CN1575171A - 新型抗糖尿病剂 - Google Patents
新型抗糖尿病剂 Download PDFInfo
- Publication number
- CN1575171A CN1575171A CNA028208544A CN02820854A CN1575171A CN 1575171 A CN1575171 A CN 1575171A CN A028208544 A CNA028208544 A CN A028208544A CN 02820854 A CN02820854 A CN 02820854A CN 1575171 A CN1575171 A CN 1575171A
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- Prior art keywords
- chemical compound
- uncle
- alkyl group
- butoxy carbonyl
- low alkyl
- Prior art date
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- Granted
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- 229940125708 antidiabetic agent Drugs 0.000 title 1
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- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
- 239000003112 inhibitor Substances 0.000 claims abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 150000001413 amino acids Chemical class 0.000 claims abstract description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
- 125000003435 aroyl group Chemical group 0.000 claims abstract description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 6
- 201000010099 disease Diseases 0.000 claims abstract description 6
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- 239000000651 prodrug Substances 0.000 claims abstract description 6
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- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 6
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- 238000000034 method Methods 0.000 claims description 18
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- 239000012528 membrane Substances 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- QJRYYOWARFCJQZ-UHFFFAOYSA-N pyrrolidine-1-carbonitrile Chemical compound N#CN1CCCC1 QJRYYOWARFCJQZ-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- SOPDQKNXOCUBSR-UHFFFAOYSA-N quinoxaline-2-carbonyl chloride Chemical compound C1=CC=CC2=NC(C(=O)Cl)=CN=C21 SOPDQKNXOCUBSR-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/60—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 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/02—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 containing two hetero rings
- C07D401/06—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 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/02—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 containing two hetero rings
- C07D401/12—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 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明涉及一系列具有改良特性的Dp-IV抑制剂的前药。该化合物可用于治疗许多人类疾病,包括葡萄糖耐量降低和II型糖尿病。本发明的化合物可用通式1表示:其中,R1是H或CN;R2选自CH2R5、CH2CH2R5和C(R3)(R4)-X2-(CH2) aR5;R3和R4各自独立选自H和Me;R5选自CON(R6)(R7)、N(R8)C(=O)R9、N(R8)C(=S)R9、N(R8)SO2R10和N(R8)R10;R6和R7各自独立是R11 (CH2) b或一起形成-(CH2) 2-Z-(CH2) 2-或-CH2-o-C6H4-Z-CH2-;R8是H或Me;R9选自R11 (CH2) b、R11 (CH2) bO和N(R6)(R7);R10是R11 (CH2) b;R11选自H、烷基、任选取代的芳基、任选取代的芳酰基、任选取代的芳基磺酰基和任选取代的杂芳基;R12选自H2NCH(R13)CO、H2NCH (R14) CONHCH(R15)CO、C(R16)=C(R17)COR18和R19OCO;R13、R14和R15选自蛋白质氨基酸的侧链;R16选自H、低级烷基(C1-C6)和苯基;R17选自H和低级烷基(C1-C6);R18选自H、低级烷基(C1-C6)、OH、O-(低级烷基(C1-C6))和苯基;R19选自低级烷基(C1-C6),任选取代的苯基和R20C(=O)OC(R21)(R22);R20、R21和R22各自独立选自H和低级烷基(C1-C6);Z选自共价键、-(CH2) c-、-O-、-SOd-和-N(R10)-;X1是S或CH2;X2是O、S或CH2;a是1、2或3;b是0-3;c是1或2;d是0、1或2。
Description
本发明涉及一类新化合物,它是二肽基肽酶IV抑制剂的前药。所述化合物可有效治疗II型糖尿病和葡萄糖耐量降低以及其它疾病。
背景技术
酶二肽基肽酶IV(在这里简写为D p-IV,其它地方也称为DA p-IV或DP p-IV),已知其分类号为EC.3.4.14.5,是一种丝氨酸蛋白酶,它能从以序列H-Xaa-Pro(其中Xaa是任意的氨基酸,尽管优选是亲脂性的氨基酸,Pro是脯氨酸)起始的肽中切割出N-末端二肽。它也可以接受以序列H-Xaa-Ala(其中Ala为丙氨酸)起始的肽作为底物。Dp-IV是最初被鉴定为膜伴随的(membrane-bound)蛋白。最近已经鉴定了一种可溶的形式。
对于Dp-IV的初始兴趣集中在它在活化T淋巴细胞中的作用。Dp-IV与T细胞蛋白CD26相同。有人提出Dp-IV的抑制剂能够调节T细胞应激性,从而能够发展为新的免疫调节剂。还有人提出CD26是对于HIV必需的共受体,因此Dp-IV抑制剂可用于治疗AIDS。
过去注意的是Dp-IV在免疫系统外部的作用。有人认为Dp-IV在一些肽激素的降解中具有关键性的作用,所述肽激素包括生长激素释放激素(GHRH)和胰高血糖素类肽-1和-2(GL对-1和GL p-2)。因为已知GL p-1在控制餐后血糖浓度中对于胰岛素的活性具有增强作用,所以很清楚Dp-IV抑制剂也可用来治疗II型糖尿病和糖耐受性的减弱。至少两种Dp-IV抑制剂现在正进行临床试验,以证明其可行性。
一些小组已经公开了Dp-IV的抑制剂。虽然从随机筛选程序中已发现了一些先导化合物(lead),但在该领域中的大部分工作都集中于研究底物类似物。作为底物类似物的Dp-IV抑制剂已经公开在例如美国专利5462928、美国专利5543396、WO95/15309(等价于美国专利5939560和欧洲专利0731789)、WO98/19998(等价于美国专利6011155)、WO99/46272和WO99/61431。最有效的抑制剂是氨酰基吡咯烷硼酸,但它们不稳定且会环化,而比较稳定的吡咯烷和噻唑烷衍生物对酶的亲和力较低,因此在临床上需要较大剂量。吡咯烷腈由于对酶有较高亲和力同时作为游离碱在溶液中有较长的半衰期因而似乎更有前景。然而,还需要具有改良特性的Dp-IV抑制剂。
