CN1525978A - 用作ICE/ced-3家族半胱氨酸蛋白酶抑制剂的C-端修饰的草氨酰二肽 - Google Patents
用作ICE/ced-3家族半胱氨酸蛋白酶抑制剂的C-端修饰的草氨酰二肽 Download PDFInfo
- Publication number
- CN1525978A CN1525978A CNA028052781A CN02805278A CN1525978A CN 1525978 A CN1525978 A CN 1525978A CN A028052781 A CNA028052781 A CN A028052781A CN 02805278 A CN02805278 A CN 02805278A CN 1525978 A CN1525978 A CN 1525978A
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- Prior art keywords
- substituted
- phenyl
- naphthyl
- alkyl
- cycloalkyl
- Prior art date
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- KZAUOCCYDRDERY-UHFFFAOYSA-N oxamyl Chemical group CNC(=O)ON=C(SC)C(=O)N(C)C KZAUOCCYDRDERY-UHFFFAOYSA-N 0.000 title abstract description 47
- 239000003112 inhibitor Substances 0.000 title abstract description 12
- 101150055276 ced-3 gene Proteins 0.000 title abstract description 9
- 108010016626 Dipeptides Proteins 0.000 title abstract description 4
- 108010005843 Cysteine Proteases Proteins 0.000 title description 6
- 102000005927 Cysteine Proteases Human genes 0.000 title description 6
- 210000004899 c-terminal region Anatomy 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 173
- 238000000034 method Methods 0.000 claims abstract description 55
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- 230000004770 neurodegeneration Effects 0.000 claims abstract description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 7
- -1 2-benzoxazolyl group Chemical group 0.000 claims description 284
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 172
- 125000000217 alkyl group Chemical group 0.000 claims description 133
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 73
- 125000001624 naphthyl group Chemical group 0.000 claims description 64
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 57
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 57
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 54
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 239000001257 hydrogen Substances 0.000 claims description 52
- 125000001072 heteroaryl group Chemical group 0.000 claims description 49
- 229910052757 nitrogen Inorganic materials 0.000 claims description 37
- 125000000623 heterocyclic group Chemical group 0.000 claims description 35
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 34
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 32
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 150000001413 amino acids Chemical class 0.000 claims description 10
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- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 210000004698 lymphocyte Anatomy 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 210000001616 monocyte Anatomy 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
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- 150000001975 deuterium Chemical group 0.000 claims description 2
- 229910052805 deuterium Inorganic materials 0.000 claims description 2
- 210000005064 dopaminergic neuron Anatomy 0.000 claims description 2
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- 210000003714 granulocyte Anatomy 0.000 claims description 2
- 125000004970 halomethyl group Chemical group 0.000 claims description 2
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- 150000002431 hydrogen Chemical class 0.000 claims 13
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- 238000004321 preservation Methods 0.000 abstract 1
- 238000002054 transplantation Methods 0.000 abstract 1
- 239000011734 sodium Substances 0.000 description 174
- 239000000243 solution Substances 0.000 description 129
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 117
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 103
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- 150000002500 ions Chemical class 0.000 description 82
- 238000003756 stirring Methods 0.000 description 81
- 239000000460 chlorine Substances 0.000 description 72
- 229910001868 water Inorganic materials 0.000 description 69
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 67
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 61
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 56
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 52
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 44
- 239000012074 organic phase Substances 0.000 description 41
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 38
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 33
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 29
- 239000012299 nitrogen atmosphere Substances 0.000 description 29
- 238000003818 flash chromatography Methods 0.000 description 28
- SOWBFZRMHSNYGE-UHFFFAOYSA-N oxamic acid Chemical compound NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 description 28
- 125000006239 protecting group Chemical group 0.000 description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 27
- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- 239000003921 oil Substances 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 24
- 235000019198 oils Nutrition 0.000 description 24
- 125000002114 valyl group Chemical group 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
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- CKLJMWTZIZZHCS-REOHCLBHSA-N aspartic acid group Chemical group N[C@@H](CC(=O)O)C(=O)O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 22
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 20
- 125000001309 chloro group Chemical group Cl* 0.000 description 20
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- 229950003188 isovaleryl diethylamide Drugs 0.000 description 19
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- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 18
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- 125000001246 bromo group Chemical group Br* 0.000 description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 15
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 15
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
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- ZHZZWIQPCAMTIM-UHFFFAOYSA-N [C]1=CC=CC2=CC=CC=C12 Chemical compound [C]1=CC=CC2=CC=CC=C12 ZHZZWIQPCAMTIM-UHFFFAOYSA-N 0.000 description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 12
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- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
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Abstract
本发明涉及新的草氨酰二肽ICE/ced-3家族抑制剂化合物。本发明还涉及包含这些化合物的药物组合物以及这类组合物在治疗患有炎症性、自身免疫性和神经变性疾病的患者方面、以及在预防局部缺血性损伤和保存移植手术用器官方面的应用。
Description
技术领域
本发明涉及一类用作白介素-1β转化酶和相关蛋白酶(“ICE/ced-3半胱氨酸蛋白酶家族”)的新化合物,以及包含这些化合物的药物组合物和使用这类药物组合物的方法。
发明背景
白介素1(“IL-1”)是一种主要的促炎和免疫调节蛋白,能刺激成纤维细胞分化或增殖,刺激滑液细胞和软骨细胞产生前列腺素、胶原酶和磷脂酶,刺激嗜碱和嗜酸性粒细胞脱粒和嗜中性白细胞活化。Oppenheim,J.H.等,
Immunology Today,7:45-56(1986).因此,它与慢性和急性炎症性和自身免疫性疾病的发病机理有关。作为炎性反应的一部分,IL-1主要由外周血单核细胞产生。Mosely,B.S.等,
Pro.Nat.Acad.Sci.,84:4572-4576(1987);Lonnemann,G等,
Eur.J.Immunol.19:1531-1536(1989).
IL-1β是以非生物活性前体proIL-1β形式合成的。ProIL-1β在Asp-116和Ala-117之间被称为白介素-1β转化酶(“ICE”)的半胱氨酸蛋白酶裂解,产生在人血清和滑液中可见的生物活性C-端片断。Sleath,P.R.等,
J.Biol.Chem.,265:14526-14528(1992);A.D.Howard等,
J.Immunol.,147:2964-2969(1991)。
ICE是一种主要位于单核细胞上的半胱氨酸蛋白酶。除了促进IL-1β的促炎性和免疫调节特性外,ICE,尤其是其同系物,也表现出与细胞死亡或编程性细胞死亡的调控有关。Yuan,J.等,
Cell,75:641-652(1993);Miura,M.等,
Cell,75:653-660(1993);Nett-Giordalisi,M.A.等,
J.Cell Biochem.,17B:117(1993).特别是,ICE或ICE/ced-3同系物还被认为与神经变性疾病如阿耳茨海默氏病和帕金森氏病中的编程性细胞死亡的调节有关。Marx,J.和M.Baringa,
Science,259:760-762(1993);Gagliardini,V.等,Science,263:826-828(1994).
因此,可使用ICE/ced-3半胱氨酸蛋白酶家族抑制剂作为治疗剂进行治疗的疾病包括:传染病,如脑膜炎和输卵管炎;浓毒性休克;呼吸道疾病;炎症,如关节炎,胆管炎,结肠炎,脑炎,子宫颈内膜炎,肝炎,胰腺炎和再灌注损伤,局部缺血性疾病如心肌梗塞、中风和局部缺血性肾病;基于免疫的疾病,如过敏症;自身免疫病,如多发性硬化;骨病;和某些神经变性疾病,如阿耳茨海默氏病和帕金森氏病。这类抑制剂还可用于在化疗和放疗后再恢复造血细胞的数量和在器官移植中延长器官的存活能力。
ICE/ced-3抑制剂代表一类可用于控制上述疾病的化合物。已经报道的有ICE的肽类和肽基抑制剂。然而,这些抑制剂通常具有不希望的药理学性质,例如口服吸收差、稳定性差和代谢迅速等性质。Plattner,J.J.和D.W.Norbeck,
Drug Discovery Technologies,C.R.Clark和W.H.Moos编辑(Ellis Horwood,Chichester,England,1990),pp.92-126。这些不良特性阻碍了将它们开发成有效药物的可能。
因此,需要这样一些化合物,它们能有效地抑制ICE/ced-3蛋白酶家族的作用、用作预防不希望的编程性细胞死亡和治疗慢性和急性类型的IL-1介导疾病如炎症性、自身免疫性或神经变性疾病用的药剂。本发明满足了这一需要并且进一步提供了其它相关的优点。
发明概述
概括地讲,本发明化合物引入(N-取代的)草氨酰基团作为二肽模拟物。所得化合物显示出优于它们的肽对应物的改进特性,例如具有改进的细胞渗透性或改善的吸收能力和代谢稳定性,从而提高了生物利用度。本申请要求了1998年7月2日递交的申请号为60/091,689的美国临时申请和1998年10月22日递交的申请号为09/177,549的美国申请作为优先权(这两份申请的全文在此引入用作参考)。
本发明的一个方面涉及式I化合物及其可药用盐:
式I
其中A,B,R1,R1’和R2如下文所定义。
本发明的另一个方面涉及包含上述式I化合物与可药用载体的药物组合物。
本发明的另一个方面涉及治疗自身免疫病的方法,包括给需此治疗的患者施用有效量的上述药物组合物。
本发明的再一个方面涉及治疗炎症性疾病的方法,包括给需此治疗的患者施用有效量的上述药物组合物。
本发明的又一个方面涉及治疗神经变性疾病的方法,包括给需此治疗的患者施用有效量的上述药物组合物。
本发明的另一个方面涉及预防患有与局部缺血性损伤相关疾病的患者发生局部缺血性损伤的方法,包括给需此治疗的患者施用有效量的上述药物组合物。
本发明的再一个方面涉及一种通过使造血细胞与有效量的上述药物组合物接触从而扩增造血细胞群体和/或提高其存活性的方法。包括在本发明方法中的细胞群体包括(但不限于)用于细胞转输的粒细胞、单核细胞、红细胞、淋巴细胞和血小板。
本发明的另外一个方面涉及一种延长用于进一步移植手术目的而从供体身上取下的器官存活性的方法,该方法包括对器官施用有效量的上述组合物,从而延长所述器官的存活性(与未处理器官相比)。所述器官可以是完整器官,或者是从器官上分离的细胞(例如分离的胰岛细胞,分离的多巴胺能神经元、血细胞和造血细胞)。
通过参考下面的详细描述,本发明的这些和其它方面将变得显而易见。
发明祥述
如上所述,本发明的一个方面涉及式I化合物或其可药用盐:
式I
其中:
A是式IIa-i的天然或非天然氨基酸:
B是氢原子,氘原子,烷基,环烷基,苯基,取代苯基,萘基,取代萘基,2-苯并噁唑基,取代的2-噁唑基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),(CH2)n(取代的1-或2-萘基),(CH2)n(杂芳基),(CH2)n(取代杂芳基),卤代甲基,CO2R12,CONR13R14,CH2ZR15,CH2OCO(芳基),CH2OCO(杂芳基),或CH2OPO(R16)R17,其中Z为氧或硫原子,或者B为式IIIa-c的基团:
R1是烷基,环烷基,取代环烷基,(环烷基)烷基,取代的(环烷基)烷基,苯基,取代苯基,苯烷基,取代的苯烷基,萘基,取代萘基,(1-或2-萘基)烷基,取代的(1-或2-萘基)烷基,杂环,取代杂环,(杂环)烷基,取代的(杂环)烷基,R1a(R1b)N,或R1cO;
R1’是氢,烷基,苯基,取代苯基,萘基,取代萘基,杂环或取代杂环;
或者R1和R1’与它们所连接的氮原子一起形成杂环或取代杂环;
R2是氢,低级烷基,环烷基,(环烷基)烷基,苯基,取代苯基,苯烷基,取代的苯烷基,萘基,取代萘基,(1-或2-萘基)烷基,或取代的(1-或2-萘基)烷基;
并且其中:
R1a和R1b独立地是氢,烷基,环烷基,(环烷基)烷基,苯基,取代苯基,苯烷基,取代的苯烷基,萘基,取代萘基,(1-或2-萘基)烷基,取代的(1-或2-萘基)烷基,杂芳基,取代杂芳基,(杂芳基)烷基,或取代的(杂芳基)烷基,条件是R1a和R1b不能同时为氢;
R1c是烷基,环烷基,(环烷基)烷基,苯基,取代苯基,苯烷基,取代的苯烷基,萘基,取代萘基,(1-或2-萘基)烷基,取代的(1-或2-萘基)烷基,杂芳基,取代杂芳基,(杂芳基)烷基,或取代的(杂芳基)烷基;
R3是C1-6低级烷基,环烷基,苯基,取代苯基,(CH2)nNH2,(CH2)nNHCOR9,(CH2)nN(C=NH)NH2,(CH2)mCO2R2,(CH2)mOR10,(CH2)mSR11,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),或(CH2)n(杂芳基),其中杂芳基包括吡啶基,噻吩基,呋喃基,噻唑基,咪唑基,吡唑基,异噁唑基,吡嗪基,嘧啶基,三嗪基,四唑基,和吲哚基;
R3a是氢或甲基,或者R3和R3a一起表示-(CH2)d-,其中d是整数2-6;
R4是苯基,取代苯基,(CH2)m苯基,(CH2)m(取代苯基),环烷基,或苯并稠合的环烷基;
R5是氢,低级烷基,环烷基,苯基,取代苯基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R6是氢,氟,氧代,低级烷基,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),OR10,SR11,或NHCOR9;
R7是氢,氧代(即=O),低级烷基,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R8是低级烷基,环烷基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),或COR9;
R9是氢,低级烷基,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),OR12,或NR13R14;
R10是氢,低级烷基,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R11是低级烷基,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R12是低级烷基,环烷基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R13是氢,低级烷基,环烷基,苯基,取代苯基,萘基,取代萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R14是氢或低级烷基;
或者R13和R14一起形成五至七元碳环或杂环,例如吗啉或N-取代的哌嗪;
R15是苯基,取代苯基,萘基,取代萘基,杂芳基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),或(CH2)n(杂芳基);
R16和R17独立地为低级烷基,环烷基,苯基,取代苯基,萘基,苯烷基,取代的苯烷基,或(环烷基)烷基;
R18和R19独立地为氢,烷基,苯基,取代苯基,(CH2)n苯基,(CH2)n(取代苯基),或者R18和R19一起表示-(CH=CH)2-;
R20是氢,烷基,苯基,取代苯基,(CH2)n苯基,(CH2)n(取代苯基);
R21,R22和R23独立地为氢,或烷基;
X是CH2,(CH2)2,(CH2)3,或S;
Y1是O或NR23;
Y2是CH2,O,或NR23;
a是0或1;
b是1或2,条件是当a为1时,则b也是1;
c是1或2,条件是当c为1时,则a是0并且b是1;
m是1或2;和
n是1,2,3或4。
本文所用的术语“烷基”是指直链或支链的C1-C10碳链,例如甲基、乙基、叔丁基、异丙基、正辛基等。术语“低级烷基”是指直链或支链的C1-C6碳链,例如甲基、乙基、异丙基等。
术语“环烷基”是指完全饱和、部分完全饱和、或芳香性的单环、二环或三环。这类环的实例包括环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基、环辛基、顺式或反式十氢化萘、二环[2.2.1]庚-2-烯、环己-1-烯基、环戊-1-烯基、1,4-环辛二烯基等。
术语“(环烷基)烷基”是指被上述环烷基环之一取代的上述烷基基团。此类基团的实例包括(环己基)甲基,3-(环丙基)-正丙基,5-(环戊基)己基,6-(金刚烷基)己基等。
术语“取代苯基”是指被一个或多个选自以下的取代基取代的苯基:卤素、羟基、被护羟基、氰基、硝基、三氟甲基、烷基、烷氧基、酰基、酰氧基、羧基、被护羧基、羧甲基、被护羧甲基、羟甲基、被护羟甲基、氨基、被护氨基、(单取代)氨基、被护的(单取代)氨基、(二取代)氨基、氨基甲酰基(carboxamide),被护氨基甲酰基,N-(低级烷基)氨基甲酰基,被护的N-(低级烷基)氨基甲酰基,N,N-二(低级烷基)氨基甲酰基,N-((低级烷基)磺酰基)氨基,N-(苯磺酰基)氨基,取代或未取代的杂环,取代或未取代的环烷基,或者是指被取代或未取代的苯基取代的苯基,这样在后一种情况下得到联苯基或萘基,或者其中取代苯环上的两个相邻烷基取代基一起形成环烷基,得到例如四氢萘基或2,3-二氢化茚基。
术语“取代苯基”的实例包括单-、二-、三-、四-或五(卤代)苯基如2-,3-或4-氯苯基,2,6-二氯苯基,2,5-二氯苯基,3,4-二氯苯基,2-,3-或4-溴苯基,3,4-二溴苯基,3-氯-4-氟苯基,2-,3-或4-氟苯基,2,4,6-三氟苯基,2,3,5,6-四氟苯基,2,3,4,5-四氟苯基,2,3,4,5,6-五氟苯基等;一或二(羟基)苯基如2-,3-,或4-羟基苯基,2,4-二羟基苯基,它们的被护羟基衍生物等;硝基苯基如2-,3,或4-硝基苯基;氰基苯基,例如2-,3-或4-氰基苯基;单-或二(烷基)苯基如2-,3-,或4-甲基苯基,2,4-二甲基苯基,2-,3-或4-(异丙基)苯基,2-,3-或4-乙基苯基,2-,3-或4-(正丙基)苯基等;单或二(烷氧基)苯基,例如,2,6-二甲氧基苯基,2-,3-或4-(异丙氧基)苯基,2-,3-或4-(叔丁氧基)苯基,3-乙氧基-4-甲氧基苯基等;2-,3-或4-三氟甲基苯基;单-或二羧基苯基或(被护羧基)苯基如2-,3-或4-羧基苯基或2,4-二(被护羧基)苯基;单-或二(羟甲基)苯基或(被护羟甲基)苯基如2-,3-或4-(被护羟甲基)苯基或3,4-二(羟甲基)苯基;单-或二(氨基甲基)苯基或(被护氨甲基)苯基如2-,3-或4-(氨甲基)苯基或2,4-(被护氨基甲基)苯基;或单-或二(N-(甲磺酰基氨基)苯基如2,3或4-(N-(甲磺酰基氨基))苯基。还有,术语“取代苯基”也表示其中取代基互不相同的二取代苯基,例如,3-甲基-4-羟基苯基,3-氯-4-羟基苯基,2-甲氧基-4-溴苯基,4-乙基-2-羟基苯基,3-羟基-4-硝基苯基,2-羟基-4-氯苯基等。
术语“苯烷基”是指与上述烷基基团之一连接的上述苯基基团,并且术语“取代苯烷基”是指苯基或烷基之一或者二者都被一个或多个上文所述的取代基取代。这些基团的实例包括2-苯基-1-氯乙基,2-(4’-甲氧基苯基)乙基,4-(2’,6’-二羟基苯基)正己基,2-(5’-氰基-3’-甲氧基苯基)正戊基,3-(2’,6’-二甲基苯基)正丙基,4-氯-3-氨基苄基,6-(4’-甲氧基苯基)-3-羧基(正己基),5-(4’-氨基甲基苯基)-3-(氨基甲基)正戊基,5-苯基-3-氧代-正戊-1-基,(4-羟基萘-2-基)甲基等。
术语“取代萘基”是指被一个或多个上文定义的取代基取代的萘基,并且术语“(1-或2-萘基)烷基”是指在(1或2位)与上述烷基基团之一连接的萘基。
术语“卤代”和“卤素”是指氟、氯、溴或碘基。这些术语也可以用于描述一个或多个相同或不同的卤素。在本文中,优选的卤素是指氯和氟。
术语“芳基”是指五或六元芳香碳环。优选六元环。
术语“杂环”是指含有1-4个杂原子例如氧、硫和/或氮原子,特别是只含氮原子或者还含有硫或氧环原子的任选取代的五元或六元杂环,并且包括芳族杂环(在本文中也称作“杂芳基”)。下列环系是术语杂芳基(取代或未取代的)表示的芳族杂环基的代表性实例:噻吩基,呋喃基,吡咯基,吡咯烷基,咪唑基,异噁唑基,三唑基,噻二唑基,噁二唑基,四唑基,噻三唑基,噁三唑基,吡啶基,嘧啶基,吡嗪基,哒嗪基,噁嗪基,三嗪基,噻二嗪基四唑并,1,5-[b]哒嗪基和嘌啉基,以及苯并稠合的衍生物,例如苯并噁唑基,苯并噻唑基,苯并咪唑基和吲哚基。非芳香杂环包括,例如,吗啉基,吡咯烷酮基,吡咯烷基,哌啶基,哌嗪基,乙内酰脲基,戊内酰胺基,环氧乙烷基,氧杂环丁烷基,四氢呋喃基,四氢吡喃基,四氢吡啶基,四氢嘧啶基,四氢噻吩基,四氢噻喃基,四氢嘧啶基,四氢噻吩基,四氢噻喃基等。
上述任选取代的环烷基或杂环的取代基如上文取代苯基中所述,更具体地说包括1-3个卤素,三卤代甲基,氨基,被护氨基,氨基盐,单取代氨基,二-取代的氨基,羧基,被护羧基,羧酸盐,羟基,被护羟基,羟基的盐,低级烷氧基,低级烷硫基,低级烷基,取代的低级烷基,环烷基,取代环烷基,(环烷基)烷基,取代的(环烷基)烷基,苯基,取代苯基,苯烷基,和取代的苯烷基。在杂环的任何给定原子上可以存在多于一个的取代基,包括形成螺结的碳环或杂环取代基。“三卤代甲基”可以是三氟甲基,三氯甲基,三溴甲基或三碘甲基。“低级烷氧基”是指C1-C4烷氧基,同样,“低级烷硫基”是指C1-C4烷硫基。术语“取代的低级烷基”是指被以下基团取代一至三次的上文定义的低级烷基:羟基,被护羟基,氨基,被护氨基,氰基,卤素,三氟甲基,一取代的氨基,二取代的氨基,低级烷氧基,低级烷硫基,羧基,被护羧基,或羧基、氨基和/或羟基的盐。
术语“取代的(环烷基)烷基”和“取代环烷基”如上面(环烷基)烷基和环烷基所定义,但被上面取代的苯基、环烷基和/或杂环中所述的一个或多个取代基取代。术语“(一取代的)氨基”是指具有一个选自以下取代基的氨基:苯基、取代苯基、烷基、取代烷基、C1-C7酰基、C2-C7链烯基、C2-C7的取代链烯基、C2-C7炔基、C7-C16烷芳基、C7-C16的取代的烷基芳基,和杂芳基。(一取代的)氨基也可以带有术语“被护的(一取代)氨基”所包含的氨基保护基。术语“(二取代的)氨基”是指带有两个选自以下的取代基的氨基:苯基、取代苯基、烷基、取代烷基、C1-C7酰基、C2-C7链烯基、C2-C7炔基、C7-C16烷芳基、C7-C16的取代的烷基芳基和杂芳基。两个取代基可以相同或不同。术语“杂芳基(烷基)”表示在任何位置上被上文所定义的杂芳基取代的上述烷基基团。
更具体地说,除了上文所公开的取代基外,本文所用的术语“取代的”还指其中至少一个氢原子被取代基置换的化学实体。在酮基取代基(“C(=O)”)的情况下,两个氢原子被置换。取代基包括卤素,羟基,烷基,取代烷基(如卤代烷基、单-或二-取代的氨基烷基、烷氧基烷基等),芳基,取代芳基,芳烷基,取代的芳烷基,杂环,取代的杂环,杂环烷基,取代的杂环烷基,-NRaRb,-NRaC(=O)Rb,-NRaC(=O)NRaRb,-NRaC(=O)ORb,-NRaSO2Rb,-ORa,-C(=O)Ra,-C(=O)ORa,-C(=O)NRaRb,-OC(=O)Ra,-OC(=O)ORa,-OC(=O)NRaRb,-NRaSO2Rb,或式-Y-Z-Ra的基团,其中Y为亚烷基,取代的亚烷基,或直接键,Z为-O-,-S-,-S(=O)-,-S(=O)2-,-N(Rb)-,-C(=O)-,-C(=O)O-,-OC(=O)-,-N(Rb)C(=O)-,-C(=O)N(Rb)-或直接键,其中Ra和Rb相同或不同,并且独立地为氢,氨基,烷基,取代烷基(包括卤代烷基),芳基,取代芳基,芳基烷基,取代的芳基烷基,杂环,取代的杂环,杂环烷基或取代的杂环烷基,或者其中的Ra和Rb与它们所连接的氮原子一起形成杂环或取代的杂环。
此外,上述任选取代的五元或六元杂环和上述的环烷基环还可以任选地与芳香性的5-元或6-元芳基,碳环或杂环体系稠合。例如,上述环可任选地与芳香性的5元或6元环系如吡啶或三唑环系稠合,优选与苯环稠合。
术语“可药用盐”包括与羧酸根阴离子形成的那些盐,并且包括与无机和有机阳离子形成的盐,这些阳离子例如为选自碱金属和碱土金属(例如锂、钠、钾、镁、钡和钙)的阳离子;和铵离子;和有机阳离子(例如二苄基铵、苄基铵、2-羟基乙基铵、双(2-羟基乙基)铵、苯基乙基苄基-铵、二苄基乙二铵等阳离子)。上述术语所包括的其它阳离子包括质子化形式的普鲁卡因、奎宁和N-甲基葡糖胺,质子化形式的碱性氨基酸例如甘氨酸、鸟氨酸、组氨酸、苯甘氨酸、赖氨酸和精氨酸。另外,该术语还指由羧酸和氨基形成的两性离子形式的本发明化合物。适合于羧酸根阴离子的优选阳离子是钠阳离子。此外,该术语还包括通过标准酸-碱反应与碱性基团(如氨基)形成的盐,这样的酸包括盐酸、硫酸、磷酸、乙酸、琥珀酸、柠檬酸、乳酸、马来酸、富马酸、棕榈酸、胆酸、双羟萘酸、粘酸、D-谷氨酸、D-樟脑酸、戊二酸、邻苯二甲酸、酒石酸、月桂酸、硬脂酸、水杨酸、甲磺酸、苯磺酸、山梨酸、苦味酸、苯甲酸、肉桂酸等酸。
式I化合物还可以以溶剂化物和水合物形式存在。因此,这些化合物可以与水合水或者一种、多种或者任何比例的母液溶剂分子一起结晶析出。这类化合物的溶剂化物或水合物均包括在本发明的范围之内。
本文所用术语“羧基保护基”是指羧基的酯类衍生物之一,常用于封闭或保护羧基,从而使反应在化合物的其它官能团上进行。这种羧基保护基的实例包括叔丁基,4-硝基苄基,4-甲氧基苄基,3,4-二甲氧基苄基,2,4-二甲氧基苄基,2,4,6-三甲氧基苄基,2,4,6-三甲基苄基,五甲基苄基,3,4-亚甲二氧基苄基,二苯甲基,4,4’-二甲氧基三苯甲基,4,4’,4’-三甲氧基三苯甲基,2-苯基丙基,三甲基甲硅烷基,叔丁基二甲基甲硅烷基,苯甲酰甲基,2,2,2-三氯乙基,β-(三甲基甲硅烷基)乙基,β-(二(正丁基)甲基甲硅烷基)乙基,对-甲苯磺酰基乙基,4-硝基苄基磺酰基乙基,烯丙基,肉桂基,1-(三甲基甲硅烷基)-丙烯基等基团。采用的羧基保护基的种类没有严格限制,只要求衍生化的羧酸在后续的反应条件下是稳定的,并且能够在适当的时候除去而不影响分子的其余部分。这些基团的其它实例分别见C.B.Reese和E.Haslam,“Protective Groups in OrganicChemistry,”J.G.W.McOmie,Ed.,Plenium Press,New York,NY,1973,第5章,和T.W.Greene和R.G.M.Wuts,“ProtectiveGroups in Organic Synthesis,”第2版,John Wiley and Sons,New York,NY,1991,第5章,这些内容均引入本文用作参考。相关的术语是“被护羧基”,它是指被上述羧基保护基之一取代的羧基。
术语“羟基保护基”是指与羟基键合的易于裂解的基团,例如四氢吡喃基,2-甲氧基丙-2-基,1-乙氧基乙-1-基,甲氧基甲基,β-甲氧基乙氧基甲基,甲硫基甲基,叔丁基,叔戊基,三苯甲基,4-甲氧基三苯甲基,4,4’-二甲氧基三苯甲基,4,4’,4’-三甲氧基三苯甲基,苄基,烯丙基,三甲基甲硅烷基,(叔丁基)二甲基甲硅烷基,2,2,2-三氯乙氧基羰基等。
羟基保护基的其它实例分别记载于C.B.Reese和E.Haslam,“有机化学中的保护基”(Protective Groups in OrganicChemistry),J.G.W.McOmie,Ed.,Plenum Press,New York,NY,1973,第3和第4章,和T.W.Greene和P.G.M.Wuts,“有机合成中的保护基”(Protective Groups in Organic Synthesis),第二版,John Wiley and Sons,New York,NY,1991,第2和第3章。优选的羟基保护基是叔丁基。相关术语“被护羟基”表示与上述羟基保护基之一结合的羟基。
本文所用的术语“氨基保护基”是指常用于封闭或保护氨基官能团的氨基的取代基,从而使反应在化合物的其它官能团上进行。术语“被护的(一取代)氨基是指一取代氨基氮原子上存在氨基保护基。
这类氨基保护基的实例包括甲酰基(“For”),三苯甲基,邻苯二甲酰亚氨基,三氯乙酰基,三氟乙酰基,氯乙酰基,溴乙酰基和碘乙酰基,氨基甲酸酯类保护基,例如叔丁氧羰基(“Boc”)、2-(4-联苯基)丙基-2-氧基羰基(“Bpoc”)、2-苯基丙基-2-氧基羰基(“Poc”)、2-(4-联苯基)异丙氧基羰基、1,1-二苯基乙基-1-氧基羰基、1,1-二苯基丙基-1-氧基羰基、2-(3,5-二甲氧基苯基)丙基-2-氧基羰基(“Ddz”)、2-(对甲苯基)丙基-2-氧基羰基、环戊氧基羰基、1-甲基环戊烷基氧基羰基、环己烷基氧基羰基、1-甲基-环己烷基氧基羰基、2-甲基环己烷基氧基羰基、2-(4-甲苯磺酰基)乙氧基羰基、2-(甲磺酰基)乙氧基羰基、2-(三苯膦基)乙氧基羰基、9-芴基甲氧基羰基(“Fmoc”)、2-(三甲基甲硅烷基)乙氧基羰基、烯丙氧基羰基、1-(三甲基甲硅烷基甲基)丙-1-烯基氧基羰基、5-苯并异噁唑基甲氧基羰基、4-乙酰氧基苄氧基羰基、2,2,2-三氯乙氧基羰基、2-乙炔基-2-丙氧基羰基、环丙基甲氧基羰基、异冰片基氧基羰基、1-哌啶基氧基羰基、苄氧基羰基(“Cbz”)、4-苯基苄氧基羰基、2-甲基苄氧基羰基、α-2,4,5-四甲基苄基-氧基羰基(“Tmz”)、4-甲氧基苄氧基羰基、4-氟苄基氧基羰基、4-氯苄氧基羰基、3-氯苄氧基羰基、2-氯苄氧基羰基、2,4-二氯苄氧基羰基、4-溴苄氧基羰基、3-溴苄氧基羰基、4-硝基苄氧基羰基、4-氰基苄氧基羰基、4-(癸氧基)苄氧基羰基等;苯甲酰基甲磺酰基,2,2,5,7,8-五甲基苯并二氢吡喃-6-磺酰基(“PMC”),二硫代琥珀酰基(“Dts”),2-(硝基)苯基亚磺酰基(“Nps”),二苯基氧化膦基团等氨基保护基。对使用的氨基保护基的种类没有限制,只要衍生的氨基基团能在后续反应条件下保持稳定并且能够在适当时机除去而不会干扰分子的其它结构部分即可。优选的氨基保护基是Boc,Cbz和Fmoc。上述术语包括的氨基保护基的其它实例是有机合成和肽领域中公知的,并且记载于例如T.W.Greene和P.G.M.Wuts,“有机合成中的保护基”(Protective Groups inOrganic Synthesis),第2版,John Wiley and Sons,New York,NY,1991,第7章,M.Bodanzsky,“肽合成原理”(Principlesof Peptide Synthesis),第1和第2修订版,Springer-Verlag,New York,NY,1984和1993,以及J.M.Stewart和J.D.Young,“固相肽合成”(Solid Phase Peptide Synthesis),第2版,Pierce Chemical Co.,Rockford,IL,1984,E.Atherton andR.C.Shephard,“固相肽合成-一种实用方法”(Solid PhasePeptide Synthesis-A Practical Approach)IRL Press,Oxford,England(1989),这些文献均引入本文用作参考。相关术语“被护氨基”是指被上述氨基保护基取代的氨基。
术语“天然或非天然的氨基酸”是指天然存在的氨基酸和肽化学领域在制备天然存在肽的合成类似物时常用的其它非蛋白原性α-氨基酸,包括D和L型。天然存在的氨基酸是甘氨酸,丙氨酸,缬氨酸,亮氨酸,异亮氨酸,丝氨酸,甲硫氨酸,苏氨酸,苯丙氨酸,酪氨酸,色氨酸,半胱氨酸,脯氨酸,组氨酸,天冬氨酸,天冬酰胺,谷氨酸,谷氨酰胺,γ-羧基谷氨酸,精氨酸,鸟氨酸和赖氨酸。非天然的α-氨基酸实例包括羟基赖氨酸,瓜氨酸,犬尿氨酸,(4-氨基苯基)丙氨酸,3-(2’-萘基)丙氨酸,3-(1’-萘基)丙氨酸,甲硫氨酸砜,(叔丁基)丙氨酸,(叔丁基)甘氨酸,4-羟基苯基-甘氨酸,氨基丙氨酸,苯基甘氨酸,乙烯基丙氨酸,炔丙基丙氨酸,1,2,4-三唑-3-丙氨酸,甲状腺原氨酸,6-羟基色氨酸,5-羟基色氨酸,3-羟基-犬尿氨酸,3-氨基酪氨酸,三氟甲基丙氨酸,2-噻吩基丙氨酸,(2-(4-吡啶基)乙基)半胱氨酸,3,4-二甲氧基-苯丙氨酸,3-(2’-噻唑基)丙氨酸,鹅膏蕈氨酸,1-氨基-1-环戊烷-羧酸,1-氨基-1-环己烷羧酸,使君子氨酸(quisqualic acid),3-(三氟甲基苯基)丙氨酸,(环己基)甘氨酸,硫代组氨酸,3-甲氧基酪氨酸,正亮氨酸,正缬氨酸,别异亮氨酸,高精氨酸,硫代脯氨酸,二氢脯氨酸,羟基脯氨酸,高脯氨酸,2,3-二氢吲哚-2-羧酸,1,2,3,4-四氢异喹啉-3-羧酸,1,2,3,4-四氢异喹啉-2-羧酸,α-氨基-正丁酸,环己基丙氨酸,2-氨基-3-苯基丁酸,在苯基的邻位-、间位或对位被一个或两个下列基团取代的苯丙氨酸:(C1-C4)烷基、(C1-C4)烷氧基、卤素或硝基,或者被亚甲二氧基取代的苯丙氨酸;β-2-和3-噻吩基丙氨酸;β-2-和3-呋喃基丙氨酸;β-2-,3-和4-吡啶基丙氨酸;β-(苯并噻吩-2-和3-基)丙氨酸;β-(1-和2-萘基)丙氨酸;丝氨酸、苏氨酸和酪氨酸的O-烷基化衍生物;S-烷基化的半胱氨酸,S-烷基化的高半胱氨酸,酪氨酸的O-硫酸、O-磷酸和O-羧酸酯;3-(磺基)酪氨酸,3-(羧基)酪氨酸,3-(磷酸)酪氨酸,酪氨酸的4-甲磺酸酯,酪氨酸的4-甲烷膦酸酯,3,5-二碘代酪氨酸,3-硝基酪氨酸,ε-烷基丝氨酸和δ-烷基鸟氨酸。这些α-氨基酸中的任何一个都可在α-位被甲基取代,在α-氨基侧链上的芳香残基的任何位置可被卤素取代,或者在侧链残基的O、N或S原子上被适宜的保护基取代。适宜的保护基见上所述。
根据所选择的溶剂和其它本领域普通技术人员已知的条件,本发明的化合物还可呈缩酮或缩醛的形式,这些形式均包括在本发明范围内。尤其是当R2为氢时,式Ia化合物可以下文所示的式Ia’的环状缩酮或缩醛形式存在:
(式Ia) (式Ia′)
同样,当式I中的R2为非氢基团时,根据如上所述对溶剂的选择(例如R2OH),环状缩酮或缩醛的化合物包括如下所示的具式Ia”的化合物:
(式Ia) (式Ia″)
此外,应该理解本发明化合物的平衡形式包括互变异构形式。这些化合物的所有这些形式都明确包括在本发明的范围内。
本发明的化合物可以用合适的官能物进行修饰以提高选择性生物性质。这些修饰是本领域中已知的,包括增强进入给定生物体系(例如血液、淋巴系统、中枢神经系统)的生物渗透性、提高口服利用度、增大溶解性以便于注射给药、改变代谢和改变排泄速率的那些修饰。另外,可以将化合物变为前药形式,从而通过前药的代谢作用或其它生物化学过程而在患者体内产生所需化合物。前药形式的某些例子包括含酮或醛基(尤其是存在于式I中以及以“A”表示的基团或与“A”表示的基团相连的修饰的天冬氨酸残基中的酮或醛基)的化合物的缩酮、缩醛、肟和腙形式。
相对于式I中的基团“R1”,本发明化合物包括这些化合物,其中:
R1是苯基,取代苯基,苯基烷基,取代的苯基烷基,萘基,取代的萘基,(1-或2-萘基)烷基,杂芳基或(杂芳基)烷基。
更典型地,相对于基团“R1”,本发明化合物包括这些化合物,其中:
R1是苯基,取代苯基,苯基烷基,取代的苯基烷基,萘基,取代的萘基,或(1或2-萘基)烷基。
相对于基团“R1’”,本发明化合物包括这些化合物,其中:
R1’是氢,低级烷基和芳基。
相对于式I中的基团“A”,本发明化合物包括这些式IIa化合物,其中:
R3是低级烷基,环烷基,苯基,取代苯基,(CH2)nNH2,(CH2)mOR10,(CH2)mSR11,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R3a是氢;
R10是氢,低级烷基,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R11是低级烷基,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);和
n=1-4和m=1或2。
相对于式I中的基团“A”,本发明化合物还包括式IIb这些化合物,其中:
R4是苯基,取代苯基,(CH2)m苯基,(CH2)m(取代苯基),环烷基,或2,3-二氢化茚-2-基;和
m=1或2。
相对于式I中的基团“A”,另一组化合物包括式IId这些化合物,其中:
R6是氢,氟,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),OR10,或SR11;
R10和R11独立地是环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);和
n=1-4。
相对于式I中的基团“A”,第4组化合物包括这些式IIe化合物,其中:
R7是氢,氧代,环烷基,苯基,取代苯基,或萘基;和
X=CH2,(CH2)2,(CH2)3,或S。
相对于式I中的基团“A”,另一组化合物包括这些式IIh化合物,其中:
a=0或b=1或2。
相对于式I中的基团“B”,本发明化合物包括这些化合物,其中:
B是氢,2-苯并噁唑基,取代的2-噁唑基,CH2ZR15,CH2OCO(芳基),或CH2OPO(R16)R17,其中Z为氧或硫原子;
R15是苯基,取代苯基,萘基,取代萘基,杂芳基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),或(CH2)n(杂芳基);
R16和R17独立地为烷基,环烷基,苯基,取代苯基,萘基,苯烷基,取代的苯烷基,或(环烷基)烷基;
相对于式I中的基团“B”,另一组本发明化合物包括这些式IIIa-c的化合物,其中:
Y1是O或NR23;
Y2是CH2,O,或NR23;
R18和R19独立地为氢,烷基,或苯基,或者R18和R19一起表示-(CH=CH)2-;
R20是氢,烷基,苯基,取代苯基,(CH2)n苯基,或(CH2)n(取代苯基);
R21,R22和R23独立地为氢或烷基。
式I化合物可以用下文所述的常规技术合成。有利的是,这些化合物能够由易得原料方便地合成。
合成本发明化合物的一条合成路线如下面方案1所示:
方案1
在上述方案1中,式(V),即H2N-C,是式Va-Vd的修饰天冬氨酸残基:
Va; 式Vb;
Vc;或 式Vd.
