TWI438197B - 六氫吡啶/六氫吡衍生物(四) - Google Patents
六氫吡啶/六氫吡衍生物(四) Download PDFInfo
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- TWI438197B TWI438197B TW097121020A TW97121020A TWI438197B TW I438197 B TWI438197 B TW I438197B TW 097121020 A TW097121020 A TW 097121020A TW 97121020 A TW97121020 A TW 97121020A TW I438197 B TWI438197 B TW I438197B
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- Prior art keywords
- group
- alkyl
- alkyloxy
- aryl
- optionally substituted
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Description
本發明有關DGAT抑制劑,尤其是DGAT1抑制劑,用以製造供預防或治療因為一或多種飽食激素(尤其是GLP-1)濃度升高所致之疾病使用之藥劑的用途。
本發明亦有關具有DGAT抑制活性-尤其是DGAT1抑制活性-的六氫吡啶/六氫吡衍生物。本發明另外有關其製備方法及含彼之醫藥組成物。本發明亦關於該等化合物用以製造供預防或治療由DGAT(尤其是DGAT1)所中介之疾病使用的藥劑的之途。
三酸甘油酯表示儲存於真核細胞中的主要能量形式。三酸甘油酯代謝障礙或不平衡與肥胖、胰島素抵抗症候群及第II型糖尿病、非酒精性脂肪肝疾病及冠心症之發病機制及風險增高有關(參見Lewis等人,Endocrine Reviews
(2002)23:201及Malloy and Kane,Adv
.Intern
.Med
.(2001)47:11 1)。此外,血中三酸甘油酯過高經常為癌症療法之負面結果(參見Bast等人,Cancer Medicine
,5th Ed.,(2000)B.C.Decker,Hamilton,Ontario,CA)。
合成三酸甘油酯之關鍵酶係為醯基CoA:二醯基甘油醯基轉移酶或DGAT。DGAT係為廣泛表現於哺乳類組織中且於內質網催化1,2-二醯基甘油(DAG)及脂肪醯基CoA結合形成三酸甘油酯(TG)的微粒體酶(評論於
Chen and Farese,Trends Cardiovasc
.Med
.(2000)10:188 and Farese等人,Curr
.Opin
.Lipidol
.(2000)11:229)中。原先認為DGAT專一性地控制三酸甘油酯合成之兩個主要路徑-甘油磷酸酯及單醯基甘油路徑-的二醯基甘油醯化成三酸甘油酯之最終步驟的催化。因為三酸甘油酯被視為是生存所必需,故認為其合成係經由單一機制發生,大體上未探究經由抑制DGAT之活性來抑制三酸甘油酯合成。
編碼鼠DGAT1及相關人類同源物ARGP1(人類DGAT1)及ARGP2(人類ACAT2)的基因現在已被無性繁殖且進行特性分析(Cases等人,Pro
.c Nat
.l Acad
.Sci
.(1998)95:13018;Oelkers等人,J
.Biol
.Chem
.(1998)273:26765)。已使用鼠DGAT1之基因來產生DGAT基因剔除小鼠,以更充分地說明DGAT基因之功能。
出乎意料的是無法表現功能性DGAT1酶的小鼠(DGAT1-/-小鼠)存活且仍可合成三酸甘油酯,顯示造成三酸甘油酯合成的多重催化機制(Smith等人,Nature Genetics(2000)25:87)。亦已鑑定出其他催化三酸甘油酯合成之酶,例如DGAT2及二醯基甘油醯基轉移酶(Cases等人,J
.Biol
.Chem
.(2001)276:38870)。小鼠之基因剔除研究顯示DGAT2在哺乳類三酸甘油酯合成中扮演著必要之角色且係存活所需。缺乏DGAT2之小鼠脂肪過少且在出生後迅即死亡,此點可由能量代謝用受質明顯減少及皮膚滲透屏蔽功能不良顯現(Farese等人,J
.Biol
.Chem
.(2004)279:11767)。
有意思的是,DGAT1-/-小鼠抵抗由飲食誘發之肥胖且保持清瘦。即使以高脂肪飲食(21%脂肪)飼養,DGAT1-/-小鼠仍保持等同於以正常飲食(4%脂肪)飼養之小鼠的體重,且具有較低之體內三酸甘油酯總濃度。DGAT1-/-小鼠之抗肥胖性並非因為熱量攝取降低,而是增加能量消耗且降低對胰島素及纖瘦素之抵抗的結果(Smith等人,Nature Genetics(2000)25:87;Chen and Farese,Trends Cardiovasc
.Med
.(2000)10:188;及Chen等人,J
.Clin
.Invest
.(2002)109:1049)。此外,DGAT1-/-小鼠具有較低之三酸甘油酯吸收率(Buhman等人,J
.Biol
.Chem
.(2002)277:25474)。除了改善之三酸甘油酯代謝之外,DGAT1-/-小鼠亦具有改良之葡萄糖代謝,在攝入葡萄糖後,具有較野生型小鼠低之葡萄糖及胰島素濃度(Chen and Farese,Trends Cardiovasc
.Med
.(2000)10:188)。
多種酶對催化自二醯基甘油合成三酸甘油酯具有貢獻的發現極具意義,因為表示有機會調節此生化反應之一催化機制,而在最低副作用下對個體達到治療結果。發現抑制二醯基甘油轉化成三酸甘油酯-例如明確地說是抑制DGAT1之活性-的化合物可用於降低三酸甘油酯之體內濃度及吸收,以治療性地對抗於肥胖、胰島素抵抗症候群及顯性第II型糖尿病、充血性心臟衰竭及動脈粥樣硬化中由三酸甘油酯之異常代謝所致及因癌症治療
的結果之致病作用。
因為全世界社會上肥胖、第II型糖尿病、心臟病及癌症愈來愈普及,故迫切地需要發展有效地治療及預防此等疾病之新穎療法。因此有興趣發展可強效且專一性地抑制DGAT(尤其是DGAT1)之催化活性的化合物。
現在無意中發現本發明化合物具有DGAT抑制活性,尤其是DGAT1抑制活性,因此可用於預防或治療與DGAT有關或由DGAT中介之疾病,諸如例如肥胖、第II型糖尿病、心臟病及癌症。本發明化合物與先前技術化合物之結構、醫藥活性、醫藥功效及/或藥理性質相異。
亦於無意中發現DGAT抑制劑可用以提高一或多種飽食激素之濃度,尤其是升糖激素樣肽-1(GLP-1),因此提高DGAT抑制劑(尤其是DGAT1抑制劑)之濃度,亦可用於預防或治療可因高濃度飽食激素,尤其是GLP-1而產生療效之疾病。升糖激素樣肽1(GLP-1)為腸道激素,通常於血糖過高期間刺激胰島素分泌、抑制升糖激素分泌、刺激胰島素(原)生物合成且減緩胃排空及酸分泌。GLP-1係於攝取脂肪及蛋白質之後自小腸及大腸之L細胞分泌。在所有適應症中,特別建議GLP-1為處理第2型非胰島素依賴型糖尿病及相關代謝病症(諸如肥胖)的可能療劑。
因為此項發現,因此可使用小分子(與大分子諸如蛋白質或蛋白質樣化合物,例如GLP-1類似物比較)治療可因高GLP-1濃度而產生療效之疾病。
WO 2006/034441揭示雜環衍生物及其作為硬脂醯CoA脫飽和酶抑制劑(SCD-1抑制劑)之用途。
WO 2006/086445係有關SCD-1抑制劑及另一種治療負面之體重增加的藥物之組合療法。
WO 2006/004200及JP2007131584係有關具有DGAT抑制活性之脲及胺基衍生物。
WO 2004/047755係有關具有DGAT抑制活性之稠合雙環含氮雜環類。
WO2005/072740係有關具有DGAT抑制活性之化合物的食慾抑制作用。
本發明有關DGAT抑制劑之用途,其係用於製造用以預防或治療,尤其是用以治療可因高濃度之一或多種飽食激素(尤其是GLP-1)而產生療效之疾病的藥劑。
本發明另外有關一種下式之化合物
包括其任何立體化學異構形式,其中A係表示CH或N;虛線在A表示碳原子時係表示視情況存在之鍵;X係表示-O-C(=O)-;-C(=O)-C(=O)-;-NRx
-C(=O)-;
-Z-C(=O)-;-Z-NRx
-C(=O)-;-C(=O)-Z-;-NRx
-C(=O)-Z-;-C(=S)-;-NRx
-C(=S)-;-Z-C(=S)-;-Z-NRx
-C(=S)-;-C(=S)-Z-;-NRx
-C(=S)-Z-;Z係表示選自以下基團之二價基團:C1-6
烷二基、C2-6
烯二基或C2-6
炔二基;其中該C1-6
烷二基、C2-6
烯二基或C2-6
炔二基各可視情況經羥基或胺基所取代;且其中連接於C1-6
烷二基中同一碳原子之兩氫原子可視情況由C1-6
烷二基置換;Rx
係表示氫或C1-4
烷基;Y係表示-C(=O)-NRx
-或-NRx
-C(=O)-;R1
係表示金剛烷基;C3-6
環烷基;芳基1
或Het1
;R2
係表示C3-6
環烷基、苯基、萘基、2,3-二氫-1,4-苯并二氧雜環己烯基、1,3-苯并二氧雜環戊烯基、2,3-二氫苯并呋喃基或含有1或2個N原子之6員芳族雜環,其中該C3-6
環烷基、苯基、萘基、2,3-二氫-1,4-苯并二氧雜環己烯基、1,3-苯并二氧雜環戊烯基或含有1或2個N原子之6員芳族雜環可視情況經至少一個取代基所取代,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;羧基;鹵基;視情況經羥基取代之C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基-C1-6
烷基氧基;C1-6
烷基氧基羰基,其中C1-6
烷基可
視情況經芳基取代;氰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;C1-4
烷基羰基胺基;-S(=O)p
-C1-4
烷基;R4
R3
N-C(=O)-;R4
R3
N-C1-6
烷基;C3-6
環烷基;C3-6
環烷基C1-4
烷基;C3-6
環烷基-C(=O)-;芳基;芳基氧基;芳基C1-4
烷基;芳基-C(=O)-C1-4
烷基;芳基-C(=O)-;Het;HetC1-4
烷基;Het-C(=O)-C1-4
烷基;Het-C(=O)-;Het-O-;R3
係表示氫;視情況經羥基或C1-4
烷基氧基取代之C1-4
烷基;R6
R5
N-C1-4
烷基;C1-4
烷基氧基;Het;Het-C1-4
烷基;芳基;R6
R5
N-C(=O)-C1-4
烷基;R4
係表示氫或C1-4
烷基;R5
係表示氫;C1-4
烷基;C1-4
烷基羰基;R6
係表示氫或C1-4
烷基;或R5
及R6
可與其所連接之氮一起形成可另外含有一或多個各獨立選自O,S,S(=O)p
或N之雜原子的飽和單環5,6或7-員雜環;且該雜環可視情況經C1-4
烷基取代;R7
係表示氫、鹵基、C1-4
烷基、經羥基取代之C1-4
烷基;芳基係表示苯基或經至少一個取代基所取代之苯基,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;羧基;鹵基;視情況經以下基團所取代之C1-6
烷基:C1-4
烷基氧基、胺基或單-或二(C1-4
烷基)胺基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷
基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基氧基羰基;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;-S(=O)p
-C1-4
烷基;芳基1
係表示苯基、萘基或茀基;該苯基、萘基或茀基各視情況經至少一個取代基所取代,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;酮基;羧基;鹵基;視情況經以下基團所取代之C1-6
烷基:羧基、C1-4
烷基氧基羰基或芳基-C(=O)-;視情況經芳基或芳基-C(=O)-所取代之羥基C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基所取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基氧基-羰基,其中C1-6
烷基可視情況經芳基取代;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-6
烷基)胺基;R4
R3
N-C1-6
烷基;C3-6
環烷基-NRx
-;芳基-NRx
-;Het-NRx
-;C3-6
環烷基C1-4
烷基-NRx
-;芳基C1-4
烷基-NRx
-;HetC1-4
烷基-NRx
-;-S(=O)p
-C1-4
烷基;C3-6
環烷基;C3-6
環烷基C1-4
烷基;C3-6
環烷基-C(=O)-;芳基;芳基氧基;芳基C1-4
烷基;芳基-C(=O)-C1-4
烷基;芳基-C(=O)-;Het;HetC1-4
烷基;Het-C(=O)-C1-4
烷基;Het-C(=O)-;Het-O-;
Het係表示含有至少一個各獨立選自O、S、S(=O)p
或N之雜原子的單環非芳族或芳族雜環;或含有至少一個各獨立選自O、S、S(=O)p
或N之雜原子的雙環或參環非芳族或芳族雜環;該單環雜環或該雙環或參環雜環視情況經至少一個取代基所取代,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;酮基;羧基;鹵基;視情況經以下基團所取代之C1-6
烷基:C1-4
烷基氧基、胺基或單-或二(C1-4
烷基)胺基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基氧基羰基;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;-S(=O)p
-C1-4
烷基;Het1
係表示含有至少一個各獨立選自O、S、S(=O)p
或N之雜原子的單環非芳族或芳族雜環;或含有至少一個各獨立選自O、S、S(=O)p
或N之雜原子的雙環或參環非芳族或芳族雜環;該單環雜環或該雙環或參環雜環視情況經至少一個取代基所取代,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;酮基;羧基;鹵基;視情況經以下基團所取代之C1-6
烷基:芳基-C(=O)-;視情況經芳基或芳基-C(=O)-所取代之羥基C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;
多鹵基C1-6
烷基氧基;C1-6
烷基氧基-羰基,其中C1-6
烷基可視情況經芳基取代;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-6
烷基)胺基;R4
R3
N-C1-6
烷基C3-6
環烷基-NRx
-;芳基-NRx
-;Het-NRx
-;C3-6
環烷基C1-4
烷基-NRx
-;芳基C1-4
烷基-NRx
-;HetC1-4
烷基-NRx
-;-S(=O)p
-C1-4
烷基;C3-6
環烷基;C3-6
環烷基C1-4
烷基;C3-6
環烷基-C(=O)-;芳基;芳基氧基;芳基C1-4
烷基;芳基-C(=O)-C1-4
烷基;芳基-C(=O)-;Het;HetC1-4
烷基;Het-C(=O)-C1-4
烷基;Het-C(=O)-;Het-O-;p係表示1或2;其限制條件為不包括以下化合物
其N-氧化物、其醫藥上可接受之鹽或溶劑合物。
本發明另外有關式(I"')化合物之用途,其係用於製造供預防或治療由DGAT中介之疾病所使用的藥劑,尤其
本發明有關式(I"')化合物之用途,其係用於製造供預防或治療可因抑制DGAT而得到療效之疾病所使用的藥劑,尤其用於治療可因抑制DGAT(尤其是DGAT1)而得到療效之疾病,其中該式(I"')化合物係為下式化合物
包括其任何立體化學異構形式,其中A係表示CH或N;當A係表示碳原子時,虛線係表示視情況存在之鍵結;X係表示-O-C(=O)-;-C(=O)-C(=O)-;-NRx
-C(=O)-;-Z-C(=O)-;-Z-NRx
-C(=O)-;-C(=O)-Z-;-NRx
-C(=O)-Z-;-C(=S)-;-S(=O)p-;-NRx
-C(=S)-;-Z-C(=S)-;-Z-NRx
-C(=S)-;-C(=S)-Z-;-NRx
-C(=S)-Z-;Z係表示選自以下之二價基團:C1-6
烷二基、C2-6
烯二基或C2-6
炔二基;其中該C1-6
烷二基、C2-6
烯二基或C2-6
炔二基各可視情況經羥基或胺基所取代;且其中連接於C1-6
烷二基中同一碳原子的兩氫原子可視情況由C1-6
烷二基置換;Rx
係表示氫或C1-4
烷基;Y係表示-C(=O)-NRx
-或-NRx
-C(=O)-;R1
係表示金剛烷基;C3-6
環烷基;芳基1
或Het1
;R2
係表示氫、C1-6
烷基、C2-6
烯基、C3-6
環烷基、苯基、
萘基、2,3-二氫-1,4-苯并二氧雜環己烯基、1,3-苯并二氧雜環戊烯基、2,3-二氫苯并呋喃基或含有1或2個N原子之6員芳族雜環,其中該C3-6
環烷基、苯基、萘基、2,3-二氫-1,4-苯并二氧雜環己烯基、1,3-苯并二氧雜環戊烯基或含有1或2個N原子之6員芳族雜環可視情況經至少一個取代基所取代,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;羧基;鹵基;視情況經羥基取代之C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基-C1-6
烷基氧基;C1-6
烷基氧基羰基,其中C1-6
烷基可視情況經芳基取代;氰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;C1-4
烷基羰基胺基;-S(=O)p
-C1-4
烷基;R4
R3
N-C(=O)-;R4
R3
N-C1-6
烷基;C3-6
環烷基;C3-6
環烷基C1-4
烷基;C3-6
環烷基-C(=O)-;芳基;芳基氧基;芳基C1-4
烷基;芳基-C(=O)-C1-4
烷基;芳基-C(=O)-;Het;HetC1-4
烷基;Het-C(=O)-C1-4
烷基;Het-C(=O)-;Het-O-;R3
係表示氫;視情況經羥基或C1-4
烷基氧基取代之C1-4
烷基;R6
R5
N-C1-4
烷基;C1-4
烷基氧基;Het;Het-C1-4
烷基;芳基;R6
R5
N-C(=O)-C1-4
烷基;R4
係表示氫或C1-4
烷基;R5
係表示氫;C1-4
烷基;C1-4
烷基羰基;R6
係表示氫或C1-4
烷基;或
R5
及R6
可與其所連接之氮一起形成可另外含有一或多個各獨立選自O,S,S(=O)p
或N之雜原子的飽和單環5,6或7-員雜環;且該雜環可視情況經C1-4
烷基取代;R7
係表示氫、鹵基、C1-4
烷基、經羥基取代之C1-4
烷基;芳基係表示苯基或經至少一個取代基所取代之苯基,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;羧基;鹵基;視情況經以下基團所取代之C1-6
烷基:C1-4
烷基氧基、胺基或單-或二(C1-4
烷基)胺基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基氧基羰基;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;-S(=O)p
-C1-4
烷基;芳基1
係表示苯基、萘基或茀基;該苯基、萘基或茀基各視情況經至少一個取代基所取代,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;酮基;羧基;鹵基;視情況經以下基團所取代之C1-6
烷基:羧基、C1-4
烷基氧基羰基或芳基-C(=O)-;視情況經芳基或芳基-C(=O)-所取代之羥基C1-6
烷基;多鹵基C1-6
烷基;
視情況經C1-4
烷基氧基所取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基氧基-羰基,其中C1-6
烷基可視情況經芳基取代;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-6
烷基)胺基;R4
R3
N-C1-6
烷基;C3-6
環烷基-NRx
-;芳基-NRx
-;Het-NRx
-;C3-6
環烷基C1-4
烷基-NRx
-;芳基C1-4
烷基-NRx
-;HetC1-4
烷基-NRx
-;-S(=O)p
-C1-4
烷基;C3-6
環烷基;C3-6
環烷基C1-4
烷基;C3-6
環烷基-C(=O)-;芳基;芳基氧基;芳基C1-4
烷基;芳基-C(=O)-C1-4
烷基;芳基-C(=O)-;Het;HetC1-4
烷基;Het-C(=O)-C1-4
烷基;Het-C(=O)-;Het-O-;Het係表示含有至少一個各獨立選自O、S、S(=O)p
或N之雜原子的單環非芳族或芳族雜環;或含有至少一個各獨立選自O、S、S(=O)p
或N之雜原子的雙環或參環非芳族或芳族雜環;該單環雜環或該雙環或參環雜環視情況經至少一個取代基所取代,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;酮基;羧基;鹵基;視情況經以下基團所取代之C1-6
烷基:C1-4
烷基氧基、胺基或單-或二(C1-4
烷基)胺基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基氧基羰
