CN101351452A - Hiv整合酶抑制剂 - Google Patents
Hiv整合酶抑制剂 Download PDFInfo
- Publication number
- CN101351452A CN101351452A CNA2006800473117A CN200680047311A CN101351452A CN 101351452 A CN101351452 A CN 101351452A CN A2006800473117 A CNA2006800473117 A CN A2006800473117A CN 200680047311 A CN200680047311 A CN 200680047311A CN 101351452 A CN101351452 A CN 101351452A
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- CN
- China
- Prior art keywords
- alkyl
- hiv
- coc
- inhibitor
- och
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229940099797 HIV integrase inhibitor Drugs 0.000 title claims description 13
- 239000003084 hiv integrase inhibitor Substances 0.000 title claims description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 122
- 208000030507 AIDS Diseases 0.000 claims abstract description 85
- 238000000034 method Methods 0.000 claims abstract description 47
- -1 bicyclic pyrimidinone compounds Chemical class 0.000 claims abstract description 41
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 83
- 125000000217 alkyl group Chemical group 0.000 claims description 70
- 239000000203 mixture Substances 0.000 claims description 68
- 239000003814 drug Substances 0.000 claims description 56
- 239000003112 inhibitor Substances 0.000 claims description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 32
- 125000004193 piperazinyl group Chemical group 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 125000005936 piperidyl group Chemical group 0.000 claims description 19
- 239000012453 solvate Substances 0.000 claims description 18
- 125000003368 amide group Chemical group 0.000 claims description 17
- 125000002757 morpholinyl group Chemical group 0.000 claims description 17
- 239000002777 nucleoside Substances 0.000 claims description 17
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- 125000002393 azetidinyl group Chemical group 0.000 claims description 16
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 15
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- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 claims description 9
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 5
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- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 2
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- KQOATKAFTRNONV-UHFFFAOYSA-N oxolan-2-amine Chemical compound NC1CCCO1 KQOATKAFTRNONV-UHFFFAOYSA-N 0.000 claims description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明的名称是HIV整合酶抑制剂。本发明包括一系列式I的双环嘧啶酮化合物,其抑制HIV整合酶并阻止病毒整合到人类DNA中。这种作用使得该化合物用于治疗HIV感染和AIDS。本发明也包括用于治疗感染HIV的那些对象的药物组合物和方法。
Description
相关申请的交叉引用
[0001]本申请要求2005年11月16日提交的美国临时申请序列号60/737,062的权益。
背景技术
[0002]人免疫缺陷病毒(HIV)已被鉴定为引起获得性免疫缺陷综合症(AIDS)的病原,AIDS是一种致命疾病,其特征是免疫系统破坏和不能抵抗威胁生命的机会性感染。最近的统计(UNAIDS:Report on theGlobal HIV/AIDS Epidemic,December 1998)表明,全球多达3千3百万人感染该病毒。除了大量已被感染的个体外,该病毒继续播散。1998年的估计指出,仅那一年就有接近600万的新感染者。在当年有大约250万例死亡与HIV和AIDS有关。
[0003]目前有许多抗病毒药物可用来抗感染。根据这些药物靶向的病毒蛋白和它们的作用模式,所述药物可分为三类。具体而言,沙奎那韦(saquinavir)、茚地那韦(indinavir)、利托那韦(ritonavir)、奈非那韦(nelfinavir)和安普那韦(amprenavir)是HIV表达的天冬氨酰蛋白酶的竞争性抑制剂。齐多夫定(Zidovudine)、去羟肌苷(didanosine)、司他夫定(stavudine)、拉米夫定(lamivudine)、扎西他滨(zalcitabine)和阿巴卡韦(abacavir)是核苷逆转录酶抑制剂,它们作为底物模拟物停止病毒cDNA的合成。非核苷逆转录酶抑制剂nevaripine、地拉韦啶(delavirdine)和依法韦伦(efavirenz)通过非竞争性(或不竞争性)机制抑制病毒cDNA的合成。单独使用这些药物有效减少病毒复制。该效果只是暂时的,因为病毒容易对所有已知的药剂产生抗性。然而,在许多患者中,已证实联合治疗对减少病毒和抑制抗药性产生都很有效。在美国,联合治疗被广泛采用,与HIV有关的死亡数量减少了(Palella,F.J.;Delany,K.M.;Moorman,A.C.;Loveless,M.O.;Furher,J.;Satten,G.A.;Aschman,D.J.;Holmberg,S.D.N.Engl.J.Med.1998,338,853-860)。
[0004]遗憾的是,并不是所有的患者都具有响应性,并且这种治疗对大量的患者无效。事实上,联合治疗对大约30-50%的患者最终无效。大多数情况下治疗无效是由病毒产生耐药性造成的。病毒耐药性又是由感染期间HIV-1的快速周转连同高的病毒突变率引起。在这些情况下,由药物效力不足造成的不完全的病毒抑制、对复杂给药方案的不良依从性以及内在药学暴露屏障提供了产生耐药性的肥沃土壤。更令人不安的是,最近的发现表明,甚至当病毒的血浆水平下降到可检测水平以下(<50个拷贝/ml)时,仍继续着低水平的复制(Carpenter,C.C.;Cooper,D.A.;Fischl,M.A.;Gatell,J.M.;Gazzard,B.G.;Hammer,S.M.;Hirsch,M.S.;Jacobsen,D.M.;Katzenstein,D.A.;Montaner,J.S.;Richman,D.D.;Saag,M.S.;Schechter,M.;Schooley,R.T.;Thompson,M.A.;Vella,S.;Yeni,P.G.;Volberding,P.A.JAMA 2000,283,381-390)。明显需要新的抗病毒药剂——优选地靶向其它病毒酶——以更进一步降低耐药速率和抑制病毒复制。
[0005]HIV表达3种酶,逆转录酶、天冬氨酰蛋白酶和整合酶。这三种酶都是用于治疗AIDS和HIV感染的靶标。HIV整合酶催化病毒cDNA插入宿主细胞基因组,这是病毒生命周期的关键步骤。HIV整合酶抑制剂属于二酮酸类化合物,其阻止病毒整合和抑制细胞中的HIV-1复制(Hazuda等人,Science 2000,287,646)。最近,HIV整合酶抑制剂已被接受到临床试验中,用于治疗AIDS和HIV感染(NeamatiExpert.Opin.Ther.Patents 2002,12,709,Pais and Burke Drugs Fut.2002,27,1101)。
发明内容
[0006]本发明包括式I的化合物,其包括药学上可接受的盐,它们的药物组合物,以及它们在抑制HIV整合酶和治疗感染了HIV或AIDS的对象中的应用。
[0007]本发明的一方面是式I的化合物
R1是(Ar1)烷基;
R2是氢、烷基、羟基或烷氧基;
R3是SO2N(R6)(R7);
R4是氢、卤素、羟基、氰基、烷基、烷氧基、卤烷基或卤烷氧基;
R5是氢、卤素、羟基、氰基、烷基、烷氧基、卤烷基或卤烷氧基;
R6和R7与它们所连接的氮一起是氮杂环丁烷基、(R8)-氮杂环丁烷基、吡咯烷基、(R8)-吡咯烷基、哌啶基、(R8)-哌啶基、二烷基哌啶基、三烷基哌啶基、哌嗪基、4-(R9)-哌嗪基、二烷基哌嗪基、二烷基-4-(R9)-哌嗪基、高哌啶基、吗啉基、硫代吗啉基、
R8是羟基、烷基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、烷基CONH、烷基CON(烷基)、(甲硫基)四氢呋喃基、(氨基)四氢呋喃基、(烷基氨基)四氢呋喃基、(二烷基氨基)四氢呋喃基、氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、高哌啶基、吗啉基、(氮杂环丁烷基)烷基、(吡咯烷基)烷基、(哌啶基)烷基、(哌嗪基)烷基、(高哌啶基)烷基或(吗啉基)烷基;
R9是烷基、(环烷基)烷基、SO2R10或COR11;
R10是氢、烷基、氨基、烷基氨基、二烷基氨基、氮杂环丁烷基、吡咯烷基、哌啶基、羟基哌啶基、哌嗪基、4-(烷基)哌嗪基、吗啉基、或硫代吗啉基;
R11是氢、烷基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、氮杂环丁烷基、吡咯烷基、哌啶基、羟基哌啶基、哌嗪基、4-(烷基)哌嗪基、吗啉基、或硫代吗啉基;
R12是氢或烷基;
或两个R12在一起是CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CH2CH2CH2CH2CH2、CH2CH2CH2CH2CH2CH2、OCH2CH2、CH2OCH2、OCH2CH2CH2、CH2OCH2CH2、OCH2CH2CH2CH2、CH2OCH2CH2CH2、CH2CH2OCH2CH2、OCH2CH2CH2CH2CH2、CH2OCH2CH2CH2CH2、CH2CH2OCH2CH2CH2、N(R13)CH2CH2、CH2N(R13)CH2、N(R13)CH2CH2CH2、CH2N(R13)CH2CH2、N(R13)CH2CH2CH2CH2、CH2N(R13)CH2CH2CH2、CH2CH2N(R13)CH2CH2、N(R13)CH2CH2CH2CH2CH2、CH2N(R13)CH2CH2CH2CH2或CH2CH2N(R13)CH2CH2CH2,条件是两个R12连接到共同的碳原子上;
R13是氢或烷基;
R14和R15在一起是C3-5亚烷基;
Ar2是被选自卤素、烷基和烷氧基的0-2个取代基取代的苯基或吡啶基;
和
X-Y-Z是C(R12)2OC(R12)2、C(R12)2OC(R12)2C(R12)2、C(R12)2OC(R12)2C(R12)2C(R12)2、C(R12)2CH2CH2、C(R12)2CH2CH2CH2、C(R12)2CH2CH2CH2CH2、C(Ar2)=CHCH2、C(Ar2)=CHCH2CH2、C(Ar2)=CHCH2CH2CH2、(R12)2N(R13)C(R12)2、C(R12)2N(R13)C(R12)2C(R12)2、C(R12)2N(R13)C(R12)2C(R12)2C(R12)2、N(R12)COC(R12)2、N(R12)COC(R12)2C(R12)2、N(R12)COC(R12)2C(R12)2C(R12)2、N(R12)SO2C(R12)2、N(R12)SO2C(R12)2C(R12)2、N(R12)SO2C(R12)2C(R12)2C(R12)2、N(R12)N(R12)COC(R12)2、N(R12)N(R12)COC(R12)2C(R12)2、N(R14)N(R15)COC(R12)2、N(R14)N(R15)COC(R12)2C(R12)2、C(R12)2N(R12)CO、C(R12)2N(R12)COC(R12)2、C(R12)2N(R12)COC(R12)2C(R12)2、C(R14)2N(R15)CO、C(R14)2N(R15)COC(R12)2、C(R14)2N(R15)COC(R12)2C(R12)2、SC(R12)2C(R12)2、SC(R12)2C(R12)2C(R12)2或SC(R12)2C(R12)2C(R12)2C(R12)2;
或其药学上可接受的盐。
[0008]本发明的另一个方面是式I的化合物
R1是(Ar1)烷基;
R2是氢、烷基、羟基或烷氧基;
R3是SO2N(R6)(R7);
R4是氢、卤素、羟基、氰基、烷基、烷氧基、卤烷基或卤烷氧基;
R5是氢、卤素、羟基、氰基、烷基、烷氧基、卤烷基或卤烷氧基;
R6和R7与它们连接的氮一起为氮杂环丁烷基、吡咯烷基、哌啶基、(R8)-哌啶基、哌嗪基、4-(R9)-哌嗪基、高哌啶基、吗啉基或硫代吗啉基;
R8是羟基或烷基;
R9是烷基、(环烷基)烷基、SO2R10或COR11;
R10是氢、烷基、氨基、烷基氨基、二烷基氨基、氮杂环丁烷基、吡咯烷基、哌啶基、羟基哌啶基、哌嗪基、4-(烷基)哌嗪基、吗啉基、或硫代吗啉基;
R11是氢、烷基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、氮杂环丁烷基、吡咯烷基、哌啶基、羟基哌啶基、哌嗪基、4-(烷基)哌嗪基、吗啉基、或硫代吗啉基;
R12是氢或烷基;
或两个R12在一起是CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CH2CH2CH2CH2CH2、CH2CH2CH2CH2CH2CH2、OCH2CH2、CH2OCH2、OCH2CH2CH2、CH2OCH2CH2、OCH2CH2CH2CH2、CH2OCH2CH2CH2、CH2CH2OCH2CH2、OCH2CH2CH2CH2CH2、CH2OCH2CH2CH2CH2、CH2CH2OCH2CH2CH2、N(R13)CH2CH2、CH2N(R13)CH2、N(R13)CH2CH2CH2、CH2N(R13)CH2CH2、N(R13)CH2CH2CH2CH2、CH2N(R13)CH2CH2CH2、CH2CH2N(R13)CH2CH2、N(R13)CH2CH2CH2CH2CH2、CH2N(R13)CH2CH2CH2CH2或CH2CH2N(R13)CH2CH2CH2,条件是两个R12结合到共同的碳原子上;
