TWI831339B - 化合物用於製備Ｃｉｓｄ２不足相關病症的藥物的用途 - Google Patents
化合物用於製備Ｃｉｓｄ２不足相關病症的藥物的用途 Download PDFInfo
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- TWI831339B TWI831339B TW111131843A TW111131843A TWI831339B TW I831339 B TWI831339 B TW I831339B TW 111131843 A TW111131843 A TW 111131843A TW 111131843 A TW111131843 A TW 111131843A TW I831339 B TWI831339 B TW I831339B
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- compound
- amino
- methylthiophene
- dimethylphenyl
- methyl
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- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本發明揭露一種治療Cisd2不足相關病症的方法。該方法包含向有需要
的一主體施用式(I)化合物。也揭露了一種增加Cisd2基因表現的方法。
Description
本發明係關於一種治療Cisd2不足相關病症之方法。
CDGSH鐵硫結構域2(CDGSH iron sulfur domain 2,Cisd2)是由Cisd2基因編碼的鐵硫跨膜蛋白。這個蛋白位於粒線體外膜、內質網(endoplasmic reticulum,ER)膜、和其他粒線體或ER相關的膜。
Cisd2是透過維持細胞溶質(cytosolic)Ca2+的恆定(homeostasis)、ER完整性和粒線體功能來調節老化和新陳代謝的基本調節因子。參見Wu et al.,Human Molecular Genetics 21,3956-68(2012).。
Cisd2不足會導致多種組織和器官(例如腦、心臟、肝臟、骨骼肌(skeletal muscle)、皮膚、白色脂肪組織(white adipose tissue)和胰臟的β細胞)的退化和致病性(pathogenesis)。
已經報導了Cisd2調升(upregulation)可減弱(attenuate)阿滋海默氏症(Alzheimer’s disease)中Aβ-介導的(Aβ-mediated)神經元(neuron)損失，並改善各種老化相關的疾病，包含心臟功能異常(dysfunction)、脂肪肝疾病和炎症、肌肉
變性(muscle degeneration)和肌少症(sarcopenia)、皮膚老化、葡萄糖不耐性(glucose intolerance)、糖尿病(diabetes)、以及高血壓心肌症(hypertensive cardiomyopathy)。
Cisd2活化劑是上述疾病的潛在療法。然而，開發一種有效且安全的Cisd2活化劑是一項挑戰，因為沒有夠多的出版物提供指導。事實上，美國食品藥物管理局尚未批准任何Cisd2活化劑用於醫療用途。
需要發展Cisd2活化劑作為有效療法，以治療與Cisd2不足相關的疾病。
本案出乎意料地發現，某些噻吩化合物通過增加Cisd2含量對治療患有與Cisd2不足相關病症的主體是有效的。
因此，本發明之一態樣涉及一種治療Cisd2不足相關病症之方法。該方法包含步驟(i)識別患有Cisd2不足相關病症的一主體；以及(ii)向該主體施用一有效劑量的式(I)之噻吩化合物：
該方法適用於治療以下Cisd2不足相關病症：非酒精性脂肪肝症(non-alcoholic fatty liver disease)、非酒精性脂肪肝炎(non-alcoholic
steatohepatitis)、化療引起的心臟毒性(chemotherapy-induced cardiotoxicity)、化療引起的惡病質(chemotherapy-induced cachexia)、肝毒性(hepatotoxicity)、老化相關的心律失常(aging-related arrhythmogenesis)、老化相關的心臟病變(aging-related cardiac pathological change)和高血壓心肌症(hypertensive cardiomyopathy)。
較佳的化合物具有一或多個以下特徵：R1為H；R2為H或C(O)CH3；R3為CN、CO2CH3、CO2CH2CH3、CO2C(CH3)3、或COCH3；R4為甲基；以及R5為芳基或雜芳基。示例性的R5部分包含：
下表1列出35個示例性噻吩化合物，包含他們可用於本發明的方法的結構。
表1
在以上化合物1-35中，較佳的化合物為化合物1、5、6、9、10、13、16、19、20、21、25、30和32。
本發明的另一態樣涉及一種增加Cisd2基因表現的方法，包含步驟(i)識別需要增加Cisd2基因表現的一主體；以及(ii)向該主體施用一有效劑量的如上所述之式(I)化合物。
本發明的範圍內還包含一醫藥組成物，該醫藥組成物包含上述任何化合物和醫藥學上可接受之載體。該醫藥組成物可用於治療Cisd2不足相關病症或增加Cisd2基因表現。
本文所述術語「烷基」是指一直鏈或支鏈的徑類，含有1-20個(例如1-10個和1-6個)碳原子。例子包含甲基、乙基、正丙基、異丙基、正丁基、異丁基和叔丁基。烷基包含其鹵素取代的衍生物，即鹵代烷基，其是指被一或多個鹵素(氯、氟、溴或碘)原子取代的烷基。例子包含三氟甲基、溴甲基和4,4,4-三氟丁基。術語「烷氧基」是指-O-烷基。例子包含甲氧基、乙氧基、丙氧基和異丙氧基。烷氧基包含鹵代烷氧基，是指被一或多個鹵素原子取代的烷氧基。例子包含-O-CH2Cl和-O-CHClCH2Cl。
術語「芳基」是指6-碳單環、10-碳雙環、14-碳三環芳香環系統，其中每個環可具有1-5個取代基。芳基的例子包含苯基、萘基和蒽基。
術語「雜芳基」是指具有一或多個雜原子(例如O、N、P和S)的芳香族5-8員單環、8-12員雙環或11-14員三環系統。例子包含三唑基(triazolyl)、噁唑基(oxazolyl)、噻二唑基(thiadiazolyl)、四唑基(tetrazolyl)、吡唑基、吡啶基、
呋喃基、咪唑基、苯並咪唑基、嘧啶基、噻吩基、喹啉基(quinolinyl)、吲哚基、噻唑基和苯並噻唑基。
術語「鹵素」是指氟、氯、溴或碘自由基。
本文所述之烷基、芳基、雜芳基和烷氧基包含取代和未取代的部分。取代基的例子包含但不限於鹵素、羥基、胺基、腈基、硝基、巰基(mercapto)、烷氧基羰基、醯胺基、羧基(carboxy)、烷磺醯基(alkanesulfonyl)、烷基羰基、脲基(carbamido)、胺甲醯基(carbamyl)、羧基(carboxyl)、硫脲基(thioureido)、氰硫基(thiocyanato)、磺醯胺基(sulfonamide)、烷基、烯基、炔基、烷氧基、芳基、雜芳基、環烷基和雜環烷基，其中，烷基、烯基、炔基、烷氧基、芳基、雜芳基、環烷基和雜環烷基可以進一步被取代。
當提到式(I)之化合物時，術語「化合物」也包含其鹽類、溶劑合物和前驅藥。陰離子和化合物上的正電荷基團(例如胺基)之間可形成鹽類；合適的陰離子的例子包含氯離子、溴離子、碘離子、硫酸根、硝酸根、磷酸根、檸檬酸根、甲磺酸根、三氟乙酸根、乙酸根、蘋果酸根、甲苯磺酸根、酒石酸根、富馬酸根、麩胺酸根、葡萄醣醛酸根(glucuronate)、乳酸根、戊二酸根和馬來酸根(maleate)。也可以在陽離子和帶負電荷的基團之間形成鹽類。合適的陽離子的例子包含鈉離子、鉀離子、鎂離子、鈣離子和銨陽離子，例如四甲基銨離子。此外，鹽類可包含季氮原子。溶劑合物是指在活性化合物和藥學上可接受的溶劑之間形成的複合物。藥學上可接受的溶劑的例子包含水、乙醇、異丙醇、乙酸乙酯(“EtOAc”)、乙酸和乙醇胺。前驅藥是指在施用後代謝成藥學活性藥物的化合物。前驅藥的例子包含酯類和其他藥學上可接受的衍生物，它們在施用於主體時能夠提供本發明的活性化合物。
本發明的幾個實施例的細節在以下描述和例子中闡述。本發明的所有特徵、目的和優點將從說明書和申請專利範圍中顯而易見。
本發明是基於對某些噻吩化合物的驚人發現，其可有效增加Cisd2基因表現，並因此可用於治療Cisd2不足相關病症。
該噻吩化合物如上述式(I)所表示。他們的合成是透過本領域已知的方法來實現。參考例如R.Larock,Comprehensive Organic Transformations(3rd Ed.,John Wiley and Sons 2018)；P.G.M.Wuts and T.W.Greene,Greene’s Protective Groups in Organic Synthesis(4th Ed.,John Wiley and Sons 2007)；L.Fieser and M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis(John Wiley and Sons 1994)；以及L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis(2nd ed.,John Wiley and Sons 2009)及其後續版本。
某些噻吩化合物的製備描述於以下實施例1以及國際申請公開WO 2005/033102中。
如此製備的化合物可按照常規方法純化，例如結晶、蒸餾/真空蒸餾、二氧化矽的急速層析法和製備級液相層析法。
一些可用於本發明的噻吩化合物含有非芳香族雙鍵或一或多個不對稱中心。它們每個以外消旋物(racemate)或外消旋(racemic)混合物、單一R
