CN1269806A - 用于治疗骨代谢疾病的含有一种精氨酸模拟物的肽,其制备方法,和含有这种化合物的药物 - Google Patents
用于治疗骨代谢疾病的含有一种精氨酸模拟物的肽,其制备方法,和含有这种化合物的药物 Download PDFInfo
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- CN1269806A CN1269806A CN98808822A CN98808822A CN1269806A CN 1269806 A CN1269806 A CN 1269806A CN 98808822 A CN98808822 A CN 98808822A CN 98808822 A CN98808822 A CN 98808822A CN 1269806 A CN1269806 A CN 1269806A
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- 239000003814 drug Substances 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
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- 229910052734 helium Inorganic materials 0.000 description 6
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- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 6
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
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- 239000012317 TBTU Substances 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
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Abstract
本发明涉及通式(Ⅰ)的化合物,它们的互变异构体,光学异构体,药学上可接受的盐和前药:其中R1,R2,R3和X可以相同或不同,其中R1,R2表示氢,一个氨基酸,肽基,烷基或芳基残基;R3表示羟基,低级烷氧基,或一个-NR31R32残基,其中R31,R32独立地表示氢,一个氨基酸,肽基,烷基或芳基残基;X表示一个氨基酸或一个肽;R4表示氢,羟基,氨基或C1-C4-烷基;m表示一个0到5之间的数字;R5表示一个任选取代的饱和的或不饱和的单或二环半分子,它可含有一个或多个杂原子;一个C1-C11烷基,它可具有取代基或间断的杂原子,以及它们的制备和作为药物的应用。
Description
本发明涉及新的用于治疗骨疾病的肽模拟物,其制备方法,和含有这种化合物的药物。
在健康个体中,骨的形成和降解过程实际上处于平衡状态,也就是说成骨细胞和破骨细胞的活性是平衡的。但是,如果这一平衡被打破,倾向破骨和/或倾向成骨将导致骨质降低以及骨结构和功能的退化。
截至目前,诸如雌性激素、降钙素和二膦酸(bisphosphonates)的骨吸回作用抑制剂被主要用于治疗骨代谢疾病。但是,这些药物的使用是受限制的,此外,并不是在所有的情况下都能显示出期望的效果。因而在骨疾病的治疗中,对骨形成具有刺激作用并且提高已经消失的骨质的化合物是特别重要的。
已知PTHrP(107-111)及其肽衍生物对骨吸回作用的抑制具有正面的影响(WO9210511;WO9424153)。但是,Valin等在细胞生理学杂志(J.CellPhysiol.)170(2),209-15(1997)上描述了PTHrP(107-111)对UMR106细胞的抗增殖效应。Whitfield等在细胞生理学杂志166(1),1-11(1996)描述了PTHrP(107-111)对PKC的刺激效应和对角质化细胞增殖的调节,而Kali等在内分泌学(Endocrinology)136(3),842-8(1995),描述了PTHrP(107-111)对破骨细胞的刺激。
令人惊奇的是现已发现本发明的肽模拟物对骨形成具有刺激效应,因而适用于骨疾病的一般的治疗。特别是它们可用于其中骨形成被干扰的情况下,也就是说它们特别适用于治疗骨骼系统的骨疾病,例如骨质疏松,脆骨病等,以及用于在例如矫形外科和正牙科,骨折愈合,骨合成,假关节中的骨重新形成的局部促进和骨诱导,以及骨移植物的整合。
由于这些性能,它们也可用于骨质疏松的预防。
而且,对于它们对骨代谢的影响,含有本发明的肽模拟物作为活性成分的药物构成类风湿关节炎、骨关节炎和退化性关节病的局部和全身治疗的基础。
本发明涉及通式(I)的化合物,它们的互变异构体,光学异构体,药学上可接受的盐和前药:其中R1,R2,R3和X可以相同或不同,其中R1,R2表示氢,一个氨基酸,肽基,烷基或芳基残基;R3表示羟基,低级烷氧基,或一个-NR31R32残基,
其中R31,R32独立地表示氢,一个氨基酸,肽基,烷基或芳基残基;X表示一个氨基酸或一个肽;R4表示氢,羟基,氨基或C1-C4-烷基;m表示一个0和5之间的数字;R5表示一个任选取代的饱和的或不饱和的单或二环半分子,它可含有一个或多个杂原子;一个C1-C11烷基,它可具有取代基或间断的杂原子。X最好是一个ω-氨基酸或二肽serinylalaryl;R4最好表示甲基或羟基;R1和R2最好独立地是氢;R3最好是羟基或氨基;m最好是1至3,优选1;特别优选残基(CHR4)mR5表示一个连接在一个蛋白原或非蛋白原的氨基酸的Cα上的残基。
碱金属盐,碱土金属盐,例如钙盐或镁盐,铵盐,乙酸盐或盐酸盐被主要用作药学上可接受的盐类,它们可通过通常的方式制备,例如,用无机或有机碱或无机酸例如氢氧化钠,氢氧化钾,氨水,C1-C4-烷基胺例如三乙基胺或盐酸滴定该化合物。这些盐通常是通过从水/丙酮中重新沉淀进行纯化的。
本发明的化合物的前药是在体内被转化成药学活性的化合物。最常见的前药是羧酸酯类,例如乙基酯类。
肽基表示肽残基。肽应被理解为由2至10个蛋白原或非蛋白原的相同或不同的氨基酸组成。肽最好含有2-5个氨基酸;特别优选的是具有2个氨基酸的肽。
氨基酸残基通常是指蛋白原或非蛋白原的氨基酸的残基。非蛋白原的氨基酸是指α-,β-,γ-,和ω-氨基羧酸,它们可任选地具有取代基或间断杂原子。
优选的ω-氨基羧酸是-NH-(CH2)n-CO-,n=1-10;-(CH2)n-基团可以是支链的或非支链的。
这种氨基酸的例子是L-和D-氨基酸,例如2-氨基-3-羟基-4-甲基戊酸,2-氨基-3-羟基-4-甲基戊酸,2-氨基-3-甲氧基丁酸,2,3-二氨基丙酸,2-氨基-2-甲基-3-羟基丙酸,2-氨基-2-甲基丁二酸,2-氨基-3-羟基-3-甲基丁酸,2-氨基-3-羟基-3-甲基丁酸,2,3-二氨基丙酸,2-氨基-2-甲基-3-羟基丙酸,2-氨基-2-甲基丁酸,2-氨基-2-甲基丁酸,2-氨基-2-甲基-4-戊烯酸,2-氨基-3-甲氧基丙酸,1-氨基-1-环己烷羧酸,1-氨基-1-环戊烷羧酸,1-氨基环丁烷羧酸,1-氨基环丙烷羧酸,2-(2-呋喃基)甘氨酸,2-氨基-3-氟丁酸,2-氨基异丁酸,3-氯丙氨酸,3-氟正亮氨酸,3-氟缬氨酸,3-氟丙氨酸,3-甲氧基缬氨酸,α-氰基丙氨酸,α-甲基亮氨酸,β-氯丙氨酸,β-氰基丙氨酸,β-羟基亮氨酸,β-羟基天冬氨酸,3-羟基天冬氨酸,2-氨基丁酸,烯丙基甘氨酸,γ-甲基亮氨酸,高丝氨酸,正亮氨酸,正缬氨酸,叔亮氨酸,2,3-二氨基丙酸,2,3-二氨基琥珀酸,2-氨基-4-戊烯酸,2-氨基丁酸,2-氨基庚酸,2-环丙基-2-甲基甘氨酸,4-硫代异亮氨酸,异苏氨酸,α-甲基天冬氨酸,α-甲基丝氨酸,β-羟基正缬氨酸,β-甲基天冬氨酸,高半胱氨酸,高丝氨酸,正亮氨酸,正缬氨酸,O-甲基丝氨酸,青霉胺,炔丙基甘氨酸,β-羟基天冬氨酸,乙烯基甘氨酸,β-羟基天冬氨酸,H-4,5-二氢-LEU-OH,H-α-MeVAL-OH,H-炔丙基-GLY-OH,H-另-ILE-OH,H-PRA-OH,H-反-4,5-脱氢LYS-OH,3-羟基天冬氨酸,6-羟基正亮氨酸,别-异亮氨酸,烯丙基甘氨酸,α-氨基-N-丁酸,γ-甲基亮氨酸,高丝氨酸,正缬氨酸,青霉胺,叔亮氨酸,乙烯基甘氨酸,内消旋-α,β-二氨基琥珀酸,O-氨基甲酰基-丝氨酸,S-甲基半胱氨酸,2-氨基-2-甲基丁烷二酸,2-氟-β-丙氨酸,β-丙氨酸,β-氨基丁酸,2,3-二氨基琥珀酸,β-氨基异丁酸,异丝氨酸。
优选的氨基酸是丙氨酸,丝氨酸,色氨酸,酪氨酸,苯丙氨酸,苏氨酸,组氨酸,瓜氨酸,高半胱氨酸,羟脯氨酸,羟基赖氨酸,鸟氨酸,肌氨酸,凝血酸,Cha(环己基丙氨酸),氨基丁酸,氨基戊酸,和氨基丙酸。
低级烷氧基表示甲氧基,乙氧基,丙氧基,异丙氧基或丁氧基,优选甲氧基。
烷基通常表示具有1至6个碳原子的线性或支链的烷基残基。
芳基通常表示具有6至14个碳原子的碳环半分子,或者5-或6-员的具有1,2或3个选自O,N,S的杂原子的杂环半分子,这些半分子可任选地具有一个或多个取代基,其中优选非取代的或任选取代的苯基或萘基残基。
单环半分子应被理解为饱和的或不饱和的具有3-8,优选5-7个碳原子,的环系统,它可任选地具有一个或多个间断的杂原子,例如氮,氧或硫,特别是环戊基,环己基,环庚基,吗啉基,硫代吗啉基,哌啶基,哌嗪基,四氢呋喃基,四氢吡喃基,苯基,吡啶基,嘧啶基,哒嗪基,吡嗪基,呋喃基,苯硫基,咪唑基,噻唑基,噁唑基,异噻唑基,异噁唑基,1,2,3-三唑基,或1,2,4-三唑基残基。特别是,低级烷基,烷氧基和卤素可作为取代基。
R5表示的双环半分子优选为一种残基,例如,萘基,四氢萘基,萘烷基,喹啉基,异喹啉基,四氢喹啉基,四氢异喹啉基,吲哚基,苯并咪唑基,吲唑基,羟吲哚基,苯并呋喃基,苯并苯硫基,苯并噻唑基,苯并噁唑基或嘌呤基残基,特别是一个吲哚基,萘基,苯并咪唑基,喹啉基,四氢喹啉基,苯并苯硫基,和苯并呋喃基残基。
术语“几个”当与单环或双环中的杂原子结合在一起使用时优选表示1,2或3,更优选表示1或2,最优选的杂原子是氮。
术语“几个”当与取代基结合使用时优选1至5,更优选1,2或3,最优选1或2。
R5表示的单环或双环的取代基是卤素,硝基,羟基,烷氧基,氨基,烷基氨基,二烷基氨基,卤代甲基,二卤代甲基,三卤代甲基,膦酰基,烷基膦酰基,二烷基膦酰基,SO2NH2,SO2NH(烷基),SO2N(烷基)2,SO2(烷基),乙酰基,甲酸基,腈,COOH,COO烷基,-OC(O)烷基,-NHC(O)O烷基,OC(O)O-芳基,-NHC(S)NH2,-NHC(S)NH烷基,-NHC(O)-芳基。