R13是氢或烷基;
R14和R15在一起是C3-5亚烷基;
Ar2是被选自卤素、烷基和烷氧基的0-2个取代基取代的苯基或吡啶基;
和
X-Y-Z是C(R12)2OC(R12)2、C(R12)2OC(R12)2C(R12)2、C(R12)2OC(R12)2C(R12)2C(R12)2、C(R12)2CH2CH2、C(R12)2CH2CH2CH2、C(R12)2CH2CH2CH2CH2、C(Ar2)=CHCH2、C(Ar2)=CHCH2CH2、C(Ar2)=CHCH2CH2CH2、(R12)2N(R13)C(R12)2、C(R12)2N(R13)C(R12)2C(R12)2、C(R12)2N(R13)C(R12)2C(R12)2C(R12)2、N(R12)COC(R12)2、N(R12)COC(R12)2C(R12)2、N(R12)COC(R12)2C(R12)2C(R12)2、N(R12)SO2C(R12)2、N(R12)SO2C(R12)2C(R12)2、N(R12)SO2C(R12)2C(R12)2C(R12)2、N(R12)N(R12)COC(R12)2、N(R12)N(R12)COC(R12)2C(R12)2、N(R14)N(R15)COC(R12)2、N(R14)N(R15)COC(R12)2C(R12)2、C(R12)2N(R12)CO、C(R12)2N(R12)COC(R12)2、C(R12)2N(R12)COC(R12)2C(R12)2、C(R14)2N(R15)CO、C(R14)2N(R15)COC(R12)2、C(R14)2N(R15)COC(R12)2C(R12)2、SC(R12)2C(R12)2、SC(R12)2C(R12)2C(R12)2或SC(R12)2C(R12)2C(R12)2C(R12)2;
或其药学上可接受的盐。
[0009]本发明的另一个方面是式I的化合物,其中R1是
[0010]本发明的另一个方面是式I的化合物,其中R4是氢或卤素。
[0011]本发明的另一个方面是式I的化合物,其中R2是氢。
[0012]本发明的另一个方面是式I的化合物,其中X-Y-Z是C(R12)2OC(R12)2、C(R12)2OC(R12)2C(R12)2或C(R12)2OC(R12)2C(R12)2C(R12)2。
[0013]本发明的另一个方面是式I的化合物,其中X-Y-Z是C(R12)2CH2CH2、C(R12)2CH2CH2CH2或C(R12)2CH2CH2CH2CH2。
[0014]本发明的另一个方面是式I的化合物,其中X-Y-Z是C(Ar2)=CHCH2、C(Ar2)=CHCH2CH2或C(Ar2)=CHCH2CH2CH2。
[0015]本发明的另一个方面是式I的化合物,其中X-Y-Z是(R12)2N(R13)C(R12)2、C(R12)2N(R13)C(R12)2C(R12)2或C(R12)2N(R13)C(R12)2C(R12)2C(R12)2。
[0016]本发明的另一个方面是式I的化合物,其中X-Y-Z是N(R12)COC(R12)2、N(R12)COC(R12)2C(R12)2、N(R12)COC(R12)2C(R12)2C(R12)2、N(R12)SO2C(R12)2、N(R12)SO2C(R12)2C(R12)2、N(R12)SO2C(R12)2C(R12)2C(R12)2、N(R12)N(R12)COC(R12)2、N(R12)N(R12)COC(R12)2C(R12)2、N(R14)N(R15)COC(R12)2、N(R14)N(R15)COC(R12)2C(R12)2、C(R12)2N(R12)CO、C(R12)2N(R12)COC(R12)2、C(R12)2N(R12)COC(R12)2C(R12)2、C(R14)2N(R15)CO、C(R14)2N(R15)COC(R12)2或C(R14)2N(R15)COC(R12)2C(R12)2。
[0017]本发明的另一个方面是式I的化合物,其中X-Y-Z是SC(R12)2C(R12)2、SC(R12)2C(R12)2C(R12)2或SC(R12)2C(R12)2C(R12)2C(R12)2。
[0018]本发明的另一个方面是选自以下的化合物:
并且其中:
R1是(Ar1)烷基;
R2是氢、烷基、羟基或烷氧基;
R3是SO2N(R6)(R7);
R4是氢、卤素、羟基、氰基、烷基、烷氧基、卤烷基或卤烷氧基;
R5是氢、卤素、羟基、氰基、烷基、烷氧基、卤烷基或卤烷氧基;
R6和R7与它们连接的氮一起为氮杂环丁烷基、吡咯烷基、哌啶基、(R8)-哌啶基、哌嗪基、4-(R9)-哌嗪基、高哌啶基、吗啉基或硫代吗啉基;
R8是羟基或烷基;
R9是烷基、(环烷基)烷基、SO2R10或COR11;
R10是氢、烷基、氨基、烷基氨基、二烷基氨基、氮杂环丁烷基、吡咯烷基、哌啶基、羟基哌啶基、哌嗪基、4-(烷基)哌嗪基、吗啉基、或硫代吗啉基;
R11是氢、烷基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、氮杂环丁烷基、吡咯烷基、哌啶基、羟基哌啶基、哌嗪基、4-(烷基)哌嗪基、吗啉基、或硫代吗啉基;
R12是氢或烷基;
或两个R12在一起是CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CH2CH2CH2CH2CH2、CH2CH2CH2CH2CH2CH2、OCH2CH2、CH2OCH2、OCH2CH2CH2、CH2OCH2CH2、OCH2CH2CH2CH2、CH2OCH2CH2CH2、CH2CH2OCH2CH2、OCH2CH2CH2CH2CH2、CH2OCH2CH2CH2CH2、CH2CH2OCH2CH2CH2、N(R13)CH2CH2、CH2N(R13)CH2、N(R13)CH2CH2CH2、CH2N(R13)CH2CH2、N(R13)CH2CH2CH2CH2、CH2N(R13)CH2CH2CH2、CH2CH2N(R13)CH2CH2、N(R13)CH2CH2CH2CH2CH2、CH2N(R13)CH2CH2CH2CH2或CH2CH2N(R13)CH2CH2CH2,条件是两个R12结合到共同的碳原子上;
R13是氢或烷基;
R14和R15在一起是C3-5亚烷基;和
Ar1是
或其药学上可接受的盐。
[0019]对于式I的化合物,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、Ar1、Ar2、Ar3和X-Y-Z的任何范围,可以与任何其它取代基的任何范围独立地使用。变量的每个例子独立于另一个例子。
[0020]除非另外说明,这些术语具有下面的意思。“烷基”表示由1到6个碳构成的直链或支链烷基。“链烯基”表示由2到6个碳和至少一个双键构成的直链或支链链烯基。“环烷基”表示由3到7个碳构成的单环的环体系。“羟烷基”、“烷氧基”和含有取代烷基部分的其它术语的烷基部分包括由1到6个碳原子构成的直链或支链异构体。“卤烷基”和“卤烷氧基”包括从一卤取代烷基至全卤取代烷基的所有卤代异构体。“芳基”包括碳环和杂环芳族取代基。插入的(Parenthetic)和多个插入的术语旨在向本领域技术人员阐明结合关系。例如,术语如((R)烷基)表示烷基取代基进一步被取代基R取代。
[0021]本发明包括化合物的所有药学上可接受的盐形式。药学上可接受的盐是其中反荷离子对化合物的生理活性或毒性没有显著贡献,并且因此起药物等价物的作用的那些盐。这些盐可以根据普通的有机技术利用商业购买的试剂制备。一些阴离子盐形式包括醋酸盐、醋硬脂盐(acistrate)、苯磺酸盐、溴化物、氯化物、柠檬酸盐、富马酸盐、葡糖醛酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、碘化物、乳酸盐、马来酸盐、甲磺酸盐(mesylate)、硝酸盐、双羟萘酸盐(pamoate)、磷酸盐、琥珀酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐和xinofoate。一些阳离子盐形式包括铵、铝、苄星(benzathine)、铋、钙、胆碱、二乙胺、二乙醇胺、锂、镁、甲葡胺、4-苯基环己胺、哌嗪、钾、钠、氨丁三醇和锌。
[0022]本发明的一些化合物以立体异构的形式存在。本发明包括化合物的所有立体异构形式,包括对映异构体和非对映异构体。对映异构体的一个例子如下所示,制备和分离立体异构体的方法是本领域已知的。
[0023]本发明包括化合物的所有互变异构形式。互变异构对的一个例子如下所示。
合成方法
[0024]本发明的化合物可以通过本领域已知的各种方法制备,包括以下方案的方法和具体实施方式部分中的方法。合成方案中所示的变量与权利要求中或说明书其它部分中的变量不同并且也不应当与它们混淆。方案中的变量仅仅旨在说明如何制备本发明的一些化合物。
[0025]一些化合物可根据方案I从适当取代的杂环I-1合成,其中Ra和P可以充当保护基(见Greene,T.W.和Wutz,P.G.M.Protective Groupsin Organic Synthesis,Second Edition,1991,John Wiley and Sons,NewYork)。当P是苄基或取代的苄基时,它可以通过氢解(H2-Pd/C)或酸解(三氟乙酸)除去以产生中间体I-2。I-2可以通过与胺I-3反应被转氨基为I-4。在许多情况下,该反应可以通过在碱存在下一起加热I-3和I-2来进行。可选地,标准的酰胺偶联剂可以用于使酰胺键形成。当Ra是低碳烷基时,Ra可以在酯水解条件下被除去,如用NaOH、LiOH或KOH处理以产生相应的羧酸I-5。可选地,Ra可以通过用NaI亲核置换除去。当Ra是苄基和取代的苄基时,Ra可以通过氢解除去。用酰胺键形成试剂如BOP、DCC、EDCI、PyBrop、PyBop或者其它试剂可以偶联中间体I-5(见March,J.Advanced Organic Chemistry,Fourth Edition1992 John Wiley & Sons,New York)。得到的中间体I-6可以如针对中间体I-1所述脱保护。
方案I.
[0026]在方案II中,中间体II-3可以用与Sunderland,J.S.;Botta,M.;Aime,S.;Raymond,K.N.Inorg.Chem.(2001),40,6756-6756所述的那些相似的方法制备,其中II-1和II-2缩合,以提供中间体II-3。该反应通常在碱如氢化钠(NaH)、乙醇钠(EtONa)或六甲基二硅基胺基锂(lithium hexamethyldisilazide,LiHMDS)的存在下进行。利用该参考文献中描述的方法,II-3可以与适当取代的脒II-4缩合以形成II-5。取代基B可以是离去基团,如-卤素(Cl、Br或I),或可以在合适的条件下被转变为离去基团,如通过形成相应的甲磺酸酯。当取代基B是二甲硫基(methyl sulphide group)时,它可以用碘代甲烷处理以形成二甲基锍中间体,该中间体通过亲核攻击被活化,以引起环合。
方案II.
[0027]在方案III中,中间体II-3可以与环状脒缩合以产生中间体I-1。中间体III-1可以用已知的方法制备(见Patai,S.and Rappoport,Z.TheChemistry of Amidines and Imidates,Volume 2,1991,John Wiley & Sons,New York)。
方案III.
[0028]在方案IV中,具有可能离去基团B的腈IV-1可以与羟胺反应形成中间体IV-2。该中间体可以与适当保护的炔反应形成IV-3,IV-3可以根据文献的方法重排,形成中间体IV-4(Culbertson,T.P.Journal ofHeterocyclic Chemistry,1979,16,1423-1424)。
方案IV.
[0029]如方案V所示,2-(甲硫基)乙醇可以用合适的α-卤代乙酸(V-1)烷基化,形成中间体V-2,其中是X离去基团,如Cl、Br、OTs、OMs或OTf。接着,可以用已知的合成方法将羧酸转变为相应的脒衍生物(Geilen等人,Tetrahedron Letters 2002,43,419-421)。如上所述,在碱(例如,乙醇钠)存在下,脒可以进一步与中间体V-5反应,获得中间体V-6。通过用碘代甲烷处理V-6可完成硫醚的甲基化,并用碱处理形成的锍衍生物(V-7),形成双环模板V-8。用方案I所述的方法,该中间体可以用于合成最终的化合物。
方案V
[0030]在方案VI中,用熟知的化学方法将3-甲硫基丙醛转变为二氧戊环VI-1。在碘化锌(ZnI2)存在下,用氰化三甲基硅烷(TMSCN)处理,产生中间体VI-2。与氨反应生成脒VI-3,其可按照前面方案所述的方法用于合成嘧啶酮VI-4。随后用CH3SO2Cl和三乙胺(Et3N)处理生成相应的双环中间体VI-5。合成的完成可如方案I所示进行。
方案VI
[0031]另一方法在方案VII中进行说明。该合成途径起始于适当取代的酮,该酮可以被转变为相应的腈中间体VII-1。其又可以与2-氯乙醇反应,产生化合物VII-2,它可以与羟胺和乙炔二羧酸酯反应,产生中间体VII-4。加热该中间体可以产生中间体VII-5。可以按照方案I完成相应的酰胺衍生物的合成。
方案VII
[0032]在方案VIII中,可以在碱性条件下(例如,K2CO3或NaH)用苄基溴实现VII-5羟基的苄基化——其为官能团的保护手段。VIII-1的酯基的皂化可以产生VIII-2,用已知的酰胺键形成试剂如苯并三唑-1-基氧代-三-吡咯烷基-鏻六氟磷酸酯(PyBOP)或O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(HATU),VIII-2可以与适当取代的胺(R1R2NH)偶联。可选地,通过用草酰氯处理和与合适的胺反应形成酰胺键,可以形成相应的酰基氯。在多种条件下,包括用CF3CO2H或H2(Pd-C)处理,可以实现苄基的去除。
方案VIII
[0033]在另一个方法中,本发明的一些化合物可以根据方案IX合成。在方案IX中,嘧啶酮IX-3可以用与先前方案所述的方法类似的方法产生。按照各种途径,这一中间体可以进行到终产物。在一个途径中,羟基可以被苯甲酰化,产生中间体IX-4,该中间体可以进一步用K2CO3处理,引起环合以形成双环模板IX-5。可选地,用K2CO3直接处理IX-3可以产生中间体IX-6。用方案I所述的方法,中间体IX-5,IX-6可以用于合成终产物。
方案IX
[0034]在方案X中,IX-3可以被用来合成苄基化中间体X-1。用与方案VIII所述方法类似的方法,该中间体可以被进行至终产物。
方案X
[0035]在另一个方法中,方案XI说明了从5-氟-2-甲苯-1-磺酰氯开始合成含有氨磺酰的实例。
方案XI
[0036]在另一个方法中,方案XII说明了从2,4-二氟苯基氰开始合成含有氨磺酰的苄胺的可选途径。
方案XII
[0037]根据方案XIII-XXIX所示的方法,可以合成本发明的一些实例。
方案XIII
方案XIV
方案XV
方案XVI
方案XVII
方案XVIII
方案XIX
方案XX
方案XXI
方案XXII
方案XXIII
方案XXIV
方案XXV
方案XXVI
方案XXVII
方案XXVIII
方案XXIX
生物学方法
[0038]HIV-整合酶抑制活性。为了评价针对HIV-整合酶的体外活性,将5皮摩(pmole)生物素标记底物DNA结合在100μg链霉亲和素包被的PVT SPA珠子(Amersham Pharmacia Biotech)上。重组整合酶(0.26ng)与珠子在37℃下温育90分钟。通过洗涤该复合物除去未结合的酶,接着加入抑制剂和0.1飞摩(fmol)P33标记的靶DNA。通过加入EDTA至终浓度10mM终止反应。在TopCountNXT(Packard)中计数样品,用CPM作为整合的度量。反应条件如在A.Engelman和R.Craigie,J.Virol.69,5908-5911(1995)中所述。底物和靶DNA的序列在Nucleic AcidResearch 22,1121-1122(1994)中描述。
[0039]结果示于表1中。活性等于A指化合物具有IC50=0.002至0.10μM,而B和C分别表示化合物具有IC50=0.1至1.0μM和IC50≥1.0μM。
表1.