基;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;-S(=O)p
-C1-4
烷基;Het1
係表示含有至少一個各獨立選自O、S、S(=O)p
或N之雜原子的單環非芳族或芳族雜環;或含有至少一個各獨立選自O、S、S(=O)p
或N之雜原子的雙環或參環非芳族或芳族雜環;該單環雜環或該雙環或參環雜環視情況經至少一個取代基所取代,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;酮基;羧基;鹵基;視情況經以下基團所取代之C1-6
烷基:芳基-C(=O)-;視情況經芳基或芳基-C(=O)-所取代之羥基C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基氧基-羰基,其中C1-6
烷基可視情況經芳基取代;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-6
烷基)胺基;R4
R3
N-C1-6
烷基;C3-6
環烷基-NRx
-;芳基-NRx
-;Het-NRx
-;C3-6
環烷基C1-4
烷基-NRx
-;芳基C1-4
烷基-NRx
-;HetC1-4
烷基-NRx
-;-S(=O)p
-C1-4
烷基;C3-6
環烷基;C3-6
環烷基C1-4
烷基;C3-6
環烷基-C(=O)-;芳基;芳基氧基;芳基C1-4
烷基;芳基-C(=O)-C1-4
烷基;芳基-C(=O)-;Het;HetC1-4
烷基;Het-C(=O)-C1-4
烷基;
Het-C(=O)-;Het-O-;p係表示1或2;其N-氧化物、其醫藥上可接受之鹽或溶劑合物。
本發明亦有關式(I)化合物之用途,其係用於製造供預防或治療由DGAT中介之疾病所使用的藥劑,尤其本發明有關式(I)化合物之用途,其係用於製造供預防或治療可因抑制DGAT而得到療效之疾病所使用的藥劑,尤其用於治療可因抑制DGAT(尤其是DGAT1)而得到療效之疾病。
本發明亦有關式(I)或(I"')化合物之用途,其係用於製造供預防或治療可因提高一或多種飽食激素(尤其是GLP-1)之濃度而得到療效的疾病所使用之藥劑,尤其本發明有關式(I)或(I"')化合物之用途,其係用於製造供治療可因提高GLP-1之濃度而得到療效的疾病所使用之藥劑。
前文或後文所使用之C0-3
烷基作為基團或基團之一部分時係定義具有0(此係表示直接鍵結)至3個碳原子之直鏈或分支鏈飽和烴基,諸如甲基、乙基、丙基、1-甲基乙基;C1-2
烷基作為基團或基團之一部分時係定義具有1或2個碳原子之直鏈或分支鏈飽和烴基諸如甲基、乙基;C1-4
烷基作為基團或基團之一部分時係定義具有1至4個碳原子之直鏈或分支鏈飽和烴基,諸如甲基、乙基、丙基、1-甲基乙基、丁基;C1-5
烷基作為基團或基團之一部分時係定義具有1至5個碳原子之直鏈或
分支鏈飽和烴基,諸如C1-4
烷基所定義之基團及戊基、2-甲基丁基及諸如此類者;C1-6
烷基作為基團或基團之一部分時係定義具有1至6個碳原子之直鏈或分支鏈飽和烴基,諸如C1-4
烷基及C1-5
烷基所定義之基團及己基、2-甲基戊基及諸如此類者;C1-12
烷基作為基團或基團之一部分時係定義具有1至12個碳原子之直鏈或分支鏈飽和烴基,諸如C1-6
烷基所定義之基團及庚基、2-甲基庚基及諸如此類者;C1-6
烷二基係定義具有1至6個碳原子之直鏈或分支鏈飽和二價烴基,諸如亞甲基、1,2-乙二基或1,2-亞乙基、1,3-丙二基或1,3-亞丙基、1,4-丁二基或1,4-亞丁基、1,5-戊二基及諸如此類者;C2-4
烯基作為基團或基團之一部分時係定義具有2至4個碳原子且具有雙鍵之直鏈或分支鏈烴基,諸如乙烯基、丙烯基、丁烯基及諸如此類者;C2-6
烯基作為基團或基團之一部分時係定義具有2至6個碳原子且具有雙鍵之直鏈或分支鏈烴基,諸如C2-4
烯基所定義之基團及戊烯基、己烯基、3-甲基丁烯基及諸如此類者;C2-6
烯二基係定義直鏈或分支鏈雙價烴基具有2至6個碳原子且具有雙鍵諸如1,2-乙烯二基、1,3-丙烯二基、1,4-丁烯二基、1,5-戊烯二基及諸如此類者;C2-6
炔二基作為基團或基團之一部分時係定義具有2至6個碳原子且具有參鍵之直鏈或分支鏈雙價烴基,諸如1,2-乙炔二基、1,3-丙炔二基、1,4-丁炔二基、1,5-戊炔二基及諸如此類者;
C3-6
環烷基係為環丙基、環丁基、環戊基及環己基之總稱。
術語鹵基係為氟、氯、溴及碘之總稱。前文或後文所使用之多鹵基C1-6
烷基在作為基團或基團之一部分時係定義為經一或多個(諸如例如2、3、4或5個)鹵原子所取代之C1-6
烷基,例如經一或多個氟原子取代之甲基,例如二氟甲基或三氟甲基、1,1-二氟-乙基、1,1-二氟-2,2,2-三氟-乙基及諸如此類者。若有一個以上之鹵原子連接於多鹵基C1-6
烷基之定義內的C1-6
烷基,則其可相同或相異。
如前文所使用,術語(=O)在連接於碳原子時形成羰基部分,連接於硫原子時為亞碸部分,而當兩個該術語連接於硫原子時,則為磺醯基部分。酮基係表示=O。
前文所定義之基團Het或Het1
可為視情況經取代之含有至少一個雜原子之單環非芳族或芳族雜環,尤其是含有1、2或3個雜原子,各獨立選自O、S、S(=O)p
或N;或視情況經取代之含有至少一個雜原子的雙環或參環非芳族或芳族雜環,尤其是含有1、2、3、4或5雜原子,其各獨立選自O、S、S(=O)p
或N。該等未經取代單環性雜環之實例係包含但不限於非芳族(完全飽和或部分飽和)或芳族4-、5-、6-或7-員單環性雜環,諸如例如吖丁啶基、四氫呋喃基、吡咯啶基、二氧戊環基、咪唑啶基、噻唑烷基、四氫噻吩基、二氫唑基、異噻唑烷基、異唑啶基、二唑啶基、三唑啶基、噻二唑啶基、
吡唑啶基、六氫吡啶基、六氫嘧啶基、六氫吡基、二烷基、嗎褔啉基、二噻烷基、硫代嗎褔啉基、六氫吡基、三噻烷基、六氫二氮呯基、吡咯啉基、咪唑啉基、吡唑啉基、吡咯基、呋喃基、噻吩基、咪唑基、唑基、異唑基、噻唑基、異噻唑基、吡唑基、三唑基、噻二唑基、二唑基、四唑基、吡啶基、嘧啶基、吡基、嗒基、三基、哌喃基及諸如此類者。該等未經取代雙環或參環雜環之實例係包含但不限於非芳族(完全飽和或部分飽和)或芳族8-至17-員雙環或參環雜環,諸如例如十氫喹啉基、八氫吲哚基、2,3-二氫苯并呋喃基、1,3-苯并二氧雜環戊烯基、2,3-二氫-1,4-苯并二氧雜環己烯基、吲哚啉基、苯并呋喃基、異苯并呋喃基、苯并噻吩基、異苯并噻吩基、吲哚基、吲哚基、異吲哚基、苯并唑基、苯并咪唑基、吲唑基、苯并異唑基、苯并異噻唑基、苯并吡唑基、苯并二唑基、苯并噻二唑基、苯并三唑基、嘌呤基、喹啉基、異喹啉基、噌啉基、喹基、酞基、喹啉基、喹唑啉基、啶基、喋啶基、苯并哌喃基、吡咯并吡啶基、噻吩并吡啶基、呋喃并吡啶基、異噻唑并吡啶基、噻唑并吡啶基、異唑并吡啶基、唑并吡啶基、吡唑并吡啶基、咪唑并吡啶基、吡咯并吡基、噻吩并吡基、呋喃并吡基、異噻唑并吡基、噻唑并吡基、異唑并吡基、唑并吡基、吡唑并吡基、咪唑并吡基、吡咯并嘧啶基、噻吩并嘧啶基、呋喃并嘧啶基、異噻唑并嘧啶基、噻唑并嘧啶基、
異唑并嘧啶基、唑并嘧啶基、吡唑并嘧啶基、咪唑并嘧啶基、吡咯并嗒基、噻吩并嗒基、呋喃并嗒基、異噻唑并嗒基、噻唑并嗒基、異唑并嗒基、唑并嗒基、吡唑并嗒基、咪唑并嗒基、二唑并吡啶基、噻二唑并吡啶基、三唑并吡啶基、二唑并吡基、噻二唑并吡基、三唑并吡基、二唑并嘧啶基、噻二唑并嘧啶基、三唑并嘧啶基、二唑并嗒基、噻二唑并嗒基、三唑并嗒基、咪唑并唑基、咪唑并噻唑基、咪唑并咪唑基、咪唑并吡唑基;異唑并三基、異噻唑并三基、吡唑并三基、唑并三基、噻唑并三基、咪唑并三基、二唑并三基、噻二唑并三基、三唑并三基、咔唑基、吖啶基、吩基、吩噻基、吩基及諸如此類者。Het雜環之視情況存在的取代基有羥基;酮基;羧基;鹵基;視情況經C1-4
烷基氧基、胺基或單-或二(C1-4
烷基)胺基所取代之C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基-氧基羰基;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;-S(=O)p
-C1-4
烷基。Het1
取代基之視情況存在的取代基有羥基;酮基;羧基;鹵基;視情況經芳基-C(=O)-所取代之C1-6
烷基;視情況經芳基或芳基-C(=O)-所取代之羥基C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基
C1-6
烷基氧基;C1-6
烷基氧基-羰基,其中C1-6
烷基可視情況經芳基所取代;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-6
烷基)胺基;R5
R4
N-C1-6
烷基;C3-6
環烷基-NRx
-;芳基-NRx
-;Het-NRx
-;C3-6
環烷基C1-4
烷基-NRx
-;芳基C1-4
烷基-NRx
-;HetC1-4
烷基-NRx
-;-S(=O)p
-C1-4
烷基;C3-6
環烷基;C3-6
環烷基C1-4
烷基;C3-6
環烷基-C(=O)-;芳基;芳基氧基;芳基C1-4
烷基;芳基-C(=O)-C1-4
烷基;芳基-C(=O)-;Het;HetC1-4
烷基;Het-C(=O)-C1-4
烷基;Het-C(=O)-;Het-O-。
R2
定義中含有1或2個N原子之6員芳族雜環的實例有吡啶基、嘧啶基、嗒基、吡基。
當任何變數於任何組份(例如芳基,Het)中出現一次以上時,每一個定義各係獨立。
術語Het或Het1
係包括雜環之所有可能異構形式,例如,吡咯基包含1H
-吡咯基及2H
-吡咯基。
例如術語芳基、芳基1
、Het、Het1
或R3
所涵蓋之碳環或雜環若未另外描述,則可視需要經由任一環碳或雜原子連接於式(I)分子之其餘部分。因此,例如當雜環係為咪唑基時,其可為1-咪唑基、2-咪唑基、4-咪唑基及諸如此類者,或碳環係為萘基時,其可為1-萘基、2-萘基及諸如此類者。
自取代基繪入環系統內之線係表示該鍵結可連接於任何適當之環原子。
當X定義為例如-NRx
-C(=O)-時,意指NRx
之氮係鍵結於R2
取代基,且C(=O)之碳原子係鍵結於環之氮。因此X定義中雙價基團之左邊部分係鍵結於R2
取代基,且X定義中雙價基團之右邊部分係鍵結於環部分
某些式(I)化合物亦可以其互變異構形式存在。該等形式雖未明確表示於前述式中,但要包括於本發明範圍內。
前文或後文中不論何時使用取代基可各自獨立選自許多定義之列示,諸如例如R4
及R5
,皆包括所有化學上可能之組合。
就治療用途而言,式(I)化合物之鹽係為其中相對離子係醫藥上可接受之鹽。然而,非醫藥上可接受之酸及鹼的鹽亦發現可使用於例如製備或純化醫藥上可接受之化合物。所有鹽類,不論是否為醫藥上可接受,皆包括於本發明範圍內。
前文或後文所提及之醫藥上可接受之鹽係包含式(I)化合物可形成之治療活性無毒性酸加成鹽形式。後者可適宜地藉適當之酸處理鹼形式而製得,該酸係諸如無機酸,例如氫鹵酸,例如鹽酸、氫溴酸及諸如此類者;硫酸;硝酸;磷酸及諸如此類者;或有機酸,例如乙酸、丙酸、羥基乙酸、2-羥基丙酸、2-酮基丙酸、草酸、丙
二酸、琥珀酸、順丁烯二酸、反丁烯二酸、蘋果酸、酒石酸、2-羥基-1,2,3-丙烷三羧酸、甲烷磺酸、乙烷磺酸、苯磺酸、4-甲基苯磺酸、環己烷磺酸、2-羥基苄酸、4-胺基-2-羥基苄酸及諸如此類酸。反之,該鹽形式可藉以鹼處理轉化成游離鹼形式。
含有酸性質子之式(I)化合物可藉以適當之有機及無機鹼處理而轉化成其治療活性無毒性金屬或胺加成鹽形式。前文或後文所提及之醫藥上可接受之鹽亦包含式(I)化合物可形成之治療活性無毒性金屬或胺加成鹽形式(鹼加成鹽形式)。適當之鹼加成鹽形式係包含例如銨鹽,鹼金屬及鹼土金屬鹽,例如鋰、鈉、鉀、鎂、鈣鹽及諸如此類者,與有機鹼例如一級、二級及三級脂族及芳族胺諸如甲基胺、乙基胺、丙基胺、異丙基胺、四種丁基胺異構物、二甲基胺、二乙基胺、二乙醇胺、二丙基胺、二異丙基胺、二正丁基胺、吡咯啶、六氫吡啶、嗎褔啉、三甲基胺、三乙基胺、三丙基胺、啶、吡啶、喹啉及異喹啉、苄星、N
-甲基-D-葡糖胺、2-胺基-2-(羥基甲基)-1,3-丙烷二醇之鹽、海巴胺鹽及與胺基酸,諸如例如精胺酸、離胺酸及諸如此類者之鹽。
反之,鹽形式可藉酸處理轉化成游離酸形式。
術語鹽亦包含式(I)化合物可藉由式(I)化合物之鹼性氮與適當之季鹼化劑(諸如例如視情況經取代之C1-6
烷基鹵、芳基鹵、C1-6
烷基-羰基鹵、芳基羰基鹵或芳基C1-6
烷基鹵,例如甲基碘或苄基碘)之間的反應形成之四級銨
鹽(四級胺)。亦可使用其他具有良好脫離基之反應物,諸如例如三氟甲烷磺酸C1-6
烷基酯、甲烷磺酸C1-6
烷基酯及對-甲苯磺酸C1-6
烷基酯。四級胺具有帶正電之氮。醫藥上可接受之相對離子係包括氯、溴、碘、三氟乙酸根、乙酸根、三氟甲磺酸根、硫酸根、磺酸根。所選擇之相對離子可使用離子交換樹脂導入。
術語溶劑合物係包含式(I)化合物可形成之水合物及溶劑加成形式及其鹽。該等形式之實例有例如水合物、醇合物及諸如此類者。
本發明化合物之N-氧化物形式係包含其中一或數個三級氮原子氧化成所謂之N-氧化物的式(I)化合物。
應瞭解某些式(I)化合物及其N-氧化物、鹽及溶劑合物可含有一或多個對掌性中心且存在為立體化學異構形式。
前文或後文所使用之術語「立體異構形式」係定義式(I)化合物及其N-氧化物、鹽或溶劑合物可具有之所有可能立體異構形式。除非另有提及或指示,否則化合物之化學名稱係表示所有可能立體化學異構形式之混合物,該混合物含有具有基本分子結構之所有非鏡像異構物及鏡像異構物及各個別異構形式及其N-氧化物、鹽或溶劑合物,其實質上不含,即連同低於10%,較佳低於5%,尤其是低於2%且最佳低於1%之其他異構物。因此,當式(I)化合物係例如描述為(E)時,此意指該化合物實質上不含(Z)異構物。尤其,立體原中心可具有R-或
S-組態;位於雙價環狀(部分)飽和基團上之取代基可具有順式-或反式-組態。涵蓋雙鍵之化合物可於該雙鍵上具有E(逆)或Z(同)-立體化學。術語順、反、R、S、E及Z係熟習此技術者所熟知。式(I)化合物之立體化學異構形式顯然要涵蓋於本發明範圍內。
根據CAS-命名規則,當分子中存在具有已知絕對組態之兩個立體原中心時,R
或S
描述符號係屬於(基於Cahn-Ingold-Prelog順序規則)最低編號之對掌性中心,參考中心。第二個立體原中心之組態係使用相對描述符號[R * ,R *
]或[R * ,S *
]表示,其中第一個R *
始終描述為參考中心,且[R * ,R *
]表示具有相同對掌性之中心,而[R *
,S *
]表示具有不同對掌性之中心。例如,若分子中具有最低碼號之對掌性中心具有S
組態且第二個中心係為R
,則立體描述符號係表示為S
-[R * ,S *
]。若使用「α
」及「β
」:則具有最低環編碼之環系統中不對稱碳原子上最優先之位置絕對始終位於由該環系統所決定之平均平面的「α
」位置。環系統中另一不對稱碳原子上最優先取代基相對於位在參考原子上之最優先取代基的位置之位置若位於由環系統決定之平均平面的同側,則稱為「α
」,若位於由環系統決定之平均平面的另一側,則稱為「β
」。
式(I)化合物可合成為鏡像異構物之消旋混合物形式,該等鏡像異構物可依技術界已知之離析方法彼此分離。消旋之式(I)化合物可藉著與適當之對掌性酸反應而轉化成對應之非鏡像異構鹽形式。該等非鏡像異構鹽形
式隨之例如藉由選擇或分步結晶分離,並藉鹼自該等鹽釋出鏡像異構物。分離式(I)化合物之鏡像異構形式的備擇方式包括使用對掌性靜態相之液相層析。該等純立體化學異構物形式亦可自適當之起始物質的對應純立體化學異構形式衍生,其限制條件為反應係立體專一性地進行。較佳係若期望專一性立體異構物,則藉立體專一性製備方法來合成該化合物。此等方法較佳係採用鏡像異構純起始物質。
下文不論何處使用術語「式(I)化合物」或其任一子集,皆亦包括其N-氧化物形式、其鹽、其立體化學異構形式及其溶劑合物。特別重要的是立體化學純式(I)化合物。
本發明第一具體實施態樣係為具有下式之式(I)化合物
包括其任何立體化學異構形式,其中A係表示CH或N;當A係表示碳原子時,虛線係表示視情況存在之鍵結;X係表示-NRx
-C(=O)-;-Z-C(=O)-;-Z-NRx
-C(=O)-;-C(=O)-Z-;-NRx
-C(=O)-Z-;-C(=S)-;-NRx
-C(=S)-;-Z-C(=S)-;-Z-NRx
-C(=S)-;-C(=S)-Z-;-NRx
-C(=S)-Z-;Z係表示選自以下之二價基團:C1-6
烷二基、C2-6
烯二基
或C2-6
炔二基;其中該C1-6
烷二基、C2-6
烯二基或C2-6
炔二基各可視情況經羥基所取代;Rx
係表示氫或C1-4
烷基;Y係表示-C(=O)-NRx
-或-NRx
-C(=O)-;R1
係表示C3-6
環烷基;芳基1
或Het1
;R2
係表示C3-6
環烷基、苯基、萘基、2,3-二氫-1,4-苯并二氧雜環己烯基、1,3-苯并二氧雜環戊烯基,其中該C3-6
環烷基、苯基、萘基、2,3-二氫-1,4-苯并二氧雜環己烯基、1,3-苯并二氧雜環戊烯基可視情況經至少一個取代基所取代,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;羧基;鹵基;視情況經羥基取代之C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基-C1-6
烷基氧基;C1-6
烷基氧基羰基,其中C1-6
烷基可視情況經芳基取代;氰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;-S(=O)p
-C1-4
烷基;R4
R3
N-C(=O)-;R4
R3
N-C1-6
烷基;C3-6
環烷基;C3-6
環烷基C1-4
烷基;C3-6
環烷基-C(=O)-;芳基;芳基氧基;芳基C1-4
烷基;芳基-C(=O)-;Het;HetC1-4
烷基;Het-C(=O)-;Het-O-;R3
係表示氫;視情況經羥基或C1-4
烷基氧基取代之C1-4
烷基;R6
R5
N-C1-4
烷基;C1-4
烷基氧基;Het;芳基;R6
R5
N-C(=O)-C1-4
烷基;R4
係表示氫或C1-4
烷基;
R5
係表示氫;C1-4
烷基;C1-4
烷基羰基;R6
係表示氫或C1-4
烷基;或R5
及R6
可與其所連接之氮一起形成飽和單環5、6或7-員雜環,其可另外含有一或多個選自O、S、S(=O)p
或N之雜原子;且該雜環可視情況經C1-4
烷基取代;芳基係表示苯基或經至少一個取代基所取代之苯基,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;羧基;鹵基;視情況經以下基團所取代之C1-6
烷基:C1-4
烷基氧基、胺基或單-或二(C1-4
烷基)胺基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基氧基羰基;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;-S(=O)p
-C1-4
烷基;芳基1
係表示苯基、萘基或茀基;該苯基、萘基或茀基各視情況經至少一個取代基所取代,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;酮基;羧基;鹵基;視情況經以下基團所取代之C1-6
烷基:芳基-C(=O)-;視情況經芳基或芳基-C(=O)-所取代之羥基C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基氧基-羰基,其中C1-6
烷基可視情況經芳基取代;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-6
烷基)胺基;C3-6
環烷基-NRx
-;芳基-NRx
-;Het-NRx
-;C3-6
環烷基C1-4
烷基-NRx
-;芳基C1-4
烷基-NRx
-;HetC1-4
烷基-NRx
-;-S(=O)p
-C1-4
烷基;C3-6
環烷基;C3-6
環烷基C1-4
烷基;C3-6
環烷基-C(=O)-;芳基;芳基氧基;芳基C1-4
烷基;芳基-C(=O)-;Het;HetC1-4
烷基;Het-C(=O)-;Het-O-;Het係表示含有至少一個選自O、S、S(=O)p
或N之雜原子的單環非芳族或芳族雜環;或含有至少一個選自O、S、S(=O)p
或N之雜原子的雙環或參環非芳族或芳族雜環;該單環雜環或該雙環或參環雜環視情況經至少一個取代基所取代,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;酮基;羧基;鹵基;視情況經以下基團所取代之C1-6
烷基:C1-4
烷基氧基、胺基或單-或二(C1-4
烷基)胺基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基-氧基羰基;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;
-S(=O)p
-C1-4
烷基;Het1
係表示含有至少一個選自O、S、S(=O)p
或N之雜原子的單環非芳族或芳族雜環;或含有至少一個選自O、S、S(=O)p
或N之雜原子的雙環或參環非芳族或芳族雜環;該單環雜環或該雙環或參環雜環視情況經至少一個取代基所取代,尤其是一、二、三、四或五個取代基,每一取代基各獨立選自羥基;酮基;羧基;鹵基;視情況經以下基團所取代之C1-6
烷基:芳基-C(=O)-;視情況經芳基或芳基-C(=O)-所取代之羥基C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基氧基-羰基,其中C1-6
