TWI385178B - 新穎香葉木素（ｄｉｏｓｍｅｔｉｎ）化合物、其製備方法及包含該等化合物之醫藥組合物 - Google Patents
新穎香葉木素（ｄｉｏｓｍｅｔｉｎ）化合物、其製備方法及包含該等化合物之醫藥組合物 Download PDFInfo
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- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- 238000004879 turbidimetry Methods 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
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Description
本發明係關於新穎香葉木素化合物、其製備方法及含有該等化合物之醫藥組合物。
專利說明書EP 0 709 383中已闡述香葉木素化合物及其在治療靜脈功能不全中之活性。
本發明之化合物係黏附分子抑制劑、NADPH氧化酶抑制劑及抗血小板凝聚劑。
在慢性靜脈疾病之治療中白細胞黏附抑制及NADPH氧化酶抑制之性質甚為重要，此係鑒於以下事實：在此病變中，下肢微循環網絡之炎症與白細胞浸潤有關已得以廣泛闡述(Verbeuren TJ,Bouskela E,Cohen RA等人，Regulation of adhesion molecules:a new target for the treatment of chronic venous insuffciiency
,2000,Microcirculation,7,S41-S48)。
血小板凝聚抑制之性質表明，本發明化合物不僅在靜脈及動脈血栓形成之預防及治療中、而且在慢性靜脈疾病之治療中(其中血小板可藉由炎症介質活化)、或在患有血栓形成後症候群之患者中具有抗血栓形成潛力。
已證實在慢性靜脈疾病中存在毛細血管/小靜脈微血管病。此微血管病係由靜脈高血壓引起的且會導致毛細血管/小靜脈濾過(滲透性過高)之問題，且因此造成微水腫(Barbier等人，Microcirculation and rheology
,1994,Presse med. 23,213-224)。大量研究表明在靜脈高血壓中內皮細胞活化與黏附分子之循環濃度增加有關(Saharay M,Shields DA,Georgiannos SN等人，Endothelial activation in patients with chronic venous disease
,1998,Eur J Vasc Surg,15,342-349；Verbeuren TJ,Bouskela E,Cohen RA等人，Regulation of adhesion molecules：a new target for the treatment of chronic venous insufficiency
,2000,Microcirculation,7,S41-S48)。
本發明之化合物不僅具有消炎活性，而且具有抗滲透性過高活性。
此外，已證實在慢性靜脈疾病中自由基會增加且因此使NADPH氧化酶活化。人們認為此氧化應激與內皮細胞活化及白細胞浸潤有關(Glowinski J及Glowinski S，Generation of reactive oxygen metabolites by the varicose vein wall
,2002,Eur. J. Vasc. Endovasc. Surg.,23,5550-555)。
已證實在許多血管病變中存在內皮細胞浸潤及黏附分子及NADPH氧化酶之誘導(Bedard K及Krause KH，The NOX family of ROS-generating oxidases：Physiology and pathophysiology
,2007,Physiol. Rev. 87,245-313)。