发明概述
本发明涉及一系列具有改良特性的Dp-IV抑制剂的前药。该化合物可用于治疗许多人类疾病,包括葡萄糖耐量降低和II型糖尿病。因此,本发明还涉及所述化合物在药物组合物制造中的应用,涉及这种组合物本身以及涉及所述组合物在人类治疗中的应用。本发明的化合物可用通式1表示:
在上述通式中,R1是H或CN;R2选自CH2R5、CH2CH2R5和C(R3)(R4)-X2-(CH2)aR5;R3和R4各自独立选自H和Me;R5选自CON(R6)(R7)、N(R8)C(=O)R9、N(R8)C(=S)R9、N(R8)SO2R10和N(R8)R10;和R6和R7各自独立是R11(CH2)b或一起形成-(CH2)2-Z-(CH2)2-或-CH2-o-C6H4-Z-CH2-;R8是H或Me;R9选自R11(CH2)b、R11(CH2)bO和N(R6)(R7);R10是R11(CH2)b;R11选自H、烷基、任选取代的芳基、任选取代的芳酰基、任选取代的芳基磺酰基和任选取代的杂芳基;R12选自H2NCH(R13)CO、H2NCH(R14)CONHCH(R15)CO、C(R16)=C(R17)COR18和R19OCO;R13、R14和R15选自蛋白质氨基酸的侧链;R16选自H、低级烷基(C1-C6)和苯基;R17选自H和低级烷基(C1-C6);R18选自H、低级烷基(C1-C6)、OH、O-(低级烷基(C1-C6))和苯基;R19选自低级烷基(C1-C6),任选取代的苯基和R20C(=O)OC(R21)(R22);R20、R21和R22各自独立选自H和低级烷基(C1-C6);Z选自共价键、-(CH2)c-、-O-、-SOd-和-N(R10)-;X1是S或CH2;X2是O、S或CH2;a是1、2或3;b是0-3;c是1或2;d是0、1或2。
发明详述
第一方面,本发明涉及一系列具有改良特性的Dp-IV抑制剂的前药。本发明的化合物可用通式1表示:
在上述通式中,R1是氢原子(H)或腈基(-CN),X1是硫原子(S)或CH2。在本发明一个优选的实施方案中,R1是H。在另一个优选的实施方案中,R1是CN。
R2选自基团CH2R5、CH2CH2R5和C(R3)(R4)-X2-(CH2)aR5,其中,R3和R4各自独立选自H和甲基(Me),X2是O、S或CH2,a是1、2或3。优选地,R2选自基团CH2CH2R5和C(R3)(R4)-X2-(CH2)aR5。更优选地,R2选自基团CH2CH2R5和C(R3)(R4)-X2-(CH2)aR5其中,R3和R4都是H,X2是CH2,a是1或2。最优选地,R2选自基团CH2CH2CH2R5和CH2CH2CH2CH2R5。
R5选自基团CON(R6)(R7)、N(R8)C(=O)R9、N(R8)C(=S)R9、N(R8)SO2R10和N(R8)R10。在本发明一个优选的实施方案中,R5是基团CON(R6)(R7)。在另一个优选的实施方案中,R5选自基团N(R8)C(=O)R9、N(R8)C(=S)R9、N(R8)SO2R10和N(R8)R10。
R6和R7可各自独立为基团R11(CH2)b,其中,b是0-3。或者,它们可一起形成链-(CH2)2-Z-(CH2)2-或-CH2-o-C6H4-Z-CH2-,其中,Z选自共价键、-(CH2)c-、-O-、-SOd-和-N(R10)-,c是1或2;d是0、1或2,这样,它们和所结合的氮原子一起形成五元、六元或七元环。
R8是H或Me。
R9选自基团R11(CH2)b、R11(CH2)bO和N(R6)(R7)。
R10是基团R11(CH2)b。
R11选自H,烷基、任选取代的芳基、任选取代的芳酰基、任选取代的芳基磺酰基和任选取代的杂芳基。
所述术语烷基表示具有1-10个碳原子的饱和烃基,包括直链、支链以及单-和多环烷基,如甲基、乙基、丙基、异丙基、正丁基、叔丁基、环戊基、环己基、环己基甲基、2-环己基-2-丙基、二环〔2.2.2〕辛基等。
所述术语芳基表示单环和稠合二环芳香族基团,包括碳环基团(如苯基和萘基)和最多3个选自氮、氧和硫的杂原子的杂芳基,如吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噻唑基、吡啶基、嘧啶基、吲哚基、喹啉基等。除非有其它说明,芳基、芳酰基、芳基磺酰基或杂芳基可任选由最多3个基团取代,所述基团分别选自烷基、OH、烷氧基、O-烷基、Cl、F、Br、NH2、氨基(包括烷基氨基NH-烷基和二烷基氨基N(烷基)2)、CO2H、CO2-烷基、CONH2、CONH-烷基、CON(烷基)2、酰基、羧基、羧基烷基、羧酰氨基、NO2和CN。
R12选自基团H2NCH(R13)CO、H2NCH(R14)CONHCH(R15)CO、C(R16)=C(R17)COR18和R19OCO.在本发明一个优选的实施方案中R12选自基团H2NCH(R13)CO和H2NCH(R14)CONHCH(R15)CO。在本发明另一个优选的实施方案中,R12是基团R19OCO。
R13、R14和R15选自蛋白质氨基酸的侧链,如下表所示。
R16选自H、低级烷基(C1-C6烷基)和苯基。
R17选自H和低级烷基(C1-C6)。
R18选自H、低级烷基(C1-C6)、OH、O-(低级烷基(C1-C6))和苯基。
R19选自低级烷基(C1-C6),任选取代的苯基和R20C(=O)OC(R21)(R22)。
R20、R21和R22各自独立选自H和低级烷基(C1-C6)。
在优选的实施方案中,X1是CH2,R1是CN。对于此实施例,优选的R5基是CON(R6)(R7)、N(R8)C(=O)R9、N(R8)C(=S)R9和N(R8)R10。在另一个优选的实施方案中,X1是CH2,R1是H。在另一个优选的实施方案中X1是S。在另一个优选地实施方案中,X1是S和R1是H。
本发明优选的组合物可具有改进的活性和/或改进的药理特性。优选的组合物具有体内稳定的特性,这使得它们特别适合用作前药。
本发明的一些化合物具有酸性或碱性特征并可以盐的形式出现。凡是无毒或药学上可接受的盐都在本发明范围内。这些盐的例子包括但不限于碱性化合物的醋酸盐、盐酸盐、硫酸盐、磷酸盐和苯甲酸盐以及酸性化合物的钠盐、钾盐和四烷基铵盐。
施用后,本发明的化合物被转化成通式2的化合物。这些化合物是二肽基肽酶IV的有效抑制剂。
因此,本发明的化合物可用于治疗多种人类疾病,包括葡萄糖耐量降低和II型糖尿病。因此,本发明的其它特征涉及所述化合物在制备药物组合物中的应用,涉及这种组合物本身以及这种组合物在人类治疗中的应用。
本发明的化合物可用有机化学,尤其是肽化学领域熟知的方法制备。一种方法是制造与通式2相应的伯胺,然后将其衍生化。
当R12是H2NCH(R13)CO时,最终的转化可通过两个步骤实现,即使2与被保护的氨基酸衍生物反应,然后去保护。
在上述流程中,PG是保护基,如叔-丁氧羰基(BOC)、9-芴基甲氧羰基(FMOC)或苄氧羰基。
当R12是H2NCH(R14)CONHCH(R15)CO时,则最终的转化可类似地通过使2与被保护的二肽衍生物反应然后去保护进行,或用相对较长的途径用两次偶合和去保护循环进行。
或
当R12是C(R16)=C(R17)COR18时,则最终的转化可通过使2与合适的1,3-二羰基化合物反应进行。
当R12是R19OCO时,最终的转化可通过使2与合适的活性碳酸半酯衍生物,如氯甲酸酯或对-硝基苯基碳酸酯反应进行。
中间体2可将被保护的氨基酸与吡咯烷或噻唑烷衍生物偶合,然后去保护来制备。
或者,可以更简单地可在与2的主链结合后改变R2的官能度。
在以下非限制性实施例中将进一步阐述这些常规方法。
实施例1
(2S)-1-[Nα-(1’-乙酰氧基乙氧基羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]-吡咯烷-2-甲腈
1A.N-(2-硝基苯次磺酰基)-L-脯氨酸
将L-脯氨酸(25g,217mmol)溶于2M NaOH(110ml,220mmol)二噁烷(120ml)。与2M NaOH(110ml,220mmol)同时缓慢加入溶于二噁烷(60ml)的2-硝基苯次磺酰氯溶液(42g,222mmol)。混合物在室温下搅拌2小时,然后倒入水中(500ml)。通过过滤除去固体。用2M HCl将滤液调至pH3,溶液用乙酸乙酯提取(3×500ml)。合并的有机提取物用水(4×200ml)和盐水(1×200ml)洗涤,干燥(Na2SO4)并在真空下蒸发以得到桔黄色固体状的N-(2-硝基苯次磺酰基)-L-脯氨酸(58.1g,217mmol,100%)。
1B.N-(2-硝基苯次磺酰基)-L-脯氨酸琥珀酰亚胺酯
N-(2-硝基苯次磺酰基)-L-脯氨酸(57.9g,216mmol)溶于CH2Cl2/DMF(9∶1,500ml)。加入N-羟基琥珀酰亚胺(37.3g,324mmol)和水溶性碳二亚胺(51.8g,260mmol)。混合物在室温下搅拌18小时,然后在真空下除去溶剂并将残余物放入乙酸乙酯(1000ml)。溶液用水(4×200ml)和盐水(1×200ml)洗涤,干燥(Na2SO4)并在真空下蒸发以得到黄色固体状的N-(2-硝基苯次磺酰基)-L-脯氨酸琥珀酰亚胺酯(78.9g,216mmol,100%)。
1C.N-(2-硝基苯次磺酰基)-L-脯氨酰胺
