CN1520293A - 作为抗糖尿病药物的3-氟-吡咯烷类 - Google Patents
作为抗糖尿病药物的3-氟-吡咯烷类 Download PDFInfo
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- CN1520293A CN1520293A CNA028127196A CN02812719A CN1520293A CN 1520293 A CN1520293 A CN 1520293A CN A028127196 A CNA028127196 A CN A028127196A CN 02812719 A CN02812719 A CN 02812719A CN 1520293 A CN1520293 A CN 1520293A
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- chemical compound
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- pharmaceutically acceptable
- acceptable salt
- alkyl
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
根据通式(1)的化合物及其药学可接受盐是新的。这些化合物是二肽基肽酶IV的抑制剂或其前体药物,并且用于治疗特别是II型糖尿病和受损的葡萄糖耐受性。在通式中,A是F或H;R1A和R1B之一是H或CN,而另一个是H;R2是H,烷基,芳烷基或R5;R3是H或取代的氨基烷基和R4是H或酰基。
Description
本发明涉及二肽基肽酶IV的抑制剂或者其前体药物的新的化合物。所述化合物用于治疗,特别是,II型糖尿病和受损的葡萄糖耐受性。
发明背景
酶二肽基肽酶IV,这里缩写是DP-IV(还缩写为DAP-IV或DPP-IV)并且已知分类是EC.3.4.14.5,是从开头是序列H-Xaa-Pro(其中Xaa是任何氨基酸,但是优选亲脂性氨基酸,Pro是脯氨酸)的肽裂解N-末端二肽的丝氨酸蛋白酶。还认可它是开头是序列H-Xaa-Ala(其中Ala是丙氨酸)的底物肽。DP-IV首先被鉴定是膜结合蛋白质。最近鉴定了一种可溶形式。
最初对DP-IV的兴趣集中在它在T淋巴细胞激活中的作用。DP-IV与T细胞蛋白质CD26相同。提示DP-IV的抑制剂能调制T细胞响应,因此有可能会被开发为新的免疫调制剂。进一步提出CD26对于HIV是一种必需的共同受体,因此DP-IV抑制剂可以用于治疗AIDS。
注意到免疫系统之外的DP-IV的作用。认识到DP-IV在几种肽激素、包括生长激素释放激素(GHRH)和高血糖样肽-1和-2(GLP-1和GLP-2)的降解中起关键作用。因为已知GLP-1对饭后血糖水平控制中胰岛素的作用有加强作用,很清楚DP-IV抑制剂还可以有用地用于治疗II型糖尿病和受损的葡萄糖耐受性。至少两种DP-IV抑制剂最近进行了临床试验以揭示它的可能性。
一些集团公开了DP-IV的抑制剂。尽管从随机筛选中发现一些,但该领域该项工作大部分针对底物类似物的研究。例如US5,462,928,US5,543,396,WO95/15309(等价于US 5,939,560和EP0 731789),WO98/19998(等价于US6,011,155),WO99/46272和WO99/61431中公开了是底物类似物的DP-IV的抑制剂。大多数有潜力的抑制剂是氨基酰基吡咯烷硼酸,但是这些是不稳定的并且有环化倾向,同时更稳定的吡咯烷和噻唑烷衍生物对于所述酶具有更低的亲和性,这样临床情形下将需要大剂量。吡咯烷腈类表现出提供好的折中方案,因为它们对于所述酶具有高亲和性并且在溶液中作为游离碱有合理长的半寿期。但是对于具有改进性质的DP-IV的抑制剂仍然有着需要。
发明概述
本发明涉及对于所述酶具有改进的亲和性的一系列DP-IV的抑制剂和它的前体药物。所述化合物能被用于治疗很多人类疾病,包括受损的葡萄糖耐受性和II型糖尿病。因此,本发明进一步涉及所述化合物制备药物组合物的用途,涉及这样的组合物本身,和涉及这样的组合物在对人治疗中的用途。通式1描述了本发明的化合物:
在该通式中,A是F或H;R1A和R1B之一选自H和CN,而另一个是H;R2选自H,C1-C8烷基,任选被取代的苯基,任选被取代的苄基和R5;R3选自H,R6OCO,H2NCH(R7)CO,H2NCH(R8)CONHCH(R9)CO,和根据通式2的基团;
R4选自H,C1-C8烷基,金刚烷基,金刚烷基甲基,金刚烷基乙基,和Het-NH(CH2)a;或者R2和R4一起构成三个或四个亚甲基的链,这样与它们连接的原子一起形成吡咯烷或哌啶环,这个环可以进一步与苯环样的环稠合;R5选自CH2R13,CH2CH2R13和C(R14)(R15)-X1-R16;R6选自C1-C6烷基,任选被取代的苯基,任选被取代的苄基和R17CO2C(R18)(R19);R7,R8和R9各自独立的选自蛋白质的氨基酸的侧链;R10选自C1-C8烷基,苯基和O-(C1-C8烷基);R11选自H和C1-C8烷基;R12选自H,C1-C8烷基,苯基;R13选自CO-N(R20)(R21),N(R22)-C(=X2)R23和N(R22)(R24);R14和R15各自独立的选自H和甲基,或者一起是-(CH2)2-;R16选自C1-C8烷基,任选被取代的苯基,任选被取代的苄基和-(CH2)b-R13;R17选自H和C1-C8烷基;R18和R19各自独立的选自H和C1-C8烷基,或者一起是-(CH2)y-;R20和R21各自独立的选自H,C1-C8烷基,任选被取代的苯基,任选被取代的苯基烷基,Het和-(CH2)cHet,或者R20和R21一起构成四个或五个亚甲基的链,这样与它们连接的氮原子一起形成吡咯烷或哌啶环,这个环可以进一步与苯环样的环稠合;R22选自H和甲基;R23选自R25,O-R25和N(R26)(R27);R24选自任选被取代的苯基,Het和-CH2-Het;R25选自C1-C8烷基,任选被取代的苯基,任选被取代的苯基烷基,Het和-(CH2)cHet;R26和R27各自独立的选自H,C1-C8烷基,任选被取代的苯基,任选被取代的苯基烷基,Het和-(CH2)cHet,或者R26和R27一起构成四个或五个亚甲基的链,这样与它们连接的氮原子一起形成吡咯烷或哌啶环,这个环可以进一步与苯环样的环稠合;Het是任选被取代的芳香的含氮杂环或者其苯并稠合类似物;X1选自-O-,-S-和-CH2-;X2选自O和S;a是2或3;b是1,2或3;c是1或2;y和z是2,3或4。
本发明的详细描述
第一方面,本发明包括是酶DP-IV的抑制剂并且用于治疗某些人类疾病的一系列新的化合物或者其前体药物。通式1描述所述化合物。
在通式1中,原子A可以是氢(H)或氟(F)。优选是F。R1A和R1B之一可以是腈基(CN)而另一个是H。或者,R1A和R1B两者都是H。在本发明的一个优选的实施方案中,R1A和R1B两者都是H。在本发明的另一个优选的实施方案中,R1A是CN而R1B是H。
在一个特别优选的实施方案中,A是F,而R1A和R1B两者都是H。在另一个特别优选的实施方案中,A是F,R1A是CN而R1B是H。
在本发明的一个实施方案中,R2是选自H,C1-C8烷基,任选被取代的苯基,任选被取代的苄基和根据R5的基团的基团。苯基或苄基上可有可无的合适的取代基是低级烷基,低级烷氧基,选自氟和氯原子的卤原子,羟基,选自NH2,NH-(低级烷基)和N(低级烷基)2的氨基,腈基,硝基,COOH,CO2-(低级烷基),CONH2,CONH-(低级烷基)和CON(低级烷基)2。苯基残基或苄基可以至多有三个取代基,它们可以是相同的或不同的。在这个实施方案中,R3是选自H,C1-C8烷基,金刚烷基,金刚烷基甲基,金刚烷基乙基,和根据Het-NH(CH2)a的基团,其中a是2或3。
在本发明的第二个实施方案中,R2和R3一起构成三个或四个亚甲基的链,这样与它们连接的原子一起形成吡咯烷或哌啶环。这个环可以进一步与苯环样的环稠合形成二氢吲哚,异二氢吲哚,四氢喹啉或四氢异喹啉基团。
对于是DP-IV抑制剂的根据本发明的那些化合物,R4是H。对于这些是直接的抑制剂的前体药物的根据本发明的那些化合物,R4选自根据R6OCO的基团,根据H2NCH(R7)CO的基团,根据H2NCH(R8)CONHCH(R9)CO的基团,和根据通式2的基团。
这些前体药物对患者施用之后被转化为相应的DP-IV的抑制剂。
基团R5选自根据CH2R13的基团,根据CH2CH2R13的基团,和根据C(R14)(R15)-X1-R16的基团,其中X1选自-O-,-S-,和-CH2-。
