TW201501711A - 吡唑-醯胺化合物及其醫藥用途 - Google Patents
吡唑-醯胺化合物及其醫藥用途 Download PDFInfo
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- TW201501711A TW201501711A TW103109400A TW103109400A TW201501711A TW 201501711 A TW201501711 A TW 201501711A TW 103109400 A TW103109400 A TW 103109400A TW 103109400 A TW103109400 A TW 103109400A TW 201501711 A TW201501711 A TW 201501711A
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Classifications
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Landscapes
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Abstract
下述式表示的化合物或其製藥上可容許的鹽:
□[I][式中,n表示1或2。],
□[II]、□[IIh]或
□[III]及該等的醫藥用途。
Description
本發明是關於吡唑-醯胺化合物及其醫藥用途。更詳細而言,關於具有丙酮酸脫氫酶激酶(pyruvic acid dehydrogenasekinase,以下,簡稱為PDHK。)抑制活性的吡唑-醯胺化合物或其製藥上可容許的鹽、含有該等的醫藥組成物、及糖尿病(1型糖尿病、2型糖尿病等)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障等)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病(Chronic Obstructive Pulmonary Disease,COPD)、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌、肺高血壓症、或阿滋海默症的預防或治療劑等。
在組織內,在使用能量的反應,例如,生物合成、主動運輸、肌肉的收縮等是由腺核苷三磷酸(ATP)的加水分解而供給能量。例如ATP是葡萄糖或遊離脂肪酸
等高能量的代謝燃料的氧化而生成。例如肌肉等氧化性的組織中,ATP的大部分是由進入檸檬酸循環的乙醯輔酶A產生。乙醯輔酶A是葡萄糖經由醣解途徑(glycolytic pathway)的氧化或遊離脂肪酸的β氧化而生成。扮演調節由葡萄糖產生乙醯輔酶A的指揮角色的酶是PDH。PDH是在丙酮酸氧化生成乙醯輔酶A及二氧化碳之同時,菸鹼醯胺腺二核苷酸(NAD)還原成為NADH的觸媒(例如,非專利文獻1、2)。
PDH是由局部存在粒線體基質的3個酶成分(E1、E2及E3)及若干個次單元所成的多酶複合體。E1、E2及E3是各分別進行丙酮酸的脫碳酸、乙醯輔酶A的生成及還原NAD而生成NADH。
在PDH結合具有調節功能的2種酶。一種PDHK,是對PDH表現特異性的蛋白激酶。其功能是將複合體的E1 α次單元磷酸化而不活化。另外一種是PDH磷酸酶,經由E1 α次單元的脫磷酸化而將PDH活化的特異性的蛋白磷酸酶。活性(脫磷酸化)狀態的PDH的比率是由激酶活性與磷酸酶活性的平衡決定。激酶活性受代謝基質的相對濃度的調節。例如,激酶活性是由NADH/NAD、乙醯輔酶A/輔酶A及ATP/腺核苷二磷酸(ADP)的各比率的上昇而活化,而被丙酮酸抑制(例如,非專利文獻3)。
哺乳類的組織中已鑑定4種的PDHK同工異構酶(isozyme)。其中尤以PDHK2是在與糖代謝相關的包括肝臟、骨格肌、脂肪組織的廣範圍的組織中表現。再者,
由於PDHK2對NADH/NAD及乙醯輔酶A/輔酶A的上昇的活化及對丙酮酸的抑制的感受性比較高,暗示與短期的糖代謝調節相關(例如,非專利文獻4)。
又,PDHK1多數表現在心肌、骨格肌、胰β細胞等。再者,PDHK1在缺血狀態中,經由缺氧誘發因子(hypoxia inducible factor,HIF)1的活化而被誘發表現,暗示有缺血性疾病及癌性疾病相關(例如,非專利文獻5)。
在胰島素依賴型(1型)糖尿病及非胰島素依賴型(2型)糖尿病等疾病中,脂質的氧化亢進,同時葡萄糖的利用降低。此葡萄糖利用降低成為呈現高血糖的原因之一。如1型及2型糖尿病、肥胖等由於在氧化性葡萄糖代謝降低的狀態下PDH活性降低,暗示在1型及2型糖尿病中的葡萄糖利用的降低與PDH活性的降低有關連(例如,非專利文獻6、7)。
又,在1型及2型糖尿病中,肝臟有糖新生的亢進,這也成為呈現高血糖的原因之一。PDH活性的降低使丙酮酸上昇,其結果,在肝臟作為糖新生基質的乳酸利用能增大。由此,在1型及2型糖尿病的糖新生的亢進可能與PDH活性的降低有關聯(例如,非專利文獻8、9)。
由PDHK的抑制而使PDH活化,則可認為葡萄糖氧化速度增加。其結果,由生體的葡萄糖利用亢進,又,在肝臟的糖新生受抑制,而可期待能改善1型及2型糖尿病的高血糖(例如,非專利文獻10、11、12)。
參與糖尿病的其他因子是胰島素分泌障礙,對此已知
與在胰β細胞的PDH活性的降低及PDHK1、2及4的誘發有關聯(例如,非專利文獻13、14)。
又,已知由糖尿病引起的持續性的高血糖會引起糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症等併發症。硫胺及α-類脂酸成為輔酶(coenzyme)而有助於PDH的活化。暗示該等,或,硫胺衍生物及α-類脂酸衍生物對糖尿病併發症的治療具有期望的效果。因此,PDH的活化可期待能改善糖尿病併發症(例如,非專利文獻15、16)。
在缺血狀態下,由於氧供給被限制,葡萄糖及脂肪酸雙方的氧化降低,在組織中由氧化磷酸化作用(oxidative phosphorylation)產生ATP的量減少。沒有足夠的氧的狀態下,為了要維持ATP位準而厭氣性醣解作用亢進。其結果,引起乳酸的增加及細胞內pH的降低。為了維持離子的穩定性而要消耗能量,但異常低的ATP位準及細胞的滲透性崩壞的結果,引起細胞死亡。此外,腺苷磷酸活化激酶在缺血中活化而磷酸化,使乙醯輔酶A羧酶不活化。組織的丙二醯輔酶A位準降低,肉鹼棕櫚醯基轉移酶-I(Carnitine Palmitoyltransferase 1)活性上昇,促進醯基輔酶A(acyl CoA)輸送至粒線體內,因此脂肪酸氧化比葡萄糖氧化較為有利。葡萄糖的氧化在消費每1分子氧的ATP產生量比脂肪酸的氧化高。因此,在缺血狀態下,可認為如能將PDH活化而使能量代謝優位地移向於葡萄糖氧化,則可提高維持ATP位準的能力(例如,非專利文獻17)。
又,將PDH活化,則經由醣解作用所生成的丙酮酸被
氧化,而降低乳酸的產生,因而可認為在缺血組織中的質子負荷的淨值會降低。因此,由PDHK抑制造成的PDH活化,在缺血性疾病,例如,心肌缺血病,可期待有保護的作用(例如,非專利文獻18、19)。
PDHK抑制而造成活化PDH的藥劑,可認為由丙酮酸代謝的亢進,而減少乳酸的產生。因此,可認為對如粒線體病、粒線體腦肌病或敗血症等高乳酸血症治療會有用(例如,非專利文獻20)。
在癌細胞中,PDHK1或2的表現上昇。又,在癌細胞中,在粒線體中的由氧化性磷酸化的ATP產生降低,經由在細胞質的厭氣性醣解系的ATP產生增加。由PDHK抑制而造成活化PDH,則在粒線體內的氧化性磷酸化亢進,活性氧的產生昇高,而可期待誘發癌細胞的細胞凋亡。因此,可認為PDHK抑制而造成活化PDH是有用於癌性疾病治療(例如,非專利文獻21)。
又,肺高血壓症是肺動脈的細胞增殖亢進,肺動脈的一部分縮小而使血壓升高為特徴的疾病。在肺高血壓症中活化肺動脈細胞的PDH,則粒線體內的氧化性磷酸化亢進,活性氧的產生升高,而可期待會誘發肺動脈細胞的細胞凋亡。因此,PDHK抑制造成的PDH的活化,可認為會有用於肺高血壓症的治療(例如,非專利文獻22)。
在阿滋海默症的大腦的能量的產生及葡萄糖的代謝降低,又,PDH活性降低。PDH活性降低則乙醯輔酶A的產生降低。乙醯輔酶A是經由檸檬酸循環在電子
傳達系中利用於ATP的產生。又,乙醯輔酶A是合成神經傳遞物質之一的乙醯膽鹼的原料。因此,在阿滋海默症的腦PDH活性降低,可認為由於ATP產生的降低引起神經細胞死亡。又,可認為在膽鹼性神經(cholinergic nerve)中,其傳遞物質的乙醯膽鹼的合成受抑制而引起記憶力降低等。在阿滋海默症中活化腦的PDH,則可期待會使能量的產生及乙醯膽鹼的合成的亢進。因此,可認為PDHK抑制而造成PDH的活化,會有用於阿滋海默症的治療(例如,非專利文獻23、24)。
具有PDH活化作用的藥劑的二氯乙酸,顯示對糖尿病,心肌缺血、心肌梗塞,狹心症、心臟衰竭、高乳酸血症、腦缺血病、腦中風、末梢動脈疾病、慢性阻塞性肺病,癌性疾病,肺高血壓症的治療具有希望的效果(例如,非專利文獻10、18、20、22、25、26、27)。
由這些知見,可認為PDHK抑制劑是對於葡萄糖利用障礙有關連的疾病,例如,糖尿病(1型糖尿病,2型糖尿病等)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障等)的治療或預防有益。又,PDHK抑制劑是對於對組織的能量基質供給受限制的疾病,例如,心臟衰竭(急性心臟衰竭,慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病及腦中風的治療或預防有益。再者,
可認為PDHK抑制劑是對粒線體病、粒線體腦肌病、癌、肺高血壓症等的治療或預防有益。
因此,可認為PDHK抑制劑是對糖尿病(1型糖尿病,2型糖尿病等)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障等)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌、肺高血壓症、或阿滋海默症的治療或預防有益。
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本發明是關於下述者。
[1]式[I]表示的化合物或其製藥上可容許的鹽:
[式中,n表示1或2。]
[2]式[II]或[IIh]表示的化合物:
[3]式[II]表示的如上述[2]所述的化合物:
[4]式[IIh]表示的如上述[2]所述的化合物:
[5]式[III]表示的化合物:
[6]醫藥組成物,係含如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,及製藥上許容的載體,[7]PDHK抑制劑,係含有如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[8]PDHK1抑制劑,係含有如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[9]PDHK2抑制劑,係含有如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[10]血糖降低劑,係含有如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,
