、前記１）の方法により得た式（１）の化合物のうち、Ｒ1がアセトアミド基で置換されたフェニル基であり、Ｒ2が水素原子、ニトロ基またはジメチルアミノ基である化合物を、酸、又はアルカリ化合物存在下、加水分解することにより得ることができる。
加水分解は、塩酸などの酸、又は水酸化ナトリウムなどのアルカリ化合物を用いて通常の方法により実施することができる。
本発明のピリジン誘導体又はその塩は、ＮＧＦ産生促進作用及び神経栄養因子作用の一方あるいは両方を有し、神経変性疾患の改善もしくは治療に有用である。かかるピリジン誘導体又はその塩は通常ヒトに対して経口または非経口的に投与される。
経口投与する場合は、ピリジン誘導体又はその塩を、賦形剤、崩壊剤、結合剤、滑沢剤、坑酸化剤、コーティング剤、着色剤、矯味矯臭剤、界面活性剤、可塑剤などと混合して、顆粒剤、散剤、カプセル剤、錠剤として投与され、非経口投与する場合は、注射剤、点滴剤および坐剤で投与され得る。
上記製剤化するに際しては、通常の製剤化の方法が使用できる。
賦形剤としては、たとえばマンニトール、キシリトール、ソルビトール、ブドウ糖、白糖、乳糖、結晶セルロース、結晶セルロース・カルボキシメチルセルロースナトリウム、りん酸水素カルシウム、コムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン、カルボキシメチルスターチナトリウム、デキストリン、α−シクロデキストリン、β−シクロデキストリン、カルボキシビニルポリマー、軽質無水ケイ酸、酸化チタン、メタケイ酸アルミン酸マグネシウム、ポリエチレングリコール、中鎖脂肪酸トリグリセリドなどが挙げられる。
崩壊剤としては、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、カルボキシメチルセルロースナトリウム、クロスカルメロースナトリウム・Ａ型（アクチゾル）、デンプン、結晶セルロース、ヒドロキシプロピルスターチ、部分アルファー化デンプンなどが挙げられる。
結合剤としては、たとえばメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニールピロリドン、ゼラチン、アラビアゴム、エチルセルロース、ポリビニルアルコール、プルラン、アルファー化デンプン、寒天、タラガント、アルギン酸ナトリウムアルギン酸プロピレングリコールエステルなどが挙げられる。
滑沢剤としては、たとえばステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸ポリオキシル、セタノール、タルク、硬化油、ショ糖脂肪酸エステル、ジメチルポリシロキサン、マイクロクリスタリンワックス、ミツロウ、サラシミツロウなどが挙げられる。
抗酸化剤としては、たとえばジブチルヒドロキシトルエン（ＢＨＴ）、没食子酸プロピル、ブチルヒドロキシアニソール（ＢＨＡ）、α−トコフェロール、クエン酸などが挙げられる。
コーティング剤としては、たとえばヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース、ポリビニルアセタールジエチルアミノアセテート、アミノアルキルメタアクリレートコポリマー、ヒドロキシプロピルメチルセルロースアセテートサクシネート、メタアクリル酸コポリマー、セルロースアセテートトリメリテート（ＣＡＴ）、ポリビニルアセテートフタレート、セラックなどが挙げられる。
着色剤としては、たとえばタール色素、酸化チタンなどが挙げられる。
矯味矯臭剤としては、クエン酸、アジピン酸、アスコルビン酸、メントールなどが挙げられる。
界面活性剤としては、たとえばポリオキシエチレン硬化ヒマシ油、モノステアリン酸グリセリン、モノステアリン酸ソルビタン、モノパルミチン酸ソルビタン、モノラウリン酸ソルビタン、ポリオキシエチレンポリオキシプロピレンブロックコポリマー、ポリソルベート類、ラウリル硫酸ナトリウム、マクロゴール類、ショ糖脂肪酸エステルなどが挙げられる。
可塑剤としては、クエン酸トリエチル、トリアセチン、セタノールなどが挙げられる。
実施例
以下、参考例、実施例及び試験例をあげて本発明を更に詳細に説明する。
表１〜３に、以下に述べる実施例及び試験例で具体的に例示されるピリジン誘導体の構造式を示す。
Figure 0003884476
Figure 0003884476
Figure 0003884476
参考例１
（Ｅ）−３−（４−メチルフェニル）−１−フェニル−２−プロペン−１−オン
アセトフェノン６．００ｇ、ｐ−トルアルデヒド６．００ｇ及びエタノール２０mlの混合物に、０℃撹拌下、水酸化カリウム３．１０ｇを５０mlの水に溶解した溶液を適下し、さらに０〜１０℃で４時間撹拌した。反応終了後、得られた生成物を濾取し、エタノールで再結晶することにより標記化合物６．０６ｇを得た。
ｍ．ｐ．８９．２〜９０．０℃。
相当するアセトフェノン誘導体とアルデヒドを用い、実質的に参考例１と同様にして以下の化合物を得た。
（Ｅ）−３−（４−メチルフェニル）−１−（２−ニトロフェニル）−２−プロペン−１−オン。
（Ｅ）−３−（４−メチルフェニル）−１−（３−ニトロフェニル）−２−プロペン−１−オン。
（Ｅ）−３−（４−メチルフェニル）−１−（４−ニトロフェニル）−２−プロペン−１−オン。
（Ｅ）−１−（３−ジメチルアミノフェニル）−３−（４−メチルフェニル）−２−プロペン−１−オン。
（Ｅ）−１−（４−ジメチルアミノフェニル）−３−（４−メチルフェニル）−２−プロペン−１−オン。
（Ｅ）−３−（３−ニトロフェニル）−１−フェニル−２−プロペン−１−オン。
（Ｅ）−３−（４−ニトロフェニル）−１−フェニル−２−プロペン−１−オン。
（Ｅ）−３−（４−アセトアミドフェニル）−１−フェニル−２−プロペン−１−オン。
（Ｅ）−３−（４−メチル−３−ニトロフェニル）−１−フェニル−２−プロペン−１−オン。
（Ｅ）−３−（２−イミダゾリル）−１−フェニル−２−プロペン−１−オン。
参考例２
１−〔２−オキソ−２−（２−ピリジル）エチル〕ピリジニウム＝ヨージド
２−アセチルピリジン５５．１６ｇ、ピリジン１５０ml及びヨウ素１２０ｇの混合物を、撹拌下、２０分を要して１００℃に除々に加熱し、さらに１００℃で３０分加熱した。室温まで冷却後、反応物をベンゼンでよく洗浄し、エタノール−水で再結晶することにより標記化合物１３０．７８ｇを得た。
ｍ．ｐ．１９８〜１９９℃（分解）。
実施例１
４−（４−メチルフェニル）−２−フェニル−６−（２−ピリジル）ピリジン（化合物１）
参考例１で得た（Ｅ）−３−（４−メチルフェニル）−１−フェニル−２−プロペン−１−オン５．００ｇ、参考例２で得た１−〔２−オキソ−２−（２−ピリジル）エチル〕ピリジニウム＝ヨージド３．４１ｇ及び酢酸アンモニウム６．００ｇに、メタノール４０mlを加え、１０時間還流した。冷却後、生成物を濾取し、アセトンで再結晶することにより標記化合物１．６３ｇを得た。
ｍ．ｐ．１２５．２〜１２６．７℃。
