TWI537238B - 苯甲胺衍生物 - Google Patents
苯甲胺衍生物 Download PDFInfo
- Publication number
- TWI537238B TWI537238B TW101124538A TW101124538A TWI537238B TW I537238 B TWI537238 B TW I537238B TW 101124538 A TW101124538 A TW 101124538A TW 101124538 A TW101124538 A TW 101124538A TW I537238 B TWI537238 B TW I537238B
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- TW
- Taiwan
- Prior art keywords
- phenyl
- aminomethyl
- ethyl
- ethoxy
- benzylaminemethanyl
- Prior art date
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- 150000003939 benzylamines Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 107
- 125000000217 alkyl group Chemical group 0.000 claims description 86
- 125000003118 aryl group Chemical group 0.000 claims description 62
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- ZGWGSEUMABQEMD-UHFFFAOYSA-N 4-methyl-1,3-thiazole-5-carboxylic acid Chemical compound CC=1N=CSC=1C(O)=O ZGWGSEUMABQEMD-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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Description
本發明係關於苯甲胺衍生物,及含此等衍生物之醫藥組合物及其用途。
本發明苯甲胺衍生物係血漿激肽釋放酶之抑制劑,且具有多種治療應用,尤其於治療與糖尿病性視網膜病及糖尿病性黃斑水腫相關之視網膜血管通透性。
血漿激肽釋放酶係一種可以使激肽原(kininogen)釋放出激肽(kinin)之胰蛋白酶樣絲胺酸蛋白酶(參見K.D.Bhoola等人,「Kallikrein-Kinin Cascade」,Encyclopedia of Respiratory Medicine,p483-493;J.W.Bryant等人,「Human plasma kallikrein-kinin system:Physiological and biochemical parameters」Cardiovascular and haematological agents in medicinal chemistry,7,p234-250,2009;K.D.Bhoola等人,Pharmacological Rev.,1992,44,1;及D.J.Campbell,「Towards understanding the kallikrein-kinin system:insights from the measurement of kinin peptides」,Brazilian Journal of Medical and Biological Research 2000,33,665-677)。雖然血漿激肽釋放酶在血液凝集級聯機制(blood coagulation cascade)中未涉及緩激肽(bradykinin)的釋放或酵素切解,但其卻係人體內固有凝血級聯機制之重要成員。血漿前激肽釋放酶係由單一基因所編碼,並係在肝臟中合成。肝細胞會以活性的血漿前激肽釋放酶分泌,
該血漿前激肽釋放酶會與高分子量激肽原鍵結成為異二聚體複合物於血漿中循環,其經活化會產生具有活性的血漿激肽釋放酶。激肽是可透過G-蛋白偶合受體發揮作用的炎症之強力媒介體,且激肽的拮抗劑(諸如,緩激肽拮抗劑)先前業已經研究可作為治療多種病症之潛在治療劑(F.Marceau and D.Regoli,Nature Rev.,Drug Discovery,2004,3,845-852)。
血漿激肽釋放酶被認為在多種炎症病症中會發揮作用。
血漿激肽釋放酶之主要抑制劑為絲胺酸蛋白酶抑制劑C1酯酶抑制劑(serpin C1 esterase inhibitor)。具有C1酯酶抑制劑遺傳缺陷之患者身受遺傳性血管性水腫(hereditary angioedema;HAE)之苦,會導致臉部、手、咽喉、胃腸道、及生殖器的間歇性腫脹。急性發病期間所形成之水泡包含高濃度血漿激肽釋放酶,該酵素會切解高分子量激肽原釋放出緩激肽,因而導致血管通透性增加。利用大蛋白血漿激肽釋放酶抑制劑的治療業經證明可藉由阻礙會造成血管通透性增加之緩激肽的釋放而能有效治療HAE(A.Lehmann「Ecallantide(DX-88),a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery」Expert Opin.Biol.Ther.8,p1187-99)。
血漿激肽釋放酶-激肽系統(plasma kallikrein-kinin system)在患有晚期糖尿病性黃斑水腫之患者中異常地充足。最近已發表,血漿激肽釋放酶會造成糖尿病大鼠之視
網膜血管功能障礙(A.Clermont等人「Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats」Diabetes,2011,60,p1590-98),除此之外,投與血漿激肽釋放酶抑制劑ASP-440可紓緩糖尿病大鼠之視網膜血管通透性及視網膜血液流動異常。因此,血漿激肽釋放酶抑制劑應該具有減輕與糖尿病性視網膜病及糖尿病性黃斑水腫相關之視網膜血管通透性的治療效用。
先前業已描述合成小分子血漿激肽釋放酶抑制劑,例如Garrett等人(「Peptide aldehyde...」J.Peptide Res.52,p62-71(1998))、T.Griesbacher等人(「Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitus in rats」British Journal of Pharmacology 137,p692-700(2002))、Evans(「Selective dipeptide inhibitors of kallikrein」WO 03/076458)、Szelke等人(「Kininogenase inhibitors」WO 92/04371)、D.M.Evans等人(Immunolph armacology,32,p115-116(1996))、Szelke等人(「Kininogen inhibitors」WO 95/07921)、Antonsson等人(「New peptides derivatives」WO 94/29335)、J.Stürzbecher等人(Brazilian J.Med.Biol.Res 27,p1929-34(1994))、Kettner等人(US 5,187,157)、N.Teno等人(Chem.Pharm.Bull.41,p1079-1090(1993))、W.B.Young等人(「Small molecule inhibitors of plasma kallikrein」Bioorg.
Med.Chem.Letts.16,p2034-2036(2006))、Okada等人(「Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship」Chem.Pharm.Bull.48,p1964-72(2000))、Steinmetzer等人(「Trypsin-like serine protease inhibitors and their preparation and use」WO 08/049595)、Zhang等人(「Discovery of highly potent small molecule kallikrein inhibitors」Medicinal Chemistry 2,p545-553(2006))、Sinha等人(「Inhibitors of plasma kallikrein」WO 08/016883),及Brandl等人(「N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein」WO 2012/017020)。另外,Steinmetzer等人(「Serine protease inhibitors」WO 2012/004678)描述環狀肽類似物,該等類似物是人類纖溶酶(plasmin)及血漿激肽釋放酶之抑制劑。
至今,沒有小分子合成性血漿激肽釋放酶抑制劑係經批准作為醫學用途。已知技藝中所述之分子受到侷限性,諸如在諸如KLK1、凝血酶及其他絲胺酸蛋白酶有關的酵素方面具有不良的選擇性及不良的口服可利性。大蛋白血漿激肽釋放酶抑制劑存在過敏性休克反應之風險,正如已報導之曲安奈德(Ecallantide)。因此,仍有可選擇性抑制血漿激肽釋放酶、但不會誘發過敏性休克反應且具適口性之化合物之需求。另外,技藝中已知之分子具有強極性及可電子化胍或脒官能性的特徵。眾所周知,該等官能性可能
侷限於腸通透性,且因此局限於口服可利用性。
糖尿病之其他併發症,諸如腦出血、腎病、心肌病及神經病變,所有與血漿激肽釋放酶相關之併發症亦可視為血漿激肽釋放酶抑制劑之標的。
本發明係關於一系列為血漿激肽釋放酶之抑制劑的苯甲胺。該等化合物顯示對血漿激肽釋放酶具有良好選擇性,且可潛在有效治療下列病狀:受損視力、糖尿病性視網膜病、黃斑水腫、遺傳性血管性水腫、糖尿病、胰腺炎、腦出血、腎病、心肌症、神經病變、發炎性腸病、關節炎、炎症、敗血性休克、低血壓、癌症、成人呼吸窘迫症候群、彌漫性血管內凝血症、心肺繞道手術及術後出血。本發明進一步係關於該等抑制劑之醫藥組合物、該等組合物作為治療劑之用途及利用該等組合物治療之方法。
在一態樣中,本發明提供式(I)化合物
及其互變異構體、異構體、立體異構體(包括對映異構體、非對映異構體及其外消旋及非消旋性混合物)、醫藥上可接受之鹽及溶劑化物,其中:
R1係選自H、烷基、-CO烷基、-CO芳基、-CO雜芳基、-CO2烷基、-(CH2)aOH、-(CH2)bCOOR10、-(CH2)cCONH2、-SO2烷基、-SO2芳基、-SO2(CH2)hR13、-CO(CH2)iR14、-CO環烷基、-COCH=CHR15、-CO(CH2)jNHCO(CH2)kR16及-CONR17R18;R2係選自H及烷基;R3係選自H、烷基、-(CH2)d芳基、-(CH2)e雜芳基、-(CH2)f環烷基、-(CH2)g雜環烷基、-CH(環烷基)2、-CH(雜環烷基)2及-(CH2)l芳基-O-(CH2)m-芳基;R4及R6係獨立地選自H及烷基;R5係選自H、烷基、烷氧基及OH;或R4及R5,與其所附接的原子一起結合形成5-或6-員氮雜環烷基結構;R7及R8係獨立地選自H、烷基、烷氧基、CN、鹵基及CF3;R9為芳基或雜芳基;R10為H或烷基;a、b、c、d、e、f、g、h、i、j、l及m獨立地為1、2或3;k為0、1、2或3;*1及*2表示對掌性中心;烷基為具有可多達10個碳原子(C1-C10)之直鏈飽和烴,或具有3至10個碳原子(C3-C10)之具支鏈飽和烴;烷基可視情況經1或2個獨立地選自(C3-C10)環烷基、(C1-C6)烷氧
基、OH、CN、CF3、COOR11、氟及NR11R12之取代基取代;環烷基為具有3至10個碳原子之單環或雙環飽和烴;環烷基可視情況與芳基稠合;或環烷基為金剛烷基;雜環烷基為C-連接或N-連接的3至10員飽和、單環或雙環基團,其中該雜環烷基基團可能包含1、2或3個獨立地選自N、NR11及O之雜原子;烷氧基為具有1至6個碳原子(C1-C6)之直鏈經O-連接烴或具有3至6個碳原子(C3-C6)之具支鏈經O-連接烴;烷氧基可視情況經1或2個獨立地選自(C3-C10)環烷基、OH、CN、CF3、COOR11、氟及NR11R12之取代基取代;芳基為苯基、聯苯基或萘基;芳基可視情況經可多達5個獨立地選自烷基、烷氧基、OH、鹵基、CN、COOR11、CF3及NR11R12之取代基取代;雜芳基為5、6、9或10員單環或雙環芳香環,可能包含1、2或3個獨立地選自N、NR11、S及O之環成員;雜芳基可視情況經1、2或3個獨立地選自烷基、烷氧基、OH、鹵基、CN、COOR11、CF3、NR11R12及NHR19之取代基取代;R11及R12為獨立地選自H及烷基;R13為芳基或雜芳基;R14為芳基、雜芳基、環烷基或雜環烷基;R15為H、烷基、芳基、雜芳基、環烷基或雜環烷基;R16為H、芳基或雜芳基;R17為H、烷基、芳基、雜芳基或雜環烷基;
R18為-(CH2)mR21,其中m為0、1、2或3,及R21為H、芳基或雜芳基;R19為-CO烷基、-CO芳基或-CO雜芳基。
在另一態樣中,本發明提供如本文所定義之式(I)化合物的前藥,或其醫藥上可接受之鹽。
在還有另一態樣中,本發明提供如本文所定義之式(I)化合物之N-氧化物、或其前藥或其醫藥上可接受之鹽。
咸應瞭解,本發明之若干化合物可以溶劑化物(例如水合物)及非溶劑化物形式存在。亦應瞭解,本發明涵蓋所有此等溶劑化物形式。
在一態樣中,本發明包括式(I)化合物之子集,及其互變異構體、異構體、立體異構體(包括對映異構體、非對映異構體及其外消旋及非消旋性混合物)、醫藥上可接受之鹽及溶劑化物,其中:R1係選自H、烷基、-CO烷基、-CO芳基、-CO雜芳基、-CO2烷基、-(CH2)aOH、-(CH2)bCOOR10、-(CH2)cCONH2、-SO2烷基及-SO2芳基;R2係選自H及烷基;R3係選自H、烷基、-(CH2)d芳基、-(CH2)e雜芳基、-(CH2)f環烷基、-(CH2)g雜環烷基、-CH(環烷基)2及-CH(雜環烷基)2;R4及R6係獨立地選自H及烷基;R5係選自H、烷基、烷氧基及OH;或R4及R5,與其所附接的原子一起結合形成5-或6-員氮
雜環烷基結構;R7及R8係獨立地選自H、烷基、烷氧基、CN及鹵基;R9為芳基或雜芳基;R10為H或烷基;a、b、c、d、e、f及g獨立地為1、2或3;*1及*2表示對掌性中心;烷基為具有可多達10個碳原子(C1-C10)之直鏈飽和烴,或具有3至10個碳原子(C3-C10)之具支鏈飽和烴;烷基可視情況經1或2個獨立地選自(C3-C10)環烷基、(C1-C6)烷氧基、OH、CN、CF3、COOR11、氟及NR11R12之取代基取代;環烷基為具有3至10個碳原子之單環或雙環飽和烴;環烷基可視情況與芳基稠合;雜環烷基為C-連接或N-連接的3至10員飽和、單環或雙環基團,其中該雜環烷基環可能包含1、2或3個獨立地選自N、NR11及O之雜原子;烷氧基為具有1至6個碳原子(C1-C6)之直鏈經O-連接烴或3至6個碳原子(C3-C6)之具支鏈經O-連接烴;烷氧基可視情況經1或2個獨立地選自(C3-C10)環烷基、OH、CN、CF3、COOR11、氟及NR11R12之取代基取代;芳基為苯基、聯苯基或萘基;芳基可視情況經可多達5個獨立地選自烷基、烷氧基、OH、鹵基、CN、COOR11、CF3及NR11R12之取代基取代;雜芳基為5、6、9或10員單環或雙環芳香環,包含可能
1、2或3個獨立地選自N、NR11、S及O之環成員;雜芳基可視情況經1、2或3個獨立地選自烷基、烷氧基、OH、鹵基、CN、COOR11、CF3及NR11R12之取代基取代;R11及R12為獨立地選自H及烷基。