烷基可視情況經芳基取代;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-6
烷基)胺基;C3-6
環烷基-NRx
-;芳基-NRx
-;Het-NRx
-;C3-6
環烷基C1-4
烷基-NRx
-;芳基C1-4
烷基-NRx
-;HetC1-4
烷基-NRx
-;-S(=O)p
-C1-4
烷基;C3-6
環烷基;C3-6
環烷基C1-4
烷基;C3-6
環烷基-C(=O)-;芳基;芳基氧基;芳基C1-4
烷基;芳基-C(=O)-;Het;HetC1-4
烷基;Het-C(=O)-;Het-O-;p係表示1或2;其限制條件為不包括以下化合物
其N-氧化物、其醫藥上可接受之鹽或溶劑合物。
本發明第二具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中X係表示-O-C(=O)-;-NRx
-C(=O)-;-Z-C(=O)-;-Z-NRx
-C(=O)-;-C(=O)-Z-;-NRx
-C(=O)-Z-;-NRx
-C(=S)-;尤其是其中X係表示-NRx
-C(=O)-;-Z-C(=O)-;-Z-NRx
-C(=O)-;-C(=O)-Z-;-NRx
-C(=O)-Z-;-NRx
-C(=S)-;特別是其中X係表示-NRx
-C(=O)-;-Z-C(=O)-;-Z-NRx
-C(=O)-;更特別是X係表示-NRx
-C(=O)-或-Z-NRx
-C(=O)-;或X係表示-NRx
-C(=O)-或-Z-C(=O)-。或X係表示-O-C(=O)-;-C(=O)-C(=O)-;-NRx
-C(=O)-;-Z-C(=O)-;-Z-NRx
-C(=O)-;-C(=S)-;-NRx
-C(=S)-;-Z-C(=S)-;-Z-NRx
-C(=S)-。
本發明第三具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中A係表示N。
本發明第四具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中A係表
示CH,尤其是其中A係表示CH且虛線不表示鍵結。
本發明第五具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中R1
係表示芳基1
或Het1
;尤其是視情況經取代之苯基、視情況經取代之茀基或含有至少一個各獨立選自O、S、S(=O)p
或N之雜原子(尤其S或N)的視情況經取代單環非芳族或芳族雜環;特別是苯基或茀基,該苯基或茀基視情況經一或兩個取代基所取代,該取代基係獨立選自酮基、羧基、鹵基、視情況經羧基或C1-4
烷基氧基羰基所取代之C1-6
烷基、C1-6
烷基氧基、C1-6
烷基氧基羰基、胺基、芳基、Het或多鹵基C1-6
烷基;或4-、5-或6-員非芳族或芳族雜環,諸如例如吖丁啶基、噻唑烷基、噻唑基、吡咯啶基、六氫吡啶基,該5-或6-員雜環視情況經一或兩個取代基所取代,該取代基係獨立選自羥基、酮基、C1-6
烷基、C1-6
烷基氧基羰基、芳基或Het。
本發明第六具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中R2
係表示C3-6
環烷基、苯基、2,3-二氫-1,4-苯并二氧雜環己烯基或含有1或2個N原子之6員芳族雜環,諸如例如吡啶基,其中該苯基或雜環係視情況經一至四個取代基所取代,較佳係每一取代基各獨立選自鹵基、C1-6
烷基、C1-6
烷基氧基、C1-6
烷基硫基、C1-6
烷基氧基羰基、硝基、胺基、單-或二(C1-4
烷基)胺基、芳基氧基、R4
R3
N-C1-6
烷基、Het-C(=O)-C1-4
烷基。
本發明第七具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中該式(I)化合物係為下式(I')之化合物
其中R3a
及R3a
各獨立地表示氫;羥基;羧基;鹵基;C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基氧基羰基;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;-S(=O)p
-C1-4
烷基;且其中R3c
係表示氫;羥基;羧基;鹵基;C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基-C1-6
烷基氧基;C1-6
烷基氧基羰基,其中C1-6
烷基可視情況經芳基取代;氰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;-S(=O)p
-C1-4
烷基;R4
R3
N-C(=O)-;R4
R3
N-C1-6
烷基;C3-6
環烷基;芳基;芳基氧基;芳基C1-4
烷基;芳基-C(=O)-C1-4
烷基;芳基-C(=O)-;Het;HetC1-4
烷基;Het-C(=O)-C1-4
烷基;Het-C(=O)-;Het-O-。
本發明第八具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中該式(I)
化合物係為下式(I")之化合物
其中R3a
及R3a
各獨立地表示氫;羥基;羧基;鹵基;C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基C1-6
烷基氧基;C1-6
烷基氧基羰基;氰基;胺基羰基;單-或二(C1-4
烷基)胺基羰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;-S(=O)p
-C1-4
烷基;且其中R3c
係表示氫;羥基;羧基;鹵基;C1-6
烷基;多鹵基C1-6
烷基;視情況經C1-4
烷基氧基取代之C1-6
烷基氧基;C1-6
烷基硫基;多鹵基-C1-6
烷基氧基;C1-6
烷基氧基羰基,其中C1-6
烷基可視情況經芳基取代;氰基;C1-6
烷基羰基;硝基;胺基;單-或二(C1-4
烷基)胺基;-S(=O)p
-C1-4
烷基;R4
R3
N-C(=O)-;R4
R3
N-C1-6
烷基;C3-6
環烷基;芳基;芳基氧基;芳基C1-4
烷基;芳基-C(=O)-C1-4
烷基;芳基-C(=O)-;Het;HetC1-4
烷基;Het-C(=O)-C1-4
烷基;Het-C(=O)-;Het-O-。
本發明第九具體實施態樣前文提及作為具體實施態樣之式(I)化合物或其任一子集,其中該式(I)化合物係為下式(I')或(I")化合物且其中R3a
及R3b
各獨立地表示鹵基、C1-6
烷基或C1-6
烷基氧基;尤其是鹵基或C1-6
烷基;
特別是R3a
及R3b
兩基團皆表示鹵基,特別是R3a
及R3b
兩基團皆表示氯。
本發明第十具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中該式(I)化合物係為下式(I')或(I")化合物且其中R3c
係表示胺基;單-或二(C1-4
烷基)胺基;R4
R3
N-C(=O)-;R4
R3
N-C1-6
烷基;Het-C(=O)-或HetC1-4
烷基;或R3c
係表示氫。
本發明第十一具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中p係表示2。
本發明第十二具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中Z係表示C1-6
烷二基或C2-6
烯二基、尤其是C1-6
烷二基,特別是-CH2
-。
本發明第十三具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中Rx
係表示氫。
本發明第十四具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中Y係表示-NRx
-C(=O)-。
本發明第十五具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中Y係表示-C(=O)-NRx
-。
本發明第十六具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中R7
係表示氫。
本發明第十七具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中R7
係表示鹵基、C1-4
烷基或經羥基取代之C1-4
烷基;尤其是鹵基。
本發明第十八具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中芳基係表示苯基或經鹵基、C1-6
烷基、多鹵基C1-6
烷基或C1-6
烷基氧基羰基取代之苯基。
本發明第十九具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中Het係表示含有至少一個各獨立選自O、S、S(=O)p
或N之雜原子的單環非芳族或芳族雜環;或含有至少一個各獨立選自O、S、S(=O)p
或N之雜原子(尤其N)的雙環非芳族或芳族雜環;該單環雜環或該雙環雜環視情況經一或二個取代基所取代,每一取代基各獨立選自酮基;或C1-6
烷基。
本發明第二十具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中符合以下一或多項(較佳係所有項)之限制:a)X係表示-NRx
-C(=O)-;-Z-NRx
-C(=O)-;或-NRx
-C(=S)-;
b)R1
係表示芳基1
或Het1
;c)R2
係表示C3-6
環烷基、苯基或2,3-二氫-1,4-苯并二氧雜環己烯基,其中該苯基係視情況經一至四個取代基所取代,每一取代基各獨立選自鹵基、C1-6
烷基、C1-6
烷基氧基、C1-6
烷基硫基、C1-6
烷基氧基羰基、硝基、胺基、單-或二(C1-4
烷基)胺基、芳基氧基;d)A係表示N;e)A係表示CH;f)Z係表示C1-6
烷二基或C2-6
烯二基;g)Rx
係表示氫。
h)芳基1
係表示苯基或茀基,該苯基或茀基視情況經鹵基、C1-6
烷基或多鹵基C1-6
烷基所取代;i)Het1
係表示4-、5-或6-員非芳族或芳族雜環,諸如例如吖丁啶基、噻唑烷基、噻唑基、吡咯啶基、六氫吡啶基,該5-或6-員雜環視情況經以下基團所取代:羥基、酮基、C1-6
烷基、C1-6
烷基氧基羰基、芳基或Het;j)Y係表示-NRx
-C(=O)-;k)R7
係表示氫。
本發明第二十一具體實施態樣係為前文提及作為具體實施態樣之式(I)化合物或其任何可能之子集,其中符合以下一或多項(較佳係所有項)之限制:a)A係表示CH;b)A係表示N;c)當A表示碳原子時,虛線係表示鍵結;
d)當A表示碳原子時,虛線不表示鍵結;e)X係表示-O-C(=O)-;-NRx
-C(=O)-;-Z-C(=O)-;-Z-NRx
-C(=O)-;-NRx
-C(=S)-;f)Z係表示C1-6
烷二基;g)Rx
係表示氫;h)Y係表示-C(=O)-NRx
-或-NRx
-C(=O)-;i)R1
係表示芳基1
或Het1
;j)R2
係表示C3-6
環烷基、苯基、2,3-二氫-1,4-苯并二氧雜環己烯基或含有1或2個N原子之6員芳族雜環,其中該C3-6
環烷基、苯基、2,3-二氫-1,4-苯并二氧雜環己烯基或含有1或2個N原子之6員芳族雜環可視情況經至少一個取代基所取代,尤其是一至四個取代基,每一取代基各獨立選自鹵基;C1-6
烷基;C1-6
烷基氧基;C1-6
烷基硫基;C1-6
烷基氧基羰基;硝基;單-或二(C1-4
烷基)胺基;R4
R3
N-C1-6
烷基;芳基氧基;et-C(=O)-C1-4
烷基;k)R3
係表示C1-4
烷基;l)R4
係表示C1-4
烷基;m)R7
係表示氫或鹵基;n)芳基係表示苯基或經以下基團取代之苯基:鹵基;C1-6
烷基;多鹵基C1-6
烷基;C1-6
烷基氧基羰基;o)芳基1
係表示苯基或茀基;該苯基或茀基各視情況經一或兩個取代基所取代,每一取代基各獨立選自酮基;羧基;鹵基;視情況視情況經羧基或C1-4
烷基氧
基羰基所取代之C1-6
烷基;C1-6
烷基氧基;C1-6
烷基氧基-羰基;胺基;芳基;Het;p)Het係表示含有至少一個各獨立選自O、S、S(=O)p
或N之雜原子的單環非芳族或芳族雜環;或含有至少一個各獨立選自N之雜原子的雙環非芳族或芳族雜環;該單環雜環或該雙環雜環視情況經一或二個取代基所取代,每一取代基各獨立選自酮基或C1-6
烷基;q)Het1
係表示含有至少一個各獨立選自S或N之雜原子的單環非芳族或芳族雜環;該單環雜環視情況經至少一個取代基所取代,尤其是一或二個取代基,每一取代基各獨立選自羥基;酮基;C1-6
烷基;C1-6
烷基氧基-羰基;芳基;Het;r)p係表示2。
較佳之式(I)化合物係選自
其N-氧化物、其醫藥上可接受之鹽或溶劑合物。
本發明另一具體實施態樣係為前文所示之式(I"')化合物的用途,其中該式(I"')化合物係為其中R2
係表示氫、C1-6
烷基或C2-6
烯基之化合物。
前文針對式(I)化合物列出之具體實施態樣亦可於任何可能之情況下應用於式(I"')化合物。
通常,式(I)化合物,其中Y係表示-NRx
-C(=O)-,該化合物係表示為式(I-a),可藉由式(II)中間物與式(III)中間物於適當之脫水(偶合)劑(諸如例如N'-(乙基甲醯亞胺基)-N,N-二甲基-1,3-丙烷二胺單鹽酸鹽(EDCI)、二環己基碳化二亞胺(DCC)、羰基二咪唑(CDI)、六氟磷酸1-[雙(二-甲基胺基)亞甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU)、六氟磷酸1-[雙(二甲基-胺基)亞甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU)、四氟硼酸O-苯并三唑基四甲基異脲鎓(TBTU)或氰基膦酸二乙酯(DECP))存在下,視情況連同使用羥基苯并三唑或氯羥基苯并三唑,於適當之溶劑(諸如例如N,N-二甲基甲醯胺、四氫呋喃或二氯甲烷)存在下,且視情況於適當之鹼(諸如例如N,N-二異丙基-乙胺或N,N-二乙基-乙胺)存在下,進行反應而製備。
前述反應可以快速合成反應之形式進行,因而使用快速合成熟知之適當試劑,諸如例如連接於適當之載體(例如聚苯乙烯)之二環己基碳化二亞胺(DCC)。純化反應混合物時,亦可使用適當之快速合成試劑,諸如例如1-乙烯基-4-(異氰醯基甲基)-苯聚合物與乙烯基苯。
式(I-a)化合物亦可藉由式(II)中間物與式(III')中間物,其中W1
係表示適當之脫離基,諸如例如鹵基,例
如氯及諸如此類者,於適當之鹼(諸如例如氫化鈉、碳酸氫鈉、N
,N
-二異丙基-乙胺或N
,N
-二乙基-乙胺)及適當之溶劑(諸如例如N,N-二甲基甲醯胺、二氯甲烷、乙腈或四氫呋喃)存在下,進行反應而製備。
式(I-a)化合物亦可藉由式(II)中間物與式(III")中間物於適當之脫水(偶合)劑(諸如例如DECP)及其前脫水劑(如前述者)、適當之鹼(諸如例如N
,N
-二乙基-乙胺及適當之溶劑諸如例如二氯甲烷存在下進行反應而製備。
式(I)化合物,其中X係表示X1
-NH-C(=O)-,而X1
係表示直接鍵結或Z,該化合物係表示為式(I-b),可藉由式(IV)中間物與式(V)中間物於適當之溶劑(諸如例如乙腈、N,N-二甲基甲醯胺或二氯甲烷或醇(例如甲醇))存在下,視情況於適當之鹼諸如例如N,N-二乙基-乙胺存在下,進行反應而製備。式(IV)中間物係市售品或可藉由R2
-X1
-NH2
與光氣於適當之溶劑諸如例如甲苯存在下進行反應而製備。
前述反應亦可以快速合成反應形式進行,因而使用快速合成熟知之適當試劑,諸如例如純化反應混合物時,可使用1-乙烯基-4-(異氰醯基甲基)-苯聚合物與乙烯基苯之混合物及連接於聚苯乙烯的參-2-胺基乙基胺。
式(I-b)化合物,其中X1
係表示直接鍵結,該化合物係表示為式(I-b-1),可藉由式(IV')中間物與Cl3
COC(=O)-Cl或C(=O)Cl2
視情況於適當之鹼諸如例如N,N-二乙基-乙胺或N,N-二異丙基-乙胺存在下,或視情況於HCl二乙醚溶液及適當之溶劑(諸如例如甲苯或乙腈)存在下進行反應,接著與式(v)中間物於適當之溶劑諸如例如乙腈、N,N-二甲基甲醯胺或二氯甲烷存在下,視情況於適當之鹼諸如例如N,N-二乙基-乙胺或N,N-二異丙基-乙胺存在下進行反應而製備。
式(I)化合物,其中X係表示X1
-NH-C(=S)-,而X1
係表示直接鍵結或Z,該化合物係表示為式(I-c),可藉由式(VI)中間物與式(V)中間物於適當之鹼諸如例如
N,N-二乙基-乙胺及適當之溶劑諸如例如二氯甲烷或四氫呋喃存在下,進行反應而製備。
式(I)化合物,其中X係表示-X1
-C(=O)-,而X1
係表示直接鍵結或Z,該化合物係表示為式(I-d),可藉由式(VII)中間物與式(V)中間物於適當之脫水(偶聯)劑存在下(諸如例如N
'-(乙基甲醯亞胺基)-N,N
-二甲基-1,3-丙烷二胺單鹽酸鹽(EDCI)、二環己基碳化二亞胺(DCC)、羰基二咪唑(CDI)、六氟磷酸1-[雙(二-甲基胺基)亞甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU)、六氟磷酸1-[雙(二甲基-胺基)亞甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU)、四氟硼酸O-苯并三唑基四甲基異脲鎓(TBTU)或氰基膦酸二乙酯(DECP))存在下,視情況連同使用羥基苯并三唑或氯羥基苯并三唑,於適當之溶劑(諸如例如N,N-二甲基甲醯胺、二氯甲烷、乙腈或四氫呋喃)存在下,且視情況於適當之鹼(諸如例如N,N-二異丙基-乙胺或N,N-二乙基-乙胺)存在下,進行反應而製備。
式(I-d)化合物,其中X1
係表示直接鍵結,該化合物係表示為式(I-d-1),可藉由式起始劑(其中W1
係表示適當之脫離基,諸如例如鹵基,例如氯及諸如此類者)與式(V)中間物於適當之鹼諸如例如N-甲基嗎褔啉及適當之溶劑諸如例如N,N-二甲基甲醯胺存在下,進行反應而製備。
式(I'")化合物,其中X係表示-S(=O)p
-,該化合物係表示為式(I"'-e),可藉由式(XVII)中間物(其中W3
係表示適當之脫離基,諸如例如鹵基,例如氯及諸如此類者)與式(V)中間物於適當之鹼諸如例如N,N-二異丙基-乙胺或N,N-二乙基-乙胺及適當之溶劑諸如例如二氯甲烷存在下進行反應而製備。
式(I)化合物,其中X係表示-C(=O)-Z-,該化合物係表示為式(I-f),可藉由式(XVIII)中間物與式(V)中間物於適當之溶劑諸如例如醇(例如乙醇)存在下進行反應而製備。
式(I)化合物,其中R2
係經R4
R3
N-C1-6
烷基取代,該R2
係表示為-R2'
-C1-6
烷基-NR3
R4
且該化合物係表示為式(I-g),可藉由式(IXX)中間物(其中W4
係表示適當之脫離基,諸如例如CH3
-S(=O)2
-O-)與NHR3
R4
於適當之溶劑諸如例如乙腈存在下進行反應而製備。式(IXX)中間物可藉由對應之OH衍生物與CH3
-S(=O)2
-Cl於適當之鹼諸如例如吡啶及適當之溶劑諸如例如二氯甲烷存在下進行反應而製備。
式(I)化合物,其中R1
取代基係經胺基取代,可於適當之酸(諸如例如三氟乙酸)及適當之溶劑(諸如例如二氯甲烷)存在下自其中胺基官能基由適當之保護基(諸如例如第三丁基氧基羰基)保護的對應之化合物製備。該經保護之化合物可根據前文始自式(II)中間物的式(I)化合物所述合成方法製備。
式(I)化合物,其中Y係表示-C(=O)-NRx
-,該化合物
係表示為式(I-h),可藉由式(XXV)中間物與式(XXXVI)中間物於DECP、適當之鹼諸如例如N
,N
-二乙基-乙胺或N
,N
-二異丙基-乙胺及適當之溶劑諸如例如二氯甲烷或乙腈存在下進行反應而製備。
式(I)化合物,其中R7
係表示經羥基取代之C1-4
烷基,該化合物係表示為式(I-i),可藉由式(XLIII)中間物與適當之酸諸如例如HCl及諸如此類者,於適當之溶劑諸如例如醇(例如2-丙醇)存在下進行反應而製備。
式(I)化合物,其中X含有Z1
,該Z1
係經胺基取代之Z,該X係表示為Z1
(NH2
)-X2
,其中X2
係表示鍵合基X之其餘部分,且該化合物係表示為式(I-j),可藉由於適當之溶劑諸如例如二氯甲烷存在下,以適當之酸諸如例如三氟乙酸將式(XLIV)中間物(其中P係表示適當之脫離基,諸如例如第三丁氧基羰基)脫保護而製備。
式(I)化合物另可根據技術界已知之基團轉變反應將式(I)化合物彼此轉化而製備。
式(I)化合物可依技術界已知將三價氮轉化成其N
-氧化物形式的方法轉化成對應之N
-氧化物形式。該N
-氧化反應通常可藉由式(I)之起始物質與適當之有機或無機過氧化物反應而進行。適當之無機過氧化物係包含例如過氧化氫、鹼金屬或鹼土金屬過氧化物,例如過氧化鈉、過氧化鉀;適當之有機過氧化物可包含過氧酸,諸如例如苯過甲酸或經鹵素取代之苯過甲酸,例如3-氯苯過甲酸,過氧烷酸,例如過氧乙酸,烷基過氧化氫,例如第三丁基過氧化氫。適當之溶劑有例如水,低碳醇,例如乙醇及諸如此類者,烴類,例如甲苯,酮類,例如2-丁酮,鹵化烴類,例如二氯甲烷,及該等溶劑之混合物。
式(I)化合物,其中R1
或R2
係未經取代,可藉由與C1-4
烷基-S(=O)p
-W6
(其中W6
係表示適當之脫離基,諸如例如鹵基,例如氯及諸如此類者)於適當之鹼,諸如例如N,N-二乙基-乙胺存在下且於適當之溶劑,諸如例如乙腈存在下反應,轉化成其中R1
或R2
含有C1-4
烷基-S(=O)p
-取代基之化合物。
式(I)化合物,其中R1
或R2
含有C1-6
烷基氧基羰基取代基,可藉由於適當之溶劑,諸如例如二烷存在下與