N-(2-硝基苯次磺酰基)-L-脯氨酸琥珀酰亚胺酯(78.5g,215mmol)溶于二噁烷(500ml)。加入氨水(35%,100ml)。混合物在室温下搅拌2小时然后倒入水中(700ml)。收集沉淀,用水洗涤(200ml),通过P2O5干燥并从乙酸乙酯/石油醚60-80重结晶以得到黄色固体状的N-(2-硝基苯次磺酰基)-L-脯氨酰胺(49.6g,185mmol,86%)。
1D.(2S)-1-(2-硝基苯次磺酰基)吡咯烷-2-甲腈
N-(2-硝基苯次磺酰基)-L-脯氨酰胺(49g,183mmol)溶于无水THF(300ml)。溶液冷却至0C,加入三乙胺(36.7g,367mmol)然后缓慢加入三氟乙酸酐(77g,367mmol)。用三乙胺调节pH至pH9。混合物搅拌30min然后用乙酸乙酯稀释(500ml),用水(1×200ml)和盐水(l×200ml)洗涤,干燥(Na2SO4)并在真空下蒸发以得到橙色油状物,将其在硅胶上通过快速层析纯化(洗脱液:80%石油醚60-80,20%乙酸乙酯)以得到黄色固体(2S)-1-(2-硝基苯次磺酰基)吡咯烷-2-甲腈(38.9g,150mmol,82%)。
1E.(2S)-吡咯烷-2-甲腈氢氯化物
(2S)-1-(2-硝基苯次磺酰基)吡咯烷-2-甲腈(38.5g,149mmol)溶于二乙醚(200ml)。缓慢加入4M HCl/二噁烷(150ml,600mmol)。混合物在室温下搅拌2小时然后倒入二乙醚(1000ml)。收集固体,用二乙醚洗涤(500ml)并从甲醇/二乙醚在重结晶以得到白色固体(2S)-吡咯烷-2-甲腈氢氯化物(18.9g,142.5mmol,96%)。
1F.(2S)-1-[Nα-(叔-丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈
Nα-(叔-丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酸(2.5g,7.4mmol)溶于CH2Cl2(50ml)。溶液冷却至0℃,加入(2S)-吡咯烷-2-甲腈氢氯化物(1.2g,9.1mmol)和PyBOP(4.3g,8.23mmol),用三乙胺调节pH至pH9。混合物在0至室温下搅拌18h,然后在真空下除去溶剂并将残余物放入乙酸乙酯(200ml)。溶液用0.3MKHSO4(2×50ml)、饱和NaHCO3(2×50ml)、水(2×50ml)和盐水(1×50ml)洗涤,干燥(Na2SO4)并在真空下蒸发以得到黄色油状物,将其在硅胶上通过快速层析纯化(洗脱液:80%乙酸乙酯,20%石油醚,60-80)以得到无色油状物(2S)-1-[Nα-(叔-丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈(2.98g,7.16mmol,97%)。
1G.(2S)-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]吡咯烷-2-甲腈(2.8g,6.7mmol)溶于三氟乙酸(5ml)。混合物在室温下搅拌1小时,然后在真空下除去溶剂以得到无色油状物(2S)-1-[Nω-(吡嗪基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈三氟乙酸盐(1.5g,3.48mmol,52%)。
1H.(2S)-1-[Nα-(1’-乙酰氧基乙氧基羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈
将(2S)-1-[Nα-(吡嗪基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈三氟乙酸盐(200mg,0.47mmol),α-乙酰氧基乙基对-硝基苯碳酸酯(140mg,0.52mmol;按Alexander等,J.Med.Chem.31,318,1988的方法制备)和三乙胺(60mg,0.6mmol)的二氯甲烷溶液(25ml)在室温下搅拌18小时然后在真空下蒸发。将残余物置于乙酸乙酯(70ml)。溶液用饱和NaHCO3、水和盐水洗涤,干燥(Na2SO4)并蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:98%氯仿,2%甲醇)以得到白色固体(2S)-1-[Nα-(1’-乙酰氧基乙氧基羰基)-Nω-(吡嗪基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈(30mg,0.07mmol,14%)。
[M+H]+=447.2
1H NMR(CDCl3):δ1.41-1.48(3H,m),1.72-1.86(4H,m),2.02(3H,d,J=7.7Hz),2.11-2.28(4H,m),3.51-3.57(2H,m),3.68-3.69(2H,m),4.47-4.48(1H,m),4.74-4.76(1H,m),5.55-5.59(1H,m),6.75-6.78(1H,m),7.89-7.91(1H,m),8.52(1H,d,J=1.9Hz),8.76(1H,d,J=2.5Hz),9.3(1H,d,J=1.5Hz)ppm。
实施例2
(4R)-3-[Nα-甲氧基羰基)-Nω-(吡嗪基-2-羰基)-L-赖氨酰]噻唑烷-4-甲腈
2A.(4R)-3-(叔-丁氧羰基)噻唑烷-4-羧酰胺
(4R)-3-(叔-丁氧羰基)噻唑烷-4-羧酸(12.5g,54.1mmol)溶于CH2Cl2/DMF(9∶1,150ml)。在0℃溶液中加入1-羟基苯并三唑水合物(14.6g,108mmol)和水溶性碳二亚胺(13.0g,65mmol)。混合物在0℃搅拌1小时然后加入氨水(35%,50ml)。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(500ml)。溶液用0.3M KHSO4(2×100ml)、饱和NaHCO3(2×100ml)、水(2×100ml)和盐水(1×100ml)洗涤,干燥(Na2SO4)并在真空下蒸发以得到黄色油状物。残余物在硅胶上通过快速层析纯化(洗脱液:2%甲醇,98%氯仿)以得到无色油状物(4R)-3-(叔-丁氧羰基)噻唑烷-4-羧酰胺(8.9g,38.4mmol,71%)。
2B.(4R)-噻唑烷-4-羧酰胺氢氯化物
(4S)-3-(叔-丁氧羰基)噻唑烷-4-羧酰胺(8.6g,37.1mmol)溶于4M HCl/二噁烷(50ml)。混合物在室温下搅拌1小时,然后将溶剂在真空下蒸发以得到白色固体(4R)-噻唑烷-4-羧酰胺氢氯化物(6.2g,36.8mmol,99%)。
2C.(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰]噻唑烷-4-羧酰胺
Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酸(5g,10.7mmol)溶于CH2Cl2(100ml)。溶液冷却至0℃,加入(4R)-噻唑烷-4-羧酰胺氢氯化物(1.78g,11.7mmol)和PyBOP(6.7g,12.8mmol),然后用三乙胺将pH调至pH9。混合物在0至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(200ml)。溶液用0.3M KHSO4(2×50ml)、饱和NaHCO3(2×50ml)、水(2×50ml)和盐水(1×50ml)洗涤,干燥(Na2SO4)并在真空下蒸发以得到黄色油状物。残余物在硅胶上通过快速层析纯化(洗脱液:2%甲醇,98%氯仿)以得到无色油状物(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰]噻唑烷-4-羧酰胺(2.81g,4.8mmol,44%)。
2D.(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰]噻唑烷-4-甲腈
(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰]噻唑烷-4-羧酰胺(2.7g,4.7mmol)溶于无水THF(100ml)。溶液冷却至0℃并加入三乙胺(1.0g,10mmol),然后缓慢加入三氟乙酸酐(2.0g,9.5mmol)。用三乙胺将pH调至pH9。混合物搅拌30min然后用乙酸乙酯稀释(100ml),用水(1×50ml)和盐水(1×50ml)洗涤,干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:60%石油醚60-80,40%乙酸乙酯)以得到无色油状物(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰]噻唑烷-4-甲腈(2.14g,3.81mmol,82%)。
2E.(4R)-3-[Nα-(叔-丁氧羰基)-L-赖氨酰]噻唑烷-4-甲腈
(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-赖氨酰]噻唑烷-4-甲腈(1.9g,3.4mmol)溶于THF(40ml)。加入二乙胺(10ml)。混合物在室温下搅拌2小时然后在真空下除去溶剂。残余物在硅胶上通过快速层析纯化(洗脱液:90%氯仿,7%甲醇,3%三乙胺)以得到无色油状物(4R)-3-[Nα-(叔-丁氧羰基)-L-赖氨酰]噻唑烷-4-甲腈(863mg,2.5mmol,75%)。
2F.(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-赖氨酰]噻唑烷-4-甲腈
