TWI826928B - 具抗發炎活性之三環和四環京尼平衍生物之製備及其用途 - Google Patents
具抗發炎活性之三環和四環京尼平衍生物之製備及其用途 Download PDFInfo
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Abstract
本發明涉及新穎的京尼平衍生物及其製備方法，包括三環環戊咪唑並吡啶、環戊吡啶並嘧啶、八氫環戊吡啶並二氮雜和四環十氫苯並咪唑並環戊吡啶。該京尼平衍生物經實驗證實對LPS誘導RAW264.7細胞生成的一氧化氮具有顯著的抑制效果。另一方面，以蛋白質印跡分析，其對iNOS和COX-2的蛋白質表現具有顯著抑制效果，因此本發明所製備的化合物可應用於製備治療各種炎症及其相關疾病的藥物。
Description
本發明係關於一種新穎三環和四環京尼平衍生化學合成物；詳言之，本發明係關於一種具有抗發炎活性之三環和四環京尼平衍生物之製備及其用途。
發炎反應是受傷後的生物基本機制，由一系列細胞和微血管反應組成，可去除受損組織並生成新組織進行修復(Schmid-Schönbein,G.W.,Annu.Rev.Biomed.Eng. 2006, 8,93-151)。然而，持續的發炎會導致多種疾病，例如淋巴細胞和白細胞聚集的組織浸潤嵌入增殖滑膜的纖維細胞、膠原蛋白與膠原纖維變形和DNA氧化促進腫瘤轉化(Nathan,C.,Nature 2002, 420,846-852)。
目前抗發炎治療藥物可依藥物結構區分兩大類，分別為類固醇類(Steroid)和非類固醇消炎止痛藥(Nonsteroidal anti-inflammatory drugs,NSAID)。類固醇為以四環脂質結構為主，運用在治療腎上腺素分泌之荷爾蒙藥物，其功能可減緩免疫發炎反應，並調節蛋白質、醣類及脂肪之新陳代謝。類固醇之抗發炎治病機轉，主要利用血管的通透性及肥大細胞之細
胞膜，抑制組織胺之釋放、白血球於發炎部位之聚集現象和花生四烯酸之生成。常見之類固醇市售藥物有Prednisolone、Betamethasone、Dexamethasone等，該類藥物不具選擇性，若長期服用會產生皮膚變薄、有刺痛感、微血管擴張、庫欣氏症、月亮臉和水牛肩等常見之副作用，因此類固醇非為治療抗發炎優先考量之藥物。
非類固醇止痛消炎藥物(NSAID)，為目前治療抗發炎藥物的優先選擇之藥物。其作用機轉為抑制環氧化酶(Cyclooxygenase，COX)之作用，進而阻止花生四烯酸(Arachidonic acid)代謝成前列腺素(Prostaglandins)及血栓素(Thromboxane)等促發炎物質所引起之發炎反應。市面上常見的藥物有：Aspirin、Indomethacin、Ibuprofen及Naproxen等。而此類藥物常見的副作用為腸胃道不適、潰瘍，因此若患者本身有消化性潰瘍病史或其他危險因素者，會在服用NSAID的同時，預防性地給予抗潰瘍藥物。
環烯醚萜係一種廣泛存在於植物中具有生物活性的化合物，包括京尼平和梔子苷。(Wang’C.,Gong’X.,Agula Bo,A.,Lei Zhang,L.,Mingxu Zhang,M.,Zang,E.,Zhang,C.,Li,M.,Molecules 2020,25,287-135.)它們具有多種生物活性，如抗發炎(Bentes,A.de S.,Mercadante,A.Z.,J.Agric.Food Chem. 2014,62,10800-10808.)、與抑制胃炎(Dániello,A.,Dónofrio,G.,Pischetola,M.,Strazzullo,L.,Anal.Biochem. 1985,144,610-611.)等生物活性。