在另一態樣中,本發明包括式(I)化合物之子集,及其互變異構體、異構體、立體異構體(包括對映異構體、非對映異構體及其外消旋及非消旋性混合物)、醫藥上可接受之鹽及溶劑化物,其中:R1係選自H、烷基、-CO烷基、-CO芳基、-CO2烷基、-CH2CH2OH、-CH2COOR10、-CH2CONH2、-SO2烷基及-SO2芳基;R2係選自H及烷基;R3係選自烷基、-CH2芳基、-CH2環烷基及-CH(環烷基)2;R4及R6係獨立地選自H及烷基;R5係選自H、烷基、及OH;或R4及R5,與其所附接的原子一起結合形成5-或6-員氮雜環烷基結構;R7及R8係獨立地選自H、F及Cl;R9為芳基;R10為H或烷基;*1及*2表示對掌性中心;烷基為具有可多達6個碳原子(C1-C6)之直鏈飽和烴,或
具有3至6個碳原子(C3-C6)之具支鏈飽和烴;烷基可視情況經1或2個獨立地選自(C3-C10)環烷基、(C1-C6)烷氧基、OH、CN、CF3、COOR11、氟及NR11R12之取代基取代;環烷基為具有3至10個碳原子之單環或雙環飽和烴;烷氧基為具有1至6個碳原子(C1-C6)之直鏈經O-連接烴或3至6個碳原子(C3-C6)之具支鏈經O-連接烴;烷氧基可視情況經1或2個獨立地選自(C3-C10)環烷基、OH、CN、CF3、COOR11、氟及NR11R12之取代基取代;芳基為苯基、聯苯基或萘基;芳基可視情況經可多達5個獨立地選自烷基、烷氧基、OH、鹵基、CN、COOR11、CF3及NR11R12之取代基取代;R11及R12為獨立地選自H及烷基。
本發明亦包括以下態樣及其組合:在本發明之一態樣中,R1係選自H、烷基、-CO烷基、-CO芳基、-(CH2)aOH、-(CH2)bCOOR10、-(CH2)cCONH2、-SO2烷基及-SO2芳基。
在本發明之一態樣中,R1係選自H、烷基、-CO烷基、-CO芳基、-(CH2)aOH、-CH2COOR10、-CH2CONH2、-SO2烷基及-SO2芳基,其中a為1或2。
在本發明之一態樣中,R1係選自H、-CO芳基、-CO烷基、-CH2COOH、-SO2Ph及-SO2CH3。
在本發明之一態樣中,R1係選自H、-CO乙基、甲基、甲烷磺醯基、-CO苯基、苯基碸、-CH2COOH、-CO-i丙基、丙基、-CH2COOCH3、-CH2CONH2、-CH2CH2OH及
-CO萘基。
在本發明之一態樣中,R1係選自-CO烷基及-CO苯基。
在本發明之一態樣中,R1係選自H、-CO芳基、CO雜芳基、-CO烷基、-CH2COOH、-SO2Ph及-SO2CH3。
在本發明之一態樣中,R1係選自-CO烷基、CO雜芳基及-CO芳基。
在本發明之一態樣中,R2係選自H及甲基。
在本發明之一態樣中,R2係選自H。
在本發明之一態樣中,R3係選自烷基、-(CH2)d芳基、-(CH2)f環烷基及-CH(環烷基)2;其中d及f係獨立的1或2。
在本發明之一態樣中,R3係選自烷基、-CH2芳基、-CH2環烷基及-CH(環烷基)2。
在本發明之一態樣中,R3係選自-CH2芳基、-CH2環烷基及-CH(環烷基)2。
在本發明之一態樣中,R3係選自:
在本發明之一態樣中,R4係選自H、甲基。
在本發明之一態樣中,R4為H。
在本發明之一態樣中,R5係選自H、甲基及OH。
在本發明之一態樣中,R5係選自H及OH。
在本發明之一態樣中,R5為H。
在本發明之一態樣中,R4及R5,與其所附接的原子一起
結合形成吡咯啶部分。
在本發明之一態樣中,R4及R5,與其所附接的原子一起結合形成六氫吡啶部分。
在本發明之一態樣中,R6係選自H及甲基。
在本發明之一態樣中,R6為H。
在本發明之一態樣中,R7係選自H、甲基及鹵基。
在本發明之一態樣中,R7係選自H、F及Cl。
在本發明之一態樣中,R7為H。
在本發明之一態樣中,R8係選自H、甲基及鹵基。
在本發明之一態樣中,R8係選自H、F及Cl。
在本發明之一態樣中,R8係選自H及F。
在本發明之一態樣中,R8為H。
在本發明之一態樣中,R9為芳基。
在本發明之一態樣中,R9係選自苯基及萘基,其中苯基可視情況經可多達3個獨立地選自烷基、烷氧基、OH、鹵基、CN、COOR11、CF3及NR11R12之取代基取代。
在本發明之一態樣中,R9為苯基,其中苯基可視情況經可多達2個獨立地選自烷基、鹵基及CF3之取代基取代。
在本發明之一態樣中,R9係選自苯基、1-萘、2,4-二氯苯基、3,4-二氯苯基、3,4-二氟苯基、4-氯苯基、4-三氟甲基苯基及4-乙氧苯基。
在本發明之一態樣中,R9係選自苯基、雜芳基及萘基,其中苯基可視情況經可多達3個獨立地選自烷基、烷氧基、OH、鹵基、CN、COOR11、CF3及NR11R12之取代基取
代。
在本發明之一態樣中,R9係選自苯基、1-萘、3,4-二氯苯基、3,4-二氟苯基、4-氯苯基、4-氟苯基、3-氟苯基、4-三氟甲基苯基、吡啶-3-基、吡啶-2-基、吡啶-4-基、苯并噻吩-3-基、噻吩-2-基、噻吩-3-基、吲哚-3-基及噻唑-4-基。
在本發明之一態樣中,R10為H或甲基。
在本發明之一態樣中,關於對掌中心*1的立體組態為R。
在本發明之一態樣中,關於對掌中心*2的立體組態為S。
在本發明之一態樣中,a為2,且b、c、d、e、f及g為1。
在本發明之一態樣中,a為2,且及b、c、d、e、f、g、h、j、l及m為1。
在本發明之一態樣中,k為0或1。
在一態樣中,本發明包括一種選自以下之化合物及其醫藥上可接受之鹽及溶劑化物:(S)-N-(4-胺基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;{(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-環己基-乙基胺基}-乙酸;
(S)-N-(4-胺基甲基-3-氟-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯胺;(S)-N-(4-胺基甲基-2-氯-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯胺;(S)-N-(4-胺基甲基-苄基)-3-(3,4-二氯-苯基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-丙醯胺;(S)-N-(4-胺基甲基-3-氯-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯胺;(S)-N-(4-胺基甲基-苄基)-2-{[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基]-甲基-胺基}-3-苯基-丙醯胺;({(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-環己基-乙基}-甲基-胺基)-乙酸;(S)-N-(4-胺基甲基-3-氟-苄基)-2-{[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基]-甲基-胺基}-3-苯基-丙醯胺;N-[(R)-1-{[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基]-甲基-胺甲醯基}-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-{[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基]-甲基-胺甲醯基}-2-(4-乙氧基-苯基)-乙基]-異丁醯胺;萘-1-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2,4-二氯-苯甲醯胺;
N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,4-二氟-苯甲醯胺;(R)-2-胺基-N-[(1S,2S)-1-(4-胺基甲基-苄基胺甲醯基)-2-羥基-2-苯基-乙基]-3-(4-乙氧基-苯基)-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-菸鹼醯胺;(2S,3S)-N-(4-胺基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-羥基-3-苯基-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-異菸鹼醯胺;噻吩-3-羧酸-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]2-(4-乙氧基-苯基)-乙基]-醯胺;噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;環己烷羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;異噁唑-5-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;苯并[b]噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;(R)-N-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基]-2-
(4-氯-苯磺醯基胺基)-3-(4-乙氧基-苯基)-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3-氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2-氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3-三氟甲基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,4-二氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲醯胺;(S)-N-(4-胺基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-(2-苯基乙醯基胺基-乙醯基胺基)-丙醯基胺基]-3-苯基-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氟-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-6-甲基-菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2-甲基-菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基
胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2,6-二氯-菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-5,6-二氯-菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2,3,6-三氟-異菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,3,3-三氟-丙醯胺;2,4-二甲基-噻唑-5-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;2-甲基-噻唑-5-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;3-氯-噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;4-甲基-噻唑-5-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;呋喃-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;3-甲基-噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯
胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2-甲氧基-異菸鹼醯胺;3-甲基-1H-吡咯-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;3-胺基-噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-丙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(4-氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(4-氟-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(4-甲氧基-
苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-4-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3-氟-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻吩-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻吩-3-基-乙基胺甲醯基-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻唑-4-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯并[b]噻吩-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-3-氟-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-3-氯-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻吩-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲醯
胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-3-氯-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氟-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-異菸鹼醯胺;噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;(R)-N-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基]-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-3-氟-苄基胺甲醯基)-2-苯基-
乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-異菸鹼醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-3-氟-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;(R)-N-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基]-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-異菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,3,3-三氟-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲醯胺;異噁唑-5-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氟-
苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺。
在一態樣中,本發明包括一種選自以下之化合物及其醫藥上可接受之鹽及溶劑化物:N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;萘-1-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2,4-二氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,4-二氟-苯甲醯胺。
在一態樣中,本發明包括一種選自以下之化合物及其醫藥上可接受之鹽及溶劑化物:N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;萘-1-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2,4-二氯-苯甲醯胺;
N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,4-二氟-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-異菸鹼醯胺;噻吩-3-羧酸-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;環己烷羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;異噁唑-5-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;(R)-N-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基]-2-(4-氯-苯磺醯基胺基)-3-(4-乙氧基-苯基)-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,4-二氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3-氯-苯甲醯胺;
N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氟-苯甲醯胺;3-甲基-噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;3-甲基-1H-吡咯-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;3-胺基-噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-丙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(4-氟-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;
N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻吩-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻吩-3-基-乙基胺甲醯基-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯并[b]噻吩-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-3-氟-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-3-氯-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻吩-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-3-氯-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲醯胺;噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-
吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氟-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺。
如前所述,本發明化合物為血漿激肽釋放酶之有力及選擇性抑制劑。因此,該等化合物可有效治療因血漿激肽釋放酶過度活性為致病因素之疾病病狀。
因此,本發明係提供一種用於藥物之式(I)化合物。
本發明亦提供一種式(I)化合物之用途,其係用於製造治療或預防與血漿激肽釋放酶活性有關之疾病或病狀的藥物。
本發明亦提供一種式(I)化合物之用途,其係用於治療或預防與血漿激肽釋放酶活性有關之疾病或病狀。
本發明亦提供一種治療或預防與血漿激肽釋放酶活性有關之疾病或病狀的方法,該方法包括向有需要個體投與治療有效量之式(I)化合物。
在一個態樣中,與血漿激肽釋放酶活性有關之疾病或病狀係選自涉及血漿激肽釋放酶活性之疾病或病狀,包括受損視力、糖尿病性視網膜病、糖尿病性黃斑水腫、遺傳性
血管性水腫、糖尿病、胰腺炎、腦出血、腎病、心肌症、神經病變、發炎性腸病、關節炎、炎症、敗血性休克、低血壓、癌症、成人呼吸窘迫症候群、彌漫性血管內凝血症、心肺繞道手術及術後出血。
在另一態樣中,與血漿激肽釋放酶活性有關之疾病或病狀係與糖尿病性視網膜病及糖尿病性黃斑水腫相關之視網膜血管通透性。
本發明化合物可與其他治療劑組合投與。合適組合療法包括式(I)化合物與一或多種選自下列藥劑之組合:抑制血小板生長因子(platelet-derived growth factor;PDGF)、內皮生長因子(endothelial growth factor;VEGF)、整合素α5β、類固醇、抑制血漿激肽釋放酶之其他藥劑及其他炎症抑制劑。可與本發明化合物組合之治療劑之特定實例包括彼等EP2281885A中所揭示者及由S.Patel in Retina,2009 Jun;29(6 Suppl):S45-8所揭示者。
當採用組合療法時,本發明化合物及該等組合製劑可存在於相同或不同的醫藥組合物中,並可分開、依序或同時投與。
術語「烷基」包括飽和烴殘基,其包括:
- 可多達10個碳原子(C1-C10),或可多達6個碳原子(C1-C6),或可多達4個碳原子(C1-C4)之直鏈基團。此等烷基基團之實例包括(但不限於)C1-甲基、C2-乙基、C3-丙
基及C4-正丁基。
- 介於3至10個碳原子之間(C3-C10),或可多達7個碳原子(C3-C7),或可多達4個碳原子(C3-C4)之具支鏈基團。此等烷基基團之實例包括(但不限於)C3-異丙基、C4-第二丁基、C4-異丁基、C4-第三丁基及C5-新戊基。
每一基團可視情況經如上所述取代基取代。
術語「烷氧基」包括經O-連接烴殘基,其包括:
- 介於1至6個碳原子之間(C1-C6),或介於1至4個碳原子之間(C1-C4)之直鏈基團。此等烷氧基基團之實例包括(但不限於)C1-甲氧基、C2-乙氧基、C3-正丙氧基及C4-正丁氧基。
- 介於3至6個碳原子之間(C3-C6),或介於3至4個碳原子之間(C3-C4)之具支鏈基團。此等烷氧基基團之實例包括(但不限於)C3-異丙氧基及C4-第二丁氧基及第三丁氧基。
每一基團可視情況經如上所述取代基取代。
除非另有說明,否則鹵基係選自Cl、F、Br及I。
環烷基定義如上。環烷基基團可包含3至10個碳原子,或4至10個碳原子,或5至10個碳原子,或4至6個碳原子。合適單環環烷基基團之實例包括環丙基、環丁基、環戊基環己基、環庚基。合適雙環環烷基基團之實例包括十氫萘、八氫-1H-茚。當與芳基融合時,合適環烷基基團之實例包括二氫茚基及1,2,3,4-四氫萘基。
雜環烷基定義如上。合適雜環烷基基團之實例包括環氧
乙基、氮雜環丙基、氮雜環丁基、四氫呋喃基、吡咯啶基、四氫哌喃基、六氫吡啶基、N-甲基哌啶基、嗎啉基、N-甲基嗎啉基、哌基、N-甲基哌基、氮雜環庚烷基、氧氮雜環庚烷基及二氮雜環庚烷基。
芳基定義如上。典型地,芳基可視情況經1、2或3個取代基取代。選擇性取代基係選自彼等上述者。合適芳基基團之實例包括苯基及萘基(每一基團可視情況經如上所述取代)。
雜芳基定義如上。合適雜芳基基團之實例包括噻吩基、呋喃基、吡咯基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、異噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、噠嗪基、嘧啶基、吡嗪基、吲哚基、苯并咪唑基、苯并三唑基、喹啉基及異喹啉基(每一基團可視情況經如上所述取代)。
術語「C-連接」,諸如在「C-連接雜環烷基」中,意為雜環烷基基團係經由環碳原子接合至該分子其他的部分。
術語「N-連接」,諸如在「N-連接雜環烷基」中,意為雜環烷基基團係經由環氮原子接合至該分子其他的部分。
術語「經O-連接」,諸如在「經O-連接烴殘基」中,意為烴殘基係經由氧原子接合至該分子其他的部分。
在諸如-CO烷基及-(CH2)bCOOR10之基團中,「-」表示取代基基團附接至該分子其他部分的位置。
「醫藥上可接受之鹽」意為生理學或毒理學上可容忍之鹽,且在合適時包括醫藥上可接受之鹼加成鹽及醫藥上可
接受之酸加成鹽。例如(i)當本發明化合物包含一或多種酸性基團(例如,羧基基團)時,可形成之醫藥上可接受之鹼加成鹽,包括鈉鹽、鉀鹽、鈣鹽、鎂鹽及銨鹽或帶有有機胺(諸如,二乙胺、N-甲基-葡糖胺、二乙醇胺或胺基酸(例如,離胺酸))之鹽及類似物;(ii)當本發明化合物包含鹼性基團(例如,胺基基團)時,可形成之醫藥上可接受之酸加成鹽,包括氫氯酸鹽、氫溴酸鹽、硫酸鹽、磷酸鹽、乙酸鹽、檸檬酸鹽、乳酸鹽、酒石酸鹽、甲磺酸鹽、琥珀酸鹽、草酸鹽、磷酸鹽、乙磺酸鹽、甲烷磺酸鹽、苯磺酸鹽、萘二磺酸鹽、馬來酸鹽、己二酸鹽、延胡索酸鹽、馬尿酸鹽、樟腦酸酯鹽、羥萘甲酸鹽(xinafoate)、p-乙醯胺苯甲酸鹽、二羥基苯甲酸鹽、羥基萘酸鹽、琥珀酸鹽、抗壞血酸鹽、油酸鹽、重硫酸鹽以及類似物。
亦可形成酸及鹼之半鹽,例如,半硫酸鹽及半鈣鹽。
合適鹽之概述,參見Stahl及Wermuth之「Handbook of Pharmaceutical Salts:Properties,Selection and Use」(Wiley-VCH,Weinheim,Germany,2002)。
「前藥」指一種在活體內可藉由代謝手段(例如,藉由水解、還原或氧化)轉化成本發明化合物之化合物。用於形成前藥之合適基團描述於The Practice of Medicinal Chemistry,2nd Ed.pp561-585(2003)及F.J.Leinweber,Drug Metab.Res.,1987,18,379中。
本發明化合物可以非溶劑化物及溶劑化物兩種形式存在。本文所用術語「溶劑化物」係用於描述一種包括本發
明化合物及化學計量之一或多種醫藥上可接受之溶劑分子(例如,乙醇)之分子複合物。當溶劑為水時,所採用的術語是「水合物」。
當本發明化合物以一或多種幾何、光學、對映體、非對映異構及互變異構形式存在時,其包括(但不限於)順式及反式形式、E-及Z-形式、R-,S-及內消旋形式、酮基-及烯醇-形式。除非另有說明,否則所參考之特定化合物係包括所有此等異構形式,包括其消旋物及其他混合物。在適合情況下,此等異構物可應用或改變已知方法(例如,層析技術及再結晶技術)而自其混合物分離出來。在合適情況下,此等異構物可應用或改變已知方法(例如非對稱性合成作用)而製得。
在本發明範圍內,本文所引用之「治療」包括引用治癒性治療、緩解性治療及預防性治療。
式(I)化合物應針對其生物醫藥特性加以評估,諸如,溶解度及溶液穩定性(遍及pH)、通透性等等,以便選擇出用以治療所提議適應症之最適劑型及投與途徑。該等化合物可單獨投與,或與一或多種其他本發明化合組合投與,或與其他藥物組合投與(或如其任意組合)。通常,該等化合物係以與一或多種醫藥上可接受之賦形劑組合成之調配物投與。本文所用術語「賦形劑」係描述任何本發明化合物以外之成分,該成分可賦予該等調配物功能性(例如,控制藥物釋放速率)及/或非功能性(例如,加工助劑或稀釋
劑)特性。選擇賦形劑很大程度上係取決於諸如特定投與模式、賦形劑對溶解度及穩定性之影響及劑型性質等因素。
意欲作為醫藥用途之本發明化合物可以固體或液體投與,諸如,錠劑、膠囊或溶液。適合傳送本發明化合物之醫藥組合物及其製備方法是技藝熟習者可以輕易地明白的。該等組合物及其製備方法可參閱(例如)Remington's Pharmaceutical Sciences,19th Edition(Mack Publishing Company,1995)。
因此,本發明提供一種包括式(I)化合物及醫藥上可接受之載劑、稀釋劑或賦形劑之醫藥組合物。
為治療諸如與糖尿病性視網膜病及糖尿病性黃斑水腫相關之視網膜血管通透性之病狀,本發明化合物可以適於注射至患者眼部之形式投與,明確言之,適合於玻璃體內注射之形式。咸欲正視的是,適於此種用途之調配物係採用將本發明化合物溶於適當水性媒劑之無菌溶液的形式。該等組合物係在主治醫師之監督下投與患者。
本發明化合物亦可直接投與至血流、皮下組織、肌肉或內臟器官中。合適之非經腸投與方式包括靜脈內、動脈內、腹膜內、鞘內、腦室內、尿道內、胸骨內、顱內、肌肉內、滑囊腔內及皮下。合適之非經腸投與裝置包括針頭(包括微針)注射器、無針頭注射器及輸液技術。
非經腸調配物典型地為水性或油性溶液。當溶液為水性,包括賦形劑為諸如糖(包括但不限於葡萄糖、甘露糖
醇、山梨糖醇等等)、鹽、碳水化合物及緩衝劑(較佳達3至9之pH),但為了某些應用,其更合適調配成無菌非水性溶液或意欲與適當媒劑(諸如,無菌無熱原水)共同使用之乾燥形式。
非經腸調配物可包括衍生自可降解聚合物之植入體,諸如,聚酯(例如,聚乳酸、聚乳酸交酯、聚乳酸交酯-共-乙交酯、聚己內酯、聚羥基丁酯)、聚原酸酯及聚酐。該等調配物可經由手術切口投與至皮下組織、肌肉組織或直接投與至特定器官。
利用熟習技藝者所熟知的標準製藥技術可輕易地完成無菌條件下非經腸調配物之製備,例如,冷凍乾燥。
製備非經腸溶液中所用之式(I)化合物的溶解度可藉由使用合適調配技術而提高,諸如,併入共溶劑及/或溶解度促進劑(諸如,表面活性劑)、膠束結構及環糊精。
在一個實施例中,本發明化合物可經口投與。口服投藥涉及吞嚥,如此該化合物會進入腸胃道,及/或藉由頰投藥、舌投藥,或舌下投藥,化合物會直接從口腔進入血流。
適合經口投與之調配物包括固態口塞劑、固態微粒、半固體及液體(包括多元相或分散系統)(諸如錠劑);軟或硬膠囊(含多元微粒或奈米微粒、液體、乳液或粉末);口含錠(包括經液體填充);口嚼錠;凝膠;速散劑型;包膜;卵形劑;噴劑及頰貼片/黏膜貼片。
適於經口投與之調配物亦可設計為以即時釋放方式或以
持續性速率方式傳遞本發明化合物,其中釋放概況可為延遲釋放的、脈衝釋放的、經控制釋放的、緩釋的,或延遲釋放的及緩釋的或調控式釋放的,如此的方式使該等化合物之療效最優化。以持續性速率傳送化合物的手段是此項技藝中已知的,且包括可與該等化合物調配以控制該等化合物釋放之緩慢釋放聚合物。