(4R)-3-[Nα-(叔-丁氧羰基)-L-赖氨酰]噻唑烷-4-甲腈(100mg,0.29mmol)溶于CH2Cl2(20ml)。在0℃的溶液在加入2-吡嗪羧酸(43mg,0.35mmol)和PyBOP(170mg,0.33mmol)并用三乙胺将pH调至pH9。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(70ml)。溶液用0.3M KHSO4(2×20ml)、饱和NaHCO3(2×20ml)、水(2×20ml)和盐水(1×20ml)洗涤,干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:2%甲醇,98%氯仿)以得到无色油状物(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-赖氨酰]噻唑烷-4-甲腈(1 12mg,0.25mmol,86%)。
2G.(4R)-3-[(Nα-甲氧基羰基)-Nω-(吡嗪基-2-羰基)-L-赖氨酰]噻唑烷-4-甲腈
(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(吡嗪基-2-羰基)-L-赖氨酰]噻唑烷-4-甲腈(160mg,0.36mmol)溶于4M HCl/二噁烷(30ml)。混合物在室温下搅拌1小时然后在真空下除去溶剂。残余物溶于二氯甲烷(25ml)。加入氯甲酸甲酯(50mg,0.53mmol)和三乙胺(60mg,0.6mmol),溶液在室温下搅拌18小时然后在真空下蒸发溶液。将残余物置于乙酸乙酯(70ml)。溶液用饱和NaHCO3、水和盐水洗涤,干燥(Na2SO4)并蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:90%乙酸乙酯:10%石油醚60-80)以得到白色固体(4R)-3-[(Nα-甲氧基羰基)-Nω-(吡嗪基-2-羰基)-L-赖氨酰]噻唑烷-4-甲腈(52mg,0.13mmol,35%)。
[M+H]+=407.1
1H NMR(CDCl3):δ1.33-1.48(4H,m),1.63-1.82(2H,m),3.21-3.27(2H,m),3.45-3.60(2H,m),3.63(3H,s),4.44-4.46(1H,m),4.63(1H,d,J=8.4Hz),4.86(1H,d,J=8.5Hz),5.23-5.27(1H,m),5.53(1H,d,J=8.2Hz),7.85-7.87(1H,m),8.50-8.51(1H,m),8.73(1H,d,J=2.5Hz),9.38(1H,d,J=1,3Hz)ppm。
实施例3
(4R)-3-[Nα-(1’-乙酰氧基乙氧基羰基)-Nω-(3-氰基苯磺酰基)-L-鸟氨酰]噻唑烷-4-甲腈
3A.(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]噻唑烷-4-羧酰胺
Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酸(2.8g,6.2mmol)溶于CH2Cl2/DMF(9∶1,100ml)。溶液冷却至0℃,加入(4R)-噻唑烷-4-羧酰胺氢氯化物(1.78g,11.7mmol)、1-羟基苯并三唑水合物(1.1g,8.1mmol)和水溶性碳二亚胺(1.5g,7.5mmol),用N-甲基吗啉调节pH至pH8。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(200ml)。溶液用0.3MKHSO4(2×50ml)、饱和NaHCO3(2×50ml)、水(2×50ml)和盐水(1×50ml)洗涤,干燥(Na2SO4)并在真空下蒸发以得到黄色油状物。残余物在硅胶上通过快速层析纯化(洗脱液:85%乙酸乙酯,15%石油醚60-80)以得到无色油状物(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]噻唑烷-4-羧酰胺(2.26g,3.9mmol,66%)。
3B.(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]噻唑烷-4-甲腈
(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]噻唑烷-4-羧酰胺(2.1g,3.7mmol)溶于无水THF(100ml)。溶液冷却至0℃,加入三乙胺(740mg,7.4mmol)然后缓慢加入三氟乙酸酐(1.65g,7.9mmol)。用三乙胺将pH调至pH9。混合物搅拌30min然后用乙酸乙酯稀释(100ml),用水(1×50ml)和盐水(1×50ml)洗涤,干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:45%石油醚60-80,55%乙酸乙酯)以得到无色油状物(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]噻唑烷-4-甲腈(1.73g,3.14mmol,85%)。
3C.(4R)-3-[Nα-(叔-丁氧羰基)-L-鸟氨酰]噻唑烷-4-甲腈
(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]噻唑烷-4-甲腈(1.6g,2.9mmol)溶于THF(40ml)。加入二乙胺(10ml)。混合物在室温下搅拌2小时然后在真空下除去溶剂。残余物在硅胶上通过快速层析纯化(洗脱液:90%氯仿,7%甲醇,3%三乙胺)以得到无色油状物(4R)-3-[Nα-(叔-丁氧羰基)-L-鸟氨酰]噻唑烷-4-甲腈(902mg,2.75mmol,95%)。
3D.(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(3-氰基苯磺酰基)-L-鸟氨酰]噻唑烷-4-甲腈
(4R)-3-[Nα-(叔-丁氧羰基)-L-鸟氨酰]噻唑烷-4-甲腈(207mg,0.63mmol)溶于CH2Cl2(25ml)。在0℃的溶液中加入3-氰基苯磺酰氯(135mg,0.67mmol)并用三乙胺将pH调至pH9。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(70ml)。溶液用0.3M KHSO4(2×20ml)、饱和NaHCO3(2×20ml)、水(2×20ml)和盐水(1×20ml)洗涤,干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:45%乙酸乙酯:55%石油醚60-80℃)以得到无色油状物(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(3-氰基苯磺酰基)-L-鸟氨酰]噻唑烷-4-甲腈(162mg,0.33mmol,52%)。
3E.(4R)-3-[Nα-(1’-乙酰氧基乙氧基羰基)-Nω-(3-氰基苯磺酰基)-L-鸟氨酰]噻唑烷-4-甲腈
(4R)-3-[Nα-(叔-丁氧羰基)-Nω-(3-氰基苯磺酰基)-L-鸟氨酰]噻唑烷-4-甲腈(142mg,0.29mmol)溶于三氟乙酸(5ml)。混合物在室温下搅拌l小时然后在真空下除去溶剂。残余物溶于二氯甲烷(25ml),加入α-乙酰氧基乙基对-硝基苯碳酸酯(108mg,0.40mmol;照Alexander等,J.Med.Chem.31,318,1988的方法制备)和三乙胺(60mg,0.6mmol)。反应物在室温下搅拌18小时,然后在真空下蒸发。残余物置于乙酸乙酯(70ml),溶液用饱和NaHCO3、水和盐水洗涤,干燥(Na2SO4)并蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:70%乙酸乙酯:30%石油醚60-80)以得到白色固体(4R)-3-[Nα-(1’-乙酰氧基乙氧基羰基)-Nω-(3-氰基苯磺酰基)-L-鸟氨酰]噻唑烷-4-甲腈(32mg,0.06mmol,21%)。
[M+H]+=524.0
1H NMR(CDCl3):δ1.20-1.22(2H,m),1.43-1.46(3H,m),1.59-1.78(4H,m),2.03-2.06(3H,m),3.03(2H,d,J=4.2Hz),3.29-3.33(2H,m),4.61-4.66(1H,m),4.79-4.84(1H,m),5.16-5.20(1H,m),5.73-5.82(1H,m),6.74-6.76(1H,m),7.63-7.69(1H,m),7.83-7.86(1H,m),8.10-8.16(2H,m)ppm。
实施例4
(2S,2′S)-1-[2′-(1″-乙酰氧基乙氧基羰基氨基)-5′-氧代-5′-(四氢异喹啉-2-基)戊酰基]吡咯烷-2-甲腈
4A.(2S)-1-[N-(叔-丁氧羰基)-Oω-甲基-L-谷氨酰]吡咯烷-2-甲腈
N-(叔-丁氧羰基)-Oω-甲基-L-谷氨酸(1.0g,3.83mmol)溶于CH2Cl2/DMF(9∶1,20ml)。在0℃的溶液中加入1-羟基苯并三唑水合物(788mg,5.84mmol)、水溶性碳二亚胺(877mg,4.38mmol),(2S)-吡咯烷-2-甲腈氢氯化物(609mg,4.6mmol)和三乙胺(65mg,0.65mmol)。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(70ml)。溶液用0.3M KHSO4(2×20ml)、饱和NaHCO3(2×20ml)、水(2×20ml)和盐水(1×20ml)洗涤,干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:50%乙酸乙酯,50%石油醚60-80)以得到棕色油状物(2S)-1-[N-(叔-丁氧羰基)-Oω-甲基-L-谷氨酰]吡咯烷-2-甲腈(290mg,0.86mmol,22%)。