基团R6选自C1-C8烷基,任选被取代的苯基,任选被取代的苄基和根据R17CO2C(R18)(R19)的基团。苯基或苄基上合适的取代基是低级烷基,低级烷氧基,选自氟和氯原子的卤原子,羟基,选自NH2,NH-(低级烷基)和N(低级烷基)2的氨基,腈基,硝基,COOH,CO2-(低级烷基),CONH2,CONH-(低级烷基)和CON(低级烷基)2。苯基或苄基可以至多有两个取代基,它们可以是相同的或不同的。
R7,R8和R9各自独立的选自蛋白质氨基酸的侧链。下面的表中给出一些这样的氨基酸和它们的侧链。
丙氨酸 -CH3精氨酸 -(CH2)3NHC(=NH)NH2天冬酰胺-CH2CONH2天冬氨酸-CH2CO2H半胱氨酸-CH2SH甘氨酸 -H谷氨酸 -(CH2)2CO2H谷氨酰胺-(CH2)2CONH2组氨酸 -CH2C3H3N2异亮氨酸-CH(CH3)CH2CH3 | 亮氨酸 -CH2CH(CH3)2赖氨酸 -(CH2)4NH2蛋氨酸 -(CH2)2SCH3苯丙氨酸-CH2C6H5丝氨酸 -CH2OH苏氨酸 -CH(CH3)OH色氨酸 -CH2C8H6N酪氨酸 -CH2C6H4OH缬氨酸 -CH(CH3)2 |
在通式2中,基团R10选自C1-C8烷基,苯基和O-(C1-C8烷基)基团,基团R11选自H和C1-C8烷基,基团R12选自H,C1-C8烷基和苯基。
基团R13选自根据CO-N(R20)(R21)的基团,根据N(R22)-C(=X2)R23的基团,其中X2选自O和S,和根据N(R22)(R24)的基团。
基团R14和R15独立的选自H和甲基,或者一起是-(CH2)z-,其中z是2,3或4,这样与它们连接的碳原子一起形成环丙烷,环丁烷或环戊烷。
基团R16选自C1-C8烷基,任选被取代的苯基,任选被取代的苄基和根据-(CH2)b-R13的基团,其中b是1,2或3。苯基或苄基上合适的取代基是低级烷基,低级烷氧基,选自氟和氯原子的卤原子,羟基,选自NH2,NH-(低级烷基)和N(低级烷基)2的氨基,腈基,硝基,COOH,CO2-(低级烷基),CONH2,CONH-(低级烷基)和CON(低级烷基)2。苯基或苄基可以至多有两个取代基,它们可以是相同的或不同的。
基团R17选自H和C1-C8烷基。基团R18和R19独立的选自H和C1-C8烷基,或者一起是-(CH2)y-,其中y是2,3或4,这样与它们连接的碳原子一起形成环丙烷,环丁烷或环戊烷。
基团R20和R21独立的选自H,C1-C8烷基,任选被取代的苯基,任选被取代的苯基烷基,根据Het的基团和根据-(CH2)cHet的基团,其中c是1或2。苯基或苄基上合适的取代基是低级烷基,低级烷氧基,选自氟和氯原子的卤原子,羟基,选自NH2,NH-(低级烷基)和N(低级烷基)2的氨基,腈基,硝基,COOH,CO2-(低级烷基),CONH2,CONH-(低级烷基)和CON(低级烷基)2。苯基或苄基可以至多有两个取代基,它们可以是相同的或不同的。或者基团R20和R21一起构成四个或五个亚甲基的链,这样与它们连接的氮原子一起形成吡咯烷或哌啶环,这个环可以进一步与苯环样的环稠合,这样形成二氢吲哚,异二氢吲哚,四氢喹啉或四氢异喹啉基团。
基团R22选自H和甲基。基团R23选自根据R25的基团,根据O-R25的基团和根据N(R26)(R27)的基团。基团R24选自任选被取代的苯基,根据Het的基团和根据-CH2-Het的基团。苯基上合适的取代基是低级烷基,低级烷氧基,选自氟和氯原子的卤原子,羟基,选自NH2,NH-(低级烷基)和N(低级烷基)2的氨基,腈基,硝基,COOH,CO2-(低级烷基),CONH2,CONH-(低级烷基)和CON(低级烷基)2。苯基可以至多有两个取代基,它们可以是相同的或不同的。
基团R25选自C1-C8烷基,任选被取代的苯基,任选被取代的苯基烷基,根据Het的基团和根据-(CH2)cHet的基团。苯基或苯基烷基上合适的取代基是低级烷基,低级烷氧基,选自氟和氯原子的卤原子,羟基,选自NH2,NH-(低级烷基)和N(低级烷基)2的氨基,腈基,硝基,COOH,CO2-(低级烷基),CONH2,CONH-(低级烷基)和CON(低级烷基)2。苯基或苯基烷基可以至多有两个取代基,它们可以是相同的或不同的。
基团R26和R27各自独立的选自H,C1-C8烷基,任选被取代的苯基,任选被取代的苯基烷基,根据Het的基团和根据-(CH2)cHet的基团。苯基或苯基烷基上合适的取代基是低级烷基,低级烷氧基,选自氟和氯原子的卤原子,羟基,选自NH2,NH-(低级烷基)和N(低级烷基)2的氨基,腈基,硝基,COOH,CO2-(低级烷基),CONH2,CONH-(低级烷基)和CON(低级烷基)2。苯基或苯基烷基可以至多有两个取代基,它们可以是相同的或不同的。或者R26和R27一起构成四个或五个亚甲基的链,这样与它们连接的氮原子一起形成吡咯烷或哌啶环,这个环可以进一步与苯环样的环稠合以形成二氢吲哚,异二氢吲哚,四氢喹啉或四氢异喹啉基团。
Het是芳香的含氮杂环,选自吡啶基,哒嗪基,嘧啶基,吡嗪基,咪唑基,吡唑基,噻唑基,异噻唑基,噁唑基,异噁唑基和这些化合物的苯并稠合类似物,例如喹啉基,异喹啉基,喹喔啉基,苯并咪唑基等,所有这些可以任意地在一个或几个碳原子上被取代,取代基选自低级烷基,羟基,低级烷氧基,氨基,低级烷基氨基,二(低级烷基)氨基,氟,氯,溴,三氟甲基,硝基,氰基,羧基和低级烷氧羰基。
在本申请上下文中,术语"烷基",不管是其本身还是象“烷氧基”这样的组合,包括直链、支链和环饱和的烃基。C1-C8烷基的例子包括甲基,乙基,丙基,正辛基,2,2,4-三甲基戊基和双环[2.2.2]辛基。低级烷基是至多4个碳原子的烷基,即C1-C4烷基,例如甲基,乙基,丙基,异丙基,环丙基,丁基,异丁基,叔丁基和环丁基。术语“苯基烷基”包括带有苯基取代基的低级烷基。苯基烷基的例子包括苄基,苯乙基,α-甲基苄基和4-苯基丁基。
通式1的化合物可以具有一个或多个立体手性中心,因此能存在光学活性异构形式。所有的异构体,包括对映异构体,非对映异构体和差向异构体都包括在本发明范围中。此外,本发明包括单一异构体化合物和混合物,包括消旋体。根据通式1的一些化合物包括带有携带羟基或氨基取代基的杂芳基基团能以互变异构体存在。这些互变异构体,或者是分开的或者是混合物,也认为是在本发明的范围内。
其中R4是H的根据通式1的化合物具有至少一个碱性官能团。因此它们能与酸生成加成盐。其中R4不是H的根据通式1的其它化合物也具有一个碱性官能团,因此能生成加成盐。因为这些加成盐是与药学可接受酸生成的,它们包括在本发明范围内。合适的酸的例子包括乙酸,三氟乙酸,柠檬酸,富马酸,苯甲酸,棕榈酸,甲磺酸,盐酸,硝酸,硫酸,磷酸等。
根据通式1的一些化合物具有酸性基团,因此能与碱生成盐。这样的盐的例子包括钠盐,钾盐和钙盐,它们是通过酸与相应的金属氢氧化物,氧化物,碳酸盐或碳酸氢盐反应形成的。类似地,通过酸与四烷基氢氧化铵反应可以生成四烷基铵盐。伯胺、仲胺和叔胺例如三乙胺可以与酸形成加成盐。一种特殊的情况是在称作两性离子的同一分子中酸性基团和伯胺之间形成内加成盐。在它们是药学可接受的范围内,所有的这些盐包括在本发明的范围内。
一般优选的是,R2和R3不是都为H。在其中R2是H的本发明的实施方案中,R3优选选自金刚烷基,金刚烷基甲基,金刚烷基乙基,和根据Het-(CH2)a的基团。更优选它是根据Het-(CH2)a的基团,最优选它是其中a是2并且Het是5-取代的-2-吡啶基的基团。
更优选的是其中R3是H而R2选自C1-C8烷基,任选被取代的苯基,任选被取代的苄基和根据R5的基团。
本发明的一个特别优选的实施方案是其中R3是H而R2是C1-C8烷基的化合物。
另一个特别优选的实施方案是R3是H而R2是根据R5的基团的化合物。更优选的是其中R5或者是CH2CH2R13或者是C(R14)(R15)-X1-R16的那些化合物。R5是CH2CH2R13的优选的化合物是其中R13是CO-N(R20)(R21)的那些。R5是C(R14)(R15)-X1-R16的优选的化合物是其中R14和R15是H或甲基并且R15是-(CH2)b-R13的那些,特别是其中R14和R15都是H,x1是CH2并且b是1或2的那些,更特别是其中R13是N(R22)-C(=X2)R23或N(R22)(R24)的那些,更特别是R13是N(R22)-C(=X2)R23,R22是H而X2是O的那些,最特别的是其中R23是Het的那些。
本发明的另一个优选的实施方案是根据通式1的化合物,其中R2不是H并且绝对立体化学如通式3所示。在传统命名法体系中,这是“S”构型,除了其中R2是R5,R5是C(R14)(R15)-X1-R16而X1是S,在这种情况下它是R”构型。
本发明的另一个优选的实施方案是根据通式1的化合物,其中R1A是CN,R1B是H,并且绝对立体化学如通式4所示。在传统命名法体系中,这是“S”构型,