適當之鹼(諸如例如氫氧化鈉)反應,而轉化成式(I)化合物,其中R1
或R2
含有羧基取代基。
式(I)化合物,其中R1
或R2
含有C1-6
烷基氧基羰基取代基,亦可藉由與適當之還原劑,諸如例如LiBH於適當之溶劑,諸如例如四氫呋喃或二烷存在下反應,而轉化成式(I)化合物,其中R1
或R2
含有CH2
-OH取代基。
式(I)化合物,其中R1
或R2
含有C1-6
烷基氧基羰基取代基,亦可藉由與適當之酸,諸如例如鹽酸及諸如此類者反應,而轉化成式(I)化合物,其中R1
或R2
未經取代。
式(I)化合物,其中R1
或R2
含有C1-5
烷基-羰基取代基,可藉由與適當之還原劑,諸如例如NaBH4
於適當之溶劑,諸如例如醇(例如甲醇)存在下反應,而轉化成式(I)化合物,其中R1
或R2
含有C1-5
烷基-CH(OH)-取代基。
式(I)化合物,其中R1
或R2
含有C1-6
烷基氧基取代基,可藉由與適當之還原劑,諸如例如BBr3
於適當之溶劑諸如例如二氯甲烷或二氯乙烷存在下反應,而轉化成式(I)化合物,其中R1
或R2
含有OH取代基。
式(I)化合物,其中R1
或R2
含有羧基取代基,可藉由與該雜環於適當之脫水(偶合)劑(諸如例如N
'-(乙基甲醯亞胺基)-N,N
-二甲基-1,3-丙烷二胺單鹽酸鹽(EDCI)、二環己基碳化二亞胺(DCC)、羰基二咪唑(CDI)、六氟磷酸1-[雙(二-甲基胺基)亞甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU)、六氟磷酸1-[雙(二甲基-胺基)亞甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU)、四氟硼酸O-苯并三唑
基四甲基異脲鎓(TBTU)或氰基膦酸二乙酯(DECP))存在下,視情況連同使用羥基苯并三唑或氯羥基苯并三唑,於適當之溶劑(諸如例如N,N-二甲基甲醯胺、二氯甲烷、乙腈或四氫呋喃)存在下,且視情況於適當之鹼(諸如例如N,N-二異丙基-乙胺或N,N-二乙基-乙胺)存在下,進行反應而轉化成式(I)化合物,其中R1
或R2
含有Het-C(=O)-取代基,其中Het係表示含有至少一個N原子之視情況經取代單環飽和雜環,該雜環係經由N原子連接於C(=O)基團。此反應亦可以快速合成反應形式進行,因而使用快速合成熟知之連接於適當之載體(例如聚苯乙烯)的適當試劑,諸如例如二環己基碳化二亞胺(DCC)或羰基二咪唑(CDI)。純化反應混合物時,亦可使用適當之快速合成試劑,諸如例如1-乙烯基-4-(異氰醯基甲基)-苯聚合物與乙烯基苯。
式(I)化合物及某些本發明中間物可含有不對稱碳原子。該化合物及該中間物之純立體化學異構形式可藉施加技術界已知方法而製得。例如,非鏡像異構物可藉物理方法諸如選擇性結晶或層析技術而分離,例如逆流式分配、對掌性液相層析及諸如此類方法。可藉由先以適當之離析劑(諸如例如對掌性酸)將消旋混合物轉化成非鏡像異構鹽或化合物之混合物;隨之藉例如選擇性結晶或層析技術(例如液相層析及其類方法)物理性分離該非鏡像異構鹽或化合物之混合物;最後將該分離之非鏡像異構鹽或化合物轉化成對應之鏡像異構物,而製得鏡像
異構物。亦可自適當之異構物及起始物質的純立體化學異構形式製得純立體化學異構形式,其限制條件為中間反應係立體專一性地進行。
分離式(I)化合物及中間物之鏡像異構形式的備擇方式係包括液相層析或SCF(超臨界流體)層析,尤其是使用對掌性靜態相。
某些中間物及起始物質係已知化合物且可購得或可根據技術界已知方法製備。
式(II)中間物,其中X係表示-X1
-NH-C(=O)-,而X1
係表示直接鍵結或Z,該中間物係表示為式(II-a),可藉由式(IV)中間物與式(VIII)中間物(其中P係表示適當之保護基,諸如例如第三丁基氧基羰基)於適當之溶劑諸如例如二氯甲烷存在下反應,接著於適當之酸(諸如例如三氟乙酸)存在下,且於適當之溶劑(諸如例如二氯甲烷)存在下,將形成之式(IX)中間物脫保護,而製備。在進行脫保護反應之前,式(IX)中間物可視情況藉由與C1-4
烷基鹵(例如CH3
I)於適當之鹼,諸如例如NaH及適當之溶劑(諸如例如N,N-二甲基甲醯胺)存在下反應,而轉化成式(XI')中間物。
式(II-a)中間物,其中Rx
係表示氫,該中間物係表示為式(II-a-1),可藉由式(IV)中間物與式(X)中間物於適當之溶劑諸如例如二氯甲烷存在下反應,接著於適當之觸媒,諸如例如炭上鉑或阮氏鎳、視情況適當之觸媒毒素(諸如例如噻吩溶液)及適當之溶劑諸如例如四氫呋喃或醇(例如甲醇)存在下,將形成之式(XI)中間物氫化(H2
或N2
H4
.H2
O)而製備。進行氫化反應之前,式(XI)中間物可視情況藉由與C1-4
烷基鹵(例如CH3
I)於適當之鹼諸如例如NaH及適當之溶劑諸如例如N,N-二甲基甲醯胺存在下反應轉化成式(XI')中間物。
式(II-a)中間物,其中Rx
係表示氫且其中X1
係表示直接鍵結,該中間物係表示為式(II-a-2),可藉由式(XXI)中間物與Cl3
COC(=O)-Cl反應,接著與式(X)中間物於適當之鹼諸如例如N,N-二乙基-乙胺及適當之溶劑諸如例如甲苯存在下反應,接著於適當之觸媒諸如例如炭上鉑或阮氏鎳、視情況適當之觸媒毒素(諸如例如噻吩溶液)及適當之溶劑諸如例如四氫呋喃或醇(例如甲醇)存在下將形成之式(XX)中間物氫化(H2
或N2
H4
.H2
O)而製備。進行氫化反應之前,式(XX)中間物可視情況藉由與C1-4
烷基鹵(例如CH3
I)於適當之鹼諸如例如NaH及適當之溶劑諸如例如N,N-二甲基甲醯胺存在下反應,而轉化成式(XX')中間物。
式(II)中間物其中X係表示-O-C(=O)-,該中間物係表示為式(II-b),可藉由式(XXVII)中間物與式(XXVIII)中間物(其中W3
係表示適當之脫離基,諸如例如鹵基,例如氯)於NaH及適當之溶劑諸如例如四氫呋喃存在下反應,接著於次一步驟中在H2
、適當之觸媒(諸如例如炭上鉑)、適當之觸媒毒素(諸如例如噻吩)及適當之溶劑(諸如例如乙酸)存在下將形成之式(XXIX)產物氫化而製備。
式(III)中間物可藉著於適當之溶劑諸如例如水、四氫呋喃、二烷或醇(例如甲醇)存在下,以適當之鹼諸如例如氫氧化鉀或氫氧化鈉將式(XII)中間物水解而製備。式(XII)中間物,其中R1
係表示Het1
,其中該Het1
係為經視情況經取代之苯基或視情況經取代之雜環所取代的雜環,可藉由使經保護之雜環與視情況經取代之苯基於適當之觸媒諸如例如乙酸鈀存在下,於適當之觸媒配位體諸如例如1,1'-(1,5-戊烷二基)雙[1,1'-二苯基膦]、適當之鹼諸如例如乙酸鉀及適當之溶劑諸如例如N-甲基-吡咯啶-2-酮存在下進行反應,或藉著視情況經取代之雜環與帶有脫離基諸如例如鹵基(例如溴、碘及諸如此類者)之視情況經取代之苯基或帶有脫離基諸如例如鹵基(例如溴、碘及諸如此類者)之視情況經取代之雜環,於適當之觸媒諸如例如乙酸鈀存在下,於適當之觸媒配位體諸如例如1,3-丙烷二基雙[二苯基膦]、適當之鹼諸如例如乙酸鉀或碳酸銫及適當之溶劑諸如例如N
-甲基-吡咯啶-2-酮
存在下,進行反應而製備。
式(V)中間物,其中Y係表示-NRx
-C(=O)-,該中間物係表示成式(V-a),可藉由式(XIII)中間物(其中P係表示適當之脫離基,諸如例如苄基)與式(XIV)中間物(其中W2
係表示適當之脫離基,諸如例如鹵基,例如氯及諸如此類者)於適當之鹼存在下,諸如例如N
,N
-二乙基-乙胺及適當之溶劑諸如例如二氯甲烷進行反應,接著於適當之觸媒諸如例如炭上鈀及適當之溶劑諸如例如四氫呋喃及/或適當之醇(例如甲醇)存在下,以H2
將形成之式(XV)中間物脫保護而製備。
式(V-a)中間物亦可藉由式(XIII)中間物與式(III)中間物於適當之活化劑諸如例如草醯氯存在下,於適當之鹼諸如例如N,N-二乙基-乙胺及適當之溶劑諸如例如二氯
甲烷或N
,N
-二甲基甲醯胺存在下進行反應,接著於適當之觸媒諸如例如炭上鈀及適當之溶劑諸如例如四氫呋喃及/或適當之醇(例如甲醇)存在下,以H2
將形成之式(XV)中間物脫保護而製備。脫保護亦可於作為脫保護劑之1-氯乙基氯甲酸酯存在下於適當之溶劑諸如例如二氯乙烷及醇(例如甲醇)存在下進行。
式(V-a)中間物亦可根據以下反應流程圖製備,其中式(XXI)中間物(其中P係表示適當之脫離基,諸如例如苄基氧基羰基或第三丁氧基或苄基,且其中W6
係表示適當之脫離基,諸如例如鹵基,例如氯及諸如此類者)與式(X)中間物於適當之鹼諸如例如NaHCO3
及適當之溶劑諸如例如二氯甲烷存在下,產生式(XXII)中間物,接著於次一步驟中於適當之觸媒諸如例如炭上鉑及適當之溶劑諸如例如四氫呋喃及醇(例如甲醇)存在下,將該式(XXII)中間物氫化(H2
),形成式(XIII)中間物。次一步驟中,該式(XXIII)中間物與與式(XIV)中間物於適當之鹼諸
如例如NaHCO3
及適當之溶劑諸如例如乙腈存在下反應,形成式(XXIV)中間物,此中間物於次一步驟中於H2
、適當之觸媒諸如例如炭上鈀及適當之溶劑諸如例如醇(例如甲醇)存在下;或於適當之酸諸如例如三氟乙酸或HCl及適當之溶劑諸如例如二氯甲烷或二烷存在下;或於甲酸銨、適當之觸媒諸如例如炭上鈀及適當之溶劑諸如例如醇(例如甲醇)存在下進行脫保護。
前述反應流程圖中,式(XXIII)中間物亦可與式(III)中間物於適當之活化劑諸如例如SOCl2
或Cl-C(=O)-C(=O)-Cl、適當之鹼諸如例如N
,N
-二乙基-乙胺或N
,N
-二異丙基-乙胺及適當之溶劑諸如例如二氯甲
烷或N
,N
-二甲基甲醯胺存在下進行反應。或式(III)中間物可與式(XXVI)中間物於適當之脫水(偶合)劑(諸如例如N'-(乙基甲醯亞胺基)-N,N-二甲基-1,3-丙烷二胺單鹽酸鹽(EDCI)、二環己基碳化二亞胺(DCC)、羰基二咪唑(CDI)、六氟磷酸1-[雙(二-甲基胺基)亞甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU)、六氟磷酸1-[雙(二甲基-胺基)亞甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU)、四氟硼酸O-苯并三唑基四甲基異脲鎓(TBTU)或氰基膦酸二乙酯(DECP))存在下,視情況連同使用羥基苯并三唑或氯羥基苯并三唑,於適當之溶劑(諸如例如N,N-二甲基甲醯胺、二氯甲烷、乙腈或四氫呋喃)存在下,且視情況於適當之鹼(諸如例如N,N-二異丙基-乙胺或N,N-二乙基-乙胺)存在下進行反應。
式(XXIV)中間物亦可與C1-4
烷基鹵(例如CH3
I)於適當之鹼諸如例如NaH及適當之溶劑諸如例如N,N-二甲基甲醯胺存在下反應,以形成式(XXIV')中間物,其可根據前述方法脫保護產生式(V-a,)中間物。
式(V)中間物,其中Y係表示-C(=O)-NRx
-,該中間物係表示成式(V-b),可藉由式(XXX)中間物(其中P係表示適當之脫離基,諸如例如苄基或第三丁氧基羰基)與式(XXVI)中間物於適當之脫水(偶聯)劑諸如例如N'-(乙基甲醯亞胺基)-N,N-二甲基-1,3-丙二胺單鹽酸鹽(EDCI)、二環己基碳化二亞胺(DCC)、羰基二咪唑(CDI)、六氟磷酸1-[雙(二-甲基胺基)亞甲基]-1H-苯并三唑鎓(1-)3-氧化
物(HBTU)、六氟磷酸1-[雙(二甲基-胺基)亞甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU)、四氟硼酸O-苯并三唑基四甲基異脲鎓(TBTU)或氰基膦酸二乙酯(DECP)存在下,視情況結合有羥基苯并三唑或氯羥基苯并三唑,於適當之溶劑(諸如例如N,N-二甲基甲醯胺、二氯甲烷、乙腈或四氫呋喃)存在下,且視情況於適當之鹼(諸如例如N,N-二異丙基-乙胺或N,N-二乙基-乙胺)存在下,進行反應,接著於適當之觸媒諸如例如炭上鈀及適當之溶劑諸如例如醇(例如甲醇)存在下,以H2
將式(XXXI)中間物脫保護或藉著於適當之溶劑諸如例如醇(例如異丙醇或二氯甲烷)存在下以適當之酸諸如例如HCl、三氟乙酸及諸如此類者進行脫保護而製備。
式(IV)中間物,其中X1
係表示直接鍵結且R2
含有Het-C1-4
烷基取代基,其中Het係表示以式(XXXII)表示之單環飽和含N雜環,該式(IV)中間物係表示為式
(IV-a),可藉由式(XXXII)中間物與式(XXXIII)中間物於適當之脫水(偶合)劑諸如例如N
'-(乙基甲醯亞胺基)-N,N
-二甲基-1,3-丙烷二胺單鹽酸鹽(EDCI)、二環己基碳化二亞胺(DCC)、羰基二咪唑(CDI)、六氟磷酸1-[雙(二-甲基胺基)亞甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU)、六氟磷酸1-[雙(二甲基-胺基)亞甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU)、四氟硼酸O-苯并三唑基四甲基異脲鎓(TBTU)或氰基膦酸二乙酯(DECP)存在下,視情況連同使用羥基苯并三唑或氯羥基苯并三唑,於適當之溶劑(諸如例如N,N-二甲基甲醯胺、二氯甲烷、乙腈或四氫呋喃)存在下,且視情況於適當之鹼(諸如例如N,N-二異丙基-乙胺或N,N-二乙基-乙胺)存在下進行反應而製備。形成之式(XXXIV)中間物可隨之於次一步驟中於適當之還原劑諸如例如硼烷存在下,於適當之溶劑諸如例如四氫呋喃存在下,還原成式(XXXV)中間物,其可隨之於HCl二乙醚溶液及適當之溶劑諸如例如甲苯或乙腈存在下以光氣轉化成式(IX-a)中間物而製備。
式(XXXIV)中間物亦可於HCl二乙醚溶液及適當之溶劑諸如例如甲苯或乙腈或二氯甲烷存在下以光氣轉化成式(IV-b)中間物。
式(IV-a)中間物亦可藉由式(XXXII)中間物與式(XXXVI)中間物(其中W4
係表示適當之脫離基,諸如例如鹵基,例如氯及諸如此類者)於適當之溶劑諸如例如乙腈存在下反應,形成式(XXXV’)中間物,其可如前文針對中間物(XXXV)所述般地轉化成式(IV-a)中間物而製備。
式(VII)中間物可藉由式(XL)中間物於LiOH、酸諸如例如HCl及適當之溶劑(諸如例如醇,例如甲醇)存在下水解而製備。式(XL)中間物,其中R2
含有Het-C1-4
烷基作為取代基,該中間物係表示為式(XL-a)可藉由式(XLI)
中間物(其中W5
係表示適當之脫離基,諸如例如鹵基,例如溴及諸如此類者)與式(XXXII)中間物反應而製備。下述之式(XLI-a)中間物可藉由式(XLII)中間物與N-溴琥珀醯亞胺於2,2'-(1,2-二氮烯二基)雙[2-甲基丙烷腈]及適當之溶劑諸如例如CCl4
存在下反應而製備。式(XLII)中間物,其中X1
係表示CH2
,該中間物係表示為式(XLII-a),可藉由式(XLV)中間物與鈉金屬於適當之酸諸如例如硫酸及適當之C1-4
烷基-OH存在下反應而製備。式(XLV)中間物可藉由式(IV-a')中間物與1,1-二甲基乙基-亞硝酸酯、CuCl2
、1,1-二氯乙烯於適當之溶劑諸如例如乙腈中反應而製備。
式(XXV)中間物,其中X係表示-X1
-HN-C(=O)-,該中間物係表示為式(XXV-a),可藉由製備式(XXXVII)中
間物於適當之鹼諸如例如氫氧化鈉存在下,於適當之溶劑諸如例如二烷存在下進行水解而製備。式(XXXVII)中間物可藉由式(IV)中間物與式(XXXVIII)中間物於適當之鹼諸如例如N,N-二乙基-乙胺及適當之溶劑諸如例如二氯甲烷存在下反應而製備。
式(XXV)中間物,其中X係表示-X1
-C(=O)-,該中間物係表示為式(XXV-b),可藉由式(XXXVII-a)中間物於適當之鹼諸如例如氫氧化鈉存在下,於適當之溶劑諸如例如二烷及視情況之醇(例如甲醇)存在下水解而製備。式(XXXVII-a)中間物可藉由式(XXXVIII)中間物與式(XLIII)中間物於適當之脫水(偶合)劑(諸如例如N'-(乙基甲醯亞胺基)-N,N-二甲基-1,3-丙烷二胺單鹽酸鹽(EDCI)、二環己基碳化二亞胺(DCC)、羰基二咪唑(CDI)、六氟磷酸1-[雙(二-甲基胺基)亞甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU)、六氟磷酸1-[雙(二甲基-胺基)亞甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU)、四氟硼酸
O-苯并三唑基四甲基異脲鎓(TBTU)或氰基膦酸二乙酯(DECP))存在下,視情況連同使用羥基苯并三唑或氯羥基苯并三唑,於適當之溶劑(諸如例如N,N-二甲基甲醯胺、二氯甲烷、乙腈或四氫呋喃)存在下,且視情況於適當之鹼(諸如例如N,N-二異丙基-乙胺或N,N-二乙基-乙胺)存在下,進行反應而製備。
式(XXXVI-a)中間物可根據以下反應流程圖製備。第一步驟中,式LV中間物(其中W11
係表示適當之脫離基,諸如例如氟)係於4-甲基-苯磺酸及適當之溶劑諸如例如二氯甲烷存在下,與3,4-二氫-2H-哌喃反應,形成式(LVI)中間物。該中間物於次一步驟中與式(LVII)中間物(其中P係表示適當之保護基,諸如例如苄基)於Na2
CO2
及適當之溶劑諸如例如N
,N
-二甲基甲醯胺存在下反應,形成式(LVIII)中間物。於次一步驟中,該中間物係於適當之觸媒諸如例如炭上鉑、觸媒毒素諸如例如噻吩及適當之溶劑諸如例如四氫呋喃存在下以H2
氫化,形成式(LIX)中間物。此中間物隨後與式(III)中間物於適當之脫水(偶
合)劑(諸如例如N'-(乙基甲醯亞胺基)-N,N-二甲基-1,3-丙烷二胺單鹽酸鹽(EDCI)、二環己基碳化二亞胺(DCC)、羰基二咪唑(CDI)、六氟磷酸1-[雙(二-甲基胺基)亞甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU)、六氟磷酸1-[雙(二甲基-胺基)亞甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU)、四氟硼酸O-苯并三唑基四甲基異脲鎓(TBTU)或氰基膦酸二乙酯(DECP))存在下,視情況連同使用羥基苯并三唑或氯羥基苯并三唑,於適當之溶劑(諸如例如N,N-二甲基甲醯胺、二氯甲烷、乙腈或四氫呋喃)存在下,且視情況於適當之鹼(諸如例如N,N-二異丙基-乙胺或N,N-二乙基-乙胺)存在下,進行反應。此式(LIX)中間物與式(III)中間物之反應亦可於適當之活化劑(諸如例如Cl-C(=O)-C(=O)-Cl)、適當之鹼(諸如例如N,N-二乙基-乙胺)及適當之溶劑(諸如例如N,N-二甲基甲醯胺)存在下進行。此反應可以快速合成反應之形式進行,因而使用快速合成熟知之適當試劑,諸如例如連接於適當之載體(例如聚苯乙烯)之二環己基碳化二亞胺(DCC)。純化反應混合物時,亦可使用適當之快速合成試劑,諸如例如1-乙烯基-4-(異氰醯基甲基)-苯聚合物與乙烯基苯。於次一步驟中,式(LX)中間物於適當之觸媒諸如例如炭上鈀、適當之鹼諸如例如N
,N
-二乙基-乙胺及適當之溶劑諸如例如四氫呋喃存在下以H2
脫保護,形成式(LXI)中間物,其可於次一步驟中於適當之溶劑諸如例如二氯甲烷存在下與式(IX)中間物反應,以得到式(XXXVI-a)中間
物。
式(XLIV-a)中間物可藉由式(VII)中間物(其中X1
係經保護(P,諸如例如第三丁基氧基羰基)胺基,該中間物係表示為式(VII-a))與式(V)中間物於適當之脫水(偶合)劑(諸如例如N'-(乙基甲醯亞胺基)-N,N-二甲基-1,3-丙烷二胺單鹽酸鹽(EDCI)、二環己基碳化二亞胺(DCC)、羰基
二咪唑(CDI)、六氟磷酸1-[雙(二-甲基胺基)亞甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU)、六氟磷酸1-[雙(二甲基-胺基)亞甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU)、四氟硼酸O-苯并三唑基四甲基異脲鎓(TBTU)或氰基膦酸二乙酯(DECP))存在下,視情況連同使用羥基苯并三唑或氯羥基苯并三唑,於適當之溶劑(諸如例如N,N-二甲基甲醯胺、二氯甲烷、乙腈或四氫呋喃)存在下,且視情況於適當之鹼(諸如例如N,N-二異丙基-乙胺或N,N-二乙基-乙胺)存在下,進行反應而製備。
式(VII)中間物,其中X1
係表示CHOH,該中間物係表示為式(VII-b)可藉由式(LIII)中間物於ZnBr2
、Si(CH3
)3
-CN及酸諸如例如HCl存在下,於適當之溶劑諸如例如二氯甲烷存在下,進行反應而製備。式(LIII)中間物可藉由式(LIV)中間物(其中W13
係表示適當之脫離基,諸如例如鹵基,例如溴及諸如此類者)與N
,N
-二甲基甲醯胺於BuLi及適當之溶劑諸如例如四氫呋喃存在下進行反應而製備。
如前文所述,本發明有關DGAT抑制劑(尤其是DGAT1抑制劑)提高一或多種飽食激素(尤其是GLP-1)濃度之用途。本發明亦有關DGAT抑制劑(尤其是DGAT1抑制劑)用於製造供預防或治療(尤其是供治療)可因提高濃度之一或多種飽食激素而產生療效之疾病(尤其是可因提高之GLP-1濃度而產生療效之疾病)使用的藥劑之用途。尤其,提高血漿中或門靜脈血液中(特別是血漿中)之GLP-1濃度。提高之GLP-1濃度,例如提高之GLP-1血漿濃度或門靜脈血液中提高之GLP-1濃度,係表示已攝取DGAT1抑制劑之個體的GLP-1濃度較處於相同條件但未攝取DGAT1抑制劑之個體提高或增加。尤其在空腹條件或餐後(特別是餐後)提高GLP-1濃度。
提高GLP-1濃度之化合物的治療用途係包括但不限於改善學習、促進神經保護及/或舒緩中樞神經系統疾病或病症之症狀,例如,經由調節神經形成,例如帕金森氏症(Parkinson's Disease)、阿茲海默氏症(Alzheimer's Disease)、亨丁頓氏症(Huntington's Disease)、ALS、中風、出血、腦中風、ADD及神經精神症候群;將肝臟幹/袓細胞轉化成功能性胰臟細胞;防止β
