TWI837244B - 一種THRβ受體激動劑化合物及其製備方法和用途 - Google Patents
一種THRβ受體激動劑化合物及其製備方法和用途 Download PDFInfo
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- TWI837244B TWI837244B TW108145594A TW108145594A TWI837244B TW I837244 B TWI837244 B TW I837244B TW 108145594 A TW108145594 A TW 108145594A TW 108145594 A TW108145594 A TW 108145594A TW I837244 B TWI837244 B TW I837244B
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- pharmaceutically acceptable
- acceptable salt
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- dichloro
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Abstract
本發明揭示一種下式(I)表示之化合物及其醫藥學上可接受之鹽。該化合物在保持其良好之THRβ激動活性之同時改善了對THRα之選擇性,從而改善成藥特性。
Description
本發明係關於藥物合成領域,具體而言係關於一種可作為THRβ受體之新型激動劑之化合物以及其製備方法及用途。
甲狀腺激素(thyroid hormone,TH)為應答垂體分泌之甲狀腺刺激激素(thyroid stimulating hormone,TSH)而在甲狀腺中合成的。甲狀腺激素對調控身體生長、發育、代謝以及基體平衡起著非常重要之作用。甲狀腺激素主要有兩種,3,5,3`-三碘-L-甲狀腺素(T3)及甲狀腺素(T4)。人體主要分泌T4,在外周器官中,T4經脫碘酶轉化成活性更高之T3。甲狀腺生成之T3及T4處於負反饋控制之下,促甲狀腺激素(TSH)負責正常之甲狀腺功能及甲狀腺激素分泌。促甲狀腺激素在腦垂體前葉合成,且其分泌由下丘腦中合成之甲狀腺釋放激素(thyroid releasing hormone,TRH)控制。
甲狀腺激素藉由與甲狀腺激素受體(Thyroid hormone receptor,THR)結合發揮功能。甲狀腺激素受體屬於核受體大家族,調控目標基因表現。甲狀腺激素受體有兩種不同之亞型,THRα及THRβ。THRα主要分佈在心臟組織,對心臟之功能起重要調控作用。THRβ亞型主要在肝臟及腦垂體表現,調控膽固醇之代謝,以及調控促甲狀腺激素分泌。
在正常水平時,甲狀腺激素TH維持體重、代謝率、體溫、情緒且調節血清膽固醇。人們已經嘗試了用甲狀腺激素來調控血清膽固醇。但是服用天然甲狀腺激素對心臟之副作用(如心動過速及心律不齊、心衰以及引起甲狀腺軸功能抑制、肌肉代謝及骨質疏鬆)使其不能用於治療高膽固醇及肥胖。對THR基因選擇性剔除之動物研究以及一些選擇性THR配體之研究結果顯示,此等甲狀腺激素引起之心臟副作用可歸因於THRα。
甲狀腺激素受體通路調控脂代謝,包含膽固醇、三甘油脂以及脂蛋白。臨床上已經表明,降低低密度膽固醇將能降低心腦血管方面疾病之發病率。
非酒精性脂肪肝病(nonalcoholic fatty liver disease,NAFLD)亦是由於甘油三酯過度在肝臟堆積引起之一類代謝紊亂疾病,可進一步引起肝臟細胞受損,並引發炎症,導致非酒精性脂肪肝(non-alcoholic steatohepatitis,NASH)。NASH病人通常亦伴隨著第二型糖尿病、高膽固醇、高血脂及肥胖。NASH病人具有較高概率發展成肝硬化、肝衰竭,並最終發展成為肝癌。目前尚缺乏有效治療NASH之藥物。甲狀腺激素調控脂代謝之功能使得甲狀腺受體通路成為潛在治療NASH及NAFLD之靶點。在動物體內已經證實,甲狀腺激素類似物可明顯降低動物肝臟脂肪程度。
選擇性之THRβ激動劑可用來規避習知THR受體激動劑引起之心臟副作用,而選擇性地只激活THRβ,提高細胞脂代謝,發揮降膽固醇及血脂之功能。然而,選擇性之THRβ激動劑亦有可能會抑制甲狀腺軸,導致憂鬱、疲勞、骨質疏鬆等副作用。所以需要發展一種選擇性之THRβ激動劑,激活THRβ,但是降低對甲狀腺軸之抑制作用,從而規避甲狀腺軸抑制伴隨之副作用。
WO03094845、WO2007009913、WO2010122980、WO2011038207等專利披露了一些THR受體激動劑,此等激動劑結構幾乎均基於THR受體之天然配體T3而設計開發。基於此等背景,仍然需要開發既具有甲狀腺激素之有益療效又避免心臟不良副作用之選擇性THRβ受體激動劑。
本發明亦係基於THR受體之天然配體T3進行結構改造,發明人出乎意料地發現,經改造之大多數化合物保持了良好之THRβ受體激動活性,且與文獻(「Discovery of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor β Agonist in Clinical Trials for the Treatment of Dyslipidemia」 Martha等人,Journal of medicinal chemistry
, 2014, 3912-3923)里之對比化合物 53
相比,有些化合物亦改良了對THRα之選擇性。同時,本發明之一些化合物亦顯示了非常好之藥代特性。一些較佳化合物之藥代特性明顯好於對比化合物,從而改善了成藥特性。 對比化合物 53
為解決以上技術問題,本發明採取如下技術方案:
根據本發明之一個態樣,本發明提供了一種下式(I)表示之化合物及其醫藥學上可接受之鹽,
其中,
R1
係選自氫、氰基、經取代或未經取代之C1-6
烷基、或經取代或未經取代之C3-6
環烷基,該取代基係選自鹵素原子、羥基、C1-6
烷氧基;
R2
及R3
各獨立地選自鹵素原子或經取代或未經取代之C1-6
烷基,該取代基係選自鹵素原子、羥基、C1-6
烷氧基;
環A為經取代或未經取代之飽和或不飽和之C5-10
脂族環或經取代或未經取代之C5-10
芳族環,該取代基為選自氫、鹵素原子、羥基、-OCF3
、-NH2
、-NHC1-4
烷基、-N(C1-4
烷基)2
、-CONH2
、-CONHC1-4
烷基、-CON(C1-4
烷基)2
、-NHCOC1-4
烷基、C1-6
烷基、C1-6
烷氧基或C3-6
環烷基之一或多者,當含有兩個取代基時,兩個取代基可與其所連接之碳形成環狀結構;
該鹵素原子係選自F、Cl或Br。
根據本發明之該化合物具有如下式(II)所示之結構:
其中,
R1
至R3
之定義如上式(I)中所述;
L不存在或係選自-CH2
-、-CH2
CH2
-;
R4
係選自氫、鹵素原子、羥基、-OCF3
、-NH2
、-NHC1-4
烷基、-N(C1-4
烷基)2
、C1-6
烷基、C1-6
烷氧基或C3-6
環烷基;
n為1至4之整數;
m為1至4之整數;
當L不存在時,環上可以有兩個以上之取代基R4
;
該鹵素原子係選自F、Cl或Br。
較佳地,在式(II)所示之結構中,R4
係選自氫、鹵素原子、羥基、C1-3
烷基、C1-3
烷氧基或C3-6
環烷基;
L不存在或係選自-CH2
-或-CH2
CH2
-;
n為1、2或3;
m為1或2。
進一步較佳地,在式(II)所示之結構中,R4
係選自氫或C1-3
烷基;
L為-CH2
-或-CH2
CH2
-;
n為1、2或3;
m為1或2。
進一步較佳地,在式(II)所示之結構中,R4
係選自氫或C1-3
烷基;
L不存在;
n為1、2或3;
m為1或2。
根據本發明之該化合物具有如下式(III)所示之結構:
其中,
R1
至R3
之定義如上式(I)中所述;
R4
係選自氫、鹵素原子、羥基、-OCF3
、-NH2
、-NHC1-4
烷基、-N(C1-4
烷基)2
、-CONH2
、-CONHC1-4
烷基、-CON(C1-4
烷基)2
、-NHCOC1-4
烷基、C1-6
烷基、C1-6
烷氧基或C3-6
環烷基;
m為1至4之整數;
該鹵素原子係選自F、Cl或Br。
較佳地,在式(III)所示之結構中,R4
係選自氫、鹵素原子、羥基、-OCF3
、C1-6
烷基、C1-6
烷氧基或C3-6
環烷基;m為1至3之整數。
較佳地,在式(III)所示之結構中,R4
係選自氫、鹵素原子或C1-3
烷基;m為1或2。
較佳地,在根據本發明之上述具有如式(I)、(II)或(III)之結構之該化合物中,R1
係選自氫、氰基、經取代或未經取代之C1-6
烷基;進一步較佳地,R1
係選自氰基或C1-3
烷基;更進一步較佳地,R1
為氰基。
較佳地,在根據本發明之上述具有如式(I)、(II)或(III)之結構之該化合物中,R2
及R3
各獨立地選自F、Cl或Br,進一步較佳地,R2
及R3
皆為Cl。