优选的取代基为甲基,乙基,丙基,异丙基,卤基,特别是氯基,氨基,乙酰基,烷基氨基,二烷基氨基,烷氧基,羟基烷基,和0至4个碳原子的烷基碳酸。
通式(I)的化合物的制备是通过已知的方法进行的。优选这一制备是分别使用前体(II),(III)和(IV)按照反应程式1,2和3进行的,其中,Y表示一个羧基基团。
通式(IV)的化合物是新的化合物,可用于含有(IV)的骨架结构的化合物的正交合成。对于R9的优选的残基是Fmoc。
程式1
程式1中的步骤a)至d)表示下列反应:a)NaBH3CN/MeOH/RT;b)PhCOCL/py/DMAP/RT;c)DBU/甲苯/RT/16小时;d)DIBAL-H/THE/-78℃;其中R6表示一个保护基团,例如,苯甲酰基,烷氧羰基或苄氧羰基,R7表示氢或低级烷基,例如甲基,乙基,丙基,丁基或叔丁基,R8表示烷基或芳基残基,例如甲基,乙基,三氟甲基,苯基,甲苯磺酰基或4-硝基苯基残基,优选甲基或甲苯磺酰基残基,L通常表示磺酸残基,例如甲烷-或三氟甲烷磺酸或对甲苯磺酸残基,或卤素例如氯,溴,碘,或乙酸基。
Mhal表示一种金属卤化物,例如NaCl,NaBr,KI,MgCl2或MgBr2。
式(5)的化合物已由描述(J.O.C.48,1129-31(1983))。式(5)的醇转化成式(6)的磺酸或乙酸酯是按照标准方法进行的。使用N-氯-,N-溴-或N-碘琥珀酰亚胺在三苯基膦(Ph3P)的存在下将式(5)的醇转化成式(6)的卤化物是以类似于文献中描述的方式进行的(例如,Tetrahedron Asym.4,1619-24(1993))。使用金属卤化物在DMSO中在高温下对丙二酸酯的脱羧化作用是公知的(T.L.957(1973))。式(9)的化合物已有描述(JACS,114,7324-25(1992))。式(10)的化合物的环氧化物的开环产生式(11)的烯丙醇是以类似于文献描述的方法进行的(Tetrahedron 24,5827-30(1968))。式(13)的化合物通过Claisen重排转化成通式(II)的化合物是以类似于文献描述的方法进行的(Tetrahedron,52,941-54(1996))。
程式2中的步骤a)至f)表示下列反应:a)Ac2O/吡啶/DMAPb)4NHCl/16小时;(14)/EtN(i-Pr)2c)(16),R7=Et/HMDS/n-BuLi/-78℃d)1N HCl/THF/RT/30分钟e)Boc2O/EtN(i-Pr)2/乙腈/16小时f)LiOH/THF-MeOH-H2O其中,R6和R7具有上述的意义。程式3程式3中的步骤a)至e)表示下列反应:a)HDMS/n-BULi/-78℃b)CH3COOH/THF/RT/30分钟c)R9Cl/EtN(i-Pr)2/THF/16小时d)4NHCl/二噁烷e)EtN(i-Pr)2/乙腈其中,R6和R7具有上述的意义,R9表示另外一个保护基团,例如Fmoc或Troc。
式(I)的化合物可在所有的普通的非毒性的,药学上可接受的载体,佐剂和添加剂中以液体或固体的形式或以气雾剂的形式通过口腔,肠道,肠胃外,局部,鼻腔,肺或直肠途径施用。式(I)的化合物也可局部施用在骨内(可任选地通过外科手术)。术语“肠胃外“包括皮下,静脉内,肌肉内供药或灌注。口施用形式可以是,例如,片剂,胶囊,包衣片剂,糖浆,溶液,悬浮液,乳液,驰剂等,它可含有一种或多种选自下组的添加剂:例如调味物质,甜味剂,色素,和防腐剂。口施用形式含有该活性组分以及非毒性的,药学上可接受的载体,它们适用于生产片剂,胶囊,包衣片剂等,例如碳酸钙,碳酸钠,乳糖,磷酸钙或磷酸钠;淀粉,甘露醇,甲基纤维素,滑石粉,高度分散的硅酸,高分子量脂肪酸(例如硬脂酸),花生油,橄榄油,石蜡,Miglyol,明胶,琼脂,硬脂酸镁,蜂蜡,十六烷醇,卵磷脂,甘油,动物和植物脂肪,固体高分子量聚合物(例如聚乙二醇)。可以为片剂,胶囊,包衣片剂等提供一种适当的包衣例如单硬脂酸甘油酯或二硬脂酸甘油酯,以避免对胃产生副反应,或者由于在胃肠道中延缓吸收而延长活性的时间。无菌的可注射的水或油溶液或悬浮液被优选用作注射介质,它们含有普通的添加剂例如稳定剂和增溶剂。这种添加剂可以是,例如,水,等渗盐溶液,1,3-丁二醇,脂肪酸(例如油酸)单-和二甘油酯,或Miglyol。对于直肠施用来说,可以使用所有的适当的非刺激性的添加剂,它们在常温下是固体的,而在直肠温度下是液态的,例如可可油和聚乙二醇。对于气雾施用,可使用药学上普通的载体介质。对于外用,可使用含有药学上通用的添加剂的膏剂,酊剂,凝胶,溶液或悬浮液。剂量可根据各种不同的因素进行确定,例如使用方式,种类,年龄和/或个体条件。日用剂量为约1-1000mg/人,优选约10-250mg/人,并且可以一次施用或多次施用。式(I)的化合物可以在骨中局部施用(任选地进行外科手术)。在骨中的施用(任选地进行外科手术)可以在溶液中或悬浮液中进行,可通过灌注或注射,局部或结合在载体上。例如,结合在载体上的式(I)的化合物可以以凝胶,膏剂,固体或植入物的包衣的形式施用。
作为载体,可使用生物相容的和可生物降解的材料。优选这些材料本身可额外诱导伤口愈合或骨形成。
对于局部施用,优选将式(I)的化合物埋植在聚合物凝胶或薄膜中,从而将它们固定,并将这些制品直接施用在待治疗的骨的位点上。这些聚合物凝胶或薄膜是由例如甘油,甲基纤维素,透明质酸,聚乙烯氧化物和/或polyoxamer。胶原质,明胶和藻元酸盐也可使用,参见WO93/00050和WO 93/20859。其它的聚合物是聚乳酸(PLA)和乳酸和乙二醇的共聚物(PLPG)(Hollinger等,生物医学材料研究杂志,17,71-82(1983)),和“去除矿物质的骨基质”(DBM)骨衍生物(Guterman等,Kollagen Rel.Res.8,419-4319(1988))。用于吸附TGFβ的聚合物也可使用,并描述于EP-A 0616814和EP-A 0567391,以及按照WO 91/18588的合成的骨基质。
当植入骨替代物或其它的治疗活性物质时通常使用的材料也可被用作式(I)的化合物的载体。这些载体也是基于,例如,硫酸钙,磷酸三钙,羟基磷灰石及其可生物降解的衍生物,和聚酸酐。除了这些可生物降解的载体,也可使用不能生物降解但是生物相容性的材料。例如,这些载体是烧结的羟基磷灰石,生物玻璃,铝酸盐或其它的陶瓷材料(例如,铝酸磷酸钙)。优选这些材料是与所说的可生物降解的材料组合使用的,例如聚乳酸,羟基磷灰石,胶原,或磷酸三钙。其它的可降解聚合物描述于美国专利4164560。特别优选使用在作用位点持续释放式(I)的化合物的载体。特别适用于这一目的的是,例如,Innovative Research ofAmerica,Toledo,Ohio,USA的“缓释粒”。特别优选所使用的缓释粒在几天内,最好在长达100天内,以日剂量1-10mg/kg释放式(I)的化合物。
在本发明的范围内,除了在实施例中提及的化合物,和将权利要求书中所述的取代基的所有的含义组合在一起可得到的化合物之外,下述衍生物,以及它们的药学上可接受的盐,特别是盐酸盐和三氟乙酸盐是优选的。所使用的缩写的含义:Aba =氨基丁酸Ac =乙酰基Ada =(1-脒基-2,5-二氢-1H-吡咯-3-基)丙氨酸Ala =丙氨酸Ava =氨基戊酸Bn =苄基Boc =叔丁氧羰基Bu =丁基Cbz =苄氧羰基Cha =环己基丙氨酸DBU =1,8-二氮双环[5.4.0]十一碳-7-烯DIBAL-H=二异丁基铝氢化物DMAP =4-二甲基氨基吡啶DMF =二甲基甲酰胺Et =乙基Fmoc =9-芴基甲氧基羰基Gly =甘氨酸HMDS =六甲基二硅氮烷i-Pr =异丙基Me =甲基NMM =N-甲基吗啉Ph =苯基Phe =苯丙氨酸Pro =脯氨酸py =吡啶RT =室温Ser =丝氨酸t-Bu =叔丁基TBTU =2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲四氟硼酸盐TCP =三苯甲游基氯化物-聚苯乙烯THF =四氢呋喃Thr =色氨酸Troc =2,2,2-三氯乙氧基羰基Trp =酪氨酸tB =保留时间Val =缬氨酸
此外,还使用了氨基酸的单字母代号。
在本发明的范围内除了实施例中描述的化合物和通过将权利要求的优选的化合物中所述的取代基的全部含义进行组合而可得到的化合物外优选下述的肽模拟物。优选的化合物1)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰(carbamimidoyl)-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(吲哚-2-基)-丙酸2)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(7-甲基-吲哚-2-基)-丙酸3)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-苯并[b]噻吩-2-基-丙酸4)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(6-甲基-吲哚-2-基)-丙酸5)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(6-羟基-吲哚-2-基)-丙酸6)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(3-甲基-吲哚-2-基)-丙酸7)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(3-甲基苯并呋喃-2-基)-丙酸8)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(3,4-二甲基-苯并呋喃-2-基)-丙酸9)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(3,5-二甲基苯并呋喃-2-基)-丙酸10)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(3,6-二甲基-苯并呋喃-2-基)-丙酸11)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(5-乙基-3-甲基苯并呋喃-2-基)-丙酸12)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-羟基-3-(3-甲基-苯并呋喃-2-基)-丙酸13)