持續性速率聚合物之實例包括可降解及不可降解聚合物,該等聚合物可藉由擴散作用或藉由擴散作用與聚合物磨蝕作用的組合而用以釋放出該等化合物。持續性速率聚合物之實例包括羥丙甲纖維素、羥丙基纖維素、甲基纖維素、乙基纖維素、羧甲基纖維素鈉、聚乙烯醇、聚乙烯吡咯啶酮、黃原膠、聚甲基丙烯酸酯、聚環氧乙烷及聚乙二醇。
液體(包括多元相及分散系統)調配物包括乳液、溶液、糖漿及酒劑。此等調配物係以填充物存在於軟或硬膠囊(例如,由明膠或羥丙基甲基纖維素製成)中,且典型地包括載劑,例如水、乙醇、聚乙二醇、丙二醇、甲基纖維素或適當的油脂,及一或多種乳化劑及/或懸浮劑。液體調配料亦可藉由(例如)自藥囊中的固體進行重建作用而製得。
本發明化合物亦可以速溶、速崩劑型使用,諸如彼等描述於Liang及Chen,Expert Opinion in Therapeutic Patents,2001,11(6),981-986中者。
錠劑調配物論述於H.Lieberman及L.Lachman之
Pharmaceutical Dosage Forms:Tablets,Vol.1(Marcel Dekker,New York,1980)中。
以投與至人類患者而言,本發明化合物之每日總劑量典型地係在0.01 mg至1000 mg範圍,或介於0.1 mg至250 mg之間,或介於1 mg至50 mg之間,當然要取決於投與模式。例如,若藉由玻璃體內注射投與,預計本發明化合物將偶爾給藥,例如每月一次。在此狀況下,預計劑量介於0.5 mg至20 mg之間,諸如介於1 mg至10 mg之間。若更頻繁給藥,例如每日一次,預計採用介於0.005 mg至0.02 mg低很多的劑量。
總劑量可以一次或分次給藥投與,及可以在醫師指示下投與不在本文所給定之典型範圍內的劑量。該等劑量係以體重約60 kg至70 kg之一般人類個體為基礎。醫師可以輕易地決定重量不在此範圍內之個體的劑量,諸如嬰兒及老人。
本發明化合物可根據以下方案及實例之步驟,使用適當的物質製備,並進一步以下文所提供之特定實例加以舉例說明。除此之外,藉由利用本文所述之步驟,一般技藝者可輕易地製備屬於本文所主張之本發明範圍內之其他化合物。然而,實例中所說明之化合物不應理解為形成認為是本發明的唯一種類物。實例進一步闡明製備本發明化合物之細節。熟習此項技藝者可輕易地理解以下用於製備該等化合物之製備步驟之條件及方法之已知變項。
本發明化合物可以其醫藥上可接受之鹽之形式分離出來,諸如彼等上文先前所述者。
製備本發明化合物時所用的中間產物之反應性官能團(例如,羥基、胺基、硫氫基或羧基)有必要加以保護,以避免其不必要地參與會導致化合物形成之反應。可使用習知保護性基團,例如彼等由T.W.Greene及P.G.M.Wuts描述於「Protective groups in organic chemistry」John Wiley and Sons,4th Edition,2006者。例如,適於本文使用之常見保護基團為第三-丁氧基羰基(Boc),其藉由使用一種含於有機溶劑(諸如,二氯甲烷)之酸(諸如,三氟乙酸或氯化氫)處理即可輕易地移除。或者,胺基保護基團可為苄基氧羰基(Z)基團,其藉由使用鈀觸媒在氫氣氛下進行氫化作用即可移除,或胺基保護基團可為9-茀甲氧羰基(Fmoc)基團,其藉由含於有機溶劑之二級有機胺(諸如,二乙胺或六氫吡啶)溶液即可移除。羧基基團典型地係以諸如甲基酯、乙基酯、苄基酯或第三丁基酯等酯類身分加以保護,該等甲基、乙基、苄基或第三丁基基團可全部藉由在鹼(諸如,氫氧化鋰或氫氧化鈉)存在下進行水解作用而加以移除。苄基保護基團亦可藉由使用鈀觸媒在氫氣氛下進行氫化作用而加以移除,同時第三丁基基團亦可藉由三氟乙酸而加以移除。或者,三氯乙酯保護基團係使用含於乙酸之鋅而加以移除。適於本文使用之常見羥基保護基為甲醚,去保護條件包括於48%水性HBr中迴流1-24小時,或藉由於二氯甲烷中與三溴甲硼烷(borane tribromide)攪拌1-
24小時。或者,當羥基基團係以苄醚身分保護時,去保護條件包括在氫氣氛下使用鈀觸媒進行氫化作用。
根據通式I之化合物可使用習知合成方法加以製備,例如(但不限於)方案1中所概述之途徑。在典型的第一步驟中,利用標準肽胺基偶聯作用條件,將胺(2)偶合至經活化α胺基酸(1),該α胺基酸(1)係使用標準保護基團(諸如,第三-丁氧基羰基(Boc)、苄基氧羰基(Z)或9-茀甲氧羰基(Fmoc))將胺基適當地保護。活化基團(X)係為N-羥基琥珀醯亞胺。該等基團之用途在此項技藝中係眾所周知的。當R5或R9(在方案1中係以「芳基」顯示)具有諸如胺或羧酸的反應性官能團時,此基團亦要被保護。其他標準肽胺基偶聯方法包括酸與胺在存在羥基苯并三唑及碳二亞胺(諸如,水溶性碳二亞胺)下反應,或與2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基銨六氟磷酸鹽或苯并三唑-1-基-氧-參-吡咯啶并-鏻六氟磷酸鹽或溴-參吡咯啶并-鏻六氟磷酸鹽在存在有機鹼(諸如,三乙胺、二異丙基乙胺或N-甲基嗎啉)反應。在典型的第二步驟中,保護基團係使用如先前所述之標準方法加以移除的。
方案1中所舉例途徑,在接著的第三步驟係經由另一標準肽胺基偶聯繼續進行,並在第四步驟中利用如先前所描述之標準條件移除Boc保護基。接著,在第五步驟,7中所示之胺係典型地經基團R1烷基化或醯基化。醯化作用可藉由使用醯化劑(諸如,醯基氯,例如,乙醯氯或苯甲醯氯)於存在鹼(典型地為三級胺鹼,諸如,三乙胺或二異丙基
乙胺)下進行。典型地,烷化作用可藉由使用烷基鹵處理或藉由還原烷基化作用進行。典型地,在還原烷基化作用的過程中,室溫下,於存在含於合適溶劑(諸如,甲醇)之合適還原劑(諸如,氰基硼氫化鈉或乙醯氧基硼氫化鈉)下,將胺與醛或酮反應。接著,將所得腈化合物8藉由氫化作用加以還原。8轉化為10可藉由於合適溶劑(諸如,甲醇)中,在存在合適觸媒(諸如,炭上鈀觸媒)下藉由氫化作用直接將腈還原,或在室溫下,於合適溶劑(諸如,甲醇)中,與合適氫硼化物在存在合適過渡金屬(諸如,氯化鈷或氯化鎳)下發生還原作用,以單一步驟即可實現。或者,(利用(例如)如S.Caddick等人,Tetrahedron Lett.,2000,41,3513中所描述之方法)分離出經第三-丁氧基羰基(Boc)保護之胺9,隨後藉由先前所述標準方法進行去保護作用,以產生胺10。
本發明藉由以下非限定性實例說明,其中使用以下縮寫詞及定義:
除非另有說明,否則所有反應皆在氮氣氛下進行。
在Brucker Avance III(400MHz)光譜儀以氘溶劑為參考在室溫下記錄1H NMR光譜。
使用LCMS得到分子離子,其係使用Chromolith Speedrod RP-18e管柱,50×4.6 mm,在11分鐘內以10%至90%線性梯度將0.1% HCO2H/MeCN轉成為0.1% HCO2H/H2O,流動速率為1.5 mL/分鐘。使用電噴霧離子化Thermofinnigan Surveyor MSQ質譜儀併與Thermofinnigan Surveyor LC系統一起收集數據。
利用自動命名軟體產生化學名稱,該軟體係由來自MDL資訊系統的ISIS繪圖套件之部分所提供。
當產物經急驟層析法純化時,「氧化矽」指用於層析之矽膠,0.035至0.070 mm(220至440篩孔)(例如,Merck矽膠60),並施加高達10 p.s.i之氮氣加速管柱洗脫。使用Waters 2525二元梯度泵系統,通常以20 mL/分鐘之流動速率(使用Waters 2996光電二極管陣列偵測器)進行逆相製備型HPLC純化作用。
所有溶劑及市售試劑皆按所收到的原樣使用。
將H-Phe-OMe.HCl(2.3 g,10.7 mmol)溶解於CH2Cl2(100 mL)及DMF(10 mL)中,將該溶液冷卻至0℃。添加(R)-2-丁氧基氧羰基胺基-3-(4-乙氧基-苯基)-丙酸(3.0 g,9.7 mmol),接著添加HOBt(1.57 g,11.6 mmol)及三乙胺(2.9 g,29.0 mmol)。然後添加可溶性碳二亞胺(2.04 g,10.6 mmol)。18小時後,在0℃至室溫下,用氯仿(100 mL)稀釋反應混合物,並使用NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗,在真空下乾燥(Na2SO4)並蒸發,得到黃色油狀物。藉由急驟層析法(二氧化矽)純化該殘餘物(洗脫液為20%石油醚(60-80℃)、80% EtOAc)、將溶離分液合併並在真空下蒸發,以產生無色油狀物,經確認為(S)-2-[(R)-2-第三-丁氧基羰基胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-苯基-丙酸甲酯(4.25 g,9.03 mmol,93%)。
[M+H]+=471.27
將(S)-2-[(R)-2-第三-丁氧基羰基胺基-3-(4-乙氧基-苯
基)-丙醯基胺基]-3-苯基-丙酸甲酯(2.5 g,5.3 mmol)溶解於THF(100 mL)中。加入溶於水(10 mL)中的氫氧化鋰單水合物(668 mg,15.9 mmol)。室溫下攪拌該反應混合物18小時,此後以EtOAc(150 mL)稀釋該反應混合物。使用0.3 M KHSO4(1×50 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗該溶液,在真空下乾燥(Na2SO4)並蒸發,以產生白色固體,經確認為(S)-2-[(R)-2-第三-丁氧基羰基胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-苯基-丙酸(2.095 g,4.58 mmol,86%)。
[M+H]+=457.25
將4-(胺基甲基)苯甲腈鹽酸鹽(303 mg,1.80 mmol)溶解於CH2Cl2(50 mL)及DMF(5 mL)中,將該溶液冷卻至0℃。添加(S)-2-[(R)-2-第三-丁氧基羰基胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-苯基-丙酸(745 mg,1.63 mmol),接著添加HOBt(265 mg,1.96 mmol)及三乙胺(495 mg,4.9 mmol)。然後添加可溶性碳二亞胺(344 mg,1.8 mmol)。18小時後,在0℃至室溫下,用氯仿(100 mL)稀釋反應混合物,並以NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗,然後在真空下乾燥(Na2SO4)並蒸發,得到黃色油狀物。藉由急驟層析法(二氧化矽)純化該殘餘物(洗脫液為20%石油醚(60-80℃)、80% EtOAc)、將溶離分液合併並在真空下蒸發,以產生無色油狀物,經確認為[(R)-1-[(S)-
1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-胺基甲酸第三-丁基酯(493 mg,0.86 mmol,53%)。
[M+H]+=571.29
以4 M HCl/二噁烷(50 mL)處理[(R)-1-[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-胺基甲酸第三-丁基酯(225 mg,0.39 mmol)。1小時後,在室溫下移除該溶劑,以產生白色固體,經確認為(R)-2-胺基-N-[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基]-3-(4-乙氧基-苯基)-丙醯胺鹽酸鹽(200 mg,0.39 mmol,100%)。
[M+H]+=471.26
將(R)-2-胺基-N-[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基]-3-(4-乙氧基-苯基)-丙醯胺鹽酸鹽(200 mg,0.37 mol)溶解於二氯甲烷(50 mL)中,將該溶液冷卻至0℃。添加三乙胺(111 mg,1.1 mmol),接著添加丙醯氯(39 mg,0.40 mmol)。18小時後,在0℃至室溫下,用CHCl3(50 mL)稀釋反應混合物,使用飽和NaHCO3(1×20 mL)、水(1×20 mL)、鹽水(1×20 mL)清洗該溶液,然後在真空下乾燥(Na2SO4)並蒸發。藉由急驟層析法(二氧化矽)純化該殘餘
物(洗脫液為2% MeOH、98% CHCl3),將溶離分液合併並在真空下蒸發,以產生無色油狀物,經確認為(S)-N-(4-氰基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯胺(189 mg,0.36 mmol,98%)。
[M+H]+=527.27
將(S)-N-(4-氰基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯胺(100 mg,0.19 mmol)溶解於甲醇(50 mL)中,將該溶液冷卻至0℃。添加氯化鎳(II)六水合物(4.5 mg,0.0192 mmol)及二碳酸二第三丁酯(83 mg,0.38 mmol),接著逐份添加硼氫化鈉(50 mg,1.33 mmol)。在0℃至室溫下,攪拌該反應混合物18小時。藉由蒸發作用移除甲醇。將殘餘物溶解於CHCl3(70 mL)中,以飽和NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗,在真空下乾燥(Na2SO4)並蒸發,得到黃色油狀物。藉由急驟層析法(二氧化矽)純化(洗脫液為1% MeOH、99% CHCl3),以產生無色油狀物,經確認為[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯基胺基}-甲基)-苄基]-胺基甲酸第三-丁基酯(89 mg,0.14 mmol,74%)。
[M+H]+=631.39
將[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯基胺基}-甲基)-苄基]-胺基甲酸第三-丁基酯(89 mg,0.13 mmol)溶解於三氟乙酸(20 mL)中。在室溫下攪拌該溶液1小時,此後在真空下移除該溶劑,以產生黃色油狀物。藉由製備型HPLC(Sunfire製備型C18 OBD管柱19×250 mm,10 μ)純化該殘餘物。在35分鐘內以10至90%梯度將0.1% TFA/MeCN以20 mL/分鐘流速轉成為0.1% TFA/H2O。將洗脫液合併並冷凍乾燥,以產生白色固體,經確認為(S)-N-(4-胺基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯胺三氟乙酸鹽(38 mg,0.056 mmol,42%)。
[M+H]+=531.31
1H NMR:(CD3OD)1.02(3H,t,J=7.7Hz),1.42(3H,t,J=7.0Hz),2.13-2.21(2H,m),2.71-2.77(1H,m),2.81-2.92(2H,m),3.12-3.16(1H,m),4.05(2H,q,J=6.9Hz),4.13(2H,s),4.37-4.50(3H,m),4.57-4.69(1H,m),6.82(2H,d,J=8.6Hz),7.05(2H,d,J=8.6Hz),7.17-7.19(2H,m),7.24-7.31(5H,m),7.41(2H,d,J=8.1Hz)。
將(R)-2-胺基-N-[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基]-3-(4-乙氧基-苯基)-丙醯胺鹽酸鹽(150 mg,0.30 mmol)溶解於CH2Cl2(20 mL)中,將該溶液冷卻至0℃。添加甲烷磺醯氯(37 mg,0.33 mmol),接著添加三乙胺(90 mg,0.89 mmol)。18小時後,在0℃至室溫下,用氯仿(50 mL)稀釋反應混合物,並使用NaHCO3(1×20 mL)、水(1×20 mL)、鹽水(1×20 mL)清洗該溶液,在真空下乾燥(Na2SO4)並蒸發,產生黃色油狀物。藉由急驟層析法(二氧化矽)純化該殘餘物(洗脫液為2% MeOH、98% CHCl3),溶離分液合併並蒸發,以產生白色固體,經確認為(R)-N-[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基]-3-(4-乙氧基-苯基)-2-甲烷磺醯基胺基-丙醯胺(110 mg,0.20 mmol,68%)。
