JP2021534257A - 新たな亜鉛錯体、その調製、ならびにヒトおよび動物疾患の治療のためのその使用 - Google Patents
新たな亜鉛錯体、その調製、ならびにヒトおよび動物疾患の治療のためのその使用 Download PDFInfo
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- JP2021534257A JP2021534257A JP2021534108A JP2021534108A JP2021534257A JP 2021534257 A JP2021534257 A JP 2021534257A JP 2021534108 A JP2021534108 A JP 2021534108A JP 2021534108 A JP2021534108 A JP 2021534108A JP 2021534257 A JP2021534257 A JP 2021534257A
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Abstract
Description
本発明は、上皮組織のバリア機能を回復し、免疫細胞の異常な活性を抑制する、ガンマ−L−グルタミルヒスタミンの新規な亜鉛錯体に関する。本発明はまた、上皮組織バリア機能の障害および異常な炎症反応の発症に関連するアトピー性皮膚炎および他の疾患を処置するための特定の亜鉛錯体の調製および使用に関する。
上皮バリアは、ヒトおよび動物生体で重要な役割を果たしている。上皮バリアは、さまざまな物質、アレルゲンおよび細菌が体内環境に侵入するのを防ぐ。上皮組織のバリア機能の障害は、口腔の炎症性疾患(口内炎、歯肉炎、咽頭炎等)、胃腸管の疾患(大腸炎、腸炎、腸の自家中毒、過敏性腸症候群、吸収不良症候群、再発性下痢等)、アレルギー性疾患(アレルギー性鼻炎、気管支喘息、アトピー性皮膚炎等)などのいくつかの疾患の発病に大いに寄与している[Recent Pat Antiinfect Drug Discov.2015;10(2):84−97;Current Pediatrics.2013;12(2):12−19;Bulletin of Siberian Medicine.2017;16(2)32−46]。炎症性疾患およびアレルギー性疾患の発症における上皮組織のバリア機能の重要な役割を考えると、上皮組織のバリア機能を回復することを目的とした戦略は、ヒトの多くの病的状態の処置にとって最も重要である。特に、局所療法は、損傷した上皮を回復すること、皮膚のバリア機能を改善すること、皮膚を水和すること、ならびに二次感染を予防および排除することを目的とする、アトピー性皮膚炎の処置において最も重要である[Pediatrics.2014 Dec;134(6):e1735−44]。
本発明の目的は、上皮組織のバリア機能の障害および免疫細胞の異常な活性に関連する疾患、特にアトピー性皮膚炎、ならびに他の疾患の処置に有効な新規な薬物を開発することである。
上に示されるように、ガンマ−L−グルタミルヒスタミンの亜鉛錯体は先行技術に記載されていなかったが、偽ペプチドガンマ−L−グルタミルヒスタミンは、最初にラットおよび軟体動物の神経組織から微量で単離されている物質として知られている[J.Neurochem.−1976.−vol.27.−pp.1461−1463;J.Neurochemistry.−1977.−vol.29.−pp.633−638]。ガンマ−L−グルタミルヒスタミンの調製は、特許、ロシア特許第2141968号明細書にも開示されている。これらの研究は、抗酸化作用、抗ラジカル作用、脂質調節作用、血糖降下作用、抗喘息作用、抗ウイルス作用、抗菌作用、抗腫瘍作用、抗炎症作用、抗転移作用、適応作用を有する偽ペプチドであり、アラキドン酸の代謝を調節し、糖尿病、肥満、冠動脈疾患、ストレス状態、肝炎、肝硬変、中毒性肝損傷、アルコール依存症、放射線障害および老年医学的変化の徴候を予防することができる、ガンマ−L−グルタミルヒスタミンを記載している。