1Ｈ ＮＭＲ（ＣＤＣｌ3） δ（ｐｐｍ）；２．４４（３Ｈ，ｓ）、７．３０〜７．３７（３Ｈ，ｍ）、７．４５〜７．５８（３Ｈ，ｍ）、７．７１〜７．７７（２Ｈ，ｍ）、７．８２〜７．９０（１Ｈ，ｍ）、７．９８（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）、８．１７〜８．２３（２Ｈ，ｍ）、８．６４〜８．７５（３Ｈ，ｍ）。
ＭＳ（ＥＩ） ３２２（Ｍ+）。
（Ｅ）−３−（４−メチルフェニル）−１−フェニル−２−プロペン−１−オンの代わりに相当するα，β−不飽和ケトンを用いて、実質的に実施例１と同様にして以下の化合物を得た。
４−（４−メチルフェニル）−２−（２−ニトロフェニル）−６−（２−ピリジル）ピリジン（化合物３）
ｍ．ｐ．１８６．０〜１８７．０℃。
４−（４−メチルフェニル）−２−（３−ニトロフェニル）−６−（２−ピリジル）ピリジン（化合物４）
ｍ．ｐ．２１７．３〜２１７．８℃。
４−（４−メチルフェニル）−２−（４−ニトロフェニル）−６−（２−ピリジル）ピリジン（化合物５）
ｍ．ｐ．１７７．０〜１７９．０℃。
４−（３−ニトロフェニル）−２−フェニル−６−（２−ピリジル）ピリジン（化合物１２）
ｍ．ｐ．１６５．３〜１６６．５℃。
４−（４−ニトロフェニル）−２−フェニル−６−（２−ピリジル）ピリジン（化合物１３）
ｍ．ｐ．１６７．７〜１６９．０℃。
４−（４−アセトアミドフェニル）−２−フェニル−６−（２−ピリジル）ピリジン（化合物１８）
ｍ．ｐ．２８１．３〜２８２．５℃。
４−（４−メチル−３−ニトロフェニル）−２−フェニル−６−（２−ピリジル）ピリジン（化合物１９）
ｍ．ｐ．１６２．５〜１６３．９℃。
２−（３−ジメチルアミノフェニル）−４−（４−メチルフェニル）−６−（２−ピリジル）ピリジン（化合物２２）
ｍ．ｐ．１３７．２〜１３７．８℃。
２−（４−ジメチルアミノフェニル）−４−（４−メチルフェニル）−６−（２−ピリジル）ピリジン（化合物２４）
ｍ．ｐ．１７９．５〜１８１．０℃。
４−（２−イミダゾリル）−２−フェニル−６−（２−ピリジル）ピリジン（化合物２６）
ｍ．ｐ．２５４．７〜２５５．２℃。
実施例２
２−（２−アミノフェニル）−４−（４−メチルフェニル）−６−（２−ピリジル）ピリジン（化合物６）
実施例１を参考にして得た４−（４−メチルフェニル）−２−（２−ニトロフェニル）−６−（２−ピリジル）ピリジン０．４５ｇに、１Ｎ塩酸６０ml及び５％パラジウムカーボン０．０５ｇを加え、室温、常圧で、水素添加を行った。反応終了後、パラジウムカーボンを自然ろ過により除き、１０％水酸化ナトリウム水溶液を加えてアルカリ性とし、酢酸エチルで抽出した。溶媒を減圧下留去し、残査をエタノール−水で再結晶することにより標記化合物０．１６ｇを得た。
ｍ．ｐ．１３１．０〜１３２．０℃。
1Ｈ ＮＭＲ（ＣＤＣｌ3） δ（ｐｐｍ）；２．４４（３Ｈ，ｓ）、６．８１〜６．８８（２Ｈ，ｍ）、７．１８〜７．３８（４Ｈ，ｍ）、７．６２〜７．８８（５Ｈ，ｍ）、８．４１（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ）、８．６０（１Ｈ，ｄ，Ｊ＝１．６Ｈｚ）、８．７０〜８．７５（１Ｈ，ｍ）。
ＭＳ（ＣＩ） ３３８（Ｍ+＋１）。
４−（４−メチルフェニル）−２−（２−ニトロフェニル）−６−（２−ピリジル）ピリジンの代わりに、ニトロ基を持つ相当するピリジン誘導体を用いて、実質的に実施例２と同様にして以下の化合物を得た。
２−（３−アミノフェニル）−４−（４−メチルフェニル）−６−（２−ピリジル）ピリジン（化合物８）
ｍ．ｐ．１３６．０〜１３８．０℃。
２−（４−アミノフェニル）−４−（４−メチルフェニル）−６−（２−ピリジル）ピリジン（化合物１０）
ｍ．ｐ．１７２．５〜１７４．５℃（分解）。
４−（３−アミノフェニル）−２−フェニル−６−（２−ピリジル）ピリジン（化合物１４）
ｍ．ｐ．１６１．６〜１６２．３℃。
４−（３−アミノ−４−メチルフェニル）−２−フェニル−６−（２−ピリジル）ピリジン（化合物２０）
ｍ．ｐ．２０７．５〜２０９．１℃。
実施例３
４−（４−アミノフェニル）−２−フェニル−６−（２−ピリジル）ピリジン（化合物１６）
実施例１を参考にして得た４−（４−アセトアミドフェニル）−２−フェニル−６−（２−ピリジル）ピリジン０．８５ｇに、３Ｎ塩酸１００mlを加え、３時間還流した。冷却後、１０％水酸化ナトリウム水溶液を加えてアルカリ性とし、酢酸エチルで抽出した。溶媒を減圧下留去し、残査を酢酸エチル−ｎ−ヘキサンで再結晶することにより標記化合物０．６５ｇを得た。
ｍ．ｐ．１９４．５〜１９５．１℃。
1Ｈ ＮＭＲ（ＣＤＣｌ3） δ（ｐｐｍ）；６．７８〜６．８５（２Ｈ，ｍ）、７．３２〜７．９５（８Ｈ，ｍ）、８．１６〜８．２２（２Ｈ，ｍ）、８．６１〜８．７４（３Ｈ，ｍ）。
ＭＳ（ＥＩ） ３２３（Ｍ+）。
実施例４
４−（４−メチルフェニル）−２−フェニル−６−（２−ピリジル）ピリジン＝塩酸塩（化合物２）
実施例１で得た４−（４−メチルフェニル）−２−フェニル−６−（２−ピリジル）ピリジン０．８０ｇ、酢酸エチル３０mlの混合物に、撹拌下４Ｎ塩酸−酢酸エチル溶液５．０mlを加え、室温で１０分間撹拌後、ジエチルエーテル３０mlを加えた。得られた結晶を濾取することにより標記化合物０．８３ｇを得た。
ｍ．ｐ．１９４．５〜１９６．５℃。
1Ｈ ＮＭＲ（ＣＤＣｌ3） δ（ｐｐｍ）；２．４３（３Ｈ，ｓ）、７．３８（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）、７．４９〜７．６０（３Ｈ，ｍ）、７．８６〜７．９３（１Ｈ，ｍ）、８．００（２Ｈ，ｄ，Ｊ＝８．２Ｈｚ）、８．１４〜８．２０（３Ｈ，ｍ）、８．４６〜８．５４（１Ｈ，ｍ）、９．０１〜９．０７（２Ｈ，ｍ）、９．３６（１Ｈ，ｄ，Ｊ＝１．３Ｈｚ）。
ＭＳ（ＥＩ） ３２２（Ｍ+−ＨＣｌ）。
４−（４−メチルフェニル）−２−フェニル−６−（２−ピリジル）ピリジンの代わりに、相当するピリジン誘導体を用いて、実質的に実施例４と同様にして以下の化合物を得た。
２−（２−アミノフェニル）−４−（４−メチルフェニル）−６−（２−ピリジル）ピリジン＝二塩酸塩（化合物７）
ｍ．ｐ．２５０．７〜２５２．７℃（分解）。
２−（３−アミノフェニル）−４−（４−メチルフェニル）−６−（２−ピリジル）ピリジン＝三塩酸塩（化合物９）
ｍ．ｐ．２７３．８〜２７５．８℃（分解）。
２−（４−アミノフェニル）−４−（４−メチルフェニル）−６−（２−ピリジル）ピリジン＝二塩酸塩（化合物１１）
ｍ．ｐ．２２４．４〜２２６．４℃（分解）。
４−（３−アミノフェニル）−２−フェニル−６−（２−ピリジル）ピリジン＝三塩酸塩（化合物１５）
ｍ．ｐ．２０２．０〜２０４．０℃。
４−（４−アミノフェニル）−２−フェニル−６−（２−ピリジル）ピリジン＝三塩酸塩（化合物１７）
ｍ．ｐ．２７０．０〜２７２．０（分解）。
４−（３−アミノ−４−メチルフェニル）−２−フェニル−６−（２−ピリジル）ピリジン＝三塩酸塩（化合物２１）
ｍ．ｐ．２０８．０〜２１０．０℃。
２−（３−ジメチルアミノフェニル）−４−（４−メチルフェニル）−６−（２−ピリジル）ピリジン＝二塩酸塩（化合物２３）
ｍ．ｐ．１９７．０〜１９８．０（分解）。
