JP6463747B2 - チアゾール分子内塩化合物、並びにその製造方法及び使用 - Google Patents
チアゾール分子内塩化合物、並びにその製造方法及び使用 Download PDFInfo
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- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
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- 239000003792 electrolyte Substances 0.000 description 1
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- 239000008387 emulsifying waxe Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
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- 235000011187 glycerol Nutrition 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
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- 229960002897 heparin Drugs 0.000 description 1
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- 239000003547 immunosorbent Substances 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
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- 235000019388 lanolin Nutrition 0.000 description 1
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- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
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- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
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- 229910052760 oxygen Inorganic materials 0.000 description 1
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- 230000002980 postoperative effect Effects 0.000 description 1
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- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Description
MはNa又はKであって、
XはBr、Cl又はIである)
を開示している。
(1)多くの試験で、式Aの化合物の元素分析の結果は有意な差を示し、理論値からかけ離れていた(0.3%の誤差限界を超える)。
(2)品質が安定しておらず、3ヶ月間の貯蔵後、水分を吸収しやすく、凝集しやすく、変色しやすいものである(温度:40℃、湿度:75%、大気圧)。図1A及び図1Bを参照。
nが0、1、2又は3である。
3−メチルカルボニルオキシ−4−メチル−チアゾール分子内塩(n=0)、及び
3−メチルカルボニルオキシ−4−メチル−チアゾール分子内塩一水和物(n=1)から選択される。
(2)心臓血管系の硬化を改善する方法。
(3)薬物療法のために、糖尿病又は心血管疾患の感受性を増強する方法。
(4)慢性心不全の治療及び/又は予防及び/又はアジュバント療法のための方法。
(5)歯の着色を予防又は逆転させる方法。
(6)植物性タンパク質や動物性タンパク質の保存方法。
i)皮膚の弾力性の低下又は皮膚しわの増加、ii)糖尿病、iii)糖尿病の後遺症、iv)腎臓損傷、v)は血管損傷、vi)高血圧、vii)網膜症、viii)水晶体タンパク質障害、ix)白内障、x)末梢神経障害、xi)変形性関節症、xii)糖尿病関連高血圧。
本発明の実施形態は、以下の実施例に関連して詳細に説明するが、実施例を理解する当業者が本発明だけを説明することに使用されるのであって、本発明の範囲を制限するためではない。実施例に示されていなかった任意の特定の条件は、従来の条件やメーカーが提示する条件である。メーカーから与えられなかった試薬や機器は市場で市販されているすべての従来の製品である。
