CN1308542A - 白介素-1β转化酶的琥珀酰胺抑制剂 - Google Patents
白介素-1β转化酶的琥珀酰胺抑制剂 Download PDFInfo
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- CN1308542A CN1308542A CN99808265A CN99808265A CN1308542A CN 1308542 A CN1308542 A CN 1308542A CN 99808265 A CN99808265 A CN 99808265A CN 99808265 A CN99808265 A CN 99808265A CN 1308542 A CN1308542 A CN 1308542A
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- methyl
- oxo
- butyrylamino
- base
- dimethyl
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- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
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- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
- C07C255/29—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups and acylated amino groups bound to the carbon skeleton
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- C07C311/10—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
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- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
- C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
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- C07D249/18—Benzotriazoles
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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Abstract
本发明提供了式(Ⅰ)化合物,含有式(Ⅰ)化合物的药物组合物和用治疗中风、炎性疾病例如类风湿性关节炎或炎性肠疾病、脓毒性休克、再灌注损伤、阿尔茨海默氏病、志贺氏菌病和多发性硬化的方法。
Description
发明领域
本发明涉及一系列抑制白介素-1β转化酶的琥珀酰胺化合物。本发明还涉及含有这些化合物作为白介素-1β转化酶抑制剂的可药用组合物和用该组合物治疗中风、炎性疾病、脓毒性休克、再灌注损伤、阿尔茨海默氏病和志贺氏菌病的方法。
发明背景
白介素1β蛋白酶(也称作白介素-1β转化酶、ICE或Caspase 1)作用于原-白介素-1β(原-IL-1β)以产生白介素-1β(IL-1β),后者是炎性细胞因子(Kostura M.J.等,Proc.Nat.Acad.Sci.1989;86:5227-5231和Black R.A.等,FEBS Let.1989;247:386-391)。几种疾病也与白介素-1的活性有关。与白介素-1有关的疾病的实例包括炎性疾病例如类风湿性关节炎和炎性肠疾病,以及神经炎性疾病例如中风、多发性硬化和阿尔茨海默氏病(Dinarello C.A.,Eur.CytokineNetw.,1994;5:517)。其他疾病包括脓毒性休克、再灌注损伤和志贺氏菌病。
已经表明,调节IL-1β的试剂具有有益的体内作用。例如,作为白介素-1受体拮抗剂的化合物显示出抑制大鼠脑的局部缺血和兴奋毒性(excitotoxic)损伤(例如Relton J.K.等,Brain Research Bulletin1992;29:243-246)。此外,ICE抑制剂显示出减少大鼠的炎症和发热(Elford P.R.等,British Journal of Pharmacology 1995;115:601-606)。
ICE的抑制剂还可以抑制其他ICE族的半胱氨酸蛋白酶。近来,对ICE族半胱氨酸蛋白酶(也称作Caspase,其中ICE已知为Caspase-1)的命名做了进一步的明确。下列蛋白酶是采用Alnemri等的命名(Cell1996;87:171)的该类酶的典型实例:Caspase-2(也称作Ich-1);Caspase-3(也称作CPP32,Yama和apopain);Caspase-4(也称作TX,Ich-2和ICE rel-II);Caspase-5(也称作ICE rel-III);Caspase-6(也称作Mch2);Caspase-7(也称作Mch3);Caspase-8(也称作FLICE和Mch5);Caspase-9(也称作ICE-LAP6和Mch6);Caspase-10(也称作Mch4)。已经认识到该族酶的各个成员在炎症和编程性细胞死亡中起着关键的生物作用(Thornberry N.A.等,Perspectives in DrugDiscovery and Design 1994;2:389-399)。
除了对IL-1β产生的影响之外,ICE还显示出在炎性介体干扰素-γ的产生中发生作用(Ghayur等,Nature 1997;386(6625):619-623)。ICE作用于干扰素-γ诱导因子的无活性原型(proform)(IGIF;白介素-18)以活化IGIF,IGIF是一种引起T细胞和天然杀伤细胞生产干扰素-γ的蛋白质。干扰素-γ与疾病例如炎性疾病和脓毒性休克的发病机理有关。因此,可以预期,ICE抑制剂对干扰素-γ作用的疾病具有有益的影响。
本领域中所述的大多数ICE抑制剂是肽基的(例如Dolle R.等,J.Med.Chem.1994;37:563)。然而,近来报道了吡啶酮或嘧啶酮基的拟肽抑制剂的应用(Dolle R.等,WO 9526958,1995;Dolle R.等,J.Med.Chem.1996;39:2438;和Semple G.等,Bioorg.Med.Chem.Lett.1997;7:1337)。X-射线晶体照相术和分子建模表明吡啶酮基抑制剂适于替代肽基抑制剂中的P2-P3(Golec J.等,Bioorg.Med.Chem.Lett.1997;7:2181-2186)。
WO 9526958公开了ICE的嘧啶酮基抑制剂的应用。除在体外模型中具有某些活性外,据报道,在WO 9526958中公开的化合物的体内IC50值为0.1至10μm,该IC50值反映了IL-1β释放的百分抑制。尽管这些值反映了某些活性,但是仍然需要研制治疗这些疾病例如炎症、阿尔茨海默氏病、中风和脓毒性休克的更好的ICE抑制剂。
发明概述
本发明提供了式I的化合物及其可药用盐
-OH、-(CH2)n芳基、
-(CH2)n-取代的芳基、
-(CH2)n-O-芳基、
-(CH2)n-O-取代的芳基、
-(CH2)n-S-芳基、
-(CH2)n-S-取代的芳基、
-(CH2)n-S-杂芳基、
-(CH2)n-S-取代的杂芳基、
-(CH2)n-NR’-芳基、
-(CH2)n-NR’-取代的芳基、
-(CH2)n-NR’-杂芳基、
-(CH2)n-NR’-取代的杂芳基、
-(CH2)n-杂芳基、或
-(CH2)n-取代的杂芳基;每个n独立地为0-6;R3是氢或C1-C6烷基;R4是C1-C6烷基或氢;和X是氢、 -(CH2)n-S-(CH2)n-芳基,-(CH2)n-S-(CH2)n-取代的芳基,,或
在优选的式I化合物的具体实例中,R’是氢或甲基。
在另一优选的具体实例中,每个R’是氢。
在另一优选的具体实例中,R3是氢,并且R4是甲基、乙基或异丙基。
在另一优选的具体实例中,R1是氢或甲基,并且R2是-(CH2)n-苯基,
氢,
-(CH2)n-O-苯基,
-OH,
-(CH2)n-苯并咪唑基,
-(CH2)n-吲哚基,或
-(CH2)n-酚。
在另一优选的具体实例中,
在又一优选的具体实例中,其中
Y是
Y是
,或每个R’独立地是氢或甲基;每个n独立地是2-3;R1和R2独立地为氢-(CH2)n-苯基,-(CH2)n-O-苯基,-OH, ,或Ra、Rb和Rc独立地是卤素、-OC1-C6烷基或氢;R3是氢;R4是甲基、乙基或异丙基;并且X是氢,-CH2-S-CH2CH2CH2-苯基,或
在优选的式I的具体实例中,R1是氢,并且R2是-(CH2)n-吲哚基,-(CH2)n-取代的吲哚基,-(CH2)n-NH-苯基,-(CH2)n-O-苯基,-(CH2)n-四唑基,-(CH2)n-苯基,-(CH2)n-取代的苯基,-(CH2)n-取代的苯并咪唑基,-(CH2)n-苯并三唑基,-(CH2)n-吲唑基,-(CH2)n-苯并咪唑基,-(CH2)n-吡啶基,-(CH2)n-萘基,或-(CH2)n-喹啉基。
在最优选的具体实例中,本发明提供了下列化合物:
3-(2-甲基-3-苯乙基氨基甲酰基-丙酰氨基)-4-氧代-5-(2-苯基乙磺酰氨基)-戊酸;
3-(2-氨基甲酰基甲基-3-甲基-丁酰氨基)-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-[3-甲基-2-(苯乙基氨基甲酰基-甲基)-丁酰氨基]-4-氧代-戊酸;
3-(2-氨基甲酰基甲基-3-甲基-丁酰氨基)-4-氧代-5-(2-苯基乙磺酰氨基)-戊酸;
3-[3-甲基-2-(苯乙基氨基甲酰基-甲基)-丁酰氨基]-4-氧代-5-(2-苯基乙磺酰氨基)-戊酸;
5-(7,7-二甲基-双环[2.2.1]庚-1-基甲磺酰氨基)-3-[3-甲基-2-(苯乙基氨基甲酰基-甲基)-丁酰氨基]-4-氧代-戊酸;
(S,S)-3-{3-甲基-2-[(3-苯基丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-丁酸;
3-{3-甲基-2-[(3-苯氧基乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-丁酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-苯氧基乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
3-[3-甲基-2-(苯乙基氨基甲酰基-甲基)-丁酰氨基]-4-氧代-5-(3-苯基丙基硫烷基)-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(甲基-苯乙基-氨基甲酰基)-甲基]-丁酰氨基}-4-氧代戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代戊酸;
3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-5-(2-氧代-2H-色烯-6-基氧)-戊酸;
5-[3-(1H-咪唑-2-基)-萘-2-基氧]-3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-羟基氨基甲酰基甲基-3-甲基-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[[3-(4-羟基苯基)-丙基氨基甲酰基]-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(7-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(6-氟-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-[3-甲基-2-({甲基-[2-(1-甲基-1H-吲哚-3-基)-乙基]-氨基甲酰基}-甲基)-丁酰氨基)-4-氧代-戊酸;
3-{2-[(2-苯并咪唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨基}-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(1H-四唑-5-基)-乙基氨基甲酰基]-甲基}-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-3-{2-[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰氨基)-4-氧代-戊酸;
3-(3-甲基-2-{[2-(1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]甲基}-丁酰氨基)-4-氧代-丁酸;
3-[3-甲基-2-({甲基-[2-(1-甲基-1H-吲哚-3-基)-乙基]氨基甲酰基}甲基)-丁酰氨基]-4-氧代-丁酸;
3-{2-[(2-苯并咪唑-1-基-乙基氨基甲酰基)甲基]-3-甲基-丁酰氨基}-4-氧代-丁酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[3-(4-羟基-苯基)-丙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-吡啶-4-基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-萘-2-基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-吡啶-4-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-喹啉-2-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-萘-2-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-吡啶-3-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-萘-2-基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(7-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(6-氟-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基}-4-氧代-戊酸;
3-[3-甲基-2-({甲基-[2-(1-甲基-1H-吲哚-3-基)-乙基]氨基甲酰基}甲基)-丁酰氨基]-4-氧代-丁酸;
3-(3-甲基-2-{[甲基-(2-苯氧基-乙基)-氨基甲酰基]甲基}-丁酰氨基)-4-氧代-丁酸;
3-(2-{[2-(5,6-二甲基苯并咪唑-1-基)-乙基氨基甲酰基]甲基}-3-甲基-丁酰氨基)-4-氧代-丁酸三氟乙酸盐;
5-(7,7-二甲基-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-吡啶-4-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-喹啉-2-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-萘-1-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-吡啶-3-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
3-{2-[(2-苯并咪唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨基}-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-吡啶-4-基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
3-(2-{[2-(5-乙酰基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(1H-四唑-5-基)-乙基氨基甲酰基]-甲基}-丁酰氨基)-4-氧代-戊酸;
N4-(2-苯并咪唑-1-基-乙基)-N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-[2-(1H-吲哚-3-基)-乙基]-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[2-(1-甲基-1H-吲哚-3-基)-乙基]-琥珀酰胺;
N4-[2-(5,6-二氯-苯并咪唑-1-基)-乙基]-N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-(2-苯氧基-乙基)-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[2-(6-甲氧基-1H-吲哚-3-基)-乙基]-琥珀酰胺;