在上述方案1中,“PG”表示氨基保护基,“A”表示上文所述的式IIa-IIi的天然或非天然氨基酸。在式Va-Vd中,R2’是如上所述的羧基保护基,或者是式I的R2定义中所述的R2部分,但R2’不能是氢原子。
式Va-d中的修饰天冬氨酸可用本领域公知的方法制备,参见,例如,欧洲专利申请519,748;PCT专利申请PCT/EP92/02472;PCT专利申请PCT/US91/06595;PCT专利申请PCT/US91/02339;欧洲专利申请623,592;世界专利申请WO 93/09135;PCT专利申请PCT/US94/08868;欧洲专利申请623,606;欧洲专利申请618,223;欧洲专利申请533,226,欧洲专利申请528,487;欧洲专利申请618,233;PCT专利申请PCT/EP92/02472;世界专利申请WO93/09135;PCT专利申请PCT/US 93/03589;和PCT专利申请PCT/US93/00481,所有这些文献均引入本文用作参考。
步骤A中进行的偶联反应在标准肽偶联剂的存在下进行,这种偶联剂例如为联用二环己基碳二亚胺(DCC)和1-羟基苯并三唑(HOBt),以及BOP(六氟磷酸苯并三唑氧基-三-(二甲氨基)磷鎓)试剂、pyBOP(六氟磷酸苯并三唑氧基-三(N-吡咯烷基)磷鎓)、HBTU(O-苯并三唑基-四甲基脲鎓-六氟磷酸盐)和EEDQ(1-乙氧基羰基-2-乙氧基-1,2-二氢喹啉)试剂,联用1-乙基(3,3’-二甲基-1’-氨基丙基)碳二亚胺(EDAC)和HOBt等,正如下列文献中所讨论的:J.Jones,“氨基酸与肽的合成”(Amino Acid and Peptide Synthesis),Steven G.Davis编著,Oxford University Press,Oxford,pp.25-41(1992);M.Bodanzky,“肽合成原理”(Principles of PeptideSynthesis),Hafner等编著,Springer-Verlag,BerlinHeidelberg,pp.9-52和pp.202-251(1984);M.Bodanzky,“肽化学-实用教材”(Peptide Chemistry,A PracticalTextbook),Springer-Verlag,Berlin Heidelberg,pp.55-73和pp.129-180;和Stewart和Young,“固相肽合成”(Solid PhasePeptide Synthesis),Pierce Chemical Company,(1984),所有这些文献的内容在此引入用作参考。然后除去氨基保护基,将所得胺与式VII的(N-取代的)草氨酸偶联(步骤B)。还有,该偶联反应也采用上述标准肽偶联反应。
或者,式VII的(N-取代的)草氨酸可以与式IX的氨基酯偶联(步骤D)。同样,该偶联反应也采用上述标准肽偶联反应。在式IX中,基团R是羧基保护基,例如甲基、烯丙基、苄基或叔丁基。在本领域公知的标准条件下除去羧基保护基之后,采用上述标准肽偶联方法偶联将所得羧酸偶联到胺V上(步骤E)。
在步骤A或步骤E描述的偶联反应使用式Vc氨基醇进行的情况下,在除去保护基之前必须将醇部分氧化为相应的羰基化合物。用于氧化反应的优选方法包括Swern氧化法(草酰氯-二甲亚砜,于-78℃下加入二氯甲烷,然后加入三乙胺);和Dess-Martin氧化法(Dess-Martin periodinane,叔丁醇和二氯甲烷)。式Va-d和A中包含的保护基(存在的话)用本领域公知的方法除去。上述方案1中步骤C包括了这些反应以及部分或全部保护基的除去。
合成本发明化合物的另一条合成路线见下面方案2所示。
方案2
(式XIII)
(式XIV) (式I)
在上述方案2中,“PG”表示氨基保护基,“A”表示如上所述的式IIa-IIi的天然或非天然氨基酸。基团R是羧基保护基,例如三甲基甲硅烷基,甲基,烯丙基,苄基或叔丁基。
步骤F和步骤G中进行的偶联反应在标准肽偶联剂的存在下进行,在步骤G中,氨基保护基必须在偶联步骤之前除去。在步骤H中。选择性除去式XIII化合物的α-羧基保护基R,随后用重氮甲烷和氢溴酸处理所得一元羧酸,产生式XIV的α-溴酮。
在步骤I中,在无机碱例如碳酸钾或氟化钾的存在下,在惰性溶剂如二甲基甲酰胺中用R15Z-H,(芳基)-CO2H,(杂芳基)-CO2H,或R16(R17)PO2H处理式XIV的溴酮,分别得到其中B是CH2ZR15,CH2OCO(芳基),CH2OCO(杂芳基)或CH2OPO(R16)R17的式I化合物。其中B是式III片段的式I化合物也可以用类似方法制备。式XI和A的亚结构中包含的保护基用本领域技术人员公知的方法除去。这些反应以及部分或全部保护基的除去包含在上述方案2的步骤I中。
制备其中R2和B都是氢的式I(即式Ib)的本发明化合物的另一种可供选择的方法如下面的方案3所示:
方案3
在方案3中,Fmoc是氨基保护基9-芴基甲氧基羰基,标记为“PS”的阴影圆圈表示聚苯乙烯树脂。
式XV的酸与负载在固体载体上的伯胺(优选氨甲基聚苯乙烯)的偶联利用标准肽偶联剂(优选使用苯并三唑氧基-三(N-吡咯烷基)磷鎓六氟磷酸盐(pyBOP)),在惰性溶剂例如二甲基甲酰胺或N-甲基吡咯烷酮中进行(步骤J)。通过用吡咯烷-二甲基甲酰胺处理除去Fmoc-保护基之后,采用上文所述的标准肽偶联条件偶联所得胺与式IVa的Fmoc-氨基酸(步骤K)。
在步骤L中,式XVII化合物中的Fmoc保护基同样用吡咯烷-二甲基甲酰胺处理除去,然后同样采用上文所述的标准肽偶联条件偶联所得胺与式VII的(N-取代的)草氨酸。在捕获剂例如茴香醚的存在下,通过用三氟乙酸-二氯甲烷处理除去式XVIII化合物的叔丁基酯,继用37%甲醛水溶液/乙酸/四氢呋喃/三氟乙酸(优选比例为1/1/5/0.025)处理将所得酸从固体载体上裂解下来,得到式Ib的门冬氨醛(步骤M)。
本发明的药物组合物包括本发明化合物及其可药用盐,以及可接受的载体、辅剂或赋形剂(以下统称为“可药用载体”)。可用于本发明药物组合物的可药用载体、辅剂和赋形剂包括但不限于离子交换树脂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白,如人血清白蛋白;缓冲剂如各种磷酸盐,甘氨酸,山梨酸,山梨酸钾,饱和脂肪酸的偏甘油酯混合物;水,盐或电解质,例如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,和锌盐;胶体二氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素基物质,聚乙二醇,羧甲基纤维素钠,多芳基化物,蜡,聚乙烯-聚氧丙烯嵌段共聚物,聚乙二醇和羊毛脂等。
本发明的药物组合物可以通过口服、非肠道、吸入喷雾、局部、直肠、经鼻、经颊、经阴道或通过植入的储库途径给药。优选口服或非肠道给药。本文所用术语“非肠道”包括皮下、皮内、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、损伤部位内和颅内注射或输注技术。
药物组合物可以是无菌注射剂形式,例如为水性或油性无菌注射悬浮液。这种悬浮液可按照本领域已知的技术,使用适当的分散剂或湿润剂(例如吐温80)和悬浮剂配制。无菌注射剂也可以是在无毒、非肠道可接受的稀释剂或溶剂中的无菌注射液或悬浮液形式,例如在1,3-丁二醇中的溶液。可使用的能被接受的赋形剂和溶剂是甘露醇,水,Ringer溶液和等渗氯化钠溶液。此外,无菌非挥发性油也常用作溶剂或悬浮介质。为此,可使用任何温和的脂肪油,包括合成的一或二甘油酯。脂肪酸,例如油酸及其甘油酯衍生物可用于注射剂的制备,同样,天然可药用油例如橄榄油或蓖麻油,尤其是它们的聚氧乙基化形式也可用于注射剂的制备。这些油性溶液或悬浮液还可含有长链醇稀释剂或分散剂。
本发明的药物组合物可以任何可口服的剂型口服给药,这些剂型包括但不限于胶囊剂、片剂、以及水悬浮液和水溶液。就口服片剂而言,常用的载体包括乳糖和玉米淀粉。通常还加入润滑剂,例如硬脂酸镁。对于口服给药的胶囊形式,有用的稀释剂包括乳糖和干燥玉米淀粉。当水悬浮液通过口服给药时,其中的活性成分是与乳化剂和悬浮剂混合的。如果需要,还可加入一些甜味剂和/或调味剂和/或着色剂。
本发明的药物组合物也可以栓剂形式直肠给药。这些组合物可通过将本发明化合物与适宜非刺激性赋形剂混合制备,所述赋形剂在室温下是固体但在直肠温度下为液体。此类物质包括但不限于可可脂、蜂蜡和聚乙二醇。
当所需的治疗涉及易于局部给药的表面或器官时,局部给药本发明药物组合物尤为有用。对于皮肤局部给药,药物组合物应配制成含悬浮于或溶于载体中的活性化合物的适当软膏剂。用于局部给药本发明化合物的载体包括但不限于矿物油、液体石蜡、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。另一方面,药物组合物也可以配制成含悬浮或溶于载体中的活性化合物的适宜洗剂或霜剂。合适的载体包括但不限于矿物油、脱水山梨醇一硬脂酸酯、聚山梨酯60、鲸蜡基酯蜡、鲸蜡醇,2-辛基十二烷醇、苄醇和水。本发明的药物组合物也可以直肠栓剂制剂或适宜的灌肠制剂形式局部用于下肠道。本发明还包括局部使用的透皮贴剂。
本发明的药物组合物可通过鼻气雾剂或吸入给药。这类组合物用制剂领域公知的技术制备,并且可使用苄醇或本领域已知的其它适宜的防腐剂、用于提高生物利用度的吸收促进剂、碳氟化物和/或其它增溶剂或分散剂配制成盐水溶液。
本发明的化合物可以与常用的抗炎药或基质金属蛋白酶抑制剂、脂氧合酶抑制剂和非IL-1β的细胞因子拮抗剂联用。
本发明化合物还可以与免疫调节剂(例如溴匹立明、抗人α-干扰素抗体、IL-2、GM-CSF、甲硫氨酸脑啡肽、α-干扰素、二硫代氨基甲酸二乙酯、肿瘤坏死因子、naltrexons和rEPO)或与前列腺素联合给药,用于预防或治疗IL-1介导的病症,例如炎症。
当本发明化合物以与其它药物合用的联合治疗物形式给药时,它们可相继或同时给药于患者。另一方面,本发明的药物组合物可包含式I化合物和上述其它治疗性或预防性药物的合剂。
可用本发明药物组合物治疗或预防的疾患包括但不限于炎症性疾病、自身免疫病和神经变性疾病,并且本发明的药物组合物可用于抑制不希望发生的与局部缺血性损伤,例如心脏(如心肌梗塞)、脑(如中风)和肾脏(如缺血性肾病)的局部缺血性损伤有关的编程性细胞死亡。由于本发明的药物组合物能抑制编程性细胞死亡,因此它们还可用于患者化疗后造血细胞的再生。本发明的另一方面涉及对需此治疗的哺乳动物,在本文中也称作患者(即罹患炎症性疾病、自身免疫病、神经变性疾病的患者以及进行了化疗需要再生造血细胞的癌症患者)给药有效量的上述药物组合物。最后,本发明药物组合物具有抑制编程性细胞死亡能力的另一个结果是,可以用于延长移植器官存活性的方法中。
可以治疗或预防的炎症性疾病包括例如脓毒性休克、败血病和成人呼吸窘迫综合症。靶标自身免疫病包括,例如,类风湿、关节炎、系统性红斑狼疮、硬皮病、慢性甲状腺炎、格雷夫斯病、自身免疫性胃炎、胰岛素依赖性糖尿病、自身免疫性溶血性贫血、自身免疫性中性白细胞减少、血小板减少症、慢性活动性肝炎、重症肌无力和多发性硬化。目标神经变性疾病包括,例如,肌萎缩性脊髓侧索硬化、阿耳茨海默氏病、帕金森氏病、和原发性脊髓侧索硬化。本发明的药物组合物还可用于促进伤口愈合。与有害的编程性细胞死亡有关的靶标疾病(换言之,是与局部缺血性损伤有关的疾病)包括心肌梗塞、中风和局部缺血性肾病。本发明的药物组合物也可用于治疗传染性疾病,尤其是与病毒感染有关的疾病。
本发明提供了用于治疗或预防各种不同病变(包括炎症引起的组织或细胞损伤)的组合物和方法。这种炎症可以是急性炎症,包括对有害物质,例如化学剂(如化妆品、植物或昆虫源物质)、身体创伤、烧伤或瞬态微生物感染的速发性和早期反应。或者也可以是慢性炎症,例如因连续存在有害刺激如细胞内微生物的永久性感染、长时间与非降解性无生命材料接触、或自身免疫病所致的炎症。
本发明的组合物和方法可用于治疗或预防各种不同感染(包括细菌、真菌和病毒感染在内)引起的炎症或脓毒症。细菌感染包括革兰氏阳性菌和革兰氏阴性菌感染。革兰氏阳性菌及相关疾病的实例包括破伤风梭状芽孢杆菌(破伤风),肉毒梭状芽孢杆菌(肉毒中毒),炭疽芽孢杆菌(炭疽),金黄色葡萄球菌(痤疮、皮肤脓肿、中毒性休克综合症),肺炎链球菌(细菌性肺炎)。链球菌也是链球菌喉、脓疱病、中耳感染、猩红热、风湿性热、坏死性筋膜的病原体。病理性革兰氏阴性菌的实例包括大肠杆菌、肠炎沙门氏菌(伤寒)、绿脓杆菌、鼠疫耶尔森氏菌(腺鼠疫)、流感嗜血杆菌(细菌性脑膜炎,中耳感染)、脑膜炎奈瑟氏球菌(流行性脑脊膜炎)和淋病奈瑟氏球菌(淋病)。
本发明也可以治疗其它微生物引起的感染相关症状。这些感染性微生物包括,例如,分支杆菌(例如结核杆菌和麻风杆菌),棒状杆菌,螺旋体(例如苍白密螺旋体(梅毒)和博氏疏螺旋体(Lyme病)),支原体,立克次氏体(例如普鲁画斯克氏立克次氏体(斑疹伤寒),和衣原体(例如沙眼衣原体(骨盆炎症病,沙眼))。此外,本发明的方法和组合物还可用于治疗或预防与其它微生物引起的寄生物感染有关的细胞损伤。这种微生物包括,例如,真菌、原生动物(如疟原虫),扁虫(例如绦虫、吸虫)、线虫、昆虫(例如跳蚤,虱子)和蛛形纲动物(例如螨)。
本发明可治疗的病毒感染包括DNA和RNA病毒所致的感染。DNA病毒包括双链DNA基因组(例如天花)或单链DNA基因组(如腺伴随病毒)。RNA病毒包括具有包括反义RNA(如埃博拉(Ebola))、有义RNA(例如脊髓灰质炎病毒)、或双链RNA(例如呼肠病毒)以及逆病毒(例如HIV-1)在内基因组的病毒。可用本发明治疗的DNA病毒及相关疾病的实例包括:天花;疱疹病毒,例如单纯疱疹病毒(感冒疮),水痘-带状疱疹病毒(水痘,带状疱疹),EB病毒(单核细胞增多症,Burkitt淋巴瘤),KSHV(Kaposi肉瘤),和巨细胞病毒(失明);腺病毒;和乙型肝炎病毒。RNA病毒的实例包括脊髓灰质炎病毒,鼻病毒(rhinoviruses)黄热病,西尼罗河病毒,登革热,马脑炎,甲肝和丙肝,呼吸道合胞病毒,副流感病毒,和烟草花叶病病毒。RNA病毒与多种人体疾病有关,这些疾病可用本发明治疗,并且包括,例如,囊尾蚴,流行性腮腺炎,狂犬病,埃博拉和流感。本发明所治疗的病毒感染可以局限于特定细胞或组织,或者它们可以是系统性的。另外,这些病毒感染可以是溶解性或潜伏性的。
本发明还可用于治疗能引起严重的出血性发烧的系统性病毒感染。尽管许多病毒感染可能与出血性合并症有关。但一些RNA病毒引起的感染经常会导致血管缠绕和病毒出血性发烧。这些疾病的病原因子相应地包括埃博拉病毒,马堡病毒,Junin病毒,和Machupo病毒。
多种不同病毒都与病毒出血热有关,包括线状病毒(例如埃博拉病毒,马堡病毒,和Reston病毒),沙粒病毒(例如拉沙病毒,Junin病毒和Machupo病毒),和布尼亚病毒。此外,包括例如RiftValley发烧病毒在内的静脉病毒(phleboviruse)已经被鉴定是病毒出血热的病原因子。出血热及相关严重的病原体也可以包括副粘病毒,尤其是呼吸道合胞病毒,因为副粘病毒从进化上讲是与线状病毒密切相关的(Feldmann,H.等,Arch Virol Suppl 993:7:81-100),另外,已经表征过的致使人出血热的其它病毒属于下列病毒:披膜病毒(Chikungunya),黄病毒(登革热,黄热病,KyasanurForest病,鄂木斯克出血热),新露病毒(nairovirus)(Crimian-Congo出血热)和汉坦病毒(肾综合症性出血热,肾流行病)。此外,Sin Nombre病毒被鉴定为1993年西南美洲爆发的汉坦病毒肺综合症的病原体。
本发明的方法与组合物还可用于治疗或缓解与病毒感染有关的症状,包括但不限于炎症,组织损伤,以及出血热的其它身体表现。病毒感染和出血热所影响的适宜靶细胞包括,例如,单核噬吞细胞系统细胞,淋巴细胞,内皮细胞,成纤维细胞,肝细胞和很多其它细胞。
本发明的方法和组合物还能增强抗原呈递细胞的存活力,提高免疫效应器/反应细胞如淋巴细胞(例如T-淋巴细胞和B-细胞)、树突细胞、巨噬细胞等的生存力。为此,本发明不仅具有预防、缓解、或治疗组织损伤和与微生物(例如细菌、真菌或病毒等)有关的炎症的效用,而且还能提高其免疫应答的效力和寿命。因此,就能够诱导免疫系统细胞中细胞死亡的大量适应症如HIV和脓毒症而言,较长的细胞寿命能显著改变疾病进程和/或增强对这种微生物的免疫反应。
术语“有效量”是指用于治疗上述病症的约0.05毫克-约140毫克/千克体重/天的剂量水平(典型地是大约2.5毫克-约7克/患者/天)。例如,每天每千克体重给药约0.01-50毫克化合物(约0.5毫克-约3.5克/患者/天),能够有效地治疗炎症。
可以与载体物质混合以生产单剂量剂型的式I化合物的用量将根据受治疗的宿主和特定的给药方式而变化。例如,用于人口服给药的制剂可含有0.5毫克-5克式I化合物和适当量的可药用载体(其占组合物总量的约5-约95%)。单位剂型通常含有约1毫克-约500毫克的式I活性化合物。
然而,应当明白,对于特定患者,具体的“有效量”将取决于多种因素,包括所用具体化合物的活性,年龄、体重、健康状况、性别、给药时间、给药途径、排泄速率、药物联用情况以及进行预防或治疗的特定疾病的严重程度。
虽然本发明的焦点在于本文公开的化合物在预防和治疗IL-1介导的疾病方面的用途,但本发明的化合物也可以用作其它半胱氨酸蛋白酶的抑制剂。
本发明的化合物还可用作能有效地与ICE/ced-3家族半胱氨酸蛋白酶或其它半胱氨酸蛋白酶结合的商用试剂。作为商用试剂,本发明的化合物及其衍生物可用于阻断目标肽的蛋白水解作用,或者被衍生化而与稳定的树脂结合,用作亲和色谱应用的连接底物。以商用半胱氨酸蛋白酶抑制剂为特征的这些和其它用途对于本领域普通技术人员而言是显而易见的。
为更全面地理解本发明,本文给出了下列实施例。这些实施例仅仅是说明性的,不得认作是以任何方式对本发明范围构成限制。在下列实施例中,质子NMR光谱是在300MHz下测得的;化学位移是以距内标四甲基硅烷的低磁场报告的。
制备例1
(3S)-氨基-4-氧代丁酸叔丁基酯缩氨基脲,对-甲苯磺酸盐的制备
步骤A:N-(苄氧基羰基)-L-(N’-甲基-N’-甲氧基)天冬酰氨β-(叔
丁基)酯
0℃(冰浴)、氮气氛下,向N-(苄氧基羰基)-L-天冬氨酸-β-(叔丁基)酯(14.65g,45.3mmol,Bachem)的CH2Cl2(150mL)溶液中加入1-羟基苯并三唑水合物(7.29g,47.6mmol,Aldrich),接着再加入1-乙基-3-(3’,3’-二甲基-1’-氨基丙基)碳二亚胺盐酸盐(9.55g,49.8mmol,Sigma)。0℃搅拌15分钟后,加入N,O-二甲基羟胺盐酸盐(5.10g,52.3mmol,Aldrich)和N-甲基吗啉(5.8mL,53mmol,Aldrich)。3小时内温热混合物到室温,然后在室温下搅拌16小时。真空浓缩溶液,将残留物分配到乙酸乙酯-5%KHSO4(各200mL)之间。有机相依次用5%KHSO4、饱和碳酸氢钠和饱和氯化钠溶液洗涤,无水硫酸钠干燥,蒸发得到一油体。将油体用己烷结晶,得标题产物(16.10g,97%收率),为飞扬性白色结晶固体。TLC(乙酸乙酯),单一斑点(UV和PMA):Rf=0.37。
类似于上述方法,以29.3g N-(苄氧基羰基)-L-天冬氨酸-β-(叔丁基)酯(按比例放大2倍)为原料制得31.18g(94%收率)标题产物。
步骤B:(3S)-(苄氧基羰基)氨基-4-氧代丁酸叔丁基酯缩氨基脲
0℃(冰浴)、氮气氛下,将N-(苄氧基羰基)-L-(N’-甲基-N’-甲氧基)天冬酰胺-β-(叔丁基)酯(15.50g,42.3mmol)的无水乙醚(400mL)溶液逐滴加到1.0M LiAlH4的乙醚溶液(22.0mL,22.0mmol,Aldrich)中,控制滴加速度保持反应溶液的温度介于0-5℃(加料时间15-20分钟)。加入氢氧化锂水合物试剂之后,在0-5℃下搅拌混合物1小时,然后滴加0.3N KHSO4溶液(100mL)终止反应。将所得混合物转移到分液漏斗中,加入足量5%KHSO4溶液(75mL)以溶解固体。分离有机相,合并的水相用乙醚(100mL)反萃取。合并的乙醚萃取物以饱和NaCl溶液洗涤,无水硫酸钠干燥,并在微微加热下真空浓缩。TLC(乙酸乙酯):条状斑点(UV和PMA)Rf=0.48.TLC(甲醇/二氯甲烷,1∶9)主要斑点(UV和PMA):Rf=0.75。
将醛粗品随即溶于含水乙醇(45ml水/105mL乙醇),置于冰浴中,用乙酸钠(3.82g,46.6mmol)和氨基脲盐酸盐(5.20g,46.6mmol,Aldrich)处理。混合物在0℃(冰浴)和氮气氛下搅拌3小时,温热到室温,搅拌过夜(16小时)。真空除去大部分乙醇,将残留物分配到乙酸乙酯和水之间(各100mL)。有机相依次用5%KHSO4、饱和碳酸氢钠和饱和氯化钠溶液洗涤,无水硫酸钠干燥,蒸发至干。将本反应的粗产物与另两批以15.40g和4.625g N-(苄氧基羰基)-L-(N’-甲基-N’-甲氧基)天冬酰胺-β-(叔丁基酯)为原料按类似方法制得的产物合并(共计35.535g,97mmol),这些合并产物经硅胶快速色谱纯化,依次用丙酮/二氯甲烷(3∶7)、甲醇-丙酮-二氯甲烷(0.5∶3∶7)洗脱,得无色泡沫状的纯净标题产物(27.73g,78.5%)。TLC(MeOH-CH2Cl2,1∶9):单一斑点(UV和PMA),Rf=0.51。
步骤C:(3S)-氨基-4-氧代丁酸叔丁酯缩氨基脲,对-甲苯磺酸盐
向(3S)-(苄氧基羰基)氨基-4-氧代丁酸叔丁酯缩氨基脲(13.84g,38.0mmol)的无水乙醇(250mL)溶液中加入10%Pd/C(1.50g,Aldrich),在氢气氛下(气球)搅拌所得混合物,直至TLC(甲醇/二氯甲烷,1∶9)显示原料完全消耗(60分钟)。注:密切跟踪反应是重要的,因为产物可能会被过度还原。混合物通过Celite过滤,蒸发得一油体。将油体用二氯甲烷(2×75mL)、二氯甲烷/甲苯(1∶1,75mL)先后研磨,得到白色结晶固体胺粗品。TLC(EtOAc-吡啶-AcOH-H2O;60∶20∶5∶10)单一斑点(UV和PMA)Rf=0.24。注意:在该TLC体系中,任何过度还原产物的位置紧随在所需产物之后,Rf=0.18(仅用PMA)。
将胺粗品溶于CH3CN(60mL),用对-甲苯磺酸一水合物(7.22g,38.0mmol)的乙腈(60mL)溶液处理。收集结晶沉淀物,用乙腈和乙醚洗涤,风干,得到白色结晶固体标题化合物(13.95g,92%收率)。
该物质的旋光纯度通过转化成相应的Mosher酰胺[1.05当量(R)-(-)-α-甲氧基-α-(三氟甲基)苯乙酰氯,2.1当量在CH2Cl2中的i-Pr2NEt,室温,30分钟]来测定。所需产物在7.13ppm(1H,d,J=2.4Hz,CH=N)处具有双峰,而其非对映体的相应信号则在7.07ppm处。按上述方法获得的标题化合物的旋光纯度通常>95∶5。
制备例2
(3S)-(9-芴基甲氧基羰基)氨基-4-氧代丁酸叔丁酯缩氨基脲基-4-[2’-(4-乙基-苯氧基乙酸)]的制备
步骤A:4-[2’-(N-叔丁氧羰基)氨基乙基]苯氧基乙酸,甲酯
室温、氮气氛下,向4-羟基-苯乙胺(7.00g,51.1mmol,Aldrich)在无水二甲基甲酰胺(50mL)中的悬浮液内加入二碳酸二叔丁酯(11.0g,50.5mmol)。在室温下搅拌1小时后,将所得的透明溶液用溴乙酸甲酯(7.5mL,79mmol)和碳酸铯(17.5g,53.7mmol)处理。室温搅拌16小时后,TLC(Et2O-甲苯;2∶8)显示仍存在一些未烷基化的物质(Rf=0.43),故再加入另一份溴乙酸甲酯(2.0mL,21mmol)和碳酸铯(4.5g,14mmol)。另搅拌24小时后,将混合物分配到EtOAc-水(各250mL)之间,有机相依次用水(3X)、5%硫酸氢钾和饱和NaCl溶液洗涤,无水Na2SO4干燥,蒸发至干。残留物用己烷研制,得15.87g褐色固体。粗产物通过硅胶垫过滤,以EtOAc-己烷(2∶8)洗脱,并用己烷结晶,得白色粒状结晶固体标题化合物(14.75g,93%)。TLC(Et2O-甲苯;2∶8)Rf=0.53。
步骤B:4-(2’-氨基乙基)苯氧基乙酸,甲酯,盐酸盐
室温下,向4-[2’-(N-叔丁氧羰基)氨基乙基]苯氧基乙酸,甲酯(18.31g,59.3mmol)的二噁烷(55mL)溶液中加入4.0N HCl/二噁烷溶液(55mL)。室温搅拌16小时后,混合物加Et2O稀释,收集沉淀物,用Et2O充分洗涤,真空干燥,得飞扬性白色结晶固体标题化合物(14.55g,94%)。
步骤C:1-叔丁氧羰基-氨基脲基-4-[2’-(4-乙基-苯氧基乙酸)]
甲酯
室温、氮气氛下,在40分钟内向肼基甲酸叔丁酯(6.60g,50mmol)的二甲基甲酰胺(50mL)溶液中逐滴加入羰基二咪唑(8.10g,50mmol)的二甲基甲酰胺(80mL)溶液。在室温下另搅拌30分钟,单批加入4-(2’-氨基乙基)苯氧基乙酸甲酯盐酸盐固体(12.3g,50mmol),加入在30分钟内逐滴加入三乙胺(8.0mL,58mmol)。室温搅拌18小时后,将混合物分配到EtOAc-水(各300mL)之间。有机相依次用水(3X)、5%硫酸氢钾、饱和碳酸氢钠、和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用EtOAc-己烷结晶,得灰白色结晶固体标题化合物(15.50g,84%).TLC(MeOH-CH2Cl2;1∶9)Rf=0.45。
步骤D:1-叔丁氧羰基-氨基脲基-4-[2’-(4-乙基苯氧基乙酸)]
室温、氮气氛下,向1-叔丁氧羰基-氨基脲基-4-[2’-(4-乙基苯氧基乙酸)]甲酯(14.68g,40mmol)的二噁烷(50mL)溶液中加入1.0N LiOH溶液(50mL)。室温搅拌1小时后,混合物用浓HCl酸化,继用EtOAc(100mL)萃取。有机相用饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得一白色固体。粗产物用THF-EtOAc-己烷促进剂,得白色结晶固体标题化合物(13.44,95%).TLC(AcOH-MeOH-CH2Cl2;1∶1∶8)Rf=0.31。
步骤E:氨基脲基-4-[2’-(4-乙基-苯氧基乙酸)]盐酸盐
室温下,向1-叔丁氧羰基-氨基脲基-4-[2’-(4-乙基-苯氧基乙酸)](13.43g,38.0mmol)在二噁烷(80mL)-茴香醚(15mL)中的溶液内加入4.0N HCl/二噁烷溶液(35mL)。在室温下搅拌18小时,再加入4.0N HCl/二噁烷(15mL)溶液。又过6小时后,过滤收集沉淀物,先后用二噁烷、Et2O彻底洗涤,真空干燥得白色结晶固体标题化合物(11.67g,100%)。
步骤F:N-(9-芴基甲氧基羰基)-L-(N’-甲基-N’-甲氧基)天冬酰
胺β-(叔丁基)酯
0℃(冰浴)、氮气氛下,顺序向N-(9-芴基甲氧基羰基)-L-天冬氨酸-β-(叔丁基)酯(16.48g,40mmol)在CH2Cl2(80mL)-四氢呋喃(20mL)中的溶液内加入1-羟基苯并三唑水合物(7.12g,46.5mmol)和1-乙基-3-(3’,3’-二甲基-1’-氨基丙基)碳二亚胺盐酸盐(9.20g,48mmol)。0℃搅拌15分钟后,加入N,O-二甲基羟胺盐酸盐(4.68g,48mmol)和N-甲基吗啉(5.2mL,47mmol)。在2小时内使混合物的温度回升至室温,然后在室温下搅拌16小时。真空浓缩溶液,将残留物分配到乙酸乙酯-5%KHSO4(各200mL)中。有机相依次用5%硫酸氢钾、饱和碳酸氢钠和饱和NaCl溶液洗涤;无水硫酸钠干燥,蒸发得到一油体。粗产物经硅胶快速色谱纯化,以EtOAc-己烷(30∶70,然后35∶65)洗脱,得无色泡沫状标题产物(17.75g,98%收率)。TLC(EtOAc-己烷;1∶1)Rf=0.35。
