JP4226681B2 - Method for producing pyridinium compound and compound therefor - Google Patents
Method for producing pyridinium compound and compound therefor Download PDFInfo
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- JP4226681B2 JP4226681B2 JP09276898A JP9276898A JP4226681B2 JP 4226681 B2 JP4226681 B2 JP 4226681B2 JP 09276898 A JP09276898 A JP 09276898A JP 9276898 A JP9276898 A JP 9276898A JP 4226681 B2 JP4226681 B2 JP 4226681B2
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- 0 C*(C1=C2SC[C@]1*)C(C)=CC=C2[Mn] Chemical compound C*(C1=C2SC[C@]1*)C(C)=CC=C2[Mn] 0.000 description 3
- WWUVPKJYNTWYIZ-UHFFFAOYSA-N NC(CSC(C(C1O)O)OC(CO)C1O)C(O)=O Chemical compound NC(CSC(C(C1O)O)OC(CO)C1O)C(O)=O WWUVPKJYNTWYIZ-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Description
【０００１】
【発明の属する技術分野】
本発明は、ピリジニウム化合物の製造方法及びそのための化合物に関するものである。
【０００２】
【従来の技術】
周知のように、糖と蛋白アミンとのメイラード反応については、まずそれら糖と蛋白アミンとの非酵素的反応（グリケーション）によってシッフ塩基が形成され、このシッフ塩基からアマドリ転位反応により比較的短期間にメイラード反応前期生成物であるケトアミンが形成され、更に種々の段階をへてメイラード反応後期生成物が産生される。
【０００３】
このメイラード反応前期生成物としては、臨床的には糖化ヘモグロビン（ＨｂＡｌｃ）や糖化アルブミン（フルクトサミン）が、血糖コントロールの指標として利用されている。
【０００４】
一方、メイラード反応後期生成物は、コラーゲン、神経ミエリンや水晶体等生体の代謝回転の遅い蛋白で生成され、長期高血糖状態（糖尿病）により増加することも知られており、糖尿病において最も特徴的変化である持続性高血糖状態が、なぜ糖尿病に特異的である慢性合併症を引き起こすかを説明する仮説として、このメイラード反応後期生成物がその成因して注目されると共に、その産生を阻害することによって合併症の発症や進展を阻止し得る可能性が示唆されてきた。
【０００５】
又、メイラード反応後期生成物の血中、尿中や組織中の濃度を測定することによる、合併症の診断への可能性が期待されている。
【０００６】
しかしながら、これまでに開発されたメイラード反応後期生成物測定法より得られた知見は、生体内メイラード反応後期生成物の増量と各種組織障害との間には密接な因果関係があることを強く示唆しているが、未だ生体内の主要メイラード反応後期生成物の化学構造は不明である。
【０００７】
本発明の発明者の一部は、上記のようなメイラード反応後期生成物の現状に鑑み、各種組織障害との間に密接な因果関係を有する生体内メイラード反応後期生成物の構造を特定することを目的として研究を続けた結果、新規な生体内メイラード反応後期生成物を発見し、更に研究を続行して当該化合物が式、
【化９】
【０００８】
【発明が解決しようとする課題】
上記のように、式（２）で表されるピリジニウム化合物が、糖尿病又は腎不全に伴う合併症の診断試薬として有用である以上、所定の量の当該化合物を効率的に生産することが必要となるが、従来は式（２）で表されるピリジニウム化合物のかかる製造方法は知られていなかった。
【０００９】
【課題を解決するための手段】
本発明は、上記のような従来技術の現状に鑑みてなされたもので、本発明はまず、式（１）
【化１０】
で表される化合物を加水分解することを特徴とする、式（２）
【化１１】
【００１０】
本発明は又、式（１）
【化１２】
で表される化合物を加水分解して、式（３）
【化１３】
【化１４】
【００１１】
本発明は更に、式（４）
【化１５】
【化１６】
【００１２】
本発明は更に又、式（１）
【化１７】
で表されることを特徴とする、ピリジニウム化合物の製造のための化合物を提供する。
【００１３】
【発明の実施の態様】
以下、本発明を詳細に説明する。
【００１４】