因此，本發明之化合物可用於預防或治療靜脈疾病，尤其慢性靜脈疾病之所有階段(疼痛、毛細管擴張、靜脈曲張、水腫、營養失調、潰瘍)，亦可用於預防或治療血栓形成後症候群、與糖尿病有關之血管併發症、高血壓、動脈粥樣硬化、炎症、與肥胖症有關之代謝症候群、與肥胖症有關之血管併發症、心絞痛、下肢動脈炎或腦血管意外，用於治癒慢性傷口(主要包括靜脈型或混合型腿部潰瘍及糖尿病足)，用於治療或預防痔瘡發作，用於治療或預防壓力性潰瘍及用於治療多發性硬化症。
更特定而言，本發明係關於式(I)之化合物：
其中R1
、R2
及R3
可相同或不同且各自代表氫原子或式(A)之基團：
R1
、R2
及R3
中之至少一者代表基圍(A)之化合物為式(Ia)化合物之代謝產物，其中R1
、R2
及R3
各自代表氫原子。
本發明亦係關於以式(II)之香葉木素作為起始物製備式(I)化合物之方法：
使香葉木素與甲基烯丙基溴反應得到式(III)之化合物：
將式(III)之化合物加熱得到式(Ia)之化合物，其為式(I)化合物之具體實例，其中R1
、R2
及R3
各自代表氫原子：
當期望獲得其他式(I)之化合物時，使式(Ia)之化合物與式(IV)之化合物反應：
其中Ac代表乙醯基，在將基團(A)之酸官能團及醇官能團去保護之後得到式(I)之化合物，其中R1
、R2
及R3
中之至少一者不為H。
當式(I)之化合物係以混合物形式獲得時，可(例如)藉由製備型HPLC層析將其分離。
式(Ib)之化合物(其中R1
及R3
各自代表氫原子且R2
代表式(A)之基團)亦可藉由下述方法獲得：將式(Ia)之化合物乙醯化得到式(V)之化合物：
其中Ac代表乙醯基，使式(V)之化合物與式(IV)之化合物反應得到式(VI)之化合物：
其中Ac代表乙醯基，脫除式(VI)化合物之酸官能團、及醇及酚官能團之保護，得到式(Ib)之化合物。
本發明之化合物係黏附分子及NADPH氧化酶抑制劑、及抗血小板凝聚劑。
因此，其可用於預防或治療靜脈疾病，尤其慢性靜脈疾病之所有階段(疼痛、毛細管擴張、靜脈曲張、水腫、營養失調、潰瘍)，且亦可用於預防或治療血栓形成後症候群、與糖尿病有關之血管併發症、高血壓、動脈粥樣硬化、炎症、與肥胖症有關之代謝症候群、與肥胖症有關之血管併發症、心絞痛、下肢動脈炎或腦血管意外，用於治癒慢性傷口(主要包括靜脈型或混合型腿部潰瘍及糖尿病足)，用於治療或預防痔瘡發作，用於治療或預防壓力性潰瘍及用於治療多發性硬化症。
本發明亦係關於包含作為活性成份之式(I)化合物與一或多種醫藥上可接受之無毒惰性載劑或賦形劑的醫藥組合物。
在本發明醫藥組合物中尤其可提及彼等適於口服、非經腸(靜脈內、肌內或皮下)、經由或透過皮膚、鼻、直腸、舌、眼或呼吸道投與者，且尤其為錠劑或糖衣丸、可經舌下投與之錠劑、硬明膠膠囊、膠囊、栓劑、乳霜、油膏、皮膚凝膠、可注射或可飲用製劑、氣溶膠、滴眼劑及滴鼻劑。
除式(I)之化合物外，本發明之醫藥組合物包含一或多種賦形劑或載劑，例如稀釋劑、潤滑劑、黏合劑、崩解劑、吸收劑、著色劑、甜味劑。
可提及賦形劑或載劑之實例為：
◆作為稀釋劑：乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纖維素、甘油，
◆作為潤滑劑：二氧化矽、滑石、硬脂酸及其鎂鹽及鈣鹽、聚乙二醇，
◆作為黏合劑：矽酸鋁、矽酸鎂、澱粉、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉及聚乙烯基吡咯啶酮，
◆作為崩解劑：瓊脂、海藻酸及其鈉鹽、泡騰混合劑。
在醫藥組合物中，式(I)活性成份之百分比較佳為5重量%至50重量%。
可根據患者的年齡及體重、投與途徑、病症之性質及嚴重程度、及任何相關治療之施用來改變使用劑量且每天在0.5mg至1000mg範圍內，可按一或多次投與。
下列實例用以闡釋本發明。根據習用分光光度技術(紅外、核磁共振、質譜)來確定實例中所闡述化合物之結構。
DMSO：二甲基亞碸
NADPH：煙醯胺腺嘌呤二核苷酸磷酸之還原形式
HPLC：高效液相層析
向30g香葉木素中添加69.3g碳酸鉀及450ml丙酮。將混合物於回流下加熱4小時30分鐘且然後恢復至周圍溫度；然後添加54g甲基烯丙基溴。然後將反應混合物於回流下加熱過夜，且然後恢復至周圍溫度並過濾。用丙酮沖洗濾餅且然後蒸發掉濾液，得到殘餘物並將其自甲苯中重結晶，得到標題化合物。