步骤G:(3S)-(9-芴基甲氧基羰基)氨基-4-氧代丁酸叔丁酯缩氨
基脲基-4-[2’-(4-乙基-苯氧基乙酸)]
0℃(冰浴)、氮气氛下,向N-(9-芴基甲氧基羰基)-L-(N’-甲基-N’-甲氧基)天冬酰胺-β-(叔丁基)酯(13.20g,29mmol)的无水乙醚(250mL)溶液中逐滴加入1.0M LiAlH4乙醚溶液(14.5mL,14.5mmol),控制滴加速度以保持反应溶液的温度介于0-5℃(加料时间15-20分钟)。加毕氢化铝锂试剂后,在0-5℃下搅拌混合物1小时,然后滴加0.3N KHSO4溶液(100mL)终止反应。加入足量0.3N KHSO4溶液以溶解大部分无机盐,然后将混合物转移到分液漏斗内。分离有机相,水相用乙醚(100mL)反萃取。合并的乙醚萃取物用饱和NaCl溶液洗涤,无水硫酸钠干燥,在微微加热下真空浓缩。TLC(EtOAc-己烷):Rf=0.40。
随即将醛粗品溶于乙醇(105mL)-水(45mL)-四氢呋喃(75mL)中,置于冰浴中,用乙酸钠(3.20g,39mmol)和氨基脲基-4-[2’-(4-乙基-苯氧基乙酸)]盐酸盐(8.65g,30mmol)处理。混合物在0℃(冰浴)和氮气氛围中搅拌3小时,温热到室温,搅拌过夜(16小时)。混合物用旋转蒸发器浓缩,继而加水稀释,抽吸过滤产生的沉淀物。真空干燥该物质,得18.36g白色固体粗产物。将本次反应的粗产物与另以4.55g(10mmol)N-(9-芴基甲氧基羰基)-L-(N’-甲基-N’-甲氧基)天冬酰胺-β-(叔丁基酯)为原料进行的小规模反应得到的产物(6.34g)合并,分配到乙酸乙酯-四氢呋喃(1∶1)和5%KHSO4之间。有机相用5%KHSO4和饱和氯化钠溶液洗涤,无水硫酸钠干燥,蒸发至干。将残留物通过硅胶垫过滤,以四氢呋喃/二氯甲烷(1∶1)洗脱。蒸发合并的含产物馏分至干,继用四氢呋喃-Et2O重结晶,得白色固体的纯净标题产物(17.01g,69%)。TLC(AcOH-MeOH-CH2Cl2,1∶1∶40):Rf=0.19。
制备例3
ICE/ced-3蛋白酶家族活性的抑制试验
A.
IC 50 值的测定
基本上按照Thornberry等人(
Nature,356:768:774(1992))和Nicholson等人(
Nature,376:37-43(1995))的方法(上述文献内容在此引入用作参考),在96孔微量滴定板中分别使用重组ICE和CPP32酶进行测定式I化合物活性的荧光酶测定。用于ICE测定的底物是乙酰基-Tyr-Val-Ala-Asp-氨基-4-甲基香豆素(AMC),用于CPP32,Mch2,Mch3和Mch5测定的底物是乙酰基-Asp-Glu-Val-Asp-氨基-4-甲基香豆素。酶反应是在室温下在含2mM DTT的ICE缓冲液(25mM HEPES,1mM EDTA,0.1%CHAPS,10%蔗糖,pH7.5)中双份进行。测定通过混合下列组分进行:
在含8.0(ICE,Mech2,Mch3,CPP32)或20(Mch5)mM DTT的ICE缓冲液中的50μL ICE,Mch2,Mch5,CPP32(浓度分别为18.8,38,8.1和0.153nM)或Mch3(1单位)酶;
50μL式I化合物或ICE缓冲液(对照);和
100μL的20μM底物。
在加入底物启动反应之前,使酶和要测定的式I化合物在微量滴定板的孔中室温预温育30分钟。在室温下通过使用360nm的激发波长测定460nm处的荧光发射,在室温下检测1小时荧光AMC产物的形成。求复孔(对照组)荧光变化的平均值,以平均值作为抑制剂浓度的函数作图,以求出产生50%抑制的抑制剂浓度(IC50)。
B.
不可逆抑制剂的解离常数Ki和不可逆速率常数k 3 的测定
对于竞争性不可逆抑制剂对ICE/ced-3家族蛋白酶的不可逆抑制作用;使用下式表示的模型:
在时间t时产物的生成可表达为:
方程1
其中E、I、EI和E-I分别表示活性酶、抑制剂、非共价的酶-抑制剂复合物和共价的酶-抑制剂加合物。Ki值式可逆结合步骤的总解离常数,k3是不可逆速率常数。[S]和Ks值分别是底物浓度和与酶结合的底物的解离常数。[E]T是酶的总浓度。
使用上述方程式测定与ICE/ced-3家族蛋白酶结合的给定抑制剂的Ki和K3值。例如,在不同浓度的抑制剂和底物存在下,连续测定60分钟。测定物的配制基本上与上文用于获得表1中数据所述的方法相同,不同的是通过向底物-抑制剂混合物中加入酶来引发反应。将模拟产物AMC的形成作为时间的函数,用方程1求得K3和k3值。
下面是本发明化合物的实施例。
实施例1
(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-4-氧代丁酸
步骤A:N-(1-萘基)草氨酸
0℃(冰浴)、氮气氛下,向1-氨基萘(1.43g,10mmol)和三乙胺(1.5mL,10.8mmol)在CH2Cl2(10mL)中的溶液内逐滴加入甲基草酰氯(1.0mL,10.9mol)的CH2Cl2(5mL)溶液。加毕后,使混合物的温度回升至室温,搅拌1小时。浓缩混合物,将残留物分配到EtOAc-5%KHSO4之间。有机相用5%KHSO4和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到粉红色固体。粗产物用甲苯-己烷重结晶,得N-(1-萘基)草氨酸甲酯(2.066g,90%),为粉红色结晶固体。TLC(EtOAc-己烷)Rf=0.6.
将甲基酯(1.97g,8.6mmol)溶于二噁烷(10mL),用1.0N的LiOH溶液(10mL,10mmol)处理,在室温下搅拌1小时。混合物用浓HCl酸化,继用EtOAc萃取。萃取物用饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到粉红色固体。粗产物以EtOAc-己烷重结晶,得标题化合物(1.712g,85%),为粉红色结晶固体。TLC(AcOH-MeOH-CH2Cl2;1∶1∶20)Rf=0.06。
步骤B:(3S)-3-[(N-苄氧基羰基)亮氨酰]氨基-4-氧代丁酸叔丁
酯缩氨基脲
在室温和氮气氛下,(N-苄氧基羰基)亮氨酸N-羟基琥珀酰亚胺酯(1.81g,5.0mol)的二氯甲烷(30mL)溶液中加入(3S)-氨基-4-氧代丁酸叔丁酯缩氨基脲对-甲苯磺酸盐(2.58g,6.4mmol),然后加入二异丙基乙胺(12mL,6.9mmol)。室温甲苯16小时后,浓缩混合物,将残留物分配到EtOAc-5%KHSO4中。有机相用5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发后得到浅黄色泡沫体标题化合物(2.798g)。TLC(MeOH-CH2Cl2;1∶9)Rf=0.52。
步骤C:(3S)-3-(亮氨酰)氨基-4-氧代丁酸叔丁酯缩氨基脲
向(3S)-[(N-苄氧基羰基)亮氨酰基]氨基-4-氧代丁酸叔丁酯缩氨基脲粗品(2.798g,约5.0mmol)在绝对EtOH(40mL)中的溶液内加入10%Pd-C(0.40g),并在氢气氛围(气球)中搅拌形成的混合物1.5小时。混合物通过Celite过滤,用二氯甲烷洗涤滤饼,然后蒸发合并的滤液至干。残留物用CH2Cl2(2×20mL)研磨,得无色泡沫体标题产物(2.113g).TLC(MeOH-CH2Cl2;1∶9)Rf=0.23。
步骤D:(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-4-氧代丁
酸叔丁酯缩氨基脲
在0℃(冰浴)和氮气氛下,向N-(1-萘基)草氨酸(0.095g,0.44mmol)和(3S)-3-(亮氨酰)氨基-4-氧代丁酸叔丁酯缩氨基脲(0.180g,约0.41mmol)在N-甲基吡咯烷酮(1.0mL)-CH2Cl2(1.0mL)中的溶液内加入羟基苯并三唑水合物(0.100g),接着加入1-乙基-3-(3’,3’-二甲基-1’-氨基丙基)碳二亚胺盐酸盐(0.100g,0.52mmol)。0℃搅拌2小时和室温搅拌16小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得一固体。固体残留物用乙醚研制,得灰白色固体标题化合物(0.23 1g,97%)。TLC(MeOH-CH2Cl2;5∶95)Rf=0.32。
步骤E:(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-4-氧代丁
酸缩氨基脲
在室温和氮气氛下,向(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-4-氧代丁酸叔丁酯缩氨基脲(0.212g,0.39mmol)在CH2Cl2(2.0mL)-茴香醚(0.5mL)中的悬浮液内加入三氟乙酸(2.0mL)。室温搅拌产生的清亮也3小时,之后蒸发至干,用甲苯-CH2Cl2(1∶1)研磨。残留物用研磨研制后得灰白色固体标题化合物(0.181g,95%)。TLC(AcOH-MeOH-CH2Cl2;1∶1∶20)Rf=0.16。
步骤F:(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-4-氧代丁
酸
在室温和氮气氛下搅拌(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-4-氧代丁酸缩氨基脲(0.173g,0.36mmol)在37%甲醛水溶液(1.0mL)-乙酸(1.0mL)-甲醇(3.0mL)中的悬浮液18小时。加水稀释产生的清亮溶液,抽滤收集产生的白色沉淀物,并加以水洗。合并的含水滤液用EtOAc萃取。萃取物用水和饱和NaCl溶液洗涤,无水硫酸钠干燥并蒸发得到一玻璃体。将其与过滤含水混合物得到的固体合并,溶于二氯甲烷,通过Celite过滤,蒸发至干。粗产物通过将残留物溶于二氯甲烷,进而用乙醚-己烷沉淀进行纯化。抽滤收集沉淀物,得到白色固体标题化合物(0.129g,84%).TLC(AcOH-MeOH-CH2Cl2;1∶1∶20)Rf=0.22.MS(ES)C22H25N3O6(MW 427.46):正离子450(M+Na);负离子426(M-H)。
实施例2
(3RS)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-5-氟-4-氧代戊
酸
步骤A:(3RS,4RS)-3-[(N-苄氧基羰基)亮氨酰]氨基-5-氟-4-羟
基戊酸叔丁酯
室温、氮气氛下,向(3RS,4RS)-3-氨基-5-氟-4-羟基戊酸叔丁酯(0.230g,1.1mmol,如Tetrahedron Letters 1994,35,9693-9696所述制备)的二氯甲烷(2.0mL)溶液中加入(N-苄氧基羰基)亮氨酸N-羟基琥珀酰亚胺酯(0.402g,1.1mmol)。在室温下搅拌16小时后,蒸发混合物至干,残留物用硅胶快速色谱纯化,以EtOAc-己烷(1∶2)相同,得标题化合物(0.332g,66%),为无色粘稠油体。TLC(EtOAc-己烷;2∶1)Rf=0.51。
步骤B:(3RS,4RS)-3-(亮氨酰)氨基-5-氟-4-羟基戊酸叔丁酯对
甲苯磺酸盐
向(3RS,4RS)-3-[(N-苄氧基羰基)亮氨酰]氨基-5-氟-4-羟基戊酸叔丁酯(0.332g,0.734mmol)的MeOH(100mL)溶液中加入对-甲苯磺酸水合物(0.140g,0.737mmol)和10%Pd-C(0.033g),所得混合物在氢气氛围(气球)中搅拌2小时。混合物通过Celite过滤,用二氯甲烷洗涤滤饼,蒸发合并的滤液至干。残留物用二氯甲烷研磨,得无色泡沫状标题产物(0.371g)。
步骤C:(3RS,4RS)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-5-
氟-4-羟基戊酸叔丁酯
在室温和氮气氛下,向N-(1-萘基)草氨酸(0.161g,0.749mmol,见实施例1步骤A)在N-甲基吡咯烷酮(1.5mL)-CH2Cl2(1.5mL)中的溶液内加入六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓(0.313g,0.823mmol)。搅拌0.5小时后,混合物用(3RS,4RS)-3-(亮氨酰基)氨基-5-氟-4-羟基戊酸叔丁酯对甲苯磺酸盐(0.371g,0.749mmol)和二异丙基乙胺(0.39mL,2.25mmol)在N-甲基吡咯烷酮(2.0mL)-CH2Cl2(2.0mL)中的溶液。室温搅拌16小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶快速色谱纯化,以EtOAc-己烷(1∶1)洗脱,得无色泡沫体标题化合物(0.213g,55%).TLC(Et2O-CH2Cl2-己烷;2∶1∶2,两次展开)Rf=0.12。
步骤D:(3RS)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-5-氟-4-
氧代戊酸叔丁酯
室温下,向(3RS,4RS)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-5-氟-4-羟基戊酸叔丁酯(0.163g,0.315mmol)的二氯甲烷(3.0mL)溶液中加入Dess-Martin periodinane(0.160g,0.378mmol)。室温搅拌0.5小时后,混合物加EtOAc稀释,继用Na2S2O3稀溶液、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶快速色谱纯化,以EtOAc-己烷(1∶3)洗脱,得白色固体标题化合物(0.155g,95%).TLC(Et2O-CH2Cl2-己烷;2∶1∶2,两次展开)Rf=0.35。
MS(ES)C27H34FN3O6(MW 515.57):正离子538(M+Na);负离子514(M-H)。
步骤E:(3RS)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-5-氟-4-
氧代戊酸
在室温和氮气氛下,向(3RS)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-5-氟-4-氧代戊酸叔丁酯(0.147g,0.285mmol)在CH2Cl2(1.0mL)-茴香醚(0.5mL)中的溶液内加入三氟乙酸(.10mL)。室温搅拌产生的清亮溶液1小时,蒸发至干,继用甲苯-CH2Cl2(1∶1)研磨。残留物用Et2O-己烷研制后得白色固体标题化合物(0.100g,76%)。MS(ES)C23H26FN3O6(MW 459.47):正离子482(M+Na);负离子458(M-H)。
实施例3
(3RS)-3-[N-(N’-(1-萘基)草氨酰)缬氨酰]氨基-5-氟-4-氧代戊酸
步骤A:(3RS,4RS)-3-[(N-苄氧基羰基)缬氨酰]氨基-5-氟-4-羟
基戊酸叔丁酯
在0℃(冰浴)和氮气氛下,向(N-苄氧基羰基)缬氨酸(0.332g,1.32mmol)的CH2Cl2(7.0mL)溶液中顺序加入羟基苯并三唑水合物(0.219g)和1-乙基-3-(3’,3’-二甲基-1’-氨基丙基)碳二亚胺盐酸盐(0.317g,1.65mmol)。0℃搅拌10分钟后,混合物用(3RS,4RS)-3-氨基-5-氟-4-羟基戊酸叔丁酯(0.228g,1.1mmol)处理,并温热反应到室温。室温搅拌24小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶快速色谱纯化,以EtOAc-己烷(1∶1)洗脱,得无色玻璃状标题化合物(0.423g,87%).TLC(MeOH-CH2Cl2;5∶95)Rf=0.17。
步骤B:(3RS)-3-[N-(N’-(1-萘基)草氨酰)缬氨酰]氨基-5-氟-4-
氧代戊酸
以(3RS,4RS)-3-[(N-苄氧基羰基)缬氨酰]氨基-5-氟-4-羟基无水叔丁酯为原料,按照实施例2,步骤B-E中描述的方法制得白色固体标题化合物.MS(ES)C22H24FN3O6(MW 445.45):正离子468(M+Na),484(M+K);负离子444(M-H)。
实施例4
(3S)-3-[N-(N’-(1-萘基)草氨酰)缬氨酰]氨基-5-
(2’,6’-二氯苯甲酰氧基)-4-氧代戊酸
步骤A:[(N-苄氧基羰基)缬氨酰]天冬氨酸,β-叔丁基,α-甲基酯
在0℃和氮气氛下,向(N-苄氧基羰基)缬氨酸(2.10g,8.36mmol)的二氯甲烷(20mL)溶液中顺序加入羟基苯并三唑水合物(1.74g)和1-乙基-3-(3’,3’-二甲基-1’-氨基丙基)碳二亚胺盐酸盐(2.40g,12.5mmol)。0℃搅拌10分钟后,将混合物用天冬氨酸,β-叔丁基,α-甲基酯盐酸盐(2.00g,8.34mmol)和N-甲基吗啉(1.1mL,10mmol)处理,并温热反应到室温。在室温下搅拌2.5小时后,浓缩混合物,将残留物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发,在用Et2O-己烷研制后得到白色固体标题化合物(3.55g,97%)。TLC(EtOAc-己烷;1∶1)Rf=0.48。
步骤B:(缬氨酰)天冬氨酸,β-叔丁基,α-甲基酯对甲苯磺酸盐向[(N-苄氧基羰基)缬氨酰]天冬氨酸,β-叔丁基,α-甲基酯(3.55g,8.12mmol)的甲醇(300mL)溶液中加入对甲苯磺酸水合物(1.55g,8.12mmol)和10%Pd-C(0.30g),并在氢气氛围(气球)中搅拌所得混合物2小时。混合物通过Celite过滤,用二氯甲烷洗涤滤饼,蒸发合并的滤液至干。残留物用二氯甲烷研磨,得无色泡沫状标题产物(3.85g,定量)。
步骤C:[N-(N’-(1-萘基)草氨酰)缬氨酰]天冬氨酸,β-叔丁基,α-
甲基酯
在室温和氮气氛下,向N-(1-萘基)草氨酸(0.683g,3.18mmol,见实施例1步骤A)在N-甲基吡咯烷酮(7.0mL)-CH2Cl2(7.0mL)中的溶液内加入六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓(1.329g,3.49mmol)。搅拌15分钟后,混合物用N-(缬氨酰)-天冬氨酸,β-叔丁基,α-甲基酯对甲苯磺酸盐(1.506g,3.18mmol)和二异丙基乙胺(1.66mL,9.53mmol)。室温搅拌2小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶快速色谱纯化,以EtOAc-己烷(1∶1)洗脱,得白色固体标题化合物(1.153g,73%).TLC(EtOAc-己烷;2∶1)Rf=0.48。
步骤D:[N-(N’-(1-萘基)草氨酰)缬氨酰]天冬氨酸,β-叔丁基酯
向[N-(N’-(1-萘基)草氨酰)缬氨酰]天冬氨酸,β-叔丁基,α-甲基酯(0.490g,0.98mmol)的二噁烷(2.4mL)溶液中加入1.0N LiOH溶液(1.0mL,1.0mmol)。室温搅拌1小时后,混合物用1.0N HCl酸化,继用EtOAc萃取。萃取物用饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到白色固体标题化合物(0.481g,定量).TLC(MeOH-CH2Cl2:1∶9)Rf=0.15。
步骤E:(3S)-3-[N-(N’-(1-萘基)草氨酰)缬氨酰]氨基-5-重氮
基-4-氧代戊酸叔丁酯
在-10℃(NaCl/冰浴)和氮气氛下,向[N-(N’-(1-萘基)草氨酰)缬氨酰]天冬氨酸,β-叔丁基酯(0.095g,0.20mmol)和N-甲基吗啉(22μL,0.20mmol)的四氢呋喃(2.0mL)溶液中加入氯甲酸异丁酯(28μL,0.22mmol)。在-10℃搅拌0.5小时后,将产生的混合酐用过量的重氮甲烷/Et2O溶液(由0.072g,0.49mmol 1-甲基-3-硝基-1-亚硝基胍,1.0mL 40%KOH/1.0ml Et2O制得)处理。在-10℃又搅拌1小时后,浓缩混合物,残留物用硅胶快速色谱纯化,以CH2Cl2-Et2O-己烷(1∶2∶2)洗脱,得白色固体标题化合物(0.062g,62%)。TLC(EtOAc-己烷;2∶1)Rf=0.63。
步骤F:(3S)-3-[N-(N’-(1-萘基)草氨酰)缬氨酰]氨基-5-溴-4-
氧代戊酸叔丁酯
0℃下,向(3S)-3-[N-(N’-(1-萘基)草氨酰)缬氨酰]氨基-5-重氮基-4-氧代戊酸叔丁酯(0.135g,0.265mmol)的四氢呋喃(3.0mL)溶液中加入48%HBr水溶液(30μl,0.27mmol)。观察到有气体逸出。15分钟后,将混合物分配到EtOAc-饱和NaHCO3中。有机相用饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到白色固体标题化合物(0.147g,定量).TLC(EtOAc-己烷;2∶1)Rf=0.72。
步骤G:(3S)-3-[N-(N’-(1-萘基)草氨酰)缬氨酰]氨基-5-
(2’,6’-二氯苯甲酰氧基)-4-氧代戊酸叔丁酯
在室温和氮气氛下,向(3S)-3-[N-(N’-(1-萘基)草氨酰)缬氨酰]氨基-5-溴-4-氧代戊酸叔丁酯(0.100g,0.18mmol)和2,6-二氯苯甲酸(0.037g,0.20mmol)在二甲基甲酰胺(1.0mL)中的溶液内加入氟化钾(0.031g,0.53mmol)。室温搅拌16小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶快速色谱纯化,以EtOAc-己烷(1∶1)洗脱,得标题化合物(0.084g,70%),为粘稠油体。TLC(EtOAc-己烷;2∶1)Rf=0.71。
步骤H:(3S)-3-[N-(N’-(1-萘基)草氨酰)缬氨酰]氨基-5-
(2’,6’-二氯苯甲酰氧基)-4-氧代戊酸
室温、氮气氛下,向(3S)-3-[N-(N’-(1-萘基)草氨酰)缬氨酰]氨基-5-(2’,6’-二氯苯甲酰氧基)-4-氧代戊酸叔丁酯(0.084g,0.125mmol)在CH2Cl2(1.0mL)-茴香醚(0.5mL)中的溶液内加入三氟乙酸(1.0mL)。室温搅拌形成的清亮溶液1小时,蒸发至干,用甲苯-CH2Cl2(1∶1)研磨。残留物用Et2O研制后得到灰白色固体标题化合物(0.060g,78%).MS(ES)C29H27Cl2N3O8(MW 616.45):正离子638/640(M+Na);负离子614/616(M-H)。
实施例5-21
以(3S)-3-[N-(N’-(1-萘基)草氨酰)缬氨酰]氨基-5-溴-4-氧代戊酸叔丁酯(见实施例4,步骤F)为原料,按照实施例4,步骤G-H中描述的方法,还可制得下表3中所示的化合物:
表3
MS(ES) | |||||
Ex. | B | 分子式 | MW | 正离子 | 负离子 |
5 | CH2O(2,6-diF-Ph) | C28H27F2N3O7 | 555.53 | 578(M+Na) | 554(M-H) |
6 | CH2O(2,4,6-triF-Ph) | C28H26F3N3O7 | 573.52 | 596(M+Na) | 572(M-H) |
7 | CH2O(2,3,5,6-tetraF-Ph) | C28H25F4N3O7 | 591.51 | 614(M+Na) | 590(M-H) |
8 | CH2O(6-Me-2-pyro-4-基) | C28H29N3O9 | 551.55 | 574(M+Na) | 550(M-H) |
9 | CH2O(2-Ph-5,6-苯并吡喃-4-酮-3-基) | C37H33N3O9 | 663.68 | 686(M+Na) | 662(M-H) |
10 | CH2OPO(Me)Ph | C29H32N3O8P | 581.56 | 582(M+H)604(M+Na) | 580(M-H)694(M+TFA) |
11 | CH2OPOPh2 | C34H34N3O8P | 643.63 | 666(M+Na) | 642(M-H) |
12 | CH2O(2-CF3-嘧啶-4-基) | C27H26F3N5O7 | 589.53 | 612(M+Na) | 588(M-H) |
13 | CH2O(5-CO2Me-异噁唑-3-基) | C27H28N4O10 | 568.54 | 591(M+Na) | 567(M-H) |
14 | CH2OPO(Me)(1-萘基) | C33H34N3O8P | 631.62 | 654(M+Na) | 630(M-H)744(M+TFA) |
15 | CH2O(4-羟基-Ph) | C28H29N3O8 | 535.55 | 537/538(M+Na) | 535/536/537(M-H) |
16 | CH2O(4-OCOOCHCHCH3-Ph) | C32H33N3O10 | 619.63 | 637(M+NH4) | 618(M-H) |
17 | CH2O(4-OCHCHCH3-Ph) | C31H33N3O8 | 575.62 | 576(M+H) | 574(M-H) |
18 | CH2O(1-萘基) | C32H31N3O7 | 569.6128 | ||
19 | CH2O(4-丙氧基苯基) | C30H35N3O6 | 533.25 | 534(M+H)551(M+NH4) | |
20 | CF3 | C22H22F3N3O6 | 481.15 | 482(M+H) | |
21 | NH(CH2)2Ph | C29H32N4O6 | 532.23 | 533(M+H) | 531(M-H) |
实施例22
(*)非对映体混合物
N-[1-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-乙基]-
N’-(2-叔丁基-苯基)-草酰胺
步骤A:3-(9H-芴-9-基甲氧基羰基氨基)-N-甲氧基-N-甲基琥珀
酰胺酸叔丁酯
0℃、氮气氛下,向2-(9H-芴-9-基甲氧基羰基氨基)-琥珀酸4-叔丁基酯(5.00g,12.15mmol)的二氯甲烷(50mL)溶液中加入1.2当量的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDAC)(2.79g,14.58mmol)和1.1当量的HOBt.H2O(2.05g,13.37mmol)。混合物在0℃和氮气氛围中搅拌15分钟,然后加入HCl HN(OMe)Me(1.42g,14.58mmol),接着再加入4-甲基吗啉(NMM)(2.00mL,18.23mmol)。在0℃-室温下搅拌5小时后,将混合物分配到EtOAc/水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到标题化合物粗品。将此残留物用硅胶快速柱色谱纯化,以EtOAc/己烷(20%)洗脱,得白色泡沫状标题化合物(4.62g,85%).TLC(40%)(EtOAc-己烷)Rf=0.44.