4B.(2S)-1-[N-(叔-丁氧羰基)-L-谷氨酰]吡咯烷-2-甲腈
(2S)-1-[N-(叔-丁氧羰基)-Oω-甲基-L-谷氨酰]吡咯烷-2-甲腈(250mg,0.74mmol)溶于二噁烷(5ml)。加入1M氢氧化锂(1.1ml,1.1mmol)。混合物在室温下搅拌1小时然后在真空下除去溶剂并将残余物置于乙酸乙酯(70ml)。溶液用1MKHSO4(2×20ml)、水(2×20ml)和盐水(1×20ml)洗涤,干燥(Na2SO4)并在真空下蒸发以得到无色油状物(2S)-1-[N-(叔-丁氧羰基)-L-谷氨酰]吡咯烷-2-甲腈(200mg,0.61mmol,83%)。
4C.(2S,2′S)-1-[2′-(叔-丁氧羰基氨基)-5′-氧代-5′-(四氢异喹啉-2-基)戊酰基]吡咯烷-2-甲腈
(2S)-1-[N-(叔-丁氧羰基)-L-谷氨酰]吡咯烷-2-甲腈(200mg,0.61mmol)溶于CH2Cl2/DMF(9∶1,20ml)。在0℃的溶液中加入1-羟基苯并三唑水合物(98mg,0.73mmol)、水溶性碳二亚胺(140mg,0.73mmol),四氢异喹啉(109mg,0.82mmol)和三乙胺(150mg,1.5mmol)。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(70ml)。溶液用0.3M KHSO4(2×20ml)、饱和NaHCO3(2×20ml)、水(2×20ml)和盐水(1×20ml)洗涤,干燥(Na2SO4)并在真空下蒸发以得到黄色油状物。残余物在硅胶上通过快速层析纯化(洗脱液:5%甲醇,97%氯仿)以得到无色油状物。(2S,2′S)-1-[2′-(叔-丁氧羰基氨基)-5′-氧代-5′-(四氢异喹啉-2-基)戊酮基]吡咯烷-2-甲腈(149mg,0.34mmol,56%)。
4D.(2S,2′S)-1-[2′-(1″-乙酰氧基乙氧基羰基氨基)-5′-氧代-5′-(四氢异喹啉-2-基)戊酰基]吡咯烷-2-甲腈
(2S,2′S)-1-[2′-(叔-丁氧羰基氨基)-5′-氧代-5′-(四氢异喹啉-2-基)戊酰基]吡咯烷-2-甲腈(149mg,0.34mmol)溶于三氟乙酸(20ml)。混合物在室温下搅拌1小时然后在真空下除去溶剂。残余物溶于二氯甲烷(25ml),加入α-乙酰氧基乙基对-硝基苯碳酸酯(100mg,0.37mmol;按Alexander等,J.Med.Chem.31,318,1988的方法制备)和三乙胺(40mg,0.4mmol)。反应物在室温下搅拌18小时然后在真空下蒸发并将残余物置于乙酸乙酯(70ml)。溶液用饱和NaHCO3、水和盐水,干燥(Na2SO4)并蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:90%乙酸乙酯,10%石油醚60-80℃)以得到白色固体(2S,2′S)-1-[2′-(1″-乙酰氧基乙氧基羰基氨基)-5′-氧代-5′-(四氢异喹啉-2-基)戊酰基]吡咯烷-2-甲腈(58mg,0.12mmol,36%)。
[M+H]+=471.2
1H NMR(CDCl3):δ1.40-1.44(3H,m),2.00-2.07(3H,m),2.13-2.40(9H,m),2.82-2.91(2H,m),3.63-3.70(2H,m),3.96-4.18(1H,m),4.57-4.61(2H,m),4.72-4.75(2H,m),5.78-5.80(1H,m),6.69-6.75(1H,m),7.10-7.25(4H,m)ppm。
实施例5
(2S)-1-[Nα-(4′-氧代戊-2′-烯-2′-基)-Nω-(喹喔啉基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈
5A.1-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]-L-脯氨酰胺
Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酸(5g,11.0mmol)溶于CH2Cl2(40ml)。溶液冷却至0℃,加入L-脯氨酰胺(1.4g,12.2mmol)和PyBOP(6.3g,12.1mmol),并用三乙胺将pH调至pH9。混合物在0从至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于氯仿(200ml)。溶液用0.3M KHSO4(2×50ml)、饱和NaHCO3(2×50ml)、水(2×50ml)和盐水(1×50ml),干燥(Na2SO4)并在真空下蒸发以得到黄色油状物。残余物在硅胶上通过快速层析纯化(洗脱液:98%氯仿,2%甲醇)以得到无色油状物3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]-L-脯氨酰胺(4.2g,7.6mmol,69%)。
5B.(2S)-1-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]吡咯烷-2-甲腈
N-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]-L-脯氨酰胺(4.1g,7.4mmol)溶于无水THF(100ml)。溶液冷却至0℃并加入三乙胺(820mg,8.2mmol),然后缓慢加入三氟乙酸酐(1.7g,8.1mmol)。用三乙胺将pH调至pH9。混合物搅拌30min然后用乙酸乙酯稀释(100ml),用水(1×50ml)和盐水(1×50ml)洗涤,干燥(Na2S04)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:20%乙酸乙酯,80%石油醚60-80)以得到无色油状物(2S)-1-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]吡咯烷-2-甲腈(3.5g,6.5mmol,87%)。
5C.(2S)-1-[Nα-(叔-丁氧羰基)-L-鸟氨酰]吡咯烷-2-甲腈
(2S)-1-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]吡咯烷-2-甲腈(3.4g,6.4mmol)溶于THF(40ml)。加入二乙胺(10ml)。混合物在室温下搅拌2小时然后在真空下除去溶剂。残余物在硅胶上通过快速层析纯化(洗脱液:90%氯仿,7%甲醇,3%三乙胺)以得到无色油状物(2S)-1-[Nα-(叔-丁氧羰基)-L-鸟氨酰]吡咯烷-2-甲腈(1.48g,4.77mmol,759%)。
5D.(2S)-1-[Nα-(叔-丁氧羰基)-Nω-(喹喔啉基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈
(2S)-1-[Nα-(叔-丁氧羰基)-L-鸟氨酰]吡咯烷-2-甲腈(300mg,0.97mmol)溶于CH2Cl2(25ml)。在0℃的溶液中加入2-喹喔啉甲酰氯(2-quinoxaloylchloride)(200mg,104mmol)并用三乙胺将pH调至pH9。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(70ml)。溶液用0.3MKHSO4(2×20ml)、饱和NaHCO3(2×20ml)、水(2×20ml)和盐水(1×20ml)洗涤,干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:60%乙酸乙酯,409%石油醚60-80)以得到无色油状物(2S)-1-[Nα-(叔-丁氧羰基)-Nω-(喹喔啉基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈(310mg,0.67mmol,69%)。
5E.(2S)-1-[Nα-(4′-氧代戊-2′-烯-2′-基)-Nω-(喹喔啉基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈
(2S)-1-[Nα-(叔-丁氧羰基)-Nω-(喹喔啉基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈(160mg,0.34mmol)溶于三氟乙酸(20ml)。混合物在室温下搅拌1小时,然后在真空下除去溶剂。残余物溶于二氯甲烷(25ml),加入乙酰基丙酮(48mg,0.48mmol)和三乙胺(100mg,1.0mmol)。反应物在室温下搅拌18小时然后在真空下蒸发。残余物置于乙酸乙酯(70ml)。溶液用饱和NaHCO3、水和盐水洗涤,干燥(Na2SO4)并蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:98%氯仿,2%甲醇)以得到白色固体(2S)-1-[Nα-(4′-氧代戊-2′-烯-2′-基)-Nω-(喹喔啉基-2-羰基)-L-鸟氨酰]吡咯烷-2-甲腈(87mg,0.l9mmol,57%)。
[M+H]+=449.2