本发明的另一个优选的实施方案是根据通式1的化合物,其中R1A是H,R1B是CN,并且绝对立体化学如通式5所示。在传统命名法体系中,这是R”构型,
应用常规合成方法能制备通式1的化合物。
从其中R4是H的相应的化合物一般可得到其中R4不是H的化合物。当R4是R6OCO-时,通常通过胺官能团与合适的碳酸衍生物反应来制备期望的化合物。
这里X是离去基团,例如氯原子(Cl)或者对硝基苯氧基(O2NC6H4O)。
通过胺官能团与1,3-二羰基化合物例如1,3-二酮或β-酮酯反应,能制备其中R4是根据通式2的基团的化合物。
通过肽合成的常规方法能制备其中R4是氨基酰基H2NCH(R7)CO-的化合物。
在第一步中,在偶联剂存在下,胺与保护的氨基酸反应。PG1是保护基团,例如叔丁氧羰基(BOC),苄基氧基羰基(Z)或9-芴基甲氧羰基(Fmoc)。这样的基团的使用是本领域公知的。其中R7具有反应官能团,例如胺或羧酸,该基团也被保护。在第二步骤中,保护基团被去除。
通过肽合成的常规方法也能制备其中R4是基团H2NCH(R8)CONHCH(R9)CO-的化合物。
在这里,PG2和PG3是保护基团。侧链R8和R9如果需要也可以是保护基团。以一步一步的方法或者直接通过二肽片段的偶联可以组装目标化合物。
获得其中R4是H的本发明的化合物的最直接的途径是通过偶联适当官能化的保护的氨基酸和吡咯烷衍生物。
在某些情况下,例如当要制备大量不同的化合物时,制备能作为通用中间体的化合物更方便。例如当要求其中R2是CH2CH2CON(R20)(R21)的大量化合物时,通过与不同的胺反应方便地制备R2是CH2CH2CO2H的通用中间体和衍生物。
吡咯烷衍生物是已知的或者能通过公开的合成途径的简单修饰来制备。实施例中详细地描述了这些制备。
第二方面,本发明包括用于人类治疗用途的药物组合物。组合物特征在于其含有至少一种上述化合物作为活性物质。这样的一种组合物在对人类疾病的治疗中是有用的。组合物一般含有一种或多种选自药学可接受赋形剂和除本发明之外的药物活性物质的另外的成分。
根据想要的给药途径,组合物可以制成固体或液体剂型。固体剂型的例子包括用于口服的丸剂、片剂、胶囊和粉末剂、用于直肠或阴道给药的栓剂、用于鼻或肺给药的粉末剂、用于经皮或跨粘膜(例如颊)给药的贴剂。液体剂型的例子包括用于静脉内、皮下或肌内注射和口服、鼻或肺给药的溶液或混悬剂。特别优选的是口服给药的片剂。特别用于急诊和特护的另一种优选是静脉内注射灭菌溶液。
组合物含有至少一种根据前面描述的化合物。组合物可以含有一种以上这样的化合物,但是一般优选它应该只含有一种。组合物中使用的化合物的量是这样的量,使得活性物质总的日剂量能以一至四方便的剂量单位施用。例如,组合物可以是含有等于需要的总的日剂量的化合物的量的片剂,所述片剂每日服用一次。或者,片剂可以含有日剂量的一半(或者三分之一或四分之一),每天服药两次(或三次或四次)。可以将这样的片剂划分以有利于分开给药,这样,例如,含有全日剂量的片剂可以被分成两半分两次给药。优选地,片剂或者其它单位剂量形式含有0.1毫克和1克之间的活性化合物。更优选地,含有1毫克至250毫克。
组合物一般包括一种或多种赋形剂,选自被识别是药学可接受的那些。合适的赋形剂包括但不限于膨胀剂、粘合剂、稀释剂、溶剂、防腐剂和矫味剂。改变组合物释放性质的试剂,例如在肠中选择性溶解的聚合物(“肠包衣”)也认为在本发明上下文中是合适的赋形剂。
除了本发明的化合物之外,组合物可以含有第二药物活性物质。例如,组合物可以含有抗糖尿病药物、生长促进剂、抗炎药物或者抗病毒药物。但是,一般优选组合物只含有一种活性物质。
第三方面,本发明包括上述化合物和组合物治疗人类疾病的用途。该方面同样被认为包括这样的疾病的治疗方法。容许治疗的疾病是其中DP-IV或CD26的抑制直接或间接导致临床利益的那些。直接作用包括阻断T淋巴细胞激活作用。间接作用包括通过防止这些激素的降解的肽激素活性的提高。疾病的例子包括但不限于自身免疫疾病和炎症疾病,例如肠炎和类风湿性关节炎,导致身材矮小的生长激素缺乏,多囊卵巢综合征,受损的葡萄糖耐受和II型糖尿病。特别优选的是使用化合物和组合物治疗受损的葡萄糖耐受和II型糖尿病,还有通过施用有效量的如前所述化合物或组合物治疗这些疾病的方法。
临床医生考虑到患者一般状况和疾病的严重程度,确定治疗的精确的详情,包括给药方案。对于一些疾病,例如有静止期分开的活跃病症的急性期的肠炎,医生可以选择在急性期用相对高剂量,在静止期使用较低保持剂量。对于慢性病,例如II型糖尿病和受损的葡萄糖耐受,在延长期需要将剂量保持在相同的水平。在这样的情况下,每天1-4片的给药方案,每片含有0.1毫克至1克(优选1毫克至250毫克)的活性化合物应该是典型的。
用下面的非限制性实施例进一步详细描述本发明。
实施例
实施例1
(2S)-4,4-二氟-1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰(ornithinyl)]-吡咯烷-2-甲腈三氟乙酸盐
1A.(2S)-N-(叔丁氧羰基)-4-吡咯烷酮-2-甲酸甲酯
N-(叔丁氧羰基)-L-4-反式-羟基脯氨酸甲酯(2.5克,10.2毫摩尔)溶解于CH2Cl2(70毫升)。加入Dess-Martin高碘烷(5.0克,12.1毫摩尔)并且在室温下将混合物搅拌3小时。真空去除溶剂,残余物溶解于乙酸乙酯(300毫升)。溶液用饱和NaHCO3、水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到无色油状物。通过急骤层析纯化残余物(洗脱剂:10%乙酸乙酯,90%石油醚60-80),得到无色油状物,经鉴定是(2S)-N-(叔丁氧羰基)-4-吡咯烷酮-2-甲酸甲酯(2.4克,9.7毫摩尔,95%)。
1B.(2S)-N-(叔丁氧羰基)-4,4-二氟吡咯烷-2-甲酸甲酯
(2S)-N-(叔丁氧羰基)-4-吡咯烷酮-2-甲酸甲酯(2.3克,9.3毫摩尔)溶解于CH2Cl2(70毫升)。0℃下向该溶液加入(二乙基氨基)硫三氟化物(4.5克,27.9毫摩尔),并且在0℃至室温下将混合物搅拌18小时。将反应混合物小心倒入饱和NaHCO3(100毫升),并且将混合物搅拌15分钟后用CH2Cl2萃取。有机萃取物用水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到橙色油状物。通过急骤层析纯化残余物(洗脱剂:1 0%乙酸乙酯,90%石油醚60-80),得到无色油状物,经鉴定是(2S)-N-(叔丁氧羰基)-4,4-二氟吡咯烷-2-甲酸甲酯(2.4克,8.9毫摩尔,96%)。
1C.(2S)-N-(叔丁氧羰基)-4,4-二氟吡咯烷-2-甲酸
(2S)-N-(叔丁氧羰基)-4,4-二氟吡咯烷-2-甲酸甲酯(2.2克,8.3毫摩尔)溶解于THF(100毫升)。加入氢氧化锂(1M,10.6毫升,10.6毫摩尔)。混合物在室温下搅拌3小时之后用乙酸乙酯(150毫升)稀释,用1M HCl,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到橙色油状物。通过急骤层析纯化残余物(洗脱剂:95%氯仿,4%甲醇,1%乙酸),得到橙色油状物,经鉴定是(2S)-N-(叔丁氧羰基)-4,4-二氟吡咯烷-2-甲酸(2.1克,8.3毫摩尔,100%)。
1D.(2S)-N-(叔丁氧羰基)-4,4-二氟吡咯烷-2-甲酰胺
(2S)-N-(叔丁氧羰基)-4,4-二氟吡咯烷-2-甲酸(1.0克,4.0毫摩尔)溶解于CH2Cl2/DMF(9∶1,50毫升)。0℃下向该溶液加入1-羟基苯并三唑水合物(1.1克,8.1毫摩尔)和水溶性碳化二亚胺(960毫克,4.8毫摩尔)。0℃下将混合物搅拌1小时之后加入氨水(35%,5毫升)。在0℃至室温下将混合物搅拌18小时后真空去除溶剂,并且将残余物溶解于乙酸乙酯(200毫升)。溶液用0.3M KHSO4,饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到黄色油状物。通过急骤层析纯化残余物(洗脱剂:85%乙酸乙酯,15%石油醚60-80),得到无色油状物,经鉴定是(2S)-N-(叔丁氧羰基)-4,4-二氟吡咯烷-2-甲酰胺(945毫克,3.8毫摩尔,95%)。
1E.(2S)-1-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]-4,4-二氟吡咯烷-2-甲酰胺
