TWI422368B - 治療慢性阻塞性肺疾之組成物 - Google Patents
治療慢性阻塞性肺疾之組成物 Download PDFInfo
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- TWI422368B TWI422368B TW096106639A TW96106639A TWI422368B TW I422368 B TWI422368 B TW I422368B TW 096106639 A TW096106639 A TW 096106639A TW 96106639 A TW96106639 A TW 96106639A TW I422368 B TWI422368 B TW I422368B
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- 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
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
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Description
本發明係有關一種用以治療哺乳類對象之慢性阻塞性肺疾之組成物，其包括有效量之特定雙環化合物。
慢性阻塞性肺疾(COPD)是一種特徵為不完全可逆性氣流限制(airflow limitation)之疾病狀態。氣流限制通常是進行性，而且與對肺有害的顆粒或氣體產生的異常發炎反應相關。COPD為一個綜合術語，其時常用以敘述兩種固定型氣道疾病、慢性支氣管炎以及肺氣腫，但排除氣喘(可逆性氣流限制)。
COPD最重要的風險因子是抽香菸。在許多國家中廣受歡迎的煙斗、香菸以及其他種類的菸草吸用亦為COPD的風險因子。
COPD其它起因包含職業性粉塵與化學品(蒸氣劑、刺激劑以及煙)，當曝露夠強或時間延長時，在通風差的住宅內使用生質燃料烹調和加熱所造成的室內空氣污染或室外空氣污染增加肺吸進顆粒的總負荷，雖然其在導致COPD上所扮演的具體角色未明。被動性的曝露於香菸煙霧中亦會導致呼吸道症狀與COPD。嬰幼兒期的呼吸道感染與成人期的肺功能降低以及呼吸道症狀之增加相關(Global Initiative for Chronic Obstructive Lung Disease,POCKET GUIDE TO COPD DIAGNOSIS,MANAGEMENT,AND PREVENTION,A Guide for Health Care Professionals,UPDATED July,2005)。
醫師表示目前的治療僅提供症狀舒緩，而因此歡迎能透過減緩肺功能之進行性流失或，更重要地，逆轉已建立之疾病本身，以改變COPD發展的療法。然而，尚未有任何一種療法能將這些概念轉化成臨床效益。多種治療類別中的許多作用製劑正被審查。然而，此等作用製劑並不預期能滿足緩和或逆轉肺功能之進行性流失的主要未滿足之需求。
前列腺素類(後文中稱為PG(s))為有機羧酸類別的成員，該前列腺素類係含括於人類或其他哺乳類的組織或器官中，而且展示寬的生理活性範圍。自然中發現的PGs(初級PGs)通常具有如下式(A)中顯示的前列腺酸骨架：
在另一方面，初級PGs的某些合成類似物具有經修飾的骨架。初級PGs係根據5－員環部份之結構分類成PGAs、PGBs、PGCs、PGDs、PGEs、PGFs、PGGs、PGHs、PGIs以及PGJs，並且進一步根據碳鏈部份的不飽和鍵結的數目與位置分類成以下三種類型：下標1：13,14－不飽和－15－OH下標2：5,6－與13,14－二不飽和－15－OH下標3：5,6－、13,14－以及17,18－三不飽和－15－OH。
