CN1173872A - 凝血酶抑制剂 - Google Patents
凝血酶抑制剂 Download PDFInfo
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- CN1173872A CN1173872A CN96191860A CN96191860A CN1173872A CN 1173872 A CN1173872 A CN 1173872A CN 96191860 A CN96191860 A CN 96191860A CN 96191860 A CN96191860 A CN 96191860A CN 1173872 A CN1173872 A CN 1173872A
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- alkyl
- pro
- aryl
- acid
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Classifications
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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- C—CHEMISTRY; METALLURGY
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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- C—CHEMISTRY; METALLURGY
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Abstract
式Ⅰ凝血酶抑制剂其中R1、A、B和D如说明书中所定义,以及用于制备它的中间体。该式Ⅰ化合物适于控制疾病。
Description
本发明涉及带有N-末端磺酰基或氨基磺酰基的肽的对-脒基苄基酰胺,其制备方法及其作为凝血酶抑制剂的用途。
EP601459、EP672658、WO94/29336和WO95/23609记述了肽凝血酶抑制剂。
本发明涉及式I凝血酶抑制剂及其立体异构体和其与生理上接受的酸的盐,其中脒官能团可以是单-或双保护形式和其中取代基具有下述含义:R1:OH,C1-C20烷基,C1-C3氟代烷基,C3-C8环烷基,芳基-C1-C10烷基,芳基杂芳基,R2OOC-(CH2)n或R3R2N,其中的R2和R3相同或不同是氢、C1-C10烷基、芳基、芳基-C1-C10烷基或一起形成C2-C7亚烷基链,该亚烷基链可任选稠合上芳基或杂芳基或其中含有杂原子(O、S、NH或被取代的N),和n是1、2、3或4。A:式IIα-氨基酸残基其中
R4是氢,C1-C8烷基,C3-C7环烷基,芳基或芳基-C1-C3烷基;
R5是氢,C1-C8烷基,C3-C7环烷基或C3-C7环烷基-CH2-,其中环上的一个CH2可以被O、S、NR6替代,或双环烷基-(CH2)0,1〔原文如此〕、金刚烷基-(CH2)0-1、(CH3)3Si-C1-C4烷基、芳基或芳基-C1-C3烷基、杂芳基或杂芳基-C1-C3烷基,如果R4=H,则为C1-C8烷基,其中一个H被SR6、OR6、CO-OR6(R6=H、C1-C8烷基或芳基-C1-C3烷基)或CONR7R8(R7、R8相同或不同为H、C1-C4烷基、C3-C7环烷基或一起为C3-C6亚烷基链)替代;或
R4和R5一起形成可含有稠和在上面的芳基的C2-C6亚烷基链;B:式III环α-氨基酸残基其中
m是2、3或4,并且环上的一个氢可被羟基或C1-C3烷基所取代,和当m是3或4时,环上的一个CH2可被氧、硫、NH或N-C1-C4烷基所取代和/或两个邻位的氢原子可被双键或稠和在上面的芳族系或带有4-6个碳原子的亚甲基链所取代;D:式IV、V或VI结构片段其中
R9是F,Cl,Br,NO2,R15O,R15OOC,R15OCH2,R15NH,R15CONH,R15NH-CO或R15OOCCH2O,其中R15是H、C1-C6烷基、苄基或苯基;
R10,R11是H,C1-C4烷基或R15O,其中R9和R10或R11可一起形成稠和的亚苯基环或由3至5个碳原子组成的亚烷基链,其中的一或二个碳原子可被氧所取代;
R12是H或C1-C4烷基;
R13是C1-C4烷基,苯基-C1-C4烷基,R15CO,CF3CO,C2F5CO,R15OCH2,R15OOC,R15OCH2CO,R15OOCCO或R15NHCOCO;
R14是H,C1-C4烷基,F,Cl,Br,NO2,R15O,R15OOC,R15OCH2,R15NH,R15CONH,R15NH-CO或R15OOCCH2O;和
W、X、Y、Z是CH或N,但是,取代基W、X、Y或Z中至少有一个是N和在VI的环可被1或2的下述取代基所取代:C1-C4烷基、OH、O-C1-C4烷基、CF3、F、Cl、Br、S-C1-C4烷基、O(CH2)nCOOR6(n=1-4)。
各处的术语“芳基”是指在环系上含有6至10个碳原子的单-或双环芳族基,例如苯基或萘基,且可带有至多3个相同或不同的取代基。
各处的术语“杂芳基”是指含1或2个杂原子(例如N、O或S)的5-或6-元芳族环,且其上可稠合有芳环(例如苯环)。
术语“环烷基”是指有3至7个碳原子的饱和的环烃基,例如环戊基、环己基、环庚基,该环可被卤素、C1-C4烷基和O-C1-C4烷基所取代。优选下述化合物组Ia至Ig:其中,取代基R和片段A和B具有下述含义:R1:OH,C1-C10烷基,CF3CH2,苯基,萘基,苯基-C1-C4烷基(特别是苄基和苯乙基),萘基-C1-C4烷基,吡啶基异喹啉基,NH2,C1-C4-单-和二烷基氨基,哌啶基;A:甘氨酸,丙氨酸,缬氨酸,亮氨酸,异亮氨酸,苯基-和环己基甘氨酸,苯基-和环己基丙氨酸,四氢吡喃基甘氨酸,四氢吡喃基缬氨酸,α-甲基环己基丙氨酸,二苯基-和二环己基丙氨酸,在残基上存在的苯环可被至多3个相同或不同的C1-C4烷基、O-C1-C4烷基,OH、F、Cl或COOR6基所取代;天冬氨酸,谷氨酸,天冬酰胺,谷氨酰胺,如果需要,氮原子可带有1或2个烷基或是C4-C8环的一部分;丝氨酸,高丝氨酸,苏氨酸,其中的羧基或羟基可被C1-C8烷基所酯化或醚化;
氨基酸A优选具有D构型;B:
B片段优选具有L构型;R9:是Cl,Br,NO2,R15O,R15OOC,R15OCH2,R15NH,R15CONH或R15OOCCH2O,其中R15是H、C1-C6烷基、苄基或苯基;R10:是H,C1-C4烷基或R15O;
特别优选的取代基R和片段A和B具有下述含义:R1:HO,CH3,CH3-CH2,CH3-(CH2)3,CF3-CH2,苯基,苄基,苯乙基,吡啶基,(CH3)2N,CH3-NH,NH2和哌啶基,A:环己基甘氨酸或环己基丙氨酸,四氢-4-吡喃基甘氨酸,四氢-4-吡喃基缬氨酸,二环己基-或二苯基丙氨酸或苯基丙氨酸,其中的苯环可被至多3个相同或不同的CH3O、CH3、HO、F或Cl基所取代,丝氨酸或叔丁基丝氨酸;
该氨基酸优选具有D构型;
B片段优选具有L构型;R9:Cl,CH3O或HOR10:H,CH3或CH3O 其中取代基R1、片段A和B以及X的含义如下:R1:OH,C1-C10烷基,CF3CH2,苯基,萘基,苯基-C1-C4烷基(特别是苄基和苯乙基),萘基-C1-C4烷基,吡啶基,异喹啉基,NH2,C1-C4-单-和二烷基氨基,哌啶基;A:甘氨酸,丙氨酸,缬氨酸,亮氨酸,异亮氨酸,苯基-和环己基甘氨酸,苯基-和环己基丙氨酸,四氢吡喃基甘氨酸,四氢吡喃基缬氨酸,二苯基-和二环己基丙氨酸,在残基上存在的苯环可被至多3个相同或不同的C1-C4烷基、O-C1-C4烷基、OH、F、Cl或COOR6基所取代;天冬氨酸,谷氨酸,天冬酰胺,谷氨酰胺,如果需要,氮原子可带有1或2个烷基或是C4-C8环的-部分;丝氨酸,高丝氨酸,苏氨酸,其中的羧基或羟基可被C1-C8烷基所酯化或醚化;
B片段优选具有L构型;X:CH或N。
特别优选的取代基R1、片段A和B以及X的含义如下:R1:HO,CH3,CH3-CH2,CH3-(CH2)3,CF3-CH2,苯基,苄基,苯乙基,吡啶基,(CH3)2N,CH3-NH,NH2和哌啶基;A:环己基甘氨酸或环己基丙氨酸,四氢-4-吡喃基甘氨酸,四氢-4-吡喃基缬氨酸,二环己基-或二苯基丙氨酸或苯基丙氨酸,其中的苯环可被至多3个相同或不同的CH3O、CH3、HO、F或Cl基所取代,丝氨酸或叔丁基丝氨酸;
B片段优选具有L构型;X:CH或N或者