京尼平是梔子果實中的一種活性成分，具有有效的抗發炎和抗血管生成劑。根據研究證明京尼平具有抗脂質過氧化和抗發炎活性，通過抑制iNOS可開發有效的抗發炎與抗血管生成藥物。因此，京尼平在抗發炎之藥物開發具有重要性(Koo,H.-J.；Song,Y.S.；Kim,H.-J.；Lee,Y.-H.；
Hong,S.-M.；Kim,S.-J.；Kim,B.-C.；Jin,C.；Lim,C.-J.；Park,E.-H.Eur.J.Pharmacol. 2004, 495,201-208.)。
本發明提供治療發炎反應之方法，其包含投與治療上有效量之式(I)、(II)與(III)之三環和四環京尼平衍生化合物，其立體化學異構物或其醫藥上可接受鹽類至有需求之個體：
其中，R1獨立地為氫、烷基(-CnH2n+1，n=1~3)，R2獨立地為氫、烷基(-CnH2n+1，n=1~3)，R3獨立地為氫、烷基(-CnH2n+1，n=1~3)，Y獨立地為氫、甲基、乙基、正丙基、異丙基、正丁基、異丁基、叔丁基、苄基、鄰、間、對位氟苄基；n獨立地為碳數(n=1~3)。
其中R獨立地為氫、烷基(-CnH2n+1，n=1~3)，R1獨立地為氫、烷基(-CnH2n+1，n=1~3)，Y獨立地為氫、甲基、乙基、正丙基、異丙基、正丁基、異丁基、叔丁基、苄基、鄰、間、對位氟苄基。
其中，R1獨立地為氫、烷基(-CnH2n+1，n=1~3)，Y獨立地為氫、甲基、乙基、正丙基、異丙基、正丁基、異丁基、叔丁基、苄基、鄰、間、對位氟苄基。
本發明另提供一種我們提出之用以合成具有抗發炎活性三環和四環京尼平衍生物之新穎製備方法(C.Y.,Chiang,ChemistrySelect,2023,7,e202104327與S.M.,Li,Bioorganic Chemistry,2022,126,105881)，係以京尼平為起始物，經如式(IV)2,2-二甲基-1,3-丙二胺(2i)或1,2-二氨基環己烷(2j)等各種二胺和如式(V)之鹵烷類化合物反應之化學合成方法，合成出三環和四環京尼平衍生物，以應用於治療各種炎症及其相關疾病的藥物。
其中，R1獨立地為氫、烷基(-CnH2n+1，n=1~3)，R2獨立地為氫、烷基(-CnH2n+1，n=1~3)，R3獨立地為氫、烷基(-CnH2n+1，n=1~3)，n為獨立地為碳數(n=1~3)。
X-Y 式(V)
其中，Y獨立地為氫、甲基、乙基、正丙基、異丙基、正丁基、異丁基、叔丁基、苄基、鄰、間、對位氟芐基；X獨立地為鹵素(氯、溴或碘)。
下列描述僅在說明本發明之各具體實施例。因此，本文所論及之特定具體實施例或改良不可解釋為侷限本發明之範疇。熟習本領域之技術人員可顯見的是，所進行的各種變更或等同物並未背離本發明之範疇。
為了使本發明更明確且易於理解，必須先定義特定術語。額外的定義係列於實施方式全文中。除非另有定義，本文所使用的技術性及科學性術語具有本發明領域之技術人員所能常規理解的意義。
本文所使用的冠詞「一」與「一者」是指一或大於一者(亦即，至少一者)的該冠詞語法對象。舉例而言，「一元件」是指一元件或大於一者之元件。
1.材料及方法
1.1 材料
本發明之所用化學品均為市售試藥級，分別購自Aifa Chemical Co、DUKSAN PURE Chemical Co.、Merck Chemical Co.、Tedia Chemical Co.、ACROS Chemical Co.及Lancaster Chemical Co.，所用測試藥品純度皆為95%以上，根據文獻方法合成(C.Y.,Chiang,ChemistrySelect,2023,7,e202104327與S.M.,Li,Bioorganic Chemistry,2022,126,105881)。LPS(源自於大腸桿菌的內毒素，0127：B8)、3-(4，5-二甲基噻唑-2)-2，5-二苯基四氮唑溴鹽及吲哚美辛(Indomethacin)皆購自Sigma Chemical Co.。