較佳地,根據發明之該化合物及其醫藥學上可接受之鹽為以下化合物中之一者:
根據本發明之另一個態樣,本發明提供了該化合物之製備方法,該製備方法包含以下步驟:
1) 內酐類化合物I-a與鹽酸肼反應,得到通式I-b化合物;
2) 得到之通式化合物I-b在三氯氧磷中加熱生成通式I-c化合物;
3) 得到之通式化合物I-c與化合物I-d進行高溫偶合反應,得到通式I-e化合物,該條件下之催化劑較佳為碘化亞銅;
4) 得到之通式化合物I-e在酸性或鹼性高溫下反應得到通式化合物I-f;
5) 得到之通式化合物I-f在酸性水溶液中與亞硝酸鈉反應,然後加入化合物I-g進一步反應,且在高溫下閉環,得到通式化合物I,該條件下之酸較佳為鹽酸。
本發明通式I化合物亦可藉由如下步驟製備:
通式I-B-1化合物在酸性水溶液中高溫水解,得到通式I-B-2化合物,該條件下之酸較佳為鹽酸;得到之通式I-B-2化合物在巰基乙酸存在下,高溫反應消除羧基,得到通式I化合物。
本發明通式I化合物亦可藉由如下方法製備:
通式I-f化合物在酸性條件下,與亞硝酸鈉反應,生成重氮鹽化合物,加入鹵化物負離子,得到通式化合物I-g;得到之通式I-g化合物在過渡金屬催化下,與中間物I-h偶合,得到通式I化合物。
根據本發明之另一個態樣,本發明提供了該化合物在製備代謝相關疾病治療藥物中之用途。
根據本發明之另一個態樣,本發明提供了一種藥物組合物,該藥物組合物包含治療有效量之根據本發明之該化合物及其醫藥學上可接受之鹽作為活性成分,以及醫藥學上可接受之佐劑。
較佳地,該代謝相關疾病係選自:肥胖、高脂血症、高膽固醇血症、糖尿病,以及非酒精性脂肪肝病(NASH)、肝脂肪變性、動脈粥樣硬化、甲狀腺功能減退及甲狀腺癌;較佳地,該代謝相關疾病係選自:非酒精性脂肪肝病(NASH)、甲狀腺功能減退及甲狀腺癌。
根據本發明之另一個態樣,本發明提供了一種治療代謝相關疾病之方法,該方法包含向個體施用有效量之根據本發明之該化合物或包括該化合物及其醫藥學上可接受之鹽作為活性成分之藥物組合物。
較佳地,根據所述治療代謝相關疾病之方法,該代謝相關疾病係選自:肥胖、高脂血症、高膽固醇血症、糖尿病,以及非酒精性脂肪肝病(NASH)、肝脂肪變性、動脈粥樣硬化、甲狀腺功能減退及甲狀腺癌;較佳地,該代謝相關疾病係選自:非酒精性脂肪肝病(NASH)、甲狀腺功能減退及甲狀腺癌。
以下將詳細地描述本發明。在進行描述之前,應當理解,在本說明書及隨附申請專利範圍中使用之術語不應解釋為受限於一般含義及字典含義,而應當在允許發明人適當定義術語以進行最佳解釋之原則之基礎上,根據與本發明之技術方面相應之含義及概念進行解釋。因此,此處提出之描述僅僅是出於舉例說明目的之較佳實例,並非意圖限制本發明之範疇,從而應當理解,在不偏離本發明之精神及範疇之情況下,可由其獲得其他等價方式或改良方式。
根據本發明,若無另外說明,此處引用之所有術語具有與熟習此項技術者理解之本發明相同之含義。
如本文所用之術語「鹽」係指含陽離子及陰離子之化合物,其可藉由可接受質子部位之質子化及/或可供質子部位之去質子化來產生。值得注意的,可接受質子部位之質子化導致形成陽離子類物質,其電荷藉由生理陰離子之存在而平衡,而可供質子部位之去質子化導致形成陰離子類物質,其電荷藉由生理陽離子之存在而平衡。
術語「醫藥學上可接受之鹽」意指該鹽為醫藥學上可接受的。醫藥學上可接受之鹽之實例包含但不限於:(1)酸加成鹽,與無機酸形成,如鹽酸、氫溴酸、硫酸、硝酸、磷酸等等;或與有機酸形成,如羥基乙酸、丙酮酸、乳酸、丙二酸、蘋果酸、順丁烯二酸、反丁烯二酸、酒石酸、檸檬酸、3-(4-羥基苯甲醯基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羥基乙烷磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4對甲苯磺酸、樟腦酸、十二烷基硫酸、葡萄糖酸、麩胺酸、水楊酸、順式-已二烯二酸等等;或(2)鹼加成鹽,及上述無機酸中之任一者之共軛鹼形成,其中共軛鹼包括選自Na+
、K+
、Mg2+
、Ca2+
、NHx
R4-x +
中之陽離子組分,其中NHx
R4-x +
(R為C1-4
烷基,下標x為選自0、1、2、3或4之整數)表示四級銨鹽中之陽離子。應理解,所有涉及醫藥學上可接受之鹽皆包含相同酸加成鹽之本文中所定義之溶劑加成形式(溶劑合物)或晶體形式(多晶型物)。
術語「C1-M
烷基」係指包括1-M個碳原子之烷基,例如其中M為具有以下數值之整數:2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30。例如術語「C1-6
烷基」係指含有1-6個碳原子之烷基。烷基之實例包含但不限於低碳數烷基,包含甲基、乙基、丙基、異丙基、正丁基、異丁基、第三丁基或戊基、異戊基、新戊基、己基、庚基及辛基。
術語「芳基」指芳族體系,可為單環或原本稠合的或連接在一起之多芳環,從而使至少一部分稠合或連接之環形成共軛之芳系。芳基包含但不限於:苯基、萘基、四氫萘基。芳基可視情況經取代,如可經1-4個選自以下群組之基團所取代之芳基或雜環:鹵素、-CN、-OH、-NO2
、胺基、烷基、環烷基、烯基、炔基、烷氧基、芳氧基、經取代之烷氧基、烷基羰基、烷基羧基、烷基胺基或芳硫基。
術語「經取代」指參考基團可經一或多個額外基團所取代,額外基團單獨地且獨立地選自烷基、環烷基、芳基、雜芳基、雜脂環烴、羥基、烷氧基、烷硫基、芳硫基、烷基亞磺醯基、芳基亞磺醯基、烷基磺醯基、芳基磺醯基、氰基、鹵基、羰基、硫代羰基、硝基、鹵烷基、氟烷基及胺基,包含單取代及雙取代之胺基及其經保護之衍生物。
本發明所提供之由式(I)表示之化合物或其醫藥學上可接受之鹽,及包括該化合物之藥物組合物可呈多種形式,如錠劑、膠囊、粉劑、糖漿、溶液狀、懸浮液及氣溶膠等,並可存在於適宜之固體或液體之載體或稀釋液中以及適宜之用於注射或滴注之消毒器具中。
本發明之藥物組合物之各種劑型可按照醫藥學領域之習知製備方法製備。例如其製劑配方之單位劑量中包括0.05-200 mg式(I)化合物或其醫藥學上可接受之鹽,較佳地,製劑配方之單位劑量中包括0.1 mg-100 mg式(I)化合物。
本發明之由通式(I)表示之化合物及藥物組合物可對哺乳動物臨床使用,包含人類及動物,可藉由口、鼻、皮膚、肺或者胃腸道等給藥途徑。最佳為口服。最好較佳日劑量為每千克體重0.01-200 mg,一次性服用,或每千克體重0.01-100 mg,分次服用。不管用何種服用方法,個人之最佳劑量應依據具體之治療而定。通常情況下係自小劑量開始,逐漸增加劑量直至找到最適合之劑量。
本發明中,術語「有效量」可指代為實現預期之效果所需之劑量及時段的有效之量。此有效量可能因某些因素而產生不同之變化,如疾病之種類或治療時疾病之病症、所施用之特定目標器官之構造、病人體型、或疾病或症狀之嚴重性。一般熟習此項技術者不需要過度實驗即可憑經驗決定特定化合物之有效量。
典型之配方係藉由混合本發明之通式(I)表示之化合物及載體、稀釋劑或賦形劑製備而成。適宜之載體、稀釋劑或賦形劑為熟習此項技術者所熟知,包含諸如碳水化合物、蠟、水溶性及/或可膨脹性聚合物、親水性或疏水性物質、明膠、油、溶劑、水等物質。
所用之特定載體、稀釋劑或賦形劑將根據本發明之化合物之使用方式及目的而定。一般以熟習此項技術者認為可安全有效地給藥至哺乳類動物之溶劑為基礎而選擇溶劑。一般而言,安全之溶劑為無毒性含水溶劑(諸如水),以及其他可溶於水或與水混溶之無毒性溶劑。適宜之含水溶劑包含水、乙醇、丙二醇、聚乙二醇(如PEG400、PEG300)等中之一或多者。該配方亦可包含一或多種緩衝劑、安定劑、界面活性劑、潤濕劑、潤滑劑、乳化劑、懸浮劑、防腐劑、抗氧化劑、遮光劑、助流劑、加工助劑、著色劑、增甜劑、香料劑、調味劑或其他已知之添加劑,使該藥物以可接受之形式製造或使用。
本發明所述之如式(I)之化合物與至少一種其他藥物組合使用時,兩種藥物或多種藥物可分開使用,亦可組合使用,較佳以醫藥組合物之形式給藥。本發明之如式(I)之化合物或藥物組合物能以任一已知之口服、靜脈注射、直腸給藥、陰道給藥、透皮吸收、其他局部或全身給藥形式,分開或一起給藥至個體。
此等藥物組合物亦可含有一或多種緩衝劑、安定劑、界面活性劑、潤濕劑、潤滑劑、乳化劑、懸浮劑、防腐劑、抗氧化劑、遮光劑、助流劑、加工助劑、著色劑、增甜劑、香料劑、調味劑或其他已知之添加劑,使該藥物組合物以可接受之形式製造或使用。
本發明藥物偏好口服給藥途徑。用於口服給藥之固態劑型可包含膠囊、錠劑、粉末或顆粒製劑。在固態劑型中,本發明之化合物或藥物組合物與至少一種惰性賦形劑、稀釋劑或載劑混合。適宜之賦形劑、稀釋劑或載劑包含諸如檸檬酸鈉或磷酸氫鈣之物質,或澱粉、乳糖、蔗糖、甘露糖醇、矽酸等;黏合劑如羧甲基纖維素、褐藻酸鹽、明膠、聚乙烯基吡咯啶酮、蔗糖、阿拉伯膠等;濕潤劑如甘油等;崩解劑如瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、褐藻酸、特定之錯合矽酸鹽、碳酸鈉等;溶液阻滯劑如石蠟等;吸收促進劑如四級銨化合物等;吸附劑如高嶺土、膨潤土等;潤滑劑如滑石、硬脂酸鈣、硬脂酸鎂、固態聚乙二醇、月桂基硫酸鈉等。在膠囊與錠劑之情況下,該劑型亦可包含緩衝劑。類似類型之固態組合物亦可作為軟式與硬式填充明膠膠囊中之填料,其使用乳糖以及高分子量聚乙二醇等作為賦形劑。