-細胞受損及β
-細胞刺激;治療胰臟炎;治療肥胖;抑制食慾且誘發飽食感;治療腸激躁症或發炎性腸疾,諸如克隆氏症
(Crohn's disease)及潰瘍性結腸炎;降低與心肌梗塞及中風有關之發病率及/或死亡率;治療具有非Q波心肌梗塞特徵之急性冠心症;減輕手術後代謝改變;治療心肌休眠或糖尿病性心肌病變;抑制血漿血液去甲腎上腺素濃度;增加尿鈉排泄,降低尿鉀濃度;治療與中毒性血容量過多有關之病況或病症,例如腎衰竭、充血性心臟衰竭、腎病症候群、肝硬化、肺水腫及高血壓;誘發肌收縮反應且增加心肌收縮能力;治療多囊性卵巢症候群;治療呼吸困難;經由非腸道路徑改善營養,即經由靜脈內、皮下、肌內、腹膜或其他注射或輸液;治療腎病變;治療左心室收縮功能不全,例如左心室射血分率異常;抑制十二指腸逆流,例如用以治療或預防腸胃病症,諸如腹瀉、手術後傾食症候群及腸激躁症,及作為內視鏡手術之術前用藥;治療危重症多發性神經病變(CIPN)及全身性發炎反應症候群(SIRS);調節三酸甘油酯濃度及治療血脂異常;治療在局部缺血後因血流再灌注所致之器官組織損傷(例如腦組織損傷);改善局部缺血及再灌流後之腦組織的功能;處理冠心症危險因子(CHDRF)症候群。其他可因提高之GLP-1濃度而產生療效之疾病係包括但不限於局部缺血性心肌頓抑;局部缺血/再灌流損傷;急性心肌梗塞;左心室功能不全;血管疾病;神經病變,包括與第II型糖尿病有關之末梢感覺神經病變;與骨骼有關之病症,包括骨質疏鬆症、肥胖、糖尿病。因為對GLP-1之作用,DGAT抑制劑亦可用以提供心臟
保護。
支持以上陳述之參考資料包括Experimental Neurology,Vol.203(2)、pp293-301(2007);US7,186,683;J.Pharm.Exp.Ther.vol.312,No.1,pp 303-308(2005);Diabetes,vol.54,pp 146-151(2005);US2007/0021339,該等資料係以引用方式併入本文。
鑑於DGAT抑制活性,尤其是DGAT1抑制活性,本發明式(I)化合物、其N
-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,可作為藥劑。尤其,本發明有關作為藥劑之式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,尤其是作為供預防或治療可因提高之GLP-1濃度而產生療效之疾病使用的藥劑。尤其,本發明亦有關式(I)化合物之用途,其係用以製造供預防或治療可因提高之GLP-1濃度而產生療效之疾病使用的藥劑,諸如前述疾病及病症。
鑑於DGAT抑制劑(尤其是DGAT1抑制劑)之前述用途,提供一種治療患有疾病之溫血動物包括人類之方法或一種預防溫血動物包括人類罹患疾病之方法,該疾病可因提高之GLP-1濃度而產生療效,尤其是一種治療患有可因提高之GLP-1濃度而產生療效的疾病之溫血動物包括人類的方法。該方法係包含投予有效量之DGAT抑制劑(尤其是DGAT1抑制劑)至溫血動物包括人類。
鑑於式(I)化合物之DGAT抑制活性,提供一種治療患有疾病之溫血動物包括人類之方法或一種預防溫血動
物包括人類罹患疾病之方法,該疾病可因提高之GLP-1濃度而產生療效,尤其是一種治療患有可因提高之GLP-1濃度而產生療效的疾病之溫血動物包括人類的方法。該方法係包含投予有效量之式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物至溫血動物包括人類。
鑑於DGAT抑制活性,尤其是DGAT1抑制活性,本發明亦有關作為藥劑之式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,尤其是作為供預防或治療可因抑制DGAT(尤其是DGAT1)而產生療效之疾病使用的藥劑。本發明亦關於式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物之用途,其係用以製造供預防或治療可因抑制DGAT(尤其是DGAT1)而產生療效之疾病或病症使用的藥劑。可因抑制DGAT(尤其是DGAT1)而產生療效之疾病或病症係包括但不限於代謝病症,諸如肥胖及與肥胖相關之病症(包括末梢血管疾病、心臟衰竭、心肌局部缺血、腦部局部缺血、心肌病變),糖尿病,尤其是第II型糖尿病及其所致之併發症(諸如視網膜病變,神經病變,腎病變),X症候群,胰島素抵抗,葡萄糖耐受性不良,空腹血糖異常之病況,血糖過低,血糖過高、血中尿酸過高,血中胰島素過高,胰臟炎,血中膽固醇過高,血脂過高,血脂異常,混合型血脂異常,血中三酸甘油酯過高及非酒精性脂肪肝疾病,脂肪肝,腸脂增加,非酒精性硬脂性肝炎,肝纖維
化,代謝性酸中毒,酮症,代謝不良症候群;皮膚病況,諸如痤瘡,牛皮癬;心血管疾病,諸如動脈粥樣硬化、動脈硬化、急性心臟衰竭、充血性心臟衰竭、冠狀動脈疾病、心肌病變、心肌梗塞、心絞痛、高血壓、低血壓、中風、局部缺血、局部缺血性再灌流損傷、動脈瘤、再狹窄及動脈狹窄;腫瘤疾病,諸如實體腫瘤、皮膚癌、黑色素瘤、淋巴瘤及內皮癌,例如乳癌、肺癌、結腸直腸癌、胃癌、其他腸胃道癌症(例如食道癌及胰腺癌)、前列腺癌、腎癌、肝癌、膀胱癌、子宮頸癌、子宮癌、睪丸癌及卵巢癌;及其他對於DGAT功能(尤其是DGAT1功能)之調節(尤其是抑制)具有敏感性或有反應之疾病及病況。
可因抑制DGAT(尤其是DGAT1)而產生療效之特別疾病或病症係選自肥胖、血中膽固醇過高、血脂過高、血脂異常、混合型血脂異常、血中三酸甘油酯過高、脂肪肝、非酒精性脂肪肝疾病、肝纖維化、非酒精性硬脂性肝炎及糖尿病,尤其是第II型糖尿病。
鑑於式(I)化合物之DGAT抑制活性,提供一種治療患有疾病之溫血動物包括人類之方法或一種預防溫血動物包括人類罹患疾病之方法,該疾病係為可因抑制DGAT而產生療效之疾病,尤其是一種治療患有可因抑制DGAT而產生療效之疾病的溫血動物包括人類之方法。該方法係包含投予有效量之式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物至溫血動物
包括人類。
本發明亦提供用以預防或治療可因提高之GLP-1濃度而產生療效或可因抑制DGAT(尤其是DGAT1)而產生療效之疾病的組成物,尤其是用以治療可因提高之GLP-1濃度而產生療效或可因抑制DGAT(尤其是DGAT1)而產生療效之疾病。該等組成物係包含治療有效量之式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,及醫藥上可接受之載劑。
本發明化合物可調配成各種用於投藥之醫藥形式。至於適當之組成物,可例出所有一般用於全身投藥藥物之組成物。製備本發明醫藥組成物時,作為活性成份之有效量特定化合物(視情況為鹽形式)與醫藥上可接受之載劑組合為均勻摻合物,該載劑視投藥所需之製劑形式而可採用各種形式。期望此等醫藥組成物係為適於(特別)經口、直腸、經皮或藉非經腸注射投藥之單元劑型。例如,製備經口劑型組成物時,可採用任一種一般醫藥介質,諸如例如若為經口液體製劑諸如懸浮液、糖漿、酊劑、乳液及溶液時,則為水、二醇、油、醇及諸如此類者;或若為粉劑、丸劑、膠囊及錠劑時,則為固體載劑,諸如澱粉、糖、高嶺土、稀釋劑、潤滑劑、黏合劑、崩解劑及諸如此類者。因為投藥簡易,故錠劑及膠囊代表最佳經口劑量單元形式,此時顯然採用固體醫藥載劑。就非經腸組成物而言,載劑通常包含無菌水,至少大部分,唯可包括其他成份,例如增進溶解度。可製備例如
注射溶液,其中該載劑係包含鹽水溶液、葡萄糖溶液或鹽水與葡萄糖溶液之混合物。亦可製備注射懸浮液,此時可採用適當之液體載劑、懸浮劑及諸如此類者。亦包括在使用前之短時間內轉化成液體形式製劑的固體形式製劑。適於經皮投藥之組成物中,該載劑視情況包含滲透促進劑及/或適當之潤濕劑,視情況結合較低比例之具有任何性質的適當添加劑,該等添加劑不會對皮膚造成明顯傷害。該等添加劑可幫助投藥至皮膚且/或有助於製備所需之組成物。此等組成物可依各種方式投藥,例如以經皮貼劑形式、以滴塗劑形式、以軟膏形式。
本發明化合物亦可經由吸入或吹入藉此方式投藥技術所採用的方法及調配物投藥。因此,本發明化合物通常可於溶液、懸浮液或乾燥粉劑形式投藥於肺部。針對經口或鼻吸入或吹入輸送溶液、懸浮液或乾燥粉劑而發展的任何系統皆適用於本發明化合物之投藥。
本發明化合物亦可於滴劑形式局部投藥,尤其是眼用滴劑。該眼用滴劑可為溶液或懸浮液形式。針對輸送作為眼用滴劑之溶液或懸浮液所發展的任何系統皆適用於本發明化合物之投藥。
特佳係將前述醫藥組成物調配成單元劑型,因為投藥簡便且劑量均勻。本發明所使用之單元劑型係表示適於作為單元劑量之物理上不連續單元,每一單元各含有經計算與所需之醫藥載劑結合而產生所需療效之預定量的活性成份。該等單元劑型之實例有錠劑(包括刻痕錠或
塗錠)、膠囊、丸劑、粉包、薄藥片、栓劑、注射溶液或懸浮液及諸如此類者,及其分離多劑物。
如熟習此技術者所熟知,實際劑量及投藥頻率係視所使用之特定式(I)化合物、所治療之特定病況、特定患者之年齡、體重、性別、病症程度及一般身體狀況及個體可能服用之其他藥劑而定。此外,顯然該有效日劑量可視所治療之個體之反應且/或視處方本發明化合物之醫師的評估而降低或增加。
視投藥模式而定,醫藥組成物較佳係包含0.05至99重量%,更佳0.1至70重量%,再更佳0.1至50重量%之式(I)化合物,及1至99.95重量%,更佳30至99.9重量%,再更佳50至99.9重量%之醫藥上可接受之載劑,所有百分比皆以組成物之總重計。
鑑於前述DGAT抑制劑之影響及/或DGAT抑制劑對GLP-1濃度之影響,本發明亦有關a)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物與二肽基肽酶-4抑制劑(DPP-4抑制劑)之組合物。
DPP-4是一種廣泛表現於許多組織(諸如肝、肺、腎、腸刷狀緣膜、淋巴細胞、內皮細胞)中之跨膜細胞表面胺基肽酶。DPP-4裂解胜肽,使脯胺酸或丙胺酸殘基位於第二胺基末端位置。許多胃腸激素係為DPP-4之受質,尤其是GLP-1。DPP-4抑制劑因而抑制GLP-1之裂解,藉以提供GLP-1濃度之增加。因此,前述組合物可用以
結合DGAT抑制劑及DPP4抑制劑之活性,以提高GLP-1濃度。藉由投予DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物、其醫藥上可接受之鹽或其溶劑合物,與DPP4抑制劑,可定靶不同機制,來達到提高之GLP-1濃度。如此,可使用該種組合物使得提高GLP-1濃度所需之DGAT抑制劑及DPP4抑制劑的劑量較投予DGAT抑制劑或DPP4抑制劑作為單一療劑時降低。因此,此等組合物可降低或消除單一療劑之副作用,而不妨礙增加GLP-1濃度之活性。
而且,DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物及DPP4抑制劑之組合物可作為藥劑。本發明亦有關一種產品,其包含(a)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,及(b)DPP4抑制劑,作為用以同時、分別或依序用於治療可因提高之GLP-1濃度而產生療效之疾病的組合製劑。該種組合物或產品之不同藥物可連同醫藥上可接受之載劑一起組合成單一製劑或其各可連同醫藥上可接受之載劑一起存在於個別製劑。
可與本發明DGAT抑制劑(尤其是DGAT1抑制劑)組合之該DPP4抑制劑可為已知之DPP4抑制劑,諸如例如西他列汀(sitagliptin)、維格列汀(vildagliptin)及蕯沙列汀(saxagliptin)。
b)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物與GLP-1類似物之組合物。該GLP-1類似物可視為在GLP-1受體之促效劑。
而且,DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物及GLP-1類似物之組合物可作為藥劑。本發明亦有關一種產品,其含有(a)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,及(b)GLP-1類似物,作為用以同時、分別或依序用於治療可因提高之GLP-1濃度而產生療效之疾病的組合製劑。該種組合物或產品之不同藥物可連同醫藥上可接受之載劑一起組合成單一製劑或其各可連同醫藥上可接受之載劑一起存在於個別製劑。
可與本發明DGAT抑制劑組合之該GLP-1類似物可為已知之GLP-1類似物,諸如例如艾塞那肽(exenatide)、艾塞那肽(exenatide)LAR或利拉魯肽(liraglutide)。
c)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物與抗糖尿病劑(anti-diabeticum)之組合物。
而且,DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物及抗糖尿病劑(anti-diabeticum)之組合物可
作為藥劑。本發明亦有關一種產品,其含有(a)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,及(b)抗糖尿病劑(anti-diabeticum),作為用以同時、分別或依序用於治療可因提高之GLP-1濃度或DGAT抑制而產生療效之疾病的組合製劑,諸如例如糖尿病,尤其是第II型糖尿病。該種組合物或產品之不同藥物可連同醫藥上可接受之載劑一起組合成單一製劑或其各可連同醫藥上可接受之載劑一起存在於個別製劑。可與本發明DGAT抑制劑組合之該抗糖尿病劑(anti-diabeticum)可為已知之抗糖尿病劑(anti-diabeticum),諸如例如二甲雙胍(metformin)、葛本克醯胺(glibenclamide)、若西葛塔宗(rosiglitazon)、匹格列酮(pioglitazon)、瑞格列奈(repaglinide)、革美皮瑞(glimepiride)、阿卡伯斯(acarbose)、革列齊特(glicazide)、葛皮吉(glipizide)、耐特葛尼(nateglinide)、甲苯磺丁脲(tolbutamide)、蛋白質酪胺酸磷酸酶1抑制劑或11-β-羥基類固醇脫氫酶抑制劑。
d)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物與磷酸二酯酶(PDE)抑制劑,尤其是PDE10A或PDE11A抑制劑之組合物。磷酸二酯酶(PDE)抑制劑,尤其是PDE10A或PDE11A抑制劑,已知係為胰島素促泌劑,藉由抑制劑cAMP之水解來促進GLP-1之訊息傳遞。
而且,DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物及磷酸二酯酶(PDE)抑制劑,尤其是PDE10A或PDE11A抑制劑之組合物可作為藥劑。本發明亦有關一種產品,其含有(a)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,及(b)磷酸二酯酶(PDE)抑制劑,尤其是PDE10A或PDE11A抑制劑,作為用以同時、分別或依序用於治療可因提高之GLP-1濃度或DGAT抑制而產生療效之疾病的組合製劑,諸如例如糖尿病,尤其是第II型糖尿病或肥胖。該種組合物或產品之不同藥物可連同醫藥上可接受之載劑一起組合成單一製劑或其各可連同醫藥上可接受之載劑一起存在於個別製劑。可與本發明DGAT抑制劑組合之該磷酸二酯酶(PDE)抑制劑,尤其是PDE10A或PDE11A抑制劑可為已知之PDE抑制劑,諸如例如罌粟鹼、PQ-10、二吡啶達摩(dipyridamole)、異丁司特(ibudilast)或他達拉非(tadalafil)。
e)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物與食慾抑制劑之組合物。
而且,DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物及食慾抑制劑之組合物可作為藥劑。本發
明亦有關一種產品,其含有(a)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,及(b)食慾抑制劑,作為用以同時、分別或依序用於治療可因提高之GLP-1濃度或DGAT抑制而產生療效之疾病的組合製劑,諸如例如糖尿病,尤其是第II型糖尿病或肥胖。該種組合物或產品之不同藥物可連同醫藥上可接受之載劑一起組合成單一製劑或其各可連同醫藥上可接受之載劑一起存在於個別製劑。可與本發明DGAT抑制劑組合之該食慾抑制劑可為已知之食慾抑制劑,諸如例如若美婷(sibutramine)及吩他明(phentermine)。
f)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物與具有CNS(中樞神經系統)作用模式之抗肥胖藥物,諸如例如CB1拮抗劑或反向促效劑之組合物。
而且,DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物及具有CNS(中樞神經系統)作用模式之抗肥胖藥物的組合物可作為藥劑。本發明亦有關一種產品,其含有(a)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,及(b)具有CNS(中樞神經系統)作用模式之抗肥胖藥物,作為用以同時、分別或依序用於治療可因提高之GLP-1濃度或DGAT抑制而產生療效之疾
病的組合製劑,諸如例如糖尿病,尤其是第II型糖尿病或肥胖。該種組合物或產品之不同藥物可連同醫藥上可接受之載劑一起組合成單一製劑或其各可連同醫藥上可接受之載劑一起存在於個別製劑。可與本發明DGAT抑制劑組合之該具有CNS(中樞神經系統)作用模式的抗肥胖藥物可為已知之抗肥胖藥物,諸如例如利莫那班(Rimonabant)、羅氏鮮(orlistat)、SLV-319或MK-0364。
g)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物與降血脂藥物,諸如例如3-羥基-3-甲基-戊二醯基輔酶A(HMG-CoA)還原酶抑制劑、鯊烯合成酶抑制劑、FXR(法尼酯衍生物X受體)及LXR(肝X受體)配位體、消膽胺(cholestyramine)、纖維酸衍生物、菸鹼酸及阿斯匹靈之組合物。
而且,DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物及降血脂藥物之組合物可作為藥劑。本發明亦有關一種產品,其含有(a)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,及(b)降血脂藥物,作為用以同時、分別或依序用於治療可因提高之GLP-1濃度或DGAT抑制而產生療效之疾病的組合製劑,諸如例如糖尿病,尤其是第II型糖尿病或肥胖。該種組合物或產品之不同藥物可連同醫藥上可接受之載劑一起組合
成單一製劑或其各可連同醫藥上可接受之載劑一起存在於個別製劑。可與本發明DGAT抑制劑組合之該降血脂藥物可為已知之降血脂藥物,諸如例如洛唯司汀(lovastatin)、辛唯司汀(simvastatin)、普瑞唯司汀(pravastatin)、西瑞唯司汀(cerivastatin)、美唯司特汀(mevastatin)、維洛司汀(velostatin)、弗唯司汀(fluvastatin)、達唯司汀(dalvastatin)、阿托唯司汀(atorvastatin)、羅蘇代他汀(rosuvastatin)及瑞唯司汀(rivastatin)。
h)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物與過氧化物酶體增殖物活化物之促效劑(諸如例如非諾貝特(fenofibrate))之組合物。
而且,DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物及過氧化物酶體增殖物活化物之促效劑,諸如例如非諾貝特(fenofibrate)的組合物可作為藥劑。本發明亦有關一種產品,其含有(a)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,及(b)過氧化物酶體增殖物活化物之促效劑,諸如例如非諾貝特(fenofibrate),作為用以同時、分別或依序用於治療可因提高之GLP-1濃度或DGAT抑制而產生療效之疾病的組合製劑,諸如例如糖尿病,尤其是第II型糖尿病或肥胖。
該種組合物或產品之不同藥物可連同醫藥上可接受之載劑一起組合成單一製劑或其各可連同醫藥上可接受之載劑一起存在於個別製劑。
i)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物與抗高血壓劑之組合物。
而且,DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物及抗高血壓劑之組合物可作為藥劑。本發明亦有關一種產品,其含有(a)DGAT抑制劑,尤其是DGAT1抑制劑,特別是式(I)化合物、其N-氧化物形式、其醫藥上可接受之鹽或其溶劑合物,及(b)抗高血壓劑,作為用以同時、分別或依序用於治療可因提高之GLP-1濃度或DGAT抑制而產生療效之疾病的組合製劑,諸如例如糖尿病,尤其是第II型糖尿病或肥胖。該種組合物或產品之不同藥物可連同醫藥上可接受之載劑一起組合成單一製劑或其各可連同醫藥上可接受之載劑一起存在於個別製劑。可與本發明DGAT抑制劑組合之該抗高血壓劑可為已知之抗高血壓劑,例如亨利環利尿劑,諸如伊他尼酸(ethacrynic acid)、呋塞米(furosemide)及托塞米(torsemide),血管收縮素轉化酶(ACE)抑制劑,諸如本那扎比(benazepril)、巰甲丙脯酸(captopril)、乙氧苯丙脯酸(enalapril)、弗辛諾普利(fosinopril)、里辛諾普利(lisinopril)、莫西普利(moexipril)、貝諾普利