1H NMR(CDCl3):δ1.89-2.02(10H,2×s+m),2.13-2.24(4H,m),3.57-3.62(5H,m),4.3-4.6(1H,m),4.70-4.81(1H,m),5.02(1H,s),7.83-7.88(2H,m),8.10-8.19(3H,m),9.62(1H,s),11.0-11.2(1H,m)ppm。
实施例6
(2S)-1-[N-乙酰氧基甲氧基羰基-S-(3-吡啶甲基氨基甲酰甲基)-L-半胱氨酰]吡咯烷-2-甲腈
6A.S-(苄氧羰基甲基)-N-(叔-丁氧羰基)-L-半胱氨酸
N-(叔-丁氧羰基)-L-半胱氨酸(3.5g,15.8mmol)、2-溴乙酸苄酯(3.7g,16.1mmol)和三乙胺(1.8g,18.0mmol)溶于THF(100ml)。混合物在室温下搅拌18小时然后用乙酸乙酯稀释(100ml),用0.3M KHSO4、饱和NaHCO3、水和盐水洗涤,干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:95%氯仿,4%甲醇,1%乙酸)以得到无色油状物S-(苄氧羰基甲基)-N-(叔-丁氧羰基)-L-半胱氨酸(5.2g,14.1mmol,89%)。
6B.(2S)-1-[S-(苄氧羰基甲基)-N-(叔-丁氧羰基)-L-半胱氨酰]吡咯烷-2-甲腈
S-(苄氧羰基甲基)-N-(叔-丁氧羰基)-L-半胱氨酸(5.10g,13.8mmol)溶于CH2Cl2(200ml)。溶液冷却至0℃,加入(2S)-吡咯烷-2-甲腈氢氯化物(2.1g,15.8mmol)和PyBOP(8.0g,15.3mmol),用三乙胺调节pH至pH9。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(150ml)。溶液用0.3MKHSO4(1×50ml)、饱和NaHCO3(1×50ml)、水(1×50ml)和盐水(1×50ml),干燥(Na2SO4)并在真空下蒸发以得到黄色油状物将其在硅胶上通过快速层析纯化(洗脱液:40%乙酸乙酯,60%石油醚60-80)以得到无色油状物(2S)-1-[S-(苄氧羰基甲基)-N-(叔-丁氧羰基)-L-半胱氨酰]吡咯烷-2-甲腈(5.82g,13.0mmol,94%)。
6C.(2S)-1-[N-(叔-丁氧羰基)-S-(羧基甲基)-L-半胱氨酰]吡咯烷-2-甲腈
(2S)-1-[S-(苄氧羰基甲基)-N-(叔-丁氧羰基)-L-半胱氨酰]吡咯烷-2-甲腈(1.31g,2.9mmol)溶于THF(100ml)。加入1M氢氧化锂(3.5ml,3.5mmol)。混合物在室温下搅拌3小时,然后和乙酸乙酯(100ml),用1M柠檬酸、水和盐水洗涤,干燥(Na2SO4)并在真空下蒸发以得到无色油状物,将其在硅胶上通过快速层析纯化(洗脱液:97%氯仿,2%甲醇,1%乙酸)以得到无色油状物(2S)-1-[N-(叔-丁氧羰基)-S-(羧基甲基)-L-半胱氨酰]吡咯烷-2-甲腈(860mg,2.4mmol,82%)。
6D.(2S)-1-[N-(叔-丁氧羰基)-S-(3-吡啶甲基氨基甲酰甲基))-L-半胱氨酰]吡咯烷-2-甲腈
(2S)-1-[N-(叔-丁氧羰基)-S-(羧基甲基)-L-半胱氨酰]吡咯烷-2-甲腈(150mg,0.42mmol)溶于CH2Cl2(20ml)。溶液冷却至0℃,加入3-(氨基甲基)吡啶(53mg,0.5mmol)和PyBOP(270mg,0.52mmol),并用三乙胺将pH调至pH9。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物溶于乙酸乙酯(70ml)。溶液用0.3M KHSO4(1×20ml)、饱和NaHCO3(1×20ml)、水(1×20ml)和盐水(1×20ml)洗涤,干燥(Na2SO4)并在真空下蒸发以得到黄色油状物将其在硅胶上通过快速层析纯化(洗脱液:96%氯仿,4%甲醇)以得到无色油状物(2S)-1-[N-(叔-丁氧羰基)-S-(3-吡啶甲基氨基甲酰甲基))-L-半胱氨酰]吡咯烷-2-甲腈(170mg,0.38mmol,91%)。
6E.(2S)-1-[Nα-乙酰氧基甲氧基羰基-S-(3-吡啶甲基氨基甲酰甲基)-L-半胱氨酰]吡咯烷-2-甲腈
(2S)-1-[N-(叔-丁氧羰基)-S-(3-吡啶甲基氨基甲酰甲基)-L-半胱氨酰]吡咯烷-2-甲腈(130mg,0.29mmol)溶于三氟乙酸(20ml)。溶液在室温下搅拌1小时然后在真空下除去溶剂。残余物溶于二氯甲烷(25ml),加入乙酰氧基甲基对-硝基苯碳酸酯(80mg,0.3lmmol;按Alexander等,J.Med.Chem.31,318,1988的方法制备)和三乙胺(40mg,0.4mmol)。溶液在室温下搅拌18小时然后在真空下蒸发并将残余物置于乙酸乙酯(70ml)。溶液用饱和NaHCO3、水和盐水洗涤,干燥(Na2SO4)并蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:90%乙酸乙酯,10%石油醚60-80)以得到白色固体(2S)-1-[Nα-乙酰氧基甲氧基羰基-S-(3-吡啶甲基氨基甲酰甲基)-L-半胱氨酰]吡咯烷-2-甲腈(33mg,0.071mmol,24%)。
[M+H]+=464.0
1H NMR(CDCl3):δ2.08(3H,s),2.13-2.29(4H,m),2.89(2H,d,J=6.9Hz),3.20-3.29(2H,m),3.61-3.74(2H,m),4.46(2H,d,J=5.9Hz),4.60-4.71(2H,m),5.68(2H,s),6.12(1H,d,J=8.6Hz),7.16-7.27(2H,m),7.66(1H,d,J=8.1Hz),8.50(1H,d,J=4.7Hz),8.56(1H,s)ppm。
实施例7
3-[Nα-(1′-乙酰氧基乙氧基羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酰]噻唑烷
7A.3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]噻唑烷
Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酸(2.73g,6mmol)溶于CH2Cl2/DMF(9∶1,100ml)。在0℃的溶液中加入1-羟基苯并三唑水合物(1.53g,10mmol)、水溶性碳二亚胺(1.34g,7mmol)、噻唑烷(1.28g,18mmol)和三乙胺(80mg,8mmol)。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(100ml)。溶液用0.3M KHSO4(2×25ml)、饱和NaHCO3(2×25ml)、水(2×25ml)和盐水(1×25ml),干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:75%乙酸乙酯,25%石油醚60-80)以得到白色固体3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]噻唑烷(2.55g,4.85mmol,81%)。
7B.3-[Nα-(叔-丁氧羰基)-L-鸟氨酰]噻唑烷
3-[Nα-(叔-丁氧羰基)-Nω-(9-芴基甲氧羰基)-L-鸟氨酰]噻唑烷(1.15g,2.13mmol)溶于乙腈(20ml)。加入二乙胺(5ml)。混合物在室温下搅拌90min,然后在真空下除去溶剂,残余物在硅胶上通过快速层析纯化(洗脱液:90%氯仿,7%甲醇,3%三乙胺)以得到淡黄色油状物3-[Nα-(叔-丁氧羰基)-L-鸟氨酰]噻唑烷(530mg,1.67mmol,78%)。
7C.3-[Nα-(叔-丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酰]噻唑烷
3-[Nα-(叔-丁氧羰基)-L-鸟氨酰]噻唑烷(600mg,1.96mmol)溶于CH2Cl2/DMF(9∶1,50ml)。在0℃的溶液中加入1-羟基苯并三唑水合物(360mg,2.36mmol)、水溶性碳二亚胺(472mg,2.36mmol),5,6-二氯烟酸(416mg,2.16mmol)和三乙胺(360mg,3.6mmol)。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(70ml)。溶液用0.3M KHSO4(2×20ml)、饱和NaHCO3(2×20ml)、水(2×20ml)和盐水(1×20ml)洗涤,干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:2%甲醇,98%氯仿)以得到粘性白色固体3-[Nα-(叔-丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酰]噻唑烷(512mg,1.08mmol,56%)。
7D.3-[Nα-(1′-乙酰氧基乙氧基羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酰]噻唑烷
