CN1756547A - 用作半胱氨酸天冬氨酸蛋白酶激活剂和细胞凋亡诱导物的3,5-二取代-[1,2,4]-噁二唑及类似物和其用途 - Google Patents
用作半胱氨酸天冬氨酸蛋白酶激活剂和细胞凋亡诱导物的3,5-二取代-[1,2,4]-噁二唑及类似物和其用途 Download PDFInfo
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- CN1756547A CN1756547A CNA2003801064405A CN200380106440A CN1756547A CN 1756547 A CN1756547 A CN 1756547A CN A2003801064405 A CNA2003801064405 A CN A2003801064405A CN 200380106440 A CN200380106440 A CN 200380106440A CN 1756547 A CN1756547 A CN 1756547A
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- CN
- China
- Prior art keywords
- chlorothiophene
- oxadiazoles
- chloro
- phenyl
- oxadiazole
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- -1 3,5-disubstituted-[1,2,4]-oxadiazoles Chemical class 0.000 title claims abstract description 152
- 230000006907 apoptotic process Effects 0.000 title abstract description 67
- 108010076667 Caspases Proteins 0.000 title abstract description 53
- 102000011727 Caspases Human genes 0.000 title abstract description 53
- 239000000411 inducer Substances 0.000 title abstract description 38
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- 150000001875 compounds Chemical class 0.000 claims abstract description 226
- 230000030833 cell death Effects 0.000 claims abstract description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 115
- 238000000034 method Methods 0.000 claims description 73
- 150000003839 salts Chemical class 0.000 claims description 58
- 125000003118 aryl group Chemical group 0.000 claims description 56
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 54
- 229910052794 bromium Inorganic materials 0.000 claims description 53
- 206010028980 Neoplasm Diseases 0.000 claims description 46
- 150000004866 oxadiazoles Chemical class 0.000 claims description 41
- 201000011510 cancer Diseases 0.000 claims description 37
- 229940002612 prodrug Drugs 0.000 claims description 35
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- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 30
- 238000011282 treatment Methods 0.000 claims description 30
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- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
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- PNNBWTSDUXWEEO-UHFFFAOYSA-N 4-[5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazol-3-yl]morpholine Chemical class C1=CSC(C=2ON=C(N=2)N2CCOCC2)=C1Cl PNNBWTSDUXWEEO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
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- ULHQRBIAFHAWLV-UHFFFAOYSA-N 3-(4-chloro-2-methylphenyl)-5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazole Chemical class CC1=CC(Cl)=CC=C1C1=NOC(C2=C(C=CS2)Cl)=N1 ULHQRBIAFHAWLV-UHFFFAOYSA-N 0.000 claims description 7
- KPDIJLFFUDCTBZ-UHFFFAOYSA-N 3-(4-chloro-3-methylphenyl)-5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazole Chemical class C1=C(Cl)C(C)=CC(C=2N=C(ON=2)C2=C(C=CS2)Cl)=C1 KPDIJLFFUDCTBZ-UHFFFAOYSA-N 0.000 claims description 7
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- NHFPEQFMSJBYAI-UHFFFAOYSA-N 5-(3-chlorothiophen-2-yl)-3-piperidin-1-yl-1,2,4-oxadiazole Chemical class C1=CSC(C=2ON=C(N=2)N2CCCCC2)=C1Cl NHFPEQFMSJBYAI-UHFFFAOYSA-N 0.000 claims description 7
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- RVZHYVZMRBOIDY-UHFFFAOYSA-N 2-(3-chlorothiophen-2-yl)-5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazole Chemical class C1CN(C)CCN1C1=NN=C(C2=C(C=CS2)Cl)O1 RVZHYVZMRBOIDY-UHFFFAOYSA-N 0.000 claims description 6
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- KYJYEFIZHJODEF-UHFFFAOYSA-N 3-(4-chloro-3-nitrophenyl)-5-(3-chlorothiophen-2-yl)-1,2,4-oxadiazole Chemical class C1=C(Cl)C([N+](=O)[O-])=CC(C=2N=C(ON=2)C2=C(C=CS2)Cl)=C1 KYJYEFIZHJODEF-UHFFFAOYSA-N 0.000 claims description 6
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract
本文公开的是由式(I)表示的3,5-二取代-[1,2,4]-噁二唑及其类似物,其中Ar1、R2、A、B和D如本文定义。本发明涉及具有式(I)的化合物是半胱氨酸天冬氨酸蛋白酶激活剂和细胞凋亡诱导物的发现。因此,本发明半胱氨酸天冬氨酸蛋白酶激活剂和细胞凋亡诱导物可在发生异常细胞的细胞生长和扩散失控的各种临床情况下用于诱导细胞死亡。
Description
发明背景
发明领域
本发明涉及医用化学领域。尤其,本发明涉及3,5-二取代-[1,2,4]-噁二唑及类似物,及其这些化合物作为半胱氨酸天冬氨酸蛋白酶激活剂和细胞凋亡诱导物的发现。本发明也涉及这些化合物作为有疗效抗癌剂的用途。
相关技术
有机体通过各种已知的调节性细胞死亡、程序性细胞死亡或细胞凋亡过程消除多余的细胞。所述细胞死亡是作为动物发育的正常方面以及在组织内环境稳定和老化过程中发生的。(Glucksmann,A.,Biol.Rev.Cambridge Philos.Soc.26:59-86(1951);Glucksmann,A.,Archives de Biologie 76:419-437(1965);Ellis等人,Dev.112:591-603(1991);Vaux等人,Cell 76:777-779(1994))。细胞凋亡调节细胞数量、促进形态形成、除去有害的或其他异常的细胞并且消除已经履行完其功能的细胞。因此,细胞凋亡发生是对各种生理性应激反应如缺氧或缺血的响应(PCT公开的申请W096/20721)。
经历调节性细胞死亡,包括质膜和核膜出泡(blebbing)、细胞皱缩(核浆和胞浆收缩)或细胞器再定位和贴近、染色质凝聚和细胞凋亡体产生(膜上围绕的含有细胞内物质的微粒)的细胞共享许多形态学改变(Orrenius,S.,J.Internal Medicine 237:529-536(1995))。
细胞凋亡是通过细胞自杀的内源性机制完成的(Wyllie,A.H.,in细胞Death in Biology and Pathology,Bowen and Lockshin,eds.、Chapman and Hall(1981),pp.9-34)。作为内部或外部信号的结果,细胞激活其内编码自杀程序。该自杀程序通过激活谨慎调节的遗传程序来完成(Wyllie等人,Int.Rev.Cyt.68:251(1980);Ellis等人,Ann.Rev.细胞Bio.7:663(1991))。凋亡的细胞和小体通常在溶解前由相邻的细胞或巨噬细胞识别和清除。因为该清除机制,尽管清除大量细胞,但不引起炎症(Orrenius,S.,J.Internal Medicine237:529-536(1995))。
已经发现一组蛋白酶是细胞凋亡中的关键元素(例如,见Thornberry、Chemistry and Biology 5:R97-R103(1998);Thornberry,British Med.Bull.53:478-490(1996))。线虫Caenorhabditis elegans的遗传研究揭示凋亡性细胞死亡涉及至少14个遗传基因,其中2个是凋亡前(促死亡)ced(细胞死亡异常)基因,ced-3和ced-4。CED-3是与白细胞介素1β-转换酶同源的,半胱氨酸蛋白酶,已知现称作半胱氨酸天冬氨酸蛋白酶-1。当这些数据最终用于哺乳动物和更广泛的研究中时,发现哺乳动物的细胞凋亡系统似乎涉及半胱氨酸天冬氨酸蛋白酶级联,或如同半胱氨酸天冬氨酸蛋白酶级联一样运转的系统。目前,半胱氨酸天冬氨酸蛋白酶族的半胱氨酸蛋白酶包含14个不同的成员并且将来可能发现更多的成员。所有已知的半胱氨酸天冬氨酸蛋白酶都是以酶原形式合成的,所述酶原需要在形成活性酶之前在天冬氨酰基处裂开。因此,半胱氨酸天冬氨酸蛋白酶能够以放大级联的方式激活其它半胱氨酸天冬氨酸蛋白酶。
细胞凋亡和半胱氨酸天冬氨酸蛋白酶被认为在癌症发展过程中是至关重要的(细胞凋亡和癌症的化学疗法,Hickman和Dive,eds.,Humana Press(1999))。越来越多的证据表明癌细胞尽管含有半胱氨酸天冬氨酸蛋白酶,但缺少激活半胱氨酸天冬氨酸蛋白酶级联的分子机构。这使得癌细胞丧失其细胞内自杀的能力并且细胞变成癌细胞。已知在细胞凋亡过程中存在控制点,它表示干涉导致激活的点。这些控制点包括CED-9-BCL-样和CED-3-ICE-样基因族产物,它们分别是调节细胞存活或死亡决定和完成部分细胞自身死亡过程的内在蛋白质(见Schmitt等人,Biochem.Cell.Biol.75:301-314(1997))。BCL-样蛋白质包括BCL-xL和BAX-α,它们似乎在半胱氨酸天冬氨酸蛋白酶激活的上游行使功能。BCL-xL似乎阻止细胞凋亡蛋白酶级联的激活,而BAX-α加速细胞凋亡蛋白酶级联的激活。