1HNMR(CDCl3)δ7.75(d,J=7.5Hz,2H),7.50(t,J=6.9Hz,2H),7.40(t,J=7.5Hz,2H),7.33-7.28(dt,J=7.5,1.2Hz,2H),5.71(d,J=9.0Hz,1H),5.04(bq,J=7.8Hz,1H),4.36(d,J=7.2Hz,2H),4.23(t J=7.2Hz,1H),3.79(s,3H),3.24(s,3H),2.78-2.71(dd,J=15.0,5.4Hz,1H),2.62-254(15.0,6.9Hz,1H),1.45(s,9H).MS(ES)
C23H25NO6(MW=454.52):正离子455(MH+).
步骤B:3-(9H-芴-9-基甲氧基羰基氨基)-4-氧代丁酸叔丁酯
在-5℃下,向3-(9H-芴-9-基甲氧基羰基氨基)-N-甲氧基-N-甲基琥珀酰胺酸叔丁酯(4.57g,10.04mmol)的乙醚(30mL)悬浮液中逐滴加入0.5当量的1.0M氢化铝锂(LAH)乙醚溶液(5.02mL,5.02mmol)。于-5℃至室温下搅拌1小时后,将反应混合物用5%KHSO4(200 mL)处理,搅拌5分钟,然后分配到EtOAc/水中。有机相用饱和NaCl溶液(200mL)洗涤,硫酸钠干燥,蒸发至干。残留物用硅胶快速柱色谱纯化,以EtOAc/己烷(20%)洗脱,得透明油状标题化合物(2.18g,55%).TLC(30%EtOAc/己烷)Rf=0.35;
1HNMR(CDCl3)δ9.65(s,1H),7.77(d,J=7.2Hz,2H),7.50(d,J=7.5Hz,2H),7.41(t,J=7.5Hz,2H),7.33(dt,J=7.5,1.2Hz,2H),5.88(d,J=7.2Hz,1H),4.50-4.36(m,2H),4.24(t,J 6.6Hz,1H),3.54-3.45(m,1H),3.00-2.93(dd,J=17.4,4.8Hz,1H),2.82-274(dd,J=17.7,5.1s Hz,1H),1.45(s,9H).MS(ES)C23H25NO5(MW=395.45):正离子396(MH+).
步骤C:4,4-双-苄氧基-3-(9H-芴-9-基甲氧基羰基氨基)-丁酸叔
丁酯
室温下,向3-(9H-芴-9-基甲氧基羰基氨基)-4-氧代丁酸叔丁酯(1.24g,3.14mmol)的二氯甲烷(10mL)悬浮液中加入0.20当量的TsOH.H2O(0.12g,0.63mmol),接着逐滴加入5.0当量的苄醇(1.62mL,15.68mmol)。在室温下搅拌18小时后,将反应混合物通过硅藻土过滤,真空浓缩滤液得到标题化合物粗品。残留物用硅胶快速柱色谱纯化,以EtOAc/己烷(10-40%)洗脱,得透明油状标题化合物(0.75g,40%).TLC(40%EtOAc/己烷)Rf=0.68.
1HNMR(CDCl3)δ7.76(d,J=7.2Hz,2H),7.59(d,J=7.5Hz,2H),7.39(t,J=7.5Hz,2H),7.35-7.27(m,12H),5.37(d,J=9.6Hz,1H),4.73-4.52(m,5H),4.35(d,J=6.6Hz,2H),4.24-4.16(q,J=6.6Hz,2H),2.55-2.50(m,2H),1.39(s,9H).MS(ES)
C37H39NO9(MW=593.71):正离子611(M+NH4+).
步骤D:4,4-双-苄氧基-3-{2-[(2-叔丁基-苯基氨基草酰)-氨
基]-丙酰氨基}-丁酸叔丁酯
室温下,在5%哌啶/DMF(3mL)中搅拌4,4-双-苄氧基-3-(9H-芴-9-基甲氧基羰基氨基)-丁酸叔丁酯(0.63g,1.06mmol)。室温搅拌15分钟后,加水(20mL)处理反应混合物,搅拌5分钟,然后分配到EtOAc/水中。有机相用水(3×20mL)、饱和NaCl溶液(3×20mL)洗涤,硫酸钠干燥,蒸发至干,得3-氨基-4,4-双-苄氧基-丁酸叔丁酯(1)粗品。粗制残留物1可作为粗产物直接用于偶联反应。
在室温和氮气氛下,向(2S)-2-[(2-叔丁基苯基氨基草酰)-氨基]-丙酸(0.37g,1.27mmol)的CH2Cl2/NMP(1∶1,3mL)溶液中加入1.5当量的HBTU(0.61g,1.59mmol)。混合物溶液在室温和氮气氛下搅拌45分钟,然后加入1,接着再加入Et3N(0.44mL,3.18mmol)。室温搅拌18小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到标题化合物粗品。将此残留物用硅胶快速柱色谱纯化,以EtOAc/己烷(20%)洗脱,得黄色泡沫状标题化合物(0.29g,42%)。TLC(30%EtOAc/己烷)Rf=0.59。
1HNMR(CDCl3)δ9.53(s,1H),8.06(dd,J=8.1,3.6Hz,1H),8.01(dt,J=8.1,1.2Hz,1H),7.42(d,J=7.5Hz,1H),7.37-7.25(m,11H),7.17(tt,J=7.5,1.2Hz,1H),6.62-6.53(dd,J=16.2,9.0Hz,1H),4.72-4.35(m,7H),2.66(d,J=6.0Hz,2H),1.45(s,9H),1.38(d,J=4.2Hz,3H);MS(ES)C37H47N3O7(MW-645.79):负离子654([M-H]-).
步骤E:N-[1-(2-苄氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-乙
基]-N’-(2-叔丁基-苯基)草酰胺
室温下,在205%TFA/CH2Cl2(2mL)中搅拌4,4-双-苄氧基-3-{2-[(2-叔丁基苯基氨基草酰)-氨基]丙酰氨基}-丁酸叔丁酯(0.16g,0.25mmol)。室温搅拌15分钟后,浓缩反应混合物至干,得到标题化合物粗品。将此残留物用硅胶快速柱色谱纯化,以EtOAc/己烷(20-40%)洗脱,得白色泡沫体标题化合物(0.09g,74%)。
主要非对映体:TLC(40%EtOAc/己烷):Rf=0.29;1HNMR(CDCl3)δ9.53(d,J=7.2Hz,1H),8.09(t,J=7.8Hz,1H),7.93(m,1H),7.42(d,J=9.0Hz,1H),7.35-7.15(m,7H),6.70(d,J=8.1Hz,1H),5.45(d,J=5.1Hz,1H),4.90-4.41(m,4H),3.06-2.83(m,1H),2.53-2.35(m,1H),1.47(d,J=7.2Hz,3H),1.44(s,9H);MS(ES)C26H31N3O6(MW=481.54):正离子482(MH+)。
次要非对映体:TLC(40%EtOAc/己烷)Rf=0.22;1HNMR(CDCl3)δ9.52(s,1H),8.02-7.93(m,2H),7.44(dd,J=8.1,1.5Hz,1H),7.36-8.28(m,6H),7.19(dt,J=9.30,1.5Hz,1H)6.67(d,J=7.8Hz,1H),5.54(d,J=5.4Hz,1H),4.92-4.44(m,4H),2.95-2.85(m,1H),2.55-2.44(m,1H),1.49(d,J=7.2Hz,3H),1.44(s,9H);MS(ES)C26H31N3O6(MW=481.54):正离子482(MH+)。
实施例23
(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基
-5-(二苯基亚膦酰氧基)-4-氧代戊酸
步骤A:[(N-苄氧基羰基)亮氨酰]天冬氨酸,β-叔丁基,α-甲基酯
室温、氮气氛下,向(N-苄氧基羰基)亮氨酸,N-羟基琥珀酰亚胺酯(4.54g,12.5mmol)和天冬氨酸,β-叔丁基,α-甲基酯盐酸盐(3.00g,12.5mmol)在CH2Cl2(20mL)中的溶液内加入N-甲基吗啉(1.65mL,15mmol)。室温搅拌18小时,将混合物分配到EtOAc-水中。有机相用5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到标题化合物(5.56g,99%),为粘稠油体。TLC(EtOAc-己烷;1∶1)Rf=0.48。
步骤B:(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-5-溴-4-
氧代戊酸叔丁酯
以[(N-苄氧基羰基)亮氨酰]天冬氨酸,β-叔丁基,α-甲基酯为原料,按照实施例4,步骤B-F中描述的方法制得白色固体标题化合物。TLC(CH2Cl2-Et2O-己烷;1∶2∶2)Rf=0.32。
步骤C:(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-5-(二苯
基亚膦酰氧基)-4-氧代戊酸叔丁酯
室温、氮气氛下,向(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-5-溴-4-氧代戊酸叔丁酯(0.108g,0.187mmol)和二苯亚膦酸(0.046g,0.21mol)在二甲基甲酰胺(1.0mL)中的溶液内加入氟化钾(0.033g,0.58mmol)。在室温下搅拌48小时,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶快速色谱纯化,以CH2Cl2-Et2O-己烷(1∶2∶2)洗脱,得白色固体标题化合物(0.114g,85%).TLC(EtOAc-己烷;2∶1)Rf=0.26。
步骤D:(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-5-(二苯
基亚膦酰氧基)-4-氧代戊酸
在室温和氮气氛下,向(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-5-(二苯基亚膦酰氧基)-4-氧代戊酸叔丁酯(0.114g,0.16mmol)在CH2Cl2(1.0mL)-茴香醚(0.5mL)中的溶液内加入三氟乙酸(1.0mL)。在室温下搅拌形成的清亮溶液1小时,蒸发至干,用甲苯-CH2Cl2(1∶1)研磨。残留物用Et2O-己烷研制,得到灰白色固体标题化合物(0.062g,59%).MS(ES)C34H34N3O8P(MW 657.66):正离子680(M+Na);负离子656(M-H)。
实施例24-27
以(3S)-3-[N-(N’-(1-萘基)草氨酰)亮氨酰]氨基-5-溴-4-氧代戊酸叔丁酯(见实施例23,步骤B)为原料,按照实施例23,步骤C-D中描述的方法,也可以制备下表4中所列化合物:
表4
MS(ES) | |||||
Ex. | B | 分子式 | MW | 正离子 | 负离子 |
24 | CH2OCO(2,6-diCl-Ph) | C30H29Cl2N3O8 | 630.48 | 652/654(M+Na) | 628/630(M-H) |
25 | CH2O(2,4,6-triF-Ph) | C29H28F3N3O7 | 587.55 | 610(M+Na) | 586(M-H) |
26 | CH2O(2,3,5,6-tetraF-Ph) | C29H27F4N3O7 | 605.54 | 628(M+Na) | 604(M-H) |
27 | CH2OPO(Me)Ph | C30H34N3O8P | 595.59 | 596(M+H)618(M+Na) | 594(M-H)708(M+TFA) |
实施例28-77
按照实施例4,步骤A-H中描述的通用方法,在步骤A中用(N-苄氧基羰基)丙氨酸替代(N-苄氧基羰基)缬氨酸,在步骤C中用适当的草氨酸替代N-(1-萘基)草氨酸,并在步骤G中用适当的酸或苯酚替代2,6-二氯苯甲酸,还可以制备下表5中所示的化合物。
表5
MS(ES) | ||||||
Ex. | R1 | B | 分子式 | MW | 正离子 | 负离子 |
28 | (2-Ph)Ph | CH2O(2-F-Ph) | C28H26FN3O7 | 535.53 | 558(M+Na) | 534(M-H) |
MS(ES) | ||||||
Ex. | R1 | B | 分子式 | MW | 正离子 | 负离子 |
29 | (2-Ph)Ph | CH2OCO(2,6-di-Cl-Ph) | C29H25Cl2N3O8 | 614.44 | 652/654(M+K) | 612/614(M-H) |
30 | (2-Ph)Ph | CH2OPOPh2 | C34H32N3O8P | 641.61 | 664(M+Na)680(M+K) | 640(M-H) |
31 | (2-t-Bu)Ph | CH2O(2-F-Ph) | C26H30FN3O7 | 515.54 | 516(M+H)538(M+Na)554(M+K) | 514(M-H) |
32 | (2-t-Bu)Ph | CH2OPOPh2 | C32H36N3O8P | 621.63 | 644(M+Na)666(M+K) | 620(M-H) |
33 | 1-萘基-CH2 | CH2O(2,3,5,6-tetra-F-Ph) | C27H23F4N3O7 | 577.48 | 600(M+Na)616(M+K) | 576(M-H) |
34 | 1-萘基-CH2 | CH2OCO(2,6-di-Cl-Ph) | C28H25Cl2N3O8 | 602.42 | 624/626(M+Na)640/642(M+K) | 600/602(M-H)714/716(M+TFA) |
35 | 1-萘基-CH2 | CH2OPOPh2 | C33H32N3O8P | 629.60 | 652(M+Na)668(M+K) | 628(M-H) |
36 | (2-tBu)Ph | CH2O(2,3,5,6-tetra-F-4-Br)Ph) | C26H26BrF4N3O7 | 648.40 | 646(M-H) | |
37 | (2-tBu)Ph | CH2OCO(2,6-di-Cl-Ph) | C27H29Cl2N3O8 | 594.45 | 616/618(M+Na) | 492/594(M-H) |
38 | (2-1)Ph | CH2OCO(2,6-di-Cl-Ph) | C23H20Cl2IN3O8 | 664.24 | ||
39 | (2-1)Ph | CH2OCO(2,6-di-Cl-Ph) | C23H20Cl2FN3O8 | 556.33 | ||
40 | (2,5-di-tBu)Ph | CH2O(2,3,5,6-tetra-F-Ph) | C30H35F4N3O7 | 625.62 | 626(M+H)648(M+Na) | 624(M-H) |
41 | (2-Cl)Ph | CH2OPOPh2 | C28H27CIN3O8P | 599.96 | 598(M-H) | |
42 | (2-Cl)Ph | CH2OCO(2,6-di-Cl-Ph) | C23H20Cl3N3O8 | 572.79 | 572/574/576(M+H) | 570/572/574(M-H) |
43 | (4-F)Ph | CH3OPOPh2 | C28H27FN3O8P | 583.51 | 606(M+H) | 582(M-H) |
44 | (4-F)Ph | CH2OCO(2,6-di-Cl-Ph) | C23H20Cl2FN3O8 | 556.33 | 578/480(M+Na) | 554/556(M-H) |
45 | (2-吗啉-4-基-5-三氟甲基Ph | CH2OPOPh2 | C35H35F6N4O11P | 832.65 | 741(M+Na) | 717(M-H) |
46 | (2-吡咯烷-1-基-5-三氟甲基)Ph | CH2OPOPh2 | C35H35F6N4O10P | 816.65 | 725(M+Na) | 701(M-H) |
47 | (2-tBu)Ph | CH2OPOPh2 | C32H36N3O8P | 621.63 | 644(M+Na) | 620(M-H) |
MS(ES) | ||||||
Ex. | R1 | B | 分子式 | MW | 正离子 | 负离子 |
48 | 5,6,7.8-四氢-1-萘基 | CH2OPOPh2 | C32H34N3O8P | 619.61 | 620(M+H)642(M+Na) | 618(M-H) |
49 | 5,6,7.8-四氢-1-萘基 | CH2OCO(2,6-di-Cl-Ph) | C27H27Cl2N3O8 | 592.43 | 614/616(M+Na) | 590/592(M-H) |
50 | 5,6,7.8-四氢-1-萘基 | CH2O(2,3,5,6-tetra-F-ph) | C26H25F4N3O7 | 567.49 | 590(M+Na) | 566(M-H) |
51 | PhCH2 | CH2O(2,3,5,6-tetra-F-Ph) | C23H23Cl2N3O8 | 552.37 | 550/552(M-H) | |
52 | PhCH2 | CH2OCO(2,6-di-Cl-Ph) | C24H23Cl2N3O8 | 552.37 | 550/552(M-H) | |
53 | 1-金刚烷基 | CH2OPOPh2 | C32H38N3O8P | 623.64 | 646(M+Na) | 622(M-H) |
54 | 1-金刚烷基 | CH2OCO(2,6-di-Cl-Ph) | C27H31Cl2N3O8 | 596.46 | 594/596(M-H) | |
55 | 环己基 | CH2OCO(2,6-di-Cl-Ph) | C23H27Cl2N3O8 | 544.39 | 566(M+Na) | |
56 | 环己基 | CH2OPOPh2 | C28H34N3O8P | 571.57 | 594(M+Na)610(M+K) | 570(M-H) |
57 | (2-Cl)Ph | CH2OPOPh2 | C28H27CIN3O8P | 5999.96 | 622/624(M+Na) | 598/600(M-H) |
58 | (2-Cl)Ph | CH2OCO(2,6-di-Cl-Ph) | C23H20Cl3N3O8 | 572.79 | 594(M+Na) | |
59 | (2,5-di-6Bu)Ph | CH2OPOPh2 | C36H44N3O8P | 677.73 | 700(M+Na) | 676(M-H) |
60 | (2,5-di-6Bu)Ph | CH2OCO(2,6-di-Cl-Ph) | C31H37Cl2N3O8 | 650.55 | 650/652(M+H)672/674(M+Na) | 648/650(M-H) |
61 | 1,2,3,4-四氢-1-萘基 | CH2OPOPh2 | C32H34N3O8P | 619.61 | 620(M+H)642(M+Na) | 618(M-H) |
62 | 1,2,3,4-四氢-1-萘基 | CH2OCO(2,6-di-Cl-Ph) | C27H27Cl2N3O8 | 592.43 | 614/616(M+Na) | 590/592(M-H) |
63 | 1-金刚烷基 | CH2O(2,3,5,6-tetra-F-Ph) | C30H23F4N3O7 | 613.52 | 636(M+Na) | 612(M-H) |
64 | 1-金刚烷基 | CH2OPOPh2 | C36H32N3O8 | 665.64 | 688(M+Na) | 664(M-H) |
65 | 1-金刚烷基 | CH2OCO(2,6-di-Cl-Ph) | C31H25Cl2N3O8 | 638.46 | 660/662(M+Na) | 636/638(M-H) |
66 | (2-F)Ph | CH2O(2,3,5,6-tetra-F-Ph) | C22H18F5N3O7 | 531.39 | 554(M+Na) | 530(M-H) |
67 | (2-F)Ph | CH2OPOPh2 | C28H27FN3O8P | 583.51 | 606(M+Na) | 582(M-H) |
MS(ES) | ||||||
Ex. | R1 | B | 分子式 | MW | 正离子 | 负离子 |
68 | (2-F)Ph | CH2OCO(2,6-di-Cl-Ph) | C23H20Cl2FN3O8 | 556.33 | 578/580(M+Na) | 554/556(M-H) |
69 | (4-正庚基)Ph | CH2OPOPh2 | C35H42N3O8P | 663.71 | 686(M+Na) | 662(M-H) |
70 | (4-正庚基)Ph | CH2OCO(2,6-di-Cl-Ph) | C30H35Cl2N3O8 | 636.53 | 658/660(M+Na) | 634/636(M-H) |
71 | Ph(CH2)2 | CH2O(2,3,5,6-tetra-F-Ph) | C24H23F4N3O7 | 541.46 | 542(M+H)564(M+Na) | 540(M-H) |
72 | Ph(CH2)2 | CH2OPOPh2 | C30H32N3O8P | 593.57 | 594(M+H)616(M+Na) | 592(M-H)566/568(M+H) |
73 | Ph(CH2)2 | CH2OCO(2,6-di-Cl-Ph) | C25H25Cl2N3O8 | 566.39 | 566/568(M+H)588/590(M+Na) | 564/566(M-H)714(M+Na) |
74 | (2-1)Ph | CH2OPOPh2 | C28H27IN3O8P | 691.41 | 714(M+Na) | 690(M-H) |
75 | (2-1)Ph | CH2OCO(2,6-di-Cl-Ph) | C23H20Cl2IN3O8 | 664.24 | 686/688(M+Na) | 662/664(M-H)776(M+TFA) |
76 | (2-tBu)Ph | CH2OCO(2,6-di-Cl-Ph) | C27H29Cl2N3O8 | 594.45 | 616/618(M+Na) | 592/594(M-H) |
77 | (2-PhCH2)Ph | CH2O(2,3,5,6-tetra-F-Ph) | C29H30N3O8P | 579.57 | 578(M-H) |
(3S)-3-[N-(N’-(1-萘基甲基)草氨酰)缬氨酰]氨基-5-
(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
步骤A:[(N-苄氧基羰基)缬氨酰基]天冬氨酸,β-叔丁基酯
在室温和氮气氛下,向天冬氨酸,β-叔丁基酯(3.784g,20mmol)的乙腈(200mL)悬浮液中加入双(三甲基甲硅烷基)乙酰胺(9.9mL,40mmol)。在室温下搅拌30分钟后,用(N-苄氧基羰基)缬氨酸N-羟基琥珀酰亚胺酯(6.97g,20mmol)处理形成的清亮溶液。室温再搅拌18小时后,将混合物用水(20mL)处理,用旋转蒸发器处理,然后分配到EtOAc/水中。有机相用水、5%KHSO4、和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。用Et2O-己烷研制得白色固体标题化合物(8.37g,99%)。TLC(EtOAc-己烷;1∶1)Rf=0.06。
步骤B:(3S)-3-[(N-苄氧基羰基)缬氨酰]氨基-5-溴-4-氧代戊酸
叔丁酯
在-10℃(NaCl/冰浴)和氮气氛下,向[(N-苄氧基羰基)缬氨酰]天冬氨酸,β-叔丁酯(8.37g,19.9mmol)和N-甲基吗啉(3.50mL,32mmol)在四氢呋喃(100mL)中形成的溶液内滴加氯甲酸叔丁酯(3.87mL,29.8mmol)进行处理。在-10℃下搅拌20分钟后,过滤(烧结玻璃)混合物滤入到预冷却的接收器中(冰浴),滤饼另用四氢呋喃(约30mL)洗涤。合并的滤液在0℃(冰浴)和氮气氛下用过量的重氮甲烷/Et2O溶液(由7.32g,50mmol 1-甲基-3-硝基-1-亚硝基胍,40mL 40%KOH/65ml Et2O制备)处理。0℃搅拌15分钟和室温搅拌30分钟后,再次冷却反应混合物到0℃,用48%HBr(10mL,60mmol)/乙酸(10mL)处理。在0℃搅拌15分钟和室温搅拌30分钟之后,将混合物分配到EtOAc-水中。有机相用水、饱和NaHCO3、和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。用己烷研制,得白色固体标题化合物粗品(9.71g,98%)。TLC(EtOAc-己烷;1∶1)Rf=0.63。
步骤C:(3S)-3-[(N-苄氧基羰基)缬氨酰]氨基-5-(2’,3’,5’,6’-
四氟苯氧基)-4-氧代戊酸叔丁酯
室温、氮气氛下,向(3S)-3-[(N-苄氧基羰基)缬氨酰]氨基-5-溴-4-氧代戊酸叔丁酯(9.71g,19.4mmol)和2,3,5,6-四氟苯酚(3.65g,22mmol)在四氢呋喃(20mL)中的溶液中加入氟化钾(2.91g,50mmol)。室温搅拌4小时后,混合物加EtOAc(约100mL)稀释,用饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶快速色谱纯化,以EtOAc-己烷(1∶3)洗脱,在用Et2O-己烷研制后得到白色固体标题化合物(9.19g,79%)。TLC(EtOAc-己烷;1∶1)Rf=0.70。
步骤D:(3S,4RS)-3-[(N-苄氧基羰基)缬氨酰]氨基-5-
(2’,3’,5’,6-四氟苯氧基)-4-羟基戊酸叔丁酯
在0℃和氮气氛下,向(3S)-3-[(N-苄氧基羰基)缬氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸叔丁酯(9.19g,15.7mmol)在MeOH(200mL)/四氢呋喃(200mL)中的溶液内加入硼氢化钠(0.594g,15.7mmol)。0℃搅拌1小时后,浓缩混合物,将残留物分配到EtOAc-半饱和NH4Cl溶液中。有机相用饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶快速色谱纯化,以EtOAc-己烷(1∶3)洗脱,得白色固体标题化合物(7.99g,87%)。TLC(EtOAc-己烷;1∶1)Rf=0.54。
步骤E:(3S,4RS)-3-(缬氨酰)氨基-5-(2’,3’,5’,6-四氟苯氧
基)-4-羟基戊酸叔丁酯
向(3S,4RS)-3-[(N-苄氧基羰基)缬氨酰]氨基-5-(2’,3’,5’,6-四氟苯氧基)-4-羟基戊酸叔丁酯(7.99g,13.6mmol)的MeOH(130mL)溶液中加入10%Pd-C(0.80g),并在氢气氛围(气球)中搅拌形成的混合物2小时。然后通过Celite过滤混合物,滤饼用二氯甲烷洗涤,蒸发合并的滤液至干。残留物用硅胶快速色谱纯化,先以EtOAc-己烷(1∶3)洗脱,后用甲醇洗脱,得到粘稠油状标题化合物(5.13g,83%)。TLC(EtOAc-己烷;1∶1)Rf=0.07。
步骤F:(3S,4RS)-3-[N-(N’-(1-萘基甲基)草氨酰)缬氨酰]氨
基-5-(2’,3’,5’,6-四氟苯氧基)-4-羟基戊酸叔丁酯
室温、氮气氛下,向N-(1-萘甲基)草氨酸(0.051g,0.22mmol,以1-萘基甲胺为原料按实施例1,步骤A所述方法制得)在N-甲基吡咯烷酮(1.0mL)-CH2Cl2(1.0mL)中的溶液内加入六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓(0.092g,0.24mmol)。搅拌15分钟后,将混合物用(3S,4RS)-3-(缬氨酰)氨基-5-(2’,3’,5’,6-四氟苯氧基)-4-羟基戊酸叔丁酯(0.100g,0.22mmol)和二异丙基乙胺(115μL,0.66mmol)。室温搅拌16小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤。无水硫酸钠干燥,蒸发得到标题化合物粗品(0.157g,100%),为粘稠油体。TLC(EtOAc-己烷;1∶1)Rf=0.44。
步骤G:(3S)-3-[N-(N’-(1-萘基甲基)草氨酰)缬氨酰]氨基-5-
(2’,3’,5’,6-四氟苯氧基)-4-氧代戊酸叔丁酯
室温、氮气氛下,向(3S,4RS)-3-[N-(N’-(1-萘基甲基)草氨酰)缬氨酰]氨基-5-(2’,3’,5’,6-四氟苯氧基)-4-羟基戊酸叔丁酯(0.157g,约0.22mmol)的二甲亚砜(5mL)溶液中加入Dess-MartinPeriodinane(0.600g,1.42mmol)。室温搅拌16小时后,将混合物分配到EtOAc-水中。有机相用饱和NaHCO3和饱和NaCl溶液洗涤。无水硫酸钠干燥,蒸发至干。残留物(0.175g)用硅胶快速色谱纯化,以EtOAc-己烷(3∶7)纯化,得白色固体标题化合物(0.111g,77%).TLC(EtOAc-己烷;1∶1)Rf=0.58,
步骤H:(3S)-3-[N-(N’-(1-萘基甲基)草氨酰)缬氨酰]氨基-5-
(2’,3’,5’,6-四氟苯氧基)-4-氧代戊酸
室温、氮气氛下,向(3S)-3-[N-(N’-(1-萘基甲基)草氨酰)缬氨酰]氨基-5-(2’,3’,5’,6-四氟苯氧基)-4-氧代戊酸叔丁酯(0.108g,0.16mmol)在CH2Cl2(2.0mL)-茴香醚(0.1mL)-水(0.05mL)中的溶液内加入三氟乙酸(2.0mL)。室温搅拌所得清亮溶液2小时,蒸发至干,用甲苯-CH2Cl2(1∶1)研磨。残留物用Et2O研制,得白色固体标题化合物(0.098g,100%)。MS(ES)C29H27F4N3O7(MW 605.54):正离子628(M+Na);负离子604(M-H)。
实施例79-125
以(3S,4RS)-3-(缬氨酰)氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(见实施例78,步骤E)为原料,按照实施例78,步骤F-H中描述的方法,还可以制备下表6中所列化合物:
表6
MS(ES) | |||||
Ex. | R1 | 分子式 | MW | 正离子 | 负离子 |
79 | PhCH2 | C25H25F4N3O7 | 555.48 | 556(M+H)578(M+Na) | 554(M-H) |
80 | Ph(CH2)2 | C26H27F4N3O7 | 569.51 | 592(M+Na) | 568(M-H) |
81 | Ph2CH | C31H29F4N3O7 | 631.58 | 654(M+Na) | 630(M-H) |
82 | Ph | C24H23F4N3O7 | 541.46 | 564(M+Na) | 540(M-H) |
83 | (2-Ph)Ph | C30H27F4N3O7 | 617.55 | 640(M+Na) | 616(M-H)730(M+TFA) |
84 | (2-PhCH2)Ph | C31H29F4N3O7 | 631.58 | 654(M+Na) | 630M-H) |
85 | (3-PhO)Ph | C30H27F4N3O8 | 633.55 | 634(M+H)656(M+Na) | 632(M-H) |
86 | 4-Cl-1-萘基 | C28H24CIF4N3O7 | 625.96 | 648/650(M+Na) | 624/626(M-H) |
87 | 2-蒽基 | C32H27F4N3O7 | 641.57 | 642(M+H) | 640(M-H) |
88 | 2-苯并咪唑基 | C25H23F4N5O7 | 581.48 | 582(M+H)604(M+Na) | 580(M-H) |
89 | 1-金刚烷基 | C28H33F4N3O7 | 599.58 | 600(M+H) | 598(M-H) |
90 | (2-F)Ph | C24H22F5N3O7 | 559.45 | 582(M+Na) | 558(M-H)672(M+TFA) |
91 | (4-F)Ph | C24H22F5N3O7 | 559.45 | 582(M+Na) | 558(M-H)672(M+TFA) |
92 | (2-CF3)Ph | C25H22F7N3O7 | 609.45 | 632(M+Na) | 608(M-H)722(M+TFA) |
93 | (2-t-Bu)Ph | C28H31F4N3O7 | 597.56 | 620(M+Na) | 596(M-H)710(M+TFA) |
94 | (4-正庚基)Ph | C31H37F4N3O7 | 639.64 | 662(M+Na) | 638(M-H) |
95 | (2-CH3O)Ph | C25H25F4N3O8 | 571.48 | 594(M+Na) | 570(M-H) |
96 | (2-PhO)Ph | C30H27F4N3O8 | 633.55 | 656(M+Na) | 632(M-H)746(M+TFA) |
97 | 2-萘基 | C28H25F4N3O7 | 591.51 | 614(M+Na) | 590(M-H) |
MS(ES) | |||||
Ex. | R1 | 分子式 | MW | 正离子 | 负离子 |
98 | 5,6,7,8-四氢-1-萘基 | C28H29F4N3O7 | 595.55 | 618(M+Na) | 594(M-H) |
99 | 1-蒽基 | C32H27F4N3O7 | 641.57 | 664(M+Na) | 640(M-H) |
100 | 2-吡啶基 | C23H22F4N4O7 | 542.44 | 543(M+H) | 541(M-H) |
101 | 4-吡啶基 | C23H22F4N4O7 | 542.44 | 543(M+H) | 541(M-H) |
102 | 2,3,5,6,-四氟 -4-吡啶基 | C23H18F8N4O7 | 614.40 | 615(M+H) | 613(M-H) |
103 | 2-吡嗪基 | C22H21F4N5O7 | 543.43 | 544(M+H) | 542(M-H) |
104 | 1,2,3,4-四氢-1-萘基 | C28H29F4N3O7 | 595.55 | 596(M+H)618M+Na)634(M+K) | 594(M-H)708(M+TFA) |
105 | (2-Cl)Ph | C24H22ClF4N3O7 | 575.90 | 598/600(M+Na) | 574/576(M-H) |
106 | (2-Br)Ph | C24H22BrF4N3O7 | 620.35 | 644/642(M+Na) | 620/618(M-H)734/732(M+TFA) |
107 | (2-I)Ph | C24H22F4IN3O7 | 667.35 | 690(M+Ma)706(M+K) | 666(M-H)780(M+TFA) |
108 | (2,6-di-F)Ph | C24H22F6N3O7 | 577.44 | 600(M+Na) | 576(M-H)690(M+TFA) |
109 | (2,5-di-t-Bu)Ph | C32H39F4N3O7 | 653.67 | 654(M+H)676(M+Na)692(M+K) | 652(M-H)688(M+C)766(M+TFA) |
110 | 2,3-二氢茚-5-基 | C27H27F4N3O7 | 581.52 | 604(M+Na)620(M+K) | 580(M-H)694(M+TFA) |
111 | (3,4,5-tri-MeO)PhCH2 | C28H31F4N3O10 | 645.56 | 646(M+H)668(M+Na)684(M+K) | 644(M-H) |
112 | 甲基 | C19H21F4N3O7 | 479.38 | 502(M+Na) | 478(M-H)592(M+TFA) |
113 | 正庚基 | C25H33F4N3O7 | 563.55 | 586(M+Na)602(M+K) | 562(M-H)676(M+TFA) |
114 | 叔辛基 | C26H35F4N3O7 | 577.57 | 600(M+Na) | 576(M-H) |
115 | 环己基 | C24H29F4N3O7 | 547.50 | 548(M+H)570(M+Na)586(M+K) | 546(M-H)660(M+TFA) |
116 | 5-Ph-3-吡唑基 | C27H25F4N5O7 | 607.52 | 630(M+Na)646(M+K) | 606(M-H) |
117 | (2-F-4-I)Ph | C24H21F5IN3O7 | 685.34 | 686(M+H)708(M+Na)724(M+K) | 684(M-H)720(M+Cl) |
MS(ES) | |||||
Ex. | R1 | 分子式 | MW | 正离子 | 负离子 |
118 | (2,3,4,5-tetra-F)Ph | C24H19F8N3O7 | 613.41 | 614(M+H)636(M+Na)652(M+K) | 612(M-H)726(M+TFA) |