[11]乳酸降低劑,係含有如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[12]糖尿病、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症、心臟衰竭、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌或肺高血壓症的預防或治療劑,係含有如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[12’]糖尿病、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症、心臟衰竭、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌、肺高血壓症、或阿滋海默症的預防或治療劑,係含有如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[13]如上述[12]所述的預防或治療劑,其中糖尿病是1型糖尿病或2型糖尿病,[14]如上述[12]所述的預防或治療劑,其中糖尿病併發症是由糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症及白內障所成群組選出,[15]如上述[12]所述的預防或治療劑,其中心臟衰竭是急性心臟衰竭或慢性心臟衰竭,[16]一種醫藥組成物,係含有:
(a)如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,以及(b)含有對於預防或治療由糖尿病(1型糖尿病、2型糖尿病)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌及肺高血壓症所成的群選出的疾病有效的至少1個其他的藥劑,[16’]一種醫藥組成物,係含有:(a)如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,以及(b)含有對於預防或治療由糖尿病(1型糖尿病、2型糖尿病)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌、肺高血壓症、及阿滋海默症所成的群選出的疾病有效的至少1個其他的藥劑,[17]一種組合醫藥,係將
(a)如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,以及(b)對於預防或治療由糖尿病(1型糖尿病、2型糖尿病)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌及肺高血壓症所成的群選出的疾病有效的至少1個其他的藥劑,同時、分別或連續地投藥,[17’]一種組合醫藥,係將(a)如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,以及(b)對於預防或治療糖尿病(1型糖尿病、2型糖尿病)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌、肺高血壓症、及阿滋海默症所成的群選出的疾病有效的至少1個其他的藥劑,同時、分別或連續地投藥,
[18]哺乳動物的PDHK抑制方法,係包含對該哺乳動物投藥含有醫藥上有效量的如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[19]哺乳動物的PDHK1抑制方法,係包含對該哺乳動物投藥含有醫藥上有效量的如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[20]哺乳動物的PDHK2抑制方法,係包含對該哺乳動物投藥含有醫藥上有效量的如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[21]哺乳動物的糖尿病(1型糖尿病,2型糖尿病)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌或肺高血壓症的預防或治療方法、係包含對該哺乳動物投藥含有醫藥上有效量的如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[21’]哺乳動物的糖尿病(1型糖尿病、2型糖尿病)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常
血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌、肺高血壓症或阿滋海默症的預防或治療方法,係包含對該哺乳動物投藥含有醫藥上有效量的如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[22]哺乳動物的血糖值的降低方法,係包含對該哺乳動物投藥含有醫藥上有效量的如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[23]哺乳動物的乳酸值的降低方法,係包含對該哺乳動物投藥含有醫藥上有效量的如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽,[24]如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽的使用,係用於PDHK抑制劑的製造,[25]如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽的使用,係用於PDHK1抑制劑的製造,[26]如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽的使用,係用於PDHK2抑制劑的製造,[27]如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽的使用,係用於血糖值降低劑的製造,[28]如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽的使用,係用於乳酸值降低劑的製造,[29]如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽的使用,係用於糖尿病(1型糖尿病、2型糖尿病)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血
症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌或肺高血壓症的預防或治療劑的製造,[29’]如上述[1]至[5]任一項所述的化合物或其製藥上可容許的鹽的使用,係用於糖尿病(1型糖尿病、2型糖尿病)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌、肺高血壓症、或阿滋海默症的預防或治療劑的製造,[30]如上述[24]至[29]任一項所述的使用,係用於與對預防或治療由糖尿病(1型糖尿病、2型糖尿病)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、
癌或肺高血壓症所成的群選出的疾病的有效的至少1種其他的藥劑組合的使用,以及[30’]如上述[24]至[29]任一項所述的使用,係用於與對預防或治療由糖尿病(1型糖尿病、2型糖尿病)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌、肺高血壓症或阿滋海默症所成的群選出的疾病有效的至少1種其他的藥劑組合的使用等。
本發明化合物或其製藥上可容許的鹽由於抑制PDHK活性,因此做為糖尿病(1型糖尿病、2型糖尿病)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌、肺高血壓症、或阿滋海默症等的治療劑或預防劑而有用。
第1圖表示供試化合物對非絶食SD(IGS)大鼠的肝PDH活性的效果(對肝total PDH活性的肝active PDH活性的百分率)(平均±標準偏差(n=3))。
第2圖表示供試化合物對非絶食SD(IGS)大鼠的脂肪組織PDH活性的效果(對脂肪組織total PDH活性的脂肪組織active PDH活性的百分率)(平均±標準偏差(n=3))。
以下將本發明詳細說明。
本發明化合物是通式[I]表示的化合物(以下,也稱為化合物(1))或其製藥上可容許的鹽。
[式中,n表示1或2。]
本發明化合物是式[II]:
表示的化合物(2-{4-[(9R)-9-羥基-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙烷醯胺)(以下,也稱為化合物(2))。
本發明化合物是式[IIh]:
表示的化合物(2-{4-[(9R)-9-羥基-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙烷醯胺‧1水合物)(以下,也稱為化合物(2h))。
本發明化合物是式[III]:
表示的化合物(2-{4-[(9R)-9-羥基-2-(4-羥基-4-甲基苄氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙烷醯胺)(以下,也稱為化合物(3))。
本發明化合物的製藥上可容許的鹽,可為與本發明化合物形成無毒鹽的任何鹽,例如,可列舉與無機酸的鹽,與有機酸的鹽,與胺基酸的鹽等。
與無機酸的鹽,例如,可列舉與鹽酸、硝酸、硫酸、磷酸、臭化氫酸等的鹽。
與有機酸的鹽,例如,可列舉與草酸、順丁烯二酸、檸檬酸、反丁烯二酸、乳酸、蘋果酸、琥珀酸、酒石酸、乙酸、三氟乙酸、葡萄糖酸、抗壞血酸、甲基磺酸、苯磺酸、對甲苯磺酸等的鹽。
與胺基酸的鹽,例如,可列舉與離胺酸、精胺酸、天冬胺酸、麩胺酸等的鹽。
作為本發明化合物的製藥上可容許的鹽,理想是與無機酸的鹽。
又,本發明化合物或其製藥上可容許的鹽是,也可以同位元素(例如,3H,2H,14C,35S等)標誌。
作為本發明化合物或其製藥上可容許的鹽而言,實質上精製的化合物(1)或其製藥上可容許的鹽為理想。更理想是,精製成80%以上的純度的本發明化合物或其製藥上可容許的鹽。
通式[I]表示的化合物或其製藥上可容許的鹽也有成為溶劑合物而存在的情況。「溶劑合物」就是在通式[I]表示的化合物或其醫藥上可容許的鹽,有溶媒分子配位的化合物,也包含水合物。溶劑合物是製藥上可容許的溶劑合物為理想。例如,可列舉通式[I]表示的化合物或其醫藥上可容許的鹽的水合物,乙醇合物,二甲基亞碸合物等。具體而言,可列舉通式[I]表示的化合物的半水合物、1水合物、2水合物或1乙醇合物,或通式[I]表示的化合物的製藥上可容許的鹽的1水合物或2鹽酸鹽的2/3乙醇合物等。可依照公知的方法而得其溶劑合物。
「醫藥組成物」而言,可列舉錠劑、膠囊劑、顆粒劑、散劑、喉錠劑、糖漿劑、乳劑、懸液劑等經口劑,或外用劑、栓劑、注射劑、點眼劑、經鼻劑、經肺劑等非經口劑。
本發明的醫藥組成物,依照醫藥製劑的技術領域中本身公知的方法,將本發明化合物或其製藥上可容許的鹽,與至少1種以上的製藥上可容許的載體等,適宜、適量混合等,而可製造。該醫藥組成物中的本發明化合物或其製藥上可容許的鹽的含有率,因劑形、投藥量等而有不同,但例如,組成物全量的0.1至100重量%。
該「製藥上可容許的載體」而言,可列舉作為製劑素材而慣用的各種有機或無機載體物質,例如,可列舉固形製劑時的賦形劑、崩壞劑、黏合劑、流動化劑、潤滑劑等,或液狀製劑的溶劑、溶解佐劑、懸浮劑、等張化劑、緩衝劑、無痛化劑等。再有必要時,可使用保存劑、抗氧化劑、著色劑、甘味劑等添加物。
「賦形劑」而言,例如,可列舉乳糖,白糖,D-甘露糖醇,D-山梨糖醇,玉米澱粉,糊精,微結晶纖維素,結晶纖維素,羧甲基纖維素,羧甲基纖維素鈣,羧甲基澱粉鈉,低取代度羥丙基纖維素,阿拉伯樹膠等。
「崩壞劑」而言,例如,可列舉羧甲基纖維素、羧甲基纖維素鈣、羧甲基纖維素鈉、羧甲基澱粉鈉、交聯羧甲基纖維素鈉、交聯聚維酮、低取代度羥丙基纖維素、羥丙基甲基纖維素、結晶纖維素等。
「黏合劑」而言,例如,可列舉羥丙基纖維素,羥丙基甲基纖維素,聚維酮,結晶纖維素,白糖,糊精,澱粉,明膠,羧甲基纖維素鈉,阿拉伯樹膠等。
「流動化劑」而言,例如,可列舉輕質無水矽酸,硬脂酸鎂等。
「潤滑劑」而言,例如,可列舉硬脂酸鎂,硬脂酸鈣,滑石等。
「溶劑」而言,例如,可列舉精製水,乙醇,丙二醇,聚乙二醇,胡麻油,玉米油,橄欖油等。
「溶解佐劑」而言,例如,可列舉丙二醇,
D-甘露糖醇,安息香酸苄酯,乙醇,三乙醇胺,碳酸鈉,檸檬酸鈉等。
「懸浮劑」而言,例如,可列舉羥基氯苯胺,羧甲基纖維素,羥丙基纖維素,丙二醇,聚維酮,甲基纖維素,單硬脂酸甘油等。