鏡像異構物(enantiomer)、單一S鏡像異構物、個別的非鏡像異構物(individual diastereomer)、非鏡像異構物混合物、順式異構物、或反式異構物存在。這種異構物形式的化合物也在本發明的範圍內。他們可以混合物存在或使用掌性合成或掌性分離技術分離。
可以使用體外方法初步篩選式(I)的噻吩化合物以確定Cisd2活化活性。
典型的體外篩選方法包含以下步驟：(i)在一批表現Cisd2的人類胚胎腎臟細胞株293(human embryonic kidney cells 293,HEK-293 cells)中獲得一初始含量的Cisd2，(ii)以本發明的化合物處理該批HEK-293細胞，以及(iii)分析處理後Cisd2的含量，從而確定化合物作為Cisd2活化劑的效力。
如以下實施例所示，式(I)化合物是有效的Cisd2活化劑。他們可用於治療Cisd2不足相關病症，例如肝臟疾病、代謝疾病、心臟疾病、惡病質、和老化相關疾病。
式(I)化合物優選為配製成含有醫藥載體的醫藥組成物。然後將該醫藥組成物給予需要的主體，以治療Cisd2不足相關病症或增加Cisd2基因表現。
為了實施本發明的方法，具有一或多個上述噻吩化合物的組成物可以腸胃外(parenterally)、口服、經鼻(nasally)、經直腸(rectally)、局部(topically)或經頰(buccally)給藥。
本文所用之術語「腸胃外」是指無菌可注射的組成物的皮下(subcutaneous)、皮內(intracutaneous)、靜脈內(intravenous)、腹腔(intraperitoneal)、肌肉內(intramuscular)、關節內(intraarticular)、動脈內(intraarterial)、滑膜內
(intrasynovial)、胸骨內(intrasternal)、鞘內(intrathecal)、病灶內(intralesional)或顱內注射(intracranial injection)。確實地，該術語是指任何適合的輸注(infusion)技術。
無菌可注射組成物可以是在無毒的腸胃外可接受的稀釋劑或溶劑中的溶液或懸浮液，例如在1,3-丁二醇(1,3-butanediol)中的溶液。可以使用的可接受的載體和溶劑為甘露醇(mannitol)、水、林格氏溶液(Ringer’s solution)和等張氯化鈉溶液。此外，不揮發油(fixed oil)通常做為溶劑或懸浮介質(例如合成的甘油單酯或二酯(mono-or di-glycerides))。脂肪酸，例如油酸(oleic acid)及其甘油酯(glyceride)衍生物可用於製備注射劑，天然藥學上可接受的油，例如橄欖油及蓖麻油，特別是其聚氧乙醇化(polyoxyethylated)形式。這些油溶液或懸浮液也可以包含長鏈醇稀釋劑或分散劑、羧甲基纖維素(carboxymethyl cellulose)或類似的分散劑。其他常用的表面活性劑，例如Tweens及Spans或其他類似的乳化劑或生物利用度增強劑，其通常用於製備藥學上可接受的固體、液體或其他劑型，也可用於配製目的。
口服給藥的組成物可以是任何口服可接受的劑型，包含膠囊、片劑、乳劑和水性懸浮液、分散體及溶液。在片劑中，常用的載體包含乳糖和玉米澱粉。通常也添加例如硬脂酸鎂(magnesium stearate)的潤滑劑。對於以膠囊形式的口服給藥而言，有用的稀釋劑包含乳糖和乾燥的玉米澱粉。當口服給予水性懸浮液或乳劑時，活性成分可以懸浮或溶解在與乳化劑或懸浮劑結合的油相中。如果需要，可以添加某些甜味劑、調味劑或著色劑。口服固體劑型可通過噴霧乾燥技術；熱熔擠出策略、微晶化和奈米研磨技術來製備。
可以依據藥物製劑領域中已知的技術來製備鼻用噴霧劑(nasal aerosol)或吸入劑(inhalation)組成物。例如，使用本領域已知的苯甲醇(benzyl
alcohol)或其他合適的防腐劑、提升生物利用度的吸收促進劑、碳氟化合物(fluorocarbons)及/或其他助溶劑或分散劑，可以將這種組成物製備成鹽水溶液。具有活性化合物的組成物也可以栓劑(suppository)的形式用於直腸給藥。
醫藥組成物中的載體必須是「可接受的」，在某種意義上它與組成物的活性成分是相容的(compatible)(且優選為能夠穩定該活性成分)，且對於治療的主體無害。一或多種助溶劑可用作醫藥賦形劑，用於遞送活性化合物。其他載體的例子包含膠體氧化矽(colloidal silicon oxide)、硬脂酸鎂、纖維素、月桂基硫酸鈉(sodium lauryl sulfate)和D&C Yellow #10。
本發明的特徵還在於一或多種式(I)化合物用於製備藥物或治療和預防Cisd2不足相關病症或增加Cisd2基因表現的用途。
術語「治療」是指為了治癒、緩和、緩解、改變、補救、改善或影響疾病、症狀或體質(predisposition)的目的將化合物施用或給予主體。「有效劑量」是指賦予主體期望的效果時所需的化合物的量。如本領域技術人員所認知的，有效劑量會依據給藥途徑、賦形劑的使用、以及與其他治療方法(例如使用其他活性劑)共同使用的可能性而改變。
無須進一步詳細闡述，相信本領域技術人員可基於以上描述充分利用本發明。以下實施例應被解釋為僅是說明性的，而不以任何方式限制本揭露的其餘部分。本文所引用的所有出版物全數併入本發明以供參考。
以下為說明式(I)之噻吩化合物的製備和功效評估的實施例。
實施例
如以下實施例1所示製備化合物1-35。通過實施例2-9所述之體內和體外研究評估它們的功效。
實施例1：製備化合物1-35
化合物1-20、22、25、26、34和35各自根據類似於Meng et al.,J.Med.Chem.58,8166-81(2015)所述的程序製備。
2-胺基-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸甲酯(Methyl 2-amino-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylate)(化合物1)：1H NMR(300MHz,d6-DMSO)δ 9.04(s,1H),7.71(s,2H),7.20(d,1H),7.03(s,1H),6.97(d,1H),3.74(s,3H),2.53(s,3H),2.26(s,3H),2.15(s,3H)；LC-MS(ESI)m/z：319.1[M+H]+。
5-胺基-4-氰基-N-(2,4-二甲基苯基)-3-甲基噻吩-2-甲醯胺(5-Amino-4-cyano-N-(2,4-dimethylphenyl)-3-methylthiophene-2-carboxamide)(化合物2)：1H NMR(300MHz,d6-DMSO)δ 8.99(s,1H),7.69(s,2H),7.20(d,1H),7.04(s,1H),6.98(d,1H),2.38(s,3H),2.26(s,3H),2.14(s,3H)；LC-MS(ESI)m/z：286.1[M+H]+。
2-胺基-4-甲基-5-(吡啶-3-基胺甲醯基)噻吩-3-羧酸甲酯(Methyl 2-amino-4-methyl-5-(pyridin-3-ylcarbamoyl)thiophene-3-carboxylate)(化合物3)：1H NMR(400MHz,CD3OD)δ 8.75(d,1H),8.27(dd,1H),8.10(ddd,1H),7.41(dd,1H),3.83(s,3H),2.59(s,3H)；LC-MS(ESI)m/z：292.1[M+H]+。
2-叔丁基4-甲基5-胺基-3-甲基噻吩-2,4-二羧酸酯(2-tert-Butyl 4-methyl 5-amino-3-methylthiophene-2,4-dicarboxylate)(化合物4)：1H NMR(300MHz,CDCl3)δ 6.43(brs,2H),3.84(s,3H),2.66(s,3H),1.53(s,9H)；LC-MS(ESI)m/z：294.1[M+Na]+。
2-胺基-5-[(4-氟苯基)胺甲醯基]-4-甲基噻吩-3-羧酸乙酯(Ethyl 2-amino-5-[(4-fluorophenyl)carbamoyl]-4-methylthiophene-3-carboxylate)(化合物5)：1H NMR(400MHz,CDCl3)δ 7.51-7,45(m,2H),7.25(brs,1H),7.07-7.01(m,2H),6.43(brs,2H),4.33(q,2H),2.68(s,3H),1.38(t,3H)；LC-MS(ESI)m/z：323.1[M+H]+。
2-胺基-5-[(4-甲氧基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸甲酯(Methyl 2-amino-5-[(4-methoxyphenyl)carbamoyl]-4-methylthiophene-3-carboxylate)(化合物6)：1H NMR(300MHz,CD3OD)δ 7.46-7.41(m,2H),6.92-6.87(m,2H),3.82(s,3H),3.78(s,3H),2.56(s,3H)；LC-MS(ESI)m/z：321.2[M+H]+。
2-胺基-4-甲基-5-[(2-甲基苯基)胺甲醯基]噻吩-3-羧酸甲酯(Methyl 2-amino-4-methyl-5-[(2-methylphenyl)carbamoyl]thiophene-3-carboxylate)(化合物7)：1H NMR(400MHz,CDCl3)δ 7.93(d,1H),7.26-7.20(m,3H),7.08(ddd,1H),6.42(s,2H),3.87(s,3H),2.70(s,3H),2.31(s,3H)；LC-MS(ESI)m/z：305.2[M+H]+。