已经显示,化疗(抗癌)药物可通过激活休眠期的半胱氨酸天冬氨酸蛋白酶级联触发癌细胞进行自杀。这可能使大多数(如果不是全部)已知抗癌药物作用方式至关重要的方面(Los等人,Blood 90:3118-3129(1997);Friesen等人,Nat.Med.2:574(1996))。现有抗肿瘤药物的作用机理通常涉及在细胞周期的特定期发挥作用。简单地说,细胞周期是指细胞在其生命过程中正常进行的阶段。通常,细胞存在于称作Go期的静止期。在繁殖过程中,细胞发育到称作S期的DNA合成阶段。随后,在M期发生细胞分化或有丝分裂。抗肿瘤药物,如阿糖胞苷、羟基脲、6-巯基嘌呤和甲氨蝶呤是S期特效药,而抗肿瘤药物,如长春新碱,长春碱和紫杉醇是M期特效药。很多缓慢生长的肿瘤,例如结肠癌最初存在于Go期,而快速增殖的正常组织,例如骨髓最初存在于S或M期。因此,药物如6-巯基嘌呤可引起骨髓毒性,同时对缓慢生长的肿瘤无效。肿瘤性疾病其他方面的化学治疗是本领域技术人员已知的(例如,见Hardman等人,eds.,Goodman andGilman′s The Pharmacological Basis of Therapeutics,NinthEdition,McGraw-Hill,New York(1996),pp.1225-1287)。因此,尽管在这一点对这样做的确切机理并不清楚,但很清楚,激活半胱氨酸天冬氨酸蛋白酶级联的可能性是存在的。同样清楚,半胱氨酸天冬氨酸蛋白酶级联的活性不足和随之发生的细胞凋亡事件在各种类型的癌症中涉及到。开发半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物是开发有疗效抗肿瘤药中令人非常满意的目标。此外,因为自身免疫性疾病和某些退化性疾病也涉及异常细胞的增殖,所以这些疾病的治疗可能也涉及通过给与适当的半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物促进细胞凋亡进程。
发明概述
本发明涉及由式I表示的3,5-二取代-[1,2,4]-噁二唑及其类似物是半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物的发现。因此,本发明的一个方面涉及式I化合物作为细胞凋亡诱导物的用途。
本发明化合物由式I:
或其可药用盐或前药或互变异构体表示,其中:
Ar1为未取代的或取代的芳基或未取代的或取代的杂芳基;
R2为未取代的或取代的并选自芳烷基、芳基链烯基、芳氧基、芳烷氧基、苯氧基甲基、苯胺基、苄基氨基、亚苄基氨基、苯甲酰基氨基、杂环,碳环和Ar2,其中Ar2为未取代的或取代的芳基或未取代的或取代的杂芳基;并且A、B和D独立地为C、CR10、C(R10)R11、N、NR12、O或S,其中R10和R11各自独立地为氢、未取代的或取代的烷基、未取代的或取代的环烷基或未取代的或取代的芳基并且R12各自独立地为氢、未取代的或取代的烷基、未取代的或取代的环烷基或未取代的或取代的芳基,前提条件是不违反化合价规则。
本发明第二方面是通过给予需要所述治疗的哺乳动物一种式I化合物提供治疗、预防或改善瘤形成和癌症的方法。
本发明范围内很多化合物是新化合物。因此,本发明第三方面是提供新的式I化合物,并且也提供这些化合物在治疗、预防或改善瘤形成和癌症中的用途。
本发明第四方面是提供用于治疗对诱导细胞凋亡有反应疾病的药物组合物,该组合物含有有效量的一种式I化合物和一种或多种可药用载体或稀释剂的混合物。
本发明第五方面涉及制备新式I化合物的方法。
发明详述
本发明源于由式I表示的3,5-二取代-[1,2,4]-噁二唑及类似物是有效的和非常灵验的半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物的发现。因此,式I化合物用于治疗对诱导细胞凋亡有反应的疾病。
具体地说,本发明化合物由式I:
或其可药用盐或前药或互变异构体表示,其中:
Ar1为未取代的或取代的芳基或未取代的或取代的杂芳基;
R2为未取代的或取代的并选自芳烷基、芳基链烯基、芳氧基、芳烷氧基、苯氧基甲基、苯胺基、苄基氨基、亚苄基氨基、苯甲酰基氨基、杂环、碳环和Ar2,其中Ar2为未取代的或取代的芳基或未取代的或取代的杂芳基;并且A、B和D独立地为C、CR10、C(R10)R11、N、NR12、O或S,其中R10和R11各自独立地为氢、未取代的或取代的烷基、未取代的或取代的环烷基或未取代的或取代的芳基并且R12各自独立地为氢、未取代的或取代的烷基、未取代的或取代的环烷基或未取代的或取代的芳基,前提条件是不违反化合价规则。优选地,R10、R11和R12为氢、烷基、环烷基或芳基;更优选地,R10、R11和R12为氢、烷基或环烷基。
优选的式I化合物包括其中A为N,B为O并且D为N的化合物。另一组优选的式I化合物包括其中A为N,B为NR12并且D为N的化合物。另一组优选的式I化合物包括其中A为N,B为C(R10)R11并且D为N的化合物。另一组优选的式I化合物包括化合物,其中A为N,B为C(R10)R11并且D为CR10。另一组优选的式I化合物包括化合物,其中A为CR10,B为NR12并且D为N。另一组优选的式I化合物包括化合物,其中A为CR10,B为O并且D为N。另一组优选的式I化合物包括化合物,其中A为CR10,B为NR12并且D为CR10。另一组优选的式I化合物包括化合物,其中A为CR10,B为O并且D为CR10。
优选的式I化合物包括下列化合物,其中Ar1为苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,各基团为未取代的或取代的。更优选地,Ar1为异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基。
优选的式I化合物包括下列化合物,其中R2为苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基、吡咯基、吡唑并[1,5-α]嘧啶基、吗啉基、哌嗪基、哌啶基、环己基、苄基、苄氧基、苯基乙烯基、苯乙基、苯氧基甲基、苄基氨基、苯甲酰基氨基、或亚苄基氨基,各基团为未取代的或取代的。更优选地,R2为苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基、吡咯基、吗啉基、哌嗪基、哌啶基、或环己基。最优选地R2为苯基、吡啶基或吗啉基。
本发明一组优选的化合物由式II:
或其可药用盐、前药或互变异构体表示,其中:
Ar1为未取代的或取代的芳基或未取代的或取代的杂芳基;
R2为未取代的或取代的并选自芳烷基、芳基链烯基、芳氧基、芳烷氧基、苯氧基甲基、苯胺基、苄基氨基、亚苄基氨基、苯甲酰基氨基、杂环,碳环和Ar2,其中Ar2为未取代的或取代的芳基或未取代的或取代的杂芳基。
优选的式II化合物包括下列化合物,其中Ar1为苯基、萘基、吡啶基、喹啉基、异喹啉基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基;优选地,Ar1为苯基、吡啶基、异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,各基团为未取代的或取代的;更优选地,Ar1为异噁唑基、吡唑基、咪唑基、噻吩基、呋喃基或吡咯基,各基团为未取代的或取代的。
优选地,可用于本发明这一方面的化合物由式III:
或其可药用盐,前药或互变异构体表示,其中:
R1-R8独立地为氢、卤素、卤代烷基、芳基、稠芳基、碳环基、杂环基、杂芳基、烷基、链烯基、炔基、芳烷基、芳基链烯基、芳基炔基、杂芳烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、硝基、氨基、氰基、酰基氨基、羟基、巯基、酰氧基、叠氮基、烷氧基、芳氧基、杂芳氧基、芳基烷氧基、杂芳基烷氧基、卤代烷氧基、羧基、羰基酰氨基或烷基巯基,各基团为未取代的或取代的;
Q为S、O或NR9,其中R9为氢、未取代的或取代的烷基、未取代的或取代的环烷基或未取代的或取代的芳基。优选地R9为氢、烷基、环烷基或芳基;更优选地,R9为氢、烷基或环烷基。
优选的式III化合物包括其中Q为S或O;并且其中R3不为氢的化合物。
本发明另一组优选的化合物由式IV:
及其可药用盐、前药和互变异构体表示,其中:
R1-R3独立地为氢、卤素、卤代烷基、芳基、稠芳基、碳环基、杂环基、杂芳基、烷基、链烯基、炔基、芳烷基、芳基链烯基、芳基炔基、杂芳基链烷基、杂芳烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、硝基、氨基、氰基、酰基氨基、羟基、巯基、酰氧基、叠氮基、烷氧基、芳氧基、杂芳氧基、芳基烷氧基、杂芳基烷氧基、卤代烷氧基、羧基、羰基酰氨基或烷基巯基,各基团为未取代的或取代的;
Q为S、O或NR9,其中R9为氢、未取代的或取代的烷基、未取代的或取代的环烷基或未取代的或取代的芳基。优选地R9为氢、烷基、环烷基或芳基;更优选地,R9为氢、烷基或环烷基;并且
环A为未取代的或取代的杂环或碳环。
优选的式IV化合物包括其中环A为吗啉基、哌嗪基、哌啶基或环己基的化合物。
可在本发明方法中使用的优选化合物的实例包括但不限制于:
3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(3-二甲基氨基-4-氯-苯基)-[1,2,4]-噁二唑;
3-(3-氨基-4-氯-苯基)-5-(3-溴呋喃-2-基)-[1,2,4]-噁二唑;
5-(3-溴呋喃-2-基)-3-(3-二甲基氨基-4-氯-苯基)-[1,2,4]-噁二唑;
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯基}-2-(4-甲基-哌嗪1-基)-乙酰胺;
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯基}-琥珀酰胺酸乙酯;
5-(3-氯噻吩-2-基)-3-(4-氯-3-氰基-苯基)-[1,2,4]-噁二唑;
3-(4-氯-苄氧基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(4-氯-3-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(4-氯-3-硝基-苯基)-[1,2,4]-噁二唑;
3-(5-氯-吡啶-2-基)-5-(3-甲氧基-噻吩-2-基)-[1,2,4]-噁二唑;
3-(5-氯-吡啶-2-基)-5-(3-甲基-3H-咪唑-4-基)-[1,2,4]-噁二唑;
3-[2-(4-氯-苯基)-乙烯基]-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-1H-吡咯-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(3-氯-1H-吡咯-2-基)-[1,2,4]-噁二唑;
5-(3-氯-1-甲基-1H-吡咯-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-[3-氯-1-(2-二甲基氨基乙基)-1H-吡咯-2-基]-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(1-哌啶基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(4-吗啉基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(吗啉-4-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(吡咯烷-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(4-甲基哌啶-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(2-甲基哌啶-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(4-三氟甲基哌啶-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(4-甲基哌嗪-1-基)-[1,2,4]噁二唑;
4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸苄酯;
4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯;
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-氨基甲酸叔丁酯;
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-乙酸乙酯;
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-3-基}-乙酸乙酯;
5-(3-氯噻吩-2-基)-2-(哌啶-1-基)-[1,3,4]噁二唑;
5-(3-氯噻吩-2-基)-2-(噁啉-4-基)-[1,3,4]噁二唑;
5-(3-氯噻吩-2-基)-2-(4-甲基哌嗪-1-基)-[1,3,4]噁二唑;
4-[5-(3-溴呋喃-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸苄酯;
4-[5-(3-溴呋喃-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯;
5-(3-氯噻吩-2-基)-2-(哌嗪1-基)-[1,3,4]噁二唑三氟乙酸盐;
5-(3-溴呋喃-2-基)-2-(哌嗪1-基)-[1,3,4]噁二唑三氟乙酸盐;
5-(3-氯噻吩-2-基)-3-(4-氨基哌啶-1-基)-[1,2,4]噁二唑三氟乙酸盐;
5-(3-氯噻吩-2-基)-3-(噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(1H-吡咯-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(呋喃-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(呋喃-3-基)-[1,2,4]噁二唑;
3-(4-氯-2-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(5-甲基呋喃-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(5-硝基呋喃-2-基)-[1,2,4]噁二唑;
3-(4-氯-2-氟-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(3-甲基-吡啶-2-基)-[1,2,4]噁二唑;
3-(4-氯-3-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-溴呋喃-2-基)-3-(4-氯-2-甲基-苯基)-[1,2,4]噁二唑;
5-(3-溴呋喃-2-基)-3-(5-氯-3-甲基-吡啶-2-基)-[1,2,4]噁二唑;