「等張化劑」而言,例如,可列舉葡萄糖,D-山梨糖醇,氯化鈉,D-甘露糖醇等。
「緩衝劑」而言,例如,可列舉磷酸氫鈉,乙酸鈉,碳酸鈉,檸檬酸鈉等。
「無痛化劑」而言,例如,可列舉苄醇等。
「保存劑」而言,例如,可列舉對氧安息香酸乙酯,氯丁醇,苄醇,脫氫乙酸鈉,山梨酸等。
「抗氧化劑」而言,例如,可列舉亞硫酸鈉,抗壞血酸等。
「著色劑」而言,例如,可列舉食用色素(例:食用紅色2號或3號,食用黄色4號或5號等),β-胡蘿蔔素等。
「甘味劑」而言,可列舉例如,糖精鈉,甘草酸二鉀,阿斯巴甜等。
本發明的醫藥組成物是,對人當然可以,對人以外的哺乳動物(例:小鼠,大鼠,倉鼠,天竺鼠,兔,貓,狗,豬,牛,馬,羊,猴等),也可經口或非經口(例:局部,肌肉內,皮下,直腸,靜脈投藥等)投藥。投藥量,因投藥對象,疾病,症狀,劑形,投藥途徑等而不同,但
例如,對成人的患者(體重:約60kg)經口投藥時的投藥量,以有效成分的化合物(1),每日通常約1mg至1g的範圍。將這個量可分成1次至數次投藥。
本發明化合物或其製藥上可容許的鹽,有抑制PDHK(PDHK1及/或PDHK2)的活性,所以可認為對與葡萄糖利用障礙有關連的疾病,例如,糖尿病(1型糖尿病、2型糖尿病等)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障等)的治療或預防有益。又,PDHK抑制劑,可認為對組織的能量基質供給受限制的疾病,例如,心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病及腦中風的治療或預防有益。再者,PDHK抑制劑可認為對粒線體病、粒線體腦肌病、癌、肺高血壓症、阿滋海默症等的治療或預防有益。
糖尿病,例如,1型糖尿病、2型糖尿病。
糖尿病併發症而言,例如,可列舉糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障。
心臟衰竭,例如,急性心臟衰竭、慢性心臟衰竭。
「抑制PDHK」就是抑制PDHK的機能而消除或減弱其活性的意思。「抑制PDHK」理想是「抑制人PDHK」。「PDHK抑制劑」理想是,「人PDHK抑制劑」。
「抑制PDHK1」就是抑制PDHK1的機能而消除或減弱其活性的意思,例如,基於後述的試驗例1的條件,抑制PDHK1的機能的意思。「抑制PDHK1」理想是「抑制人PDHK1」。「PDHK1抑制劑」理想是「人PDHK1抑制劑」。更理想是「人標靶器官的PDHK1抑制劑」。
「抑制PDHK2」就是抑制PDHK2的機能而消除或減弱其活性的意思,例如,基於後述的試驗例1的條件,抑制PDHK2的機能的意思。「抑制PDHK2」理想是「抑制人PDHK2」。「PDHK2抑制劑」理想是「人PDHK2抑制劑」。更理想是「人標靶器官的PDHK2抑制劑」。
「活化PDH」就是將標靶器官(例,肝臟,骨格肌,脂肪組織,心臟,腦)等或癌等的PDH活化的意思。
「降低血糖值」就是,降低血中(含血清中或血漿中)的葡萄糖濃度的意思,理想是將高血糖值降低的意思。更理想是將血糖值降低成為對治療學上有效的人的正常值的意思。
「降低乳酸值」就是,將血中(含血清中或血漿中)的乳酸濃度降低的意思,理想是將高的乳酸值降低的意思。更理想是將乳酸值降低成為治療學上有效的人的正常值的意思。
將本發明化合物或其製藥上可容許的鹽以在醫藥領域所行的一般性的方法,可以與1種或多數的其他的藥劑(以下,也稱為併用藥劑)組合使用(以下,也稱為
併用)。
本發明化合物或其製藥上可容許的鹽,及併用藥劑的投藥時期沒有限定,將這些作為配合劑而對投藥對象投藥也可以,將兩製劑同時或隔一定的間隔投藥也可以。又,使用由本發明的醫藥組成物及併用藥劑所成的套組為特徴的醫藥也可以。併用藥劑的投藥量,依照臨床上所使用的投藥量即可,可由投藥對象、疾病、症狀、劑形、投藥途徑、投藥時間、組合等而適宜選擇。併用藥劑的投藥形態是沒有特別的限定,有本發明化合物或其製藥上可容許的鹽與併用藥劑組合即可。
併用藥劑而言,例如,可列舉糖尿病(1型糖尿病、2型糖尿病)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌、肺高血壓症或阿滋海默症的治療劑及/或預防劑等,可由這些之中將1劑至多數劑與本發明化合物或其製藥上可容許的鹽組合使用。
「糖尿病的治療劑及/或預防劑」而言,例如,可列舉胰島素製劑、磺醯基脲系血糖下降劑、甲福明(Metformin)、DPP-4抑制劑、胰島素抵抗性改善藥(例如四氫噻唑(thiazolidine)衍生物)、GLP-1受體促效藥等。
接下來,將本發明化合物或其製藥上可容許的鹽的製造方法以實施例具體說明。但是,本發明並不受這些實施例所限定。
沒有在本製法中說明,但必要時可藉由在官能基導入保護基,在後製程實施脫保護;將官能基作為前驅物而在各製程中處理,在適當的階段變換為所希望的官能基;改變各製法及製程的順序等過程而實施效率好的製造。
又,在各製程中,反應後的處理是通常所行的方法實行即可,單離精製是必要時適宜選擇,結晶化,再結晶,蒸餾,分液,矽膠層析法,分取HPLC等慣用方法,或組合實行即可。所有的試藥及溶媒都具有市售用品質,沒有精製而使用。
百分率%是表示重量%。其他在本文中所用的代號表示下述的意思。
s:單峰
d:雙峰
t:三峰
q:四峰
m:多峰
br:寬峰
dd:雙雙峰
td:三雙峰
ddd:雙雙雙峰
J:耦合常數
CDCl3:重三氯甲烷
DMSO-D6:重二甲基亞碸
1H NMR:質子核磁共振
HPLC:高速液體層析法
DPPA:疊氮磷酸二苯酯(diphenylphosphoryl azide)
1H-NMR譜是CDCl3或DMSO-D6中,以四甲基矽烷作為內部標準而測定,所有的δ值都以ppm表示。
(10mM磷酸鹽緩衝液(pH2.0))
將磷酸二氫鈉(3.60g)溶解於水(3000ml),用磷酸調節pH為2.0,得標題緩衝液。
HPLC分析條件
分析條件1
測定機器:HPLC系統 島津製作所 高速液體層析儀Prominence
管柱:DAICEL CHIRALCEL OD-3R 4.6mm ×150mm
管柱溫度:40℃
移動相:(A液)10mM磷酸鹽緩衝液(pH2.0),(B液)乙腈移動相的組成(A液:B液)由50:50在20分鐘內直線變化
至20:80,其後,於20:80保持5分鐘。
流速:0.5ml/min
檢出:UV(220nm)
分析條件2
測定機器:HPLC系統 島津製作所 高速液體層析儀
Prominence
管柱:DAICEL CHIRALCEL OJ-RH 4.6mm ×150mm
管柱溫度:40℃
移動相:(A液)10mM磷酸鹽緩衝液(pH2.0),(B液)乙腈移動相的組成(A液:B液)由70:30在20分鐘內直線變化
至40:60,其後,於40:60保持10分鐘。
流速:0.5ml/min
檢出:UV(220nm)
分析條件3
測定機器:HPLC系統 島津製作所 高速液體層析儀Prominence
管柱:DAICEL CHIRALPAK AD-3R 4.6mm ×150mm
管柱溫度:40℃
移動相:(A液)10mM磷酸鹽緩衝液(pH2.0),(B液)乙腈移動相的組成(A液:B液)50:50在20分鐘內直線變化至
20:80,其後,於20:80保持5分鐘。
流速:0.5ml/min
檢出:UV(220nm)
實施例1
2-{4-[(9R)-9-羥基-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-
9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙烷醯胺(化合物(2))的
合成
製程1
2’-氯-4’-甲氧基聯苯-2-羧酸乙酯
在氬氣環境下,將1-溴-2-氯-4-甲氧基苯(44.3g)溶解於甲苯(220ml),添加2-(4,4,5,5-四甲基[1,3,2]二氧雜硼雜環戊烷-2-基)安息香酸乙酯(60.8g),水(132ml),碳酸氫鈉(33.6g)及二氯雙(三苯基膦)鈀(II)(2.8g)後,在油浴溫度120℃攪拌7小時。在反應混合物追加2-(4,4,5,5-四甲基[1,3,2]二氧雜硼雜環戊烷-2-基)安息香酸乙酯(5.2g),再攪拌2小時。將反應混合物冷却至室溫,添加甲苯(100ml)及水(200ml),攪拌一夜。在反應混合物添加活性碳(3g),再攪拌1小時。將不溶物以矽藻土濾去,將過濾物以甲苯(100ml)及水(200ml)清洗。將所得的濾液合併而分層。將所得的有機層以水(100ml)清洗後,餾去溶媒,得標題化合物(67.7g)。
1H-NMR(400MHz,DMSO-D6)δ:7.88-7.86(1H,m),7.63(1H,td,J=7.6,1.4Hz),7.51(1H,td,J=7.6,1.4Hz),7.27(1H,dd,J=7.6,0.9Hz),7.18(1H,d,J=8.6Hz),7.06(1H,d,J=2.6Hz),6.95(1H,dd,J=8.6,2.6Hz),4.01(2H,m),3.80(3H,s),0.96(3H,t,J=7.1Hz).
製程2
2’-氯-4’-甲氧基聯苯-2-羧酸
將2’-氯-4’-甲氧基聯苯-2-羧酸乙酯(67.7g)溶解於乙醇(100ml),添加4N氫氧化鈉水溶液(100ml),在油浴溫度110℃攪拌4.5小時。將反應混合物冷卻至室溫,添加水(200ml)及甲苯(100ml)而攪拌一夜。在反應混合物添加活性碳(3.6g),再攪拌1小時。將不溶物以矽藻土濾去,將過濾物以甲苯(30ml)及水(300ml)清洗。將所得的濾液合併而分層。將所得的水層以甲苯(100ml)清洗後,在水層添加濃鹽酸(40ml)成為酸性,在室溫攪拌1小時。濾取析出的固體。將所得的固體風乾3小時後,在60℃減壓乾燥一夜,得標題化合物(50.2g)。
1H-NMR(400MHz,DMSO-D6)δ:12.57(1H,s),7.90-7.88(1H,m),7.60(1H,td,J=7.6,1.3Hz),7.49(1H,td,J=7.6,1.3Hz),7.24(1H,dd,J=7.6,1.0Hz),7.19(1H,d,J=8.4Hz),7.06(1H,d,J=2.4Hz),6.95(1H,dd,J=8.5,2.4Hz),3.81(3H,s).
製程3
4-氯-2-甲氧基-9H-茀-9-酮
在氬氣環境下,在2’-氯-4’-甲氧基聯苯-2-羧酸(65.4g)添加EATON試藥(五氧化磷-甲基磺酸(重量比1:10)溶液)(330ml),在油浴溫度100℃攪拌1小時。將反應混合物冰冷,將水(650ml)緩緩滴入後,在室溫攪拌1小時。濾取析出的固體,以水(500ml)清洗。將所得的固體風乾一夜,得標題化合物(92.0g)。
1H-NMR(400MHz,DMSO-D6)δ:8.01(1H,d,J=7.4Hz),7.64-7.60(2H,m),7.36(1H,td,J=7.4,0.9Hz),7.17(2H,dd,J=8.4,2.3Hz),3.85(3H,s).
製程4
4-氯-2-羥基-9H-茀-9-酮
在氬氣環境下,在4-氯-2-甲氧基-9H-茀-9-酮(92.0g)添加N-甲基吡咯酮(120ml)及吡啶鹽酸鹽(144g)。將反應混合物以迪安-斯塔克(Dean-Stark)裝置餾去水,同時在油浴溫度200℃攪拌3小時。將反應混合物冷却至90
℃後,將水(600ml)滴入,在室溫攪拌2小時。濾取析出的固體,將過濾物以水(400ml)清洗。將所得的固體風乾3日後,添加己烷及乙酸乙酯的混合溶媒(己烷:乙酸乙酯 1:1,300ml)並在室溫攪拌1小時。濾取固體,將過濾物以己烷及乙酸乙酯的混合溶媒(己烷:乙酸乙酯=1:1,500ml)清洗。將所得的固體在50℃減壓乾燥3小時,得標題化合物(48.6g)。
1H-NMR(400MHz,DMSO-D6)δ:10.56(1H,s),7.96(1H,d,J=8.4Hz),7.61-7.57(2H,m),7.32(1H,td,J=7.4,0.9Hz),6.97(1H,d,J=2.2Hz),6.94(1H,d,J=2.2Hz).