「化合物I」という用語は、金属:配位子比が1:1のガンマ−L−グルタミルヒスタミンの亜鉛錯体を指す。
本発明の主題はまた、治療上有効量の本発明の化合物を、適切な処置を必要とする対象に投与するステップを含む。治療上有効量は、患者が処置(予防)に対する所望の応答を示す可能性が最も高いように患者に投与または送達される化合物の量である。正確な必要量は、対象の年齢、体重および全身状態、疾患の重症度、薬物投与の方法、他の薬物と組み合わせて使用されるかどうかなどに応じて、対象ごとに異なり得る。
本発明はまた、本発明の化合物(またはプロドラッグまたは他の薬理学的に許容される誘導体)と、1つまたは複数の薬学的に許容される担体、アジュバント、希釈剤および/または賦形剤、例えば、この化合物の薬理活性に影響を及ぼさず、治療量の化合物を送達するのに十分な用量で投与した場合に、非毒性である条件下で、本発明の化合物と組み合わせて対象に同時投与することができるものとを含有する医薬組成物に関する。
本発明に記載される化合物は、以下の組成物の形態で、ヒトまたは動物の疾患を予防および/または処置するために使用することができる:
有効成分 40mg
エタノール 300μl
水 300μl
1−ドデシルアザシクロヘプタノン 50μl
プロピレングリコール 1mlまで
有効成分 0.005〜0.5
油成分 10.0〜15.0
化粧品用ステアリン 2.0〜3.0
乳化剤 1.0〜3.0
エマルジョンワックス 1.0〜3.0
トリエタノールアミン 0.1〜0.6
ビタミンA 0.003〜0.05
蒸留グリセリン 2.0〜3.0
抗酸化剤 0.05〜0.075
保存剤 0.15〜0.25
ティーツリーオイル 0.3〜0.5
精製飲料水 100%まで
有効成分 0.01
植物油 15.0
化粧品用ステアリン 0.75
乳化剤PG−3 2.25
エマルジョンワックス 2.25
トリエタノールアミン 0.1
ビタミンA 0.028
ソルビトール 2.0〜3.0
ビタミンE 1.5
Monomuls(登録商標)90−O18 0.75
ニパゾール 0.2
ニパギン 0.3
ティーツリーオイル 0.3〜0.5
精製飲料水 100%まで
有効成分 0.1
植物油 15.0
化粧品用ステアリン 0.75
乳化剤PG−3 2.25
エマルジョンワックス 2.25
トリエタノールアミン 0.1
ビタミンA 0.028
ソルビトール 2.0〜3.0
ビタミンE 1.5
Monomuls(登録商標)90−O18 0.75
ニパゾール 0.2
ニパギン 0.3
ティーツリーオイル 0.3〜0.5
精製飲料水 100%まで
有効成分 0.3
植物油 15.0
化粧品用ステアリン 0.75
乳化剤PG−3 2.25
エマルジョンワックス 2.25
トリエタノールアミン 0.1
ビタミンA 0.028
ソルビトール 2.0〜3.0
ビタミンE 1.5
Monomuls(登録商標)90−O18 0.75
ニパゾール 0.2
ニパギン 0.3
ティーツリーオイル 0.3〜0.5
精製飲料水 100%まで
本発明の化合物Iは、独立した有効成分として投与することができるが、これはまた、1つまたは複数の他の薬剤と組み合わせて使用することができ、特に、他の薬剤が、抗生物質、NSAID(非ステロイド性抗炎症薬)または他の抗炎症剤、糖質コルチコイド、カルシニューリン阻害剤、抗ヒスタミン剤、膜安定剤、免疫向性剤(immunotropic agent)等によって表され得る。一緒に投与する場合、治療剤が同時にもしくは異なる時間に順次に投与される異なる剤形であることができる、または治療剤を組み合わせて単一剤形にすることができる。
試料の元素分析
