TWI439265B - (羧基伸烷基苯基)苯基草醯胺類,製備彼等之方法及其作為藥物之用途 - Google Patents
(羧基伸烷基苯基)苯基草醯胺類,製備彼等之方法及其作為藥物之用途 Download PDFInfo
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- TWI439265B TWI439265B TW097135728A TW97135728A TWI439265B TW I439265 B TWI439265 B TW I439265B TW 097135728 A TW097135728 A TW 097135728A TW 97135728 A TW97135728 A TW 97135728A TW I439265 B TWI439265 B TW I439265B
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- C07C235/80—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
Description
本發明係關於(羧基伸烷基苯基)苯基草醯胺類及其生理上耐受鹽類。
類似結構之化合物已描述於先前技術(參見US2005/0124667)中,以及其作為抗血栓劑之用途。
本發明係以提供展現治療上有效效用之化合物為目標。此目標特言之係找出適合治療高血糖症及糖尿病之新穎的化合物。
本發明因此係關於式I之化合物
其中各意義為R3 相互獨立地為H、F、Cl、Br、CN、CF3
、OH、OCF3
、OCHF2
、SCH3
、SCF3
、苯基、O苯基、COOH、COO-(C1
-C6
)-烷基、CO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、(C3
-C8
)-環烷基、O-(C1
-C6
)-烷基、OBn、SO2
-(C1
-C4
)-烷基、SO3
H、SO2
NR9R10、NR9R10或SO2
-N-哌啶基,其中烷基及苯基可經R12取代一或多次;R1、R5 相互獨立地為H、F、Cl、Br、CN、CF3
、SCH3
、SCF3
、苯基、O苯基、COOH、COO-(C1
-C6
)-烷基、CO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、SO2
-(C1
-C4
)-烷基、SO3
H、SO2
NR9R10、NR9R10或SO2
-N-哌啶基,其中烷基及苯基可經R12取代一或多次;R2、R4 各自獨立地為H、F、Cl、Br、CN、CF3
、OCF3
、OCHF2
、SCH3
、SCF3
、苯基、O苯基、COOH、COO-(C1
-C6
)-烷基、CO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、O-(C1
-C6
)-烷基、OBn、SO2
-(C1
-C4
)-烷基、SO3
H、SO2
NR9R10、NR9R10或SO2
-N-哌啶基,其中烷基及苯基可經R12取代一或多次;R7、R8 相互獨立地為H或(C1
-C6
)-烷基;X 為(C2
-C3
)-伸烷基,其中伸烷基可經R11取代一或多次;M 為0、1、2、3或4;R6 為OH、F、Cl、Br、CN、OCH3
、OCF3
、CH3
、CF3
、(C1
-C6
)-烷基或O-(C1
-C6
)-烷基,其中烷基可經OH、F、Cl、Br或CN取代一或多次;R9、R10相互獨立地為H、(C1
-C6
)-烷基或苯基,其中烷基可經F、Cl或Br取代一或多次,而苯基可經R6取代一或多次;R11 為F、Cl、Br、CN、OH、O-(C1
-C6
)-烷基、(C1
-C6
)-烷基、(C2
-C6
)-烯基、(C2
-C6
)-炔基或NR9R10;R12 為F、Cl、Br、CN、OH、O-(C1
-C6
)-烷基、(C1
-C6
)-烷基、(C2
-C6
)-烯基、(C2
-C6
)-炔基、NR9R10、COOH、COO-(C1
-C4
)-烷基、SCH3
、SCF3
、SO2
-(C1
-C4
)-烷基、SO3
H或SO2
NR9R10;及其生理上耐受鹽類。
較佳的係給予式I化合物其中一或多個基具有下列意義:R3 相互獨立地為H、F、Cl、Br、CF3
、OCF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、(C3
-C8
)-環烷基、苯基、O苯基,其中烷基及苯基可經R12取代一或多次;R1、R5 相互獨立地為H、F、Cl、Br、CF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、苯基、O苯基,其中烷基及苯基可經R12取代一或多次;R2、R4 相互獨立地為H、F、Cl、Br、CF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基;R6 為OH、F、Cl、Br、CN、OCH3
、OCF3
、CH3
、CF3、(C1
-C6
)-烷基或O-(C1
-C6
)-烷基,其中烷基可經OH、F、Cl、Br或CN取代一或多次;R7、R8 為H;X 為(C2
-C3
)-伸烷基,其中伸烷基可經R11取代一或多次;M 為0;R9、R10相互獨立地為H、(C1
-C6
)-烷基或苯基,其中烷基可經F、Cl或Br取代一或多次,而苯基可經R6取代一或多次;R11 為F、Cl、Br、CN、OH、O-(C1
-C6
)-烷基、(C1
-C6
)-烷基、(C2
-C6
)-烯基、(C2
-C6
)-炔基或NR9R10;R12 為F、Cl、Br、CN、OH、O-(C1
-C6
)-烷基、(C1
-C6
)-烷基、(C2
-C6
)-烯基、(C2
-C6
)-炔基、NR9R10、COOH、COO-(C1
-C4
)-烷基;及其生理上耐受鹽類。
特佳的係給予式I化合物其中一或多個基具有下列意義:R3 相互獨立地為H、F、Cl、Br、CF3
、OCF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、(C3
-C8
)-環烷基、苯基;R1、R5 相互獨立地為H、F、Cl、Br、CF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、苯基;R2、R4 相互獨立地為H、F、Cl、Br、CF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基;R7、R8 為H;X 為(C2
-C3
)-伸烷基,其中伸烷基可經R11取代一或多次;M 為0;R11 為(C2
-C6
)-炔基;及其生理上耐受鹽類。
特佳的係進一步給予式I化合物其中一或多個基具有下列意義:R3 相互獨立地為H、F、Cl、Br、CF3
、OCF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、(C3
-C8
)-環烷基、苯基;R1、R5 相互獨立地為H、F、Cl、Br、CF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、苯基;R2、R4 相互獨立地為H、F、Cl、Br、CF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基;R7、R8 為H;X 為(C2
-C3
)-伸烷基,其中X在位置4與環相連結;m 為0;及其生理上耐受鹽類。
在另一實施例中,較佳的係給予式I化合物其中一或多個基具有下列意義:R3 相互獨立地為H、F、Cl、Br、CN、CF3
、OH、OCF3
、OCHF2
、SCH3
、SCF3
、苯基、O苯基、COOH、COO-(C1
-C6
)-烷基、CO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、O-(C1
-C6
)-烷基、OBn、SO2
-(C1
-C4
)-烷基、SO3
H、SO2
NR9R10、NR9R10或SO2
-N-哌啶基,其中烷基及苯基可經R12取代一或多次;R1、R5 相互獨立地為H、F、Cl、Br、CN、CF3
、SCH3
、SCF3
、苯基、O苯基、COOH、COO-(C1
-C6
)-烷基、CO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、SO2
-(C1
-C4
)-烷基、SO3
H、SO2
NR9R10、NR9R10或SO2
-N-哌啶基,其中烷基及苯基可經R12取代一或多次;R2、R4 相互獨立地為H、F、Cl、Br、CN、CF3
、OCF3
、OCHF2
、SCH3
、SCF3
、苯基、O苯基、COOH、COO-(C1
-C6
)-烷基、CO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、O-(C1
-C6
)-烷基、OBn、SO2
-(C1
-C4
)-烷基、SO3
H、SO2
NR9R10、NR9R10或SO2
-N-哌啶基,其中烷基及苯基可經R12取代一或多次;R7、R8 相互獨立地為H或(C1
-C6
)-烷基;X 為(C2
-C3
)-伸烷基,其中伸烷基可經R11取代一或多次;M 為0、1、2、3或4;R6 為OH、F、Cl、Br、CN、OCH3
、OCF3
、CH3
、CF3
、(C1
-C6