N4-(2-苯并三唑-1-基-乙基)-N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-(2-吲唑-1-基-乙基)-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-(2-苯氨基-乙基)-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-[2-(6-氟-1H-吲哚-3-基)-乙基]-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-[2-(7-甲基-1H-吲哚-3-基)-乙基]-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[2-(2-甲基-苯并咪唑-1-基)-乙基]-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[3-(3,4,5-三甲氧基-苯基)-丙基]-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[2-(苯基)-乙基]-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[4-(苯基)-丁基]-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-(2-吲哚-1-基-乙基)-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[4-(苯基)-丙基]-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-[2-(5-氟-1H-吲哚-3-基)-乙基]-2-异丙基-琥珀酰胺;
3-{2-[(2-苯并咪唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨基}-4-氧代-丁酸;
3-(3-甲基-2-{[2-(1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰氨基)-4-氧代-丁酸;
3-(2-{[2-(5-氟-1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-丁酸;
3-(2-{[2-(5,6-二氯-苯并咪唑-1-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-丁酸;
3-(2-{[(2-苯并咪唑-1-基-乙基)-甲基-氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-丁酸;
3-{2-[(2-苯并三唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨基}-4-氧代-丁酸;
3-{2-[(2-吲唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨基}-4-氧代-丁酸;
3-[2-({[2-(5,6-二甲基-苯并咪唑-1-基)-乙基]-甲基氨基甲酰基}-甲基)-3-甲基-丁酰氨基]-4-氧代-丁酸;
3-[2-({[2-(2-甲基-苯并咪唑-1-基)-乙基]-甲基氨基甲酰基}-甲基)-3-甲基-丁酰氨基]-4-氧代-丁酸;
3-(3-甲基-2-{[3-(3,4,5-三甲氧基苯基)-丙基氨基甲酰基]-甲基}-丁酰氨基)-4-氧代-丁酸;
3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-丁酸乙酯;
3-氰基-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-丙酸乙酯;和
3-氰基-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-丙酸。
本发明还提供了药物组合物,该组合物含有式I化合物。
本发明还提供了治疗或预防中风的方法,该方法包括对患有、曾患有中风、或处于患中风危险中的患者施用治疗有效量的式I化合物。
本发明还提供了治疗炎性疾病的方法,该方法包括对患有炎性疾病的患者施用治疗有效量的式I化合物。
在优选的治疗炎性疾病方法的具体实例中,炎性疾病是类风湿性关节炎或炎性肠疾病。
本发明还提供了治疗脓毒性休克的方法,该方法包括对患有脓毒性休克的患者施用治疗有效量的式I化合物。
本发明还提供了治疗再灌注损伤的方法,该方法包括对患有再灌注损伤的患者施用治疗有效量的式I化合物。
本发明还提供了治疗阿尔茨海默氏病的方法,该方法包括对患有阿尔茨海默氏病的患者施用治疗有效量的式I化合物。
本发明还提供了治疗志贺氏菌病的方法,该方法包括对患有志贺氏菌病的患者适用于治疗有效量的式I化合物。
本发明还提供了治疗多法性硬化的方法,该方法包括对患有多法性硬化的患者施用治疗有效量的式I化合物。
本发明还提供了抑制白介素-1β转化酶的方法,该方法包括对需要抑制白介素-1β转化酶的患者施用治疗有效量的式I化合物。
发明详述
术语″烷基″是指直链或支链烃。烷基的典型实例是甲基、乙基、丙基、异丙基、异丁基、丁基、叔丁基、仲丁基、戊基和己基。优选的烷基是C1-C6烷基。
术语″烷氧基″是指与氧原子相连的烷基。烷氧基的典型实例是甲氧基、乙氧基、叔丁氧基、丙氧基和异丁氧基。
术语″卤素″包括氟、氯、溴和碘
术语″链烯基″是指具有一个或多个碳碳双键的支链或直链烃。
术语″链炔基″是指具有一个或多个碳碳三键的支链或直链烃。
术语″芳基″是指芳香烃。芳基的典型实例包括苯基和萘基。
术语″杂原子″包括氧、氮和硫。
术语″杂芳基″是指芳香烃中的一个或多个碳原子被杂原子置换的芳基。杂芳基的实例包括、但不限于吡啶基、咪唑基、吡咯基、苯并咪唑基、四唑基、苯并三唑基、吲唑基、噻吩基、呋喃基、吡喃基、嘧啶基、哒嗪基、吲哚基、喹啉基、1,5-二氮杂萘基和异噁唑基。
术语″环烷基″是指环烃。环烷基的典型实例包括环丙基、环丁基、环戊基和环己基。
符号“-”表示键。
术语“患者”是指所有动物,包括人。患者的实例包括人、牛、狗、猫、山羊、绵羊和猪。
术语“取代的”是指具有一个或多个取代基的基本有机基团。例如取代的环己基是指具有一个或多个取代基的环己基。取代基包括、但不限于:卤素、-CF3、C1-C8烷基、-CN、CF3、-NO2、-NH2、-O-苯基、-NHC1-C8烷基、-N(C1-C8烷基)2、-SC1-C6烷基、-OC1-C8烷基和-OH。特别优选的取代基包括、但不限于:叔丁基、甲基、-OH、-NH2、-SCH3、-CN、-OCH3、溴、氟和氯、
术语“环烯基”是指具有至少一个碳碳双键的环烷基。环烯基的实例包括环戊烯、环丁烯和环己烯。
术语“杂环”或“杂环烷基”是指其中一个或多个碳原子被杂原子置换的环烷基。杂环基的实例包括、但不限于吡咯烷基、哌啶基和哌嗪基。
式I化合物可以单独或者作为药物组合物的一部分对患者给药。该组合物可以经口、直肠、非肠道(静脉内、肌内或皮下)、脑池内、阴道内、腹膜内、膀胱内、局部(粉末、油膏或滴剂)或经颊或鼻喷雾对患者例如人和动物给药。
适于非肠道注射的组合物可以含有生理可接受的无菌水溶液或非水溶液、分散液、悬浮液或乳液,以及重新配制成无菌可注射溶液或分散液的无菌粉末。合适的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇(例如丙二醇、聚乙二醇、甘油等)、其合适的混合物、植物油(例如橄榄油)、和可注射的有机酯例如油酸乙酯。例如,通过使用包衣例如卵磷脂、如果是分散液则通过保持所需的粒径以及通过使用表面活性剂可以保持适当的流动性。
这些组合物还可以含有辅剂例如防腐剂、润湿剂、乳化剂和分散剂。用各种抗菌剂和杀真菌剂例如对羟基苯甲酸酯、氯丁醇、苯酚和山梨酸等可以防微生物。还希望包括等渗剂例如糖和氯化钠等。通过使用延迟吸收剂例如单硬脂酸铝和明胶可以制成延长吸收的可注射药物形式。
口服固体剂型包括胶囊、片剂、丸剂、粉末和颗粒。在该固体剂型中,活性化合物与至少一种惰性常规赋形剂(或载体)例如柠檬酸钠或磷酸二钙或,(a)填充剂或膨胀剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸;(b)粘合剂,例如羧甲基纤维素、藻酸盐(alignate)、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;(c)保温剂,例如甘油;(d)崩解剂,例如琼脂、碳酸钙、土豆或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠;(e)溶液阻滞剂,例如石蜡;(f)吸收促进剂,例如季铵化合物;(g)润湿剂,例如鲸蜡醇和甘油单硬脂酸酯;(h)吸附剂,例如高岭土和膨润土;以及(i)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠或其混合物混合。对于胶囊、片剂和丸剂,这些剂型还可以包括缓冲剂。
类似形式的固体组合物还可以用作软和硬明胶胶囊的填料,其中使用例如乳糖以及高分子量聚乙二醇等作为赋形剂。
可以用包衣和壳例如肠溶衣和本领域公知的其他材料制备固体剂型例如片剂、糖衣丸、胶囊、丸剂和颗粒。它们可以含有遮光剂,并且可以是在肠道的某些部位、以延迟的方式释放活性化合物的组合物。可以用于包埋组合物的实例是聚合物和蜡。活性化合物还可以是微囊形式,如果需要,其中可以含有一种或多种上述赋形剂。
口服液体剂型包括可药用乳剂、溶液、悬浮液、糖浆和酏剂。除了活性化合物之外,液体剂型可以含有本领域常用的惰性稀释剂,例如水或其它溶剂、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄基醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨醇的脂肪酸酯或这些物质的混合物等。
除了这些惰性稀释剂之外,该组合物还可以包括辅剂例如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物之外,悬浮液可以含有悬浮剂例如乙氧基化异硬脂醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、偏氢氧化铝(aluminum metahydroxide)、膨润土、琼脂和黄蓍胶或这些物质的混合物等。
直肠给药组合物优选栓剂,通过将本发明化合物与合适的无刺激性赋形剂或载体例如可可脂、聚乙二醇或栓剂蜡混合可以制备栓剂,栓剂在常温为固体、而在体温为液体,因此其在直肠或阴道腔中融化并释放出活性成分。
本发明化合物的局部给药剂型包括油膏、粉末、喷雾剂和吸入剂。在无菌条件下,将活性成分与生理可接受的载体以及根据需要与任何防腐剂、缓冲剂或推进剂混合。眼用制剂、眼用软膏、粉末和溶液也包括在本发明的范围之内。
本发明化合物可以以约每天约0.1至约1,000毫克的剂量给药。对于体重约70公斤的正常成年人来说,优选的剂量范围是每天约0.01至约100毫克/公斤体重。然而所用具体剂量可以改变。例如,该剂量可以随多种因素变化,这些因素包括患者的需要、所治疗疾病的严重程度、所用化合物的药学活性。对具体患者最适剂量的确定是本领域专业人员公知的。
本文所用术语可药用盐、酯、酰胺和前药是指落入合理的医学判断范围内的本发明化合物的羧酸盐、氨基酸加成盐、酯、酰胺和前药,它们适用于与患者的组织接触,而没有过分的毒性、刺激性和过敏性反应等,具有合理的有益/危险比,并且对其打算的应用有效,如果可能,可以包括本发明化合物的两性离子形式。术语“盐”是指相对无毒的、本发明化合物的无机和有机酸加成盐。这些盐可以在最终分离和纯化化合物中就地制备,或者将游离碱形式的纯化化合物单独与合适的有机或无机酸反应、并分离所形成的盐进行制备。典型的盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、naphthylate、甲磺酸盐(mesylate)、葡庚糖酸盐、乳糖酸盐、和月桂基磺酸盐等。这些盐可以包括碱金属和碱土金属阳离子(例如钠、锂、钾、钙和镁等)以及无毒铵、季铵和胺阳离子(包括、但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺和乙胺等)(参见,例如,Berge S.M.等,“药用盐,”J.Pharm.Sci.1977;66:1-19,该文献引入本文作为参考。)
本发明化合物的可药用无毒酯的实例包括C1-C6烷基酯,其中烷基是直链或支链的。可接受的酯还包括C5-C7环烷基酯以及芳烷基酯,例如、但不限于苄基酯。优选C1-C4烷基酯。本发明化合物的酯可以通过常规方法制备。
本发明化合物的可药用无毒酰胺的实例包括由氨、伯C1-C6烷基胺和仲C1-C6二烷基胺(其中烷基是直链或支链的)衍生的酰胺。如果是仲胺,则胺可以是含一个氮原子的5-或6-元杂环。优选由氨、C1-C3烷基伯胺和C1-C2二烷基仲胺衍生的酰胺。本发明化合物的酰胺可以采用常规方法制备。
术语“前药”是指在体内例如通过在血液中水解迅速转化形成上式的母体化合物的化合物。在下述文献中进行了彻底的讨论:HiguchiT.和Stella V.“新的给药系统前药,”A.C.S.专题论文集系列,第14卷,以及“药物设计中的生物可逆载体,”ed.Edward B.Roche,American Pharmaceutical Association and Pergamon Press,1987,这两篇文献均引入本文作为参考。
此外,本发明化合物可以以非溶剂化物和与可药用溶剂例如水、乙醇等的溶剂化物形式存在。通常,对于本发明目的而言,溶剂化物形式被认为是与非溶剂化物的形式等同的。
由于在化合物中存在不对称中心,本发明化合物可以以不同的立体异构形式存在;即,每个不对称碳原子可以具有R或S构型。该化合物的所有立体异构形式及其混合物、包括外消旋混合物均构成本发明的一部分。
将本发明化合物对需要ICE抑制的患者给药。通常,需要ICE抑制的患者是那些患有其中ICE起作用的疾病或病症的患者。这些疾病包括、但不限于炎性疾病例如类风湿性关节炎和炎性肠疾病、神经炎性疾病例如中风和脓毒性休克。其它疾病包括再灌注损伤、阿尔茨海默氏病和志贺氏菌病。
“治疗有效量”是当对患有可用式I化合物治疗的疾病的患者给药时,可以改善疾病症状的式I化合物的量。式I化合物的治疗有效量可以由本领域专业人员通过对患者给药并观察结果容易地确定。
在反应方案I-VII中对本发明化合物的制备进行说明。
反应方案III
反应方案V
反应方案VI
反应方案VII
本领域专业人员将会认识到,正如通过下列实施例证明的,原料可以变化,并且用于制备化合物的附加步骤包括在本发明范围内。
如反应方案I所示,用衣康酸酐将合适的胺酰化得到所需的丙烯酸,该丙烯酸又氢化形成相应的丙酸。然后使该酸与适当的氨基酸在标准肽偶合条件(例如在碱例如4-甲基吗啉存在下的HOBT和EDCI)下偶合,产生所需的琥珀酸酯。该甲酯用碱例如氢氧化钠水解。然后,例如通过由酸形成混合酸酐、用重氮甲烷处理混合酸酐、然后用HBr在乙酸中进行溴化,将所得叔丁基酯酸转化为溴甲基酮。用N-Boc磺酰胺的钾盐置换溴,得到所需的磺酰基化合物。然后在酸例如三氟乙酸存在下将叔丁酯水解成酸。
如反应方案II所示,在碱存在下、用酰氯使(4S)-(-)-4-异丙基-2-噁唑烷酮酰化,形成所需的噁唑烷酮,然后在碱存在下、用溴乙酸叔丁酯进行烷基化。然后基本上按照Tet.Lett.1987;28:6141-6144中所述方法,将所得N-酰基噁唑烷酮水解,得到琥珀酸叔丁酯。然后在如上面的反应方案I中所定义的标准肽偶合条件下,使该酸与(S)-2-氨基-琥珀酸1-烯丙酯4-苄基酯偶合。然后将该产物的叔丁酯裂解,并在相似的肽偶合条件下、用O-苄基羟胺处理所得酸,得到所需的苄氧基氨基甲酰基。然后基本上按照Tet.Lett.1995;36:5741-5744中所述方法,将所得烯丙基酯裂解,并且如上面的反应方案I所述将所得酸转化为溴甲基酮。用N-Boc磺酰胺的钾盐置换溴,用酸将Boc基团裂解,并且用例如Pd/C或兰尼镍(Raney nickel)使苄基酯氢化,得到所需的戊酸。
在反应方案III中,在脱水剂例如EDCI存在下、由苄醇制备反应方案II中琥珀酸苄基酯(产物3),并用酸将叔丁酯水解。然后在如反应方案I中所述的标准肽偶合条件下,使琥珀酸苄基酯与合适的胺偶合,之后如反应方案II所述,通过氢化裂解苄基酯,得到丁酸。然后如步骤5所示,将该酸与氨基醇偶合,之后基本上按照Dess和Martin在J.Org.Chem.1993;58:2899和J.Org.Chem.1983;48:4156-4158中所述方法,将所得醇氧化成醛。用酸将叔丁酯水解得到最终产物。
如反应方案IV所示,在如上面反应方案I中所述的肽偶合条件下,使反应方案II的琥珀酸(产物3)与步骤1的氨基酯偶合。该酯用碱例如氢氧化锂水解,如上面反应方案II所述将所得酸转化为溴甲基酮。用合适的亲核试剂的钾盐置换溴,并用酸使叔丁酯水解,得到所需产物。
如反应方案VI所示,通过用20%Pd/C作为催化剂进行氢解,除去Cbz-Asp(OtBu)-H的二乙基乙缩醛的苄氧羰基(Cbz)保护基。在标准肽条件(例如在碱例如4-甲基吗啉存在下的HOBT和EDCI)下使该胺与反应方案II的单保护的琥珀酸(产物3)偶合。用例如在二氯甲烷中的三氟乙酸除去叔丁基,得到环O-乙基缩醛。在如上所述的标准肽偶合条件下,该酸与各种胺偶合,得到所需产物。
如反应方案VII所示,反应方案V的环O-乙基缩醛(产物4)例如在稀盐酸的乙腈溶液中酸解,得到醛酸。
在本申请中公开的所有文章和参考文献、包括专利均引入本文作为参考。
原料和各种中间体可以通过商业渠道获得、由可购买到的有机化合物制备、或者采用公知的合成方法制备。
下面给出的实施例将对本发明的具体实施方案进行说明,而非以任何方式限制说明书、包括权利要求书的范围。
实施例13-(2-甲基-3-苯乙基氨基甲酰基-丙酰氨基)-4-氧代-5-(2-苯基乙磺
将衣康酸酐(5.00g,44.6mmol)与苯乙胺(5.95g,49.1mmol)在100毫升乙腈中的溶液在室温和氮气氛下搅拌72小时。将该混合物(固体形式)浓缩,然后在乙酸乙酯和1N HCl之间分配。有机提取液用盐水洗涤、用硫酸镁干燥、浓缩,并将残余物从乙醚中结晶,得到5.24g(50%)2-(苯乙基氨基甲酰基-甲基)-丙烯酸,为白色固体:熔点133-140℃。MS(APCI)m/z 234.2(M+1,67.4%)和216.2(M-17,100%)。C13H15NO3(233.269)的分析计算值:C,66.94;H,6.48;N,6.00。实测值:C,66.74;H,6.56;N,6.00。步骤B