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基氨基}-乙酸乙酯;
N′-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-N,N-二乙基-乙烷-1,2-二胺;
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-(2-吗啉-4-基-乙基)-胺;
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸乙酯;
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸;
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸N-羟基琥珀酰亚胺基酯;
5-(3-溴呋喃-2-基)-3-(3-甲基-吡啶-2-基)-[1,2,4]噁二唑;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸甲酯;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸N-羟基琥珀酰亚胺基酯;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-1-(4-甲基-哌嗪1-基)-丁-1-酮;
N-丁基-4({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酰胺;
4-(2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸辛酯;
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-乙胺;
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-乙酰胺;
3-(3-溴甲基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(2-溴甲基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(4-氯-3-吡咯烷-1-基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(4-氯-3-二甲基氨基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(4-氯-2-吡咯烷-1-基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;和
3-(4-氯-2-二甲基氨基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;及其可药用盐或前药。
本文单独或作为其它基团一部分使用的术语″烷基″是指高达10个碳原子的直链和支链基团。有用的烷基包括直链和支链C1-10烷基、更优选地C1-6烷基。典型的C1-10烷基包括甲基、乙基、丙基、异丙基、丁基、仲-丁基、叔-丁基、3-戊基、己基和辛基,它们可以是未取代的或取代的。
除非另外限制链长度,本文单独或作为其它基团一部分使用的术语″链烯基″是指2-10个碳原子、其中链中两个碳原子之间至少包含一个双键的直链或支链基团。典型的链烯基包括乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基和2-丁烯基。
除非另外限制链长度,本文所使用的术语″炔基″是指2-10个碳原子、其中链中两个碳原子之间至少包含一个三键的直链或支链基团。典型的炔基包括乙炔基、1-丙炔基、1-甲基-2-丙炔基、2-丙炔基、1-丁炔基和2-丁炔基。
有用的烷氧基包括由一个上述C1-10烷基取代的氧,它可以是未取代的或取代的。烷氧基取代基包括但不限制于卤素、吗啉代、氨基包括烷基氨基和二烷基氨基和羧基包括其酯。
有用的烷硫基包括由一个上述C1-10烷基取代的硫,它可以是未取代的或取代的。也包括所述烷硫基亚砜和砜。
有用的氨基包括-NH2、-NHR15和-NR15R16,其中R15和R16为C1-10烷基或环烷基、或者R15和R16与N原子一起组合形成环结构,如哌啶,或者R15和R16与N原子和其它基团一起组合形成环,如哌嗪。烷基可以是未取代的或取代的。
烷基、链烯基、炔基、环烷基、碳环基和杂环基上任选的取代基包括一个或多个卤素、羟基、羧基、氨基、硝基、氰基、C1-C6酰基氨基、C1-C6酰氧基、C1-C6烷氧基、芳氧基、烷硫基、C6-C10芳基、C4-C7环烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、饱和的和不饱和的杂环或杂芳基。
芳基、芳烷基、芳基链烯基、芳基炔基及杂芳基和杂芳烷基上任选的取代基包括一个或多个卤素、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C1-C6烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C1-C6)烷基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、C1-C6羟基烷基、硝基、氨基、脲基、氰基、C1-C6酰基氨基、羟基、巯基、C1-C6酰氧基、叠氮基、C1-C6烷氧基或羧基。
本文单独或作为其它基团一部分使用的术语″芳基″是指环部分含有6-14个碳原子的单环、二环或三环芳基。
有用的芳基包括C6-14芳基、优选C6-10芳基。典型的C6-14芳基包括苯基、萘基、菲基、蒽基、茚基、薁基、二苯基、二亚苯基和芴基。
本文所使用的术语″碳环″包括环烷基和部分饱和的碳环基。有用的环烷基为C3-8环烷基。典型的环烷基包括环丙基、环丁基、环戊基、环己基和环庚基。
有用的饱和的或部分饱和的碳环基为上述环烷基、以及环烯基如环戊烯基、环庚烯基和环辛烯基。
有用的卤或卤素基团包括氟、氯、溴和碘。
本文所使用的术语″芳烷基″是指由任一上述C6-14芳基取代的任一上述C1-10烷基。优选芳烷基为苄基、苯乙基或萘基甲基。
本文所使用的术语″芳基链烯基″是指由任一上述C6-14芳基取代的任一上述C2-10链烯基。
本文所使用的术语″芳炔基″是指由任一上述C6-14芳基取代的任一上述C2-10炔基。
本文所使用的术语″芳氧基″是指由任一上述C6-14芳基取代的氧,它可以是未取代的或取代的。有用的芳氧基包括苯氧基和4-甲基苯氧基。
本文所使用的术语″芳烷氧基″是指由任一上述芳基取代的任一上述C1-10烷氧基,它可以是未取代的或取代的。有用的芳基烷氧基包括苄氧基和苯乙氧基。
有用的卤代烷基包括由一个或多个氟、氯、溴或碘原子取代的C1-10烷基、例如,氟甲基、二氟甲基、三氟甲基、五氟乙基、1,1-二氟乙基、氯甲基、氯氟甲基和三氯甲基。
有用的酰基氨基(酰氨基)为任一与氨基上的氮连接的C1-6酰基(烷酰基),例如,乙酰氨基、氯乙酰氨基、丙酰氨基、丁酰氨基、戊酰氨基和己酰氨基以及芳基-取代的C1-6酰基氨基、例如,苯甲酰氨基和五氟苯甲酰氨基。
有用的酰氧基为任一与氧基(-O-)连接的C1-6酰基(烷酰基),例如,甲酰氧基、乙酰氧基、丙酰氧基、丁酰氧基、戊酰氧基和己酰氧基。
本文所使用的术语杂环是指饱和的或部分饱和的3-7元单环,或7-10元二环系统,它含有碳原子和1-4个独立地选自O、N和S的杂原子,其中氮和硫杂原子可以是未氧化的或氧化的,氮可以是未季铵化或季铵化的,并且包括其中任一上述杂环与苯环稠合的任一二环基、并且其中所述杂环可以在碳或氮原子上被取代,前提条件是所得到的化合物是稳定的。
有用的饱和的或部分饱和的杂环基包括四氢呋喃基、吡喃基、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、咪唑啉基、二氢吲哚基、异二氢吲哚基、奎宁环基、吗啉基、异苯并二氢吡喃基、苯并二氢吡喃基、吡唑烷基吡唑啉基、tetronoyl和tetramoyl。
本文所使用的术语″杂芳基″是指含有5-14个环原子;环状排列中共享6、10或14个π电子;并且含有碳原子和1、2或3个氧、氮或硫杂原子的基团。
有用的杂芳基包括噻吩基(苯硫基),苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基、呋喃基(呋喃基)、吡喃基、异苯并呋喃基、苯并吡喃基、呫吨基、phenoxanthiinyl、吡咯基,包括但不限制于2H-吡咯基、咪唑基、吡唑基、吡啶基(吡啶基),包括但不限制于2-吡啶基、3-吡啶基和4-吡啶基、吡嗪基、嘧啶基、哒嗪基、中氮茚基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、phthalzinyl、萘啶基、quinozalinyl、噌啉基、蝶啶基、咔唑基、β-咔啉基、菲啶基、吖啶基、萘嵌间二氮杂苯基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异噁唑基、呋咱基、吩噁嗪基、1,4-二氢喹喔啉-2,3-二酮、7-氨基异香豆素、吡啶并[1,2-α]嘧啶-4-酮、吡唑并[1,5-α]嘧啶基,包括但不限制于吡唑并[1,5-α]嘧啶-3-基、1,2-苯并异噁唑-3-基、苯并咪唑基、2-羟吲哚基和2-氧苯并咪唑基。当所述杂芳基环中含有氮原子,所述氮原子可以是N-氧化物形式,例如,吡啶基N-氧化物、吡嗪基N-氧化物和嘧啶基N-氧化物。
本文所使用的术语″杂芳氧基″是指由一个上述杂芳基取代的氧,它可以是未取代的或取代的。有用的杂芳氧基包括吡啶氧基、吡嗪氧基、吡咯氧基、吡唑氧基、咪唑氧基和噻吩氧基。
本文所使用的术语″杂芳基烷氧基″是指由任一上述杂芳基取代的任一上述C1-10烷氧基,它可以是未取代的或取代的。
本发明某些化合物可以以立体异构体包括光学异构体形式存在。本发明包括所有立体异构体和所述立体异构体的外消旋混合物以及可按照本领域普通技术人员公知的方法分离的个别对映异构体。
可药用加成盐的实例包括无机和有机酸加成盐、如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、延胡索酸盐、扁桃酸盐和草酸盐;及其与碱,如氢氧化钠、三(羟基甲基)氨基甲烷(TRIS,氨丁三醇(tromethane))和N-甲基-葡糖胺的无机和有机碱加成盐。
本发明化合物前药的实例包括简单的含羧酸化合物的酯(例如,按照本领域已知方法,通过与C1-4醇缩合获得的那些);含羟基化合物的酯(例如,按照本领域已知方法,通过与C1-4羧酸、C3-6二酸或其酸酐如琥珀酸和富马酸酸酐缩合获得的那些);含氨基化合物的亚胺(例如,按照本领域已知方法,通过与C1-4醛或酮缩合获得的那些);含氨基化合物的氨基甲酸酯,如Leu,et.al.,(J.Med.Chem.42:3623-3628(1999))和Greenwald,et.al.,(J.Med.Chez.42:3657-3667(1999))描述的那些;和含醇化合物的缩醛和缩酮(例如,按照本领域已知方法,通过与氯甲基甲醚或氯甲基乙醚缩合获得的那些)。
本发明化合物可以利用本领域技术人员已知的方法或本发明新方法制备。具体地说,本发明式I-IV化合物可如方案1反应实例所述制备。将3-氯噻吩-2-碳酰氯与3-氨基-4-氯苄胺肟在吡啶中反应得到产物3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑。或者,该反应也可以在1,4-二噁烷中进行,然后用BF3OEt2处理,或者在二噁烷/吡啶中进行,并且得到相同的噁二唑产物。
方案1
本发明式I-IV化合物也可以如方案2反应实例所述制备。将1-哌啶腈与羟基胺在乙醇中反应得到偕胺肟中间体,然后与3-氯噻吩-2-碳酰氯在回流吡啶中反应得到产物5-(3-氯噻吩-2-基)-3-(1-哌啶基)-[1,2,4]-噁二唑。
方案2
本发明重要的方面是发现式I-IV化合物为半胱氨酸天冬氨酸蛋白酶激活剂和细胞凋亡诱导物。因此,这些化合物在异常细胞的细胞生长和扩散失控的各种临床情况下,如在癌症情况下是有用的。
本发明另一重要的方面是发现式I-IV化合物在耐药癌细胞如乳腺和前列腺癌细胞中是有效的和非常灵验的半胱氨酸天冬氨酸蛋白酶激活剂和细胞凋亡诱导物,它使得这些化合物能够杀死这些耐药癌细胞。相比之下,大多数标准的抗癌药在相同的条件下,在杀死耐药癌细胞方面是无效的。因此,本发明化合物可用于治疗耐药癌,如动物的乳腺癌。
本发明包括用于调节体内细胞凋亡或体内肿瘤性疾病的治疗方法,它包括给予需要所述治疗的受试体有效量的、以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的式I-IV化合物或其可药用盐或前药。
本发明也包括含给予动物有效量的所述式I-IV化合物或其可药用盐或前药的治疗方法,其中所述治疗方法用于治疗癌症,即一组以异常细胞的生长和扩散失控为特征的疾病。所述疾病包括但不限制于何杰金病、非何杰金性淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、肺癌、维尔姆斯瘤、宫颈癌、睾丸癌、软组织肉瘤、原发性巨球蛋白血症、膀胱癌、慢性粒细胞性白血病、原发性脑癌、恶性黑色素瘤、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌、绒毛癌、蕈样霉菌病、头颈癌、骨源性肉瘤、胰腺癌、急性粒细胞性白血病、毛细胞性白血病、成神经细胞瘤、横纹肌肉瘤、卡波济肉瘤、泌尿生殖器癌、甲状腺癌、食道癌、恶性高钙血症、宫颈增生、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌和前列腺癌。
在实施治疗方法中,将配制成口服、静脉内、局部和表面应用,治疗肿瘤性疾病和其它涉及半胱氨酸天冬氨酸蛋白酶级联介导的生理反应疾病的有效量的含有治疗有效浓度所述化合物的组合物给予表现这些疾病中一种或多种症状的个体。该量有效地改善或消除这些疾病的一种或多种症状。治疗特定疾病化合物的有效量为足以改善或以某种方式减轻与所述疾病有关症状的量。该量可以以单剂量形式给予或者可以按照有效的给药方案给予。该剂量可治愈所述疾病,但通常给药是为了改善所述疾病的症状。通常需要重复给药以便获得所预期的症状改善。