)-烷基或O-(C1
-C6
)-烷基,其中烷基可經OH、F、Cl、Br或CN取代一或多次;R11 為F、Cl、Br、CN、OH、O-(C1
-C6
)-烷基、(C1
-C6
)-烷基、(C2
-C6
)-烯基、(C2
-C6
)-炔基或NR9R10;R12 為F、Cl、Br、CN、OH、O-(C1
-C6
)-烷基、(C1
-C6
)-烷基、(C2
-C6
)-烯基、(C2
-C6
)-炔基、NR9R10、COOH、COO-(C1
-C4
)-烷基、SCH3
、SCF3
、SO2
-(C1
-C4
)-烷基、SO3
H或SO2
NR9R10;及其生理上耐受鹽類。
在另一實施例中,較佳的係給予式I化合物其中一或多個基具有下列意義:R3 相互獨立地為H、F、Cl、Br、CF3
、OCF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、苯基、O苯基,其中烷基及苯基可經R12取代一或多次;R1、R5 相互獨立地為H、F、Cl、Br、CF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、苯基、O苯基,其中烷基及苯基可經R12取代一或多次;R2、R4 相互獨立地為H、F、Cl、Br、CF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基;R6 為OH、F、Cl、Br、CN、OCH3
、OCF3
、CH3
、CF3
、(C1
-C6
)-烷基或O-(C1
-C6
)-烷基,其中烷基可經OH、F、Cl、Br或CN取代一或多次;R7、R8 為H;X 為(C2
-C3
)-伸烷基,其中伸烷基可經R11取代一或多次;M 為0;R9、R10相互獨立地為H、(C1
-C6
)-烷基或苯基,其中烷基可經F、Cl或Br取代一或多次,而苯基可經R6取代一或多次;R11 為F、Cl、Br、CN、OH、O-(C1
-C6
)-烷基、(C1
-C6
)-烷基、(C2
-C6
)-烯基、(C2
-C6
)-炔基或NR9R10;R12 為F、Cl、Br、CN、OH、O-(C1
-C6
)-烷基、(C1
-C6
)-烷基、(C2
-C6
)-烯基、(C2
-C6
)-炔基、NR9R10、COOH、COO-(C1
-C4
)-烷基;及其生理上耐受鹽類。
在另一實施例中,較佳的係給予式I化合物其中一或多個基具有下列意義:R3 相互獨立地為H、F、Cl、Br、CF3
、OCF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、苯基;R1、R5 相互獨立地為H、F、Cl、Br、CF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、苯基;R2、R4 相互獨立地為H、F、Cl、Br、CF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基;R7、R8 為H;X 為(C2
-C3
)-伸烷基;m 為0;及其生理上耐受鹽類。
在另一實施例中,較佳的係給予式I化合物其中一或多個基具有下列意義:R3 為相互獨立地為H、F、Cl、Br、CF3
、OCF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基;R1、R5 相互獨立地為H、F、Cl、Br、CF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基、苯基;R2、R4 相互獨立地為H、F、Cl、Br、CF3
、COOH、COO-(C1
-C6
)-烷基、(C1
-C6
)-烷基;R7、R8 為H;X 為(C2
-C3
)-伸烷基,其中X在位置4與環相連結;m 為0;及其生理上耐受鹽類。
在一實施例中式I化合物較佳的為該等其中X為-(CH2
)2
-之化合物。
在一實施例中式I化合物較佳的為該等其中X為-(CH2
)3
-之化合物。。
在一實施例中式I化合物較佳的為該等其中-X-COOH基團係在位置3與環相連結之化合物。
在一實施例中式I化合物較佳的為該等其中-X-COOH基團係在位置4與環相連結。
若基或取代基在式(I)化合物中出現一次以上時,其全部皆相互獨立地具有所述之意義且可相同或不同。
在X、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11及R12基中之烷基、烯基、炔基及伸烷基可為直鏈或支鏈。
本發明化合物係關於式I化合物其鹽類型式、外消旋物、外消旋混合物及純的鏡像異構物,和非對映異構物及其混合物。
本發明進一步係關於式I化合物立體異構物之混合物和式I化合物之純的立體異構物混合物,以及式I化合物非對應異構物之混合物和純的非對映異構物。混合物可用例如層析法來分離。
本發明包括式I化合物之所有可能的互變異構物形式。
因為其水中溶解度比原始或鹼性化合物大,所以醫藥上可接受之鹽類特別適合作為醫藥應用。這些鹽類必須具有醫藥上可接受的陰離子或陽離子。本發明化合物之適合的醫藥上可接受酸加成鹽有無機酸例如鹽酸、氫溴酸、磷酸、偏磷酸、硝酸及硫酸之鹽類,以及有機酸例如乙酸、苯磺酸、苯甲酸、檸檬酸、乙磺酸、延胡索酸、葡萄糖酸、甘醇酸、羥乙基磺酸、乳酸、乳糖酸、馬來酸、蘋果酸、甲磺酸、琥珀酸、對甲苯磺酸及酒石酸之鹽類。適合的醫藥上可接受鹼鹽有銨鹽、鹼金屬鹽類(例如鈉及鉀鹽)、鹼土金屬鹽類(例如鎂及鈣鹽)、胺丁三醇(trometamol)(2-胺基-2-羥甲基-1,3-丙二醇)、二乙醇胺、離胺酸或乙二胺。
帶有醫藥上不可接受陰離子之鹽類,例如三氟乙酸鹽同樣屬於本發明之架構內,可用作製備或純化醫藥上可接受鹽類之中間物及/或用於非治療上,例如體外應用。
本發明化合物亦可以各種同質異形物之形式存在,例如非晶及晶體同質異形物形式。本發明化合物之所有同質異形物形式係屬於本發明架構內中且為本發明另一態樣。
下文所有所指之「式I化合物」係指如上述之式I化合物及如本文所述之其鹽類和溶劑化物。
烷基係指直鏈或支鏈烴鏈,例如甲基、乙基、異丙基、第三丁基、己基。烷基可如上述經取代一或多次。
本發明亦包括式I化合物之溶劑化物、水合物及醇加合物。
式I化合物亦可與另外的活性成份組合給藥。
達到所欲生物效用所需之式I化合物之量係依許多因素而定,例如所選的特定化合物、所欲的用途、給藥模式及病患之臨床症狀。每日劑量一般係在每天及每公斤體重從0.3毫克至100毫克(典型的係從3毫克至50毫克)之範圍內,例如3-10毫克/公斤/天。靜脈給劑可在例如從0.3毫克至1.0毫克/公斤之範圍內,其可以每公斤每分鐘10奈克至100奈克之輸液適當的給藥。適合此等目的之輸注溶液每毫升可含有例如從0.1奈克至100毫克,典型的係從1奈克至100毫克。單一劑量可含有例如從1毫克至10克之活性成份。因此,注射用之安瓶可含有例如從1毫克至100毫克,而可口服給藥之單一劑量調配物(例如膠囊或錠劑)可含有例如從1.0至1000毫克,典型的係從10至600毫克。就上述症狀之治療,可使用式I化合物本身,但其最好係為帶有可接受載劑之醫藥組合物形式。在與組合物的其他成份相容之觀念下,當然載劑必須為可接受的,且對病患的健康為無害的。載劑可為固態或液態或二者,且較佳地係與化合物調配成單一劑量(例如錠劑),其可含有從0.05%至95%重量比之活性成份。同樣的可有其他的醫藥活性物質存在(包括其他的式I化合物)。本發明之醫藥組合物可藉由已知的醫藥方法之一來製造,其基本上係將該等成份與藥理上可接受載劑及/或賦形劑混合所組成。
雖然最適合的給藥模式係依照各別個體所欲治療之症狀本質及嚴重度之情況及依各情況所用之式I化合物之性質而定,但是本發明之醫藥組合物為適合口服、直腸、局部、經口(例如舌下)及非經腸(例如皮下、肌肉內、皮膚、皮膚滲透或靜脈內)給藥之組合物。包膜調配物及包膜慢性釋放調配物亦屬於本發明之架構內。較佳係給予抗酸及抗胃酸調配物。適合的抗胃酸膜衣包括纖維素乙酸鄰苯二甲酸、聚乙烯乙酸酯鄰苯二甲酸、羥丙基甲基纖維素鄰苯二甲酸以及甲基丙烯酸和甲基丙烯酸甲酯之陰離子聚合物。
用於口服給藥之適合的醫藥化合物可為分開單位之形式,例如各含有至少一種定義量之式I化合物之膠囊、袋劑、可吸式錠劑或錠劑;為散劑或顆粒;為溶於水性或非水溶性液體之溶液或懸浮液;或為水包油或油包水乳液。這些組合物,如所提的,可藉由其中包括將活性成份與載劑(其可由一或多種另外的成份組成)接觸之步驟之任何適合的醫藥方法來製備。組合物一般係藉由將活性成份與液體及/或細粉狀固體載劑均勻或均質混合來製造,之後視需要將產物塑形。因此,例如錠劑可藉由將化合物之粉末或顆粒,(若適合)與一或多種另外的成份打壓或鑄模來製造。壓製錠可藉由將自由流體形式之化合物,例如粉末或顆粒,(若適當)與結著劑、滑動劑、惰性稀釋劑及/或一種(或多種)介面活性劑/分散劑以適合的機器壓成錠劑來製造。模製錠可藉由將粉末形式及經惰性液體稀釋劑濕化之化合物以適合的機器鑄模來製造。
適合經口(舌下)給藥之醫藥組合物包括含有式I化合物與調味劑(通常為蔗糖及阿拉伯膠或角叉菜膠)之可吸式錠劑以及將化合物包含於惰性基底(例如明膠及甘油或蔗糖和阿拉伯膠)之粒劑。
適合非經腸給藥之醫藥組合物,較佳地包括式I化合物之無菌水性製備物,其較佳地係與預期接受者之血液等張。雖然這些製備物亦可以皮下、肌肉內或真皮注射來給藥,但較佳地係以靜脈給藥。這些製備物較佳地可藉由將化合物與水混合並使產生的溶液為無菌及與血液等張來產生。本發明之可注射組合物一般係含有從0.1至5%重量比之活性化合物。