119 | (2,3,4,6-tetra-F)Ph | C24H19F8N3O7 | 613.41 | 614(M+H)636(M+Na)652(M+K) | 612(M-H)726(M+TFA) |
120 | (2,3,5,6-tetra-Cl)Ph | C24H19Cl4F4N3O7 | 679.23 | 700/702/704(M+Na)716/718/720(M+K) | 676/678/680(M-H)790/792/794(M+TFA) |
121 | (2,3,4,5,6-penta-F)Ph | C24H18F9N3O7 | 631.40 | 654(M+Na)670(M+K) | 630(M-H)666(M+Cl) |
122 | Ph2N | C30H28F4N4O7 | 632.57 | 633(M+H)655(M+Na) | 631(M-H)745(M+TFA) |
123 | PHCH2(Ph)N | C31H30F4N4O7 | 646.59 | 647(M+H)669(M+Na)685(M+K) | 645(M-H)681(M+Cl) |
124 | PhCH2O | C25H25F4N3O7 | 571.48 | 594(M+Na) | 570(M-H)684(M+TFA) |
125 | 5-喹啉基 | C29H25F7N4O9 | 706.53 | 593(M+H) | 591(M-H) |
实施例126
(3S)-3-[N-(N’-(2-叔丁基苯基)草氨酰)丙氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
步骤A:[(N-苄氧基羰基)丙氨酰]天冬氨酸,β-叔丁基酯
室温、氮气氛下,向天冬氨酸β-叔丁酯(3.784g,20mmol)的二甲基甲酰胺(150mL)悬浮液中加入双(三甲基甲硅烷基)-三氟乙酰胺(10.6mL,40mmol)。室温搅拌30分钟后,将所形成的清亮溶液用(N-苄氧基羰基)丙氨酸N-羟基琥珀酰亚胺酯(6.406g,20mmol)处理。在室温下另搅拌48小时后,混合物用水(20mL)处理,搅拌15分钟,然后分配到EtOAc/水中。有机相用水、5%KHSO4和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。将残留物溶于Et2O,用饱和NaHCO3萃取。含水萃取物用浓盐酸酸化(pH2.0),继用EtOAc萃取。EtOAc萃取液用饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到白色泡沫体标题化合物(6.463g,82%)。TLC(EtOAc-己烷-AcOH;70∶30∶2)Rf=0.50。
步骤B:(3S,4RS)-3-(丙氨酰)氨基-5-(2’,3’,5’,6’-四氟苯氧
基)-4-羟基戊酸叔丁酯
以[(N-苄氧基羰基)丙氨酰]天冬氨酸,β-叔丁酯为原料,按照实施例28,步骤B-E中描述的方法,制得无色、粘稠油状标题化合物。TLC(EtOAc-己烷;1∶1)Rf=0.06。
步骤C:(3S,4RS)-3-[N-(N’-(2-叔丁基苯基)草氨酰)丙氨酰]氨
基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯
0℃、氮气氛下,向N-(2-叔丁基苯基)草氨酸(0.041g,0.19mmol,以2-叔丁基苯胺为原料按照实施例1,步骤A中描述的方法制备)的二氯甲烷(6.0mL)溶液中顺序加入羟基苯并三唑水合物(0.030g)和1-乙基-3-(3’,3’-二甲基-1’-氨基丙基)-碳二亚胺盐酸盐(0.050g,0.26mmol)。0℃搅拌10分钟后,混合物用(3S,4RS)-3-(丙氨酰)氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(0.079g,0.19mmol)和N-甲基吗啉(22μL,0.20mmol)处理。室温搅拌16小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到粘稠油状标题化合物粗品(0.090g,77%)。TLC(EtOAc-己烷;1∶1)Rf=0.70。
步骤D:(3S)-3-[N-(N’-(2-叔丁基苯基)草氨酰)丙氨酰]氨基-5-
(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸叔丁酯
在室温和氮气氛下,向(3S,4RS)-3-[N-(N’-(2-叔丁基苯基)草氨酰)丙氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(0.0.092g,约0.15mmol)的二氯甲烷(6.5mL)溶液中依次加入碘苯二乙酸酯(iodobenzene diacetate)(0.188g,0.58mmol)和催化量的2,2,6,6-四甲基-1-哌啶氧基游离基(TEMPO,0.0046g,0.03mmol)。室温搅拌16小时后,将混合物分配到EtOAc-水中。有机相用饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶制层色谱纯化,以EtOAc-己烷(3∶7)洗脱,得无色玻璃体标题化合物(0.071g,77%)。TLC(EtOAc-己烷;2∶3)Rf=0.60。
步骤E:(3S)-3-[N-(N’-(2-叔丁基苯基)草氨酰)丙氨酰]氨基-5-
(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
在室温和氮气氛下,向(3S)-3-[N-(N’-(2-叔丁基苯基)草氨酰)丙氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸叔丁酯(0.071g,0.11mmol)在CH2Cl2(2.5mL)-茴香醚(0.05mL)中的溶液内加入三氟乙酸(1.5mL)。室温搅拌所形成的清澈溶液1小时,蒸发至干,用甲苯-CH2Cl2(1∶1)研磨。残留物(0.061g)用硅胶制层色谱纯化,以MeOH-CH2Cl2(1∶9)洗脱,得到无色玻璃体标题化合物(0.044g,69%)。MS(ES)C26H27F4N3O7(MW 569.51):正离子570(M+H);负离子568(M-H)。
实施例127-178
以(3S,4RS)-3-(丙氨酰)氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(见实施例79,步骤B)为原料,按照实施例79,步骤C-E中描述的方法,还可以制备下表7中所列化合物:
表7
MS(ES) | |||||
Ex. | R1 | 分子式 | MW | 正离子 | 负离子 |
127 | (2-CF3)Ph | C23H18F7N3O7 | 581.40 | 604(M+Na) | 580(M-H) |
128 | (2-Ph)Ph | C28H23F4N3O7 | 589.50 | 612(M+Na) | 588(M-H) |
129 | (2-PhCH2)Ph | C29H25F4N3O7 | 603.53 | 604(M+H) | 602(M-H) |
130 | (2-PhO)Ph | C28H23F4N3O8 | 605.50 | 628(M+Na) | 604(M-H) |
131 | (3-PhO)Ph | C28H23F4N3O8 | 605.50 | 628(M+Na) | 604(M-H) |
132 | 5,6,7,8-四氢-1-萘基 | C26H25F4N3O7 | 567.49 | 590(M+Na) | 566(M-H) |
133 | 1-萘基 | C26H21F4N3O7 | 563.46 | 586(M+Na)608(M+K) | 562(M-H) |
134 | Ph | C22H19F4N3O7 | 513.40 | 552(M+K) | 512(M-H) |
135 | (2,6-di-F)Ph | C22H17F6N3O7 | 549.38 | 572(M+Na) | 548(M-H)662(M+TFA) |
136 | (4-Ph)Ph | C28H23F4N3O7 | 589.50 | - | 588(M-H) |
137 | (4-MeO)Ph | C23H21F4N3O8 | 543.43 | 582(M+K) | 542(M-H) |
138 | Ph2CH | C29H25F4N3C7 | 603.53 | 642(M+K) | 602(M-H) |
139 | 4-吡啶基 | C22H20F4N4O9 | 560.42 | 515(M+H) | 513(M+H)) |
140 | 2-吡啶基 | C21H18F4N4O7 | 514.39 | 515(M+H) | |
141 | (2-Cl)Ph | C22H18CIF4N3O7 | 547.85 | ||
142 | (2,3,4,5-tetra-Cl)Ph | C22H15F8N3O7 | 585.36 | 584(M-H) | |
143 | 2,3-二氢化茚-5-基 | C25H23F4N3O7 | 553.47 | 552(M-H) | |
144 | (2-Br)Ph | C22H18BrF4N3O7 | 592.30 | 590/592(M-H) | |
145 | (2,3,5,6-tetra-F)Ph | C22H15Cl4F4N3O7 | 651.18 | 648/650/652(M-H) | |
146 | 1-蒽基 | C30H23F4N4O7 | 613.52 | 636(M+Na) | 612(M-H) |
147 | PhCH2 | C23H21F4N3O7 | 527.43 |
MS(ES) | |||||
Ex. | R1 | 分子式 | MW | 正离子 | 负离子 |
148 | Ph(CH2)2 | C24H23F4N3O7 | 541.46 | 542(M+H)564(M+Na) | 540(M-H) |
149 | (2-F)Ph | C22H18F5N3O7 | 531.39 | 554(M+Na) | 530(M-H) |
150 | (4-F)Ph | C22H18F5N3O7 | 531.39 | 554(M+Na) | 530(M-H) |
151 | (2-吡咯烷-1-基)Ph | C28H27F7N4O9 | 696.53 | 583(M+H) | 581(M-H)695(M+TFA) |
152 | (2-吗啉-4-基)Ph | C28H27F7N4O10 | 712.53 | 599(M+H) | 597(M-H)711(M+TFA) |
153 | (2-吗啉-4-基--5-三氟甲基)Ph | C29H26F10N4O10 | 780.53 | 689(M+Na) | 664(M-H) |
154 | (2-吡咯烷-1-基-5-三氟甲基)Ph | C29H26F10N4O9 | 764.53 | 651(M+H)673(M+Na) | 649(M-H) |
155 | PhCH2 | C23H21F4N3O7 | 527.43 | 594(M+Na) | 590(M-H) |
156 | 金刚烷-1-基 | C26H29F4N3O7 | 571.52 | 594(M+Na) | 570(M-H) |
157 | 环己基 | C22H25F4N3O7 | 519.45 | 558(M+K) | 518(M-H) |
158 | (2-Cl)Ph | C22H18ICF4N3O7 | 547.85 | 570/572(M+Na) | 546/548(M-H) |
159 | (2,5,di-t-Bu)Ph | C30H35F4N3O7 | 625.61 | ||
160 | 1,2,3,4-四氢萘-1-基 | C26H25F4N3O7 | 567.49 | 590(M+Na) | 566(M-H) |
161 | (4-正庚基)Ph | C29H33F4N3O7 | 611.49 | 634(M+Na) | 610(M-H) |
162 | (2-I)Ph | C22H18F4IN3O7 | 639.30 | 662(M+Na) | 638(M-H) |
163 | 萘-1-基甲基 | C27H23F4N3O7 | 577.49 | 600(M+Na) | 576(M-H) |
164 | 吡咯烷-1-基 | C20H22F4N4O7 | 506.14 | 507.22(M+H) | |
165 | 1-吡咯烷 | C20H21F4N3O7 | 491.13 | 509(M+NH4)492(M+H) | |
166 | 1-哌啶 | C21H23F4N3O7 | 505.15 | 504(M+H) | |
167 | 哌啶-1-基 | C23H28F4N4O9 | 580.18 | 519(M-H) | |
168 | (2-tBu-5-AcNH)Ph | C28H30F4N4O8 | 626.2 | 625(M-H) | |
169 | (2-tBu-5-NH(CO(CH2)3NHGmoc)Ph | C45H45F4N5O10 | 891.31 | 890(M-H) | |
170 | (2,3,5,6-tetra-F)Ph | C21H16F8N4O6 | 572.09 | 573(M+H) | |
171 | (2-(3-CH3O-Ph))Ph | C29H25F4N3O8 | 619.16 | 642(M+Na) | 618(M-H) |
172 | (2-(4-CH3O-Ph))Ph | C29H25F4N3O8 | 619.16 | 620(M+H) | 618(M-H) |
MS(ES) | |||||
Ex. | R1 | 分子式 | MW | 正离子 | 负离子 |
173 | (2-(2-CH3O-Ph))Ph | C29H25F4N3O8 | 619.16 | 620(M+H) | 618(M-H) |
174 | (2-(1-萘基))Ph | C32H25F4N3O7 | 639.55 | 662(M+Na) | 638(M-H) |
175 | [2-{(3-CH3)Ph}]Ph | C29H25F4N3O7 | 603.19 | 626(M+Ha) | 602(M-H) |
176 | [2-{(4-CH3)Ph}]Ph | C29H25F4N3O7 | 603.19 | 626(M+Na) | 602(M-H) |
177 | [2-{(2-CH3)Ph}]Ph | C29H25F4N3O7 | 603.19 | 626(M+Na) | 602(M-H) |
实施例178
(3S)-3-[N-(N’-(2’-苯氧基苯基)草氨酰)环己基丙氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
步骤A:(3S)-3-(N-苄氧基羰基)氨基-5-溴-4-氧代戊酸叔丁酯
在-10℃(NaCl/冰浴)和氮气氛下,通过注射器滴加氯甲酸异丁酯(1.1mL,8.5mmol)处理(N-苄氧基羰基)天冬氨酸,β-叔丁酯(2.28g,7.06mmol)和N-甲基吗啉(0.85mL,7.7mmol)在四氢呋喃(40mL)中的溶液。在-10℃搅拌20分钟后,通过过滤(烧结玻璃)将混合物滤入到预冷却的接收器中(冰浴),滤饼另用四氢呋喃(约10mL)洗涤。合并的滤液在0℃(冰浴)和氮气氛下用过量的重氮甲烷/Et2O溶液(由3.10g,21mmol的1-甲基-3-硝基-1-亚硝基胍,20mL 40%KOH/10mL Et2O制得)处理。在0℃搅拌15分钟和室温搅拌30分钟后,再次冷却反应混合物到0℃,用48%的HBr(2.0mL,12mmol)/乙酸(2.0mL)处理。于0℃搅拌15分钟和室温搅拌15分钟后,将混合物分配到EtOAc-水中。有机相用水、饱和NaHCO3、和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。己烷研制后得到黄色油状标题化合物粗品(3.32g)。TLC(EtOAc-己烷;1∶1)Rf=0.60(中间体重氮酮Rf=0.52)。
步骤B:(3S,4RS)-3-(N-苄氧基羰基)氨基-5-(2’,3’,5’,6’-四氟
苯氧基)-4-羟基戊酸叔丁酯
在室温和氮气氛下,向(3S)-3-(N-苄氧基羰基)氨基-5-溴-4-氧代戊酸叔丁酯(0.857g,2.14mmol)和2,3,5,6-四氟苯酚(0.410g,2.45mmol)在二甲基甲酰胺(5.0mL)中的溶液内加入氟化钾(0.40g,6.9mmol)。室温搅拌16小时后,混合物加EtOAc稀释,继用饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到粗制四氟苯氧基甲基酮(1.08g,98%),为黄色、粘稠油体。TLC(EtOAc-己烷;1∶1)Rf=0.57。
在0℃和氮气氛下,向上述酮粗品(1.08g,约2.14mmol)的乙醇(10mL)溶液中加入硼氢化钠(0.057g,1.5mmol)。0℃搅拌1小时后,通过用丙酮(1.0mL)处理分解过量的还原剂,浓缩混合物,将残留物分配到EtOAc-半饱和NH4Cl溶液中。有机相用饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶快速色谱纯化,以EtOAc-己烷(1∶3)洗脱,得无色油体标题化合物(1.012g,94%).TLC(EtOAc-己烷;1∶1)Rf=0.48。
步骤C:(3S,4RS)-3-[(N-9-芴基甲氧基羰基)环己基丙氨酰]氨
基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯
向(3S,4RS)-3-(N-苄氧基羰基)氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(1.012g,2.08mmol)的MeOH(25mL)溶液中加入10%Pd-C(0.30g),在气球氛围(气球)中搅拌所形成的混合物4小时。混合物通过Celite过滤,滤饼用二氯甲烷洗涤,蒸发合并的滤液,得到胺粗品(0.682g,93%),为粘稠油体.TLC(MeOH-CH2Cl2;5∶95)Rf=0.21。
在0℃(冰浴)和氮气氛下,向(N-9-芴基甲氧基羰基)环己基丙氨酸(0.763g,1.94mmol)的二氯甲烷(10mL)溶液中顺序加入羟基苯并三唑水合物(0.282g)和1-乙基-3-(3’,3’-二甲基-1’-氨基丙基)碳二亚胺盐酸盐(0.447g,2.33mmol)。0℃搅拌10分钟后,混合物用上述粗制胺(0.682g,约1.93mmol)处理,并温热反应到室温。室温搅拌3小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用快速色谱纯化,以EtOAc-己烷(1∶2)洗脱,得黄色泡沫状标题化合物(1.028g,73%)。TLC(EtOAc-己烷;1∶2)Rf=0.20。
步骤D:(3S,4RS)-3-[N-环己基丙氨酰]氨基-5-(2’,3’,5’,6’-四
氟苯氧基)-4-羟基戊酸叔丁酯
在室温和氮气氛下搅拌(3S,4RS)-3-[(N-9-芴基甲氧基羰基)环己基丙氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(1.028g,1.4mmol)和10%哌啶/二甲基甲酰胺(3.0mL)构成的混合物2小时。混合物加二氯甲烷稀释,用水和饱和NaHCO3溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用快速色谱纯化,以异丙醇-CH2Cl2(7∶93)洗脱,得白色固体标题化合物(0.561g,78%)。TLC(MeOH-CH2Cl2;5∶95)Rf=0.43。
步骤E:(3S,4RS)-3-[N-(N’-(2’-苯氧基苯基)草氨酰)环己基丙
氨酰)氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯
在0℃(冰浴)和氮气氛下,向N-(2-苯氧基苯基)草氨酸(0.064g,0.25mmol,以2-苯氧基丙氨酸为原料按实施例1,步骤A的方法制得)和(3S,4RS)-3-[环己基丙氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(0.124g,0.245mmol)在CH2Cl2(5.0mL)形成的溶液内顺序加入羟基苯并三唑水合物(0.051g)和1-乙基-3-(3’,3’-二甲基-1’-氨基丙基)碳二亚胺盐酸盐(0.061g,0.32mmol)。0℃搅拌10分钟和室温搅拌18小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到标题化合物粗品(0.194g),为黄色泡沫物。TLC(EtOAc-己烷;1∶2)Rf=0.40。
步骤F:(3S)-3-[N-(N’-(2’-苯氧基苯基)草氨酰)环己基丙氨酰)
氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸叔丁酯
室温、氮气氛下,向(3S,4RS)-3-[N-(N’-(2’-苯氧基苯基)草氨酰)环己基丙氨酰)氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯粗品(0.194g,约0.245mmol)的二氯甲烷(5mL)溶液中加入Dess-Martin Periodinane(0.150g,0.35mmol)。室温搅拌2小时后,混合物加EtOAc稀释,继用1.0M Na2S2O3、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶快速色谱纯化,以EtOAc-己烷(1∶3)洗脱,得无色粘稠油体标题化合物(0.142g,80%)。TLC(EtOAc-己烷;1∶2)Rf=0.50。
步骤G:(3S)-3-[N-(N’-(2’-苯氧基苯基)草氨酰)环己基丙氨酰)
氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
室温、氮气氛下,向(3S)-3-[N-(N’-(2’-苯氧基苯基)草氨酰)环己基丙氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸叔丁酯(0.142g,0.19mmol)的CH2Cl2(2.0mL)溶液中加入三氟乙酸(1.0mL)。室温搅拌形成的清澈溶液0.5小时,蒸发至干,用甲苯-CH2Cl2(1∶1)研磨,得标题化合物(0.123g,93%),为白色泡沫物。MS(ES)C34H33F4N3O8(MW 687.64):正离子688(M+H),710(M+Na),726(M+K);负离子686(M-H),800(M+TFA)。
实施例179-181
以(3S,4RS)-3-[环己基丙氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(见实施例178,步骤D)为原料,按照实施例178,步骤E-G中描述的方法,也可以制得下表8中所列化合物:
表8
MS(ES) | |||||
Ex. | R1 | 分子式 | MW | 正离子 | 负离子 |
179 | (2-Ph)Ph | C34H33F4N3O7 | 671.64 | 672(M+H)694(M+Na) | 670(M-H)784(M+TFA) |
180 | (2-PhCH2)Ph | C35H35F4N3O7 | 685.67 | 708(M+Na) | 684(M-H)798(M+TFA) |
181 | 1-萘基 | C32H31F4N3O7 | 645.61 | 668(M+Na) | 644(M-H)758(M+TFA) |
实施例182
(3S)-3-[N-(N’-(5,6,7,8-四氢-1-萘基)草氨酰)环己基丙氨酰]氨基-5-(2’,6’-二氯苯甲酰氧基)-4-氧代戊酸
步骤A:天冬氨酸,β-叔丁基,α-甲基酯对-甲苯磺酸盐
0℃(冰浴)下,向N-(苄氧基羰基)-L-天冬氨酸,β-叔丁基酯(10.57g,32.7mmol)的甲醇(20mL)-CH2Cl2(30mL)溶液中分批加入2.0M的(三甲基甲硅烷基)重氮甲烷己烷溶液(20mL,40mmol)。0℃搅拌45分钟后,用甲酸(1.0mL)分解过量的试剂。混合物用饱和NaHCO3溶液洗涤,无水硫酸钠干燥,蒸发得到浅黄色油体(11.34g)。
将该粗产物(11.34g,约32.7mmol)溶于甲醇(100mL),用对甲苯磺酸-水合物(6.20g,32.6mmol)和10%Pd-C(0.5g)处理,在气球氛围(气球)中搅拌3小时。混合物通过Celite过滤,浓缩得白色固体标题化合物(12.68g)。
步骤B:[(N-苄氧基羰基)环己基丙氨酰]天冬氨酸,β-叔丁基,α-
甲基酯
在0℃(冰浴)和氮气氛下,向(N-苄氧基羰基)-环己基丙氨酸二环己基胺盐(0.866g,1.77mmol)的二氯甲烷(10mL)溶液中顺序加入羟基苯并三唑水合物(0.100g)和1-乙基-3-(3’,3’-二甲基-1’-氨基丙基)碳二亚胺盐酸盐(0.41g,2.14mmol)。于0℃搅拌10分钟后,混合物用天冬氨酸,β-叔丁基,α-甲基酯对甲苯磺酸盐(0.665g,1.77mmol)和N-甲基吗啉(0.2mL,1.8mmol)处理,并温热反应到室温。室温搅拌2.5小时后浓缩混合物,并将残留物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到-油体。经硅胶快速色谱纯化(以EtOAc-己烷(1∶3)洗脱),得粘稠油体标题化合物(0.764g,88%).TLC(EtOAc-己烷;1∶2)Rf=0.46。
步骤C:(3S)-3-[N-(N’-(5,6,7,8-四氢-1-萘基)草氨酰)环己基
丙氨酰]氨基-5-(2’,6’-二氯苯甲酰氧基)-4-氧代戊酸
以[(N-苄氧基羰基)环己基-丙氨酰基]天冬氨酸,β-叔丁基,α-甲基酯为原料,按照实施例4,步骤B-H中描述的通用方法制得白色固体标题化合物。MS(ES)C33H37Cl2N3O8(MW 674.58):正离子696/698(M+Na);负离子672/674(M-H),786/788(M+TFA)。
实施例183-189
以[(N-苄氧基羰基)环己基-丙氨酰基]天冬氨酸,β-叔丁基,α-甲基酯为原料(见实施例182,步骤B),按照实施例4,步骤B-H中描述的通用方法,也可以制得下表9中所示的化合物:
表9
MS(ES) | ||||||
Ex. | R1 | B | 分子式 | MW | 正离子 | 负离子 |
183 | 5,6,7,8-四氢-1-萘基 | CH2O(2,3,5,6-tetra-F-Ph) | C32H35F4N3O7 | 649.64 | 672(M+Na) | 648(M-H) |
184 | 5,6,7,8-四氢-1-萘基 | CH2OPO(Me)Ph | C33H42N3O8P | 639.68 | 662(M+Na) | 638(M-H)752(M+TFA) |
185 | 5,6,7,8-四氢-1-萘基 | CH2OPOPh2 | C38H44N3O8P | 701.75 | 724(M+Na)740(M+K) | 700(M+H) |
186 | (2-PhCH2)Ph | CH2OPO(Me)Ph | C36H42N3O8P | 675.72 | 698(M+Na)714(M+K) | 674(M-H)788(M+TFA) |
187 | (2-PhCH2)Ph | CH2OPOPh2 | C41H44N3O8P | 737.79 | 760(M+Na)776(M+K) | 736(M-H)850(M+TFA) |
188 | (2-Ph)Ph | CH2OPO(Me)Ph | C40H42N3O8P | 661.68 | 684(M+Na)700(M+K) | 66(M-H)774(M+TFA) |
189 | (2-Ph)Ph | CH2OPOPh2 | C35H40N3O8P | 723.75 | 746(M+Na)762(M+K) | 722(M-H)836(M+TFA) |
实施例190
(3S)-3-[N-(N’-(1-萘基)草氨酰)高脯氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
步骤A:[N-(1-萘基)草氨酰]高脯氨酸
在室温和氮气氛下,向N-(1-萘基)草氨酸(0.108g,0.50mmol,见实施例1,步骤A)在N-甲基吡咯烷酮(1.0mL)-CH2Cl2(1.0mL)中的溶液内加入六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓(0.209g,0.55mmol)。搅拌20分钟后,混合物用高脯氨酸甲酯(0.072g,0.50mmol)和二异丙基乙胺(0.26mL,1.5mmol)处理。室温搅拌4小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到[N-(1-萘基)草氨酰]高脯氨酸粗品(0.156g,92%),为无色玻璃体。TLC(EtOAc-己烷;1∶1)Rf=0.70。
向上述粗制甲酯(0.156g,约0.46mmol)的二噁烷(0.75mL)-水(0.25mL)溶液中加入1.0 N LiOH溶液(0.5mL,0.5mmol)。室温搅拌1小时后,混合物用1.0 N HCl酸化,继用EtOAc萃取。萃取物用饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发,经乙醚研制后得到白色固体标题化合物(0.105g,70%)。
步骤B:(3S,4RS)-3-[N-(N’-(1-萘基)草氨酰)高脯氨酰基]氨
基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯
在0℃和氮气氛下,向[N-(1-萘基)草氨酰]高脯氨酸(0.483g,1.48mmol)的N-甲基吡咯烷酮(0.5mL)-CH2Cl2(14mL)溶液中加入六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓(0.676g,1.78mmol)。搅拌20分钟后,混合物依次用(3S,4RS)-3-氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(0.540g,1.54mmol,见实施例49,步骤C)的二氯甲烷(4.0mL)溶液和二异丙基乙胺(0.50mL,2.9mmol)处理。0℃搅拌3小时和室温搅拌16小时之后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。经快速色谱纯化(以EtOAc-己烷(1∶2)洗脱),得褐色泡沫标题化合物(0.268g,27%)。TLC(EtOAc-己烷;1∶1)Rf=0.39。
步骤C:(3S)-3-[N-(N’-(1-萘基)草氨酰)高脯氨酰]氨基-5-
(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸叔丁酯
在室温和氮气氛下,向(3S,4RS)-3-[N-(N’-(1-萘基)草氨酰)高脯氨酰基]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(0.251g,0.38mmol)的二氯甲烷(4mL)溶液中加入Dess-MartinPeriodinane(0.201g,0.475mmol)。室温搅拌30分钟后加EtOAc稀释混合物,用1.0 M Na2S2O3、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶快速色谱纯化,先后以CH2Cl2-Et2O-己烷(1∶2∶2)、EtOAc-己烷(1∶2)洗脱,得白色泡沫体标题化合物(0.160g,64%)。TLC(EtOAc-己烷;1∶1)Rf=0.57。
步骤D:(3S,4RS)-3-[N-(N’-(1-萘基)草氨酰)高脯氨酰]氨基-
5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
在室温和氮气氛下,向(3S)-3-[N-(N’-(1-萘基)草氨酰)高脯氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸叔丁酯(0.152g,0.23 mmol)在CH2Cl2(1.0mL)-茴香醚(0.4mL)中的溶液内加入三氟乙酸(1.0mL)。室温搅拌所生成的清澈溶液1小时,然后蒸发至干,并用甲苯-CH2Cl2(1∶1)研磨。残留物用己烷研制,得灰白色固体标题化合物(0.103g,74%)。TLC(MeOH-CH2Cl2;1∶9)Rf=0.33.MS(ES)C29H25F4N3O7(MW 603.53):正离子626(M+Na);负离子602(M-H)。
实施例191
(3S)-3-[N-(N’-(1-萘基)草氨酰)-2,3-二氢吲哚-2-羰基]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
步骤A:[N-(1-萘基)草氨酰]-2,3-二氢吲哚-2-羧酸乙酯
0℃(冰浴)、氮气氛下,向N-(1-萘基)草氨酸(2.37g,11mmol,见实施例1,步骤A)在N-甲基吡咯烷酮(7.0mL)-CH2Cl2(40mL)中的溶液内加入1,1’-羰基二咪唑(1.96g,12.1mmol)。0℃搅拌1.5小时和室温搅拌0.5小时之后,加入(S)-2,3-二氢吲哚-2-羧酸乙酯盐酸盐(1.25g,5.5mmol)和二异丙基乙胺(1.1mL,6.4mmol)。在室温下搅拌18小时后,混合物加EtOAc稀释,依次用5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。粗产物经硅胶快速色谱纯化,以CH2Cl2-Et2O-己烷(1∶1∶3)洗脱,得标题化合物(0.472g,22%),为浅黄色油体。TLC(CH2Cl2-Et2O-己烷;1∶1∶3)Rf=0.48。
步骤B:(3S)-3-[N-(N’-(1-萘基)草氨酰)-2,3-二氢吲哚-2-羰基]
氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
以[N-(1-萘基)草氨酰]-2,3-二氢吲哚-2-羧酸乙酯为原料,按照实施例104,步骤A-D中描述的方法,制得标题化合物。MS(ES)C32H23F4N3O7(MW 637.54):正离子660(M+Na),676(M+K);负离子636(M-H),672(M+Cl),750(M+TFA)。
实施例192
(3S)-3-[N-(N’-(1-萘基)草氨酰)-环己基甘氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
步骤A:(3S,4RS)-3-[(N-9-芴基甲氧基羰基)环己基甘氨酰]氨
基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯
0℃(冰浴)、氮气氛下,向(N-9-芴基甲氧基羰基)环己基甘氨酸(0.514g,1.35mmol)和(3S,4RS)-3-氨基-5-(2’,3’,5,’6’-四氟苯氧基)-4-羟基戊酸叔丁酯(0.479g,1.36mmol,见实施例92,步骤C)在CH2Cl2(10ml)中的溶液内加入六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓(0.619g,1.62mmol)和二异丙基乙胺(0.47mL,2.7mmol)。0℃搅拌3小时后,温热反应到室温。在室温下搅拌16小时后,将混合物分配到EtOAc-水之间。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水Na2SO4干燥,蒸发至干。残留物经快速色谱纯化,以EtOAc-己烷(1∶2)洗脱,得白色固体标题化合物(0.481g,50%)。TLC(EtOAc-己烷;1∶2)Rf=0.42。
步骤B:(3S,4RS)-3-[环己基甘氨酰基]氨基-5-(2’,3’,5’,6’-四
氟苯氧基)-4-羟基戊酸叔丁酯
在氮气氛围中,室温搅拌(3S,4rs)-3-[(N-9-芴基甲氧基羰基)环己基甘氨酰基]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(0.478g,0.67mmol)在哌啶(0.1mL)/二甲基甲酰胺(2.0mL)中的溶液1小时。混合物加EtOAc稀释,用水和饱和NaCl溶液洗涤,无水Na2SO4干燥,蒸发至干。残留物经快速色谱纯化,以EtOAc-己烷(1∶2)洗脱,得到白色固体标题化合物(0.121g,45%)。TLC(MeOH-CH2Cl2;5∶95)Rf=0.38。
步骤C:(3S,4RS)-3-[N-(N’-(1-萘基)草氨酰)环己基甘氨酰]氨
基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯
0℃、氮气氛下,向N-(1-萘基)草氨酸(0.088g,0.41mmol,见实施例1,步骤A)和(3S,4RS)-3-(环己基甘氨酰)氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(0.110g,0.27mmol)在N-甲基吡咯烷酮(0.5mL)-CH2Cl2(3.0mL)中的溶液内加入六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓(0.125g,0.32mmol)和二异丙基乙胺(90μL,0.54mmol)。0℃搅拌3小时和室温搅拌16小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水Na2SO4干燥,蒸发至干。残留物通过硅胶快速色谱纯化,以EtOAc-己烷(1∶2)洗脱,得标题化合物(0.094g,50%),为白色泡沫体。TLC(EtOAc-己烷;1∶1)Rf=0.50。
步骤D:(3S)-3-[N-(N’-(1-萘基)草氨酰)环己基甘氨酰]氨基-5-
(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸叔丁酯
室温、氮气氛下,向(3S,4RS)-3-[N-(N’-(1-萘基)草氨酰)环己基甘氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(0.082g,0.12mmol)在CH2Cl2(1mL)-CH3CN(2mL)-DMSO(0.2mL)中的溶液内加入Dess-Martin Periodinane(0.145g,0.34mmol)。室温搅拌1小时后,混合物加EtOAc稀释,用1.0 M Na2S2O3、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物用硅胶快速色谱纯化,以EtOAc-己烷(1∶2,随后1∶1)洗脱,得标题化合物(0.068g,83%),为褐色泡沫物。TLC(EtOAc-己烷,1∶1)Rf=0.63。
步骤F:(3S,4RS)-3-[N-(N’-(1-萘基)草氨酰)环己基甘氨酰]氨
基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
室温、氮气氛下,向(3S)-3-[N-(N’-(1-萘基)草氨酰)环己基甘氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸叔丁酯(0.065g,0.23mmo1)的CH2Cl2(1.0mL)-茴香醚(0.2mL)溶液中加入三氟乙酸(1.0mL)。在室温下搅拌所形成的清亮溶液30分钟,蒸发至干,用甲苯-CH2Cl2(1∶1)研磨。残留物用Et2O研制,得灰白色固体标题化合物(0.034g,56%)。TLC(MeOH-AcOH-CH2Cl2;1∶1∶32)Rf=0.45。MS(ES)C31H29F4N3O7(MW 631.58):正离子654(M+Na);负离子630(M-H)。
实施例193-200
以(3S,4RS)-3-氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(见实施例178,步骤C)为原料,按照实施例192,步骤A-E描述的方法,同样还制得下表10中所示的化合物。
表10
MS(ES) | |||||
Ex. | A | 分子式 | MW | 正离子 | 负离子 |
193 | 正亮氨酸 | C29H27F4N3O7 | 605.54 | 628(M+Na)644(M+K) | 604(M-H)640(M+Cl)718(M+TFA) |
194 | (叔丁基)甘氨酸 | C29H27F4N3O7 | 605.54 | 606(M+H)628(M+Na)644(M+K) | 604(M-H)640(M+C)718(M+TFA) |
195 | (叔丁基)丙氨酸 | C20H29F4N3O7 | 619.57 | 620(M+H)642(M+Na)658(M+K) | 618(M-H)732(M+TFA) |
196 | 苯甘氨酸 | C31H23F4N3O7 | 625.53 | 626(M+H)648(M+Na)664(M+K) | 624(M-H)660(M+C)738(M+TFA) |
197 | 苯丙氨酸 | C32H25F4N3O7 | 639.56 | 640(M+H)662(M+Na)678(M+K) | 638(M-H)674(M+Cl)712(M+TFA) |
MS(ES) | |||||
Ex. | A | 分子式 | MW | 正离子 | 负离子 |
198 | 高苯丙氨酸 | C33H27F4N3O7 | 653.59 | 654(M+H)676(M+Na)692(M+K) | 652(M-H)688(M+Cl)766(M+TFA) |
199 | 1-氨基环戊烷羧酸 | C29H25F4N3O7 | 603.53 | 626(M+Na)642(M+K) | 602(M-H) |
200 | 组氨酸 | C29H23F4N5O7 | 629.15 | 630(M+H) | 28(M-H) |
实施例201
(3S)-3-[N-(N’-(1-萘基)草氨酰基)甲硫氨酰基(亚砜)]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
步骤A:(3S,4RS)-3-[N-(N’-(1-萘基)-草氨酰基)甲硫氨酰基]氨
基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯
以(N-9-芴基甲氧基羰基)甲硫氨酸为原料,按照实施例106,步骤A-C中描述的方法,同样也制得标题化合物.TLC(EtOAc-己烷;1∶2)Rf=0.39。
步骤B:(3S)-3-[N-(N’-(1-萘基)-草氨酰)甲硫氨酰(亚砜)]氨
基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸叔丁酯
室温、氮气氛下,向(3S,4RS)-3-[N-(N’-(1-萘基)草氨酰)甲硫氨酰]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-羟基戊酸叔丁酯(0.251g,0.37mmol)的CH2Cl2(4.0mL)溶液中加入Dess-MartinPeriodinane(0.203g,0.48mmol)。在室温下搅拌1小时后,加EtOAc稀释混合物,用1.0 M Na2S2O3、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发至干。残留物通过硅胶快速色谱纯化,先后以EtOAc-己烷)(1∶2,然后1∶1)、MeOH-CH2Cl2(5∶95,然后1∶9)洗脱,得两种亚砜异构体的混合物(0.225g);TLC(MeOH-CH2Cl2;1∶9)Rf 0.48和0.43。混合物再经硅胶色谱纯化,以异丙醇-CH2Cl2(2.5%-5%-10%)洗脱,得亚砜异构体A(低极性的,0.051g)、亚砜异构体B(高极性的,0.086g)以及异构体A与B的混合物(0.040g)。事实上,这两种异构体具有相同的质谱.MS(ES)C32H33F4N3O8S(MW 695.68):正离子718(M+Na);负离子694(M-H)。
步骤C:(3S,4RS)-3-[N-(N’-(1-萘基)-草氨酰)甲硫氨酰(亚砜)]
氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸
室温、氮气氛下,向(3S)-3-[N-(N’-(1-萘基)草氨酰)甲硫氨酰(亚砜)]氨基-5-(2’,3’,5’,6’-四氟苯氧基)-4-氧代戊酸叔丁酯(异构体A,0.046g,0.07mmol)的CH2Cl2(2.0mL)-茴香醚(0.1mL)溶液中加入三氟乙酸(1.0mL)。在室温下搅拌形成的清亮溶液30分钟,然后蒸发至干,用甲苯-CH2Cl2(1∶1)研磨。残留物用Et2O-己烷研制,得灰白色固体标题化合物,异构体A(0.034g,81%)。TLC(MeOH-AcOH-CH2Cl2;1∶1∶32)Rf=0.20.MS(ES)C28H25F4N3O8S(MW639.57):正离子640(M+H),678(M+K);负离子638(M-H),752(M+TFA).在同样的条件下,由亚砜异构体B(0.081g,0.12mmol)制得标题化合物,异构体B(0.055g,74%).MS(ES)C28H25F4N3O8S(MW 639.57):正离子640(M+H),662(M+Na),678(M+K);负离子638(M-H),674(M+Cl),752(M+TFA)。
实施例202
(3S)-3-[N-(N’-(1-萘基)草氨酰)高脯氨酰]氨基-4-氧代丁酸
步骤A:(3S)-3-[N-(N’-(1-萘基)-草氨酰)高脯氨酰]氨基-4-氧
代丁酸叔丁酯缩氨基脲
0℃、氮气氛下,向[N-(1-萘基)草氨酰]高脯氨酸(0.103g,0.32mmol,见实施例104,步骤A)的CH2Cl2(3.0mL)溶液中顺序加入羟基苯并三唑水合物(0.058g)和1-乙基-3-(3’,3’-二甲基)-1’-氨基丙基)碳二亚胺盐酸盐(0.91g,0.47mmol)。0℃搅拌10分钟后,混合物用(3S)-氨基-4-氧代丁酸叔丁酯缩氨基脲,对-甲苯磺酸盐(0.127g,0.32mmol)和N-甲基吗啉(42μL,0.38mmol)。0℃搅拌2小时后,浓缩混合物,将残留物分配到EtOAc-5%KHSO4中。有机相用5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水Na2SO4干燥,蒸发后得到无色玻璃状标题化合物(0.119g,70%)。
步骤B:(3S)-3-[N-(N’-(1-萘基)-草氨酰)高脯氨酰]氨基-4-氧
代丁酸缩氨基脲
室温、氮气氛下,向(3S)-3-[N-(N’-(1-萘基)草氨酰)高脯氨酰]氨基-4-氧代丁酸缩氨基脲叔丁酯(0.119g,0.21mmol)在CH2Cl2(2.0mL)-茴香醚(0.05mL)-水(0.05mL)中的溶液内加入三氟乙酸(0.32mL)。在室温下搅拌形成的清亮溶液18小时,蒸发至干,用甲苯-CH2Cl2(1∶1)研磨。残留物用Et2O研制,得白色固体标题化合物(0.079g,74%)。
步骤C:(3S)-3-[N-(N’-(1-萘基)-草氨酰)高脯氨酰]氨基-4-氧
代丁酸
在氮气氛围中室温搅拌(3S)-3-[N-(N’-(1-萘基)草氨酰)高脯氨酰]氨基-4-氧代丁酸缩氨基脲(0.079g,0.16mmol)在37%甲醛水溶液(0.6mL)-乙酸(0.6mL)-甲醇(1.8mL)中的悬浮液共计18小时。加水稀释形成的清亮溶液,混合物用旋转蒸发器浓缩。然后冷却并冻干水溶液。将残留物溶于甲醇,通过Celite过滤,蒸发滤液至干。残留物用Et2O研制,得白色固体标题化合物(0.037g,53%).MS(ES)C22H23N3O6(MW 425.44):正离子448(M+Na);负离子424(M-H)。
实施例203
(3S)-3-[N-(N’-(2-(1H-四唑-5-基)苯基)草氨酰)缬氨酰]氨基-4-氧代丁酸
步骤A:2-(1’-苯甲基-5’-四唑基)苯胺盐酸盐
加热回流2-氰基-N-乙酰苯胺(0.810g,5.0mmol)和叠氮化三正丁基锡(2.05mL,7.5mmol)在无水甲苯(10mL)中形成的溶液共计48小时。冷却混合物到室温,用2.0N HCl/Et2O(5.0mL)处理。抽滤收集产生的沉淀物,用己烷洗涤,真空干燥得到白色固体2-(1H-四唑-5-基)-N-乙酰苯胺(0.917g,90%)。
0℃、氮气氛下,向2-(1H-四唑-5-基)-N-乙酰苯胺(0.203g,1.0mmol)的四氢呋喃(2.0mL)悬浮液中加入三乙胺(0.170mL,1.2mmol)和苄基溴(0.125mL,1.05mmol)。0℃搅拌3小时和室温搅拌16小时后,将混合物分配到EtOAc-水之间。有机相用饱和NaHCO3和饱和NaCl溶液洗涤,无水Na2SO4干燥,蒸发至干。残留物用己烷研制,得白色固体2-(1’-苯甲基-5’-四唑基)-N-乙酰苯胺(0.218g,74%)。1H NMR表明产物为单一的区域异构体。区域化学的归属应认为是假定的。1H-NMR(CDCl3):δ2.22ppm(3H,s),5.84(2H,s),7.16(1H,dt,J=7.8,1.5Hz),7.40(6H,m),8.19(1H,dd,J=7.8,1.5Hz),8.63(1H,d,J=8.4Hz),10.58(1H,bs)。
回流由2-(1’-苯甲基-5’-四唑基)-N-乙酰苯胺(0.216g,0.74mmol)和10%盐酸水溶液(3.0mL)组成的混合物共计18小时。然后蒸发混合物至干,残留物用Et2O研制,得白色固体标题化合物(0.187g,88%)。
步骤B:N-[2-(1’-苯甲基-5’-四唑基)苯基]草氨酸
0℃(冰浴)、氮气氛下,向2-(1’-苯甲基-5’-四唑基)苯胺盐酸盐(0.177g,0.615mmol)、4-二甲氨基吡啶(0.008g,0.065mmol)和三乙胺(0.19mL,1.4mmol)在CH2Cl2(1.0mL)中的溶液内加入甲基草酰氯(62μL,0.67mmol)。0℃搅拌2小时后,使混合物温度自然回复到室温,搅拌18小时,然后分配到EtOAc-5%KHSO4之间。有机相用饱和NaCl溶液洗涤,无水Na2SO4干燥,蒸发至干。
将所得甲酯粗品(0.207g,约0.615mmol)溶于二噁烷(2.0mL),用1.0N LiOH溶液(0.68mL,0.68mmol)处理,在室温下搅拌1小时。混合物用1.0N HCl酸化,继用EtOAc萃取。萃取液用饱和NaCl溶液洗涤,无水Na2SO4干燥,蒸发至干。用己烷研制粗产物,得白色固体标题化合物(0.121g,61%)。
步骤C:(3S)-3-[N-(N’-(2-(1’-苯甲基-5’-四唑基)苯基)草氨酰)
缬氨酰]氨基-4-氧代丁酸缩氨基脲叔丁基酯
0℃、氮气氛下,向N-[2-(1’-苯甲基-5’-四唑基)苯基]草氨酸(0.065g,0.20mmol)的CH2Cl2(2.0mL)溶液中顺序加入羟基苯并三唑水合物(0.037g)和1-乙基-3-(3’,3’-二甲基-1’-氨基丙基)-碳二亚胺盐酸盐(0.058g,0.30mmol)。0℃搅拌10分钟后,混合物用(3S)-3-(缬氨酰)氨基-4-氧代丁酸叔丁酯缩氨基脲(0.066g,0.20mmol,按照实施例1,步骤B和C中制备相应亮氨酸类似物所述方法制备)和N-甲基吗啉(26μL,0.24mmol)。在室温下搅拌16小时后,将混合物分配到EtOAc-水之间。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水Na2SO4干燥,蒸发得到无色玻璃状标题化合物粗品(0.090g,62%)。
步骤D:(3S)-3-[N-(N’-(2-(1’H-5’-四唑基)苯基)草氨酰)缬氨
酰]氨基-4-氧代丁酸缩氨基脲叔丁基酯
向(3S)-3-[N-(N’-(2-(1’-苯甲基-5’-四唑基)苯基)草氨酰)缬氨酰]氨基-4-氧代丁酸缩氨基脲叔丁基酯粗品(0.089g,约0.14mmol)的MeOH(1.0mL)溶液中加入10%Pd-C(0.009g),在氢气氛围(气囊)中搅拌所得混合物48小时。混合物通过Celite过滤,滤饼用CH2Cl2洗涤,蒸发合并的滤液至干。残留物用Et2O研制,得白色固体标题产物(0.060g,79%)。
步骤E:(3S)-3-[N-(N’-(2-(1’H-5’-四唑基)苯基)草氨酰)缬氨
酰]氨基-4-氧代丁酸缩氨基脲
室温、氮气氛下,向(3S)-3-[N-(N’-(2-(1’H-5’-四唑基)苯基)草氨酰)缬氨酰]氨基-4-氧代丁酸叔丁基酯(0.058g,0.11mmol)的CH2Cl2(1.0mL)-茴香醚(0.05mL)溶液中加入6.0 M HCl/AcOH(1.0mL)。室温搅拌形成的溶液18小时,蒸发至干,用甲苯-CH2Cl2(1∶1)研磨。残留物用Et2O研制,得白色固体标题化合物(0.048g,92%)。
步骤F:(3S)-3-[N-(N’-(2-(1’H-5’-四唑基)苯基)草氨酰)缬氨
酰]氨基-4-氧代丁酸
室温下,在氮气氛围中搅拌由(3S)-3-[N-(N’-(2-(1’H-5’-四唑基)苯基)草氨酰)缬氨酰]氨基-4-氧代丁酸缩氨基脲(0.048g,0.10mmol)在37%甲醛水溶液(0.4mL)-乙酸(0.4mL)-甲醇(1.2mL)中形成的溶液共18小时。加水稀释产生的清亮溶液,混合物继用旋转蒸发器浓缩。然后冷冻水溶液,继而冻干。将残留物溶于甲醇,通过Celite过滤,并蒸发滤液至干。残留物用Et2O研制,得白色固体标题化合物(0.025g,59%).MS(ES)C18H21N7O6(MW 431.41):正离子454(M+Na);负离子430(M-H)。
实施例204
(3S)-3-[N-(N’-(1-金刚烷基)草氨酰)缬氨酰]氨基-4-氧代丁酸
步骤A:(3S)-3-[N-(9-芴基甲氧基羰基)缬氨酰]氨基-4-氧代丁
酸(叔丁基)酯缩氨基脲基-4-[2’-(4-乙基-苯氧基乙酰基)]氨基甲基
聚苯乙烯
在配有真空活塞和玻璃料的200mL滤管中放入氨甲基聚苯乙烯树脂(10.0g,100-200目,0.71meq/g),顺序用CH2Cl2(50-mL)/二甲基甲酰胺(50mL)、二异丙基乙胺(5mL)/二甲基甲酰胺(30mL)、二甲基甲酰胺(2×50mL)和四氢呋喃(30mL)洗涤。然后在通过吹入氮气搅动底部玻璃料情形下将树脂悬浮在四氢呋喃(20mL)/N-甲基吡咯烷酮(20mL)中,用二异丙基乙胺(1.9mL,10.9mmol)和(3S)-3-(9-芴基甲氧基羰基)氨基-4-氧代丁酸(叔丁基)酯缩氨基脲基-4-[2’-(4-乙基-苯氧基乙酸)](2.24g,3.56mmol)处理。待所有固体都溶解后(约10分钟),单批加入pyBOP[六氟磷酸苯并三唑氧基三(N-吡咯烷基)膦鎓,2.78g,5.34mmol)处理混合物。在通过氮气搅动混合3小时之后,吸出上清液,树脂依次用四氢呋喃(2×50mL)、二甲基甲酰胺(3×50mL)和CH2Cl2(2×50mL)处理。未反应的氨基通过用乙酐(10mL)/二甲基甲酰胺(30mL)/二异丙基乙胺(1.0mL)混合物处理封闭。在氮气搅动混合1小时后,吸出上清液,树脂用二甲基甲酰胺(4×50mL)洗涤。
树脂用哌啶(10mL)/二甲基甲酰胺(40mL)处理,并通过氮气搅动混合1小时。吸去上清液,树脂用二甲基甲酰胺(4×50mL)和四氢呋喃(50mL)处理。
将树脂悬浮在四氢呋喃(20mL)/N-甲基吡咯烷酮(20mL)中,用N-(9-芴基甲氧基羰基)缬氨酸(3.63g,10.7mmol)、二异丙基乙胺(5.7mL,32.7mmol)和pyBOP(8.34g,16.0mmol)处理,通过氮气搅动混合2.5小时。吸去上清液,树脂依次用二甲基甲酰胺(3×40mL)和CH2Cl2(3×40mL)、甲醇(2×40mL)和Et2O(2×40mL)洗涤。真空干燥树脂,得标题产物(12.69g,定量)。按原料缩氨基脲-酸计,计算出的树脂填充量为大约0.28meq/g。
步骤B:(3S)-3-[N-(N’-(1-金刚烷基)草氨酰)缬氨酰]氨基-4-氧
代丁酸
取等分量步骤A的树脂(0.125g,约0.035mmol)放入6mL装有20μm聚苯乙烯釉料的SupelcoTM滤管内,用哌啶-二甲基甲酰胺(1.0mL,1∶4 v/v)处理,在球形振动器上混合1小时。吸去上清液,树脂用二甲基甲酰胺(4×1.0mL)和CH2Cl2(3×1.0mL)洗涤。树脂继用0.5 M iPr2NEt的N-甲基吡咯烷酮溶液(0.40mL,0.20mmol)、(1-金刚烷基)草氨酸(0.0246g,0.11mmol)和0.25 M O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-三甲基脲鎓六氟磷酸盐的N-甲基吡咯烷酮溶液(0.40mL,0.10mmol)处理。混合物在氮气氛围中用球形振动器混合16小时。吸出上清液,树脂依次用二甲基甲酰胺(3×1.0mL)和CH2Cl2(3×1.0mL)、甲醇(2×1.0mL)和Et2O(2×1.0mL)洗涤。
树脂继用1.0mL CH2Cl2处理,让其再膨胀15分钟。吸出溶剂,树脂用三氟乙酸-CH2Cl2-茴香醚(1.0mL,4∶3∶1 v/v/v)处理。在氮气氛围中用球形振荡器处理5.5小时后,吸出上清液,树脂用CH2Cl2(4×1.0mL)洗涤。所得树脂再用37%甲醛水溶液-乙酸-四氢呋喃-三氟乙酸(1.0mL,1∶1∶5∶0.025 v/v/v/v)处理。在氮气氛围中用球形振荡器混合4.5小时。抽吸收集上清液,将树脂用四氢呋喃(3×0.5mL)洗涤。合并的滤液在氮气氛围中排出。将残留物溶于甲醇(0.5mL),过滤,直接施加到3mL SupelcoTM LC-18反相萃取管上(预先用水平衡过),依次用各3mL的10%MeOH-水、30 MeOH-水、60% MeOH-水和90% MeOH-水洗脱。合并含产物馏分(TLC),蒸发至干,得无色玻璃状标题化合物(0.0114g,77%)。TLC(AcOH-MeOH-CH2Cl2;1∶1∶20),Rf=0.23。MS(ES)C21H31N3O6(MW 421.49):正离子444(M+Na),460(M+K);负离子420(M-H),534(M+TFA)。
实施例205-219
以(3S)-3-[N-(9-芴基甲氧基羰基)缬氨酰]氨基-4-氧代丁酸(叔丁酯)缩氨基脲基-4-[2’-(4-乙基-苯氧基乙酰基)]氨甲基聚苯乙烯(参见实施例204,步骤A)为原料,按照实施例204,步骤B描述的方法,同样也制得下表11所示的化合物。
表11
MS(ES) | |||||
Ex. | R1 | 分子式 | MW | 正离子 | 负离子 |
205 | Ph | C17H21N3O6 | 363.37 | 386(M+Na)402(M+K) | 362(M-H) |
206 | PhCH2 | C18H23N3O6 | 377.40 | 400(M+Na) | 376(M-H) |
207 | Ph(CH2)2 | C19H25N3O6 | 391.42 | 414(M+Na)430(M+K) | 390(M-H)504(M+TFA) |
208 | (2-CF3)Ph | C18H20F3N3O6 | 431.37 | 454(M+Na) | 430(M-H) |
209 | (2-t-Bu)Ph | C21H29N3O6 | 419.48 | 442(M+Na)458(M+K) | 418(M-H)532(M+TFA) |
210 | (2-Ph)Ph | C23H25N3O6 | 439.47 | 462(M+Na)478(M+K) | 438(M-H)552(M+TFA) |
211 | (2-PhCH2)Ph | C24H27N3O6 | 453.49 | 476(M+Na)492(M+K) | 452(M-H)566(M+TFA) |
212 | (2-PhO)Ph | C23H25N3O7 | 455.47 | 478(M+Na)494(M+K) | 454(M-H)568(M+TFA) |
213 | 2-萘基 | C21H23N3O6 | 413.43 | 436(M+Na)452(M+K) | 412(M-H)526(M+TFA) |
214 | 1-萘基 | C21H23N3O6 | 413.43 | 436(M+Na)452(M+K) | 412(M-H)526(M+TFA) |
215 | 4-Cl-1-萘基 | C21H22ClN3O6 | 447.87 | 470/472(N+Na)486/488(M+K) | 446/448(M-H) |
216 | 5,6,7,8-四氢-1-萘基 | C21H27N3O6 | 417.46 | 440(M+Na)456(M+K) | 416M-H)530(M+TFA) |
217 | 1,2,3,4-四氢-1-萘基 | C21H27N3O6 | 417.46 | 440(M+Na)456(M+K) | 416(M-H)530(M+TFA) |
218 | (1-萘基)CH2 | C22H25N3O6 | 427.46 | 450(M+Na)466(M+K) | 426(M-H)540(M+TFA) |
219 | 2-苯并咪唑基 | C18H21N5O6 | 403.39 | --- | --- |
实施例220
N-(5-乙酰氨基-2-叔丁基苯基)-N’-[1-(2-羟基-5-氧代-四氢呋喃-3-基氨基甲酰基)-乙基]-草酰胺
步骤A:2-叔丁基-5-硝基-苯胺
向H2SO4(50.0g,509.79mmol)中缓慢加入2-叔丁基丙氨酸(5.0g,33.50mmol)。混合物在室温下搅拌至变为均相,然后冷却到-10℃,通过粉末加料漏斗分小批量缓慢加入KNO3(5.00g,49.45mmol)。在-10℃搅拌1小时后,将反应混合物倒入在250mL烧杯中的少量冰上,放置10分钟,然后过滤,弃去白色沉淀物。水溶液用NH4OH中和到pH8-9(Litmus pH试纸),进而分配到EtOAc/水之间。有机相用水、饱和NaCl溶液洗涤,无水Na2SO4干燥,蒸发至干(棕色油体)。棕色残留物用甲醇/水重结晶,得到深棕色结晶所需化合物(4.1g,63%)。TLC(20%EtOAc/己烷)Rf=0.66;
1HNMR(CDCl3)δ7.55(dd,J=8.4,2.4Hz,1H),7.46(d,J=2.7Hz,1H),7.35-7.33(d,J=8.7Hz),4.16(br.s,2H),1.44(s,9H)。
步骤B:N-(2-叔丁基-5-硝基-苯基)-草氨酸甲酯
0℃下,向2-叔丁基-5-硝基-苯胺(4.04g,20.80mmol)的CH2Cl2(20mL)悬浮液中加入1.1当量的氯氧代乙酸甲酯(2.10mL,22.88mmol),接着逐滴加入1.1当量的Et3N(3.19mL,22.99mmol)。在0℃下搅拌并在4小时内温热到室温后,反应混合物用水(20mL)处理,搅拌10分钟,然后分配到EtOAc/水之间。有机相用0.5 N HCl(2×25mL)、饱和NaCl溶液(50mL)洗涤,Na2SO4干燥,蒸发至干。残留物用硅胶快速色谱纯化,以EtOAc/己烷(5-25%)洗脱,得亮黄色结晶标题化合物(3.25g,56%)。TLC(30%EtOAc/己烷)Rf=0.39;
1HNMR(CDCl3)δ9.36(br.s,1H),8.97
(d,J=2.4Hz,1H),8.02(dd,J=9.0,2.4Hz,1H),7.60(d,J=9.0Hz,1H),4.03(s,3H),1.52(s,9H)。
步骤C:N-(5-氨基-2-叔丁基-苯基)-草氨酸甲酯
向N-(2-叔丁基-5-硝基-苯基)-草氨酸甲酯(1.50g,5.32mmol)的MeOH(100mL)悬浮液中加入Pd/C 10mol%(0.10g)。反应烧瓶用H2(1atm)/真空冲洗三遍,然后在室温下于H2氛围(1atm)中搅拌。搅拌45分钟后,反应物通过硅藻土过滤,蒸发至干。残留物用己烷研制,得灰色固体标题化合物(1.12g,84%)。TLC(40%EtOAc/己烷)Rf=0.21;
1HNMR
(CDCl3)δ9.21(br.s,1H),7.47(d,J=2.4Hz,1H),7.18(d,J=8.7Hz,1H),6.50(dd,J=8.4,2.7Hz,1H),4.00(s,3H),1.42(s,9H);MS(ES)Cl3H18N2O5(MW=250.29)正离子251(MH+)。
步骤D:N-(5-乙酰氨基-2-叔丁基-苯基)-草氨酸甲酯
室温下,向N-(5-氨基-2-叔丁基-苯基)-草氨酸甲酯(1.10g,4.39mmol)的吡啶(5mL)悬浮液中加入1.1当量的乙酐(0.45mL,4.83mmol)。室温搅拌30分钟后,反应混合物用0.5 N CuSO4(50mL)处理,搅拌5分钟,然后分配到EtOAc/水之间。有机相用0.5NHCl(2×25mL)、和饱和NaCl溶液(50mL)洗涤,硫酸钠干燥,蒸发至干,得白色泡沫体标题化合物(1.28g,>98%)。TLC(70%EtOAc/己烷)Rf=0.43;1HNMR(CDCl3)δ9.26(br.s,1H),7.90(d,J=2.4Hz,1H),7.65-7.61(dd,J=8.7,2.4Hz,1H),7.47(br.s,1H),7.35(d,J=8.7Hz,1H),4.10(s,3H),2.16(s,3H),1.44(s,9H);MS(ES)C15H20N2O4(MW=292.33):正离子293(MH+)。
步骤E:N-(5-氨基-2-叔丁基苯基)-草氨酸
室温下,向N-(5-乙酰氨基-2-叔丁基-苯基)-草氨酸甲酯(1.28g,4.38mmol)的1,4-二噁烷(5mL)悬浮液中加入1.05当量的1.0NLiOH(4.60mL,4.60mmol)。室温搅拌30分钟后,将反应混合物用0.5 N HCl(20mL)处理,搅拌5分钟,然后分配到EtOAc/水中。有机相用饱和NaCl溶液(50mL)洗涤,Na2SO4干燥,蒸发至干。油状残留物用CH2Cl2/己烷重结晶,得白色细小结晶标题化合物(1.74g,96%)。
1HNMR(DMSO-d6)δ10.05(s,1H),9.96(s,1H),7.50(d,J=2.1Hz,1H),7.42(dd,J=9.0,2.1Hz,1H),7.33(d,J=8.7Hz,1H),2.02(s,3H),1.30(s,9H);MS(ES)C14H18N2O4(MW=278.30):负离子277([M-H]-)。
步骤F:(2S)-2-[(5-乙酰氨基-2-叔丁基-苯基氨基草酰)-氨基]-
丙酸甲酯(-propaneperoxoic acid methyl ester)
室温、氮气氛下,向N-(5-氨基-2-叔丁基-苯基)-草氨酸(0.35g,1.36mmol)在CH2Cl2/1-甲基-2-吡咯烷酮(NMP)(1∶1)(3mL)中形成的溶液内加入1.5当量的O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(HATU)(0.72g,1.89mmol)。混合物溶液在氮气氛围中室温搅拌45分钟,然后加入HCl.H-Ala-OMe(0.16g,1.51mmol),接着再加入Et3N(0.53mL,3.78mmol)。在室温下搅拌2小时后,将混合物分配到EtOAc-水之间。有机相用水、5%KHSO4、饱和NaHCO3、和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发后得到标题化合物粗品。残留物经硅胶快速色谱纯化,以EtOAc/己烷(20-60%)洗脱,得白色固体标题化合物(0.34g,74%)。TLC(80%EtOAc/己烷)Rf=0.51;1HNMR(CDCl3)δ9.63(br.s,1H),8.11(d,J=7.8Hz,1H),8.01(d,J=2,4Hz,1H),7.60(dd,J=8.4,2.1Hz,1H),7.50(s,1H),7.35(d,J=98.7Hz,1H),4.71-4.61(dq,J=15,7.5Hz,1H),3.80(s,3H),2.15(s,3H),1.55(d,J=7.2Hz,3H),1.44(s,9H).MS(ES)C18H25N3O6(MW=363.41):正离子381([M+NH4]+)。
步骤G:(2S)-2-[(5-乙酰氨基-2-叔丁基苯基氨基草酰)-氨基]-
丙酸
室温下,向(2S)-2-[(5-乙酰氨基-2-叔丁基苯基氨基草酰)氨基]-丙酸甲酯(0.32g,0.88mmol)的1,4-二噁烷(2mL)悬浮液中加入1.05当量的1.0 N LiOH(0.92mL,0.92mmol)。室温搅拌30分钟后,用0.5 N HCl(10mL)处理反应混合物,搅拌5分钟,然后分配到EtOAc/水之间。有机相用饱和NaCl溶液(50mL)洗涤,硫酸钠干燥,蒸发至干。油状残留物用EtOAc/己烷重结晶,得到标题化合物,为白色细密粉末(0.31g,99%).1HNMR(CDCl3)δ9.66(s,1H),8.42(d,J=8.4Hz,1H),8.14(s,1H),7.91(s,1H),7.55-7.52(dd,J=8.4,1.8Hz,1H),7.33(d,J=9.0Hz,1H),4.72-4.63(q,J=7.5Hz,1H),4.20-3.90(bs,1H),2.13(s,3H),1.53(d,J=7.2Hz,3H),1.41(s,3H);MS(ES)C14H18N2O4(MW=349.38):负离子348([M-H]-)。
步骤H:3-苄氧基羰基氨基-N-甲氧基-N-甲基-琥珀酰胺酸叔丁酯
0℃、氮气氛下,向2-苄氧基羰基氨基-琥珀酸4-叔丁基酯(15.00g,46.39mmol)的CH2Cl2(150mL)溶液中加入1.2当量的1-(3-二甲氨基丙基)-3-乙基碳二亚胺HCl(EDAC)(10.67g,55.67mmol)和1.1当量的HOBt.H2O(7.81g,51.03mmol)。0℃下,在氮气氛围中搅拌混合物15分钟,然后顺序加入HCl.HN(Ome)Me(5.88g,60.31mmol)和4-甲基吗啉(NMM)(7.65mL,69.59mmol)。在0℃-室温下搅拌18小时后,将混合物分配到EtOAc/水之间。有机相用水、5%KHSO4、饱和NaHCO3、和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发后得到标题化合物粗品。残留物以Et2O/正己烷结晶,得到白色固体标题化合物(14.61g,86%).TLC(50%EtOAc/己烷)Rf=0.58;
1HNMR(CDCl3)δ7.34(m,5H),5.64(d,J=9.3Hz,1H),5.15-5.05(dd,J=18.3,12.3Hz,2H),5.05-5.00(m,1H),3.78(s,3H),3.22(s,1H),2.74-2.68(dd,J=15.0,5.4Hz,1H),2.58-2.51(dd,J=15.6,7.2Hz,1H,1.42(s,9H).MS(ES)C18H26N2O6(MW=366.4):正离子367(MH+)。
步骤I:3-苄氧基羰基氨基-4-氧代-丁酸叔丁酯
在-5℃下,向3-苄氧基羰基氨基-N-甲氧基-N-甲基-琥珀酰胺酸叔丁酯(10.00g,27.29mmol)的乙醚(200mL)悬浮液中逐滴加入0.5当量的1.0M氢化铝锂(LAH)的乙醚溶液(13.65mL,13.65mmol)。在-5℃至室温下搅拌1小时后,反应混合物用5%KHSO4(200mL)处理,搅拌5分钟,然后分配到EtOAc/水中。有机相用饱和NaCl溶液(200mL)洗涤,硫酸钠干燥,蒸发至干。残留物经硅胶快速柱色谱纯化,以EtOAc/己烷(20-80%)洗脱,得到标题化合物(6.00g,71%),为清亮油体。TLC(40%EtOAc/己烷)Rf=0.38;
1HNMR(CDCl3)δ9.62(s,1H),7.39(s,5H),5.88(d,J=7.8Hz,1H),5.15(s,2H),4.43-4.37(dt,J=9.3,4.5Hz,1H),3.01-2.94(dd,J=17.4,4.8Hz,1H),2.80-2.73(dd,J=17.4,4.8Hz,1H),1.42(s,9H).MS(ES)C16H21NO5(MW=307.14):正离子308(MH+)。
步骤J:3-苄氧基羰基氨基-4,4-二乙氧基-丁酸叔丁酯
0℃下,向3-苄氧基羰基氨基-4-氧代丁酸叔丁酯(4.46g,14.53mmol)的乙醇(40mL)悬浮液中加入0.20当量的TsOH.H2O(0.55g,2.91mmol),接着逐滴加入8.0当量的CH(OEt)3(19.34mL,116.25mmol)。在0℃-室温下搅拌16小时后,将反应混合物用饱和NaHCO3(100mL)处理,搅拌5分钟,然后分配到EtOAc/水之间。有机相用饱和NaCl溶液(200mL)洗涤,硫酸钠干燥,蒸发至干。残留物经硅胶快速色谱纯化,以EtOAc/己烷(20%)洗脱,得清亮油状标题化合物(4.88g,88%).TLC(30%EtOAc/己烷)Rf=0.33;
1HNMR(CDCl3)δ7.38(n,5H),5.28(d,J=9.9Hz,1H),5.15-5.05(dd,J=18.0,12.3Hz,2H),4.48(d,J=3.6Hz,1H),4.21-4.16(m,1H),3.75-3.65(m,2H),3.59-3.47(m,2H),2.59-2.46(dd,J=15.6,5.7Hz,2H),1.42(s,9H),1.21-1.16(t,J=6.9Hz,3H)。
步骤K:3-氨基-4,4-二乙氧基-丁酸叔丁酯
室温下,向3-苄氧基羰基氨基-4,4-二乙氧基-丁酸叔丁酯(0.50g,1.31mmol)的乙酸乙酯(50mL)悬浮液中加入10mol%Pd/C(~0.05g)。将反应烧瓶在H2(1atm)和真空之间清洗三遍,然后在室温下于H2(1atm)中搅拌。室温搅拌3小时后,反应混合物通过硅藻土过滤,之后蒸发至干,得清亮油状标题化合物(0.32g,98%)。
1HNMR(CDCl3)δ4.29(d,J=5.4Hz,1H),3.79-3.67(m,2H),3.61-3.49(m,2H),3.29-3.21(m,1H),2.60-2.53(dd,J=16.2,4.2Hz,1H),2.30-2.21(dd,J=16.2,9.0Hz,1H),1.46(s,9H),1.25-1.19(m,3H).