(2S)-N-(叔丁氧羰基)-4,4-二氟吡咯烷-2-甲酰胺(130毫克,0.54毫摩尔)溶解于4M HCl/二噁烷(30毫升)。室温下将溶液搅拌1小时之后真空去除溶剂,残余物溶解于CH2Cl2/DMF(9∶1,20毫升)。0℃下向该溶液加入Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酸(180毫克,0.53毫摩尔),1-羟基苯并三唑水合物(90毫克,0.67毫摩尔)和水溶性碳化二亚胺(1 36毫克,0.65毫摩尔)。0℃下将混合物搅拌1 5分钟之后用N-甲基吗啉将pH调节至pH8。在0℃至室温下将混合物搅拌18小时后真空去除溶剂,并且将残余物溶解于乙酸乙酯(70毫升)。溶液用0.3M KHSO4,饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到黄色油状物。通过急骤层析纯化残余物(洗脱剂:92%氯仿,8%甲醇),得到白色固体,经鉴定是(2S)-1-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]-4,4-二氟吡咯烷-2-甲酰胺(195毫克,0.41毫摩尔,77%)。
1F.(2S)-1-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]-4,4-二氟吡咯烷-2-甲腈
(2S)-1-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]-4,4-二氟吡咯烷-2-甲酰胺(175毫克,0.37毫摩尔)溶解于无水THF(30毫升)。将该溶液冷却到0℃后加入三乙胺(75毫克,0.75毫摩尔),接着加入三氟乙酸酐(190毫克,0.9毫摩尔)。将混合物搅拌5分钟之后用三乙胺将pH调节至pH9。将混合物再搅拌30分钟之后用乙酸乙酯稀释(1 50毫升),用水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到黄色油状物。通过急骤层析纯化残余物(洗脱剂:70%乙酸乙酯,30%石油醚60-80),得到白色固体,经鉴定是(2S)-1-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]-4,4-二氟吡咯烷-2-甲腈(148毫克,0.33毫摩尔,88%)。
1G.(2S)-4,4-二氟-1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰]-吡咯烷-2-甲腈三氟乙酸盐
(2S)-1-[Nα-(叔丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]-4,4-二氟吡咯烷-2-甲腈(1 35毫克,0.3毫摩尔)溶解于三氟乙酸(10毫升)。室温下将混合物搅拌1小时之后真空去除溶剂,得到无色油状物,经鉴定是(2S)-4,4-二氟-1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰]-吡咯烷-2-甲腈三氟乙酸盐(140毫克,0.3毫摩尔,100%)。
[M+H]+=353.1
1H NMR(CD3OD):1.74-1.82(2H,m),1.90-2.02(2H,m),2.82-2.89(2H,m),3.30-3.32(1H,m),3.51(2H,t,J=6.7Hz),4.12(2H,t,J=11.9Hz),4.25-4.29(1H,m),4.88(2H,s),5.09-5.14(1H,m),8.67-8.68(1H,m),8.7(1H,d,J=2.5Hz),9.23(1H,d,J=1.4Hz)ppm。
实施例2
1-[Nω-(5,6-二氯烟酰)-L-鸟氨酰]-3,3-二氟吡咯烷盐酸盐
2A.1-(叔丁氧羰基)-3-吡咯烷酮
(3R)-N-(叔丁氧羰基)-3-羟基脯氨酸甲酯(980毫克,5.3毫摩尔)溶解于CH2Cl2(40毫升)。加入Dess-Martin高碘烷(2.5克,5.8毫摩尔)。在室温下将混合物搅拌3小时后真空去除溶剂,残余物溶解于乙酸乙酯(300毫升)。溶液用饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到无色油状物。通过急骤层析纯化残余物(洗脱剂:20%乙酸乙酯,80%石油醚60-80),得到无色油状物,经鉴定是1-(叔丁氧羰基)-3-吡咯烷酮(842毫克,4.6毫摩尔,87%)。
2B.1-(叔丁氧羰基)-3,3-二氟吡咯烷
1-(叔丁氧羰基)-3-吡咯烷酮(810毫克,4.4毫摩尔)溶解于CH2Cl2(30毫升)。0℃下向该溶液加入(二乙基氨基)硫三氟化物(2.2克,13.7毫摩尔),并且在0℃至室温下将混合物搅拌18小时之后将反应混合物小心倒入饱和NaHCO3(100毫升)。将混合物搅拌15分钟后用CH2Cl2萃取。有机萃取物用水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到橙色油状物。通过急骤层析纯化残余物(洗脱剂:10%乙酸乙酯,90%石油醚60-80),得到无色油状物,经鉴定是1-(叔丁氧羰基)-3,3-二氟吡咯烷(580毫克,2.8毫摩尔,64%)。
2C.3,3-二氟吡咯烷盐酸盐
1-(叔丁氧羰基)-3,3-二氟吡咯烷(540毫克,2.6毫摩尔)溶解于4M HCl/二噁烷(30毫升)。室温下将溶液搅拌1小时之后真空去除溶剂,得到白色固体,经鉴定是3,3-二氟吡咯烷盐酸盐(370毫克,2.6毫摩尔,100%)。
2D.Nα-(叔丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酸叔丁酯
Nα-(叔丁氧羰基)-L-鸟氨酸叔丁酯盐酸盐(650毫克,2.0毫摩尔)溶解于CH2Cl2/DMF(9∶1,40毫升)。0℃下向该溶液加入5,6-二氯烟酸(383毫克,2.0毫摩尔),1-羟基苯并三唑水合物(459毫克,3.0毫摩尔)和水溶性碳化二亚胺(461毫克,2.4毫摩尔)。0℃下将混合物搅拌15分钟之后用N-甲基吗啉将pH调节至pH8。在0℃至室温下将混合物搅拌18小时后真空去除溶剂,并且将残余物溶解于乙酸乙酯(100毫升)。溶液用0.3M KHSO4,饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到黄色油状物。通过急骤层析纯化残余物(洗脱剂:50%乙酸乙酯,50%石油醚60-80),得到白色固体,经鉴定是Nα-(叔丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酸叔丁酯(660毫克,1.42毫摩尔,71%)。
2E.Nα-(叔丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酸
Nα-(叔丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酸叔丁酯(650毫克,1.40毫摩尔)溶解于三氟乙酸/二氯甲烷(1∶1,20毫升)。将混合物在室温下搅拌2小时之后真空去除溶剂。残余物溶解于二噁烷(20毫升)和碳酸氢钾水溶液(1M,10毫升),并且加入二碳酸二叔丁酯(327毫克,1.5毫摩尔)。将混合物在室温下搅拌18小时之后真空去除二噁烷。残余物用水稀释,用乙醚洗涤,用1M HCl酸化至pH2,并且用氯仿萃取。有机萃取物用水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到无色油状物,经鉴定是Nα-(叔丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酸(530毫克,1.34毫摩尔,96%)。
2F.1-[Nα-(叔丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酰]-3,3-二氟吡咯烷
Nα-(叔丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酸(98毫克,0.24毫摩尔)溶解于CH2Cl2(20毫升)。0℃下向该溶液加入3,3-二氟吡咯烷盐酸盐(36毫克,0.25毫摩尔),PyBOP(1 39毫克,0.27毫摩尔)和三乙胺(60毫克,0.6毫摩尔)。在0℃至室温下将混合物搅拌18小时后真空去除溶剂,并且将残余物溶解于乙酸乙酯(70毫升)。溶液用0.3M KHSO4,饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到橙色油状物。通过急骤层析纯化残余物(洗脱剂:60%乙酸乙酯,40%石油醚60-80),得到无色油状物,经鉴定是1-[Nα-(叔丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酰]-3,3-二氟吡咯烷(79毫克,0.16毫摩尔,68%)。