適合直腸給藥之醫藥組合物較佳地係為單一劑量栓劑之形式。這些可藉由將式I化合物與一或多種習用的固體載劑(例如可可脂)混合並將生成的混合物塑形來製造。
適合局部用於皮膚之醫藥組合物較佳地為軟膏、乳霜、乳液、糊漿、噴霧、氣霧或油之形式。可使用的載劑有石臘、羊毛脂、聚乙二醇、醇類及二或多種這些物質之組合物。活性成份一般係以組合物之重量計從0.1至15%之濃度存在,例如從0.5至2%。
亦可用皮膚滲透給藥。適合皮膚滲透用途之醫藥組合物可為適合長期與病患表皮緊密接觸之單一貼布形式。此等貼布適當地係含有溶於水溶液之活性成份,(若適當)其可經緩衝、溶解及/或分散於黏性聚合物中。適合的活性成份濃度為約1%至35%,較佳地約3%至15%。活性成份最可能地係藉由例如Pharmaceutical Research,2(6):318(1986)中所述之電轉運或離子電滲來釋放。
適合用於組合產品之另外的活性成份有:
在Rote Liste 2007,第12章中所提及之所有抗糖尿病劑;在Rote Liste 2007,第1章中所提及之所有減重劑及/或食慾抑制劑;在Rote Liste 2007,第58章中所提及之所有降脂劑。其可與本發明之化合物組合特別是作為協同增進效用。活性成份組合之給藥可藉由將活性成份分開的投予病患或以組合產物之形式(其中數種活性成份係存在於一種醫藥製備物中)來進行。大多數下文所提及的活性成份係揭示於USP Dictionary of USAN及International Drug Names,US Pharmacopeia,Rockville 2001中。
抗糖尿病劑包括胰島素及胰島素衍生物,例如Lantus(參見www.lantus.com)或HMR 1964或Levemir(地特胰島素)或該等描述於WO2005005477(Novo Nordisk)之藥劑、速效胰島素(參見US 6,221,633)、可吸式胰島素,例如Exubera或口服胰島素例如IN-105(Nobex)或Oral-lynTM
(Generex生物科技公司)、GLP-1衍生物及GLP-1促進劑例如艾塞那肽(exenatide)、利拉魯肽(liraglutide)或該等已揭示於Novo Nordisk A/S之WO98/08871或WO2005027978,WO2006037811,WO2006037810、紐西蘭WO01/04156或博福-益普生公司(Beaufour-Ipsen)之WO00/34331之化合物、醋酸普蘭林肽(pramlintide acetate)(Symlin;Amylin製藥公司)、BIM-51077、PC-DAC:Exendin-4(與重組的人類白蛋白共價鍵結之Exendin-4類似物)、如該等描述於例如D. Chen等人,Proc. Natl. Acad. Sci. USA 104(2007)943中之促進劑、該等描述於WO2006124529之化合物以及口服上具效用之降血糖活性成份。
抗糖尿病藥劑亦包括如該等描述於WO2006121860中之葡萄糖依賴促胰島素肽(GIP)受體之促劑進。
較佳地,口服上具效用之降血糖活性成份包括磺醯尿素、雙胍類、美格替奈類(meglitinide)、二唑啶二酮、噻唑啶二酮、葡萄糖苷酶抑制劑、肝醣磷酸酶抑制劑、升糖素拮抗劑、葡萄糖激酶活化劑、果糖1,6-二磷酸酶之抑制劑、葡萄糖轉運體4(GLUT4)之調節劑、麩胺酸-果糖-6-磷酸醯胺基轉移酶(GFAT)之抑制劑、GLP-促進劑、鉀通道開放劑,例如吡那地爾(Pinacidil)、克羅卡林(Cromakalim)、二氮嗪(Diazoxide)或該等描述於R. D. Carr等人之Diabetes52
,2003,
2513,2518、J. B. Hansen等人之Current Medicinal Chemistry11, 2004,
1595-1615、T. M. Tagmose等人之J. Med. Chem.47
,2004,
3202-3211或M. J. Coghlan等人之J. Med. Chem. 44, 2001,
1627-1653中之化合物,或該等已揭示於Novo Nordisk A/S之WO 97/26265及WO 99/03861之化合物、二肽基胜肽酶IV(DPP-IV)之抑制劑胰島素敏化劑、與糖質新生及/或肝糖分解刺激有關之肝酵素抑制劑、葡萄糖吸收、葡萄糖轉運及葡萄糖再吸收之調節劑、11β-HSD1抑制劑、蛋白質酪胺酸磷酸酶1B(PTP 1B)之抑制劑、鈉依賴葡萄糖轉運體1或2(SGLT1,SGLT2)之調節劑、改變脂質代謝之化合物,例如抗高脂血活性成份及降脂血活性成份、降低食物攝入之化合物、增加產熱作用之化合物、PPAR及RXR調節劑(類維生素A酸X受體),及作用在β細胞之ATP-依賴鉀通道的活性成份。
在本發明一實施例中,式I化合物係與HMGCoA還原酶抑制劑(3-羥基-3-甲基戊二醯基輔酶A),例如辛伐他汀(simvastatin)、氟伐他汀(fluvastatin)、普伐他汀(pravastatin)、洛伐他汀(lovastatin)、阿托伐他汀(atorvastatin)、西立伐他汀(cerivastatin)、羅蘇伐他汀(rosuvastatin)或L-659699,組合給藥。
在本發明一實施例中,式I化合物係與膽固醇吸收抑制劑,例如依澤替米貝(ezetimibe)、替奎安(tiqueside)、帕馬苷(pamaqueside)、FM-VP4(穀固醇/菜油固醇維生素C磷酸鹽;Forbes Medi-Tech公司,W02005042692、W02005005453)、MD-0727(Microbia公司,WO2005021497、W02005021495)或如W02002066464、W02005000353(Kotobuki製藥公司)或W02005044256或W02005062824(Merck公司)或W02005061451和W02005061452(AstraZeneca AB公司)及W02006017257(Phenomix公司)或W02005033100(Lipideon生技公司)或於描述於W02004097655、W02004000805、WO2004000804、WO2004000803、WO2002050068、WO2002050060、WO2005047248、WO2006086562、WO2006102674、WO2006116499、WO2006121861、WO2006122186、WO2006122216、WO2006127893、WO2006137794、WO2006137796WO2006137782,WO2006137793、WO2006137797、WO2006137795、WO2006137792、WO2006138163中之化合物,組合給藥。
在本發明一實施例中,式I化合物係與VytorinTM(一種依澤替米貝及辛伐他汀之固定量組合劑)組合給藥。
在本發明一實施例中,式I化合物係與依澤替米貝及阿托伐他汀之固定量組合劑組合給藥。
在本發明一實施例中,式I化合物係與依澤替米貝及非諾貝特(fenofibrate)之固定量組合劑組合給藥。
在本發明另一實施例中,式I化合物係與非諾貝特及羅蘇伐他汀之固定量組合劑組合給藥。
在本發明另一實施例中,式I化合物係與Synordia(R)(一種非諾貝特及美弗明(metformin)之固定量組合劑)組合給藥。
在本發明一實施例中,式I化合物係與ISIS-301012(一種能調節載脂蛋白(apolipoprotein)B基因之反義寡核苷酸)組合給藥
在本發明一實施例中,式I化合物係與PPAR(過氧化小體增生活化受體)γ促進劑,例如例如羅格列酮(rosiglitazone)、吡格列酮(pioglitazone)、JTT-501、Gl 262570、R-483、CS-011(利格列酮,rivoglitazone)組合給藥。
在本發明一實施例中,式I化合物係與CompetactTM
(一種吡格列酮鹽酸鹽及美弗明鹽酸鹽之固定量組合劑)組合給藥。
在本發明一實施例中,式I化合物係與TandemactTM
(一種吡格列酮和格列美脲(glimepiride)之固定量組合劑)組合給藥。
在本發明另一實施例中,式I化合物係與吡格列酮鹽酸鹽和血管收縮素II之固定量組合劑,例如TAK-536,組合給藥。
在本發明一實施例中,式I化合物係與PPAR(過氧化小體增生活化受體)α促進劑,例如GW9578、GW-590735、K-111、LY-674、KRP-101、DRF-10945、LY-518674或該等描述於WO2001040207、WO2002096894、WO2005097076之化合物,組合給藥。
在本發明一實施例中,式I化合物係與PPAR(過氧化小體增生活化受體)α/γ促進劑,例如那衛他札(naveglitazar)、LY-510929、ONO-5129、E-3030、AVE 8042、AVE 8134、AVE 0847、CKD-501(洛貝格列酮(lobeglitazone)硫酸鹽)或如描述於PCT/US 00/11833、PCT/US 00/11490、DE10142734.4或J. P. Berger等人之TRENDS in Pharmacological Sciences 28(5)、244-251、2005之化合物,組合給藥。
在本發明一實施例中,式I化合物係與PPAR(過氧化小體增生活化受體)δ促進劑例如GW-501516或如描述於WO2006059744、WO2006084176、WO2006029699、WO2007039172-W02007039178中,組合給藥。