实施例 | 活性 |
1 | A |
2 | A |
3 | A |
4 | A |
5 | A |
6 | A |
7 | A |
8 | A |
9 | A |
10 | A |
11 | A |
12 | A |
13 | A |
14 | A |
15 | A |
16 | A |
17 | A |
18 | A |
19 | A |
20 | A |
21 | A |
22 | A |
23 | A |
24 | A |
25 | A |
26 | A |
27 | A |
28 | A |
29 | A |
30 | A |
31 | A |
实施例 | 活性 |
32 | A |
33 | A |
34 | A |
35 | A |
36 | A |
37 | A |
38 | A |
39 | A |
40 | A |
41 | A |
42 | A |
[0040]HIV复制的抑制。构建重组NL-Rluc病毒,其中来自NL4-3的nef基因部分被海肾(Renilla)萤光素酶基因置换。通过共转染两种质粒pNLRLuc和pVSVenv制备NL-RLuc病毒。pNLRLuc含有克隆到pUC18的PvuII位点的NL-Rluc DNA,而pVSVenv含有连接到LTR启动子的VSV G蛋白的基因。按照制造商的说明书,用来自Invitrogen(Carlsbad,CA)的LipofectAMINE PLUS试剂盒,以1∶3的pNLRLuc比pVSVenv比例在293T细胞上进行转染,并且将产生的假型病毒在MT-2细胞中滴定。
[0041]通过在连续稀释化合物存在的情况下温育,测定病毒对化合物的敏感性。通过用指数形式的半数有效方程(median effect equation)计算50%有效浓度(EC50),其中(Fa)=1/[1+(ED50/药物浓度)m](Johnson VA,Byington RT.Infectivity Assay。在Techniques in HIV Research.ed.Aldovini A,Walker BD.71-76.New York:Stockton Press.1990)。在三种血清条件下——10%FBS、15mg/ml人血清白蛋白/10%FBS或40%人血清/5%FBS,评价化合物的抗病毒活性,用至少2个实验的结果计算EC50值。结果示于表2中。活性等于A指化合物具有EC50=0.003到0.10μM,而B和C分别表示化合物具有EC50=0.1到1.0μM和EC50≥1.0μM。
表2.
实施例 | 活性 |
1 | A |
2 | A |
3 | A |
4 | A |
5 | A |
6 | A |
7 | A |
8 | A |
9 | A |
10 | B |
11 | A |
12 | A |
13 | A |
14 | A |
15 | A |
16 | A |
17 | A |
18 | A |
19 | A |
20 | A |
21 | A |
22 | A |
23 | A |
24 | A |
25 | A |
26 | A |
27 | A |
28 | A |
29 | A |
30 | A |
31 | A |
32 | A |
实施例 | 活性 |
33 | A |
34 | A |
35 | A |
36 | A |
37 | A |
38 | A |
39 | A |
40 | A |
41 | A |
42 | A |
药物组合物及应用方法
[0042]本发明的化合物抑制HIV整合酶。属于二酮酸化合物类的HIV整合酶抑制剂阻止病毒的整合和抑制HIV-1在细胞中复制(Hazuda等人,Science 2000,287,646)。最近,已经接受HIV整合酶抑制剂进入临床试验,用于治疗AIDS和HIV感染(Neamati Expert.Opin.Ther.Patents 2002,12,709,Pais and Burke Drugs Fut.2002,27,1101)。
[0043]因此,本发明的另一个方面是用于治疗人类患者中HIV感染的方法,包括给予治疗有效量的式I化合物或其药学上可接受的盐或溶剂化物与药学上可接受的载体。
[0044]本发明的另一个方面是用于治疗人类患者中HIV感染的方法,包括给予治疗有效量的式I化合物,或其药学上可接受的盐或溶剂化物,与治疗有效量的至少一种用于治疗AIDS或HIV感染的其它药剂,所述其它药剂选自核苷HIV逆转录酶抑制剂、非核苷HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、HIV融合抑制剂、HIV附着抑制剂(HIVattachment inhibitor)、CCR5抑制剂、CXCR4抑制剂、HIV出芽或成熟抑制剂(HIV budding or maturation inhibitor)和HIV整合酶抑制剂。
[0045]本发明的另一个方面是方法,其中药剂是核苷HIV逆转录酶抑制剂。
[0046]本发明的另一个方面是方法,其中核苷HIV逆转录酶抑制剂选自阿巴卡韦、去羟肌苷、恩曲他滨(emtricitabine)、拉米夫定、司他夫定、替诺福韦(tenofovir)、扎西他滨和齐多夫定,或它们药学上可接受的盐或溶剂化物。
[0047]本发明的另一个方面是方法,其中药剂是非核苷HIV逆转录酶抑制剂。
[0048]本发明的另一个方面是方法,其中非核苷HIV逆转录酶抑制剂选自地拉韦啶、依法韦伦和nevaripine,或它们药学上可接受的盐或溶剂化物。
[0049]本发明的另一个方面是方法,其中药剂是HIV蛋白酶抑制剂。
[0050]本发明的另一个方面是方法,其中HIV蛋白酶抑制剂选自安普那韦、阿扎那韦(atazanavir)、茚地那韦、洛匹那韦(lopinavir)、奈非那韦、利托那韦、沙奎那韦和夫沙那韦(fosamprenavir),或它们药学上可接受的盐或溶剂化物。
[0051]本发明的另一个方面是方法,其中药剂是HIV融合抑制剂。
[0052]本发明的另一个方面是方法,其中HIV融合抑制剂是恩夫韦地(enfuvirtide)或T-1249,或它们药学上可接受的盐或溶剂化物。
[0053]本发明的另一个方面是方法,其中药剂是HIV附着抑制剂。
[0054]本发明的另一个方面是方法,其中药剂是CCR5抑制剂。
[0055]本发明的另一个方面是方法,其中CCR5抑制剂选自Sch-C、Sch-D、TAK-220、PRO-140和UK-427,857,或它们药学上可接受的盐或溶剂化物。
[0056]本发明的另一个方面是方法,其中药剂是CXCR4抑制剂。
[0057]本发明的另一个方面是方法,其中CXCR4抑制剂是AMD-3100,或其药学上可接受的盐或溶剂化物。
[0058]本发明的另一个方面是方法,其中药剂是HIV出芽或成熟抑制剂。
[0059]本发明的另一个方面是方法,其中HIV出芽或成熟抑制剂是PA-457,或其药学上可接受的盐或溶剂化物。
[0060]本发明的另一个方面是方法,其中药剂是HIV整合酶抑制剂。
[0061]本发明的另一个方面是药物组合物,包括治疗有效量的式I化合物,或其药学上可接受的盐或溶剂化物;与至少一种用于治疗AIDS或HIV感染的其它药剂,所述其它药剂选自核苷HIV逆转录酶抑制剂、非核苷HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、HIV融合抑制剂、HIV附着抑制剂、CCR5抑制剂、CXCR4抑制剂、HIV出芽或成熟抑制剂和HIV整合酶抑制剂;和药学上可接受的载体。
[0062]本发明的另一个方面是组合物,其中药剂是核苷HIV逆转录酶抑制剂。
[0063]本发明的另一个方面是组合物,其中核苷HIV逆转录酶抑制剂选自阿巴卡韦、去羟肌苷、恩曲他滨、拉米夫定、司他夫定、替诺福韦、扎西他滨和齐多夫定,或它们药学上可接受的盐或溶剂化物。
[0064]本发明的另一个方面是组合物,其中药剂是非核苷HIV逆转录酶抑制剂。
[0065]本发明的另一个方面是组合物,其中非核苷HIV逆转录酶抑制剂选自地拉韦啶、依法韦伦和奈韦拉平,或它们药学上可接受的盐或溶剂化物。
[0066]本发明的另一个方面是组合物,其中药剂是HIV蛋白酶抑制剂。
[0067]本发明的另一个方面是组合物,其中HIV蛋白酶抑制剂选自安普那韦、阿扎那韦、茚地那韦、洛匹那韦、奈非那韦、利托那韦、沙奎那韦和夫沙那韦,或它们药学上可接受的盐或溶剂化物。
[0068]本发明的另一个方面是组合物,其中药剂是HIV融合抑制剂。
[0069]本发明的另一个方面是组合物,其中HIV融合抑制剂是恩夫韦地或T-1249,或它们药学上可接受的盐或溶剂化物。
[0070]本发明的另一个方面是组合物,其中药剂是HIV附着抑制剂。
[0071]本发明的另一个方面是组合物,其中药剂是CCR5抑制剂。
[0072]本发明的另一个方面是组合物,其中CCR5抑制剂选自Sch-C、Sch-D、TAK-220、PRO-140和UK-427,857,或它们药学上可接受的盐或溶剂化物。
[0073]本发明的另一个方面是组合物,其中药剂是CXCR4抑制剂。
[0074]本发明的另一个方面是组合物,其中CXCR4抑制剂是AMD-3100,或其药学上可接受的盐或溶剂化物。
[0075]本发明的另一个方面是组合物,其中药剂是HIV出芽或成熟抑制剂。
[0076]本发明的另一个方面是组合物,其中HIV出芽或成熟抑制剂是PA-457,或其药学上可接受的盐或溶剂化物。
[0077]本发明的另一个方面是组合物,其中药剂是HIV整合酶抑制剂。
[0078]关于给予式I化合物和至少一种抗-HIV药剂的“组合”、“同时给药”、“同时”和类似术语意味着,各组分是联合抗逆转录病毒治疗或高活性抗逆转录病毒治疗(HAART)的一部分,如AIDS和HIV感染领域的技术人员所理解。
[0079]“治疗有效的”指如AIDS和HIV感染领域的技术人员所理解的、提供有意义的患者益处所需的药剂量。一般地,治疗目标是抑制病毒量,恢复和保持免疫功能,改善生活质量和降低HIV-相关的发病率和死亡率。
[0080]“患者”指如AIDS和HIV感染领域的技术人员所理解的感染HIV病毒并适于治疗的人。
[0081]“治疗(treatment)”、“疗法(therapy)”、“方案(regimen)”、“HIV感染”、“ARC”、“AIDS”和相关的术语如AIDS和HIV感染领域的技术人员所理解而使用。
[0082]本发明的化合物一般作为药物组合物给出,它们由治疗有效量的式I化合物或其药学上可接受的盐和药学上可接受的载体构成,并可以含有常规的赋形剂。治疗有效量是指提供有意义的患者益处所需的量。药学上可接受的载体是那些常规已知的具有可接受的安全性的载体。组合物包括所有普通的固体和液体形式,包括胶囊、片剂、锭剂和粉末剂以及液体悬浮剂、糖浆、酏剂和溶液。组合物用普通的配制技术制备,并且常规的赋形剂(如粘结剂和润湿剂)和载体(如水和醇)通常用于组合物。
[0083]固体组合物通常以剂量单位配制,优选每剂量提供大约1到1000mg活性成分的组合物。剂量的一些例子是1mg、10mg、100mg、250mg、500mg和1000mg。一般地,其它抗逆转录病毒药剂将以与临床上使用的该类药剂相似的单位范围存在。典型地,是0.25-1000mg/单位。
[0084]液体组合物通常处于剂量单位范围。一般地,液体组合物会在1-100mg/mL的剂量单位范围。一些剂量的例子是1mg/mL、10mg/mL、25mg/mL、50mg/mL和100mg/mL。一般地,其它抗逆转录病毒药剂将以与临床上使用的该类药剂相似的单位范围存在。典型地,是1-100mg/mL。
[0085]本发明包括所有常规的给药方式,优选口服和胃肠外方法。一般地,给药方案与临床上使用的其它抗逆转录病毒剂类似。典型地,每日剂量将是每日1-100mg/kg体重。一般地,较多的化合物需要口服,较少的化合物需要胃肠外给药。然而,具体的给药方案将由医生用合理的医学判断来确定。
[0086]本发明也包括在联合治疗中给予化合物的方法,也就是说,该化合物可以与用于治疗AIDS和HIV感染的其它药物联合应用,但与所述其它药物分开应用。一些这样的药物包括HIV附着抑制剂、CCR5抑制剂、CXCR4抑制剂、HIV细胞融合抑制剂、HIV整合酶抑制剂、HIV核苷逆转录酶抑制剂、HIV非核苷逆转录酶抑制剂、HIV蛋白酶抑制剂、出芽和成熟抑制剂、免疫调节剂和抗感染剂。在这些联合方法中,式I化合物一般以每日1-100mg/kg体重的日剂量与其它药物联合给予。其它药物一般将以治疗上使用的量给予。然而,具体的给药方案将由医生用合理的医学判断来确定。
[0087]表3列出了一些用于治疗AIDS和HIV感染的药物,它们适合于本发明。
表3.抗病毒药
药物名称 | 制造商 | 适应症 |
097(非-核苷逆转录酶抑制剂) | Hoechst/Bayer | HIV感染,AIDS,ARC |
安普那韦141 W94GW 141(蛋白酶抑制剂) | Glaxo Wellcome | HIV感染,AIDS,ARC |
阿巴卡韦(1592U89)GW 1592(RT抑制剂) | Glaxo Wellcome | HIV感染,AIDS,ARC |
药物名称 | 制造商 | 适应症 |
醋孟南(Acemannan) | Carrington Labs(Irving,TX) | ARC |
阿昔洛韦(Acyclovir) | Burroughs Wellcome | HIV感染,AIDS,ARC,与AZT联合 |
AD-439 | Tanox Biosystems | HIV感染,AIDS,ARC |
AD-519 | Tanox Biosystems | HIV感染,AIDS,ARC |
阿德福韦二匹伏酯AL-721 | Gilead SciencesEthigen(Los Angeles,CA) | HIV感染,ARC,PGLHIV阳性,AIDS |
α干扰素HIV与齐多夫定(Retrovir)联用 | Glaxo Wellcome | 卡波西肉瘤 |
安莎霉素LM 427 | Adria Laboratories(Dublin,OH)Erbamont(Stamford,CT) | ARC |
中和pH不稳定的α异常干扰素的抗体 | Advanced BiotherapyConcepts(Rockville,MD) | AIDS,ARC |
AR177 | Aronex Pharm | HIV感染,AIDS,ARC |
β-氟-ddA | Nat′l Cancer Institute | 与AIDS有关的疾病 |
BMS-232623(CGP-73547)(蛋白酶抑制剂) | Bristol-Myers Squibb/Novartis | HIV感染,AIDS,ARC |
BMS-234475(CGP-61755)(蛋白酶抑制剂) | Bristol-Myers Squibb/Novartis | HIV感染,AIDS,ARC |
CI-1012 | Warner-Lambert | HIV-1感染 |
药物名称 | 制造商 | 适应症 |
西多福韦 | Gilead Science | CMV视网膜炎,疱疹,乳头瘤病毒 |
凝胶多糖硫酸酯(curdlansulfate) | AJI Pharma USA | HIV感染 |
巨细胞病毒免疫球蛋白 | MedImmune | CMV视网膜炎 |
赛美维(Cytovene) | Syntex | 视力恶化(sightthreatening) |
更昔洛韦 | CMV,外周;CMV视网膜炎 | |
Delaviridine(RT抑制剂) | Pharmacia-Upjohn | HIV感染,AIDS,ARC |
硫酸葡聚糖 | Ueno Fine Chem.Ind.Ltd.(Osaka,Japan) | AIDS,ARC,无症状的HIV阳性 |
ddC双脱氧胞苷 | Hoffman-La Roche | HIV感染,AIDS,ARC |
ddI双脱氧肌苷 | Bristol-Myers Squibb | HIV感染,AIDS,ARC;与AZT/d4T联用 |
DMP-450(蛋白酶抑制剂) | AVID(Camden,NJ) | HIV感染,AIDS,ARC |
依法韦伦(DMP 266)(-)6-氯-4-(S)-环丙基乙炔基-4(S)-三氟-甲基-1,4-二氢-2H-3,1-苯并噁嗪-2-酮,施多宁(非核苷RT抑制剂) | DuPont Merck | HIV感染,AIDS,ARC |