本発明の製造方法の目的化合物である上記ピリジニウム化合物（２）は、一種のメイラード反応後期生成物であり、例えば、アルブミン、リゾチーム、カゼイン、リボヌクレアーゼやグロブリン等の蛋白質と、グルコース、ダイアセチル、グリオキザールやフルクトース等のカルボニル化合物との、非酵素的反応によって産生されるものである。
【００１５】
上記ピリジニウム化合物（２）は、ウサギ赤血球とグルコースとを３７℃で２週間反応させた系の反応液を４８時間透析して加水分解した後、ＯＤＳ−５カラムによる高速液体クロマトグラフィーにより、励起波長３４０ｎｍ、蛍光波長４０２ｎｍにより検出され、その生成量はグルコースの濃度と反応時間並びに反応液の褐変化に比例して増加し、その生成はメイラード反応阻害物質であるアミノグアニジンによって阻害され、又、ウシ血清アルブミンとグルコースとの系においても、同様に生成するものである。
【００１６】
上記ピリジニウム化合物（２）の構造は、ウシ血清アルブミンとグルコースの反応で生成したメイラード反応後期生成物を加水分解した後、蛍光波長を利用した高速液体クロマトグラフィーにより分取した後、グリセロールとニトロベンジルアルコールとの混合物をマトリクスとしたＦＡＢ−マススペクトルを用いて測定することにより、まずその分子量が２１２と決定された。
【００１７】
次いで、高分解能マススペクトルを利用することにより、上記ピリジニウム化合物（２）の組成式がＣ9Ｈ10Ｏ3Ｎ1Ｓ1と決定され、更に二次元を含むＮＭＲ解析の結果、上記メイラード反応後期生成物は、式
【化１８】
【００１８】
尚、上記ピリジニウム化合物（２）は、牛の肝臓より蛍光を有する加水分解物としてすでに単離されているものである。
【００１９】
而して、本発明は上記ピリジニウム化合物（２）を以下のようにして製造するものである。
【００２０】
即ち、本発明の製造方法では、式（１）
【化１９】
【００２１】
上記式（１）中、Ａｃはアセチル基等のアシル基を、Ｒはメチル基、エチル基、プロピル基やブチル基等の低級アルキル基をそれぞれ表している。
【００２２】
上記本発明の化合物は、Elofsson, M; Walse B, ; Kihlberg, J. Tetrahedron Lett, 1991, 32, 7613に記載の方法に準じ、グルコースペンタアセテートと、式（５）
【化２０】
【化２１】
【００２３】
尚、上記式（５）の化合物におけるＦｍｏｃは、以下のような構造の保護基を表している。
【化２２】
本発明の製造方法では、上記化合物（１）を加水分解することにより、上記ピリジニウム化合物（２）を得るものであるが、この加水分解は、例えば６Ｎ塩酸等による酸性条件下、必要に応じて加熱することにより行うことができる。
【００２５】
尚、上記ピリジニウム化合物（２）の製造方法としては、Acta, Chem, Scand., 23, 371, 1969にも報告があるが、比較的長い工程によるもので、本発明の製造方法のように１工程で上記ピリジニウム化合物（２）を製造する方法は知られていない。
【００２６】
又、上記ピリジニウム化合物（２）は、上記式（１）で表される化合物を加水分解して、一旦、式（３）
【化２３】
【００２７】
上記の方法において、前者の加水分解は、例えばメタノール等の溶媒中で、リジウムメトキシド等によるアルカリ性条件下で行うことができ、後者の加水分解は、例えば６Ｎ塩酸等による酸性条件下、必要に応じて加熱することにより行うことができる。
【００２８】
更に、上記ピリジニウム化合物（２）は、式（４）
【化２４】
【００２９】
上記の方法における加水分解は、例えば６Ｎ塩酸等による酸性条件下、必要に応じて加熱することにより行うことができる。
【００３０】
上記式（４）で表される化合物は、H. Masaki, A. Imahoriの方法(JP. 09067226 A2)によって合成することができ、この式（４）で表される化合物は、上記式（３）で表される化合物における糖部分をガラクトースに変更したものである。
【００３１】
尚、本発明の製造方法により得られた上記ピリジニウム化合物（２）の物理化学的データは、文献記載の値と一致した。
【００３２】
本発明の製造方法により得られた上記ピリジニウム化合物（２）は、糖尿病病態において大量に産生して腎、腱、皮膚、神経等の組織に沈着すると共に、腎機能の低下に伴い尿中に大量に排泄されてくることから、糖尿病病態のバイオマーカ一として適用することが可能である。
【００３３】
【実施例】
以下に本発明を実施例に基づいて詳細に説明するが、これらは本発明を何ら限定するものではない。
【００３４】
実施例１
N-(9-Fluorenylmethoxycarbonyl)-S-triphenylmethyl-L-cysteine methyl esterの合成