試料の元素組成試験をマルチEA 5000 Elemental Analyzer、Analytik Jenaを使用して行った。分析のために、秤量した試料約20mg(正確に秤量)をオートサンプラーセルに入れた。装置に不活性ガス(ヘリウム)を充填した後、窒素、炭素および水分から精製した酸素10cm3を添加し、試験試料を約1000℃の温度で燃焼させた。過剰な酸素を除去するために、燃焼生成物を750℃の温度で金属銅に通した。次いで、ガスの混合物(CO2、N2およびH2O)を吸着トラップに通して水分を捕捉し、水素の量を決定した。次いで、窒素と一酸化炭素の混合物をガスクロマトグラフィーカラムに供給し、成分に分離し、これらをキャリアガスによって化学発光検出器CLD(ガス混合物中の窒素含有量を分析する)およびNDIR赤外線検出器(ガス混合物中の一酸化炭素の含有量を分析する)に移した。試験試料で決定された元素の各々の含有量の計算を、ソフトウェアパッケージmultiWinを使用して行った。
この実施例は、これらの条件下では、亜鉛塩と遊離ガンマ−L−グルタミルヒスタミンの混合物が形成されるので、ガンマ−L−グルタミルヒスタミンの亜鉛錯体を、亜鉛塩とガンマ−L−グルタミルヒスタミンなどの成分の単純な混合によって調製することができなかったことを実証している。例えば、塩化亜鉛水溶液をガンマ−L−グルタミルヒスタミンと1:2の比で混合し、アンモニア水を(媒体がわずかにアルカリ性になるまで)添加し、引き続いて生成物を沈殿させると、白色結晶性物質が形成される。元素分析データ(表1参照)は、錯体化合物の計算値に近いデータ値を示しているが、このデータを錯体形成の証拠と見なすことはできない。試料中の炭素および窒素の過小評価された含有量は、おそらく分析中に部分的に水を失う水酸化亜鉛の形成が他の元素の値を過小評価し得ることを示している。追加の冷水洗浄後に錯体の元素分析を繰り返すと、試料中の水素量がさらに過大評価される。
さらなる試験で、本著者は、水性酢酸亜鉛の使用を含む、ガンマ−L−グルタミルヒスタミンとの亜鉛錯体を得る方法を開発した。
本発明による本方法の修正の目標は、得られた生成物の濾過性を改善すること、ならびに反応混合物中の水酸化亜鉛の最も均一な分布を確実にすることである。
インビトロでのグルタミニルシクラーゼの酵素活性に対する化合物1(本発明の主題である)の効果の試験において、組換え細胞内ヒトグルタミニルシクラーゼに対する化合物1の直接的阻害効果が発見された。
実験技術.アトピー性皮膚炎のモデルにおける化合物1活性の試験を、標準的な技術を使用して行った[Evidence−based Complementary and Alternative Medicine.2012.Article ID 545497,9 pages]。実験群では、偏差の兆候のない平均的外観の動物を選択し、動物の体重は性別の平均値から±20%以下とした。
1)表皮肥厚−乳頭間突起の伸長を伴う表皮および上皮の肥厚:
0点−病理なし;
0.5点−病理が検出されたが、極めて弱く発現;
1点−中等度から重度の病理;
2点−重度の病理。
2)角質増殖は、角質層の著しい肥厚または正常な拒絶反応の遅延を特徴とする皮膚状態の非炎症性特徴である:
0点−病理なし;
0.5点−病理が検出されたが、極めて弱く発現;
1点−示される病理の明確な存在。
3)膿疱(膿瘍)−化膿性内容物を伴う空洞性の急性炎症要素:
0.5点−病理の単一徴候;
1点−軽度の病理;
2点−中等度から重度の病理;
3点−重度の病理;
4点−全体的病理。
4)嚢胞は、重層扁平角質化上皮によって裏打ちされ、角質塊の層で満たされた、上皮の過形成(表皮肥厚)が存在する場合に発生する、丸みを帯びたまたは楕円形の構造である:
0点−病理なし;
0.5点−病理が検出されたが、極めて弱く発現;
1点−示される病理の明確な存在。
5)炎症:
0点−病理なし;
0.5点−病理の単一徴候;
1点−軽度の病理;
2点−中等度から重度の病理;
3点−重度の病理;
4点−全体的病理。
6)浮腫:
0点−病理なし;