在化合物Ic,Id和Ie中取代基R,片段A和B以及X具有下述含义:R1:OH,C1-C10烷基,CF3CH2,苯基,萘基,苯基-C1-C4烷基(特别是苄基和苯乙基),萘基-C1-C4烷基,吡啶基,异喹啉基,NH2,C1-C4-单-和二烷基氨基,哌啶基;A:环己基甘氨酸或环己基丙氨酸,四氢吡喃基甘氨酸,四氢吡喃基缬氨酸,二环己基-或二苯基丙氨酸或可被2或3个相同或不同选自CH3O、CH3、HO、F或Cl的基团所取代的苯基丙氨酸,丝氨酸或叔丁基丝氨酸;
B片段优选具有L构型;X:CH或N。 其中,取代基R,片段A和B以及X具有下述含义:R1:OH,C1-C10烷基,CF3CH2,苯基,萘基,苯基-C1-C4烷基(特别是苄基和苯乙基),萘基-C1-C4烷基,吡啶基,异喹啉基,NH2,C1-C4-单-和二烷基氨基,哌啶基;A:甘氨酸,丙氨酸,缬氨酸,亮氨酸,异亮氨酸,苯基-和环己基甘氨酸,苯基-和环己基丙氨酸,四氢-4-吡喃基甘氨酸,四氢-4-吡喃基缬氨酸,α-甲基环己基丙氨酸,二苯基-和二环己基丙氨酸,在残基上存在的苯环可被至多3个相同或不同的C1-C4烷基、O-C1-C4烷基、OH、F、Cl或COOR6基所取代;天冬氨酸,谷氨酸,天冬酰胺,谷氨酰胺,如果需要,氮原子可带有1或2个烷基或是C4-C8环的一部分;丝氨酸,高丝氨酸,苏氨酸,其中的羧基或羟基可被C1-C8烷基所酯化或醚化;
片段B优选具有L构型;R′:CH3或CH3OX:CH或N。
特别提及下述物质:MeSO2-(D)-α-Me-Cha-Pro-NH-(2-MeO)-4-ambEtSO2-(D,L)-Cog-Pro-NH-(2-MeO)-4-ambEtSO2-(D)-(3,4-二甲氧基)Phe-Pro-NH-(2-MeO)-4-ambMeSO2-(D,L)-(1-四氢化萘基)Gly-Pro-NH-(2-MeO)-4-ambMeSO2-(D,L)-Dpa-Pro-NH-(2-MeO)-4-ambMeSO2-(D,L)-(5- 二苯并环庚基)Gly-Pro-NH-(2-MeO)-4-ambEtSO2-(D)-(4-甲氧基)Phe-Pro-NH-(2MeO)-4-ambMeSO2-(D,L)-(3,4,5-三甲氧基)Phe-Pro-NH-(2-MeO)-4-ambCF3SO2-(D)-(4-氯代)Phe-Pro-NH-(2-MeO)-4-ambCF3SO2-(D,L)-(Me3Si)Ala-Pro-NH-(2-MeO)-4-ambMeSO2-(D)-Chg-Pro-NH-(2-MeO)-4-ambCF3CH2SO2-(D)-Chg-Pro-NH-(2-MeO)-4-ambMeSO2-(D)-Phe-Aze-NH-(2-MeO)-4-ambMeSO2-(D)-(叔丁基)Ser-Pro-NH-(2-MeO)-4-ambMeSO2-(D)-Cha-Pro-NH-(2-MeO)-4-ambBz-SO2-(D)-Cha-Pro-NH-(2-MeO)-4-ambn-Bu-SO2-(D)-Cha-Pro-NH-(2-MeO)-4-ambHO-SO2-(D)-Chg-Pro-NH-(2-MeO)-4-ambH2N-SO2-(D)-Chg-Pro-NH-(2-MeO)-4-ambH2N-SO2-(D)-Chg-Pro-NH-(2-MeO)-4-ambHOOC-CH2-CH2-SO2-(D)-Chg-Pro-NH-(2-MeO)-4-amb2-萘-SO2-(D)-Phe-Pro-NH-(2-MeO)-4-ambMeSO2-(D,L)-(B-苯基)Pro-Pro-NH-(2-MeO)-4-ambMeSO2-(D)-Chg-Aze-NH-(2-MeO)-4-ambMeSO2-(D)-Chg-Pic-NH-(2-MeO)-4-ambMeSO2-(D)-Chg-Hyp-NH-(2-MeO)-4-ambMeSO2-(D)-Chg-Pyr-NH-(2-MeO)-4-ambEtSO2-(D)-Chg-(N-环丙基)Gly-NH-(2-MeO)-4-ambMeSO2-(D)-Chg-l-Tic-NH-(2-MeO)-4-ambMeSO2-(D)-Chg-2-Ind-NH-(2-MeO)-4-ambMeSO2-(D)-Chg-2-Phi-NH-(2-MeO)-4-ambEtSO2-(D)-Chg-(环)Leu-NH-(2-MeO)-4-ambPro-SO2-(D)-Chg-Pro-NE-(2-iPrO)-4-ambPh-SO2-(D)-Chg-Pro-NH-(2-OH)-4-ambMeSO2-(D)-Chg-Pro-NH-(2-OCH2-COOH)-4-ambMeSO2-(D)-Chg-Pro-NH-(2-NH-COMe)-4-ambMeSO2-(D)-Chg-Pro-NH-(2-NH2)-4-ambEtSO2-(D)-Chg-Pro-NH-(2-COOH)-4-ambMeSO2-(D)-Chg-Pro-NH-(2-COOMe)-4-ambMeSO2-(D)-Chg-Pro-NH-(2-CH2OH)-4-ambEtSO2-(D)-Chg-Pro-NH-(2-Cl)-4-ambHO-SO2-(D)-Chg-Pro-NH-(2-Br)-4-ambH2N-SO2-(D)-Chg-Pro-NH-(2,6-二甲氧基)-4-ambMeSO2-(D)-Chg-Pro-NH-(2,3-二甲氧基)-4-ambEtSO2-(D)-Chg-Pro-NH-(3-MeO)-4-ambHOSO2-(D)-Chg-Pro-NH-(3-OH)-4-ambCF3SO2-(D)-Chg-Pro-NH-(3-iPrO)-4-ambMeSO2-(D)-Chg-Pro-NH-(3-Cl)-4-ambEtSO2-(D)-Chg-Pro-NH-(4-am)-napmeMeSO2-(D)-Chg-Pro-NH-4-amb(Me)MeSO2-(D)-Chg-Pro-NH-4-amb(COOH)MeSO2-(D)-Chg-Pro-NH-4-amb(COOMe)MeSO2-(D)-Phe-Pro-NH-4-amb(CH2OH)MeSO2-(D)-Phe-Pro-NH-4-amb(CO-CH2Ph)MeSO2-(D)-Chg-Pro-NH-4-amb(CO-CF3)MeSO2-(D)-Chg-Pro-NH-4-amb(CHO)MeSO2-(D)-Chg-Pro-NH-4-amb(COCH2OH)MeSO2-(D)-Chg-Pro-NH-4-amb(COCONHCH3)MeSO2-(D)Phe-Pro-NH-(6-am)-3-picMeSO2-(D)Phe-Pro-NH-(5-am)-2-picMeSO2-(D)Phe-Pro-NH-(2-am-5-pyrim)甲基MeSO2-(D)Phe-Pro-NH-(5-am-2-pyrim)甲基MeSO2-(D)Phe-Pro-NH-(6-am-2-MeO)-3-picMeSO2-(D)Phe-Pro-NH-(2-am-5-pyraz)甲基EtSO2-(D)Phe-Pro-NH-(6-am-2-F)-3-picCF3-CH2-SO2-(D)Phe-Pro-NH-(6-am-2-OH)-3-picn-BuSO2-(D)-Phe-Pro-NH-(6-am-2-BzO)-3-picn-BuSO2-(D)-Phe-Pro-NH-(6-am-2-OH)-3-picn-辛基-SO2-(D)-Phe-Pro-NH-(6-am-2-i-PrO)-3-pic苄基-SO2-(D)-Phe-Pro-NH-(6-am-2-OCH2COOM)e-3-pic异丙基-SO2-(D)Phe-Pro-NH-(5-am-6-Cl)-2-pic苯基-SO2-(D)Phe-Pro-NH-(5-am-3-MeO)-2-pic2-萘基-SO2-(D)Phe-Pro-NH-(5-am-3-OH)-2-pic3-吡啶基-SO2-(D)Phe-Pro-NH-(5-am-3-Me)-2-pic2-噻吩基-SO2-(D)Phe-Pro-NH-(5-am-4-Me)-2-picN-哌啶基-SO2-(D)Phe-Pro-NH-(5-am-3-MeO)-2-picH2N-SO2-(D)Phe-Pro-NH-(5-am-4,6-Cl2-2-pyrim)甲基Me2N-SO2-(D)Phe-Pro-NH-(2-am-4,6-(OH)2-5-pyrim)甲基EtHiN-SO2-(D)Phe-Pro-NH-(2-am-4,6-Cl2-5-pyrim)甲基MeSO2-(D)Phe(4-OMe)-Pro-NH-(2-am-4,6-Me2-5-pyrim)甲基MeSO2-(D)Phe(3-OMe)-Pro-NH-(5-am-4,6-(OH)2-2-pyrim)甲基MeSO2-(D)Phe(4-Cl)-Pro-NH-(5-am-4,6-Me2-2-pyrim)甲基MeSO2-(D)Cha-Pro-NH-(6-am)-3-picMeSO2-(D)Cha-Pyr-NH-(6-am)-3-picMeSO2-(D)Cha-Pro-NH-(5-am)-2-picMeSO2-(D)Cha-Pro-NH-(2-am-5-pyrim)甲基MeSO2-(D)Cha