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(3,7-二甲基苯并呋喃-2-基)-丙酸14)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(7-乙基-3-甲基-苯并呋喃-2-基)-丙酸15)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(3,6-二甲基苯并呋喃-2-基)-3-羟基-丙酸16)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(3,5-二甲基-苯并呋喃-2-基)-3-羟基-丙酸17)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(3,4-二甲基苯并呋喃-2-基)-3-羟基-丙酸18)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(3,7-二甲基-苯并呋喃-2-基)-3-羟基-丙酸19)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(7-氯-3-甲基苯并呋喃-2-基)-3-羟基-丙酸20)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(5-乙基-3-甲基-苯并呋喃-2-基)-3-羟基-丙酸21)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(7-乙基-3-甲基苯并呋喃-2-基)-3-羟基-丙酸22)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-呋喃-2-基-丙酸23)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-呋喃-2-基-3-羟基-丙酸24){5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-噻吩-2-基-乙酸25)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-噻吩-2-基-丙酸26)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(吡咯-2-基)-丙酸27)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(5-甲基-3-噻吩-2-基)-丙酸28)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-羟基-3-(5-甲基-噻吩-2-基)-丙酸29)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(5-乙基-3-噻吩-2-基)-丙酸30)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(5-丙基-噻吩-2-基)-丙酸31)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(5-羟基甲基-呋喃-2-基)-丙酸32)5-(2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-2-羧基-乙基)-2-甲基-呋喃-3-羧酸33)5-(2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-2-羧基-乙基)-2-乙基-呋喃-3-羧酸34)5-(2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-2-羧基-乙基)-2-甲基-吡咯-3-羧酸乙基酯35)5-(2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-2-羧基-乙基)-2-丙基-呋喃-3-羧酸36)3-(5-乙酰基亚氨基-4,5-二氢-噻吩-2-基)-2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-羟基-丙酸37)5-(2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-2-羧基-乙基)-2-异丁基-呋喃-3-羧酸38)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-环戊-1-烯基-丙酸39)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-羟基-3-噻吩-2-基-丙酸40){5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-(3-甲基-苯并[b]噻吩-7-基)-乙酸41){5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-苯基-乙酸42)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(3,4-二羟基-苯基)-3-羟基-丙酸43){5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-(4-羟基-苯基)-乙酸44)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-苯基-丁酸45)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-(3,4-二苄氧基-苯基)-3-羟基-丙酸46)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-羟基-琥珀酸47)2-({5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-羧基-甲基)-苯甲酸48)5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-(3-氧代-2,3-二氢-异噁唑-5-基)-乙酸49){5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-环己基-乙酸50){5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-环己-1,4-二烯基-乙酸51){5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-环己-1,5-二烯基-乙酸52)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-羟基-3-吡啶-3-基-丙酸53)2-{5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-羟基-3-吡啶-4-基-丙酸54)4-({5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-羧基-甲基)-2-羟基-苯甲酸55)4-({5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-羧基-甲基)-苯甲酸56)2-{5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-3-苯基sulfanyl-丁酸57){5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-(四唑-5-基)-乙酸58){5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-(吲哚-3-基)-乙酸59){5-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-(3,4-二羟基-苯基)-乙酸60){5-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-戊酰基氨基}-(3,5-二羟基-苯基)-乙酸61)2-{4-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丁酰基氨基}-3-(吲哚-2-基)-丙酸62)2-{4-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丁酰基氨基}-3-(7-甲基-吲哚-2-基)-丙酸63)2-{4-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基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-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-3-(3-甲基-吲哚-2-基)-丙酸127)2-{3-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-3-(3-甲基-苯并呋喃-2-基)-丙酸128)2-(2-{2-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-3-(3,4-二甲基-苯并呋喃-2-基)-丙酸129)2-{6-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-己酰基氨基}-3-(3,5-二甲基-苯并呋喃-2-基)-丙酸130)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-3-(5-乙基-3-甲基-苯并呋喃-2-基)-丙酸131)2-{3-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-3-羟基-3-(3-甲基-苯并呋喃-2-基)-丙酸132)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-3-(3,7-二甲基-苯并呋喃-2-基)-丙酸133)2-{6-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-己酰基氨基}-3-(7-乙基-3-甲基-苯并呋喃-2-基)-丙酸134)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