(perinodopril)、喹哪普利(quinapril)、瑞普利(rampril)及垂朵普利(trandolapril);Na-K-ATP酶膜泵之抑制劑,諸如地高辛(digoxin);中性內肽酶(NEP)抑制劑;ACE/NEP抑制劑諸如歐馬帕垂列(omapatrilat)、山帕垂列(sampatrilat)及法西朵垂(fasidotril);血管收縮素II拮抗劑,諸如坎得沙滇(candesartan)、伊波沙滇(eprosartan),以爾貝沙滇(irbesartan)、洛沙滇(losartan)、特米少滇(telmisartan)及唯沙滇(valsartan),尤其是唯沙滇(valsartan);腎素抑制劑,諸如地替吉崙(ditekiren)、札吉崙(zankiren)、特列吉崙(terlakiren)、阿利吉崙(aliskiren)、RO 66-1132及RO-66-1168;β-腎上腺素受體阻斷劑,諸如醋丁洛爾(acebutolol)、阿滇洛爾(atenolol)、貝他洛爾(betaxolol)、比索洛爾(雙oprolol)、美托洛爾(metoprolol)、那得洛爾(nadolol)、普潘洛爾(propranolol)、索塔洛爾(sotalol)及提莫洛爾(timolol);強心劑,諸如地高辛(digoxin)、多巴酚丁胺(dobutamine)及米力農(milrinone);鈣通道阻斷劑,諸如恩洛氐平(amlodipine)、苄普地爾(bepridil)、地爾硫(diltiazem)、非洛氐平(felodipine)、尼卡氐平(nicardipine)、尼莫氐平(nimodipine)、尼非氐平(nifedipine)、尼索氐平(nisoldipine)及維拉帕米(verapamil);醛固酮受體拮抗劑;且醛固酮合成酶抑制劑。
以下實施例係用以說明本發明。
下文中,術語「m.p.」表示熔點,「THF」係表示四氫呋喃,「EtOAc」係表示乙酸乙酯,「MeOH」係表示甲醇,「DIPE」係表示二異丙基醚,「DMF」係表示N,N
-二甲基甲醯胺,「Et3
N」或「TEA」係表示三乙基胺,「DPPENT」係表示1,1'-(1,5-戊二基)雙[1,1'-二苯膦],「連接樹脂-N=C=O」係表示經異氰醯基官能化以聚苯乙烯為主之樹脂,諸如例如1-乙烯基-4-(異氰醯基甲基)-苯聚合物與乙烯基苯,「PS-碳化二亞胺」係表示鍵結於聚苯乙烯樹脂之N
-環己基碳化二亞胺,「PS-NMM」表示3-(嗎褔啉基)丙基聚苯乙烯磺醯胺(鍵結於樹脂之等效N
-甲基嗎褔啉),「PS-TsOH」係表示聚苯乙烯-對-甲苯磺酸,“PS-Trisamine”係表示參-(2-胺基乙基)-胺基甲基聚苯乙烯HL(200-400目),「DECP」係表示氰基膦酸二乙酯,「Et2
O」係表示二乙醚,「p.a.」係表示分析專用,「eq.」係表示當量,「DIPEA」係表示二異丙基乙基胺,「TFA」係表示三氟乙酸,「TBTU」係表示四氟硼酸O-苯并三唑基四甲基異脲鎓,且「MP-碳酸鹽」係為粗孔性甲基聚苯乙烯碳酸三乙基銨(粗孔性聚苯乙烯陰離子-交換樹脂,其係鍵結於樹脂之等效碳酸四烷基銨)。
ArgoScoopTM
樹脂(Biotage)分配器係為設計用以便利地分配聚合物清除劑及試劑的可變體積樹脂勺。
MiniBlockTM
(Mettler Toledo)係為設計用於併行合成之可變通、易使用之工具。
a.製備中間物1
[4-(4-六氫吡啶基)苯基]胺基甲酸1,1-二甲基乙基酯(0.025莫耳)於CH2
Cl2
(100毫升)中之混合物在冰浴上冷卻下加以攪拌。逐滴添加1,3-二氯-2-異氰醯基苯(0.027莫耳)於CH2
Cl2
(25毫升)中之溶液。使反應混合物溫至室溫。反應混合物於室溫攪拌一小時。濾出形成之沉澱物,以DIPE洗滌並乾燥。產量:6.2克之中間物1。蒸發對應之濾液溶劑。殘留物於DIPE下濕磨,濾出並乾燥。產量:4.2克之中間物1。
b.製備中間物2
中間物1(根據A1.a製備)(0.022莫耳)及三氟乙酸(25毫升)於CH2
Cl2
(250毫升)中之混合物於室溫攪拌2小時。蒸發溶劑。殘留物於DIPE下濕磨,濾出並乾燥。此部分(11.2 g)藉添加氨水轉化成游離鹼。此混合物以DCM萃取。分離之有機層經乾燥,過濾並蒸發溶劑。產量:7.6克之中間物2。
c.製備中間物3
3-[[(1,1-二甲基乙氧基)羰基]胺基]-2-甲基丙酸(0.001莫耳)溶解於DMF(5毫升)以得到儲液(I)。部分儲液(I)(1.2毫升,含有0.00024莫耳之3-[[(1,1-二甲基乙氧基)羰基]胺基]-2-甲基丙酸)置入MiniBlock內。以ArgoScoop添加PS-碳化二亞胺,1.9毫莫耳/克(0.0004莫耳)。添加1-羥基-1H
-苯并三唑(0.00030莫耳)於DMF(1毫升)中之溶液,混合物迴盪30分鐘。添加中間物2(根據A1.b製備)(0.0002莫耳)於DMF(3.5毫升)中之溶液反應混合物迴盪隔夜。以ArgoScoop添加MP-碳酸鹽,2.8毫莫耳/克(0.00090莫耳)及連接樹脂-N=C=O,1.8毫莫耳/克(0.0002莫耳)。反應混合物迴盪隔夜,然後過濾。添加CH2
Cl2
(4毫升),混合物迴盪2小時。過濾混合物並蒸發濾液溶劑(Genevac溶劑蒸發器)。殘留物(±0.120克)藉HPLC純化。收集產物溶離份且加以處理。產量:0.008克之中間物3。
a.製備中間物4
1-(4-硝基苯基)-六氫吡(0.02413莫耳)於CH2
Cl2
p.a.(100毫升)中之混合物在冰浴上攪拌。之後在反應混合物於冰浴上攪拌下逐滴添加在CH2
Cl2
p.a.(20毫升)中之1,3-二氯-2-異氰醯基苯(0.02660莫耳)。在2小時期間,使反應混合物溫至室溫且於室溫攪拌。過濾反應混合物且以DIPE洗滌(適量)於真空中乾燥沉澱物。產量:8.923克之中間物4(94%;黃色粉末)
b.製備中間物5
中間物4(根據A2.a製備)(0.047莫耳)於MeOH(200毫升)、THF(200毫升)及CH3
OH中之NH3
(100毫升)中之混合物於室溫攪拌15分鐘,隨後於室溫(大氣壓)以Pt/C 5%(4克)作為觸媒於噻吩溶液存在下(3毫升;於DIPE中4%)氫化。吸收H2
後(3當量),濾出觸媒(產物亦為沉澱物,因此藉以DCM洗滌過濾殘留物而溶解)。蒸發結合之濾液溶劑。產量:14.616克之中間物5。
a.製備中間物6
2-甲基-4-噻唑甲酸乙基酯(0.1莫耳)、1-碘-4-(1-甲基乙基)苯(0.3莫耳)、KOAc(0.3莫耳)、Pd(OAc)2
(0.005莫耳)及DPPENT(0.001莫耳)於1-甲基-2-吡咯啶酮(150毫升)中之混合物於140℃攪拌24小時。反應混合物倒出至水中且以EtOAc萃取四次。結合有機層,水洗兩次,乾燥,過濾並蒸發溶劑。產量:中間物6(粗製物,使用於後續反應步驟,不另外純化)。
b.製備中間物7
中間物6(根據A3.a製備)(約0.1莫耳;粗製物)於H2
O(500毫升)及MeOH(500毫升)中之混合物於室溫攪拌。分批添加KOH(0.3莫耳)且反應混合物於室溫攪拌過週末。蒸發溶劑。殘留物溶入水中。此混合物以3 x CH2
Cl2
洗滌。分層。水相酸化至pH=3。酸性混合物以CH2
Cl2
萃取四次。分離之有機層經乾燥,過濾並蒸發溶劑。殘留物(21克)藉HPLC純化(梯度溶離使用(於水中0.5% NH4
OAc/CH3
CN 90/10)/MeOH/CH3
CN)。收集產物溶離份並蒸發溶劑。殘留物溶入水中且酸化至pH=2-3。此混合物以CH2
Cl2
萃取。分離之有機層經乾燥,過濾並蒸發溶劑。殘留物(10克)於DIPE中攪拌,濾出並乾燥。產量:中間物7(粗製物;於原有狀態使用於後
續反應步驟)。
a.製備中間物8
4-[4-(苯基甲基)-1-六氫吡基]苯胺(0.185莫耳)於CH2
Cl2
p.a.(1500毫升)及Et3
N(50毫升)中之混合物於冰浴上攪拌5分鐘。逐滴添加4'-(三氟甲基)-[1,1'-聯苯]-2-羰基氯(0.37莫耳)。混合物攪拌3小時。有機層經水洗、乾燥,過濾並蒸發溶劑。殘留物於DIPE中濕磨。濾出沉澱物並乾燥。產量:99.8克之中間物8(100%)。
b.製備中間物9及10
中間物8(根據A4.a製備)(0.19莫耳)於MeOH(600毫升)及THF(600毫升)中之混合物使用Pd/C 10%(3克)作為觸媒氫化隔夜。吸收H2
後(1當量),濾出觸媒且蒸發濾液。殘留物於DIPE中濕磨。濾出沉澱物並乾燥。產量:76克(94%)。一部分化合物依技術界已知方法轉
化成HCl鹽,產生中間物10(HCl-鹽)。(一部分(1克)之此溶離份自2-丙醇再結晶。濾出沉澱物並乾燥。產量:0.36克之中間物10)。其餘粗產物溶於H2
O。此混合物服Na2
CO3
調鹼且隨之以CH2
Cl2
萃取。分離有機層,乾燥,過濾並蒸發溶劑。殘留物於DIPE中濕磨。濾出沉澱物並乾燥。產量:中間物9。
a.製備中間物11
[4'-(三氟甲基)-[1,1'-聯苯]-2-甲酸(0.09莫耳)於CH2
Cl2
(500毫升)及DMF(5毫升)中之混合物進行攪拌。逐滴添加乙二醯氯(0.09莫耳)。混合物攪拌1小時(混合物A)。4-[1-(苯基甲基)-4-六氫吡啶基]-苯胺.鹽酸鹽(0.046莫耳)於CH2
Cl2
(500毫升)及Et3
N(20毫升)中於冰浴上攪拌且此混合物逐滴添加至混合物A。反應混合物攪拌並回流隔夜,隨之冷卻並水洗。分離有機層,乾燥,過濾並蒸發溶劑。殘留物藉著於矽膠上管柱層析純化(溶離劑:CH2
Cl2
/CH3
OH 98/2)。收集所需之產物溶離份並蒸發溶劑。殘留物於DIPE中濕磨。濾出沉澱物並乾燥。產量:5.6克之中間物11。
b.製備中間物12
中間物11(根據A5.a製備)(0.025莫耳)於CH3
OH(250毫升)中之混合物使用Pd/C 10%(2克)作為觸媒於50℃氫化隔夜。吸收H2
後(1當量),濾出觸媒且蒸發濾液。殘留物於DIPE中濕磨。濾出沉澱物並乾燥。產量:7.7克之中間物12(73%)。
a.製備中間物13
[4'-(三氟甲基)-1,1'-聯苯]-2-羰基氯(0.12莫耳)逐滴添加至4-[1,2,3,6-四氫-1-(苯基甲基)-4-吡啶基]苯胺(根據WO2002/081460
中之教示製備,該內容係以引用方式併入本文)(0.095莫耳)於CH2
Cl2
p.a.(300毫升)及Et3
N(50毫升)中之攪拌混合物中。混合物攪拌隔夜,倒出至水中且隨之攪拌30分鐘。分離有機層,洗滌,乾燥,過濾並蒸發溶劑。殘留物於DIPE中濕磨。濾出沉澱物並乾燥。產量:43克(88%)。一部分(2克)之此溶離份自EtOH再結晶。濾出沉澱物並乾燥。產量:1.32克之中間物13。
b.製備中間物14
氯甲酸1-氯乙酯(0.078莫耳)逐滴添加至中間物13(根據A6.a製備)(0.039莫耳)於1,2-二氯乙烷(500毫升)中之攪拌混合物中。混合物攪拌30分鐘且隨之攪拌並回流隔夜。蒸發溶劑。添加CH3
OH(500毫升)。混合物攪拌並回流隔夜。蒸發溶劑。殘留物於DIPE中濕磨。濾出沉澱物並乾燥。產量:20.8克之中間物14(126%)。
a.製備中間物15
2-碘-苄酸甲基酯(0.20莫耳)、2-乙基-4-甲基噻唑(0.20莫耳)、Pd(OAc)2
(1.120克)、1,3-丙烷二基雙[二苯基膦](4.120克)及Cs2
CO3
(65克)於1-甲基-2-吡咯啶酮(200毫升)中之混合物於140℃攪拌36小時。添加更多Cs2
CO3
(32.5克)及2-碘-苄酸甲基酯(0.1莫耳)及觸媒且反應混合物於140℃攪拌16小時。反應混合物倒出至水中且以EtOAc萃取。結合有機層,水洗、乾燥,過濾並蒸發溶
劑。產量:中間物15(粗製物;於原有狀態使用於後續反應步驟)。
b.製備中間物16
中間物15(根據A7.a製備)(0.00765莫耳)於THF(20毫升)、CH3
OH(20毫升)及NaOH,1N(20毫升)中之混合物於室溫攪拌16小時。蒸發溶劑。殘留物溶入水中。此混合物以3 x CH2
Cl2
洗滌。分層。水相以1N HCl酸化(20毫升)。酸性混合物以CH2
Cl2
萃取。分離之有機層經乾燥,過濾並蒸發溶劑。殘留物於DIPE中攪拌,濾出並乾燥。產量:0.450克之中間物16。
a.製備中間物17
2-甲基-4-噻唑甲酸乙基酯(0.054莫耳)、5-溴-1,3-苯并二氧雜環戊烯(0.18莫耳)、Pd(OAc)2
(1.041克)、1,3-丙烷二基雙[二苯基膦](3.831克)及KOAc(18.6克)於1-甲基-2-吡咯啶酮(30毫升)中之混合物於140℃攪拌16小
時。反應混合物倒出至水中且以EtOAc萃取。結合有機層,水洗、乾燥,過濾並蒸發溶劑。產量:中間物17(粗製物,於原有狀態使用於後續反應步驟)。
b.製備中間物18
中間物17(根據A8.a製備)(0.054莫耳)於CH3
OH(100毫升)及NaOH,1 N(100毫升)中之混合物於室溫攪拌16小時。蒸發溶劑。殘留物溶入水中。此混合物以CH2
Cl2
洗滌3次。分層。水相以1N HCl中和(100毫升)。混合物以CH2
Cl2
萃取(3次)。分離之有機層經乾燥,過濾並蒸發溶劑。產量:2.5克之中間物18。
因而製得中間物2-甲基-5-(3-三氟甲基-苯基)-噻唑-4-甲酸(參見B1.b)
a.製備中間物19
3-吡咯啶-1-基苯胺(8克,0.0478莫耳)溶於CH2
Cl2
(50毫升)。首先添加Et3
N(25毫升,0.178莫耳)且隨之4-[4-(苯基甲基)-1-六氫吡基]-苄酸(11.27克,0.038莫耳),且添加更多CH2
Cl2
(100毫升)。最後,添加DECP(11.37毫升,0.0761莫耳)且反應混合物攪拌18小時。之後,混合物於NaHCO3
溶液中攪拌。分層且將有機層乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發。殘留物藉著於矽膠上管柱層析純化(溶離劑:CH2
Cl2
/MeOH 98/2)。收集最純之溶離份並蒸發溶劑。殘留物於Et2
O中攪拌,濾出並洗滌(Et2
O)。將產物乾燥(50℃,48小時,於真空中)。產量:9.437克之中間物19(55%)。
b.製備中間物20
Pd/C 10%(1克)於N2
流下懸浮於MeOH(150毫升)中。添加中間物19(5.62克,0.0126莫耳)且反應混合物50℃在H2
氛圍下攪拌直至吸收1當量H2
。以矽藻土(Dicalite)濾出觸媒。蒸發溶劑並以甲苯共同蒸發。殘留物於Et2
O中攪拌並濾出。將產物乾燥(50℃,18小時,
於真空中)。產量:4.23克之中間物20(96%)。
a.製備中間物21
將CH2
Cl2
(75毫升)添加至4-胺基-3,5-二氯-苯乙酸(2.86克,0.013莫耳)並攪拌混合物。添加Et3
N(5.5毫升,0.0391莫耳)及吡咯啶(1.3毫升,0.0158莫耳)。最後添加DECP(2.5毫升,0.015莫耳)。反應混合物置於N2
流下數分鐘且隨之關閉容器。18小時後,添加NaHCO3
溶液並分層。將分離之有機層乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發。殘留物(4.317克)藉著於矽膠上管柱層析純化(溶離劑:CH2
Cl2
/MeOH 97/3)。收集所需之溶離份,蒸發溶劑並以甲苯共同蒸發。產量:3.104克之中間物21(88%)。
b.製備中間物22
硼烷於THF中之溶液(30毫升,0.03莫耳;1 M溶液)添加至在THF(60毫升;無水)中之中間物21(2.88克,0.0105莫耳)中且反應混合物回流18小時。之後,混合物冷卻至室溫,混合物添加至H2
O(300毫升)及濃HCl
(300毫升)於冰浴上之攪拌溶液中。此混合物回流30分鐘。之後,混合物冷卻,置於冰浴上,並緩緩添加K2
CO3
粉末以鹼化混合物。在pH 8下,將CH2
Cl2
及H2
O添加於混合物(進行萃取)。分層。將有機層乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發。殘留物於Et2
O中攪拌且此混合物以HCl(1 N)萃取兩次。結合HCl層,以(NaHCO3
)中和至pH 8,且以CH2
Cl2
及H2
O萃取。分層且將有機層乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發。將殘留物乾燥(50℃,18小時,於真空中)。產物於Et2
O中以HCl/Et2
O(15毫升;1 M)攪拌。濾出產物並以Et2
O洗滌產生3.05克之中間物22(98%;.HCl)。
c.製備中間物23
中間物22(3克,0.0101莫耳)於室溫下溶於HCl於Et2
O中之溶液(10毫升,0.01莫耳;1 M溶液)及CH3
CN(150毫升;無水)中。混合物攪拌30分鐘。20%光氣之甲苯溶液(7.6毫升,0.0152莫耳)分批添加並攪拌混合物20小時。過濾混合物,蒸發混濁濾液並以甲苯共同蒸發(無水)產生2.89克之粗製中間物23(99%最大產量)。
a.製備中間物24及25
2,6-二氯-4-氯甲基-苯基胺(11克,0.0445莫耳)分批添加於吡咯啶(15.84克,0.223莫耳)於CH3
CN(250毫升)中之攪拌溶液中。反應混合物置於水浴中(放熱反應)。蒸發溶劑且殘留物溶於CH2
Cl2
(150毫升)及50%飽和NaHCO3
溶液(100毫升)。混合物攪拌15分鐘。分離有機層,乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發。油狀殘留物(11.46克)於DIPE中攪拌(30毫升)15分鐘,隨之再次蒸發DIPE。殘留物與2.65克之另一批物質結合,整體之粗產物藉著於矽膠上管柱層析純化(溶離劑:CH2
Cl2
/MeOH 95/5)。結合純溶離份,蒸發溶劑並以甲苯共同蒸發。殘留物於DIPE(25毫升)中攪拌。自固體傾除DIPE,產生DIPE層(*
)及固體。將固體上殘留之DIPE蒸發且將固體乾燥(50℃,於真空中
),產生2.75克之中間物24(28.18%)。結合管柱之不純溶離份,蒸發溶劑並以甲苯共同蒸發。殘留物(7.45克)溶於DIPE(20毫升),在劇烈攪拌混合物下添加6N HCl之2-丙醇溶液(5毫升)。形成帶黃色之油,此油在持續攪拌後變成固體。濾出固體並以DIPE洗滌,產生濾液(*
)及固體。將固體乾燥(50℃,於真空中
)。產量:5.19克之中間物25(41.37%;.HCl)。結合濾液(*
)及DIPE層(*
)並蒸發溶劑。殘留物(2.59克)溶於CH2
Cl2
及NaHCO3
之H2
O溶液中。分層
且將有機層乾燥(MgSO4
),過濾並將溶劑部分蒸發。濃縮溶液於矽膠上再次純化(溶離劑:CH2
Cl2
/MeOH 95/5)。收集純溶離份,蒸發溶劑並以甲苯共同蒸發。將殘留物乾燥(50℃,18小時,於真空中)。產量:1.85克之中間物24(17%)。
b.製備中間物26
HCl之Et2
O溶液(10.32毫升,0.0206莫耳;1 M)添加至中間物24(4.6克,0.0188莫耳)於CH3
CN(75毫升;p.a.,以分子篩乾燥)及CH2
Cl2
(10毫升;p.a.)中之攪拌溶液中。混合物攪拌1小時。形成沉澱物。反應混合物於冰浴上冷卻,添加20%光氣之甲苯溶液(14.073毫升)。反應混合物攪拌3小時。添加額外量之20%光氣之甲苯溶液(7毫升),且反應混合物於室溫再攪拌18小時。濾出產物,以CH3
CN(3x)洗滌並乾燥(50℃,1小時,於真空中),產生5.45克之中間物26(94%;.HCl)。此中間物立即使用於後續反應步驟(吸濕性中間物)。
c-1.製備中間物27
1-(4-乙氧基羰基苯基)六氫吡(3.732克,0.0159莫耳)添加至中間物26(4.9克,0.0159莫耳)及CH2
Cl2
(100毫升)之攪拌混合物中。添加Et3
N(4.478毫升)且溶液於室溫攪拌18小時。之後,混合物以飽和NaHCO3
水溶液洗滌,乾燥(MgSO4
),過濾並蒸發溶劑。殘留物於Et2
O中攪拌並濾出固體,以Et2
O(3 x)洗滌並乾燥(50℃,於真空中
)。產量:6.55克之中間物27(81%)。
c-2.製備中間物37
中間物26(約24毫莫耳,粗製物)分批添加於1-(4-硝基苯基)六氫吡(5克,24毫莫耳)於Et3
N(10毫升,7.2毫莫耳)及CH2
Cl2
(125毫升;p.a.)中之攪拌溶液(溫度達到約30℃)。反應混合物於室溫攪拌4小時,隨後以H2
O洗滌。將分離之有機層乾燥(MgSO4
),過濾並蒸發溶劑。殘留物以二氧化矽過濾(溶離劑:CH2
Cl2
/MeOH 96/4)。結合最純之溶離份,蒸發溶劑並以甲苯共同蒸發。殘留物於DIPE中攪拌,濾出並乾燥(50℃,於真空中
)。產量:2.9克之中間物37。
d-1.製備中間物28
中間物27(5.88克,0.0116莫耳)添加至1,4-二烷(75毫升)中並攪拌混合物。添加NaOH溶液(35毫升,0.035莫耳;1 M)並於室溫攪拌混合物72小時。之後,添加MeOH(25毫升)並再次攪拌混合物72小時。之後添加HCl(35毫升;1 N)並攪拌混合物18小時。濾出固體並以H2
O洗滌。將固體乾燥(50℃,24小時,於真空中)。產量:4.88克之中間物28(88%)。
d-2.製備中間物38
中間物37(2.19克,0.00458莫耳)於乙酸(125毫升)中之溶液於噻吩溶液存在下(0.3毫升;於DIPE中4%)使用Pt/C 5%(0.5克)作為觸媒進行氫化。吸收3當量H2