[M+H]+=549.11
將(R)-N-[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基]-3-
(4-乙氧基-苯基)-2-甲烷磺醯基胺基-丙醯胺(110 mg,0.20 mmol)溶解於甲醇(50 mL)中,將該溶液冷卻至0℃。添加氯化鎳(II)六水合物(4.8 mg,0.02 mmol)及二碳酸二第三丁酯(88 mg,0.4 mmol),接著逐份添加硼氫化鈉(53 mg,1.4 mmol)。在0℃至室溫下,攪拌該反應混合物18小時。藉由蒸發作用移除MeOH。將殘餘物溶解於CHCl3(70 mL)中,使用飽和NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗,在真空下乾燥(Na2SO4)並蒸發,以得到黃色油狀物。藉由急驟層析法(二氧化矽)純化(洗脫液為2% MeOH、98% CHCl3),以產生白色固體,經確認為[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-甲烷磺醯基胺基-丙醯基胺基]-3-苯基-丙醯基胺基}-甲基)-苄基]-胺基甲酸第三-丁基酯(86 mg,0.13 mmol,66%)。
[M+H]+=653.23、675.19(M+Na)
使用三氟乙酸(20 mL)處理[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-甲烷磺醯基胺基-丙醯基胺基]-3-苯基-丙醯基胺基}-甲基)-苄基]-胺基甲酸第三-丁基酯(86 mg,0.13 mmol)。1小時後,在室溫下真空下蒸發該溶劑。藉由製備型HPLC(Sunfire製備型C18 OBD管柱19×250 mm,10 μ)純化該殘餘物,在35分鐘內以10至90%梯度將0.1% TFA/MeCN以20 mL/分鐘流速轉成為0.1% TFA/H2O。將溶離分
液合併並冷凍乾燥,以產生白色固體,經確認為(R)-N-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基]-3-(4-乙氧基-苯基)-2-甲烷磺醯基胺基-丙醯胺三氟乙酸鹽(28 mg,0.042 mmol,32%)。
[M+H]+=553.08
1H NMR:(CD3OD)1.41(3H,t,J=7.0Hz),2.60(3H,s),2.69-2.75(1H,m),2.81-2.91(2H,m),3.09(1H,dd,J=13.7,6.5Hz),4.04(2H,q,J=7.0Hz),4.13(3H,m),4.39(2H,s),4.62(1H,dd,J=8.1,6.6Hz),6.87(2H,d,J=8.6Hz),7.13(2H,d,J=8.6Hz),7.23(2H,t,J=6.6Hz),7.25-7.32(5H,m),7.41(2H,d,J=8.1Hz)。
將(S)-2-苄基氧羰基胺基-3-苯基-丙酸2,5-二氧-吡咯啶-1-基酯(4.25 g,10.72 mmol)溶解於CH2Cl2(100 mL)中,將該溶液冷卻至0℃。添加1-(N-Boc-胺基甲基)-4-(胺基甲基)
苯(2.79 g,11.79 mmol),接著添加三乙胺(3.25 g,32.16 mmol)。18小時後,在0℃至室溫下,用氯仿(100 mL)稀釋反應混合物,並使用NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗,在真空下乾燥(Na2SO4)並蒸發,得到黃色油狀物。使用石油醚(60-80℃)及EtOAc濕磨該殘餘物,以產生白色固體,經確認為{(S)-1-[4-(第三-丁氧基羰基胺基-甲基)-苄基胺甲醯基]-2-苯基-乙基}-胺基甲酸苄基酯(3.88 g,7.49 mmol,70%)。
[M+H]+=518.28、540.32(M+Na)。
將{(S)-1-[4-(第三-丁氧基羰基胺基-甲基)-苄基胺甲醯基]-2-苯基-乙基}-胺基甲酸苄基酯(3.66 g,7.08 mmol)溶解於甲醇(200 mL)中。在10% Pd/C(500 mg)上,在大氣壓及室溫下氫化該溶液1小時。此後經由矽藻土濾去該觸媒,並用甲醇(30 mL)清洗該殘餘物,將合併的濾液在真空下蒸發,以產生白色固體,經確認為{4-[((S)-2-胺基-3-苯基-丙醯基胺基)-甲基]-苄基}-胺基甲酸第三-丁基酯(2.627 g,6.85 mmol,97%)。
[M+H]+=384.37
將(R)-2-丁氧基羰基胺基-3-(4-乙氧基-苯基)-丙酸(4.0 g,12.93 mmol)溶解於含於二噁烷(150 mL)之4 M HCl中。1小時後,在室溫下,在真空下移除該溶劑,以產生白色
固體,經確認為(R)-2-胺基-3-(4-乙氧基-苯基)-丙酸鹽酸鹽(3.18 g,12.9 mmol,100%)。
[M+H]+=210.18
將(R)-2-胺基-3-(4-乙氧基-苯基)-丙酸鹽酸鹽(3.17 g,12.9 mmol)溶解於溶於水(100 mL)之氫氧化鈉(1.14 g,28.38 mmol)溶液中。加入溶於二噁烷(100 mL)之氯甲酸苄基酯(2.64 g,15.48 mmol)。在室溫下攪拌反應混合物18小時,此後在真空下移除二噁烷。使用二乙醚(1×100 mL)清洗該水性殘餘物,用1 M HCl酸化至pH 2,並用氯仿(2x200 mL)萃取。以水(1×50 mL)、鹽水(1×50 mL)清洗該合併萃取物,在真空下乾燥(Na2SO4)並蒸發,以產生白色固體,經確認為(R)-2-苄基氧羰基胺基-3-(4-乙氧基-苯基)-丙酸(4.0 g,11.65 mmol,90%)。
[M+H]+=344.20。
將{4-[((S)-2-胺基-3-苯基-丙醯基胺基)-甲基]-苄基}-胺基甲酸第三-丁基酯(2.63 g,6.86 mmol)溶解於CH2Cl2(100 mL)及DMF(5 mL)中,將該溶液冷卻至0℃。添加(R)-2-苄基氧羰基胺基-3-(4-乙氧基-苯基)-丙酸(2.59 g,7.54 mmol),接著添HOBt(1.11 g,8.23 mmol)及三乙胺(2.08 g,20.57 mmol)。然後添加水溶性碳二亞胺(1.45 g,7.54
mmol)。18小時後,在0℃至室溫下,用氯仿(100 mL)稀釋反應混合物,並使用NaHCO3(1×50 mL)、水(1×50 mL)、鹽水(1×50 mL)清洗,在真空下乾燥(Na2SO4)並蒸發,得到黃色油狀物。使用乙酸乙酯及石油醚(60-80℃)濕磨該殘餘物,以產生白色固體,經確認為[(R)-1-{(S)-1-[4-(第三-丁氧基羰基胺基-甲基)-苄基胺甲醯基]-2-苯基-乙基胺甲醯基}-2-(4-乙氧基-苯基)-乙基]-胺基甲酸苄基酯(3.55 g,5.01 mmol,73%)。
[M+H]+=709.34。
將[(R)-1-{(S)-1-[4-(第三-丁氧基羰基胺基-甲基)-苄基胺甲醯基]-2-苯基-乙基胺甲醯基}-2-(4-乙氧基-苯基)-乙基]-胺基甲酸苄基酯(3.55 g,5.00 mmol)溶解於甲醇(200 mL)中。在10% Pd/C(500 mg)上,在大氣壓及室溫下氫化該溶液1小時,此後經由矽藻土濾去該觸媒,並用甲醇(30 mL)清洗殘餘物,在真空下蒸發經合併濾液,以產生白色固體,經確認為[4-({(S)-2-[(R)-2-胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-苯基-丙醯基胺基}-甲基)-苄基]-胺基甲酸第三-丁基酯(2.8 g,4.87 mmol,97%)。
[M+H]+=575.37。
將[4-({(S)-2-[(R)-2-胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-苯基-丙醯基胺基}-甲基)-苄基]-胺基甲酸第三-丁基酯(3.45 g,5.99 mmol)溶解於二氯甲烷(150 mL)中。添加苯甲醯氯(1.01 g,7.19 mmol),接著添加三乙胺(1.82 g,17.98 mmol)。在室溫下,攪拌該反應混合物5小時,並用CHCl3(150 mL)稀釋,使用0.3 M KHSO4(1×50 mL)、飽和NaHCO3(1×50 mL)、水(1×50 mL)、鹽水(1×50 mL)清洗該溶液,在真空下乾燥(Na2SO4)並蒸發。使用石油醚(60-80℃)及EtOAc濕磨該殘餘物,以產生白色固體,經確認為[4-({(S)-2-[(R)-2-苯甲醯基胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-苯基-丙醯基胺基}-甲基)-苄基]-胺基甲酸第三-丁基酯(3.06 g,4.51 mmol,75%)。
[M+H]+=679.34
將[4-({(S)-2-[(R)-2-苯甲醯基胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-苯基-丙醯基胺基}-甲基)-苄基]-胺基甲酸第三-丁基酯(2.86 g,4.21 mmol)溶解於含於二噁烷(150 mL)之4 M HCl中。1小時後,在室溫下,在真空下移除該溶劑。自乙醇中沈澱出該殘餘物,以產生白色固體,經確認為N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺鹽酸鹽(2.1 g,3.41 mmol,81%)。
[M+H]+=579.34
1H NMR:(CD3OD),1.40(3H,t,J=6.9 Hz),2.91-2.99(3H,m),3.14-3.19(1H,m),4.02(2H,q,J=6.9 Hz),4.08(2H,s),4.41(1H,d,J=15.5 Hz),4.51(1H,d,J=15.5 Hz),4.66-4.69(2H,m),6.82(2H,d,J=8.4 Hz),7.10(2H,d,J=8.2 Hz),7.18-7.20(2H,m),7.25-7.38(7H,m),7.44-7.59(3H,m),7.72(2H,d,J=7.8 Hz)。
將4-胺基甲基苯甲腈鹽酸鹽(1.53 g,9.1 mmol)溶解於CH2Cl2(100 mL)中,將溶液冷卻至0℃。添加(S)-2-第三-丁氧基羰基胺基-3-苯基丙酸2,5-二氧-吡咯啶-1-基酯(3.00 g,8.3 mmol),接著添加三乙胺(2.51 g,25 mmol)。18小時後,在0℃至室溫下,用氯仿(100 mL)稀釋反應混合物,並使用NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗,在真空下乾燥(Na2SO4)並蒸發,得到黃色油狀物。自EtOAc/石油醚(60-80℃)再結晶出該殘餘物,以產生白色
固體,經確認為[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基]-胺基甲酸第三-丁基酯(2.71 g,7.1 mmol,86%)。
[M+H]+=380.13
使用4 M HCl/二噁烷(150 mL)處理[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基]-胺基甲酸第三-丁基酯(2.71 g,7.1 mmol)。1小時後,在室溫下移除該溶劑,以產生白色固體,經確認為(S)-2-胺基-N-(4-氰基-苄基)-3-苯基-丙醯胺鹽酸鹽(2.24 g,7.1 mmol,99%)。
[M+H]+=280.14
將(S)-2-胺基-N-(4-氰基-苄基)-3-苯基-丙醯胺鹽酸鹽(500 mg,1.58 mmol)溶解於CH2Cl2(30 mL)及DMF(3 mL)中,將該溶液冷卻至0℃。添加Boc-DCha-OH(473 mg,1.74 mmol),接著添加HOBt(257 mg,1.74 mmol)及三乙胺(481 mg,4.75 mmol)。然後添加水溶性碳二亞胺(339 mg,1.74 mmol)。18小時後,在0℃至室溫下,用氯仿(100 mL)稀釋反應混合物,並使用NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗,在真空下乾燥(Na2SO4)並蒸發,得到黃色油狀物。藉由急驟層析法(二氧化矽)純化該殘餘物(洗脫液為60%環己烷、40% EtOAc),將溶離分液合併並在真空下蒸發,以產生泡沫狀白色固體,經確認為{(R)-1-[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基胺甲醯
基]-2-環己基-乙基}-胺基甲酸第三-丁基酯(799 mg,1.50 mmol,95%)。
[M+H]+=533.18
使用4 M HCl/二噁烷(50 mL)處理{(R)-1-[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-環己基-乙基}-胺基甲酸第三-丁基酯(799 mg,1.5 mmol)。1小時後,在室溫下移除該溶劑,以產生白色固體,經確認為(R)-2-胺基-N-[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基]-3-環己基-丙醯胺鹽酸鹽(703 mg,1.5 mmol,100%)。
[M+H]+=433.06
將(R)-2-胺基-N-[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基]-3-環己基-丙醯胺鹽酸鹽(290 mg,0.62 mmol)溶解於乙腈(10 mL)中。添加溴乙酸第三丁酯(144 mg,0.74 mmol),接著添加二異丙基乙胺(160 mg,1.24 mmol)。在60℃攪拌該反應混合物2天,此後使用氯仿(100 mL)稀釋,使用水(1×30 mL)、鹽水(1×30 mL)清洗,在真空下乾燥(Na2SO4)並蒸發,產生黃色油狀物。藉由急驟層析法(二氧化矽)純化該殘餘物(洗脫液為25%石油醚(60-80℃)、75% EtOAc),將溶離分液合併並蒸發,以產生無色油狀物,經確認為{(R)-1-[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基
胺甲醯基]-2-環己基-乙基胺基}-乙酸第三-丁基酯(240 mg,0.44 mmol,71%)。
[M+H]+=547.30
將{(R)-1-[(S)-1-(4-氰基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-環己基-乙基胺基}-乙酸第三-丁基酯(240 mg,0.44 mmol)溶解於甲醇(25 mL)中,將該溶液冷卻至0℃。添加氯化鎳(II)六水合物(10.4 mg,0.44 mmol)及二碳酸二第三丁酯(192 mg,0.88 mmol),接著逐份添加硼氫化鈉(116 mg,3.1 mmol)。在0℃至室溫下攪拌該反應混合物3天。藉由蒸發作用移除MeOH。將殘餘物溶解於CHCl3(70 mL)中,使用飽和NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗,在真空下乾燥(Na2SO4)並蒸發,得到黃色油狀物。藉由急驟層析法(二氧化矽)純化(洗脫液為40%石油醚(60-80℃)、60% EtOAc),以產生無色油狀物,經確認為((R)-1-{(S)-1-[4-(第三-丁氧基羰基胺基-甲基)-苄基胺甲醯基]-2-苯基-乙基胺甲醯基}-2-環己基-乙基胺基)-乙酸第三-丁基酯(65 mg,0.10 mmol,23%)。
[M+H]+=651.44