1.2 細胞培養
將鼠巨噬細胞株Raw 264.7於含有10% FBS、100U/mL青黴素和100mg/mL鏈黴素的DMEM培養基中，於37℃，5% CO2條件下進行培養。
1.3 一氧化氮生成抑制試驗
將RAW264.7細胞以5×105個細胞/mL的密度接種在96孔盤中，並在37℃下孵育24小時。將細胞用100ng/mL脂多醣和載體與不同濃度的化合物預處理24小時。亞硝酸鹽之水平會反應細胞內NO合成酶之活性。收集細胞上清液與相同體積的Griess試劑(1%磺胺，0.1%萘乙二胺二鹽酸鹽和5%磷酸)混合。使用亞硝酸鈉獲得標準曲線，並且通過ELISA在540nm處測量每個樣品。
1.4 西方墨點轉漬法
將RAW264.7細胞以5×105個細胞/mL的密度接種在6孔盤中，並在37℃下孵育24小時。將細胞用100ng/mL脂多醣和載體與不同濃度的化合物預處理24小時。收集細胞放置在冰冷緩衝液裂解1小時，接續在4℃溫度下以15,000rpm離心20分鐘，收集上清液作為西方墨點轉漬法的樣品溶液。配置10% SDS PAGE，再將完成濃縮細胞上清液樣品注入樣本槽中，利用110V功率進行電泳分析，再經由濕式轉漬系統，將SDS PAG上之蛋白質轉漬PVDF membrane。轉漬後PVDF membrane浸泡在5%脫脂牛奶/TBST溶液作用1小時，分別加入一級抗體：anti-COX-II、anti-iNOS或anti-β-actin於4℃反應至隔天，以TBST清洗3次，加入二級抗體於室溫反應1小時，再以TBST清洗3次，最後以ECL於冷光膠體影像分析系統反應呈色。
2.下面所列的例子為簡易便捷的製程合成三環和四環京尼平衍有關實例，用以更詳細地解釋本發明；但本發明不為這些實例所限。
3.實施案例一至三
本發明之實施案例一至三為合成不同碳數碳環之三環環烷基咪唑並吡啶-6-羧酸甲酯，其反應步驟如圖1，以1.2當量Diamine(二胺，包括2a-c)試劑與1當量Genipin(京尼平，1)，在無水四氫呋喃溶液中，以室溫與氮氣條件下反應2-3小時，可得到產率82-89%之化合物(3a-c)，如表1所示。
4.實施案例四至八
本發明之實施案例四至八為合成碳環碳數為1且不同R1、R2與R3取代之三環環烷基咪唑並吡啶-6-羧酸甲酯，其反應步驟如圖1，以1.2當量Diaminc(二胺，包括2d-h)試劑與1當量Genipin(京尼平，1)，在無水四氫呋喃溶液中，以無氧與室溫下進行反應2-3小時，可得到產率72-85%之化合物(3d-h)，如表2所示。
5.實施案例九與十
本發明之實施案例九與十為合成三環和四環環烷基咪唑並吡啶-6-羧酸甲酯，其反應步驟如圖1，以1.2當量之2,2-二甲基-1,3-丙二胺(2i)或1,2-二氨基環己烷(2j)試劑與1當量Genipin(京尼平，1)，在無水四氫呋喃溶液中，以無氧與室溫下進行反應下反應2-3小時，可得到產率81-90%之化合物(3i,j)，如表3所示。
6.實施實例十一至十六
本發明之實施案例十一至十六為合成O-烷基化三環環戊咪唑並吡啶，其反應步驟如圖2，在鹼性試劑催化與低溫至回流，有氧或無氧條件下與三環環烷基咪唑並吡啶-6-羧酸甲酯反應2-3小時後，加入1.5當量之鹵烷類化物，例如甲基碘、乙基溴、正丙基溴、正丁基溴、芐基氯或對氟苯基溴，在室溫下反應12小時以上。可得到產率61-79%之O-烷基化三環環戊咪唑並吡啶產物(4-9)，如表4所示。
5.抗發炎活性測試