将2-(苯乙基氨基甲酰基-甲基)-丙烯酸(2.76g,11.8mmol,实施例1,步骤A)在100毫升THF中的溶液用5%Pd/C(0.2g)处理,并在室温和52psig氢气压下氢化2.5小时。将该混合物过滤并浓缩,得到2.39g(86%)2-(苯乙基氨基甲酰基-甲基)-丙酸,为灰白色固体。MS(APCI)m/z 236.0(M+1,100%)。C13H17NO3(235.285)的分析计算值:C,66.36;H,7.28;N,5.95。实测值:C,65.31;H,7.05;N,5.80。步骤C
将2-(苯乙基氨基甲酰基-甲基)-丙酸(1.63g,6.93mmol,实施例1,步骤B)、H-Asp(OtBu)-OMe·HCl(1.83g,7.64mmol,购自BachemBioscience Inc.)、1-羟基苯并三唑水合物(HOBT·H2O,1.17g,7.64mmol)、N-乙基-N’-(3-二甲氨基丙基)-碳化二亚胺盐酸盐(EDCI·HCl,1.46g,7.62mmol)和4-甲基吗啉(0.95ml,8.64mmol)在100毫升二氯甲烷中的混合物在室温搅拌24小时。将该混合物浓缩,然后在乙酸乙酯和饱和碳酸氢钠溶液之间分配。有机提取液用饱和磷酸二氢钾和盐水溶液洗涤,用硫酸镁干燥,过滤,浓缩并进行色谱纯化(硅胶,25%己烷/75%EtOAc),得到2.54g(87%)2-(2-甲基-3-苯乙基氨基甲酰基-丙酰氨基)-琥珀酸,4-叔丁酯1-甲酯,为蜡状白色固体。MS(APCI)m/z 420.9(M,100%)。C22H32N2O6(420.510)的分析计算值:C,62.84;H,7.67;N,6.66。实测值:C,62.68;H,7.69;N,6.54。步骤D
将2-(2-甲基-3-苯乙基氨基甲酰基-丙酰氨基)-琥珀酸,4-叔丁酯1-甲酯(2.11g,5.01mmol,实施例1,步骤C)和0.1N氢氧化钠溶液(60.1mL,6.01mmol)在60毫升乙醇中的溶液在室温搅拌12小时。将该溶液浓缩,用饱和KH2PO4溶液酸化至pH约5,并用氯仿(2×100mL)萃取。合并的氯仿提取液用硫酸镁干燥、过滤并浓缩,得到2.23g(约100%)2-(2-甲基-3-苯乙基氨基甲酰基-丙酰氨基)-琥珀酸,4-叔丁酯,为无色油,该产物无需进一步纯化即可使用。
在Clear-Seal连接250 mL圆底烧瓶中,将2-(2-甲基-3-苯乙基氨基甲酰基-丙酰氨基)-琥珀酸,4-叔丁酯(2.23g,5.49mmol)和4-甲基吗啉(0.61mL,5.73mmol)在50 mL THF中的溶液冷却至约-45℃(干冰-乙腈浆),并用氯甲酸异丁酯(0.75mL,5.78mmol)处理。立即形成固体,并搅拌该混合物15分钟,然后用0.25-0.5M重氮甲烷的乙醚溶液(55mL,27.5mmol,由Diazald并新蒸馏制得)处理。移去冷浴,所得淡黄色溶液在室温搅拌2小时,冷却至0℃,滴加在10mL乙酸中的48%氢溴酸溶液(10mL,184mmol)进行处理。在室温搅拌该无色溶液30分钟,然后在EtOAc和水(各约200mL)之间分配。有机提取液用水、饱和碳酸氢钠和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩,得到1.40g(53%)5-溴-2-(2-甲基-3-苯乙基氨基甲酰基-丙酰氨基)-4-氧代-戊酸,叔丁酯,为淡黄色固体。步骤E
将1,1-二甲基乙基[(2-苯乙基)磺酰基]氨基甲酸酯(0.47g,1.66mmol)在3.0mL DMF中的溶液在室温和氮气氛下用叔丁醇钾(0.21g,1.66mmol)进行处理。该样品在室温搅拌1小时,冷却至0℃,然后用2-(2-甲基-3-苯乙基氨基甲酰基-丙酰氨基)-5-溴-4-氧代-戊酸,叔丁酯(0.67g,1.38mmol,实施例1,步骤D)进行处理。使该样品温热至室温过夜。将样品在EtOAc和饱和碳酸氢钠溶液之间分配。有机提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩。残余物经色谱纯化(硅胶,50%己烷/50%EtOAc),得到0.43g(52%)5-[[(1,1-二甲基乙氧基)羰基][(2-苯乙基)磺酰基]氨基]-3-[[2-甲基-1,4-二氧代-4-[(2-苯乙基)氨基]丁基]氨基]-4-氧代戊酸1,1-二甲基乙基酯,为泡沫状淡黄色固体。步骤F
将3-(2-甲基-3-苯乙基氨基甲酰基-丙酰氨基)-4-氧代-5-[(2-苯基-乙磺酰基)-N-Boc-氨基]-戊酸,5-叔丁酯(0.40g,0.58mmol,实施例1,步骤E)和三氟乙酸在20毫升二氯甲烷中的溶液在室温搅拌2小时。将该溶液浓缩,得到黄色油。加入乙醚(约50mL),油固化。该样品在室温搅拌过夜,过滤,用新鲜的乙醚洗涤,并真空干燥,得到0.28g(89%)3-(2-甲基-3-苯乙基氨基甲酰基-丙酰氨基)-4-氧代-5-(2-苯基乙磺酰氨基)-戊酸,为白色固体。MS(APCI)m/z 532.1(M+1,100%)。C26H33N3O7S(531.633)的分析计算值:C,58.74;H,6.26;N,7.90。实测值:C,58.38;H,6.23;N,7.71。
实施例23-(2-氨基甲酰基甲基-3-甲基-丁酰氨基)-5-(7,7-二甲基-2-氧代-双
在-78℃和氮气氛下,通过滴加正丁基锂(64.5ml,0.161mol,2.5M己烷溶液)对(4S)-(-)-4-异丙基-2-噁唑烷酮(19.85g,0.154mol)在400mL THF中的溶液进行处理,形成固体。将该混合物在-78℃搅拌30分钟,然后滴加异戊酰氯(20.6mL,0.169mol)进行处理。将该反应物缓缓温热至室温过夜。浓缩样品,然后在EtOAc和饱和磷酸二氢钾溶液之间分配。有机提取液用盐水洗涤,用硫酸镁干燥,所得黄色油经色谱纯化(MPLC,硅胶,10%EtOAc的己烷溶液)得到29.8g(91%)(S)-4-异丙基-3-(3-甲基-丁酰基)-噁唑烷-2-酮,为淡黄色的油。步骤B
将(S)-4-异丙基-3-(3-甲基-丁酰基)-噁唑烷-2-酮(20.8g,97.5mmol,实施例2,步骤A)在500mL THF中的溶液在-78℃和氮气氛下,通过滴加双(三甲基甲硅烷基)氨基钠(107mL,107mmol,在THF中的1.0M溶液)进行处理。该溶液在-78℃搅拌30分钟,然后滴加在100mLTHF中的溴乙酸叔丁酯(18.0mL,121.9mmol)进行处理。样品在-78℃搅拌1小时,然后滴加饱和KH2PO4溶液(约125mL)终止反应。将该混合物温热至室温,浓缩(以除去大部分THF),然后用乙醚萃取。有机提取液用饱和碳酸氢钠和盐水溶液洗涤,用硫酸镁干燥,浓缩,并从乙醚-石油醚中结晶,得到21.1g(66%)[S-(R*,R*)]-3-(4-异丙基-2-氧代-噁唑烷-3-羰基)-4-甲基-戊酸叔丁酯,为白色固体。C17H29NO5(327.424)的分析计算值:C,62.36;H,8.93;N,4.28。实测值:C,62.30;H,9.07;N,4.09。步骤C
按照Evans D.A.等(Tet.Lett.1987;28:6141-6144)所述方法,用氢过氧化锂使N-酰基噁唑烷酮水解。在0℃,向搅拌着的[S-(R*,R*)]-3-(4-异丙基-2-氧代-噁唑烷-3-羰基)-4-甲基-戊酸叔丁酯(9.05g,27.64mmol,实施例2,步骤B)在250ml THE中的溶液中滴加过氧化氢(14.1mL,138mmol,在水中的30wt%溶液),然后滴加1.0M氢氧化锂溶液(55.3mL,55.3mmol)。使反应物缓缓温热至室温过夜。浓缩反应物以除去大部分THF,然后用二氯甲烷(2×100mL)洗涤该碱性溶液。将水相冷却,用饱和KH2PO4溶液酸化至pH约5,并用乙酸乙酯萃取。有机提取液用盐水溶液洗涤,用硫酸镁干燥并浓缩,得到5.66g(95%)(S)-2-异丙基琥珀酸4-叔丁酯,为无色油,该产物无需进一步纯化即可使用。步骤D
将(S)-2-异丙基琥珀酸4-叔丁酯(10.77g,49.80mmol,实施例2,步骤C)、(S)-2-氨基-琥珀酸1-烯丙酯4-苄基酯盐酸盐(14.93g,49.81mmol)、HOBT·H2O(8.4g,54.8mmol)、EDCI·HCl(10.5g,54.8mmol)和4-甲基吗啉(8.2mL,74.6mmol)在250毫升CH2Cl2中的混合物在室温搅拌12小时。将该混合物浓缩、然后在EtOAc和饱和NaHCO3溶液之间分配。EtOAc提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤,浓缩并经色谱纯化(MPLC,硅胶,在己烷中的20%EtOAc),得到19.21g(84%)[S-(R*,R*)]-2-(2-叔丁氧羰基甲基-3-甲基-丁酰氨基)-琥珀酸1-烯丙基酯4-苄基酯,为淡黄色油。步骤E
将[S-(R*,R*)]-2-(2-叔丁氧羰基甲基-3-甲基-丁酰氨基)-琥珀酸1-烯丙基酯4-苄基酯(9.3g,23.0mmol,实施例2,步骤D)和三氟乙酸(35mL)在35毫升二氯甲烷中的溶液在室温和氮气氛下搅拌2小时。将样品浓缩,再溶于二氯甲烷中,然后用EDCI·HCI(8.8g,46.0mmol)、HOBT·H2O(6.2g,46.0mmol)和O-苄基羟胺盐酸盐(7.3g,46.0mmol)处理。滴加4-甲基吗啉(11.6g,115mmol),并将反应混合物在室温搅拌过夜、样品用二氯甲烷稀释,并依次用5%盐酸和饱和碳酸氢钠溶液洗涤。有机提取液用硫酸钠干燥并浓缩,得到10.25g(88%)2-[2-(苄氧基氨基甲酰基-甲基)-3-甲基-丁酰氨基]-琥珀酸1-烯丙酯4-叔丁酯,为白色固体,该产物无需进一步纯化即用于下一步反应。步骤F
采用Dessolin M.等(Tet.Lett.1995;36:5741-5744)所述方法将烯丙酯裂解。在0℃和氮气氛下,向2-[2-(苄氧基氨基甲酰基-甲基)-3-甲基-丁酰氨基]-琥珀酸1-烯丙酯4-叔丁酯(10.25g,19.7mmol,实施例2,步骤E)和四(三苯膦)钯(O)(0.462g,0.40mmol)在二氯甲烷中的溶液中滴加苯基硅烷(4.26g,39.4mmol)。用1小时将反应混合物温热至室温,然后用饱和磷酸二氢钾溶液洗涤。有机层用0.5NNaOH萃取。碱性水相用浓HCl酸化,并用EtOAc萃取。有机提取液用硫酸钠干燥,过滤并浓缩,得到6.2g(72%)取代的琥珀酸4-苄基酯,为泡沫状白色固体。
在-42℃,向上述酸(6.0g,12.8mmol)和4-甲基吗啉(1.3g,12.8mmol)在THF(50mL)中的溶液中滴加氯甲酸异丁酯(1.8g,12.8mmol)。搅拌30分钟后,在0℃,将反应混合物加入重氮甲烷的乙醚溶液(约0.5M,200mL)中。将反应混合物在室温搅拌2小时,然后冷却至0℃。滴加48%HBr(20mL)和HOAc(20mL)的溶液,并在0℃搅拌反应物30分钟。样品用乙醚稀释,用水(2x)和饱和NaHCO3溶液(2x)洗涤。有机层用硫酸钠干燥并浓缩。将残余物溶解在二氯甲烷中,产物用己烷沉淀。过滤收集固体,用己烷充分洗涤并干燥,得到1.5g(15%)3-[2-(苄氧基氨基甲酰基-甲基)-3-甲基-丁酰氨基]-5-溴-4-氧代-戊酸苄基酯,为白色固体。步骤G
向(S)-1,1-二甲基乙基[[(7,7-二甲基-2-氧代双环[2.2.1]庚-1-基)甲基]磺酰基]氨基甲酸酯(0.273g,0.82mmol)在无水DMF(3mL)中的溶液中加入叔丁醇钾(0.092g,0.82mmol)。在氮气氛下搅拌反应物1小时。然后将该溶液滴加至3-[2-(苄氧基氨基甲酰基-甲基)-3-甲基-丁酰氨基]-5-溴-4-氧代-戊酸苄基酯(0.400g,0.75nmol,实施例2,步骤F)在无水DMF(3mL)中的溶液中,并搅拌该反应物过夜。样品用EtOAc稀释,并用盐水(2x)洗涤。EtOAc层用硫酸钠干燥并浓缩。残余物经色谱纯化(硅胶,40%EtOAc/60%己烷),得到0.271g苯甲基-5-[[(1,1-二甲基乙氧基)羰基]-[[(7,7-二甲基-2-氧代双环[2.2.1]庚-1-基)-甲基]磺酰基]氨基]-3-[[2-(1-甲基乙基)-1,4-二氧代-4-[(苯基甲氧基)氨基]丁基]氨基]-4-氧代戊酸酯,为白色泡沫状固体。
样品用在二氯甲烷(6mL)中的50%三氟乙酸处理1小时。该样品用二氯甲烷稀释,并用饱和碳酸氢钠溶液洗涤。有机层用硫酸钠干燥并浓缩,得到0.237g白色固体,该产物无需进一步纯化即用于下一步反应。步骤H
向上述化合物(0.237g,实施例2,步骤G)在75mL THF中的溶液中加入10%Pd/C(0.50g),并在50psi氢气压下、在室温将使混合物氢化3小时。将反应混合物过滤,加入兰尼镍(0.10g)。在50psi使反应混合物再氢化15小时。过滤样品,浓缩滤液。残余物在EtOAc和饱和碳酸氢钠溶液之间分配。分离水层,用盐酸酸化,并用乙酸乙酯萃取。有机层用硫酸钠干燥并浓缩,得到0.065g 3-(2-氨基甲酰基甲基-3-甲基-丁酰氨基)-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-戊酸(化合物2),为带粉红色的固体。C22H35N3O8S×0.27C4H8O2(525.392)的分析计算值:C,52.76;H,7.13;N,8.00。实测值:C,52.36;H,7.06;N,7.65。
可以按照实施例2的方法制备下列化合物。
实施例35-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-[3-甲基
-2-(苯乙基氨基甲酰基-甲基)-丁酰氨基]-4-氧代-戊酸褐色泡沫状固体。MS(APCI)m/z 606.4(M+1,25.0%),346.3(100%)。C30H43N3O8S×0.50H2O(614.764)的分析计算值:C,58.61;H,7.21;N,6.84。实测值:C,58.62;H,7.18;N,6.41。
实施例4
3-(2-氨基甲酰基甲基-3-甲基-丁酰氨基)-4-氧代-5-(2-苯基乙
磺酰氨基)-戊酸MS(APCI)m/z 456.3(M+1,74.7%),242.2(100%)。C20H29N3O7S×0.13CF3CO2H(470.357)的分析计算值:C,51.74;H,6.24;N,8.93。实测值:C,51.70;H,5.97;N,8.61。
实施例53-[3-甲基-2-(苯乙基氨基甲酰基-甲基)-丁酰氨基]-4-氧代-5-
(2-苯基乙磺酰氨基)-戊酸白色固体。MS(APCI)m/z 560.4(M+1,50.7%),346.3(100%)。C28H37N3O7S×0.27H2O(564.551)的分析计算值:C,59.57;H,6.70;N,7.44。实测值:C,59.56;H,6.52;N,7.41。
实施例65-(7,7-二甲基-双环[2.2.1]庚-1-基甲磺酰氨基)-3-[3-甲基-2-
(苯乙基氨基甲酰基-甲基)-丁酰氨基]-4-氧代-戊酸为灰白色固体。C30H45N3O7S(591.773)的分析计算值:C,60.89;H,7.66;N,7.10。实测值:C,60.61;H,7.65;N,7.03。
通过(1S)-(+)-10-樟脑磺酰胺的Wolff-Kishner还原、然后按照实施例2步骤B的方法用二-(叔丁基)-二碳酸酯酰化,制备原料N-Boc磺酰胺。Neustadt R.(Tet.Lett.1994;35:379-380)。
实施例7
(S,S)-3-{3-甲基-2-[(3-苯基丙基氨基甲酰基)-甲基]-丁酰氨
(S)-2-异丙基琥珀酸4-叔丁酯(14.5g,67.0mmol,实施例2,步骤C)、EDCI·HCl(15.4g,80.3mmol)、苄醇(8.7mL,84.1mmol)和4-二甲氨基吡啶(1.5g,12.3mmol)在500mL二氯甲烷中的混合物在室温搅拌12小时。将样品浓缩,然后在乙酸乙酯和饱和碳酸氢钠溶液之间分配。有机提取液用饱和磷酸二氢钾和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩。所得黄色油经色谱纯化(MPLC,硅胶,在己烷中的10%EtOAc),得到15.6g(76%)(S)-2-异丙基琥珀酸1-苄基酯4-叔丁酯,为无色油。MS(APCI)m/z 307.2(M+1,92.2%),252.2(M-54,90.9%)和251.1(M-55,100%)。
在室温,用在二氯甲烷中的20%三氟乙酸使叔丁酯水解,得到(S)-2-异丙基-琥珀酸1-苄基酯,为淡黄色油。MS(APCI)m/z 251.1(M+1,100%)。步骤B
将(S)-2-异丙基琥珀酸1-苄基酯4-叔丁酯(3.45g,13.78mmol,实施例3,步骤A)、3-苯基-1-丙胺(2.15mL,15.12mmol)、HOBT·H2O(2.32g,15.15mmol)、EDCI·HCI(2.91g,15.18mmol)和2.3mL(20.65mmol)4-甲基吗啉在100毫升二氯甲烷中的混合物在室温搅拌12小时。将样品浓缩,然后在EtOAc和饱和碳酸氢钠溶液之间分配。有机提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩,得到5.0g(98%)(S)-2-(苯丙基氨基甲酰基-甲基)-3-甲基丁酸苄基酯,为淡黄色油。MS(APCI)m/z 369.2(M+2,100%),368.2(M+1,97.4%)。
在球压下,用在乙醇中的20%Pd/C使(S)-2-(苯丙基氨基甲酰基-甲基)-3-甲基丁酸苄基酯氢化,得到(S)-2-(苯丙基氨基甲酰基-甲基)-3-甲基丁酸,为无色油。MS(APCI)m/z 279.1(M+2,83.1%),278.1(M+1,83.1%)和260.1(M-17,100%)。步骤C
将(S)-2-(苯丙基氨基甲酰基-甲基)-3-甲基丁酸(2.04g,7.34mmol,实施例3,步骤B)、3-氨基-4-羟基-丁酸叔丁酯单盐酸盐(1.71g,8.08mmol)、HOBT·H2O(1.24g,8.10mmol),EDCI·HCl(1.55g,8.08mmol)和4-甲基吗啉在50毫升二氯甲烷中的混合物在室温搅拌12小时。将样品浓缩,然后在乙酸乙酯和饱和碳酸氢钠溶液之间分配。有机提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩。样品经色谱纯化(MPLC,硅胶,25%己烷/75%EtOAc),得到1.64g(52%)(S,S)-3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]丁酰氨基}-4-羟基-丁酸叔丁酯,为泡沫状白色固体。MS(APCI)m/z 436.3(M+2,100%)和435.3(M+1,83.1%)。步骤D