向10g先前步驟中所獲得之化合物中添加120ml N,N-二甲基苯胺；然後將混合物於回流下加熱1小時。然後在低壓下蒸發掉溶劑並將所得殘餘物自異丙醇中重結晶，得到標題化合物。
藉由利用相轉移催化根據出版物Synth Commun
1999,29
(16), 2775-2781中所闡述之程序使實例1之化合物(250mg)與式(IV)之化合物(429mg)反應得到標題化合物。
將步驟A中所得化合物溶於甲醇中，且然後添加氫氧化鈉。將混合物回流1小時30分鐘且然後用2N鹽酸溶液中和，然後將其蒸發至乾燥，得到標題化合物。
將實例1之化合物(3g)溶於吡啶中，且然後於周圍溫度下添加乙酸酐(0.61ml)。然後將反應混合物攪拌16小時且隨後蒸發至乾燥。將殘餘物溶解於冰冷水中且然後用二氯甲烷萃取、乾燥、過濾並蒸發。將由此獲得之粗產物在矽膠上純化，且然後藉助反相製備型HPLC純化，得到標題化合物。
以先前步驟中所得化合物作為起始物根據實例2步驟A之程序來獲得標題化合物。
以先前步驟中所得化合物作為起始物根據實例2步驟B之程序來獲得標題化合物。
在以下實例中，術語「參考化合物」係指EP 0 709 383之實例69。
血液樣品係自經麻醉新西蘭兔子之頸動脈中採集並經0.109M檸檬酸鹽處理。藉由離心得到富含血小板之血漿。然後藉由離心來洗滌血小板。
將經洗滌之血小板重新懸浮於Tyrode緩衝液中。將血小板懸浮液放置於量測池(cell)中並然後於37℃下在實例1化合物(30μM)或參考化合物(30μM)(每一者皆係在相同溶劑(0.1% DMSO)中稀釋)之存在下邊攪拌邊將其放置於凝集計中。2分鐘後，利用膠原(4μg/ml)產生凝聚；然後記錄響應6分鐘。藉助比濁法(亦即，相對於含有Tyrode緩衝液之量測池及含有溶劑(0.1% DMSO)之量測池所透過血小板懸浮液之光之百分比)對血小板凝聚進行定量分析。
根據血小板凝聚抑制百分比之變化來評估本發明香葉木素化合物且尤其實例1化合物之抗凝聚功效，抑制百分比越大，則活性越大。實例1之化合物(30μM)產生36.6±9.9%之抑制，而參考化合物不產生顯著效果(4.1±1.8%)；(P<0.01，實例1之化合物相對於參考化合物，Student's t檢驗，n=7)。
該測試證實實例1之化合物具有抗血小板凝聚活性，且因此具有抗血栓形成潛力。
在此研究中使用3組(每組3隻)重量為90-110g之倉鼠。在麻醉前30分鐘，用單劑量的安慰劑(10%阿拉伯樹膠)、實例1之化合物(3mg/kg)或參考化合物(3mg/kg)經口治療倉鼠。藉由經腹膜內投與戊巴比妥(pentobarbital)50mg/kg來麻醉動物。將倉鼠放置於顯微鏡下並分離出頰囊並將其浸於灌注溶液(NaCl 110.0mM、KCl 4.7mM、CaCl2
2.0mM、MgSO4
1.2mM、NaHCO3
18.0mM、Hepes 15.39mM及Hepes Na+
鹽14.61mM)中，(Duling,The preparation and use of the hamster cheek pouch for studies of the microcirculation,
1973,Microvasc. Res. 5:423-429；等人，The hamster cheek pouch preparation as a model for studies of macromolecular permeability of the microvasculature,
1978,Uppsala J. Med. Sci. 83:71-79)。
藉助安裝於頰囊入口處之乳膠管造成局部缺血。藉助校正注射器將乳膠管之小管內壓力增加至200-220mm Hg。此完全性閉塞進行30分鐘，然後再灌注45分鐘。在開始缺血後，立即在6mm2
區域中定量分析黏附至毛細血管後小靜脈中之內皮細胞之白血球行(定義為100%)，然後在再灌注後的不同時間點(0、15、30及45分鐘)進行定量分析。
在倉鼠頰囊中由缺血性再灌注而產生之白細胞黏附模式能夠證明本發明香葉木素化合物(尤指實例1化合物)及參考化合物作為抗黏附劑之功效。
在缺血/再灌注後，根據6mm2
區域中黏附至內皮細胞之白細胞之數目變化來評估實例1化合物及參考化合物之活性，白細胞之數目越低且因此相對於缺血後黏附白細胞之數目而言黏附白細胞之百分比越低，則活性越大。