2-胺基-4-甲基-5-[(4-甲基苯基)胺甲醯基]噻吩-3-羧酸甲酯(Methyl 2-amino-4-methyl-5-[(4-methylphenyl)carbamoyl]thiophene-3-carboxylate)(化合物8)：1H NMR(300MHz,CDCl3)δ 7.42-7.39(m,2H),7.25(brs,1H),7.14(d,2H),6.42(brs,2H),3.86(s,3H),2.66(s,3H),2.33(s,3H)；LC-MS(ESI)m/z：305.3[M+H]+。
2-胺基-4-甲基-5-(苯基胺甲醯基)噻吩-3-羧酸甲酯(Methyl 2-amino-4-methyl-5-(phenylcarbamoyl)thiophene-3-carboxylate)(化合物9)：1H NMR(400MHz,CDCl3)δ 7.53(d,2H),7.35(dd,2H),7.28(brs,1H),7.13(dd,1H),6.42(brs,2H),3.86(s,3H),2.68(s,3H)；LC-MS(ESI)m/z：291.2[M+H]+。
2-胺基-4-甲基-5-{[4-(三氟甲基)苯基]胺甲醯基}噻吩-3-羧酸甲酯(Methyl 2-amino-4-methyl-5-{[4-(trifluoromethyl)phenyl]carbamoyl}thiophene-3-carboxylate)(化合物10)：1H NMR(400MHz,CD3OD)δ 7.77(d,2H),7.61(d,2H),3.83(s,3H),2.58(s,3H)；LC-MS(ESI)m/z：359.2[M+H]+。
2-胺基-5-{[4-(二甲基胺基)苯基]胺甲醯基}-4-甲基噻吩-3-羧酸甲酯(Methyl 2-amino-5-{[4-(dimethylamino)phenyl]carbamoyl}-4-methylthiophene-3-carboxylate)(化合物11)：1H NMR(400MHz,d6-DMSO)δ 9.40(s,1H),7.70(s,2H),7.40(d,2H),6.68(d,2H),3.73(s,3H),2.84(s,6H),2.46(s,3H)；LC-MS(ESI)m/z：334.3[M+H]+。
5-胺基-N 2-(2,4-二甲基苯基)-3-甲基噻吩-2,4-二甲醯胺(5-Amino-N 2-(2,4-dimethylphenyl)-3-methylthiophene-2,4-dicarboxamide)(化合物12)：1H NMR(400MHz,d6-Acetone)δ 8.06(brs,1H),7.46(d,1H),7.29(brs,2H),7.03(s,1H),6.98(d,1H),6.43(brs,2H),2.71(s,3H),2.27(s,3H),2.25(s,3H)；LC-MS(ESI)m/z：304.3[M+H]+。
2-胺基-5-[(4-氟苯基)胺甲醯基]-4-甲基噻吩-3-羧酸甲酯(Methyl 2-amino-5-[(4-fluorophenyl)carbamoyl]-4-methylthiophene-3-carboxylate)(化合物13)：1H NMR(400MHz,d6-DMSO)：δ 9.74(s,1H),7.77(s,2H),7.62-7.59(m,2H),7.17-7.12(m,2H),3.74(s,3H),2.48(s,3H)；LC-MS(ESI)m/z：309.2[M+H]+。
2-胺基-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸丙-2-基酯(Propan-2-yl 2-amino-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-
carboxylate)(化合物14)：1H NMR(400MHz,CDCl3)δ 7.72(d,1H),7.14(s,1H),7.04-7.02(m,2H),6.47(s,2H),5.22(sept,1H),2.69(s,3H),2.30(s,3H),2.26(s,3H),1.36(d,6H)；LC-MS(ESI)m/z：347.3[M+H]+。
2-胺基-5-[(4-氰基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸甲酯(Methyl 2-amino-5-[(4-cyanophenyl)carbamoyl]-4-methylthiophene-3-carboxylate)(化合物15)：1H NMR(400MHz,CD3OD)δ 7.78-7.76(m,2H),7.68-7.66(m,2H),3.82(s,3H),2.57(s,3H)；LC-MS(ESI)m/z：316.2[M+H]+。
2-胺基-4-甲基-5-[(3-甲基苯基)胺甲醯基]噻吩-3-羧酸甲酯(Methyl 2-amino-4-methyl-5-[(3-methylphenyl)carbamoyl]thiophene-3-carboxylate)(化合物16)：1H NMR(300MHz,CD3OD)δ 7.37-7.33(m,2H),7.20(dd,1H),6.94(d,1H),3.82(s,3H),2.56(s,3H),2.33(s,3H)；LC-MS(ESI)m/z：305.2[M+H]+。
2-胺基-4-甲基-5-[(2,4,6-三甲基苯基)胺甲醯基]噻吩-3-羧酸甲酯(Methyl 2-amino-4-methyl-5-[(2,4,6-trimethylphenyl)carbamoyl]thiophehe-3-carboxylate)(化合物17)：1H NMR(300MHz,CDCl3)δ 6.90(s,2H),6.75(brs,1H),6.39(brs,2H),3.85(s,3H),2.67(s,3H),2.27(s,3H),2.22(s,6H)；LC-MS(ESI)m/z：333.3[M+H]+。
2-胺基-4-甲基-5-[(3,4,5-三甲氧基苯基)胺甲醯基]噻吩-3-羧酸甲酯(Methyl 2-amino-4-methyl-5-[(3,4,5-trimethoxyphenyl)carbamoyl]thiophene-3-carboxylate)(化合物18)：1H NMR(400MHz,d6-DMSO)δ 9.55(s,1H),7.75(brs,2H),7.04(s,2H),3.75(s,3H),3.73(s,6H),3.62(s,3H),3.32(s,3H)；LC-MS(ESI)m/z：381.3[M+H]+。
2-胺基-4-甲基-5-(1,3-噻唑-2-基胺甲醯基)噻吩-3-羧酸甲酯(Methyl 2-amino-4-methyl-5-(1,3-thiazol-2-ylcarbamoyl)thiophene-3-carboxylate)(化合物19)：1H NMR(400MHz,CDCl3)δ 7.39(d,1H),6.81(d,1H),6.59(brs,2H),3.87(s,3H),2.72(s,3H)；LC-MS(ESI)m/z：298.2[M+H]+。
2-胺基-5-[(3-甲氧基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸甲酯(Methyl 2-amino-5-[(3-methoxyphenyl)carbamoyl]-4-methylthiophene-3-carboxylate)(化合物20)：1H NMR(300MHz,CDCl3)δ 7.34-7.33(m,2H),7.23(dd,1H),6.97(dd,1H),6.68(dd,1H),6.46(brs,2H),3.86(s,3H),3.82(s,3H),2.66(s,3H)；LC-MS(ESI)m/z：321.2[M+H]+。
2-胺基-5-[(2,4-二甲基苯基)胺甲醯基]噻吩-3-羧酸甲酯(Methyl 2-amino-5-[(2,4-dimethylphenyl)carbamoyl]thiophene-3-carboxylate)(化合物22)：1H NMR(300MHz,CDCl3)δ 7.64(d,1H),7.48(s,1H),7.29-7.26(m,1H),7.03(s,2H),6.35(s,2H),3.84(s,3H),2.30(s,3H),2.28(s,3H)；LC-MS(ESI)m/z：305.1[M+H]+。
2-胺基-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸乙酯(Ethyl 2-amino-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylate)(化合物25)：1H NMR(400MHz,CDCl3)δ 7.73(d,1H),7.13(s,1H),7.04-7.02(m,2H),6.42(brs,2H),4.33(q,2H),2.69(s,3H),2.30(s,3H),2.26(s,3H),1.38(t,3H)；LC-MS(ESI)m/z：333.1[M+H]+。
2-胺基-5-{[3-(乙氧基羰基)苯基]胺甲醯基}-4-甲基噻吩-3-羧酸乙酯(Ethyl 2-amino-5-{[3-(ethoxycarbonyl)phenyl]carbamoyl}-4-methylthiophene-3-
carboxylate)(化合物26)：1H NMR(300MHz,CDCl3)δ 8.00-7.93(m,2H),7.81-7.78(m,1H),7.44-7.39(m,2H),6.50(brs,2H),4.41-4.29(m,4H),2.69(s,3H),1.41-1.36(m,6H)；LC-MS(ESI)m/z：377.2[M+H]+。