在另一具体实施方案中,本发明提供含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的所述式I-IV化合物或其可药用盐和可药用载体的药物组合物。
本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的所述式I-IV化合物或其可药用盐或前药,和至少一种已知的癌症化疗药物或所述药物可药用盐的组合物。已知的可用于联合治疗的癌症化疗药物的实例包括但不限制于烷化剂,如白消安、顺铂、丝裂霉素C和卡铂;抗有丝分裂药物,如秋水酰碱、长春碱、紫杉醇和多西他赛;I型拓扑异构酶抑制剂,如喜树碱和拓扑替康;II型拓扑异构酶抑制剂,如阿霉素和依托泊甙;RNA/DNA抗代谢物,如5-氮杂胞苷、5-氟尿嘧啶和甲氨蝶呤;DNA抗代谢物,如5-氟-2′-脱氧-尿苷,ara-C,羟基脲和硫鸟嘌呤;抗体,如campath、赫赛汀或Rituxan。其它已知的可用于联合治疗的癌症化疗药物包括美法仑、苯丁酸氮芥、环磷酰胺(cyclophosamide)、异环磷酰胺、长春新碱、米托胍腙、表柔比星、阿柔比星、博来霉素、米托蒽醌、羟吡咔唑(elliptinium)、氟达拉滨、奥曲肽、视黄酸、他莫西芬、Gleevec和阿拉诺新。
在实施本发明方法中,本发明化合物可以与至少一种已知的作为药物组合物整体一部分的化疗药一起给予。或者,本发明化合物可以与至少一种已知的癌症化疗药物分开给予。在一个具体实施方案中,本发明化合物和至少一种已知的癌症化疗药物基本上同时给予,即只要所述化合物同时达到血中治疗水平,所述化合物可同时或相继给予。在另一具体实施方案中,只要所述化合物达到血中治疗水平,本发明化合物和至少一种已知的癌症化疗药物可按照其各自的给药时间表给予。
据报道,α-1-肾上腺素受体拮抗剂,如多沙唑嗪、特拉唑嗪和坦索罗辛可通过诱导细胞凋亡抑制前列腺癌细胞的生长(Kyprianou,N.等人、Cancer Res 60:4550-4555,(2000))。因此,本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述的化合物或其可药用盐或前药,和至少一种已知的α-1-肾上腺素受体拮抗剂或所述药物可药用盐的组合物。已知的可用于联合治疗的α-1-肾上腺素受体拮抗剂的实例包括但不限制于多沙唑嗪、特拉唑嗪和坦索罗辛。
据报道,δ-2受体以高密度表达在各种类型的肿瘤细胞中(Vilner,B.J.等人、Cancer Res.55:408-413(1995))并且δ-2受体激动剂,如CB-64D、CB-184和氟哌啶醇激活新的细胞凋亡途径并加强乳腺肿瘤细胞系中抗肿瘤药物的作用。(Kyprianou,N.等人、Cancer Res.62:313-322(2002))。因此,本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述的化合物或其可药用盐或前药,和至少一种已知的δ-2受体激动剂或所述激动剂可药用盐的组合物。已知的可用于联合治疗的δ-2受体激动剂的实例包括但不限制于CB-64D、CB-184和氟哌啶醇。
据报道,与洛伐他汀,即HMG-CoA还原酶抑制剂和丁酸盐,即鼠Lewis肺癌模型中细胞凋亡诱导物联合治疗显示抗肿瘤作用加强(Giermasz,A.等人,Int.J.Cancer 97:746-750(2002))。因此,本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述的化合物或其可药用盐或前药,和至少一种已知的HMG-CoA还原酶抑制剂或所述药物可药用盐的组合物。已知的可用于联合治疗的HMG-CoA还原酶抑制剂的实例包括但不限于洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀和cerivastatin。
据报道,HIV蛋白酶抑制剂,如印地那韦或沙奎那韦,具有有效的抗血管生成活性并促进卡波西肉瘤消退(Sgadari、C.等人,Nat.Med.8:225-232(2002))。因此,本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述的化合物或其可药用盐或前药,和至少一种已知的HIV蛋白酶抑制剂或所述药物可药用盐的组合物。已知的可用于联合治疗的HIV蛋白酶抑制剂的实例包括但不限于安普那韦,阿巴卡韦,CGP-73547、CGP-61755,DMP-450,印地那韦,那非那韦,替普拉那韦、利托那韦,沙奎那韦,ABT-378,AG 1776和BMS-232,632。
据报道,合成类维生素A,如芬维A胺(N-(4-羟基苯基)retinamide,4HPR)与其它化疗药,如顺铂、依托泊甙或紫杉醇组合在小细胞肺癌细胞系具有良好的活性(Kalemkerian,G.P.等人、Cancer Chemother.Pharmacol.43:145-150(1999))。也有报道,4HPR与γ-射线组合对膀胱癌细胞系有良好的活性(Zou、C.等人,Int.J.Oncol.13:1037-1041(1998))。因此,本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述的化合物或其可药用盐或前药,和至少一种已知的类维生素A和合成类维生素A或所述药物的可药用盐的组合物。已知可用于联合治疗的类维生素A和合成类维生素A的实例包括但不限制于,bexarotene,维甲酸、13-顺式-视黄酸、9-顺式-视黄酸、α-二氟甲基鸟氨酸、ILX23-7553,芬维A胺和N-4-羧基苯基retinamide。
据报道蛋白酶体抑制剂,如乳胱氨酸,在体内和在体外肿瘤细胞包括耐常规化疗药的肿瘤细胞中发挥抗肿瘤活性。通过抑制NF-κB转录活性,蛋白酶体抑制剂也可以抑制体内血管发生和转移并进一步增加癌症细胞对细胞凋亡的敏感性(Almond,J.B.等人,Leukemia 16:433-443(2002))。因此,本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述的化合物或其可药用盐或前药,和至少一种已知的蛋白酶体抑制剂或所述药物可药用盐的组合物。已知的可用于联合治疗的蛋白酶体抑制剂的实例包括但不限制于,乳胱氨酸、MG-132和PS-341。
据报道酪氨酸激酶抑制剂,如STI571(Imatinib mesilate,Gleevec),与其它抗白血病药物,如依托泊甙具有有效的协同作用(Liu,W.M.等人Br.J.Cancer 86:1472-1478(2002))。因此,本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述的化合物或可其药用盐或前药,和至少一种已知的酪氨酸激酶抑制剂或所述药物的可药用盐的组合物。已知的可用于联合治疗的酪氨酸激酶抑制剂的实例包括但不限制于,Gleevec(,ZD1839(Iressa)、SH268、染料木黄酮、CEP2563、SU6668、SU11248和EMD121974。
据报道,异戊烯蛋白转移酶抑制剂,如法尼基蛋白转移酶抑制剂R115777具有临床前抗人乳腺癌的抗肿瘤活性(Kelland,L.R.等人,Clin.Cancer Res.7:3544-3550(2001))。蛋白质法尼基转移酶抑制剂SCH66336与顺铂在人癌细胞系中的协同作用也有报道(Adjei,A.A.等人、Clin.Cancer.Res.7:1438-1445(2001))。因此,本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述的化合物或可其药用盐或前药,和至少一种已知的异戊烯蛋白转移酶抑制剂,包括法尼基蛋白转移酶抑制剂,I型香叶基香叶基-蛋白转移酶(GGPTase-I)抑制剂和II型香叶基香叶基-蛋白转移酶抑制剂,或所述药物可药用盐的组合物。已知的可用于联合治疗的异戊烯蛋白转移酶抑制剂的实例包括但不限制于R115777、SCH66336、L-778,123、BAL9611和TAN-1813。
据报道,依赖于细胞周期蛋白的蛋白激酶(CDK)抑制剂,如黄酮吡啶酚,与其它抗癌药物,如CPT-11、DNA拓扑异构酶I抑制剂在人结肠癌细胞中具有协同作用(Motwani,M.等人、Clin.Cancer Res.7:4209-4219,(2001))。因此,本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述的化合物或可其药用盐或前药,和至少一种已知的依赖于细胞周期蛋白的蛋白激酶抑制剂或所述药物可药用盐的组合物。已知可用于联合治疗的依赖于细胞周期蛋白的蛋白激酶抑制剂的实例包括但不限制于黄酮吡啶酚、UCN-01、Roscovitine和olomoucine。
据报道,在临床前研究中,发现COX-2抑制剂阻滞血管生成,抑制固体肿瘤转移并减缓移植的胃肠癌症细胞的生长(Blanke、C.D.,Oncology(Huntingt)16(No.4 Suppl.3):17-21(2002))。因此,本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述的化合物或可其药用盐或前药,和至少一种已知的COX-2抑制剂或所述抑制剂可药用盐的组合物。已知可用于联合治疗的COX-2抑制剂的实例包括但不限制于塞来昔布、valecoxib和罗非昔布。
本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述化合物的生物轭合物和至少一种已知的有疗效抗体,如Herceptin或Rituxan,生长因子,如DGF、NGF;细胞因子类,如IL-2、IL-4或与细胞表面结合的任何分子的生物轭合的组合物。所述抗体和其它分子将本文所描述的化合物释放到其靶位并使得它成为有效的抗癌药物。该生物轭合物也可能提高有疗效抗体如Herceptin或Rituxan的抗癌活性。
类似地,本发明另一具体实施方案涉及有效地抑制瘤形成的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述的化合物或可其药用盐或前药和放射治疗的组合物。在该具体实例中,本发明化合物可以在放射治疗的同时或在不同的时间给予。
本发明另一具体实施方案涉及癌症术后治疗有效的、含有以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的本文所描述的化合物或可药用盐或前药的组合物。本发明也涉及通过外科手术摘除癌,然后用本文所描述的一种药物组合物治疗所述动物癌症治疗方法。
广泛的免疫机制在接触到传染性介质后迅速启动。依赖于感染的类型,T和B淋巴细胞迅速克隆扩增来抗击感染。感染后消除效应细胞是维持免疫内环境稳定的主要机理之一。已显示,消除效应细胞是由细胞凋亡调节的。最近已确定,自发生身免疫性疾病是细胞死亡反常的结果。在某些自身免疫性疾病中,免疫系统指挥其强大的细胞毒性效应机制来对抗特定细胞,如多发硬化中的少突细胞,糖尿病中胰腺的β细胞和淋巴瘤性甲状腺肿中的甲状腺细胞(Ohsako,S.& Elkon,K.B.,Cell Death Differ.6:13-21(1999))。据报道,编码淋巴细胞细胞凋亡受体Fas/APO-1/CD95的基因突变与缺陷性淋巴细胞细胞凋亡和以慢性组织学上良性的脾肿大、全身性淋巴结病、高丙球蛋白血症和自身抗体形成为特征的自身免疫性淋巴增殖综合征(ALPS)有关。(Infante,A.J.等人,J.Pediatr.133:629-633(1998)和Vaishnaw,A.K.等人,J.Clin.Invest.103:355-363(1999))。据报道,在T细胞依赖性共刺激信号存在下,转基因小鼠发育B细胞中Bcl-2(它是具有抗程序性细胞死亡活性的bcl-2基因类程序性细胞死亡调节剂)的过度表达导致产生修饰的B细胞所有组成成分并产生致病的自身抗体(Lopez-Hoyos,M.等人,Int.J Mol.Med.1:475-483(1998))。因此证明多种自身免疫性疾病显然是由细胞凋亡过程缺损引起的。治疗这些疾病的一种策略是开启引起自身免疫性疾病的淋巴细胞的细胞凋亡(O′Reilly,L.A.& Strasser,A.,Inflamm.Res.48:5-21(1999))。
已经知道Fas-Fas配体(FasL)的相互作用对于维持免疫动态平衡是必需的。实验性自身甲状腺炎(EAT)的特点是自身反应的T和B细胞应答并且甲状腺中明显的淋巴细胞浸润,它是研究FasL治疗作用的好模型。Batteux,F.等人,(J.Immunol.162:603-608(1999))报告通过直接注射编码FasL的DNA表达载体到发炎的甲状腺中,抑制甲状腺淋巴细胞浸润的发展并且观察到渗透T细胞死亡的诱导作用。这些结果表明FasL在甲状腺细胞上的表达可以通过诱导致病的自身反应浸润T淋巴细胞死亡对进行性EAT具有治疗作用。
已知双吲哚基马来酰亚胺VIII加强人星细胞瘤1321N1细胞和Molt-4T细胞的Fas-介导的细胞凋亡;它们在缺乏双吲哚基马来酰亚胺VIII的情况下对由抗-Fas抗体诱导的细胞凋亡都是耐受的。报告了双吲哚基马来酰亚胺VIII对Fas-介导的细胞凋亡的增强作用对激活的而不是非激活的T细胞是选择性的并且是Fas-依赖性的。Zhou T.等人,(Nat.Med.5:42-48(1999))报告在自身抗原刺激的过程中给予大鼠双吲哚基马来酰亚胺VIII防止两种模型中T细胞介导的自身免疫疾病症状的发展,所述两种模型是实验性过敏性脑炎的Lewis大鼠模型和Lewis佐剂性关节炎模型。因此,使用Fas-依赖性细胞凋亡增强剂,如双吲哚基马来酰亚胺VIII,对于更有效地消除有害细胞和抑制T细胞介导的自身免疫疾病可具有治疗作用。因此,有效量的以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的,式I-IV化合物,或可药用盐或前药,对自身免疫疾病具有治疗作用。牛皮癣是一种以鳞状红色片为特征的慢性皮肤疾病。补骨脂素加紫外线A(PUVA)是一种广泛使用并且有效的普通牛皮癣治疗方法。Coven等人,Photodermatol.Photoimmunol.Photomed.15:22-27(1999)报告了用补骨脂素8-MOP或TMP和UVA处理的淋巴细胞显示凋亡性细胞死亡的有代表性的DNA降解模式。Ozawa等人,J.Exp.Med.189:711-718(1999)报告了T细胞凋亡的诱导作用可能是312-nmUVB解决牛皮癣皮肤损伤的主要机制。低剂量甲氨蝶呤可用于治疗牛皮癣使其恢复到临床上正常的皮肤。Heenen等人,Arch.Dermatol.Res.290:240-245(1998)报道,低剂量甲氨蝶呤可诱导细胞凋亡并且该作用方式可解释为甲氨蝶呤治疗牛皮癣过程中表皮过度增生的复原作用。因此,以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的有效量的式I-IV化合物或可药用盐或前药可有效地用于治疗高增殖性皮肤病,如牛皮癣。