-3-(3,6-二甲基-苯并呋喃-2-基)-3-羟基-丙酸135)2-{3-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-3-(3,5-二甲基-苯并呋喃-2-基)-3-羟基-丙酸136)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-3-(3,4-二甲基-苯并呋喃-2-基)-3-羟基-丙酸137)2-{6-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-己酰基氨基}-3-(3,7-二甲基-苯并呋喃-2-基)-3-羟基-丙酸138)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-3-(7-氯-3-甲基-苯并呋喃-2-基)-3-羟基-丙酸139)2-{3-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-3-(5-乙基-3-甲基-苯并呋喃-2-基)-3-羟基-丙酸140)2-{6-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-己酰基氨基}-3-(7-乙基-3-甲基-苯并呋喃-2-基)-3-羟基-丙酸141)2-{6-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-己酰基氨基}-3-呋喃-2-基-丙酸142)2-{3-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-3-呋喃-2-基-3-羟基-丙酸143){3-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-噻吩-2-基-乙酸144)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-3-噻吩-2-基-丙酸145)2-{6-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-己酰基氨基}-3-(吡咯-2-基)-丙酸146)2-{3-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-3-(5-甲基-噻吩-2-基)-丙酸147)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-3-(5-乙基-噻吩-2-基)-丙酸148)2-{3-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-3-(5-丙基-噻吩-2-基)-丙酸149)2-(2-{3-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-3-(5-羟基甲基-呋喃-2-基)-丙酸150)5-(2-{6-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-己酰基氨基}-2-羧基-乙基)-2-甲基-呋喃-3-羧酸151)5-(2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-2-羧基-乙基)-2-乙基-呋喃-3-羧酸152)5-(2-{3-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-2-羧基-乙基)-2-甲基-吡咯-3-羧酸乙基酯153)5-(2-{6-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-己酰基氨基)-2-羧基-乙基)-2-丙基-呋喃-3-羧酸154)5-(2-{3-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-2-羧基-乙基)-2-异丁基-呋喃-3-羧酸155)(2-{2-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-3-环戊-1-烯基-丙酸156)2-{3-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基)-3-羟基-3-噻吩-2-基-丙酸157)2-{6-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-己酰基氨基}-3-(3,4-二羟基-苯基)-3-羟基-丙酸158)2-{3-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-3-苯基-丁酸159)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-3-羟基-丙酰基氨基}-丙酰基氨基)-3-(3,4-双苄氧基-苯基)-3-羟基-丙酸160)2-{6-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-己酰基氨基}-3-羟基-琥珀酸161){3-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-环己-1,4-二烯基-乙酸162)2-{3-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-3-羟基-3-吡啶-3-基-丙酸163)4-({6-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-己酰基氨基}-羧基-甲基)-2-羟基-苯甲酸164)2-{3-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-3-苯基sulfanyl-丁酸165){6-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-己酰基氨基}-(吲哚-3-基)-乙酸166){3-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-(3,5-二羟基-苯基)-乙酸167)(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-3-(6-羟基-吲哚-2-基)-丙酸168)(2-{2-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-3-(3,6-二甲基-苯并呋喃-2-基)-丙酸169)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-3-(3,4-二甲基-苯并呋喃-2-基)-3-羟基-丙酸170)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-3-(7-乙基-3-甲基-苯并呋喃-2-基)-3-羟基-丙酸171)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-3-噻吩-2-基--丙酸172)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-3-(5-甲基-噻吩-2-基)-丙酸173)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-3-(5-羟基甲基-呋喃-2-基)-丙酸174)3-(5-乙酰基亚氨基-4,5-二氢-噻吩-2-基)-(2-{2-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-3-羟基-丙酸175)(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-苯基-乙酸176)(2-{2-[2-氨基-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-3-(3,4-二羟基-苯基)-3-羟基-丙酸177)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-3-(3,4-双苄氧基-苯基)-3-羟基-丙酸178)2-((2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-羧基-甲基)-苯甲酸179)2-(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-3-羟基-3-吡啶-4-基-丙酸180)(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-(四唑-5-基)-乙酸181)(2-{2-[2-(2-氨基-3-羟基-丁酰基氨基)-3-(1-亚胺甲酰-2,5-二氢-吡咯-3-基)-丙酰基氨基]-丙酰基氨基}-丙酰基氨基)-(3,4-二羟基-苯基)-乙酸
下述实施例举例说本发明的化合物的合成。化合物的结构是通过1H-,13C-NMR-s波谱和任选地通过质谱得到的。物质的纯度是通过C,H,N分析和通过色谱得到的。实施例1(±)-3-(2-叔-丁氧基羰基-氨基-2-羟基羰基)-乙基-2,5-二氢吡咯-1-(N,N’-二叔-丁氧羰基)酰脒[Boc-Ada(Boc)2OH]a)4-氧代-吡咯烷-1,3-二羧酸1-叔丁基酯3-乙基酯(J.Cooper等,J.Chem.Soc.Perkin Trans.1,1993,1313-1318)
向回流中的1.58克的(66mmol)氢化钠在100ml THF的悬浮液中逐滴加入12.79克的(60mmol)N-叔-丁氧羰基-甘氨酸乙基酯和7.15克的(66mmol)丙烯酸乙酯在100ml THF中的溶液。在加入操作完成后,再在回流下加热2小时。将清澈的溶液冷却至室温,倒在100ml乙醚/100ml水上,并在剧烈搅拌下用1N盐酸对着甲基橙进行酸化。将各层分离并将含水层用乙醚抽提三次。将合并的有机层用饱和的碳酸氢钠和盐水洗涤,在硫酸镁上干燥并蒸发。将残留物进行短路蒸馏得到10.92克的(71%)无色油形式的4-氧代-吡咯烷-1,3-二羧酸1-叔丁基酯3-乙基酯,沸点119-122℃(0.2毫巴),在冷冻箱中长时间放置后固化。
GC/MS(HP 5890 II/HP 5972;柱:HP5,30米×25毫米×0.25微米膜厚度,载体气体:氦;温度梯度:50℃,3分钟;然后用20℃/分钟至250℃)tR=9.68分钟m/z[%]=185(2),130(10),112(18),85(6),57(100)。b)4-羟基-吡咯烷-1,3-二羧酸1-叔丁基酯3-乙基酯