製程5
4-(4-氯-9-側氧基-9H-茀-2-基氧基)酪酸乙酯
將4-氯-2-羥基-9H-茀-9-酮(48.6g)溶解於N,N-二甲基甲醯胺(150ml),添加碳酸鉀(58.3g)及4-溴酪酸乙酯(33.5ml),在60℃攪拌2小時。將反應混合物冷却至40℃,添加甲苯(300ml)及水(300ml),分層。將所得的水層以甲苯(100ml)再萃取。將所得的有機層合併,以水(100ml)清洗2次後,添加無水硫酸鈉及活性碳(2.5g),在室溫攪拌5分鐘。將不溶物以矽藻土濾去,將濾液的溶媒餾去。在所得的殘渣添加己烷(220ml),在50℃攪拌10分鐘後,在
室溫攪拌1小時。濾取析出的固體,將過濾物以己烷清洗。將所得的固體減壓乾燥,得標題化合物(66.9g)。又,將所得的濾液餾去溶媒,在殘渣添加乙酸乙酯(5ml)及己烷(20ml),在室溫攪拌1小時。濾取析出的固體,將過濾物以己烷清洗。將所得的固體減壓乾燥,再得標題化合物(2.5g)。
1H-NMR(400MHz,DMSO-D6)δ:8.01(1H,d,J=7.6Hz),7.65-7.61(2H,m),7.37(1H,t,J=7.6Hz),7.17-7.14(2H,m),4.13-4.05(4H,m),2.47(2H,t,J=7.3Hz),2.02-1.95(2H,m),1.19(3H,td,J=7.2,0.7Hz).
製程6
4-[(9R)-4-氯-9-羥基-9-(三氟甲基)-9H-茀-2-基氧基]酪酸乙酯
在氬氣環境下,將4-(4-氯-9-側氧基-9H-茀-2-基氧基)酪酸乙酯(69.4g)溶解於THF(700ml),添加N-(4-三級-丁苄基)辛可尼汀鎓(cinchonidium)4-甲氧基苯氧化物(6.4g)。在反應混合物在-16℃滴入三甲基(三氟甲基)矽烷(52.0ml)的THF(140ml)溶液,在同溫度攪拌15分鐘。在反應混合液依序添加乙酸(23.0ml)及1M四丁基銨氟化物/THF溶液(222ml)後,在室溫攪拌1小時。將反應混合液的溶媒
餾去,在所得的殘渣添加甲苯(500ml)及飽和碳酸氫鈉水(200ml),分層。將所得的有機層以飽和碳酸氫鈉水(150ml)2次,1N氫氧化鈉水溶液(100ml),水(100ml),1N鹽酸(100ml),水(100ml),飽和食鹽水(100ml)依序清洗。在所得的有機層添加無水硫酸鎂及矽膠(150g),攪拌10分鐘。濾去不溶物,將過濾物以甲苯(300ml)及乙酸乙酯(800ml)依序清洗。將所得的濾液與甲苯清洗液合併而餾去溶媒,得標題化合物(72.1g)。又,將乙酸乙酯清洗液的溶媒餾去,在所得的殘渣添加矽膠(40g)以及己烷與乙酸乙酯的混合溶媒(乙酸乙酯:己烷 2:1,300ml),在室溫攪拌。濾去不溶物,將過濾物以己烷與乙酸乙酯的混合溶媒(乙酸乙酯:己烷=2:1,300ml)清洗。由所得的濾液餾去溶媒而得標題化合物(20.3g)。
1H-NMR(400MHz,DMSO-D6)δ:8.14(1H,d,J=7.7Hz),7.66(1H,d,J=7.5Hz),7.53(1H,t,J=7.6Hz),7.42-7.38(2H,m),7.14(2H,s),4.11-4.05(4H,m),2.47(2H,t,J=7.5Hz),2.03-1.96(2H,m),1.19(3H,td,J=7.1,0.8Hz).
(關於絕對立體組態(absolute configuration))
在後述的製程10中鑑定4-氯-2-甲基-9-(三氟甲基)-9H-茀-9-醇的絕對立體組態,確認在本製程所得的標題化合物是(R)體。光學純度是52.9%e.e.。
光學純度是,以HPLC分析條件1決定。(S)體的保持時間19.6分,(R)體的保持時間23.0分。
製程7
4-[(9R)-4-氯-9-羥基-9-(三氟甲基)-9H-茀-2-基氧基]酪酸
將4-[(9R)-4-氯-9-羥基-9-(三氟甲基)-9H-茀-2-基氧基]酪酸乙酯(92.2g)溶解於乙醇(100ml),添加4N氫氧化鈉水溶液(100ml),在80℃攪拌一夜。將反應混合物冷卻至室溫後,添加水(200ml),以甲苯(100ml)清洗2次。將所得的水層以濃鹽酸(40ml)中和,以乙酸乙酯(300ml)萃取2次。將所得的乙酸乙酯萃取液以水(100ml)2次,飽和食鹽水(100ml)依序清洗後,添加無水硫酸鎂及活性碳(4.2g),在室溫攪拌10分鐘。濾去不溶物,將濾液的溶媒餾去。在所得的殘渣添加三氯甲烷(80ml),加熱至50℃後,滴入己烷(400ml),在同溫度攪拌30分鐘後,室溫攪拌2小時。濾取析出的固體,以己烷與三氯甲烷的混合溶媒(己烷:三氯甲烷=9:1,50ml)清洗後,在80℃減壓乾燥2小時,得標題化合物(72.5g)。
1H-NMR(400MHz,DMSO-D6)δ:12.17(1H,br s),8.14(1H,d,J=7.7Hz),7.66(1H,d,J=7.5Hz),7.54(1H,td,J=7.7,1.2Hz),7.42-7.30(2H,m),7.18-7.15(2H,m),4.09(2H,t,J=6.4Hz),2.41(2H,t,J=7.3Hz),2.00-1.93(2H,m).
製程8
4-[(9R)-4-氯-9-羥基-9-(三氟甲基)-9H-茀-2-基氧基]酪酸的(1S)-1-(4-甲基苯基)乙基胺的鹽
在氮氣環境下,將(1S)-1-(4-甲基苯基)乙基胺(19.5g)溶解於乙酸乙酯(720ml),添加4-[(9R)-4-氯-9-羥基-9-(三氟甲基)-9H-茀-2-基氧基]酪酸(72.5g)。將反應混合物在60℃攪拌2小時後,室溫攪拌一夜。濾取析出的固體,將過濾物以乙酸乙酯(100ml)清洗。將所得的固體在60℃減壓乾燥5小時,得標題化合物(68.6g)。另一方面,由濾液得到4-[(9S)-4-氯-9-羥基-9-(三氟甲基)-9H-茀-2-基氧基]酪酸。
(關於光學純度)
4-[(9R)-4-氯-9-羥基-9-(三氟甲基)-9H-茀-2-基氧基]酪酸的光學純度,以HPLC分析條件1決定(光學純度90.2%e.e.)。(R)體的保持時間12.9分,(S)體的保持時間10.4分。
1H-NMR(400MHz,DMSO-D6)δ:8.14(1H,d,J=7.7Hz),7.66(1H,d,J=7.7Hz),7.53(1H,td,J=7.6,1.1Hz),7.40(1H,td,J=7.6,1.0Hz),7.26(2H,d,J=7.9Hz),7.16-7.10(4H,m),4.08(2H,t,J=6.5Hz),4.01(1H,q,J=6.7Hz),2.32(2H,t,J=7.3Hz),2.26(3H,s),1.98-1.91(2H,m),1.26(3H,
d,J=6.7Hz).
製程9
4-[(9R)-4-氯-9-羥基-9-(三氟甲基)-9H-茀-2-基氧基]酪酸
在4-[(9R)-4-氯-9-羥基-9-(三氟甲基)-9H-茀-2-基氧基]酪酸與(1S)-1-(4-甲基苯基)乙基胺的鹽(68.6g)添加乙酸乙酯(500ml)、2N鹽酸(300ml),在室溫攪拌10分鐘。將此混合液分層。將所得的有機層以水(250ml)、飽和食鹽水(200ml)依序清洗。將所得的有機層以無水硫酸鎂乾燥後,濾去不溶物,將濾液的溶媒餾去,得標題化合物(60.0g)。
1H-NMR(400MHz,DMSO-D6)δ:12.17(1H,br s),8.14(1H,d,J=7.7Hz),7.66(1H,d,J=7.5Hz),7.54(1H,td,J=7.7,1.2Hz),7.42-7.30(2H,m),7.18-7.15(2H,m),4.09(2H,t,J=6.4Hz),2.41(2H,t,J=7.3Hz),2.00-1.93(2H,m).
製程10
(9R)-4-氯-9-(三氟甲基)-9H-茀-2,9-二醇
在4-[(9R)-4-氯-9-羥基-9-(三氟甲基)-9H-茀-2-基氧基]酪酸(50g),添加N-甲基吡咯酮(200ml)及吡啶鹽酸鹽(298g),在油浴溫度200℃攪拌2日。將反應混合液冷卻至室溫後,以乙酸乙酯(500ml)稀釋,以水清洗2次。將所得的水層以乙酸乙酯(300ml)再萃取,與先前所得的有機層合併,以水、1N鹽酸、飽和食鹽水依序清洗。在所得的有機層添加無水硫酸鎂及活性碳(10g),在室溫攪拌後,將不溶物以矽藻土濾去。將所得的有機層的溶媒餾去,在殘渣添加己烷,在室溫攪拌。濾取析出的固體,在室溫減壓乾燥。將所得的粗生成物溶解於乙酸乙酯(500ml),以水清洗3次後,以無水硫酸鎂乾燥。濾去不溶物,將濾液的溶媒餾去。在殘渣添加己烷,在室溫攪拌。濾取析出的固體,在室溫減壓乾燥,得標題化合物(22.4g)。
1H-NMR(400MHz,DMSO-D6)δ:10.37(1H,br s),8.09(1H,d,J=7.5Hz),7.63(1H,d,J=7.5Hz),7.50(1H,td,J=7.6,1.0Hz),7.36(1H,td,J=7.6,1.0Hz),7.32(1H,br s),7.06(1H,s),6.91(1H,br d,J=2.0Hz).
