TW202328118A - 用於預防或治療特發性肺纖維化(ipf)之組合物 - Google Patents
用於預防或治療特發性肺纖維化(ipf)之組合物 Download PDFInfo
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- TW202328118A TW202328118A TW111140937A TW111140937A TW202328118A TW 202328118 A TW202328118 A TW 202328118A TW 111140937 A TW111140937 A TW 111140937A TW 111140937 A TW111140937 A TW 111140937A TW 202328118 A TW202328118 A TW 202328118A
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Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本發明係關於用於預防或治療特發性肺纖維化之醫藥組合物,其包含由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽作為有效成分;使用該化合物預防或治療特發性肺纖維化之方法;該化合物用於預防或治療特發性肺纖維化之用途;以及該化合物用於製備用以預防或治療特發性肺纖維化之藥劑之用途。
Description
本發明係關於用於預防或治療特發性肺纖維化之醫藥組合物,其包含由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽作為有效成分;使用該化合物預防或治療特發性肺纖維化之方法;該化合物用於預防或治療特發性肺纖維化之用途;以及該化合物用於製備用以預防或治療特發性肺纖維化之藥劑之用途。
特發性肺纖維化(IPF)為一種原因未明的疾病,其中肺實質在肺泡上皮細胞受損後由於異常組織修復機制而變成纖維狀。IPF顯示諸如慢性乾咳、呼吸短促等症狀且為具有不良預後之疾病,在由於出現症狀而確診後,存活期通常僅為約3至5年。已知在超過50歲之男性中,發病率較高。
當前,主要使用兩種藥物,即尼達尼布(nintedanib)及吡非尼酮(pirfenidone),治療特發性肺纖維化,但該等藥物僅減緩疾病進展而不會改善存活率。因此,迫切需要研發能夠有效治療特發性肺纖維化之藥物。
[相關技術參照]
[專利文獻]
(專利文獻1)韓國未審查專利申請公開案第10-2014-0128886號
技術問題本發明提供用於預防或治療特發性肺纖維化之醫藥組合物,其包括由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽作為有效成分。
本發明提供用於預防或治療特發性肺纖維化之方法,其包括向個體投與由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽。
本發明提供由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽的用途,其係用於預防或治療特發性肺纖維化。
本發明提供由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽的用途,其係用於製備用以預防或治療特發性肺纖維化之藥劑。
技術解決方案技術解決方案詳細地描述於下文中。同時,本發明中所揭示之各說明及實施例亦可分別適用於其他說明及實施例。換言之,本發明中所揭示之各種要素的所有組合均屬於本發明之範疇內。此外,可發現本發明之範疇不限於下文所描述之特定說明。
本發明提供用於預防或治療特發性肺纖維化之醫藥組合物,其包括由以下式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽作為有效成分。
[式I]
其中
A為
,
Xa及Xb各自獨立地為CH或N,
L
1及L
2各自獨立地為氫、鹵素、-CF
3或-C
1 - 3直鏈或分支鏈烷基,
Q為C(=O)、S(=O)
2、S(=O)或C(=NH),
Y係選自以下基團:
,
M為C、N、O、S或S(=O)
2(此時,若M為C,則l及m為1;若M為N,則l為1且m為0;且若M為O、S或S(=O)
2,則l及m為0),
R
a1及R
a2各自獨立地為氫;羥基;-C
1 - 4直鏈或分支鏈烷基,其未經取代或經至少一個鹵素取代;-C
1 - 4直鏈或分支鏈醇;二苯甲基;-C
1 - 4直鏈或分支鏈烷基,其經具有一至三個選自N、O或S之雜原子作為環成員的飽和或不飽和五員至七員雜環化合物取代(此時,雜環化合物可為未經取代的或至少一個氫可視情況經OH、OCH
3、CH
3、CH
2CH
3或鹵素取代);具有一至三個選自N、O或S之雜原子作為環成員的飽和或不飽和五員至七員雜環化合物(此時,雜環化合物可為未經取代的或至少一個氫可視情況經OH、OCH
3、CH
3、CH
2CH
3或鹵素取代);苯基,其未經取代或其中至少一個氫經鹵素、C
1 - 4烷氧基、C
1 - 2烷基或羥基取代;苯甲基,其未經取代或其中至少一個氫經鹵素、C
1-4烷氧基、C
1-2烷基或羥基取代;-S(=O)
2CH
3;鹵素;-C
1 - 6直鏈或分支鏈烷氧基;-C
2 - 6烷氧基烷基;-C(=O)R
x,其中R
x為C
1 - 3直鏈或分支鏈烷基或C
3 - 10環烷基;
,其中R
c及R
d獨立地為氫或C
1 - 3直鏈或分支鏈烷基;
或
,
n為0、1或2之整數,
R
b為氫;羥基;-C
1 - 6直鏈或分支鏈烷基,其未經取代或其中至少一個氫經鹵素取代;-C(=O)CH
3;-C
1 - 4直鏈或分支鏈羥基烷基;-C
1 - 6直鏈或分支鏈烷氧基;-C
2 - 6直鏈或分支鏈烷氧基烷基;-CF
3;鹵素;或
,
R
e及R
f各自獨立地為氫或-C
1 - 3直鏈或分支鏈烷基,且
Z係選自以下基團:
,
P
a及P
b各自獨立地為
;氫;羥基;-C
1 - 4直鏈或分支鏈烷基,其未經取代或其中至少一個氫經鹵素取代;鹵素;-CF
3;-OCF
3;-CN;-C
1 - 6直鏈或分支鏈烷氧基;-C
2 - 6直鏈或分支鏈烷基烷氧基;-CH
2F;或-C
1 - 3醇,
其中
係選自苯基、吡啶、嘧啶、噻唑、吲哚、吲唑、哌𠯤、喹啉、呋喃、四氫吡啶、哌啶或以下基團之環:
,
x、y及z各自獨立地為0或1之整數,且
R
g1、R
g2及R
g3各自獨立地選自氫;羥基;-C
1 - 3烷基;-CF
3;-C
1 - 6直鏈或分支鏈烷氧基;-C
2 - 6直鏈或分支鏈烷基烷氧基;-C(=O)CH
3;-C
1 - 4直鏈或分支鏈羥基烷基;-N(CH
3)
2;鹵素;苯基;-S((=O)
2)CH
3;或以下基團:
。
在本發明中,由以上式I表示之化合物為由以下式Ia表示之化合物:
[式Ia]
其中