向5.15克的(20mmol)4-氧代-吡咯烷-1,3-二羧酸1-叔丁基酯3-乙基酯在30ml甲醇的溶液中加入1.88克的(30mmol)氰基硼氢化钠和少量的甲基橙。在搅拌下通过逐滴加入1N盐酸将pH值调整至3(颜色从黄色变化至橙色)。在酸不能被进一步加入之后,将混合物搅拌1小时。在真空中将溶剂蒸发并将残留物在乙酸乙酯和水之间进行分配。将有机层用水洗涤两次,然后用盐水洗涤,在硫酸镁上干燥并蒸发。残留的黄色油被用于下一个步骤中,不需要进一步的纯化。
GC/MS(HP 5890 II/HP 5972;柱:HP5,30米×25毫米×0.25微米膜厚度,载体气体:氦;温度梯度:50℃,3分钟;然后用20℃/分钟至250℃)tR=12.44分钟(没有非对映体的分离)m/z[%]=259(M+,0.3),241(0.7),202(5),186(7),158(10),112(14),68(31),57(100)。c)4-苯甲酰氧基-吡咯烷-1,3-二羧酸1-叔丁基酯3-乙基酯
向上述反应中得到的粗的4-羟基-吡咯烷-1,3-二羧酸1-叔丁基酯3-乙基酯的冰冷溶液和244mg(2mmol)DMAP在40ml吡啶的溶液中加入3.51克的(25mmol)苄基氯。在加入操作完成之后,将冰浴移去并将混合物在室温下搅拌2小时。将混合物用乙酸乙酯稀释并倒在冰上。将有机层分离,用水,饱和的硫酸铜,水和盐水洗涤,在硫酸镁上干燥并蒸发。残留的黄色油被用于下一个步骤中,不需要进一步的纯化。
GC/MS(HP 5890 II/HP 5972;柱:HP5,30米×25毫米×0.25微米膜厚度,载体气体:氦;温度梯度:50℃,3分钟;然后用20℃/分钟至250℃)tR=17.28分钟(顺/反式同分异构物1∶1混合物)m/z[%]=318(0.1),290(5),262(2),241(2),185(29),141(10),112(23),105(53),77(27),68(100),57(97)。d)2,5-二氢-吡咯-1,3-二羧酸1-叔丁基酯3-乙基酯
向上述的苯甲酰氧基化反应中得到的粗的4-苯甲酰氧基-吡咯烷-1,3-二羧酸1-叔丁基酯3-乙基酯在75ml干燥的甲苯溶液中加入4.11克的(27mmol)DBU。将该黑色的,异质性的混合物在室温下搅拌16小时。在这之后,通过TLC和GC分析检测不到初始材料。将混合物通过一个短的硅柱(用石油醚/乙酸乙酯1∶1洗脱)进行过滤并蒸发。将残留的微黄色的油进行球管-到-球管(bulb-to-bulb)蒸馏得到4.16克的(86%)无色油形式的2,5-二氢-吡咯-1,3-二羧酸1-叔丁基至3-乙基酯,沸点110℃/0.2毫巴,在冷冻箱中放置后固化成一种蜡状物。
GC/MS(HP 5890 II/HP 5972;柱:HP5,30米×25毫米×0.25微米膜厚度,载体气体:氦;温度梯度:50℃,3分钟;然后用20℃/分钟至250℃)tR=11.94分钟m/z[%]=241(M+,1.4),196(0.4),185(11),168(11),140(14),112(17),68(24),57(100)。1H-NMR(CDCl3,300MHz)d=1.27(t,J=7.1Hz,3H,OCH2CH3),1.43,1.44[2s,9H,C(CH3)3]#,4.25(d,J=7.1Hz,2H,OCH2CH3),4.15-4.27(br.m,4H,2-H,5-H),6.66-6.71(m,1H,4-H)ppm.#“由于位阻旋转得到两套数据”.13C-NMR(CDCl3,75MHz)d=14.16,14.20(q,OCH2-CH3)*,28.45[q,-C(CH3)3],51.76,51.99,53.62,53.84(4t,C-2,C-5)*,60.69(t,-CH2-CH3),79.84[s,-C(CH3)3],132.29(s,C-3),136.44,136.55(2d,C-4)*,153.86,154.08(2s,-NCOO-)*,162.75(s,COOEt)ppm.e)3-羟基甲基-2,5-二氢-吡咯-1-羧酸1-叔丁基酯
向冷却至-78℃,50mlTHF中的5.43克的(22.5mmol)的2,5-二氢-吡咯-1,3-二羧酸1-叔丁基酯3-乙基酯中加入50ml的1N的DIBAL-H在己烷中的溶液。将混合物过夜放置使其恢复到室温。在TLC分析显示初始材料被完全消耗之后,将混合物在冰浴中冷却并将1.90克的水小心加入,然后加入1.90克的15%的氢氧化钠水溶液和5.70克的水。将白色的沉淀物滤除,用乙醚彻底洗涤,将合并的滤液蒸发。将残留的淡黄色的油进行bulb-to-bulb蒸发之后得到4.13克的(93%)的无色油形式的3-羟基甲基-2,5-二氢-吡咯-1-羧酸1-叔丁基酯,沸点130℃/0.2毫巴。GC/MS(HP 5890 II/HP 5972;柱:HP5,30米×25毫米×0.25微米膜厚度,载体气体:氦;温度梯度:50℃,3分钟;然后用20℃/分钟至250℃)tR=11.34分钟m/z[%]=199(M+,1),143(10),142(13),126(13),112(12),80(10),68(45),57(100)。1H-NMR(CDCl3,300MHz)d=1.44(s,9H,t-Bu),4.09(br.m,4H,2-H,4-H),4.18(br,s,2H,CH2OH),5.63(br,d,1H,4-H)ppm.13C-NMR(CDCl3,75MHz)d=28.5[q,C(CH3)3],52.8,53.0,53.2,53.3(4t,C-2,C-5)*,57.7,59.8(2d,CH2OH),79.5[s,C(CH3)3],120.0,120.3(2d,C-4),139.6(s,C-3),154.4(s,COOtBu)ppm.*“由于位阻旋转得到两套数据”.f)3-乙酸基甲基-2,5-二氢-吡咯-1-羧酸1-叔丁基酯
向冰冷的4.13克的(20.7mmol)3-羟基甲基-2,5-二氢-吡咯-1-羧酸1-叔丁基酯和244mg(2mmol)DMAP在50ml吡啶的溶液中加入3.06克的(30mmol)乙酸酐。将混合物在0℃搅拌30分钟,然后在室温下搅拌60分钟。将混合物倾倒在冰上并用以醚抽提两次。将合并的有机层在真空中蒸发,溶解在乙醚中,用饱和的硫酸铜,水和盐水洗涤并在硫酸镁上干燥。进行蒸发和bulb-to-bulb蒸馏后得到4.82克的(97%)无色油形式的3-乙酸基甲基-2,5-二氢-吡咯-1-羧酸1-叔丁基酯,沸点105℃/0.2毫巴。GC/MS(HP 5890 II/H 5972;柱:HP5,30米×25毫米×0.25微米膜厚度,载体气体:氦;温度梯度:50℃,3分钟;然后用20℃/分钟至250℃)tR=11.87分钟m/z[%]=241(M+,0.2),226(0.1),185(5),166(5),125(18),108(3),81(13),80(23),57(100)。1H-NMR(CDCl3,300MHz)d=1.43,1.44[2s,9H,C(CH3)3]*,2.04,2.06(2s,3H,OOCCH3),4.05-4.12(br.m,4H,2-H,5-H),4.61(br,d,J=5.7Hz,2H,CH2O),5.66-5.73(br,m,1H,4-H)ppm.13C-NMR(CDCl3,75MHz)d=20.7[q,OOCCH3),28.4[q,C(CH3)3],53.0,53.2,53.3(3t,2-C,5-C)*,60.8(t,CH2OAc),79.5[s,C(CH3)3],123.4,123.8(2d,C-4)*,134.5,134.6(2s,C-3),154.1(s,NCOO),170.5(s,OOCCH3),ppm.*“由于位阻旋转得到两套数据”.g)3-乙酸基甲基-2,5-二氢-吡咯-1-(N,N’-二叔丁氧羰基)酰脒
向冰冷的实施例3f中的1.21克的(5mmol)3-乙酸基甲基-2,5-二氢-吡咯-1-羧酸叔丁基酯在10ml干燥的二噁烷中的溶液中加入10ml 4N在二噁烷中的氯化氢。将混合物在0℃搅拌16小时。将混合物在没有加热的情况下蒸发至干燥然后在高度真空下抽滤几个小时。将黑色的残留物悬浮在20ml干燥的乙腈和776mg(6mmol)乙基二异丙胺中,然后加入1.71克的(5.5mmol)的N,N’-双叔丁氧羰基-1H-吡唑-1-酰脒。将混合物在室温下搅拌2小时然后蒸发,并通过闪烁层析纯化(石油醚/乙酸乙酯3∶1至2∶1),得到1.87克的(97%)无色粘性固体形式的3-乙酸基甲基-2,5-二氢-吡咯-1-(N,N’-二叔丁氧羰基)酰脒。1H-NMR(CDCl3,300MHz)d=1.45[s,18H,2t-Bu],2.03(s,3H OAc),4.38(br.m,4H,2-H,5-H),4.61(s,2H,CH2OAc),5.72(br.m,1H,4-H),10.22(br.S,1H,NH)ppm13C-NMR(CDCl3,75MHz)d=20.4[q,OOCCH3),27.7,27.9[2q,C(CH3)3],55.0(br.t.C-2,C-5),60.2(t,CH2OAc),79.3,81.8[2br.s,C(CH3)3],122.4(d,C-4),133.5(s,C-3),150(br.s,NCOO),153.9(s,NC=N),162(br.s,NCOO),170.2(s,OOCH2CH3)ppm.h)3-(2-Benzhydrilideneamino-2-乙氧基羰基-乙基)-2,5-二氢-吡咯-1-
(N,N’-二叔丁氧羰基)酰脒