2G.1-[Nω-(5,6-二氯烟酰)-L-鸟氨酰]-3,3-二氟吡咯烷盐酸盐
1-[Nα-(叔丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酰]-3,3-二氟吡咯烷(68毫克,0.14毫摩尔)溶解于4M HCl/二噁烷(20毫升)。室温下将溶液搅拌1小时之后真空去除溶剂,得到无色油状物,经鉴定是1-[Nω-(5,6-二氯烟酰)-L-鸟氨酰]-3,3-二氟吡咯烷盐酸盐(49毫克,0.117毫摩尔,83%)。
[M+H]+=395.1
1H NMR(CD3OD):δ1.28-1.34(2H,m),1.72-1.76(2H,m),1.85-1.92(2H,m),2.25-2.71(2H,m),3.30-3.41(2H,m),3.87-4.30(6H,m),8.36-8.39(1H,m),8.73-8.79(1H,m)ppm。
实施例3
3,3-二氟-1-[Nω-(2-喹喔啉酰(quinoxaloyl))-L-赖氨酰]-吡咯烷盐酸盐
3A.Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酸甲酯
Nα-(叔丁氧羰基)-L-赖氨酸甲酯乙酸盐(640毫克,2.0毫摩尔)溶解于CH2Cl2(40毫升)。0℃下向该溶液加入2-喹喔啉酰氯(385毫克,2.0毫摩尔)和三乙胺(60毫克,0.6毫摩尔)。在0℃至室温下将混合物搅拌18小时后真空去除溶剂,并且将残余物溶解于乙酸乙酯(100毫升)。溶液用0.3M KHSO4,饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到黄色油状物。通过急骤层析纯化残余物(洗脱剂:65%乙酸乙酯,35%石油醚60-80),得到白色固体,经鉴定是Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酸甲酯(580毫克,1.4毫摩尔,70%)。
3B.Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酸
Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酸甲酯(570毫克,1.37毫摩尔)溶解于THF(50毫升)。加入氢氧化锂水溶液(1M,2毫升,2.0毫摩尔)。将混合物在室温下搅拌3小时之后反应混合物用乙酸乙酯(150毫升)稀释,用1M HCl,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到白色固体,经鉴定是Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酸(440毫克,1.1毫摩尔,80%)。
3C.1-[Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酰(Lysinyl)]-3,3-二氟吡咯烷
Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酸(95毫克,0.24毫摩尔)溶解于CH2Cl2(20毫升)。0℃下向该溶液加入3,3-二氟吡咯烷盐酸盐(34毫克,0.24毫摩尔),PyBOP(145毫克,0.28毫摩尔)和三乙胺(60毫克,0.6毫摩尔)。在0℃至室温下将混合物搅拌18小时后真空去除溶剂,并且将残余物溶解于乙酸乙酯(70毫升)。溶液用0.3M KHSO4,饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到橙色油状物。通过急骤层析纯化残余物(洗脱剂:60%乙酸乙酯,40%石油醚60-80),得到无色油状物,经鉴定是1-[Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酰]-3,3-二氟吡咯烷(87毫克,0.18毫摩尔,75%)。
3D.3,3-二氟-1-[Nω-(2-喹喔啉酰)-L-赖氨酰]-吡咯烷盐酸盐
1-[Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酰]-3,3-二氟吡咯烷(87毫克,0.18毫摩尔)溶解于4M HCl/二噁烷(20毫升)。室温下将溶液搅拌1小时之后真空去除溶剂,得到无色油状物,经鉴定是3,3-二氟-1-[Nω-(2-喹喔啉酰)-L-赖氨酰]-吡咯烷盐酸盐(75毫克,0.18毫摩尔,100%)。
[M+H]+=392.3
1H NMR(CD3OD):δ1.51-1.59(2H,m),1.70-1.78(2H,m),1.81-1.90(2H,m),2.37-2.58(2H,m),3.51-3.59(2H,m),3.62-4.32(8H,m),7.88-7.91(2H,m),8.10-8.21(2H,m),9.41(1H,s)ppm.
实施例4
3,3-二氟-1-[Nω-(3-羟基-2-喹喔啉酰)-L-赖氨酰]-吡咯烷盐酸盐
4A.1-[Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰]-3,3-二氟吡咯烷
Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酸(1.14克,2.4毫摩尔)溶解于CH2C12/DMF(9∶1,100毫升)。0℃下向该溶液加入1-羟基苯并三唑水合物(394毫克,2.9毫摩尔),水溶性碳化二亚胺(680毫克,3.4毫摩尔),3,3-二氟吡咯烷盐酸盐(380毫克,2.43毫摩尔)和三乙胺(400毫克,4毫摩尔)。在0℃至室温下将混合物搅拌18小时后真空去除溶剂,并且将残余物溶解于乙酸乙酯(200毫升)。溶液用0.3M KHSO4,饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,通过急骤层析纯化残余物(洗脱剂:65%乙酸乙酯,35%石油醚60-80),得到白色固体,经鉴定是1-[Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰]-3,3-二氟吡咯烷(1.0克,1.8毫摩尔,75%)。
4B.1-[Nα-(叔丁氧羰基)-L-赖氨酰]-3,3-二氟吡咯烷
1-[Nα-(叔丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰]-3,3-二氟吡咯烷(1.01克,1.8毫摩尔)溶解于THF(20毫升)。加入二乙胺(5毫升)。将混合物在室温下搅拌3小时之后真空蒸发,通过急骤层析纯化残余物(洗脱剂:90%氯仿,7%甲醇,3%三乙胺),得到浅黄色油状物,经鉴定是1-[Nα-(叔丁氧羰基)-L-赖氨酰]-3,3-二氟吡咯烷(598毫克,1.78毫摩尔,99%)。
4C.1-[Nα-(叔丁氧羰基)-Nω-(3-羟基-2-喹喔啉酰)-L-赖氨酰]-3,3-二氟吡咯烷
1-[Nα-(叔丁氧羰基)-L-赖氨酰]-3,3-二氟吡咯烷(147毫克,0.44毫摩尔)溶解于CH2Cl2(20毫升)。0℃下向该溶液加入3-羟基-2-喹喔啉甲酸(83毫克,0.44毫摩尔),PyBOP(274毫克,0.53毫摩尔)和三乙胺(100毫克,1.0毫摩尔)。在0℃至室温下将混合物搅拌18小时后真空去除溶剂,并且将残余物溶解于乙酸乙酯(70毫升)。溶液用0.3M KHSO4,饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到橙色油状物。通过甲醇,得到黄色胶粘固体,经鉴定是1-[Nα-(叔丁氧羰基)-Nω-(3-羟基-2-喹喔啉酰)-L-赖氨酰]-3,3-二氟吡咯烷(106毫克,0.21毫摩尔,47%)。
4D.3,3-二氟-1-[Nω-(3-羟基-2-喹喔啉酰)-L-赖氨酰]-吡咯烷盐酸盐
1-[Nα-(叔丁氧羰基)-Nω-(3-羟基-2-喹喔啉酰)-L-赖氨酰]-3,3-二氟吡咯烷(106毫克,0.3毫摩尔)溶解于4M HCl/二噁烷(20毫升)。室温下将混合物搅拌1小时之后真空去除溶剂,得到无色油状物,经鉴定是3,3-二氟-1-[Nω-(3-羟基-2-喹喔啉酰)-L-赖氨酰]-吡咯烷盐酸盐(66毫克,0.15毫摩尔,50%)。
[M+H]+=408.1
1H NMR(CD3OD):δ1.85-1.87(6H,m),2.3-2.7(2H,brm),3.29-3.31(6H,m),3.4-3.7(5H,brm),7.35-7.5(2H,m),7.6-7.8(1H,m),7.9-8.0(1H,m)ppm。
实施例5
1-[Nω-(3,4-二氯苄基)-谷氨酰胺酰(glutaminyl)]-3,3-二氟吡咯烷盐酸盐