Y係選自以下基團:
其中M、l、m、n、R
a1、R
a2及R
b各自與以上式I中所定義的相同,
Z為
,且
P
a及P
b各自獨立地為氫;羥基;-C
1 - 4直鏈或分支鏈烷基,其未經取代或其中至少一個氫經鹵素取代;鹵素;-CF
3;-OCF
3;-CN;-C
1 - 6直鏈或分支鏈烷氧基;-C
2 - 6直鏈或分支鏈烷基烷氧基;-CH
2F;或-C
1 - 3醇。
根據本發明之一個實施例態樣,
Y係選自以下基團:
,
其中n及R
b分別與以上式I中所定義的相同,
Z為
,且
P
a及P
b各自獨立地為氫;鹵素;-CF
3;或-C
1 - 6直鏈或分支鏈烷氧基。
在本發明中,「鹵素」為F、Cl、Br或I。
根據本發明之特定實施例,由以上式I表示之化合物可為下表中所描述之化合物。
根據本發明之特定實施例,由以上式I表示之化合物可為下表中所描述之化合物。
在本發明中,由以上式I表示之化合物可藉由韓國未審查專利申請公開案第10-2014-0128886號中所揭示之方法製備,但不限於此。
在本發明中,由以上式I表示之化合物可含有至少一個不對稱碳,且因此可以鏡像異構物混合物形式存在,該鏡像異構物混合物包括外消旋混合物、單一鏡像異構物(光學異構物)、非鏡像異構物之混合物及單一非鏡像異構物。此類異構物可根據相關技術(例如,管柱層析法、HPLC或其類似技術)藉由拆分來分離。或者,異構物可藉由使用一系列已知的光學純起始物質及/或試劑以立體特異性方式合成。特定言之,該異構物可為光學異構物(鏡像異構物)。
在本發明中,術語「醫藥學上可接受」可指在向個體投與時為生理學上可接受的且通常不會引起胃腸紊亂、過敏性反應,諸如眩暈或與其類似之其他反應。
根據本發明之實施例的醫藥學上可接受之鹽可藉由熟習此項技術者已知之習知方法來製備。
根據本發明之實施例的醫藥學上可接受之鹽可包括例如:由鈣、鉀、鈉、鎂等製備之無機離子鹽;由氫氯酸、硝酸、磷酸、溴酸、碘酸、過氯酸、硫酸、氫碘酸等製備之無機酸鹽;由乙酸、三氟乙酸、檸檬酸、順丁烯二酸、丁二酸、草酸、苯甲酸、酒石酸、反丁烯二酸、杏仁酸、丙酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、麩胺酸、戊二酸、葡萄糖醛酸、天冬胺酸、抗壞血酸、碳酸、香草酸等製備之有機酸鹽;由甲磺酸、乙磺酸、苯磺酸、對甲苯磺酸、萘磺酸等製備之磺酸鹽;由甘胺酸、精胺酸、離胺酸等製備之胺基酸鹽;由三甲胺、三乙胺、氨、吡啶、甲吡啶等製備之胺鹽;及其類似鹽,但不限於此。在本發明之實施例中,鹽可包括氫氯酸、三氟乙酸、檸檬酸、溴酸、順丁烯二酸、磷酸、硫酸或酒石酸。
在本發明中,術語「特發性肺纖維化(IPF)」可指其中肺實質在肺泡上皮細胞不明原因受損後由於異常組織修復機制而變成纖維狀之疾病。
在本發明中,術語「預防」可指藉由投與本發明之式I化合物、其光學異構物或其醫藥學上可接受之鹽來抑制或延緩疾病之發生的所有行為。
在本發明中,術語「治療」可指藉由投與本發明之式I化合物、其光學異構物或其醫藥學上可接受之鹽而使可能發展或患有疾病之個體的症狀得到改善或發生好轉的所有行為。
本發明之由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽可有利地用於預防或治療特發性肺纖維化。
包括本發明之由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽作為活性成分的醫藥組合物可有利地用於預防或治療特發性肺纖維化。
就此而言,在本發明之一個特定實施例中,已證實本發明之由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽抑制TGF-β1誘導之纖維化蛋白(原COL1A1及LOXL2)之表現(圖1)。
此外,證實在患有由BLM誘發之肺纖維化的小鼠中,本發明之由式I表示的化合物、其光學異構物或其醫藥學上可接受之鹽恢復所減少之體重(圖2);減少所增加之總細胞、嗜中性球、淋巴細胞及巨噬細胞之數目以抑制炎性細胞之浸潤(圖3);減少所增加之肺重量(圖4);抑制所增加之纖維化基因(COK1A1、FN1、PAI1、TIMP-1及SPP1)之表現(圖5);以及減少所增加之阿希克夫評分(Ashcroft score)及新生膠原蛋白1A1 (
de novocollagen 1A1)之沈積,從而展現抗纖維化作用(圖6及圖7)。
此外,證實本發明之由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽抑制由TGF-β1誘發之膠原蛋白收縮(圖8及圖9);抑制纖維母細胞、DHLF-IPF細胞之遷移(圖10及圖11);以及抑制由PDGF-BB誘發之細胞增殖,從而展現抗纖維化作用(圖12)。
本發明之由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽可展示預防或治療特發性肺纖維化之作用,其作用程度類似於或基本上等同於或優於用以預防或治療特發性肺纖維化之習知已知藥物。
包括本發明之由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽作為活性成分的醫藥組合物可展示預防或治療特發性肺纖維化之作用,其作用程度類似於或基本上等同於或優於用以預防或治療特發性肺纖維化之習知已知藥物。
除了由以上式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽之外,根據本發明之實施例之醫藥組合物可進一步包括至少一種醫藥學上可接受之載劑。醫藥學上可接受之載劑可為習知地用於此項技術中之載劑,尤其包括(但不限於)乳糖、右旋糖、蔗糖、山梨醇、甘露醇、澱粉、阿拉伯膠(acacia rubber)、磷酸鈣、海藻酸鹽、明膠、矽酸鈣、微晶纖維素、聚乙烯吡咯啶、纖維素、水、糖漿、甲基纖維素、羥基苯甲酸甲酯、羥基苯甲酸丙酯、滑石、硬脂酸鎂或礦物油。除以上成分之外,根據本發明之實施例之醫藥組合物可進一步包括潤滑劑、保濕劑、甜味劑、調味劑、乳化劑、懸浮劑、防腐劑、分散劑、穩定劑等。另外,根據本發明之實施例之醫藥組合物可藉由使用醫藥學上可接受之載劑及賦形劑而調配成口服劑型,諸如錠劑、散劑、顆粒劑、丸劑、膠囊、懸浮液、乳液、內用液體、油劑、糖漿等,以及外用形式、栓劑或注射用無菌溶液,且因此可以單位劑型製備或藉由插入多劑量容器中來製備。此類製劑可根據此項技術中用於調配之習知方法或Remington's Pharmaceutical Science (第19版,1995)中所揭示之方法製備,且可根據各種疾病或成分而調配成多種製劑。
使用本發明之醫藥組合物的用於經口投與之製劑的非限制性實例可包括錠劑、糖衣錠、口含錠、水溶性懸浮液、油懸浮液、調理散劑、顆粒劑、乳液、硬膠囊、軟膠囊、糖漿、酏劑或其類似物。為了將根據本發明之實施例之醫藥組合物調配成用於經口投與之製劑,可使用以下:黏合劑,諸如乳糖、蔗糖、山梨醇、甘露醇、澱粉、支鏈澱粉、纖維素、明膠或其類似物;賦形劑,諸如磷酸二鈣等;崩解劑,諸如玉米澱粉、甜馬鈴薯澱粉或其類似物;潤滑劑,諸如硬脂酸鎂、硬脂酸鈣、硬脂醯反丁烯二酸鈉、聚乙二醇蠟或其類似物;等,其中亦可使用甜味劑、調味劑、糖漿等。此外,就膠囊而言,除以上所提及之材料以外,亦可使用液體載劑,諸如脂肪油等。