用於口服給藥之液態劑型包含醫藥學上可接受之乳化液、溶液、懸浮液、糖漿液與酏劑。除了本發明之化合物或其藥物組合物之外,該液態劑型可含有此項技術中常用之惰性稀釋劑,諸如水或其他溶劑;增溶劑及乳化劑,諸如乙醇、異丙基醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、二甲基甲醯胺;油類(如棉籽油、落花生油、玉米胚芽油、橄欖油、蓖麻油、芝麻油等);甘油;四氫糠基醇;聚乙二醇與脫水山梨糖醇之脂肪酸酯;或此等物質中之幾種之混合物等。
除了此等惰性稀釋劑之外,該組合物亦可包含賦形劑,諸如潤濕劑、乳化劑、懸浮劑、增甜劑、調味劑與香料劑中之一或多者。
就懸浮液而言,除了本發明之由通式(I)表示之化合物或其醫藥學上可接受之鹽或者包括其之藥物組合物之外,可進一步含有載劑,諸如懸浮劑,如乙氧基化異硬脂醇、聚氧乙烯山梨醣醇、脫水山梨醣醇酯、微晶纖維素、偏氫氧化鋁、膨潤土、瓊脂及黃耆膠,或此等物質中幾種之混合物等。
本發明之由通式(I)表示之化合物或其醫藥學上可接受之鹽或者包括其之藥物組合物可採用其他局部給藥劑型給藥,包含膏、粉末、噴劑及吸入劑。該藥物可在無菌條件下與醫藥學上可接受之賦形劑、稀釋劑或載劑以及所需要之任一防腐劑、緩衝劑或推進劑混合。眼用配方、眼用油膏、粉末與溶液亦意欲涵蓋於本發明之範疇內。
此外,本發明亦涵蓋了套組(例如製藥包裝)。提供之套組可包括本文所述之藥物組合物或化合物及容器(例如,藥瓶、安瓿、瓶子、注射器及/或分裝包裝或其他合適之容器)。在一些實施方案中,提供之套組可視情況進一步包含第二容器,其包括用於稀釋或懸浮本文所述之藥物組合物或化合物之藥用賦形劑。在一些實施方案中,設置在第一容器及第二容器中之本文所述之藥物組合物或化合物組合形成一個單元劑量形式。
在某些實施方案中,本文所述之套組進一步包含包括於套組中之用於使用該化合物或藥物組合物之用法說明。本文所述之套組亦可包含管理機構(如美國食品藥品監督管理局(FDA))所要求之資訊。在某些實施方案中,在套組中包含之資訊為處方資訊。在某些實施方案中,套組及用法說明提供用於治療需要其之個體之增生性疾病及/或預防需要其之個體之增生性疾病。本文所述之套組可包括一或多種額外之藥物製劑作為單獨之組合物。
以下結合具體之實施例對本發明做進一步詳細之說明,但本發明不限於以下實施例,實施例係為了更好地闡釋本發明之某些具體體現而不能被解釋為以任何方式限定本發明之範疇。實施例中未註明之條件為習知條件。除非特別說明,以下實施例中使用之試劑及儀器均為市售可得產品。
以下實施例中化合物之結構係藉由核磁共振(NMR)或/及質譜(MS)來判定。NMR位移(δ)以10-6(ppm)之單位給出。NMR之測定使用Bruker AVANCE-400核磁儀,測定溶劑為氘化二甲亞碸(DMSO-d6)、氘化氯仿(CDCl3)、氘化甲醇(CD3OD),內標為四甲基矽烷(TMS)。
MS之測定用FINNIGAN LCQAd(ESI)質譜儀(生產商:Thermo,型號:Finnigan LCQ advantage MAX)。
薄層層析矽膠板使用煙台黃海HSGF254或青島GF254矽膠板,薄層層析(TLC)使用之矽膠板採用之規格為0.15 mm-0.2 mm,薄層層析分離純化產品採用之規格為0.4 mm-0.5 mm。
管柱層析一般使用煙台黃海矽膠200-300目矽膠為載體。
實施例中無特殊說明,反應之溫度為室溫,20攝氏度至30攝氏度。
實施例中之反應進程之偵測採用薄層層析(TLC),所使用之展開劑體系以及純化化合物採用之管柱層析之溶離劑體系包含有:A:二氯甲烷及甲醇體系,B:正己烷及乙酸乙酯體系,C:石油醚及乙酸乙酯體系,D:丙酮及石油醚體系,溶劑之體積比例根據化合物之極性不同而進行調節。
實施例 1 :
2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈之製備
第一步:2,3,5,6,7,8-六氫酞嗪-1,4-二酮(化合物1b)之製備
向化合物3,4,5,6,-四氫苯二甲酸酐1a
(4.56 g,30 mmol)於醋酸(50 ml)及水(100 ml)中之溶液中,依次加入醋酸鈉(3.69 g,45 mmol)、鹽酸肼(3.08 g,45 mmol)。加完後升溫至100℃,攪拌3h,停止反應,自然冷卻至室溫,析出固體,過濾出固體得到化合物1b (4.2 g),產品直接用於下一步反應。1
H NMR (400 MHz, DMSO-d 6
): 11.26 (s, 2H), 2.36 (s,4H), 1.65(s, 4H)。
第二步:1,4-二氯-5,6,7,8-四氫酞嗪(化合物1c)之製備
將化合物1b (1 g,6.02 mmol)溶於三氯氧磷(8 ml)中,用氮氣置換體系內之空氣3次,升溫至110℃,攪拌3h,停止反應後自然冷卻。將反應液緩慢滴入冰水中,用1N之氫氧化鈉水溶液調節pH=10,用乙酸乙酯萃取3次,合併有機相,再用飽和食鹽水洗滌有機相,濃縮無水有機相得到化合物1c (1.1 g)。產品直接用於下一步反應。
第三步:3,5-二氯-4-((4-氯-5,6,7,8-四氫酞嗪-1-基)氧基)苯胺(化合物1d)之製備
向化合物1c (1.0 g,5.0 mmol)、2,6-二氯-4-胺基苯酚(0.93 g,6 mmol)、碳酸鉀(2.76 g,20 mmol)及CuI (0.57 g,3 mmol)混合物中加入二甲亞碸(8 ml),用氮氣置換體系中之空氣3次,升溫至100℃,攪拌3h。停止反應後,冷卻,先過濾出反應液中之固體,用乙酸乙酯反覆洗滌濾渣,向濾液加入80 ml水,再用乙酸乙酯反應萃取水相,合併有機相,用飽和食鹽水洗滌。過濾,濃縮溶劑後管柱層析得到化合物1d (450 mg)。
第四步:4-(4-胺基-2,6-二氯苯氧基)-5,6,7,8-四氫酞嗪-1(2氫)-酮(化合物1e)之製備
將化合物1d (100 mg,0.3 mmol)溶於醋酸(4 ml)中,加入醋酸鈉(200 mg,2.5 mmol),加熱至120℃,攪拌12h。停止反應後,減壓除去溶劑,加入10 ml水,然後再加1N氫氧化鈉水溶液調節pH=8,再用乙酸乙酯(10 ml * 3)萃取,合併有機相。有機相分別用飽和碳酸氫鈉水溶液及飽和食鹽水洗滌,減壓濃縮後得到灰色固體。向得到之固體中加入10 ml甲醇及10 ml 1N之氫氧化鈉水溶液,加熱至120℃,攪拌12h。停止反應後,減壓濃縮甲醇,剩下之水相用乙酸乙酯反覆萃取3次,合併有機相。減壓濃縮溶劑後,薄層層析分離純化得到化合物1e (80 mg)。
第五步:2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物1)之製備
將亞硝酸鈉(16 mg)溶於水(0.5 mL)中,冰浴下,將此溶液慢慢滴加至化合物1e (60 mg,0.185 mmol)、水(2.5 mL)及飽和鹽酸水溶液(1.25 mL)之混合物中,保持冰浴攪拌0.5 h,直至溶液澄清。在此溫度下,再滴加N-氰基乙醯胺基甲酸酯(32 mg)於水(4.2 ml)及吡啶(1.3 ml)中之混合溶液,滴加完後攪拌過夜。停止反應後,過濾出黃色固體,用水及石油醚洗滌。向得到之固體中加入醋酸(5 ml)及醋酸鈉(160 mg,2 mmol),加熱至120℃,攪拌6h,冷卻至室溫,加入100 ml 水,析出淡黃色固體,薄層層析分離純化(DCM:MeOH=8:1)得到化合物1 (12.0 mg)。1
H NMR (400 MHz, DMSO-d 6
) δ 12.03 (s, 1H), 7.75 (s,2H), 2.68-2.63 (m, 2H), 2.45-2.39 (m, 2H), 1.80-1.67 (m, 4H)。
MS m/z (ESI): 447.4 [M+1]。
實施例 2 :
2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫-5,8-乙橋酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物2b)之製備。
採用實施例1之合成路徑,將第一步原料3,4,5,6,-四氫苯二甲酸酐1a
替換為雙環[2.2.2]辛-2-烯-2,3-二甲酸酐,製得標題產物2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫-5,8-乙橋酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物2)。1
H NMR (400 MHz, DMSO-d 6
): 12.13 (s, 1H), 7.77 (s,2H), 1.88-1.73 (m, 4H), 1.39-1.17 (m, 6H)。