2-胺基-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸叔丁酯(tert-Butyl 2-amino-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylate)(化合物34)：1H NMR(300MHz,CDCl3)δ 7.72(d,1H),7.12(brs,1H),7.04-7.02(m,2H),6.39(brs,2H),2.67(s,3H),2.30(s,3H),2.26(s,3H),1.58(s,9H)；LC-MS(ESI)m/z：361.3[M+H]+。
2-胺基-5-[(2-甲氧基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸甲酯(Methyl 2-amino-5-[(2-methoxyphenyl)carbamoyl]-4-methylthiophene-3-carboxylate)(化合物35)：1H NMR(300MHz,CDCl3)δ 8.39(dd,1H),8.17(brs,1H),7.08-6.96(m,2H),6.90(dd,1H),6.43(brs,2H),3.91(s,3H),3.86(s,3H),2.70(s,3H)；LC-MS(ESI)m/z：321.2[M+H]+。
製備2-胺基-5-[(4-羥基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸鉀酯(methyl 2-amino-5-[(4-hydroxyphenyl)carbamoyl]-4-methylthiophene-3-carboxylate)(化合物21)
步驟1. 2-胺基-5-[(4-{[叔丁基(二甲基)甲矽烷基]氧基}苯基)胺甲醯基]-4-甲基噻吩-3-羧酸甲酯(Methyl 2-amino-5-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)carbamoyl]-4-methylthiophene-3-carboxylate)
在無水甲醇(“MeOH”)中，使用N-(4-{[叔丁基(二甲基)甲矽烷基]氧基}苯基)-3-氧代丁醯胺(N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-oxobutanamide)、氰基乙酸甲酯(methyl cyanoacetate)、嗎啉(morpholine)和硫，以與上述相似的方法製備2-胺基-5-[(4-{[叔丁基(二甲基)甲矽烷基]氧基}苯基)胺甲醯基]-4-甲基噻吩-3-羧酸甲酯。
步驟2. 2-胺基-5-[(4-羥基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸鉀酯
在0℃下，將溶於四氫呋喃(“THF”,0.48mL)的1M四正丁基氟化銨(tetra-n-butylammonium fluoride)溶液加入至溶於THF(1mL)的2-胺基-5-[(4-{[叔丁基(二甲基)甲矽烷基]-氧基}苯基)胺甲醯基]-4-甲基噻吩-3-羧酸甲酯(100mg,0.24mmol)溶液中，將反應混合物逐漸升溫至室溫並攪拌3小時。在減壓下移除溶劑。將飽和氯化銨(NH4Cl)水溶液添加至殘餘物中，並將生成的混合物以二氯甲烷(CH2Cl2)萃取。有機層以硫酸鈉乾燥、過濾並在真空下濃縮。殘餘物以管柱層析法(乙酸乙酯/二氯甲烷(EtOAc/CH2Cl2)=1/3)純化，以提供白色固體的2-胺基-5-[(4-羥基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸鉀酯(61mg,84%)。
1H NMR(400MHz,CD3OD)δ 7.32(d,2H),6.75(d,2H),3.82(s,3H),2.55(s,3H).LC-MS(ESI)m/z：307.1[M+H]+。
製備2-胺基-4-溴-5-[(2,4-二甲基苯基)胺甲醯基]噻吩-3-羧酸甲酯(methyl 2-amino-4-bromo-5-[(2,4-dimethylphenyl)carbamoyl]thiophene-3-carboxylate)(化合物23)
步驟1. 4-溴-2-{[(9H-芴-9-基甲氧基)羰基]胺基}-5-甲醯基噻吩-3-羧酸甲酯(Methyl 4-bromo-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-5-formylthiophene-3-carboxylate)
在0℃下，將無水二甲基甲醯胺(“DMF”,60μL,0.76mmol)加入至溶於無水CH2Cl2(7.5mL)的三溴氧磷(POBr3,470mg,1.64mmol)溶液中並攪拌1小時。加入溶於無水CH2Cl2(7.5mL)的2-{[(9H-芴-9-基甲氧基)羰基]胺基}-4-側氧基-4,5-二氫噻吩-3-羧酸甲酯(methyl 2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxo-4,5-dihydrothiophene-3-carboxylate)溶液，接著將生成的混合物在50℃下加熱17小時。反應在冰浴中冷卻，並以2N氫氧化鈉水溶液中和。混合物以CH2Cl2萃取。有機層以硫酸鎂乾燥、過濾並在真空下濃縮。如此獲得的殘餘物以管柱層析法(EtOAc/己烷=1/30至1/20)純化，以提供4-溴-2-{[(9H-芴-9-基甲氧基)羰基]胺基}-5-甲醯基噻吩-3-羧酸甲酯(77mg,62%)。
步驟2. 3-溴-5-{[(9H-芴-9-基甲氧基)羰基]胺基}-4-(甲氧基羰基)-噻吩-2-羧酸(3-Bromo-5-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-(methoxycarbonyl)-thiophene-2-carboxylic acid)
將溶於1,4-二噁烷(1,4-dioxane)/水(3/0.2,3.2mL)的4-溴-2-{[(9H-芴-9-基甲氧基)羰基]胺基}-5-甲醯基噻吩-3-羧酸甲酯(77mg,0.16mmol)、2-甲基-2-丁烯(0.2mL,1.58mmol)、磷酸鈉(56mg,0.47mmol)和亞氯酸鈉(sodium chlorite)(43mg,0.47mmol)的反應混合物在室溫下攪拌3小時。接著將混合物以EtOAc萃取。有機層以硫酸鎂乾燥、過濾並在真空下濃縮，以提供3-溴-5-{[(9H-芴-9-基甲氧基)羰基]胺基}-4-(甲氧基羰基)噻吩-2-羧酸(75mg,95%)。
步驟3. 4-溴-5-[(2,4-二甲基苯基)胺甲醯基]-2-{[(9H-芴-9-基甲氧基)羰基]胺基}噻吩-3-羧酸甲酯(Methyl 4-bromo-5-[(2,4-dimethylphenyl)carbamoyl]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}thiophene-3-carboxylate)
在0℃下，將4滴無水DMF加入至溶於CH2Cl2(20mL)的3-溴-5-{[(9H-芴-9-基甲氧基)羰基]胺基}-4-(甲氧基羰基)-噻吩-2-羧酸(417mg,0.83mmol)和草醯氯(0.25mL,2.9mmol)的溶液中。將反應混合物逐漸升溫至室溫並攪拌4小時，接著在真空下濃縮以提供醯氯中間產物。在0℃下，將碳酸鉀(137mg,1mmol)和2,4-二甲基苯胺(92μL,0.74mmol)依序加入至溶於CH2Cl2(10mL)的醯氯(258mg,0.5mmol)溶液中。將反應混合物逐漸升溫至室溫並攪拌20小時。加入水。將生成的混合物以CH2Cl2萃取。有機層以硫酸鎂乾燥、過濾並在真空下濃縮。如此獲得的殘餘物以管柱層析法(CH2Cl2/己烷=1/1至MeOH/CH2Cl2=1/20至1/10)純化，以提供4-溴-5-[(2,4-二甲基苯基)胺甲醯基]-2-{[(9H-芴-9-基甲氧基)羰基]-胺基}噻吩-3-羧酸甲酯(186mg,62%)。
步驟4. 2-胺基-4-溴-5-[(2,4-二甲基苯基)胺甲醯基]噻吩-3-羧酸甲酯
將溶於CH2Cl2(3mL)的4-溴-5-[(2,4-二甲基苯基)胺甲醯基]-2-{[(9H-芴-9-基甲氧基)羰基]胺基}噻吩-3-羧酸甲酯(90mg,0.15mmol)和哌啶(20%於CH2Cl2中，1mL)的混合物在0℃下攪拌1小時。接著加入飽和碳酸氫鈉水溶液。將生成的混合物以CH2Cl2萃取。有機層以硫酸鎂乾燥、過濾並在真空
下濃縮。如此獲得的殘餘物以管柱層析法(EtOAc/己烷/NH4OH=30/90/0.2)純化，以提供2-胺基-4-溴-5-[(2,4-二甲基苯基)胺甲醯基]噻吩-3-羧酸甲酯(11mg,19%)。
1H NMR(400MHz,CDCl3)δ 8.88(brs,1H),7.88(d,1H),7.04-7.03(m,2H),6.56(brs,2H),3.90(s,3H),2.34(s,3H),2.30(s,3H).LC-MS(ESI)m/z：405.0[M+Na]+。
製備2-胺基-5-[(2,4-二甲基苯基)乙醯基]-4-甲基噻吩-3-羧酸鉀酯(methyl 2-amino-5-[(2,4-dimethylphenyl)acetyl]-4-methylthiophene-3-carboxylate)(化合物24)
步驟1. 5-[(2,4-二甲基苯基)乙醯基]-2-[(4-甲氧基苄基)胺基]-4-甲基噻吩-3-羧酸鉀酯(Methyl 5-[(2,4-dimethylphenyl)acetyl]-2-[(4-methoxybenzyl)amino]-4-methylthiophene-3-carboxylate)
在0℃下，將乙醯乙酸甲酯(0.11mL,0.97mmol)加入至含氫化鈉(NaH,50mg,1.25mmol)的DMF(4mL)懸浮液中。接著將生成的混合物升溫至室溫並攪拌30分鐘，之後加入異硫氰酸-4-甲氧基苄基酯4(-methoxybenzyl isothiocyanate)(0.17mL,1.03mmol)。在攪拌1.5小時後，依序加入1-溴-3-(2,4-二甲基-苯基)丙-2-酮(1-bromo-3-(2,4-dimethyl-phenyl)propan-2-one)(285mg,1.18mmol)和碳酸鉀(138mg,0.97mmol)。將生成的混合物攪拌3小時，接著以水淬滅，並以乙酸乙酯萃取。有機層以硫酸鈉乾燥、過濾並在真空下濃縮。如此獲