滑液细胞增生是风湿性关节炎(RA)患者的一个特点。相信滑液细胞的过度增殖,以及滑液细胞死亡的缺乏,是滑液细胞增生的原因。Wakisaka等人,Clin.Exp.Immunol.114:119-128(1998),发现尽管RA滑液细胞可通过Fas/FasL途径的细胞凋亡而死亡,但滑液细胞的细胞凋亡被存在于滑膜中的促炎细胞因子所抑制。Wakisaka等人也暗示促炎细胞因子对细胞凋亡的抑制作用可使滑液细胞生长并导致RA患者关节翳形成和关节的破坏。因此,以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的,有效量的式I-IV化合物,或其可药用盐或前药,是一种有效的风湿性关节炎的治疗方法。
已经积累了令人信服的证据,表明细胞凋亡在促使急性炎性反应消除中起主要作用。嗜中性粒细胞是细胞凋亡的基本组成部分,因此限制其促炎作用并导致巨噬细胞和半专业噬菌细胞的快速、特效和不发炎的识别(Savill,J.,J.Leukoc.Biol.61:375-380(1997))。Boirivant等人,Gastroenterology 116:557-565(1999)报告从Crohn′s疾病、溃疡性结肠炎和其它炎症区域分离的固有膜T细胞表明CD2途径-诱导的细胞凋亡减少。另外,对炎性Crohn′s疾病组织的细胞研究表明这种缺少伴随有Bcl-2水平的升高。因此,以半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物发挥功效的,有效量的式I-IV化合物,或其可药用盐或前药,是一种有效的治疗炎症的方法。
在病原体,如HIV、丙型肝炎和其它病毒性病原体的消除中,使用半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物也是一种理想的治疗方法。长时间保持非活动期,然后疾病发展,可以通过这些病原体抗-细胞凋亡机制导致病毒粒子持久稳固地存储在细胞中来解释。据报道HIV-1感染的T白血病细胞或外周血单核细胞(PBMCs)在半胱氨酸天冬氨酸蛋白酶抑制剂Z-VAD-fmk存在下增强病毒复制。而且,Z-VAD-fmk在激活的由HIV-1-感染无症状个体衍生的PBMC中也刺激内生病毒产生(Chinnaiyan,A.等人,Nat.Med.3:333(1997))。因此,细胞凋亡对于限制HIV传播是一种有益的宿主机制并且新的使用半胱氨酸天冬氨酸蛋白酶/细胞凋亡激活剂的治疗方法可用于从感染个体中清除病毒储库。类似地,HCV感染也触发抗-细胞凋亡机制以逃避宿主免疫监视导致病毒宿存和肝癌发生(Tai,D.I.等人Hepatology 3:656-64(2000))。因此,细胞凋亡诱导物可用于HIV和其它感染性疾病的治疗。
斯坦特固定模植入变成了新的血管成形术的标准方法。然而,斯坦特固定模再狭窄仍然是冠状斯坦特固定模成形的主要限制。开发了新的方法,是通过局部给予药物来调节局部的血管生物学。该方法允许在血管损伤的精确部位和时间使用药物。具有抗增殖特性的各种药理活性剂在临床研究中是普遍采用的,包括放射菌素D、雷帕霉素或紫杉醇包裹的斯坦特固定模(Regar E.等人,Br.Med.Bull.59:227-248(2001))。因此,具有抗增殖活性的细胞凋亡诱导物可用于斯坦特固定模再狭窄的预防性或减少性治疗。
本发明可药用组合物包括所有含有达到其预期目的的有效量本发明化合物的组合物。尽管个体需求不同,但确定各组分最佳有效量范围是本领域技术范畴。通常口服给予所治疗动物,例如哺乳动物0.0025-50mg/kg体重/天剂量的所述化合物或其相当量的可药用盐。优选地,口服给与大约0.01-大约10mg/kg体重。肌内注射的剂量通常大约为口服剂量的一半。例如,适宜的肌内注射剂量大约为0.0025-约25mg/kg体重,并且最优选地,大约为0.01-约5mg/kg体重。如果也给与一种已知的癌症化疗药,那么以达到其预期目的有效的量给与。所述已知的癌症化疗药抗癌症有效的量是本领域技术人员公知的。
单位口服剂量可以包含大约0.01-约50mg,优选地大约0.1-约10mg本发明化合物。单位剂量每天可以给予一次或多次,如一片或多片,各片含有大约0.1-约10mg,通常大约0.25-50mg所述化合物或其溶剂化物。
在局部用制剂中,所述化合物可以以每克载体中大约0.01-100mg的浓度存在。
本发明化合物除了以原料药形式给与外,还可以作为药物制剂中的一部分给与,所述药物制剂中含有适宜的可药用载体,可药用载体中包含有利于将所述化合物加工成可药用制剂的赋形剂和助剂。优选地,所述制剂,特别是那些可以口服给药并且可以以优选的给药形式使用的制剂,如片剂、糖衣丸和胶囊剂,和可以直肠给药的制剂,如栓剂,以及适宜的通过注射或口服给药的溶液含有大约0.01-99%,优选大约0.25-75%活性化合物,和赋形剂。
本发明也包括本发明化合物的无毒可药用盐。酸加成盐可通过将本发明化合物溶液与可药用无毒酸溶液混合形成,所述酸如盐酸、富马酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸、碳酸、磷酸、草酸等。碱加成盐可通过将本发明化合物溶液与可药用无毒碱溶液混合形成,所述碱如氢氧化钠、氢氧化钾、胆碱氢氧化物、碳酸钠、Tris、N-甲基-葡糖胺等。
本发明药物组合物可以给予经历本发明化合物有益作用的任何动物。尽管本发明不限制于此,但所述动物首选哺乳动物,例如人和兽医动物。
本发明药物组合物可通过任何达到其预期目的的方法给与。例如,可通过非胃肠道、皮下、静脉内、肌内、腹膜内、透皮、口腔、鞘内、颅内、鼻内或局部途径给药。可通过口服途径交替或同时给药。给药剂量将依赖于受试者的年龄、健康状况和体重、联合治疗的种类,需要时和治疗的频率及所需要作用的性质。
本发明药物制剂以本身已知的方式制备,例如,通过常规的混合、制粒、包衣、溶解或冷冻干燥过程制备。因此,口服使用的药物制剂可通过将活性化合物与固体赋形剂合并,任选地磨碎所得到的混合物并加工颗粒体的混合物,需要或必要时,加入适宜的助剂后,得到片剂或糖衣丸的片芯。
适宜的片芯特别为:填充剂,如糖类,例如乳糖或蔗糖,甘露醇或山梨糖醇;纤维素制剂和/或磷酸钙,例如,磷酸三钙或磷酸氢钙;以及粘合剂,如淀粉糊,例如,使用玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧基甲基纤维素钠和/或聚乙烯吡咯烷酮。需要时,可加入崩解剂,如上述淀粉和羧基甲基-淀粉、交联聚乙烯吡咯烷酮、琼脂或藻酸或其盐,如藻酸钠。助剂首先为,助流剂和润滑剂,例如,二氧化硅、滑石粉、硬脂酸或其盐,如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。需要时,提供含有抗胃液包衣剂的糖衣丸片芯。为此,可使用浓糖溶液,其中可不包含或包含阿拉伯胶、滑石粉、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、漆溶液和适宜的有机溶剂或溶剂混合物。为了制备抗胃液的包衣剂,使用适宜的纤维素制剂溶液,如邻苯二甲酸乙酰纤维素或邻苯二甲酸羟丙基-纤维素。例如,为了识别或者为了确定合并活性化合物的剂量,可将染料或色素加到片剂或糖衣丸包衣剂中。
其它可口服使用的药物制剂包括由明胶制成的推入配合胶囊剂,以及由明胶和增塑剂,如甘油或山梨糖醇制成的密封软胶囊剂。推入配合胶囊剂可含有颗粒体形式的活性化合物,所述颗粒体可以与填充剂,如乳糖;粘合剂,如淀粉;和/或润滑剂,如滑石粉或硬脂酸镁,任选地和稳定剂混合。在软胶囊中,活性化合物优选溶解或悬浮在适宜的液体,如脂肪油或液体石蜡中。另外,可加入稳定剂。
可能的可直肠使用的药物制剂包括,例如,由一种或多种活性化合物与栓剂基质的组合物组成的栓剂。例如,适宜的栓剂基质为天然的或合成的甘油三酯,或链烷烃。另外,也可能使用由活性化合物与基质的组合组成的明胶直肠胶囊。可能的基质原料包括,例如,液态甘油三酯、聚乙二醇或链烷烃。
适宜的非胃肠道给药制剂包括水溶性的活性化合物水溶液,例如,水溶盐溶液和碱溶液。另外,可给与适宜的油性注射用悬浮液形式的活性化合物悬浮液。适宜的亲脂性溶剂或载体包括脂肪油,例如,芝麻油,或合成的脂肪酸酯,例如,油酸乙酯或甘油三酯或聚乙二醇-400(所述化合物溶解在PEG-400中),或cremophor,或环糊精。水性注射用悬浮液中可含有增加悬浮液粘度的物质,例如包括羧甲基纤维素钠、山梨糖醇和/或葡聚糖。任选地,所述悬浮液中也可以含有稳定剂。
按照本发明一个方面,本发明化合物以局部和非胃肠道给药的制剂形式使用并用于治疗皮肤癌。
优选地,本发明局部用组合物通过选择适宜的载体配制成油、霜剂、洗剂、软膏剂等。适宜的载体包括植物油或矿物油、白凡士林(白色软石蜡)、支链脂肪或油、动物脂肪和高分子量的醇(大于C12)。优选的载体是那些活性组分可溶于其中的载体。也可以包括乳化剂、稳定剂、润湿剂和抗氧化剂,需要时,包括着色剂或芳香剂。因此,在这些局部用制剂中可使用促透皮渗透剂。所述促透皮渗透剂的实例见于美国专利号3,989,816和4,444,762。
霜剂优选地由矿物油、自乳化蜂蜡和水的混合物配制,其中混合有溶解在少量油,如杏仁油中的活性组分的混合物。该霜剂典型的实例是其中包含大约40份水、大约20分蜂蜡、大约40份矿物油和大约1份杏仁油的霜剂。
软膏剂可通过将活性组分在植物油如杏仁油中的溶液与温热的软石蜡混合并将该混合物放冷配制。所述软膏剂典型的实例是其中包含大约30%(重量比)杏仁油和大约70%(重量比)白色软石蜡的软膏剂。
下列实施例用于说明但不限制本发明方法和组合物。其它临床治疗中通常遇到的并且本领域技术人员显而易见的各种条件和参数适宜的修饰和改进都包含在本发明精神和范围内。
实施例1
3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑
a)3-氨基-4-氯-苄胺肟:将3-氨基-4-氯-苄腈(1.37g,8.96mmol)和50wt%羟基胺(1260μL,20.6mmol)的乙醇(15.0mL)溶液回流1h。将溶液旋转蒸发至干,残渣通过闪式柱色谱纯化得到1.44g(86%)白色固体产物。1H NMR(DMSO-d6):9.53(s,1H),7.17(d,J=8.24Hz,1H),7.10(d,J=1.92Hz,1H),6.81(dd,JBA=8.38Hz,JBX=2.07,1H),5.64(s,2H),5.36(s,2H)。
b)3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑:3-氨基-4-氯-苄胺肟(548mg,2.95mmol)和3-氯噻吩-2-碳酰氯(535mg,2.95mmol)的吡啶(3.0mL)溶液于室温氩环境下搅拌3分钟。然后将该溶液加热至118℃,保持20分钟并回流30分钟。将溶液冷却至室温并通过加入13mL去离子水沉淀产物。在Buchner漏斗中过滤沉淀物,用去离子水洗涤,并真空干燥至干。产物通过柱色谱(7∶2己烷/乙酸乙酯)和通过重结晶(1∶2二氯甲烷/己烷)纯化得到257mg(36%)标题化合物的白色固体。1H NMR(CDCl3):7.61(d,J=5.22Hz,1H),7.57(d,J=1.92Hz,1H),7.49(dd,J1=8.24Hz,J2=1.92Hz,1H),7.37(d,J=8.24Hz,1H),7.13(d,J=5.49Hz,1H),4.22(s,2H)。
实施例2
5-(3-氯噻吩-2-基)-3-(3-二甲基氨基-4-氯-苯基)-[1,2,4]-噁二唑
将3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑(75.5mg,0.242mmol)、硼氢化钠(54.4mg,1.44mmol)和四氢呋喃(4.5mL)的混合物加入到搅拌下的37wt%甲醛溶液(80uL,1.1mmol)、硫酸(70μL,1.2mmol)和四氢呋喃(1.5mL)的溶液中。将该溶液在室温下搅拌30分钟,然后加入甲醇(2.5mL)并将溶液搅拌30分钟。在溶液中加入水(15mL)并通过加入3M NaOH将溶液调至pH9。用乙酸乙酯(60mL)提取溶液。乙酸乙酯层用硫酸钠干燥并旋转蒸发至干。产物通过柱色谱纯化(7∶2己烷/乙酸乙酯)得到67.0mg(81%)标题化合物的白色固体。1H NMR(CDCl3):7.83(d,J=1.92Hz,1H),7.74(dd,J1=8.24Hz,J2=1.92Hz,1H),7.61(d,J=5.22Hz,1H),7.48(d,J=8.25Hz,1H),7.14(d,J=5.22Hz,1H),2.90(s,6H)。
实施例3
3-(3-氨基-4-氯-苯基)-5-(3-溴呋喃-2-基)-[1,2,4]-噁二唑
类似于实施例1b,用3-氨基-4-氯-苄胺肟(293mg,1.58mmol)和3-溴呋喃-2-碳酰氯(329mg,1.57mmol)在吡啶(2.8mL)中回流制备标题化合物,得到289mg(54%)白色固体。1H NMR(CDCl3):7.66(d,J=1.64Hz,1H),7.59(d,J=1.92Hz,1H),7.50(dd,J1=8.38Hz,J2=2.07Hz,1H),7.37(d,J=8.24Hz,1H),6.75(d,J=1.93Hz,1H),4.22(s,2H)。
实施例4
5-(3-溴呋喃-2-基)-3-(3-二甲基氨基-4-氯-苯基)-[1,2,4]-噁二唑
标题化合物制备3-(3-氨基-4-氯-苯基)-5-(3-溴呋喃-2-基)-[1,2,4]-噁二唑(275mg,0.809mmol),硼氢化钠(185mg,4.88mmol),37wt%甲醛溶液(270μL,9.74mmol)、硫酸(240μL,4.50mmol),and四氢呋喃(22.0mL),类似于实施例2,得到289mg(54%)白色固体。1HNMR(CDCl3):7.85(d,J=1.93Hz,1H),7.76(dd,J1=8.24Hz,J2=2.20Hz,1H),7.67(d,J=1.93Hz,1H),7.48(d,J=8.24Hz,1H),6.75(d,J=1.92Hz,1H),2.90(s,6H)。