-Pro-NH-(5-am-2-pyrim)甲基MeSO2-(D)Cha-Pro-NH-(6-am-2-Me)-3-picMeSO2-(D)Cha-Pro-NH-(6-am-2-MeO)-3-picMeSO2-(D)Cha-Pro-NH-(6-am-2-Cl)-3-picMeSO2-(D)Cha-Pro-NH-(2-am-4,6-(MeO)2-5-pyrim)甲基MeSO2-(D)Cha-Pro-NH-(5-am-4,6-(MeO)2-2-pyrim)甲基MeSO2-(D)Cha-Pro-NH-(2-am)-5-pyrazMeSO2-(D)Chg-Pro-NH-(6-am)-3-picMeSO2-(D)Chg-Pyr-NH-(6-am)-3-picMeSO2-(D)Chg-Pro-NH-(5-am)-2-picMeSO2-(D)Chg-Pro-NH-(2-am-5-pyrim)甲基MeSO2-(D)Chg-Pro-NH-(5-am-2-pyrim)甲基MeSO2-(D)Chg-Pro-NH-(6-am-2-Me)-3-picMeSO2-(D)Chg-Pro-NH-(6-am-2-MeO)-3-picMeSO2-(D)Chg-Pro-NH-(6-am-2-Cl)-3-picMeSO2-(D)Chg-Pro-NH-(2-am-4,6-(MeO)2-5-pyrim)甲基MeSO2-(D)Chg-Pro-NH-(5-am-4,6-(MeO)2-2-pyrim)甲基MeSO2-(D)Dpa-Pro-NH-(6-am)-3-picMeSO2-(D)Dpa-Pro-NH-(2-am-5-pyrim)甲基MeSO2-(D)Dpa(4,4′-MeO)-Pro-NH-(6-am)-3-picMeSO2-(D)Dpa(4,4′-Cl2)-Pro-NH-(6-am)-3-picMeSO2-(D,L)Phg(3,4-Cl2)-Pro-NH-(5-am)-2-picMeSO2-(D,L)Phg(3,4-Cl2)-Pro-NH-(5-am)-2-pyrim)甲基MeSO2-(D)Tbg-Pro-NH-(6-am-2-MeO)-3-picMeSO2-(D)Asp(OH)-Pro-NH-(2-am-4,6-Cl2-5-pyrim)甲基MeSO2-(D)Asp(OMe)-Pro-NH-(2-am-5-pyrim)甲基MeSO2-(D)Asp(OMe)-Pro-NH-(6-am-2-Me)-3-picMeSO2-(D)Asp(OtBu)-Pro-NH-(6-am)-3-picMeSO2-(D)Asp(OtBu)-Pro-NH-(5-am-2-pyrim)甲基MeSO2-(D)Phe-Aze-Pro-NH-(5-am)-2-picMeSO2-(D)Phe-Aze-Pro-NH-(2-am-4,6-(MeO)2-5-pyrim)甲基MeSO2-(D)Phe-Pip-Pro-NH-(6-am)-3-picMeSO2-(D)Phe-Pip-Pro-NH-(2-am-5-pyrim)甲基1-萘基-SO2-Gly-Pro-NH-(5-am-)2-pic1-萘基-SO2-Gly-Pro-NH-(6-am-2-Me)-3-picHOOC-(CH2)3-SO2-(D)Chg-Pro-NH-(6-am)-3-picHOOC-(CH2)3-SO2-(D)Chg-Pro-NH-(5-am)-2-picMeSO2-(D)Ser(t-Bu)-Pro-NH-(6-am)-3-picMeSO2-(D)Ser(t-Bu)-Pro-NH-(5-am)-2-picHO3S-(D)Chg-Pro-NH-(6-am)-3-picMeSO2-TMSiA-Pro-NH-(6-am)-3-pic作为优选提及下述物质:l. MeSO2-(D)-(4-甲氧基)Phe-Pro-NH-(2-MeO)-4-amb2. MeSO2-(D)-Chg-Pro-NH-4-amb(Me)3. MeSO2-(D)-Cha-Pro-NH-(2-MeO)-4-amb4. MeSO2-(D,L)-Dpa-Pro-NH-(2-MeO)-4-amb5. MeSO2-(D)-Phe-Pro-NH-(6-am)-3-pic6. MeSO2-(D)-Chg-Pro-NH-(6-am)-3-pic7. MeSO2-(D)-Chg-Pro-NH-(5-am)-2-pic8. MeSO2-(D)-Cha-Pyr-NH-(6-am)-3-pic9. MeSO2-(D)-Chg-Pyr-NH-(6-am)-3-pic10. HOOC-CH2-SO2-(D)-Cha-Pro-NH-(6-am)-3-pic
缩写表AIBN: 偶氮二异丁腈(Azobisisobutyrodintril)am: 脒基Ala: 丙氨酸4-amb: 4-脒基苄基Asp: 天冬氨酸Aze: 氮杂环丁烷羧酸Boc: 叔丁氧羰基Bz: 苄基Cbz: 苄氧羰基Cha: 环己基丙氨酸Chg: 环己基甘氨酸Cog: 环辛基甘氨酸Cpa: 环戊基丙氨酸(Cyclo)Leu: 1-氨基环己烷羧酸DCM: -氯甲烷Gly: 甘氨酸Hyp: 羟基脯氨酸2-Ind: 2-氢吲哚羧酸Leu: 亮氨酸napme: 萘基甲基NBS: N-溴丁二酰亚胺Ph: 苯基Phe: 苯基丙氨酸2-Phi: 2-全氢吲哚羧酸pic: 皮考基Pip: 2-哌啶酸Pro: 脯氨酸Pyr: 3,4-二氢吡咯-2-羧酸pyrim: 嘧啶基pyraz: 吡嗪基Tbg: 叔丁基甘氨酸1-Tic: 1-四氢异喹啉羧酸3-Tic: 3-四氢异喹啉羧酸TMSiA: 三甲硅烷基丙氨酸4-amb(R13)的结构是
此外,本发明涉及式VII、VIII、IX和X化合物:R1-SO2-A-B-NH-D-CN IX其中R1、A、B和D具有所述含义,且其中在式VIII和在式I的脒官能团可以是单-或双保护的形式。该中间体是新的,用于制备式I化合物并且是合成丝氨酸蛋白酶抑制剂的有价值的结构单元。
式I化合物可以其本身或它们与生理学可接受的酸的盐的形式存在;这样的酸的实例为:盐酸、柠檬酸、酒石酸、乳酸、磷酸、甲磺酸、乙酸、甲酸、马来酸、富马酸、马来酸、琥珀酸、羟基琥珀酸、硫酸、戊二酸、天冬氨酸、丙酮酸、苯甲酸、葡糖醛酸、草酸、抗坏血酸和N-乙酰甘氨酸。
式I化合物的脒官能团可以是被氨基保护基单-或双保护的;Cbz和BOC基团是特别合适的保护基,这同样适用于化合物VIII中的脒官能团。
或者,被保护的氨基酸P-A-OH与H-B-OR17可偶合得到二肽P-A-B-OR17,并且接着在反应顺序任意的情况下,在消去P后与R1SO2Cl反应,或在消去R17后与式VII或VIII反应。
R1-SO2-A-OH也可直接与H-B-NH-D-R18偶合得到终产物I或中间体VII或IX。
如果在上述反应流程中,含脒中间体以被保护的形式使用,则在最后阶段消去保护基。
如果R18是酰胺,可在联接得到
P-A-B-NH-CH2-D-CONH2
或R1-SO2-A-B-NH-CH2-D-CONH2后转化为腈并由此进一步转化为脒。
所需偶合反应在肽化学的标准条件下进行(见M. Bodansky,A.Bodansky“肽合成的实践(The Practice of PeptideSynthesis)”,Springer Verlag,(1084〔sic〕)。
Boc保护基的消去是用HCl/二噁烷或CF3COOH/二氯甲烷,和Cbz保护基的消去是用氢解或HF;酯官能团是在例如甲醇或乙醇的醇溶剂中用NaOH或LiOH水解;叔丁酯用酸(例如CF3COOH)水解。
在有机碱(例如三乙胺、吡啶或N,N-二异丙基乙胺)存在下,与磺酰氯R1-SO2Cl的反应在有机溶剂(例如CH2Cl2、THF或DMF)中进行;当有游离羧基时,该反应在碱金属氢氧化物或碳酸盐的水溶液存在下进行。
从腈前体制备脒是通过经典Pinner合成(R. Roger and D. G.Neilson,Chem. Rev. 61(1961)179)或尤其是通过以亚氨酸硫酯盐为中间体的改进的Pinner合成(H. Vieweg等人,Pharmazie 39(1984)226)进行的;在醇溶剂中,阮内镍或Pd/C存在下,通过在氰基上羟胺加成而得到的N-羟基脒的催化氢化同样生成脒(B. J. Broughton等人,J. Med.Chem. 18(1975)1117)。
该新化合物可用于凝血酶依赖性血栓栓塞疾病(例如深度静脉血栓形成、肺栓塞、心肌或大脑梗塞和不稳定心绞痛)的治疗和预防,也用于播散性血管内凝血(DIC)的治疗和预防;它们还适于与溶血栓剂(例如链激酶、尿激酶、prourokinase、t-PA、APSAC和其它纤维蛋白溶酶原活化剂)结合治疗以缩短再灌注时间和延长再闭塞时间。
此外,该化合物的用途是防止经皮的透照(transluminal)冠状血管成形术后的凝血酶依赖性的早期再闭塞和晚期再狭窄,防止凝血酶诱导的平滑肌细胞增生,防止活性凝血酶在CNS的累积(例如在阿尔咨海默病中),控制肿瘤和防止导致肿瘤细胞粘连和转移的机制。