之後,濾出觸媒。蒸發溶劑(40℃水浴)。殘留物於CH2
Cl2
中攪拌且此溶液以半飽和NaHCO3
水溶液洗滌。將有機層乾燥(MgSO4
),過濾並蒸發溶劑。殘留物於矽膠上純化(溶離劑:CH2
Cl2
/MeOH 93/7)。結合所需之溶離份,
蒸發溶劑並以甲苯共同蒸發,產生中間物38。
a.製備中間物29
於室溫將DECP(12.5毫升,0.0836莫耳)添加至1-第三丁氧基羰基-4-(4-胺基苯基)六氫吡(15.12克,0.0545莫耳)及3-(1-吡咯啶基)苄酸(11.47克,0.06莫耳)於Et3
N(23毫升,0.164莫耳)及CH2
Cl2
(200毫升)中之攪拌溶液中。20小時後,添加飽和NaHCO3
溶液並分層。將CH2
Cl2
層乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發。殘留物於Et2
O中攪拌,濾出,以E2
O洗滌並乾燥(50℃,20小時,於真空中)。產量:24.682克之中間物29(90%)。
b.製備中間物30
於室溫將TFA(25毫升)添加至中間物29(15克,0.03莫耳)於CH2
Cl2
(50毫升)中之攪拌溶液中。18小時後,蒸發溶劑。殘留物於H2
O及CH2
Cl2
中攪拌並以Na2
CO2
粉末及NaHCO3
中和直至混合物為鹼性。反應混合物攪拌48小時。之後,分層。將有機層乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發。殘留物於DIPE中攪拌,濾出並乾燥(50℃,18小時,於真空中)。之後,產物於CH3
CN中回流。混合物冷卻至室溫,濾出固體並乾燥(50℃,18小時,於真空中)。產量:8.580克之中間物30(75%)。
a.製備中間物31
將CH2
Cl2
(25毫升)添加至4-胺基-3,5-二氯-苯乙酸(0.754克,0.00343莫耳)中並攪拌混合物。添加Et3
N(1.45毫升,0.0103莫耳)及1-甲基六氫吡(0.46毫升,0.00415莫耳)。添加DECP(0.65毫升,0.00391莫耳)was added,混合物以N2
沖洗且關閉。反應混合物於室溫攪拌72小時。之後,混合物在NaHCO3
於H2
O中之飽和溶液中攪拌並分層。將有機層乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發。殘留物於CH2
Cl2
及飽和K2
CO3
水溶液中攪拌。分層(添加額外量之H2
O以進行良好分離。將CH2
Cl2
層乾燥(MgSO4
),過濾並蒸發溶劑,且以二甲苯共同蒸發。殘留物溶於DIPE,添加HCl/2-丙醇(3毫升;6 N)。混合物攪拌15小時,隨之濾出固體,以DIPE洗
滌並乾燥(50℃,1小時,於真空中)。產量:1.3克之中間物31(99%;.HCl)。
b.製備中間物32
中間物31(1.3克,0.00384莫耳)於0℃溶於HCl之Et2
O溶液(4.2毫升,0.0042莫耳;1 M溶液)及CH3
CN(20毫升;無水)中。於攪拌下添加20%光氣之甲苯溶液(5.8毫升,0.0116莫耳)。2小時後,移除冰浴,混合物於室溫攪拌50小時。添加額外量之20%光氣之甲苯溶液(1.92毫升)並攪拌混合物36小時。之後添加第三份20%光氣之甲苯溶液(1毫升)並攪拌混合物18小時。蒸發溶劑且以無水甲苯共同蒸發。殘留物(1克粗製中間物32;最大量產量)直接於原有狀態使用於後續反應步驟。
a.製備中間物33及33'
2,6-二氯-4-氯甲基-苯基胺(3.68克,0.0149莫耳)分批添加於1-甲磺醯基六氫吡(2.971克,0.0181莫耳)及二異丙基胺(8.2毫升,0.058莫耳)於CH3
CN(100毫升)在
水浴上之攪拌溶液中。反應混合物於室溫攪拌18小時。產物藉逆相高效液相層析純化(Shandon HyperprepC18 BDS(鹼去活化二氧化矽)8 μm,250克,I.D.5厘米)。以3種移動相施加梯度。A相:90%之0.5%NH4
OAc水溶液+10%CH3
CN;B相:CH3
OH;C相:CH3
CN)。收集不同產物溶離份並加以處理。蒸發溶劑並以甲苯共同蒸發,產生2.24克之中間物33'及0.732克之所需中間物33(18%)。
b.製備中間物34
中間物33(0.732克,0.00266莫耳)溶於HCl之Et2
O溶液(3.2毫升,0.0032莫耳;1 M)及CH3
CN(20毫升;無水)中,混合物於室溫攪拌30分鐘。之後分批添加20%光氣之甲苯溶液(2毫升,0.004莫耳;2 M)。反應混合物攪拌3小時,接著蒸發溶劑且以無水甲苯共同蒸發。殘留物(粗製中間物34)溶於CH2
Cl2
中且此溶液立即使用於後續反應步驟。
a.製備中間物35
NaH(0.396克,0.0099莫耳;60%)於N2
氛圍下分批添加於2,6-二氯phenol於THF(50毫升;p.a.,以分子篩乾燥)中之攪拌溶液中。混合物攪拌15分鐘且隨後添加4-(4-硝基苯基)-1-六氫吡羰基氯(0.89克,0.0033莫耳)。反應混合物於室溫持續攪拌1小時,接著回流18小時。混合物冷卻至室溫且倒入冰水(200毫升)。此混合物攪拌15分鐘,之後濾出產物,以H2
O洗滌並乾燥(50℃,於真空中
)。產量:1.3克之中間物35(99%)。
b.製備中間物36
中間物35(1.3克,0.00328莫耳)於乙酸(50毫升)及噻吩溶液(6.901毫升,0.00328莫耳;4% DIPE溶液)中之溶液以Pt/C 5%(0.3克)作為觸媒進行氫化。吸收3當量之H2
之後,濾出觸媒。蒸發濾液並以甲苯共同蒸發(2 x)。殘留物溶於CH2
Cl2
中且溶液以飽和NaHCO3
水溶液洗滌。分層且將有機層乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發。殘留物於Et2
O中攪拌,濾出並以Et2
O洗滌(3x)。將產物乾燥(50℃,於真空中
)。產量:0.94
克之中間物36。
a.製備中間物39
2,6-二氯-4-甲基-苯乙酸甲基酯(10.27克,0.044莫耳)溶於100毫升之CCl4
中。之後,將N-溴琥珀醯亞胺(0.053莫耳)及2,2'-(1,2-二氮烯二基)雙[2-甲基丙腈](0.0022莫耳)添加於溶液中。形成之混合物回流10小時。將溶液冷卻且通經矽膠層。矽膠以CCl4
(約100毫升)及己烷(約200毫升)洗滌。結合之濾液於真空中濃縮。所得之殘留物於冷卻後變成結晶(12.85克)。自己烷再結晶後得到10.30克之中間物39。
b.製備中間物40
將中間物39(8.682克)及吡咯啶(6.86毫升)混合並於90至100℃加熱5分鐘。添加H2
O(50毫升),形成之混合物以CH2
Cl2
萃取(3 x 50毫升)。分離結合之有機層,以硫酸鈉乾燥並於真空中蒸發。所得之殘留物(8.178克之棕色油)以HCl之乙醚溶液(2 M,25毫升)處理。得到半結晶之況澱物。傾除過量之HCl乙醚溶液,添加一些
乙醚(約30毫升),且於攪拌下逐滴添加一些丙酮,直至形成結晶產物。濾出所形成之沉澱物,以丙酮洗滌並風乾。產量:5.347克之中間物40(.HCl)。
c.製備中間物41
中間物40(5.00克,14.76毫莫耳)及LiOH.H2
O(1.24克,29.53毫莫耳)溶於H2
O(20毫升)及MeOH(40毫升)之混合物中並回流20分鐘。之後添加HClconc
(3毫升),混合物於真空中蒸發。之後添加HClconc
(5毫升),形成之懸浮液以丙酮(約20毫升)稀釋。懸浮液回流5分鐘且冷卻至室溫。濾出所形成之帶黃色結晶產物,以丙酮洗滌並風乾。產量:3.791克之中間物41(.HCl)(79%)。
a.製備中間物42
4-(4-胺基苯基)-1-六氫吡甲酸1,1-二甲基乙基酯(1.00克,3.61毫莫耳)、1,3-苯二甲酸1-甲基酯(4.33毫莫耳)、四氟硼酸O-苯并三唑基四甲基異脲鎓(TBTU)(5.03毫莫耳)及Et3
N(1.50毫升,10.7毫莫耳)混合於CH3
CN(10毫升)中且於室溫攪拌5小時。自反應混合物
濾出結晶產物,以H2
O洗滌並風乾。產量:1.262克之中間物42(80%)。
b.製備中間物43
將4 N HCl之1,4-二烷溶液(5毫升,20毫莫耳)添加至中間物42(1.262克,2.87毫莫耳)及15毫升二烷之混合物中。形成之漿液於45側50℃攪拌30分鐘。混合物冷卻至室溫,濾出結晶產物,以丙酮、己烷洗滌,並於真空中乾燥。產量:1.118克之中間物43(95%;.2 HCl)。
a.製備化合物1
1-(1,1-二甲基乙基)-1,3-吖丁啶二甲酸酯(0.001莫耳)溶於DMF(5毫升)中以得到儲液(I)。將一部分儲液(I)(1.2毫升,含有0.00024莫耳之1-(1,1-二甲基乙基)-1,3-吖丁啶二甲酸酯)置入MiniBlock內。以ArgoScoop添加PS-碳化二亞胺,1.9毫莫耳/克(0.0004莫耳)。添加1-羥基-1H
-苯并三唑(0.00030莫耳)於DMF(1毫升)中之溶液,
混合物迴盪30分鐘。添加中間物2(根據A1.b製備)(0.0002莫耳)於DMF(3.5毫升)中之溶液且反應混合物迴盪隔夜。以ArgoScoop添加MP-碳酸鹽,2.8毫莫耳/克(0.00090莫耳)及連接樹脂-NCO,1.8毫莫耳/克(0.0002莫耳)。反應混合物迴盪隔夜,然後過濾。添加CH2
Cl2
(4毫升),混合物迴盪2小時。過濾混合物並蒸發濾液之溶劑(Genevac溶劑蒸發器)。殘留物(±0.120克)藉HPLC純化。收集產物溶離份並加以處理。產量:0.014克之化合物1。
b.製備化合物2
中間物7(根據A3.b製備)(0.00012莫耳)溶於DMF(1.2毫升)中。添加PS-碳化二亞胺,2.1毫莫耳/克(0.0002莫耳)及1-羥基-1H
-苯并三唑(0.00015莫耳)were added.反應混合物迴盪30分鐘。添加中間物5(根據A2.b製備)(0.0001莫耳)於DMF(2毫升)中之溶液。反應混合物迴盪隔夜。添加MP-碳酸鹽、6.2毫莫耳/克(0.00045莫耳)及連接樹脂-N=C=O。混合物於室溫迴盪隔夜。過濾混合物。添加CH2
Cl2
(2毫升)。混合物迴盪一小時,然後再次過濾。蒸發濾液之溶劑(Genevac溶劑蒸發器)。不純殘留物藉HPLC純化。收集產物溶離份並加以處理。產
量:0.0128克之化合物2。
化合物65係根據前述方法製備,不同處係反應物中間物7應置換為2-甲基-5-(3-三氟甲基-苯基)-噻唑-4-甲酸(根據A8.b製備)。
化合物18係根據前述方法製備,不同處係反應物中間物7應置換為中間物16(根據A7.b製備)。
c.製備化合物3
中間物7(根據A3.b製備)(0.00012莫耳)溶於DMF(1.2毫升)中。添加PS-碳化二亞胺,2.1毫莫耳/克(0.0002莫耳)及1-羥基-1H
-苯并三唑(0.00015莫耳)。反應混合物迴盪30分鐘。添加中間物2(根據A1.b製備)(0.0001莫耳)於DMF(2毫升)中之溶液。反應混合物迴盪隔夜。添加MP-碳酸鹽、6.2毫莫耳/克(0.00045莫耳)及連接樹脂-N=C=O(0.0001莫耳)。混合物於室溫迴盪隔夜。過濾混合物。添加CH2
Cl2
(2毫升)。混合物迴盪一小時,然後再次過濾。蒸發濾液之溶劑(Genevac溶劑蒸發器)。不純殘留物藉HPLC純化。收集產物溶離份並加以處理。產量:0.015克之化合物3。
化合物54係根據前述方法製備,不同處係反應物中間物7應置換為2-甲基-5-(3-三氟甲基-苯基)-噻唑-4-甲
酸(根據A8.b製備)。
化合物55係根據前述方法製備,不同處係反應物中間物7應置換為中間物18(根據A8.b製備)。
d.製備化合物4
PS-碳化二亞胺及1-羥基-1H
-苯并三唑於DMF(1毫升)中之溶液添加至2-(2-呋喃基)苄酸於DMF(1.2毫升)中之溶液中,接著於室溫迴盪1。之後將中間物5(根據A2.b製備)於DMF(1毫升)中之溶液添加至反應混合物。反應混合物於室溫迴盪隔夜。將MP-碳酸鹽(適量)及連接樹脂之N=C=O聚合物(適量)添加於反應混合物且再次迴盪隔夜。過濾反應混合物以產生濾液F1。殘留物於CH2
Cl2
(3毫升)中迴盪2小時。此過濾混合物以產生濾液F2。結合F1及F2並蒸發溶劑。殘留物藉逆相高效液相層析純化(Shandon HyperprepC18 BDS(鹼去活化二氧化矽)8 μm,250克,I.D.5厘米)。施加所述移動相之梯度(A相:(於H2
O中0.5% NH4
OAc)/CH3
CN 90/10);B相:CH3
OH(視情況使用);C相:CH3
CN)。收集所需之產物溶離份並加以處理。產量:0.002克之化合物4。
a.製備化合物5
(異氰醯甲基)-環己烷(0.00011莫耳)溶於DMF(3毫升)。添加中間物9(根據A4.b製備)(0.0001莫耳)。反應混合物於室溫迴盪2小時。添加PS-Tris胺(3.2毫莫耳/克)(0.0001莫耳)及連接樹脂-N=C=O,1.8毫莫耳/克(0.0001莫耳)。反應混合物於室溫迴盪隔夜。過濾混合物。添加CH2
Cl2
(2毫升)。混合物迴盪一小時,過濾並蒸發濾液之溶劑。產量:0.051克之化合物5。
b.製備化合物6
中間物9(根據A4.b製備)(0.00023莫耳)及PS-NMM(2.03毫莫耳/克)(0.00023莫耳)於DMF(3毫升)中之混合物攪拌15分鐘。添加2,6-二氯苄醯氯(0.00035莫耳)於DMF(1毫升)中之溶液並攪拌混合物2小時。添加更多PS-NMM(2.03毫莫耳/克;Argonaut)(0.05克)並攪拌混合物10分鐘。添加額外2,6-二氯苄醯氯且反應混合物於室溫攪拌隔夜。添加PS-Tris胺(4.35毫莫耳/克;
Novabiochem)(0.0002莫耳)並攪拌混合物4小時。過濾反應混合物,濾液與PS-TsOH(0.1克)一起攪拌隔夜。過濾混合物且濾液藉HPLC以Purospher Star RP-18純化(20克,5 μm;溶離劑:((0.5%於H2
O中0.5% NH4
OAc)/CH3
CN 90/10)/CH3
OH/CH3
CN(0分鐘)75/25/0,(10.00分鐘)0/50/50,(16.00分鐘)0/0/100,(18.10-20分鐘)75/25/0)。收集所需之溶離份並蒸發有機溶劑。水性濃縮物以CH2
Cl2
萃取並蒸發溶劑。產量:0.127克之化合物6。
c.製備化合物7
1-異氰醯-2-甲基苯(0.00011莫耳)溶於DMF(3毫升)中。添加中間物12(根據A5.b製備)(0.0001莫耳)。反應混合物於室溫迴盪2小時。添加PS-Tris胺(0.0001莫耳;3.2毫莫耳/克)及連接樹脂-N=C=O,1.8毫莫耳/克(0.0001莫耳)。反應混合物於室溫迴盪隔夜。過濾混合物。添加CH2
Cl2
(2毫升)。混合物迴盪一小時,過濾並蒸發濾液之溶劑。較不純殘留物藉HPLC純化。收集產物溶離份並加以處理。產量:0.0048克之化合物7。
a.製備化合物8
中間物9(根據A4.b製備)(0.00023莫耳)及Et3
N(0.1毫升)於CH2
Cl2
(5毫升)中之混合物攪拌直至完全溶解。添加1,3-二氯-2-異硫代氰醯基苯(0.0003莫耳),混合物迴盪隔夜。混合物以飽和NH4
Cl水溶液(2毫升)洗滌,然後經Extrelut過濾且蒸發萃取液之溶劑。殘留物藉HPLC於Hyperprep RP-C18 BDS上純化(100克,100,8 μm;溶離劑:[(0.5%於H2
O中0.5% NH4
OAc)/CH3
CN 90/10])/CH3
OH/CH3
CN(0分鐘)75/25/0,(10分鐘)0/50/50,(16分鐘)0/0/100,(18.10-20.00分鐘)75/25/0)。收集純溶離份並加以處理。產量:0.059克之化合物8。熔點:224.5℃
b.製備化合物9
中間物9(根據A4.b製備)(0.00023莫耳)及Et3
N(0.1
毫升)於無水CH2
Cl2
(5毫升)中之混合物攪拌直至完全溶解。添加1,3-二氯-2-異氰醯苯(0.0003莫耳)且反應混合物迴盪隔夜,然後過濾,況澱物以CH2
Cl2
洗滌,然後乾燥。產量:0.104克之化合物9。
熔點:289.0℃
製備化合物10
中間物3(根據A1.c製備)(0.0002莫耳;約略,粗製中間物)及三氟乙酸(0.2毫升)於CH2
Cl2
(2毫升)中之混合物在室溫迴盪4小時。將溶劑部分蒸發(Genevac溶劑蒸發器)。甲苯添加至該濃縮物,混合物於旋轉蒸發器上共沸。產量:0.008克之化合物10。
製備化合物11
將N'
-(乙基甲醯亞胺基)-N,N
-二甲基-1,3-丙二胺單鹽酸鹽(0.000302莫耳)添加至中間物5(根據A2.b製備)(0.000275莫耳)、1-甲基-5-酮基-3-吡咯啶甲酸(0.000275
莫耳)、1-羥基-1H
-苯并三唑(0.000028莫耳)及N-乙基-N
-(1-甲基乙基)-2-丙胺(0.000329莫耳)於以3分子師乾燥之THF(5毫升)中之混合物中且隨之於室溫攪拌64小時。蒸發溶劑(於N2
下)。殘留物於CH3
OH(5毫升)及H2
O(5毫升)中攪拌,隨之加熱至沸點。在不攪拌下使混合物冷卻至室溫。濾出沉澱物,以CH3
OH洗滌並乾燥(真空,隔夜)。產量:0.082克之化合物11。
製備化合物129
中間物20(0.55克,1.569毫莫耳)(根據A9.b製備)溶於Et3
N(1.1毫升)及CH2
Cl2
(50毫升)。添加粗製中間物23(0.448克)(根據A10.c製備)及CH2
Cl2
(100毫升)。反應混合物攪拌48小時,隨後混合物於飽和NaHCO3
於H2
O中之溶液中攪拌。添加CH2
Cl2
/MeOH 90/10及H2
O並分層。將分離之有機層乾燥(MgSO4
),過濾並蒸發溶劑。殘留物於DIPE中攪拌並濾出。產物以EtOH及DIPE洗滌(一次)。將產物乾燥(50℃,18小時,於真空中)。產量:0.727克之化合物129(73%)。
製備化合物130
於室溫將DECP(0.357毫升,0.00239莫耳)添加至中間物28(0.57克,0.00119莫耳)(根據A11.d-1製備)及3-(1-吡咯啶基)-苯胺(0.25克,0.00143莫耳)於Et3
N(0.671毫升,0.00478莫耳)及CH2
Cl2
(35毫升)中之攪拌溶液中。48小時後,添加更多DECP(0.0893毫升),混合物於室溫攪拌3小時。添加更多Et3
N(0.336毫升)並攪拌混合物18小時。添加飽和NaHO3
水溶液並攪拌混合物。分層且將CH2
Cl2
層乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發。殘留物藉快速層析純化(二氧化矽;溶離劑:CH2
Cl2
/MeOH自99/1至97/3)。收集所需之溶離份並蒸發溶劑。殘留物(0.491克)藉逆相高效液相層析純化(Shandon HyperprepC18 BDS(鹼去活化二氧化矽)8 μm,250克,I.D.5厘米)。以3種移動相施加梯度。A相:90%之0.5% NH4
OAc水溶液+10% CH3
CN;B相:CH3
OH;C相:CH3
CN)。收集所需之溶離份並部分蒸發溶劑。添加飽和NaHCO3
水溶液且有機產物以CH2
Cl2
萃取。分層且將CH2
Cl2
層乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發。殘留物於DIPE中攪拌,濾出固體
並乾燥(50℃,72小時,於真空中)。產量:0.184克之化合物130。
製備化合物131
將2,6-二氯-苯乙酸(0.102克,0.499毫莫耳)及DIPEA(0.6毫升)添加於中間物20(0.175克,0.499毫莫耳)於CH3
CN(5毫升;無水)及DMF(2毫升;無水)中之溶液。反應混合物於室溫攪拌1小時。蒸發溶劑且殘留物藉快速二氧化矽層析純化。收集所需之溶離份並蒸發溶劑產生0.155克之化合物131(58%)。
製備化合物136
中間物32(0.5克,0.00152莫耳)(根據A13.b製備)於CH2
Cl2
(10毫升)攪拌。此混合物添加於中間物30(0.54克,0.00153莫耳)(根據A12.b製備)於Et3
N(1毫
升,0.00712莫耳)及CH2
Cl2
(20毫升)中之攪拌溶液。2小時後,添加CH2
Cl2
(50毫升)及半飽和NaHCO3
溶液(適量)並攪拌混合物。之後,添加MeOH(10毫升)及CH2
Cl2
(10毫升)並攪拌混合物18小時。之後不攪拌混合物歷經48小時,但未適當地分層。因此,以矽藻土(Dicalite)過濾混合物。分層且將有機層乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發,產生1.006克。粗製化合物藉逆相高效液相層析純化(Shandon HyperprepC18 BDS(鹼去活化二氧化矽)8 μm,250克,I.D.5厘米)。以3種移動相施加梯度。A相:a 0.25% NH4
HCO3
水溶液;B相:CH3
OH;C相:CH3
CN)。收集所需之溶離份並蒸發溶劑直至僅得到水層。此水層以NaHCO3
中和且以CH2
Cl2
萃取。將分離之有機層乾燥(MgSO4
),過濾,蒸發溶劑並以甲苯共同蒸發。殘留物於Et2
O中攪拌並濾出固體,產生0.032 of化合物136。
製備化合物137
中間物30(0.465克,0.00133莫耳)(根據A12.b製備)溶於CH2
Cl2
(10毫升)及Et3
N(1毫升,0.00712莫耳)中產生棕色混濁混合物。將中間物34(0.4克,0.00133莫
耳)(根據A14.b製備)溶於CH2
Cl2
(10毫升)中且此溶液添加至該棕色混濁混合物。反應混合物攪拌1小時,之後濾出並洗滌(2 x CH2
Cl2
,1 x CH3