(關於絕對立體組態)
標題化合物的絕對立體組態,使用下述製程(製程A-1至製程A-2及製程B-1)調製化合物(100A)及化合物(100B)
的光學活性管柱的HPLC分析而決定。
製程A-1
對4-氯-2-甲基-9H-茀-9-酮,實施三氟甲基化、與溴乙酸乙酯的反應、及加水分解,得[4-氯-2-甲基-9-(三氟甲基)-9H-茀-9-基氧基]乙酸。將此化合物使用(1R)-1-苯基乙基胺做光學分割,將所得的(1R)-1-苯基乙基胺的鹽(100AA)由單結晶X光構造解析,決定為(R)。
製程A-2
由化合物100AA經由酸處理等,合成(9R)-4-氯-2-甲基-9-(三氟甲基)-9H-茀-9-醇(化合物(100A))。
製程B-1
在製程10所得的4-氯-9-(三氟甲基)-9H-茀-2,9-二醇的2位羥基,由上述的方法變換為甲基,得4-氯-2-甲基-9-(三氟甲基)-9H-茀-9-醇(化合物(100B))。
(使用光學活性管柱的HPLC分析)
化合物(100)的鏡像異構物對(enantiomeric pairs),能以使用光學活性管柱的HPLC分離(HPLC分析條件3)。由化合物100A的HPLC分析結果,闡明(R)體的保持時間為18.4分,(S)體的保持時間為17.0分。由此HPLC條件,分析化合物(100A)及化合物(100B)的結果,表示保持時間一致。
上述化合物(100A)及化合物(100B)的製造時,可認為不對稱碳的立體配置不會發生變換。由此結果,確認在製程10所得的4-氯-9-(三氟甲基)-9H-茀-2,9-二醇是有(R)的絕對立體組態。
製程11
(9R)-4-氯-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-9-醇
在氮氣環境下,將(9R)-4-氯-9-(三氟甲基)-9H-茀-2,9-二醇(55.5g)溶解於N,N-二甲基甲醯胺(550ml),添加甲苯-4-磺酸3-羥基-3-甲基丁酯(49.6g)及碳酸鉀(39.5g),在油浴溫度70℃攪拌一夜。在反應混合液追加甲苯-4-磺酸3-羥基-3-甲基丁酯(4.0g)的N,N-二甲基甲醯胺(5ml)溶液,在同溫度再攪拌9.5小時。將反應混合液冰冷後,添加水(800ml),以乙酸乙酯(900ml)萃取。將所得的有機層以水(500ml)清洗3次,飽和食鹽水(500ml)1次。將所得的有機層以無水硫酸鈉乾燥,濾去不溶物,將濾液的溶媒餾去。將所得的殘渣以矽膠管柱層析法(洗出溶媒是使用己烷及乙酸乙酯的混合液。先以混合比3:1(己烷:乙酸乙酯)的混合液溶出。繼而以混合比2:1的混合液溶出,再以混合比3:2的混合液溶出。)精製,而得標題化合物(49.5g)。
1H-NMR(400MHz,DMSO-D6)δ:8.12(1H,d,J=7.6Hz),7.64(1H,d,J=7.4Hz),7.52(1H,td,J=7.6,0.9Hz),7.40-7.36(2H,m),7.15-7.13(2H,m),4.41(1H,s),4.16(2H,t,J=7.1Hz),1.85(2H,t,J=7.1Hz),1.17(6H,s).
製程12
2-{4-[(9R)-9-羥基-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙酸乙酯
在氬氣環境下,將(9R)-4-氯-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-9-醇(49.5g)溶解於甲苯(445ml),添加2-甲基-2-[4-(4,4,5,5-四甲基[1,3,2]二氧雜硼雜環戊烷-2-基)-1H-吡唑-1-基]丙酸乙酯(59.2g),水(149ml)、磷酸三鉀(54.3g)、乙酸鈀(2.9g)及2-二環己基膦基-2’,6’-二甲氧基聯苯(SPhos)(10.5g),在油浴溫度100℃攪拌3.5小時。將反應混合液冷卻至室溫,添加水(300ml)後,將不溶物以矽藻土濾去,以甲苯(150ml)及水(50ml)清洗。將所得的濾液合併分層。將所得的有機層以水(500ml)、飽和食鹽水(500ml)依序清洗。將所得的有機層以無水硫酸鈉乾燥,濾去不溶物,將濾液的溶媒餾去。將所得的殘渣以矽膠管柱層析法(溶出溶媒是使用己烷及乙酸乙酯的混合液。首先以混合比2:1(己烷:乙酸乙酯)的混合液溶出。繼而以混合比1:1、2:3的混合液溶出,再以混合比1:2的混合液溶出。)精製。再以矽膠管柱層析法(溶出溶媒是
使用己烷及丙酮的混合液。首先以混合比2:1(己烷:丙酮)的混合液溶出。繼而以混合比4:1、3:1、2:1、1:1、2:3的混合液依序溶出,再以混合比1:2的混合液溶出。)精製,得標題化合物(68.4g)。
1H-NMR(400MHz,DMSO-D6)δ:8.18(1H,s),7.65(1H,s),7.59-7.57(1H,m),7.25-7.21(4H,m),7.13(1H,br d,J=1.6Hz),6.84(1H,d,J=2.3Hz),4.38(1H,s),4.16-4.11(4H,m),1.86(2H,t,J=7.1Hz),1.84(6H,s),1.16(6H,s),1.13(3H,t,J=7.0Hz).
製程13
2-{4-[(9R)-9-羥基-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙酸
將2-{4-[(9R)-9-羥基-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙酸乙酯(68.4g)溶解於乙醇(256ml),添加4N氫氧化鈉水溶液(128ml),在室溫攪拌2.5小時。將反應混合物冰冰冷,滴入2N鹽酸(333ml)後,以乙酸乙酯(500ml)萃取。將所得的
有機層以水(400ml)2次、飽和食鹽水(400ml)依序清洗。將所得的有機層以無水硫酸鈉乾燥,濾去不溶物,將濾液的溶媒餾去,得標題化合物(70.0g)。
1H-NMR(400MHz,DMSO-D6)δ:13.06(1H,br s),8.14(1H,s),7.62(1H,s),7.57(1H,dd,J=6.4,0.6Hz),7.27-7.19(4H,m),7.12(1H,s),6.84(1H,d,J=2.3Hz),4.38(1H,s),4.14(2H,t,J=7.2Hz),1.85(2H,t,J=7.2Hz),1.82(3H,s),1.81(3H,s),1.16(6H,s).
製程14
2-{4-[(9R)-9-羥基-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙烷醯胺(化合物(2))
氮氣環境下,將2-{4-[(9R)-9-羥基-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙酸(66.7g)溶解於N,N-二甲基甲醯胺(480ml),添加1-羥基苯并三唑(HOBT)1水合物(27.6g)、1-乙酯-3-(3’-二甲基胺丙基)碳二亞胺(WSC)鹽酸鹽(34.6g)及28%氨水(24.5ml),在室溫攪拌一夜。將反應混合物冰冰冷,滴入水
(630ml)及2N鹽酸(330ml)後,以乙酸乙酯(800ml)萃取。將所得的水層以乙酸乙酯(500ml)再萃取。將所得的有機層合併,以水(500ml)2次,飽和碳酸氫鈉水(500ml),飽和食鹽水(500ml)依序清洗。將所得的有機層以無水硫酸鈉乾燥,濾去不溶物,將濾液的溶媒餾去,得標題化合物(60.0g)。
1H-NMR(400MHz,DMSO-D6)δ:8.08(1H,s),7.66(1H,s),7.58-7.56(1H,m),7.32-7.30(1H,m),7.25-7.22(4H,m),7.12(1H,br s),6.96(1H,br s),6.87(1H,d,J=2.3Hz),4.38(1H,s),4.14(2H,t,J=7.2Hz),1.85(2H,t,J=7.2Hz),1.78(3H,s),1.78(3H,s),1.17(6H,s).
製程15
2-{4-[(9R)-9-羥基-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙烷醯胺‧1水合物(化合物(2h))
將在前製程所得的2-{4-[(9R)-9-羥基-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙烷醯胺(化合物(2))(60.0g)溶解於乙酸乙酯(109ml),添加水(2ml),加熱至50℃。在此混合液依序滴
入己烷(226ml),己烷及乙酸乙酯的混合溶媒(己烷:乙酸乙酯2:1,150ml)後,回復到室溫攪拌一夜。濾取析出的固體,將過濾物以己烷及乙酸乙酯的混合溶媒(己烷:乙酸乙酯=2:1,180ml)清洗。將所得的固體在室溫減壓乾燥一夜,得標題化合物(52.2g,光學純度98.6%e.e.)。光學純度是以HPLC分析條件2決定。(R)體的保持時間11.3分,(S)體的保持時間13.9分。
比旋光度[α]D+37.9°(C=1.01 MeOH 25℃).
1H-NMR(400MHz,DMSO-D6)δ:8.08(1H,s),7.66(1H,s),7.58-7.56(1H,m),7.32-7.30(1H,m),7.25-7.22(4H,m),7.12(1H,br s),6.96(1H,br s),6.87(1H,d,J=2.3Hz),4.38(1H,s),4.14(2H,t,J=7.2Hz),1.85(2H,t,J=7.2Hz),1.78(3H,s),1.78(3H,s),1.17(6H,s).
(元素分析測定)
元素分析結果是,與化合物(2h)的理論值很一致。
計算值:C,59.88;H,5.80;N,8.06(1水合物的計算值)
實測值:C,59.86;H,5.74;N,8.00.
製程16
2-{4-[(9R)-9-羥基-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙烷醯胺(化合物(2))
在前製程所得的2-{4-[(9R)-9-羥基-2-(3-羥基-3-甲基丁氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2甲基丙烷醯胺‧1水合物(化合物(2h))(22.63g)添加甲苯(340ml)。在氮氣環境下,將反應混合物以迪安-斯塔克裝置在脫水中,在油浴溫度130℃攪拌2小時。將反應混合物在油浴溫度70℃再攪拌1小時半後,回復到室溫攪拌一夜。濾取析出的固體,將過濾物以甲苯(100ml)清洗。將所得的固體在室溫減壓乾燥3日後,再在60℃下減壓乾燥1日,得標題化合物(21.5g)。
1H-NMR(400MHz,DMSO-D6)δ:8.08(1H,s),7.66(1H,s),7.58-7.56(1H,m),7.32-7.30(1H,m),7.25-7.22(4H,m),7.12(1H,br s),6.96(1H,br s),6.87(1H,d,J=2.3Hz),4.38(1H,s),4.14(2H,t,J=7.2Hz),1.85(2H,t,J=7.2Hz),1.78(3H,s),1.78(3H,s),1.17(6H,s).
(元素分析測定)
元素分析結果是,與化合物(2)的理論值很一致。
計算值:C,62.02;H,5.61;N,8.35(無水合物的計算值)
實測值:C,62.17;H,5.60;N,8.47.
製程C-1
N-(4-三級-丁基苄基)辛可尼汀鎓溴化物的合成
將辛可尼汀(cinchonidine)(10.6g)溶解於四氫呋喃(200ml),添加4-三級-丁基苄基溴化物(10.1g)、四丁基銨碘化物(0.66g),在70℃攪拌一夜。將反應混合物冷卻至室溫後,濾取固體,以乙酸乙酯(50ml)清洗。將所得的固體減壓乾燥一夜,得標題化合物(18.5g)。
1H-NMR(400MHz,DMSO-D6)δ:8.99(1H,d,J=4.4Hz),8.27(1H,d,J=8.2Hz),8.11(1H,dd,J=8.5,1.0Hz),7.89-7.79(2H,m),7.78-7.71(1H,m),7.63(2H,d,J=8.4Hz),7.59(2H,t,J=8.4Hz),6.72(1H,d,J=4.2Hz),6.57-6.51(1H,br s),5.67(1H,ddd,J=17.0,10.4,6.4Hz),5.14(1H,d,J=17.2Hz),5.08(1H,d,J=12.6Hz),5.00-4.90(2H,m),4.30-4.18(1H,m),3.91(1H,t,J=8.7Hz),3.74-3.64(1H,m),3.35-3.18(2H,m),2.76-2.65(1H,m),2.18-1.94(3H,m),1.90-1.78(1H,m),1.40-1.22(1H,m),1.34(9H,s).