在本發明一實施例中,式I化合物係與米他格塔森(metaglidasen)或與MBX-2044或其他部分PPAR(過氧化小體增生活化受體)γ促進劑/拮抗劑,組合給藥。
在本發明一實施例中,式I化合物係與纖維酸類,例如非諾貝特(fenofibrate)、氯貝丁酯(clofibrate)或苯扎貝特(bezafibrate),組合給藥。
在本發明一實施例中,式I化合物係與MTP抑制劑(微粒體三酸甘油酯轉運蛋白),例如印波他匹(implitapide)、BMS-201038、R-103757、AS-1552133或該等描述於WO2005085226、WO2005121091、WO2006010423之化合物,組合給藥。
在本發明一實施例中,式I化合物係與CETP(膽固醇酯轉運蛋白)抑制劑,例如妥西挫比(torcetrapib)或JTT-705或該等描述於WO2006002342、WO2006010422、WO2006012093、WO2006073973、WO2006072362、WO2006097169、WO2007041494之化合物,組合給藥。
在本發明一實施例中,式I化合物係與膽酸吸收抑制劑(參見,例如US 6,145,744、US 6,221,897或WO00/61568),例如HMR 1741或該等描述於DE 10 2005 033099.1及DE 10 2005 033100.9、WO2007009655-56之化合物,組合給藥。
在本發明一實施例中,式I化合物係與聚合性膽酸吸收劑,例如膽苯烯胺(cholestyramine)或考來維崙(colesevelam),組合給藥。
在本發明一實施例中,式I化合物係與LDL受體誘發劑(低密度脂蛋白,參見US 6,342,512),例如HMR1171、HMR1586或該等描述於WO2005097738之化合物,組合給藥。
在本發明一實施例中,式I化合物係與ABCA1表現增進劑,例如WO2006072393中所描述,組合給藥。
在本發明另一實施例中,式I化合物係與針對抗PCSK9(前蛋白轉化酶枯草桿菌素/Kexin第9型)的RNAi治療劑組合給藥。
在一實施例中,式I化合物係與Omacor(ω-3脂肪酸;二十碳五烯酸及二十二碳六烯酸之高濃縮乙酯)組合給藥。
在本發明一實施例中,式I化合物係與ACAT抑制劑(醯基-CoA,膽固醇醯基轉移酶)例如阿瓦辛貝(avasimibe)或SMP-797,組合給藥。
在本發明一實施例中,式I化合物係與抗氧化劑,例如OPC-14117、普羅布考(probucol)、生育醇、抗壞血酸、β-胡蘿蔔素或硒,組合給藥。
在本發明一實施例中,式I化合物係與維生素,例如維生素B6或維生素B12,組合給藥。
在本發明一實施例中,式I化合物係與脂蛋白脂解酶調節劑,例如艾溴利平(ibrolipim)(NO-1886),組合給藥。
在本發明一實施例中,式I化合物係與ATP-檸檬酸裂酶抑制劑(腺核苷三磷酸),例如SB-204990,組合給藥。
在本發明一實施例中,式I化合物係與較鯊烯合成酶抑制劑,例如BMS-188494、BMS-188494、TAK-475或如描述於WO2005077907、P2007022943,組合給藥。
在本發明一實施例中,式I化合物係與脂蛋白(a)拮抗劑,例如傑卡賓(gemcabene)(CI-1027)組合給藥。
在本發明一實施例中,式I化合物係與GPR109A促進劑(HM74A受體促進劑;NAR促進劑(菸鹼酸受體促進劑)),例如菸鹼酸或延長釋放菸鹼酸與MK-0524A結合或該等描述於WO2006045565、WO2006045564、WO2006069242、WO2006124490、WO2006113150、WO2007017261、WO2007017262、WO2007017265、WO2007015744、WO2007027532之化合物,組合給藥。
在本發明一實施例中,式I化合物係與GPR116促進劑,如描述於例如WO2006067531、WO2006067532,組合給藥。
在本發明一實施例中,式I化合物係與脂肪酶抑制劑,例如奧利司他(orlistat)或西替利司他(cetilistat)(ATL-962),組合給藥。
在本發明一實施例中,式I化合物係與胰島素組合給藥。
在一實施例中,式I化合物係與磺醯尿素,例如甲苯磺丁脲(tolbutamide)、格列本脲(glibenclamide)、格列吡嗪(glipizide)或格列美脲(glimepiride),組合給藥。
在一實施例中,式I化合物係與促進胰島素分泌之物質,例如KCP-265(W02003097064)或該等描述於WO2007026761之化合物,組合給藥。
在本發明一實施例中,式I化合物係與葡萄糖依賴性促胰島素受體(GDIR),例如APD-668,組合給藥。
在一實施例中,式I化合物係與雙胍,例如美弗明組合給藥。
又在另一實施例中,式I化合物係與美格替奈(meglitinide),例如瑞格列奈(repaglinide)、那格列奈(nateglinide)或米格列奈(mitiglinide),組合給藥。
在另一實施例中,式I化合物係與美格替奈和格列酮(glitazone)例如吡格列酮鹽酸鹽之組合劑給藥。
在另一實施例中,式I化合物係與米格列奈和α-葡萄糖苷酶抑制劑之組合劑給藥。
在一實施例中,式I化合物係與噻唑啶二酮,例如曲格列酮(troglitazone)、環格列酮(ciglitazone)、吡格列酮(pioglitazone)、羅格列酮(rosiglitazone)或瑞迪博士(Dr. Reddy)研究基金會之WO 97/41097中所述的化合物,特別是5-[[4-[(3,4-二氫-3-甲基-4-酮基-2-喹唑啉甲氧基]苯基]甲基]-2,4-噻唑啶二酮組合給藥。
在一實施例中,式I化合物係與α-葡萄糖苷酶抑制劑,例如米格列醇(miglitol)或阿卡波糖(acarbose)組合給藥。
在一實施例中,式I化合物係與作用在β細胞之ATP-依賴鉀通道之活性成份,例如甲苯磺丁脲(tolbutamide)、格列苯脲(glibenclamide)、格列吡嗪(glipizide)、格列美脲(glimepiride)或瑞格列奈(repaglinide)組合給藥。
在一實施例中,式I化合物係與一種以上之前述化合物組合給藥,例如與磺醯尿素及美弗明、與磺醯尿素及阿卡波糖、瑞格列奈及美弗明、胰島素及磺醯尿素、胰島素及美弗明、胰島素及曲格列酮、胰島素及洛伐他汀等組合給藥。
在一實施例中,式I化合物係與肝醣磷酸酶抑制劑,例如PSN-357或FR-258900或該等描述於WO2003084922、WO2004007455、WO2005073229-31或WO2005067932之化合物,組合給藥。
在一實施例中,式I化合物係與升糖素受體拮抗劑,例如A-770077或NNC-25-2504或如WO2004100875或WO2005065680中所描述,組合給藥。
在一實施例中,式I化合物係與葡萄糖激酶活化劑,例如R-1511、R-1440、LY-2121260(W02004063179)、PSN-105、PSN-110、GKA-50或該等例如描述於WO2004072031、WO2004072066、WO2005080360、WO2005044801、WO2006016194、WO2006058923、WO2006112549、WO2006125972、WO2007017549、WO2007017649、WO2007007910、WO2007007040-42、WO2007006760-61、WO2007006814、WO2007007886、WO2007028135、WO2007031739、WO2007041365、WO2007041366、WO2007037534、WO2007043638、WO2007053345、WO2007051846、WO2007051845、WO2007053765、WO2007051847之化合物組合給藥。
在一實施例中,式I化合物係與糖質新生作用之抑制劑,例如FR-225654組合給藥。
在一實施例中,式I化合物係與果糖-1,6-二磷酸酶(FBPase),例如CS-917(MB-06322)或MB-07803或該等描述於WO2006023515、WO2006104030、WO2007014619之化合物組合給藥。
在一實施例中,式I化合物係與葡萄糖轉運體4(GLUT4)之調節劑,例如KST-48(D.-O. Lee等人:Arzneim.-Forsch. Drug Res. 54(12),835(2004))組合給藥。
在一實施例中,式I化合物係與TNF促進劑(腫瘤壞死因子)組合給藥。
在一實施例中,式I化合物係與CRF促進劑(促腎上腺皮質激素釋放因子)組合給藥。
在一實施例中,式I化合物係與5HT促進劑(血清素再吸收)組合給藥。
在一實施例中,式I化合物係與TR-β促進劑(甲狀腺受體)組合給藥。
在一實施例中,式I化合物係與麩胺酸-果糖-6-磷酸醯胺基轉移酶(GFAT),例如於WO2004101528中所描述,組合給藥。