メタノール９ｍｌとベンゼン３０ｍｌの混合液に、１．７７ｇ（３ｍｍｏｌ）のN-(9-Fluorenylmethoxycarbonyl)-S-triphenylmethyl-L-cysteineを溶解し、この溶液にトリメチルシリルジアゾメタン５．５ｍｌ（４．８ｍｍｏｌ）を加えて、室温で１５分間撹拌した。反応溶液より溶媒を減圧で留去することにより、粗メチルエステルが得られ、これを精製することなく使用した。
1ＨＭＭＲ（２７０ＭＨｚ，ＣＤＣｌ3，ＴＭＳ）：δ２．６６（ｄ，Ｊ＝５．３Ｈｚ，２Ｈ）、３．７１（ｓ，３Ｈ）、４．２３（ｔ，Ｊ＝６．８Ｈｚ，１Ｈ）、４．３０〜４．３９（ｍ，３Ｈ）、５．２３（ｄ，Ｊ＝８．３Ｈｚ，１Ｈ）、７．１８〜７．３２（ｍ，１１Ｈ）、７．３８〜７．４１（ｍ，８Ｈ）、７．６０（ｄ，Ｊ＝６．３Ｈｚ，２Ｈ）、７，７６（ｄ，Ｊ＝７．３Ｈｚ，２Ｈ）
【００３５】
N-(9-Fluorenylmethoxycarbonyl)-L-cysteine methyl ester［式（５）においてR=CH3の化合物］の合成
ジクロロメタン１．５ｍｌ中に粗N-(9-Fluorenylmethoxycarbonyl)-S-triphenylmethyl-L-cysteine methyl esterを溶解した溶液に、４１９ｍｇ（３．６ｍｍｏｌ）のトリエチルシランと１．５ｍｌのトリフルオロ酢酸を加え、混合溶液を室温で１時間撹拌し、溶媒を留去した。残査をシリカゲルカラムクロマトグラフィによりヘキサン／酢酸エチル＝４：１→２：１で精製し、１．０４ｇ（９７％）の目的化合物を得た。
1ＨＭＭＲ（２７０ＭＨｚ，ＣＤＣｌ3，ＴＭＳ）：δ１．３６（ｔ，Ｊ＝９．１Ｈｚ，１Ｈ）、２．９８〜３．０２（ｍ，２Ｈ）、３．８０（ｓ，３Ｈ）、４．２４（ｔ，Ｊ＝６．８Ｈｚ，１Ｈ）、４．４４（ｄ，Ｊ＝７．９Ｈｚ，２Ｈ）、４．６７（ｄｔ，Ｊ＝７．４，３．８Ｈｚ，１Ｈ）、５．６８（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）、７．２８〜７．４４（ｍ，４Ｈ）、７．６１（ｄ，Ｊ＝７．３Ｈｚ，２Ｈ）、７．７７（ｄ，Ｊ＝７．３Ｈｚ，２Ｈ）
13ＣＮＭＲ（６７．８ＭＨｚ，ＣＤＣｌ3）δ２７．０，４７．１，５２．８，５５．２，６７．０，１２０．０，１２４．９８，１２５．０１，１２７．０，１２７．７，１４１．３，１４３．６，１４３．７，１５５．６，１７０．４
【００３６】
N-(9-Fluorenylmethoxycarbonyl)-S-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-L-cysteine methyl ester［式（６）においてAc=COCH3、R=CH3の化合物］の合成
1,2,3,4,6-penta-O-acetyl-b-D-glucopyranose１．５６ｇ（４ｍｍｏｌ）とN-(9-Fluorenylmethoxycarbonyl)-L-cysteine methyl ester［式（５）においてR=CH3の化合物］１．００ｇ（２．８ｍｍｏｌ）との２０ｍｌジクロルメタン溶液に、四塩化スズ０．４８ｍｌ（４．１ｍｍｏｌ）を添加した。混合溶液を室温で１時間撹拌し、更に1,2,3,4,6-penta-O-acetyl-b-D-glucopyranose１．５６ｇ（４ｍｍｏｌ）と四塩化スズ０．４８ｍｌ（４．１ｍｍｏｌ）を加えた。室温で１時間撹拌後、反応溶液をジクロロメタンで希釈し、１０％塩酸、水及び塩水で水洗し、硫酸マグネシウムで乾燥後、溶媒を留去した。残査をシリカゲルカラムクロマトグラフィ（ヘキサン／酢酸エチル＝３：２）で製精し、１．６９ｇ（８８％）の目的化合物を得た。
1ＨＭＭＲ（２７０ＭＨｚ，ＣＤＣｌ3，ＴＭＳ）：δ２．０１（ｓ，３Ｈ）、２．０２（ｓ，６Ｈ）、２．０４（ｓ，３Ｈ）、２．９９（ｄｄ，Ｊ＝１４．２，６．８Ｈｚ，１Ｈ）、３．２６（ｄｄ，Ｊ＝１４．２，４．０Ｈｚ，１Ｈ）、３．６７（ｄｔ，Ｊ＝９．９，４．０Ｈｚ，１Ｈ）、３．７５（ｓ，３Ｈ），４．０９〜４．１５（ｍ，２Ｈ）、４．２４（ｂｔ，Ｊ＝９．９，９．４，１Ｈ）、４．３６〜４．６１（ｍ，４Ｈ）、５．０１（ｄｄ，Ｊ＝９．９，９．４Ｈｚ，１Ｈ）、５．０６（ｄｄ，Ｊ＝９．９，９．４，１Ｈ）、５．２３（ｔ，Ｊ＝９．４Ｈｚ，１Ｈ）、５，９３（ｄ，Ｊ＝７．９Ｈｚ，１Ｈ）、７．２８〜７．３４（ｍ，４Ｈ）、７．５９〜７．６１（ｍ，２Ｈ）、７．７６（ｄ，Ｊ＝６．９Ｈｚ，２Ｈ）
13ＣＮＭＲ（６７．８ＭＨｚ，ＣＤＣｌ3）δ２０．４，２０．５，３１．８，４７．０，５２．６，５３．８，６１．９，６６．８，６８．１，６９．５，７４．３，７５．９，８２．９，１１９．９，１２４．８５，１２４．９１，１２７．０，１２７．６，１４１．１，１４３．５８，１４３．６１，１５５．７，１６９．２，１６９．３，１６９．９，１７０．４，１７０．７
【００３７】
S-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-L-cysteine methyl ester［式（１）においてAc=COCH3、R=CH3の化合物］の合成