在缺血/再灌注後，實例1之化合物相對於安慰劑能夠明顯且顯著降低黏附至內皮細胞之白細胞之數目。實例1化合物之活性比參考化合物之活性更有效。
該測試表明實例1之化合物對白細胞黏附具有抑制活性且因此能夠用於治療靜脈疾病以及動脈血管疾病，例如動脈粥樣硬化或與糖尿病有關之血管併發症。
在該研究中使用4組(每組8隻)缺乏載脂蛋白E(ApoE-/-
，在其主動脈中自發地產生粥樣斑塊)之小鼠。在第9周時，藉由經5天5次腹腔內注射100mg/kg鏈脲黴素使小鼠患上糖尿病。在第10周時，將動物分成4組：實例1化合物之對照組、實例1化合物之治療組(130mg/kg/天於食物中，共6周)、參考化合物對照組、參考化合物治療組(130mg/kg/天於食物中，共6周)。在第15周時使用異氟烷將小鼠麻醉後將其處死。將主動脈移除、解剖並於液氮中冷凍。
將主動脈冷凍磨碎並使用RNeasy微型套組(Qiagen)提取總RNA。然後使用SuperscriptTM
III第一鏈cDNA合成套組(Invitrogen)對1μg總RNA實施反轉錄。利用實時PCR對VCAM-1之表現進行定量分析並相對於3種參考基因：β-肌動蛋白、次黃嘌呤-鳥嘌呤磷酸核糖基轉移酶(HPRT)及磷酸甘油醛脫氫酶(GAPDH)將其標準化。使用帶有2μl cDNA及150nM各引物之IQTM
SYBRGreen Supermix套組(Biorad)。使樣品於95℃下變性5分鐘並根據下述方案擴增40個循環：於95℃下變性20秒並對VCAM-1、β-肌動蛋白及HPRT在54℃下且對GAPDH在56℃下進行雜交並延伸1分鐘。將未經治療動物之VCAM-1之閾值循環(定義為認為螢光顯著高於背景噪聲之循環)相對於參考基因標準化(且認為是100%)且然後將其與經治療動物進行比較。
所用特異性引物如下所示：VCAM-1：5'-AGA GCA GAC TTT CTA TTT CAC-3'(正義)及5'-CCA TCT TCA CAG GCA TTT C-3'(反義)；β-肌動蛋白：5'-AAG ACC TCT ATG CCA ACA CAG-3'(正義)及5'-AGC CAC CGA TCC ACA CAG-3'(反義)；HPRT：5'-AGC TAC TGT AAT GAT CAG TCA ACG-3'(反義)；GAPDH：5'-GCC TTC CGT GTT CCT ACC C-3'(正義)及5'-TGC CTG CTT CAC CAC CTT-3'(反義)。
在缺乏ApoE之小鼠中造成糖尿病之模型能夠證明本發明香葉木素化合物作為抗黏附劑之功效。
根據與未經治療之動物相比主動脈中VCAM-1表現之程度變化來評估實例1化合物及參考化合物之活性，VCAM-1表現之程度越低，則此活性越大。用實例1化合物治療之小鼠相對於未經治療小鼠具有65.9±10.1%之VCAM-1表現程度(P<0.01，Student’s t檢驗，n=8)，而用參考化合物治療之小鼠具有83.0±6.6%之VCAM-1表現程度(P<0.05，Student's t檢驗，n=8)。
相對於未經治療組，實例1之化合物能夠明顯且顯著減少糖尿病ApoE-/-
小鼠主動脈中VCAM-1之表現。實例1化合物之活性比參考化合物之活性更有效。
該測試表明實例1化合物對黏附分子之表現具有抑制活性，且因此能夠用於治療靜脈疾病以及動脈病變，例如與糖尿病有關之血管併發症、高血壓、動脈粥樣硬化、炎症、與肥胖症有關之代謝症候群、與肥胖症有關之血管併發症、心絞痛、下肢動脈炎及腦血管意外。
該研究係在人類內皮細胞HUVEC(人類臍靜脈內皮細胞，
Clonetics公司)上進行。將細胞在補充有2% FCS(胎牛血清)及EGM2(內皮生長培養基，Clonetics公司)之EBM2培養基(內皮基礎培養基，Clonetics公司)中培養。
將細胞在溶劑(0.1%DMSO，實例1化合物之對照)、EBM2(實例2化合物之對照及實例3化合物之對照)、實例1之化合物(100μM)、實例2之化合物(100μM)或實例3之化合物(100μM)之存在下培育15分鐘，且然後使用血管收縮素II(1μM)將其活化30分鐘以使NADPH氧化酶活化。用EBM2洗滌細胞，且然後添加NADPH氧化酶受質(NADPH，200μM)及光澤精(lucigenin)(25μM)。使用光度計對由NADPH氧化酶產生之超氧陰離子所造成的光澤精之減少進行定量分析。將對照組之每秒計數(cps)之數目與治療組進行比較。認為對照組所獲得之cps具有100%NADPH氧化酶活性。