MS m/z (ESI): 473.2 [M+1]。
實施例 3 :
2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫-5,8-甲橋酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物3)之製備。
第一步:二甲基-二環[2.2.1]七-2,5-二烯-2,3-二甲酸酯之製備
向環戊二烯(化合物3a) (1.475 g,22.3 mmol)中緩慢滴入丁炔二酸二甲酯(化合物3b)(2.75 ml,22.3 mmol),加完後,室溫攪拌2小時。停止反應,得到油狀產物3c (4.0克),粗物質不純化直接用於下一步反應。
第二步:二甲基-二環[2.2.1]七-2-烯-2,3-二甲酸酯之製備:
將化合物3c (1.0 g,4.8 mmol)、鈀炭(0.05 g)及15 ml丙酮置於反應瓶中,氫氣球置換3次,室溫攪拌1小時。過濾,減壓濃縮無水溶劑,得到淡綠色液體產物3d (0.9 g)。
第三步:二環[2.2.1]七-2-烯-2,3-二酸之製備:
向化合物3d (3.0 g,14.3 mmol)、氫氧化鋰一水合物(1.54 g,35.8 mmol)混合物中加入四氫呋喃(20 ml)及水(20 ml),室溫攪拌2小時。用2N稀鹽酸調節pH值至1,用乙酸乙酯萃取3次,無水硫酸鈉乾燥,過濾,減壓濃縮得到白色固體化合物3e (2.0 g)。
第四步:4,5,6,7-四氫-4,7-甲橋異苯基呋喃1,3-二酮之製備:
向化合物3e (200 mg,1.1mmol)中加入乙酸酐(10 mL),加熱至100攝氏度攪拌2小時。減壓濃縮除去溶劑,得到固體化合物3f
粗物質(200 mg)。
第五步:2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫-5,8-甲橋酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈之製備:
採用實施例1之合成路徑,將第一步原料4,5,6,7-四氫異苯并呋喃-1,3-二酮(化合物1a
)替換為4,5,6,7-四氫-4,7-甲橋異苯基呋喃1,3-二酮化合物3f
),製得標題產物2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫-5,8-甲橋酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物3
)。1
H NMR (400 MHz, DMSO-d 6
) δ 12.08 (s, 1H), 7.77 (s,2H), 2.75-2.65 (m, 2H), 1.80-1.72 (m, 4H), 1.55-1.50 (m, 2H)。
MS m/z (ESI): 459.0 [M+1]。
實施例 4 :
1-(3,5-二氯-4-((7,7-二甲基-1-側氧-2,5,6,7-四氫-1H-環戊烷[d]噠嗪-4-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈(化合物4)之製備
第一步:3,3-二甲基-2-氧環戊基-1-甲酸甲酯之製備
向化合物2,2-二甲基環戊烷-1-酮(1.12 g,10 mmol)及MeOH (0.5 ml)於DMC (11 ml)中之溶液中加入NaH (480 mg,12 mmol),加熱至82℃,攪拌3小時,冷卻,依次向體系中加入甲醇(0.5 ml),醋酸(1 ml)後,將體系倒入冰水中,用二氯甲烷萃取,乾燥,減壓除去溶劑得到無色油狀物化合物4a (1.7 g),直接用於下一步。
第二步:3,3-二甲基-2-(((三氟甲基)磺酸基)氧基)環戊-1-烯-1-甲酸甲酯之製備
-60℃下,向化合物4a (1.7 g,10 mmol)及二異丙基乙基胺(8.2 ml,50 mmol)於二氯甲烷(17 ml)中之溶液中,滴加三氟乙酸酐(2 ml,12 mmol),加完後緩慢升溫至室溫,攪拌16h,加入50 ml水,用乙酸乙酯萃取,減壓除去溶劑,管柱層析純化(PE:EA=50:1)得到無色油狀物化合物4b (1.8 g)。
第三步:2-(甲氧基羰基)-5,5-二甲基環戊-1-烯-1-甲酸之製備
氮氣氣球氛圍下,向4b (1.8 g,5.96 mmol)、二異丙基乙基胺(1.97 ml,11.92 mmol)、醋酸酐(1.13 ml,11.92 mmol)、甲酸鈉(1.22 g,5.96 mmol)、二醋酸鈀(66.9 mg,0.30 mmol)及氯化鋰(758 mg,17.88 mmol)之混合物中,加入DMF(25 ml),加完後室溫攪拌16小時,向體系中加入300 ml乙酸乙酯,體系用水及飽和食鹽水各洗滌1次,減壓除去溶劑,得到無色油狀物4c (1.2 g)。
第四步:3,3-二甲基環戊-1-烯-1,2-二甲酸之製備
向化合物4c (1.2 g,6 mmol)及一水合氫氧化鋰(756 mg,18 mmol)之混合物中,加入甲醇(6 ml)及水(6 ml),室溫下攪拌3h,減壓除去甲醇,再用濃鹽酸調節pH至1,用乙酸乙酯萃取,減壓除去溶劑後得到白色固體化合物4d (1.0 g)。
第五步:4,4-二甲基-5,6-二氫-1H-環戊基[c]呋喃-1,3(4H)-二酮之製備
向化合物4d (1.0 g,5.43 mmol)中加入醋酸酐(10 ml),升溫至100攝氏度,攪拌3h,冷卻,減壓除去多餘之醋酸酐,得到淡棕色液體化合物4e (875 mg),直接用於下一步合成。
第六步:1-(3,5-二氯-4-((7,7-二甲基-1-側氧-2,5,6,7-四氫-1H-環戊烷[d]噠嗪-4-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈之製備
採用實施例1之合成路徑,將第一步原料3,4,5,6,-四氫苯二甲酸酐(化合物1a)
替換為4,4-二甲基-5,6-二氫-1H-環戊基[c]呋喃-1,3(4H)-二酮(化合物4e
),製得標題產物1-(3,5-二氯-4-((7,7-二甲基-1-側氧-2,5,6,7-四氫-1H-環戊烷[d]噠嗪-4-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈(化合物4
)。1
H NMR (400 MHz, DMSO-d 6
) δ 12.09 (s, 1H), 7.79 (s,2H), 2.97-2.93 (m, 2H), 2.01-1.98 (m, 2H), 1.34-1.20 (m, 6H)。
MS m/z (ESI): 460.9 [M+1]。
實施例 5 :
1-(3,5-二氯-4-((5-甲基-4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈(化合物5)之製備
第一步:3-甲基-2-側氧基環己烷-1-甲酸甲酯5b之製備:
向2-甲基環己酮(化合物5a) (4.48 g,40 mmol)於二氯甲烷(50 ml)中之溶液中加入鈉氫(60%含量,1.92 g,48 mmol),加熱至回流,攪拌3小時,冷卻,加入甲醇(0.5 ml)及醋酸(1 ml)淬滅後,將反應體系加入冰浴中,用二氯甲烷萃取,減壓除去溶劑,管柱層析純化得到油狀物化合物5b (5.6 g)。
第二步:3-甲基-2-(((三氟甲基)磺酸基)氧基)環己基-1-烯-1-甲酸甲酯之製備
冰浴下,將NaH (60%含量,600 mg,25 mmol)加入含化合物5b (0.85g,5 mmol)之無水乙醚(20 ml)中,攪拌0.5 h後,向體系中滴加三氟甲磺酸酐(2.8 g,10 mmol),0℃下,繼續攪拌1 h。加H2O (50 ml)淬滅,加入1N 之HCl調節pH至1,二氯甲烷萃取,減壓除去溶劑,管柱層析(PE:EA=20:1)純化得無色油狀物化合物5c (1.04 g)。
第三步:2-(甲氧基羰基)-6-甲基環己基-1-烯-1-甲酸之製備
氮氣氛圍下,向化合物5c
(0.714 g,10.5 mmol),甲酸鈉(0.714 g,10.50 mmol)之N,N-二甲基甲醯胺(15 ml)溶液中依次滴加二異丙基乙基胺(0.714 g,7.00 mmol)及醋酐(0.903 g,7.00 mmol),室溫攪拌1小時後,再加入醋酸鈀(40 mg,0.18 mmol)及氯化鋰(445 mg,10.50 mmol),室溫攪拌過夜,加入乙酸乙酯(30 ml),用水洗滌,減壓除去溶劑,得淡黃色油狀物化合物5d (590 mg)。
第四步:3-甲基環己基-1-烯-1,2-二酸5e之製備
向化合物5d (0.590 g,2.98 mmol)於甲醇(3 ml)及水(3 ml)中之溶液中加入氫氧化鋰一水合物(0.375 g,8.94 mmol),室溫攪拌3h後,減壓除去甲醇,加入1N之鹽酸水溶液調節pH至1,用乙酸乙酯萃取三次,合併有機相,減壓濃縮除去溶劑得到油狀物化合物5e (0.550 g)。
第五步:4-甲基-4,5,6,7-四氫異苯基呋喃-1,3-二酮5f之製備