ＤＭＦ（１０ｍｌ）中、N-(9-Fluorenylmethoxycarbonyl)-S-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-L-cysteine methyl ester３９０ｍｇ（０．５７ｍｍｏｌ）を、２０％ピペリジンで１時間、室温下に処理した。混合溶液から減圧で溶媒を留去した後、酢酸エチルとエーテル１：１の混合溶液で希釈した。水と塩水で水洗し、硫酸マグネシウムで乾燥後、溶媒を留去し、残査をシリカゲルカラムクロマトグラフィ（クロロホルム／メタノール＝４０：１）製精し、２４３ｍｇ（９１％）の目的化合物を得た。
1ＨＭＭＲ（２７０ＭＨｚ，ＣＤＣｌ3，ＴＭＳ）：δ１．７７（ｂｓ，２Ｈ）、２．０１（ｓ，３Ｈ）、２．０３（ｓ，３Ｈ）、２．０７（ｓ，３Ｈ）、２．０９（ｓ，３Ｈ）、２．８３（ｄｄ，Ｊ＝１３．９，７．９Ｈｚ，１Ｈ）、３．１７（ｄｄ，Ｊ＝１３．９，４．３Ｈｚ，１Ｈ）、３．６９〜３．７５（ｍ，２Ｈ），３．７５（ｓ，３Ｈ）、４．１６（ｄｄ，Ｊ＝１２．５，２．６Ｈｚ，１Ｈ）、４．２４（ｄｄ，Ｊ＝１２．５，４．６Ｈｚ，１Ｈ）、４．５９（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ）、５．０４（ｔ，Ｊ＝９．６Ｈｚ，１Ｈ）、５，０９（ｔ，Ｊ＝９．６Ｈｚ，１Ｈ）、５．２３（ｔ，Ｊ＝９．４Ｈｚ，２Ｈ）
13ＣＮＭＲ（６７．８ＭＨｚ，ＣＤＣｌ3）δ２０．５，２０．６，３４．８，５２．３，５４．７，６１．９，６８．１，６９．６，７３．７，７５．９，８３．５，１６９．４，１７０．１，１７０．６，１７３．９
【００３８】
8-hydroxy-5-methyldihydrothiazolo[3,2-a]pyridinium-3-carboxylate［化合物（２）］の合成
ミクロチューブにS-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-L-cysteine methyl ester［式（１）においてAc=COCH3、R=CH3の化合物］１．５ｍｇを入れ、６Ｎ塩酸で１１０℃、２４時間の気相加水分解を行った後、フィルター処理し、ＯＤＳ−ＨＧ−５カラムを用い、３％アセトニトリル／０．１％トリフルオロ酢酸を流速２ｍｌ／ｍｉｎで流し、励起波長３４０ｎｍ、蛍光波長４０２ｎｍにて高速液体クロマトグラフィーにおいて、目的化合物に相当する溶出時間１０分のピークを分取した。これを繰り返した結果、S-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl-L-cysteine methyl ester［式（１）においてAc=COCH3、R=CH3の化合物］２２．５ｍｇから、精製された化合物（２）０．９ｍｇ（収率４．３５％）を得た。
【００３９】
実施例２
3-S-(b-D-glucopyranosyl)-L-cysteine ［化合物（３）］の合成
２００ｍｇ（０．３ｍｍｏｌ）のS-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-L-cysteine methyl ester［式（１）においてAc=COCH3、R=CH3の化合物］の１ｍｌメタノール溶液に、メタノール０．４ｍｌ中の０．１Ｎナトリウムメトキシドを４℃で滴下し、同温度で４８時間撹拌した。アンバーリスト１５を加えて中和し、次いで濾過して濾液を濃縮した。９３ｍｇの残渣を少量のメタノールに溶解し、塩化メチレンを加えることにより固体１２ｍｇを得た。母液を濃縮し、再度メタノール−塩化メチレンで処理することにより、２７ｍｇの固定を得た。両固体を合わせることにより、３９ｍｇの目的化合物を２８％の収率で得た。得られた目的化合物の1ＨＭＭＲは文献（Monsigny, M.L.P.; Delay, D.; Vaculik, M. Carbohydr. Res. 1977, 59, 589）記載の値と一致した。
【００４０】
3-S-(b-D-glucopyranosyl)-L-cysteine ［化合物（３）］１．５ｍｇを、実施例１と同様に加水分解、後処理して、化合物（３）３０ｍｇから、精製された化合物（２）２．５ｍｇ（収率１１．２３％）を得た。
【００４１】
実施例３
S-D-galactopyranosyl-L-cysteine ［化合物（４）］１．５ｍｇを、実施例１と同様に加水分解、後処理して、化合物（３）３０ｍｇから、精製された化合物（２）２．４ｍｇ（収率１０．８２％）を得た。尚、化合物（４）は上記文献に記載の方法に準じて合成した。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a pyridinium compound and a compound therefor.