向六甲基二硅氮化锂(在己烷中2.29mmol/g)的溶液中(被冷却至-78℃)加入1.069克的(4mmol)乙基N-(二苯基亚甲基)-甘氨酸酯在8mlTHF的溶液。该六甲基二硅氮化锂是在0℃从710mg(4.4mmol)六甲基二硅氮烷在8ml TH-F和1.92克的(4.4mmol)正丁基锂新鲜制备的。将该橙色的enolate溶液在-78℃搅拌30分钟,然后逐滴加入1.039克(3.7mmol)3-乙氧基甲基-2,5-二氢-吡咯-1-(N,N’-二叔丁氧羰基)酰脒和426mg(0.4mmol)Pd(PPh3)4在12ml THF中的溶液。让反应混合物在2小时内加热至室温,并再搅拌12小时。将混合物用乙醚稀释并加入饱和的碳酸氢钠骤冷。将有机层用饱和的碳酸氢钠和盐水洗涤,在硫酸镁上干燥并蒸发。用闪蒸色谱法(乙酸乙酯/石油醚1∶5+1%三乙胺)得到1.03克的(47%)的无色无形固体的3-(2-Benzhydrilideneamino-2-乙氧基羰基-乙基)-2,5-二氢-吡咯-1-(N,N’-二叔丁氧羰基)酰脒。1H-NMR(CDCl3,300MHz)d=1.23(t,J=7.1Hz,3H,OCH2CH3),1.46[br.s,18H,C(CH3)3],2.68(br.m,2H,3-CH2-),3.96(br.m,1H,CH-N),4.15(q,J=7.1Hz,2H,OCH2CH3),4.16-4.29(br.m,4H,2-H,5-H),5.41(br.m,1H,4-H),7.07-7.60(m,10H,Ar-H)ppm.13C-NMR(CDCl3,75MHz)d=13.9(q,OCH2CH3),28.0[q,C(CH3)3],32.5(t,3-CH2),55.2,56.9(2t,C-2,C-5),60.9(t,OCH2CH3),63.6(d,CH-NH2),79,81.6[2br.s,C(CH3)3],120.7(d,C-4),127.5,127.8,128.4,128.5,128.6,130.2(6d,Ar-CH),134.8(s,C-3),135.8,139.1(2s,Ar-C),150(br.s,NCOO),153.7(s,NC=N),162(br.s,NCOO),170.7(s,N=CPh2),171.2(s,OOCH2CH3)ppm.i)3-(2-氨基-2-乙氧基羰基-乙基)-2,5-二氢-吡咯-1-(N,N’二叔丁氧羰基)
酰脒
向118mg(0.2mmol)的3-(2-Benzhydrilideneamino-2-乙氧基羰基-乙基)-2,5-二氢-吡咯-1-(N,N’-二叔丁氧羰基)酰脒在2ml THF的溶液中加入1ml 1N的盐酸。将混合物在室温下搅拌30分钟。加入水(5ml),将含水层分离,并用乙醚洗涤两次。通过加入1N的碳酸氢钠将水层的pH调整至8.5并用乙醚抽提5次。将合并的乙醚层用盐水洗涤,在硫酸镁上干燥。将残留物通过闪烁层析纯化(氯仿/甲醇20∶1),得到79mg(93%)无色油形式的3-(2-氨基-2-乙氧基羰基-乙基)-2,5-二氢-吡咯-1-(N,N’-二叔丁氧羰基)酰脒。1H-NMR(CDCl3,300MHz)d=1.22(t,J=7.1Hz,3H,OCH2CH3),1.45[s,18H,C(CH3)3],2.33(dd,2J=16.6Hz,3J=8.1Hz,1H,CHaHbCHNH2),2.54(dd,2J=16.6Hz,3J=5.3Hz,1H,CHaHbCHNH2),3.54(dd,3J=81,5.3Hz,1H,CHaHbCHNH2),4.13(q,J=7.1Hz,2H,OCH2CH3),4.33(br.m,4H,2-H,5-H),5.53(br.m,1H,4-H)ppm13C-NMR(CDCl3,75MHz)d=13.9(q,OCH2CH3),27.9[q,C(CH3)3],34.1(t,3-CH2),52.7(d,CHNH2),55.3,56.9(2d,C-2,C-5),61.1(t,OCH2CH3),ca80[2br.s.C(CH3)3],120.7(d,C-4),134.6(s,C-3),153.8(s,NC=N),174.6(s,OOCH2CH3)ppmj)3-(2-叔丁氧羰基-氨基-2-乙氧基羰基-乙基)-2,5-二氢-吡咯-1-(N,N’-二
叔丁氧羰基)酰脒
向79mg(0.19mmol)的3-(2-氨基-2-乙氧基羰基-乙基)-2,5-二氢-吡咯-1-(N,N’-二叔丁氧羰基)酰脒在1ml干燥的乙腈的溶液中加入40mg(0.3mmol)乙基二异丙基胺和65mg(0.3mmol)二叔丁基二碳酸酯(Boc2O),并将混合物在室温下搅拌16小时。将溶剂蒸发并将残留物通过闪烁层析纯化(石油醚/乙酸乙酯2∶1),得到83mg(76%)无色油形式的3-(2-叔丁氧羰基-氨基-2-乙氧基羰基-乙基)-2,5-二氢-吡咯-1-(N,N’-二叔丁氧羰基)酰脒。1H-NMR(CDCl3,200MHz)d=1.22(t,J=7.1Hz,3H,OCH2CH3),1.42,1.47,1.48[3s,9H each,C(CH3)3],2.41-2.66(br.m,2H,3-CH2-),4.17(q,J=7.1Hz,2H,OCH2CH3),4.32(br.m,4H,2-H,5-H),5.02(br.m,1H,CHNH),5.52(br.s,1H,4-H)ppm.13C-NMR(CDCl3,50MHz)d=14.1(q,OCH2CH3),28.1,28.3,28.5[3q,C(CH3)3],31.8(t,3-CH2),48.3(d,CHNH),52.0,55.3(2t,C-2,C-5),61.6(t,OCH2CH3),121.3(d,C-4),133.5(s,C-3),153.9(s,N=C-N),171.8(s,COOEt)ppm.NCOO-,C(CH3)3-由于线条加宽无法看到信号k)3-(2-叔丁氧羰基-氨基-2-羧基-乙基)-2,5-二氢吡咯-1-(N,N’-二叔丁氧
羰基)酰脒
向267mg(0.63mmol)的3-(2-叔丁氧羰基-氨基-2-乙氧基羰基-乙基)-2,5-二氢-吡咯-1-(N,N’-二叔丁氧羰基)酰脒在5ml THF/甲醇/水3∶1∶1中的溶液中加入50mg(1.2mmol)LiOH*H2O。将混合物在室温下搅拌30分钟后通过TLC检测不到初始材料。通过加入1N HCl使混合物酸化,用水洗涤并用乙醚抽提三次。将合并的有机提取物用盐水洗涤,在硫酸镁上干燥并蒸发。将残留物通过闪烁层析纯化,得到98mg(31%)无色无定形固体形式的3-(2-叔丁氧羰基-氨基-2-羧基-乙基)-2,5-二氢吡咯-1-(N,N’-二叔丁氧羰基)酰脒(Boc-Ada(Boc2)-OH)。1H-NMR(CDCl3,300MHz)δ=1.39,1.44[2s,9H,18H,C(CH3)3],2.49-2.67(br.m,2H,3-CH2-),4.33(br.m,4H,2-H,5-H),5.30(br.d,1H,CHNH),5.56(br.s,1H,4-H)ppm.13C-NMR(CDCl3,75MHz)δ=27.7,28.9,28.0[3q,C(CH3)3],31.3(t,3-CH2),52.0(d,CHNH),55.3,56.9(2t,C-2,C-5),80.0,80.9[2s,(C(CH3)3],121.1(d,C-4),133.6(s,C-3),153.2(s,N=C-N),155.2(br.s,NCOO),176.5(s,COOH)ppm.实施例2(±)-3-(2-芴基甲氧基羰基-氨基-2-羟基羰基-乙基)-2,5-二氢吡咯-1-(N,N’-二叔-丁氧羰基)酰脒[Fmoc-Ada(Boc)2OH]a)(±)-3-(2-Benzhydrylidene-2-叔丁氧羰基-乙基-2,5-二氢吡咯-1-羧酸叔丁基酯
向六甲基二硅氮化锂[在0℃从1.53克的(9.5mmol)六甲基二硅氮烷在和4.09克的(9.5mmol)n-BuLi(己烷中2.32mmol/g)]在20ml THF中的溶液中在-78℃加入2.79克的(9.5mmol)叔丁基-N-(二苯基亚甲基)-甘氨酸酯在20ml THF中的溶液中。将该橙色的enolate溶液在-78℃搅拌30分钟,然后逐滴加入2.70克的(8.6mmol)3-乙氧基甲基-2,5-二氢-吡咯-1-羧酸叔丁基酯和243mg(0.21mmol)Pd(PPh3)4在20ml THF中的溶液。将反应混合物过夜放置加热至室温,并再搅拌12小时。将混合物用乙醚稀释并通过加入饱和的氯化铵淬灭。将有机相用饱和的氯化铵和盐水洗涤,在硫酸镁上干燥并蒸发。通过闪烁层析纯化(乙酸乙酯/石油醚1∶10+0.5%三乙基胺)得到3.70克的(90%)淡黄色油形式的3-(2-Benzhydrylidene-2-叔丁氧羰基-乙基-2,5-二氢吡咯-1-羧酸叔丁基酯。1H-NMR(CDCl3,300MHz)d=1.41,1.42[2s,9H each,C(CH3)3],2.62-2.71(m,2H,3-CH2-),3.80-4.10(br.m,4H,2-H,5-H,CHN),5.41(br.m,1H,4-H),7.09-7.81(m,10H,Ar-H)ppm.13C-NMR(CDCl3,75MHz)d=27.8,28.3[2q,C(CH3)3],33.0(t,3-CH2),52.7,53.1,54.5,55.0(4t,C-2,C-5)*,64.2,64.4(2d,CH-NH2)*,78.9[s,C(CH3)3],81.07,81.13[2s,C(CH3)3]*,121.4,121.5(2d,C-4)*,127.5,127.6,128.1,128.2,128.3,128.4,128.6,128.7 130.1(9d,Ar-CH)*,135.8,135.9,136.1(3s,Ar-C)*,139.2,139.3(s,C-3)*,153.8,153.9(2s,NCOO)*,170.1,170.2[2s,C(CH3)3]170.4(s,N=CPh2)ppm.HR-MS(FAB+)[M++H] C29H37N2O4 理论值:477.2753
实测值:477.2769[M++Na] C29H36N2O4Na 理论值:499.2573
实测值:499.2570b)(±)-3-(2-氨基-2-叔丁氧羰基-乙基)-2,5-二氢吡咯-1-羧酸叔丁基酯
向1.57克的(3.3mmol)3-(2-benzhydrylidene-2-叔丁氧羰基-乙基)-2,5-二氢吡咯-1-羧酸叔丁基酯在10ml THF和5ml水中的溶液中加入5ml冰乙酸,并将混合物在室温下搅拌过夜。在真空下将THF蒸发,将残留物用水稀释并通过小心加入固体的碳酸钾(或氨水溶液)使期碱性化。将混合物用乙酸乙酯抽提三次并再硫酸镁上干燥。通过闪烁层析纯化(用二氯甲烷/甲醇20∶1洗脱)得到1.03克的(90%)无色蜡状固体形式的3-(2-氨基-2-叔丁氧羰基-乙基)-2,5-二氢吡咯-1-羧酸叔丁基酯。1H-NMR(CDCl3,300MHz)d=1.41,1.42[2s,9H each,C(CH3)3],2.35(dd,2J=14.6Hz,3J=7.4Hz,1H,CHaHbCHNH2),2.49(dd,2J=14.6Hz,3J=5.8Hz,1H,CHaHbCHNH2),3.44(dd,3J=7.4,5.8Hz,1H,CHaHbCHNH2),4.04(m,4H,2-H,5-H),5.49(br.m,1H,4-H)ppm.13C-NMR(CDCl3,75MHz)d=27.8,28.3[2q,C(CH3)3],34.46,34.52(2t,3-CH2)*,52.7,53.0,54.4,54.6(4d,C-2,C-5)*,53.2(d,CHNH2),79.0,79.1,81.18,81.23[4s,C(CH3)3]*,121.6,122.0(2d,C-4)*,135.4,135.6(2s,C-3)*,153.9(s,NCOO),174.2(s,COOtBu)ppm.HR-MS(FAB+)[M++H] C16H29N2O4 理论值:313.2127