实施例5
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯基}-2-(4-甲基-哌嗪1-基)-乙酰胺
在室温下,将3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑(56.5mg,0.181mmol)、三乙胺(75.0μL,0.540mmol)和溴-乙酰溴(48.0μL,0.549mmol)和二氯甲烷(15.0mL)的溶液搅拌30分钟。溶液用5%盐酸溶液洗涤,用硫酸钠干燥,并旋转蒸发至干。残渣中加入乙醇(10mL)、四氢呋喃(10mL)和1-甲基-哌嗪(525μL,4.73mmol)并将所得到的溶液在氩气下回流20分钟。溶液在乙酸乙酯(25mL)和10%碳酸氢钠(15mL)之间分配。乙酸乙酯层用水(15mL)洗涤,用硫酸钠干燥并旋转蒸发至干产生68.7mg(84%)的白色固体标题化合物。1H NMR(CDCl3):10.04(s,1H),9.25(d,J=1.92Hz,1H),7.85(dd,J1=8.24Hz,J2=1.64Hz,1H),7.60(d,J=5.22Hz,1H),7.52(d,J=8.24Hz,1H),7.12(d,J=5.49Hz,1H),3.24(s,2H),2.73(s,4H),2.57(s,4H),2.35(s,3H)。
实施例6
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯基}-琥珀酰胺酸乙酯
类似于实施例5,由3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑(107mg,0.343mmol)、三乙胺(960μL,6.91mmol)和乙基琥珀酰氯(298.0μL,2.10mmol)和二氯甲烷(10.0mL)制备标题化合物,产生112mg(73%)的白色固体。1H NMR(CDCl3):9.13(s,1H),7.97(s,1H),7.84(dd,J1=8.38Hz,J2=2.06Hz,1H),7.60(d,J=5.49Hz,1H),7.51(d,J=8.52Hz,1H),7.12(d,J=5.22Hz,1H),3.24(s,2H),4.19(t,J=7.14Hz,2H),2.79(s,4H),1.28(t,J=7.14Hz,3H)。
实施例7
5-(3-氯噻吩-2-基)-3-(4-氯-3-氰基-苯基)-[1,2,4]-噁二唑
将亚硝酸钠(76.8mg,1.11mmol)和水(650μL)滴加到在冰浴上搅拌的3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑(335mg,1.07mmol)的硫酸(3.0ml)、水(8ml)和一些碎冰的悬浮液中。将溶液搅拌1.25小时并倾入在冰浴中的氰化亚铜(152mg,1.70mmol)、氰化钾(231mg,3.55mmol)和水(8ml)的溶液中。溶液搅拌10分钟,然后加入乙酸乙酯(50ml),再加入碳酸钠使溶液的pH为7,溶液平衡至室温。通过旋转蒸发浓缩乙酸乙酯层并将产物通过柱色谱纯化得到75.7mg(22%)淡黄色固体的标题化合物。1H NMR(CDCl3):8.49(d,J=2.20Hz,1H),8.33(dd,J1=8.52Hz,J2=2.20Hz,1H),7.67(m,2H),7.16(d,J=5.50Hz,1H)。
实施例8
3-(4-氯-苄氧基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑
a)(3-氯噻吩-2-羰基)-硫代氨基甲酸O-(4-氯-苄基)酯:3-氯噻吩-2-碳酰氯(105.5mg,0.583mmol)加到搅拌下的硫氰酸钾(197.1mg,2.03mmol)和丙酮(10.0mL)的溶液中,并将该溶液在室温下搅拌30分钟。溶液通过Celite过滤。滤液中加入4-氯苄基醇(257.0mg,1.80mmol)并且溶液在氩气下回流23h。将溶液冷却至室温并旋转蒸发至干。产物通过柱色谱(9∶1二氯甲烷/乙酸乙酯)纯化得到63.2mg(31%)白色固体。1HMR(CDCl3):10.07(s,1H),7.63(d,J=5.49Hz,1H),7.43(d,J=8.24Hz,1H),7.37(d,J=8.52Hz,1H),7.04(d,J=5.49Hz,1H),5.62(s,2H)。
b)将搅拌下的(3-氯噻吩-2-羰基)-硫代氨基甲酸、O-(4-氯-苄基)酯(52.3mg,0.151mg)、羟基胺盐酸盐(20.7mg,0.298mmol)的溶液在氩气下回流1h。溶液冷却至室温,然后加入水(6mL)以便沉淀产物,并过滤该混合物。滤饼溶解在二氯甲烷中,通过玻璃棉过滤,并旋转蒸发至干。产物在二氯甲烷/甲醇中重结晶,得到3.1mg(6.2%)标题化合物的白色固体。1HMR(CDCl3):7.58(d,J=5.7Hz,1H),7.44(d,J=8.4Hz,1H),7.37(d,J=8.4Hz,1H),7.10(d,J=5.1Hz,1H),5.36(s,2H)。
实施例9
5-(3-氯噻吩-2-基)-3-(4-氯-3-氟-苯基)-[1,2,4]-噁二唑
a)4-氯-3-氟-苄胺肟:类似于实施例1a,用4-氯-3-氟-苄腈(4.90g,31.5mmol)、50wt%羟基胺(2.10mL,34.3mmol)和乙醇(78mL)制备标题化合物,得到2.65g(45%)白色固体。1HMR(DMSO-d6):9.89(s,1H),7.66(dd,J1=10.99Hz,J2=1.93Hz,1H),7.60-7.54(m,2H),5.97(s,2H)。
b)5-(3-氯噻吩-2-基)-3-(4-氯-3-氟-苯基)-[1,2,4]-噁二唑:类似于实施例1b,用4-氯-3-氟-苄胺肟(2.55g,13.5mmol)和3-氯噻吩-2-碳酰氯(2.45g,13.5mmol)在吡啶(17mL)中制备标题化合物,得到4.17g(98%)白色固体。1H NMR(CDCl3):7.98-7.89(m,2H),7.63(d,J=5.22Hz,1H),7.54(t,J=7.69Hz,1H),7.14(d,J=5.22Hz,1H)。
实施例10
5-(3-氯噻吩-2-基)-3-(4-氯-3-硝基-苯基)-[1,2,4]-噁二唑
a)4-氯-3-硝基-苄胺肟:类似于实施例1a,用4-氯-3-硝基-苄腈(5.14g,28.1mmol)、50wt%羟基胺(1.90mL,31.0mmol)、四氢呋喃(36.0mL)和乙醇(22.0mL)制备标题化合物,得到2.82g(47%)白色固体。1H NMR(DMSO-d6):10.06(s,1H),8.31(dd,J1=2.09Hz,J2=0.99Hz,1H),7.98(ddd,J1=6.87Hz,J2=2.06Hz,J3=1.24Hz,1H),7.80(dd,J1=8.52Hz,J2=0.82Hz,1H),6.11(s,2H)。
b)5-(3-氯噻吩-2-基)-3-(4-氯-3-硝基-苯基)-[1,2,4]-噁二唑:类似于实施例1b,用4-氯-3-硝基-苄胺肟(2.76g,12.8mmol)和3-氯噻吩-2-碳酰氯(2.32g,12.8mmol)在吡啶(17.0mL)中制备标题化合物,得到1.84g(42%)白色固体。1H NMR(CDC13):8.67(d,J=1.92Hz,1H),8.31(dd,J1=8.37Hz,J2=2.06Hz,1H),7.71(d,J=8.24Hz,1H),7.66(d,J=5.22Hz,1H),7.16(d,J=5.22Hz,1H)。
实施例11
3-(5-氯-吡啶-2-基)-5-(3-甲氧基-噻吩-2-基)-[1,2,4]-噁二唑
a)3-甲氧基-噻吩-2-羧酸:将氢氧化锂(605mg,14.4mmol)和水(10.0mL)的溶液加到搅拌下的3-甲氧基-噻吩-2-羧酸甲酯(1.24g,7.22mmol)和四氢呋喃(15.0mL)的溶液中并将该溶液在氩气下回流3.5h。将溶液冷却至室温并在二氯甲烷(50mL)和5%碳酸氢钠溶液(20mL)之间分配。水层用10%盐酸溶液调至pH 3并用乙酸乙酯(2×50mL)提取。乙酸乙酯层用硫酸钠干燥并通过旋转蒸发浓缩至干,得到876mg(77%)白色固体。1H NMR(DMSO-d6):7.77(d,J=5.22Hz,1H),7.10(d,J=5.49Hz,1H),3.88(s,3H)。
b)3-甲氧基-噻吩-2-羧酸5-氯吡啶-2-偕胺肟-O-酯:将5-氯吡啶-2-偕胺肟(100.9mg,0.588mmol)、3-甲氧基-噻吩-2-羧酸(112mg,0.707mmol)、1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺(135.1mg,(0.705mmol)、4-二甲基氨基-吡啶(89.3mg,0.731mmol)和二氯甲烷(15.0mL)的溶液在室温下搅拌5h。溶液用饱和碳酸氢钠溶液(20mL)和水(20mL)洗涤。二氯甲烷层旋转蒸发至干,产物通过柱色谱(9∶1二氯甲烷/乙酸乙酯)纯化,得到161mg(88%)产物的白色固体。1HNMR(CDCl3):8.54(dd,J1=2.33Hz,J2=0.69Hz,1H),8.23(dd,J1=8.51Hz,J2=0.82Hz,1H),7.75(dd,J1=8.52Hz,J2=2.19Hz,1H),7.52(d,J=5.50Hz,1H),6.92(d,J=5.49Hz,1H),6.13(s broad,2H),4.04(s,3H)。
c)3-(5-氯-吡啶-2-基)-5-(3-甲氧基-噻吩-2-基)-[1,2,4]-噁二唑:将搅拌下的3-甲氧基-噻吩-2-羧酸5-氯吡啶-2-偕胺肟-O-酯(102.0mg,0.327mmol)和吡啶(1.5mL)的溶液在密封管中用微波加热至180℃13分钟。产物在40℃下旋转蒸发至干并通过柱色谱(95∶5二氯甲烷/乙酸乙酯)纯化,得到54.4mg(57%)标题化合物的白色固体。1H NMR(CDCl3):8.76(dd,J1=2.47Hz,J2=0.83Hz,1H),8.16(dd,J1=8.38Hz,J2=0.68Hz,1H),7.83(dd,J1=8.51Hz,J2=2.47Hz,1H),7.57(d,J=5.50Hz,1H),6.96(d,J=5.49Hz,1H),4.09(s,3H)。
实施例12
3-(5-氯-吡啶-2-基)-5-(3-甲基-3H-咪唑-4-基)-[1,2,4]-噁二唑
将3-甲基-3H-咪唑-4-碳酰氯(91mg,0.5mmol)、5-氯-N-羟基-吡啶-2-甲脒(carboxamidine)(85.8mg,0.5mmol)在吡啶(5ml)中的混合物回流4h然后冷却至室温。向该溶液中加入水(20ml),产物从溶液中沉淀出来。通过过滤收集固体并用水洗涤,干燥,得到6mg(5%)标题化合物。1H NMR(CDCl3):8.78(d,J=2.4Hz,1H),8.15(d,J=8.4Hz,1H),8.05(s,1H),7.87(dd,J=2.7Hz,J=8.7Hz,1H),7.70(s,1H),4.14(s,3H)。
实施例13
3-[2-(4-氯-苯基)-乙烯基]-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑
将3-(4-氯-苯基)-丙烯腈(1.63g,10mmol)和羟基胺(0.74ml,12mmol)的乙醇(10ml)溶液在室温下搅拌过夜。蒸发溶剂,残渣通过柱色谱(EtOAc∶己烷=1∶3)纯化,得到1.0g(51%)of 3-(4-氯-苯基)-N-羟基-丙烯脒。
类似于实施例12,由3-氯噻吩-2-碳酰氯(138.2mg,0.76mmol)和3-(4-氯-苯基)-N-羟基-丙烯脒(150mg,0.76mmol)制备标题化合物,得到24mg(10%)标题化合物。1H NMR(CDCl3):7.74(d,J=15.9Hz,1H),7.61(d,J=5.1Hz,1H),7.54-7.51(m,2H),7.39(d,J=8.7Hz,2H),7.14-7.05(m,2H)。
实施例14
5-(3-氯-1H-吡咯-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑
类似于实施例12,由3-氯-1H-吡咯-2-碳酰氯(282.2mg,1.72mmol)和5-氯-N-羟基-吡啶-2-甲脒(295mg,1.72mmol)制备标题化合物,得到29mg(6%)标题化合物。1H NMR(CDCl3):9.68(brs,1H),8.77(d,J=2.1Hz,1H),8.16(d,J=8.4Hz,1H),7.86(dd,J=8.4Hz,J=2.4Hz,1H),7.03-7.01(m,1H),6.39-6.37(m,1H)。
实施例15
3-(4-氯-苯基)-5-(3-氯-1H-吡咯-2-基)-[1,2,4]-噁二唑
类似于实施例12,由3-氯-1H-吡咯-2-碳酰氯(856.4mg,5.22mmol)和4-氯-N-羟基-苄脒(890.5mg,5.22mmol)制备标题化合物,得到418mg(28.6%)标题化合物。1HNMR(CDCl3):9.41(brs,1H),8.06-8.03(m,2H),7.47-7.45(m,2H),7.00(t,J=3.0Hz,1H),6.37(t,J=3.0Hz,1H)。
实施例16
5-(3-氯-1-甲基-1H-吡咯-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑
将3-(4-氯-苯基)-5-(3-氯-1H-吡咯-2-基)-[1,2,4]-噁二唑(30.0mg,0.11mmol)、碘甲烷(0.08ml,0.17mmol)和碳酸钾(23mg,0.17mmol)在二甲基甲酰胺(2ml)中的混合物在85℃下加热4h。用水(20ml)稀释,混合物用EtOAc提取。蒸发提取物,残渣通过柱色谱(EtOAc∶己烷=1∶1)纯化,得到12.0mg(37%)标题化合物。1H NMR(CDCl3):8.11-8.07(m,2H),7.50-7.45(m,2H),6.84(d,J=3.0Hz,1H),6.28(d,J=3.3Hz,1H),4.08(s,3H)。
实施例17