它们的优点尤其是甚至在口服给药后也有效。
按照本发明的化合物可以常规的途径口服或肠胃外(皮下、静脉内、肌内、腹膜内、直肠)给药;还可通过鼻咽腔用蒸汽或喷雾给药。
剂量取决于患者的年龄、状态和体重以及给药的方式;通常,每人每天活性成份的剂量是口服给药约10-2000mg和肠胃外给药约1-200mg;该剂量可以2至4个单个剂量或以一天的累积形式一次性给药。
该新化合物可以常规的固体或液体剂型使用,例如作为未包衣或包衣片剂、胶囊、粉剂、粒剂、丸剂、栓剂、溶液、膏剂、霜剂或喷雾剂;它们以常规方法制备。为此目的活性成份可与常规的药用助剂(例如片剂粘合剂、填充剂、防腐剂、片剂崩解剂、流动调节剂、成形剂、润湿剂、分散剂、乳化剂、溶剂、缓释剂、抗氧化剂和/或推进气体)(参见H. Sucker等人:Pharmazeutische Technologie,Thieme-Verlag,Stuttgart,1978)一起加工;以此方式得到的剂型通常含有以重量计0.1至99%的量的活性成份。
实施例1:N-甲基磺酰基-(D)-苯基丙氨酰-脯氨酸2-甲氧基-4-脒基苄基酰胺乙酸盐(a)3-硝基-4-甲基苄腈
-10℃,在90分钟的过程内,将399g(2.56mol)4-甲基苄腈加入1升发烟硝酸;在加入1小时后,将该混合物倒入2.5升冰水,随后沉淀出固体,接着将其在吸滤漏斗上分离出并用水洗至中性pH;产量为
363g(88%).1H-NMR(CDCl3;δin ppm):8,3(d,1H);7,8(dd,1H);7,5(dd,1H);2,7(s,3H)(b)3-氨基-4-甲基苄腈
在室温下,将120g 3-硝基-4-甲基苄腈悬浮于1.2升EtOH中,并在7gPd/C(10%)存在下,用50升氢气来氢化;除去催化剂后,除掉溶剂;得到95g纯产物(97%)。1H-NMR(DMSO-d6;δin ppm):7,1(dd,1H);6,90(d,1H); 6,85(dd,1H);5,35(s,2H,NH2);2,15(s,3H)(c)3-羟基-4-甲基苄腈
0-5℃,在0.5小时的过程内,将49.2g(0.72mol)NaNO2在217ml水中的溶液滴加入85g(0.72mol)3-氨基-4-甲基苄腈在1.8升6N HCI的溶液中;接着,将该混合物在0-5℃再搅拌30分钟后,继而在沸点搅拌1小时;冷却溶液后,将产物用乙酸乙酯萃取,并由此用冰冷却的5N NaOH以酚盐的形式萃取;然后,用6N HCL酸化水相至pH为3,并用乙酸乙酯萃取产物,得到41g(43%)。1H-NMR(DMSO-d6;δinppm):10,3(s,OH);7,25(dd,1H);7,15(d,1H);7,1(dd,1H);2,20(s,3H)(d)3-甲氧基-4-甲基苄腈
将溶于30ml DMF的15g(0.11mol)3-羟基-4-甲基苄腈滴加入0.11mol NaH在30mlMf中的悬浮液中,并搅拌该混合物直至观察不到有H2放出;接着,滴加10.6ml(0.17mol)甲基碘后,在室温搅拌混合物1小时;将溶液倒入冰水,并用***/乙酸乙酯7∶1萃取产物;除掉溶剂后,产物开始缓慢结晶,得到14.8g(89%)。
1H-NMR(CDCl3;δin ppm):7,2(m,2H);
7,02(s,1H);3,85(s,3H);2,25(s,3H).(e)4-溴甲基-3-甲氧基苄腈
将14.7g(0.1mol)3-甲氧基-4-甲基苄腈溶于210ml1,2-二氯乙烷后,在82℃催化剂量的偶氮二异丁腈存在下,用19.1g(0.11mol)NBS在1小时的过程内分批溴化;加料结束后,在82℃再搅拌30分钟;加入正庚烷后,除去沉淀出的琥珀酰亚胺,并除掉溶剂;产量为18.5(82%)。1H-NMR(DMSO-d6;δin ppm):7,60(dd,1H);7,50(d,1H);7,40(dd,1H);4,68(s,2H);3,96(s,3H)(f)4-邻苯二甲酰亚氨基甲基-3-甲氧基苄腈
将24.4g(108mol)4-溴甲基-3-甲氧基苄腈溶于125ml DMF,和20.0g邻苯二甲酰亚胺钾-起在室温下搅拌24小时后,接着在50℃搅拌1小时;将该混合物倒入水中,由此沉淀出固体的产物,得到21.5g(68%)。1H-NMR(DMSO-d6;δinppm):7,9(m,4H);7,5(d,1H);7,35-7,25(m,2H);7,78(s,2H);3,92(s,3H)(g)4-氨基甲基-3-甲氧基苄腈
将10.6ml水合肼加入21.2g(73mmol)4-邻苯二甲酰亚氨基甲基-3-甲氧基苄腈在290ml THF中的溶液中,在室温搅拌该混合物20小时;然后,滴加180ml 2NHCl,并在1.5小时后,完全除掉溶剂;将剩余物吸收在MTBE中,用1N HCl萃取,而后,用2H NaOH将pH调为9-10后,再用二氯甲烷萃取;得到8.0g(68%)产物。1H-NMR(DMSO-d6;δin ppm):7,55(dd,1H);7,40(dd,1H;7,37(d,1H);3,85(s,3H);3,70(s,2H);2,5-1,6(NH2).(h)Boc-脯氨酸4-氰基-2-甲氧基苄基酰胺
将16.0g Boc-脯氨酸(50mmol)溶于80ml THF,在0℃与5.7g羟基琥珀酰亚胺和10.2gDCC在二氯甲烷中的溶液一起搅拌30分钟;接着,在0℃滴加8.0g(50mmol)4-氨基甲基-3-甲氧基苄腈在50mlTHF中的溶液,并在室温搅拌该混合物20小时;滤除固体,将滤液与等体积的乙酸乙酯混合后,用冷却的5%浓度NaHSO4溶液和饱和NaCl溶液洗涤;得到11.5g(65%)产物。1H-NMR(DMSO-d6;δin ppm):8,38(m,NH);7,50-7,35(m,3H);4,40-4,05(m,3H,N-CH2-Ar/N-CH-CO);3,87(s,OCH3);3,50-3,25(m,2H,N-CH2);2,2,5-2,00(m,1H);1,90-1,65(m,3H);1,40 und 1,30(2s;9H)(i)脯氨酸2-甲氧基-4-氰基苄基酰胺
将11.4g(31.7mmol)Boc-脯氨酸2-甲氧基-4-氰基苄基酰胺溶于130ml二氯甲烷,并在0-5℃用HCI饱和;2小时后Boc基被完全消去;减压除去溶剂,且该产物无需进一步纯化就用于下一反应。
1H-NMR(DMSO-d6;δin ppm):10,25(s,1H);8,60(s,1H);7,50(d,1H;7,42(dd,1H);7,39(d,1H);4,40-4,20(m,3H);3,88(s,3H);3,20(m,2H);2,35(m,1H);2,00-1,80(m,3H)(j)Boc-(D)-4-甲氧基苯基丙氨酰脯氨酸2-甲氧基-4-氰基苄基酰胺
在-5℃,将1.55g(5.25mmol)Boc-(D)-Phe-(4-OMe) -OH,3.9ml二异丙基乙胺和1.55g(5.25mmol)脯氨酸2-甲氧基-4-氰基苄基酰胺盐酸盐与4.4ml(5.9mmol)丙膦酸酐(50%浓度在乙酸乙酯中的溶液)在35ml二氯甲烷中混合,并于0℃搅拌1小时;将反应混合物连续用1N NaOH、1N HCl和饱和盐水洗涤,用Na2SO4干燥;除掉溶剂而留下2.4g固体。1H-NMR(DMSO-d6;δin ppm):8,72和7,87(t,2H);7,42(1H;7,35(m,3H);7,15(d,2H);6,85(d,2H);7,00+6,70(2d)1H;4,40-4,10(m,4H);3,85(s,3H;3,70(s,3H);3,05-2,55(m,4H);1,95-1,55(m,4H);1,2(s,9H)(k)(D)-4-甲氧基苯基丙氨酰脯氨酸2-甲氧基-4-脒基苄基酰胺二盐酸盐
以已知方法(DE4121947)通过硫代酰胺阶段将腈转化为脒;由腈起始,得到2-2g硫代酰胺。
1H-NMR(DMSO-d6;δin ppm):9,85(s,1H);9,45(s,1H);8,65/7,85(2t,1H);7,55-6,65(m,7H,Ar-H);4,40.4,10(m,4H);3,86/3,85(2s,3H);3,71/3,70(2s,3H);3,05-2,60(m,4H);2,10-1,55(m,4H);1,35-1,10(s,9H)
由2.2g硫代酰胺起始,并在与甲基碘和氨的甲醇溶液反应和在硅胶柱通过色谱(流动相:DCM/MeOH9∶1)纯化后,得到1.7g作为氢碘化物的脒。1H-NMR(DMSO-d6;δin ppm):9,28(s,2H);8,87(s,2H);8,75/7,95(st,1H);7,40-6,65(m,7H,Ar-H);4,45-4,10(m,4H);3,90(s,3H);3,70(s,3H);3,7-3,4/3,0-2,6(m,4H);1,95-1,55(m,4H);1,30/1,22(2s,9H).