製程C-2
N-(4-三級-丁基苄基)辛可尼汀鎓4-甲氧基苯氧化物的合成
添加N-(4-三級-丁基苄基)辛可尼汀鎓溴化物(18.5g),Amberlyst(註冊商標)A26(苯乙烯,二乙烯苯基質的強鹼性離子交換樹脂)(18.5g)及甲醇(280ml),在室溫攪拌一夜。將不溶物以矽藻土濾去,以甲醇(100ml)清洗。在濾液添加4-甲氧基苯酚(4.8g),餾去溶媒。將殘渣以甲苯(100ml)共沸3次後,添加甲苯(20ml),繼而滴入二異丙醚(200ml),在室溫攪拌3小時。濾取析出的固體,以二異丙基醚(50ml)清洗後,在室溫減壓乾燥一夜而得標題化合物(21.8g)。
1H-NMR(400MHz,DMSO-D6)δ:8.91(1H,d,J=4.4Hz),8.17(1H,d,J=8.2Hz),8.07(1H,d,J=8.4Hz),7.89(1H,d,J=4.4Hz),7.79(1H,t,J=7.6Hz),7.64(1H,t,J=7.5Hz),7.57-7.52(5H,m),6.56-6.55(2H,m),6.43-6.42(3H,m),5.67-5.59(1H,m),5.28(1H,d,J=12.1Hz),5.12(1H,d,J=17.2Hz),4.92(1H,d,J=10.6Hz),4.84(1H,d,J=12.1Hz),4.65-4.53(1H,m),3.80(1H,t,J=8.8Hz),3.65-3.63(1H,m),3.57(3H,s),3.25(1H,t,J=11.6Hz),3.10-3.07(1H,m),2.67(1H,br s),2.07-2.02(2H,m),1.95(1H,br s),1.79-1.76(1H,br m),1.33(9H,s),1.16-1.11(1H,m).
製程D
甲苯-4-磺酸3-羥基-3-甲基丁酯的合成
在氮氣環境下,將3-甲基丁基-1,3-二醇(300g)溶解於吡啶(900ml),歷經2小時滴入4-甲基苯磺醯氯(500g)的甲苯(900ml)、乙腈(125ml)溶液。將反應混合物在室溫攪拌4小時後,添加甲苯(500ml)及水(1800ml),分層。將所得的有機層以硫酸水、水2次依序清洗。將所得的有機層的溶媒餾去後,以甲苯(500ml)共沸,得標題化合物(535g)。
1H-NMR(CDCl3)δ:7.81-7.76(2H,m),7.36-7.31(2H,m),4.20(2H,td,J=6.8,1.6Hz),2.44(3H,s),1.85(2H,td,J=6.8,1.6Hz),1.33(1H,s),1.21(6H,s).
實施例2
2-{4-[(9R)-9-羥基-2-(4-羥基-4-甲基苄氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙烷醯胺(化合物(3))的合成
製程1
4-[(9R)-4-氯-9-羥基-9-(三氟甲基)-9H-茀-2-基氧基]酪酸乙酯
將在實施例1製程10所得的(9R)-4-氯-9-(三氟甲基)-9H-茀-2,9-二醇(200mg)溶解於N,N-二甲基甲醯胺(2ml),添加碳酸鉀(185mg)及4-溴酪酸乙酯(105μl),在室溫攪拌7小時。在反應混合物添加水,以乙酸乙酯萃取2次。將所得的有機層,以水2次,飽和食鹽水依序清洗。將所得的有機層以無水硫酸鎂乾燥,濾去不溶物,將濾液的溶媒餾去。將所得的殘渣以矽膠管柱層析法(溶出溶媒是使用己烷及乙酸乙酯的混合液。首先以混合比5:1(己烷:乙酸乙酯)的混合液溶出。繼而以混合比3:1的混合液依序溶出,再以混合比2:1的混合液溶出。)精製,得標題化合物(197mg)。
1H-NMR(400MHz,CDCl3)δ:8.19(1H,d,J=7.7Hz),7.66(1H,d,J=7.7Hz),7.46(1H,td,J=7.6,1.0Hz),7.32(1H,td,J=7.6,1.0Hz),7.16(1H,br s),6.93(1H,d,J=2.1Hz),4.14(2H,q,J=7.1Hz),4.05(2H,t,J=7.1Hz),2.82(1H,s),2.50(2H,t,J=7.1Hz),2.15-2.06(2H,m),1.25(3H,t,J=7.1Hz).
製程2
(9R)-4-氯-2-(4-羥基-4-甲基苄氧基)-9-(三氟甲基)-9H-茀-9-醇
在氮氣環境下,將4-[(9R)-4-氯-9-羥基-9-(三氟甲基)-9H-茀-2-基氧基]酪酸乙酯(197mg)溶解於THF(2ml),在0℃滴入甲基鋰/二乙基醚溶液(1.07M,2.2ml)。將反應混合液在同溫度攪拌2小時後,添加水,以乙酸乙酯萃取2次。將所得的有機層以水2次,飽和食鹽水依序清洗。將所得的有機層以無水硫酸鎂乾燥,濾去不溶物,將濾液的溶媒餾去。將所得的殘渣以矽膠管柱層析法(溶出溶媒是使用己烷及乙酸乙酯的混合液。首先以混合比3:1(己烷:乙酸乙酯)的混合液溶出。繼而以混合比2:1的混合液溶出。)精製,得標題化合物(169mg)。
1H-NMR(400MHz,CDCl3)δ:8.19(1H,d,J=7.7Hz),7.66(1H,d,J=7.7Hz),7.47(1H,td,J=7.7,1.0Hz),7.32(1H,td,J=7.7,1.0Hz),7.17(1H,br s),6.93(1H,d,J=2.3Hz),4.02(2H,t,J=6.4Hz),2.82(1H,s),1.92-1.85(2H,m),1.65-1.62(2H,m),1.26(3H,s),1.25(3H,s).
製程3
2-{4-[(9R)-9-羥基-2-(4-羥基-4-甲基苄氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙酸乙酯
在氬氣環境下,將(9R)-4-氯-2-(4-羥基-4-甲基苄氧基)-9-(三氟甲基)-9H-茀-9-醇(169mg)溶解於1,4-二噁烷(1.5ml),添加2-甲基-2-[4-(4,4,5,5-四甲基[1,3,2]二氧雜硼雜環戊烷-2-基)-1H-吡唑-1-基]丙酸乙酯(194mg)、水(0.5ml)、磷酸三鉀(178mg)、乙酸鈀(9mg)、SPhos(33mg),在100℃攪拌4.5小時。將反應混合液冷卻至室溫後,添加水,以乙酸乙酯萃取2次。將所得的有機層,以水2次,飽和食鹽水依序清洗。將所得的有機層以無水硫酸鎂乾燥,濾去不溶物,將濾液的溶媒餾去。將所得的殘渣以氧化矽凝膠管柱層析法(溶出溶媒是使用混合比1:1(己烷:乙酸乙酯)的混合液溶出。)精製,得標題化合物(218mg)。
1H-NMR(400MHz,CDCl3)δ:7.69(1H,s),7.63-7.62(2H,m),7.21-7.19(4H,m),6.81(1H,d,J=2.3Hz),4.21(2H,q,J=7.1Hz),4.04(2H,t,J=6.3Hz),2.82(1H,s),1.92(3H,s),1.91(3H,s),1.89-1.88(2H,m),1.66-1.64(2H,m),1.26(6H,s),1.26-1.23(3H,m).
製程4
2-{4-[(9R)-9-羥基-2-(4-羥基-4-甲基苄氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙酸
將2-{4-[(9R)-9-羥基-2-(4-羥基-4-甲基苄氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙酸乙酯(218mg)溶解於乙醇(2.2ml),添加4N氫氧化鈉水溶液(320μl),在室溫攪拌一夜。將反應混合液以1N鹽酸中和,以乙酸乙酯萃取2次。將所得的有機層以水2次,飽和食鹽水依序清洗。將所得的有機層以無水硫酸鎂乾燥,濾去不溶物,將濾液的溶媒餾去,得標題化合物(179mg)。
1H-NMR(400MHz,CDCl3)δ:7.73(1H,s),7.68(1H,s),7.63-7.62(1H,m),7.23-7.09(4H,m),6.78(1H,d,J=2.6Hz),4.02(2H,t,J=6.3Hz),1.93(6H,s),1.89-1.86(2H,m),1.65-1.61(2H,m),1.25(6H,s).
製程5
2-{4-[(9R)-9-羥基-2-(4-羥基-4-甲基苄氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙烷醯胺(化合物(3))
在氮氣環境下,將2-{4-[(9R)-9-羥基-2-(4-羥基-4-甲基苄氧基)-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙酸(89mg)溶解於N,N-二甲基甲醯胺(1ml),添加氯化銨(28mg)、N,N-二異丙基乙基胺(148μl)及1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶-1-鎓3-氧化物三氟磷酸鹽(HATU)(99mg),在室溫攪拌一夜。在反應混合液添加水,以乙酸乙酯萃取2次。將所得的有機層,以食鹽水2次、飽和食鹽水1次依序清洗。將所得的有機層以無水硫酸鎂乾燥,濾去不溶物,將濾液的溶媒餾去。將所得的殘渣以矽膠薄層層析法(展開溶媒是使用三氯甲烷及甲醇的混合液。以混合比9:1(使用三氯甲烷:甲醇)的混合液。)精製,得標題化合物(48mg,光學純度96.9%e.e.)。光學純度是以HPLC分析條件2決定。(R)體的保持時間13.0分,(S)體的保持時間14.4分。
比旋光度[α]D+37.5°(C=1.04 MeOH 25℃).
1H-NMR(400MHz,DMSO-D6)δ:8.07(1H,s),7.66(1H,s),7.57-7.55(1H,m),7.34-7.31(1H,m),7.24-7.23(3H,m),7.18(1H,s),7.11(1H,br s),6.94(1H,br s),6.86(1H,d,J=2.3Hz),4.16(1H,s),4.03(2H,t,J=6.5Hz),1.80(3H,s),1.79
(3H,s),1.80-1.75(2H,m),1.51-1.47(2H,m),1.11(6H,s).