[0002]
[Prior art]
As is well known, in the Maillard reaction between a sugar and a protein amine, first, a Schiff base is formed by a non-enzymatic reaction (glycation) between the sugar and the protein amine, and this Schiff base undergoes a relatively short time by an Amadori rearrangement reaction. In the meantime, ketoamine which is the early product of Maillard reaction is formed, and the late product of Maillard reaction is produced through various stages.
[0003]
Clinically, glycated hemoglobin (HbAlc) or glycated albumin (fructosamine) is used as an index of blood glucose control as the Maillard reaction early product.
[0004]
On the other hand, late products of Maillard reaction are known to increase with long-term hyperglycemia (diabetes), and are produced by proteins with slow biological turnover, such as collagen, neuromyelin and lens. As a hypothesis explaining why persistent hyperglycemia, which is the cause of chronic complications specific to diabetes, this late product of Maillard reaction is noted as its origin and inhibits its production Has suggested the possibility of preventing the onset and progression of complications.
[0005]
In addition, the possibility of diagnosing complications by measuring the concentration of the late Maillard reaction product in blood, urine, or tissue is expected.
[0006]
However, the findings obtained from the late Maillard reaction product measurement method developed so far strongly suggest that there is a close causal relationship between the increase in in vivo Maillard reaction late product and various tissue disorders. However, the chemical structure of the late product of the major Maillard reaction in vivo is still unknown.
[0007]
Some of the inventors of the present invention identify the structure of the in-vivo Maillard reaction late product having a close causal relationship with various tissue disorders in view of the current state of the Maillard reaction late product as described above. As a result of continuing research for the purpose of, we discovered a novel late product of Maillard reaction in vivo, and continued further research to find that the compound has the formula:
[Chemical 9]
[0008]
[Problems to be solved by the invention]
As described above, since the pyridinium compound represented by the formula (2) is useful as a diagnostic reagent for complications associated with diabetes or renal failure, it is necessary to efficiently produce a predetermined amount of the compound. However, conventionally, such a method for producing a pyridinium compound represented by the formula (2) has not been known.
[0009]
[Means for Solving the Problems]
The present invention has been made in view of the current state of the prior art as described above.
[Chemical Formula 10]
Wherein the compound represented by formula (2) is hydrolyzed.
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[0010]
The present invention also provides formula (1)
Embedded image
The compound represented by the formula (3)
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[0011]
The present invention further provides formula (4)
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[0012]
The present invention still further provides formula (1)
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The compound for manufacture of a pyridinium compound characterized by these is provided.
[0013]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in detail.
[0014]
The pyridinium compound (2), which is the target compound of the production method of the present invention, is a kind of late product of the Maillard reaction, such as proteins such as albumin, lysozyme, casein, ribonuclease and globulin, and glucose, diacetyl, and glyoxal. It is produced by a non-enzymatic reaction with a carbonyl compound such as fructose.
[0015]
The pyridinium compound (2) was prepared by dialysis of a reaction solution of a system in which rabbit erythrocytes and glucose were reacted at 37 ° C. for 2 weeks for 48 hours, followed by hydrolysis, followed by excitation wavelength by high performance liquid chromatography using an ODS-5 column. 340 nm, fluorescence wavelength 402 nm, and the amount of production increases in proportion to the concentration of glucose and reaction time and browning of the reaction solution, and its production is inhibited by aminoguanidine, a Maillard reaction inhibitor, It is produced similarly in the system of serum albumin and glucose.