２−（４−ジメチルアミノフェニル）−４−（４−メチルフェニル）−６−（２−ピリジル）ピリジン＝三塩酸塩（化合物２５）
ｍ．ｐ．１７８．０〜１８０．０℃（分解）。
４−（２−イミダゾリル）−２−フェニル−６−（２−ピリジル）ピリジン＝二塩酸塩（化合物２７）
ｍ．ｐ．２７７．２〜２７９．２℃（分解）。
試験例１ ＮＧＦ産生促進作用試験
ＮＧＦ産生促進作用試験は、以下の方法を用い評価した。
検体
表１〜表３に示した各化合物をＤＭＳＯに溶解し、濃度を２mg／ml〜５０mg／mlとした。
試験細胞
マウス前脳由来アストログリア細胞（ＮＧＦ産生細胞）。
試験方法
マウス前脳より調製したアストログリア細胞を２０％牛胎児血清、１００ユニット／mlペニシリン、１００μg／mlストレプトマイシンを含有するダルベッコ改変イーグル培地（ギブコ社製，高グルコース含有）にて、８×１０5細胞／mlに調製し、９６孔プレート（培養孔あたりの面積０．３２cm2，ファルコン社製）へ、０．１ml／孔ずつまき、３７℃、５％ＣＯ2で培養した。
７２時間後、培地を除き、新たに０．５％牛アルブミン粉末（アーマー社製）、１００ユニット／mlペニシリン、１００μg／mlストレプトマイシンを含有するダルベッコ改変イーグル培地０．１ml／孔を加えた後、３７℃、５％ＣＯ2で培養した。７２時間後、各種濃度の検体を含む上記培地０．１ml／孔と交換した。
ここで、各検体はＤＭＳＯに溶解し、最終濃度が下記表４、５に示す各種濃度となるように添加した。なお、比較として、ＤＭＳＯのみを加えた培地（対照）も調製した。
このような各種培地にて２４時間培養した後、培地中のＮＧＦ濃度を酵素免疫測定法〔古川ら；J.Neurochem.、第４０巻、第７３４頁〜第７４４頁（１９８４年）〕によって測定した。
本発明化合物のＮＧＦ産生促進活性は、対照（ＤＭＳＯ）のＮＧＦ量を１．０としたときの比で示した。
結果
結果を表４及び５に示す。
Figure 0003884476
Figure 0003884476
試験例２ 神経栄養因子作用試験
神経栄養因子作用は、以下の方法を用いて評価した。
検体
表１〜表３に示した各化合物をＤＭＳＯに溶解し、濃度を２mg／ml〜１０mg／mlとした。
試験細胞
胎生１８日ラット大脳皮質由来神経細胞
試験方法
試験細胞を、２０％牛胎児血清を含有するダルベッコの最少必須培地（ギブコ社製）及びハムＦ−１２培地（ギブコ社製）を等量混合したＤＦ培地にて、３．２×１０6細胞／mlに調製し、ポリエチレンイミンを塗布した２４孔プレート（培養孔あたりの面積２cm2、コーニング社製）へ、０．５ml／孔ずつまき、３７℃、５％ＣＯ2で培養した。
２４時間後、培地を除き、新たに各種濃度の検体、５μg／mlトランスフェリン、５μg／mlインスリン、２０pmole／mlプロゲステロンを含有する無血清の上記ＤＦ培地０．５ml／孔を加えた。
ここで、本発明化合物はＤＭＳＯに溶解し、最終濃度が下記表６、７に示す各種濃度となるように添加した。なお、比較として、ＤＭＳＯのみを加えた培地も調製した。
この段階で、同じプレートを２枚用意した。各種培地にて７２時間培養後、１枚のプレートに対しＮ2−Ｏ2−ＣＯ2インキュベーター（タバイ社製，ＢＮＰ−１００型）により、酸素濃度を最低設定濃度の１％に下げ４時間培養する低酸素負荷を施した。もう１枚のプレートは負荷をかけずに、５％ＣＯ2、９５％Ａirのまま培養を続けた。さらに４８時間培養し、生細胞数を定量した。
培地を除き、Fluorescien Diacetate（ＦＤＡ）試薬を作用させた。リン酸緩衝液（pH７．４）で洗浄後、蛍光強度（Ｅｘ４８５／Ｅｍ５３０）を測定した（ミリポア社製，CytoFlour TM２３００）。
本発明化合物の神経栄養因子活性は、対照（ＤＭＳＯ添加）の蛍光強度を１．０としたときの比で表した。
結果
結果を表６及び７に示す。
Figure 0003884476
Figure 0003884476
試験例３ スナネズミ脳虚血による遅発性神経細胞死に対する作用試験
脳虚血により生じる神経細胞障害の抑制作用を、スナネズミ両側総頚動脈閉塞モデルを用いて評価した。
実験動物
体重６０〜９０ｇ雄性スナネズミ（新日本動物、埼玉、日本）を用いた。
試験方法
スナネズミはエーテルで軽度に麻酔し、背位に固定した。キシロカインで局部浸潤麻酔後、両側総頚動脈を頚部正中線を切開して露出し注意深く近傍の迷走神経から剥離した。動脈を動脈瘤クリップで３分間止め、その後クリップをはずし皮膚を縫合した。偽手術群は両側総頚動脈を閉塞しないこと以外は同様に処置した。
３分間脳虚血の７日後に動物をエーテル麻酔し脳を１０％ホルマリン緩衝液で左心室から潅流した。海馬領域は３〜４mmの厚さのスライスとして冠状に切り出し、パラフィン包埋後切片を作成した。スライスはヘマトキシリン＆エオジンで染色した。
虚血性細胞障害は０〜３の４段階に分けて評価した。０（−）：正常神経細胞、１（＋）：数個の神経細胞障害（１つかあるいは数個の神経細胞の障害）、２（＋＋）：多数の神経細胞の障害、３（＋＋＋）：ほとんどの神経細胞の障害。
検体
検体はアラビアゴムに懸濁し、虚血終了直後に、１００mg／kgを腹腔内投与した。
結果
偽手術群のスナネズミ海馬ＣＡ１神経細胞は全く障害を受けていないが、３分間両側総頚動脈閉塞モデルでは、海馬ＣＡ１神経細胞は光学顕微鏡所見で明らかに障害されていた。しかし、海馬ＣＡ１神経細胞の崩壊と消失は、本発明の化合物を腹腔内投与することにより抑制された。結果を表８に示す。
Figure 0003884476
産業上の利用の可能性
ＮＧＦは、ある種の神経細胞の生存・機能維持を担っており、変性修復・保護作用を有している。本発明のピリジン誘導体は、ＮＧＦ産生促進活性及び培養大脳皮質神経細胞の生存延長活性の一方あるいは両方を示している。従って、本発明のピリジン誘導体は、生体内で、直接、あるいは間接に神経細胞に働き、神経変性に伴う神経障害の改善・治療効果を示すことが期待される。例えば、外傷性、アルコールや抗癌剤などの薬剤性、炎症性、糖尿病などに見られる代謝性、さらには特発性の末梢性神経変性に伴う症状・疾患の改善・治療剤として用いることができる。また、中枢性神経変性に伴う症状・疾患、例えば、アルツハイマー型及び脳血管性痴呆、ダウン症候群、パーキンソン病、ハンチントン舞踏病、脳虚血・脳梗塞・脳出血・頭部外傷などの後遺症、健忘症、脊髄性神経麻ひ症などの改善・治療剤としても用いることができる。Technical field
The present invention relates to a pyridine derivative having a nerve growth factor (hereinafter referred to as NGF) production promoting action or a neurotrophic factor action and a salt thereof, and pharmaceutical use thereof.
Background art