将(S,S)-3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]丁酰氨基}-4-羟基-丁酸叔丁酯(1.54g,3.54mmol,实施例3,步骤C)和DessMartin试剂(2.26g,5.33mmol,按照R.E.Ireland和L.Liu所述方法制备(J.Org.Chem.1993;58:2899)在100毫升二氯甲烷中的溶液在室温搅拌2小时。采用D.B.Dess和J.C.Martin所述方法(J.Org.Chem.1983;48:4156-4158)对该样品进行还原处理,得到1.16g(77%)(S,S)-3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]丁酰氨基}-4-氧代-丁酸叔丁酯,为蜡状白色固体。MS(APCI)m/z 434.3(M+2 83.1%)和433.3(M+1,100%)。C24H36N2O5×0.50H2O(441.573)的分析计算值:C,65.28;H,8.45;N,6.34。实测值:C,65.31;H,8.13;N,6.16。步骤E
将(S,S)-3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]丁酰氨基}-4-氧代-丁酸叔丁酯(1.10g,2.54mmol,实施例3,步骤D)和5.0mL三氟乙酸在20毫升二氯甲烷中的溶液在室温搅拌1小时。将该溶液浓缩,然后在乙酸乙酯和饱和KH2PO4溶液之间分配。有机提取液用饱和KH2PO4溶液和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩,得到0.83g(86%)(S,S)-3-{3-甲基-2-[(3-苯基丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-丁酸,为灰白色泡沫状固体(化合物7)。MS(APCI),m/z 377.2(M+1,100%)。C20H28N2O5×0.25H2O(380.960)的分析计算值:C,63.06;H,7.54;N,7.35。实测值:C,63.08;H,7.25;N,6.98。
可以按照实施例7所述方法制备下列化合物。
实施例8
3-{3-甲基-2-[(3-苯氧基乙基氨基甲酰基)-甲基]-丁酰氨基}-4-
氧代-丁酸为泡沫状白色固体。MS(APCI)m/z 379.1(M+1,100%)。C19H26N2O6×0.50H2O(387.437)的分析计算值:C,58.90;H,7.02;N,7.23。实测值:C,58.91;H,6.78;N,7.02。
实施例9
将(S)-2-(3-苯氧基-乙基氨基甲酰基-甲基)-3-甲基丁酸(3.51g,12.56mmol,采用实施例3步骤A和B所述方法制备)、H-Asp(OtBu)Ome×HCl(3.31g,13.82mmol)、HOBT×H2O(2.12g,13.82mmol)、EDCI·HCl(12.65g,13.82mmol)和4-甲基吗啉(2.9mL,26.38mol)在100mL二氯甲烷中的混合物在室温搅拌12小时。将样品浓缩,并在EtOAc和饱和碳酸氢钠溶液之间分配。有机提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩。样品经色谱纯化(MPLC,硅胶,25%己烷/75%EtOAc),得到4.70g(81%)(S,S)-2-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)甲基]-丁酰氨基)-琥珀酸4-叔丁酯1-甲酯,为白色固体。MS(APCI)m/z 465.2(M+1,100%)。C24H36N2O7(464.564)的分析计算值:C,62.05;H,7.81;N,6.03。实测值:C,62.07;H,7.85;N,5.97。步骤B
在室温和搅拌下,向(S,S)-2-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)甲基]-丁酰氨基)-琥珀酸4-叔丁酯1-甲酯(4.18g,9.00mmol,实施例4,步骤A)在100毫升THF中的溶液中滴加0.2M氢氧化锂溶液(47.3mL,9.46mmol)。将该样品搅拌30分钟,用饱和KH2PO4溶液酸化,浓缩(以除去大部分THF)并用EtOAc萃取。有机提取液用盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩,得到淡黄色油。样品从二氯甲烷-己烷中结晶,得到1.96g(48%)(S,S)-2-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)甲基]-丁酰氨基)-琥珀酸4-叔丁酯,为白色固体。MS(APCI)m/z 451.2(M+1,100%)。C23H34N2O7(450.537)的分析计算值:C,61.32;H,7.61;N,6.22。实测值:C,61.29;H,7.71;N,6.08。步骤C
采用实施例1步骤D所述方法,将(S,S)-2-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)甲基]-丁酰氨基)-琥珀酸4-叔丁酯(2.92g,6.47mmol)转化为3.25g(95.2%)(S,S)-5-溴-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)甲基]-丁酰氨基}-4-氧代-戊酸叔丁酯,为灰白色固体。MS(APCI)m/z 529.1/527.1(M+1,100/98.7%)。步骤D
在室温和搅拌下,向N-Boc樟脑磺酰胺(1.04g,3.14mmol,按照步骤B的酰化方法由(1S)-(+)-10-樟脑磺酰胺制备,Neustadt R.,Tel.Lett.1994;35:379-380)在5.0mL DMF中的溶液中一次性加入叔丁醇钾(0.35g,3.13mmol)。将该样品在室温搅拌30分钟,冷却至0℃,然后一次性用(S,S)-5-溴-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)甲基]-丁酰氨基}-4-氧代-戊酸叔丁酯(1.50g,2.84mmol,实施例4,步骤C)处理。使该样品缓缓温热至室温过夜。样品在EtOAc和饱和KH2PO4溶液之间分配。有机提取液用盐水溶液洗涤,用硫酸镁干燥,过滤,浓缩并经色谱纯化(MPLC,硅胶,50%己烷/50%EtOAc),得到1.43g(64%)1,1-二甲基乙基5-[[(1,1-二甲基乙氧基)羰基][[(7,7-二甲基-2-氧代双环[2.2.1]庚-1-基)甲基]磺酰基]氨基]-3-[[2-(1-甲基乙基)-1,4-二氧代-4-[(2-苯氧基乙基)氨基]丁基]氨基]-4-氧代戊酸酯,为泡沫状白色固体。MS(APCI)m/z 778.3(M+1,100%)。步骤E
将5-[[(1,1-二甲基乙氧基)羰基][[(7,7-二甲基-2-氧代双环[2.2.1]庚-1-基)甲基]磺酰基]氨基]-3-[[2-(1-甲基乙基)-1,4-二氧代-4-[(2-苯氧基乙基)氨基]丁基]氨基]-4-氧代戊酸1,1-二甲基乙基酯(1.38g,1.77mmol,实施例4,步骤D)和10毫升三氟乙酸在20mL二氯甲烷中的溶液在室温搅拌1小时。将该溶液浓缩成泡沫状固体。将固体溶解在0.1M氢氧化钠溶液中,并用乙酸乙酯(25mL)洗涤。碱性水相(pH~10-11)用饱和KH2PO4溶液酸化至pH约5.0,并用乙酸乙酯萃取。有机提取液用盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩,得到0.57g(52%)5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-苯氧基乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸,为泡沫状白色固体(化合物9)。MS(APCI)m/z 622.1(M+1,40.3%)和362.1(100%)。C30H43N3O9S(621.756)的分析计算值:C,57.95;H,6.97;N,6.76。实测值:C,57.63;H,7.15;N,6.59。
按照实施例9的方法可以制备下列化合物。
实施例10
3-[3-甲基-2-(苯乙基氨基甲酰基-甲基)-丁酰氨基]-4-氧代-5-
(3-苯基丙基硫烷基)-戊酸为白色固体。MS(APCI)m/z 527.2(M+1,100%)。C29H38N2O5S(526.701)的分析计算值:C,66.13;H,7.27;N,5.32。实测值:C,65.99;H,7.24;N,5.20。
实施例11
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(甲基-苯乙基-氨基甲酰基)-甲基]-丁酰氨基}-4-氧代戊酸为灰白色泡沫状固体。MS(APCI)m/z 620.2(M+1,40.3%),360.2(100%)。C31H45N3O8S×0.70H2O(632.394)的分析计算值:C,58.88;H,7.40;N,6.64。实测值:C,58.89;H,7.48;N,6.39。
实施例12
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代戊酸为泡沫状白色固体。MS(APCI)m/z 620.2(M+1,37.7%),360.2(100%)。C31H45N3O8S×0.50H2O(628.791)的分析计算值:C,59.22;H,7.37;N,6.68。实测值:C,59.22;H,7.37;N,6.50。
实施例13
3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-
氧代-5-(2-氧代-2H-色烯-6-基氧)-戊酸褐色固体。MS(APCI)m/z 551.2(M+1,62.3%),345.2(100%)。C30H34N2O8×0.50H2O(559.622)的分析计算值:C,64.39;H,6.30;N,5.01。实测值:C,64.39;H,6.18;N,5.00。
实施例14
5-[3-(1H-咪唑-2-基)-萘-2-基氧]-3-{3-甲基-2-[(3-苯基-丙基
氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸MS(APCI)m/z 599(M+1,13%)。C34H38N4O6×CF3CO2H×H2O(730.745)的分析计算值:C,59.17;H,5.66;N,7.67。实测值:C,58.84;H,5.61;N,7.68。
实施例15
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-
采用实施例2步骤F所述方法,将[S-(R*,R*)]-2-(2-叔丁氧羰基甲基-3-甲基-丁酰氨基)-琥珀酸1-烯丙酯4-苄基酯(10.68g,23.52mmol,实施例2,步骤D)转化为7.70g(78%)[S-(R*,R*)]-2-(2-叔丁氧羰基甲基-3-甲基-丁酰氨基)-琥珀酸4-苄基酯,为白色固体。MS(APCI)m/z 422.3(M+1,12.1%)和366.2(M-55,100%)。C22H31NO7(421.495)的分析计算值:C.62.69;H,7.41;N,3.32。实测值:C,62.42;H,7.33;N,3.17。步骤B
采用实施例1步骤D所述方法,将[S-(R*,R*)]-2-(2-叔丁氧羰基甲基-3-甲基-丁酰氨基)-琥珀酸4-苄基酯(6.08g,14.43mmol,实施例4,步骤A)转化为4.62g(64%)[S-(R*,R*)]-5-溴-3-(2-叔丁氧羰基甲基-3-甲基-丁酰氨基)-4-氧代戊酸苄基酯,为白色固体。MS(APCI)m/z 498.2/500.2(M+1,76.5/74.7%)和442.2/444.2(M-55,100/97.1%)。C23H32BrNO6(498.424)的分析计算值:C,55.43;H,6.47;N,2.81。实测值:C,55.28;H,6.33;N,2.77。步骤C
向(S)-1,1-二甲基乙基[[(7,7-二甲基-2-氧代双环[2.2.1]庚-1-基)甲基]磺酰基]氨基甲酸酯(0.862g,2.60mmol)在无水DMF(4mL)中的溶液中加入叔丁醇钾(0.307g,2.74mmol)。在氮气氛下搅拌反应物30分钟。然后将该溶液滴加至[S-(R*,R*)]-5-溴-3-(2-叔丁氧羰基甲基-3-甲基-丁酰氨基)-4-氧代戊酸苄基酯(1.18g,2.37mmol,实施例5,步骤B)在无水DMF(4mL)中的溶液中,并搅拌该反应物过夜。样品用乙酸乙酯稀释,并用盐水(2x)洗涤。乙酸乙酯层用硫酸钠干燥并浓缩。残余物经色谱纯化(硅胶,在己烷中的20%EtOAc),得到0.850g苯甲基-5-[[(1,1-二甲基乙氧基)羰基]-[[(7,7-二甲基-2-氧代双环[2.2.1]庚-1-基)甲基]磺酰基]氨基]-3-[[4-(1,1-二甲基乙氧基)-2-(1-甲基乙基)-1,4-二氧代丁基]氨基]-4-氧代戊酸酯,为泡沫状固体。步骤D
用三氟乙酸/二氯甲烷(1∶1,15mL)处理苯甲基-5-[[(1,1-二甲基乙氧基)羰基]-[[(7,7-二甲基-2-氧代双环[2.2.1]庚-1-基)甲基]磺酰基]氨基]-3-[[4-(1,1-二甲基乙氧基)-2-(1-甲基乙基)-1,4-二氧代丁基]氨基]-4-氧代戊酸酯(0.850g,1.15mmol,实施例5,步骤C)1小时。将样品浓缩,得到油状残余物,该残余物无需进一步纯化即进行下一步反应。将残余物溶于20毫升二氯甲烷中,用EDCI·HCl(0.441g,2.3mmol)处理,滴加HOBT·H2O(0.311g,2.3mmol)和O-苄基羟胺盐酸盐(0.276g,1.73mmol)。滴加4-甲基吗啉(0.506g,5.0mmol),并在室温搅拌反应混合物过夜。该样品用乙酸乙酯稀释,并依次用5%HCl和饱和碳酸氢钠溶液洗涤。有机提取液用硫酸钠干燥并浓缩。残余物经色谱纯化(硅胶,在己烷中的10%EtOAc),得到0.400g3-[2-(苄氧基氨基甲酰基-甲基)-3-甲基-丁酰氨基]-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-戊酸苄基酯,为白色固体。步骤E
向3-[2-(苄氧基氨基甲酰基-甲基)-3-甲基-丁酰氨基]-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-戊酸苄基酯(0.237g,实施例5,步骤D)在75mL THF中的溶液中加入10%Pd/C(0.50g),并在室温和50psi氢气压下将该混合物氢化5小时。将反应混合物过滤并浓缩。残余物在乙酸乙酯和0.5 N NaOH溶液之间分配。水层用HCl酸化并用EtOAc萃取。有机提取液用硫酸钠干燥并浓缩,残余物在乙醚/己烷中研制。过滤收集固体并干燥,得到5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-羟基氨基甲酰基甲基-3-甲基-丁酰氨基)-4-氧代-戊酸(化合物15)。MS(APCI)m/z 518.1(M+1,100%)。C22H35N3O9S×0.45C4H8O2×0.59H2O(567.880)的分析计算值:C,50.34;H,7.06;N,7.40。实测值:C,50.34;H,6.80;N,7.40。
按照实施例15所述方法可以制备下列化合物。
实施例16
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-
氧代-戊酸为白色泡沫状固体。MS(APCI)m/z 645.3(M+1,79.2%)和285.1(100%)。C32H44N4O8S×0.85H2O(660.107)的分析计算值:C,58.23;H,6.98;N,8.49。实测值:C,58.23;H,6.74;N,8.26。
实施例17
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[[3-(4-羟基苯基)-丙基氨基甲酰基]-甲基]-丁酰氨基}-4-氧
代-戊酸为灰白色固体。MS(APCI)m/z:636.2(M+1,36.1%)和376.1(100%)。C31H45N3O9S×0.40H2O(642.989)的分析计算值:C,57.91;H,7.18;N,6.54。实测值:C,58.10;H,7.46;N,6.14。
按照与实施例2类似的方法,使用合适的原料,可以制备相应的化合物(实施例18-20)。
实施例18
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-萘-2-基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊
酸为白色固体。MS(APCI)m/z 656.2(M+1,31.2%),217.1(100%)。C34H45NO8S×0.90H2O(672.031)的分析计算值:C,60.77;H,7.02;N,6.25。实测值:C,60.80;H,6.95;N,5.93。
实施例19
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(7-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰
氨基)-4-氧代-戊酸为粉红色固体。MS(APCI)m/z 659.3(M+1,31.2%),399.2(100%)。C33H46N4O8S×0.2H2O(662.424)的分析计算值:C,59.84;H,7.06;N,8.46。实测值:C,59.98;H,7.35;N,8.08。
实施例20
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(6-氟-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨
基)-4-氧代-戊酸为泡沫状灰白色固体。MS(APCI)m/z 663.3(M+1,14.1%),403.2(100%)。C32H43FN4O8S×0.90H2O(678.998)的分析计算值:C,56.61;H,6.65;N,8.25。实测值:C,56.92;H,6.78;N,7.86。
按照与实施例7类似的方法,使用合适的原料,可以制备相应的化合物(实施例21-23)。
实施例21
3-[3-甲基-2-({甲基-[2-(1-甲基-1H-吲哚-3-基)-乙基]氨基甲
酰基}甲基)-丁酰氨基]-4-氧代-丁酸为泡沫状灰白色固体。MS(APCI)m/z 428.3(M-1,100%)。C23H31N3O5×0.35CF3CO2H(469.429)的分析计算值:C,60.64;H,6.73;N,8.95。实测值:C,60.46;H,6.93;N,8.78。
实施例22
3-(3-甲基-2-{[甲基-(2-苯氧基-乙基)-氨基甲酰基]甲基}-丁酰
氨基)-4-氧代-丁酸为泡沫状白色固体。MS(APCI)m/z 393.2(M+1,100%)。C20H28N2O6×0.85H2O(407.769)的分析计算值:C,58,91;H,7.34;N,6.87。实测值:C,58.87;H,7.02;N,6.59。
实施例23
3-(2-{[2-(5,6-二甲基苯并咪唑-1-基)-乙基氨基甲酰基]甲基}-
3-甲基-丁酰氨基)-4-氧代-丁酸三氟乙酸盐为白色固体。MS(APCI)m/z 431.1(M+1,35.7%),190.2(100%)。C22H30N4O5×1.30CF3CO2H(578.740)的分析计算值:C,51.06;H,5.45;N,9.68。实测值:C,51.03;H,5.50;N,9.38。
按照与实施例9类似的方法,用合适的原料,可以制备相应的化合物(实施例24-25)。
实施例24
5-(7,7-二甲基-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-
[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸为灰白色固体。MS(APCI)m/z 606.1(M+1),360.1(100%)。C31H47N3O7S×0.25CF3CO2H(634.306)的分析计算值:C,59.65;H,7.51;N,6.62。实测值:C;59.73;H,7.67;N,6.27。
实施例25
5-(7,7-二甲基-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基}-4-氧代
-戊酸为褐色固体。MS(APCI)m/z 645.2(M+1),399.1(100%)。C33H48N4O7S×0.34CF3CO2H(683.605)的分析计算值:C,59.18;H,7.13;N,8.20。实测值:C,59.34;H,7.13;N,7.81。
按照与实施例15类似的方法,用合适的原料,可以制备下列化合物(实施例26-34)。
实施例26
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-吡啶-4-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-
戊酸为灰白色固体。MS(APCI)m/z 621.1(M+1,5.1%),261.1(100%)。C30H44N4O8S×1.26CF3CO2H(764.442)的分析计算值:C,51.10;H,5.97;N,7.33。实测值:C,51.06;H,6.06;N,7.08。
实施例27
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-喹啉-2-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-
戊酸为灰白色固体。MS(APCI)m/z 671.3(M+1,70.5%),158.1(100%)。C34H46N4O8S×0.95H2O(687.946)的分析计算值:C,59.36;H,7.02;N,8.14。实测值:C,59.60;H,6.71;N,7.75。
实施例28
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-萘-1-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊
酸为灰白色固体。MS(APCI)m/z 670.3(M+1,79.2%),410.2(100%)。C35H47N3O8S×0.90EtOAc(749.141)的分析计算值:C,61.89;H,7.29;N,5.61。实测值:C,61.90;H,7.28;N,5.57。
实施例29
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-吡啶-3-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-
戊酸为灰白色固体。MS(APCI)m/z 621.1(M+1,6.5%),261.1(100%)。C30H44N4O8S×1.20CF3CO2H(757.600)的分析计算值:C,51.37;H,6.23;N,7.34。实测值:C,51.37;H,6.01;N,7.40。
实施例30
3-{2-[(2-苯并咪唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨基}-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-
氧代-戊酸为泡沫状白色固体。MS(APCI)m/z 646.2(M+1,10.4%),286.1(100%)。C31H43N5O8S×1.46CF3CO2H(812.256)的分析计算值:C,50.16;H,5.52;N,8.62。实测值:C,50.18;H,5.73;N,8.46。
实施例31
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰
氨基}-4-氧代-戊酸为白色固体。MS(APCI)m/z 659.2(M+1,41.6%),399.1(100%)。C33H46N4O8S×0.17CF3CO2H(678.205)的分析计算值:C,59.05;H,6.86;N,8.26。实测值:C,59.07;H,6.95;N,7.98。
实施例32
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-吡啶-4-基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-
戊酸为白色固体。MS(APCI)m/z 608.2(M+2,64.9%),607.2(M+1,54.5%),347.2(100%)。C29H42N4O8S×1.66CF3CO2H(796.024)的分析计算值:C,48.77;H,5,53;N,7.04。实测值:C,49.12;H,5.43;N,6.60。
实施例33
3-(2-{[2-(5-乙酰基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺
酰氨基)-4-氧代-戊酸为白色固体。MS(APCI)m/z 687.3(M+1,18.7%),327.2(100%)。C34H46N4O9S×0.75H2O(700.343.)的分析计算值:C,58.31;H,6.84;N,8.00。实测值:C,58.51;H,6.88;N,7.61。
实施例34
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(1H-四唑-5-基)-乙基氨基甲酰基]-甲基}-丁酰氨基)-4-
氧代-戊酸为灰色固体。MS(APCI)m/z 596.3(M-1,24.7%),113.2(100%)。C25H39N7O8S×CF3CO2H×0.27Et2O(731.733)的分析计算值:C,46.09;H,5.88;N,13.40。实测值:C,46.08;H,5.78;N,13.37。
实施例35
N4-(2-苯并咪唑-1-基-乙基)-N1-(2-乙氧基-5-氧代-四氢呋喃-3-
基)-2-异丙基-琥珀酰胺步骤A
将N-苄氧羰基-3-氨基-4-氧代-丁酸β-叔丁酯二乙基乙缩醛(24.1g,63.2mmol,按照Chapman K.T.的方法(Bioorganic & MedicinalChemistry Letters 1992;2:613-618、由Cbz-Asp(OtBu)-OH制备)在150mL乙醇中的溶液用1.0g 20%的Pd/C处理。样品在室温和51psi氢气压下氢化3.5小时。将样品过滤并浓缩,得到15.8g(约100%)3-氨基-4-氧代-丁酸β-叔丁酯二乙基乙缩醛,为黄色液体。MS(APCI)m/z 248.1(M+1,100%)。步骤B
将3-氨基-4-氧代-丁酸β-叔丁酯二乙基乙缩醛(15.8g,63.9mmol,实施例35,步骤A)、(S)-2-异丙基-琥珀酸4-叔丁酯(15.2g,70.3mmol,实施例2,步骤C)、EDCI×HCl(13.5g,70.4mmol)、HOBT×H2O(10.8g,70.5mmol)和4-甲基吗啉(8.8mL,80.0mmol)在250毫升二氯甲烷中的混合物在室温搅拌12小时。将该溶液浓缩,在乙酸乙酯和饱和碳酸氢钠溶液之间分配。有机提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩。所得深棕色油经色谱纯化(MPLC,硅胶,100%二氯甲烷至2%甲醇的二氯甲烷溶液),得到13.9g(49%)3-(2-叔丁氧羰基甲基-3-甲基-丁酰氨基)-4-氧代-丁酸β-叔丁酯二乙基乙缩醛,为淡黄色油。MS(APCI)m/z 224.1(100%)。步骤C
将3-(2-叔丁氧羰基甲基-3-甲基-丁酰氨基)-4-氧代-丁酸β-叔丁酯二乙基乙缩醛(8.3g,18.6mmol,实施例35,步骤B)在100毫升二氯甲烷中的溶液用20毫升三氟乙酸处理。该溶液在室温搅拌2小时,浓缩,然后在EtOAc和饱和KH2PO4溶液之间分配。有机提取液用盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩,得到3.8g(71%)N-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-琥珀酰胺酸,为黄色油。MS(APCI)m/z 288.1(M+1,100%)。步骤D
将N-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-琥珀酰胺酸(3.8g,13.1mmol,实施例35,步骤C)、1-(2-氨基乙基)苯并咪唑(3.2g,19.8mmol,采用Cuadro A.M.等的方法(Synthetic.Communications,1991;21:535-544)、由苯并咪唑制备)、HOBT×H2O(2.4g,15.8mmol)、EDCI×HCl(3,0g,15.8mmol)和N-甲基吗啉(2.2mL,20.0mmol)在100mL二氯甲烷中的混合物在室温搅拌12小时。将该溶液浓缩,然后在乙酸乙酯和饱和碳酸氢钠溶液之间分配。有机提取液用饱和KH2PO4和盐水溶液洗涤、用硫酸镁干燥,过滤并浓缩。所得褐色油状固体经色谱纯化(MPLC,硅胶,在二氯甲烷中的5%甲醇),得到2.8g(49%)N4-(2-苯并咪唑-1-基-乙基)-N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-琥珀酰胺,为白色泡沫状固体。MS(APCI)m/z 432.2(M+2,100%)。C22H30N4O5(430.508)的分析计算值:C,61.38;H,7.02;N,13.01。实测值:C,61.18;H,6.95;N,13.05。
按照与实施例35类似的方法,用合适的原料,可以制备相应的化合物(实施例36-52)。非市售的2-芳基-乙胺可以按照Cuadro A.M.等的方法制备(Synthetic.Communications,1991;21:535-544)。
实施例36
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-[2-(1H-吲哚-3-基)-
乙基]-2-异丙基-琥珀酰胺为灰白色固体。MS(APCI)m/z 430.3(M+1,100%)。C23H31N3O5×0.25H2O(434.024)的分析计算值:C,63.65;H,7.32;N,9.68。实测值:C,63.68;H,7.34;N,9.36。
实施例37
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[2-(1-甲基
-1H-吲哚-3-基)-乙基]-琥珀酰胺为灰白色固体。MS(APCI)m/z 444.3(M+1,53.5%),299.2(100%)。C24H33N3O5(443.548)的分析计算值:C 64.99;H,7.50;N,9.47。实测值:C,65.16;H,7.47;N,9.40。
实施例38
N4-[2-(5,6-二氯-苯并咪唑-1-基)-乙基]-N1-(2-乙氧基-5-氧代-
四氢呋喃-3-基)-2-异丙基-琥珀酰胺为白色固体。MS(APCI)m/z 354.1(100%)。C22H28Cl2N4O5(499.398)的分析计算值:C,52.91;H,5.65;N,11.22。实测值:C,52.91;H,5.70;N,11.07。
实施例39
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-(2-苯氧基-
乙基)-琥珀酰胺为白色固体。MS(APCI)m/z 407.2(M+1,66.2%),262.1(100%)。C21H30N2O6(406.483)的分析计算值:C,62.05;H,7.44;N,6.89。实测值:C,62.29;H,7.49;N,6.74。
实施例40
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[2-(6-甲氧
基-1H-吲哚-3-基)-乙基]-琥珀酰胺为白色固体。MS(APCI)m/z 460.1(M+1,100%)。C24H33N3O6(459.547)的分析实测值:C,62.73;H,7.24;N,9.14。实测值:C,63.11;H,7.02;N,9.11。
实施例41
N4-(2-苯并三唑-1-基-乙基)-N1-(2-乙氧基-5-氧代-四氢呋喃-3-
基)-2-异丙基-琥珀酰胺为黄色固体。MS(APCI)m/z 432.1(M+1,100%)。C21H29N5O5(431.496)的分析实测值:C,58.46;H,6.77;N,16.23。实测值:C,56.96;H,6.45;N,15.64。
实施例42
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-(2-吲唑-1-基-乙基)-
2-异丙基-琥珀酰胺为黄色固体。MS(APCI)m/z 431.2(M+1,100%)。C22H30N4O5(430.508)的分析计算值:C,61.38;H,7.02;N,13.01。实测值:C,60.91;H,7.16;N,12.81。
实施例43
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-(2-苯氨基-
乙基)-琥珀酰胺为灰白色固体。MS(APCI)m/z 406.1(M+1,100%)。C21H31N3O5×0.15H2O(408.201)的分析计算值:C,61.79;H,7.73;N,10.29。实测值:C,61.77;H,7.56;N,10.20。
实施例44
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-[2-(6-氟-1H-吲哚-3-
基)-乙基]-2-异丙基-琥珀酰胺为白色固体。MS(APCI)m/z 446.1(M-1,100%)。C23H30FN3O5(447.511)的分析计算值:C,61.73;H,6.76;N,9.39。实测值:C,62.22;H,6.59;N,10.45。
实施例45
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-[2-(7-甲基-1H-吲哚-
3-基)-乙基]-2-异丙基-琥珀酰胺为白色固体。MS(APCI)m/z 442.1(M-1,100%)。C24H33N3O5(443.548)的分析计算值:C,64.99;H,7.50;N,9.47。实测值:C,65.28;H,7.65;N,9.46。
实施例46
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[2-(2-甲基
-苯并咪唑-1-基)-乙基]-琥珀酰胺为泡沫状灰白色固体。MS(APCI)m/z 446.2(M+2,55.9%),445.2(M+1,51.5%),300.1(100%)。C23H32N4O5×0.50H2O(453.543)的分析计算值:C,60.91;H,7.33;N,12.35。实测值:C,60.94;H,7.04;N,12.05。
实施例47N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[3-(3,4,5-
三甲氧基-苯基)-丙基]-琥珀酰胺为白色固体。MS(APCI)m/z 495.1(M+1,100%)。C25H38N2O8(494.590)的分析计算值:C,60.71;H,7.74;N,5.66。实测值:C,60.47;H,7.85;N,5.77。
实施例48
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[2-(苯基)-
乙基]-琥珀酰胺为白色固体。MS(APCI)m/z 389.1(M-1,100%)。C21H30N2O5(390.484)的分析计算值:C,64.60;H,7.74;N,7.17。实测值:C,64.50;H,7.90;N,6.83。