使用根據本發明之實施例之醫藥組合物的非經腸製劑之非限制性實例可包括可注射溶液、栓劑、用於呼吸道吸入之散劑、用於噴霧之噴霧劑、軟膏、用於塗覆之散劑、油、乳膏等。為了將根據本發明之實施例之醫藥組合物調配成用於非經腸投與之製劑,可使用以下:無菌水溶液、非水性溶劑、懸浮液、乳液、冷凍乾燥製劑、外用製劑等。關於該等非水性溶劑及懸浮液,可使用(但不限於)以下:丙二醇、聚乙二醇、植物油(諸如橄欖油)、可注射酯(諸如油酸乙酯)等。
根據本發明之實施例之醫藥組合物可根據目標方法經歷經口投與或非經腸投與,較佳為經口投與,但不限於此。
本發明之由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽的每日劑量可尤其為(但不限於)約0.1至約10,000 mg/kg、約1至約8,000 mg/kg、約5至約6,000 mg/kg或約10至約4,000 mg/kg,且更特定言之,約50至約2,000 mg/kg,且亦可每日一次或藉由將化合物之每日劑量分割而每日若干次投與。
根據本發明之實施例的醫藥組合物之醫藥學上有效劑量及有效劑量可視用於調配醫藥組合物之方法、投與模式、投與時間、投與途徑及/或其類似因素而變化,且可根據各種因素而多樣化,該等因素包括藉由投與醫藥組合物所達成之反應類型及程度、接受投藥之個體類型、個體之年齡、體重、一般健康狀況、疾病症狀或嚴重程度、性別、飲食及排泄、同時或在不同時間用於相應個體之其他藥物組合物的成分等,以及醫藥學領域中熟知之其他類似因素,且熟習此項技術者可容易地確定及指定用於所欲治療的有效劑量。
可每日一次或每日若干次投與根據本發明之實施例之醫藥組合物。根據本發明之實施例之醫藥組合物可以單獨治療劑或與其他治療劑之組合形式投與,且可與習知治療劑依序或同時投與。考慮到以上所有因素,根據本發明之實施例之醫藥組合物可按以下量進行投與:可藉由最小量來達成最大效果而無副作用,且此類量可易於由熟習本發明所屬領域之技術者確定。
即使在單獨使用時,根據本發明之實施例之醫藥組合物仍可展示極佳效果,且可進一步與各種方法(諸如激素療法、藥物治療等)組合使用以提高治療效率。
本發明可提供用於預防或治療特發性肺纖維化之方法,其包括向個體投與由以上式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽。
該等術語「特發性肺纖維化」、「預防」及「治療」可與上文所描述的相同。
在本發明中,術語「投與」可指藉由適當方法將預定物質引入個體中。
在本發明中,術語「個體」可指已發展或可能發展特發性肺纖維化的所有動物,諸如(但不限於)大鼠、小鼠、家畜等,包括人類,且可尤其為哺乳動物,包括人類。
根據本發明之實施例之用於預防或治療特發性肺纖維化的方法可包括投與治療有效量之由以上式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽。
在本發明中,術語「治療有效量」可指足以在適用於醫學治療之合理風險/益處比下治療疾病且不引起副作用之量,且可由熟習此項技術者根據包括患者之性別、年齡、體重、健康狀況、疾病類型、嚴重程度、藥物活性、對藥物之敏感性、投與方法、投與時間、投與途徑、排泄率、治療期、組合或同時使用之藥物之因素,以及醫藥學領域中熟知之其他因素來確定。較佳根據各種因素(包括由其達成之反應類型及程度、包括在一些情況下使用之其他製劑之特定組合物、患者之年齡、體重、一般健康狀況、性別及飲食、投與時間、投與途徑、組合物之分泌速率、治療期及與特定組合物一起使用或與其同時使用之藥物以及醫藥學領域中熟知之其他類似因素)而以不同方式對某一患者施用特定治療有效量。
根據本發明之實施例之用於預防或治療特發性肺纖維化的方法可包括不僅在其症狀表現之前處理疾病本身,而且藉由投與由以上式I表示之化合物、其異構物或其醫藥學上可接受之鹽來抑制或避免此類症狀。在管理疾病時,某一活性成分之預防劑量或治療劑量可視疾病或病況之特徵及嚴重程度,以及投與活性成分之途徑而變化。其劑量及頻率可視個別患者之年齡、體重及反應而變化。適合之劑量及用法可由熟習此項技術者自然地考慮此類因素而容易地選擇。另外,根據本發明之實施例之用於預防或治療特發性肺纖維化的方法可進一步包括與由以上式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽一起投與治療有效量之額外活性劑(其有助於預防或治療疾病),且該額外活性劑可與由以上式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽一起展示協同作用或累加作用。
本發明可提供由以上式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽的用途,其係用於預防或治療特發性肺纖維化。
本發明可提供由以上式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽的用途,其係用於製備用以預防或治療特發性肺纖維化之藥劑。
該等術語「特發性肺纖維化」、「預防」及「治療」可與上文所描述的相同。
對於藥劑之製備,由以上式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽可與醫藥學上可接受之佐劑、稀釋劑、載劑等混合,且可與其他活性劑一起製備成複合製劑,由此提供協同作用。
若彼此不矛盾,則本發明之醫藥組合物、治療方法及用途中所提及之物質同樣適用。
有利作用本發明之由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽及包括由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽作為有效成分之醫藥組合物可有利地用於預防或治療特發性肺纖維化。
本發明之模式將參考下文中之實例詳細地描述本發明。然而,實例係僅出於說明本發明之目的且對熟習此項技術者而言顯而易見的是,本發明之範疇不限於下文中所揭示之實例。
合成實例 1. N -( 4 -( 羥基胺甲醯基 ) 苯甲基 )- N -( 3 -( 三氟甲基 ) 苯基 ) 𠰌 啉 - 4 - 甲醯胺 [ 化合物 42 ] 之合成 [ 步驟 1 ]4-((3-(三氟甲基)苯胺基)甲基)苯甲酸甲酯之合成
將3-(三氟甲基)苯胺(0.30 g,1.84 mmol)及碳酸鉀(0.76 g,5.53 mmol)溶解於二甲基甲醯胺(DMF,5 mL)中,接著添加4-(溴甲基)苯甲酸甲酯(0.42 g,1.84 mmol)。將所得溶液在室溫下反應一天,且用乙酸乙酯稀釋。將反應物用水及飽和氯化鈉水溶液洗滌,接著用無水硫酸鎂乾燥及過濾,且接著在減壓下濃縮。將經由管柱層析法(二氧化矽;乙酸乙酯/己烷=20%)純化殘餘物,從而獲得標題化合物(0.37 g,65%)。