(化合物(3)的結晶的調製例)
在以上述實施例的步驟合成的化合物(3)(40mg)添加MeOH及水的混合液(容量比1:3(0.5mL))。繼而在此溶液添加化合物(2h)的結晶(0.5mg)而在室溫攪拌3日。濾取析出固體,得化合物(3)的結晶(41mg)。
(化合物(A)、(B)、(C)、及(D)的合成)
下述式表示的化合物(A)、化合物(B)、化合物(C)及化合物(D)是,依照國際公開第2010/041748號所述的製造方法,分別得到光學活性體。
化合物(A)
2-(4-{(9R)-9-羥基-2-[2-(3-羥基金剛烷-1-基)乙氧基]-9-(三氟甲基)-9H-茀-4-基}-1H-吡唑-1-基)乙醯胺
化合物(B)
(9R)-2-(2-羥基-2-甲基丙氧基)-4-(1-甲基-1H-吡唑-4-基)-9-(三氟甲基)-9H-茀-9-醇
化合物(C)
(9R)-4-[1-(2-羥基乙基)-1H-吡唑-4-基]-2-(2-羥基-2-甲基丙氧基)-9-(三氟甲基)-9H-茀-9-醇
化合物(D)
2-{4-[(9R)-2-氟-9-羥基-9-(三氟甲基)-9H-茀-4-基]-1H-吡唑-1-基}-2-甲基丙烷醯胺
本發明的製劑例而言,例如可列舉下述的製劑。但是,本發明並不受製劑例所限定。
製劑例1(膠囊的製造)
將1)、2)、3)及4)混合,裝填於明膠膠囊。
製劑例2(錠劑的製造)
將1),2)、3)的全量及30g的4)以水揑合,真空乾燥
後,實施整粒。將整粒末與14g的4)及1g的5)混合,以打錠機打錠。如此,得每1錠含有實施例1的化合物(化合物(2))10mg的錠劑1000錠。
試驗例1:在體外的(in vitro)PDHK活性抑制作用
PDHK活性抑制作用是在供試化合物存在下進行激酶反應,其後,測定殘留PDH活性而間接評估。
(PDHK1活性抑制作用)
人PDHK1(hPDHK1,基因庫(Genbank)寄存編號L42450.1)的情況時,將編碼該蛋白質的1.3kbp片段以聚合酶連鎖反應(PCR)由人肝cDNA單離。由PCR製作在N末端附加FLAG-Tag序列的修飾hPDHK1 cDNA,轉殖到載體(vector,pET17b-Norvagen公司)。將重組構築體在大腸菌(DH5 α-TOYOBO公司)內做形質轉換。鑑定重組轉殖,單離質體DNA,而做DNA序列分析。選擇具有預想核酸排列的1轉殖株做為表現作業用。
為了hPDHK1活性之表現,將含有修飾hPDHK1 cDNA的pET17b載體在大腸菌株BL21(DE3)(Norvagen公司)內做形質轉換。將大腸菌在30℃增殖到達到光學濃度0.6(600nmol/L)。由添加500μmol/L的異丙基-β-半乳哌喃糖苷(isopropyl-β-thiogalactopyranoside)誘發蛋白質表現。將大腸菌在30℃培養5小時後,離心分離而採集。將大腸菌漿再懸浮以高壓均質機(microfluidizer)破碎。將FLAG-Tag附加蛋白質以FLAG親和性凝膠(Sigma
公司)分離。
以20mmol/L N-(2-羥基乙酯)哌啶-N’-2-乙烷磺酸-氫氧化鈉(HEPES-NaOH)、500mmol/L氯化鈉、1%乙二醇、0.1%聚氧乙烯-聚氧丙烯崁段共聚物(PLURONIC F-68)(pH8.0)將凝膠清洗後,以20mmol/L HEPES-NaOH、100μg/mL FLAG PEPTIDE、500mmol/L氯化鈉、1%乙二醇、0.1% PLURONIC F-68(pH8.0)將結合蛋白質溶離。
將含有FLAG-Tag附加蛋白質的溶離部分匯合,對20mmol/L HEPES-NaOH、150mmol/L氯化鈉、0.5mmol/L乙二胺四乙酸(EDTA)、1%乙二醇、0.1% PLURONIC F-68(pH8.0)透析,在-80℃保存。用於分析時,將hPDHK1的酶濃度設定在表示超過抑制90%PDH活性的最低濃度。
在緩衝液(50mmol/L 3-(N-嗎啉基)丙烷磺酸(pH7.0)、20mmol/L磷酸氫二鉀、60mmol/L氯化鉀、2mmol/L氯化鎂、0.4mmol/L EDTA、0.2%PLURONIC F-68、2mmol/L二硫蘇糖醇(dithiothreitol))中,將0.05U/mL PDH(豬心臟PDH複合體,Sigma公司P7032)與1.0μg/mL hPDHK1混合,在4℃保持一夜而調製PDH/hPDHK1複合體。
將供試化合物以二甲基亞碸(DMSO)稀釋。在96孔半邊UV透過性微量盤(Corning公司3679)添加PDH/hPDHK1複合體20μL、供試化合物1.5μL及3.53μmol/L ATP(以緩衝液稀釋)8.5μL,在室溫進行PDHK反應45分鐘。在對照孔代替供試化合物而添加DMSO 1.5μL。又,
在用於測定PDH反應的最大速度的空白孔,代替供試化合物而添加DMSO1.5μL,除掉hPDHK1。
繼而,添加基質(5mmol/L丙酮酸鈉、5mmol/L CoA、12mmol/L NAD、5mmol/L硫胺焦磷酸,以緩衝液稀釋)10μL,在室溫保持90分鐘,而測定殘留PDH活性。
將PDH反應前後的340nm的吸光度以微量盤讀出器測定,而檢出由PDH反應所產生的NADH。供試化合物的hPDHK1抑制率(%)是由式[{(供試化合物的PDH活性-對照的PDH活性)/空白的PDH活性-對照的PDH活性)}×100]算出。IC50值是由hPDHK1抑制率50%上下2點的供試化合物濃度算出。
作為供試化合物而使用化合物(2)、化合物(2h)及化合物(3)時所得的結果示於下列第1表。
(PDHK2活性抑制作用)
人PDHK2(hPDHK2,基因庫(Genbank)寄存編號BC040478.1)的情況時,hPDHK2 cDNA轉殖(PRECEivEr-M01/PDK2-GeneCopoeia公司)為基礎,製作以PCR在N末端附加FLAG-Tag序列的修飾hPDHK2 cDNA,在載體(PET17b-Norvagen公司)轉殖。將重組構築體在大腸菌(DH5 α-TOYOBO公司)內形質轉換。鑑定重組轉殖,將質體DNA單離,而做DNA序列分析。選擇具有預想核酸排列的1轉殖株做為表現作業用。
為了hPDHK2活性之表現,將含有修飾hPDHK2 cDNA的PET17b載體在大腸菌株BL21(DE3)
(Norvagen公司)內做形質轉換。將大腸菌在30℃增殖到達到光學濃度0.6(600nmol/L)。由添加500μmol/L的異丙基-β-半乳哌喃糖苷誘發蛋白質表現。將大腸菌在30℃培養5小時後,離心分離而採集。將大腸菌漿再懸液以高壓均質機破碎。將FLAG-Tag附加蛋白質以FLAG親和性凝膠分離。
以20mmol/L HEPES-NaOH,500mmol/L氯化鈉、1%乙二醇、0.1% PLURONIC F-68(pH8.0)將凝膠清洗後,以20mmol/L HEPES-NaOH,100μg/mL FLAG PEPTIDE、500mmol/L氯化鈉、1%乙二醇、0.1% PLURONIC F-68(pH8.0)將結合蛋白質溶離。將含有FLAG-Tag附加蛋白質的溶離部分匯合,對20mmol/L HEPES-NaOH、150mmol/L氯化鈉、0.5mmol/L乙二胺四乙酸(EDTA)、1%乙二醇、0.1% PLURONIC F-68(pH8.0)透析,在-80℃保存。用於分析時,將hPDHK2的酶濃度設定在表示超過抑制90%PDH活性的最低濃度。
在緩衝液(50mmol/L 3-(N-嗎啉基)丙烷磺酸(pH7.0)、20mmol/L磷酸氫二鉀、60mmol/L氯化鉀、2mmol/L氯化鎂、0.4mmol/L EDTA、0.2%PLURONIC F-68、2mmol/L二硫蘇糖醇)中,將0.05U/mL PDH及0.8μg/mL hPDHK2混合,在4℃保持一夜而調製PDH/hPDHK2複合體。將供試化合物以二甲基亞碸(DMSO)稀釋。在96孔半邊UV透過性微量盤添加PDH/hPDHK2複合體20μL、供試化合物1.5μL及3.53μmol/L ATP(以緩衝液稀釋)8.5μL,在室溫進行
PDHK反應45分鐘。在對照孔代替供試化合物而添加DMSO 1.5μL。又,在用於測定PDH反應的最大速度的空白孔,則代替供試化合物而添加DMSO1.5μL,除掉hPDHK2。繼而,添加基質(5mmol/L丙酮酸鈉、5mmol/L CoA、12mmol/L NAD、5mmol/L硫胺焦磷酸,以緩衝液稀釋)10μL,在室溫保溫90分鐘,而測定殘留PDH活性。將PDH反應前後的340nm的吸光度以微量盤讀出器測定,而檢出由PDH反應所產生的NADH。供試化合物的hPDHK2抑制率(%)是由式[{(供試化合物的PDH活性-對照的PDH活性)/空白的PDH活性-對照的PDH活性)}×100]算出。IC50值是由hPDHK2抑制率50%上下2點的供試化合物濃度算出。
作為供試化合物而使用化合物(2)、化合物(2h)、化合物(3)、化合物(A)、化合物(B)、化合物(C)、及化合物(D)時所得的結果示於下示第1表。
試驗例2:擬體內(Ex vivo)PDH活化試驗
(試驗方法)
將在投藥供試化合物的動物的組織的PDH活化作用加以評估。經由對碘硝基四唑紫(p-iodonitrotetrazolium violet,INT)共軛系檢出NADH生成而測定PDH活性。
正常的雄性Sprague-Dawley大鼠隨機分成媒劑群及供試化合物群。對大鼠經口投藥媒劑(0.5%甲基纖維素水溶液,5mL/kg)或供試化合物。投藥後,5或20小時後,將戊巴比妥鈉60mg/kg在腹腔內投藥而麻醉,摘出肝切片及副睾丸上脂肪組織。
在摘出肝切片迅速添加濕重量的9倍容積的冰冰冷均質緩衝液(0.25mol/L蔗糖、5mmol/L三(羥甲基)胺基甲烷鹽酸鹽(pH7.5)、2mmol/L EDTA),用POLYTRON均質機均質化。將均質液以600×g、4℃離心10分鐘而回收上清液。將上清液1mL以16000×g、4℃離心10分鐘而得沉澱。將該沉澱以均質緩衝液1mL再懸浮,同樣離心而清洗沉澱。將該沉澱作為肝粒線體部分,以液態氮冷凍後,在-80℃保存。
在摘出脂肪組織迅速添加濕重量的3倍容積的冰冰冷均質緩衝液,使用POLYTRON均質機均質化。將均質液以600×g、4℃離心10分鐘而回收上清液。將上清液全量以16000×g、4℃離心10分鐘而得沉澱。將該沉澱以均質緩衝液1mL再懸浮,同樣離心而清洗沉澱。將該沉澱作為脂肪組織粒線體部分,以液態氮冷凍後,在-80℃保存。