為了證實本發明之京尼平衍生物對Raw 264.7細胞僅具有抗發炎作用，並無細胞毒殺作用，其以本領域的技術人員所熟知的MTT(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)呈色試驗法進行，在此不再詳述本專利所發明之所有化合物即使在100μM濃度下，細胞表現出低細胞毒性(細胞活力>85%)。請參閱圖3。給藥一系列之京尼平衍生物，經給藥處理24h後，評估一系列之京尼平衍生物對於鼠科巨噬細胞株Raw 264.7之抗發炎效果。如表5所示，化合物3f-h與5-9可顯著減少LPS誘導之鼠巨噬細胞的NO產生，具有良好抗發炎效果。
7.京尼平衍生物對iNOS和COX-2的蛋白質表現抑制之探討
研究抗發炎途徑，通過西方墨點轉漬法分析在LPS誘導的Raw 264.7細胞中，檢測化合物3f影響發炎過程中iNOS和COX-2的蛋白質表達。如圖4所示，化合物3f可顯著降低LPS誘導的Raw 264.7細胞中iNOS和COX-2的蛋白質表達，具有良好抗發炎效果。
第(一)圖為合成環和四環環烷基咪唑並吡啶-6-羧酸甲酯的方法。
第(二)圖為合成O-烷基化三環環戊咪唑並吡啶的方法。
第(三)圖為京尼平衍生物給藥後之細胞存活率。
第(四)圖為京尼平衍生物對LPS誘導的細胞在iNOS和COX-2的蛋白質表達的抑制。
Claims (8)
- 一種如式(I)之化合物，
- 一種如式(II)之化合物，
- 一種如式(III)之化合物，
- 一種用於合成如請求項1至3所述式(I)、(II)與(III)之化合物的製造方法，其方法包含：a)以京尼平為起始物與如式(IV)或2,2-二甲基-1,3-丙二胺或1,2-二氨基環己烷之二胺試劑在無氧與室溫下進行反應，其中，二胺 試劑係如式(IV)所表示之化合物，
- 一種使用如請求項1所述式(I)之化合物或其在藥學上可接受的鹽用於製造具抗發炎活性作用藥物之用途。
- 一種使用如請求項1所述式(I)之化合物或其在藥學上可接受的鹽用於製造參與抑制前列腺素(PGs)、環加氧酶(COXs)和一氧化氮合酶(iNOS)相關細胞內發炎路徑藥物之用途。
- 一種具抗發炎之組合物，其係包含如請求項1所述式(I)之三環京尼平衍生物及鹽類、稀釋劑、賦型劑或載體。
- 一種參與前列腺素(PGs)、環加氧酶(COXs)和一氧化氮合酶(iNOS)等相關細胞內抗發炎路徑之組合物，其係包含如請求項1所述式(I)之三 環京尼平衍生物及鹽類、稀釋劑、賦型劑或載體。
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| TW200642688A (en) * | 2005-03-01 | 2006-12-16 | Pfizer Ltd | New use of PDE7 inhibitors |
| TWI729406B (zh) * | 2019-06-04 | 2021-06-01 | 翁豐富 | 具抗發炎活性之1,2,4-三氮唑衍生物之製備及其用途 |
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| TW326600B (en) * | 1995-03-28 | 1998-02-11 | United Microelectronics Corp | Method and apparatus of error control coding for rank three mask ROM |
| TW200642688A (en) * | 2005-03-01 | 2006-12-16 | Pfizer Ltd | New use of PDE7 inhibitors |
| TWI729406B (zh) * | 2019-06-04 | 2021-06-01 | 翁豐富 | 具抗發炎活性之1,2,4-三氮唑衍生物之製備及其用途 |
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