[0016]
The structure of the pyridinium compound (2) is obtained by hydrolyzing a late product of the Maillard reaction generated by the reaction of bovine serum albumin and glucose, and then fractionating the product by high performance liquid chromatography using a fluorescence wavelength, followed by glycerol and nitrobenzyl. The molecular weight was first determined to be 212 by measurement using a FAB-mass spectrum with a mixture of alcohol as a matrix.
[0017]
Next, by using a high-resolution mass spectrum, the composition formula of the pyridinium compound (2) was determined as C 9 H 10 O 3 N 1 S 1, and as a result of NMR analysis including two dimensions, the late stage of the Maillard reaction The product has the formula:
[0018]
The pyridinium compound (2) has already been isolated as a hydrolyzate having fluorescence from bovine liver.
[0019]
Thus, the present invention is to produce the pyridinium compound (2) as follows.
[0020]
That is, in the production method of the present invention, the formula (1)
Embedded image
[0021]
In the above formula (1), Ac represents an acyl group such as an acetyl group, and R represents a lower alkyl group such as a methyl group, an ethyl group, a propyl group, or a butyl group.
[0022]
The compound of the present invention is prepared by reacting glucose pentaacetate with formula (5) according to the method described in Elofsson, M; Walse B,; Kihlberg, J. Tetrahedron Lett, 1991, 32, 7613.
Embedded image
Embedded image
[0023]
In addition, Fmoc in the compound of the said Formula (5) represents the protecting group of the following structures.
Embedded image
In the production method of the present invention, the above-mentioned pyridinium compound (2) is obtained by hydrolyzing the above-mentioned compound (1). This hydrolysis is carried out as necessary under acidic conditions such as 6N hydrochloric acid. This can be done by heating.
[0025]
The production method of the pyridinium compound (2) is also reported in Acta, Chem, Scand., 23, 371, 1969, but it is a relatively long process. A method for producing the pyridinium compound (2) in a process is not known.
[0026]
In addition, the pyridinium compound (2) hydrolyzes the compound represented by the formula (1), and once the formula (3)
Embedded image
[0027]
In the above method, the former hydrolysis can be carried out under alkaline conditions such as with lithium methoxide in a solvent such as methanol, and the latter hydrolysis is necessary under acidic conditions such as with 6N hydrochloric acid. It can carry out by heating according to it.
[0028]
Furthermore, the pyridinium compound (2) has the formula (4)
Embedded image
[0029]
Hydrolysis in the above method can be performed by heating as necessary under acidic conditions such as with 6N hydrochloric acid.
[0030]
The compound represented by the above formula (4) can be synthesized by the method of H. Masaki, A. Imahori (JP. 09067226 A2). The compound represented by the above formula (4) is synthesized by the above formula (3). The sugar moiety in the compound represented by) is changed to galactose.
[0031]
In addition, the physicochemical data of the said pyridinium compound (2) obtained by the manufacturing method of this invention corresponded with the value described in literature.
[0032]
The pyridinium compound (2) obtained by the production method of the present invention is produced in a large amount in a diabetic state and deposited in tissues such as the kidney, tendon, skin, and nerve, and a large amount in the urine with a decrease in renal function. Therefore, it can be applied as a biomarker for diabetic conditions.
[0033]
【Example】
The present invention will be described in detail below based on examples, but these do not limit the present invention.
[0034]
Example 1
Synthesis of N- (9-Fluorenylmethoxycarbonyl) -S-triphenylmethyl-L-cysteine methyl ester To a mixture of 9 ml of methanol and 30 ml of benzene, 1.77 g (3 mmol) of N- (9-Fluorenylmethoxycarbonyl) -S-triphenylmethyl-L- Cysteine was dissolved, and 5.5 ml (4.8 mmol) of trimethylsilyldiazomethane was added to the solution, followed by stirring at room temperature for 15 minutes. The solvent was distilled off from the reaction solution under reduced pressure to obtain a crude methyl ester, which was used without purification.
1 HMMR (270 MHz, CDCl 3 , TMS): δ 2.66 (d, J = 5.3 Hz, 2H), 3.71 (s, 3H), 4.23 (t, J = 6.8 Hz, 1H), 4.30 to 4.39 (m, 3H), 5.23 (d, J = 8.3 Hz, 1H), 7.18 to 7.32 (m, 11H), 7.38 to 7.41 (m , 8H), 7.60 (d, J = 6.3 Hz, 2H), 7, 76 (d, J = 7.3 Hz, 2H)
[0035]
Synthesis of N- (9-Fluorenylmethoxycarbonyl) -L-cysteine methyl ester [compound of R = CH 3 in formula (5)] Crude N- (9-Fluorenylmethoxycarbonyl) -S-triphenylmethyl-L-cysteine in 1.5 ml of dichloromethane To the solution in which methyl ester was dissolved, 419 mg (3.6 mmol) of triethylsilane and 1.5 ml of trifluoroacetic acid were added, the mixed solution was stirred at room temperature for 1 hour, and the solvent was distilled off. The residue was purified by silica gel column chromatography with hexane / ethyl acetate = 4: 1 → 2: 1 to obtain 1.04 g (97%) of the desired compound.