在一實施例中,式I化合物係與二肽基胜肽酶IV(DPP-IV)之抑制劑,例如維格列汀(vildagliptin)(LAF-237)、西他列汀(sitagliptin)(MK-0431)、西他列汀磷酸鹽、沙卡沙列汀saxagliptin(BMS-477118)、GSK-823093、PSN-9301、SYR-322、SYR-619、TA-6666、TS-021、GRC-8200、GW-825964X、KRP-104、DP-893、ABT-341、ABT-279或其另外的鹽類或該等描述於WO2003074500、WO2003106456、WO2004037169、WO200450658、WO2005058901、WO2005012312、WO2005/012308、WO2006039325、WO2006058064、PCT/EP2005/007821、PCT/EP2005/008005、PCT/EP2005/008002、PCT/EP2005/008004、PCT/EP2005/008283、DE 10 2005 012874.2、DE 10 2005 012873.4、JP2006160733、WO2006071752、WO2006065826、WO2006078676、WO2006073167、WO2006068163、WO2006090915、WO2006104356、WO2006127530、WO2006111261、WO2007015767、WO2007024993、WO2007029086之化合物,組合給藥。
在本發明一實施例中,式I化合物係與JanumetTM
(一種西他列汀磷酸鹽與美弗明鹽酸鹽之固定量組合劑)組合給藥。
在一實施例中,式I化合物係與11-β-羥基類固醇去氫酶1(11β-HSD1),例如BVT-2733、JNJ-25918646、1NCB-13739或該等例如描述於WO200190090-94、WO200343999、WO2004112782、WO200344000、WO200344009、WO2004112779、WO2004113310、WO2004103980、WO2004112784、WO 2003065983、WO2003104207、WO2003104208、WO2004106294、WO2004011410、WO2004033427、WO2004041264、WO2004037251、WO2004056744、WO2004058730、WO2004065351、WO2004089367、WO2004089380、WO2004089470-71、WO2004089896、WO2005016877、WO2005097759、WO2006010546、WO2006012227、WO2006012173、WO2006017542、WO2006034804、WO2006040329、WO2006051662、WO2006048750、WO2006049952、WO2006048331、WO2006050908、WO2006024627、WO2006040329、WO2006066109、WO2006074244、WO2006078006、WO2006106423、WO2006132436、WO2006134481、WO2006134467、WO2006135795、WO2006136502、WO2006138695、WO2006133926、WO2007003521、WO2007007688、US2007066584、WO2007047625、WO2007051811、WO2007051810之化合物,組合給藥。
在一實施例中,式I化合物係與蛋白質酪胺酸磷酸酶1B(PTP 1B)之抑制劑,如描述於例如WO200119830-31、WO200117516、WO2004506446、WO2005012295、WO2005116003、PCT/EP2005/005311、PCT/EP2005/005321、PCT/EP2005/007151、DE 10 2004 060542.4、WO2007009911、WO2007028145中,組合給藥。
在一實施例中,式I化合物係與鈉依賴葡萄糖轉運體1或2(SGLT1、SGLT2)之調節劑,例如KGA-2727、T-1095、SGL-0010、AVE 2268、SAR 7226及舍格列淨(sergliflozin)或如描述於例如W02004007517、W0200452903、W0200452902、PCT/EP2005/005959、WO2005085237、JP2004359630、WO2005121161、WO2006018150、WO2006035796、WO2006062224、WO2006058597、WO2006073197、WO2006080577、WO2006087997、WO2006108842、WO2007000445、WO2007014895或A. L. Handlon之Expert Opin. Ther. Patents(2005)15(11),1531-1540,組合給藥。
在一實施例中,式I化合物係與GPR119b之調節劑,如描述於例如WO2004041274,組合給藥。
在一實施例中,式I化合物係與GPR119之調節劑,如描述於例如WO2005061489(PSN-632408)、WO2004065380、WO2007003960-62及WO2007003964,組合給藥。
在另一實施例中,式I化合物係與GPR120之調節劑組合給藥。
在一實施例中,式I化合物係與荷爾蒙敏感脂肪酶(HSL)及/或磷脂酶之抑制劑,如描述於例如WO2005073199、WO2006074957、WO2006087309、WO2006111321、WO2007042178,組合給藥。
在一實施例中,式I化合物係與乙醯基-CoA羧基酶(ACC)之抑制劑,例如該等描述於WO199946262、WO200372197、WO2003072197、WO2005044814、WO2005108370、JP2006131559、WO2007011809、WO2007011811,WO2007013691之化合物,組合給藥。
在另一實施例中,式I化合物係與黃嘌呤氧化還原酶(XOR)之調節劑組合給藥。
在一實施例中,式I化合物係與磷酸烯醇丙酮酸羧化激酶(PEPCK),例如該等描述於WO2004074288之化合物,組合給藥。
在一實施例中,式I化合物係與肝醣合成酶激酶3β(GSK-3β)之抑制劑,如描述於例如US2005222220、WO2005085230、PCT/EP2005/005346、WO2003078403、WO2004022544、WO2003106410、WO2005058908、US2005038023、WO2005009997、US2005026984、WO2005000836、WO2004106343、EP1460075、WO2004014910、WO2003076442、WO2005087727或WO2004046117中,組合給藥。
在一實施例中,式I化合物係與血清/糖皮質素調節激酶(SGK)之抑制劑,如描述於例如WO2006072354,組合給藥。
在一實施例中,式I化合物係與RUP3受體之促進劑,如描述於例如WO2007035355,組合給藥。
在一實施例中,式I化合物係與蛋白質激酶Cβ(PKCβ),例如魯伯斯塔(ruboxistaurin)組合給藥。
在另一實施例中,式I化合物係與編碼共濟失調-毛細血管擴張突變(ATM)蛋白激酶基因之活化劑,例如氯喹(chloroquine)組合給藥。
在一實施例中,式I化合物係與內皮素A受體拮抗劑,例如阿弗先他(avosentan)(SPP-301)組合給藥。
在一實施例中,式I化合物係與"I-kappaB激酶"抑制劑(IKK抑制劑),如描述於例如WO2001000610、WO2001030774、WO2004022553、WO2005097129,組合給藥。
在一實施例中,式I化合物係與糖皮質素受體(GR)之調節劑,如該等描述於例如WO2005090336、WO2006071609、WO2006135826之化合物,組合給藥。
在另一實施例中,式I化合物係與CART調節劑,(參見"可卡因-苯丙胺調節轉錄對小鼠能量代謝、焦慮及胃排空之影響"Asakawa,A.等人:激素與代謝研究(2001),33(9),554-558);
NPY拮抗劑(神經肽Y),例如萘-1-磺酸{4-[(4-胺基喹唑啉-2-基胺基)甲基]環己基甲基)醯胺鹽酸鹽(CGP 71683A);
NPY-5受體拮抗劑例如L-152804或如該等如描述於例如WO2006001318之化合物;
NPY-4受體拮抗劑如該等如描述於例如WO2007038942之化合物;
NPY-2受體拮抗劑如該等如描述於例如WO2007038943之化合物;
胜肽YY 3-36(PYY3-36)或類似化合物,例如CJC-1682(PYY3-36經由Cys34與人類血清白蛋白結合)、CJC-1643(與活體中血清白蛋白結合之PYY3-36衍生物)或該等如描述於WO2005080424、WO2006095166之化合物;
胜肽肥胖抑制素之衍生物,如描述於WO2006096847;