得的殘餘物以管柱層析法(EtOAc/己烷=1/12)純化，以提供5-[(2,4-二甲基苯基)-乙醯基]-2-[(4-甲氧基苄基)胺基]-4-甲基噻吩-3-羧酸鉀酯(181mg,41%)。
步驟2. 2-胺基-5-[(2,4-二甲基苯基)乙醯基]-4-甲基噻吩-3-羧酸鉀酯
將溶於CH2Cl2(1mL)的5-[(2,4-二甲基苯基)乙醯基]-2-[(4-甲氧基苄基)-胺基]-4-甲基噻吩-3-羧酸鉀酯(41mg,0.13mmol)和三氟甲磺酸(“TfOH”,115μL,1.3mmol)的混合物在0℃下攪拌1小時。將飽和碳酸氫鈉水溶液加入以淬滅反應。將生成的混合物以CH2Cl2萃取。有機層以硫酸鈉乾燥、過濾並在真空下濃縮。如此獲得的殘餘物以管柱層析法(EtOAc/己烷=1/10至1/5)純化，以提供2-胺基-5-[(2,4-二甲基-苯基)乙醯基]-4-甲基噻吩-3-羧酸鉀酯(21mg,51%)。
1H NMR(400MHz,CDCl3)δ 7.02-6.94(m,3H),6.57(brs,2H),3.94(s,2H),3.85(s,3H),2.71(s,3H),2.29(s,3H),2.23(s,3H).LC-MS(ESI)m/z：318.1[M+H]+。
製備2-胺基-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸(2-amino-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylic acid)(化合物27)
步驟1：2-胺基-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸苄酯(Benzyl 2-amino-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylate)
在苯甲醇中，使用N-(2,4-二甲基苯基)-3-氧代丁醯胺(N-(2,4-dimethylphenyl)-3-oxobutyramide)、氰基乙酸甲酯(benzyl cyanoacetate)、嗎啉和硫，以與上述相似的方法製備2-胺基-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸苄酯。
步驟2. 2-胺基-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸
於1atm氫氣(H2(g))中，將含2-胺基-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸苄酯(4g,10.1mmol)和氫氧化鈀(Pd(OH)2,0.71g)的THF/EtOH(2/1,75mL)混合物在室溫下攪拌12小時。反應混合物通過矽藻土過濾。濾液在減壓下濃縮。如此獲得的殘餘物以CH2Cl2再結晶，以提供灰白色固體的2-胺基-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸(2.3g,75%)。
1H NMR(400MHz,d6-DMSO)δ 12.29(brs,1H),8.99(s,1H),7.72(brs,2H),7.21(d,1H),7.03(s,1H),6.97(d,1H),2.54(s,3H),2.26(s,3H),2.15(s,3H).LC-MS(ESI)m/z：305.3[M+H]+。
製備5-胺基-N 4-(氰基甲基)-N 2-(2,4-二甲基苯基)-3-甲基噻吩-2,4-二甲醯胺(5-amino-N 4-(cyanomethyl)-N 2-(2,4-dimethylphenyl)-3-methylthiophene-2,4-dicarboxamide)(化合物28)
步驟1. 2-[(叔丁氧基羰基)胺基]-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸乙酯(Ethyl 2-[(tert-butoxycarbonyl)amino]-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylate)
在室溫下，將叔丁氧基羰基酸酐(tert-Butyloxycarbonyl anhydride,“Boc2O”,0.23mL,1.02mmol)緩慢加入至溶於THF(5mL)的化合物25(307mg,0.92mmol)、二甲胺基吡啶(“DMAP”,11mg,0.09mmol)和三乙胺(0.77mL,5.54mmol)的溶液中並攪拌23小時。反應混合物以飽和碳酸氫鈉水溶液淬滅，並以乙酸乙酯萃取。有機層以硫酸鈉乾燥、過濾並在真空下濃縮。如此獲得的殘餘物以管柱層析法(EtOAc/己烷=1/4至1/2)純化，以提供2-[(叔丁氧基羰基)胺基]-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸乙酯(122mg,31%)。
步驟2. 2-[(叔丁氧基羰基)胺基]-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸(2-[(tert-Butoxycarbonyl)amino]-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophene-3-carboxylic acid)
在室溫下，將溶於水(2mL)中的氫氧化鈉(85mg,2.12mmol)溶液加入至溶於MeOH(2mL)的2-[(叔丁氧基羰基)胺基]-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸乙酯(458mg,1.06mmol)的溶液中。將生成的混合物在90℃下加熱3小時，接著在冰浴中冷卻。反應物以2N的鹽酸水溶液酸化。將生成的沉澱物過濾、收集並在真空下乾燥，以提供2-[(叔丁氧基羰基)胺基]-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸(348mg,81%)。
步驟3. 3-[(氰基甲基)胺甲醯基]-5-[(2,4-二甲基苯基)-胺甲醯基]-4-甲基噻吩-2-基}胺基甲酸叔丁酯(tert-Butyl
{3-[(cyanomethyl)carbamoyl]-5-[(2,4-dimethylphenyl)-carbamoyl]-4-methylthiophen-2-yl}carbamate)
在室溫下，將三乙胺(0.08mL,0.54mmol)和
50wt.%丙基膦酸酐(propylphosphonic anhydride,“T3P”)之乙酸乙酯溶液(0.29mL,0.27mmol)依序加入至溶於DMF(1.5mL)的2-[(叔丁氧基羰基)胺基]-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸(55mg,0.14mmol)和胺基乙腈鹽酸鹽(aminoacetonitrile hydrochloride)(19mg,0.2mmol)的溶液中並攪拌18小時，接著以水淬滅並以乙酸乙酯萃取。有機層以硫酸鈉乾燥、過濾並在真空下濃縮。殘餘物以管柱層析法(EtOAc/己烷=3/1至MeOH/CH2Cl2=1/30)純化，以提供3-[(氰基甲基)胺甲醯基]-5-[(2,4-二甲基苯基)-胺甲醯基]-4-甲基噻吩-2-基}胺基甲酸叔丁酯(17mg,28%)。
步驟4. 5-胺基-N 4-(氰基甲基)-N 2-(2,4-二甲基苯基)-3-甲基噻吩-2,4-二甲醯胺
將溶於CH2Cl2(2mL)的3-[(氰基甲基)胺甲醯基]-5-[(2,4-二甲基苯基)-胺甲醯基]-4-甲基噻吩-2-基}胺基甲酸叔丁酯(16mg,0.04mmol)和溴化鋅(ZnBr2,42mg,0.19mmol)的混合物在室溫下攪拌20小時。加入水並將生成的混合物以CH2Cl2萃取。有機層以硫酸鈉乾燥、過濾並在真空下濃縮。殘餘物以管柱層析法(EtOAc/己烷=1/1)純化，以提供5-胺基-N 4-(氰基甲基)-N 2-(2,4-二甲基苯基)-3-甲基噻吩-2,4-二甲醯胺(5mg,40%)。
1H NMR(300MHz,CD3OD)δ 7.18(d,1H),7.08(s,1H),7.02(d,1H),4.27(s,2H),2.57(s,3H),2.30(s,3H),2.23(s,3H).LC-MS(ESI)m/z：343.1[M+H]+。
製備5-胺基-N-(2,4-二甲基苯基)-4-(羥基乙醯基)-3-甲基噻吩-2-甲醯胺(5-amino-N-(2,4-dimethylphenyl)-4-(hydroxyacetyl)-3-methylthiophene-2-carboxamide)(化合物29)
步驟1. {5-[(2,4-二甲基苯基)胺甲醯基]-3-[甲氧基(甲基)胺甲醯基]-4-甲基噻吩-2-基}甲酸叔丁酯(tert-Butyl{5-[(2,4-dimethylphenyl)carbamoyl]-3-[methoxy(methyl)carbamoyl]-4-methylthiophen-2-yl}carbamate)