1 HMMR (270 MHz, CDCl 3 , TMS): δ 1.36 (t, J = 9.1 Hz, 1H), 2.98 to 3.02 (m, 2H), 3.80 (s, 3H), 4. 24 (t, J = 6.8 Hz, 1H), 4.44 (d, J = 7.9 Hz, 2H), 4.67 (dt, J = 7.4, 3.8 Hz, 1H), 5.68 (D, J = 7.4 Hz, 1H), 7.28-7.44 (m, 4H), 7.61 (d, J = 7.3 Hz, 2H), 7.77 (d, J = 7. 3Hz, 2H)
13 C NMR (67.8 MHz, CDCl 3 ) δ 27.0, 47.1, 52.8, 55.2, 67.0, 120.0, 124.98, 125.01, 127.0, 127.7, 141.3, 143.6, 143.7, 155.6, 170.4
[0036]
N- (9-Fluorenylmethoxycarbonyl) -S- (2,3,4,6-tetra-O-acetyl-bD-glucopyranosyl) -L-cysteine methyl ester [Ac = COCH 3 in formula (6), R = CH 3 Of Compound]
1,2,3,4,6-penta-O-acetyl-bD-glucopyranose 1.56 g (4 mmol) and N- (9-Fluorenylmethoxycarbonyl) -L-cysteine methyl ester [compound with R = CH 3 in formula (5) ] To a 20 ml dichloromethane solution with 1.00 g (2.8 mmol), 0.48 ml (4.1 mmol) of tin tetrachloride was added. The mixed solution was stirred at room temperature for 1 hour, and 1.56 g (4 mmol) of 1,2,3,4,6-penta-O-acetyl-bD-glucopyranose and 0.48 ml (4.1 mmol) of tin tetrachloride were added. . After stirring at room temperature for 1 hour, the reaction solution was diluted with dichloromethane, washed with 10% hydrochloric acid, water and brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3: 2) to obtain 1.69 g (88%) of the target compound.
1 HMMR (270 MHz, CDCl 3 , TMS): δ 2.01 (s, 3H), 2.02 (s, 6H), 2.04 (s, 3H), 2.99 (dd, J = 14.2, 6.8 Hz, 1H), 3.26 (dd, J = 14.2, 4.0 Hz, 1H), 3.67 (dt, J = 9.9, 4.0 Hz, 1H), 3.75 (s) 3H), 4.09 to 4.15 (m, 2H), 4.24 (bt, J = 9.9, 9.4, 1H), 4.36 to 4.61 (m, 4H), 5 .01 (dd, J = 9.9, 9.4 Hz, 1H), 5.06 (dd, J = 9.9, 9.4, 1H), 5.23 (t, J = 9.4 Hz, 1H) ), 5, 93 (d, J = 7.9 Hz, 1H), 7.28-7.34 (m, 4H), 7.59-7.61 (m, 2H), 7.76 (d, J = 6.9Hz, 2H)
13 C NMR (67.8 MHz, CDCl 3 ) δ 20.4, 20.5, 31.8, 47.0, 52.6, 53.8, 61.9, 66.8, 68.1, 69.5 74.3, 75.9, 82.9, 119.9, 124.85, 124.91, 127.0, 127.6, 141.1, 143.58, 143.61, 155.7, 169. 2, 169.3, 169.9, 170.4, 170.7
[0037]
Synthesis of S- (2,3,4,6-tetra-O-acetyl-bD-glucopyranosyl) -L-cysteine methyl ester [Compound of Ac = COCH 3 and R = CH 3 in Formula (1)] DMF (10 ml ) 390 mg (0.57 mmol) of N- (9-Fluorenylmethoxycarbonyl) -S- (2,3,4,6-tetra-O-acetyl-bD-glucopyranosyl) -L-cysteine methyl ester with 20% piperidine Treated at room temperature for hours. After the solvent was distilled off from the mixed solution under reduced pressure, the mixture was diluted with a mixed solution of ethyl acetate and ether 1: 1. The extract was washed with water and brine, dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol = 40: 1) to obtain 243 mg (91%) of the target compound.