药物名称 | 制造商 | 适应症 |
EL10 | Elan Corp,PLC(Gainesville,GA) | HIV感染 |
泛昔洛韦(Famciclovir) | Smith Kline | 带状疱疹,单纯性疱疹 |
FTC(逆转录酶抑制剂) | Emory University | HIV感染,AIDS,ARC |
GS 840(逆转录酶抑制剂) | Gilead | HIV感染,AIDS,ARC |
HBY097(非核苷逆转录酶抑制剂) | Hoechst MarionRoussel | HIV感染,AIDS,ARC |
金丝桃素 | VIMRx Pharm. | HIV感染,AIDS,ARC |
重组人干扰素β | Triton Biosciences(Almeda,CA) | AIDS,卡波西肉瘤,ARC |
干扰素α-n3 | Interferon Sciences | ARC,AIDS |
茚地那韦 | Merck | HIV感染,AIDS,ARC,无症状HIV阳性,也与AZT/ddI/ddC联用 |
ISIS 2922 | ISIS Pharmaceuticals | CMV视网膜炎 |
KNI-272 | Nat′l Cancer Institute | 与HIV有关的疾病 |
拉米夫定,3TC(逆转录酶抑制剂) | Glaxo Wellcome | HIV感染,AIDS,ARC,也与AZT联用 |
洛布卡韦 | Bristol-Myers Squibb | CMV感染 |
奈非那韦(蛋白酶抑制剂) | AgouronPharmaceuticals | HIV感染,AIDS,ARC |
奈韦拉平(RT抑制剂) | BoeheringerIngleheim | HIV感染,AIDS,ARC |
药物名称 | 制造商 | 适应症 |
Novapren | Novaferon Labs,Inc.(Akron,OH) | HIV抑制剂 |
T肽八肽序列 | Peninsula Labs(Belmont,CA) | AIDS |
膦甲酸三钠(TrisodiumPhosphonoformate) | Astra Pharm.Products,Inc. | CMV视网膜炎,HIV感染,其它CMV感染 |
PNU-140690(蛋白酶抑制剂) | Pharmacia Upjohn | HIV感染,AIDS,ARC |
普罗布考 | Vyrex | HIV感染,AIDS |
RBC-CD4 | Sheffield Med.Tech(Houston,TX) | HIV感染,AIDS,ARC |
利托那韦(蛋白酶抑制剂) | Abbott | HIV感染,AIDS,ARC |
沙奎那韦(蛋白酶抑制剂) | Hoffmann-LaRoche | HIV感染,AIDS,ARC |
司他夫定;d4T双脱氢脱氧胸苷 | Bristol-Myers Squibb | HIV感染,AIDS,ARC |
伐昔洛韦(Valaciclovir) | Glaxo Wellcome | 生殖HSV和CMV感染 |
病毒唑(Virazole)利巴韦林 | Viratek/ICN(Costa Mesa,CA) | 无症状HIV-阳性,LAS,ARC |
VX-478 | Vertex | HIV感染,AIDS,ARC |
扎西他滨 | Hoffmann-LaRoche | HIV感染,AIDS,ARC,与AZT联用 |
齐多夫定;AZT | Glaxo Wellcome | HIV感染,AIDS,ARC,卡波西肉瘤,与其它疗法联用 |
免疫调节剂
药物名称 | 制造商 | 适应症 |
AS-101 | Wyeth-Ayerst | AIDS |
溴匹立明 | Pharmacia Upjohn | 晚期AIDS |
醋孟南 | Carrington Labs,Inc.(Irving,TX) | AIDS,ARC |
CL246,738 | American CyanamidLederle Labs | AIDS,卡波西肉瘤 |
EL10 | Elan Corp,PLC(Gainesville,GA) | HIV感染 |
FP-21399 | Fuki ImmunoPharm | 阻断HIV与CD4+细胞融合 |
药物名称 | 制造商 | 适应症 |
γ干扰素 | Genentech | ARC,与TNF(肿瘤坏死因子)联用 |
粒细胞巨噬细胞集落刺激因子 | Genetics InstituteSandoz | AIDS |
粒细胞巨噬细胞集落刺激因子 | Hoechst-RousselImmunex | AIDS |
粒细胞巨噬细胞集落刺激因子 | Schering-Plough | AIDS,与AZT联用 |
HIV核心颗粒免疫刺激剂 | Rorer | 血清阳性HIV |
IL-2白细胞介素-2 | Cetus | AIDS,与AZT联用 |
IL-2白细胞介素-2 | Hoffman-LaRocheImmunex | AIDS,ARC,HIV,与AZT联用 |
IL-2白细胞介素-2(aldeslukin) | Chiron | AIDS,CD4细胞数增加 |
免疫球蛋白静脉内(人类) | Cutter Biological(Berkeley,CA) | 儿童AIDS,与AZT联用 |
IMREG-1 | Imreg(New Orleans,LA) | AIDS,卡波西肉瘤,ARC,PGL |
IMREG-2 | Imreg(New Orleans,LA) | AIDS,卡波西肉瘤,ARC,PGL |
依木疏二乙基二硫氨基甲酸酯(Imuthiol DiethylDithio Carbamate) | Merieux Institute | AIDS,ARC |
α-2干扰素 | Schering Plough | 卡波西肉瘤与AZT联用,AIDS |
药物名称 | 制造商 | 适应症 |
蛋氨酸-脑啡肽 | TNI Pharmaceutical(Chicago,IL) | AIDS,ARC |
MTP-PE胞壁酰-三肽粒细胞集落刺激因子 | Ciba-Geigy Corp.Amgen | 卡波西肉瘤AIDS,与AZT联用 |
Remune | Immune ResponseCorp. | 免疫治疗 |
rCD4重组可溶性人CD4 | Genentech | AIDS,ARC |
rCD4-IgG杂合物 | AIDS,ARC | |
重组可溶性人CD4 | Biogen | AIDS,ARC |
干扰素α2a | Hoffman-La Rochein combination w/AZT | 卡波西肉瘤,AIDS,ARC |
SK&F106528可溶性T4 | Smith Kline | HIV感染 |
胸腺五肽(Thymopentin) | ImmunobiologyResearch Institute(Annandale,NJ) | HIV感染 |
肿瘤坏死因子;TNF | Genentech | ARC,与γ干扰素联用 |
抗感染剂
药物名称 | 制造商 | 适应症 |
克林霉素与伯氨喹 | Pharmacia Upjohn | PCP |
氟康唑 | Pfizer | 隐球菌性脑膜炎,念珠菌病 |
锭剂制霉菌素(Nystatin)锭剂 | Squibb Corp. | 预防口腔念珠菌病 |
药物名称 | 制造商 | 适应症 |
盐酸依氟鸟氨酸依洛尼塞(Eflornithine) | Merrell Dow | PCP |
依西酸喷他脒(经肌肉和经静脉(IM &IV)) | LyphoMed(Rosemont,IL) | PCP治疗 |
甲氧苄啶 | 抗菌剂 | |
联磺甲氧苄啶(Trimethoprim/sulfa) | 抗菌剂 | |
吡曲克辛(Piritrexim) | Burroughs Wellcome | PCP治疗 |
吸入用依西酸喷他脒 | Fisons Corporation | PCP预防 |
螺旋霉素(Spiramycin) | Rhone-Poulencdiarrhea | 隐孢子虫感染 |
伊曲康唑(Intraconazole)-R51211 | Janssen-Pharm. | 组织胞浆菌病;隐球菌性脑膜炎 |
三甲曲沙(Trimetrexate) | Warner-Lambert | PCP |
柔红霉素 | NeXstar,Sequus | 卡波西肉瘤 |
重组人促红细胞生成素 | Ortho Pharm.Corp. | 与AZT治疗有关的严重贫血 |
重组人生长激素 | Serono | AIDS相关的消瘦,恶病质 |
醋酸甲地孕酮 | Bristol-Myers Squibb | 治疗与AIDS相关的厌食 |
睾酮 | Alza,Smith Kline | AIDS相关的消瘦 |
全肠内营养 | Norwich EatonPharmaceuticals | AIDS相关的腹泻和吸收障碍 |
具体实施方式
中间体1
[0088]1-(5-氯-2-甲苯磺酰基)哌嗪:将5-氟-2-甲苯磺酰氯(35.1g,168.5mmol)的二乙醚溶液(50mL)逐滴地加入到哌嗪(28.8g,337.0mmol)的二乙醚(500mL)和三乙胺(47mL,337.0mmol)悬浮液中。在室温下搅拌白色悬浮液1.5小时。用饱和碳酸钠水溶液洗涤混合物。用水和盐水洗涤有机相并干燥(Na2SO4)。浓缩获得白色固体,用二乙醚研制该白色固体得到白色固体的标题化合物(30.95g,收率36%)。1H NMR(300MHz,CDCl3)δ:7.57(1H,dd,J=8.6,2.7Hz),7.25(1H,dd,J=8.4,5.1Hz),7.12(1H,td,J=8.1,2.8Hz),3.13-3.10(4H,m),2.98-2.85(4H,m),2.55(3H,s),1.69(1H,bs)。C11H16FN2O2S的LCMS(M+H)计算值:259.09;测定值:259.18。
中间体2
[0089]2,2,2-三氯-1-(4-(5-氯-2-甲苯磺酰基)哌嗪-1-基)乙酮:在室温下搅拌中间体1(30.9g,120mmol)、三乙胺(16.8mL,120mmol)和三氟乙酸乙酯(18mL,150mmol)在甲醇(60mL)中的混合物18小时。将混合物浓缩,残余物在乙酸乙酯和水之间分配,过滤除去不溶的固体。用1NHCl水溶液、饱和碳酸氢钠水溶液、水和盐水洗涤有机相。干燥(Na2SO4)和浓缩后,获得无色油状的标题化合物,静置后固化为白色的固体(37.5g,收率88%)。1H NMR(300MHz,CDCl3)δ:7.58(1H,dd,J=8.4,2.9Hz),7.29(1H,dd,J=8.4,5.1Hz),7.18(1H,td,J=8.0,2.8Hz),3.76-3.73(2H,m),3.68-3.65(2H,m),3.28-3.23(4H,m),2.55(3H,s)。C13H15F4N2O3S的LCMS(M+H)计算值为:355.07;实测值:355.14。
中间体3
[0090]1-(4-(2-(溴甲基)-5-氟苯磺酰基)哌嗪-1-基)-2,2,2-三氟乙酮。使中间体2(37.5g,105.9mmol)、NBS(19.4g,105.9mmol)和AIBN(0.45g,2.8mmol)在四氯化碳(500mL)中的混合物回流4小时。将混合物冷却、浓缩和通过用EtOAc洗脱的硅胶纯化,获得被原料和二溴化副产物污染的琥珀色油状标题化合物(41.0g)。C13H14F4N2O3SBr的LCMS(M+H)计算值:433.97;实测值:433.01。
中间体4
1-(4-(2-(叠氮甲基)-5-氟苯磺酰基)哌嗪-1-基)-2,2,2-三氟乙酮:将中间体3(41.0g,不纯)溶于DMF(100mL)中。加入叠氮钠(6.2g,94mmol),在80℃下搅拌混合物4小时。将混合物冷却并浓缩到接近干燥。将残余物在EtOAc和水之间分配。用水、盐水洗涤有机相,干燥(Na2SO4)和浓缩。通过用10%EtOAc/己烷洗脱的急骤层析(flashchromatography)纯化,产生无色油状的标题化合物(23.8g,经过两个步骤收率为57%)。1H NMR(300MHz,CDCl3)δ:7.64-7.56(2H,m),7.36-7.27(1H,m),4.72(2H,s),3.78-3.64(4H,m),3.28-3.23(4H,m)。
中间体5
1-(4-(2-(氨甲基)-5-氟苯磺酰基)哌嗪-1-基)-2,2,2-三氟乙酮:使N2鼓泡通过中间体4(23.8g,60.2mmol)溶解在EtOH(100mL)、EtOAc(30mL)和1N HCl水溶液(60mL,60mmol)中的溶液,对该溶液进行脱气。接着加入10%Pd/C(1.0g),并在50psi(磅/平方英尺)在H2下振荡混合物18h(小时)。反应混合物通过C盐(C celite)过滤,并浓缩溶液。在EtOAc和水之间分配残余物。冻干水相,获得为白色固体盐酸盐的标题化合物(7.91g,收率32%)。C13H16F4N3O3S的LCMS(M+H)计算值:370.08;实测值:370.17。
中间体6
(4-氯-2-(哌嗪-1-基磺酰基)苯基)甲胺:将中间体5(7.9g,19.5mmol)和氢氧化钾(5.6g,98mmol)在MeOH(50mL)中的溶液在室温下搅拌30min(分钟)。通过过滤除去反应中形成的固体,浓缩溶液。将获得的油状物溶于水,并用1N盐酸水溶液调成酸性。用EtOAc洗涤该水溶液并冻干,得到为白色固体盐酸盐的标题化合物(6.7g,收率100%)。1H NMR(300MHz,DMSO-d6)δ:9.47(1H,bs),8.66(2H,bs),7.92(1H,dd,J=8.4,5.1Hz),7.80-7.73(2H,m),4.32(2H,s),3.38-3.32(4H,m),3.20-3.17(4H,m)。C11H17FN3O2S的LCMS(M+H)计算值:274.10;实测值:274.20。
中间体7
4-(5-氟-2-甲苯磺酰基)吗啉:按照中间体1的程序,使用5-氟-2-甲苯磺酰氯(10.0g,48mmol)、三乙胺(13.9mL,100mmol)和吗啉(8.37g,96mmol)产生白色固体的标题化合物(10.07g,收率81%)。1H NMR(300MHz,CDCl3)δ:7.58(1H,dd,J=8.6,2.7Hz),7.27(1H,dd,J=8.4,5.1Hz),7.15(1H,td,J=8.1,2.8Hz),3.72-3.68(4H,m),3.16-3.13(4H,m),2.57(3H,s)。C11H15FNO3S的LCMS(M+H)计算值:260.07;实测值:260.15。
中间体8
4-(2-(溴甲基)-5-氟苯磺酰基)吗啉:按照中间体3的程序,使用中间体7(10.0g,38.6mmol),产生黄色油状的标题化合物,其不进行纯化而继续使用。
中间体9
4-(2-(叠氮甲基)-5-氟苯磺酰基)吗啉:按照中间体4的程序,使用中间体8(粗制),得到淡黄色油状的标题化合物(8.21g,通过两步的收率为71%)。
中间体10
(4-氟-2-(吗啉基磺酰基)苯基)甲胺:按照中间体5的程序,使用中间体9产生为棕色固体盐酸盐的标题化合物(4.29g,收率51%)。1H NMR(300MHz,CD3OD)δ:7.80-7.73(2H,m),7.57(1H,td,J=8.1,2.8Hz),4.43(2H,s),3.76-3.73(4H,m),3.19-3.15(4H,m)。C11H16FN2O3S的LCMS(M+H)计算值:275.08;实测值:275.15。
中间体11
按照中间体10的程序,使用4-羟基哌啶进行制备。1H NMR(300MHz,CD3OD)δ:7.78-7.71(2H,m),7.54(1H,t,J=8.2,2.9Hz),4.43(2H,s),3.82-3.74(1H,m),3.56-3.49(2H,m),3.12-3.04(2H,m),1.98-1.89(2H,m),1.66-1.55(2H,m)。C12H18N2O3FS的LCMS(M+H)计算值:289.10;实测值:289.16。
中间体12