向化合物5e (0.550 g,2.99 mmol)中加入醋酐(6 ml),升溫至100攝氏度,攪拌2小時。冷卻,減壓除去溶劑,得棕色油狀物化合物5f (0.34 g),直接用於下一步合成。
第六步:1-(3,5-二氯-4-((5-甲基-4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈(化合物5)之製備
採用實施例1之合成路徑,將第一步原料3,4,5,6,-四氫苯二甲酸酐(化合物1a)
替換為4-甲基-4,5,6,7-四氫異苯基呋喃-1,3-二酮(化合物5f)
,製得標題產物1-(3,5-二氯-4-((5-甲基-4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈(化合物5)
。
MS m/z (ESI): 460.1 [M+1]
實施例 6 :
1-(3,5-二氯-4-((5,5-二甲基-4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈之製備
採用實施例5
之合成路徑,將第一步原料2-甲基環己酮(化合物5a
)替換為2,2-二甲基環己酮,製得標題產物1-(3,5-二氯-4-((5,5-二甲基-4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈(化合物6)。
MS m/z (ESI): 474.1 [M+1]
實施例 7 :
1-(3,5-二氯-4-((7-甲基-1-側氧-2,5,6,7-四氫-1H-環戊基[d]噠嗪-4-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈(化合物7)之製備。
採用實施例5
之合成路徑,將第一步原料2-甲基環己酮(化合物5a
)替換為2-甲基環戊酮,製得標題產物1-(3,5-二氯-4-((7-甲基-1-側氧-2,5,6,7-四氫-1H-環戊基[d]噠嗪-4-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈(化合物7
)。
MS m/z (ESI): 446.0 [M+1]
實施例 8 :
1-(3,5-二氯-4-((7-乙基-1-側氧-2,5,6,7-四氫-1H-環戊烷[d]噠嗪-4-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈(化合物8)之製備
採用實施例5
之合成路徑,將第一步原料2-甲基環己酮(化合物5a
)替換為2-乙基環戊酮,製得標題產物1-(3,5-二氯-4-((7-乙基-1-側氧-2,5,6,7-四氫-1H-環戊烷[d]噠嗪-4-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈(化合物8
)。
MS m/z (ESI): 460.1 [M+1]
實施例 9 :
2-(3,5-二氯-4-((4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物9)之製備
採用實施例1之合成路徑,將第三步原料1,4-二氯-5,6,7,8-四氫酞嗪(化合物1c
)替換為1,4-二氯酞嗪,製得標題產物2-(3,5-二氯-4-((4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物9)
。1
H NMR (400 MHz, DMSO-d 6
): 12.00(s, 1H), 8.31(d,J
=8.0Hz, 1H), 8.26 (d,J
=8.0Hz, 1H), 8.09 (t,J
=12.0Hz 1H), 8.03 (t,J
=16.0Hz 1H), 7.81 (s, 2H)。
MS m/z (ESI): 443.0 [M+1]。
實施例 10 :
2-(3,5-二氯-4-((5-氯-4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物10)之製備:
採用實施例1之合成路徑,將第一步原料3,4,5,6,-四氫苯二甲酸酐(化合物1a
)替換為3-氯苯二甲酸酐,製得標題產物2-(3,5-二氯-4-((5-氯-4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物10
)。1
H NMR (400 MHz, DMSO-d 6
): 12.00(s, 1H), 8.30 (d,J
=8.0Hz, 1H), 8.15 (d,J
=8.0Hz, 1H), 7.95 (m, 1H), 7.80 (s, 2H)。
MS m/z (ESI): 477.0 [M+1]。
實施例 11 :
2-(3,5-二氯-4-((5-甲基-4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物11)之製備:
採用實施例1之合成路徑,將第一步原料3,4,5,6,-四氫苯二甲酸酐(化合物1a
)替換為3-甲基鄰苯二甲酸酐,製得標題產物2-(3,5-二氯-4-((5-甲基-4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物11
)。
MS m/z (ESI): 456.9 [M+1]。
實施例 12 :
2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫-5,8-乙橋酞嗪-1-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮(化合物12)之製備:
第一步:2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫-5,8-乙橋酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲酸之製備
向化合物2
(77 mg)中分別加入醋酸(4 ml)及濃鹽酸(1 ml),加熱至120攝氏度,攪拌5小時,冷卻,反應液用水稀釋,得到之固體過濾,水洗,石油醚洗,乾燥,得到固體化合物12a (35 mg),直接用於下一步反應。
第二步:2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫-5,8-乙橋酞嗪-1-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮之製備
向化合物12a (35.0 mg)中加入巰基乙酸(2 ml),將混合物加熱至170攝氏度,攪拌2小時。冷卻,加入1N氫氧化鈉水溶液調節pH至8,用乙酸乙酯萃取3次,合併有機相,減壓除去溶劑,薄層層析分離純化(DCM:MeOH=8:1)得到化合物12 (10.0 mg)。1
H NMR (400 MHz, DMSO-d 6
): 12.10 (s, 1H), 7.77 (s, 2H), 7.33 (s, 1H), 2.01 (m, 2H), 1.93-1.75 (m, 4H), 1.39-1.27 (m, 4H)。
MS m/z (ESI): 448.0 [M+1]。
實施例 13 :
2-(3,5-二氯-4-((7,7-二甲基-1-側氧-2,5,6,7-四氫-1H-環戊基[d]噠嗪-4-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮(化合物13)之製備
採用實施例12
之合成路徑,將第一步原料2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫-5,8-乙橋酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物2
),替換為1-(3,5-二氯-4-((7,7-二甲基-1-側氧-2,5,6,7-四氫-1H-環戊烷[d]噠嗪-4-基)氧基)苯基)-2,4-二側氧-1,2,3,4-四氫嘧啶-5-甲腈(化合物4
),製得標題產物2-(3,5-二氯-4-((7,7-二甲基-1-側氧-2,5,6,7-四氫-1H-環戊基[d]噠嗪-4-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮(化合物13
)。1
H NMR (400 MHz, DMSO-d 6
): 12.02(s, 1H), 7.77 (s, 2H), 7.35 (s, 1H), 2.94-2.90 (m, 2H), 1.99-1.95 (m, 2H), 1.32 (d, 6H)。
MS m/z (ESI): 436.0 [M+1]。
實施例 14 :
2-(3,5-二氯-4-((4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-1,2,4-三嗪-3,5-(2H,4H)二酮(化合物14)之製備
採用實施例12