將粒線體部分解凍,以試樣緩衝液(0.25mol/L蔗糖、20mmol/L三(羥基甲基)胺基甲烷鹽酸鹽(pH7.5)、50mmol/L氯化鉀、1mL/L 4-(1,1,3,3-四甲基丁基)苯基-聚乙二醇(TRITON X-100))懸浮。PDH活性是測定活性型PDH活性(PDHa活性)及總PDH活性(PDHt活性)2種。為了測定PDHa活性,將粒線體懸液及活化緩衝液(0.25mol/L蔗糖、20mmol/L三(羥基甲基)胺基甲烷鹽酸鹽(pH7.5)、50mmol/L氯化鉀、1mL/L TRITON X-100、4mmol/L氯化鈣、40mmol/L氯化鎂、10mmol/L二氯乙酸鈉)等量混合,在37℃保溫10分鐘。以試樣緩衝液稀釋粒線體懸液40μL作為活性測定用及空白測定用而分別添加於96孔微量盤。添加180μL的反應混合液(0.056mmol/L磷酸鉀緩衝液(pH7.5)、5.6mmol/L DL-肉鹼(carnitine)、2.8mmol/L NAD、0.22mmol/L硫胺焦磷酸、0.11mmol/L CoA、1.1mL/L TRITON X-100、1.1mmol/L氯化鎂、1.1g/L牛血清白蛋白、0.67mmol/L INT、7.2μmol/L吩嗪硫酸甲酯(phenazine methosulfate)、28mmol/L草醯胺酸鈉)。活性測定時將50mmol/L丙酮酸鈉,空白測定時將精製水,各分別添加20μL,在室溫、遮光下保溫。將最終電子受體的INT的還原所引起的在500至750nm的吸光度以微量盤讀出器,測定該吸光度隨時間的變化。由活性測定孔的吸光度變化減去空白孔的吸光度變化,而算出PDH活性。及對PDHt活性的PDHa活性的百分率,作為PDH活化的指標。
將使用供試化合物及化合物(2h)、化合物(3)、化合物
(A)、化合物(B)、化合物(C)及化合物(D)時所得的結果示於第2表、第1圖(肝)及第2圖(脂肪組織)。又,將使用化合物(2)時所得的結果示於第3表。
試驗例3:在ZDF大鼠反復投藥供試化合物對HbA1c的效果
(試驗方法)
餵食精製飼料(5.9% fat diet,東洋酵母工業)的2型糖尿病模式Zucker Diabetic Fatty大鼠(雄,7週齡,日本Charles River)分成在血糖值、血漿中胰島素濃度、HbA1c及體重上無差異的媒劑群及供試化合物群。對大鼠將供試化合物(1mg/kg/5mL)在暗期3小時前1日1次反復經口投藥。對媒劑群的大鼠則將0.5%甲基纖維素水溶液同樣經口投藥。投藥第14日由尾靜脈採血,測定HbA1c(%)。統計上的顯著性是以Dunnett法檢定,將顯著水準P<0.05視為顯著。
作為供試化合物而使用化合物(2)及化合物(3)時所得的結果示於下面的第4表。
試驗例4:hERG(人乙醚阿哥哥關聯基因(Human Ether-a-go-go Related Gene))全細胞膜箝制(whole patch clamp)試驗
(試驗方法)
使用人乙醚阿哥哥關聯基因(hERG)導入HEK293細胞(Cytomix Limited),以全細胞膜箝制法檢討對hERG電流的影響。hERG導入HEK293細胞是使用CO2恆溫箱(BNA-111,Tabai Espec股份有限公司),以溫度37℃、二氧化碳氣體濃度5%、飽和濕度的設定條件下繼代培養。培養容器是使用Collagen Type I Coated 75cm2燒瓶(4123-010,旭Techno Glass股份有限公司)及Collagen Type I Coated 35mm培養皿(4000-010,旭Techno Glass股份有限公司)。培養液是使用添加10%FCS(胎牛血清,BioWest公司)1%MEM非必需胺基酸溶液(NEAA,Invitrogen股份有限公司)的E-MEM(Eeagle最低必需培養液(Earle’s Salts,股
份有限公司日研生物醫學研究所))。在此添加用於選別hERG基因表現細胞的遺傳黴素(geneticin)成為400μg/mL濃度。作為測定用的細胞是在hERG電流測定的4至7日前,在35mm培養皿播種3×104個導入hERG的HEK293細胞。在製作用於測定的培養皿內,則使用在上述培養液沒有添加遺傳黴素(Invitorogen股份有限公司)的培養液。
各化合物的評估最高濃度,設定為在標準細胞外液(NaCl:140mmol/L、KCl:2.5mmol/L、MgCl2:2mmol/L、CaCl2:2mmol/L、HEPES:10mmol/L、葡萄糖:10mmol/L(以Tris-base調整為pH7.4))中沒有析出的最高濃度。施用方法是由靠近於細胞(約2mm)的先端直徑約0.25mm的Y字形管將各施用液噴出而施用於細胞。噴出速度設定為約0.4mL/min。
實驗是在室溫,位相差顯微鏡下實施。將播種細胞的35mm培養皿設置於測定裝置上,對細胞由Y字形管常時給予標準細胞外液。在測定用玻璃電極內裝填細胞內液(葡萄糖酸鉀:130mmol/L、KCl:20mmol/L,MgCl2:1mmol/L、ATP-Mg:5mmol/L、EGTA:3.5mmol/L、HEPES:10mmol/L(以Tris-base調整為pH7.2))。對細胞施用慣用的全細胞膜箝制法,將保持電位設定為-80mV。在電位固定下將全細胞電流以箝制用放大器(AXOPATCH-200B,Axon Instruments,INC.)放大,使用數據取得解析軟體(PCLAMP 9.2,Axon Instruments,INC.)將數據輸入於電腦(IMC-P642400,Intermedical Co.,LTD.)。
hERG電流的測定是以下述的2階段實施。這裏,在該2階段都施加Command Potential(保持電位-80mV,Prepulse+20mV,1.5秒,Test-pulse-50mV,1.5秒)而引發hERG電流。
製程(1):將上述Command Potential以0.1Hz施加2分鐘。
製程(2):在上述Command Potential實施pCLAMP 9.2的P/3相減,除掉漏(leak)電流,重複該操作3次而將其平均作為hERG電流。
繼製程(1)實施製程(2)(約3分鐘),將在製程(2)的方法所得的hERG電流的Test-Pulse的尾(Tail)電流的最大值作為hERG電流值。以後,到實驗終了為止重複交替實施(1)、(2)的操作,測定hERG電流值。
將穩定後的hERG電流值紀錄3次(約10分鐘)後,將標準細胞外液在一瞬間交換為各施用液。施用液灌流中也同樣將hERG電流值測定3次(約10分鐘),在第3次的測定所得的電流值作為施用液灌流後的hERG電流值。
數據是在各細胞變換為施用液灌流前的約10分鐘的紀錄3次的hERG電流值的平均值(Before值)作為100%的相對值。將此對2細胞測定,算出其平均值作為相對電流(Relative Current)(%)。
Relative current(%)=100×A÷B
A:施用液灌流後的hERG電流值
B:施用液灌流前的約10分鐘的紀錄3次的hERG電
流值的平均值(Before值)
又,將對DMSO群的抑制率以下述式算出。
抑制率(%)=100-(C÷D)×100
C:各供試化合物群的Relative current(%)的平均值
D:DMSO群的Relative current(%)的平均值
作為供試化合物而使用化合物(2)、化合物(3)、化合物(A)、化合物(B)、化合物(C)及化合物(D)時所得的結果示於第5表。
試驗例5:在肝微粒體中的代謝安定性試驗
(試驗方法)
將人的肝微粒體(Xenotach公司製,H0620,終濃度(稀釋後),0.2mg Protein/mL)懸浮於100mM磷酸鉀緩衝液(pH 7.4,含β-菸鹼醯胺腺嘌呤二核苷酸磷酸:1.3mM、D-葡萄糖-6-磷酸鹽:3.3mM、氯化鎂:3.3mM、葡萄糖-6-磷酸鹽脫氫酶:0.45U/mL),再與溶解於MeCN/DMSO(95/5)的供試化合物(終濃度5μM)混合。將混合液在37℃保溫10分鐘及60分鐘後,添加含甲酸(終濃度0.1%)的乙腈,離心分離上清液中的供試化合物(未變化體)以高速液體層析儀/質譜分析儀(LC/MS)(Waters公司製,LC:Acquity UPLC,MS:SQ檢出器或TQ檢出器)測定。由所得的測定值算出殘留率(%)。
作為供試化合物而使用化合物(2)、化合物(3)、化合物(A)、化合物(B)、化合物(C)及化合物(D)所得的結果示於第6表。
本發明化合物或其製藥上可容許的鹽,因有PDHK抑制活性,有用於作為糖尿病(1型糖尿病,2型糖尿病等)、胰島素抵抗性症候群、代謝症候群、高血糖症、高乳酸血症、糖尿病併發症(糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症、白內障等)、心臟衰竭(急性心臟衰竭、慢性心臟衰竭)、心肌病、心肌缺血病、心肌梗塞、狹心症、異常血脂症、動脈粥樣硬化症、末梢動脈疾病、間歇性跛行、慢性阻塞性肺病、腦缺血病、腦中風、粒線體病、粒線體腦肌病、癌、肺高血壓症、或阿滋海默症的預防或治療用的醫藥的有效成分。
由於本案的圖為供試化合物的活性結果圖,並非本案的代表圖。故本案無指定代表圖。
Claims (15)
- 一種式[I]表示的化合物或其製藥上可容許的鹽:
- 一種下式表示的化合物:
- 如申請專利範圍第2項所述的化合物,其係式[II]表示者:
- 如申請專利範圍第2項所述的化合物,其係式[IIh]表示 者:
- 一種式[III]表示的化合物:
- 一種醫藥組成物,係含有如申請專利範圍第1項至第5項中任一項所述的化合物或其製藥上可容許的鹽,及製藥上可容許的載體。
- 一種PDHK抑制劑,係含有如申請專利範圍第1項至第5項中任一項所述的化合物或其製藥上可容許的鹽。
- 一種PDHK1抑制劑,係含有如申請專利範圍第1項至第5項中任一項所述的化合物或其製藥上可容許的鹽。
- 一種PDHK2抑制劑,係含有如申請專利範圍第1項至第5項中任一項所述的化合物或其製藥上可容許的鹽。
- 一種血糖降低劑,係含有如申請專利範圍第1項至第5項中任一項所述的化合物或其製藥上可容許的鹽。
- 一種乳酸降低劑,係含有如申請專利範圍第1項至第5項中任一項所述的化合物或其製藥上可容許的鹽。
- 一種糖尿病,胰島素抵抗性症候群,代謝症候群,高血糖症,高乳酸血症,糖尿病併發症,心臟衰竭,心肌病,心肌缺血病,心肌梗塞,狹心症,異常血脂症,動脈粥樣硬化症,末梢動脈疾病,間歇性跛行,慢性阻塞性肺病(Chronic Obstructive Pulmonary Disease,COPD),腦缺血病,腦中風,粒線體病,粒線體腦肌病,癌或肺高血壓症的預防或治療劑,係含有如申請專利範圍第1項至第5項中任一項所述的化合物或其製藥上可容許的鹽。
- 如申請專利第12項所述的預防或治療劑,其中糖尿病是1型糖尿病或2型糖尿病。
- 如申請專利第12項所述的預防或治療劑,其中糖尿病併發症是由糖尿病性神經障礙、糖尿病性視網膜症、糖尿病性腎症及白內障所成的群選出。
- 如申請專利第12項所述的預防或治療劑,其中心臟衰竭是急性心臟衰竭或慢性心臟衰竭。
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