再者，PGFs係根據在9－位置的羥基之構型分類成α型(羥基是α－構型)與β型(羥基是β－構型)。
PGE1
、PGE2
以及PGE3
已知具有血管舒張、低血壓、胃分泌降低、腸道蠕動強化、子宮收縮、利尿、支氣管擴張以及抗潰瘍活性。PGF1 α
、PGF2 α
以及PGF3 α
已知具有高血壓、血管收縮、腸道蠕動強化、子宮收縮、黄體萎縮以及支氣管擴張活性。
某些15－酮(亦即，15－位置具有側氧而非羥基)－PGs與13,14－二氫(亦即，於13－位置與14－位置之間具有單鍵)－15－酮－PGs已知為經由初級PGs的代謝過程中之酵素作用而自然產生的物質。
Ueno等人的美國專利第5,254,588號中敘述某些15－酮－PG化合物適用於肺功能不足之治療。
Ueno等人的美國專利第5,362,751號中敘述某些15－酮－PG化合物適用為氣管支氣管擴張劑。
Ueno等人的美國專利第6,197,821號中敘述某些15－酮－PG化合物為內皮素的拮抗物，該內皮素被認為與高血壓、柏格氏症(Buerger disease)、氣喘、眼底疾病等等有關係。
Ueno等人的美國專利第7,064,148號與美國專利公開第2003/0166632號中敘述前列腺素化合物開啟並且活化氯通道，特別是ClC通道，更特別是ClC－2通道。
以上文獻以引用方式納入本文。
目前並不知特定的雙環化合物如何作用於COPD上。
本發明的一目的為提供一種於哺乳類患者中用以治療慢性阻塞性肺疾的方法。於一態樣中，本發明的一目的為提供一種於哺乳類患者中用以治療慢性阻塞性肺疾的醫藥組成物。本發明者進行密集的研究，並且發現特定的雙環化合物適用於COPD的治療，其造成本發明之完成。
亦即，本發明係有關於哺乳類對象中用以治療慢性阻塞性肺疾的方法，其包括對有需要之對象投予有效量之式(I)表示之雙環化合物或其醫藥上可接受之鹽類、醚類、酯類或醯胺類、及/或其互變異構物：
其中A1
與A2
為相同或不同的鹵素原子以及B為－CH3
、－CH2
OH、－COCH2
OH、－COOH。
本發明亦提供一種醫藥組成物，其包括有效量之上式(I)表示之雙環化合物及/或其互變異構物以於哺乳類對象中用以治療慢性阻塞性肺疾。
本發明進一步提供上式(I)表示之雙環化合物及/或其互變異構物的用途，係用於製造於哺乳類患者中用以治療慢性阻塞性肺疾的醫藥組成物。
式(I)表示之使用於本發明之雙環化合物或其醫藥上可接受之鹽類、醚類、酯類或醯胺類：
其中A1
與A2
為相同或不同的鹵素原子以及B為－CH3
、－CH2
OH、－COCH2
OH、－COOH。
術語“鹵素”是習知用以包含氟、氯、溴以及碘原子。A1
與A2
特別較佳的鹵素原子為氟原子。
適當的“醫藥上可接受的鹽類”包含習知使用的無毒性鹽類，例如：具有無機鹼的鹽，如：鹼金屬鹽(諸如：鈉鹽與鉀鹽)、鹼土金屬(諸如：鈣鹽與鎂鹽)、銨鹽；或具有有機鹼的鹽，例如：胺鹽(諸如：甲基胺鹽、二甲基胺鹽、環己基胺鹽、芐基胺鹽、六氫吡啶鹽、乙二胺鹽、乙醇胺鹽、二乙醇胺鹽、三乙醇胺鹽、三(羥基甲基胺)乙烷鹽)、單甲基－單乙醇胺鹽、普羅卡因鹽以及咖啡鹼鹽)、鹼性胺基酸鹽(諸如：精胺酸鹽與離胺酸鹽)、四烷基胺鹽等等。這些鹽類可經由習知製法進行製備，例如：來自對應的酸與鹼或經由鹽互換。
醚類之例子包含烷基醚類，例如：低碳數烷基醚類，諸如，甲基醚、乙基醚、丙基醚、異丙基醚、丁基醚、異丁基醚、三級丁基醚、戊基醚以及1－環丙基醚；以及中等或較高碳數的烷基醚類，如：辛基醚、二乙基己基醚、十二基醚以及十六基醚；不飽和醚類，如：油基醚與亞麻基醚；低碳數烯基醚類，如：乙烯基醚、烯丙基醚；低碳數炔基醚類，如：乙炔基醚與丙炔基醚；羥基(低碳數)烷基醚類，如：羥基乙基醚與羥基異丙基醚；低碳數烷氧基(低碳數)烷基醚類，如：甲氧基甲基醚與1－甲氧基乙基醚；視需要經取代之芳基醚類，如：苯基醚、甲苯磺醯基醚、三級丁基苯基醚、水楊基醚、3,4－二－甲氧基苯基醚以及苯甲醯胺基苯基醚(Benzamidophenyl ether)；以及芳基(低碳數)烷基醚類，如：苄基醚、三苯甲基醚以及二苯甲基醚。