1 H NMR(400 MHz, DMSO-d
6) δ 7.93 (d, 2 H, J = 8.3 Hz), 7.49 (d, 2 H, J = 8.3 Hz), 7.24 (t, 1 H, J = 7.9 Hz), 6.88-6.78 (m, 4 H), 4.42 (d, 2 H, J = 6.1 Hz), 3.83 (s, 3H),
MS(ESI) m/z 310 (M
++ H)。
[ 步驟 2 ]4-(((4-硝基苯氧基)羰基)(3-(三氟甲基)苯基)胺基)甲基)苯甲酸甲酯之合成
將4-((3-(三氟甲基)苯胺基)甲基)苯甲酸甲酯(0.26 g,0.82 mmol)及氯甲酸4-硝基苯酯(0.33 g,1.65 mmol)溶解於乙腈(10 mL)中,接著添加碳酸鉀(0.34 g,2.47 mmol)。將所得溶液在室溫下反應一天,且用乙酸乙酯稀釋。將反應物用水及飽和氯化鈉水溶液洗滌,接著用無水硫酸鈉乾燥及過濾,且接著在減壓下濃縮。經由管柱層析法(二氧化矽;乙酸乙酯/己烷=20%)純化殘餘物,從而獲得呈無色油狀之標題化合物(0.35 g,89%)。
1 H NMR(400 MHz, CDCl
3) δ 8.20 (d, 2 H, J = 10.2 Hz), 8.01 (d, 2 H, J = 7.8 Hz), 7.56-7.46 (m, 3H), 7.35 (d, 3 H, J = 8.0 Hz), 7.26 (d, 2 H, J = 8.1 Hz), 5.01 (bs, 2H), 3.90 (s, 3H)。
[ 步驟 3 ]4-((N-(3-(三氟甲基)苯基)𠰌啉-4-甲醯胺基)甲基)苯甲酸甲酯之合成
將4-((((4-硝基苯氧基)羰基)(3-(三氟甲基)苯基)胺基)甲基)苯甲酸甲酯(0.29 g,0.60 mmol)溶解於二甲基甲醯胺(10 ml)中,接著添加碳酸鉀(0.25 g,1.81 mmol)及𠰌啉(0.05 mL,0.60 mmol)。將所得溶液在60℃下反應兩天,且接著用飽和氯化銨溶液稀釋。用乙酸乙酯進行萃取,接著將所得萃取物用無水硫酸鈉乾燥及過濾,且接著在減壓下濃縮。經由管柱層析法(二氧化矽;乙酸乙酯/己烷=50%)純化殘餘物,從而獲得標題化合物(0.15g,60%)。
1 H NMR(400 MHz, DMSO-d
6) δ 7.97 (d, 2 H, J = 8.2 Hz), 7.43-7.32 (m, 5H), 7.20 (d, 1 H, J = 8.0 Hz), 4.94 (s, 2H), 3.90 (s, 3H), 3.50 (t, 4 H, J = 4.8 Hz), 3.25 (t, 4 H, J = 4.8 Hz);
MS(ESI) m/z 423 (M
++ H)。
[ 步驟 4 ]N-(4-(羥基胺甲醯基)苯甲基)-N-(3-(三氟甲基)苯基)𠰌啉-4-甲醯胺之合成
將4-((N-(3-(三氟甲基)苯基)𠰌啉-4-甲醯胺基)甲基)苯甲酸甲酯(0.15 g,0.36 mmol)溶解於甲醇(5 mL)中,接著添加羥胺水溶液(50 wt%,1 mL)及氫氧化鉀(0.10 g,1.81 mmol)且攪拌隔夜。在反應完成之後,將所得溶液在減壓下進行蒸餾以自其中移除甲醇,接著用乙酸乙酯及水進行萃取,從而完成處理。將所得萃取物用無水硫酸鈉乾燥及過濾,且接著在減壓下濃縮。在乙醚中攪拌殘餘物,從而得到固體產物,過濾及乾燥,獲得呈白色固體狀之標題化合物(0.082 g,54%)。
1 H NMR(400 MHz, MeOD-d
3) δ 11.14 (brs, 1 H), 8.99 (brs, 1 H), 7.85 (d, 2 H, J = 8.0 Hz), 7.66-7.27 (m, 6 H), 4.94 (s, 2 H), 3.41 (s, 2 H), 3.15 (s, 2 H).
MS(ESI) m/z 424 (M
++ H)。
合成實例 2. N -( 2 , 4 - 二氟苯基 )- N -( 4 -( 羥基胺甲醯基 ) 苯甲基 ) 𠰌 啉 - 4 - 甲醯胺 [ 化合物 68 ] 之合成 [ 步驟 1 ]4-((2,4-二氟苯基胺基)甲基)苯甲酸甲酯之合成
將2,4-二氟苯胺(3.0 g,23.2 mmol)及4-甲醯基苯甲酸甲酯(3.81 g,23.2 mmol)溶解於甲醇(500 ml)中且在室溫下攪拌兩小時,接著添加乙酸(1.33 mL,23.2 mmol)及氰基硼氫化鈉(1.46 g,23.2 mmol)且攪拌一天。藉由空氣稍微移除甲醇,接著將固體沈澱、過濾及乾燥,從而獲得呈白色固體狀之標題化合物(2.9 g,45%)。
[ 步驟 2 ]4-(((2,4-二氟苯基)((4-硝基苯氧基)羰基)胺基)甲基)苯甲酸甲酯之合成
將4-((2,4-二氟苯基胺基)甲基)苯甲酸甲酯(2 g,7.21 mmol)及4-硝基苯基氯甲酸甲酯(1.45 g,7.21 mmol)溶解於二氯甲烷(50 mL)中且在室溫下攪拌三天,接著添加水以自其萃取有機層。有機層用飽和氯化鈉水溶液洗滌,接著藉由無水硫酸鎂脫水,且接著在減壓下濃縮。將殘餘物乾燥,從而獲得呈黃色油狀之標題化合物(2.5 g,78%)。
[ 步驟 3 ]4-((N-(2,4-二氟苯基)𠰌啉-4-甲醯胺基)甲基)苯甲酸甲酯之合成
將4-(((2,4-二氟苯基)((4-硝基苯氧基)羰基)胺基)甲基)苯甲酸甲酯(0.50 g,1.13 mmol)及𠰌啉(0.098 mL,1.13 mmol)溶解於二甲基甲醯胺(10 mL)中且在60℃下加熱及攪拌兩天。在減壓下移除二甲基甲醯胺,接著將水倒入反應混合物中且用乙酸乙酯進行萃取。用飽和氯化鈉水溶液洗滌有機層,接著藉由無水硫酸鎂脫水,且接著在減壓下濃縮。經由管柱層析法(二氧化矽;乙酸乙酯/己烷=30%)純化殘餘物且濃縮,從而獲得呈無色油狀之標題化合物(0.44 g,98%)。
[ 步驟 4 ]N-(2,4-二氟苯基)-N-(4-(羥基胺甲醯基)苯甲基)𠰌啉-4-甲醯胺之合成
將4-((N-(2,4-二氟苯基)𠰌啉-4-甲醯胺基)甲基)苯甲酸甲酯(0.10 g,0.256 mmol)溶解於甲醇(20 mL)中,接著添加羥胺鹽酸鹽(0.089 g,1.28 mmol)及氫氧化鉀(0.144 g,2.56 mmol)且攪拌,以便逐滴添加羥胺(50 wt%水溶液;0.329 mL,5.12 mmol)且在室溫下攪拌三小時。在反應完成之後,在減壓下移除甲醇,接著將水倒入反應混合物中且用乙酸乙酯進行萃取。有機層用飽和氯化鈉水溶液洗滌,接著藉由無水硫酸鎂脫水,且接著在減壓下濃縮。隨後,將所得濃縮物溶解於二氯甲烷中,接著添加己烷且將固體沈澱、過濾及乾燥,從而獲得呈淡黃色固體狀之標題化合物(0.076 g,76%)。
1 H NMR(400 MHz, MeOD-d