实施例49N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[4-(苯基)-
丁基]-琥珀酰胺为蓬松的白色固体。MS(APCI)m/z 419.1(M+1,100%)。C23H34N2O5(418.538)的分析计算值:C,66.01;H,8.19,N,6.69。实测值:C,65.91;H,8.21;N,6.50。
实施例50
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-(2-吲哚-1-基-乙基)-
2-异丙基-琥珀酰胺为深红棕色固体。MS(APCI)m/z 430.1(M+1,100%)。C23H31N3O5(429.521)的分析计算值:C,64.32;H,7.28;N,9.78。实测值:C,64.68;H,7.02;N,10.07。
实施例51N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[4-(苯基)-
丙基]-琥珀酰胺为褐色固体。MS(APCI)m/z 405.1(M+1,100%)。C22H32N2O5(404.511)的分析计算值:C,65.32;H,7.97;N,6.93。实测值:C,66.27;H,8.07;N,7.21。
实施例52
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-[2-(5-氟-1H-吲哚-3-
基)-乙基]-2-异丙基-琥珀酰胺为灰白色固体。MS(APCI)m/z 446.1(M-1,100%)。C23H30FN3O5(447.5 11)的分析计算值:C,61.73;H,6.76;N,9.39。实测值:C,61.35;H,6.78;N,9.36。
实施例53
3-{2-[(2-苯并咪唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰
将N4-(2-苯并三唑-1-基-乙基)-N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-琥珀酰胺(1.25g,2.54mmol,实施例35,步骤D)在25毫升乙腈中的溶液用25毫升5%HCl溶液处理。将该样品搅拌1小时,然后浓缩得到灰白色固体。样品用丙酮洗涤,过滤并真空干燥,得到1.10g 3-{2-[(2-苯并咪唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨基}-4-氧代-丁酸盐酸盐,为白色固体,熔点134-141℃(分解)。MS(APCI)m/z 403.3(M+1,100%)。C20H26N4O5×HCl×1.18H2O(460.173)的分析计算值:C,52.20;H,6.43;N,12.18。实测值:C,52.21;H,6.70;N,11.52。
按照与实施例53类似的方法,使用合适的原料,可以制备相应的化合物(实施例54-62)。
实施例54
3-(3-甲基-2-{[2-(1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲
将反应混合物碱化,萃取,然后经色谱纯化(MPLC,硅胶,1%CF3CO2H-20%丙酮的二氯甲烷溶液),得到标题化合物,为灰色固体。MS(APCI)m/z 416.2(M+1,32.5%),398.1(M-17,100%)。C22H29N3O5×0.05CF3CO2H(421.195)的分析计算值:C,63.02;H,6.95;N,9.98。实测值:C,63.16;H,6.84;N,9.62。
实施例55
3-(2-{[2-(5-氟-1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲
基}-3-甲基-丁酰氨基)-4-氧代-丁酸
将反应混合物碱化,萃取,然后经色谱纯化(MPLC,硅胶,1%HCO2H-20%丙酮的二氯甲烷溶液),得到标题化合物,为白色固体。MS(APCI)m/z 434.2(M+1,100%)。C22H28FN3O5×0.96HCO2H(477.669)的分析计算值:C,57.73;H,6.31;N,8.80。实测值:C,57.73;H,6.39;N,8.65。
实施例56
3-(2-{[2-(5,6-二氯-苯并咪唑-1-基)-乙基氨基甲酰基]-甲基}-
3-甲基-丁酰氨基)-4-氧代-丁酸为白色固体。MS(APCI)m/z 354.1/356.1/358.1(M+1,100/48.6/14.3%)。C20H24Cl2N4O5×HCl×0.50H2O(516.813)的分析计算值:C,46.48;H,5.07;N,10.84。实测值:C,46.56;H,5.31;N,10.17。
实施例57
3-(2-{[(2-苯并咪唑-1-基-乙基)-甲基-氨基甲酰基]-甲基}-3-
甲基-丁酰氨基)-4-氧代-丁酸为浅褐色固体。MS(APCI)m/z 417.2(M+1,100%)。C21H28N4O5×2.57HCl(510.186)的分析计算值:C,49.44;H,6.04;N,10.98。实测值:C,49.46;H,6.41;N,10.63。
实施例58
3-{2-[(2-苯并三唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰
氨基}-4-氧代-丁酸为灰白色固体。MS(APCI)m/z 404.0(M+1,100%)。C19H25N5O5×1.54HCl×0.59H2O(470.221)的分析计算值:C,48.53;H,5.94;N,14.89。实测值:C,48.54;H,5.94;N,14.51。
实施例59
3-{2-[(2-吲唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨
基}-4-氧代-丁酸为灰白色固体。MS(APCI)m/z 403.1(M+1,100%)。C20H26N4O5×1.34HCl×1.22H2O(473.290)的分析计算值:C,50.76;H,6.34;N,11.84。实测值:C,50.75;H,6.34;N,11.71。
实施例60
3-[2-({[2-(5,6-二甲基-苯并咪唑-1-基)-乙基]-甲基氨基甲酰
基}-甲基)-3-甲基-丁酰氨基]-4-氧代-丁酸为白色固体。MS(APCI)m/z 443.1(M-1,100%)。C23H32N4O5×2.0HCl×0.35H2O(523.763)的分析计算值:C,52.74;H,6.68;N,10.70。实测值:C,52.75;H,6.88;N,10.39。
实施例61
3-[2-({[2-(2-甲基-苯并咪唑-1-基)-乙基]-甲基氨基甲酰基}-
甲基)-3-甲基-丁酰氨基]-4-氧代-丁酸为灰白色固体。MS(APCI)m/z 415.1(M-1,100%)。C21H28N4O5×1.1HCl(456.588)的分析计算值:C,55.24;H,6.42;N,12.27。实测值:C,55.14;H,6.64;N,11.01。
实施例62
3-(3-甲基-2-{[3-(3,4,5-三甲氧基苯基)-丙基氨基甲酰基]-甲
基}-丁酰氨基)-4-氧代-丁酸为白色固体。MS(APCI)m/z 467.1(M+1,100%)。C23H34N2O8×0.70H2O(479.147)的分析计算值:C,57.66;H,7.45;N,5.85。实测值:C,57.44;H,7.13;N,5.72。
实施例63
3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-
氧代-丁酸乙酯步骤A
将(S)-2-异丙基琥珀酸1-苄基酯(10.1g,40.2mmol,实施例3,步骤A)、2-苯氧基-1-乙胺(6.1g,44.2mmol)、HOBT×H2O(7.7g,50.2mmol)、EDCI×HCl(9.6g,50.2mmol)和N-甲基吗啉(6.6mL,60.0mmol)在100毫升二氯甲烷中的混合物在室温搅拌12小时。将样品浓缩,然后在乙酸乙酯和饱和碳酸氢钠溶液之间分配。有机提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩。所得棕色液体经色谱纯化(MPLC,硅胶,80%己烷-20%EtOAc至50%己烷-50%EtOAc),得到12.3g(83%)(S)-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-3-甲基-丁酸苄基酯,为淡黄色液体。MS(APCI)m/z 370.0(M+1,100%)。
在100毫升乙醇中,在球压下,用20%Pd/C将(S)-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-3-甲基-丁酸苄基酯(12.3g,33.2mmol)氢化,得到9.6g(约100%)(S)-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-3-甲基-丁酸,为淡黄色油。MS(APCI)m/z 280.0(M+1,100%)。步骤B
将(S)-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-3-甲基-丁酸(4.8g,17.2mmol,实施例63,步骤A)、3-氨基-4-戊酸乙酯盐酸盐(3.8g,21.2mmol,采用Hauser F.M.等,J.Org.Chem.1987;52:5041-5044的方法制备)、HOBT×H2O(3.3g,21.5mmol)、EDCI×HCl(4.1g,21.5mmol)和N-甲基吗啉(4.7mL,42.7mmol)在150毫升二氯甲烷中的混合物在室温搅拌12小时。将样品浓缩,然后在EtOAc和饱和碳酸氢钠溶液之间分配。有机提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩。所得黄色油状固体经色谱纯化(MPLC,硅胶,25%己烷-75%EtOAc),得到4.2g(60%)3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-戊酸乙酯,为蜡状淡黄色固体。MS(APCI)m/z 405.1(M+1,100%)。步骤C
在-78℃,向3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-戊酸乙酯(4.2g,10.3mmol,实施例63,步骤B)在100mL二氯甲烷中的溶液中通入臭氧,直至变成蓝色。在-78℃,通过滴加二甲基亚砜(2.3mL,31.3mmol)终止反应。将样品浓缩,然后在EtOAc和饱和碳酸氢钠溶液之间分配。有机提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤,浓缩并经色谱纯化(MPLC,硅胶,25%己烷-75%EtOAc),得到3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-丁酸乙酯,为白色固体、MS(APCI)m/z 407.1(M+1,100%)。C21H30N2O6×0.17H2O(409.546)的分析计算值:C,61.59;H,7.47;N,6.84。实测值:C,61.57;H,7.46;N,6.69。
实施例64
3-氰基3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰
将4-氨基-3-[(苄氧羰基)-氨基]-4-氧代-丁酸(8.9g,33.6mmol)和10滴浓硫酸在250毫升乙醇中的溶液回流12小时。将该溶液冷却,浓缩,然后在EtOAc和饱和碳酸氢钠溶液之间分配。有机提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩,得到4.7g(48%)4-氨基-3-[(苄氧羰基)-氨基]-4-氧代-丁酸乙酯,为白色固体。MS(APCI)m/z 295.0(M+1,100%)。C14H18N2O5(294.310)的分析计算值:C,57.14;H,6.16;N,9.52。实测值:C,57.28;H,6.11;N,9.45。
在100毫升乙醇中,在球压下,用20%Pd/C将4-氨基-3-[(苄氧羰基)-氨基]-4-氧代-丁酸乙酯(2.1g,7.4mmol)氢化,得到1.2g(约100%)3,4-二氨基-4-氧代丁酸乙酯,为无色油状固体。
MS(APCI)m/z 161.1(M+1,100%)。步骤B
将(S)-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-3-甲基-丁酸(2.5g,9.0mmol,实施例63,步骤A)、3,4-二氨基-4-氧代丁酸乙酯(1.2g,7.4mmol,实施例64,步骤A)、HOBT×H2O(1.4g,19.1mmol)、EDCI×HCl(3.6g,18.6mmol)和N-甲基吗啉(2.1mL,19.1mmol)在100毫升二氯甲烷中的混合物在室温搅拌12小时。将样品浓缩,然后在EtOAc和饱和碳酸氢钠溶液之间分配。有机提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩。所得灰白色油状固体经色谱纯化(MPLC,硅胶,5%甲醇的氯仿溶液),得到0.35g(11%)4-氨基-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-丁酸乙酯,为白色固体。MS(APCI)m/z 420.1(M-1,30.9%),374.1(100%)。C21H31N3O6(421.498)的分析计算值:C,59.84;H,7.41;N,9.97。实测值:C,60.23;H,7.38;N,9.90。步骤C
在0℃和氮气氛下,向搅拌着的4-氨基-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-丁酸乙酯(0.35g,0.83mmol,实施例64,步骤B)和三乙胺(0.29mL,2.08mmol)在50毫升THF中的溶液中滴加三氟乙酸酐(0.14mL,0.99mmol)。将样品在0℃搅拌1小时,然后在0℃通过滴加饱和碳酸氢钠溶液(约10mL)终止反应。将样品浓缩,然后用乙酸乙酯萃取。有机提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩。经色谱纯化(MPLC,硅胶,25%己烷-45%EtOAc),得到0.21g(63%)3-氰基-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-丙酸乙酯,为白色固体。MS(APCI)m/z 404.1(M+1,100%)。C21H29N3O5×0.35H2O(409.788)的分析计算值:C,61.55;H,7.30;N,10.25。实测值:C,61.73;H,7.23;N,9.87。
实施例65
3-氰基-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰
将(S)-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-3-甲基-丁酸(1.67g,5.99mmol,实施例63,步骤A)、H-Asp(OtBu)-Ome·HCl(1.58g,6.59mmol)、HOBT·H2O(1.00g,6.53mmol)、EDCI·HCl(1.26g,6.57mmol)和N-甲基吗啉(1.5mL,13.64mmol)在50毫升二氯甲烷中的混合物在室温搅拌12小时。将样品浓缩,然后在EtOAc和饱和碳酸氢钠溶液之间分配。有机提取液用饱和KH2PO4和盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩。所得黄色油经色谱纯化(MPLC,硅胶,25%己烷/75%乙酸乙酯),得到1.69g(61%)2-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-琥珀酸4-叔丁酯1-甲酯,为蜡状白色固体。MS(APCI)m/z 465.2(M+1,100%)。步骤B
在室温,用1.0M氢氧化锂溶液(4.4mL,4.40mmol)处理2-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-琥珀酸4-叔丁酯1-甲酯(1.69g,3.65mmol,实施例65,步骤A)在20毫升THF中的溶液。将浑浊的样品在室温搅拌1小时,用饱和KH2PO4溶液(约50mL)酸化,浓缩(以除去大部分THF),然后用乙酸乙酯萃取。有机提取液用盐水溶液洗涤,用硫酸镁干燥并过滤,得到1.38g(84%)2-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-琥珀酸4-叔丁酯,为白色固体。MS(APCI)m/z 451.2(M+1,76.5%),179.1(100%)。C23H34N2O7×0.20H2O(454.140)的分析计算值:C,60.83;H,7.64;N,6.17。实测值:C,60.84;H,7.63;N,5.98。步骤C
在搅拌下,通过滴加氯甲酸异丁酯(0.32mL,2.47mmol)对2-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-琥珀酸4-叔丁酯(1.00g,2.23mmol,实施例65,步骤B)和N-甲基吗啉(0.31mL,2.82mmol)在25毫升二氯甲烷中的溶液(在约-45℃,干冰-乙腈浆状物)进行处理。将该样品搅拌15分钟,然后通过滴加浓氢氧化铵溶液(5mL)终止反应。使样品温热至室温,浓缩,然后用乙酸乙酯萃取。有机提取液用盐水溶液洗涤,用硫酸镁干燥并过滤,得到1.12g(>100%)4-氨基-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-丁酸叔丁酯,为白色固体。MS(APCI)m/z 448.1(M-1,92.6%),374.0(100%)。