1,4,8-三氧杂-螺[4.5]癸烷。使四氢-4-吡喃酮(10g,99.9mmol)、乙二醇(20mL,150mmol)和催化性甲苯磺酸的混合物在苯(120mL)中回流5h。冷却至室温后,将苯层从烧瓶底部的深色油状物滗去并浓缩。形成的油状物在二氯甲烷中溶解并在分液漏斗中振荡。从不溶的油状物中倒出CH2Cl2层。浓缩CH2Cl2层产生淡黄色油状的中间体16(11.62g,收率81%)。1H-NMR(300MHz,CDCl3)δ:3.91(4H,s),3.71(4H,t,J=5.5Hz),1.68(4H,t,J=5.7Hz)。
中间体13
(E)-2-{[4-(2-羟乙氧基)四氢吡喃-4-碳亚氨基]-氨氧基}丁-2-烯二酸二乙酯。将中间体12(6.0g,41.7mmol)和ZnI2(45mg,催化的)的搅拌混合物放在水浴中,通过注射器向其加入氰化三甲基硅烷(5.6mL,41.7mmol)。18h后加入另外的ZnI2(1.63g,13.76mol%),在室温下搅拌2h。质子NMR分析表明反应完成50%,加入另外的氰化三甲基(2.8mL,20.85mmol)并搅拌1h。向该粗制的反应混合物中加入EtOH(50mL),接着加入50%羟胺水溶液(2.56mL,41.7mmol),在80℃下搅拌2h。接着,在冰水浴中冷却反应混合物,并在5分钟期间加入丁炔二酸二乙酯(diethyl acetylenedicarboxylate)(7.0mL,56.25mmol)。接着移走冷浴,在室温下搅拌15h,浓缩并在利用己烷/EtOAc混合物的硅胶柱上通过急骤层析纯化残余物,得到黄色油状的中间体13(9.3g,60%)。1H-NMR(300MHz,CDCl3)δ:5.72(1H,d,J=22.7Hz),5.50(1H,bs),5.29(1H,bs),4.33-4.23(2H,m),4.19-4.04(2H,m),3.95-3.87(1H,m),3.79-3.63(6H,m),3.43-3.39(2H,m),2.15-1.74(4H,m),1.35-1.19(6H,m)。C16H27N2O8的LCMS[M+H]+计算值:375.17;实测值:375.19。
中间体14
[0091]5-羟基-2-[4-(2-羟乙氧基)四氢吡喃-4-基]-6-氧代-1,6-二氢嘧啶-4-羧酸乙酯。使中间体13(9.3g,25mmol)在二甲苯(150mL)中的溶液回流18h。冷却至室温后,用0.2M Na2CO3振荡混合物。用EtOAc洗涤水相,用浓盐酸调节成酸性并用CH2Cl2萃取。干燥(Na2SO4)有机相并浓缩。用醚研制获得的残余物,获得为棕色固体的中间体14(0.87g,收率10%)和不纯的产物(2.36g)。C14H21N2O7的LCMS[M+H]+计算值:329.13;实测值:329.15。
中间体15
[0092]向在0℃下的THF(10mL)中的中间体14(0.86g,2.6mmol)的搅拌溶液加入甲磺酰氯(0.613mL,7.9mmol),接着加入三乙胺(1.07mL,7.9mmol)。混合物搅拌4h同时逐渐升至室温,随后用EtOAc稀释。用水、盐水洗涤混合物并干燥(Na2SO4)和浓缩,得到深色油状物。将其溶于EtOH(20mL)和THF(10mL)中并加入碳酸钾(0.56g,4.04mmol)。在室温下搅拌混合物18h,用EtOAc(200mL)稀释,过滤除去固体。浓缩溶液并用甲醇研制残余物。过滤得到为白色固体的中间体15(0.23g,23%)。1H-NMR(300MHz,CDCl3)δ:4.41(2H,q,J=7.2Hz),4.03-3.98(4H,m),3.88-3.82(2H,m),3.74(2H,t,J=11.2Hz),3.50(3H,s),2.44(2H,dt,J=13.1,4.9Hz),1.76(2H,d,J=13.9Hz),1.38(3H,t,J=7.1Hz)。C15H21N2O8S3的LCMS[M+H]+计算值:389.10;实测值:389.13。
中间体16
[0093]向中间体15(1.1g,2.8mmol)的EtOH(20mL)悬浮液中加入乙醇钠(0.25g,3.66mmol),将获得的混合物回流1小时,冷却和浓缩。残余物在EtOAc和水之间分配,用1N HCl将水相调成酸性,用EtOAc萃取。将所有的有机相合并并用盐水洗涤,干燥(Na2SO4)和浓缩。用Et2O研制残余物,过滤收集为白色固体的标题化合物(0.84g,收率97%)。1H-NMR(300MHz,CDCl3)δ:10.62(1H,s),4.42(2H,q,J=7.2Hz),4.00(4H,s),3.89-3.84(2H,m),3.76(2H,t,J=11.8,1.9Hz),2.41(2H,td,J=1.3,5.5Hz),1.75(2H,dd,J=13.9,1.8Hz),1.41(3H,t,J=7.1Hz)。C14H19N2O6的LCMS[M+H]+计算值:311.12;实测值:311.21。
中间体17
[0094]1-(2-氯乙氧基)环戊腈:向在5℃下的环戊酮乙二醇缩酮(128.17g,1mole)和氰化三甲基硅烷(100g,1mole)的搅拌混合物中一次性加入碘化锌(1.3g,4mmol)。1h后移走冷浴在室温下过夜(18h)。向其加入2N的盐酸水溶液(500mL)和MeOH(100mL),在室温下搅拌1h。随后将反应混合物转移到分液漏斗并用CH2Cl2(4×250mL)萃取。干燥合并的CH2Cl2萃取物(Na2SO4)、过滤和浓缩,获得棕色液体。
[0095]将上述在CH2Cl2(200mL)中的棕色液体的溶液通过套管在1h内加到CH2Cl2(250mL)中的亚硫酰氯搅拌溶液(91.2mL,1.25mole)中。用CH2Cl2(50mL)冲洗加料烧瓶并加到反应混合物中。回流得到的棕色反应混合物3h,将其冷却和浓缩,得到深色液体。该液体用醚(250mL)稀释,用水(2×100mL)、饱和NaHCO3(2×100mL)洗涤,干燥(Na2SO4),过滤和浓缩,得到深褐色的液体,其蒸馏后得到为无色液体的标题化合物(129.146g,74.4%,BP 68-71℃ @ 0.8mmHg)。1HNMR(500MHz,CDCl3)δ:3.79(2H,t,J=5.5Hz),3.61(2H,t,J=5.5Hz),2.16-1.99(4H,m),1.85-1.71(4H,m)。
中间体18
[0096]在室温下,搅拌中间体17(129.14g,0.7437mole(摩尔))、50%羟胺水溶液(54.7mL,0.8925mole)和Na2CO3(31.532g,0.2975mole)在MeOH/H2O(2∶1,500mL)中的混合物6h,和在65℃下搅拌2h。冷却获得的澄清反应混合物并减压浓缩。得到的残余物重溶于EtOH/H2O(1∶3,500mL),在冰水浴中冷却,并用丁炔二酸二乙酯(119.1mL,0.7437mol)处理15分钟。室温下搅拌2h后,用醚(500mL)稀释反应混合物,排走水层,用水(2×100mL)、盐水(100mL)洗涤有机层,干燥(Na2SO4),过滤和浓缩,获得黄色油状物。用10-30%EtOAc/Hex混合物在硅胶柱上进行急骤层析,获得为黄色液体的纯产物(196g,77.43%)。1HNMR(500MHz,CDCl3)δ:4.36-4.20(2H,m),4.18-4.12(2H,m),3.99-3.90(2H,m),3.59-3.56(1H,m),3.51-3.47(1H,m),3.30(1H,d,JAB=16.2Hz),2.92(1H,d,JAB=16.2Hz),2.27-2.21(1H,m),2.13-2.07(1H,m),2.01-1.91(2H,m),1.79-1.68(2H,m),1.29(3H,t,J=7.0Hz),1.24(3H,t,J=7.0Hz)。C16H25N2O6的HRMS(M+H)计算值:341.1713,实测值:341.1711。
中间体19
[0097]在155℃下加热中间体18(196g,0.5758mole)在1,2,4-三甲苯(1.5Lit.(升))中的溶液7h,并缓慢地冷却该深色反应混合物至室温。过滤结晶产物并用己烷洗涤,得到浅褐色的粉末(58.622g)。浓缩滤液,研制得到的残余物,形成另外的38.484g为浅褐色粉末的产物。再次浓缩滤液,将得到的深色残余物溶于醚(500mL),并用0.5M Na2CO3水溶液(2×200mL)萃取。弃去有机层,合并水层,小心地用浓盐酸(40mL)酸化。过滤沉淀的产物,干燥成黄色粉末产物(6.1876g)。合并的产量为103.2936g(61%)。1H NMR(500MHz,CDCl3)δ:10.49(1H,s),4.44(2H,q,J=7.0Hz),4.03-3.97(4H,m),2.28-2.22(2H,m),2.06-2.01(2H,m),1.93-1.81(4H,m),1.42(3H,t,J=7.0Hz)。C14H19N2O5的HRMS(M+H)计算值:295.1294;实测值:295.1293。
中间体20
[0098]5,8-二氧杂-螺[3.4]辛烷。用迪安-斯达克分水器(Dean-Stark trap)回流下加热环丁酮(7.7g,0.11mol)、乙二醇(6.82g,0.11mol)和对甲苯磺酸一水合物(200mg,1mmol)的苯(200mL)溶液14小时。冷却后,用碳酸氢钠水溶液(饱和的,15mL),接着用盐水洗涤混合物,并干燥(硫酸镁)、过滤和浓缩,获得为无色液体的9.37g(82%)中间体24:1H NMR(CDCl3,500MHz)δ:3.87(4H,s),2.31(4H,t,J=8Hz),1.67(2H,qt,J=8Hz);13C NMR(CDCl3,125.77Hz)δ:109.08,63.87,35.58,11.42。
中间体21
[0099]2-{[1-(2-羟乙氧基)环丁烷碳亚氨基]-氨氧基}丁-2-二烯二酸二乙酯。向~10℃冷水浴中的中间体20(5.70g,50mmol)和氰化三甲基硅烷(5.05g,50mmol)的混合物中加入催化量的ZnI2(12mg),在室温下搅拌5小时,获得10.7g为流性油状物的1-(2-三甲基硅烷基氧基乙氧基)环丁腈(1-(2-trimethylsilanyloxyethoxy)cyclobutanecarbonitrile):1H NMR(CDCl3,500MHz)δ:3.75(2H,t,J=5Hz),3.55(2H,t,J=5Hz),2.51-2.56(2H,m),2.30-2.37(2H,m),1.91-1.98(2H,m),0.124(9H,s,);13C NMR(CDCl3,125.77Hz)δ:120.43,72.05,67.71,61.49,34.02,12.91,-0.29。LC/MS m/z 142(M+H-SiMe3)。
[0100]在80℃下加热的油浴中,搅拌1-(2-三甲基硅烷基氧基乙氧基)环丁腈(3.5g,16.4mmol)和50%羟胺水溶液(1.08g,16.4mmol)的EtOH(16mL)溶液2.5小时,接着冷却至室温。在冰浴上向溶液中滴加丁炔二酸二乙酯(2.93g,17.2mmol),并在室温下搅拌混合物5小时。真空下浓缩该混合物,获得6.16g的含有中间体21的粗制褐色油状物:1HNMR(500MHz,CDCl3)δ:1.19-1.38(6H,m)1.72-1.86(2H,m)2.06-2.24(2H,m)2.29-2.49(2H,m)3.26-3.38(2H,m)3.65-3.76(2H,m)4.11-4.19(2H,m)4.24-4.38(2H,m)5.67(0.25H,s)5.85(0.5H,s)。C15H25N2O7的HRMS(M+H)计算值:345.1662;实测值:345.1648。
中间体22
[0101]5-羟基-2-[1-(2-羟基-乙氧基)-环丁基]-6-氧代-1,6-二氢-嘧啶-4-羧酸乙酯。在150-155℃下加热粗制中间体21(5.9g)的二甲苯(30mL)溶液20h。真空浓缩混合物,将残余物重溶于EtOAc(30mL)中,用1M碳酸钠水溶液(3×20mL)萃取。通过小心加入浓盐酸酸化水性萃取物,并用CH2Cl2(2×20ml)萃取该混合物。干燥合并的有机萃取物(Na2SO4),过滤并浓缩,获得褐色油状物22(1.19g,经三个步骤的收率为24%):LC/MS m/z 299(M+H)。
中间体23
[102]1-(甲磺酰基)-5-(甲基磺酰氧基)-2-(1-(2-(甲基磺酰氧基)乙氧基)-环丁基)-6-氧代-1,6-二氢嘧啶-4-羧酸乙酯:用甲磺酰氯(Aldrich)通过逐滴加入处理22(7.23g,25mmol)的无水四氢呋喃冷(0℃)溶液。将溶液升至室温并搅拌4小时。真空浓缩反应,将粗制产物溶于乙酸乙酯(75mL)并用饱和的碳酸氢钠溶液洗涤。干燥有机溶液(硫酸钠),过滤除去固体,并真空浓缩,获得褐色油状物23。该物质在随后的反应中使用,不用进一步纯化。1H NMR(500MHz,CDCl3)δ:4.49(2H,q,J=7.0Hz),4.35-4.38(2H,m),3.93-4.00(1H,m),3.66-3.67(3H,s),3.62-3.65(2H,m),3.44-3.46(3H,s),3.05-3.07(3H,s),2.74-2.82(1H,m),2.60-2.67(2H,m),2.41-2.49(2H,m),1.43(3H,t,J=7.0Hz)。LCMS(M+H):532.94。
中间体24
[103]向上述获得的23在无水乙醇(50mL)和无水四氢呋喃(75mL)中的溶液中加入无水碳酸钾(3.46g,25mmol),加热下(65℃)搅拌反应20小时。真空中除去溶剂,将粗制产物溶于水(150mL),用乙酸乙酯(2×100mL)萃取。用6.0N盐酸将水层调成酸性(pH~1-2),得到的固体用乙酸乙酯(2×75mL)萃取。干燥合并的萃取物(硫酸钠),过滤除去固体,浓缩获得淡褐色固体24(4.30g,61%)。1H NMR(500MHz,CDCl3)δ:10.57(1H,s),4.46(2H,q,J=7.2Hz),3.97(4H,s),2.67-2.73(2H,m),2.27-2.33(2H,m),2.10-2.18(1H,m),1.98-2.06(1H,m),1.44(3H,t,J=7.2Hz)。13C NMR(126MHz,CDCl3):169.56,157.68,150.41,148.19,125.24,79.09,62.63,58.52,42.66,34.72,14.18,13.87;LC/MS(M+H):281.13。
中间体25
[0104]2-(2-氯乙氧基)-2-甲基丙腈。(Navalokina,R.等人,J.Org.Chem.USSR(Engl.Trans.),1980,16,1382-1386.2)Ramalingam,K.US-4,864,051,1989.)。向250mL圆底烧瓶中加入ZnCl2(68.14g,0.5mole),其接着通过真空加热熔融。回至室温后,将该物质在N2气氛下放置。向其加入丙酮合氰化氢(45.66mL,0.5mole),接着加入2-氯乙醇(50.24mL,0.75mole),并将混合物放在预热的油浴(60℃)中。在60℃搅拌18-20h后,冷却反应混合物,用水(300mL)稀释并用CH2Cl2(5×100mL)洗涤。干燥合并的CH2Cl2萃取物(Na2SO4),过滤和真空浓缩,获得黄色液体粗制品。通过用维格罗分馏柱真空蒸馏(10mm Hg)完成纯化。收集在65-75℃之间沸腾的馏分,获得期望的无色油状产物(47.1g,收率63.8%)。1H NMR(500MHz,CDCl3)δ:3.85(2H,t,J=5.8Hz),3.64(2H,t,J=5.8Hz),1.60(6H,s)。
中间体26
[0105]2-(2-乙氧基-2-氧代乙基)-8,8-二甲基-2,5,6,8-四氢-[1,2,4]噁二唑并[3,2-c][1,4]噁嗪-2-羧酸乙酯。向中间体25(14.7g,0.10mole)和NaI(1.5g,10mmol)的乙醇(50mL)搅拌溶液中加入羟胺(18.4g,0.30mole)的水溶液(50%),产生放热反应。接着将反应混合物在80℃加热2h。冷却至室温后除去溶剂。将获得的残余物溶于1∶1乙醇/H2O(100mL),在冰浴中冷却。在10分钟内向其中加入丁炔二酸二乙酯(17.6mL,0.110mole)。将反应混合物升至室温和搅拌1h。接着,用乙酸乙酯(250mL)稀释,用H2O(2×100mL)、盐水(50mL)洗涤,经Na2SO4干燥,过滤和浓缩,获得黄色油状的粗制物。在硅胶柱上急骤层析,其用20-40%乙酸乙酯/己烷洗脱,获得粘性的浅黄色油状标题化合物(15.29g,收率48.6%)。1H NMR(500MHz,CDCl3)δ:4.35-4.28(2H,m),4.18-4.12(2H,m),3.60-3.56(1H,m),3.51-3.47(1H,m),3.30(1H,d,J=16.2Hz),2.94(1H,d,J=16.2Hz),1.52(3H,s),1.51(3H,s),1.29(3H,t,J=7.0Hz),1.24(3H,t,J=7.0Hz)。C14H23N2O7的LCMS(M+H)计算值:315.16;实测值:315.33。