经IRA420离子交换剂,脒氢碘化物转化为脒盐酸盐,接着,将其溶于50ml二氯甲烷并在0-5℃用HCI饱和;搅拌1小时后,除掉溶剂,得到1.0g作为二盐酸盐的脒。FAB-MS(M+)=4531H-NMR(DMSO-d6,δin ppm):9,50(5(宽),2H),9,25(s(宽),2H),8,85-8,65(宽信号,3H);7,40(s,1H),7,35(d,1H),7,30(d,1H),7,15(d,2H),6,90(d,2H),4,35-4,10(m,4H),3,85(s,3H),3,75(s,3H),3,75-3,55(m,2H),3,20-2,80(m,2H),1,90-1,40(m,4H)(1)N-甲磺酰基-(D)-(4-甲氧基)苯基丙氨酰脯氨酸2-甲氧基-4-脒基苄基酰胺乙酸盐
在0℃,将0.23g(2mmol)甲磺酰氯加入0.9g(2mmol)上述脒盐酸盐在20ml吡啶中的溶液中,并将该混合物在室温下搅拌过夜;蒸除溶剂后,将剩余物通过柱色谱(洗脱剂CH2Cl2)甲醇/50%浓度乙酸,45/5/1.5)纯化;蒸馏纯馏份的洗脱液,且接近结束时加入甲苯;冷冻干燥剩余物,得到白色无定形粉末状的乙酸盐0.5g。FAB-MS:531(M+)。实施例2N-甲磺酰基-(D)-苯基丙氨酰脯氨酸(α-甲基-4-脒基)苄基酰胺(a)二苯甲酮N-(对-氰基苄基)亚胺
将270g(2.0mol)无水K2CO3加入150g(0.8mol)97%二苯甲酮亚胺和144.8g(0.74mol)对氰基苄基溴化物在450ml乙腈中的溶液中,并在室温搅拌该混合物6小时;吸滤除去无机盐,然后通过蒸馏以基本上除去溶剂,在剩余物中加入300ml水,并用乙酸乙酯萃取该混合物数次;将有机相用水洗2次后,用Na2SO4干燥并蒸发至干;用***浸提而生成180g白色晶体,熔点101-102℃。(b)1-(4-氰基苯基)乙胺
在-70℃,将20.7g(0.07mol)二苯甲酮N-(对-氰基苄基)亚胺滴加入二异丙基氨化锂(由8.15g(0.08mol)二异丙胺和48.3ml(0.08mol)15%浓度丁基锂的己烷溶液制备)在100ml无水四氢呋喃中的溶液中,并搅拌该混合物15分钟;接着,滴加9.94g(0.07mol)甲基碘,并将混合物的温度升至室温;加入100ml水并用***萃取数次后,将***相用5%浓度柠檬酸溶液、5%浓度NaHCO3溶液和水洗后,用Na2SO4干燥,再蒸除***;将剩余物溶于150ml四氢呋喃,加入100ml 1N HCl,在室温下搅拌混合物过夜;从反应混合物中减压蒸除四氢呋喃后,用***数次萃取剩下的酸相以除去二苯甲酮,接着,在用冰冷却时用K2CO3水溶液将酸相变碱性,并用二氯甲烷萃取该油状碱;用K2CO3干燥萃取液,在除掉二氯甲烷后,剩下9.7g(95%)淡黄色油,且该产物无需进一步纯化就用于下一反应。(c)Boc-(D)-苯基丙氨酰脯氨酸(α-甲基-4-氰基)苄基酰胺
在-5℃,将16.2g二异丙胺和22ml(30mmol)丙膦酸酐(50%浓度在乙酸乙酯中的溶液)滴加入3.65g(25mmol)1-(4-氰基苯基)乙胺和9.1g(25mmol)Boc-D-Phe-Pro-OH在150ml二氯甲烷中的溶液中;接着,在温度从-5℃升至20℃期间,搅拌该混合物2小时;将有机相用水、5%浓度碳酸氢钠溶液和5%浓度柠檬酸溶液洗后,用Na2SO4干燥并蒸发至干;得到淡黄色的晶状剩余物且无需进一步纯化就用于下一反应。(d)(D)-苯基丙氨酰脯氨酸(α-甲基-4-脒基)苄基酰胺二盐酸盐
将4.1g上述化合物和4ml三乙胺溶于40ml吡啶,在0℃用H2S饱和,并在室温下静置过夜;TLC检验(CH2Cl2/MeOH,9/1)显示向硫代酰胺的转化已完全;为了分离,减压蒸馏以基本上除去吡啶,且将剩余物吸收在250ml乙酸乙酯中和用盐水、5%浓度的柠檬酸溶液和NaHCO3溶液洗涤;干燥和通过蒸馏除去溶剂而得到4.1g纯晶状的硫代酰胺。
将该硫代酰胺溶于150ml丙酮,并在加入7ml甲基碘后,在室温下静置6小时;将除掉溶剂后的无定形剩余物通过与干燥***一起搅拌来萃取,然后干燥;将S-甲基-硫代亚氨酸甲酯氢碘化物溶于50ml乙醇后,加入15ml 10%浓度乙酸铵溶液,并将混合物在60℃加热3小时;为了分离,除掉溶剂,将剩余物溶于100ml CH2Cl2,滤除不溶物,然后蒸除CH2Cl2;用乙酸乙酯/二***混合物进行浸提以除去其中可溶性的杂质;将剩下的碘化物/乙酸盐混合盐溶于丙酮/水(3/2)并使用IRA乙酸盐离子交换转化为纯的乙酸盐;而后冷冻干燥;分离出白色粉末,熔点为110-115℃。
将上述化合物溶于70ml CH2Cl2,并加入80mlHCl-饱和的乙酸乙酯;短时间后分离出沉淀并通过加入***达到完全;吸滤出沉淀,用***洗至不含HCI并减压干燥;得到白色晶体,熔点为190-195℃,FAB-MS:407(M+)。(e)N-甲磺酰基-(D)-苯基丙氨酰脯氨酸(α-甲基-4-脒基)苄基酰胺乙酸盐
类似实施例1e得到白色无定形粉末状的标题化合物;FAB-MS:485(M+)。实施例3N-甲磺酰基-(D)-环己基丙氨酰脯氨酸(2-甲氧基-4-脒基)苄基酰胺
将1.70g(6.26mmol)Boc-(D)-Cha-OH与1.85g(6.26mmol)脯氨酸(2-甲氧基-4-氰基)苄基酰胺盐酸盐(实施例1i)如在实施例1j中一样缩合,得到2.7g Boc-(D)-Cha-Pro(2-MeO-4-CN)苄基酰胺,继而在DCM中用HCl气消去Boc保护基;在0℃,2.0g(4.45mmol)H-(D)-Cha-Pro(2-MeO-4-CN)苄基酰胺盐酸盐在40ml DCM和8.9mmol二异丙基乙胺中与0.7ml甲磺酰氯反应,得到2.0g相应的磺酰胺;以已知方法(DE4121947)通过硫代酰胺阶段将腈转化为脒;将脒的氢碘化物转换为脒的水合乙酸盐(hydroacetate)(见实施例4b)后生成0.8gMe-SO2-(D)-Cha-Pro(2-甲氧基-4-脒基)苄基酰胺,并如实施例11所述用柱色谱纯化。FAB-MS:(M+H)+=496。实施例4N-甲磺酰基-(D,L)-二苯基丙氨酰脯氨酸(2-甲氧基-4-脒基)苄基酰胺(a)Boc-(D,L)-Dpa-Pro(2-MeO-4-CN)苄基酰胺
将6.0g(17.6mmol)Boc-(D,L)-Dpa-OH与5.2g(17.6mmol)H-Pro(2-MeO-4-CN)苄基酰胺盐酸盐如实施例1j所述反应,并继而在硅胶上通过柱色谱(流动相:DCM/4.5%MeOH)纯化,得到5.6g产物。1H-NMR(DMSO-d6;δin ppm):8,45 und 7,95(1H,NH,(2非对映体或几何异物体)),7,5-6,9(14H),5,35-4,95(m,1H),4,5-4,1(3H),4,0-3,0(3H),3,90 und 3,85(s,3H)(2非对映体)),2,1-1,1(13H)(b)Me-SO2-(D,L)-Dpa-Pro(2-MeO-4-脒基)苄基酰胺
将3.55g(6.0mmol)Boc-保护的化合物(实施例4a)在30ml DCM中用HCl气裂开,得到3.1gH-(D,L)-Dpa-Pro(2-MeO-4-CN)苄基酰胺盐酸盐;并在0℃,将1.5g(2,9mmol)该盐酸盐在30ml DCM和1.1ml二异丙基乙胺中与0.24ml甲磺酰氯一起搅拌2小时;将有机相用0.5N HCl、水和饱和NaCl溶液洗后接着干燥;并在硅胶上通过柱色谱(流动相:DCM/5%MeOH)纯化产物;得到1.15g Me-SO2-(D,L)-Dpa-Pro(2-MeO-4-CN)苄基酰胺;以已知方法(DE4121947)通过硫代酰胺阶段将1.15g(2.1mmol)该腈转化为脒;得到1.3g硫代酰胺和0.95g脒氢碘化物;将其在离子交换树剂(IRA420)上转化为脒水合乙酸盐;得到0.77gMe-SO2-(D,L)-Dpa-Pro(2-MeO-4-脒基)苄基酰胺水合乙酸盐(HPLC纯度95%)。FAB-MS:(M +H)+=578。实施例5N-甲磺酰基-(D)-苯基丙氨酰脯氨酸(6-脒基)-3-皮考基酰胺乙酸盐(a)2-氰基-5-(叠氮基甲基)吡啶
室温下,将溶于20ml二氯甲烷的14.5g(0.07mol)三氟乙酸酐滴加入8.8g(0.07mol)2-氰基-5-(羟甲基)吡啶(WO83/01446)和6.9g三乙胺在200ml二氯甲烷中的溶液中,并将该混合物搅拌2小时;通过蒸馏除去二氯甲烷后,将剩余物溶于50ml甲苯和50ml二甲亚砜的混合物中,加入11.2g(0.17mol)叠氮化钠和0.7g溴化四丁铵后,在室温下搅拌该混合物过夜。
将反应混合物倒入300ml水和用***萃取数次;用Na2SO4干燥和通过蒸馏除去***后,剩下6.8g淡黄色晶体且无需进一步纯化而用于下一反应。(b)2-氰基-5-(氨基甲基)吡啶
将(a)中所得化合物溶于45ml四氢呋喃和1.2ml水中,边搅拌,边分批加入11.2g三苯膦;在室温下,静置反应混合物过夜;通过蒸馏除去溶剂后,将剩余物吸收在100ml***中,通过吸滤除去沉淀出的氧化三苯膦,并用盐酸***溶液将滤液的pH调到2;将沉淀出的盐酸盐吸滤出,用***洗后先后用甲苯和热的异丙醇浸提;分离出4.7g(40%)盐酸盐,熔点为253-256℃(分解)。(c)Boc-(D)-苯基丙氨酰脯氨酸(6-氰基)-3-皮考基酰胺
在-5℃,将8.12g二异丙基乙胺,继而11ml(15mmol)丙膦酸酐(50%浓度在乙酸乙酯中的溶液)滴加入2.11g(12.5mmol)2-氰基-5-(氨基甲基)吡啶和4.5g(12.5mmol)Boc-D-Phe-Pro-OH在70mlCH2Cl2中的溶液中;接着,随着温度从-5℃升至20℃,搅拌混合物2小时;将有机相用水、5%浓度碳酸氢钠溶液和5%浓度柠檬酸溶液洗后,用Na2SO4干燥并蒸发至干;得到淡黄色晶状剩余物,熔点:167-170℃,且无需进一步纯化而用于下一反应。(d)N-甲磺酰基-(D)-苯基丙氨酰脯氨酸(6-脒基)-3-皮考基酰胺乙酸盐