5A.2-[N-(叔丁氧羰基)-Oω-甲基谷氨酰(glutamyl)]-3,3-二氟吡咯烷
N-(叔丁氧羰基)-Oω-甲基谷氨酸(462毫克,1.04毫摩尔)溶解于CH2Cl2/DMF(9∶1,20毫升)。0℃下向该溶液加入1-羟基苯并三唑水合物(192毫克,1.25毫摩尔),水溶性碳化二亚胺(277毫克,1.46毫摩尔),3,3-二氟吡咯烷盐酸盐(1 50毫克,1.04毫摩尔)和三乙胺(200毫克,2.0毫摩尔)。在0℃至室温下将混合物搅拌18小时后真空去除溶剂,并且将残余物溶解于乙酸乙酯(70毫升)。溶液用0.3M KHSO4,饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,通过急骤层析纯化残余物(洗脱剂:40%乙酸乙酯,60%石油醚60-80),得到无色油状物,经鉴定是1-[N-(叔丁氧羰基)-Oω-甲基谷氨酰]-3,3-二氟吡咯烷(362毫克,1.03毫摩尔,99%)。
5B.1-[N-(叔丁氧羰基)-谷氨酰]-3,3-二氟吡咯烷
1-[N-(叔丁氧羰基)-Oω-甲基谷氨酰]-3,3-二氟吡咯烷(362毫克,1.03毫摩尔)溶解于二噁烷(5毫升)。加入氢氧化锂(1M,2.5毫升,2.5毫摩尔)。将混合物在室温下搅拌1小时之后真空蒸发,并且将残余物溶解于乙酸乙酯(70毫升)。溶液用1M KHSO4,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到无色油状物,经鉴定是1-[N-(叔丁氧羰基)-谷氨酰]-3,3-二氟吡咯烷(200毫克,0.66毫摩尔,58%)。
5C.1-[Nα-(叔丁氧羰基)-Nω-(3,4-二氯苄基)-谷氨酰胺酰]-3,3-二氟吡咯烷
1-[N-(叔丁氧羰基)-谷氨酰]-3,3-二氟吡咯烷(100毫克,0.30毫摩尔)溶解于CH2Cl2/DMF(9∶1,20毫升)。0℃下向该溶液加入1-羟基苯并三唑水合物(53毫克,0.36毫摩尔),水溶性碳化二亚胺(80毫克,0.42毫摩尔),3,4-二氯苄基胺(53毫克,0.4毫摩尔)和三乙胺(61毫克,0.6毫摩尔)。在0℃至室温下将混合物搅拌18小时后真空去除溶剂,并且将残余物溶解于乙酸乙酯(200毫升)。溶液用0.3M KHSO4,饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,通过急骤层析纯化残余物(洗脱剂:75%乙酸乙酯,25%石油醚60-80),得到白色固体,经鉴定是1-[Nα-(叔丁氧羰基)-Nω-(3,4-二氯苄基)-谷氨酰胺酰]-3,3-二氟吡咯烷(144毫克,0.29毫摩尔,100%)。
5D.1-[Nω-(3,4-二氯苄基)-谷氨酰胺酰]-3,3-二氟吡咯烷盐酸盐
1-[Nα-(叔丁氧羰基)-Nω-(3,4-二氯苄基)-谷氨酰胺酰]-3,3-二氟吡咯烷(144毫克,0.29毫摩尔)溶解于4M HCl/二噁烷(20毫升)。
室温下将混合物搅拌1小时之后真空去除溶剂,得到白色固体,经鉴定是1-[Nω-(3,4-二氯苄基)-谷氨酰胺酰]-3,3-二氟吡咯烷盐酸盐(120毫克,0.28毫摩尔,100%)。
[M+H]+=394.0,395.7
1H NMR(CD3OD):δ2.00-2.20(2H,m),2.30-2.50(4H,m),3.25-3.35(3H,m),3.60-4.20(4H,m),4 20-4.40(3H,m),7.20-7.30(1H,m),7.40-7.50(2H,m)ppm
实施例6
(3S)-3-氟-1-[Nω-(2-喹喔啉酰)-L-赖氨酰]-吡咯烷盐酸盐
6A.(3S)-1-[N-(叔丁氧羰基)-3-氟吡咯烷
(3R)-N-(叔丁氧羰基)-3-羟基吡咯烷(1.0克,5.34毫摩尔)溶解于CH2Cl2(30毫升)。-78℃下向该溶液加入(二乙基氨基)硫三氟化物(860克,5.34毫摩尔)。在-78℃至室温下将混合物搅拌18小时后小心将反应混合物倒入饱和NaHCO3(100毫升)中,并且搅拌15分钟,用CH2Cl2萃取。有机萃取物用水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,得到橙色油状物。通过急骤层析纯化残余物(洗脱剂:28%乙酸乙酯,72%石油醚60-80),得到无色油状物,经鉴定是(3S)-1-[N-(叔丁氧羰基)-3-氟吡咯烷(507毫克,2.67毫摩尔,50%)。
6B.(3S)-3-氟吡咯烷盐酸盐
(3S)-1-(叔丁氧羰基)-3-氟吡咯烷(5.7毫克,2.68毫摩尔)溶解于4M HCl/二噁烷(30毫升)。室温下将混合物搅拌1小时之后真空去除溶剂,得到灰白色固体,经鉴定是(3S)-3-氟吡咯烷盐酸盐(320毫克,2.6毫摩尔,95%)。
6C.(3S)-1-[Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酰]-3-氟吡咯烷
Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酸(50毫克,0.124毫摩尔)溶解于CH2Cl2(20毫升)。0℃下向该溶液加入(3S)-3-氟吡咯烷盐酸盐(1 7毫克,0.136毫摩尔),1-羟基苯并三唑水合物(20毫克,0.149毫摩尔),水溶性碳化二亚胺(35毫克,0.17毫摩尔)和三乙胺(30毫克,0.3毫摩尔)。在0℃至室温下将混合物搅拌18小时后真空去除溶剂,并且将残余物溶解于乙酸乙酯(70毫升)。溶液用0.3M KHSO4,饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且真空蒸发,通过急骤层析纯化残余物(洗脱剂:60%乙酸乙酯,40%石油醚60-80),得到无色油状物,经鉴定是(3S)-1-[Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酰]-3-氟吡咯烷(50毫克,0.107毫摩尔,86%)。
6D.(3S)-3-氟-1-[Nω-(2-喹喔啉酰)-L-赖氨酰]-吡咯烷盐酸盐
(3S)-1-[Nα-(叔丁氧羰基)-Nω-(2-喹喔啉酰)-L-赖氨酰]-3-氟吡咯烷(50毫克,0.105毫摩尔)溶解于4M HCl/二噁烷(10毫升)。室温下将混合物搅拌1小时之后真空去除溶剂,得到灰白色固体,经鉴定是(3S)-3-氟-1-[Nω-(2-喹喔啉酰)-L-赖氨酰]-吡咯烷盐酸盐(43毫克,0.105毫摩尔,100%)。
[M+H]+=374.0
1H NMR(CD3OD):δ1.53-1.57(2H,m),1.72-1.75(2H,m),1.92-1.94(2H,m),2.21-2.31(1H,m),3.43-4.01(8H,m),4.16-4.18(1H,m),5.19-5.39(1H,m),7.96-7.97(2H,m).8.16-8.21(2H,m),9.41(1H,s)ppm。
实施例7
(2S)-1-[Nα-(1’-乙酰氧基乙氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]-4,4-二氟吡咯烷-2-甲腈
室温下,将二氯甲烷(25毫升)中的(2S)-1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰]-4,4-二氟吡咯烷-2-甲腈三氟乙酸盐(40毫克,0.086毫摩尔),α-乙酰氧基乙基对-硝基苯基碳酸酯(28毫克,0.11毫摩尔;根据Alexander等,J.Med.Chem.31,318,1988制备)和三乙胺(20毫克,0.2毫摩尔)的溶液搅拌18小时之后真空蒸发。残余物溶解于乙酸乙酯(70毫升)。溶液用饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且蒸发,通过急骤层析纯化残余物(洗脱剂:98%氯仿,2%甲醇),得到白色固体,经鉴定是(2S)-1-[Nα-(1’-乙酰氧基乙氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈(26毫克,0.053毫摩尔,62%)。
[M+H]+=483.1
1H NMR(CDCl3):δ1.41-1.46(3H,m),1.72-1.83(4H,m),2.01-2.05(3H,m),2.68-2.74(2H,m),3.49-3.58(2H,m),4.03-4.11(2H,m),4.41-4.43(1H,m),4.94-4.98(1H,m),5.56(1H,d,J=8.6Hz),6.73-6.76(1H,m),7.90-7.93(1H,m),8.51-8.52(1H,m),8.75(1H,d,J=2.4Hz),9.37(1H,d,J=1.4Hz)ppm.