中间体27
[0106]3-羟基-9,9-二甲基-4-氧代-4,6,7,9-四氢嘧啶并[2,1-c][1,4]噁嗪-2-羧酸乙酯。在180℃下加热中间体26(31.16g)的1,2,4-三甲苯(200mL)溶液5h。冷却获得的深色反应溶液,接着浓缩,获得深褐色糊状物,将其溶于乙酸乙酯(250mL),并用0.5M Na2CO3水溶液(4×50mL)萃取。弃去有机层,在用CH2Cl2(4×50mL)萃取前,通过小心加入浓盐酸(20mL)酸化水层。干燥合并的CH2Cl2层(Na2SO4),过滤和浓缩,获得深色糊状物,将其溶于醚(100mL),并使其在开口烧瓶中室温下放置。过滤形成的褐色/浅黄色固体,获得标题化合物。再加工含有产物的母液,产生另外的物质(两个步骤的合并收率为~18-20%)。1H NMR(500MHz,CDCl3)δ:10.55(1H,s),4.45(2H,q,J=7.0Hz),4.02(4H,s),1.61(6H,s),1.43(3H,t,J=7.0Hz)。C12H17N2O5的HRMS(M+H)计算值:269.1138;实测值:269.1149。C12H16N2O5的分析计算值:C,53.72;H,6.01;N,10.44。实测值:C,53.71;H,6.04;N,10.30。
中间体28
[0107]1-(3-氯丙基)环戊腈。在-78℃下,通过注射器向环戊腈(1.04mL,10mmol)在THF(20mL)中的搅拌溶液中加入LiHMDS(1M,于THF中,11mL)。30min后,立刻加入1-氯-3-碘丙烷(1.6mL,15mmol)并缓慢升至室温。20h后,用饱和氯化铵(1mL)猝灭反应混合物,用EtOAc(100mL)稀释,干燥(MgSO4),过滤和浓缩,产生黄色油状中间体28,其在下步骤使用,无需进一步纯化。
中间体29
[0108]在5分钟期间,向前述实验获得的中间体28和盐酸羟胺(1.39g,20mmol)在1∶1 EtOH/水(30mL)中的搅拌混合物中加入碳酸钠(1.6g,15mmol)。接着在80℃下将反应混合物搅拌15h并浓缩到干燥。将获得的白色残余物重溶于1∶1 EtOH/水(30mL)中,加入丁炔二酸二乙酯(2.4mL,15mmol)。1小时后,用水(50mL)稀释反应混合物,并用EtOAc(3×50mL)萃取。干燥合并的EtOAc萃取物(Na2SO4),过滤和浓缩,形成褐色油状物。用9∶1、4∶1和7∶1的己烷/EtOAc混合物急骤层析,得到浅黄色油状中间体29(1.03g,30%)。1H NMR(500MHz,CDCl3)δ:4.34-4.11(4H,m),3.50-3.46(1H,m),3.38-3.34(1H,m),3.31(1H,d,J=16.2Hz),2.91(1H,d,J=16.2Hz),2.23-2.13(2H,m),1.95-1.89(2H,m),1.74-1.69(2H,m),1.62(2H,t,J=5.9Hz),1.54-1.48(2H,m),1.34-1.23(8H,m)。C17H27N2O5的HRMS(M+H)计算值:339.1920;实测值:339.1923。
中间体30
[0109]在210℃下加热中间体29(1.0g,2.955mmol)的3,4-二氯甲苯(10mL)溶液15h。接着真空下浓缩反应混合物,通过制备型HPLC用含有0.1%TFA的MeOH/水纯化残余物(梯度洗脱)。合并含有产物的馏分,并浓缩产生为深色糊状物的中间体30(0.8639g,28.6%)。1H NMR(500MHz,CDCl3)δ:10.75(1H,br s),4.43(2H,q,J=7.0Hz),4.03(2H,t,J=5.8Hz),2.25-2.20(2H,m),1.99-1.93(4H,m),1.79-1.64(6H,m),1.42(3H,t,J=7.0Hz)。C15H21N2O4的HRMS(M+H)计算值:293.1501;实测值:293.1513。
中间体31
[0110]应用氮杂环丁烷按照中间体10的程序制备。1H NMR(500MHz,DMSO-d6)δ:1.81-2.26(m,2H)3.82(t,J=7.63Hz,4H)4.30(s,2H)7.66-7.82(m,2H)7.90(dd,J=8.55,5.19Hz,1H)8.52(s,3H);LC/MSm/z 245(M+H)。
中间体32
[0111]向甲苯硫醇(4.2mL,36mmol)的甲苯(40mL)溶液中加入氢化钠(0.96g,36mmol,90wt%),在室温下搅拌该混合物1h。向该反应混合物中加入2,4-二氟苯基氰(5.0g,36mmol),在110℃下搅拌3h。将混合物冷却至室温,用EtOAc稀释并用水、饱和NaHCO3水溶液洗涤,干燥(Na2SO4)和过滤。浓缩滤液直到产物从溶液中析出。通过过滤收集固体,并用己烷/EtOAc(2∶1)洗涤,获得为白色晶体的标题化合物(6.25g,收率71%)。1H NMR(500MHz,CDCl3)δ:7.59(1H,dd,J=8.5,5.8Hz),7.35-7.26(5H,m),7.04(1H,dd,J=8.8,2.4Hz),6.92(1H,td,J=8.1,2.3Hz),4.23(2H,s)。LC/MS m/z 244(M+H)。
中间体33
[0112]在30分钟期间,使氯鼓泡通过中间体32(3.98g,16.4mmol)的冰醋酸(20mL)的搅拌悬浮液,其维持在30℃以上。将得到的黄色溶液用水稀释并用EtOAc萃取产物。合并的有机相用饱和的NaHCO3水溶液(2×)洗涤,干燥(Na2SO4)和过滤。浓缩滤液得到为粘性白色固体的标题化合物,其可以不经纯化而使用。1H NMR(300MHz,CDCl3)δ:7.99(1H,dd,J=8.4,4.7Hz),7.90(1H,dd,J=7.3,2.6Hz),7.57-7.51(1H,m)。
中间体34
[0113]按照中间体1的程序,使用中间体33(4.00mmol)和六亚甲基亚胺(0.68mL,6mmol),接着通过急骤层析(10%-50%EtOAc/己烷)纯化,得到黄色油状标题化合物(0.68g,收率61%)。1H NMR(300MHz,CDCl3)δ:7.83(1H,dd,J=8.6,4.9Hz),7.77(1H,dd,J=8.0,2.6Hz),7.34-7.28(1H,m),3.43-3.39(4H,m),1.77-1.71(4H,m),1.63-1.59(4H,m)。LC/MS m/z 283(M+H)。
中间体35
[0114]向LAH(2.6mL,2.6mmol,1M,于THF中)在THF(3mL)中的搅拌溶液混合物中逐滴加入中间体34(0.68g,2.4mmol)的THF(2mL)溶液。在室温下搅拌得到的混合物1.5h,接着用NaOH(2mL,0.5M)猝灭。过滤除去固体,用水洗涤剩余的溶液并浓缩。残余物溶于Et2O,用醚盐酸(ethereal HCl)(1N)搅拌。将获得的产物溶于水并冻干,得到为粘性橙色固体盐酸盐的标题化合物(0.35g,收率45%)。LC/MS m/z 287(M+H)。
中间体36
[0115]按照中间体1的程序,使用中间体33(17mmol)和3-吡咯烷醇(1.7mL,20.4mmol),接着通过急骤层析(10%-100%EtOAc/己烷)得到为白色固体的标题化合物(1.08g,收率24%)。1H NMR(300MHz,CDCl3)δ:7.85(1H,dd,J=8.4,5.1Hz),7.79(1H,dd,J=8.0,2.6Hz),7.37-7.31(1H,m),4.49(1H,s),3.61-3.45(4H,m),2.11-1.92(2H,m),1.75-1.74(1H,m)。LC/MS m/z 271(M+H)。
中间体37
[116]按照中间体35的程序,使用中间体36获得为黄色固体盐酸盐的标题化合物(0.43g,收率35%)。LC/MS m/z 275(M+H)。
中间体38
[0117]按照中间体1的程序,使用中间体33(3.8mmol)和哌啶(0.99mL,10mmol),接着通过急骤层析(10%-80%EtOAc/己烷),得到为浅黄色固体的标题化合物(0.835g,收率81%)。1H NMR(300MHz,CDCl3)δ:7.85(1H,dd,J=8.6,4.9Hz),7.71(1H,dd,J=8.0,2.6Hz),7.37-7.31(1H,m),3.25-3.21(4H,m),1.68-1.60(4H,m),1.53-1.46(2H,m)。LC/MS m/z269(M+H)。
中间体39
[0118]按照中间体35的程序,使用中间体38得到为浅褐色的固体盐酸盐的标题化合物(0.61g,收率65%)。1H NMR(300MHz,D2O)δ:7.76-7.68(2H,m),7.51(1H,td,J=8.2,2,6Hz),4.44(2H,s),3.19-3.16(4H,m),1.64-1.57(4H,m),1.52-1.47(2H,m)。LC/MS m/z 273(M+H)。
中间体40
[119]按照中间体1的程序,使用中间体33(3.8mmol)和1,4-二氧杂-8-氮杂螺[4,5]癸烷(1.43g,10mmol),接着通过急骤层析(10%-100%EtOAc/己烷),获得为浅黄色固体的标题化合物(0.877g,收率71%)。1HNMR(300MHz,CDCl3)δ:7.85(1H,dd,J=8.6,4.9Hz),7.71(1H,dd,J=8.0,2.6Hz),7.38-7.32(1H,m),3.90(4H,s),3.41-3.47(4H,m),1.79-1.76(4H,m)。LC/MS m/z 327(M+H)。
中间体41
[0120]根据中间体35的程序,使用中间体40,得到为白色粉末盐酸盐的标题化合物(0.88g,收率89%)。1H NMR(300MHz,D2O)δ:7.79-7.69(2H,m),7.52(1H,td,J=8.1,2.7Hz),4.44(2H,s),3.99(4H,s),3.36-3.32(4H,m),1.86-1.82(4H,m)。LC/MS m/z 331(M+H)。
中间体42
[0121]根据中间体1的程序,使用中间体33(3.8mmol)和4-螺[3-(2-吡咯烷酮)]哌啶盐酸盐(0.41g,2.1mmol),接着通过急骤层析(5%MeOH/CH2Cl2),得到为黄色泡沫的标题化合物(0.264g,收率37%)。1HNMR(300MHz,CDCl3)δ:7.85(1H,dd,J=8.6,4.9Hz),7.72(1H,dd,J=8.0,2.6Hz),7.37-7.31(1H,m),5.71(1H,s),3.71-3.63(2H,m),3.33-3.21(4H,m),1.98-1.90(4H,m),1.63-1.55(2H,m)。LC/MS m/z 338(M+H)。
中间体43
[0122]根据中间体35的程序,使用中间体42,获得为白色粉末盐酸盐的标题化合物(0.265g,收率90%)。1H NMR(300MHz,D2O)δ:7.79-7.69(2H,m),7.52(1H,td,J=8.2,2.6Hz),4.45(2H,s),3.76-3.69(2H,m),3.35-3.31(2H,m),2.90-2.81(2H,m),2.04-1.99(2H,m),1.83-1.73(2H,m),1.64-1.60(2H,m)。LC/MS m/z 342(M+H)。
中间体44
[0123]根据中间体1的程序,使用中间体33(3.8mmol)和吡咯烷(0.83mL,10mmol),接着通过急骤层析(10%-100%EtOAc/己烷),得到为白色固体的标题化合物(0.57g,收率58%)。1H NMR(300MHz,CDCl3)δ:7.85(1H,dd,J=8.6,4.9Hz),7.77(1H,dd,J=8.0,2.6Hz),7.36-7.30(1H,m),3.44-3.40(4H,m),1.2-1.88(4H,m)。LC/MS m/z 255(M+H)。
中间体45
[0124]按照中间体35的程序,使用中间体44,得到为白色固体盐酸盐的标题化合物(0.265g,收率90%)。1H NMR(300MHz,D2O)δ:7.76-7.68(2H,m),7.50(1H,td,J=8.2,2.9Hz),4.46(2H,s),3.35-3.30(4H,s),1.91-1.86(4H,s)。LC/MS m/z 259(M+H)。
中间体46
[0125]按照中间体1的程序,使用中间体33(7.7mmol)和3-(N-乙酰基-N-甲氨基)吡咯烷(1.42g,10mmol),接着通过急骤层析(30%-100%EtOAc/己烷-10%MeOH/CH2Cl2),获得为黄色泡沫的标题化合物(0.887g,收率35%)。1H NMR(300MHz,CDCl3)δ:7.87(1H,dd,J=8.6,4.9Hz),7.75(1H,dd,J=7.7,2.6Hz),7.40-7.34(1H,m),5.23-5.13(1H,m),3.76-3.69(1H,m),3.48-3.42(1H,m),3.35-3.26(2H,m),2.90(3H,s),2.11-1.98(2H,m),2.05(3H,s)。LC/MS m/z 326(M+H)。
中间体47
[0126]根据中间体35的程序,使用中间体46,得到为白色泡沫盐酸盐的标题化合物(0.947g,收率>100%)。1H NMR(300MHz,D2O)δ:7.79-7.69(2H,m),7.55-7.48(1H,m),5.00-4.89(1H,m),4.44(2H,s),3.64-3.39(2H,m),3.31-3.20(2H,m),2.89(2H,s),2.73(1H,s),2.22-2.00(2H,m),2.10(1H,s),2.05(2H,s)。LC/MS m/z 330(M+H)。
中间体48
[0127]按照中间体1的程序,使用中间体33(5.5mmol)和2,6-二甲基哌嗪(0.81g,7.1mmol),接着通过急骤层析(0%-10%MeOH/CH2Cl2),得到为黄褐色固体的标题化合物(1.258g,收率77%)。1H NMR(300MHz,CDCl3)δ:7.85(1H,dd,J=8.4,5.1Hz),7.70(1H,dd,J=8.0,2.6Hz),7.38-7.32(1H,m),3.74-3.73(1H,m),3.71-3.69(1H,m),2.98-2.87(2H,m),2.18(2H,dd,J=11.5,10.8Hz),1.40(1H,bs),1.04(3H,s),1.02(3H,s)。LC/MS m/z 298(M+H)。
中间体49
[0128]按照中间体35的程序,使用中间体48获得为白色固体盐酸盐的标题化合物(0.711g,收率100%)。1H NMR(300MHz,D2O)δ:7.80(1H,dd,J=8.4,2.9Hz),7.72(1H,dd,J=8.8,5.1Hz),7.56(1H,td,J=8.2,2.6Hz),4.44(2H,s),4.00(2H,dd,J=13.3,2.0Hz),3.59-3.48(2H,m),2.77(2H,dd,J=13.2,11.7Hz),1.31(3H,s),1.29(3H,s)。LC/MS m/z302(M+H)。
中间体50
[0129]回流中间体48(0.625g,2.1mmol)在丙酮(10mL)和碳酸钾(2.4g,15.0mmol)中的混合物5min。在回流下,以2h的间隔,向该混合物加入2批碘代甲烷(0.6g,3mmol)的丙酮(5mL)溶液。4h后,将混合物冷却,过滤和浓缩。将获得的残余物溶于CH2Cl2,过滤和通过急骤层析(2%MeOH/CH2Cl2)纯化,得到为无色油状物的标题化合物(0.318g,收率49%)。1H NMR(300MHz,CDCl3)δ:7.85(1H,dd,J=8.6,4.9Hz),7.69(1H,dd,J=7.7,2.6Hz),7.39-7.32(1H,m),3.66(2H,d,J=11.7Hz),2.48-2.40(2H,m),2.34-2.28(2H,m_,2.21(3H,s),1.08(3H,s),1.06(3H,s)。LC/MS m/z 312(M+H)。