5-[3-氯-1-(2-二甲基氨基乙基)-1H-吡咯-2-基]-3-(4-氯-苯基)-[1,2,4]-噁二唑
类似于实施例16,由3-(4-氯-苯基)-5-(3-氯-1H-吡咯-2-基)-[1,2,4]-噁二唑(48.0mg,0.17mmol)、2-二甲基氨基乙基氯盐酸盐(37mg,0.26mmol)和碳酸钾(35.5mg,0.26mmol)制备标题化合物,得到4mg(7.0%)标题化合物。1H NMR(CDCl3):8.08(d,J=8.7Hz,2H),7.48(d,J=8.7Hz,2H),6.96(d,J=2.7Hz,1H),6.29(d,J=2.7Hz,1H),4.59(t,J=6.9Hz,2H),2.69(t,J=6.9Hz,2H),2.30(s,6H)。
实施例18
5-(3-氯噻吩-2-基)-3-(1-哌啶基)-[1,2,4]-噁二唑
a)N-羟基-哌啶-1-甲脒在氩气和室温下,向火焰干燥的、安装有磁搅拌棒的100mL圆底反应烧瓶中加入1-哌啶腈(1.00g,9.07mmol)和无水乙醇(18mL)。10分钟后,将羟基胺(0.61mL,9.9mmol,50%wt/水)加到该搅拌下的澄清的溶液中,然后将该溶液加热至80℃。将澄清的溶液在80℃下加热1.5h,冷却至室温,然后真空浓缩至澄清的油状物。粗品偕胺肟原料不必进一步纯化即可继续进行反应。
b)5-(3-氯噻吩-2-基)-3-(1-哌啶基)-[1,2,4]-噁二唑。向火焰干燥的、安装有磁搅拌棒的密封反应烧瓶中加入粗品偕胺肟(0.171g,1.19mmol)、3-氯噻吩-2-碳酰氯(0.216g,1.19mmol)和吡啶(2.4mL)。当加热至120℃时,粘稠的溶液变成黄色溶液。将黄色溶液在120℃加热1h并冷却至室温,搅拌过夜。反应溶液用乙酸乙酯(50mL)稀释,用1M HCl(3×20mL)、NaHCO3(2×20mL)、盐水(15mL)洗涤,用MgSO4干燥,过滤并浓缩得到黄色残渣。通过柱色谱(用EtOAc∶己烷,1∶2洗脱)纯化,得到0.022g(6.8%)黄色固体:1HNMR(CDCl3)7.51(d,1H,J=5.22),7.05(d,1H,J=5.22Hz),3.46(m,4H),1.65(m,6H)。
实施例19
5-(3-氯噻吩-2-基)-3-(4-吗啉基)-[1,2,4]-噁二唑
(a)N-羟基-吗啉-4-甲脒。通过类似于实施例18a的方法,用4-吗啉腈和羟基胺制备标题化合物,收率99%。1H-NMR(CDCl3)4.36(brs,2H),3.72(m,4H),3.09(m,4H)。
(b)5-(3-氯噻吩-2-基)-3-(4-吗啉基)-[1,2,4]-噁二唑。通过类似于实施例18b的方法,用N-羟基-吗啉-4-甲脒、3-氯噻吩-2-碳酰氯和吡啶制备标题化合物,收率49%。1H-NMR(CDCl3)7.53(dd,1H,J=5.22and 0.55Hz),7.07(dd,1H,J=5.22 and 0.55Hz),3.82(m,4H),3.51(m,4H)。
实施例20
5-(3-氯噻吩-2-基)-3-(吗啉-4-基)-[1,2,4]噁二唑
(a)N-羟基-吗啉-4-甲脒。标题化合物以类似于实施例18a的方法制备用4-吗啉腈(1.00g,8.92mmol)、EtOH(17.8mL)和羟基胺(0.600mL,9.81mmol,50% wt/water)得到1.24g(96%)标题化合物的白色固体。1H NMR(CDCl3):4.36(brs,2H),3.72(t,4H,J=4.8Hz),3.09(t,4H,J=4.8Hz)。
(b)5-(3-氯噻吩-2-基)-3-(吗啉-4-基)-[1,2,4]噁二唑。在类似于实施例18b的方法中,用N-羟基-吗啉-4-甲脒(0.172g,1.19mmol)、3-氯噻吩-2-碳酰氯(0.216g,1.19mmol)和吡啶(2.4mL)制备标题化合物,得到0.160g(49%)标题化合物的白色固体。1H NMR(CDCl3):7.54(dd,1H,J=5.4 and 0.7Hz),7.08(dd,1H,J=5.4 and 0.7Hz),3.83-3.80(m,4H),3.53-3.50(m,4H)。
实施例21
5-(3-氯噻吩-2-基)-3-(吡咯烷-1-基)-[1,2,4]噁二唑
(a)吡咯烷-1-腈。在0℃下,向吡咯烷(0.500g,7.03mmol)、无水THF(23mL)和无水Et3N(0.99mL,7.03mmol)的溶液中一次加入溴化氰(0.744g,7.03mmol)。所得到的白色悬浮液在0℃下搅拌2h,然后平衡至室温并搅拌48h。蒸发溶剂,白色固体用乙酸乙酯(100mL)稀释,用水(2×20mL)、盐水(15mL)洗涤,用MgSO4干燥,过滤并浓缩,得到0.67g(100%)标题化合物的黄色油状物。1H NMR(CDCl3):3.42-3.64(m,4H),1.94-1.88(m,4H)。
(b)N-羟基-吡咯烷-1-甲脒。在类似于实施例18a的方法中,用吡咯烷-1-腈(0.670g,6.96mmol)、羟基胺(0.253mL,7.66mmol,50% wt/water)制备标题化合物,得到0.662g(74%)标题化合物的黄色油状物。1H NMR(CDCl3):4.62-4.55(brs,2H),3.24-3.20(m,4H),1.90-1.85(m,4H)。
(c)5-(3-氯噻吩-2-基)-3-(吡咯烷-1-基)-[1,2,4]噁二唑。在类似于实施例18b的方法中,用N-羟基-吡咯烷-1-甲脒(0.041g,0.32mmol)、3-氯噻吩-2-碳酰氯(0.057g,0.32mmol)和无水吡啶(1.0mL)制备标题化合物,得到0.006g(7%)标题化合物的白色固体。1H NMR(CDCl3):7.52-7.50(m,1H),7.07-7.05(m,1H),3.52-3.47(m,4H),2.02-1.97(m,4H)。
通过类似于实施例21的方法,在三步反应中,用相应的胺和溴化氰开始制备实施例22-30化合物。
实施例22
5-(3-氯噻吩-2-基)-3-(4-甲基哌啶-1-基)-[1,2,4]噁二唑
(a)4-甲基-哌啶-1-腈。1H NMR(CDCl3):3.42-3.36(m,2H),3.05-2.95(m,2H),1.69-1.64(m,2H),1.51-1.45(m,1H),1.37-1.29(m,2H),0.97(d,3H,J=6.3Hz)。
(b)N-羟基-4-甲基哌啶-1-甲脒。1H NMR(CDCl3):4.58-4.51(brs,2H),3.55-3.51(m,2H),2.64-2.56(m,2H),1.63-1.59(m,4H),1.45-1.41(m,1H),1.22-1.20(m,3H)。
(c)5-(3-氯噻吩-2-基)-3-(4-甲基哌啶-1-基)-[1,2,4]噁二唑。1HNMR(CDCl3):7.51(d,1H,J=5.5Hz),7.06(d,1H,J=5.5Hz),4.06-4.02(m,2H),2.98-2.89(m,2H),1.72-1.58(m,3H),1.30-1.24(m,2H),0.98(d,3H,J=6.3Hz)。
实施例23
5-(3-氯噻吩-2-基)-3-(2-甲基哌啶-1-基)-[1,2,4]噁二唑
(a)2-甲基-哌啶-1-腈.′H NMR(CDCl3):3.42-3.41(m,1H),3.07-2.99(m,2H),1.84-1.80(m,1H),1.72-1.61(m,3H),1.35-1.25(m,5H)。
(b)N-羟基-2-甲基哌啶-1-甲脒。13C NMR(CDCl3,E/Z异构体,2个额外的峰):158.4,156.4,57.7,49.5,46.4,41.4,38.8,30.6,29.9,25.4,25.3,19.3,18.3,18.2,15.4,13.9。
(c)5-(3-氯噻吩-2-基)-3-(2-甲基哌啶-1-基)-[1,2,4]噁二唑。1HNMR(CDCl3):7.50(d,1H,J=5.5Hz),7.05(d,1H,J=5.2Hz),4.39-4.34(m,1H),3.89-3.83(m,1H),3.10(dt,1H,J=12.4 and3.0Hz),1.80-1.59(m,6H),1.22(d,3H,J=6.9Hz)。
实施例24
5-(3-氯噻吩-2-基)-3-(4-三氟甲基哌啶-1-基)-[1,2,4]噁二唑
(a)4-三氟甲基-哌啶-1-腈。1H NMR(CDCl3):3.56-3.50(m,2H),3.09-3.04(m,3H),2.20-2.12(m,1H),1.96-1.90(m,2H),1.80-1.65(m,2H),1.30-1.25(m,1H)。
(b)N-羟基-4-三氟甲基-哌啶-1-甲脒。1H NMR(CDCl3):4.29(brs,2H),3.71-3.66(m,2H),2.67-2.58(m,2H),2.17-2.10(m,1H),1.88-1.84(m,2H),1.67-1.53(m,3H),1.19-1.10(m,1H)。
(c)5-(3-氯噻吩-2-基)-3-(4-三氟甲基哌啶-1-基)-[1,2,4]噁二唑。1H NMR(CDCl3):7.53(d,1H,J=5.2Hz),7.07(d,1H,J=5.5Hz),4.21(d,2H,J=12.9Hz),2.95(dt,2H,J=12.8和2.5Hz),2.30-2.22(m,1H),1.96(d,2H,J=12.6Hz),1.68(ddd,2H,J=12.9,12.6,4.4和4.1Hz)。
实施例25
5-(3-氯噻吩-2-基)-3-(4-甲基哌嗪-1-基)-[1,2,4]噁二唑
(a)4-甲基-哌嗪-1-腈。1H NMR(CDCl3):3.26(t,4H,J=5.1Hz),2.47(t,4H,J=5.1Hz),2.31(d,3H,J=0.9Hz)。
(b)N-羟基-4-甲基-哌嗪-1-甲脒。1H NMR(CDCl3):4.39(brs,2H),3.44-3.42(m,1H),3.15-3.12(m,3H),2.45-2.39(m,4H),2.30-2.27(m,3H)。
(c)5-(3-氯噻吩-2-基)-3-(4-甲基哌嗪-1-基)-[1,2,4]噁二唑。1HNMR(CDCl3):7.98(d,1H,J=5.5Hz),7.26(d,1H,J=5.2Hz),3.48-3.44(m,4H,J=5.2和5.0Hz),2.447-2.44(m,4H,J=5.2和5.0Hz),2.27(s,3H)。
实施例26
4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸苄酯
(a)4-氰基-哌嗪-1-羧酸苄酯。1H NMR(CDCl3):7.35(m,5H),5.14(s,2H),3.62-3.59(m,4H),3.23-3.21(m,4H)。
(b)4-(N-羟基氨基亚胺羰基)-哌嗪-1-羧酸苄酯。1H NMR(DMSO-d6):8.37(s,1H),7.38-7.36(m,5H),5.21(brs,2H),5.08(s,2H),3.41-3.39(m,4H),2.98-2.95(m,4H)。
(c)4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸苄酯。1H NMR(CDCl3):7.54(d,1H,J=5.2Hz),7.39-7.33(m,5H),7.07(d,1H,J=5.2Hz),5.17(s,2H),3.65-3.62(m,4H),3.52(m,4H)。
实施例27
4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯
(a)4-氰基-哌嗪-1-羧酸叔-丁酯。1H NMR(CDCl3):3.53(t,4H,J=5.1Hz),3.20(t,4H,J=5.1Hz),1.46(s,9H)。
(b)4-(N-羟基氨基亚胺羰基)-哌嗪-1-羧酸叔丁酯。1HNMR(DMSO-d6):8.35(s,1H),5.19(s,2H),3.33-3.28(m,4H),2.94-2.91(m,4H),1.40(s,9H)。
(c)4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯。1H NMR(CDCl3):7.53(dd,1H,J=5.2和1.1Hz),7.07(dd,1H,J=5.2和1.1Hz),3.55-3.51(m,8H),1.48(s,9H)。
实施例28
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-氨基甲酸叔丁酯
(a)(1-氰基-哌啶-4-基)-氨基甲酸叔丁酯。1H NMR(CDCl3):4.52(brs,1H),3.57-3.52(m,1H),3.45-3.41(m,2H),3.13-3.04(m,2H),2.00-1.96(m,2H),1.56-1.44(m,11H)。
(b)[1-(N-羟基氨基亚胺羰基)-哌啶-4-基]-氨基甲酸叔-丁酯。1HNMR(DMSO-d6):8.21(s,1H),6.81(d,1H,J=6.9Hz),5.08(s,2H),1.63-1.61(m,2H),1.37-1.31(m,11H)。
(c){1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-氨基甲酸叔丁酯.′H NMR(DMSO-d6):8.10(d,1H,J=5.2Hz),7.35(d,1H,J=5.2Hz),6.90(d,1H,J=7.4Hz),3.83(d,2H,J=12.1Hz),3.48(m,1H),3.03(m,2H,J=11.8 and 10.7Hz),1.80(d,2H,J=12.1Hz),1.39(s,9H)。
实施例29
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-乙酸乙酯
(a)(1-氰基-哌啶-4-基)-乙酸乙酯。1H NMR(CDCl3):4.14(q,2H,J=7.1Hz),3.44-3.39(m,2H),3.09-3.04(m,2H),2.27-2.24(m,2H),1.94-1.90(m,1H),1.79-1.74(m,2H),1.42-1.36(m,2H),1.26(t,3H,J=7.1Hz)。
(b)[1-(N-羟基氨基亚胺羰基)-哌啶-4-基]-乙酸乙酯。1HNMR(DMSO-d6):5.16-5.14(brs,2H),4.05(q,2H,J=7.1Hz),3.56-3.50(m,2H),3.07(q,1H,J=7.1Hz),2.47-2.42(m,1H),2.22-2.20(m,2H),1.78-1.72(m,1H),1.61-1.57(m,2H),1.09-0.96(m,5H)。