將溶於CH2Cl2(20mL)的2-[(叔丁氧基羰基)胺基]-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-3-羧酸(542mg,1.34mmol)、N,O-二甲基羥基胺鹽酸鹽(N,O-dimethylhydroxylamine hydrochloride)(196mg,2mmol)、1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,“EDC”,308mg,1.61mmol)、羥基苯並三唑(hydroxybenzotriazole,“HOBt”,181mg,1.34mmol)和N,N-二異丙基乙基胺(N,N-diisopropylethylamine,“DIPEA”,0.8mL,4.69mmol)的混合物在室溫下攪拌21小時。加入水並將生成的混合物以乙酸乙酯萃取。有機層以硫酸鎂乾燥、過濾並在真空下濃縮。殘餘物以管柱層析法(EtOAc/己烷=
1/3 to 1/1)過濾，以提供{5-[(2,4-二甲基苯基)胺甲醯基]-3-[甲氧基(甲基)胺甲醯基]-4-甲基噻吩-2-基}甲酸叔丁酯(268mg,45%)。
步驟2. {3-[(苄氧基)乙醯基]-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-2-基}胺基甲酸叔丁酯(tert-Butyl{3-[(benzyloxy)acetyl]-5-[(2,4-dimethylphenyl)carbamoyl]-4-methylthiophen-2-yl}carbamate)
在-60℃下，將溶於無水THF(7mL)的{5-[(2,4-二甲基苯基)胺甲醯基]-3-[甲氧基(甲基)胺甲醯基]-4-甲基噻吩-2-基}甲酸叔丁酯(197mg,0.44mmol)緩慢加入原位(in situ)製備的溶於THF的苄氧基甲基氯化鎂(benzyloxymethyl magnesium chloride)(1.44M,5mL)的溶液中。將反應逐漸升溫至室溫並攪拌21小時，接著以飽和氯化銨水溶液淬滅並以乙酸乙酯萃取。有機層以硫酸鎂乾燥、過濾並在真空下濃縮。如此獲得的殘餘物以管柱層析法(EtOAc/CH2Cl2=1/100至1/20)純化，以提供{3-[(苄氧基)乙醯基]-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-2-基}胺基甲酸叔丁酯(173mg,77%)。
步驟3. {5-[(2,4-二甲基苯基)胺甲醯基]-3-(羥基乙醯基)-4-甲基噻吩-2-基}胺基甲酸叔丁酯(tert-Butyl{5-[(2,4-dimethylphenyl)carbamoyl]-3-(hydroxyacetyl)-4-methylthiophen-2-yl}carbamate)
在室溫下，於混合溶劑(EtOH/EtOAc=2/3,5mL)中，將{3-[(苄氧基)乙醯基]-5-[(2,4-二甲基苯基)胺甲醯基]-4-甲基噻吩-2-基}胺基甲酸叔丁酯(103mg,0.2mmol)以10% Pd/C(80mg)氫化17小時。反應混合物通過矽藻土過濾。濾液在真空下濃縮。如此獲得的殘餘以管柱層析法(EtOAc/己烷=1/3至1/2)純化，以提供{5-[(2,4-二甲基苯基)胺甲醯基]-3-(羥基乙醯基)-4-甲基噻吩-2-基}胺基甲酸叔丁酯(43mg,51%)。
步驟4. 5-胺基-N-(2,4-二甲基苯基)-4-(羥基乙醯基)-3-甲基噻吩-2-甲醯胺
在0℃下，將溶於CH2Cl2的50%TFA(1mL)溶液加入至溶於CH2Cl2(2mL)的{5-[(2,4-二甲基苯基)胺甲醯基]-3-(羥基乙醯基)-4-甲基噻吩-2-基}胺基甲酸叔丁酯(43mg,0.1mmol)的溶液中。將反應混合物在室溫下攪拌3小時，以飽和碳酸氫鈉水溶液淬滅，接著以CH2Cl2萃取。有機層以硫酸鎂乾燥、過濾並往真空下濃縮。殘餘物以CH2Cl2/己烷再結晶，以提供5-胺基-N-(2,4-二甲基苯基)-4-(羥基乙醯基)-3-甲基噻吩-2-甲醯胺(9.0mg,27%)。
1H NMR(400MHz,d6-DMSO)δ 9.18(s,1H),8.50(s,2H),7.16(d,1H),7.02(s,1H),6.96(d,1H),4.71(t,1H),4.47(d,2H),2.53(s,3H),2.24(s,3H),2.13(s,3H).LC-MS(ESI)m/z：319.1[M+H]+。
製備4-乙醯基-5-胺基-N-(2,4-二甲基苯基)-3-甲基噻吩-2-甲醯胺(4-acetyl-5-amino-N-(2,4-dimethylphenyl)-3-methylthiophene-2-carboxamide)(化合物30)
步驟1. {[2-乙醯基-1-(苄基胺基)-3-側氧基丁-1-烯-1-基]硫烷基}乙酸苄酯(Benzyl{[2-acetyl-1-(benzylamino)-3-oxobut-1-en-1-yl]sulfanyl}acetate)
在0℃下，將NaH(419mg,10.5mmol)加入至溶於DMF(10mL)的乙醯丙酮(1g,10mmol)溶液中。30分鐘後，加入異硫氰酸芐酯(benzyl isothiocyanate)(1.32mL,10mmol)。將生成的反應混合物逐漸升溫至室溫並攪拌3小時。加入溴乙酸苄酯(benzyl bromoacetate)(1.72mL,11mmol)並攪拌過夜，隨後以水淬滅，並以乙酸乙酯萃取。有機層以硫酸鎂乾燥、過濾在真空下並濃縮。如此獲得的殘餘物以管柱層析法(EtOAc/己烷=1/20)純化，以提供{[2-乙醯基-1-(苄基胺基)-3-側氧基丁-1-烯-1-基]硫烷基}乙酸苄酯(2.18g,55%)。
步驟2. 4-乙醯基-5-(苄基胺基)-3-甲基噻吩-2-羧酸苄酯(Benzyl 4-acetyl-5-(benzylamino)-3-methylthiophene-2-carboxylate)
將溶於THF(40mL)的{[2-乙醯基-1-(苄基胺基)-3-側氧基丁-1-烯-1-基]硫烷基}乙酸苄酯(2.13g,5.36mmol)和K2CO3(1.1g,8.03mmol)溶液在75℃下加熱3小時。將反應混合物冷卻至室溫，以水淬滅並以乙酸乙酯萃取。有機層以硫酸鎂乾燥、過濾並在真空下濃縮。如此獲得的殘餘物以管柱層析法(EtOAc/己烷=1/20至1/10)純化，以提供4-乙醯基-5-(苄基胺基)-3-甲基噻吩-2-羧酸苄酯(1.44g,71%)。
步驟3. 4-乙醯基-5-(苄基胺基)-3-甲基噻吩-2-羧酸(4-Acetyl-5-(benzylamino)-3-methylthiophene-2-carboxylic acid)
將溶於THF(20mL)的4-乙醯基-5-(苄基胺基)-3-甲基噻吩-2-羧酸苄酯(682mg,1.8mmol)和7N的KOH水溶液(4mL)的混合物在100℃下加熱24小時。將反應混合物冷卻至0℃，以2N鹽酸水溶液酸化，並以乙酸乙酯萃取。有機層以硫酸鎂乾燥、過濾並在真空下濃縮。如此獲得的殘餘物以管柱層析法(MeOH/CH2Cl2=1/50至1/20)純化，以提供4-乙醯基-5-(苄基胺基)-3-甲基噻吩-2-羧酸(315mg,61%)。
步驟4. 4-乙醯基-5-(苄基胺基)-N-(2,4-二甲基苯基)-3-甲基噻吩-2-甲醯胺(4-Acetyl-5-(benzylamino)-N-(2,4-dimethylphenyl)-3-methylthiophene-2-carboxamide)
將溶於DMF(5mL)的4-乙醯基-5-(苄基胺基)-3-甲基噻吩-2-羧酸(245mg,0.85mmol)、EDC(177mg,0.92mmol)、HOBt(104mg,0.77mmol)、2,4-二甲基苯胺(95μL,0.77mmol)和DIPEA(0.46mL,2.69mmol)的混合物在50℃下加熱16小時。冷卻至室溫，以水淬滅並以乙酸乙酯萃取。有機層以硫酸鎂乾燥、過濾並在真空下濃縮。如此獲得的殘餘物以管柱層析法(EtOAc/CH2Cl2=1/100)純化，以提供4-乙醯基-5-(苄基胺基)-N-(2,4-二甲基苯基)-3-甲基噻吩-2-甲醯胺(140mg,42%)。
步驟5. 4-乙醯基-5-胺基-N-(2,4-二甲基苯基)-3-甲基噻吩-2-甲醯胺
將溶於二氯甲烷(3mL)的4-乙醯基-5-(苄基胺基)-3-甲基-N-苯基噻吩-2-甲醯胺(4-acetyl-5-(benzylamino)-3-methyl-N-phenylthiophene-2-carbox-amide)(60mg,0.15mmol)和三氟甲磺酸(0.13mL,1.53mmol)在60℃下加熱1小時。在冰浴下冷卻，以6N氫氧化鈉水溶液中和，接著以乙酸乙酯萃取。有機層以硫酸鎂乾燥、過濾並在真空下濃縮。殘餘物以管柱層析法(EtOAc/CH2Cl2=1/4)純化，以提供4-乙醯基-5-胺基-N-(2,4-二甲基-苯基)-3-甲基噻吩-2-甲醯胺(8.4mg,18%)。
1H NMR(300MHz,d6-DMSO)δ 9.16(s,1H),8.47(s,2H),7.19(d,1H),7.04(s,1H),6.98(d,1H),2.59(s,3H),2.42(s,3H),2.26(s,3H),2.15(s,3H).LC-MS(ESI)m/z：303.1[M+H]+.
化合物31和32
兩種化合物以與化合物30相似的方法製備。
4-乙醯基-5-胺基-3-甲基-N-苯基噻吩-2-甲醯胺(4-Acetyl-5-amino-3-methyl-N-phenylthiophene-2-carboxamide)(化合物31)：1H NMR(400MHz,d6-DMSO)δ 9.80(s,1H),8.50(s,2H),7.60(d,2H),7.31(dd,2H),7.06(dd,1H),2.54(s,3H),2.42(s,3H)；LC-MS(ESI)m/z：275.1[M+H]+。
4-乙醯基-5-胺基-N-(4-氟苯基)-3-甲基噻吩-2-甲醯胺(4-Acetyl-5-amino-N-(4-fluorophenyl)-3-methylthiophene-2-carboxamide)(化合物32)：1H NMR(400MHz,CD3OD)δ 7.57-7.53(m,2H),7.09-7.04(m,2H),2.62(s,3H),2.49(s,3H)；LC-MS(ESI)m/z：293.0[M+H]+.