采用实施例64步骤C中所述同样的条件,使上述伯酰胺脱水,然后经色谱纯化(MPLC,硅胶,25%己烷-75%EtOAc),得到0.64g(62%)3-氰基-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-丙酸叔丁酯,为白色固体。MS(APCI)m/z 305.1(100%)。步骤D
将3-氰基-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-丙酸叔丁酯(0.64g,1.48mmol,实施例65,步骤C)和5.0毫升三氟乙酸在25毫升二氯甲烷中的溶液在室温搅拌1小时。将该溶液浓缩,然后在EtOAc和饱和KH2PO4溶液之间分配。有机提取液用盐水溶液洗涤,用硫酸镁干燥,过滤并浓缩,得到淡黄色油。加入乙醚(约50毫升),并使油缓缓固化。将样品过滤并真空干燥,得到0.28g(49%)3-氰基-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-丙酸,为白色固体。MS(APCI)m/z 377.0(M+2,100%)。C19H25N3O5×1.20H2O(397.047)的分析计算值:C,57.48;H,6.96;N,10.58。实测值:C,57.53;H,6.68;N,10.28。
生物分析抑制作用研究
正如采用本文所述的方案、通过测量Ki(μM)和IC50(μM)值所证明的,式I化合物是ICE的抑制剂。用HGE(100mM HEPES,20%甘油v/v,0.5mM EDTA)进行最初8倍稀释的DMSO储液制备一系列本发明各化合物的稀释液,然后用HGE+12.5%DMSO进行7个系列的2倍稀释。将10微升的稀释储液或赋形剂(HGE+12.5%DMSO)一式三份置于96孔微滴板内。用分析缓冲剂(HGE,5mM DTT,15μM Ac-Tyr-Val-Ala-Asp-AMC;0.5nM最终酶浓度,预先温热至30℃)稀释酶,并以90μL/孔的浓度将该反应混合物加入微滴板中。在30℃,使用分别为385和460nm的激发和发射滤波器对底物的水解进行300秒的监测。对三条曲线计算平均值,并采用线性回归方法得出斜率。为了评价Ki值,百分抑制对抑制剂浓度的绘图符合可逆的、竞争性模型的非线性回归:其中竞争因子是(1+[S]/KM)=2。ICE比色剂量-反应(IC50)分析
通过由最初储液2倍系列稀释制备稀释的抑制剂储液,所选择的浓度应使大多数浓度的孔中达到约95%的抑制(以筛选结果或先前对IC50评价的尝试为基础)。将等分量的每种稀释液一式三份转入微滴板中。
用HGE缓冲剂(100mM Hepes pH 7.5,0.5mM EDTA,20%甘油,0.1%牛血清白蛋白(BSA))将ICE酶稀释至约24nM,并通过加入最终浓度为5mM的二硫苏糖醇激活活性。然后将活化的酶等分至含有抑制剂或赋形剂的各孔中,并将微滴板在室温预孵育60分钟。向各孔中加入至最终浓度50μM的底物(Ac-Tyr-Val-Ala-Asp-pNA),并将微滴板置于25℃恒温的微滴板读数器中。在加入底物后5分钟开始对各孔的吸光度(405nm)进行1小时的监测,并以此间吸光度的平均变化速率计算活性。PBMC细胞分析-IC50值的测定
通过本文所述的式I化合物抑制人外周血单核细胞(PBMCs)的IL-1β产生的能力,可以进一步证实它们是ICE的抑制剂。经用ficoll垫离心,从肝素化的血液中分离PBMC,然后用磷酸盐缓冲的盐水洗涤三次。将PBMC悬浮于含有RPMI 1640和谷酰胺、青霉素、链霉素和2%人AB血清的培养基中,然后以106细胞/孔的浓度涂布到96孔平底板上。PBMC用含有或不含式I化合物的10ng/mL脂多糖(LPS,E.Coli菌0111:B4;Calbiochem)刺激过夜。收获培养基,用ELISA试剂盒(R&D Systems)测定成熟的IL-1β的含量。在溴化3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓(MTT)存在下将细胞再培养4小时,以测定其生存能力。Ich-2比色剂量-反应(IC50)分析
如上所述对Ich-2酶的抑制作用进行分析,不同的是使用64nM的酶和60μM的Ich-2-特异性底物Ac-Leu-Glu-Val-Asp-pNA代替ICE底物Ac-Tyr-Val-Ala-Asp-pNA。
这些试验的结果示于表2中。
表2
ICE Ki ICE IC50 PBMC IC50 ICH2 IC50
实施例编号
(μM) (μM) (μM) (Caspase 4)
(μM)1 1.60 14.50 82.50 88.962 0.106 0.790 6.25 3.313 0.045 0.40 3.00 4.654 2.18 16.80 65.00 9.725 0.336 3.55 35.00 9.026 0.142 1.060 3.25 9.597 0.115 0.444 6.00 20.728 0.0150 0.54 3.75 --9 0.0234 0.053 2.10 4.2210 0.539 3.270 21.50 25.7411 0.058 0.440 5.50 15.6912 0.0128 0.061 1.20 1.7113 0.0067 0.052 2.35 0.2514 0.1066 0.0087 19.00 --15 0.441 2.050 17.50 13.0816 0.0025 0.0051 0.35 1.4717 0.0329 0.0790 2.25 4.6818 0.0236 0.0894 2.05 3.0119 0.0009 0.0085 0.40 2.3820 0.0015 0.0110 2.45 61.9721 0.0280 0.130 7.50 209.0722 0.1330 1.6700 19.00 --23 0.0029 0.0145 3.60 4.4324 0.0207 0.3600 1.60 8.6625 0.0058 0.0483 1.10 3.5426 0.0266 0.1360 2.00 9.9127 0.0175 0.1470 1.00 9.9328 0.0061 0.2540 0.55 5.5829 0.0245 0.1130 1.90 4.7930 0.0011 0.0052 0.41 3.1431 0.0004 0.0059 0.24 1.2432 0.0260 0.4580 3.30 14.1233 0.0065 0.0230 1.60 3.0934 0.0166 0.1150 2.60 1.10
ICE Ki ICE IC50 PBMC IC50 ICH2 IC50
实施例编号
(μM) (μM) (μM) (Caspase 4)
(μM)35 0.0511 1.0600 5.50 --36 0.6300 0.5990 1.30 101.1737 0.0297 0.5810 2.00 127.6038 0.0164 0.3770 3.40 18.7339 0.4465 13.2000 5.00 --40 0.0354 1.1500 2.90 --41 0.4090 13.0000 17.50 --42 0.1910 1.7300 7.50 --43 0.0981 2.2800 7.50 --44 0.0475 1.2200 2.50 --45 0.0370 0.7500 2.60 173.8346 0.0284 0.4380 6.50 366.5747 1.9300 112.0000 11.00 --48 1.0060 59.9000 13.50 --49 2.1500 123.0000 -- --50 0.0538 0.9240 2.00 --51 0.259 15.00 16.25 --52 0.0185 0.4855 0.75 --53 0.0200 0.0737 8.30 32.5154 0.0040 0.0370 2.85 11.1355 0.0079 0.0370 5.30 11.4856 0.0044 0.0286 3.25 4.0257 0.0229 0.2270 3.75 38.0358 0.0318 0.3360 7.75 10.6359 0.0332 0.0566 3.75 10.4060 0.0092 0.4680 5.00 12.7161 0.0047 0.0233 2.90 --62 0.274 2.560 23.0063 6.92 197.00 14.5064 >100 -- >100 --65 107.00 -- >100 --
下面的缩写用于该整个专利申请中:HEPES 4-(2-羟甲基)-1-哌嗪乙磺酸DTT 二硫苏糖醇EDTA 乙二胺四乙酸Ac 乙酰基Glu 谷氨酸LEU 亮氨酸Tyr 酪氨酸Val 缬氨酸Ala 丙氨酸Asp 天冬氨酸AMC 7-氨基-4-甲基香豆素PNA 对硝基苯胺mp 熔点EtOAc 乙酸乙酯MS 质谱THF 四氢呋喃t-Bu 叔丁基Me 甲基DMF 二甲基甲酰胺MPLC 中压液相色谱psig 磅/每平方英寸(标准度量)HOBt 1-羟基苯并三唑EDCI N-乙基-N′-二甲氨基丙基碳化二亚胺
Claims (35)
-OH、-(CH2)n芳基、
-(CH2)n-取代的芳基、
-(CH2)n-O-芳基、
-(CH2)n-O-取代的芳基、
-(CH2)n-S-芳基、
-(CH2)n-S-取代的芳基、
-(CH2)n-S-杂芳基、
-(CH2)n-S-取代的杂芳基、
-(CH2)n-NR’-芳基、
-(CH2)n-NR’-取代的芳基、
-(CH2)n-NR’-杂芳基、
-(CH2)n-NR’-取代的杂芳基、
-(CH2)n-杂芳基、或
2.权利要求1的化合物,其中
R’是氢或甲基。
3.权利要求1的化合物,其中
每个R’是氢。
4.权利要求1的化合物,其中
R3是氢,并且
R4是甲基、乙基或异丙基。
5.权利要求1的化合物,其中
R1是氢或甲基,并且
R2是-(CH2)n-苯基,
氢,
-(CH2)n-O-苯基,
-OH,
-(CH2)n-苯并咪唑基,
-(CH2)n-吲哚基,或
-(CH2)n-酚。
9.权利要求1的化合物,其中
R1是氢,并且
R2是-(CH2)n-吲哚基,
-(CH2)n-NH-苯基,
-(CH2)n-O-苯基,
-(CH2)n-取代的吲哚基,
-(CH2)n-四唑基,
-(CH2)n-苯基,
-(CH2)n-取代的苯基,
-(CH2)n-取代的苯并咪唑基,
-(CH2)n-苯并三唑基,
-(CH2)n-吲唑基,
-(CH2)n-苯并咪唑基,
-(CH2)n-吡啶基,
-(CH2)n-萘基,或
-(CH2)n-喹啉基。
10.下列化合物:
3-(2-甲基-3-苯乙基氨基甲酰基-丙酰氨基)-4-氧代-5-(2-苯基乙磺酰氨基)-戊酸;
3-(2-氨基甲酰基甲基-3-甲基-丁酰氨基)-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-[3-甲基-2-(苯乙基氨基甲酰基-甲基)-丁酰氨基]-4-氧代-戊酸;
3-(2-氨基甲酰基甲基-3-甲基-丁酰氨基)-4-氧代-5-(2-苯基乙磺酰氨基)-戊酸;
3-[3-甲基-2-(苯乙基氨基甲酰基-甲基)-丁酰氨基]-4-氧代-5-(2-苯基乙磺酰氨基)-戊酸;
5-(7,7-二甲基-双环[2.2.1]庚-1-基甲磺酰氨基)-3-[3-甲基-2-(苯乙基氨基甲酰基-甲基)-丁酰氨基]-4-氧代-戊酸;
(S,S)-3-{3-甲基-2-[(3-苯基丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-丁酸;
3-{3-甲基-2-[(3-苯氧基乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-丁酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-苯氧基乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
3-[3-甲基-2-(苯乙基氨基甲酰基-甲基)-丁酰氨基]-4-氧代-5-(3-苯基丙基硫烷基)-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(甲基-苯乙基-氨基甲酰基)-甲基]-丁酰氨基}-4-氧代戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代戊酸;
3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-5-(2-氧代-2H-色烯-6-基氧)-戊酸;
5-[3-(1H-咪唑-2-基)-萘-2-基氧]-3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-羟基氨基甲酰基甲基-3-甲基-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-戊酸;或
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[[3-(4-羟基苯基)-丙基氨基甲酰基]-甲基]-丁酰氨基}-4-氧代-戊酸。
11.下列化合物:
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(7-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(6-氟-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-[3-甲基-2-({甲基-[2-(1-甲基-1H-吲哚-3-基)-乙基]-氨基甲酰基}-甲基)-丁酰氨基)-4-氧代-戊酸;
3-{2-[(2-苯并咪唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨基}-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(1H-四唑-5-基)-乙基氨基甲酰基]-甲基}-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-3-{2-[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰氨基)-4-氧代-戊酸;
3-(3-甲基-2-{[2-(1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]甲基}-丁酰氨基)-4-氧代-丁酸;
3-[3-甲基-2-({甲基-[2-(1-甲基-1H-吲哚-3-基)-乙基]氨基甲酰基}甲基)-丁酰氨基]-4-氧代-丁酸;
3-{2-[(2-苯并咪唑-1-基-乙基氨基甲酰基)甲基]-3-甲基-丁酰氨基}-4-氧代-丁酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[3-(4-羟基-苯基)-丙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-吡啶-4-基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-萘-2-基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-吡啶-4-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-喹啉-2-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-萘-2-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;或
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-吡啶-3-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸。
12.下列化合物:
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-萘-2-基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(7-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(6-氟-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基}-4-氧代-戊酸;
3-[3-甲基-2-({甲基-[2-(1-甲基-1H-吲哚-3-基)-乙基]氨基甲酰基}甲基)-丁酰氨基]-4-氧代-丁酸;
3-(3-甲基-2-{[甲基-(2-苯氧基-乙基)-氨基甲酰基]甲基}-丁酰氨基)-4-氧代-丁酸;
3-(2-{[2-(5,6-二甲基苯并咪唑-1-基)-乙基氨基甲酰基]甲基}-3-甲基-丁酰氨基)-4-氧代-丁酸三氟乙酸盐;
5-(7,7-二甲基-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-苯基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(2-{[2-(1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-吡啶-4-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-喹啉-2-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-萘-1-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(3-吡啶-3-基-丙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;或
3-{2-[(2-苯并咪唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨基}-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-戊酸。
13.下列化合物:
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-{3-甲基-2-[(2-吡啶-4-基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-戊酸;
3-(2-{[2-(5-乙酰基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-4-氧代-戊酸;
5-(7,7-二甲基-2-氧代-双环[2.2.1]庚-1-基甲磺酰氨基)-3-(3-甲基-2-{[2-(1H-四唑-5-基)-乙基氨基甲酰基]-甲基}-丁酰氨基)-4-氧代-戊酸;
N4-(2-苯并咪唑-1-基-乙基)-N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-[2-(1H-吲哚-3-基)-乙基]-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[2-(1-甲基-1H-吲哚-3-基)-乙基]-琥珀酰胺;
N4-[2-(5,6-二氯-苯并咪唑-1-基)-乙基]-N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-(2-苯氧基-乙基)-琥珀酰胺;或
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[2-(6-甲氧基-1H-吲哚-3-基)-乙基]-琥珀酰胺。
14.下列化合物:
N4-(2-苯并三唑-1-基-乙基)-N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-(2-吲唑-1-基-乙基)-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-(2-苯氨基-乙基)-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-[2-(6-氟-1H-吲哚-3-基)-乙基]-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-[2-(7-甲基-1H-吲哚-3-基)-乙基]-2-异丙基-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[2-(2-甲基-苯并咪唑-1-基)-乙基]-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[3-(3,4,5-三甲氧基-苯基)-丙基]-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[2-(苯基)-乙基]-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[4-(苯基)-丁基]-琥珀酰胺;或
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-(2-吲哚-1-基-乙基)-2-异丙基-琥珀酰胺。
15.下列化合物:
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-2-异丙基-N4-[4-(苯基)-丙基]-琥珀酰胺;
N1-(2-乙氧基-5-氧代-四氢呋喃-3-基)-N4-[2-(5-氟-1H-吲哚-3-基)-乙基]-2-异丙基-琥珀酰胺;
3-{2-[(2-苯并咪唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨基}-4-氧代-丁酸;
3-(3-甲基-2-{[2-(1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-丁酰氨基)-4-氧代-丁酸;
3-(2-{[2-(5-氟-1-甲基-1H-吲哚-3-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-丁酸;
3-(2-{[2-(5,6-二氯-苯并咪唑-1-基)-乙基氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-丁酸;
3-(2-{[(2-苯并咪唑-1-基-乙基)-甲基-氨基甲酰基]-甲基}-3-甲基-丁酰氨基)-4-氧代-丁酸;
3-{2-[(2-苯并三唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨基}-4-氧代-丁酸;
3-{2-[(2-吲唑-1-基-乙基氨基甲酰基)-甲基]-3-甲基-丁酰氨基}-4-氧代-丁酸;
3-[2-({[2-(5,6-二甲基-苯并咪唑-1-基)-乙基]-甲基氨基甲酰基}-甲基)-3-甲基-丁酰氨基]-4-氧代-丁酸;
3-[2-({[2-(2-甲基-苯并咪唑-1-基)-乙基]-甲基氨基甲酰基}-甲基)-3-甲基-丁酰氨基]-4-氧代-丁酸;
3-(3-甲基-2-{[3-(3,4,5-三甲氧基苯基)-丙基氨基甲酰基]-甲基}-丁酰氨基)-4-氧代-丁酸;
3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-4-氧代-丁酸乙酯;
3-氰基-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-丙酸乙酯;或
3-氰基-3-{3-甲基-2-[(2-苯氧基-乙基氨基甲酰基)-甲基]-丁酰氨基}-丙酸。
16.药物组合物,含有权利要求1的化合物。
17.药物组合物,含有权利要求8的化合物。
18.治疗或预防中风的方法,该方法包括对患有中风、或处于患中风危险中的患者施用治疗有效量的权利要求1的化合物。
19.治疗或预防中风的方法,该方法包括对患有中风、或处于患中风危险中的患者施用治疗有效量的权利要求8的化合物。
20.治疗炎性疾病的方法,该方法包括对患有炎性疾病的患者施用治疗有效量的权利要求1的化合物。
21.治疗炎性疾病的方法,该方法包括对患有炎性疾病的患者施用治疗有效量的权利要求8的化合物。
22.权利要求20的方法,其中所述炎性疾病是类风湿性关节炎或炎性肠疾病。
23.权利要求21的方法,其中所述炎性疾病是类风湿性关节炎或炎性肠疾病。
24.治疗脓毒性休克的方法,该方法包括对患有脓毒性休克的患者施用治疗有效量的权利要求1的化合物。
25.治疗脓毒性休克的方法,该方法包括对患有脓毒性休克的患者施用治疗有效量的权利要求8的化合物。
26.治疗再灌注损伤的方法,该方法包括对患有再灌注损伤的患者施用治疗有效量的权利要求1的化合物。
27.治疗再灌注损伤的方法,该方法包括对患有再灌注损伤的患者施用治疗有效量的权利要求8的化合物。
28.治疗阿尔茨海默氏病的方法,该方法包括对患有阿尔茨海默氏病的患者施用治疗有效量的权利要求1的化合物。
29.治疗阿尔茨海默氏病的方法,该方法包括对患有阿尔茨海默氏病的患者施用治疗有效量的权利要求8的化合物。
30.治疗志贺氏菌病的方法,该方法包括对患有志贺氏菌病的患者施用治疗有效量的权利要求1的化合物。
31.治疗志贺氏菌病的方法,该方法包括对患有志贺氏菌病的患者施用治疗有效量的权利要求8的化合物。
32.治疗多法性硬化的方法,该方法包括对患有多法性硬化的患者施用治疗有效量的权利要求1的化合物。
33.治疗多法性硬化的方法,该方法包括对患有多法性硬化的患者施用治疗有效量的权利要求8的化合物。
34.抑制白介素-1β转化酶的方法,该方法包括对需要抑制白介素-1β转化酶的患者施用治疗有效量的权利要求1的化合物。
35.抑制白介素-1β转化酶的方法,该方法包括对需要抑制白介素-1β转化酶的患者施用治疗有效量的权利要求8的化合物。
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US8432098P | 1998-05-05 | 1998-05-05 | |
US60/084,320 | 1998-05-05 |
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CN1308542A true CN1308542A (zh) | 2001-08-15 |
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CN99808265A Pending CN1308542A (zh) | 1998-05-05 | 1999-04-30 | 白介素-1β转化酶的琥珀酰胺抑制剂 |
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EP (1) | EP1082127B1 (zh) |
JP (1) | JP2002513766A (zh) |
KR (1) | KR20010052307A (zh) |
CN (1) | CN1308542A (zh) |
AP (1) | AP2000001992A0 (zh) |
AT (1) | ATE298242T1 (zh) |
AU (1) | AU758120B2 (zh) |
BG (1) | BG105002A (zh) |
BR (1) | BR9911010A (zh) |
CA (1) | CA2327507A1 (zh) |
DE (1) | DE69925914T2 (zh) |
EA (1) | EA200001152A1 (zh) |
EE (1) | EE200000644A (zh) |
ES (1) | ES2242394T3 (zh) |
HR (1) | HRP20000744A2 (zh) |
HU (1) | HUP0101963A3 (zh) |
ID (1) | ID30124A (zh) |
IL (1) | IL139416A0 (zh) |
IS (1) | IS5674A (zh) |
NO (1) | NO20005537L (zh) |
OA (1) | OA11550A (zh) |
PL (1) | PL343837A1 (zh) |
SK (1) | SK16732000A3 (zh) |
TR (1) | TR200003252T2 (zh) |
WO (1) | WO1999056765A1 (zh) |
YU (1) | YU67900A (zh) |
ZA (1) | ZA200006881B (zh) |
Families Citing this family (16)
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JP2002538151A (ja) | 1999-03-02 | 2002-11-12 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | カテプシンの可逆的インヒビターとして有用な化合物 |
DE60035037T2 (de) | 1999-04-09 | 2008-01-31 | Cytovia, Inc., San Diego | Caspase inhibitoren und ihre verwendung |
WO2001009110A1 (en) * | 1999-07-30 | 2001-02-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Novel succinate derivative compounds useful as cysteine protease inhibitors |
BR0013666A (pt) | 1999-08-27 | 2002-05-14 | Cytovia Inc | "alfa"-hidróxi-ácidos substituìdos inibidores de caspases e o seu uso |
US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
US20020052323A1 (en) * | 2000-08-30 | 2002-05-02 | Jinhai Wang | Quinoline-(C=O)-(multiple amino acids)-leaving group compounds for pharmaceutical compositions and reagents |
CA2447999C (en) * | 2001-05-23 | 2011-04-26 | Vertex Pharmaceuticals Incorporated | Caspase inhibitors and uses thereof |
CA2463770A1 (en) | 2001-10-29 | 2003-05-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as reversible inhibitors of cysteine proteases |
US7115654B2 (en) | 2002-06-05 | 2006-10-03 | Sunesis Pharmaceuticals, Inc. | Caspase-1 inhibitors and methods for their use |
US7297714B2 (en) * | 2003-10-21 | 2007-11-20 | Irm Llc | Inhibitors of cathepsin S |
AU2005249503B2 (en) | 2003-11-10 | 2011-08-25 | Vertex Pharmaceuticals Incorporated | ICE inhibitors for the treatment of autoinflammatory diseases |
ZA200610133B (en) | 2004-05-15 | 2008-05-28 | Vertex Pharma | Treating seizures using ice inhibitors |
WO2007115231A2 (en) * | 2006-03-30 | 2007-10-11 | Chemocentryx, Inc. | Cxcr4 modulators |
US7671069B2 (en) | 2006-03-30 | 2010-03-02 | Chemocentryx, Inc. | Tricyclic, heteroaromatic compounds modulating CXCR4 and/ or CXCR7 |
US9365612B2 (en) | 2010-01-29 | 2016-06-14 | United States Of America As Represented By The Secretary, Department Of Health And Human Services | Caspase inhibitors |
JP6006908B2 (ja) | 2010-11-05 | 2016-10-12 | ブランダイス ユニバーシティBrandeis University | Ice阻害化合物およびその使用 |
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TW394760B (en) * | 1993-09-07 | 2000-06-21 | Hoffmann La Roche | Novel Carboxamides, process for their preparation and pharmaceutical composition containing the same |
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ID30124A (id) | 2001-11-08 |
EP1082127A1 (en) | 2001-03-14 |
EP1082127A4 (en) | 2002-10-09 |
HRP20000744A2 (en) | 2001-06-30 |
AU758120B2 (en) | 2003-03-13 |
HUP0101963A3 (en) | 2003-07-28 |
PL343837A1 (en) | 2001-09-10 |
NO20005537L (no) | 2000-12-20 |
EA200001152A1 (ru) | 2001-06-25 |
EP1082127B1 (en) | 2005-06-22 |
DE69925914D1 (de) | 2005-07-28 |
BG105002A (bg) | 2001-07-31 |
SK16732000A3 (sk) | 2001-06-11 |
AU3673099A (en) | 1999-11-23 |
IS5674A (is) | 2000-10-20 |
HUP0101963A2 (hu) | 2001-10-28 |
BR9911010A (pt) | 2005-12-06 |
CA2327507A1 (en) | 1999-11-11 |
AP2000001992A0 (en) | 2000-12-31 |
EE200000644A (et) | 2002-04-15 |
YU67900A (sh) | 2002-12-10 |
DE69925914T2 (de) | 2006-05-11 |
KR20010052307A (ko) | 2001-06-25 |
NO20005537D0 (no) | 2000-11-02 |
TR200003252T2 (tr) | 2001-04-20 |
IL139416A0 (en) | 2001-11-25 |
WO1999056765A1 (en) | 1999-11-11 |
JP2002513766A (ja) | 2002-05-14 |
ES2242394T3 (es) | 2005-11-01 |
OA11550A (en) | 2004-06-04 |
ATE298242T1 (de) | 2005-07-15 |
ZA200006881B (en) | 2002-05-25 |
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