CB 1R(類大麻素受體1)拮抗劑(例如,利莫那班(rimonabant)、SR147778、SLV-319、AVE-1625、MK-0364或其鹽類或該等描述於例如EP 0656354、WO 00/15609、WO 02/076949、WO2005080345、WO2005080328、WO2005080343、WO2005075450、WO2005080357、WO200170700、WO2003026647-48、WO200302776、WO2003040107、WO2003007887、WO2003027069、US6,509,367、WO200132663、WO2003086288、WO2003087037、WO2004048317、WO2004058145、WO2003084930、WO2003084943、WO2004058744、WO2004013120、WO2004029204、WO2004035566、WO2004058249、WO2004058255、WO2004058727、WO2004069838、US20040214837、US20040214855、US20040214856、WO2004096209、WO2004096763、WO2004096794、WO2005000809、WO2004099157、US20040266845、WO2004110453、WO2004108728、WO2004000817、WO2005000820、US20050009870、WO200500974、WO2004111033-34、WO200411038-39、WO2005016286、WO2005007111、WO2005007628、US20050054679、WO2005027837、WO2005028456、WO2005063761-62、WO2005061509、WO2005077897、WO2006047516、WO2006060461、WO2006067428、WO2006067443、WO2006087480、WO2006087476、WO2006100208、WO2006106054、WO2006111849、WO2006113704、WO2007009705、WO2007017124、WO2007017126、WO2007018459、WO2007016460、WO2007020502、WO2007026215、WO2007028849、WO2007031720、WO2007031721、WO2007036945、WO2007038045、WO2007039740、US20070015810、WO2007046548、WO2007047737)之化合物;
類大麻素受體/類大麻素受體2(CB1/CB2)-調節化合物,如該等如描述於例如WO2007001939、WO2007044215、WO2007047737之化合物;
MC4促進劑(黑皮質素-4)(例如1-胺基-1,2,3,4-四氫萘-2-羧酸[2-(3a-苯甲基-2-甲基-3-氧基-2,3,3a,4,6,7-六氫吡唑并[4,3-c]吡啶-5-基)-1-(4-氯苯基)-2-氧乙基]醯胺;(WO 01/91752));或LB53280、LB53279、LB53278或THIQ、MB243、RY764、CHIR-785、PT-141或該等描述於W02005060985、W02005009950、W02004087159、W02004078717、W02004078716、W02004024720、US20050124652、W02005051391、W02004112793、WOUS20050222014、US20050176728、US20050164914、US20050124636、US20050130988、US20040167201、W02004005324、W02004037797,W02005042516、W02005040109、W02005030797、US20040224901、W0200501921、W0200509184、W02005000339、EP1460069、W02005047253、W02005047251、W02005118573、EP1538159、W02004072076、W02004072077、W02006021655-57、W02007009894、W02007015162、W02007041061、W02007041052之化合物;
食慾素(orexin)受體拮抗劑(例如1-(2-甲基苯并唑-6-基)-3-[1,5]萘啶-4-基尿素鹽酸鹽(SB-334867-A));或該等描述於例如W0200196302、W0200185693、W02004085403、W02005075458、W02006067224之化合物);
組織胺H3受體促進劑(例如3-環己基-1-(4,4-二甲基-1,4,6,7-四氫咪唑并[4,5-c]吡啶-5-基)丙-1-酮草酸鹽(WO00/63208);或該等描述於W0200064884、W02005082893、W02006107661、W02007003804、W02007016496、W02007020213之化合物);
組織胺H1/組織胺H3調節劑,例如倍他司汀(betahistine)或其鹽酸鹽;
CRF拮抗劑(例如[2-甲基-9-(2,4,6-三甲基苯基)-9H-1,3,9-三氮雜茀-4-基]二丙基胺(WO 00/66585));
CRF BP拮抗劑(例如優可汀(urocortin));
優可汀促進劑;
β3腎上腺素受體之促進劑(例如1-(4-氯-3-甲磺醯基甲基苯基)-2-[2-(2,3-二甲基-1H-吲哚-6-基氧基)乙基胺基]乙醇鹽酸鹽(WO 01/83451));或索拉貝拱(solabegron)(GW-427353)或N-5984(KRP-204)或或該等描述於JP2006111553、W02002038543、W02007048840-843之化合物;
MSH(促黑激素)促進劑;
MCH(黑色素凝集激素)受體拮抗劑(例如NBI-845、A-761、A-665798、A-798、ATC-0175、T-226296、T-71、GW-803430或該等描述於WO2005085200、WO2005019240、WO2004011438、WO2004012648、WO2003015769、WO2004072025、WO2005070898、WO2005070925、WO2004039780、WO2004092181、WO2003033476、WO2002006245、WO2002089729、WO2002002744、WO2003004027、FR2868780、WO2006010446、WO2006038680、WO2006044293、WO2006044174、JP2006176443、WO2006018280、WO2006018279、WO2006118320、WO2006130075、WO2007018248、WO2007012661、WO2007029847、WO2007024004、WO2007039462、WO2007042660、WO2007042668、WO2007042669、US2007093508、US2007093509、WO2007048802、JP2007091649之化合物);
CCK-A促進劑(例如{2-[4-(4-氯-2,5-二甲氧基苯基)-5-(2-環己基乙基)噻唑-2-基胺甲醯基]-5,7-二甲基吲哚-1-基}乙酸(WO 99/15525);或SR-146131(WO 0244150)或SSR-125180)或該等描述於WO2005116034之化合物;
血清素再吸收抑制劑(例如右芬氟拉明(dexfenfluramine));
混合血清素/多巴胺再吸收抑制劑(例如丁基丙酸(bupropion))或丁基丙酸與納曲酮(naltrexone)之組合劑;
混合血清素及去甲基正腎上腺素化合物(例如WO 00/71549);
5-HT促進劑,例如1-(3-乙基苯并呋喃-7-基)哌草酸鹽(WO 01/09111);
混合的多巴胺/正腎上腺素/乙醯膽鹼再吸收抑制劑(例如泰索分辛(tesofensine));
5-HT2C受體促進劑(例如羅卡蘇寧(lorcaserine)鹽酸鹽(APD-356)或BVT-933或或該等描述於WO200077010、WO200077001-02、WO2005019180、WO2003064423、WO200242304、WO2005035533、WO2005082859、WO2006077025、WO2006103511之化合物);
5-HT6受體調節劑,例如E-6837或BVT-74316或該等描述於例如WO2005058858、WO2007054257之化合物;
蛙皮素(bombesin)受體促進劑(BRS-3促進劑);
甘丙肽(galanin)受體拮抗劑;
生長激素(例如人類生長激素或AOD-9604);
生長激素釋放化合物(6-苯甲基氧基-1-(2-二異丙基胺基-乙基胺甲醯基)-3,4-二氫-1H-異喹啉-2-羧酸第三丁酯(WO01/85695));
生長激素分泌受體拮抗劑(格瑞林(ghrelin)拮抗劑)例如A-778193或該等描述於WO2005030734之化合物;
TRH促進劑(促甲狀腺激素釋放激素,參見例如EP 0 462 884);
去偶合蛋白2或3調節劑;
瘦體素促進劑(參見例如Lee,Daniel W.;Leinung,Matthew C.;Rozhayskaya-Arena,Marina;Grasso,Patricia.受體素促進劑作為潛在治療肥胖症之方法,Drugs of the Future(2001),26(9),873-881);
DA促進劑(多巴胺促進劑,溴麥角隱亭(bromocriptine)或多普辛(Doprexin));
脂肪酶/澱粉酶抑制劑(例如WO 00/40569);
二醯甘油酯O-醯基轉移酶(DGAT)之抑制劑,如等描述於例如BAY-74-4113或描述於例如US2004/0224997、WO2004094618、WO200058491、WO2005044250、WO2005072740、JP2005206492、WO2005013907、WO2006004200、WO2006019020、WO2006064189、WO2006082952、WO2006120125、WO2006113919、WO2006134317、WO2007016538;