In Alzheimer type senile dementia, which has been increasing in recent years, it has been suggested that degeneration and loss of acetylcholinergic neurons, which are basal ganglia neurons, are deeply involved in memory impairment and intellectual activity decline [Witehorse et al., Science, 215, 1237 (1982)].
NGF inhibits degeneration and loss of central acetylcholinergic nerves by fiber cutting [Korsing et al., Neuroscience Lett., 66, 175 (1986)] and improves maze learning impairment in aged rats In addition, it has been reported to suppress atrophy of acetylcholinergic neurons (Takushi Mono et al., History of Medicine, 145, 579 (1986)). These facts indicate that NGF can be a therapeutic agent for Alzheimer-type senile dementia.
Furthermore, NGF has been confirmed to prevent hippocampal neuronal cell death in cerebral ischemic gerbils, and is thought to be useful as a therapeutic agent for stroke sequelae.
On the other hand, NGF has the effect of accelerating the recovery of peripheral nerve damage and has been shown to be useful as a therapeutic agent for peripheral neuropathy.
In addition to NGF, a number of biological components exhibiting a survival / function maintaining action or a degenerative repair activity of nerve cells have been found and are called neurotrophic factors. Therefore, these neurotrophic factors are thought to be useful as therapeutic agents for central neuropathy and peripheral neuropathy associated with neuronal degeneration.
Biological components called neurotrophic factors, including NGF, are all proteins. When used as a therapeutic agent for central neuropathy, proteins are expected to require direct intraventricular administration, judging from their physical properties, and there are many practical problems. Therefore, a therapeutic agent for a low molecular weight compound having a neurotrophic factor action itself or a neurotrophic factor production promoting action capable of a simpler administration method is desired.
An object of the present invention is to provide a novel compound that has one or both of NGF production promoting action and neurotrophic factor action and is useful for improving or treating neurodegenerative diseases.
Disclosure of the invention
As a result of various studies on a large number of compounds in order to achieve the above object, the present inventors have found that certain pyridine derivatives have one or both of NGF production promoting action and neurotrophic factor action, and are The present inventors have found that the compound is useful for improvement or treatment and have completed the present invention.
The object of the present invention is to formula (1)
Figure 0003884476
(Wherein R1Represents a phenyl group substituted with one or two or more substituents selected from the group consisting of a methyl group, a nitro group, an amino group, and an acetamide group, or an imidazolyl group;2Represents a hydrogen atom, a nitro group, an amino group or a dimethylamino group. And a salt thereof.
Another object of the present invention is to provide the above pyridine derivatives and salts thereof for use as active ingredients in pharmaceutical compositions.