实施例8
1-[Nα-(乙酰氧基甲氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酰]-3,3-二氟吡咯烷
1-[Nα-(叔丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酰]-3,3-二氟吡咯烷(88毫克,0.18毫摩尔)溶解于4M HCl/二噁烷(20毫升)。室温下,将混合物搅拌1小时之后真空去除溶剂。残余物溶解于二氯甲烷(25毫升),加入乙酰氧基甲基对-硝基苯基碳酸酯(60毫克,0.24毫摩尔;根据Alexander等,J.Med.Chem.31,318,1988制备)和三乙胺(60毫克,0.6毫摩尔),混合物在室温下搅拌18小时。真空蒸发溶液,残余物溶解于乙酸乙酯(70毫升)。溶液用饱和NaHCO3,水和盐水洗涤,干燥(Na2SO4)并且蒸发,通过急骤层析纯化残余物(洗脱剂:80%乙酸乙酯,20%石油醚60-80),得到白色固体,经鉴定是1-[Nα-乙酰氧基甲氧羰基-Nω-(5,6-二氯烟酰)-L-鸟氨酰]-3,3-二氟吡咯烷(64毫克,0.126毫摩尔,71%)。
[M+H]+=512.8
1H NMR(CDCl3):δ1.66-1.78(4H,m),2.01(3H,s),2.36-2.67(2H,m),3.49-3.53(2H,m),3.63-3.87(4H,m),4.25-4.70(1H,m),5.62-5.65(1H,m),5.72-5.76(1H,m),5.97-6.01(1H,m),6.85-7.09(1H,m),8.26(1H,d,J=2Hz),8.61(1H,d,J=2.2Hz)ppm。
利用相似方法制备下面的化合物。
实施例9-22
实施例23-29
实施例30-36
实施例序号 | S3 | S4 | S5 |
31 | CN | H | H |
32 | NO2 | H | H |
33 | Cl | H | Cl |
34 | H | Cl | H |
35 | Cl | H | H |
36 | CH3 | H | H |
实施例37-61
实施例序号 | n | S2 | A4 | S5 | S6 |
37 | 3 | H | CH | H | Cl |
38 | 3 | H | CH | H | CH3 |
39 | 3 | H | CH | H | CF3 |
40 | 3 | Cl | CH | H | Cl |
41 | 3 | Cl | CH | H | CH3 |
实施例序号 | n | S2 | A4 | S5 | S6 |
42 | 3 | CH3 | CH | H | CF3 |
43 | 3 | H | N | -CH=CH-CH=CH- | |
44 | 3 | H | N | H | CH3 |
45 | 3 | H | CH | -CH=CH-CH=CH- | |
46 | 3 | H | CH | Br | H |
47 | 3 | H | CH | H | SH |
48 | 3 | H | CH | H | CN |
49 | 3 | OH | N | -CH=CH-CH=CH- | |
50 | 3 | Cl | CH | H | H |
51 | 4 | CO2H | CH | H | H |
52 | 4 | H | CH | Cl | OH |
53 | 4 | H | C(Cl) | -C(CH3)=N-N(CH3)- | |
54 | 4 | H | CH | Cl | Cl |
55 | 4 | H | CH | -CH=CH-CH=CH- | |
56 | 4 | H | CH | Br | H |
57 | 4 | H | CH | CH3 | H |
58 | 4 | H | CH | H | SH |
59 | 4 | H | CH | H | CN |
60 | 4 | H | CH | H | CF3 |
61 | 4 | H | N | H | CH3 |
实施例62-84
实施例序号 | Sa | Sb | SN | S2 | S3 | S4 | S5 |
62 | H | H | H | Cl | H | H | H |
实施例序号 | Sa | Sb | SN | S2 | S3 | S4 | S5 |
63 | H | H | H | H | F | H | H |
64 | H | H | H | H | CF3 | H | H |
65 | H | H | H | H | H | F | H |
66 | H | H | H | H | H | Cl | H |
67 | H | H | H | H | CF3 | H | CF3 |
68 | H | H | H | H | Br | H | H |
69 | H | H | H | H | l | H | H |
70 | H | H | H | H | NO2 | H | H |
71 | H | H | H | H | H | NO2 | H |
72 | H | H | H | H | Cl | H | H |
73 | H | H | H | H | Cl | F | H |
74 | H | H | H | H | H | CH3SO2 | H |
75 | H | H | -CH2-CH2- | H | H | H | |
76 | H | H | H | CH3SO2 | H | H | H |
77 | H | H | H | CH3SO2NHCO | H | H | H |
78 | H | H | H | H | H2NCO | H | H |
79 | H | H | H | -CH=CH-CH=CH- | H | H | |
80 | CH3 | H | H | H | H | H | H |
81 | H | CH3 | H | H | H | H | H |
82 | H | H | H | H | Cl | H | Cl |
83 | H | H | H | H | CH3CO | H | H |
84 | H | H | H | H | CH3 | H | H |
实施例85-100
实施例序号 | R |
85 | 异丙基 |
86 | 正丁基 |
87 | 仲丁基 |
实施例101-126
实施例127-134
实施例135-139
实施例序号 | S3 | S4 | S5 |
135 | CN | H | H |
136 | NO2 | H | H |
137 | Cl | H | Cl |
138 | H | Cl | H |
139 | Cl | H | H |
实施例140-164
实施例序号 | R/S | n | S2 | A4 | S5 | S6 |
140 | S | 3 | H | CH | H | Cl |
141 | S | 3 | OH | CH | H | CH3 |
142 | S | 3 | H | CH | H | OH |
143 | S | 3 | H | CH | H | CH3 |
144 | S | 3 | H | CH | Cl | OH |
145 | S | 3 | H | C(Cl) | -C(CH3)=N-N(CH3)- |
实施例序号 | RIS | n | S2 | A4 | S5 | S6 |
146 | S | 3 | H | CH | Cl | Cl |
147 | R | 3 | H | CH | Cl | Cl |
148 | S | 3 | Cl | CH | H | Cl |
149 | S | 3 | Cl | CH | H | CH3 |
150 | S | 3 | H | N | -CH=CH-CH=CH- | |
151 | S | 3 | H | N | H | CH3 |
152 | S | 3 | OH | N | -CH=CH-CH=CH- | |
153 | S | 3 | Cl | CH | H | H |
154 | S | 4 | CO2H | CH | H | H |
155 | S | 4 | H | CH | Cl | OH |
156 | S | 4 | H | C(Cl) | -C(CH3)=N-N(CH3)- | |
157 | S | 4 | H | CH | Cl | Cl |
158 | S | 4 | H | CH | -CH=CH-CH=CH- | |
159 | S | 4 | H | CH | Br | H |
160 | S | 4 | H | CH | Cl | OH |
161 | S | 4 | OH | CH | -CH=CH-CH=CH- | |
162 | S | 4 | H | CH | CH3 | H |
163 | S | 4 | H | CH | H | SH |
164 | R | 4 | H | N | -CH=CH-CH=CH- |
实施例165-166
实施例序号 | RIS |
165 | R |
166 | S |
实施例167
活性的测定
根据WO95/15309所述的方法,化合物被分析是DP-IV的抑制剂。除了实施例7和8之外,上面实施例中描述的所有的化合物都是DP-IV的竞争抑制剂,KI值小于300nM。实施例7和8这两个化合物是前体药物,浓度达到5μM时不表现出明显的DP-IV的抑制作用。
实施例168
体内活性的测定
应用标准口服葡萄糖耐受试验,对Zucker肥胖大鼠来证明选择的化合物的抗糖尿病作用。通过管饲法口服给与对照大鼠葡萄糖溶液,并且测定血浆葡萄糖水平。这些大鼠证实有明显的高血糖。根据本发明的化合物以各种浓度溶解于葡萄糖溶液,使得在给予不同剂量的化合物的同时进行葡萄糖攻击。接受0.1和100mg/kg之间的DP-IV抑制剂的动物,高血糖移动(hyperglycaemic excursion)以剂量依赖方式降低。
实施例169
药物制剂
从下面制备含有100毫克实施例1的化合物作为活性物质的片剂:
实施例1的化合物 200.0g
玉米淀粉 71.0g
羟丙基纤维素 18.0g
羧甲基纤维素钙 13.0g
硬脂酸镁 3.0g
乳糖 195.0g
总计 500.0g