量測由血管收縮素II所產生之內皮NADPH氧化酶活性之模型能夠證明本發明香葉木素化合物作為NADPH氧化酶活性之抑制劑之功效。
根據所獲得cps之數目變化來評估實例1、2及3之化合物之活性，即cps數目越低，則活性越大。
實例1、2及3之化合物能夠明顯且顯著降低人類內皮細胞中之NADPH氧化酶活性。
該測試表明實例1、2及3之化合物對血管NADPH氧化酶活性具有抑制活性，且因此能夠用於抑制靜脈疾病以及動脈病變(如動脈粥樣硬化、高血壓、與糖尿病有關之血管併發症及局部缺血疾病)中之自由基。
製備1000個錠劑之配方，各錠劑均含有10mg活性成份：
實例1之化合物………………………………………10g
羥丙基纖維素…………………………………………2g
小麥澱粉………………………………………………10g
乳糖…………………………………………………100g
硬脂酸鎂……………………………………………3g
滑石粉………………………………………………3g
Claims (8)
- 一種式(I)之化合物：
- 如請求項1之式(I)化合物，其係選自：6,8,2'-參(異丁-2-烯-1-基)香葉木素、(5-羥基-2-[3-羥基-4-甲氧基-2-(異丁-2-烯-1-基)苯基]-6,8-雙(異丁-2-烯-1-基)-4-側氧基-4H -烯-7-基)-β-D-葡糖醛酸、及3-[5,7-二羥基-6,8-雙(異丁-2-烯-1-基)-4-側氧基-4H -烯-2-基]-6-甲氧基-2-(異丁-2-烯-1-基)苯基-β-D-葡糖醛酸。
- 一種合成如請求項1之式(I)化合物之方法，其係以式(II)之香葉木素作為起始物：
- 一種醫藥組合物，其包含作為活性成份之如請求項1或2之式(I)化合物與一或多種醫藥上可接受之無毒惰性載劑或賦形劑之組合。
- 一種如請求項1或2之化合物在製造藥劑中之用途，該等藥劑可用於治療靜脈疾病，用於治療血栓形成後症候群、與糖尿病有關之血管併發症、高血壓、動脈粥樣硬化、炎症、與肥胖症有關之代謝症候群、與肥胖症有關之血管併發症、心絞痛、下肢動脈炎或腦血管意外，用於治癒主要包括靜脈型或混合型腿部潰瘍及糖尿病足在內之慢性傷口，用於治療痔瘡發作，用於治療壓力性潰瘍且用於治療多發性硬化症。
- 一種如請求項1或2之化合物在製造藥劑中之用途，該等藥劑可用於治療慢性靜脈疾病。
- 如請求項1或2之化合物，其用於治療靜脈疾病，用於治療血栓形成後症候群、與糖尿病有關之血管併發症、高血壓、動脈粥樣硬化、炎症、與肥胖症有關之代謝症候群、與肥胖症有關之血管併發症、心絞痛、下肢動脈炎或腦血管意外，用於治癒主要包括靜脈型或混合型腿部潰瘍及糖尿病足在內之慢性傷口，用於治療痔瘡發作，用於治療壓力性潰瘍及用於治療多發性硬化症。
- 如請求項1或2之化合物，其用於治療慢性靜脈疾病。
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| EP2166010A1 (en) | 2008-09-23 | 2010-03-24 | Genkyo Tex Sa | Pyrazolo pyridine derivatives as NADPH oxidase inhibitors |
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| FR3002543A1 (fr) * | 2013-02-28 | 2014-08-29 | Servier Lab | Procede de synthese enzymatique de flavonoides, et application a la synthese de derives de diosmetine |
| CN106031723A (zh) * | 2015-09-29 | 2016-10-19 | 西南大学 | 香叶木素的抗炎活性及其制剂应用 |