3) δ 7.65 (d, 2 H, J = 8.3 Hz), 7.41 (d, 2 H, J = 8.2 Hz), 7.27 - 7.25 (m, 1 H), 7.04 - 6.96 (m, 2 H), 4.80 (s, 2 H), 3.46 - 3.43 (m, 4 H), 3.22 - 3.19 (m, 4 H);
MS(ESI) m/z 392.1 (M
++ H)。
合成實例 3. N -( 4 -( 羥基胺甲醯基 ) 苯甲基 )- N -( 3 - 甲氧苯基 ) 𠰌 啉 - 4 - 甲醯胺 [ 化合物 104 ] 之合成 [ 步驟 1 ]4-(((3-甲氧苯基)胺基)甲基)苯甲酸甲酯之合成
將間甲氧基苯胺(3.23 g,26.2 mmol)及4-(溴甲基)苯甲酸甲酯(5.00 g,21.8 mmol)溶解於乙腈(50 mL)中,接著添加N,N-二異丙基乙胺(5.80 mL,32.7 mmol)且在室溫下攪拌16小時。當反應完成時,用乙酸乙酯及飽和碳酸氫鈉水溶液進行萃取,接著藉由無水硫酸鎂乾燥有機層且過濾。在減壓下濃縮剩餘濾液,接著經由管柱層析法(二氧化矽;乙酸乙酯/己烷=5%)純化殘餘物且濃縮,從而獲得呈亮黃色液體狀之標題化合物(5.14 g,87%)。
[ 步驟 2 ]4-(((3-甲氧苯基)((4-硝基苯氧基)羰基)胺基)甲基)苯甲酸甲酯
將4-(((3-甲氧苯基)胺基)甲基)苯甲酸甲酯(5.14 g,18.9 mmol)及氯甲酸4-硝基苯酯(4.20 g,20.8 mmol)溶解於乙腈(100 mL)中,接著添加碳酸鉀(3.93 g,28.4 mmol)且在室溫下攪拌三小時。當反應完成時,用乙酸乙酯及飽和碳酸氫鈉水溶液進行萃取,接著藉由無水硫酸鎂乾燥有機層且過濾。在減壓下濃縮剩餘濾液,接著經由管柱層析法(二氧化矽;乙酸乙酯/己烷=20%)純化殘餘物且濃縮,從而獲得呈黃色液體狀之標題化合物(5.88 g,71%)。
[ 步驟 3 ]4-((N-(3-甲氧苯基)𠰌啉-4-甲醯胺基)甲基)苯甲酸甲酯之合成
將4-(((3-甲氧苯基)((4-硝基苯氧基)羰基)胺基)甲基)苯甲酸甲酯(5.88 g,13.5 mmol)溶解於二甲基甲醯胺(50 mL)中,接著添加𠰌啉(2.35 g,27.0 mmol)及碳酸鉀(5.60 g,40.5 mmol)且在60℃下攪拌16小時。當反應完成時,用乙酸乙酯及飽和氯化銨水溶液進行萃取,接著藉由無水硫酸鎂乾燥有機層且過濾。在減壓下濃縮剩餘濾液,接著經由管柱層析(二氧化矽;乙酸乙酯/己烷=30%)純化殘餘物且濃縮,從而獲得呈黃色固體狀之標題化合物(3.69 g,71%)。
[ 步驟 4 ]N-(4-(羥基胺甲醯基)苯甲基)-N-(3-甲氧基苯基)𠰌啉-4-甲醯胺之合成
將4-((N-(3-(甲氧苯基)𠰌啉-4-甲醯胺基)甲基)苯甲酸甲酯(0.180 g,0.468 mmol)溶解於甲醇(10 mL)中,接著在室溫下添加羥胺(50.0 wt%水溶液;1.43 mL,23.4 mmol),且接著添加氫氧化鉀(0.263 g,4.68 mmol)且在相同溫度下攪拌30分鐘。隨後,在減壓下自反應混合物移除溶劑。將飽和氯化銨水溶液倒入所得濃縮物中,且用乙酸乙酯進行萃取。有機層用飽和氯化鈉水溶液洗滌,接著藉由無水硫酸鎂脫水,且接著在減壓下濃縮。在室溫下用二氯甲烷(2 mL)及己烷(10 mL)使殘餘物結晶,從而獲得呈白色固體狀之標題化合物(0.140 g,78%)。
1 H NMR(400 MHz, DMSO-d
6) δ 7.63 (d, 2 H, J = 8.1 Hz), 7.32 (m, 2 H), 7.19 (t, 1 H, J = 8.4 Hz), 6.69 - 6.67 (m, 2 H), 6.62 (m, 1 H), 4.84 (s, 2 H), 3.69 (s, 3 H), 3.39 - 3.36 (m, 4 H), 3.15 - 3.12 (m, 4 H)。
MS(ESI) m/z 386 (M
++ H)。
合成實例 4. N -( 3 - 氟苯基 )- N -( 4 -( 羥基胺甲醯基 ) 苯甲基 ) 𠰌 啉 - 4 - 甲醯胺 [ 化合物 130 ] 之合成 [ 步驟 1 ]4-(((3-氟苯胺基)甲基)苯甲酸甲酯之合成
將4-甲醯基苯甲酸甲酯(1.47 g,8.99 mmol)溶解於甲醇(50 mL)中,接著添加3-氟苯胺(1.0 g,8.99 mmol)。將所得溶液在室溫下反應三小時,接著添加氰基硼氫化鈉(NaCNBH
3,0.56 g,8.99 mmol)及乙酸(1.03 mL,17.99 mmol)。將反應物在室溫下反應一天,接著在減壓下移除反應溶劑,接著倒入飽和碳酸氫鈉水溶液,且接著藉由乙酸乙酯進行萃取。有機層藉由無水硫酸鎂脫水,且在減壓下濃縮。經由管柱層析法(二氧化矽;乙酸乙酯/己烷=20%)純化殘餘物,從而獲得標題化合物(1.84 g,79%)。
[ 步驟 2 ]4-(((3-氟苯基)((4-硝基苯氧基)羰基)胺基)甲基)苯甲酸甲酯之合成
將4-((3-氟苯胺基)甲基)苯甲酸甲酯(2.7 g,10.4 mmol)及氯甲酸4-硝基苯酯(4.20 g,20.8 mmol)溶解於乙腈(100 mL)中,接著添加碳酸鉀(4.32 g,31.2 mmol)。將所得溶液在室溫下反應一天,且用乙酸乙酯稀釋。將反應物用水及飽和氯化鈉水溶液洗滌,接著用無水硫酸鈉乾燥且過濾,且接著在減壓下濃縮。經由管柱層析法(二氧化矽;乙酸乙酯/己烷=20%)純化殘餘物,從而獲得呈無色油狀之標題化合物(2.65 g,60%)。
[ 步驟 3 ]4-((N-(3-氟苯基)𠰌啉-4-甲醯胺基)甲基)苯甲酸甲酯之合成
將4-(((3-氟苯基)((4-硝基苯氧基)羰基)胺基)甲基)苯甲酸甲酯(0.32 g,0.75 mmol)溶解於二甲基甲醯胺(5 ml)中,接著添加碳酸鉀(0.31 g,2.24 mmol)及𠰌啉(0.13 mL,1.49 mmol)。將所得溶液在60℃下反應一天,且接著用飽和氯化銨溶液稀釋。用乙酸乙酯進行萃取,接著將所得萃取物用無水硫酸鈉乾燥及過濾,且接著在減壓下濃縮。經由管柱層析法(二氧化矽;乙酸乙酯/己烷=30%)純化殘餘物,從而獲得標題化合物(0.13 g,45%)。
[ 步驟 4 ]N-(3-氟苯基)-N-(4-(羥基胺甲醯基)苯甲基)𠰌啉-4-甲醯胺之合成
將4-((N-(3-氟苯基)𠰌啉-4-甲醯胺基)甲基)苯甲酸甲酯(0.108 g,0.290 mmol)溶解於甲醇(10 mL)中,接著在室溫下添加羥胺(50.0 wt%水溶液;1.19 mL,19.4 mmol),且接著添加氫氧化鉀(0.156 g,2.78 mmol)且在相同溫度下攪拌16小時。接著,在減壓下自反應混合物移除溶劑,接著將飽和碳酸氫鈉水溶液倒入所得濃縮物中,且用乙酸乙酯進行萃取。有機層用飽和氯化鈉水溶液洗滌,接著藉由無水硫酸鎂脫水,且接著在減壓下濃縮。將沈澱之固體過濾及乾燥,從而獲得呈白色固體狀之標題化合物(0.062 g,57%)。