步骤L:(3S)-3-{(2S)-2-[(5-乙酰氨基-2-叔丁基-苯基氨基草
酰)-氨基]-丙酰基氨基}-4,4-二乙氧基-丁酸叔丁酯
室温、氮气氛下,向(2S)-2-[(5-乙酰氨基-2-叔丁基苯基氨基草酰基)-氨基]-丙酸(0.16g,0.46mmol)的CH2Cl2/NMP(1∶1,3mL)溶液中加入1.5当量的HATU(0.26g,0.69mmol)。混合物在室温和氮气氛下搅拌45分钟,然后顺序加入3-氨基-4,4-二乙氧基-丁酸叔丁酯(0.13g,0.51mmol)和Et3N(0.19mL,1.38mmol)。室温搅拌3小时后,将混合物分配到EtOAc-水之间。有机相用水、5%KHSO4、饱和NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到标题化合物粗品。残留物经硅胶快速柱色谱纯化,以EtOAc/己烷(30-70%)洗脱,得白色泡沫体标题化合物(0.26g,99%)。TLC(70%EtOAc/己烷)Rf=0.31;
1HNMR(CDCl3)δ9.80(bs,1H),8.81(d,J=8.1Hz,1H),8.54(s,1H),8.00(d,J=2.1Hz,1H),7.86-7.83(dd,J=8.7,2.1Hz,1H),7.37-7.34(d,J=8.7Hz,1H),6.85(d,J=8.7Hz,1H),4.61.-4.33(m,3H),3.77-3.39(m,4H),2.50-2.46(dd,J=6.3,2.4Hz,2H),2.18(s,3H).1.50(d,J=6.9Hz,3H),1.46(s,9H);MS(ES)C29H46N4O8(MW=578.70):正离子596([M+NH4]+)。
步骤M:N-(5-乙酰氨基-2-叔丁基-苯基)-N’-[1-(2-羟基-5-氧
代-四氢呋喃-3-基氨基甲酰基)-乙基]-草酰胺
室温下,在水/TFA/CH2Cl2(1∶1∶2,4mL)中搅拌原料(3S)-3-{(2S)-2-[(5-乙酰氨基-2-叔丁基苯基氨基草酰基)-氨基]-丙酰氨基}-4,4-二乙氧基丁酸叔丁酯(0.24g,0.42mmol)。搅拌2小时后,真空浓缩反应溶液至干,得到粗制标题化合物。残留物经制备HPLC纯化(C18柱,以10-90%的0.1%甲醛水溶液/CAN(60分钟内)),得白色固体标题化合物(0.09g,46%).MS(ES)C21H28N4O7(MW=448.47):正离子449([MH+])。
实施例221
N-(5-乙酰氨基-2-叔丁基苯基)-N’-[1-(2-乙氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-乙基]-草酰胺
步骤A:(2-乙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸苄酯
室温下,向3-苄氧基羰基氨基-4,4-二乙氧基-丁酸叔丁酯(4.61g,12.09mmol)在20%无水TFA/CH2Cl2(20mL)中的悬浮液内加入茴香醚(0.4mL)。在室温下搅拌1小时后,蒸发反应混合物至干,得到透明油状标题化合物粗品。残留物经硅胶快速柱色谱纯化,以EtOAc/己烷(10-30%)洗脱,得到:
(2S,3S)-(2-乙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸苄酯(1.54g,46%),为清亮油体。TLC(30%EtOAc/己烷)Rf=0.52。1HNMR(CDCl3)δ7.38(m,5H),5.40(br.s,1H),5.11(br.s,2H),5.00(br.s,2H),4.21(t,J=6.6Hz,1H),3.90-3.80(dd,J=7.2,2.4Hz,1H),3.66-3.61(d,J=8.1Hz,1H),2.90-2.81(dd,J=17.1,8.4Hz,1H),2.51-2.41(dd,J=17.4,10.5Hz,1H),1.24(t,J=6.9Hz,3H).MS(ES)C14H17NO5(MW=279.29):正离子278([MH+])。
(2R,3S)-(2-乙氧基-5-氧代-四氢呋喃-3-基)-氨基甲酸苄酯(0.89g,26%),为清亮油体。TLC(30%EtOAc/己烷)Rf=0.42.
1HNMR(CDCl3)δ7.37(m,5H),5.43(d,J=5.1Hz,1H),5.11(br.s,2H),5.34(d,J=9.3Hz,1H),4.61-4.50(m,1H),3.95-3.g5(dq,J=9.3,6.9Hz,1H),3.68-3.58(dq,J=9.3,6.9Hz,1H),2.90-2.81(dd,J=17.1,8.4Hz,1H),2.51-2.41(dd,J=17.4,10.5Hz,1H),1.24(t,J=6.9Hz,3H).MS(ES)C14H17NO5(MW=279.29):正离子278([MH+])。
步骤B:(4S,5S)-4-氨基-5-乙氧基-二氢-呋喃-2-酮
室温下,向(2S,3S)-(2-乙氧基-5-氧代-四氢-呋喃-3-基)-氨基甲酸苄酯(0.43g,1.54mmol)的乙酸乙酯(50mL)悬浮液中加入10%mol%Pd/C(~0.05g)。将反应烧瓶在H2(1 atm)和真空之间冲洗三遍,然后在室温下于H2(1 atm)中搅拌。室温搅拌3小时后,反应混合物通过硅藻土过滤,之后蒸发至干,得清亮油状标题化合物(0.21g,94%)。
1HNMR(CDCl3)δ5.17(d,J=1.2Hz,1H),3.93-3.82(dq,J=9.6,7.2Hz,1H),3.67-3.57(dq,J=9.3,6.9Hz,1H),2.95-287(dd,J=17.7,6.9Hz,1H),2.56-2.19(dd,J=17.4,2.7Hz,1H),1.26-1.21(t,J=7.2Hz,3H).MS(ES)C6H11NO3(MW=145.16):正离子146([MH+]).
步骤C:(4S,5R)-4-氨基-5-乙氧基-二氢-呋喃-2-酮
室温下,向(2R,3S)-(2-乙氧基-5-氧代-四氢-呋喃-3-基)-氨基甲酸苄酯(0.22g,0.86mmol)的乙酸乙酯(25mL)悬浮液中加入10%mol%Pd/C(~0.03g)。将反应烧瓶在H2(1atm)和真空之间冲洗三遍,然后在室温下于H2(1atm)中搅拌。室温搅拌3小时后,反应混合物通过硅藻土过滤,之后蒸发至干,得清亮油状标题化合物(0.12g,97%)。
1HNMR(CDCl3)δ5.31(d,J=5.1Hz,1H),3.98-3.87(dq,J=9.6,7.2Hz,1H),3.76-3.59(m,2H),3.52-3.45(q,J=7.2Hz,1H),2.72-2.64(dd,J=17.4,8.1Hz,1H),2.45-2.36(dd,J=17.1,10.2Hz,1H),1.29-1.24(t,J=6.9Hz,3H).MS(ES)C6H11NO3(MW=145.16):正离子146([MH+]).
步骤D:N-(5-乙酰氨基-2-叔丁基-苯基)-N’-[1-(2-乙氧基-5-氧
代-四氢呋喃-3-基氨基甲酰基)乙基]草酰胺
室温、氮气氛下,向(2S)-2-[(5-乙酰氨基-2-叔丁基苯基氨基草酰基)-氨基]-丙酸(0.24g,0.68mmol)在CH2Cl2/NMP(1∶1,3mL)中的溶液内加入1.5当量的O-苯并三唑-1-基-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(HBTU)(0.26g,0.69mmol)。混合物在室温和氮气氛下搅拌45分钟,之后顺序加入(4S,5S)-4-氨基-5-乙氧基-二氢-呋喃-2-酮(0.12g,0.82mmol)和Et3N(0.24mL,1.70mmol)。在室温下搅拌16小时后,将混合物分配到EtOAc-水之间。有机相用水、和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到标题化合物粗品。残留物经硅胶快速柱色谱纯化,以EtOAc/己烷(60-80%)洗脱,得白色固体标题化合物(0.14g,43%)。
TLC(100%EtOAc)Rf=0.51;1HNMR(CDCl3)δ9.82(t,J=10.5Hz,1H),8.85-8.44(m,2H),8.00-7.94(m,1H),7.80-7.68(m,1H),7.38-7.34(m,1H),5.41-5.33(dd,J=22.2,4.8Hz,1H),4.74-4.63(m,1H),4.59-4.35(m,1H),3.88-3.77(dq,J=9.6,7.2Hz,1H),3.70-3.56(m,1H),3.39-3.22(m,1H).3.03-2.88(ddd,J=18.3,7.8,2.4Hz,1H),2.56-2.35(m,1H),v2.19(s,3H),1.57-1.52(dd,J=7.2,3.0Hz,3H),1.45(s,9H);MS(ES)C23H32N4O7(MW=476.52):正离子477([MH+]).
实施例222
N-(5-乙酰氨基-2-叔丁基-苯基)-N’-[1-(2-乙氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-乙基]-草酰胺
室温、氮气氛下,向(2S)-2-[(5-乙酰氨基-2-叔丁基-苯基氨基草酰]氨基]-丙酸(0.08g,0.23mmol)的CH2Cl2/NMP(1∶1,1.5mL)溶液中加入1.5当量的HBTU(0.13g,0.35mmol)。将混合物溶液在室温和氮气氛下搅拌45分钟,之后顺序加入(4S,5R)-4-氨基-5-乙氧基-二氢-呋喃-2-酮(0.05g,0.35mmol)和Et3N(0.10mL,0.69mmol)。在室温下搅拌18小时后,将混合物分配到EtOAc-水之间。有机相用水、和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到标题化合物粗品。残留物用硅胶快速柱色谱纯化,以EtOAc/己烷(60-90%)洗脱,得白色固体标题化合物(0.10g,91%)。
TLC(100%EtOAc)Rf=0.52;1HNMR(CDCl3)δ9.77(s,1H),8.70-8.65(t,J=8.1Hz,1H),8.48(s,1H),8.00(s,1H),7.82(d,J=11.4Hz,1H),7.39-7.36(d,J=8.7Hz,1H),7.06(d,J=7.5Hz,1H),1H),4.49(d,J=5.1Hz,1H),4.78-4.57(m,2H),3.98-3.86(m,1H),3.72-3.57(m,1H),2.49-2.35(m,1H),2.17(s,3H),2.08-1.97(m,1H),1.55(d,J=7.2Hz,3H)1.46(s,9H),1.28-1.22(t,J=14.1Hz,3H).MS(ES)C23H32N4O7(MW=476.52):正离子477([MH+]),499([M+Na]+).
实施例223
N-(2-叔丁基-苯基)-N’-[1-(2-乙氧基-5-氧代-四氢-呋喃-3-基氨基甲酰基)-乙基]-草酰胺
步骤A:2-(2-叔丁基苯基氨基)-2-氧代乙酸甲酯
在配有机械搅拌器和热敏探针的3-L,3-颈圆底烧瓶中(氮气氛围)放入2-叔丁基苯胺(109g,114mL,732mmol)、三乙胺(81.4g,112mL,804mmol,1.1当量)和甲苯(600mL)。所得混合物在-30℃下以中等速度搅拌。在加料漏斗中加入氯氧代乙酸甲酯(100g,816mmol,1.11当量)和甲苯(200mL),以使内部料液温度不低于-20℃的速度将该混合物加到反应混合物中。加毕后,温热反应到室温保持1小时,加水猝灭,然后分配到EtOAc/水之间。水相用EtOAc(200mL)萃取,合并的有机层依次用KHSO4(200mL)、NaHCO3(饱和)(200mL)和盐水(200mL)洗涤,然后用硫酸镁干燥有机物。通过旋转蒸发浓缩有机相,得浅黄色固体标题化合物[2-(2-叔丁基苯基氨基)-2-氧代乙酸甲酯,160g,93.1%].MP 61.7-63.6℃.IR(KBr)3409,2954,1736,1724,1530,1299,1166,766cm-1;1H NMR(300MHz,CDCl3):δ(ppm):9.20(br,1H),7.97(dd,J=7.8Hz,J’=1.8Hz,1H),7.43(dd,J=7.8Hz,J’=1.8Hz,1H),7.31-7.16(m,2H),4.00(s,3H),1.47(s,9H).由此获得的产物可直接用于后续反应。
步骤B:2-(2-叔丁基苯基氨基)-2-氧代乙酸
在配有机械搅拌器和热敏探针的3-L,3-颈圆底烧瓶中(氮气氛围)放入2-(2-叔丁基苯基氨基)-2-氧代乙酸甲酯(154g,655mmol)和MeOH(1000mL)。然后在室温下以中等速度搅拌所得混合物。利用加料漏斗向反应混合物中逐滴加入1N NaOH/MeOH(800mL)溶液。1小时后,停止搅拌,将悬浮液转移到过滤漏斗中,过滤得到白色固体。然后将此白色固体溶于水(1200mL),搅拌下加浓盐酸调节pH至1.5-2。混合1小时后,过滤,干燥后得到白色大块结晶标题化合物(127g,574mmol,87/6%)。TLC(硅胶F254,3/1 v/v二氯甲烷/MeOH,检测254nm)显示为一个斑点,并经HPLC证实。
MP 110.9-112.6℃;IR(KBr)3405,2973,1688,1548,1300,757cm-1;1H NMR(300MHz,CDCl3):δ(ppm):9.37(br,1H),7.91(dd,J=7.8Hz,J’=1.8Hz,1H),7.44(dd,J=7.8Hz,J’=1.8Hz,1H),7.25(m,2H),1.46(s,9H);13C(300MHz,CDCl3):δ(ppm):160.87,155.24,141.18,133.19,126.92,126.69,126.63,124.24,34.21,30.49.
步骤C:(2S)-2-({N-[2-(叔丁基)苯基]氨基甲酰基}羰基氨基)丙
酸甲酯
在配有机械搅拌器和热敏探针的3-L、3-颈圆底烧瓶中(氮气氛围)加入以下固体物:2-(2-叔丁基苯基氨基)-2-氧代乙酸(70.008g,316.402mmol)、丙氨酸甲酯盐酸盐(44.368g,317.862mmol)、羟基苯并三唑水合物(HOBT)(47.324g,350.210mmol)、和1-[3-(二甲氨基)丙基]-3-乙基碳二亚胺盐酸盐(EDAC·HCl)(121.668g,635.4mmol)。利用量筒加入N,N’-二甲基甲酰胺(DMF)(1250mL),搅拌反应混合物至部分溶解,悬浮固体试剂。然后利用量筒单次加入108mL(99.36g,982mmol)N-甲基吗啉。室温搅拌18小时后,将反应混合物分配到EtOAc(约600mL)和1N HCl(约500mL)。水相用EtOAc(约300mL)洗涤两次,合并的有机层依次用1N HCl(约300mL)、H2O(约300mL)、饱和NaHCO3(约300mL)、和盐水(约300mL)洗涤。所形成的浅黄色有机溶液用硫酸镁干燥,然后浓缩得到浅黄色块状结晶(95g,97%)。TLC:(硅胶,1∶1己烷/EtOAc)Rf:0.54.MP:60.1-62.1℃;IR(KBr)3284,1747,1662,1503,1216,755cm-1;1H NMR:(CDCl3,TMS)δ9.55(br,1H),8.01(dd,J=7.8Hz,J’=1.8Hz,1H),7.42(dd,J=7.8Hz,J’=2.6Hz,1H),7.15-7.31(m,2H),4.64(p,J=7.5Hz,1H),3.80(s,3H),1.54(d,J=7.5Hz,3H),1.46(s,9H)ppm.
步骤D:(2S)-2-({N-[2-(叔丁基)苯基]氨基甲酰基}羰基氨基)丙
酸
在配有机械搅拌器和热敏探针的3-L、3-颈圆底烧瓶中(氮气氛围)加入(2S)-2-({N-[2-(叔丁基)苯基]-氨基甲酰基}羰基氨基)丙酸甲酯(85.0g,276.5mmol),溶解在二噁烷(664mL)中,并将形成的溶液在冰浴-8℃下冷却(利用内部热敏探针监测)。在搅拌下向其中加入1N LiOH(332mL)[分大约三等份加入,以使温度不高于10℃]。移去冷却浴,继续搅拌2.5小时(反应回升至室温),此时TLC分析(硅胶,1∶1 EtOAc/己烷)反应混合物显示原料已完全耗尽。将反应混合物在2L分液漏斗中分配到1N HCl(300mL)和EtOAc(500mL)之间,分离。水相的pH经试纸测试为1-2。所得水相用EtOAc(3×200mL)洗涤三(3)遍,然后合并有机部分,依次用10%柠檬酸溶液(200mL)和盐水(200mL)洗涤。随后浓缩有机相得到可流动的金色油体,进一步在真空下干燥20小时,得到黄色块状固体粗品(约90g,极度潮湿)。将此固体块用EtOAc/己烷重结晶,干燥得到高度结晶的白色固体(58.545g,200mmol,72.4%).TLC:(硅胶,19∶1CH2Cl2/MeOH)Rf:0.18;MP:164.4-166.1℃;
IR(KBr)3323,1719,1677,1517,1448,1248,762cm-1;1H NMR:(300MHz,CDCl3)δ9.57(br,1H),8.10(d,J=7.8Hz,1H),7.97(dd,J=7.8Hz,J’=1.8Hz,1H),7.43(dd,J=7.8Hz,J’=1.8Hz,1H),7.25-7.30(m,1H),7.15-7.21(m,1H),4.67(p,J=7.5Hz,1H),1.60(d,J=7.2Hz,3H),1.46(s,9H)ppm;13C NMR:(300MHz,CDCl3)δ175.71,159.97,156.33,140.92,133.77,126.79,126.47,126.01,124.01,48.31,34.21,30.42,17.50;元素分析:计算值C15H20N2O4:C,61.63;H,6.90;N,9.58.实测值:C,61.80;H,6.95;N,9.50.
步骤E:(2S)-3-{(2S)-2-[(2-叔丁基苯基氨基草酰)-氨基]-丙
酰氨基}-4,4-二乙氧基-丁酸叔丁酯
在室温和氮气氛下,向(2S)-2-[(2-叔丁基苯基氨基草酰)-氨基]-丙酸(1.20g,4.10mmol)的CH2Cl2/NMP(1∶1,10mL)溶液中加入1.5当量的HATU(0.26g,6.15mmol)。混合物溶液在室温和氮气氛下搅拌45分钟,然后顺序加入3-氨基-4,4-二乙氧基-丁酸叔丁酯(1.01g,4.10mmol)、Et3N(1.71mL,12.30mmol)。室温搅拌16小时后,将混合物分配到EtOAc-水中。有机相用水、5%KHSO4、饱和NaHCO3、和饱和NaCl溶液洗涤,无水硫酸钠干燥,蒸发得到标题化合物粗品。将此残留物用硅胶快速柱色谱纯化[以EtOAc/己烷(20%)洗脱],得白色泡沫物标题化合物(1.93g,90%).TLC(40%EtOAc/己烷)Rf=0.60;
1HNMR(CDCl3)δ9.54(s,1H),8.09(d,J=7.5Hz,1H),8.00(dd,J=8.1,1.5Hz,1H),7.42(dd,J=9.6,1.5Hz,1H),7.27(dt,J=7.2,0.9Hz,1H),7.17(dd,J=7.8,1.5Hz,1H),6.52(d,J=9.0Hz,1H),4.53(d,J=3.9,1H),4.50-4.37(m,2H),3.77-3.64(m,2H),3.60-3.46(m,2H).2.52(d,J=6.9Hz,2H),1.51-1.42(m,12H),1.29-1.16(m,6H);MS(ES)C27H43N3O7(MW=521.66):负离子521([M-H]-).
步骤F:(2-叔丁基-苯基)-N’-[1-(2-羟基-5-氧代-四氢呋喃-3-
基氨基甲酰基)-乙基]草酰胺
室温下,在水/TFA/CH2Cl2(30mL,1∶1∶2)红搅拌(2S)-3-{(2S)-2-[(2-叔丁基苯基氨基草酰)-氨基]-丙酰氨基}-4,4-二乙氧基-丁酸叔丁酯(1.39g,2.66mmol)。搅拌2小时后,真空浓缩反应溶液至干,得到标题化合物粗品。残留物经制备HPLC纯化(C18柱,在60分钟内用30-90%的0.1%甲酸水溶液/ACN洗脱),得到白色固体标题化合物(0.91g,87%)。LCMS:C19H25N3O6(MW=391.42):负离子390.32([MH-])。纯度测定使用反相Zorbax C8 4.6×150mm Rx柱(30分钟),保留时间t=10.75min。
实施例225
N-(2-叔丁基-苯基)-N’-[1-(2-乙氧基-5-氧代-四氢呋喃-3-基氨基甲酰基)-乙基]草酰胺
在室温和氮气氛下,向(2S)-2-[(2-叔丁基-苯基氨基草酰)-氨基]-丙酸(1.00g,mmol)在CH2Cl2/NMP(1∶1,3mL)中的溶液内加入1.5当量的HBTU(0.26g,3.42mmol)。混合物溶液在室温和氮气氛下搅拌45分钟,然后顺序加入(4S,5S)-4-氨基-5-乙氧基-二氢-呋喃-2-酮(0.42g,2.86mmol)和Et3N(1.20mL,8.58mmol)。室温搅拌16小时后,将混合物分配到EtOAc-水中。有机相先后用水、盐水洗涤,无水硫酸钠干燥,蒸发得到标题化合物粗品。残留物用硅胶快速柱色谱纯化,以EtOAc/己烷(10-40%)纯化,得白色固体标题化合物(0.53g,44%).TLC(50%EtOAc/己烷)Rf=0.45;
1HNMR(CDCl3)δ9.52(s,1H),7.95(m,2H),7.43(dd,J=7.8,1.5Hz,1H),7.31-7.25(dt,J=7.2,1.2Hz,1H),7.22-7.16(dt,J=7.5,1.5Hz,1H),6.88(d,J=6.9Hz,1H),5.37(s,1H),4.50-4.39(m,2H),3.89-3.79(dq,J=9.6,7.2Hz,1H),3.69-3.59(dq,J=9.3,6.6Hz,1H),3.07-2.98(dd,J=18.0,7.5Hz,1H).2.39-2.33(dd,J=19.5,1.2Hz,1H),1.50(d,J=7.2Hz,1H),1.46(s,9H),1.23(t,J=7.2Hz,3H);LCMS C21H29N3O6(MW=419.47):负离子418(MH-),正离子420(MH+]).