实测值:313.2095c)(±)-3-[2-(9-芴基甲氧基羰基-氨基)-2-叔丁氧羰基-乙基]-2,5-二氢吡咯-1-羧酸叔丁基酯
向1.03克的(3.3mmol)3-(2-氨基-2-叔丁氧羰基-乙基)-2,5-二氢吡咯-1-羧酸叔丁基酯和0.46克的(4.3mmol)二异丙基乙基胺在15ml THF的冰冷的溶液中以一个部分加入0.98克的(3.8mmol)9-芴基甲基氯甲酸酯,并将混合物在室温下搅拌过夜。将混合物用乙醚稀释并倒入冰水中,将含水层用乙醚抽提三次。将合并的有机层在硫酸镁上干燥并蒸发。通过闪烁层析纯化(乙酸乙酯/石油醚1∶3洗脱)得到1.70克的(97%)无色无定形固体形式的3-[2-(9-芴基甲氧基羰基-氨基)-2-叔丁氧羰基-乙基]-2,5-二氢吡咯-1-羧酸叔丁基酯。1H-NMR(CDCl3,300MHz)d=1.45[s,9H,C(CH3)3],2.48-2.70(br.m,2H, CH2CHNH2),4.05(br.m,4H,2-H,5-H),4.20(t,1H,CHCH2O),4.41(br.m,3H,CHNH,CHCH2O),5.36(br.m,1H,NH),5.49(br.m,1H,4-H),7.27-7.40(m,4H,Ar-H),7.56-7.61(m,2H,Ar-H),7.73-7.76(m,2H,Ar-H)ppm.13C-NMR(CDCl3,75MHz)d=27.7,28.3[2q,C(CH3)3],31.9,32.2(2t,3-CH2)*,46.9(d,CHCH2O),52.6(d,CHNH2),52.7,53.0,54.6(1br.d,2d,C-2,C-5)*,66.7(t,CHCH2O),79.1,79.2,82.46,82.51[4s,C(CH3)3]*,119.8(d,Ar-CH),122.4,122.8(2d,C-4)*,124.8,127.3,127.5(3d,Ar-CH),134.3(br.s,C-3),141.1,143.6(2s,Ar-C)153.9,155.4(2s,NCOO),170.5(s,COOtBu)ppm.HR-MS(FAB+)[M+] C31H38N2O6 理论值:535.2808
实测值:535.2789[M++Na] C31H38N2O6Na 理论值:557.2628
实测值:557.2643d)(±)-3-(2,5-二氢-1H-吡咯-3-基)-2-芴基甲氧基羰基氨基-丙酸盐酸盐
向588mg的(1.1mmol)3-[2-(9-芴基甲氧基羰基-氨基)-2-叔丁氧羰基-乙基]-2,5-二氢吡咯-1-羧酸叔丁基酯和376mg(4mmol)乙二硫醇在5ml二噁烷中的溶液中加入5ml在二噁烷中的4N的盐酸,并将混合物在室温下搅拌过夜。30分钟之后,开始沉淀一种无色的固体,加入20ml乙醚,将固体滤除,用乙醚充分洗涤,在真空中干燥,得到433mg的(95%)微色粉末形式的(±)-3-(2,5-二氢-1H-吡咯-3-基)-2-芴基甲氧基羰基氨基-丙酸盐酸盐。1H-NMR(CD3OD,300MHz)d=2.56-2.80(m,2H,CH2CHNH2),3.99(br.s,4H,2-H,5-H),4.21(t,1H,CHCH2O),4.31-4.42(m,3H,CHNH,CHCH2O),5.36(br.m,1H,NH),5.62(br.s,1H,4-H),7.28-7.41(m,4H,Ar-H),7.63-7.68(m,2H,Ar-H),7.77-7.80(m,2H,Ar-H)ppm.13C-NMR(CD3OD,75MHz)d=31.5,(t,CH2CHNH),48.3(d,CHCH2O),53.3,53.5,54.1(3d,2d,C-2,C-5,CH2CHNH),67.9(t,CHCH2O),120.9(d,Ar-CH),122.0(d,C-4),126.2,128.1,128.8(3d,Ar-CH),136.6(s,C-3),142.6.,145.2(2s,Ar-C),158.5(s,NCOO),174.4(s,COOH)ppm.e)(±)-3-(2-芴基甲氧基羰基氨基-2-羟基羰基-乙基)-2,5-二氢吡咯-1-(N,N’-二叔丁氧羰基)酰脒
向400mg的(0.96mmol)的(±)-3-(2,5-二氢-1H-吡咯-3-基)-2-芴基甲氧基羰基氨基-丙酸盐酸盐在5ml乙腈中的溶液中加入258mg(2mmol)乙基二异丙基胺,然后加入298mg(0.96mmol)N,N’-双-叔丁氧羰基-1H-吡咯-1-酰脒,并将混合物在室温下搅拌过夜,然后用乙酸乙酯稀释。用乙酸将混合物酸化并加入水。将水层用乙酸乙酯抽提三次,将合并的有机层用盐水洗涤,干燥并蒸发。闪烁层析后(石油醚/乙酸乙酯1∶1+1%乙酸)得到123mg(21%)的淡黄色无定形固体形式的(±)-3-(2-芴基甲氧基羰基氨基-2-羟基羰基-乙基)-2,5-二氢吡咯-1-(N,N’-二叔丁氧羰基)酰脒。1H-NMR(CD3OD,300MHz)d=1.45[s,18H,C(CH3)3],2.57-2.79(br.m,2H,CH2CHNH2),4.05(br.m,4H,2-H,5-H),4.20(t,1H,CHCH2O),4.41(br.m,3H,CHNH,CHCH2O),5.36(br.m,1H,NH),5.49(br.m,1H,4-H),7.24-7.37(m,4H,Ar-H),7.54-7.57(m,2H,Ar-H),7.70-7.73(m,2H,Ar-H)ppm.13C-NMR(CD3OD,75MHz)d=27.7,27.9[2q,C(CH3)3],31.3(t,CH2CHNH),46.9(d,CHCH2O),52.6(d,CH2CHNH),55.5,57.0(2d,C-2,C-5),66.8(t,CHCH2O),81.1[br s,C(CH3)3],119.7(d,Ar-CH),121.2(d,C-4),124.9,126.9,127.5(3d,Ar-CH),133.6(s,C-3),141.1,143.6(2s,Ar-C)153.0,155.8(2s,NCOO),176.5(s,COO/Bu)ppm.HRMS(FAB+)[M+] C33H41N4O8 理论值:621.2924
实测值:621.2881实施例3Ada-SAW
题述化合物是在SyRo II多用肽合成仪(MultiSynTech,Bochum)以0.03mmol的规模用固相方法合成的,使用Fmoc-L-Trp-三苯甲游基-聚苯乙烯(1%)二乙烯基苯树脂(Fmoc-L-Trp-TCP;载量:0.57mmol/g;PepChem,Tubingen)作为初始材料。蛋白原氨基酸丙氨酸和丝氨酸的α-氨基酸是由9-芴基甲氧基羰基(Fmoc)保护的,丝氨酸的侧链羟基是由叔丁基保护的。非蛋白原氨基酸Ada是以Boc-Ada(Boc)2-OH的形式使用的(来自实施例1)。该Fmoc-保护的氨基酸是以6倍过量的量在DMF中偶联的。TBTU(1当量)和NMM(1当量)被用作激活剂。Fmoc基团的切除是在哌啶/二甲基甲酰氨(1∶1,v/v)中进行2×10分钟。Boc-Ada(Boc)2-OH的偶联是在DMF中在1小时内手工进行的,使用0.048mmol的保护的氨基酸(1.65倍过量)和等摩尔量的TBTU和NMM用于激活。用750微升的乙酸/三氟乙醇/二氯甲烷(30∶10∶70)在2小时内将肽从树脂上切割下来。在用150微升的同一种溶剂混合物洗涤五次之后,将滤液合并,用10ml庚烷稀释并浓缩。将这一过程重复两次,以完全除去乙酸。将油性的残留物溶解在5ml 4N在二噁烷中的盐酸中。在这一溶液中加入270微升的乙二硫醇并在室温下搅拌3小时。然后将溶剂除去,并将残留物溶解在庚烷中并再次浓缩几次,直至乙二硫醇几乎被完全除去。将粗肽从叔丁醇/水(1∶1)中冷冻干燥并通过制备性HPLC纯化,得到9.5mg无色冷冻干燥物形式的Ada-SAW(通过HPLC测定的纯度大于90%)。
ESI-MS:m/z 543.3 M+实施例4Ada-Ava-W
题述的肽是以与实施例3相同的方式从50mg(0.03mmol)Fmoc-L-Trp-TCP树脂使用Fmoc保护的氨基戊酸制备的。产率:6.2mg无色冷冻干燥物形式的Ada-Ava-W(通过HPLC测定的纯度大于90%)。
ESI-MS:m/z 484.3 M+实施例5Ada-Aba-W
题述的肽是以与实施例3相同的方式从50mg(0.03mmol)Fmoc-L-Trp-TCP树脂使用Fmoc保护的氨基丁酸制备的。产率:4.8mg无色冷冻干燥物形式的Ada-Aba-W(通过HPLC测定的纯度大于90%)。
ESI-MS:m/z 470.3 M+实施例6T-Ada-SAW
题述化合物是在SyRo II多用肽合成仪(MultiSynTech,Bochum)以0.03mmol的规模用固相方法合成的,使用Fmoc-L-Trp-三苯甲游基-聚苯乙烯(1%)二乙烯基苯树脂(Fmoc-L-Trp-TCP;载量:0.57mmol/g;PepChem,Tubingen)作为初始材料。蛋白原氨基酸丙氨酸和丝氨酸的α-氨基基团是由9-芴基甲氧基羰基(Fmoc)保护的,丝氨酸的侧链羟基是由叔丁基保护的。非蛋白原氨基酸Ada是以Fmoc-Ada(Boc2)-OH的形式使用的(来自实施例2)。该Fmoc-保护的氨基酸是以6倍过量的量在DMF中偶联的,进行30分钟。TBTU(1当量)和NMM(1当量)被用作激活剂。Fmoc基团的切除是在哌啶/二甲基甲酰氨(1∶l,v/v)中进行2×10分钟。Boc-Ada(Boc)2-OH和苏氨酸的偶联是在DMF中在1小时内手工进行的,使用0.048mmol的保护的氨基酸Boc-Ada(Boc2)-OH(1.65倍过量),在苏氨酸的情况下是6倍过量。等摩尔量的TBTU和NMM被用于激活。用750微升的乙酸/三氟乙醇/二氯甲烷(30∶10∶70)在2小时内将肽丛树脂上切割下来。在用150微升的同一种溶剂混合物洗涤五次之后,将滤液合并,用10ml庚烷稀释并浓缩。将这一过程重复两次,以完全除去乙酸。将油性的残留物溶解在5ml 4N的在二噁烷中的盐酸中。在这一溶液中加入270微升的乙烷二硫醇并在室温下搅拌3小时。然后将溶剂除去,并将残留物溶解在庚烷中并再次浓缩几次,直至乙烷二硫醇几乎被完全除去。将粗肽从叔丁醇/水(1∶1)中冷冻干燥并通过制备性HPLC纯化,得到2.6mg无色冷冻干燥物形式的T-Ada-SAW(通过HPLC测定的纯度大于98%)。
ESI-MS:m/z 644.3 M+实施例7T-Ada-Ava-W