脂肪酸合成酶(FAS)之抑制劑,例如C75或該等描述於WO2004005277之化合物;
硬脂醯-CoAδ9去飽和酶(SCD1)之抑制劑,如該等描述於WO2007009236、WO2007044085、WO2007046867、WO2007046868、WO20070501124之化合物;
肽胃泌酸調節素(oxyntomodulin);
油醯雌酮(oleoyl-estrone);
或甲狀腺激素受體促進劑之促進劑或部分促進劑,例如:KB-2115或如該等描述於WO20058279、WO200172692、WO200194293、WO2003084915、WO2004018421、WO2005092316、WO2007003419、WO2007009913、WO2007039125之化合物,組合給藥。
在一實施例中,另外的活性成份為伐崙克林酒石酸鹽(varenicline tartrate),一種α4-β2菸鹼乙醯膽鹼受體之部分促進劑。
在一實施例中,另外的活性成份為挫達斯奎明(trodusquemine)。
在一實施例中,另外的活性成份為酵素SIRT1之調節劑。
在本發明一實施例中,另一種活性成份為瘦體素;參見例如"瘦體素治療用途之觀點",Salvador,Javier;Gomez-Ambrosi,Javier;Fruhbeck,Gema,Expert Opinion on Pharmacotherapy(2001),2(10),1615-1622。
在一實施例中,另外的活性成份為右旋安非他命(dexamphetamine)或安非他命(amphetamine)。
在一實施例中,另外的活性成份為氟苯丙胺(fenfluramine)或右旋氟苯丙胺(dexfenfluramine)。
在另一實施例中,另外的活性成份為西布曲明(sibutramine)。
在一實施例中,另外的活性成份為嗎吲哚(mazindol)或苯丁胺(phentermine)。
在一實施例中,另外992,067或US7,205,290。
在一實施例中,式I化合物係與膨鬆劑,較佳的為不溶性的膨鬆劑組合給藥(參見,例如角豆(carob)/Caromax(Zunft HJ;等人,治療高膽固醇血症之角豆製備物,ADVANCES IN THERAPY(2001 Sep-Oct),18(5),230-6)。Caromax為含有角豆之產品,係得自Nutrinova,Nutrition Specialties & Food Ingredients GmbH,Industriepark Hchst,65926 Frankfurt/Main)。與Caromax組合可在一個製備物中或將式I化合物及Caromax分開給藥。就此而論Caromax亦可以食用產品的形式,例如烘焙產品或麥果條(muesli bar)來投予。
應了解,本發明化合物與一或多種上述化合物及視需要一或多種其他的藥理活性物質之每種適合的組合,應視為落在本發明授與之保護內。
詳述於下之實例係用於說明本發明,而非限制本發明。
化合物之活性係如下進行試驗:
功能-試驗分析係藉由FLIPR技術(Molecular Devices公司之"螢光顯影盤式分析儀")來進行。就此目的,係測定表現GPCR GPR40之重組HEK293細胞中促進劑引發的胞內Ca2+
濃度之改變。
對於此研究,係將細胞種入96-孔微量滴定盤中(60000細胞/孔)並使其生長至隔夜。移除培養基並將細胞置於含螢光染劑Fluo-4之緩衝液中培養。待染劑載入後,清洗細胞,加入試驗物質並於FLIPR裝置中測量胞內Ca2+
濃度之改變。結果係以相對於對照組之百分比變化來表示(0%:無加入試驗物質;100%:加入10μM參照促進劑亞麻油酸),用來計算劑量/活性圖表及測定的EC50
值。
表中明顯的,式I化合物活化了GPR40受體而因此非常適合用於治療高血糖症及糖尿病。胰島素分泌因式I化合物而增加(參見Itoh等人,Nature 2003,422,173-176)。
由於活化了GPR40受體,式I化合物亦可用於治療或預防其他的疾病。
本發明化合物特別適合用於治療及/或預防:
1.-脂肪酸代謝病症及葡萄糖利用失調
-涉及胰島素抗性之病症
2.糖尿病特別是第2型糖尿病,包括與其相關的後遺症之預防
-與此有關的特別方面有
-高血糖症
-改善胰島素抗性
-改善葡萄糖耐受力
-保護胰臟β細胞
-預防大血管及微血管病症
3.可能與代謝症候群或X症候群有關之各種其他症狀,例如
-腰圍增加
-血脂異常(例如高三酸甘油酯血症及/或低HDL)
-胰島素抗性
-高凝固性
-高尿酸血症
-微量白蛋白血症
-血栓、高凝狀態及促血栓凝結狀態(動脈及靜脈)
-高血壓
-心臟衰竭,例如(但不限於)續發性心肌梗塞、高血壓性心臟病或心肌症
4.記憶力減損、智能不足、CNS病症例如
-老年失智症
-阿茲海默症
-注意力減損或驚醒症之治療
-精神分裂症
式I化合物可例如藉由將適合的式II起始物
與草醯氯,在適合的溶劑例如乙酸乙酯或乙腈中,轉變為式III之胺草醯氯來製備。
將以此法製備之式III化合物與式IV之經胺基苯基取代-羧酸,
在適合的溶劑例如乙腈、1,2-二氯乙烷或二氯甲烷中,在適合的溫度下,較佳地在沸點反應,得到式I化合物。
實例之通用製備係詳述如下:
將500毫克的苯胺溶於5毫升的乙酸乙酯並於一小時內逐滴加至500毫克草醯氯溶於5毫升乙酸乙酯之溶液中。將反應溶液於室溫下攪拌2小時然後濃縮。
將經胺基苯基取代之羧酸分次加至胺草醯氯之10毫升的乙酸乙酯溶液中並於100℃攪拌16小時。將生成的沉澱抽氣過濾出且,若需要,以快速層析純化(SiO2
,二氯甲烷-異丙醇)。
以LC/MS分析化合物。LC/MS可偵測到所有實例之適當的分子波峰(M+H)+。
Claims (18)
- 一種式I化合物
- 如申請專利範圍第1項之式I化合物,其中意義為:R3 相互獨立地為H、F、Cl、Br、CF3 、OCF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基、(C3 -C8 )-環烷基、苯基、O苯基,其中烷基及苯基可經R12取代一或多次;R1、R5 相互獨立地為H、F、Cl、Br、CF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基、苯基、O苯基,其中烷基及苯基可經R12取代一或多次;R2、R4 相互獨立地為H、F、Cl、Br、CF3 、COOH、 COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基;R6 為OH、F、Cl、Br、CN、OCH3 、OCF3 、CH3 、CF3 、(C1 -C6 )-烷基或O-(C1 -C6 )-烷基,其中烷基可經OH、F、Cl、Br或CN取代一或多次;R7、R8 為H;X 為經C3 炔基基團取代一次的C2 伸烷基;m 為0;R9、R10相互獨立地為H、(C1 -C6 )-烷基或苯基,其中烷基可經F、Cl或Br取代一或多次,而苯基可經R6取代一或多次;R12 為F、Cl、Br、CN、OH、O-(C1 -C6 )-烷基、(C1 -C6 )-烷基、(C2 -C6 )-烯基、(C2 -C6 )-炔基、NR9R10、COOH、COO-(C1 -C4 )-烷基;及其醫藥上可接受鹽類。
- 如申請專利範圍第1或2項之式I化合物,其中意義為:R3 相互獨立地為H、F、Cl、Br、CF3 、OCF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基、(C3 -C8 )-環烷基、苯基;R1、R5 相互獨立地為H、F、Cl、Br、CF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基、苯基;R2、R4 相互獨立地為H、F、Cl、Br、CF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基;R7、R8 為H;X 為經C3 炔基基團取代一次的C2 伸烷基; m 為0;及其醫藥上可接受鹽類。
- 如申請專利範圍第1或2項之式I化合物,其中意義為:R3 相互獨立地為H、F、Cl、Br、CF3 、OCF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基、(C3 -C8 )-環烷基、苯基;R1、R5 相互獨立地為H、F、Cl、Br、CF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基、苯基;R2、R4 相互獨立地為H、F、Cl、Br、CF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基;R7、R8 為H;X 為經C3 炔基基團取代一次的C2 伸烷基;m 為0;及其醫藥上可接受鹽類。