1 H NMR(400 MHz, DMSO-d
6) δ 11.14 (brs, 1 H), 8.99 (brs, 1 H), 7.65 (d, 2 H, J = 7.0 Hz), 7.38-7.30 (m, 3H), 7.05-6.85 (m, 3H), 4.89 (s, 1H), 3.44-3.42 (m, 4H), 3.18-3.15 (m, 4H), 2.08 (s, 3H)。
MS(ESI) m/z 374 (M
++ H)。
合成實例 5. N -( 3 - 氟苯基 )- N -( 4 -( 羥基胺甲醯基 ) 苯甲基 )- 1 , 4 - 㗁氮雜環庚烷 - 4 - 甲醯胺 [ 化合物 151 ] 之合成 [ 步驟 1 ]4-((N-(3-氟苯基)-1,4-㗁氮雜環庚烷-4-甲醯胺基)甲基)苯甲酸甲酯之合成
將在製備實例5之步驟2中所獲得的4-(((3-氟苯基)((4-硝基苯氧基)羰基)胺基)甲基)苯甲酸甲酯(0.290 g,0.683 mmol)、1,4-㗁氮雜環庚烷(0.188 g,1.367 mmol)及碳酸鉀(0.283 g,2.050 mmol)溶解於DMF (10 mL)中,接著將反應溶液在60℃下攪拌一天,接著將飽和NaHCO
3水溶液倒入反應混合物中,且接著用乙酸乙酯進行萃取。用飽和氯化鈉水溶液洗滌有機層,接著藉由無水硫酸鎂脫水,且接著在減壓下濃縮。經由管柱層析法(二氧化矽,15 g濾筒;乙酸乙酯/己烷=20%至50%)純化所得濃縮物且濃縮,從而獲得呈無色液體狀之標題化合物(0.116 g,43.9%)。
[ 步驟 2 ]N-(3-氟苯基)-N-(4-(羥基胺甲醯基)苯甲基)-1,4-㗁氮雜環庚烷-4-甲醯胺之合成
將4-((N-(3-(氟苯基)-1,4-㗁氮雜環庚烷-4-甲醯胺)甲基)苯甲酸甲酯(0.116 g,0.3 mmol)溶解於甲醇(10 mL)中,接著添加羥胺水溶液(50 wt%,1 mL)及氫氧化鉀(0.168 g,3.01 mmol)且攪拌隔夜。在反應完成之後,將所得溶液在減壓下蒸餾以自其中移除甲醇,接著用乙酸乙酯及水進行萃取,從而完成處理。將所得萃取物用無水硫酸鈉乾燥及過濾且在減壓下濃縮,接著在乙醚中攪拌殘餘物,從而得到固體產物,將其過濾及乾燥,且因此獲得呈白色固體狀之標題化合物(0.032 g,27.5%)。
< 實例 1 > 抑制纖維化蛋白之表現之作用為了證實根據本發明之化合物對預防或治療特發性肺纖維化之作用,分析纖維化蛋白之表現。
將MRC-5細胞(肺纖維母細胞株)以1×10
5個細胞/孔接種於6孔板中,且在CO
2培育箱(37℃,5% CO
2)中培養24小時。隨後,為了進行血清饑餓,將培養基更換為EMEM (1% FBS、1% P/S)培養基且在CO
2培育箱(37℃,5% CO
2)中培養24小時。在血清饑餓之後,用5 ng/mL之TGF-β1處理1 μM測試物質(化合物42、68、104、130及151),且在CO
2培育箱(37℃,5% CO
2)中培養48小時。將含有0.1% DMSO之培養基添加至對照組及僅用TGF-β1處理之組中。使用西方墨點法(western blot)來比較經完全培養之細胞中的纖維化蛋白(原COL1A1、LOXL2)之表現。
將細胞溶解於100 μL RIPA緩衝液(含有蛋白酶&磷酸酶抑制劑)中且在冰上培育30分鐘。將所得產物在13,000 g、4℃下離心20分鐘。使用BCA蛋白質分析套組來分離及定量上清液。接著,添加NuPAGE樣品還原劑及NuPAGE LDS樣品緩衝液(4X)以製備濃度為0.5 μg/μL之樣品。將所製備之樣品在100℃下沸騰五分鐘以使蛋白質變性。在負載於NuPAGE Novex 4-12% Bis-Tris凝膠上之後,在120 V下分離5 μg蛋白質且經由iBlot 2乾式墨點系統轉移至硝化纖維素(NC)膜。隨後,在室溫下用阻斷溶液(EzBlock Chemi:蒸餾水=1:4)將膜阻斷30分鐘。膜與初級抗體在4℃下反應隔夜,且接著用1× TBST洗滌三次,每次10分鐘。接著,使所得產物與由辣根過氧化酶(HRP)連接之二級抗體在室溫下反應一小時,且用1× TBST洗滌三次,每次10分鐘。在以1:4之比率混合的阻斷溶液及1×TBST的溶液中稀釋初級及二級抗體。隨後,藉由使用Amersham™ ECL select™西方墨點法偵測試劑及ChemiDoc™ MP成像系統來觀測蛋白質。使用Image Lab 5.0軟體對所觀測之蛋白質進行定量,且接著使用β-肌動蛋白水準進行校正。
使用GraphPad Prism 5.0軟體進行單因子ANOVA (事後:鄧尼特氏多重比較檢驗(Dunnett's multiple comparison test))。所有資料均表示為平均值±SEM,且將P<0.05視為統計顯著。
因此,如圖1中所示,證實在使用本發明之化合物治療時,由TGF-β1誘導之原COL1A1及LOXL2的表現受到顯著抑制。
因此,可發現本發明之化合物展示抑制纖維化蛋白之表現之作用,且因此可有利地用於預防或治療特發性肺纖維化。
< 實例 2 > 在患有 BLM 誘發之肺纖維化的動物模型中之治療效果藉由腹膜內(i.p.)投與鹽酸氯胺酮(2毫克/小鼠)及鹽酸甲苯噻𠯤(0.07毫克/小鼠)來麻醉八週齡雄性C57BL/6小鼠,且接著鼻內(i.n.)投與濃度為1 mg/kg之博萊黴素(BLM)溶液(50微升/小鼠),以便製備肺纖維化模型。自投與BLM之後一週開始投與測試物質持續總共14天。
為了證實本發明之化合物的治療效果,將患有BLM誘發之肺纖維化之小鼠根據所投與之物質[媒劑(Veh)或化合物42 (42)]、投與途徑[經口投與(PO)]及投藥間隔[每日一次(QD)]劃分成如下表1中所示之組。
表1
組 | 投藥劑量(mg/kg) | 投藥途徑 | 投藥週期 | 動物數目 |
生理鹽水/媒劑 1) | - | PO | QD | 10 |
BLM/媒劑 | - | PO | QD | 15 |
BLM/42 | 10 | PO | QD | 15 |
1)0.1%羥乙基纖維素 |
使用GraphPad Prism 8.1.1軟體進行雙因子ANOVA (曼-惠特尼檢驗(Mann-Whitney test))。所有資料均表示為平均值±SEM,且將P<0.05視為統計顯著。
< 實例 2 - 1 > 對 體重變化之分析為了證實根據本發明之化合物對預防或治療特發性肺纖維化之作用,分析小鼠之體重變化。每日量測且記錄體重。
因此,如圖2中所示,證實在患有BLM誘發之肺纖維化的小鼠中出現體重減輕,且在使用本發明之化合物治療後體重減輕得到恢復。
因此,可發現本發明之化合物展示使體重減輕得到恢復之作用,且因此可有利地用於預防或治療特發性肺纖維化。