题述的肽是以与实施例6相同的方式从50mg(0.03mmol)Fmoc-L-Trp-TCP树脂使用Fmoc保护的氨基戊酸制备的。产率:2.7mg无色冷冻干燥物形式的T-Ada-Ava-W(通过HPLC测定的纯度大于90%)。
ESI-MS:m/z 585.3 M+实施例8T-Ada-Aba-W
题述的肽是以与实施例6相同的方式从50mg(0.03mmol)Fmoc-L-Trp-TCP树脂使用Fmoc保护的氨基丁酸制备的。产率:2.7mg无色冷冻干燥物形式的Ada-Aba-W(通过HPLC测定的纯度大于95%)。
ESI-MS:m/z 585.3 M+实施例9生物学活性
将式(I)的化合物在一个体外DNA合成实验中进行检测。所使用的细胞是来自大鼠胎儿颅顶成骨细胞的初级培养物。该实验以与Pfeilschifter等,内分泌学(Endocrinology)126,703(1990)所公开的相同的方法进行的。
化合物 | 实施例 | 与对照相比(100%)的生物活性百分比 | ||||
0.001μg/ml | 0.01μg/ml | 0.1μg/ml | 1.0μg/ml | 10μg/ml | ||
Ada-SAW | (3) | 122 | 148 | 199 | 162 | 188 |
Ada-Ava-W | (4) | 116 | 152 | 182 | 183 | 229 |
Ada-Aba-W | (5) | 173 | 184 | 228 | 223 | 261 |
Claims (9)
2.按照权利要求1所述的通式I的化合物,其中R1和R2是氢。
3.按照权利要求1或2所述的通式I的化合物,其中R2是羟基或氨基。
4.按照权利要求1至3中任何一项所述的通式I的化合物,其中R4表示甲基或羟基。
5.按照权利要求1至4中任何一项所述的通式I的化合物,其中m表示1,2,或3。
6.按照权利要求1至4中任何一项所述的通式I的化合物,其中(CHR4)mR5表示一个连接在一个蛋白原或非蛋白原的氨基酸的Cα上的残基。
7.通式(IV)的化合物其中R6表示一种保护基团,例如,苯甲酰基,烷氧基羰基或苄氧基羰基基团;R9表示Fmoc或者可用于正交合成的其它的保护基团Y表示COOH或者COO-C1-C4-烷基。
8.一种含有权利要求1至6中任意一项所述的通式I的化合物中的至少一种的药物。
9.权利要求1至6中任意一项所述的通式I的化合物在制备治疗骨疾病的药物中的应用。
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US6946562B2 (en) * | 2001-12-12 | 2005-09-20 | Eastman Kodak Company | Synthesis of peptoid substituted azole compounds |
US8768642B2 (en) | 2003-09-15 | 2014-07-01 | Nvidia Corporation | System and method for remotely configuring semiconductor functional circuits |
US8775997B2 (en) | 2003-09-15 | 2014-07-08 | Nvidia Corporation | System and method for testing and configuring semiconductor functional circuits |
US8732644B1 (en) | 2003-09-15 | 2014-05-20 | Nvidia Corporation | Micro electro mechanical switch system and method for testing and configuring semiconductor functional circuits |
US8711161B1 (en) | 2003-12-18 | 2014-04-29 | Nvidia Corporation | Functional component compensation reconfiguration system and method |
US8723231B1 (en) | 2004-09-15 | 2014-05-13 | Nvidia Corporation | Semiconductor die micro electro-mechanical switch management system and method |
US8711156B1 (en) | 2004-09-30 | 2014-04-29 | Nvidia Corporation | Method and system for remapping processing elements in a pipeline of a graphics processing unit |
US8021193B1 (en) | 2005-04-25 | 2011-09-20 | Nvidia Corporation | Controlled impedance display adapter |
US7793029B1 (en) | 2005-05-17 | 2010-09-07 | Nvidia Corporation | Translation device apparatus for configuring printed circuit board connectors |
US8412872B1 (en) | 2005-12-12 | 2013-04-02 | Nvidia Corporation | Configurable GPU and method for graphics processing using a configurable GPU |
US8417838B2 (en) * | 2005-12-12 | 2013-04-09 | Nvidia Corporation | System and method for configurable digital communication |
US8724483B2 (en) | 2007-10-22 | 2014-05-13 | Nvidia Corporation | Loopback configuration for bi-directional interfaces |
US8687639B2 (en) * | 2009-06-04 | 2014-04-01 | Nvidia Corporation | Method and system for ordering posted packets and non-posted packets transfer |
US9176909B2 (en) | 2009-12-11 | 2015-11-03 | Nvidia Corporation | Aggregating unoccupied PCI-e links to provide greater bandwidth |
US9331869B2 (en) * | 2010-03-04 | 2016-05-03 | Nvidia Corporation | Input/output request packet handling techniques by a device specific kernel mode driver |
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CA2111199C (en) | 1991-06-21 | 2008-08-05 | Eyal Ron | Pharmaceutical formulations of osteogenic proteins |
WO1993020859A1 (en) | 1992-04-20 | 1993-10-28 | Board Of Regents Of The University Of Washington | Sustained release compositions for delivery of growth factors |
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1997
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- 1998-09-02 EP EP98947498A patent/EP1009770A1/en not_active Withdrawn
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- 1998-09-02 CN CN98808822A patent/CN1269806A/zh active Pending
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- 1998-09-02 JP JP2000510775A patent/JP2001515919A/ja active Pending
- 1998-09-03 AR ARP980104401A patent/AR013462A1/es unknown
- 1998-09-04 ZA ZA9808095A patent/ZA988095B/xx unknown
Also Published As
Publication number | Publication date |
---|---|
KR20010023656A (ko) | 2001-03-26 |
ZA988095B (en) | 2000-03-22 |
AR013462A1 (es) | 2000-12-27 |
BR9812056A (pt) | 2000-09-26 |
JP2001515919A (ja) | 2001-09-25 |
EP1009770A1 (en) | 2000-06-21 |
CA2301969A1 (en) | 1999-03-18 |
EP0902036A1 (en) | 1999-03-17 |
AU9439398A (en) | 1999-03-29 |
TR200000598T2 (tr) | 2000-07-21 |
WO1999012970A1 (en) | 1999-03-18 |
US6429288B1 (en) | 2002-08-06 |
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