- 如申請專利範圍第1項之式I化合物,其中意義為:R3 相互獨立地為H、F、Cl、Br、CF3 、OCF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基、苯基、O苯基,其中烷基及苯基可經R12取代一或多次;R1、R5 相互獨立地為H、F、Cl、Br、CF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基、苯基、O苯基,其中烷基及苯基可經R12取代一或多次;R2、R4 相互獨立地為H、F、Cl、Br、CF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基;R6 為OH、F、Cl、Br、CN、OCH3 、OCF3 、CH3 、 CF3 、(C1 -C6 )-烷基或O-(C1 -C6 )-烷基,其中烷基可經OH、F、Cl、Br或CN取代一或多次;R7、R8 為H;X 為經C3 炔基基團取代一次的C2 伸烷基;m 為0;R9、R10相互獨立地為H、(C1 -C6 )-烷基或苯基,其中烷基可經F、Cl或Br取代一或多次,而苯基可經R6取代一或多次;R12 為F、Cl、Br、CN、OH、O-(C1 -C6 )-烷基、(C1 -C6 )-烷基、(C2 -C6 )-烯基、(C2 -C6 )-炔基、NR9R10、COOH、COO-(C1 -C4 )-烷基;及其醫藥上可接受鹽類。
- 如申請專利範圍第1或2項之式I化合物,其中意義為:R3 相互獨立地為H、F、Cl、Br、CF3 、OCF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基、苯基;R1、R5 相互獨立地為H、F、Cl、Br、CF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基、苯基;R2、R4 相互獨立地為H、F、Cl、Br、CF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基;R7、R8 為H;X 為經C3 炔基基團取代一次的C2 伸烷基;m 為0;及其醫藥上可接受鹽類。
- 如申請專利範圍第1或2項之式I化合物,其中意義為: R3 為相互獨立地為H、F、Cl、Br、CF3 、OCF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基;R1、R5 相互獨立地為H、F、Cl、Br、CF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基、苯基;R2、R4 相互獨立地為H、F、Cl、Br、CF3 、COOH、COO-(C1 -C6 )-烷基、(C1 -C6 )-烷基;R7、R8 為H;X 為經C3 炔基基團取代一次的C2 伸烷基;m 為0;及其醫藥上可接受鹽類。
- 如申請專利範圍第1或2項之化合物,係用作為醫藥。
- 一種醫藥,係包含如申請專利範圍第1至7項中一或多項之化合物。
- 一種醫藥,係包含如申請專利範圍第1至7項中一或多項之化合物及至少一種其他的活性成份。
- 如申請專利範圍第10項之醫藥,其包含作為其他的活性成份之一或多種HMGCoA還原酶抑制劑、膽固醇吸收抑制劑、PPARγ促進劑、PPARα促進劑、PPARδ促進劑、纖維酸、MTP抑制劑、膽酸吸收抑制劑、CETP抑制劑、聚合性膽酸吸收劑、LDL受體誘發劑、ACAT抑制劑、抗氧化劑、脂蛋白脂解酶抑制劑、ATP-檸檬酸裂解酶抑制劑、鮫鯊烯合成酶抑制劑、脂蛋白(a)拮抗劑、HM74A受體促進劑、脂肪酶抑制劑、胰島素、磺醯尿素、雙胍類、美格替奈、噻唑啶二酮、α-葡萄糖苷酶抑制劑、作用 在β細胞之ATP-依賴鉀通道的活性成份、肝醣磷酸酶抑制劑、升糖素受體拮抗劑、葡萄糖激酶活化劑、糖質新生作用之抑制劑、果糖1,6-二磷酸酶之抑制劑、葡萄糖轉運體4之調節劑、麩胺酸-果糖-6-磷酸醯胺基轉移酶之抑制劑、二肽基胜肽酶IV之抑制劑、11-β-羥基類固醇去氫酶1之抑制劑、蛋白質酪胺酸磷酸酶1B之抑制劑、鈉依賴葡萄糖轉運體1或2之調節劑、荷爾蒙敏感脂肪酶、乙醯基-CoA羧基酶之抑制劑、磷酸烯醇丙酮酸羧化激酶之抑制劑、肝醣合成酶激酶-3β之抑制劑、蛋白質激酶Cβ之抑制劑、內皮素A受體拮抗劑之抑制劑、I-kappaB激酶之抑制劑、糖皮質素受體之調節劑、CART促進劑、NPY促進劑、MC4促進劑、食慾素促進劑、H3促進劑、TNF促進劑、CRF促進劑、CRF BP拮抗劑、優可汀促進劑、β3促進劑、CB1受體拮抗劑、MSH(促黑激素)促進劑、CCK促進劑、血清素再吸收抑制劑、混合血清素及去甲基正腎上腺素化合物、5HT促進劑、蛙皮素(bombesin)促進劑、甘丙肽(galanin)拮抗劑、生長激素、生長激素釋放化合物、TRH促進劑、去偶合蛋白2或3調節劑、瘦體素促進劑、DA促進劑、脂肪酶/澱粉酶抑制劑、PPAR調節劑、RXR調節劑或TR-β促進劑或安非他命(amphetamines)。
- 一種如申請專利範圍第1至7項中一或多項之化合物於製造供降血糖之醫藥品的用途。
- 一種如申請專利範圍第1至7項中一或多項之化合物於 製造供治療糖尿病之醫藥品的用途。
- 一種如申請專利範圍第1至7項中一或多項之化合物於製造供增加胰島素分泌之醫藥品的用途。
- 一種製造包含如申請專利範圍第1至7項中一或多項化合物之醫藥之方法,其包括將活性成份與醫藥上適合之載劑混合並將混合物轉變為適合給藥之形式。
- 一種如申請專利範圍第1至7項中一或多項之化合物於製造供治療CNS病症之醫藥品的用途。
- 一種如申請專利範圍第1至7項中一或多項之化合物於製造供治療精神分裂症之醫藥品的用途。
- 一種如申請專利範圍第1至7項中一或多項之化合物於製造供治療阿茲海默症之醫藥品的用途。
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DE1618197B1 (de) * | 1966-02-07 | 1971-12-09 | Ciba Geigy | Verwendung von asymmetrischen Oxalsäure-diarylamiden als Ultraviolettschutzmittel für organische Materialien |
FR2727114B1 (fr) * | 1994-11-17 | 1996-12-27 | Oreal | Nouveaux filtres solaires, compositions cosmetiques photoprotectrices les contenant et utilisations |
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ITRM20020016A1 (it) * | 2002-01-15 | 2003-07-15 | Sigma Tau Ind Farmaceuti | Derivati di acidi fenil(alchil)carbossilici e derivati fenilalchileterociclici dionici, loro uso come medicamenti ad attivita' ipoglicemizza |
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- 2008-09-04 EP EP08785815.5A patent/EP2203416B1/de active Active
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CA2700028A1 (en) | 2009-04-02 |
MX2010002461A (es) | 2010-03-26 |
AU2008303976A1 (en) | 2009-04-02 |
US20100261645A1 (en) | 2010-10-14 |
US20130231388A1 (en) | 2013-09-05 |
AU2008303976B9 (en) | 2013-09-12 |
RU2488578C2 (ru) | 2013-07-27 |
IL204555A0 (en) | 2010-11-30 |
US8518875B2 (en) | 2013-08-27 |
JP5427784B2 (ja) | 2014-02-26 |
ZA201001015B (en) | 2010-10-27 |
CN101796017A (zh) | 2010-08-04 |
KR20100061692A (ko) | 2010-06-08 |
AU2008303976B2 (en) | 2013-04-18 |
WO2009039943A1 (de) | 2009-04-02 |
RU2010115748A (ru) | 2011-10-27 |
EP2203416A1 (de) | 2010-07-07 |
CO6260062A2 (es) | 2011-03-22 |
MY149648A (en) | 2013-09-30 |
UY31350A1 (es) | 2009-04-30 |
NZ584049A (en) | 2011-05-27 |
TW200927088A (en) | 2009-07-01 |
JP2010539199A (ja) | 2010-12-16 |
AR068479A1 (es) | 2009-11-18 |
MA31710B1 (fr) | 2010-09-01 |
CL2008002742A1 (es) | 2009-01-16 |
EP2203416B1 (de) | 2016-10-26 |
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