将上述化合物溶于100ml异丙醇,加入2.3gHCl在20ml异丙醇中的溶液后,在50℃加热5小时,这期间分离出脱保护化合物的盐酸盐;将其吸滤出并用冷异丙醇洗至无HCl。
将2.5g(6.5mmol)上述盐酸盐悬浮于50m CH2Cl2;通过加入1.35g(13.5mmol)三乙胺生成溶液,在0至5℃,向该溶液中滴加0.7g(6.1mmol)甲磺酰氯在10mlCH2Cl2中的溶液;在室温下搅拌反应混合物5小时,接着通过与水、5%浓度柠檬酸溶液和5%浓度碳酸氢钠溶液一起摇动来萃取;用Na2SO4干燥和蒸除溶剂后,从乙酸乙酯/***混合物(1∶1)中重结晶粘性的油状剩余物。
将4.1g上述化合物和4ml三乙胺溶于40ml吡啶,在0℃用H2S饱和,并在室温下静置过夜;TLC检验(CH2Cl2/MeOH,9/1)显示向硫代酰胺的转化已完全;为了分离,减压蒸馏以基本上除去吡啶,且将剩余物吸收在250ml乙酸乙酯中和用盐水、5%浓度柠檬酸溶液和NaHCO3溶液洗涤;干燥和通过蒸馏除去溶剂而得到4.1g纯的晶状的硫代酰胺。
将该硫代酰胺溶于150ml丙酮,并在加入7ml甲基碘后,在室温下静置6小时;除掉溶剂后,无定形剩余物通过与干燥***一起搅拌来萃取,然后干燥;将S-甲基硫代亚氨酸甲酯氢碘化物溶于50ml乙醇后,加入15ml10%浓度乙酸铵溶液,并将混合物在60℃加热3小时;为了分离,除掉溶剂,将剩余物溶于100ml CH2Cl2,滤除不溶物,然后蒸除CH2Cl2;用乙酸乙酯/二***混合物进行浸提以除去其中可溶性的杂质;将剩下的碘化物/乙酸盐混合盐溶于丙酮/水(3/2)并使用IRA乙酸盐离子交换剂转化为纯的乙酸盐;而后冷冻干燥;分离出白色无定形粉末,熔点为128-137℃,FAB-MS:473(M+H)+。实施例6N-甲磺酰基-(D)-环己基甘氨酰脯氨酸(6-脒基)-3-皮考基酰胺乙酸盐(a)Boc-(D)-环己基甘氨酰脯氨酸
将29g(0.113mol)Boc-(D)-环己基甘氨酸和18.7g(0.113mol)脯氨酸甲酯盐酸盐悬浮于300ml CH2Cl2中,并通过滴加58.3g(0.45mol)二异丙基乙胺而溶解;冷却至-15℃后,滴加113ml(0.147mol)丙膦酸酐(50%浓度在乙酸乙酯中的溶液),并搅拌该混合物1小时;加入200ml水后,将有机相分离出并用K2CO3水溶液、0.5N盐酸和5%浓度碳酸氢钠溶液洗涤,用Na2SO4干燥后,蒸除溶剂,将油状剩余物(41g)溶于400ml乙醇后,加入120ml 1N NaOH,并在室温下搅拌混合物2小时。
蒸除醇后,将水相用水稀释,再用甲基叔丁基醚萃取数次;将该水相用KHSO4溶液酸化后,用CH2Cl2萃取3次;干燥和蒸除二氯甲烷后,从二异丙醚/正己烷(1/3)中结晶油状剩余物;分离出28g白色晶体,熔点为145-148℃。(b)Boc-(D)-环己基甘氨酰脯氨酸(6-氰基)-3-皮考基酰胺
将26.6g(0.075mol)Boc-(D)-环己基甘氨酰脯氨酸和12.7g(0.075mol)6-氰基-3-皮考基胺盐酸盐悬浮于300ml CH2Cl2中,并加入47g(0.364mol)二异丙基乙胺;接着,在-10℃滴加66ml丙膦酸酐(50%浓度在乙酸乙酯中的溶液)后,在0℃搅拌混合物1小时,再加入200ml水,并分离出CH2Cl2相;将有机相用0.1N氢氧化钠水溶液和水洗后,接着干燥,并蒸除溶剂;将剩余物吸收在100ml乙酸乙酯中,由此开始快速结晶并通过加入150ml正己烷而达到完全;吸滤和干燥后,分离出31.4g(理论值的89%)白色晶体,熔点为150-151℃。(c)N-甲磺酰基-(D)-环己基甘氨酰脯氨酸(6-脒基)-3-皮考基酰胺乙酸盐
如实施例5d所述,从上述Boc化合物中消去保护基,与甲磺酰氯进行反应,并将氰基转化为脒。以白色晶体形式分离出乙酸盐,熔点为250-256℃(分解),FAB-MS:465(M+H+)。实施例7N-甲磺酰基-(D)-环己基甘氨酰脯氨酸(5-脒基)-2-皮考基酰胺乙酸盐(a)5-甲酰氨基(carboxamido)-2-皮考基胺
将3g阮内镍加入3.5g(24mmol)2-氰基-5-甲酰氨基吡啶在80ml甲醇中的溶液和20ml浓氨水中,并在室温下进行氢化;约7小时后,氢的吸收完全。
浓缩通过吸滤除去催化剂后的滤液,并将剩余物溶于20ml2N盐酸和20ml甲醇中;加入150ml乙酸乙酯以分离出盐酸盐,将该盐酸盐吸滤并干燥(3.7g),游离碱的熔点为198-202℃。(b)5-氰基-2-皮考基胺
将41g(0.22mol)5-甲酰氨基-2-皮考基胺悬浮于150ml甲醇和300ml二氯甲烷中,冷却至10℃,并通过加入150ml三乙胺溶解;接着,滴加47.6g(0.22mol)(Boc)2O的溶液,并在室温搅拌混合物4小时。
将除掉溶剂的剩余物与饱和K2CO3溶液混合并用二氯甲烷萃取5次;将合并的萃取液干燥,并蒸除溶剂,且接近结束加入甲苯;将5.4g剩余物悬浮于40ml二噁烷和15ml二氯甲烷中,加入4.3g吡啶,接着,在0℃,滴加5.2g三氟乙酸酐,生成澄清溶液;加入100ml水后,用乙酸乙酯萃取,并用稀的柠檬酸、NaHCO3和水洗有机相;干燥和除掉溶剂后,剩下黄色油(约5g),将其溶于15ml异丙醇和30ml乙酸乙酯中,并加入35ml盐酸***溶液;静置过夜后,吸滤出沉淀出的盐酸盐后,干燥;分离出4g白色晶体;熔点为230-234℃。(c)Boc-(D)-环己基甘氨酰脯氨酸(5-氰基)-2-皮考基酰胺
如实施例6b所述,使Boc-(D)-环己基甘氨酸脯氨酸与5-氰基-2-皮考基胺偶合,生成白色晶体,熔点为128-129℃。(d)N-甲磺酰基-(D)-环己基甘氨酰脯氨酸(5-脒基)-2-皮考基酰胺乙酸盐
如实施例5d所述,从上述Boc化合物中消去保护基,与甲磺酰氯进行反应,并将氰基转化为脒。以白色晶体形式分离乙酸盐,熔点为149-150℃(分解),FAB-MS:465(M+H+)。实施例8N-甲磺酰基-(D)-环己基丙氨酰-3,4-脱氢脯氨酸(6-脒基)-3-皮考基酰胺乙酸盐(a)Boc-3,4-脱氢脯氨酸(6-甲酰氨基)-3-皮考基酰胺
将5.0gBoc-3,4-脱氢脯氨酸(23.4mmol)与5.25g 6-甲酰氨基-3-皮考基胺二盐酸盐和32.1ml二异丙基乙胺(187mmol)一起悬浮于50mlCH2Cl2中,并在0至5℃,边搅拌边滴加23.5ml丙膦酸酐(50%浓度在乙酸乙酯中的溶液);接着,在室温下搅拌该混合物过夜;将溶液用CH2Cl2稀释到150ml后,先后用20%浓度硫酸氢钠溶液和5%浓度柠檬酸溶液萃取,用硫酸钠干燥并在旋转蒸发器上浓缩;将水相用CH2Cl2反萃取三次,并将有机相干燥,在旋转蒸发器上浓缩并无需进一步纯化就与主产物一起用于下一反应。(b)H-3,4-脱氢脯氨酸(6-甲酰氨基)-3-皮考基酰胺盐酸盐
将来自(a)的粗产物溶于100ml CH2Cl2,并在加入10ml 5M HCl在***中溶液后,在室温下搅拌2小时(TLC检测);将减压完全蒸发至干和与甲苯减压共馏后的粗产物从200ml乙醇中重结晶;生成5.03g产物,通过浓缩母液后,进一步得到0.3g产物。(理论值的80.4%)。元素分析显示该产物为单盐酸盐形式。(c)Boc-(D)-环己基丙氨酰-3,4-脱氢脯氨酸(6-甲酰氨基)-3-皮考基酰胺
在75mlCH2Cl2中,将5.06gBoc-(D)-环己基丙氨酸(18.66mmol)与5.28g H-3,4-脱氢脯氨酸(6-甲酰氨基)-3-皮考基酰胺盐酸盐(18.66mmol)和9.55ml二异丙基乙胺(56mmol)一起搅拌,并在0至5℃,滴加18.6ml丙膦酸酐(50%浓度在乙酸乙酯中的溶液);接着,在室温下搅拌该混合物过夜,此期间析出沉淀;吸滤除去沉淀和每次用25m l5%浓度柠檬酸溶液萃取该溶液5次后(TLC显示在有机相中无二异丙基乙胺遗留),将有机相用饱和碳酸氢钠溶液洗数次,用硫酸钠干燥和减压浓缩;为减少丙膦酸副产物,将剩余物吸收在乙酸乙酯中,用饱和碳酸氢溶液萃取数次,并接着用硫酸钠干燥和在旋转蒸发器上浓缩。得到7.0g固化泡沫(理论值的75%)。(d)Boc-(D)-环己基丙氨酰-3,4-脱氢脯氨酸(6-氰基)-3-皮考基酰胺
将7.0g Boc-(D)-环己基丙氨酰-3,4-脱氢脯氨酸(6-甲酰氨基)-3-皮考基酰胺(14mmol)与9.5ml二异丙基乙胺(56mmol)一起溶于100ml二氯甲烷中,冷却到0至5℃后,滴加3.5ml三氟乙酸酐(25.2mmol);在室温下搅拌2小时后,原料完全被转化(TLC检测);接着,将溶液用20%浓度硫酸钠溶液萃取3次,用饱和碳酸氢钠溶液萃取3次和用饱和盐水萃取一次,在用硫酸钠干燥和在旋转蒸发器上浓缩;产量:6.6g(理论值的98%)。(e)制备H-(D)-环己基丙氨酰-3,4-脱氢脯氨酸(6-氰基)-3-皮考基酰胺
将6.6g Boc-(D)-环己基丙氨酰-3,4-脱氢脯氨酸(6-氰基)-3-皮考基酰胺(13.75mmol)溶于15ml异丙醇中,并在加入12.5ml 4N盐酸异丙醇溶液后,在40℃搅拌2小时(TLC检测);减压浓缩反应溶液,将剩余物吸收在水中,用***萃取该溶液三次,并用20%浓度氢氧化钠溶液将水相的pH调至9,且用CH2Cl2萃取数次;将有机相用饱和盐水洗后,用硫酸钠干燥和在旋转蒸发器上浓缩生成4.3g产物(理论值的82%)。(f)制备甲磺酰基-(D)-环己基丙氨酰-3,4-脱氢脯氨酸(6-氰基)-3-皮考基酰胺
如实施例5d所述,由H-(D)-环己基丙氨酰-3,4-脱氢脯氨酸(6-氰基)-3-皮考基酰胺和甲磺酰氯制备该化合物;产率:理论值的95%。(g)制备甲磺酰基-(D)-环己基丙氨酰-3,4-脱氢脯氨酸(6-脒基)-3-皮考基酰胺