中间体51
[0130]按照中间体35的程序,使用中间体50,获得为白色粉末盐酸盐的标题化合物(0.381g,收率100%)。1H NMR(300MHz,D2O)δ:7.80(1H,dd,J=8.4,2.9Hz),7.74(1H,dd,J=8.6,5.3Hz),7.56(1H,td,J=8.5,2.6Hz),4.43(2H,s),4.01-3.96(2H,m),3.55-3.47(2H,m),2.92(3H,s),3.93-2.85 2H,m),1.38(3H,s),1.36(3H,s)。LC/MS m/z 316(M+H)。
中间体52
[0131]按照中间体1的程序,使用中间体33(6mmol)和(R)-1-N-叔丁氧羰基-2-甲基哌嗪(1.0g,5mmol),接着通过急骤层析(0%-100%EtOAc/己烷),得到为黄褐色固体的标题化合物(1.461g,收率76%)。1HNMR(300MHz,CDCl3)δ:7.86(1H,dd,J=8.4,5.1Hz),7.70(1H,dd,J=8.0,2.6Hz),7.40-7.33(1H,m),4.36-4.31(1H,m),3.93(1H,d,J=13.5Hz),3.82(1H,dt,J=11.8,1.6Hz),3.59(1H,d,J=12.4Hz),3.21-3.12(1H,m),2.80(1H,dd,J=12.1,3.7Hz),2.59(1H,td,J=12.0,3.4Hz),1.40(9H,s),1.19(3H,d,J=6.9Hz)。LC/MS m/z 284(M+H)。
中间体53
[0132]按照中间体35的程序,使用中间体52,得到为白色泡沫盐酸盐的标题化合物(1.27g,收率79%)。1H NMR(300MHz,CD3OD)δ:7.80-7.71(2H,m),7.56(1H,td,J=8.1,4.0Hz),4.44(2H,s),4.40-4.36(1H,m),3.99-3.94(1H,m),3.79-3.74(1H,m),3.62(1H,td,J=12.2,1.8Hz),3.18(1H,td,J=12.9,3.4Hz),2.84(1H,dd,J=12.1,3.7Hz),2.65(1H,td,J=1f2.1,3.7Hz),1.45(9H,s),1.23(3H,d,J=6.6Hz)。LC/MSm/z 388(M+H)。
中间体54
[0133]按照中间体1的程序,使用中间体33(5mmol)和1-((3R,4S)-4-(甲硫基)四氢呋喃-3-基)哌嗪(0.5g,2.5mmol),接着通过急骤层析(0%-100%EtOAc/己烷),得到为黄色固体的标题化合物(0.741g,收率77%)。1H NMR(300MHz,CDCl3)δ:7.86(1H,dd,J=8.4,4.7Hz),7.71(1H,dd,J=7.7,2.6Hz),7.40-7.34(1H,m),4.15(1H,t,J=8.4Hz),3.88-3.83(1H,m),3.73(1H,bs),3.60(1H,dd,J=9.5,5.8Hz),3.28(4H,bs),3.12(1H,bs),2.99(1H,bs),2.75-2.69(2H,m),2.58-2.53(2H,m),2.10(3H,s)。LC/MS m/z 386(M+H)。
中间体55
[0134]按照中间体35的程序,使用中间体54,得到为褐色泡沫盐酸盐的标题化合物(0.518g,收率59%)。LC/MS m/z 390(M+H)。
中间体56
[0135]按照中间体1的程序,使用中间体33(5mmol)和2-(吡咯烷-1-基甲基)吗啉(0.5g,2.9mmol),接着通过急骤层析(5%MeOH/CH2Cl2),得到为黄色油状物的标题化合物(0.419g,收率41%)。1H NMR(300MHz,CDCl3)δ:7.87(1H,dd,J=8.6,4.9Hz),7.72(1H,dd,J=8.0,2.6Hz),7.41-7.34(1H,m),3.98-3.92(1H,m),3.74-3.60(4H,m),2.86-2.77(1H,m),2.63-2.39(7H,m),1.77-1.73(4H,m)。LC/MS m/z 354(M+H)。
中间体57
[0136]按照中间体35的程序,使用中间体56,得到为白色泡沫盐酸盐的标题化合物(0.450g,收率87%)。1H NMR(300MHz,D2O)δ:7.78-7.71(2H,m),7.54(1H,td,J=8.1,2.7),4.44-3.97(2H,m),3.77-3.59(5H,m),3.33-3.25(2H,m),3.15-3.06(2H,m),2.85(1H,td,J=11.7,3.3Hz),2.59(1H,td,J=11.7,10.2Hz),2.16-2.08(2H,m),2.00-1.96(2H,m)。LC/MS m/z 358(M+H)。
中间体58
[0137]按照中间体1的程序,使用中间体33(5mmol)和(3S,4S)-N,N-二甲基-4-哌嗪-1-基)四氢呋喃-3-胺(0.5g,2.5mmol),接着通过急骤层析(5%MeOH/CH2Cl2),得到为黄色油状物的标题化合物(0.363g,收率14%)。1H NMR(500MHz,CDCl3)δ:7.88(1H,dd,J=8.5,4.9Hz),7.73(1H,dd,J=7.8,2.6Hz),7.40-7.37(1H,m),3.82-3.70(4H,m),3.30-3.28(4H,m),3.11(1H,bs),2.98(1H,bs),2.71-2.67(2H,m),2.60-2.55(2H,m),2.27(6H,s)。LC/MS m/z 383(M+H)。
中间体59
[0138]按照中间体35的程序,使用中间体58和EtOH作为溶剂,得到为黄色泡沫盐酸盐的标题化合物(0.419g,收率89%)。1H NMR(300MHz,D2O)δ:7.78(1H,dd,J=8.2,2,7Hz),7.72(1H,dd,J=8.5,5.2Hz),7.54(1H,td,J=8.2,2.6Hz),4.42(2H,s),4.41-4.39(1H,m),4.28-4.15(4H,m),4.11-4.08(1H,m),3.51(4H,bs),3.43-3.39(2H,m),2.94(6H,s)。LC/MS m/z 387(M+H)。
实施例1
[0139]在90℃下,搅拌中间体20(0.84g,2,7mmol)、中间体6(2.8g,8.1mmol)和三乙胺(2.9mL,20mmol)在EtOH/DMF(20mL,1∶1)中的混合物24h。浓缩混合物并通过层析(YMC Combiprep ODS-A,30mm×50mm,MeOH/H2O/0.1%TFA)纯化,得到为白色固体的标题化合物(0.63g,收率36%)。1H NMR(300MHz,CDCl3)δ:8.50(1H,t,J=6.6Hz),7,26(1H,dd,J=8.6,5.3Hz),7.53(1H,dd,J=8.4,2.9Hz),7.25(1H,td,J=8.0,2.6Hz),4.80(2H,d,J=6.9Hz),3.98(4H,s),3.85-3.70(4H,m),3.31-3.28(4H,m),3.03-3.00(4H,m),2.31(2H,td,J=13.0,5.2Hz),1.74(2H,d,J=13.2Hz)。C23H29FN5O7S的HRMS(M+H)计算值:538.17718;实测值:538.1751。
实施例2
[0140]在DCE(4mL)中,将化合物1(0.07g,0.107mmol)、三乙胺(0.06mL,0.428mmol)和甲醛(0.080mL,37wt%,溶于水,1.07mmol)搅拌在一起。向该混合物中加入固体三乙酰氧基硼氢化钠(0.091g,0.428mmol),在室温下搅拌得到的混合物24h。用饱和碳酸氢钠水溶液猝灭反应。用CH2Cl2洗涤水相。合并有机相并用水洗涤,和干燥(Na2SO4)。浓缩得到为白色固体的标题化合物(0.054g,收率92%)。1H NMR(300MHz,CDCl3)δ:11.90(1H,bs),8.52(1H,t,J=6.8Hz),7.62(1H,dd,J=8.4,5.1Hz),7.51(1H,dd,J=8.4,2.6Hz),7.24(1H,td,J=8.2,3.0Hz),4.79(2H,d,J=6.6Hz),3.98(3H,s),3.85-3.70(4H,m),3.34(4H,bs),2.58(4H,bs),2.36-2.26(4H,m),1.73(2H,d,J=13.2Hz),1.56(2H,bs)。C24H31FN5O7S的HRMS(M+H)计算值:552.19283;实测值:552.1928。C24H30FN5O7S的分析计算值:C,52.26;H,5.48;N,12.70;F,3.44;S,5.81;实测值:C,52.35;H,5.41;N,12.44;F,3.24;S,5.99。
实施例3
[0141]向化合物1(0.07g,0.1mmol)和三乙胺(0.03mL,0.214mmol)在THF(3mL)中的混合物中加入氯甲酸甲酯(0.008mL,0.11mmol),在室温下搅拌得到的混合物2h。在EtOAc和水之间分配混合物。干燥有机相(Na2SO4)并浓缩,得到为白色固体的标题化合物(0.058g,收率98%)。1H NMR(300MHz,CDCl3)δ:11.81(1H,d,J=17.2Hz),8.49(1H,t,J=6.9Hz),7.63(1H,dd,J=8.4,5.1Hz),7.50(1H,dd,J=8.2,2.7Hz),7.26(1H,td,J=7.9,2.8Hz),4.79(2H,d,J=6.9Hz),3.99(4H,s),3.85-3.70(4H,m),3.67(3H,s),3.60-3.57(4H,m),3.37-3.21(4H,m),2.30(2H,td,J=13.1,5.5Hz),1.74(2H,d,J=12.8Hz)。C25H31FN5O9S的HRMS(M+H)计算值:596.1827;实测值:596.1848。
[0142]根据上述步骤,使用中间体与试剂的适当组合制备以下实施例。
化合物41
[0143]向化合物37(0.21g,0.35mmol)的CH2Cl2(2mL)溶液加入TFA(2mL),在室温下搅拌得到的混合物2h并浓缩,得到为褐色泡沫TFA盐的标题化合物(0.168g,收率77%)。1H NMR(500MHz,DMSO)δ:7.71(1H,dd,J=8.4,2.4Hz),7.64(1H,td,J=8.3,2.6Hz),7.55(1H,dd,J=8.7,5.3Hz),4.79(2H,s),4.01-3.99(2H,m),3.86-3.84(2H,m),3.82-3.76(2H,m),3.44-3.39(2H,m),3.16-3.12(1H,m),3.03-2.98(1H,m),2.83-2.79(1H,m),1.56(6H,s),1.22(3H,d,J=6.4Hz)。C22H29FN5O6S的HRMS(M+H)计算值:510.1823;实测值:510.1818。
化合物42
[0144]向化合物41(0.10g,0.16mmol)、三乙胺(0.07mL,0.5mmol)和甲醛(0.12mL,1.6mmol,37wt%,溶于H2O)在1,2-二氯乙烷(4mL)的混合物中加入三乙酰氧基硼氢化钠(0.106g,0.5mmol)。在室温下搅拌得到的混合物18h。用饱和碳酸氢钠水溶液猝灭后,用CH2Cl2洗涤水相。合并有机相和干燥(Na2SO4)并浓缩。通过急骤层析纯化(5%MeOH/CH2Cl2)纯化,得到为白色固体的标题化合物(0.0126g,收率15%)。1H NMR(500MHz,CDCl3)δ:11.83(1H,bs),8.62(1H,t,J=6.6Hz),7.66(1H,dd,J=8.5,5.2Hz),7.53(1H,dd,J=8.4,2.6Hz),7.27(1H,td,J=7.9,2.4Hz),4.77(2H,d,J=6.7Hz),3.99(4H,s),3.63-3.61(1H,m),3.53-3.51(1H,m),2.97(1H,t,J=8.8Hz),2.87-2.85(1H,m),2.58(1H,t,J=8.8Hz),2.40(1H,t,J=10.4hz),2.32(3H,s),2.30(1H,bs),1.58(6H,s),1.09(3H,d,J=6.1Hz)。C23H31FN5O6S的HRMS(M+H)计算值:524.1979;实测值:524.1996。
Claims (17)
1.式I的化合物
R1是(Ar1)烷基;
R2是氢、烷基、羟基或烷氧基;
R3是SO2N(R6)(R7);
R4是氢、卤素、羟基、氰基、烷基、烷氧基、卤烷基或卤烷氧基;
R5是氢、卤素、羟基、氰基、烷基、烷氧基、卤烷基或卤烷氧基;
R6和R7与它们所连接的氮一起为氮杂环丁烷基、(R8)-氮杂环丁烷基、吡略烷基、(R8)-吡咯烷基、哌啶基、(R8)-哌啶基、二烷基哌啶基、三烷基哌啶基、哌嗪基、4-(R9)-哌嗪基、二烷基哌嗪基、二烷基-4-(R9)-哌嗪基、高哌啶基、吗啉基、硫代吗啉基、
R8是羟基、烷基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、烷基CONH、烷基CON(烷基)、(甲硫基)四氢呋喃基、(氨基)四氢呋喃基、(烷基氨基)四氢呋喃基、(二烷基氨基)四氢呋喃基、氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、高哌啶基、吗啉基、(氮杂环丁烷基)烷基、(吡咯烷基)烷基、(哌啶基)烷基、(哌嗪基)烷基、(高哌啶基)烷基或(吗啉基)烷基;
R9是烷基、(环烷基)烷基、SO2R10或COR11;
R10是氢、烷基、氨基、烷基氨基、二烷基氨基、氮杂环丁烷基、吡咯烷基、哌啶基、羟基哌啶基、哌嗪基、4-(烷基)哌嗪基、吗啉基、或硫代吗啉基;
R11是氢、烷基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、氮杂环丁烷基、吡咯烷基、哌啶基、羟基哌啶基、哌嗪基、4-(烷基)哌嗪基、吗啉基、或硫代吗啉基;
R12是氢或烷基;
或两个R12在一起是CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CH2CH2CH2CH2CH2、CH2CH2CH2CH2CH2CH2、OCH2CH2、CH2OCH2、OCH2CH2CH2、CH2OCH2CH2、OCH2CH2CH2CH2、CH2OCH2CH2CH2、CH2CH2OCH2CH2、OCH2CH2CH2CH2CH2、CH2OCH2CH2CH2CH2、CH2CH2OCH2CH2CH2、N(R13)CH2CH2、CH2N(R13)CH2、N(R13)CH2CH2CH2、CH2N(R13)CH2CH2、N(R13)CH2CH2CH2CH2、CH2N(R13)CH2CH2CH2、CH2CH2N(R13)CH2CH2、N(R13)CH2CH2CH2CH2CH2、CH2N(R13)CH2CH2CH2CH2或CH2CH2N(R13)CH2CH2CH2,条件是两个
R12结合到共同的碳原子上;
R13是氢或烷基;
R14和R15在一起是C3-5亚烷基;
Ar2是被选自卤素、烷基和烷氧基的0-2个取代基取代的苯基或吡啶基;和