之合成路徑,將第一步原料2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫-5,8-乙橋酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物2
),替換為2-(3,5-二氯-4-((4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物9
),製得標題產物2-(3,5-二氯-4-((4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-1,2,4-三嗪-3,5-(2H,4H)二酮(化合物14
)。1
H NMR (400 MHz, DMSO-d 6
): 12.00 (s, 1H), 8.30-8.23 (m, 2H), 8.09-7.99 (m, 2H), 7.18 (s, 1H)。
MS m/z (ESI): 418.0 [M+1]。
實施例 15
:2-(3,5-二氯-4-((5-氟-4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物15
)之製備
採用實施例1之合成路徑,將第一步原料3,4,5,6,-四氫苯二甲酸酐(化合物1a
)替換為3-氟苯二甲酸酐,製得標題產物2-(3,5-二氯-4-((5-氟-4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物15
)。
MS m/z (ESI): 461.0 [M+1]。
實施例 16
:2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-6-甲基-1,2,4-三嗪-3,5(2H,4H)-二酮(化合物16
)之製備
第一步:4-(2,6-二氯-4-碘苯氧基)-5,6,7,8-四氫酞嗪-1(2H)-酮(化合物16a)之製備
冰浴下,依次將水(4 ml)、濃鹽酸(2 ml)加入至1e
(100mg)中,然後滴加亞硝酸鈉(30mg)於水(2 ml)中之溶液,保持冰浴攪拌反應1小時,滴加碘化鉀(104 mg),升至室溫,攪拌16小時。用二氯甲烷萃取,減壓除去溶劑,得黃色固體16a (100 mg),直接用於下一步反應。
第二步:2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-6-甲基-1,2,4-三嗪-3,5(2H,4H)-二酮(化合物16)之製備
向化合物16a
(20mg),6-氮雜胸腺嘧啶(6.6 mg),碘化亞銅(8.9 mg),碳酸鉀(30mg)之混合物中加入N,N-二甲醯胺(2.0ml),體系加熱至120度攪拌12小時。冷卻,過濾,加乙酸乙酯及水分液,有機相減壓除去溶劑,薄層層析分離純化(DCM:MeOH=8:1)得到化合物16(5.0 mg)。
MS m/z (ESI): 436.1 [M+1]。
實施例 17
:2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-6-異丙基-1,2,4-三嗪-3,5(2H,4H)-二酮(化合物17)之製備
採用實施例16之合成路徑,將第二步原料6-氮雜胸腺嘧啶替換為6-異丙基-1,2,4-三嗪-3,5(2H,4H)-二酮(採用公知之方法「Chemistry and Biodiversity
,2012
, 9(3) 536 - 556」製備而得),製得標題產物2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-6-異丙基-1,2,4-三嗪-3,5(2H,4H)-二酮(化合物17
)。
MS m/z (ESI): 464.1 [M+1]。
實施例 18
:6-環丙基-2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮(化合物18
)之製備
採用實施例16之合成路徑,將第二步原料6-氮雜胸腺嘧啶替換為6-環丙基-1,2,4-三嗪-3,5(2H,4H)-二酮(採用公知之方法「Collection of Czechoslovak Chemical Communications
,1975
, 40, 1038-1041」製備而得),製得標題產物2-(3,5-二氯-4-((4-側氧-3,4,5,6,7,8-六氫酞嗪-1-基)氧基)苯基)-6-環丙基-1,2,4-三嗪-3,5(2H,4H)-二酮(化合物18
)。
MS m/z (ESI): 462.1 [M+1]。
實施例 19
:2-(3,5-二氯-4-((4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-6-甲基-1,2,4-三嗪-3,5(2H,4H)-二酮(化合物19
)之製備
第一步:3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯胺(化合物19a
)之製備
採用實施例1第三步中間物1d之合成路徑,將原料1,4-二氯-5,6,7,8-四氫酞嗪(化合物1c
)替換為1,4-二氯酞嗪,製備得到標題化合物3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯胺(化合物19a
)。
第二步:4-(4-胺基-2,6-二氯苯氧基)酞嗪-1(2H)-酮(化合物19b
)之製備
採用實施例1第四步中間物1e之合成路徑,將原料3,5-二氯-4-((4-氯-5,6,7,8-四氫酞嗪-1-基)氧基)苯胺(化合物1d)替換成3,5-二氯-4-((4-氯酞嗪-1-基)氧基)苯胺(化合物19a
),製備得到標題化合物4-(4-胺基-2,6-二氯苯氧基)酞嗪-1(2H)-酮(化合物19b
)。
第三步:2-(3,5-二氯-4-((4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-6-甲基-1,2,4-三嗪-3,5(2H,4H)-二酮(化合物19
)之製備
採用實施例16之合成路徑,將第一步原料4-(2,6-二氯-4-碘苯氧基)-5,6,7,8-四氫酞嗪-1(2H)-酮(化合物16a)替換成化合物4-(4-胺基-2,6-二氯苯氧基)酞嗪-1(2H)-酮(化合物19b
)製得標題產物2-(3,5-二氯-4-((4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-6-甲基-1,2,4-三嗪-3,5(2H,4H)-二酮(化合物19
)。
MS m/z (ESI): 432.0 [M+1]。
實施例 20
:2-(3,5-二氯-4-((6-甲基-4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物20)之製備:
採用實施例1
之合成路徑,將第一步原料四氫苯二甲酸酐(1a
)替換為4-甲基苯二甲酸酐,製得標題產物2-(3,5-二氯-4-((6-甲基-4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物20
)。
MS m/z (ESI): 457.0 [M+1]。
實施例 21
:2-(3,5-二氯-4-((6-氯-4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物21
)之製備:
採用實施例1
之合成路徑,將第一步原料四氫苯二甲酸酐(1a
)替換為4-氯苯二甲酸酐,製得標題產物2-(3,5-二氯-4-((6-氯-4-側氧-3,4-二氫酞嗪-1-基)氧基)苯基)-3,5-二側氧-2,3,4,5-四氫-1,2,4-三嗪-6-甲腈(化合物21
)。
MS m/z (ESI): 477.0 [M+1]。
測試實施例 1 : 化合物對 TRα 結合力測試:
1. 主要實驗材料及儀器:
Envision 2104酶標儀,
生物素-SRC2-2共激活肽購買自生工生物工程(上海)股份有限公司
TRα LBD, GST購買自賽默飛世爾(貨號PV4762)
銪結合抗麩胱甘肽抗體購買自Cisbio(貨號61GSTKLB)
鏈親和素-D2購買自Cisbio (貨號610SADAB)
2. 化合物之製備與處理
2.1 化合物二甲亞碸儲液之製備
所有化合物溶解於二甲亞碸,製備成10毫莫耳之儲液。
2.2 化合物儲存
化合物溶解於二甲亞碸後,於乾燥器中室溫可存放三個月。長期存放,則置於-20℃冰箱中。
3. 實驗步驟
3.1 製備1x反應緩衝液
3.2 化合物之篩選:
a) 用100%二甲亞碸將陽性藥三碘甲狀腺素(T3)自10毫莫耳(100X)或待測化合物自1毫莫耳(100X)以1:3進行等比稀釋,共10個濃度。
b) 用1x反應緩衝液製備4x經過濃度梯度稀釋之化合物。
c) 加5微升4x經過濃度梯度稀釋之化合物至384孔實驗盤。
d) 用1x反應緩衝液製備4X TRα LBD以及4X RXRα。
e) 加5微升4x TRα LBD以及4X RXRα至384孔實驗盤。