使用三氟乙酸(4 mL)及CH2Cl2(2 mL)處理((R)-1-{(S)-1-
[4-(第三-丁氧基羰基胺基-甲基)-苄基胺甲醯基]-2-苯基-乙基.胺甲醯基}-2-環己基-乙基胺基)-乙酸第三-丁基酯(65 mg,0.1 mmol)。1小時後,在真空室溫下蒸發該溶劑。藉由製備型HPLC(Sunfire製備型C18 OBD管柱19×250 mm,10 μ)純化該殘餘物。在35分鐘內以10至90%梯度將0.1% TFA/MeCN以20 mL/分鐘流速轉成為0.1% TFA/H2O。將溶離分液合併並冷凍乾燥,以產生白色固體,經確認為{(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-環己基-乙基胺基}-乙酸二三氟乙酯(46 mg,0.064 mmol,64%)。
[M+H]+=495.28
1H NMR:(CD3OD)0.78-0.98(2H,m),1.10-1.25(4H,m),1.53-1.70(7H,m),2.97(1H,dd,J=14.0,10.5Hz),3.25(1H,dd,J=14.1,5.2Hz),3.74(2H,s),4.01(1H,dd,J=8.1,6.1Hz),4.15(2H,s),4.47(2H,s),4.76(1H,dd,J=10.5,5.2Hz),7.28-7.38(7H,m),7.45(2H,d,J=8.2Hz),8.83(1H,t,J=5.9Hz)。
表1至4中的化合物係如實例1至4(上文)及實例180至182(下文)所述合成的。
將4-(胺基甲基)苄基胺基甲酸第三丁基酯(7.5 g,31.74 mmol)溶解於二氯甲烷(250 mL)中,將該溶液冷卻至0℃,並添加三乙胺(9.63 g,93.2 mmol),接著加入碳酸苄基酯2,5-二氧-吡咯啶-1-基酯(9.5 g,38.09 mmol)。在0℃至室溫下,攪拌該反應混合物18小時,並用CHCl3(200 mL)稀釋,使用0.3 M KHSO4(1×50 mL)、飽和NaHCO3(1×50 mL)、水(1×50 mL)、鹽水(1×50 mL)清洗該濾液,在真空下乾燥(Na2SO4)並蒸發,以產生白色固體。使用EtOAc/石油醚60-80℃濕磨該固體,以產生白色固體,經確認為[4-(第三-丁氧基羰基胺基-甲基)-苄基]-胺基甲酸苄基酯(11.3 g,30.5 mmol,96%)。
[M+H]+=392.98(M+Na)
將[4-(第三-丁氧基羰基胺基-甲基)-苄基]-胺基甲酸苄基酯(10.8 g,29.15 mmol)溶解於含於二噁烷(400 mL)之4 M HCl中。1小時後,在室溫真空下移除該溶劑。將該殘餘物與丙酮混合成漿,並濾出固體,以產生白色固體,經確認為(4-胺基甲基-苄基)-胺基甲酸苄基酯鹽酸鹽(11.9 g,30.135 mmol,99%)。
[M+H]+=359.15
將(S)-2-第三-丁氧基羰基胺基-3-吡啶-3-基-丙酸(2.12 g,7.96 mmol)溶解於CH2Cl2(100 mL)中,添加HBTU(3.29
g,8.68 mmol)及三乙胺(2.20 g,21.71 mmol)。20分鐘後,在室溫下將該反應混合物冷卻至0℃,並添加(4-胺基甲基-苄基)-胺基甲酸苄基酯鹽酸鹽(1.96 g,7.24 mmol)。2小時後,在0℃下使用CHCl3(200 mL)稀釋該反應混合物,使用0.3 M KHSO4(1×50 mL)、飽和NaHCO3(1×50 mL)、水(1×50 mL)、鹽水(1×50 mL)清洗該溶液,在真空下乾燥(Na2SO4)並蒸發,以產生白色固體。使用EtOAc/石油醚60-80℃濕磨該固體,以產生白色固體,經確認為{(S)-1-[4-(苄基氧羰基胺基-甲基)-苄基胺甲醯基]-2-吡啶-3-基-乙基}-胺基甲酸第三-丁基酯(2.53 g,4.88 mmol,67%)。
[M+H]+=519.16
使用4 M HCl/二噁烷(50 mL)處理{(S)-1-[4-(苄基氧羰基胺基-甲基)-苄基胺甲醯基]-2-吡啶-3-基-乙基}-胺基甲酸第三-丁基酯(2.52 g,4.89 mmol)。1小時後,在室溫下移除該溶劑,以產生白色固體,經確認為{4-[((S)-2-胺基-3-吡啶-3-基-丙醯基胺基)-甲基]-苄基}-胺基甲酸苄基酯二鹽酸鹽(2.31 g,4.71 mmol,97%)。
[M+H]+=419.18
1H NMR:(d6-DMSO)δ:9.38(1H,t,J=5.7Hz),8.87(1H,s),8.81(1H,d,J=5.4Hz),8.42-8.49(2H,br s),8.41(1H,d,J=8.0Hz),7.93(1H,dd,J=7.9,5.8Hz),7.87(1H,t,J=
6.2Hz),7.28-7.38(4H,m),7.16-7.25(4H,m),5.03(2H,s),4.22-4.43(4H,m),4.18(2H,d,J=6.1Hz),3.39(1H,dd,J=14,5.6Hz),3.26(1H,dd,J=14.0,8.2Hz)。
將(R)-2-苄基氧羰基胺基-3-(4-乙氧基-苯基)-丙酸(870 mg,2.80 mmol)溶解於CH2Cl2(100 mL)中,添加HBTU(1.21 g,3.20 mmol)及三乙胺(1.35 g,13.33 mmol)。20分鐘後,在室溫下將該反應混合物冷卻至0℃,並添加{4-[((S)-2-胺基-3-吡啶-3-基-丙醯基胺基)-甲基]-苄基}-胺基甲酸苄基酯二鹽酸鹽(1.31 g,2.67 mmol)。2小時後,在0℃下使用CHCl3(200 mL)稀釋該反應混合物,使用0.3 M KHSO4(1×50 mL)、飽和NaHCO3(1×50 mL)、水(1×50 mL)、鹽水(1×50 mL)清洗該溶液,在真空下乾燥(Na2SO4)並蒸發,以產生白色固體。使用EtOAc/石油醚60-80℃濕磨該固體,以產生白色固體,經確認為[(R)-1-{(S)-1-[4-(苄基氧羰基胺基-甲基)-苄基胺甲醯基]-2-吡啶-3-基-乙基胺甲醯基}-2-(4-乙氧基-苯基)-乙基]-胺基甲酸第三-丁基酯(2.40 g,1.70 mmol,90%)。
[M+H]+=710.18
使用4 M HCl/二噁烷(100 mL)處理[(R)-1-{(S)-1-[4-(苄基氧羰基胺基-甲基)-苄基胺甲醯基]-2-吡啶-3-基-乙基胺甲醯基}-2-(4-乙氧基-苯基)-乙基]-胺基甲酸第三-丁基酯(1.70 g,2.42 mmol)。1小時後,在室溫下移除該溶劑,以產生白色固體,經確認為[4-({(S)-2-[(R)-2-胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-吡啶-3-基-丙醯基胺基}-甲基)-苄基]-胺基甲酸苄基酯二鹽酸鹽(1.50 g,2.32 mmol,97%)。
[M+H]+=609.99
1H NMR:(d6-DMSO)δ:9.29(1H,d,J=8.4Hz),8.96(1H,t,J=5.8Hz),8.83(1H,s),8.77(1H,d,J=5.4Hz),8.39(1H,d,J=8.2Hz),8.28-7.98(2H,br s),7.92(1H,dd,J=8.0,5.7Hz),7.86(1H,t,J=6.2Hz),7.28-7.38(4H,m),7.11-7.20(4H,m),6.95(2H,d,J=8.6Hz),6.79(2H,d,J=8.6Hz),5.02(2H,s),4.68-4.75(1H,m),4.23-4.25(2H,m),4.16(2H,d,J=6.1Hz),3.83-4.13(4H,m),3.22(1H,dd,J=14.0,4.4Hz),3.03(1H,dd,J=13.7,9.7Hz),2.84(1H,dd,J=14.0,5.9Hz),2.63(1H,dd,J=13.8,6.1Hz),1.29(3H,t,J=7.0Hz)。
將({(S)-2-[(R)-2-胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-吡啶-3-基-丙醯基胺基}-甲基)-苄基]-胺基甲酸苄基酯二鹽酸鹽(150 mg,0.23 mol)溶解於二氯甲烷(50 mL)中,將該溶液冷卻至0℃。添加三乙胺(70 mg,0.70 mmol),接著
添加對-甲基苯甲醯氯(39 mg,0.26 mmol)。18小時後,在0℃至室溫下使用CHCl3(50 mL)稀釋該反應混合物,使用飽和NaHCO3(1×20 mL)、水(1×20 mL)、鹽水(1×20 mL)清洗該溶液,在真空下乾燥(Na2SO4)並蒸發。藉由急驟層析法(二氧化矽)純化該殘餘物(洗脫液為2% MeOH、98% CHCl3),將溶離分液合併並在真空下蒸發,以產生無色油狀物,經確認為[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-(4-甲基-苯甲醯基胺基)-丙醯基胺基]-3-吡啶-3-基-丙醯基胺基}-甲基)-苄基]-胺基甲酸苄基酯(130 mg,0.18 mmol,77%)。
[M+H]+=728.14
將[4-({(S)-2-[(R)-3-(4-乙氧基-苯基)-2-(4-甲基-苯甲醯基胺基)-丙醯基胺基]-3-吡啶-3-基-丙醯基胺基}-甲基)-苄基]-胺基甲酸苄基酯(98 mg,0.13 mmol)溶解於甲醇(100 mL)中,添加1 M鹽酸(0.263 mL,0.263 mmol),並使該反應混合物在大氣壓下,在10% Pd/C(50 mg)上進行氫化作用2小時,此後濾去該觸媒,並使用甲醇(100 mL)清洗,經合併的濾液在真空下蒸發,以產生白色固體,該白色固體自乙醇中進行再結晶產生白色固體,經確認為N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲醯胺二鹽酸
鹽。
產率=340 mg,0.498 mmol,57%
[M+H]+=593.99
1H NMR:(d6-DMSO)δ:1.28(3H,t,J=7.05Hz),2.34(3H,s),2.72(2H,d,J=8.16Hz),3.01-3.06(1H,m),3.25-3.28(1H,m),3.91-3.98(4H,m),4.32-4.38(2H,m),4.54-4.57(1H,m),4.70-4.73(1H,m),6.75(2H,d,J=6.83Hz),7.18(2H,d,J=8.56Hz),7.24(2H,d,J=7.56Hz),7.25-7.27(1H,m),7.28(2H,d,J=6.78Hz),7.39(2H,d,J=7.51Hz),7.67(1H,d,J=7.51Hz),7.76(1H,s,br),8.22(1H,d,J=7.56Hz),8.33(3H,s,br),8.71-8.77(4H,m)。
將4-(胺基甲基)苄基胺基甲酸第三丁基酯(7.5 g,31.74 mmol)溶解於二氯甲烷(250 mL)中。將該溶液冷卻至0℃,並添加三乙胺(9.63 g,93.2 mmol),接著添加2,5-二氧-吡咯啶-1-基碳酸酯9H-茀-9-基甲酯(12.85 g,38.09 mmol)。在0℃至室溫下攪拌該反應混合物3小時,並使用CHCl3(200 mL)稀釋,使用0.3 M KHSO4(1×50 mL)、飽和NaHCO3(1×50 mL)、水(1×50 mL)、鹽水(1×50 mL)清洗該濾液,在真空下乾燥(Na2SO4)並蒸發,以產生白色固體。使用EtOAc/石油醚60-80℃濕磨該固體,以產生白色固體,經確認為[4-(第三-丁氧基羰基胺基-甲基)-苄基]-胺基甲酸9H-茀-9-基甲酯(13.96 g,30.44 mmol,96%)。
[M+H]+=359.14(M-Boc)
將[4-(第三-丁氧基羰基胺基-甲基)-苄基]-胺基甲酸9H-茀-9-基甲酯(13.9 g,31.41 mmol)溶解於含於二噁烷(400 mL)之4 M HCl中。1小時後,在室溫下,在真空中移除該溶劑。使用丙酮濕磨該殘餘物,濾出固體,以產生白色固體,經確認為(4-胺基甲基-苄基)-胺基甲酸9H-茀-9-基甲酯鹽酸鹽(11.9 g,30.135 mmol,99%)。
[M+H]+=359.15
將(S)-2-第三-丁氧基羰基胺基-3-(3,4-二氟-苯基)-丙酸(2.1 g,6.96 mmol)溶解於CH2Cl2(250 mL)及DMF(25 mL)
中,將該溶液冷卻至0℃。添加(4-胺基甲基-苄基)-胺基甲酸9H-茀-9-基甲酯鹽酸鹽(2.5 g,6.33 mmol),接著添加HOBt(940 mg,6.96 mmol)及三乙胺(1.92 g,18.99 mmol)。然後添加水溶性碳二亞胺(1.45 g,7.6 mmol)。18小時後,在0℃至室溫下使用氯仿(400 mL)稀釋反應混合物,使用0.3 M KHSO4(1×30 mL)、飽和NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗該混合物,並在真空下蒸發,產生白色固體。使用乙酸乙酯/石油醚60-80℃濕磨該殘餘物,以產生白色固體,經確認為((S)-2-(3,4-二氟-苯基)-1-{4-[(9H-茀-9-基甲氧基羰基胺基)-甲基]-苄基胺甲醯基}-乙基)-胺基甲酸第三-丁基酯(2.60 g,4.05 mmol,64%)。
[M+H]+=641.9、664.07(M+Na)
將((S)-2-(3,4-二氟-苯基)-1-{4-[(9H-茀-9-基甲氧基羰基胺基)-甲基]-苄基胺甲醯基}-乙基)-胺基甲酸第三-丁基酯(2.5 g,3.90 mmol)溶解於含於二噁烷(150 mL)之4 M HCl中。1小時後,在室溫真空下移除該溶劑,以產生白色固體,經確認為(4-{[(S)-2-胺基-3-(3,4-二氟-苯基)-丙醯基胺基]-甲基}-苄基)-胺基甲酸9H-茀-9-基甲酯鹽酸鹽(2.25 g,3.89 mmol,100%)。
[M+H]+=542.12
將(R)-2-第三-丁氧基羰基胺基-3-(4-乙氧基-苯基)-丙酸(895 mg,2.90 mmol)溶解於CH2Cl2(250 mL)及DMF(25 mL)中,將該溶液冷卻至0℃。添加(4-{[(S)-2-胺基-3-(3,4-二氟-苯基)-丙醯基胺基]-甲基}-苄基)-胺基甲酸9H-茀-9-基甲酯鹽酸鹽(1.5 g,2.63 mmol),接著添加HOBt(391 mg,2.90 mmol)及三乙胺(800 mg,7.89 mmol)。然後添加水溶性碳二亞胺(605 mg,3.16 mmol)。18小時後,在0℃至室溫下使用氯仿(200 mL)稀釋反應混合物,使用0.3 M KHSO4(1×30 mL)、NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×50 mL)清洗該混合物,並在真空下蒸發,產生白色固體。使用乙酸乙酯/石油醚60-80℃濕磨該殘餘物,以產生白色固體,經確認為[(R)-1-((S)-2-(3,4-二氟-苯基)-1-{4-[(9H-茀-9-基甲氧基羰基胺基)-甲基]-苄基胺甲醯基}-乙基胺甲醯基)-2-(4-乙氧基-苯基)-乙基]-胺基甲酸第三-丁基酯(2.1 g,2.52 mmol,96%)。
[M+H]+=733.15(M-Boc)
將[(R)-1-((S)-2-(3,4-二氟-苯基)-1-{4-[(9H-茀-9-基甲氧基羰基胺基)-甲基]-苄基胺甲醯基}-乙基胺甲醯基)-2-(4-乙
氧基-苯基)-乙基]-胺基甲酸第三-丁基酯(2.1 g,2.52 mmol)溶解於含於二噁烷(150 mL)之4 M HCl中。1小時後,在室溫下,在真空中移除該溶劑,並用丙酮濕磨該殘餘物,以產生白色固體,經確認為(4-{[(S)-2-[(R)-2-胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-(3,4-二氟-苯基)-丙醯基胺基]-甲基}-苄基)-胺基甲酸9H-茀-9-基甲酯鹽酸鹽(1.9 g,2.47 mmol,98%)。
[M+H]+=73.12