酯類之例子包含脂肪族酯類，例如：低碳數烷基酯類，如：甲基酯、乙基酯、丙基酯、異丙基酯、丁基酯、異丁基酯、三級丁基酯、戊基酯以及1－環丙基乙基酯；低碳數烯基酯類，如：乙烯基酯與烯丙基酯；低碳數炔基酯類，如：乙炔基酯與丙炔基酯；羥基(低碳數)烷基酯類，如：羥基乙基酯；低碳數的烷氧基(低碳數)烷基酯類，如：甲氧基甲基酯與1－甲氧基乙基酯；以及視需要經取代之芳基酯類，例如：苯基酯、甲苯磺醯基酯、三級丁基苯基酯、水楊基酯、3,4－二－甲氧基苯基酯以及苯甲醯胺基苯基酯；以及芳基(低碳數)烷基酯類，如：苄基酯、三苯甲基酯以及二苯甲基酯。
B之醯胺意指式－CONR’R”代表之基團，其中R’與R”中之各者為氫原子、低碳數烷基、芳基、烷基－或芳基－磺醯基、低碳數烯基以及低碳數炔基，而且包含，例如：低碳數烷基醯胺，如：甲基醯胺、乙基醯胺、二甲基醯胺以及二乙基醯胺；芳基醯胺，如：苯胺與甲苯胺；以及烷基－或芳基－磺醯胺，如：甲基磺醯胺、乙基磺醯胺以及甲苯基磺醯胺。
較佳的實施例包括式(I)代表之雙環化合物，其中A1
與A2
為氟原子，而B為－COOH。
本發明的雙環化合物是以固態的雙環形式存在，但當溶解於溶劑中時，部分形成上述化合物的互變異構物。在無水的情況下，式(I)代表之化合物主要以雙環化合物的形式存在。在水性媒介中，咸信於例如：C－15位置的酮間產生氫鍵結，因此阻礙雙環之形成。此外，咸信在C－16位置的鹵素促使雙環之形成。C－11位置的羥基與C－15位置的酮部份之間的互變異構性，如下所示，在化合物為具有13,14單鍵結以及兩個氟原子在C－16的位置之情況下特別顯著。
根據本發明，式(I)之化合物之該“互變異構物”，例如：具有酮基在C－15位置以及鹵素原子在C－16位置的單環互變異構物，亦可作為治療用途。
本發明較佳的化合物根據習知的前列腺命名法，將其單環形式命名為13,14－二氫－15－酮基－16,16－二氟－18(S)－甲基－PGE1
。
本發明使用的化合物可經由美國專利第5,739,161號(該文獻以引用方式納入本文)中揭露的方法製備。
根據本發明，哺乳類對象可經由投予本發明中使用的化合物而獲得治療。該對象可為任何哺乳類對象，包含人。該化合物可全身應用或局部應用。通常，該化合物可經由口服、鼻內投藥、吸入投藥、靜脈注射(包含浸透)、皮下注射、直腸投藥、透過皮膚投藥等等，予以投藥。
劑量可視動物品種、年齡、體重、欲治療的症狀、期望的治療效果、投藥途徑、治療期限等等而異。滿意的效果可經由每天1至4次的全身性或局部性投藥或以每天0.00001至500 μ g/kg，較佳為0.0001至100 μ g/kg，更佳為0.001至10 μ g/kg的量連續投藥獲得。
該化合物可經由習知適合投藥的方法調配醫藥組成物。該組成物適用於口服、鼻內投藥、吸入投藥、注射或滲透者，而且可為適用為外用劑、栓劑或陰道栓劑。
本發明組成物可進一步含有生理上可接受的添加劑。該等添加劑可包含與本發明化合物合用的成分，如：賦形劑、稀釋劑、填料、溶劑、潤滑劑、佐劑、黏合劑、崩解劑、塗劑、膠囊劑、軟膏基劑、栓劑基劑、噴霧劑、乳化劑、分散劑、懸浮劑、調稠劑、張力劑、緩衝劑、鎮定劑、防腐劑、抗氧化劑、矯正藥、調味劑、著色劑以及功能性物質(諸如：環糊精、生物可降解聚合物以及安定劑)。該等添加劑亦為習知，而且可選自製藥學的通用參考書中所敘述者。
本發明組成物中之上述化合物的量可視組成物的配方而變化，而且通常可為0.000001至10.0%，較佳為0.00001至5.0%，最佳為0.0001至1%。