将原料混合并且压制,得到2000片250mg的片剂,每一片含有100mg实施例1的化合物。
上面证明,根据本发明的化合物是DP-IV的抑制剂或其前体药物,因此预期可用作治疗受损的葡萄糖耐受性、II型糖尿病以及因这种酶的抑制可导致基本的病理或症状改善的其它疾病的治疗药物。
下面的权利要求书进一步定义了本发明。
Claims (33)
1.根据通式1的化合物,或者其药学可接受盐:
其中,
A是F或H;
R1A和R1B之一选自H和CN,而另一个是H;
R2选自H,C1-C8烷基,任选被取代的苯基,任选被取代的苄基和R5;和
R3选自H,C1-C8烷基,金刚烷基,金刚烷基甲基,金刚烷基乙基,和Het-NH(CH2)a;或
R2和R3一起构成三个或四个亚甲基的链,这样与它们连接的原子一起形成吡咯烷或哌啶环,所述的环可以进一步与苯环样的环稠合;
R4选自H,R6OCO,H2NCH(R7)CO,H2NCH(R8)CONHCH(R9)CO,和根据通式2的基团;
R5选自CH2R13,CH2CH2R13和C(R14)(R15)-X1-R16;
R6选自C1-C6烷基,任选被取代的苯基,任选被取代的苄基和R17CO2C(R18)(R19);
R7,R8和R9各自独立的选自蛋白质的氨基酸的侧链;
R10选自C1-C8烷基,苯基和O-(C1-C8烷基);
R11选自H和C1-C8烷基;
R12选自H,C1-C8烷基和苯基;
R13选自CO-N(R20)(R21),N(R22)-C(=X2)R23和N(R22)(R24);
R14和R15各自独立的选自H和甲基,或者-起是-(CH2)z-;
R16选自C1-C8烷基,任选被取代的苯基,任选被取代的苄基和-(CH2)b-R13;
R17选自H和C1-C8烷基;
R18和R19各自独立的选自H和C1-C8烷基,或者一起是-(CH2)y-;
R20和R21各自独立的选自H,C1-C8烷基,任选被取代的苯基,任选被取代的苯基烷基,Het和-(CH2)cHet,或者R20和R21一起构成四个或五个亚甲基的链,这样与它们连接的氮原子一起形成吡咯烷或哌啶环,所述环可以进一步与苯环样的环稠合;
R22选自H和甲基;
R23选自R25,O-R25和N(R26)(R27);
R24选自任选被取代的苯基,Het和-CH2-Het;
R25选自C1-C8烷基,任选被取代的苯基,任选被取代的苯基烷基,Het和-(CH2)cHet;
R26和R27各自独立的选自H,C1-C8烷基,任选被取代的苯基,任选被取代的苯基烷基,Het和-(CH2)cHet,或者R26和R27一起构成四个或五个亚甲基的链,这样与它们连接的氮原子一起形成吡咯烷或哌啶环,所述环可以进一步与苯环样的环稠合;
Het是芳香的含氮杂环,选自吡啶基,哒嗪基,嘧啶基,吡嗪基,咪唑基,吡唑基,噻唑基,异噻唑基,噁唑基,异噁唑基和这些化合物的苯并稠合类似物,所有这些可以任意地在一个或多个碳原子上被取代,并且其中取代基选自低级烷基,羟基,低级烷氧基,氨基,低级烷基氨基,二(低级烷基)氨基,氟,氯,溴,三氟甲基,硝基,氰基,羧基和低级烷氧羰基;
X1选自-O-,-S-和-CH2-;
X2选自O和S;
a是2或3;
b是1,2或3;
c是1或2;和
y和z是2,3或4。
2.根据权利要求1的化合物,或者其药学可接受盐,其中R1A和R1B两者都是H。
3.根据权利要求1的化合物,或者其药学可接受盐,其中R1A是CN而R1B是H。
4.根据权利要求1的化合物,或者其药学可接受盐,其中R1A是H而R1B是CN。
5.根据前面任一项权利要求的化合物,或者其药学可接受盐,其中A是F。
6.根据权利要求1-4任一项的化合物,或者其药学可接受盐,其中A是H。
7.根据前面任一项权利要求的化合物,或者其药学可接受盐,其中R4是H。
8.根据前面任一项权利要求的化合物,或者其药学可接受盐,其中R3是H。
9.根据权利要求1-7任一项的化合物,或者其药学可接受盐,其中R2是H,R3选自金刚烷基,金刚烷基甲基,金刚烷基乙基,和Het-NH(CH2)a。
10.根据权利要求9的化合物,或者其药学可接受盐,其中R3是Het-NH(CH2)a。
11.根据权利要求10的化合物,或者其药学可接受盐,其中a是2并且Het是5-取代的-2-吡啶基。
12.根据权利要求1-7任一项的化合物,或者其药学可接受盐,其中R3是H,R2选自C1-C8烷基,任选被取代的苯基,任选被取代的苄基和R5。
13.根据权利要求12的化合物,或者其药学可接受盐,其中R2是C1-C8烷基。
14.根据权利要求12的化合物,或者其药学可接受盐,其中R2是R5。
15.根据权利要求14的化合物,或者其药学可接受盐,其中R5选自CH2CH2R13和C(R14)(R15)-X1-R16。
16.根据权利要求15的化合物,或者其药学可接受盐,其中R5是CH2CH2R13而R13是CO-N(R20)(R21)。
17.根据权利要求15的化合物,或者其药学可接受盐,其中R5是C(R14)(R15)-X1-R16,R14和R15独立的选自H和甲基,并且R16是-(CH2)b-R13。
18.根据权利要求17的化合物,或者其药学可接受盐,其中R14和R15都是H,X1是CH2和b是1或2。
19.根据权利要求18的化合物,或者其药学可接受盐,其中R13选自N(R22)-C(=X2)R23和N(R22)(R24)。
20.根据权利要求19的化合物,或者其药学可接受盐,其中R13是N(R22)-C(=X2)R23,R22是H并且X2是O。
21.根据权利要求20的化合物,或者其药学可接受盐,其中R23是Het。
22.根据权利要求1的化合物,其中R2不是H并且绝对立体化学如通式3所示。
23.根据权利要求1的化合物,其中R1A是CN,R1B是H并且绝对立体化学如通式4所示。
25.用于人治疗用途的含有至少一种根据前面任一项权利要求的化合物,或者其药学可接受盐的药物组合物。
26.根据权利要求25的用于治疗II型糖尿病或受损的葡萄糖耐受性的组合物。
27.根据权利要求25的用于治疗生长激素缺乏或者多囊卵巢综合征的组合物。
28.根据权利要求25的用于治疗自身免疫和炎症疾病的组合物。
29.根据权利要求1-24任一项的化合物或者其药学可接受盐用于制备治疗II型糖尿病、受损的葡萄糖耐受性、生长激素缺乏、多囊卵巢综合征、自身免疫和炎症的药物组合物的用途。
30.根据权利要求1-24任一项的化合物或者其药学可接受盐用于治疗II型糖尿病、受损的葡萄糖耐受性、生长激素缺乏、多囊卵巢综合征、自身免疫和炎症的用途。
31.治疗II型糖尿病、受损的葡萄糖耐受性、生长激素缺乏、多囊卵巢综合征、自身免疫和炎症的方法,包括对需要这样治疗的人施用治疗有效量的根据权利要求1-24任一项的化合物或者其药学可接受盐。
32.根据权利要求1-21任一项的化合物的至少一种旋光异构体。
33.根据权利要求1-24任一项的化合物的互变异构体。
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EP2085087A1 (en) * | 2001-06-11 | 2009-08-05 | Xenoport, Inc. | Prodrugs of gaba analogs, compositions and uses thereof |
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IL111785A0 (en) * | 1993-12-03 | 1995-01-24 | Ferring Bv | Dp-iv inhibitors and pharmaceutical compositions containing them |
US6090786A (en) * | 1994-06-10 | 2000-07-18 | Fondatech Benelux N.V. | Serine proteases, their activity and their synthetic inhibitors |
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Cited By (1)
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CN115368344A (zh) * | 2022-08-22 | 2022-11-22 | 湖北科技学院 | 组氨酸类衍生物及其制备方法和应用 |
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CA2449441A1 (en) | 2003-01-03 |
AU2002302857B2 (en) | 2007-01-25 |
EP1399154A1 (en) | 2004-03-24 |
KR20040010748A (ko) | 2004-01-31 |
NO20035775L (no) | 2004-02-23 |
UY27357A1 (es) | 2002-09-30 |
WO2003000250A1 (en) | 2003-01-03 |
MXPA03011981A (es) | 2004-06-03 |
PL364902A1 (en) | 2004-12-27 |
CZ20033413A3 (cs) | 2004-05-12 |
JP2004534815A (ja) | 2004-11-18 |
AR036111A1 (es) | 2004-08-11 |
US20040235752A1 (en) | 2004-11-25 |
GB0115517D0 (en) | 2001-08-15 |
RU2003136148A (ru) | 2005-05-20 |
NZ529925A (en) | 2005-04-29 |
HUP0400365A2 (hu) | 2004-08-30 |
ZA200309624B (en) | 2004-06-11 |
IL159152A0 (en) | 2004-06-01 |
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