X-Y-Z是C(R12)2OC(R12)2、C(R12)2OC(R12)2C(R12)2、C(R12)2OC(R12)2C(R12)2C(R12)2、C(R12)2CH2CH2、C(R12)2CH2CH2CH2、C(R12)2CH2CH2CH2CH2、C(Ar2)=CHCH2、C(Ar2)=CHCH2CH2、C(Ar2)=CHCH2CH2CH2、(R12)2N(R13)C(R12)2、C(R12)2N(R13)C(R12)2C(R12)2、C(R12)2N(R13)C(R12)2C(R12)2C(R12)2、N(R12)COC(R12)2、N(R12)COC(R12)2C(R12)2、N(R12)COC(R12)2C(R12)2C(R12)2、N(R12)SO2C(R12)2、N(R12)SO2C(R12)2C(R12)2、N(R12)SO2C(R12)2C(R12)2C(R12)2、N(R12)N(R12)COC(R12)2、N(R12)N(R12)COC(R12)2C(R12)2、N(R14)N(R15)COC(R12)2、N(R14)N(R15)COC(R12)2C(R12)2、C(R12)2N(R12)CO、C(R12)2N(R12)COC(R12)2、C(R12)2N(R12)COC(R12)2C(R12)2、C(R14)2N(R15)CO、C(R14)2N(R15)COC(R12)2、C(R14)2N(R15)COC(R12)2C(R12)2、SC(R12)2C(R12)2、SC(R12)2C(R12)2C(R12)2或SC(R12)2C(R12)2C(R12)2C(R12)2;
或其药学上可接受的盐。
2.权利要求1所述的化合物,其中:
R6和R7与它们所连接的氮一起是氮杂环丁烷、吡咯烷基、哌啶基、(R8)-哌啶基、哌嗪基、4-(R9)-哌嗪基、高哌啶基、吗啉基或硫代吗啉基;
R8是羟基或烷基;和
R9是烷基、(环烷基)烷基、SO2R10或COR11。
4.权利要求3所述的化合物,其中R4是氢或卤素。
5.权利要求1所述的化合物,其中R2氢。
6.权利要求1所述的化合物,其中X-Y-Z是SC(R12)2C(R12)2、SC(R12)2C(R12)2C(R12)2或SC(R12)2C(R12)2C(R12)2C(R12)2。
7.权利要求1所述的化合物,其中X-Y-Z是C(R12)2OC(R12)2、C(R12)2OC(R12)2C(R12)2或C(R12)2OC(R12)2C(R12)2C(R12)2。
8.权利要求7所述的化合物,其中X-Y-Z是C(R12)2OCH2、C(R12)2OCHCH2或C(R12)2OCH2CH2CH2。
9.权利要求1所述的化合物,其中X-Y-Z是C(R12)2CH2CH2、C(R12)2CH2CH2CH2或C(R12)2CH2CH2CH2CH2。
10.权利要求1所述的化合物,其中X-Y-Z是C(Ar2)=CHCH2、C(Ar2)=CHCH2CH2或C(Ar2)=CHCH2CH2CH2。
11.权利要求1所述的化合物,其中X-Y-Z是N(R12)COC(R12)2、N(R12)COC(R12)2C(R12)2、N(R12)COC(R12)2C(R12)2C(R12)2、N(R12)SO2C(R12)2、N(R12)SO2C(R12)2C(R12)2、N(R12)SO2C(R12)2C(R12)2C(R12)2、N(R12)N(R12)COC(R12)2、N(R12)N(R12)COC(R12)2C(R12)2、N(R14)N(R15)COC(R12)2、N(R14)N(R15)COC(R12)2C(R12)2、C(R12)2N(R12)CO、C(R12)2N(R12)COC(R12)2、C(R12)2N(R12)COC(R12)2C(R12)2、C(R14)2N(R15)CO、C(R14)2N(R15)COC(R12)2或C(R14)2N(R15)COC(R12)2C(R12)2。
14.用于治疗HIV感染的组合物,其包括治疗量的权利要求1所述的化合物和药学上可接受的载体。
15.权利要求14所述的组合物,其进一步包括治疗有效量的至少一种用于治疗AIDS或HIV感染的其它药剂,所述其它药剂选自:核苷HIV逆转录酶抑制剂、非核苷HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、HIV融合抑制剂、HIV附着抑制剂、CCR5抑制剂、CXCR4抑制剂、HIV出芽或成熟抑制剂和HIV整合酶抑制剂,和药学上可接受的载体。
16.治疗HIV感染的方法,其包括给予需要所述治疗的患者治疗有效量的权利要求1所述的化合物或其药学上可接受的盐或其溶剂化物。
17.权利要求16所述的方法,其进一步包括给予治疗有效量的至少一种用于治疗AIDS或HIV感染的其它药剂,所述其它药剂选自:核苷HIV逆转录酶抑制剂、非核苷HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、HIV融合抑制剂、HIV附着抑制剂、CCR5抑制剂、CXCR4抑制剂、HIV出芽或成熟抑制剂和HIV整合酶抑制剂。
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CN102911124A (zh) * | 2012-10-25 | 2013-02-06 | 山东大学 | 羟基嘧啶酮类化合物及其制备方法与应用 |
CN103080113A (zh) * | 2010-07-16 | 2013-05-01 | 爱维艾珂瑟有限公司 | 7,9-氮基-4-氧代-4h-吡啶并[l,2-a]嘧啶-2-羧酸苄基酰胺抗病毒剂 |
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US7763630B2 (en) * | 2007-06-06 | 2010-07-27 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
GB0804067D0 (en) * | 2008-03-04 | 2008-04-09 | Syngenta Participations Ag | Chemical compounds |
WO2010042392A2 (en) * | 2008-10-06 | 2010-04-15 | Merck & Co., Inc. | Hiv integrase inhibitors |
US8143244B2 (en) * | 2009-02-26 | 2012-03-27 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
US8383639B2 (en) * | 2009-10-15 | 2013-02-26 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US8283366B2 (en) | 2010-01-22 | 2012-10-09 | Ambrilia Biopharma, Inc. | Derivatives of pyridoxine for inhibiting HIV integrase |
CA2856722C (en) | 2011-11-30 | 2022-11-22 | Emory University | Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections |
WO2014099586A1 (en) | 2012-12-17 | 2014-06-26 | Merck Sharp & Dohme Corp. | 4-pyridinonetriazine derivatives as hiv integrase inhibitors |
EP2986291B1 (en) | 2013-04-16 | 2020-05-27 | Merck Sharp & Dohme Corp. | 4-pyridone derivative compounds and uses thereof as hiv integrase inhibitors |
HUE036384T2 (hu) | 2013-05-17 | 2018-07-30 | Merck Sharp & Dohme | Fúzionált triciklusos heterociklikus vegyületek mint HIV integráz inhibitorok |
WO2014200880A1 (en) | 2013-06-13 | 2014-12-18 | Merck Sharp & Dohme Corp. | Fused tricyclic heterocyclic compounds as hiv integrase inhibitors |
US9861620B2 (en) | 2013-09-27 | 2018-01-09 | Merck Sharp & Dohme Corp. | Substituted quinolizine derivatives useful as HIV integrase inhibitors |
WO2016187788A1 (en) | 2015-05-25 | 2016-12-01 | Merck Sharp & Dohme Corp. | Fused tricyclic heterocyclic compounds useful for treating hiv infection |
EP3377066B1 (en) | 2015-11-17 | 2021-04-07 | Merck Sharp & Dohme Corp. | Amido-substituted pyridotriazine derivatives useful as hiv integrase inhibitors |
WO2017106071A1 (en) | 2015-12-15 | 2017-06-22 | Merck Sharp & Dohme Corp. | Spirocyclic quinolizine derivatives useful as hiv integrase inhibitors |
WO2017113288A1 (en) | 2015-12-31 | 2017-07-06 | Merck Sharp & Dohme Corp. | Fused tricyclic heterocyclic compounds as hiv integrase inhibitors |
JOP20190130A1 (ar) | 2016-12-02 | 2019-06-02 | Merck Sharp & Dohme | مركبات حلقية غير متجانسة رباعية الحلقات مفيدة كمثبطات إنزيم مدمج لفيروس نقص المناعة البشرية (hiv) |
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US20220233512A1 (en) * | 2020-11-03 | 2022-07-28 | Cassava Sciences, Inc. | Inhibiting an immune response mediated by one or more of tlr2, rage, ccr5, cxcr4 and cd4 |
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US6841558B2 (en) * | 2000-10-12 | 2005-01-11 | Merck & Co., Inc. | Aza-and polyaza-naphthalenyl carboxamides useful as HIV intergrase inhibitors |
PL377354A1 (pl) * | 2002-12-27 | 2006-01-23 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Tetrahydro-4H-pirydo[1,2-a]pirymidyny i związki pokrewne użyteczne jako inhibitory integrazy HIV |
AR046938A1 (es) | 2003-12-12 | 2006-01-04 | Merck & Co Inc | Procedimiento para preparar hexahidropirimido[1,2-a]azepin-2-carboxilatos y compuetos similares |
TW200526635A (en) | 2003-12-22 | 2005-08-16 | Shionogi & Co | Hydroxypyrimidinone derivative having HIV integrase inhibitory activity |
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US7176196B2 (en) * | 2004-05-28 | 2007-02-13 | Bristol-Myers Squibb Company | Bicyclic heterocycles as HIV integrase inhibitors |
EP1866313A1 (en) | 2005-03-31 | 2007-12-19 | Istituto di Richerche di Biologia Molecolare P. Angeletti S.p.A. | Hiv integrase inhibitors |
JP4982482B2 (ja) | 2005-05-10 | 2012-07-25 | メルク・シャープ・エンド・ドーム・コーポレイション | Hivインテグラ−ゼ阻害剤 |
-
2006
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- 2006-11-15 WO PCT/US2006/044378 patent/WO2007059229A1/en active Application Filing
- 2006-11-15 AU AU2006315446A patent/AU2006315446A1/en not_active Abandoned
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- 2006-11-15 KR KR1020087014333A patent/KR20080072718A/ko not_active Application Discontinuation
- 2006-11-15 EP EP06837693A patent/EP1948621A1/en not_active Withdrawn
- 2006-11-15 CN CNA2006800473117A patent/CN101351452A/zh active Pending
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2008
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103080113A (zh) * | 2010-07-16 | 2013-05-01 | 爱维艾珂瑟有限公司 | 7,9-氮基-4-氧代-4h-吡啶并[l,2-a]嘧啶-2-羧酸苄基酰胺抗病毒剂 |
CN102911124A (zh) * | 2012-10-25 | 2013-02-06 | 山东大学 | 羟基嘧啶酮类化合物及其制备方法与应用 |
CN102911124B (zh) * | 2012-10-25 | 2015-11-25 | 山东大学 | 羟基嘧啶酮类化合物及其制备方法与应用 |
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US7902182B2 (en) | 2011-03-08 |
KR20080072718A (ko) | 2008-08-06 |
WO2007059229A1 (en) | 2007-05-24 |
AU2006315446A1 (en) | 2007-05-24 |
EP1948621A1 (en) | 2008-07-30 |
US20070111985A1 (en) | 2007-05-17 |
NO20082135L (no) | 2008-08-13 |
JP2009515985A (ja) | 2009-04-16 |
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