作為口服投藥之固體組成物之例子包含錠劑、片劑、舌下錠、膠囊、丸劑、粉劑、顆粒等等。該固體組成物可經由將一種或多種活性成分與至少一種惰性稀釋液混合而製備。除了惰性稀釋液外，該組成物可進一步含有添加劑，例如：潤滑劑、崩解劑以及安定劑。若需要，錠劑與片劑可由腸膜或胃腸膜塗布。它們可經由兩層或多層覆蓋。它們亦可經吸附至持續釋放的物質，或經微囊化。另外，該組成物可經由使用容易分解的材料，如：明膠，之手段而經膠囊化。它們可進一步溶解於適當溶劑中，例如：脂肪酸或其單－、二－或三酸甘油酯，形成軟膠囊。舌下錠可用於快速作用特性的需求。
作為口服、鼻內投藥或吸入投藥之液體組成物之例子包含乳化物類、溶液類、懸浮物類、糖漿類、酏劑類等等。該組成物可進一步含有習知使用的惰性稀釋液，例如，纯水或乙醇。該組成物除了惰性稀釋液外，可含有其他添加劑，諸如：佐劑，例如：濕潤劑與懸浮劑、甘味劑、調味劑、風味劑以及防腐劑。
本發明組成物可以是噴灑組成物的形式，其含有一種或多種活性成分，而且可根據已知的方法製備。
鼻內投藥之例子可為包括一種或多種活性成分的水性或油性之溶液、懸浮物或乳化物。對於經由吸入投藥之活性成分而言，本發明組成物可以是溶液、懸浮物或乳化物之形式，其可提供噴霧劑或適用於亁粉劑吸入之粉劑形式。作為吸入投藥之組成物可復包括習知使用的推進劑。
作為非腸道投藥之本發明可注射的組成物之例子包含無菌水性或非水性溶液、懸浮物以及乳化物。用於水性溶液或懸浮物之稀釋液可包含，例如：用於注射之蒸餾水、生理食鹽水以及林格溶液(Ringer’s solution)。
用於溶液與懸浮物之非水性稀釋液可包含，例如：丙二醇、聚乙二醇、植物油類(諸如：橄欖油)、醇類(諸如：乙醇)以及聚山梨糖醇酯。該組成物可復包括添加劑，諸如，防腐劑、濕潤劑、乳化劑、分散劑等等。它們可透過，例如，持留細菌的過濾器(Bacteria－retaining filter)搭配滅菌器或經由氣體或放射性同位素輻射殺菌之手段，達到滅菌的效果。
該可注射之組成物亦可以經滅菌的粉劑組成物提供，於注射之前先將該組成物溶解於經滅菌的溶劑。
本發明另一形式為栓劑或陰道栓劑，其可經由將活性成分混入習知的基劑中而製備，該基劑諸如：在體溫下軟化之可可酯，以及可用於改善吸附性之具有適當軟化溫度的非離子性界面活性劑。
本文中使用的術語“治療法”或“治療”包含任何控制的手段，諸如：病症之預防、照顧以及舒緩、病症之減退以及阻止惡化。
如上述，術語“慢性阻塞性肺疾”或“COPD”包含以不完全可逆之氣流限制為特徵的疾病症狀。“COPD”為一個綜合術語，其時常用以敘述兩種固定型氣道疾病、慢性支氣管炎以及氣腫的臨床症狀。因此，本化合物適用於COPD之治療，包含慢性支氣管炎與氣腫。
COPD通常是與症狀的惡化相關，而且許多惡化係由氣管支氣管樹或空氣污染之增加所造成。根據本發明，亦提供經由使用本發明之醫藥組成物治療基於或伴隨COPD的感染。
本發明醫藥組成物可含有式(I)之一種或多種化合物，而且只要不與本發明的目的相矛盾，除了式(I)之化合物外，可復含有一種或多種藥物上具有活性的成分。
本發明進一步的細節將依循試驗樣品之參考例，然而該參考例卻不意欲限制本發明。
(方法)使用煙燻系統(INH06－CIG01A,M.I.P.S.Inc.)將天竺鼠曝露於香菸的煙中。將每一隻動物安置於曝露托架中，並且將托架固定於曝露室中。每天將30條香菸(Peace,Japan Tobacco,Inc.)所產生的煙吸取入曝露室中，每週進行5天，總共進行25天(天1至5)。在偽曝露組中，將空氣吸取入曝露室中，而非香菸所產生的煙。
化合物A(13,14－二氫－15－酮基－16,16－二氟－18(S)－甲基－PGE1
)之水性溶液經由使用加壓的噴霧器(LC Plus Nebulizer,Pari GmbH)而蒸發，並且在曝露於香菸的煙之前，先經由在吸入系統(SIS－A,Sibata Scientific Technology,Ltd.)使室中的動物吸入30分鐘至1小時。