< 實例 2 - 2 > 對 支氣管肺泡灌洗液 ( BALF ) 之分析為了證實根據本發明之化合物對預防或治療特發性肺纖維化之作用,分析支氣管肺泡灌洗液(BALF)。在將插管插入氣管中以收集BALF之後,用PBS (0.4、0.3及0.3 mL,總計1 mL)洗滌肺。將所收集之BALF置放於埃彭道夫試管(Eppendorf test tube)中,離心(5分鐘/3500 rpm/4℃)且再懸浮於600 μL PBS中。分析總細胞及經分化之細胞的數目。
因此,如圖3中所示,證實患有BLM誘發之肺纖維化的小鼠中之總細胞、嗜中性球、淋巴細胞及巨噬細胞之數目增加,且接著在使用本發明之化合物治療時,所增加之總細胞、嗜中性球、淋巴細胞及巨噬細胞的數目減少。
因此,可發現本發明之化合物展示抑制炎性細胞浸潤之作用,且因此可有利地用於預防或治療特發性肺纖維化。
< 實例 2 - 3 > 對肺重量變化之分析為了證實根據本發明之化合物對預防或治療特發性肺纖維化之作用,分析小鼠之肺重量變化。量測自小鼠移除之肺的重量。
因此,如圖4中所示,證實在患有BLM誘發之肺纖維化的小鼠中肺重量增加,且在使用本發明之化合物治療後,所增加之肺重量減少。
因此,可發現本發明之化合物展示使所增加之肺重量減少的作用,且因此可有利地用於預防或治療特發性肺纖維化。
< 實例 2 - 4 > 對基因表現之分析為了證實根據本發明之化合物對預防或治療特發性肺纖維化之作用,分析纖維化基因之表現。將肺組織置放於含有750 μL曲唑(trizol)試劑之Precelllys CK28硬組織管中且均質化。將150 μL氯仿添加至均質物中,劇烈振盪且接著在室溫下培育三分鐘,隨後在6,000 g、4℃下離心15分鐘以進行相分離。收集水相,且使用NucleoSpin 96 RNA Core套組(Macherey-Nagel)根據製造商之說明書將RNA進一步分離。在60 μL不含RNA酶之水中溶離RNA,且使用260 nm下之吸光度來測定RNA濃度。使用高容量RT套組(Life Technologies)根據製造商之說明書將總計500 ng經分離之RNA逆轉錄為cDNA。在逆轉錄反應完成之後,將所獲得之cDNA在不含RNA酶之水中稀釋五倍。使用即時PCR AriaMX儀器(Agilent Technologies)來量測COK1A1、FN1、PAI1、TIMP-1及SPP1之基因表現。
因此,如圖5中所示,證實在患有BLM誘發之肺纖維化的小鼠中,COK1A1、FN1、PAI1、TIMP-1及SPP1基因之表現增加,且在使用本發明之化合物治療後,所增加之基因表現減少。
因此,可發現本發明之化合物展示抑制纖維化基因之表現之作用,且因此可有利地用於預防或治療特發性肺纖維化。
< 實例 2 - 5 > 組織病理學分析為了證實根據本發明之化合物對預防或治療特發性肺纖維化之作用,進行組織病理學評估。將肺標本包埋於石蠟中。針對纖維狀組織對載片進行染色。使用阿希克夫評分來評估肺中之組織學變化。藉由數位影像分析(Calopix軟體,TRIBVN)來評估新生膠原蛋白1A1 (CO1A1)之沈積。
因此,如圖6中所示,證實在患有BLM誘發之肺纖維化的小鼠中阿希克夫評分增加,且在使用本發明之化合物治療後,所增加之阿希克夫評分減少。
此外,如圖7中所示,證實在患有BLM誘發之肺纖維化的小鼠中新生膠原蛋白1A1之沈積增加,且在使用本發明之化合物治療後,所增加之新生膠原蛋白1A1之沈積減少。
因此,可發現本發明之化合物展示抗纖維化作用,且因此可有利地用於預防或治療特發性肺纖維化。
< 實例 3 > 膠原蛋白凝膠收縮分析法為了證實根據本發明之化合物對預防或治療特發性肺纖維化之作用,分析膠原蛋白凝膠收縮之程度。
將3 ng/mL之TGF-β1單獨處理或與各種濃度(0.3、1、3、10 μM)之化合物42一起處理至含有4×10
5個LL29細胞(衍生自IPF患者之肺纖維化細胞)之膠原蛋白凝膠中,且培育192小時。用0.1% DMSO處理對照組及僅用TGF-β1處理之組。
使用GraphPad Prism 5.0軟體進行單因子ANOVA (事後:鄧尼特氏多重比較檢驗)。所有資料均表示為平均值±SEM,且將P<0.05視為統計顯著。
因此,如圖8及圖9中所示,證實在使用本發明之化合物治療時,由TGF-β1誘發之膠原蛋白收縮受到顯著抑制。
因此,可發現本發明之化合物展示抗纖維化作用,且因此可有利地用於預防或治療特發性肺纖維化。
< 實例 4 > 纖維母細胞遷移分析法為了證實根據本發明之化合物對預防或治療特發性肺纖維化之作用,分析纖維母細胞遷移。
將衍生自IPF患者之肺組織的患病人類肺纖維母細胞-IPF (DHLF-IPF)培養為融合單層。在24小時之血清饑餓之後,使用200 μL微量吸管尖端進行刮擦。隨後,製備化合物42且在細胞培養基中處理至1.5及3 μM之最終濃度。用0.1% DMSO處理對照組。在進一步培養15小時之後,使用相位差顯微鏡來量測細胞遷移距離。
使用GraphPad Prism 5.0軟體進行單因子ANOVA (事後:鄧尼特氏多重比較檢驗)。所有資料均表示為平均值±SEM,且將P<0.05視為統計顯著。
因此,如圖10及圖11中所示,證實在使用本發明之化合物治療時,DHLF-IPF細胞之遷移受到顯著抑制。
因此,可發現本發明之化合物展示抗纖維化作用,且因此可有利地用於預防或治療特發性肺纖維化。
< 實例 5 > 纖維母細胞增殖分析法為了證實根據本發明之化合物對預防或治療特發性肺纖維化之作用,分析纖維母細胞增殖。
將經eFluor670染料標記之正常人類肺纖維母細胞(NHLF)細胞以8×10
5個細胞接種於100 mm培養皿中(第0天)。在接種之後24小時(第1天),將30 ng/mL之PDGF-BB單獨處理或與各種濃度(0.01、0.03、0.3、1及3 μM)之化合物42一起處理,且接著培養48小時(第3天)。在第3天,將細胞胰蛋白酶化且懸浮於單細胞中,且使用流式細胞分析技術來評估細胞增殖。
使用GraphPad Prism 5.0軟體進行單因子ANOVA (事後:鄧尼特氏多重比較檢驗)。所有資料均表示為平均值±SEM,且將P<0.05視為統計顯著。
因此,如圖12中所示,證實在使用本發明之化合物治療時,由PDGF-BB誘發之細胞增殖受到抑制。
因此,可發現本發明之化合物展示抗纖維化作用,且因此可有利地用於預防或治療特發性肺纖維化。
本發明提供如下之醫藥組合物、方法及用途:
第1項.一種用於預防或治療特發性肺纖維化之醫藥組合物,其包含由上文所提及之式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽作為活性成分。
第2項.如第1項之醫藥組合物,其中由上文所提及之式I表示之化合物係選自由上文所提及之化合物1至169組成之群中之至少一者,該等化合物1至169描述於上文所提及之表中。
第3項.如第1項或第2項之醫藥組合物,其中由上文所提及之式I表示之化合物係選自由以下組成之群中之至少一者:化合物42、化合物68、化合物104、化合物130及化合物151,其描述於上文所提及之表中。