实施例226-312
以(3S)-3-[N-(9-芴基甲氧基羰基)丙氨酰]氨基-4-氧代丁酸(叔丁基)酯缩氨基脲基-4-[2’-(4-乙基-苯氧基乙酰基)]氨基甲基聚苯乙烯为原料(见实施例204,步骤A),按照实施例204,步骤B中描述的方法,或按照实施例220-225所述步骤,也可以制得下表12中所示的化合物:
表12
Ex. | R1 | 分子式 | MW | MS(ES) | |
正离子 | 负离子 | ||||
226 | (4-Ac)Ph | C17H19N3O7 | 377.35 | --- | 376(M-H) |
227 | (4-OH)Ph | C15H17N3O7 | 351.32 | --- | --- |
228 | (3,5-di-Cl-4-OH)Ph | C15H15Cl2N3O7 | 420.21 | --- | 418/420(M-H) |
229 | (3-CF3)PhCH2 | C17H18F3N3O6 | 417.34 | --- | --- |
230 | (2-F)PhCH2 | C16H18FN3O6 | 367.33 | --- | --- |
231 | (2,4-di-Cl)Ph | C17H19Cl2N3O6 | 432.26 | --- | --- |
232 | (3,4-di-OCH3)Ph | C18H23N3O8 | 409.40 | --- | --- |
233 | CH3 | C10H15N3O6 | 273.25 | --- | --- |
234 | S-(1-萘基)CH(CH3) | C21H23N3O6 | 413.43 | --- | --- |
235 | R-(1-萘基)CH(CH3) | C21H23N3O6 | 413.43 | --- | --- |
236 | (2-(1-萘基))Ph | C25H23N3O6 | 461.47 | 484(M+Na) | 460(M-H) |
237 | 5-Ph-3-吡唑基 | C18H19N5O6 | 401.38 | --- | 400(M-H) |
238 | 5,6,7,8-四氢-1-萘基 | C19H23N3O6 | 389.41 | --- | --- |
239 | Ph2CH | C22H23N3O6 | 425.44 | --- | --- |
240 | (2-I)Ph | C15H16IN3O6 | 461.21 | --- | --- |
241 | (2,3,5,6-tetra-Cl)Ph | C15H13Cl4N3O6 | 473.10 | --- | --- |
242 | (4-Ph)Ph | C21H21N3O6 | 411.41 | --- | --- |
243 | (2-PhO)Ph | C21H21N3O7 | 427.41 | --- | --- |
244 | 2-萘基 | C19H19N3O6 | 385.38 | --- | --- |
245 | 1,2,3,4-四氢-1-萘基 | C19H23N3O6 | 389.41 | --- | --- |
246 | 1-萘基CH2 | C20H21N3O6 | 399.40 | --- | --- |
247 | 1-金刚烷基 | C19H27N3O6 | 393.44 | --- | --- |
248 | 4-吡啶基 | C14H16N4O6 | 336.30 | --- | --- |
249 | (2,3,4,5,6-penta-F)Ph | C15H12F5N3O6 | 425.27 | --- | --- |
250 | (2-F-4-I)Ph | C15H15FIN3O6 | 479.20 | --- | --- |
251 | 1,1,3,3-四甲基丁基 | C17H29N3O6 | 371.43 | --- | --- |
252 | Ph(CH2)2 | C17H21N3O6 | 363.37 | --- | --- |
253 | 正庚基 | C16H27N3O6 | 357.41 | --- | --- |
254 | (4-正庚基)Ph | C22H31N3O6 | 433.50 | --- | --- |
255 | (2,5-di-tBu)Ph | C23H33N3O6 | 447.53 | --- | --- |
256 | (2-PhCH2)Ph | C22H23N3O6 | 425.44 | --- | --- |
257 | (2-吡咯烷-1基-5-CF3)Ph | C20H23F3N4O6 | 472.42 | --- | --- |
258 | 2,3,5,6-tetra-F-4-吡啶基 | C14H12F4N4O6 | 408.27 | --- | --- |
259 | (2-Ph)Ph | C21H21N3O6 | 411.41 | 450(M+K) | 410(M-H) |
260 | (3,4,5-tri-Cl)Ph | C15H14Cl3N3O6 | 438.65 | --- | --- |
261 | (4-OCH3)Ph | C16H19N3O7 | 365.34 | --- | --- |
262 | PhNH(CS)NH | C16H18N4O6S | 394.40 | --- | --- |
263 | (2,4-di-Br)Ph | C15H15Br2N3O6 | 493.11 | --- | --- |
Ex. | R1 | 分子式 | MW | MS(ES) | |
正离子 | 负离子 | ||||
264 | 6-喹啉基 | C18H18N4O6 | 386.36 | --- | --- |
265 | (3,4,5-tri-OCH3)PhCH2 | C19H25N3O9 | 439.42 | --- | --- |
266 | (4-CH3)Ph | C16H19N3O6 | 349.34 | 372(M+Na) | 348(M-H) |
267 | (2-F)Ph | C15H16FN3O6 | 353.31 | --- | --- |
268 | (2-Br-4-Cl-6-F)Ph | C15H14BrClFN3O6 | 466.65 | --- | --- |
269 | PhCH2 | C16H19N3O6 | 349.34 | --- | 348(M-H) |
270 | Ph | C15H17N3O6 | 335.32 | --- | --- |
271 | (2,6-di-F)Ph | C15H15F2N3O6 | 371.30 | --- | --- |
272 | (2,3,4,6-tetra-F)Ph | C15H13F4N3O6 | 407.28 | --- | --- |
273 | (2,4-di-Cl)Ph | C15H15Cl2N3O6 | 404.21 | --- | 402/204(M-H) |
274 | (2-CF3)Ph | C16H16F3N3O6 | 403.31 | 426(M+Na) | 402(M-H) |
275 | 2,3-二氢茚-5-基 | C18H21N3O6 | 375.38 | --- | --- |
276 | (3-OPh)Ph | C21H21N3O7 | 427.41 | --- | --- |
277 | 4-Cl-1-萘基 | C19H18ClN3O6 | 419.82 | 458/460(M+K) | 418/420(M-H) |
278 | 1,4-苯并二噁烷-6-基 | C17H19N3O8 | 393.35 | --- | --- |
279 | (2-Cl)Ph | C15H16ClN3O6 | 369.76 | --- | 368/370(M-H) |
280 | (2-Br)Ph | C15H16BrN3O6 | 414.21 | 414/416(M+H),434/436(M+Na),452/454(M+K) | 412/414(M-H),526/528(M+TFA) |
281 | 1-萘基 | C19H19N3O6 | 385.38 | --- | --- |
282 | (2-tBu)Ph | C19H25N3O6 | 391.42 | --- | 390(M-H) |
283 | (2-tBu-5-NHAc)Ph | C21H28N4O7 | 448.48 | 449(M+H) | --- |
284 | 5-异喹啉基 | C18H18N4O6 | 386.36 | 387(M+H) | 385(M-H) |
285 | 2,3-二氢化茚-1-基 | C18H21N3O6 | 375.38 | --- | --- |
286 | (2-F)Ph(CH2)2 | C17H20FN3O6 | 381.36 | --- | --- |
287 | (2,4-di-F)PhCH2 | C16H17F2N3O6 | 385.32 | 408(M+Na) | 384(M-H),498(M+TFA) |
288 | (2,4-di-Cl)PhCH2 | C16H17Cl2N3O6 | 418.23 | --- | --- |
289 | PhNNH | C21H22N4O6 | 426.43 | --- | --- |
290 | PhCONH | C16H18N4O7 | 378.34 | --- | --- |
291 | PhCH2(Ph)N | C22H24N4O6 | 440.46 | --- | --- |
292 | Ph(Me)N | C16H20N4O6 | 364.36 | --- | 439(M-H) |
293 | PhSO2 | C15H17N3O8S | 399.38 | --- | --- |
294 | PhCH2O | C16H19N3O7 | 365.34 | --- | --- |
295 | (2,6-di-Cl)Ph | C15H16Cl2N4O6 | 419.22 | --- | --- |
296 | (4-Me)Ph | C16H20N4O6 | 364.36 | --- | --- |
297 | Ph2NCONH | C22H23N5O7 | 469.45 | --- | --- |
298 | (4-Cl)Ph | C15H17ClN4O6 | 384.78 | 384/386(M+H) | 383/385(M-H) |
299 | (4-NO2)PhCONH | C16H17N5O9 | 423.34 | --- | --- |
300 | (2,4-di-NO2)PhNH | C15H16N6O10 | 440.33 | --- | --- |
301 | PhNHCONH | C16H19N5O7 | 393.36 | --- | --- |
302 | (2-NO2)PhCONH | C16H17N5O9 | 423.34 | --- | --- |
303 | (2,3,4,5,6-penta-F)PhNH | C15H13F5N4O6 | 440.28 | --- | --- |
Ex. | R1 | 分子式 | MW | MS(ES) | |
正离子 | 负离子 | ||||
304 | (4-Br)PhNH | C15H17BrN4O6 | 429.23 | --- | --- |
305 | (4-NO2)PHCHN | C16H17N5O8 | 407.34 | --- | 406(M-H) |
306 | PhNH | C15H18N4O6 | 350.33 | --- | 349(M-H) |
307 | (2,3,5,6-tetra-F)PhNH | C15H14F4N4O6 | 422.29 | --- | 421(M-H) |
308 | (4-F)PhNH | C15H17FN4O6 | 368.32 | --- | 367(M-H) |
309 | (3-Cl-4-Me)PhNH | C16H19ClN4O6 | 398.80 | 397/398/399(M+H) | 397(M-H) |
310 | (3-Cl)PhNH | C15H17FN4O6 | 368.32 | --- | 367(M-H) |
311 | 3-[2-乙基-4-(3H)]喹唑啉酮基 | C19H21N5O7 | 431.40 | --- | --- |
312 | (3-Br)PhCONH | C17H21BrN4O7 | 473.28 | 471(M-H) |
实施例313-318
按照实施例226-312所述方法,但以相应的叔胺为原料,还可以制得下表13中所示的化合物:
表13
Ex. | (R1)(R1′)N- | 分子式 | MW | MS(ES) | |
正离子 | 负离子 | ||||
313 | (1-萘基)(Me)N- | C20H21N3O6 | 399.40 | --- | --- |
314 | Ph2N- | C21H21N3O6 | 411.41 | --- | --- |
315 | 1-吡咯烷 | C20H21F4N3O7 | 491.13 | --- | 509(M+NH4)429(M+H) |
316 | 1-哌啶 | C21H23F4N3O7 | 505.15 | 504(M+H) | --- |
317 | (1-萘基)(Me)N- | C20H21N3O6 | 399.40 | --- | --- |
318 | Ph2N- | C21H21N3O6 | 411.41 | --- | --- |
实施例319-394
按照实施例22所述方法,但以2-(9H-芴-9-基甲氧基羰基氨基)-琥珀酸4-叔丁基酯和合适的醇为原料,也可以制得下表14A中所示的化合物:
表14A
Ex. | R1 | R1’ | R2 | 分子式 | MW | MS(ES) |
319 | 5-AcNH-2-tBuPh | H | 乙基 | C23H32N4O7 | 476.53 | 477(M+H),499(M+Na) |
320 | 2-BrPh | H | 乙基 | C17H20BrN3O6 | 422.27 | 480/482(M+K),464/466(M+Na),442/444(M+H) |
321 | 2-BnPh | H | 乙基 | C24H27N3O6 | 453.49 | 476(M+Na),492(M+K) |
按照上述方法,也可以制得表14B中所列的化合物:
表14B
Ex. | R1 | R1’ | R2 |
322 | 2-三氟甲基-Ph | H | 甲基 |
323 | 2-BzPh | H | 苄基 |
324 | 2-三氟甲基-Ph | H | 乙基 |
325 | 1-萘基 | 甲基 | 甲基 |
326 | 1-萘基 | 甲基 | 甲基 |
327 | 2-三氟甲基-Ph | H | tBu |
328 | 甲基Ph | H | H |
329 | PhPh | H | 甲基 |
330 | PhPh | H | 乙基 |
331 | 3,4-二甲氧基Br | H | 甲基 |
332 | 3,4-二甲氧基Br | H | 乙基 |
333 | 1-萘-1-基-乙基 | H | 甲基 |
334 | 1-萘-1-基-乙基 | H | 乙基 |
335 | 3,4,5-三甲氧基Ph | H | 甲基 |
336 | 3,4,5-三甲氧基Ph | H | 乙基 |
337 | 2-(2-F-Ph)-乙基 | H | 甲基 |
338 | 2-(2-F-Ph)-乙基 | H | 乙基 |
339 | 1-萘基 | H | 甲基 |
340 | 1-萘基 | H | 乙基 |
341 | 2-甲基Ph | H | H |
342 | 2,6-二F-Ph | H | 甲基 |
343 | 2,6-二F-Ph | H | 乙基 |
344 | 2,6-二F-Ph | h | tBu |
345 | 2,6-二F-Ph | h | Bn |
346 | Br | H | 乙基 |
347 | Br | H | 甲基 |
348 | Br | H | tBu |
349 | Br | H | Bn |
350 | 2,4-二F-Ph | H | tBu |
351 | 2-PhPh | H | tBu |
352 | 2-BrPh | H | tBu |
353 | 1-萘-1-基-乙基 | H | tBu |
354 | 2-三氟甲基Ph | H | tBu |
355 | 3,4,5-三甲氧基-Ph | H | tBu |
356 | 3-三氟甲基Ph | H | tBu |
357 | 2-(2-F-Ph)-乙基 | H | tBu |
358 | 1-萘基 | H | tBu |
359 | 2-I-Ph | H | 甲基 |
360 | 2-I-Ph | H | 乙基 |
361 | 2-I-Ph | H | tBu |
362 | 2-I-Ph | H | Bn |
363 | 2-Br-Ph | H | 甲基 |
364 | 2-Br-Ph | H | 乙基 |
365 | 2-Br-Ph | H | tBu |
366 | 2-Br-Ph | H | Bn |
367 | 1-萘基 | 甲基 | Bn |
368 | 3-三氟甲基Ph | H | Bn |
369 | 3-三氟甲基Ph | H | 甲基 |
370 | 3-三氟甲基Ph | H | 乙基 |
371 | PhCH(Ph) | H | 甲基 |
372 | PhCH(Ph) | H | 乙基 |
373 | PhCH(Ph) | H | Bn |
374 | Ph | Ph | Bn |
375 | Ph | Ph | 乙基 |
376 | Ph | Ph | 甲基 |
377 | 2-BrPh | H | 甲基 |
378 | 2-三氟甲基Ph | H | Bn |
379 | 2-tBuPh | H | 甲基 |
380 | 2-Ph-Ph | H | Bn |
381 | 3,4-二甲氧基Ph | H | Bn |
382 | 1-萘-1-基-乙基 | H | Bn |
383 | 3,4,5-三甲氧基Ph | H | Bn |
384 | 2-(3-F-Ph)-乙基 | H | Bn |
385 | 1-萘基 | H | Bn |
386 | 2,4-二F-Br | H | Bn |
387 | 2,4-二F-Br | H | tBu |
388 | 2,4-二F-Br | H | 乙基 |
389 | 2,4-二F-Br | H | 甲基 |
390 | Br | H | tBu |
391 | 3,4-二甲氧基-Br | H | tBu |
392 | 1-萘基 | 甲基 | tBu |
393 | PhCH(Ph) | H | tBu |
394 | Ph | Ph | tBu |
实施例395-397
按照实施例193-200中公开的方法,但以(N-9-芴基甲氧基羰基)-叔丁基甘氨酸为原料,还制得下表15中所示的化合物:
表15
Ex. | R1= | 分子式 | MW | MS(ES) | |
正离子 | 负离子 | ||||
395 | 2,3-二氢化茚-5-基 | C28H29F4N3O7 | 595.5466 | --- | 594(M-H) |
396 | (2,3,5,6-tetra-Cl)Ph | C25H21Cl4F4N3O7 | 693.2624 | --- | 690/692/694(M-H) |
397 | (2-Br)Ph | C25H24BrF4N3O7 | 6343781 | --- | 632/634(M-H) |
实施例398-419
按照实施例5-21中描述的方法,但以合适的氨基酸和草氨酸为原料,也制得下表16中所示的化合物:
表16
Ex. | R1 | R2 | A | B | 分子式 | MW | MS(ES) | |
正离子 | 负离子 | |||||||
398 | (2-tBu)Ph | OtBu | 缬氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C23H39F4N3O7 | 653.27 | 676(M+Na) | 652(M-H) |
399 | (2-tBu)Ph | OCH3 | 缬氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C29H33F4N3O7 | 611.58 | 634(M+Na) | 610(M-H)646(M+Cl-) |
400 | 5-喹啉-1-基 | OH | 缬氨酸 | OPOPh2CH2 | C35H34F3N3O10P | 758.2 | ||
401 | (2-Ph)Ph | OH | α-甲基苯丙氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C35H29F4N3O7 | 679.19 | 702(M+Na)718(M+JK) | |
402 | (2-tBu)Ph | OCH2Ph | 丙氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C33H33F4N3O7 | 659.62 | 660(M+H) | 568(M-H) |
403 | (2-Br)Ph | CH2O(2,3,5,6-tetraF-Ph) | 缬氨酸 | OH | C24H22BrF4N3O7 | 619.06 | 618/620(M-H) | |
404 | (2,3,4,5-tetra-F)Ph | CH2O(2,3,5,6-tetraF-Ph) | 缬氨酸 | OH | C24H19F8N3O7 | 613.11 | 612(M-H) | |
405 | (2-tBu)Ph | OCH2Ph | 丙氨酸 | CH2O(2,3,5,6-tetra-F-4-Br)Ph | C33H32BrF4N3O7 | 737.14 | 737.88/739.8(M+H) | 735.90/737.90(M-H) |
406 | (2-tBu)Ph | OH | 组氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C29H29F4N3O7 | 635.2 | 636(M+H) | |
407 | (2-CF3)Ph | OCH2Ph | 丙氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C30H24F7N3O7 | 671.15 | 672(M+H) | 670(M-H) |
408 | (2-tBu)Ph | OH | Cys(CH2Ph) | CH2O(2,3,5,6-tetra-F-Ph) | C33H33F4N3O8 | 675.22 | 674(M-H) | |
409 | (2-tBu)Ph | OH | Cys | CH2O(2,3,5,6-tetra-F-Ph) | C26H27F4N4O7 | 585.17 | 584(M-H) | |
410 | (2-tBu)Ph | OH | 色氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C34H32F4N4O7 | 684.22 | 683(M-H) | |
411 | (2-tBu)Ph | OH | 赖氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C29H34F4N4O7 | 626.24 | 625(M-H) | |
412 | 2-(2CH3O-Ph)Ph | OCH2Ph | 丙氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C36H31F4N3O8 | 709.2 | ||
413 | 哌啶-1-基 | OCH2Ph | 丙氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C28H30F4N4O7 | 610.21 | 611(M+H) | |
414 | 吡咯烷-1-基 | OCH2Ph | 丙氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C26H28F4N4O7 | 596.19 | 597.28(M+H) | |
415 | Cbz | OH | 缬氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C26H25F4N3O9 | 599.15 | 622M+Na) | 598(M-H) |
416 | 2,3-二氢化茚-5-基 | OH | (叔丁基)甘氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C28H29F4N3O7 | 595.55 | --- | 594(M-H) |
417 | (2,3,5,6-tetra-Cl)Ph | OH | (叔丁基)甘氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C25H21Cl4F4N3O7 | 693.26 | --- | 690/692/694(M-H) |
418 | (z-Br)Ph | OH | (叔丁基)甘氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C25H24BrF4N3O7 | 634.38 | -- | 632/634(M-H) |
419 | 2-(2-CH3Oph)Ph | OCH2Ph | 丙氨酸 | CH2O(2,3,5,6-tetra-F-Ph) | C36H31F4N3O8 | 709.2 | 710(M+H) | 708(M-H) |
实施例420-426
按照实施例126中描述的方法,但以具有需要立体化学的中间体为原料,还制得表17中所示的化合物:
表17
Ex. | R2 | Ala立体化学 | Asp立体化学 | 分子式 | MW | MS(ES) | |
正离子 | 负离子 | ||||||
420 | OBn | R | R | C33H33F4N3O7 | 659.62 | 660(M+H) | 658(M-H) |
421 | OBn | R | S | C33H33F4N3O7 | 659.62 | 660(M+H) | 658(M-H) |
422 | OBn | S | R | C33H33F4N3O7 | 659.62 | 660(M+H) | 658(M-H) |
423 | H | S | S | C35H29F4N3O7 | 569.5 | 570(M+H) | 568(M-H) |
424 | H | R | R | C33H33F4N3O7 | 569.5 | 570(M+H) | 568(M-H) |
425 | H | R | S | C24H22BrF4N3O7 | 569.5 | 570(M+H) | 568(M-H) |
426 | H | S | R | C24H19F8N3O7 | 569.5 | 570(M+H) | 568(M-H) |
虽然本发明已经参照上述实施例进行了描述,但应当明白,在不背离本发明的实质精神的情况下可以作各种修饰。因此,本发明仅受限于权利要求书。
Claims (23)
1.下式化合物或其可药用盐:
式I
其中:
A是式IIa-i的天然或非天然氨基酸:
B是氢原子,氘原子,烷基,环烷基,苯基,取代苯基,萘基,取代萘基,2-苯并噁唑基,取代的2-噁唑基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),(CH2)n(取代的1-或2-萘基),(CH2)n(杂芳基),(CH2)n(取代杂芳基),卤代甲基,CO2R12,CONR13R14,CH2ZR15,CH2OCO(芳基),CH2OCO(杂芳基),或CH2OPO(R16)R17,其中Z为氧或硫原子,或者B为式IIIa-c的基团:
R1是烷基,环烷基,取代环烷基,(环烷基)烷基,取代的(环烷基)烷基,苯基,取代苯基,苯烷基,取代的苯烷基,萘基,取代萘基,(1-或2-萘基)烷基,取代的(1-或2-萘基)烷基,杂环,取代杂环,(杂环)烷基,取代的(杂环)烷基,R1a(R1b)N,或R1cO;
R1’是氢,烷基,苯基,取代苯基,萘基,取代萘基,杂环或取代杂环;
或者R1和R1’与它们所连接的氮原子一起形成杂环或取代杂环;
R2是氢,低级烷基,环烷基,(环烷基)烷基,苯基,取代苯基,苯烷基,取代的苯烷基,萘基,取代萘基,(1-或2-萘基)烷基,或取代的(1-或2-萘基)烷基;
并且其中:
R1a和R1b独立地是氢,烷基,环烷基,(环烷基)烷基,苯基,取代苯基,苯烷基,取代的苯烷基,萘基,取代萘基,(1-或2-萘基)烷基,取代的(1-或2-萘基)烷基,杂芳基,取代杂芳基,(杂芳基)烷基,或取代的(杂芳基)烷基,条件是R1a和R1b不能同时为氢;
R1c是烷基,环烷基,(环烷基)烷基,苯基,取代苯基,苯烷基,取代的苯烷基,萘基,取代萘基,(1-或2-萘基)烷基,取代的(1-或2-萘基)烷基,杂芳基,取代杂芳基,(杂芳基)烷基,或取代的(杂芳基)烷基;
R3是C1-6低级烷基,环烷基,苯基,取代苯基,(CH2)nNH2,(CH2)nNHCOR9,(CH2)nN(C=NH)NH2,(CH2)mCO2R2,(CH2)mOR10,(CH2)mSR11,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),或(CH2)n(杂芳基);
R3a是氢或甲基,或者R3和R3a一起表示-(CH2)d-,其中d是整数2-6;
R4是苯基,取代苯基,(CH2)m苯基,(CH2)m(取代苯基),环烷基,或苯并稠合的环烷基;
R5是氢,低级烷基,环烷基,苯基,取代苯基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R6是氢,氟,氧代,低级烷基,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),OR10,SR11,或NHCOR9;
R7是氢,氧代(即=O),低级烷基,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R8是低级烷基,环烷基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),或COR9;
R9是氢,低级烷基,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),OR12,或NR13R14;
R10是氢,低级烷基,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R11是低级烷基,环烷基,苯基,取代苯基,萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R12是低级烷基,环烷基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R13是氢,低级烷基,环烷基,苯基,取代苯基,萘基,取代萘基,(CH2)n环烷基,(CH2)n苯基,(CH2)n(取代苯基),或(CH2)n(1-或2-萘基);
R14是氢或低级烷基;
或者R13和R14一起形成五至七元碳环或杂环,例如吗啉或N-取代的哌嗪;
R15是苯基,取代苯基,萘基,取代萘基,杂芳基,(CH2)n苯基,(CH2)n(取代苯基),(CH2)n(1-或2-萘基),或(CH2)n(杂芳基);
R16和R17独立地为低级烷基,环烷基,苯基,取代苯基,萘基,苯烷基,取代的苯烷基,或(环烷基)烷基;
R18和R19独立地为氢,烷基,苯基,取代苯基,(CH2)n苯基,(CH2)n(取代苯基),或者R18和R19一起表示-(CH=CH)2-;
R20是氢,烷基,苯基,取代苯基,(CH2)n苯基,(CH2)n(取代苯基);
R21,R22和R23独立地为氢,或烷基;
X是CH2,(CH2)2,(CH2)3,或S;
Y1是O或NR23;
Y2是CH2,O,或NR23;
a是0或1;
b是1或2,条件是当a为1时,则b也是1;
c是1或2,条件是当c为1时,则a是0并且b是1;
m是1或2;和
n是1,2,3或4。
2.权利要求1的化合物,其中A是:
3.权利要求2的化合物,其中R3是低级烷基。
4.权利要求2的化合物,其中R3a是氢。
5.权利要求1的化合物,其中R1是苯基,取代苯基,萘基,取代萘基,杂环,或取代杂环。
6.权利要求1的化合物,其中R1’是氢。
7.权利要求1的化合物,其中R1’是低级烷基。
8.权利要求1的化合物,其中R1和R1’以及它们所连接的氮原子一起形成杂环或取代的杂环。
9.权利要求1的化合物,其中B是CH2O(2,3,5,6-四氟苯基)。
10.权利要求1的化合物,其中B是氢。
11.权利要求1的化合物,其中R2是氢。
13.权利要求12的化合物,其中B是低级烷基或苄基。
14.一种药物组合物,其包含权利要求1的化合物与可药用载体。
15.一种治疗自身免疫疾病的方法,包括给需要治疗的患者施用有效量的权利要求14的药物组合物。
16.一种治疗炎症性疾病的方法,包括给需要治疗的患者施用有效量的权利要求14的药物组合物。
17.一种治疗神经变性疾病的方法,包括给需要治疗的患者施用有效量的权利要求14的药物组合物。
18.一种预防患局部缺血性损伤相关疾病的患者发生局部缺血性损伤的方法,包括给需要治疗的患者施用有效量的权利要求14的药物组合物。
19.一种扩增造血细胞群体或提高其存活性的方法,包括使所述细胞与有效量的权利要求14的药物组合物接触。
20.权利要求19的方法,其中所述细胞群体是用于细胞转输的粒细胞、单核细胞、红细胞、淋巴细胞和血小板。
21.一种延长用于进一步移植手术目的而从供体身上取出的器官或由器官得到的分离细胞的存活性的方法,该方法包括对所述器官或分离细胞施用有效量的权利要求14的药物组合物,从而与未处理的器官或分离细胞相比延长它们的存活性。
22.权利要求21的方法,其中所述器官是完整的器官。
23.权利要求21的方法,其中分离细胞是胰腺胰岛细胞、多巴胺能神经元、血细胞或造血细胞。
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US09/765,105 | 2001-01-16 | ||
US09/765,105 US7053056B2 (en) | 1998-07-02 | 2001-01-16 | C-terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases |
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US (2) | US7053056B2 (zh) |
EP (1) | EP1351975A2 (zh) |
JP (1) | JP2004521107A (zh) |
CN (1) | CN1283656C (zh) |
CA (1) | CA2433879A1 (zh) |
WO (1) | WO2002057298A2 (zh) |
Cited By (1)
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CN103923169B (zh) * | 2006-12-06 | 2017-05-24 | 科内图斯医药公司 | (3s)‑3‑[n‑(n’‑(2‑叔丁基苯基)草氨酰基)丙氨酰基]氨基‑5‑(2’,3’,5’,6’‑四氟苯氧基)‑4‑氧代戊酸的结晶形式 |
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US6184210B1 (en) * | 1997-10-10 | 2001-02-06 | Cytovia, Inc. | Dipeptide apoptosis inhibitors and the use thereof |
EP2270004A1 (en) | 2004-02-27 | 2011-01-05 | Vertex Pharmceuticals Incorporated | Caspase inhibitors and uses thereof |
WO2010033912A2 (en) | 2008-09-19 | 2010-03-25 | Henry Ford Health System | Methods, systems, and compositions for calpain inhibition |
WO2012021800A2 (en) * | 2010-08-13 | 2012-02-16 | Banyan Biomarkers | Caspase inhibitors as therapeutics for neural and organ injury and imaging |
US9539050B2 (en) * | 2011-04-12 | 2017-01-10 | Covidien Lp | System and method for process monitoring and intelligent shut-off |
RU2016148364A (ru) | 2014-05-12 | 2018-06-13 | Конатус Фармасьютикалз, Инк. | Лечение осложнений хронического заболевания печени |
WO2016057413A2 (en) * | 2014-10-06 | 2016-04-14 | Cortexyme, Inc. | Inhibitors of lysine gingipain |
WO2016144830A1 (en) | 2015-03-06 | 2016-09-15 | Concert Pharmaceuticals, Inc. | Deuterated emricasan |
WO2017079566A1 (en) | 2015-11-05 | 2017-05-11 | Conatus Pharmaceuticals, Inc. | Caspase inhibitors for use in the treatment of liver cancer |
WO2017083433A1 (en) * | 2015-11-09 | 2017-05-18 | Cortexyme, Inc. | Inhibitors of arginine gingipain |
CN108697663A (zh) | 2015-12-31 | 2018-10-23 | 科内图斯医药公司 | 在肝病治疗中使用胱天蛋白酶抑制剂的方法 |
MX2019003087A (es) | 2016-09-16 | 2019-08-12 | Cortexyme Inc | Inhibidores cetónicos de gingipain de lisina. |
CA3039283A1 (en) | 2016-10-05 | 2018-04-12 | Novartis Ag | Combination compositions comprising fxr agonists for treating or preventing a fibrotic,cirrhotic disease or disorder |
WO2022123062A1 (en) | 2020-12-11 | 2022-06-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Blocking caspase and/or fasl for preventing fatal outcome in covid-19 patients |
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US6204261B1 (en) | 1995-12-20 | 2001-03-20 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β Converting enzyme inhibitors |
EP0618223A3 (en) | 1993-03-08 | 1996-06-12 | Sandoz Ltd | Peptides, the release of Interleukin 1-Bêta, useful as anti-inflammatory agents. |
TW494094B (en) | 1993-04-29 | 2002-07-11 | Vertex Pharma | Peptide analogs as irreversible interleukin-1β protease inhibitors and pharmaceutical compositions comprising the same |
US5869519A (en) * | 1996-12-16 | 1999-02-09 | Idun Pharmaceuticals, Inc. | C-terminal modified (n-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases |
CA2265853C (en) | 1996-09-12 | 2010-08-03 | Idun Pharmaceuticals, Inc. | Inhibition of apoptosis using interleukin-1.beta.-converting enzyme (ice)/ced-3 family inhibitors |
US5968927A (en) * | 1996-09-20 | 1999-10-19 | Idun Pharmaceuticals, Inc. | Tricyclic compounds for the inhibition of the ICE/ced-3 protease family of enzymes |
US6184244B1 (en) | 1996-12-16 | 2001-02-06 | Idun Pharmaceuticals, Inc. | C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases |
US5877197A (en) * | 1996-12-16 | 1999-03-02 | Karanewsky; Donald S. | C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases |
FR2766188B1 (fr) | 1997-07-15 | 2000-02-11 | Hoechst Marion Roussel Inc | Nouveau procede de preparation de derives amines d'alkyloxy furanone, composes issus de ce procede et utilisation de ces composes |
US6544951B2 (en) | 1998-07-02 | 2003-04-08 | Idun Pharmaceuticals, Inc. | C-terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases |
US6197750B1 (en) | 1998-07-02 | 2001-03-06 | Idun Pharmaceuticals, Inc. | C-terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases |
US6242422B1 (en) | 1998-10-22 | 2001-06-05 | Idun Pharmacueticals, Inc. | (Substituted)Acyl dipeptidyl inhibitors of the ice/ced-3 family of cysteine proteases |
US6515173B1 (en) | 2000-01-13 | 2003-02-04 | Idun Pharmaceuticals, Inc. | Inhibitors of the ICE/ced-3 family of cysteine proteases |
IL152393A (en) | 2000-04-24 | 2008-03-20 | Vertex Pharma | Process for making aspartic acid acetal derivatives |
-
2001
- 2001-01-16 US US09/765,105 patent/US7053056B2/en not_active Expired - Lifetime
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- 2002-01-16 CN CNB028052781A patent/CN1283656C/zh not_active Expired - Fee Related
- 2002-01-16 CA CA002433879A patent/CA2433879A1/en not_active Abandoned
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103923169B (zh) * | 2006-12-06 | 2017-05-24 | 科内图斯医药公司 | (3s)‑3‑[n‑(n’‑(2‑叔丁基苯基)草氨酰基)丙氨酰基]氨基‑5‑(2’,3’,5’,6’‑四氟苯氧基)‑4‑氧代戊酸的结晶形式 |
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US20020042376A1 (en) | 2002-04-11 |
US7183260B2 (en) | 2007-02-27 |
JP2004521107A (ja) | 2004-07-15 |
WO2002057298A3 (en) | 2003-05-15 |
WO2002057298A2 (en) | 2002-07-25 |
EP1351975A2 (en) | 2003-10-15 |
US7053056B2 (en) | 2006-05-30 |
US20050020504A1 (en) | 2005-01-27 |
CA2433879A1 (en) | 2002-07-25 |
CN1283656C (zh) | 2006-11-08 |
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