0.5点−病理の単一徴候;
1点−軽度の病理;
2点−中等度から重度の病理;
3点−重度の病理;
4点−全体的病理。
したがって、行われた試験は、化合物1がグルタミニルシクラーゼ酵素を阻害するのに有効であることを示した。アトピー性皮膚炎のモデルでは、化合物1が、インビボでの炎症細胞(単球、樹状細胞、好酸球および好中球)の流入、ならびにアトピー性皮膚炎の他の顕微鏡的徴候を阻害することが示された。
Claims (14)
- ガンマ−L−グルタミルヒスタミンとの亜鉛錯体を調製する方法であって、
酢酸亜鉛とガンマ−L−グルタミルヒスタミンの混合物を極性溶媒中で撹拌するステップと、
その生成物を沈殿させるステップと、
金属:配位子比が1:1のガンマ−L−グルタミルヒスタミンとの亜鉛錯体である、得られた生成物を乾燥させるステップと、
を含む方法。 - 前記溶媒がメタノール、水、またはこれらの組み合わせである、請求項2に記載の方法。
- 水性酢酸亜鉛、特に酢酸亜鉛二水和物が使用される、請求項2に記載の方法。
- 前記混合物の混合が、15〜50℃、好ましくは、メタノールが溶媒として使用される場合は15〜40℃の温度、および水が溶媒として使用される場合は15〜90℃の温度で行われる、請求項3に記載の方法。
- 請求項2〜5のいずれか一項に記載の方法によって得られる、ガンマ−L−グルタミルヒスタミンとの亜鉛錯体。
- 金属/配位子のモル比が1/1である、ガンマ−L−グルタミルヒスタミンとの亜鉛錯体。
- 酢酸亜鉛とガンマ−L−グルタミルヒスタミンの等モル混合物を溶媒中で撹拌し、続いてその錯体を生成物として単離することによって調製される、請求項7に記載のガンマ−L−グルタミルヒスタミンとの亜鉛錯体。
- 錯体の固体試料のIRスペクトルが、1616cm−1、1646cm−1および3276cm−1のバンドを示す、請求項7に記載のガンマ−L−グルタミルヒスタミンとの亜鉛錯体。
- 上皮組織のバリア機能の障害によって引き起こされる障害を予防および/または処置するための、請求項1または請求項6〜9のいずれか一項に記載の錯体の使用。
- グルタミニルシクラーゼ活性に関連する障害を予防および/または処置するための、請求項1または請求項6〜9のいずれか一項に記載の錯体の使用。
- 免疫細胞の異常な活性に関連する障害を予防および/または処置するための、請求項1または請求項6〜9のいずれか一項に記載の錯体の使用。
- 免疫細胞の異常な走化性に関連する障害を予防および/または処置するための、請求項12に記載の錯体の使用。
- 前記上皮組織のバリア機能の障害および/またはグルタミニルシクラーゼ活性および/または免疫細胞の異常な活性に関連する障害がアトピー性皮膚炎である、請求項10〜13のいずれか一項に記載の使用。
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RU2697580C1 (ru) | 2019-08-15 |
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US20210246149A1 (en) | 2021-08-12 |
BR112021003147A2 (pt) | 2021-05-11 |
AU2019325083A1 (en) | 2021-03-18 |
CA3110185A1 (en) | 2020-02-27 |
KR20210046047A (ko) | 2021-04-27 |
CN112752764A (zh) | 2021-05-04 |
EA202190543A1 (ru) | 2021-05-12 |
EP3842445A4 (en) | 2022-05-11 |
WO2020040670A1 (ru) | 2020-02-27 |
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