f) 用1x反應緩衝液製備2X生物素-SRC2-2、2X銪結合抗麩胱甘肽抗體以及2X鏈親和素-d2。
g) 加10微升2X混合液(參考步驟f)至384孔實驗盤。
h) 將384孔實驗盤於離心機1000轉離心1分鐘。
i) 室溫避光孵育1小時。
j) Envision 2104酶標儀記錄384孔實驗盤每孔665奈米及615奈米波長處螢光信號值,並計算665奈米/615奈米之螢光比值。
4. 資料分析
4.1 計算每孔之相對比(比值665nm/615nm
-比值空白
)
4.2 活性百分率計算如下: :實施例化合物孔之相對比之平均值:所有陽性對照孔之相對比之平均值。:所有陰性對照孔之相對比之平均值。
4.3 曲線之繪製及EC50之計算:
用Graphpad 5.0藉由非線性回歸之方法,對活性(%)及化合物對數濃度之關係進行擬合,來計算EC50。
Y=底部 + (頂部-底部)/(1+10^((LogEC50-X)*坡度))
X:化合物對數濃度 Y:百分比活性
具體測試資料見下表1。
測試實施例 2 :化合物對 TRα 激動活性之評價
1. 主要實驗材料及儀器:
Envision 2104酶標儀
HEK293T細胞株,購買自ATCC (貨號:CRL-3216)
pGL4.35[luc2P/9XGAL4 UAS/Hygro]購買自普洛麥格 (貨號:E1370)
pBIND-TRα質體 康龍化成
pBIND- RXRα質體 康龍化成
LipoLTX轉染試劑購買自賽默飛世爾(貨號:15338-100)
2. 化合物準備
2.1 化合物溶解
化合物之粉末按照標準方案製成10毫莫耳二甲亞碸儲液。
2.2 化合物儲存
所有的溶解在二甲亞碸中之化合物短期保存在室溫乾燥器中,長時間保存在-20℃中。
2.3 準備實驗化合物
2.3.1 所有待測化合物用二甲亞碸進行3倍梯度稀釋,10個稀釋梯度,起始濃度為10微莫耳。
2.3.2 陽性對照三碘甲狀腺素(T3)用二甲亞碸進行3倍梯度稀釋,10個稀釋梯度,起始濃度為16.67微莫耳。
2.3.3 準備166.7×陽性對照(16.67微莫耳,三碘甲狀腺素(T3))及166.7×陰性對照(100% 二甲亞碸)。
2.4 將化合物盤封閉並震盪5 min。
3 實驗過程3.1
細胞懸液製備及接種盤
a) 所有細胞皆按照ATCC標準操作培養,HEK293T在指數生長期進行實驗。
b) 棄去培養基。
c) 用磷酸鹽緩衝液清洗細胞2次。
d) 加入胰酶消化液消化細胞,用完全培養基終止消化。
e) 收集細胞並計數,只有在細胞活率大於90%時才可以進行實驗。
f) 種2.5*106
HEK293-LUC細胞至60毫米細胞培養皿中。
g) 將種好細胞之培養皿置於37℃,5% CO2
培養箱過夜培養。3.2
細胞轉染
a) 將LipoLTX轉染試劑置放室溫平衡;
b) 加6微升Plus試劑、6微克之DNA至250微升Opti-MEM™培養基,注意不要碰至管壁,用移液槍吹吸混勻;
質體:分別加入2.5微克pBIND-TRα、2.5微克pBIND-RXRα及1微克pGL4.35質體
c) 加12微升Lipo LTX試劑至250微升Opti-MEM™培養基,注意不要碰至管壁,用移液槍吹吸混勻
d) 將混合好DNA Plus的試劑(見步驟3.2.b)加入至稀釋好之LipoLTX (見步驟3.2.c)轉染試劑中,室溫靜置15 min;
e) 將混好DNA之轉染試劑加至60毫米細胞培養皿中(見步驟3.1);
f) 將培養皿置於37℃,5% CO2
培養箱培養5 h。3.3
化合物處理
a) 將稀釋好之化合物(見步驟2.3)用Echo550轉移150 nl至細胞培養盤中(6007680-50, PE);
b) 將細胞(見步驟3.2)種至384細胞培養盤中(6007680-50, PE),每孔15,000細胞數,25微升含5%胎牛血清培養基;
c) 細胞在37℃,5% CO2培養箱中過夜培養。3.4 化合物偵測
a) 將Steady-Glo™偵測試劑置放室溫;
b) 將384細胞盤(見步驟3.3)置放室溫;
c) 每孔加入25微升Steady-Glo™偵測試劑於細胞培養盤(見步驟3.4b);
d) 將盤放至振盪器上避光震盪5 min;
e) 用Envision 2104酶標儀偵測化學發光值。
4 資料分析4.1 活性 (%) 之計算: *100
RLU:產生之螢光:實施例化合物孔平均值:陽性對照平均值:陰性對照平均值4.2 計算 EC50 並繪製化合物之量效曲線 :
用Graphad5.0藉由擬合活性(%)及化合物濃度之對數值來計算化合物之EC50。
Y=底部 + (頂部-底部)/(1+10^((LogIC50-X)*坡度))
X:化合物對數濃度 Y:百分比抑制率
具體測試資料見下表1。
測試實施例 3 :化合物對 TRβ 結合力測試
1. 主要實驗材料及儀器:
Envision 2104酶標儀,
生物素-SRC2-2共激活肽購買自生工生物工程(上海)股份有限公司
TRβ LBD, GST購買自賽默飛世爾(貨號PV4762)
銪結合抗麩胱甘肽抗體購買自Cisbio (貨號61GSTKLB)
鏈親和素-D2購買自Cisbio (貨號610SADAB)
2. 化合物之製備與處理
2.1 化合物二甲亞碸儲液之製備
所有化合物溶解於二甲亞碸,製備成10毫莫耳之儲液。
2.2 化合物儲存
化合物溶解於二甲亞碸後,於乾燥器中室溫可存放三個月。長期存放,則置於-20℃冰箱中。
3. 實驗步驟
3.1 製備1x反應緩衝液
3.2 化合物之篩選:
a) 用100%二甲亞碸將陽性藥三碘甲狀腺素(T3)自10微莫耳(100X)或待測化合物自1毫莫耳(100X)以1:3進行等比稀釋,共10個濃度。
b) 用1x反應緩衝液製備4x經過濃度梯度稀釋之化合物。
c) 加5微升4x經過濃度梯度稀釋之化合物至384孔實驗盤。
d) 用1x反應緩衝液製備4X TRβ LBD以及4X RXRβ。
e) 加5微升4x TRβ LBD以及4X RXRβ至384孔實驗盤。
f) 用1x反應緩衝液製備2X生物素-SRC2-2、2X銪結合抗麩胱甘肽抗體以及2X鏈親和素-d2。
g) 加10微升2X混合液(參考步驟f)至384孔實驗盤。
h) 將384孔實驗盤於離心機1000轉離心1分鐘。
i) 室溫避光孵育1小時。
j) Envision 2104酶標儀記錄384孔實驗盤每孔665 nm及615 nm螢光信號值,並計算比值665nm/615nm。
4. 資料分析
4.1 計算每孔之相對比(比值665nm/615nm
-比值空白
)
4.2 活性百分率計算如下: :實施例化合物孔之相對比之平均值:所有陽性對照孔之相對比之平均值。:所有陰性對照孔之相對比之平均值。
4.3 曲線之繪製及EC50之計算:
用Graphpad 5.0藉由非線性回歸之方法,對活性(%)及化合物對數濃度之關係進行擬合,來計算EC50。
Y=底部 + (頂部-底部)/(1+10^((LogEC50-X)*坡度))
X:化合物對數濃度 Y:百分比活性
具體測試資料見下表1。
表1化合物對甲狀腺素受體β之結合活性如下:
結論:同已揭示之對比化合物53相比,本發明之有些化合物出乎意料地顯示了很高之THRβ活性(<0.2 uM),有些化合物顯示了比對比化合物53對THRα更高之選擇性。
實施例 | IC50 | ||
THRβ結合力(uM) | THRα結合力(uM) | THRα/β選擇性(倍數) | |
實施例1 | 1.23 | >10 | > 8.1 |
實施例2 | 2.33 | >10 | >4.29 |
實施例3 | 5.2 | >10 | >1.92 |
實施例4 | 0.36 | 4.3 | >11.9 |
實施例9 | 0.17 | >10 | >58.8 |
實施例10 | 1.47 | >10 | >6.80 |
實施例11 | 1.78 | >10 | 5.61 |
實施例12 | 0.80 | 0.2 | 0.25 |
實施例13 | 0.17 | 1.22 | 7.17 |
實施例14 | 0.262 | ||
對比化合物53 | 0.26 | 5.0 | 19.2 |
T3 | 0.00052 | 0.00026 |
測試實施例 4 :化合物對 TRβ 受體激動活性之評價:
實驗概述:將TRβ-LBD及RXRα-LBD編碼序列分別插入至pBIND質體(Promega,E1581)中。該表現載體及報告載體(攜帶穩定整合之GAL4啟動子驅動之螢光素酶報告基因的pGL4.35)在宿主細胞中共表現。當激動劑與相應之嵌合受體結合時,嵌合受體與報告基因載體上之GAL4結合位點結合並刺激報告基因表現。根據化學發光信號之強弱來判定化合物對TRβ受體之激動活性。
實驗材料及儀器:
Envision 2104酶標儀
HEK293T細胞株,購買自ATCC (貨號:CRL-3216)
pGL4.35[luc2P/9XGAL4 UAS/Hygro]購買自普洛麥格(貨號:E1370)
pBIND-TR β質體 康龍化成
pBIND- RXRα質體 康龍化成