化合物33
將化合物1(100mg,0.31mmol)和乙酸酐(“Ac2O”；10mL)的混合物在迴流下攪拌2小時。接著將反應在減壓下濃縮，並將生成的粗產物以熱甲醇再結晶，以提供灰白色固體的化合物33。
1H NMR(400MHz,d6-DMSO)δ 11.04(s,1H),9.53(s,1H),7.18(d,1H),7.06(s,1H),6.99(d,1H),3.87(s,3H),2.55(s,3H),2.27(s,3H),2.26(s,3H),2.17(s,3H)；LC-MS(ESI)m/z：361.2[M+H]+。
實施例2：Cisd2-冷光素酶報導基因分析法(Cisd2-luciferase reporter assay)
使用以下所述的Cisd2-冷光素酶報導基因分析法，測定化合物1-35在人類胚胎腎臟細胞株293(HEK-293)(表現Cisd2的轉染細胞株)中增加的Cisd2含量。
轉染的HEK-293細胞穩定表現帶有螢火蟲冷光素酶報導基因(firefly luciferase reporter)的Cisd2啟動子(promoter)(HEK293-CISD2)。它們被保存在Dulbecco改良的Eagle培養基(Dulbecco's modified Eagle's medium,DMEM)(Gibco,New York,NY)中。培養基添加了10%熱去活(heat-inactivated)胎牛血清(FBS)、2mM的L-麩醯胺酸(L-Glutamine)、1mM丙酮酸鈉(sodium pyruvate)、0.1%的MEM非必需胺基酸(MEM Non-Essential Amino Acids)、1μg/ml嘌呤黴素(puromycin)和1%青黴素/鏈黴素(penicillin/streptomycin)(HyClone,Logan,UT)。細胞培養維持在37℃、含5%二氧化碳的培養箱中(Thermo Fisher Scientific,Waltham,MA)。穩定轉染的細胞以3×103細胞/孔的密度接種於384-孔盤中。與測試化合物在37℃下作用24小時後，在室溫下加入ONE-GloTM冷光素酶分析系統(ONE-GloTM Luciferase Assay System)(Promega,Madison,WI)10分鐘，以
檢測任何冷光素酶活性。發光強度以盤式分析儀BioTek Synergy Neo2TM(Agilent,Santa Clara,CA)測量。
以EC50值表示，發現化合物1-35每一個都能在一定程度上活化Cisd2。參見下表2。在此表中，EC50值以三種等級表示，即A：<1μM，B：1μM-10μM。
表2
實施例3：治療抗-非酒精性脂肪肝症(anti-nonalcoholic fatty liver disease)
依照以下描述的測試，評估化合物1的抗-非酒精性脂肪肝症(NAFLD)的效果和體內毒性。
依照Wang et al.,Hum.Mol.Genet.23,4770-85(2014)描述的步驟準備Cisd2 flox對偶基因(Cisd2 floxed allele)(Cisd2 f/f)小鼠。為了獲得Cisd2異型合
子肝細胞特異性基因剔除(Cisd2 heterozygous hepatocyte-specific knockout)(Cisd2 hKO-het，Cisd2 f/+；Alb-Cre Tg)，將Cisd2 f/f小鼠與Albumin-Cre基因轉殖(Alb-Cre Tg,JAX003574)的小鼠繁殖。一代後，獲得Cisd2 hKO-het小鼠。選擇雄性小鼠用於本研究。所有小鼠具有純的或同基因型(congenic)C57BL/6遺傳背景，並被繁殖/飼養在20-22℃以12小時照光/12小時黑暗為循環的無特定病原體(specific pathogen-free)設施中。將含有載體(0.14wt%的DMF和0.15wt%的Cremophor® EL)或化合物1(0.015wt%)的飲食(AIN93G,TestDiet)提供給8週齡的小鼠群組，持續4週。
用組織病理學評估化合物1在改善NAFLD的功效。收集肝臟組織並在4℃下以10%中性緩衝福馬林固定過夜。接著將他們在組織處理器(STP120,Microm,Thermo Fisher Scientific Inc.,Waltham,MA)中處理，然後包埋至石蠟中。通過標準程序對組織切片(3-4μm)進行H&E染色。具體地，將肝臟組織切片脫蠟(deparaffinized)、復水(rehydrated)，並以梅爾氏蘇木精(Mayer’s hematoxylin)(Muto Pure Chemicals Co.,Bunkyo-ku,Japan)和1%伊紅溶液(eosin Y solution)(Muto Pure Chemicals Co.)染色。接著將染色的肝臟組織切片脫水，以封固劑(mounting medium)(Surgipath)封固，並蓋上蓋玻片。
進行血清生化分析(Serum Biochemical analysis)以評估化合物1的體內毒性。在犧牲時，由面靜脈(facial vein)或心臟穿刺(cardiac puncture)收集全血樣本，用於在Fuji Dri-Chem 3500s analyzer(Fujifilm Corp.,Tokyo,Japan)上分析血清丙胺酸轉胺酶(alanine aminotransferase)(GPT/ALT)、天門冬胺酸轉胺酶(aspartate aminotransferase)(GOT/AST)、血尿素氮(blood urea nitrogen,BUN)和肌酸酐(creatinine,CRE)含量。
結果顯示，化合物1顯著提高了在Cisd2+/-小鼠中Cisd2蛋白的表現量(即以化合物1處理的小鼠中的蛋白表現量為0.7，而控制組中的蛋白表現量僅為0.43)，以及改善由Cisd2單套不足(haploinsufficiency)導致的NAFLD和肝臟病理學(脂肪變性(steatosis)、肝細胞紊亂(hepatocyte disorganization)和腫脹(ballooning))，沒有檢測到肝臟或腎臟毒性。
實施例4：治療非酒精性脂肪肝炎的體內研究
化合物1在上述野生型和Cisd2 hKO雄性小鼠中用於減輕非酒精性脂肪肝炎(NASH)。
Cisd2 hKO繁殖了兩代。本研究中使用的所有雄性小鼠具有純的或同基因型C57BL/6遺傳背景，並被繁殖/飼養在20-22℃以12小時照光/12小時黑暗為循環的無特定病原體設施中。餵食牠們含有30%(w/v)果糖(Alfa Aesar,Tewksbury,MA)的飲用水以建立果糖誘導的NASH模型。將含有載體(0.14wt%的DMF和0.15wt%的Cremophor® EL)或化合物1(0.015wt%)的飲食(AIN93G,TestDiet,St.Louis,MO)提供給2個月大的小鼠群組，持續5個月。以任意採食(ad libitum)方式提供食物和飲用水。
用組織病理學評估化合物1在減輕NASH的功效。如以上實施例3中所述處理肝臟組織並染色。
進行口服葡萄糖耐受性試驗(oral glucose tolerance test,GTT)和胰島素耐受性試驗(insulin tolerance test,ITT)，以研究化合物1在果糖誘導的葡萄糖不耐性(intolerance)和肝胰島素抗性(insulin resistant)小鼠模型中的效益。在口服葡萄糖耐受性試驗中，將小鼠禁食14小時(7 p.m.至9 a.m.)後，使用餵食針口服給予葡萄糖水(1.5mg/g體重)。於預定時間點，在葡萄糖處理前(0分鐘)和後，由尾
靜脈(tail vein)收集血液樣本。使用OneTouch® Ultra葡萄糖測試片(test strip)和SureStep®儀(LifeScan,Milpitas,CA)測量血糖含量。在胰島素耐受性試驗中，將小鼠禁食2小時(9 a.m.至11 a.m.)後，腹腔注射胰島素(0.75U/kg體重)(Actrapid® human regular insulin,Novo Nordisk,Bagsværd,Denmark)。在預定時間點收集和監測血液樣本。
結果顯示，化合物1顯著增加了在WT小鼠中的Cisd2蛋白量(以化合物1處理的小鼠的蛋白量為0.8，對比控制組中的蛋白量為0.4)，改善了果糖誘導的NASH，以及減輕了果糖誘導的葡萄糖不耐性和胰島素抗性，沒有顯著毒性。另一方面，化合物1在肝細胞特異性基因Cisd2剔除(hepatocyte-specific Cisd2 knockout,Cisd2 hKO)小鼠中沒有明顯的有益效果。結果暗示，化合物1的功效主要取決於涉及Cisd2的分子機制/途徑。
實施例5：免受阿黴素誘導(doxorubicin-induced)之心臟毒性的體內研究
評估化合物1在小鼠中對阿黴素誘導之心臟毒性的保護。
通過腹腔注射(i.p)化合物1(劑量1mg/kg)或載體(3.3% DMSO於生理鹽水中)處理7至8個月大的雄性C57BL/6小鼠，每天兩次，持續2天。在第0天，以化合物1處理後1小時，將阿黴素(25mg/kg,i.p.)或另一種載體(8% DMSO於生理鹽水中)注射到小鼠中。
分別將第4天和第5天的心電圖(electrocardiogram,ECG)和心臟超音波(heart echo)用於作為心臟功能的指標。在第5天收集小鼠組織，並在4℃下以10%中性緩衝福馬林固定過夜，然後以石蠟包埋和切片。
如Yeh et al.,PLoS Biol.2019,17,e3000508所述，使用ECG進行心臟功能測試。小鼠維持在早上6點開燈以12：12小時黑暗-照光循環中。所有步驟在照光階段進行。最初透過將小鼠置於充滿3 v/v%異氟醚(isoflurane)(Aesica Pharmaceuticals,Hertfordshire,UK)的腔室中3-5分鐘誘導麻醉。接著將小鼠置於溫熱墊(warm pad)(ALA Scientific Instruments Inc.,East Farmingdale,NY)上，該溫熱墊在ECG記錄期間能夠維持溫度。小鼠通過鼻錐(nose cone)自由呼吸。通過吸入1.5%異氟醚維持麻醉。使用連接在四肢的皮下電極獲得連續5分鐘ECG，並以PowerLab®資料擷取系統(data acquisition system)(model ML866,ADInstruments,Colorado Springs,CO)和Animal Bio Amp®(model ML136,ADInstruments)記錄。以無偏差方式進行ECG分析，其中使用LabChart® 7 Pro version 7.3.1(ADInstruments)進行1500次心跳分析。將QTc時間間隔(QTc interval)、QRS時間間隔(QRS interval)、Tpeak-T結束時間間隔(Tpeak-T end interval)的檢測和分析設置為小鼠ECG參數。利用曼-惠特尼U檢定(Mann-Whitney U test)對由此獲得的數值進行統計比較，且p<0.05被認為是顯著的。