第26天時，經由呼吸道功能測量系統(Pulmos－1,M.I.P.S Inc.)以雙流體積變化描記技術進行意識動物之特定呼吸道阻抗(sRaw)的測量。
測量sRaw後，將動物以氯胺酮(60mg/kg)與二甲苯胺噻(8mg/kg)麻醉，而且插套管於氣管中。使用肺功能測量系統(Biosystem Manoeuvers,Buxco Electronics,Inc.)進行肺功能的測量。測量的參數包括在100msec(FEV100
)下的殘留體積(RV)與強迫呼出體積(Forced expiratory volume)。
測量肺功能後，將動物在麻醉下放血犧牲，並且將胸切開。將5毫升鹽水通過氣管插管注入肺中，接著經由微吸將沖洗液回收。將此步驟重複，並且結合回收的沖洗液(總共10mL，支氣管肺泡沖洗液，BALF)。將BALF中的巨噬細胞(單核細胞)進行計算。
(結果)如表1所示，控制組中之特定呼吸道阻抗(sRaw)與偽曝露組進行比較，發現其經由曝露於香菸的煙中而增加。化合物A與控制組進行比較，發現其顯著地抑制香菸的煙曝露所誘導sRaw之增加。
如表2所示，與偽曝露組中者進行比較，發現經由曝露於香菸的煙而增加控制組中在100msec(FEV100
)下的殘留體積(RV)，並且減少強迫呼出體積。化合物A與控制組比較，其顯著地抑制香菸的煙曝露所誘發的這些改變。
如表3所示，與偽曝露組中者進行比較，控制組中的支氣管肺泡沖洗液中之巨噬細胞(單核細胞)的數量係經由曝露於香菸的煙而增加。與控制組進行比較，化合物A顯著地抑制香菸的煙曝露所誘發之巨噬細胞(單核細胞)在數量上的增加。
這些結果顯示化合物A對COPD之治療有益處。
(方法)將來自8條香菸的煙緩慢的吸取入不含血清的100ml培養基中，並且將產生的懸浮物通過0.20μm的濾網過濾。將溶液視為100%香菸的煙萃取物(CSE)。將人肺泡第二型細胞(A549)於具有96孔的盤中培養48小時至最終濃度為每孔1.5×105
細胞。接著，將細胞分別以100nM化合物A或1%、2.5%以及5%CSE處理。於別組中，將100nM化合物A與1%、2.5%以及5%CSE一起添加。將所有培養於37℃下進行24小時。在24小時的處理後，將所有的細胞以0至4℃ PBS洗滌三次。根據細胞色素c酵素免疫測定(Cytochrome c ELISA assay)套組中提供的說明，測量易位(Translocate)至細胞質之細胞色素C。作為細胞受傷的標記。
(結果)在24小時之處理後進行測量，發現在範圍1.0%至5%中的CSE造成從細胞粒腺體至細胞質中(易位)的細胞色素C的增加為劑量依賴性。如第1圖所示，與無1%DMSO的控制組進行比較，發現在1%CSE下，細胞色素C的易位無顯著地增加，但在2.5%與5%CSE下，細胞色素C的易位顯著地增加(分別為P<0.01與P<0.005)。當與1%、2.5%以及5%CSE下的0.1% DMSO控制組比較，觀察到相似的結果(NS,分別為P<0.01與P<0.05)。當與1%、2.5%以及5% CSE下的DMSO控制組比較，化合物A顯著地減少細胞色素C的易位(分別為P<0.05、P<0.002以及P<0.005)。
該結果證實化合物A於肺泡細胞中的保護效果。這些結果證實化合物A對COPD的治療有益處。
雖然本發明詳細敘述並參照其特定實施例，對熟悉此項技藝者，可對其內進行多種改變與修正，而不會超出其精神與範疇。