3-[Nα-(叔-丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酰]噻唑烷(l28mg,0.27mmol)溶于4M HCl/二噁烷(20ml)。混合物在室温下搅拌1小时然后在真空下除去溶剂。残余物溶于二氯甲烷(25ml),加入α-乙酰氧基乙基对-硝基苯碳酸酯(83mg,0.3mmol;按Alexander等,J.Med.Chem.31,318,1988的方法制备)和三乙胺(40mg,0.4mmol)。溶液在室温下搅拌18小时然后在真空下蒸发。将残余物置于乙酸乙酯(70ml)。溶液用饱和NaHCO3、水和盐水洗涤,干燥(Na2SO4)并蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:75%乙酸乙酯,25%石油醚60-80)以得到白色固体3-[Nα-(1′-乙酰氧基乙氧基羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酰]噻唑烷(67mg,0.13mmol,47%)。
[M+H]+=509.0
1H NMR(CDCl3):δ1.44-1.46(3H,m),1.63-1.99(3H,br m),1.99-2.04(4H,m),2.98-3.06(2H,m),3.46-3.48(2H,m),3.50-3.80(2H,m),4.47-4.56(3H,m),5.81-5.91(1H,m),6.74-6.75(1H,m),7.24-7.33(1H,m),8.24-8.25(1H,m),8.69-8.71(1H,m)ppm。
实施例8
3-[Nα-甲氧基羰基-Nω-(6-三氟甲基烟酰)-L-鸟氨酰]噻唑烷
8A.3-[Nα-(叔-丁氧羰基)-Nω-(6-三氟甲基烟酰)-L-鸟氨酰]噻唑烷
3-[Nα-(叔-丁氧羰基)-L-鸟氨酰]噻唑烷(150mg,0.49mmol)溶于CH2Cl2/DMF(9∶1,20ml)。在0℃的溶液中加入1-羟基苯并三唑水合物(100mg,0.74mmol)、水溶性碳二亚胺(118mg,0.59mmol)、6-三氟甲基烟酸(104mg,0.54mmol)和三乙胺(100mg,1.0mmol)。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(70ml)。溶液用0.3M KHSO4(2×20ml)、饱和NaHCO3(2×20ml)、水(2×20ml)和盐水(1×20ml)洗涤,干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:6%甲醇,94%氯仿)以得到粘性白色固体3-[Nα-(叔-丁氧羰基)-Nω-(6-三氟甲基烟酰)-L-鸟氨酰]噻唑烷(76mg,0.16mmol,32%)。
8B.3-[Nα-甲氧基羰基-Nω-(6-三氟甲基烟酰)-L-鸟氨酰]噻唑烷
3-[Nα-(叔-丁氧羰基)-Nω-(6-三氟甲基烟酰)-L-鸟氨酰]噻唑烷(76mg,0.16mmol)溶于4M HCl/二噁烷(20ml)。混合物在室温下搅拌1小时然后在真空下除去溶剂。残余物溶于二氯甲烷(25ml),加入甲基氯甲酸酯(17mg,0.18mmol)和三乙胺(20mg,0.2mmol)。溶液在室温下搅拌18小时然后在真空下蒸发。将残余物置于乙酸乙酯(70ml)。溶液用饱和NaHCO3、水和盐水洗涤,干燥(Na2SO4)并蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:3%甲醇,97%氯仿)以得到白色固体3-[Nα-甲氧基羰基-Nω-(6-三氟甲基烟酰)-L-鸟氨酰]噻唑烷(66mg,0.15mmol,96%)。
[M+H]+=435.1
1H NMR(CDCl3):δ1.36-1.79(4H,m),2.98-3.11(2H,m),3.48-3.60(2H,m),3.64(3H,s),3.72-4.10(3H,m),4.57-4.60(2H,m),5.63-5.76(1H,m),6.55(1H,br m),7.54-7.55(1H,m),8.77-8.79(2H,m)ppm。
实施例9
3-[Nω-(5,6-二氯烟酰)-Nα-(4′-氧代戊-2′-烯-2′-基)-L-鸟氨酰]噻唑烷
3-[Nα-(叔-丁氧羰基)-Nω-(5,6-二氯烟酰)-L-鸟氨酰]噻唑烷(162mg,0.34mmol)溶于4M HCl/二噁烷(20ml)。混合物在室温下搅拌1小时然后在真空下除去溶剂。残余物溶于二氯甲烷(25ml),加入乙酰基丙酮(100mg,0.37mmol)和三乙胺(40mg,0.4mmol)。溶液在室温下搅拌18小时然后在真空下蒸发。将残余物置于乙酸乙酯(70ml)。溶液用饱和NaHCO3、水和盐水洗涤,干燥(Na2SO4)并蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:90%乙酸乙酯,10%石油醚60-80)以得到白色固体3-[Nω-(5,6-二氯烟酰)-Nα-4′-氧代戊-2′-烯-2′-基)-L-鸟氨酰]噻唑烷(63mg,0.14mmol,40%)。
[M+H]+=461.3
1H NMR(CDCl3):δ1.74-1.86(6H,m),1.87(3H,s),1.97(3H,s),2.94-3.11(2H,m),3.46-3.51(2H,m),3.75-3.79(1H,m),4.48-4.57(2H,m),5.01(1H,s),7.60-7.90(1H,m),8.34(1H,d,J=2.0Hz),8.78(1H,d,J=2.3Hz),11.01(1H,d,J=8.2Hz)ppm。
实施例10
3-[Nα-(乙酰氧基甲氧基羰基)-Nω-(3,4-二氯苄基)-L-谷氨酰氨基]噻唑烷
10A.3-[N-(叔-丁氧羰基)-Oω-甲基-L-谷氨酰]噻唑烷
N-(叔-丁氧羰基)-Oω-甲基-L-谷氨酸(6.28g,24mmol)溶于CH2Cl2/DMF(9∶1,100ml)。在0℃的溶液中加入1-羟基苯并三唑水合物(5.5g,36mmol)、水溶性碳二亚胺(5.38g,28mmol),噻唑烷(2.48g,28mmol)和三乙胺(3.0g,30mmol)。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(150ml)。溶液用0.3M KHSO4(2×30ml)、饱和NaHCO3(2×30ml)、水(2×30ml)和盐水(1×30ml),干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:70%乙酸乙酯,30%石油醚60-80)以得到棕色油状物3-[N-(叔-丁氧羰基)-Oω-甲基-L-谷氨酰]噻唑烷(4.0g,12mmol,50%)。
10B.3-[N-(叔-丁氧羰基)-L-谷氨酰]噻唑烷
3-[N-(叔-丁氧羰基)-Oω-甲基-L-谷氨酰]噻唑烷(3.23g,9.73mmol)溶于THF(50ml)。加入1M氢氧化锂(11ml,11mmol)。混合物在室温下搅拌1小时然后在真空下除去溶剂并将残余物置于乙酸乙酯(70ml)。溶液用1M KHSO4(2×20ml)、水(2×20ml)和盐水(1×20ml)洗涤,干燥(Na2SO4)并在真空下蒸发以得到无色油状物3-[N-(叔-丁氧羰基)-L-谷氨酰]噻唑烷(3.0g,9.4mmol,97%)。
10C.3-[Nα-(叔-丁氧羰基)-Nω-(3,4-二氯苄基)-L-谷氨酰氨基]噻唑烷
3-[N-(叔-丁氧羰基)-L-谷氨酰]噻唑烷(200mg,0.63mmol)溶于CH2Cl2/DMF(9∶1,10ml)。在0℃的溶液中加入1-羟基苯并三唑水合物(119mg,0.76mmol)、水溶性碳二亚胺(163mg,0.88mmol)、3,4-二氯苄胺(111mg,0.83mmol)和三乙胺(126mg,1.26mmol)。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(70ml)。溶液用0.3M KHSO4(2×20ml)、饱和NaHCO3(2×20ml)、水(2×20ml)和盐水(1×20ml)洗涤,干燥(Na2SO4)并在真空下蒸发以得到黄色油状物。残余物在硅胶上通过快速层析纯化(洗脱液:乙酸乙酯)以得到无色油状物3-[Nα-(叔-丁氧羰基)-Nω-(3,4-二氯苄基)-L-谷氨酰氨基]噻唑烷(295mg,0.62mmol,98%)。
10D.3-[Nα-(乙酰氧基甲氧基羰基)-Nω-(3,4-二氯苄基)-L-谷氨酰氨基]噻唑烷
3-[Nα-(叔-丁氧羰基)-Nω-(3,4-二氯苄基)-L-谷氨酰氨基]噻唑烷(150mg,0.32mmol)溶于4M HCl/二噁烷(20ml)。混合物在室温下搅拌1小时然后在真空下除去溶剂。残余物溶于二氯甲烷(25ml),加入乙酰氧基甲基对-硝基苯碳酸盐(95mg,0.35mmol;按Alexander等,J.Med.Chem.31,318,1988的方法制备)和三乙胺(64mg,0.64mmol)。溶液在室温下搅拌18小时然后在真空下蒸发.残余物置于乙酸乙酯(70ml)。溶液用饱和NaHCO3、水和盐水洗涤,干燥(Na2SO4)并蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:乙酸乙酯)以得到白色固体3-[Nα(乙酰氧基甲氧基羰基)-Nω-(3,4-二氯苄基)-L-谷氨酰氨基]噻唑烷(88mg,0.18mmol,56%)。
[M+H]+=492.0
1H NMR(CDCl3):δl.44-1.46(3H,m),1.63-1.99(3H,br m),1.99-2.04(4H,m),2.98-3.06(2H,m),3.46-3.48(2H,m),3.50-3.80(2H m),4.47-4.56(3H,m),5.81-5.91(1H,m),6.74-6.75(1H,m),7.24-7.33(1H,m),8.24-8.25(1H,m),8.69-8.71(1H,m)ppm。
实施例11