將(4-{[(S)-2-[(R)-2-胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-(3,4-二氟-苯基)-丙醯基胺基]-甲基}-苄基)-胺基甲酸9H-茀-9-基甲酯鹽酸鹽(410 mg,0.53 mmol)溶解於二氯甲烷(50 mL)中。將該溶液冷卻至0℃,並添加三乙胺(162 mg,1.60 mmol),接著添加苯甲醯氯(82 mg,0.59 mmol)。在0℃至室溫下攪拌該反應混合物3小時,並使用CHCl3(100 mL)稀釋,使用0.3 M KHSO4(1×30 mL)、飽和NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗該濾液,在真空下乾燥(Na2SO4)並蒸發,以產生白色固體。使用熱乙醇濕磨該固體,過濾經冷卻懸浮液,以產生白色固體,經確認為(4-{[(S)-2-[(R)-2-苯甲醯基胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-(3,4-二氟-苯基)-丙醯基胺基]-甲基}-苄基)-胺基甲酸9H-茀-9-基甲酯(240 mg,0.34 mmol,
99%)。
[M+H]+=697.18
將(4-{[(S)-2-[(R)-2-苯甲醯基胺基-3-(4-乙氧基-苯基)-丙醯基胺基]-3-(3,4-二氟-苯基)-丙醯基胺基]-甲基}-苄基)-胺基甲酸9H-茀-9-基甲酯(180 mg,0.215 mmol)溶解於二乙胺/THF(1:1,100 mL)中,在室溫下攪拌該反應混合物3小時,此後在真空下移除該溶劑,並用乙酸乙酯/石油醚60-80℃濕磨該殘餘物,以產生經確定的白色固體,使用含於二噁烷(20 mL)之4 M HCl處理該固體,在真空下移除該溶劑,並自EtOH再結晶出該殘餘物,以產生白色固體,經確認為N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氟-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺鹽酸鹽(62 mg,0.095 mmol,44%)。
[M+H]+=614.68
1H NMR:(d6-DMSO)δ:1.26(3H,t,J=6.79Hz),2.65-2.84(3H,m),3.03-3.08(1H,m),3.92(2H,q,J=6.11Hz),3.96(2H,s),4.27-4.35(2H,m),4.57-4.63(2H,m),6.75(2H,d,J=8.03Hz),7.16(2H,d,J=8.76Hz),7.23-7.25(1H,m),7.26-7.27(2H,m),7.37-7.51(6H,m),7.43(1H,d,J=7.3Hz),7.73-7.75(2H,m),8.24(2H,s),8.50(1H,d,J=7.40Hz),8.67-8.71(2H,m)。
將(R)-2-苄基氧羰基胺基-3-(4-羥基-苯基)-丙酸(1.0 g,3.17 mmol)溶解於THF(70 mL)中,添加2,2,2-三氟甲烷磺酸三氟乙酯(883 mg,3.81 mmol)及碳酸銫(3.1 g,9.51 mmol)。在65℃下攪拌該反應混合物18小時,此後在真空下移除該溶劑,並將該殘餘物溶解於EtOAc(100 mL)中,使用1 M HCl(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗該溶液,在真空下乾燥(Na2SO4)並蒸發。藉由急驟層析法(二氧化矽)純化該殘餘物(洗脫液為1% AcOH、5% MeOH、94% CHCl3),將溶離分液合併並蒸發,以產生無色油狀物,經確認為(R)-2-苄基氧羰基胺基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙酸(380 mg,0.96 mmol,30%)。
[M+H]+=395.11
將(R)-2-苄基氧羰基胺基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙酸(200 mg,0.50 mmol)溶解於CH2Cl2(50 mL)及DMF(2.5 mL)中,將該溶液冷卻至0℃。添加{4-[((S)-2-胺基-3-苯基-丙醯基胺基)-甲基]-苄基}-胺基甲酸第三-丁基酯(231 mg,0.60 mmol),接著添加HOBt(75 mg,0.55 mmol)及三乙胺(153 mg,1.51 mmol)。然後添加水溶性碳二亞胺(116 mg,0.60 mmol)。18小時後,在0℃至室溫下使用氯仿(400 mL)稀釋該反應混合物,使用0.3 M KHSO4(1×30 mL)、NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗,並在真空下乾燥(Na2SO4)並蒸發,產生黃色油狀物。藉由急驟層析法(二氧化矽)純化該殘餘物(洗脫液為3% MeOH、97% CHCl3),將溶離分液合併並蒸發,以產生白色固體,經確認為{(R)-1-{(S)-1-[4-(第三-丁氧基羰基胺基-甲基)-苄基胺甲醯基]-2-苯基-乙基胺甲醯基}-2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-胺基甲酸苄基酯(350 mg,0.46 mmol,92%)。
[M+H]+=663.43(M-Boc)、785.44(M+Na)
將{(R)-1-{(S)-1-[4-(第三-丁氧基羰基胺基-甲基)-苄基胺
甲醯基]-2-苯基-乙基胺甲醯基}-2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-胺基甲酸苄基酯(350 mg,0.46 mmol)溶解於甲醇(100 mL)中。使該溶液在大氣壓下,在10% Pd/C(50 mg)上進行氫化作用2小時,此後濾去該觸媒,並使用甲醇(100 mL)清洗,在真空下蒸發該經合併濾液,以產生白色固體,經確認為{4-[((S)-2-{(R)-2-胺基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙醯基胺基}-3-苯基-丙醯基胺基)-甲基]-苄基}-胺基甲酸第三-丁基酯(270 mg,0.43 mmol,94%)。
[M+H]+=629.40
將{4-[((S)-2-{(R)-2-胺基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙醯基胺基}-3-苯基-丙醯基胺基)-甲基]-苄基}-胺基甲酸第三-丁基酯(250 mg,0.40 mmol)溶解於二氯甲烷(50 mL)中。將該溶液冷卻至0℃,並添加三乙胺(121 mg,1.19 mmol),接著加入苯甲醯氯(61 mg,0.44 mmol)。在0℃至室溫下攪拌該反應混合物18小時,並用CHCl3(100 mL)稀釋,使用0.3 M KHSO4(1×30 mL)、飽和NaHCO3(1×30 mL)、水(1×30 mL)、鹽水(1×30 mL)清洗該濾液,在真空下乾燥(Na2SO4)並蒸發,以產生白色固體。使用EtOAc/石油醚60-80℃濕磨該固體,以產生白色固體,經確認為{4-[((S)-2-{(R)-2-苯甲醯基胺基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙醯基胺基}-3-苯基-丙醯基胺基)-甲基]-苄
基}-胺基甲酸第三-丁基酯(190 mg,0.26 mmol,65%)。
[M+H]+=733.357、755.49(M+Na)
使用4 M HCl/二噁烷(50 mL)處理{4-[((S)-2-{(R)-2-苯甲醯基胺基-3-[4-(2,2,2-三氟-乙氧基)-苯基]-丙醯基胺基}-3-苯基-丙醯基胺基)-甲基]-苄基}-胺基甲酸第三-丁基酯(190 mg,0.26 mmol)。1小時後,在室溫下移除該溶劑。藉由製備型HPLC(Sunfire製備型C18 OBD管柱。19×250 mm,10 μ)純化該殘餘物。在35分鐘內以10至90%梯度將0.1% TFA/MeCN以20 mL/分鐘流速轉成為0.1% TFA/H2O。將溶離分液合併並低溫乾燥,以產生白色固體,經確認為N-{(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-苯甲醯胺二三氟乙酸鹽(2.31 g,4.71 mmol,97%)。
使用經公開的標準方法(Lipinski等人Advanced Drug Delivery Reviews 23(1997)3-25)以濁度計法測定溶解度。在DMSO中製備10 mM化合物儲備原液,將該儲備原液添加至25 mM pH 7.0磷酸鈉緩衝液,以產生介於12至235 μM之濃度。振盪約30秒後,測定該等樣品在650 nm光透射下之減少量(Molecular Devices Spectromax UV/可見光分光光度計),約30秒後進行第二次測量。大於0.005之吸光度係
顯示有些化合物已發生沈澱作用,且因此該化合物在此濃度下是不可溶的。
該等測量所得之數據示於下表7中。
在磷酸銨緩衝液(pH 7.4,290 mOsm)中測定化合物之熱力學溶解度。將化合物製成1 mg/mL之初始濃度,經旋搖,然後置於振盪器1小時(37℃,約950 rpm)。反應後,將樣品轉移至微量離心管中,並在37℃下,以15,000 g(r.c.f.)離心10分鐘。利用從DMSO儲存原液所製備之檢量線,藉由LC-MS/MS分析法測定上清液中化合物的濃度。
自該等測量所得之數據示於下表8中。
使用下列生物測試可測定式(I)化合物抑制血漿激肽釋放
酶之能力:
使用經公開的標準方法測定血漿激肽釋放酶在試管內的抑制活性(參見例如Johansen等人,Int.J.Tiss.Reac.1986,8,185;Shori et al.,Biochem.Pharmacol.,1992,43,1209;Stürzebecher et al.,Biol.Chem.Hoppe-Seyler,1992,373,1025)。在37℃下,將人類血漿激肽釋放酶(Protogen)與螢光受質H-DPro-Phe-Arg-AFC及多種濃度之測試化合物反應。藉由在410 nm下測量光學吸光度之變化而測定出剩餘的酵素活性(反應的起始速率),並測定測試化合物之IC50值。
自該測試所得之數據示於下表9及10中:
將經選擇的化合物進一步篩選對應相關酵素KLK1之抑制活性。使用以下生物測試可測定式(I)化合物抑制KLK1之能力:
使用經公開的標準方法測定KLK1在活體外的抑制活性(參見Johansen等人,Int.J.Tiss.Reac.1986,8,185;Shori等人,Biochem.Pharmacol.,1992,43,1209;Stürzebecher等人,Biol.Chem.Hoppe-Seyler,1992,373,1025)。在37℃下,將人類KLK1(Calbiochem)與螢光受質H-DVal-Leu-Arg-AFC及多種濃度之測試化合物反應。藉由在410 nm下測量光學吸光度之變化而測定出剩餘的酵素活性(反應之起始速率),並測定測試化合物之IC50值。
自該測試所得之數據示於下表11及12中:
將經選擇的化合物進一步篩選對抗相關酵素(纖溶酶、凝血酶、胰蛋白酶、Xa因子及XIIa因子)之抑制活性。使用以下生物測試可測定式(I)化合物對於該等酵素之能力:
使用合適的螢光受質測定人類絲胺酸蛋白酶(纖溶酶、凝血酶、胰蛋白酶、Xa因子及XIIa因子)之酵素活性。監
測5分鐘內從該受質所釋放出螢光的累積,而測定出蛋白酶活性。每分鐘螢光增加的線性速率係以活性百分比(%)表示。藉由米氏方程式(Michaelis-Menten equation)之標準換算法測定每種受質之切解Km。在受質Km濃度下進行化合物抑制劑分析法,且計算抑制劑使未受抑制之酵素活性(100%)受到50%抑制作用時之濃度(IC50)作為活性。
自該等測試所得之數據示於下表13中。
實例3化合物的活性已在大鼠中利用此活體內模型建立。在時間點為0時,大鼠以玻璃體內注射法接受5 μL磷酸鹽緩衝生理食鹽水(PBS)、CH-3457(血漿激肽釋放酶抑制劑陽性對照組)(10 μM)或實例3化合物(1 μM)。30分鐘後,以玻璃體內注射法給予第2次5 μL PBS或CA-I(200 ng/眼)。15分鐘後,輸注10%螢光素鈉,並在首次IVT注射75分鐘後,以玻璃體螢光光度測量法測定視網膜血管通透性(retinal vascular permeability;RVP)。實例3化合物的數據呈現於圖1中,其中較低虛線表示接受PBS/PBS後之基礎RVP,而較高虛線表示最大的刺激作用。相對於以玻璃體內注射法僅注射PBS而言,僅注射1 μM實例3化合物對基礎RVP沒有影響(3.64±0.48對3.29±0.21)。以玻璃體內注射法注射實例3化合物會使(受到CA-I注射刺激)RVP減少
53±21%。
對實例3化合物進行藥物動力學研究,以評估花兔(荷蘭黑帶兔)接受單一IVT劑量後之眼部及全身藥物動力學。每種劑量程度處理6隻兔,單劑、雙眼IVT注射50 μL 4.2 μg/mL(210 ng/眼)調配於磷酸鹽緩衝生理食鹽水中之實例3化合物。在每個時間點(IVT投藥後4、8、24、48、96及168小時)安樂死1隻兔子,並測定實例3化合物在玻璃體、視網膜/脈絡膜及眼房水中之眼部組織濃度。收集殘活兔子之連續血液樣本。
眼部組織濃度數據呈現於圖2中,其中代表每一眼部組織濃度之實線係為每隻兔子左眼及右眼的平均值。在7天內,實例3化合物在眼部組織濃度降低極微。IVT投與後,血漿中實例3化合物的濃度在所有時間點上皆低於1 ng/mL。
圖1顯示實例3化合物及CH-3457(陽性對照組;血漿激肽釋放酶抑制劑)在斯潑累格.多雷(Sprague Dawley)大鼠中對經CA-I刺激的RVP之抑制作用。
圖2顯示IVT投與4.2 μg/mL(210 ng/眼)實例3化合物後,眼部組織中實例3化合物的濃度。
Claims (17)
- 一種式(I)化合物
- 如請求項1之化合物,其中R9係選自苯基及萘基,其中苯基視情況係經可多達3個獨立地選自烷基、烷氧基、OH、鹵基、CN、COOR11、CF3及NR11R12之取代基取代。
- 如請求項1或請求項2之化合物,其中R9係選自苯基、1-萘、2,4-二氯苯基、3,4-二氯苯基、3,4-二氟苯基、4-氯苯基、4-三氟甲基苯基及4-乙氧苯基。
- 如請求項1或請求項2之化合物,其中R1係選自H、-CO芳基、-CO烷基、-CH2COOH、-SO2Ph及-SO2CH3。
- 如請求項1或請求項2之化合物,其中R1係選自-CO烷基及-CO芳基。
- 如請求項1或請求項2之化合物,其中R3係選自:
- 如請求項1或請求項2之化合物,其中R4及R6係選自H及CH3。
- 如請求項1或請求項2之化合物,其中關於對掌性中心*1之立體組態為R。
- 如請求項1或請求項2之化合物,其中關於對掌性中心*2之立體組態為S。
- 如請求項1或請求項2之化合物,其中a為2,且b、c、d、e、f、g、h、j、l及m為1。