第1圖描述在100nM化合物A的存在或不存在下，在24小時CSE處理後，顯示細胞色素(Cytochrome c)從A549粒腺體易位(Translocation)的圖。A549生長至聚集，並且經由1%(E)、2.5%(H)以及5%(K)CSE處理24小時。之後，測量細胞色素C的易位。單獨地0.1% DMSO(B)(化合物A的媒劑)或化合物A(C)不會顯著地影響細胞質的細胞色素C。CSE以劑量依賴性造成細胞色素C的易位顯著地增加。CSE的所有劑量中，100nM化合物A(E,G,I)避免由CSE所誘導之細胞色素C的易位。數據係以平均數±SEM pg/孔表達，每一點的孔數n顯示於圖中每一條上方。數據係以pg/孔之細胞色素C表達。每一孔含有1.5×105
個細胞。
Claims (7)
- 一種式(I)代表之雙環化合物之用途：
- 如申請專利範圍第1項之用途，其中A1 與A2 為氟原子。
- 如申請專利範圍第2項之用途，其中B為-COOH。
- 一種式(I)代表之雙環化合物之用途：
- 一種式(I)代表之雙環化合物之用途：
- 如申請專利範圍第4項或第5項之用途，其中A1 與A2 為氟原子。
- 如申請專利範圍第6項之用途，其中B為-COOH。
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|---|---|---|---|---|
| EP0978284A1 (en) * | 1997-11-28 | 2000-02-09 | R-Tech Ueno, Ltd. | Endothelin antagonist |
Non-Patent Citations (1)
| Title |
|---|
| E. Weitzenblum et al, "Medical treatment of pulmonary hypertension in chronic lung disease", European Respiratory Journal, 7:148-152, 1994. * |
Also Published As
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| WO2007102446A3 (en) | 2008-04-03 |
| CA2642744A1 (en) | 2007-09-13 |
| WO2007102446A2 (en) | 2007-09-13 |
| JP5377970B2 (ja) | 2013-12-25 |
| AU2007223469B2 (en) | 2012-06-07 |
| JP2009528259A (ja) | 2009-08-06 |
| CN101432002A (zh) | 2009-05-13 |
| KR20080104024A (ko) | 2008-11-28 |
| AR059636A1 (es) | 2008-04-16 |
| EP1988905B1 (en) | 2014-06-04 |
| US20070203228A1 (en) | 2007-08-30 |
| CN101432002B (zh) | 2012-04-04 |
| JP2013209429A (ja) | 2013-10-10 |
| MX2008011148A (es) | 2008-09-08 |
| EP1988905A2 (en) | 2008-11-12 |
| NZ571092A (en) | 2010-11-26 |
| KR101409706B1 (ko) | 2014-06-20 |
| TW200800161A (en) | 2008-01-01 |
| CA2642744C (en) | 2015-02-24 |
| BRPI0708362A2 (pt) | 2011-05-24 |
| AU2007223469A1 (en) | 2007-09-13 |
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