1-[Nα-(1′-乙酰氧基乙氧基羰基)-Nω-(2-氯烟酰)-L-鸟氨酰]吡咯烷
11A.1-[Nω-(苄氧羰基)-Nα-(叔-丁氧羰基)-L-鸟氨酰]吡咯烷
Nω-(苄氧羰基)-Nα-(叔-丁氧羰基)-L-鸟氨酸(5.49g,15mmol)溶于CH2Cl2/DMF(9∶1,100ml)。在0℃的溶液中加入1-羟基苯并三唑水合物(3.37g,22mmol)、水溶性碳二亚胺(3.46g,18mmol)、吡咯烷(1.28g,18mmol)和三乙胺(200mg,20mmol)。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(200ml)。溶液用0.3M KHSO4(2×50ml)、饱和NaHCO3(2×50ml)、水(2×50ml)和盐水(1×50ml),干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:90%乙酸乙酯,10%石油醚60-80)以得到无色油状物1-[Nω-(苄氧羰基)-Nα-(叔-丁氧羰基)-L-鸟氨酰]吡咯烷(5.15g,12.3mmol,82%)。
11B.1-[Nα-(叔-丁氧羰基)-L-鸟氨酰]吡咯烷
在1-[Nω-(苄氧羰基)-Nα-(叔-丁氧羰基)-L-鸟氨酰]吡咯烷(2.15g,5.13mmol)的甲醇溶液(80ml)中加入10%Pd/C(400mg)。混合物在氢气下搅拌2小时,然后滤去催化剂并用甲醇(50ml)洗涤。合并的滤液在真空下蒸发以得到乳白色固体1-[Nα-(叔-丁氧羰基)-L-鸟氨酰]吡咯烷(1.35g,4.74mmol,94%)。
11C.1-[Nα-(叔-丁氧羰基)-Nω-(2-氯烟酰)-L-鸟氨酰]吡咯烷
1-[Nα-(叔-丁氧羰基)-L-鸟氨酰]吡咯烷(204mg,0.72mmol)溶于CH2Cl2(20ml)。在溶液中加入2-氯烟酰氯(130mg,0.74mmol)和三乙胺(200mg,2.0mmol)。混合物在0℃至室温下搅拌18h,然后在真空下除去溶剂并将残余物置于乙酸乙酯(70ml)。溶液用0.3M KHSO4(2×20ml)、饱和NaHCO3(2×20ml)、水(2×20ml)和盐水(1×20ml)洗涤,干燥(Na2SO4)并在真空下蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:10%甲醇,90%氯仿)以得到粘性白色固体1-[Nα-(叔-丁氧羰基)-Nω-(2-氯烟酰)-L-鸟氨酰]吡咯烷(236mg,0.56mmol,78%)。
11D.1-[Nα-(1′-乙酰氧基乙氧基羰基)-Nω-(2-氯烟酰)-L-鸟氨酰]吡咯烷
1-[Nα-(叔-丁氧羰基)-Nω-(2-氯烟酰)-L-鸟氨酰]吡咯烷(206mg,0.49mmol)溶于4M HCl/二噁烷(20ml)。混合物在室温下搅拌1小时然后在真空下除去溶剂。残余物溶于二氯甲烷(25ml),加入α-乙酰氧基乙基对-硝基苯碳酸盐(140mg,0.52mmol;按Alexander等,J.Med.Chem.31,318,1988的方法制备)和三乙胺(40mg,0.4mmol)。溶液在室温下搅拌18小时然后在真空下蒸发。将残余物置于乙酸乙酯(70ml)。溶液用饱和NaHCO3、水和盐水洗涤,干燥(Na2SO4)并蒸发。残余物在硅胶上通过快速层析纯化(洗脱液:92%氯仿,8%甲醇)以得到白色固体1-[Nα-(1′-乙酰氧基乙氧基羰基)-Nω-(2-氯烟酰)-L-鸟氨酰]吡咯烷(127mg,0.28mmol,57%)。
[M+H]+=455.1
1H NMR(CDCl3):δ1.42-1.49(3H,m),1.83-1.95(8H,m),2.02(3H,d,J=1.5Hz),3.32-3.71(6H,m),4.45-4.47(1H,m),5.75-5.85(1H,m),6.72-6.77(2H.m),7.27-7.33(1H,m),7.97-8.06(1H,m),8.40-8.43(1H,m)ppm。
Claims (21)
1.如通式1所述的化合物
或其药学上可接受的盐,其中:
R1是H或CN,
R2选自CH2R5、CH2CH2R5和C(R3)(R4)-X2-(CH2)aR5,
R3和R4各自独立选自H和Me;
R5选自CON(R6)(R7)、N(R8)C(=O)R9、N(R8)C(=S)R9、N(R8)SO2R10和N(R8)R10;
R6和R7各自独立是R11(CH2)b或一起形成-(CH2)2-Z-(CH2)2-或-CH2-o-C6H4-Z-CH2-;
R8是H或Me;
R9选自R11(CH2)b、R11(CH2)bO和N(R6)(R7);
R10是R11(CH2)b;
R11选自H,烷基、任选取代的芳基、任选取代的芳酰基、任选取代的芳基磺酰基和任选取代的杂芳基;
R12选自H2NCH(R13)CO、H2NCH(R14)CONHCH(R15)CO、C(R16)=C(R17)COR18和R19OCO;
R13、R14和R15选自蛋白质氨基酸的侧链;
R16选自H、低级烷基(C1-C6)和苯基;
R17选自H和低级烷基(C1-C6);
R18选自H、低级烷基(C1-C6)、OH、O-(低级烷基(C1-C6))和苯基;
R19选自低级烷基(C1-C6),任选取代的苯基和R20C(=O)OC(R21)(R22);
R20、R21和R22各自独立选自H和低级烷基(C1-C6);
Z选自共价键、-(CH2)c-、-O-、-SOd-和-N(R10)-;
X1是S或CH2,
X2是O、S或CH2;
a是1、2或3
b是0-3;
c是1或2;和
d是0-2
2.如权利要求1所述的化合物,其中,R1是H。
3.如权利要求1所述的化合物,其中,R1是CN。
4.如权利要求1-3中任一项所述的化合物,其中,R2选自CH2CH2R5和C(R3)(R4)-X2-(CH2)aR5。
5.如权利要求2或权利要求3所述的化合物,其中,X1是CH2。
6.如权利要求1或权利要求2所述的化合物,其中,X1是S。
7.如权利要求4所述的化合物,其中,R3和R4都是H,X2是CH2,a是1或2。
8.如权利要求7所述的化合物,其中,R2选自CH2CH2CH2R5和CH2CH2CH2CH2R5。
9.如权利要求1-8中任一项所述的化合物,其中,R5是CON(R6)(R7)。
10.如权利要求1-4和6-8中任一项所述的化合物,其中,R5选自N(R8)C(=O)R9、N(R8)C(=S)R9、N(R8)SO2R10和N(R8)R10。
11.如权利要求5所述的化合物,其中,R5选自CON(R6)(R7)、N(R8)C(=O)R9、N(R8)C(=S)R9和N(R8)R10。
12.如权利要求1-11中任一项所述的化合物,其中,R12选自H2NCH(R13)CO和H2NCH(R14)CONHCH(R15)CO。
13.如权利要求1-11中任一项所述的化合物,其中,R12是R19OCO。
14.含有权利要求1-13中任一项所述的化合物的药物组合物。
15.如权利要求1-13中任一项所述化合物的应用,它是制造药物组合物的一种组分。
16.一种治疗高血糖症的方法,其特征在于,所述方法包括给予有此治疗需要的个体有效量的权利要求1-13中任一项所述的化合物。
17.如权利要求1-14中任一项所述的化合物或药物组合物,如权利要求15或21所述的应用,或如权利要求16或18-20中任一项所述的方法,条件是,R19不是叔-丁基。
18.一种治疗人或动物疾病或身体状况的方法,其特征在于,所述方法包括给予有此治疗需要的个体有效量的如通式1所述的化合物
或其药学上可接受的盐,其中:
R1是H或CN,
R2选自CH2R5、CH2CH2R5和C(R3)(R4)-X2-(CH2)aR5,
R3和R4各自独立选自H和Me;
R5选自CON(R6)(R7)、N(R8)C(=O)R9、N(R8)C(=S)R9、N(R8)SO2R10和N(R8)R10;
R6和R7各自独立是R11(CH2)b或一起形成-(CH2)2-Z-(CH2)2-或-CH2-o-C6H4-Z-CH2-;
R8是H或Me;
R9选自R11(CH2)b、R11(CH2)bO和N(R6)(R7);
R10是R11(CH2)b;
R11选自H,烷基、任选取代的芳基、任选取代的芳酰基、任选取代的芳基磺酰基和任选取代的杂芳基;
R12选自H2NCH(R13)CO、H2NCH(R14)CONHCH(R15)CO、C(R16)=C(R17)COR18和R19OCO;
R13、R14和R15选自蛋白质氨基酸的侧链;
R16选自H、低级烷基(C1-C6)和苯基;
R17选自H和低级烷基(C1-C6);
R18选自H、低级烷基(C1-C6)、OH、O-(低级烷基(C1-C6))和苯基;
R19选自低级烷基(C1-C6),任选取代的苯基和R20C(=O)OC(R21)(R22);
R20、R21和R22各自独立选自H和低级烷基(C1-C6);
Z选自共价键、-(CH2)c-、-O-、-SOd-和-N(R10)-;
X1是S或CH2,
X2是O、S或CH2;
a是1、2或3
b是0-3;
c是1或2;和
d是0-2
19.如权利要求18所述的方法,其中,所述疾病或身体状况是葡萄糖耐量降低、II型糖尿病或高血糖症。
20.如权利要求18所述的方法,其中,所述疾病或身体状况由Dp-IV介导的过程引发。
21.如权利要求1-13中任一项所述化合物的应用,所述化合物被用作Dp-IV抑制剂或作为Dp-IV抑制剂的前药。
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