第4項.一種用於預防或治療特發性肺纖維化之方法,其包括向個體投與如第1項至第3項中任一項所描述之由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽。
第5項.一種如第1項至第3項中任一項所描述之由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽的用途,其係用於預防或治療特發性肺纖維化。
第6項.一種如第1項至第3項中任一項所描述之由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽的用途,其係用於製備用以預防或治療特發性肺纖維化之藥劑。
第7項.如第1項至第3項中任一項之醫藥組合物,其中該醫藥組合物係經口投與。
第8項.如第4項之方法或如第5項或第6項之用途,其中如第項1至第3項中任一項所描述之由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽係經口投與。
雖然上文已詳細地描述本發明之特定部分,但對於熟習此項技術者而言顯而易見的是,闡述此類詳細描述以僅說明例示性實施例,而不應解釋為限制本發明之範疇。因此,應理解,本發明之實質範疇係由所附申請專利範圍及其等效物定義。
圖1為展示各組中之纖維化蛋白(原COL1A1及LOXL2)之表現量的圖。(*p<0.05,**p<0.01,***p<0.001)
圖2為展示各組之體重變化的圖。(*p<0.05)
圖3為展示各組中之總細胞、嗜中性球、淋巴細胞及巨噬細胞之數目的圖。(*p<0.05)
圖4為展示各組之肺重量的圖。(*p<0.05)
圖5為展示各組中之纖維化基因(COL1A1、FN1、TIMP1、PAI1及SPP1)之表現量的圖。(*p<0.05)
圖6為展示各組之阿希克夫評分的圖。(*p<0.05)
圖7為展示各組中之膠原蛋白1A1 (CO1A1)沈積程度的圖。(*p<0.05)
圖8為展示各組中之膠原蛋白凝膠收縮程度的影像。
圖9為展示各組中之膠原蛋白凝膠收縮程度之圖。(***p<0.001)
圖10為展示各組中之DHLF-IPF細胞遷移程度的影像。
圖11為展示各組中之DHLF-IPF細胞遷移程度的圖。(*p<0.05,**p<0.01)
圖12為展示根據本發明之化合物之濃度的細胞增殖抑制程度的圖。(**p<0.01,***p<0.001)
Claims (8)
- 一種用於預防或治療特發性肺纖維化之醫藥組合物,其包含由以下式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽作為有效成分: [式I] 其中 A為 , Xa及Xb各自獨立地為CH或N, L 1及L 2各自獨立地為氫、鹵素、-CF 3或-C 1 - 3直鏈或分支鏈烷基, Q為C(=O)、S(=O) 2、S(=O)或C(=NH), Y係選自以下基團: , M為C、N、O、S或S(=O) 2(此時,若M為C,則l及m為1;若M為N,則l為1且m為0;且若M為O、S或S(=O) 2,則l及m為0), R a1及R a2各自獨立地為氫;羥基;-C 1 - 4直鏈或分支鏈烷基,其未經取代或經至少一個鹵素取代;-C 1 - 4直鏈或分支鏈醇;二苯甲基;-C 1 - 4直鏈或分支鏈烷基,其經具有一至三個選自N、O或S之雜原子作為環成員的飽和或不飽和五員至七員雜環化合物取代(此時,該雜環化合物可為未經取代的或至少一個氫可視情況經OH、OCH 3、CH 3、CH 2CH 3或鹵素取代);具有一至三個選自N、O或S之雜原子作為環成員的飽和或不飽和五員至七員雜環化合物(此時,該雜環化合物可為未經取代的或至少一個氫可視情況經OH、OCH 3、CH 3、CH 2CH 3或鹵素取代);苯基,其未經取代或其中至少一個氫經鹵素、C 1 - 4烷氧基、C 1 - 2烷基或羥基取代;苯甲基,其未經取代或其中至少一個氫經鹵素、C 1 - 4烷氧基、C 1 - 2烷基或羥基取代;-S(=O) 2CH 3;鹵素;-C 1 - 6直鏈或分支鏈烷氧基;-C 2 - 6烷氧基烷基;-C(=O)R x,其中R x為C 1 - 3直鏈或分支鏈烷基或C 3 - 10環烷基; ,其中R c及R d獨立地為氫或C 1 - 3直鏈或分支鏈烷基; 或 , n為0、1或2之整數, R b為氫;羥基;-C 1 - 6直鏈或分支鏈烷基,其未經取代或其中至少一個氫經鹵素取代;-C(=O)CH 3;-C 1 - 4直鏈或分支鏈羥基烷基;-C 1 - 6直鏈或分支鏈烷氧基;-C 2 - 6直鏈或分支鏈烷氧基烷基;-CF 3;鹵素;或 , R e及R f各自獨立地為氫或-C 1 - 3直鏈或分支鏈烷基,及 Z係選自以下基團: , P a及P b各自獨立地為 ;氫;羥基;-C 1 - 4直鏈或分支鏈烷基,其未經取代或其中至少一個氫經鹵素取代;鹵素;-CF 3;-OCF 3;-CN;-C 1 - 6直鏈或分支鏈烷氧基;-C 2 - 6直鏈或分支鏈烷基烷氧基;-CH 2F;或-C 1 - 3醇, 其中 為選自苯基、吡啶、嘧啶、噻唑、吲哚、吲唑、哌𠯤、喹啉、呋喃、四氫吡啶、哌啶或以下基團之環: , x、y及z各自獨立地為0或1之整數,及 R g1、R g2及R g3各自獨立地選自氫;羥基;-C 1 - 3烷基;-CF 3;-C 1 - 6直鏈或分支鏈烷氧基;-C 2 - 6直鏈或分支鏈烷基烷氧基;-C(=O)CH 3;-C 1 - 4直鏈或分支鏈羥基烷基;-N(CH 3) 2;鹵素;苯基;-S((=O) 2)CH 3;或以下基團: 。
- 如請求項1之醫藥組合物,其中該由式I表示之化合物為由以下式Ia表示之化合物: [式Ia] 其中 Y係選自以下基團: 其中M、l、m、n、R a1、R a2及R b分別與請求項1中所定義的相同, Z為 ,及 P a及P b各自獨立地為氫;羥基;-C 1 - 4直鏈或分支鏈烷基,其未經取代或其中至少一個氫經鹵素取代;鹵素;-CF 3;-OCF 3;-CN;-C 1 - 6直鏈或分支鏈烷氧基;-C 2 - 6直鏈或分支鏈烷基烷氧基;-CH 2F;或-C 1 - 3醇。
- 如請求項2之醫藥組合物,其中Y係選自以下基團: , 其中n及R b分別與請求項1中所定義的相同, Z為 ,及 P a及P b各自獨立地為氫;鹵素;-CF 3;或-C 1 - 6直鏈或分支鏈烷氧基。
- 如請求項1之醫藥組合物,其中該由式I表示之化合物為下表中所描述之化合物: 。
- 如請求項1之醫藥組合物,其中該由式I表示之化合物為下表中所描述之化合物: 。
- 如請求項1之醫藥組合物,其中該醫藥組合物係經口投與。
- 一種由式I表示之化合物、其光學異構物或其醫藥學上可接受之鹽的用途,其係用於製備用以預防或治療特發性肺纖維化之藥劑,其中該由式I表示之化合物係與請求項1中所定義的相同。
- 如請求項7之用途,其中該由式I表示之化合物為下表中所描述之化合物: 。
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