| CN106822087A (zh) * | 2017-01-12 | 2017-06-13 | 西南大学 | 香叶木素在制备治疗ⅱ型糖尿病的药物中的应用 |
| AU2018262528A1 (en) * | 2017-05-04 | 2019-11-21 | Glenmark Pharmaceuticals S.A. | Substituted bicyclic heterocyclic compounds as NADPH oxidase inhibitors |
| WO2019018455A1 (en) * | 2017-07-19 | 2019-01-24 | Primus Pharmaceuticals, Inc. | METHODS OF TREATING AUTOIMMUNE MICROVASCULAR DISORDERS |
| CN109280067B (zh) * | 2017-07-21 | 2022-07-05 | 南京正大天晴制药有限公司 | 香叶木苷衍生物、其制备方法以及医药用途 |
| EP3700334A4 (en) * | 2017-10-27 | 2021-07-21 | Transfusion Health, LLC | COMPOSITIONS AND PROCESS FOR PRODUCING EXPANDED HEMATOPOETIC STEM CELLS USING FLUORENE DERIVATIVES |
| EP3479843A1 (en) | 2017-11-01 | 2019-05-08 | GenKyoTex Suisse SA | Use of nox inhibitors for treatment of cancer |
| CN109394753B (zh) * | 2018-12-24 | 2020-10-02 | 武汉轻工大学 | 香叶木素在制备预防和/或治疗高尿酸血症肾病的药物中的应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1129701A (zh) * | 1994-10-26 | 1996-08-28 | 阿迪尔公司 | 新的洋芫荽黄素化合物，其制备方法和含它们的药用组合物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2701261B1 (fr) * | 1993-02-05 | 1995-03-31 | Adir | Nouveaux composés glucuronides de la diosmétine, leur procédé de préparation et les compositions pharmaceutiques les renfermant. |
| FR2748025B1 (fr) * | 1996-04-25 | 1998-10-30 | Adir | Nouveaux acides et esters de la diosmetine, et les compositions pharmaceutiques les contenant |
| EP1063235B1 (en) * | 1998-03-12 | 2004-05-12 | Teijin Limited | Benzofurylpyrone derivatives |
| GB9920912D0 (en) * | 1999-09-03 | 1999-11-10 | Indena Spa | Novel derivatives of flavones,xanthones and coumarins |
| FR2882654B1 (fr) * | 2005-03-01 | 2007-04-27 | Servier Lab | Utilisation de derives de la diosmetine pour le traitement et la prevention des pathologies thrombotiques |
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