如实施例5d所述,由甲磺酰基-(D)-环己基丙氨酰-3,4-脱氢脯氨酸(6-氰基-3-皮考基)酰胺经硫代酰胺和S-甲基硫代酰胺酸甲酯氢碘化物制备该化合物;分离出白色无定形粉末;FAB-MS:(M+H)+=477。实施例9N-甲磺酰基-(D)-环己基甘氨酰-3,4-脱氢脯氨酸(6-脒基)-3-皮考基酰胺乙酸盐
如实施例8所述制备该化合物;白色无定形粉末,FAB-MS:(M+H)+=463。实施例10N-(羟基羰基亚甲基)磺酰基-(D)-环己基甘氨酰脯氨酸(6-脒基)-3-皮考基酰胺
使H-(D)-环己基甘氨酰脯氨酸(6-氰基)-3-皮考基酰胺(实施例6b)和甲氧羰基亚甲基磺酰氯反应(在Tetrahedron Letters 30(1989),2869中公开制备方法)以合成相应的磺酰胺;以已知方法经硫代酰胺阶段将腈官能团转化为脒基(DE4121947)。
在80℃,将生成的N-(甲氧基羰基亚甲基)磺酰基-(D)-环己基甘氨酰脯氨酸(6-氰基)-3-皮考酰胺产物在4N盐酸和二噁烷的混合物中加热以水解酯官能团(TLC检验),并接着浓缩该溶液和将剩余物在RP柱上通过HPLC纯化,然后,冷冻干燥水相,得到无定形粉末;FAB-MS:(M+H)+=509。
Claims (4)
1、式I凝血酶抑制剂及其立体异构体和其与生理学可接受酸的盐,其中脒官能团可以单-或双保护的形式存在,且其中的取代基具有下述含义:R1:OH,C1-C20烷基,C1-C3氟代烷基,C3-C8环烷基,芳基-C1-C10烷基,芳基,杂芳基,R2OOC-(CH2)n或R3R2N,其中的R2和R3相同或不同并且是氢、C1-C10烷基,芳基,芳基-C1C10烷基或一起形成C2-C7亚烷基链,该亚烷基链可任选稠合上芳基或杂芳基或其中含有杂原子(O、S、NH或被取代的N),和n是1、2、3或4。A:式IIα-氨基酸残基
其中
R4是氢,C1-C8烷基C3-C7环烷基,芳基或芳基-C1-C3烷基;
R5是氢,C1-C8烷基,C3-C7环烷基或C3-C7环烷基-CH2-,其中的一个CH2可以被O、S、NR6替代,双环烷基-(CH2)0,1、金刚烷基-(CH2)0-1、(CH3)3Si-C1-C4烷基、芳基或芳基-C1-C3烷基、杂芳基或杂芳基-C1-C3烷基,如果R4=H,为C1-C8烷基,其中一个H被SR6、OR6、CO-OR6(R6=H、C1-C8烷基或芳基-C1-C3烷基)或CONR7R8(R7、R8相同或不同为H、C1-C4烷基、C3-C7环烷基或一起为C3-C6亚烷基链)替代;或
R4和R5一起形成含有稠和在上面的芳基的C2-C6亚烷基链;B:式III环α-氨基酸残基其中
m是2、3或4,并且环上的一个氢可被羟基或C1-C3烷基所取代,和当m是3或4时,环上的一个CH2可被氧、硫、NH或N-C1-C4烷基所取代和/或两个邻位的氢原子可被双键或稠和的芳族体系或带有4-6个碳原子的亚甲基链所取代;D:式IV、V或VI结构片段其中
R9是F,Cl,Br,NO2,R15O,R15OOC,R15OCH2,R15NH-CO,R15NH,R15CONH,或R15OOCCH2O,其中R15是H、C1-C6烷基、苄基或苯基,
R10,R11是H,C1-C4烷基或R15O,其中R9和R10或R11可一起形成稠和的亚苯基环或由3至5个碳原子组成的亚烷基链,其中的一或二个碳原子可被氧所取代;
R12是H或C1-C4烷基;
R13是C1-C4烷基,苯基-C1-C4烷基,R15CO,CF3CO,C2F5CO,R15OCH2,R15OOC,R15OCH2CO,R15OOCCO或R15NHCOCO;
R14是H,C1-C4烷基,F,Cl,Br,NO2,R15O,R15OOC,R15OCH2,R15CO,R15CONH,R15NH-CO或R15OOCCH2O;和
W、X、Y、Z是CH或N,但是,取代基W、X、Y或Z中至少有一个是N和在VI的环可被1或2个下述取代基所取代:C1-C4烷基、OH、O-C1-C4烷基,CF3、F、Cl、Br、S-C1-C4烷基、O(CH2)nCOOR6(n=1-4)。
3、含有式XI结构片段的化合物其中D如权利要求1中所定义。
4、如权利要求1所要求的式I凝血酶抑制剂在控制疾病方面的用途。
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DE1995104504 DE19504504A1 (de) | 1995-02-10 | 1995-02-10 | Heterocyclische Thrombininhibitoren |
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DE1995106610 DE19506610A1 (de) | 1995-02-24 | 1995-02-24 | Thrombininhibitoren |
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Families Citing this family (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9900043D0 (sv) * | 1999-01-11 | 1999-01-11 | Astra Ab | New use |
US5707966A (en) * | 1994-03-04 | 1998-01-13 | Eli Lilly And Company | Antithrombotic agents |
US5726159A (en) * | 1994-03-04 | 1998-03-10 | Eli Lilly And Company | Antithrombotic agents |
US5705487A (en) * | 1994-03-04 | 1998-01-06 | Eli Lilly And Company | Antithrombotic agents |
US5914319A (en) * | 1995-02-27 | 1999-06-22 | Eli Lilly And Company | Antithrombotic agents |
US5710130A (en) * | 1995-02-27 | 1998-01-20 | Eli Lilly And Company | Antithrombotic agents |
SE9602263D0 (sv) | 1996-06-07 | 1996-06-07 | Astra Ab | New amino acid derivatives |
US5863929A (en) | 1996-06-25 | 1999-01-26 | Eli Lilly And Company | Anticoagulant agents |
EP1110968B1 (en) * | 1996-06-25 | 2003-10-01 | Eli Lilly & Company | Intermediate for the preparation of Thrombininhibitors as anticoagulant agents |
US6200967B1 (en) | 1996-06-25 | 2001-03-13 | Eli Lilly And Company | Anticoagulant agents |
US6369080B2 (en) | 1996-10-11 | 2002-04-09 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6194435B1 (en) | 1996-10-11 | 2001-02-27 | Cor Therapeutics, Inc. | Lactams as selective factor Xa inhibitors |
US6262047B1 (en) | 1996-10-11 | 2001-07-17 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6063794A (en) | 1996-10-11 | 2000-05-16 | Cor Therapeutics Inc. | Selective factor Xa inhibitors |
AU6896298A (en) | 1997-04-14 | 1998-11-11 | Cor Therapeutics, Inc. | Selective factor xa inhibitors |
WO1998046628A1 (en) * | 1997-04-14 | 1998-10-22 | Cor Therapeutics, Inc. | SELECTIVE FACTOR Xa INHIBITORS |
WO1998046627A1 (en) | 1997-04-14 | 1998-10-22 | Cor Therapeutics, Inc. | SELECTIVE FACTOR Xa INHIBITORS |
US7109326B2 (en) | 1997-04-15 | 2006-09-19 | Genentech, Inc. | Halo-alkoxycarbonyl prodrugs |
AR013084A1 (es) | 1997-06-19 | 2000-12-13 | Astrazeneca Ab | Derivados de amidino utiles como inhibidores de la trombina, composicion farmaceutica, utilizacion de dichos compuestos para la preparacion demedicamentos y proceso para la preparacion de los compuestos mencionados |