Furthermore, the other object of this invention is to provide the pharmaceutical composition which contains the said pyridine derivative or its salt as an active ingredient.
Furthermore, another object of the present invention is to provide use of the pyridine derivative or a salt thereof for producing a pharmaceutical composition for improving or treating neurodegenerative diseases.
Furthermore, another object of the present invention is to provide a method for improving or treating a neurodegenerative disease, comprising administering an effective amount of the above pyridine derivative or a salt thereof to a human.
BEST MODE FOR CARRYING OUT THE INVENTION
R in the pyridine derivative of formula (1)1Is a phenyl group substituted with one or more substituents selected from the group consisting of a methyl group, a nitro group, an amino group and an acetamide group, the substituent is ortho, para and meta of the phenyl group. It may be substituted at any position of the position.
R1Is a phenyl group substituted with a methyl group, R2A pyridine derivative in which is hydrogen atom, nitro group or amino group, or R1Is a phenyl group substituted by a nitro group, an amino group or an acetamide group, or an imidazolyl group, and R2A pyridine derivative in which is a hydrogen atom is preferred.
In the present invention, a salt of a pyridine derivative means a pharmacologically acceptable salt, a salt with a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, or citric acid, succinic acid, tartaric acid, methanesulfone. And salts with organic acids such as acids.
The compound of the present invention can be produced, for example, according to the methods 1) to 3) shown below.
1) In formula (1), R1Is a phenyl group substituted with one or more substituents selected from the group consisting of a methyl group, a nitro group and an acetamide group, or an imidazolyl group, and R2A compound in which is a hydrogen atom, a nitro group or a dimethylamino group can be produced as follows.
That is, first, the formula (2)
RThree-CHO (2)
(Wherein RThreeRepresents a phenyl group substituted with one or two or more substituents selected from the group consisting of a methyl group, a nitro group and an acetamide group, or an imidazolyl group. And a compound represented by formula (3)
Figure 0003884476
(Wherein RFourRepresents a hydrogen atom, a nitro group or a dimethylamino group. And a compound represented by formula (4) by condensation in the presence of an alkali compound.
Figure 0003884476
(Wherein RThree, RFourIs as defined above. ) Can be obtained.
Here, examples of the alkali compound used in the condensation reaction include potassium hydroxide, sodium hydroxide, sodium methoxide, potassium t-butoxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate. As the reaction solvent, methanol, ethanol, n-propanol, isopropanol, t-butanol, or the like can be used alone or by adding water. The reaction temperature can be appropriately selected from 0 ° C. to the boiling point of the solvent used.
The compound of formula (4) can then be prepared by the method of F. Krohnke et al. [Chemische Berichte, 92, 22 (1959)]
Figure 0003884476
The compound of this invention can be obtained by making it react with the compound represented by these in presence of ammonium acetate. Here, 1-10 times mole amount of the compound of Formula (4) is used for ammonium acetate, and methanol, ethanol, n-propanol, isopropanol, t-butanol, acetic acid, etc. can be used for the reaction solvent. The reaction temperature can be appropriately selected from room temperature to the boiling point of the solvent used.
2) In the formula (1), a compound having an amino group, that is, R1A phenyl group substituted with an amino group and / or R2Is a compound having a nitro group among the compounds of formula (1) obtained by the method of 1) above, that is, R1And phenyl substituted with nitro group or R2A compound in which is a nitro group can be obtained by reduction.
As a reduction method, a normal method can be used, for example, a catalytic hydrogenation method, a reduction method using hydrazine and Raney nickel in ethanol, or the like can be used.
3) In the formula (1), R1Is a phenyl group substituted with an amino group, and R2Is a hydrogen atom, a nitro group or a dimethylamino group, among the compounds of formula (1) obtained by the method of 1) above, R1Is a phenyl group substituted with an acetamide group, and R2Is a hydrogen atom, a nitro group or a dimethylamino group, by hydrolysis in the presence of an acid or an alkali compound.
Hydrolysis can be carried out by an ordinary method using an acid such as hydrochloric acid or an alkali compound such as sodium hydroxide.
The pyridine derivative of the present invention or a salt thereof has one or both of NGF production promoting action and neurotrophic factor action, and is useful for improving or treating neurodegenerative diseases. Such a pyridine derivative or a salt thereof is usually orally or parenterally administered to humans.
When administered orally, pyridine derivatives or their salts are mixed with excipients, disintegrants, binders, lubricants, anti-oxidants, coating agents, coloring agents, flavoring agents, surfactants, plasticizers, etc. Then, when it is administered as a granule, powder, capsule or tablet, and administered parenterally, it can be administered by injection, infusion, or suppository.
In formulating the above-mentioned preparations, a usual formulation method can be used.
Excipients include, for example, mannitol, xylitol, sorbitol, glucose, sucrose, lactose, crystalline cellulose, crystalline cellulose / sodium carboxymethylcellulose, calcium hydrogen phosphate, wheat starch, rice starch, corn starch, potato starch, carboxymethyl starch sodium , Dextrin, α-cyclodextrin, β-cyclodextrin, carboxyvinyl polymer, light anhydrous silicic acid, titanium oxide, magnesium aluminate metasilicate, polyethylene glycol, medium chain fatty acid triglyceride and the like.
Examples of disintegrants include low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium / type A (actisol), starch, crystalline cellulose, hydroxypropyl starch, and partially pregelatinized starch. It is done.
Examples of the binder include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tarragant, sodium alginate, propylene glycol alginate, and the like. .
Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane, microcrystalline wax, beeswax, and white beeswax.
Examples of the antioxidant include dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), α-tocopherol, citric acid and the like.
Examples of the coating agent include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, Examples thereof include hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer, cellulose acetate trimellitate (CAT), polyvinyl acetate phthalate, shellac and the like.
Examples of the colorant include tar dyes and titanium oxide.
Examples of flavoring agents include citric acid, adipic acid, ascorbic acid, menthol and the like.
Examples of the surfactant include polyoxyethylene hydrogenated castor oil, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polyoxyethylene polyoxypropylene block copolymer, polysorbates, sodium lauryl sulfate, macro Examples include galls and sucrose fatty acid esters.
Examples of the plasticizer include triethyl citrate, triacetin, cetanol and the like.
Example
Hereinafter, the present invention will be described in more detail with reference examples, examples and test examples.
Tables 1 to 3 show the structural formulas of pyridine derivatives specifically exemplified in Examples and Test Examples described below.