(1)グループ化及び投与方法
ラットは体重や血圧に応じてグループ分けした。薬剤投与されなかった高血圧症を伴う糖尿病ラット群(モデル群)、ニフェジピン群、実施例2化合物+ニフェジピン群。一方、同週齢の純粋な糖尿病群と正常対照群も設定した。実施例2の化合物(36mg/kg)は使用直前に蒸留水に溶解し、5週間、1日1回、胃内に投与した。投与3週間後、インプラントを腹部大動脈に埋め込み、1週間回復させ、血圧が安定するまで血圧を3日間モニターした。その後、ニフェジピン(0.75mg/kg)を1日1回、連続7日間、胃内に午前10:00に投与した。
ニフェジピン粉末を5mLのEPチューブに入れ、一定量CMC−Naを添加し、4つの鋼球(steel ball)を加え、5〜10分間攪拌した。ニフェジピンを完全に懸濁した後、体積を計測し、懸濁液を再び実施した。
投与の第3週に、各群のラットを代謝ケージへ一匹ずつ移し、餌を与えた。19、20日、21日での、24時間の水の摂取量と尿量を記録した。
操作手順は(1)、(2)、(3)と同様であり、術後の回復の1週間後、ラットのケージをDSIレシーバ上に配置して、モニターするパラメータとチャネルを設置した。磁気スイッチを使用してインプラントを起動した。デバッグ後、生体信号の記録を開始した。連続した3日後、ニフェジピン及び実施例2の化合物を毎日午前10:00に投与した。10:00〜20:00の期間のラットの心臓血管のパラメータを連続7日間、動的に記録した(この期間、生理食塩水濃度は厳密に1%に制御した)。
TXB2、6−ケト−PGF1aの決定方法:全血サンプルを採取し、抗凝固のためにインドメタシンEDTA−Na 40μLを添加し、4℃、3500rmp/分、15分間遠心分離して血漿を得て、−70℃で保存した。定量は北京華エイ市バイオ株式会社(Beijing Huaying Biotechnology Co.,Ltd.)を介したラジオイムノアッセイで行った。
テストデータは、平均±SD(平均±標準偏差)で表現し、データを処理するためにSPSS2.0ソフトウェアを使用した。統計処理は、一元配置分散分析を用いて実施し、P<0.01であるとき、有意差があるとした。
結果を表6に示した。
Claims (10)
- 式I
の化合物。 - 請求項1に記載の式Iの化合物を調製する方法であって、
化合物Aと、1,2−エポキシプロパンとを反応させて化合物Bを得る工程
を含む方法。 - 化合物Aは、
4−メチルチアゾールと、クロロ酢酸、ブロモ酢酸又はヨード酢酸とを反応させて化合物Aを得る工程
- 化合物A及び/又は化合物Bが、再結晶化を介して分離及び精製される、請求項3に記載の方法。
- 再結晶化に用いる溶媒が、アセトン、メタノール、エタノール、エチルエーテル、石油エーテル及びn−ヘキサン、又はその混合物、からからなる群から独立して選択されるいずれか一つである、請求項4に記載の方法。
- 請求項1に記載の式Iの化合物の単結晶を調製する方法であって、
3−ヒドロキシカルボニルメチル−4−メチル−チアゾール分子内塩をメタノールに溶解し、次いで、酢酸エチルを滴下して添加し、静置して単結晶を取得する工程を含む、方法。 - 1mgの3−ヒドロキシカルボニルメチル−4−メチル−チアゾール分子内塩、0.05mlのメタノール及び0.3mlの酢酸エチルを使用する、請求項6に記載の方法。
- 請求項1に記載の式Iの化合物の使用であって、該使用が、タンパク質老化関連疾患又は障害の治療及び/又は軽減及び/又は予防及び/又はアジュバント療法のための薬剤の製造における使用であり、ここで該タンパク質老化関連疾患又は障害が、以下、
i)皮膚の弾力性の増加又は皮膚しわの減少、ii)糖尿病、iii)糖尿病の後遺症、iv)腎臓損傷、v)血管損傷、vi)高血圧症、vii)網膜症、viii)水晶体タンパク質損傷、ix)白内障、x)末梢神経障害、xi)変形性関節症、及び、xii)糖尿病に関連する高血圧症、
から選択される、使用。 - 請求項1に記載の式Iの化合物の使用であって、動物の歯の着色の逆転剤、歯の着色の予防又は逆転する経口製剤、タンパク質保存剤又は動物タンパク質保存剤、架橋タンパク質のブレーカー、終末糖化産物を切断する薬剤、血漿BNPの含有量及び/又は血漿MCP−1の含有量を低減する薬剤、心血管系硬化症を改善する薬剤、糖尿病又は心血管疾患の治療感度を増強する薬剤、あるいは、慢性心不全の治療及び/又は予防及び/又はアジュバント療法のための薬剤、の製造における使用。
- 以下の項目(1)〜(3):
(1)インビトロで終末糖化産物(AGEs)を切断する方法、
(2)歯の着色を予防又は逆転する方法、及び
(3)植物性タンパク質又は動物性タンパク質の保存方法、
から選択される方法であって、
該方法が、請求項1に記載の式Iの化合物の有効量を使用する工程を含む方法。
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