1 HMMR (270 MHz, CDCl 3 , TMS): δ 1.77 (bs, 2H), 2.01 (s, 3H), 2.03 (s, 3H), 2.07 (s, 3H), 2.09 (S, 3H), 2.83 (dd, J = 13.9, 7.9 Hz, 1H), 3.17 (dd, J = 13.9, 4.3 Hz, 1H), 3.69-3. 75 (m, 2H), 3.75 (s, 3H), 4.16 (dd, J = 12.5, 2.6 Hz, 1H), 4.24 (dd, J = 12.5, 4.6 Hz) , 1H), 4.59 (d, J = 9.9 Hz, 1H), 5.04 (t, J = 9.6 Hz, 1H), 5,09 (t, J = 9.6 Hz, 1H), 5 .23 (t, J = 9.4 Hz, 2H)
13 C NMR (67.8 MHz, CDCl 3 ) δ 20.5, 20.6, 34.8, 52.3, 54.7, 61.9, 68.1, 69.6, 73.7, 75.9, 83.5, 169.4, 170.1, 170.6, 173.9
[0038]
Synthesis of 8-hydroxy-5-methyldihydrothiazolo [3,2-a] pyridinium-3-carboxylate [compound (2)] S- (2,3,4,6-tetra-O-acetyl-bD-glucopyranosyl ) -L-cysteine methyl ester [Compound of Ac = COCH3, R = CH3 in formula (1)] 1.5 mg was added and subjected to gas phase hydrolysis with 6N hydrochloric acid at 110 ° C. for 24 hours, followed by filtration. This corresponds to the target compound in high performance liquid chromatography using an ODS-HG-5 column and flowing 3% acetonitrile / 0.1% trifluoroacetic acid at a flow rate of 2 ml / min and an excitation wavelength of 340 nm and a fluorescence wavelength of 402 nm. A peak with an elution time of 10 minutes was collected. As a result of repeating this, S- (2,3,4,6-tetra-O-acetyl-bD-glucopyranosyl-L-cysteine methyl ester [compound of Ac = COCH 3 and R = CH 3 in formula (1)] From 22.5 mg, 0.9 mg (yield 4.35%) of the purified compound (2) was obtained.
[0039]
Example 2
Synthesis of 3-S- (bD-glucopyranosyl) -L-cysteine [Compound (3)] 200 mg (0.3 mmol) of S- (2,3,4,6-tetra-O-acetyl-bD-glucopyranosyl)- To a 1 ml methanol solution of L-cysteine methyl ester [compound of Ac = COCH 3 and R = CH 3 in formula (1)], 0.1N sodium methoxide in 0.4 ml of methanol was added dropwise at 4 ° C. For 48 hours. Amberlyst 15 was added to neutralize, then filtered and the filtrate was concentrated. 93 mg of the residue was dissolved in a small amount of methanol, and methylene chloride was added to obtain 12 mg of a solid. The mother liquor was concentrated and treated with methanol-methylene chloride again to obtain 27 mg of immobilization. By combining both solids, 39 mg of the target compound was obtained in 28% yield. 1 HMMR of the obtained target compound agreed with the value described in the literature (Monsigny, MLP; Delay, D .; Vaculik, M. Carbohydr. Res. 1977, 59, 589).
[0040]
3-S- (bD-glucopyranosyl) -L-cysteine [Compound (3)] (1.5 mg) was subjected to hydrolysis and post-treatment in the same manner as in Example 1, and purified from 30 mg of Compound (3) ( 2) 2.5 mg (yield 11.23%) was obtained.
[0041]
Example 3
SD-galactopyranosyl-L-cysteine [Compound (4)] (1.5 mg) was hydrolyzed and post-treated in the same manner as in Example 1 to purify Compound (2) (2.4 mg) from 30 mg of Compound (3) ( Yield 10.82%). Compound (4) was synthesized according to the method described in the above document.
Claims (5)
で表される化合物を加水分解することを特徴とする、式（２）
Wherein the compound represented by formula (2) is hydrolyzed.
で表される化合物を加水分解して、式（３）
The compound represented by the formula (3)
で表されることを特徴とする、ピリジニウム化合物の製造のための化合物。Formula (1)
A compound for the production of a pyridinium compound, characterized in that
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| CN104610390A (en) * | 2015-02-13 | 2015-05-13 | 佛山市赛维斯医药科技有限公司 | GPR119 agonist containing glucosamine and nitrile pyridine structure and application of GPR119 agonist |
| CN104610389A (en) * | 2015-02-13 | 2015-05-13 | 佛山市赛维斯医药科技有限公司 | GPR119 agonist containing glucosamine and nitropyridine structure and application of GPR119 agonist |
| CN104610392A (en) * | 2015-02-13 | 2015-05-13 | 佛山市赛维斯医药科技有限公司 | GPR119 agonist containing glucosamine and halogenated pyridine structures and application thereof |
| CN104610393A (en) * | 2015-02-13 | 2015-05-13 | 佛山市赛维斯医药科技有限公司 | Compound containing glucosamine and halogenated pyridine structures and application thereof |
| CN104628795A (en) * | 2015-02-13 | 2015-05-20 | 佛山市赛维斯医药科技有限公司 | Derivative containing glucosamine and nitrile pyridine structure and use thereof |
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