Figure 0003884476
Figure 0003884476
Figure 0003884476
Reference example 1
(E) -3- (4-Methylphenyl) -1-phenyl-2-propen-1-one
To a mixture of 6.00 g of acetophenone, 6.00 g of p-tolualdehyde and 20 ml of ethanol, a solution prepared by dissolving 3.10 g of potassium hydroxide in 50 ml of water with stirring at 0 ° C. is appropriately applied. Stir for hours. After completion of the reaction, the resulting product was collected by filtration and recrystallized from ethanol to obtain 6.06 g of the title compound.
m. p. 89.2-90.0 ° C.
Using the corresponding acetophenone derivative and aldehyde, the following compound was obtained in substantially the same manner as in Reference Example 1.
(E) -3- (4-Methylphenyl) -1- (2-nitrophenyl) -2-propen-1-one.
(E) -3- (4-Methylphenyl) -1- (3-nitrophenyl) -2-propen-1-one.
(E) -3- (4-Methylphenyl) -1- (4-nitrophenyl) -2-propen-1-one.
(E) -1- (3-Dimethylaminophenyl) -3- (4-methylphenyl) -2-propen-1-one.
(E) -1- (4-Dimethylaminophenyl) -3- (4-methylphenyl) -2-propen-1-one.
(E) -3- (3-Nitrophenyl) -1-phenyl-2-propen-1-one.
(E) -3- (4-Nitrophenyl) -1-phenyl-2-propen-1-one.
(E) -3- (4-Acetamidophenyl) -1-phenyl-2-propen-1-one.
(E) -3- (4-Methyl-3-nitrophenyl) -1-phenyl-2-propen-1-one.
(E) -3- (2-imidazolyl) -1-phenyl-2-propen-1-one.
Reference example 2
1- [2-oxo-2- (2-pyridyl) ethyl] pyridinium iodide
A mixture of 55.16 g of 2-acetylpyridine, 150 ml of pyridine and 120 g of iodine was gradually heated to 100 ° C. over 20 minutes with stirring and further heated at 100 ° C. for 30 minutes. After cooling to room temperature, the reaction product was thoroughly washed with benzene and recrystallized with ethanol-water to obtain 130.78 g of the title compound.
m. p. 198-199 ° C (decomposition).
Example 1
4- (4-Methylphenyl) -2-phenyl-6- (2-pyridyl) pyridine (Compound 1)
5.00 g of (E) -3- (4-methylphenyl) -1-phenyl-2-propen-1-one obtained in Reference Example 1 and 1- [2-oxo-2- ( 2-Pyridyl) ethyl] pyridinium = iodide 3.41 g and ammonium acetate 6.00 g were added with 40 ml of methanol and refluxed for 10 hours. After cooling, the product was collected by filtration and recrystallized from acetone to obtain 1.63 g of the title compound.
m. p. 125.2-126.7 ° C.
11 H NMR (CDClThree) Δ (ppm); 2.44 (3H, s), 7.30 to 7.37 (3H, m), 7.45 to 7.58 (3H, m), 7.71 to 7.77 (2H) M), 7.82 to 7.90 (1H, m), 7.98 (1H, d, J = 1.6 Hz), 8.17 to 8.23 (2H, m), 8.64 to 8 .75 (3H, m).
MS (EI) 322 (M+).
(E) -3- (4-Methylphenyl) -1-phenyl-2-propen-1-one is used instead of the corresponding α, β-unsaturated ketone in substantially the same manner as in Example 1. The following compounds were obtained:
4- (4-Methylphenyl) -2- (2-nitrophenyl) -6- (2-pyridyl) pyridine (Compound 3)
m. p. 186.0-187.0 ° C.
4- (4-Methylphenyl) -2- (3-nitrophenyl) -6- (2-pyridyl) pyridine (Compound 4)
m. p. 217.3-217.8 ° C.
4- (4-Methylphenyl) -2- (4-nitrophenyl) -6- (2-pyridyl) pyridine (Compound 5)
m. p. 177.0-179.0 ° C.
4- (3-Nitrophenyl) -2-phenyl-6- (2-pyridyl) pyridine (Compound 12)
m. p. 165.3 to 166.5 ° C.
4- (4-Nitrophenyl) -2-phenyl-6- (2-pyridyl) pyridine (Compound 13)
m. p. 167.7-169.0 ° C.
4- (4-acetamidophenyl) -2-phenyl-6- (2-pyridyl) pyridine (Compound 18)
m. p. 281.3-282.5 ° C.
4- (4-Methyl-3-nitrophenyl) -2-phenyl-6- (2-pyridyl) pyridine (Compound 19)
m. p. 162.5-163.9 ° C.
2- (3-Dimethylaminophenyl) -4- (4-methylphenyl) -6- (2-pyridyl) pyridine (Compound 22)
m. p. 137.2-137.8C.
2- (4-Dimethylaminophenyl) -4- (4-methylphenyl) -6- (2-pyridyl) pyridine (Compound 24)
m. p. 179.5-181.0 ° C.
4- (2-imidazolyl) -2-phenyl-6- (2-pyridyl) pyridine (Compound 26)
m. p. 254.7-255.2 ° C.
Example 2
2- (2-Aminophenyl) -4- (4-methylphenyl) -6- (2-pyridyl) pyridine (Compound 6)
To 0.45 g of 4- (4-methylphenyl) -2- (2-nitrophenyl) -6- (2-pyridyl) pyridine obtained with reference to Example 1, 60 ml of 1N hydrochloric acid and 5% palladium carbon were added. 05 g was added, and hydrogenation was performed at room temperature and normal pressure. After completion of the reaction, palladium carbon was removed by natural filtration to make it alkaline by adding a 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-water to obtain 0.16 g of the title compound.
m. p. 131.0-132.0 ° C.
11 H NMR (CDClThree) Δ (ppm); 2.44 (3H, s), 6.81 to 6.88 (2H, m), 7.18 to 7.38 (4H, m), 7.62 to 7.88 (5H) , M), 8.41 (1H, d, J = 8.0 Hz), 8.60 (1H, d, J = 1.6 Hz), 8.70-8.75 (1H, m).
MS (CI) 338 (M++1).
Substantially the same as in Example 2, except that the corresponding pyridine derivative having a nitro group was used instead of 4- (4-methylphenyl) -2- (2-nitrophenyl) -6- (2-pyridyl) pyridine. The following compounds were obtained:
2- (3-Aminophenyl) -4- (4-methylphenyl) -6- (2-pyridyl) pyridine (Compound 8)
m. p. 136.0-138.0C.
2- (4-Aminophenyl) -4- (4-methylphenyl) -6- (2-pyridyl) pyridine (Compound 10)
m. p. 172.5-174.5 ° C (decomposition).
4- (3-Aminophenyl) -2-phenyl-6- (2-pyridyl) pyridine (Compound 14)
m. p. 161.6-162.3 ° C.
4- (3-Amino-4-methylphenyl) -2-phenyl-6- (2-pyridyl) pyridine (Compound 20)
m. p. 207.5-209.1 ° C.