US6228854B1 (en) | 1997-08-11 | 2001-05-08 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6218382B1 (en) | 1997-08-11 | 2001-04-17 | Cor Therapeutics, Inc | Selective factor Xa inhibitors |
US6333321B1 (en) | 1997-08-11 | 2001-12-25 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
SE9704543D0 (sv) | 1997-12-05 | 1997-12-05 | Astra Ab | New compounds |
KR20000047461A (ko) | 1998-12-29 | 2000-07-25 | 성재갑 | 트롬빈 억제제 |
US6486193B2 (en) | 1998-12-31 | 2002-11-26 | Aventis Pharmaceuticals Inc. | 3-substituted pyrrolidines useful as inhibitors of matrix metalloproteinases |
TR200102913T2 (tr) | 1999-04-09 | 2002-01-21 | Basf Aktiengesellschaft | Tam proteazların düşük moleküler ağırlıklı inhibitörleri. |
CA2387002A1 (en) * | 2000-08-11 | 2002-02-21 | Corvas International, Inc. | Non-covalent inhibitors of urokinase and blood vessel formation |
ES2285989T3 (es) | 2000-08-11 | 2007-12-01 | Wilex Ag | Inhibidores no covalentes de la uroquinasa y de la formacion de vasos sanguineos. |
DE10049937A1 (de) * | 2000-10-06 | 2002-04-11 | Knoll Ag | Niedermolekulare Inhibitoren von Serinproteasen mit Polyhydroxyalkyl- und Polyhydroxycycloalkylresten |
US6716869B2 (en) * | 2001-12-17 | 2004-04-06 | Pharmacia Corporation | Protease inhibitors of the coagulation cascade isolated from Dysidea sponges |
WO2003070229A2 (de) * | 2002-02-22 | 2003-08-28 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Verwendung von proteinaseinhibitoren zur behandlung von autoimmunerkrankungen |
DE102004022897A1 (de) * | 2004-05-10 | 2005-12-08 | Bayer Cropscience Ag | Azinyl-imidazoazine |
DE102008041214A1 (de) | 2008-08-13 | 2010-02-18 | Bayer Cropscience Ag | N-substituierte Azinylakyl-azincarboxamide und deren Analoge |
US10597863B2 (en) | 2018-01-19 | 2020-03-24 | Resource Fiber LLC | Laminated bamboo platform and concrete composite slab system |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU675981B2 (en) * | 1992-12-02 | 1997-02-27 | Bristol-Myers Squibb Company | Guanidinyl-substituted heterocyclic thrombin inhibitors |
SE9301916D0 (sv) * | 1993-06-03 | 1993-06-03 | Ab Astra | New peptides derivatives |
AU1025795A (en) * | 1994-01-27 | 1995-08-03 | Mitsubishi Chemical Corporation | Prolineamide derivatives |
ZA951617B (en) * | 1994-03-04 | 1997-02-27 | Lilly Co Eli | Antithrombotic agents. |
-
1996
- 1996-02-06 KR KR1019970705507A patent/KR19980702112A/ko not_active Application Discontinuation
- 1996-02-06 AU AU47875/96A patent/AU706834B2/en not_active Ceased
- 1996-02-06 HU HU9800634A patent/HUP9800634A3/hu unknown
- 1996-02-06 BR BR9607412A patent/BR9607412A/pt not_active Application Discontinuation
- 1996-02-06 JP JP8523967A patent/JPH10513462A/ja not_active Abandoned
- 1996-02-06 CZ CZ972376A patent/CZ237697A3/cs unknown
- 1996-02-06 EA EA199700155A patent/EA002767B1/ru not_active IP Right Cessation
- 1996-02-06 WO PCT/EP1996/000472 patent/WO1996024609A1/de not_active Application Discontinuation
- 1996-02-06 EP EP96903987A patent/EP0809651A1/de not_active Withdrawn
- 1996-02-06 CN CN96191860A patent/CN1173872A/zh active Pending
- 1996-02-06 MX MX9705970A patent/MX9705970A/es unknown
- 1996-02-06 CA CA002210989A patent/CA2210989A1/en not_active Abandoned
- 1996-02-06 US US08/875,515 patent/US5932567A/en not_active Expired - Fee Related
-
1997
- 1997-08-08 NO NO973657A patent/NO973657L/no not_active Application Discontinuation
- 1997-08-08 FI FI973282A patent/FI973282A/fi unknown
Also Published As
Publication number | Publication date |
---|---|
MX9705970A (es) | 1997-11-29 |
CA2210989A1 (en) | 1996-08-15 |
EA199700155A1 (ru) | 1997-12-30 |
JPH10513462A (ja) | 1998-12-22 |
CZ237697A3 (cs) | 1998-04-15 |
NO973657L (no) | 1997-10-03 |
BR9607412A (pt) | 1998-07-07 |
NO973657D0 (no) | 1997-08-08 |
KR19980702112A (ko) | 1998-07-15 |
WO1996024609A1 (de) | 1996-08-15 |
EA002767B1 (ru) | 2002-08-29 |
AU706834B2 (en) | 1999-06-24 |
FI973282A0 (fi) | 1997-08-08 |
HUP9800634A2 (hu) | 1999-06-28 |
FI973282A (fi) | 1997-08-08 |
EP0809651A1 (de) | 1997-12-03 |
US5932567A (en) | 1999-08-03 |
HUP9800634A3 (en) | 2000-04-28 |
AU4787596A (en) | 1996-08-27 |
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