- 如請求項1之化合物,其係選自:(S)-N-(4-胺基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;{(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-環己基-乙基胺基}-乙酸;(S)-N-(4-胺基甲基-3-氟-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯胺;(S)-N-(4-胺基甲基-2-氯-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯胺;(S)-N-(4-胺基甲基-苄基)-3-(3,4-二氯-苯基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-丙醯胺; (S)-N-(4-胺基甲基-3-氯-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-苯基-丙醯胺;(S)-N-(4-胺基甲基-苄基)-2-{[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基]-甲基-胺基}-3-苯基-丙醯胺;({(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-環己基-乙基}-甲基-胺基)-乙酸;(S)-N-(4-胺基甲基-3-氟-苄基)-2-{[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基]-甲基-胺基}-3-苯基-丙醯胺;N-[(R)-1-{[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基]-甲基-胺甲醯基}-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-{[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基]-甲基-胺甲醯基}-2-(4-乙氧基-苯基)-乙基]-異丁醯胺;萘-1-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2,4-二氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,4-二氟-苯甲醯胺; (R)-2-胺基-N-[(1S,2S)-1-(4-胺基甲基-苄基胺甲醯基)-2-羥基-2-苯基-乙基]-3-(4-乙氧基-苯基)-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-菸鹼醯胺;(2S,3S)-N-(4-胺基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯基胺基]-3-羥基-3-苯基-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-異菸鹼醯胺;噻吩-3-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;環己烷羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;異噁唑-5-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;苯并[b]噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;(R)-N-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基]-2-(4-氯-苯磺醯基胺基)-3-(4-乙氧基-苯基)-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙 基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3-氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2-氯-苯甲醯胺N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3-三氟甲基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,4-二氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲醯胺;(S)-N-(4-胺基甲基-苄基)-2-[(R)-3-(4-乙氧基-苯基)-2-(2-苯基乙醯基胺基-乙醯基胺基)-丙醯基胺基]-3-苯基-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氟-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-6-甲基-菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙 基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2-甲基-菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2,6-二氯-菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-5,6-二氯-菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2,3,6-三氟-異菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,3,3-三氟-丙醯胺;2,4-二甲基-噻唑-5-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;2-甲基-噻唑-5-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;3-氯-噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;4-甲基-噻唑-5-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲 醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;呋喃-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;3-甲基-噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2-甲氧基-異菸鹼醯胺;3-甲基-1H-吡咯-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;3-胺基-噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-丙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(4-氯-苯 基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(4-氟-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(4-甲氧基-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-4-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3-氟-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻吩-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻吩-3-基-乙基胺甲醯基-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻唑-4-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯并[b]噻吩-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-3-氟-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-3-氯-苄基胺甲醯基)-2-苯基 -乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻吩-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-3-氯-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氟-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-異菸鹼醯胺;噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲醯 胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;(R)-N-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基]-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-3-氟-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-異菸鹼醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-3-氟-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;(R)-N-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基]-3-(4-乙氧基-苯基)-2-丙醯基胺基-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-異菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,3,3-三氟-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲醯 胺;異噁唑-5-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氟-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;及其醫藥上可接受之鹽。
- 如請求項1之化合物,其係選自:N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;萘-1-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-2,4-二氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-菸鹼醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙 基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,4-二氟-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-異菸鹼醯胺;噻吩-3-羧酸-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;環己烷羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;異噁唑-5-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;(R)-N-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基]-2-(4-氯-苯磺醯基胺基)-3-(4-乙氧基-苯基)-丙醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3,4-二氯-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-3-氯-苯甲醯胺; N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-氟-苯甲醯胺;3-甲基-噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;3-甲基-1H-吡咯-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;3-胺基-噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-丙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氯-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(4-氟-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基 -乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻吩-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻吩-3-基-乙基胺甲醯基-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-苯并[b]噻吩-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-3-氟-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-3-氯-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-噻吩-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-2-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲醯胺;吡啶-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-3-氯-苄基胺甲醯基)-2-苯基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲氧基-苯甲醯胺; 噻吩-2-羧酸[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-吡啶-3-基-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-4-甲基-苯甲醯胺;N-[(R)-1-[(S)-1-(4-胺基甲基-苄基胺甲醯基)-2-(3,4-二氟-苯基)-乙基胺甲醯基]-2-(4-乙氧基-苯基)-乙基]-苯甲醯胺;及其醫藥上可接受之鹽。
- 一種醫藥組合物,其包含如請求項1至12中任一項之化合物及醫藥上可接受之載劑、稀釋劑或賦形劑。
- 如請求項1、2、11或12之化合物,其係用於藥品。
- 一種如請求項1至12中任一項之化合物之用途,其係用於製造治療或預防涉及血漿激肽釋放酶活性之疾病或病狀之藥物。
- 如請求項15之用途,其中該涉及血漿激肽釋放酶活性之疾病或病狀係選自受損視力、糖尿病性視網膜病、糖尿病性黃斑水腫、遺傳性血管性水腫、糖尿病、胰腺炎、腦出血、腎病、心肌症、神經病變、發炎性腸病、關節炎、炎症、敗血性休克、低血壓、癌症、成人呼吸窘迫症候群、彌漫性血管內凝血症、心肺繞道手術及術後出血。
- 如請求項15之用途,其中該涉及血漿激肽釋放酶活性之 疾病或病狀係與糖尿病性視網膜病及糖尿病性黃斑水腫相關之視網膜血管通透性。
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