Example 3
4- (4-Aminophenyl) -2-phenyl-6- (2-pyridyl) pyridine (Compound 16)
To 0.85 g of 4- (4-acetamidophenyl) -2-phenyl-6- (2-pyridyl) pyridine obtained with reference to Example 1, 100 ml of 3N hydrochloric acid was added and refluxed for 3 hours. After cooling, the mixture was made alkaline with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-n-hexane to obtain 0.65 g of the title compound.
m. p. 194.5-195.1 ° C.
11 H NMR (CDClThree) Δ (ppm); 6.78 to 6.85 (2H, m), 7.32 to 7.95 (8H, m), 8.16 to 8.22 (2H, m), 8.61 to 8 .74 (3H, m).
MS (EI) 323 (M+).
Example 4
4- (4-Methylphenyl) -2-phenyl-6- (2-pyridyl) pyridine = hydrochloride (Compound 2)
To a mixture of 0.80 g of 4- (4-methylphenyl) -2-phenyl-6- (2-pyridyl) pyridine obtained in Example 1 and 30 ml of ethyl acetate, 5.0 ml of 4N hydrochloric acid-ethyl acetate solution was stirred. After stirring at room temperature for 10 minutes, 30 ml of diethyl ether was added. The obtained crystals were collected by filtration to obtain 0.83 g of the title compound.
m. p. 194.5-196.5 ° C.
11 H NMR (CDClThree) Δ (ppm); 2.43 (3H, s), 7.38 (2H, d, J = 8.0 Hz), 7.49-7.60 (3H, m), 7.86-7.93 (1H, m), 8.00 (2H, d, J = 8.2 Hz), 8.14-8.20 (3H, m), 8.46-8.54 (1H, m), 9.01 ˜9.07 (2H, m), 9.36 (1H, d, J = 1.3 Hz).
MS (EI) 322 (M+-HCl).
The following compound was obtained substantially in the same manner as in Example 4 except that the corresponding pyridine derivative was used instead of 4- (4-methylphenyl) -2-phenyl-6- (2-pyridyl) pyridine.
2- (2-Aminophenyl) -4- (4-methylphenyl) -6- (2-pyridyl) pyridine = dihydrochloride (Compound 7)
m. p. 250.7-252.7 ° C. (decomposition).
2- (3-Aminophenyl) -4- (4-methylphenyl) -6- (2-pyridyl) pyridine = trihydrochloride (Compound 9)
m. p. 273.8-275.8 ° C. (decomposition).
2- (4-Aminophenyl) -4- (4-methylphenyl) -6- (2-pyridyl) pyridine = dihydrochloride (Compound 11)
m. p. 224.4-226.4 ° C. (decomposition).
4- (3-aminophenyl) -2-phenyl-6- (2-pyridyl) pyridine = trihydrochloride (Compound 15)
m. p. 202.0-204.0 ° C.
4- (4-Aminophenyl) -2-phenyl-6- (2-pyridyl) pyridine = trihydrochloride (Compound 17)
m. p. 270.0-272.0 (decomposition).
4- (3-Amino-4-methylphenyl) -2-phenyl-6- (2-pyridyl) pyridine = trihydrochloride (Compound 21)
m. p. 208.0-210.0 ° C.
2- (3-Dimethylaminophenyl) -4- (4-methylphenyl) -6- (2-pyridyl) pyridine = dihydrochloride (Compound 23)
m. p. 197.0-198.0 (decomposition).
2- (4-Dimethylaminophenyl) -4- (4-methylphenyl) -6- (2-pyridyl) pyridine = trihydrochloride (Compound 25)
m. p. 178.0-180.0 ° C (decomposition).
4- (2-imidazolyl) -2-phenyl-6- (2-pyridyl) pyridine = dihydrochloride (Compound 27)
m. p. 277.2 to 279.2 ° C. (decomposition).
Test example 1NGF production promoting action test
The NGF production promoting action test was evaluated using the following method.
Specimen
Each compound shown in Tables 1 to 3 was dissolved in DMSO to a concentration of 2 mg / ml to 50 mg / ml.
Test cell
Mouse forebrain-derived astroglia cells (NGF-producing cells).
Test method
Astroglial cells prepared from the mouse forebrain were placed in Dulbecco's modified Eagle medium (Gibco, high glucose content) containing 20% fetal bovine serum, 100 units / ml penicillin, 100 μg / ml streptomycin, 8 × 10FivePrepared in cells / ml, 96-well plate (area 0.32 cm per culture hole)2, Manufactured by Falcon) 0.1ml / hole, 37 ° C, 5% CO2In culture.
After 72 hours, the medium was removed, and 0.5 ml of Dulbecco's modified Eagle medium containing 0.5% bovine albumin powder (manufactured by Armor), 100 units / ml penicillin and 100 μg / ml streptomycin was added, 37 ° C, 5% CO2In culture. After 72 hours, the medium was replaced with 0.1 ml / well of the medium containing various concentrations of the specimen.
Here, each specimen was dissolved in DMSO and added so that the final concentration was various concentrations shown in Tables 4 and 5 below. For comparison, a medium (control) to which only DMSO was added was also prepared.
After culturing in such various media for 24 hours, the NGF concentration in the media is measured by enzyme immunoassay [Furukawa et al., J. Neurochem., 40, 734-744 (1984)]. did.
The NGF production-promoting activity of the compound of the present invention is shown as a ratio when the amount of NGF in the control (DMSO) is 1.0.
result
The results are shown in Tables 4 and 5.
Figure 0003884476
Figure 0003884476
Test example 2Neurotrophic factor action test
Neurotrophic factor action was evaluated using the following method.
Specimen
Each compound shown in Tables 1 to 3 was dissolved in DMSO to a concentration of 2 mg / ml to 10 mg / ml.
Test cell
Embryonic day 18 rat cortex-derived neurons
Test method
The test cells were 3.2 × 10 2 in DF medium in which equal amounts of Dulbecco's minimal essential medium (Gibco) containing 20% fetal bovine serum and Ham F-12 medium (Gibco) were mixed.624-well plate prepared with cells / ml and coated with polyethyleneimine (area 2cm per culture hole)2, Corning)), 0.5ml / hole, 37 ° C, 5% CO2In culture.
After 24 hours, the medium was removed, and 0.5 ml / well of serum-free DF medium containing various concentrations of specimens, 5 μg / ml transferrin, 5 μg / ml insulin, and 20 pmole / ml progesterone were newly added.
Here, the compound of the present invention was dissolved in DMSO and added so that the final concentration was various concentrations shown in Tables 6 and 7 below. For comparison, a medium supplemented only with DMSO was also prepared.