LipoLTX轉染試劑購買自賽默飛世爾(貨號:15338-100)
Steady-Glo™螢光素酶偵測套組購買自普洛麥格(貨號:E2520)
2.3 準備實驗化合物
所有待測化合物用二甲亞碸進行3倍梯度稀釋,10個稀釋梯度,起始濃度為10毫莫耳。
陽性對照三碘甲狀腺素(T3)用二甲亞碸進行3倍梯度稀釋,10個稀釋梯度,起始濃度為16.67微莫耳。
準備166.7×陽性對照(16.67微莫耳,三碘甲狀腺素(T3))及166.7×陰性對照(100%二甲亞碸)。
將化合物盤封閉並震盪5分鐘。
實驗過程
3.1 細胞懸液製備及接種盤
a) 所有細胞皆按照ATCC標準操作培養,HEK293T在指數生長期進行實驗。
b) 棄去培養基。
c) 用磷酸鹽緩衝液清洗細胞2次。
d) 加入胰酶消化液消化細胞,用完全培養基終止消化。
e) 收集細胞並計數,只有在細胞活率大於90%時才可以進行實驗。
f) 種2.5*10 6 HEK293-LUC細胞至60毫米細胞培養皿中。
g) 將種好細胞之培養皿置於37℃,5% CO2
培養箱過夜培養。
3.2 細胞轉染
a) 將LipoLTX轉染試劑置放室溫平衡;
b) 加6微升Plus試劑 6微克之DNA至250微升Opti-MEM™培養基,注意不要碰至管壁,用移液槍吹吸混勻;質體:2.5微克pBIND-TR β、2.5微克pBIND-RXRα及1微克pGL4.35質體
c) 加12微升Lipo LTX試劑至250微升Opti-MEM™培養基,注意不要碰至管壁,用移液槍吹吸混勻
d) 將混合好DNA Plus之試劑(見步驟3.2.b)加入至稀釋好之Lipo LTX (見步驟 3.2.c)轉染試劑中,室溫靜置15分鐘;
e) 將混好DNA之轉染試劑加至60毫米細胞培養皿中(見步驟3.1);
f) 將培養皿置於37℃,5% CO2
培養箱培養5 h。
3.3 化合物處理
a) 將稀釋好之化合物(見步驟2.3)用Echo550轉移150 nl至細胞培養盤中(6007680-50,PE);
b) 將細胞(見步驟3.2)種至384細胞培養盤中(6007680-50,PE),每孔15,000個細胞,25微升培養基;
c) 細胞在37℃,5% CO2培養箱中過夜培養。
3.4 化合物偵測
a) 將Steady-Glo™ 偵測試劑置放室溫;
b) 將384細胞培養盤(見步驟3.3)置放室溫;
c) 每孔加入25微升Steady-Glo™偵測試劑於細胞培養盤(見步驟3.4b);
d) 將盤放至振盪器上避光震盪5 min;
e) 用Envision 2104酶標儀偵測化學發光值。
資料分析:
4.1 活性(%)之計算:*100
RLU:產生之螢光:實施例化合物孔平均值:陽性對照平均值:陰性對照平均值
4.2 計算EC50並繪製化合物之量效曲線:
用Graphad5.0藉由擬合活性(%)及化合物濃度之對數值來計算化合物之EC50。
Y=底部 + (頂部-底部)/(1+10^((LogIC50-X)*坡度))
X:化合物對數濃度 Y:百分比抑制率
表2:本發明化合物對甲狀腺素受體β之激動活性如下:
結論:本發明化合物能夠激活甲狀腺激素受體β下游信號。
實施例 | EC50 | |
THRβ激動活性 (uM) | THRα激動活性 (uM) | |
實施例4 | 2.45 | 4.25 |
實施例9 | 1.75 | 3.98 |
實施例12 | 0.79 | 1.08 |
實施例13 | 0.097 | 0.123 |
對比化合物53 | 2.48 | 4.57 |
T3 | 0.001 | 0.0005 |
測試實施例 5 :藥代動力學評價:
以大鼠為受試動物,測試了大鼠灌胃給予實施例4、實施例9化合物後不同時刻血漿中藥物濃度。研究本發明化合物在大鼠體內藥物代謝動力學行為,評價其藥物代謝特徵。每組實施例選用3隻體重相近之SD雄性大鼠,口服給予劑量為2 mg/kg,單次給藥。動物給藥後在15 min、30 min、1 h、2 h、4 h、6 h、10 h、24 h時間點採集血液。採用LC-MS/MS分析方法偵測血漿中化合物含量,方法之定量下限均為20 ng/mL。使用代謝動力學資料分析軟體WinNonlin 7.0對血漿中之VT088及濃度資料進行統計,利用非房室模型法(NCA)計算藥代參數,具體見下表2。
實驗方案:
實驗藥品:實施例4、實施例9化合物。
實驗動物:
健康SD雄性大鼠6隻,平均分成2組,每組3隻,購自上海西普爾-必凱實驗動物有限公司,動物生產許可證號:SCXK(滬)2008-0016。
藥物組態:取一定量藥物,加入2% Klucel LF+0.1% Tween 80水溶液,配製成呈澄清溶液或均勻懸浮液。
給藥:SD大鼠禁食過夜後灌胃給藥,給藥劑量為2 mg/kg,給藥體積均為10 mL/kg。
操作:大鼠灌胃給藥實施例4、實施例9化合物,於給藥前及給藥後15 min、30 min、1 h、2 h、4 h、6 h、10 h、24 h尾靜脈採血至少0.2 mL,置於肝素化樣品管中,4攝氏度,3500轉/分鐘離心10分鐘分離血漿,於-20攝氏度保存,給藥後2小時進食。
測定不同濃度藥物灌胃給藥後大鼠血漿中待測化合物之含量:血漿樣品室溫解凍後分別取50 μL,加入130 µL之內標工作液(1000 ng/mL,乙腈,甲苯磺丁脲),渦旋約1 min後,4 ℃,13000 rpm條件下離心10 min。取50 µL上清液與100 µL 50%乙腈水混合後進樣LC/MS/MS分析。
藥代動力學參數結果見表3。
表3:大鼠藥物代謝資料
結論:本發明之化合物藥代吸收良好,具有明顯之藥代動力學優勢。同報導之對比化合物53相比,在同等劑量及製劑情況下,本發明之有些化合物出乎意料地顯示了更高之Cmax值及暴露量。所有以上PK結果表明,本發明提供之化合物有良好之PK特性可以作為代謝相關疾病之治療藥物。
化合物 | 劑量 | 達峰時間 | 峰值血藥濃度 | 曲線面積 | 半衰期 |
(mg/kg) | (h) | (ng/mL) | (ng∙h/mL) | (h) | |
實施例4 | 2.0 | 5.33±1.15 | 727±183 | 9242±1245 | 5.14±0.83 |
實施例9 | 2.0 | 4.67±1.15 | 2007±106 | 24790±3704 | 4.56±0.42 |
對比化合物53 | 2.0 | 5.3±1.15 | 1163±97.1 | 12854 ±961 | 3.53±0.42 |
Claims (19)
- 如請求項2之化合物或其醫藥學上可接受之鹽,其中m為1至3之整數。
- 如請求項3之化合物或其醫藥學上可接受之鹽,其中R4係選自由氫、鹵素原子及C1-3烷基所組成之群;及m為1或2。
- 如請求項1之化合物或其醫藥學上可接受之鹽,其中R1為氰基。
- 如請求項1之化合物或其醫藥學上可接受之鹽,其中R2及R3皆為Cl。
- 一種藥物組合物,其包含治療有效量之如請求項1至15中任一項之化合物或其醫藥學上可接受之鹽以及醫藥學上可接受之佐劑。
- 一種如請求項1至15中任一項之化合物或其醫藥學上可接受之鹽或如 請求項16之藥物組合物之用途,其係用於製備代謝相關疾病之治療藥物。
- 如請求項17之用途,其中該代謝相關疾病係選自由肥胖、高脂血症、高膽固醇血症、糖尿病以及非酒精性脂肪肝病(NASH)、肝脂肪變性、動脈粥樣硬化、甲狀腺功能減退及甲狀腺癌所組成之群。
- 如請求項18之用途,其中該代謝相關疾病係選自由非酒精性脂肪肝病(NASH)、甲狀腺功能減退及甲狀腺癌所組成之群。
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BR112021010871A2 (pt) | 2021-08-31 |
IL283362B1 (en) | 2024-03-01 |
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US11034676B2 (en) | 2021-06-15 |
US20200399249A1 (en) | 2020-12-24 |
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JP2022512482A (ja) | 2022-02-04 |
AR117694A1 (es) | 2021-08-25 |
CN113194958B (zh) | 2023-05-23 |
AU2019398339A1 (en) | 2021-06-10 |
JP7532371B2 (ja) | 2024-08-13 |
IL310699A (en) | 2024-04-01 |
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IL283362B2 (en) | 2024-07-01 |
IL283362A (en) | 2021-07-29 |
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