CN且再次1 x CH2
Cl2
)。將固體乾燥(50℃,18小時,於真空中)。產量:0.505克之化合物137(56%)。
製備化合物139
將DECP(0.253毫升,0.00169莫耳)添加至中間物36(0.564克,0.00154莫耳)(根據A15.b製備)及3-(1-吡咯啶基)苄酸(0.309克,0.00162莫耳)於CH2
Cl2
(20毫升;p.a.)及Et3
N(0.433毫升,0.00308莫耳)中之攪拌溶液中。反應混合物於N2
氛圍下攪拌18小時。之後添加飽和NaHCO3
水溶液(15毫升)並攪拌混合物2小時。添加CH2
Cl2
/MeOH 90/10(10毫升)並攪拌混合物1小時。分層且洗滌有機層(H2
O)、乾燥(MgSO4
),過濾並蒸發溶劑。殘留物於Et2
O中攪拌/EtOAc(10毫升/10毫升)、濾出,洗滌(EtOAc/Et2
O先1/1,接著0/1)並乾燥(50℃,於真空中
)。產量:0.655克之化合物139(79%)。
製備化合物140
DECP(1.167毫升,0.00703莫耳)添加至中間物38
(2.1克,0.00468莫耳)(根據A11.d-2製備)及1,3-苯二甲酸1-甲基酯(0.886克,0.00492莫耳)於Et3
N(1.316毫升,0.00937莫耳)及CH2
Cl2
(100毫升;p.a.)中之攪拌溶液中。反應混合物於室溫攪拌18小時,之後添加飽和NaHCO3
水溶液(50毫升)及CH2
Cl2
/MeOH 1/1(40毫升)。混合物攪拌15分鐘。分層且有機層與H2
O(50毫升)一起攪拌且於分液漏斗中放置隔夜。濾出有機層中之沉澱物,洗滌(CH2
Cl2
)並乾燥(50℃,於真空中
),產生0.54克之化合物140
(19%)。蒸發濾液且殘留物於丙酮中攪拌,濾出,洗滌(丙酮)並乾燥(50℃,於真空中
),產生1克之化合物140
(35%)。
製備化合物145
將TBTU(4.20毫莫耳)及Et3
N(2.08毫升,15.0毫莫
耳)添加於中間物41
(3.60毫莫耳)(根據A16.c製備)於CH3
CN(10毫升)中之懸浮液中。混合物於室溫攪拌10分鐘。之後,將中間物43
(2.71毫莫耳)(根據A17.b製備)添加至反應混合物。混合物於室溫攪拌5小時。濾出結晶產物,以少量丙酮洗滌並風乾。產量:1.406克之化合物145
(85%)。
表1至7列出藉類似前述實施例中之一方法製備的化合物。
本發明化合物之(LC)MS特性分析係使用下列方法。
一般方法A
HPLC測量係使用Alliance HT 2790(Waters)系統進行,此系統包含具有脫氣器之四元泵、自動取樣機、管柱烘箱(設定於40℃)、二極體陣列偵測器(DAD)及管柱,如以下個別方法所詳述。來自管柱之液流分流至MS偵測器。MS偵測器構建成具有電噴霧游離化來源。使用0.1秒駐留時間於1秒中自100掃描至1000而取得質譜。微針電壓係為3 kV且來源溫度係保持於140℃。使用氮作為霧化器氣體。數據取得係以Waters-Micromass MassLynx-Openlynx數據系統達成。
一般方法B
LC測量係使用Acquity UPLC(Waters)(超效液相層析)系統達成,此系統包含二元泵、試樣編排器、管柱加熱器(設定於55℃)、二極體陣列偵測器(DAD)及管柱,如以下個別方法所詳述。來自管柱之液流分流至MS偵測器。MS偵測器構建成具有電噴霧游離化來源。使用0.02秒駐留時間於0.18秒中自100掃描至1000而取得質譜。微針電壓係為3.5 kV且來源溫度係保持於140℃(DSC)。使用氮作為霧化器氣體。數據取得係以Waters-Micromass MassLynx-Openlynx數據系統達成。
一般方法C
許多化合物之LCMS分析係於Surveyor MSQTM
(Thermo Finnigan,USA)上進行,其包含光電二極體陣列偵測器(PDA;190-800奈米)及管柱,如以下個別方法所詳述。來自管柱之液流分流至MS光譜儀。MS偵測器係建構成具有APCI(大氣壓化學游離化,+或-離子)。質譜係藉於0.3秒中自45掃描至1000(原子質量單位)而取得。一般APCI條件使用10 μA之電暈放電電流及30 V之錐電壓。APCI探針溫度係為640℃。使用氮作為霧化器氣體。數據取得係以XcaliburTM
數據系統達成。
方法1
一般方法B外:另外於橋連乙基矽氧烷/二氧化矽(BEH)C18管柱(1.7微米,2.1 x 50毫米)上進行逆相UPLC(超效液相層析),流率為0.8毫升/分鐘。使用兩種移動相(移動相A:於H2
O/甲醇95/5中0.1%甲酸;移動相B:甲醇)以進行於1.3分鐘中自95% A及5%B至5% A及95% B,保持0.2分鐘梯度條件。使用注射體積為0.5 μl。
正游離化模式之錐電壓為10 V且負游離化模式為20 V。
方法2
除一般方法A外:另外於Xterra MS C18管柱(3.5
微米,4.6 x 100毫米)上進行逆相HPLC,流率為1.6毫升/分鐘。採用三種移動相(移動相A:95% 25 mM乙酸銨+5%乙腈;移動相B:乙腈;移動相C:甲醇)以進行於6.5分鐘中自100%A至1% A,49% B及50% C,於1分鐘中達到1% A及99% B且保持此等條件歷經1分鐘並以100% A再平衡1.5分鐘的梯度條件。使用注射體積為10 μl。正游離化模式之錐電壓為10 V且負游離化模式為20 V。
方法3(僅有MS)
有數種化合物僅記錄質譜(無R(t))。該MS偵測器構建成具有電噴霧游離化來源。使用0.1秒駐留時間於1秒中自100掃描至1000而取得質譜。微針電壓係為3 kV且來源溫度係保持於140℃。使用氮作為霧化器氣體。數據取得係以Waters-Micromass MassLynx-Openlynx數據系統達成。正游離化模式之錐電壓為10 V且負游離化模式為20 V。
方法4
除一般方法A外:另外於Chromolith(4.6 x 25毫米)上進行逆相HPLC,流率為3毫升/分鐘。採用三種移動相(移動相A:95% 25 mM乙酸銨+5%乙腈;移動相B:乙腈;移動相C:甲醇)以進行自96% A,2% B及
2% C,0.9分鐘達到49% B及49% C,於0.3分鐘達到100% B,保持0.2分鐘梯度條件。使用注射體積為2 μl。正游離化模式之錐電壓為10 V且負游離化模式為20 V。
方法5
除一般方法C外:另外於Waters XTerra MS C18管柱(3.5 μm,2.1 x 30毫米)上進行逆相HPLC,流率為1.0毫升/分鐘。使用兩種移動相(移動相A:0.1%水溶液of甲酸;移動相B:乙腈)。首先,100% A保持0.1分鐘。之後於3分鐘中施加梯度至5% A及95% B,保持0.8分鐘。注射體積為1 μl。管柱處於室溫。
方法6
除一般方法A外:管柱加熱器設定於60℃。另外於Xterra MS C18管柱(3.5微米,4.6 x 100毫米)上進行逆相HPLC,流率為1.6毫升/分鐘。採用三種移動相(移動相A:95% 25 mM乙酸銨+5%乙腈;移動相B:乙腈;移動相C:甲醇)以進行於6.5分鐘中自100%A至50% B及50% C,於0.5分鐘中達到100% B且保持此等條件歷經1分鐘,並以100% A再平衡1.5分鐘之梯度條件。使用注射體積為10 μl。正游離化模式之錐電壓為10 V且負游離化模式為20 V。
方法7
除了一般方法之外:另外將管柱加熱器設定於45℃。於Atlantis C18管柱(3.5微米,4.6 x 100毫米)上進行逆相HPLC,流率為1.6毫升/分鐘。使用兩種移動相(移動相A:70%甲醇+30% H2
O;移動相B:於H2
O/甲醇95/5中0.1%甲酸)以進行於9分鐘中自100%B至5% B+95% A,且保持此等條件歷經3分鐘的梯度條件。使用注射體積為10 μl。管柱為室溫。
熔點
以DSC823e(Mettler-Toledo)測定許多化合物之熔點。以30℃/分鐘之溫度梯度測定熔點。最高溫度係為400℃。數值為波峰值。結果總列於表10。
使用Sanyo Gallenkamp之Gallenkamp裝置測量多個化合物之熔點。
化合物編號138:198-199℃;化合物編號143:249-250℃;化合物編號133:237-239℃;化合物編號145:218-221℃;化合物編號146:208-210℃。
A)本發明化合物對DGAT1活性之抑制的測量
本發明化合物對DGAT1活性之抑制活性係依單孔方法檢測使用包含DGAT1之膜製劑及包含DGAT1受質之微膠粒篩檢,藉由放射發光決定進入flashplate表面附近之所形成放射性三醯基甘油。
該檢測係詳細描述於WO2006/067071,其內容係以引用方式併入本文。
DGAT1活性係指藉DGAT1酶將經輔酶A活化之脂肪酸輸送至1,2-二醯基甘油之3-位置,因此形成三酸甘油酯分子。
檢測步驟1:DGAT1之表現
將人類DGAT1(NM012079.2)選殖至pFastBac載體內,此載體含有轉譯起點,如文獻所述位於N端之FLAG-標籤及位於ATG之前的病毒Kozak序列(AAX),以改善有昆蟲細胞中之表現。表現係如文獻所述般地(Cases,S.,Smith,S.J.,Zheng,Y.,Myers H.M.,Lear,S.R.,Sande,E.,
Novak,S.,Collins,C.,Welch,C.B.,Lusis,A.J.,Erickson,S.K.and Farese,R.V.(1998)Proc
.Natl
.Acad
.Sci
.USA 95
,13018-13023)。使用SF9細胞達成。
檢測步驟2:製備DGAT1膜
藉離心(13000rpm-15分鐘-4℃)收集轉染72h之SF9細胞且於2x 500毫升溶胞緩衝劑(0.1M蔗糖,50mM KCl,40mM KH2
PO4
,30mM EDTA pH 7.2)中進行細胞溶解。藉細胞破碎儀將細胞均質化。離心1380rpm-15min-4℃(丟棄SN)之後,離心片粒木懸浮於500毫升溶胞緩衝劑中,且藉著於34000rpm(100 000g)超高速離心60分鐘(4℃)而收集全部細胞膜。所收集之細胞膜再懸浮於細胞溶解緩衝劑中,分成小份,以10%甘油儲存於-80℃直至使用。
檢測之步驟3:製備包含DGAT受質之微膠粒
材料
a)1,2-二油醯基-sn-甘油,10毫克/毫升(1,2-二醯基甘油(DAG))
溶解於乙腈;於氮下蒸發乙腈溶液且於氯仿中復原,最終濃度為10毫克/毫升。
b)L-α-磷醯膽鹼,1毫克/毫升(磷醯膽鹼(PC))
溶於氯仿最終濃度為1毫克/毫升且儲存於4℃。
c)L-α-磷脂醯-L-絲胺酸,1毫克/毫升(磷脂醯絲胺酸
(PS))
溶於氯仿最終濃度為1毫克/毫升且儲存於4℃。
方法
將1毫升二油醯基-sn-甘油(10毫克/毫升)添加於在厚玻璃容器中之10毫升之L-α-磷醯膽鹼(1毫克/毫升)及10毫升之L-α-磷脂醯-L-絲胺酸(1毫克/毫升)。於氮下蒸發且置於冰上15分鐘。於10毫升Tris/HCl(10 mM,pH 7.4)中在冰上藉音波振動復原。音波振動程序係為在音波振動浴中10秒音波振動週期、接著10秒於冰上冷卻,重複此音波振動週期,直至得到均勻溶液(花費約15分鐘)。所得微膠粒在稍後使用之前儲存於-20℃且含有最終濃度為1.61 mM之DAG。
檢測之步驟4:DGAT FlashPlate
TM
檢測
材料
a)檢測緩衝劑
50mM參-HCl(pH 7.4),150mM MgCl2
,1mM EDTA,0.2% BSA。
b)N-乙基順丁烯二醯亞胺,5M
將5克溶解於列終體積8毫升之DMSO 100%中且在使用前分小量儲存於-20℃。
c)受質混合物(1片384孔板=3840 μl)
612 μl微膠粒儲液(51μM最終)
16.6 μl油醯基CoA 9.7mM 23 μl[3
H]-油醯基CoA(49 Ci/毫莫耳,500 μCi/毫升)3188.4 μl Tris pH 7.4,10mM
d)酶混合物(1片384孔板=3520 μl)(5 μg/毫升)
將11.73μl of DGAT膜儲液(1500 μg/毫升儲液)添加於3508 μl檢測緩衝劑。
e)終止混合物(1片384孔板=7.68毫升)(250 mM)
將384 μl N-乙基順丁烯二醯亞胺(5M)添加於3.456毫升DMSO 100%,且進一步以3.84毫升DMSO 10%稀釋3.84毫升之該溶液。
方法
膜製劑中DGAT活性係於50mM參-HCl(pH 7.4),150 mM MgCl2
,1mM EDTA及0.2% BSA中,在384孔模式最終體積50 μl含有50 μM DAG,32μg/毫升PC/PS及8.4μM[3
H]-油醯基CoA(比活性30 nCi/孔)中使用紅色位移FlashPlateTM
(Perkin Elmer Cat.No.SMP400)檢測。
詳言之,將10 μl酶混合物及10 μl受質混合物添加於30 μl檢測緩衝劑中,視情況於1 μl DMSO(空白組及對照組)或1 μl待測試化合物存在下。此反應混合物於37℃培育120分鐘,藉由添加20 μl終止混合物來停止酶反應。將板密封且於室溫使囊泡沉降隔夜。將該等板於1500rpm離心5分鐘且於Leadseeker中測量。
以不同濃度試驗化合物進行實驗,基於% CTRLmin
(經標度化對照組之%)計算並繪出曲線。% CTRLmin
係根據式1計算,式1:%CTRLmin
=(試樣-LC)/(HC-LC)其中HC(高對照組)意指在含有酶及受質但不含試驗化合物之孔中測得的放射發光值之中值,LC(低對照組)意指在含有受質而不含酶且不含試驗化合物之孔中測得的中值背景放射發光值,試樣意指在含有酶、受質及特定濃度之試驗化合物的孔中測得之放射發光值。
計算值之% CTRLmin
值形成S形劑量反應下降曲線,自此曲線計算pIC50
值(-logIC50
,其中IC50
係表示試驗化合物產生50%之DGAT1活性抑制的濃度)。表5顯示式(I)化合物之pIC50
值。
為了決定本發明化合物對DGAT1相對於對DGAT2之選擇性,亦依前述檢測決定化合物對DGAT2之抑制活性,稍加修飾以得到DGAT2之最佳檢測條件。試驗化合物未對DGAT2顯示抑制活性(人類DGAT2(NM032564)係如J.Biolog.Chem.276(42)、pp38870-38876(2001)所述般地選殖並表現)。
B)試驗化合物對GLP-1血漿濃度之影響的體內研究
藉DGAT抑制劑提高GLP-1血漿濃度係如下研究:犬隻禁食22小時之時間。在時間0時,動物以胃管灌食給予含有18%脂肪酸(w/w)之液體食物。試驗化合物係與食物一起經口投予。之後,決定GLP-1之餐後血漿曲線。因此,在預定時間間隔將血液收集於冰冷之Vacutainers EDTA-血漿管中,於投藥後0小時(灌食前即時)及0.5、1、2、4、6、8及24小時測量試樣中GLP-1濃度。每個劑量組包括六犬隻(3雄犬及3雌犬),血漿GLP-1曲線與先前在相同條件但未投予試驗化合物時所測定的自身GLP-1曲線比較。
血漿中GLP-1測定係以LINCO Research之升糖激素樣肽-1(活性)ELISA套組96-孔板進行。
此等實施例中所使用之「活性成份」(a.i)。係表示式(I)化合物,包括其任何立體化學異構形式、及N
-氧化物、其醫藥上可接受之鹽或其溶劑合物;尤其是表示例示化合物中任一種。
本發明調配物之一般配方實例如下:1.錠劑
2.懸浮液
製備經口投藥用之水性懸浮液,使得每一莫耳各含有1至5毫克之活性成份,50毫克之羧基甲基纖維素鈉,1毫克之苄酸鈉,500毫克之山梨糖醇及加至1毫升之水。
3.注射劑
藉著將1.5%(重量/體積)之活性成份攪拌至0.9% NaCl溶液中而製備非經腸組成物。
4.軟膏
Claims (18)
- 一種下式之化合物
- 如申請專利範圍第1項之化合物,其具有下式
- 如申請專利範圍第1項之化合物,其中X係表示-O-C(=O)-;-NRx -C(=O)-;-Z-C(=O)-;-Z-NRx -C(=O)-;-NRx -C(=S)-。
- 如申請專利範圍第3項之化合物,其中X係表示-NRx -C(=O)-或-Z-C(=O)-。
- 如申請專利範圍第1項之化合物,其中A係表示N。
- 如申請專利範圍第1至5項中任一項之化合物,其中R1 係表示視情況經取代之苯基、視情況經取代之茀基或含有至少一個各獨立選自S或N之雜原子的視情況經取代單環非芳族或芳族雜環。
- 如申請專利範圍第1至5項中任一項之化合物,其中 R2 係表示C3-6 環烷基、苯基、2,3-二氫-1,4-苯并二氧雜環己烯基或含有1或2個N原子之6員芳族雜環,其中該苯基或雜環係視情況經一、二、三或四個取代基所取代。
- 如申請專利範圍第1、3至5項中任一項之化合物,其中該化合物係具有下式
- 如申請專利範圍第8項之化合物,其中該化合物係具有下式
- 如申請專利範圍第8項之化合物,其中R3a 及R3b 各獨立地表示鹵基或C1-6 烷基。
- 如申請專利範圍第10項之化合物,其中R3a 及R3b 各表示鹵基。
- 如申請專利範圍第1及3至5項中任一項之化合物,其中R7 係表示氫。
- 如申請專利範圍第1項之化合物,其中X係表示-O-C(=O)-;-NRx -C(=O)-;-Z-C(=O)-;-Z-NRx -C(=O)-;-NRx -C(=S)-;Z係表示C1-6 烷二基;Rx 係表示氫;R1 係表示芳基1 或Het1 ;R2 係表示C3-6 環烷基、苯基、2,3-二氫-1,4-苯并二氧雜環己烯基或含有1或2個N原子之6員芳族雜環,其中該C3-6 環烷基、苯基、2,3-二氫-1,4-苯并二氧雜環己烯基或雜環可視情況經一、二、三或四個取代基取代,每一取代基各獨立選自鹵基;C1-6 烷基;C1-6 烷基氧基;C1-6 烷基硫基;C1-6 烷基氧基羰基;硝基;單-或二(C1-4 烷基)胺基;R4 R3 N-C1-6 烷基;芳基氧基;Het-C(=O)-C1-4 烷基;R3 係表示C1-4 烷基;R4 係表示C1-4 烷基;R7 係表示氫或鹵基;p係表示1或2。
- 如申請專利範圍第13項之化合物,其中芳基係表示苯基或經以下基團取代之苯基:鹵基;C1-6 烷基;多鹵基C1-6 烷基;C1-6 烷基氧基羰基;Het係表示含有至少一個各獨立 選自O、S、S(=O)p 或N之雜原子的單環非芳族或芳族雜環;或含有至少一個各獨立選自N之雜原子的雙環非芳族或芳族雜環;該單環雜環或該雙環雜環視情況經一或二個取代基所取代,每一取代基各獨立選自酮基或C1-6 烷基;Het1 係表示含有至少一個各獨立選自S或N之雜原子的單環非芳族或芳族雜環;該單環雜環視情況經一或二個取代基所取代,每一取代基各獨立選自羥基;酮基;C1-6 烷基;C1-6 烷基氧基-羰基;芳基;Het。
- 如申請專利範圍第1項之化合物,其中該化合物係選自
- 如申請專利範圍1至5項中任一項之化合物,其係作為藥劑。
- 一種醫藥組成物,其包含醫藥上可接受之載劑,及作為活性成份之治療有效量之如申請專利範圍第1至15項中任一項之化合物。
- 一種如申請專利範圍第1項之式(I)化合物的用途,其用於製造供治療肥胖、血中膽固醇過高、血脂過高、血脂異常、混合型血脂異常、血中三酸甘油酯過高、脂肪肝、非酒精性脂肪肝疾病、肝纖維化、非酒精性硬脂性肝炎或糖尿病的藥劑。
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CA2687243C (en) | 2016-07-12 |
AU2008258558A1 (en) | 2008-12-11 |
RU2478628C2 (ru) | 2013-04-10 |
JO2972B1 (en) | 2016-03-15 |
CN101678013B (zh) | 2014-05-07 |
TW200916449A (en) | 2009-04-16 |
US20150087629A1 (en) | 2015-03-26 |
ES2522617T3 (es) | 2014-11-17 |
US20100210618A1 (en) | 2010-08-19 |
CN101678013A (zh) | 2010-03-24 |
EP2155198B1 (en) | 2014-08-13 |
JP2010529085A (ja) | 2010-08-26 |
BRPI0812923A2 (pt) | 2014-12-09 |
WO2008148849A2 (en) | 2008-12-11 |
WO2008148849A3 (en) | 2009-04-16 |
CL2008001668A1 (es) | 2009-07-17 |
PE20090820A1 (es) | 2009-06-27 |
US8946228B2 (en) | 2015-02-03 |
JP5443343B2 (ja) | 2014-03-19 |
MX2009013334A (es) | 2010-01-20 |
RU2009148796A (ru) | 2011-07-20 |
UY31134A1 (es) | 2009-03-02 |
WO2008148849A8 (en) | 2009-07-09 |
US9227935B2 (en) | 2016-01-05 |
AR066153A1 (es) | 2009-07-29 |
EP2155198A2 (en) | 2010-02-24 |
CA2687243A1 (en) | 2008-12-11 |
PA8783401A1 (es) | 2009-01-23 |
AU2008258558B2 (en) | 2013-11-07 |
US20160081997A1 (en) | 2016-03-24 |
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