經胸前老鼠心臟超音波圖(transthoracic mouse echocardiography)用於在VisualSonics® VeVo® 2100成像系統(VisualSonics,Toronto,Ontario,Canada)上提供心臟的非侵入式(noninvasive)成像。將雄性小鼠以1%異氟醚(於95%氧氣中)麻醉。在溫熱墊(TC-1000,CWE Inc.USA)上維持體溫在36℃至37℃並監測。持續監測ECGs。如Casaclang-Verzosa et al.,J.Vis.Exp.120,e54110(2017)所述，使用高頻率30-50MHz探針評估心臟功能。使用VisualSonics®軟體進行數據分析。負責數據擷取的人員對動物組別是不知的。
結果顯示，化合物1顯著增加了Cisd2蛋白量，減少由阿黴素導致的ECG異常，並減弱在ST高度(ST height)和QRS時間間隔由阿黴素誘導的異常心電傳導。此外，整體心臟功能(cardiac performance)測試顯示，與阿黴素注射造成的損害相比，化合物1有效維持心臟功能。結果表示，化合物1出乎意料的保護免受阿黴素誘導的心臟毒性。
實施例6：治療阿黴素誘導的惡病質和肝毒性的體內研究
在以下的體內研究中，化合物1用於挽救(rescuing)阿黴素誘導的惡病質和肝毒性。
通過腹腔注射(i.p)化合物1(1mg/kg)或載體(3.3% DMSO於生理鹽水中)預處理7至8個月大的雄性C57BL/6小鼠，每天兩次，持續2天。在第0天，以化合物1處理後1小時，將阿黴素(25mg/kg,i.p.)或另一種載體(8% DMSO於生理鹽水中)注射到小鼠中。
將小鼠犧牲後，秤重並收集不同組織，包含肝臟、心肌(cardiac muscle)(左心室)、骨骼肌(skeletal muscle)(腓腸肌(gastrocnemius))、棕色脂肪組織(brown adipose tissue)、和白色脂肪組織(white adipose tissue)。組織在4℃下以10%中性緩衝福馬林固定過夜，在組織處理器中處理，接著包埋至石蠟中。通過上述的標準程序對組織切片(3-4μm)進行H&E染色。
結果顯示，化合物1在組織病理學上減輕了阿黴素誘導的心臟損傷，包含心肌細胞(cardiomyocyte)的細胞溶質(cytosolic)空泡形成(vacuolation)和肌纖維的變性(degeneration)。此外，化合物1弱化了單次高劑量阿黴素注射後整體心臟重量減少。出乎意料的，化合物1減輕阿黴素誘導的肝毒性和惡病質。
實施例7：治療年齡相關(age-related)的心律失常的體內研究
在以下的體內研究中，化合物1用於挽救與年齡相關的心律失常。
通過腹腔注射(i.p)化合物1(1mg/kg)或載體(3.3% DMSO於生理鹽水中)預處理20至21個月大的雌性C57BL/6小鼠，每天兩次，持續18天。
在第18天以化合物治療前後2-3天檢查心電圖(ECG)，作為心臟功能的指標。在第5天收集小鼠組織，並在4℃下以10%中性緩衝福馬林固定過夜，然後以石蠟包埋和切片。
如上述實施例5所述使用ECG和經胸前老鼠心臟超音波圖進行心臟功能測試。
對停經後(post-menopausal)老化(aging)小鼠相關的老化心臟功能異常(dysfunction)研究表示，短期注射化合物1可維持寬的QTc、延長的Tpeak-Tend和不規則的PR間隔(PR interval)。在注射化合物1的衰老過程中，收縮期的(systolic)收縮力(contractility)維持不變。以載體注射的，心臟的收縮(量測射出率(ejection fraction))和舒張(量測心肌效能指數(myocardial performance index))功能劣化。結果出乎意料顯示，化合物1防止與年齡相關的心律失常(age-related arrhythmogenesis)
實施例8：治療與年齡相關的心臟病變的體內研究
在以下的體內研究中，化合物1用於挽救與年齡相關的心律失常。
通過腹腔注射(i.p)化合物1(1mg/kg)或載體(3.3% DMSO於生理鹽水中)預處理20至21個月大的雌性C57BL/6小鼠，每天兩次，持續2天。在第18天以化合物治療前後2-3天檢查心電圖(ECG)和心臟超音波，作為心臟功能的指標。在第5天收集小鼠組織，並在4℃下以10%中性緩衝福馬林固定過夜，然後以石蠟包埋和切片。
將小鼠犧牲後，秤重並收集心臟組織。將組織在4℃下以10%中性緩衝福馬林固定過夜，在組織處理器中處理，然後以石蠟包埋和切片。通過上述的標準程序對組織切片(3-4μm)進行H&E染色和天狼星紅染色。
年齡相關的心臟病變的研究表示，在衰老時出現的細胞溶質(cytosolic)空泡(vacuole)在以化合物1治療後消失。此外，化合物1可以預防衰老過程中肌內膜(endomysial)纖維化增加。出乎意料地，化合物1減輕了年齡相關的心臟病變。
除了上述研究外，已發現增加Cisd2表現可以減弱阿滋海默氏症中Aβ-介導的神經元損失、改善肌肉變性和減緩皮膚老化。參見Chen et al.,Journal of Pathology 250,299-311(2020)；和Wu et al.,Human Molecular Genetics 21(18),3956-68(2012)。此外，提高Cisd2的含量也可以改善葡萄糖不耐性。此外，Cisd2調升可以減弱年老動物和炎症(inflammatory)細胞模型中損傷誘導的(injury-induced)發炎。參見Lin et al.,Injury 46(12),2341-50(2015)；和Lin et al.,Nutrients 11(3),700(2019).。因此，式(I)的噻吩化合物也適用於治療阿滋海默氏症、肌肉變性、皮膚老化、葡萄糖不耐性和發炎。
實施例9：治療高血壓心肌症的體內研究
化合物1用於改善在野生型雌性小鼠的高血壓心肌症。
本研究中使用的所有雌性小鼠具有純的或同基因型C57BL/6遺傳背景，並被繁殖/飼養在20-22℃以12小時照光/12小時黑暗為循環的無特定病原體設施中。11至12個月大的雌性C57BL/6小鼠在治療前半個月接受雙側(bilateral)卵巢切除術(ovariectomy)。將含有載體(0.14wt%的DMF和0.15wt%的Cremophor® EL)或化合物1(0.015wt%)的飲食(AIN93G,TestDiet)提供給12個月
大的卵巢切除小鼠群組，持續3個月。治療1個月後，將含有血管收縮素II(angiotensin II)(1μg/kg/min)的滲透泵每月植入所有實驗動物中，持續2個月以建立高血壓心肌症模型。以任意採食方式提供食物和飲用水。
分別使用卵巢切除術之前和治療3個月後的收縮壓(Systolic blood pressure,SBP)、心電圖(ECG)和心臟超音波作為心肺功能(cardiovascular function)的指標。在有意識的(conscious)小鼠中用尾套系統(tail cuff system)測量SBP。以上述實施例5中所述的方法進行ECG和心臟超音波。收集治療3個月後的小鼠組織，並在4℃下以10%中性緩衝福馬林固定過夜，然後以石蠟包埋和切片。通過上述實施例8中所述的標準程序對組織切片(3-4μm)進行H&E染色和天狼星紅染色。
對停經後小鼠相關的高血壓誘導的心臟功能異常研究表示，化合物1顯著地降低SBP。該研究也顯示，透過餵食小鼠化合物1可以保留高P波幅(amplitude)和束支傳導阻滯(bundle branch block)。此外，整體心臟功能測試顯示，與高血壓造成的損害相比，化合物1有效維持心臟功能。在高血壓期間以化合物1餵食，收縮期的(systolic)收縮力(contractility)維持不變。相比之下，以載體注射的，心臟的收縮功能劣化。
此外，觀察到化合物1在組織病理學程度上改善了高血壓誘導的心臟損傷，包含心室壁(ventricular wall)的肥大性(hypertrophic)變化和血管周圍的(perivascular)纖維化。出乎意料地，化合物1改善了高血壓心肌症。
其他實施例
此說明書中揭露的所有特徵可以以任何組合進行結合。此說明書中揭露的每個特徵可以由具有相同、等同或相似目的的替代特徵取代。因此，
除非另有明確地說明，否則所揭露的每個特徵僅是一系列等同或相似特徵的示例。
自以上描述，本領域技術人員可以容易地確定本發明的實質特徵，並在不脫離其精神及範圍的情況下，可以對本發明進行各種改變及修改以使其適用於各種用途及條件。例如也可以製備結構類似於本發明化合物的化合物，篩選它們在治療與Cisd2不足相關病症和增加Cisd2基因表現的功效。因此，其他實施例也在所附請求項的範圍內。
Claims (9)
- 一種式(I)化合物用於製備治療Cisd2不足相關病症的藥物的用途：
- 如請求項1所述之用途，其中，R1為H，且R2為H或C(O)CH3。
- 如請求項1所述之用途，其中，R3為CN、CO2CH3、CO2CH2CH3、CO2C(CH3)3、或COCH3。
- 如請求項1所述之用途，其中，R4為甲基。
- 如請求項1所述之用途，其中，R5為芳基或雜芳基。
- 如請求項5所述之用途，其中，R5選自由以下所組成之群組：
- 如請求項2所述之用途，其中，R3為CN、CO2CH3、CO2CH2CH3、CO2C(CH3)3、或COCH3；R4為甲基；以及R5為芳基或雜芳基。
- 如請求項1所述之用途，其中，該化合物選自由化合物1-35所組成之群組。
- 如請求項8所述之用途，其中，該化合物選自由化合物1、5、6、9、10、13、16、19、20、21、25、30和32所組成之群組。
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| TW201322998A (zh) * | 2011-11-03 | 2013-06-16 | Univ Nat Yang Ming | 防止皮膚老化相關症狀的醫藥組合物及其使用方法 |
| TW201920679A (zh) * | 2017-07-31 | 2019-06-01 | 香港商映像生物有限公司 | 眼部疾病之細胞模式及用於眼部疾病的療法 |
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