At this stage, two identical plates were prepared. After culturing in various media for 72 hours, N per plate2-O2-CO2The oxygen concentration was lowered to 1% of the minimum set concentration by an incubator (Tabai Co., Ltd., BNP-100 type), and a low oxygen load was applied to culture for 4 hours. The other plate is 5% CO without any load.2The culture was continued with 95% Air. The cells were further cultured for 48 hours, and the number of viable cells was quantified.
The medium was removed and Fluorescien Diacetate (FDA) reagent was allowed to act. After washing with a phosphate buffer (pH 7.4), fluorescence intensity (Ex485 / Em530) was measured (Millipore, CytoFluor).TM2300).
The neurotrophic factor activity of the compound of the present invention was expressed as a ratio when the fluorescence intensity of the control (DMSO added) was 1.0.
result
The results are shown in Tables 6 and 7.
Figure 0003884476
Figure 0003884476
Test example 3Tests on delayed neuronal death caused by gerbil cerebral ischemia
The inhibitory effect on neuronal damage caused by cerebral ischemia was evaluated using a gerbil bilateral common carotid artery occlusion model.
Experimental animals
Male gerbils (new Japanese animals, Saitama, Japan) weighing 60-90 g were used.
Test method
Gerbils were lightly anesthetized with ether and fixed in the dorsal position. After local infiltration anesthesia with xylocaine, the bilateral common carotid arteries were exposed by incising the midline of the neck and carefully detached from the nearby vagus nerve. The artery was stopped with an aneurysm clip for 3 minutes, after which the clip was removed and the skin was sutured. The sham-operated group was treated similarly except that it did not occlude the bilateral common carotid artery.
The animals were ether anesthetized 7 days after cerebral ischemia for 3 minutes and the brain was perfused from the left ventricle with 10% formalin buffer. The hippocampus region was cut into a coronal shape as a slice having a thickness of 3 to 4 mm, and a section was prepared after embedding in paraffin. Slices were stained with hematoxylin & eosin.
Ischemic cell damage was evaluated by dividing into 4 stages of 0-3. 0 (−): normal neuron, 1 (+): several neuronal cell disorders (one or several neuron disorders), 2 (++): many neuronal disorders, 3 (++++): Most nerve cell disorders.
Specimen
The specimen was suspended in gum arabic, and 100 mg / kg was intraperitoneally administered immediately after the end of ischemia.
result
In the sham-operated group, gerbil hippocampal CA1 neurons were not damaged at all, but in a 3 minute bilateral common carotid artery occlusion model, hippocampal CA1 neurons were clearly impaired by light microscopy findings. However, the collapse and disappearance of hippocampal CA1 neurons were suppressed by intraperitoneal administration of the compound of the present invention. The results are shown in Table 8.
Figure 0003884476
Industrial applicability
NGF is responsible for the survival and function maintenance of certain types of nerve cells, and has a degenerative repair / protective action. The pyridine derivative of the present invention exhibits one or both of NGF production promoting activity and survival prolonging activity of cultured cerebral cortical neurons. Therefore, the pyridine derivative of the present invention is expected to act on nerve cells directly or indirectly in a living body and exhibit an improvement / treatment effect on neuropathy associated with neurodegeneration. For example, it can be used as an agent for ameliorating or treating symptoms / diseases associated with traumatic properties, drug properties such as alcohol and anticancer drugs, inflammatory properties, metabolic properties seen in diabetes, and idiopathic peripheral neurodegeneration. Symptoms and diseases associated with central neurodegeneration, such as Alzheimer's type and cerebrovascular dementia, Down's syndrome, Parkinson's disease, Huntington's chorea, sequelae such as cerebral ischemia / cerebral infarction / cerebral hemorrhage / head trauma, amnesia It can also be used as an agent for improving / treating spinal neuroparalysis.

Claims (8)

下記式（１）
Figure 0003884476
（式中、Ｒ1はメチル基、ニトロ基、アミノ基及びアセトアミド基からなる群より選ばれた一種または二種以上の置換基で置換されたフェニル基、またはイミダゾリル基を示し、Ｒ2は水素原子、ニトロ基、アミノ基、またはジメチルアミノ基を示す。）で表されるピリジン誘導体またはその塩。Following formula (1)
Figure 0003884476
(In the formula, R 1 represents a phenyl group substituted with one or two or more substituents selected from the group consisting of a methyl group, a nitro group, an amino group, and an acetamide group, or an imidazolyl group, and R 2 represents a hydrogen atom. atom, a nitro group, an amino group or a pyridine derivative or a salt thereof.) showing a dimethylamino group. Ｒ1がメチル基で置換されたフェニル基であり、Ｒ2が水素原子、ニトロ基またはアミノ基である請求項第１項記載のピリジン誘導体またはその塩。The pyridine derivative or a salt thereof according to claim 1, wherein R 1 is a phenyl group substituted with a methyl group, and R 2 is a hydrogen atom, a nitro group or an amino group. Ｒ1が、ニトロ基、アミノ基もしくはアセトアミド基で置換されたフェニル基、あるいはイミダゾリル基であり、Ｒ2が水素原子である請求項第１項記載のピリジン誘導体またはその塩。The pyridine derivative or a salt thereof according to claim 1, wherein R 1 is a phenyl group substituted with a nitro group, an amino group or an acetamide group, or an imidazolyl group, and R 2 is a hydrogen atom. 医薬組成物の活性成分として使用するための請求項第１項から第３項のいずれかに記載のピリジン誘導体及びその塩。The pyridine derivative and the salt thereof according to any one of claims 1 to 3, for use as an active ingredient of a pharmaceutical composition. 請求項第１項から第３項のいずれかに記載のピリジン誘導体またはその塩を活性成分として含有する、神経変性疾患の改善もしくは治療用に用いる医薬組成物。A pharmaceutical composition used for improving or treating a neurodegenerative disease, comprising the pyridine derivative or a salt thereof according to any one of claims 1 to 3 as an active ingredient. 神経成長因子産生促進作用及び／又は神経栄養因子作用を発揮する請求項第５項記載の医薬組成物。The pharmaceutical composition according to claim 5, which exhibits a nerve growth factor production promoting action and / or a neurotrophic factor action. 神経変性疾患の改善もしくは治療用に用いる医薬組成物を製造するための、請求項第１項から第３項のいずれかに記載のピリジン誘導体またはその塩の使用。Use of the pyridine derivative or a salt thereof according to any one of claims 1 to 3, for producing a pharmaceutical composition used for improvement or treatment of a neurodegenerative disease. 医薬組成物が神経成長因子産生促進作用及び／又は神経栄養因子作用を発揮するものである請求項第７項記載の使用。Pharmaceutical composition for use according to claim 7 wherein wherein is to exert nerve growth factor production promoting action and / or neurotrophic factor activity.
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