(c){1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-乙酸乙酯。1H NMR(CDCl3):7.52(dd,1H,J=5.2和0.8Hz),7.06(dd,1H,J=5.5 and 0.8Hz),4.16(q,2H,J=7.1Hz),4.07(dd,2H,J=10.9和2.3Hz),2.98(td,2H,J=12.7和2.8Hz),2.28(d,2H,J=6.9Hz),2.03(m,1H),1.80(d,2H),1.35(m,2H),1.27(t,3H,J=7.1Hz)。
实施例30
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-3-基}-乙酸乙酯
(a)(1-氰基-哌啶-3-基)-乙酸乙酯。13C NMR(CDCl3):171.2,118.0,60.6,54.1,49.7,45.9,37.9,31.9,29.3,23.7,14.2,12.9。
(b)[1-(N-羟基氨基亚胺羰基)-哌啶-3-基]-乙酸乙酯。1HNMR(DMSO-d6):5.06(s,2H),4.05(q,2H,J=7.1Hz),3.04(q,1H,J=7.1Hz),2.47-2.43(m,1H),2.27-2.16(m,3H),1.89-1.85(m,1H),1.73-1.69(m,1H),1.56-1.44(m,2H),1.20-1.15(m,3H),1.08-0.95(m,2H)。
(c){1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-3-基}-乙酸乙酯。1H NMR(CDCl3):7.52(d,1H,J=5.2Hz),7.06(d,1H,J=5.2Hz),4.16(q,2H,J=7.1Hz),4.01-3.89(m,2H),3.05-2.96(m,1H),2.79(dd,1H,J=12.6 and 9.9Hz),2.36-2.15(m,3H),1.94-1.89(m,1H),1.75-1.64(m,1H),1.28(t,3H,J=7.1Hz)。
实施例31
5-(3-氯噻吩-2-基)-2-(哌啶-1-基)-[1,3,4]噁二唑(a)3-氯噻吩-2-羧酸酰肼。在0℃下,向肼(0.860mL,27.6mmol)的溶液中加入澄清的3-氯噻吩-2-碳酰氯(1.00g,5.52mmol)和CH2Cl2(11.0mL)溶液。反应物在0℃下搅拌0.5h,然后平衡至室温。蒸发溶剂,黄色固体用乙酸乙酯(70mL)稀释,用水(2×20mL)洗涤,用MgSO4干燥,过滤并浓缩,得到0.80g(82%)标题化合物的白色固体。1H NMR(CDCl3):9.41(s,1H),7.81(d,1H,J=5.2Hz),7.13(d,1H,J=5.5Hz),4.57(s,2H)。
(b)哌啶-1-羧酸N-(3-氯噻吩-2-羰基)-酰肼。将3-氯噻吩-2-羧酸酰肼(0.150g,0.852mmol)、THF(1.7mL)和Et3N(0.12mL,0.852mmol)的黄色溶液冷却至0℃并滴加1-哌啶碳酰氯(0.106mL,0.852mmol)。黄色溶液平衡至室温并搅拌18h。反应溶液用水(20mL)稀释,然后用乙酸乙酯(30mL)提取。有机层用水(15mL)、盐水(10mL)洗涤,用MgSO4干燥,然后浓缩,得到0.210g(86%)标题化合物的白色固体。1H NMR(CDCl3):9.29(d,1H,J=5.2Hz),7.51-7.48(m,2H),7.00(d,1H,J=5.2Hz),3.45-3.43(m,4H),1.64-1.60(m,6H)。
(c)5-(3-氯噻吩-2-基)-2-(哌啶-1-基)-[1,3,4]噁二唑。哌啶-1-羧酸N-(3-氯噻吩-2-羰基)-酰肼(0.100g,0.347mmol)和亚硫酰氯(1.4mL)的黄色溶液在85℃下加热2h。蒸发溶剂,棕色固体通过闪式柱色谱(硅胶,用EtOAc∶己烷,1∶2洗脱)纯化得到0.047g(50%)标题化合物的黄色固体。1H NMR(丙酮-d6):7.76(d,1H,J=5.5Hz),7.16(d,1H,J=5.2Hz),3.55(m,4H),1.69(m,6H)。
通过类似于实施例21的方法,用3-氯噻吩-2-羧酸酰肼和相应的胺-碳酰氯分两步制备实施例32-33化合物。
实施例32
5-(3-氯噻吩-2-基)-2-(吗啉-4-基)-[1,3,4]噁二唑
(a)吗啉-4-羧酸N-(3-氯噻吩-2-羰基)-酰肼。1H NMR(CDCl3):9.16(brs,1H),7.53-7.51(m,2H),7.02-7.00(m,1H),3.73(t,4H,J=4.8Hz),3.50(t,4H,J=4.9Hz)。
(b)5-(3-氯噻吩-2-基)-2-(吗啉-4-基)-[1,3,4]噁二唑。1H NMR(丙酮-d6):7.79(d,1H,J=5.5Hz),7.17(d,1H,J=5.2Hz),3.82-3.79(m,4H),3.57-3.54(m,4H)。
实施例33
5-(3-氯噻吩-2-基)-2-(4-甲基哌嗪-1-基)-[1,3,4]噁二唑
(a)4-甲基-哌嗪-1-羧酸N-(3-氨噻吩-2-羰基)-酰肼。1HNMR(CDCl3):9.25(brs,1H),8.00(brs,1H),7.51(dd,1H,J=5.4和0.7Hz),7.00(dd,1H,J=5.4和0.7Hz),3.53(t,4H,J=5.1Hz),2.43(t,4H,J=5.1Hz),2.31(s,3H)。
(b)5-(3-氯噻吩-2-基)-2-(4-甲基哌嗪-1-基)-[1,3,4]噁二唑。1H NMR(丙酮-d6):7.74(d,1H,J=5.5Hz),7.15(d,1H,J=5.2Hz),3.89-3.84(m,4H),3.44-3.40(m,4H),2.94(s,3H)。
实施例34
4-[5-(3-溴呋喃-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸苄酯
以类似于实施例18b的方法制备标题化合物。由4-(N-羟基氨甲酰基)-哌嗪-1-羧酸苄酯(0.100g,0.360mmol)、3-溴呋喃-2-碳酰氯(0.075g,0.360mmol)和吡啶(0.9mL)得到0.040g(26%)标题化合物的白色固体。1H NMR(CDCl3):7.59(d,1H,J=2.0Hz),7.38-7.37(m,5H),6.69(d,1H,J=1.9Hz),5.17(s,2H),3.65-3.62(m,4H),3.54(m,4H)。
实施例35
4-[5-(3-溴呋喃-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯
以类似于实施例18b的方法制备标题化合物。由4-(N-羟基氨基亚胺羰基)-哌嗪-1-羧酸叔丁基酯(0.470g,1.92mmol)、3-溴呋喃-2-碳酰氯(0.400g,1.92mmol)和吡啶(4.8mL)得到0.447g(58%)标题化合物的白色固体。1H NMR(CDCl3):7.59(d,1H,J=1.9Hz),6.68(d,1H,J=1.5Hz),3.53(m,8H),1.49(s,9H)。
实施例36
5-(3-氯噻吩-2-基)-2-(哌嗪1-基)-[1,3,4]噁二唑三氟乙酸盐
在安装有磁搅拌棒的火焰干燥的反应烧瓶中加入4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯(0.200g,0.540mmol)和TFA(3.33mL,43.2mmol)。将黄色溶液在室温下搅拌30分钟并蒸发溶剂得到黄色残渣。用乙醚稀释,形成黄色沉淀,过滤并收集得到0.171g(82%)标题化合物的黄色固体。1H NMR(DMSO-d6):8.85(brs,2H),8.13(dd,1H,J=5.2和0.6Hz),7.38(dd,1H,J=5.2和0.6Hz),3.62(t,4H,J=5.2Hz),3.24(t,4H,J=5.2Hz)。
实施例37
5-(3-溴呋喃-2-基)-2-(哌嗪1-基)-[1,3,4]噁二唑三氟乙酸盐
以类似于实施例36的方法制备标题化合物。由4-[5-(3-溴呋喃-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯(0.398g,1.00mmol)和TFA(6.20mL,80.1mmol)得到0.260g(63%)标题化合物的白色固体。1H NMR(DMSO-d6):8.91(brs,2H),8.18(d,1H,J=1.9Hz),7.11(d,1H,J=1.9Hz),3.63(t,4H,J=5.1Hz),3.25(t,4H,J=5.1Hz)。
实施例38
5-(3-氯噻吩-2-基)-3-(4-氨基哌啶-1-基)-[1,2,4]噁二唑三氟乙酸盐
以类似于实施例36的方法制备标题化合物。由{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-氨基甲酸叔丁酯(0.050g,0.13mmol)和TFA(0.80mL,10mmol)得到0.030g(58%)标题化合物的白色固体。1H NMR(DMSO-d6):8.12(dd,1H,J=5.2和0.8Hz),7.88(brs,3H),7.37(dd,1H,J=5.2和0.8Hz),3.93(m,2H,J=12.9Hz),3.05(m,2H,J=11.5Hz),1.96(m,2H,J=11.0Hz),1.55(m,2H,J=12.2和4.3Hz),1.09(t,3H,J=7.0Hz)。
以类似于实施例21两个步骤的方法从相应的芳基腈和羟基胺开始制备实施例39-48的化合物。
实施例39
5-(3-氯噻吩-2-基)-3-(噻吩-2-基)-[1,2,4]噁二唑
(a)N-羟基-噻吩-2-甲脒。1H NMR(DMSO-d6):9.60(s,1H),7.46(dd,1H,J=3.6和1.1Hz),7.42(dd,1H,J=5.2和1.1Hz),7.04(dd,1H,J=5.0和3.6Hz),5.91(s,2H)。
(b)5-(3-氯噻吩-2-基)-3-(噻吩-2-基)-[1,2,4]噁二唑。1HNMR(CDCl3):7.88(dd,1H,J=3.6和1.2Hz),7.61(d,1H,J=5.5Hz),7.54(dd,1H,J=5.0和1.2Hz),7.18(dd,1H,J=5.0和3.6Hz),7.13(d,1H,J=5.2Hz)。
实施例40
5-(3-氯噻吩-2-基)-3-(1H-吡咯-2-基)-[1,2,4]噁二唑
(a)N-羟基-1H-吡咯-2-甲脒。1H NMR(DMSO-d6):10.81(s,1H),9.12(s,1H),6.68(dd,1H,J=4.1和2.5Hz),6.43-6.41(m,1H),6.01-5.99(m,1H),5.26(s,2H)。
(b)5-(3-氯噻吩-2-基)-3-(1H-吡咯-2-基)-[1,2,4]噁二唑。1HNMR(丙酮-d6):11.08(brs,1H),8.05(d,1H,J=5.5Hz),7.31(d,1H,J=5.2Hz),7.11(m,1H),6.91(m,1H),6.32(m,1H)。
实施例41
5-(3-氯噻吩-2-基)-3-(呋喃-2-基)-[1,2,4]噁二唑
(a)N-羟基-呋喃-2-甲脒。1H NMR(DMSO-d6):9.60(s,1H),7.67(dd,1H,J-1.7和0.8Hz),6.75(dd,1H,J=3.3和0.8Hz),6.52(dd,1H,J=3.3和1.7Hz),5.70(s,2H)。
(b)5-(3-氯噻吩-2-基)-3-(呋喃-2-基)-[1,2,4]噁二唑。1HNMR(CDCl3):7.66-7.65(m,1H),7.63-7.61(m,1H),7.24-7.23(m,1H),7.14-7.12(m,1H),6.61-6.59(m,1H)。
实施例42
5-(3-氯噻吩-2-基)-3-(呋喃-3-基)-[1,2,4]噁二唑
(a)N-羟基-呋喃-3-甲脒。1H NMR(DMSO-d6):9.40(s,1H),7.99(dd,1H,J=1.5和0.7Hz),7.64-7.63(m,1H),6.61(dd,1H,J=1.9和0.8Hz),5.68(brs,2H)。
(b)5-(3-氯噻吩-2-基)-3-(呋喃-3-基)-[1,2,4]噁二唑。1H NMR(CDCl3):8.18(dd,1H,J=1.4和0.8Hz),7.60(d,1H,J=5.5Hz),7.55(t,1H,J=1.7Hz),7.13(d,1H,J=5.2Hz),6.95(dd,1H,J=1.9和0.8Hz)。
实施例43
3-(4-氯-2-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑
(a)4-氯-N-羟基-2-甲基-苄脒。1H NMR(DMSO-d6):9.41(s,1H),7.32(s,1H),7.27(m,2H),5.78(brs,2H),2.34(s,3H)。
(b)3-(4-氯-2-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑。1H NMR(CDCl3):8.04(d,1H,J=8.0Hz),7.61(dd,1H,J=5.2和1.4Hz),7.35-7.28(m,2H),7.14(dd,1H,J=5.4和1.2Hz),2.64(s,3H)。
实施例44
5-(3-氯噻吩-2-基)-3-(5-甲基呋喃-2-基)-[1,2,4]噁二唑
(a)N-羟基-5-甲基呋喃-2-甲脒。1H NMR(DMSO-d6):9.46(s,1H),6.62(t,1H,J=1.7Hz),6.13-6.11(m,1H),5.58(brs,2H),2.27(s,3H)。
(b)5-(3-氯噻吩-2-基)-3-(5-甲基呋喃-2-基)-[1,2,4]-噁二唑。1H NMR(CDCl3):7.60(d,1H,J=5.2Hz),7.12(d,1H,J 5.2Hz),7.12(m,1H),6.19(dd,1H,J=3.3和1.1Hz),2.44(s,3H)。
实施例45
5-(3-氯噻吩-2-基)-3-(5-硝基呋喃-2-基)-[1,2,4]噁二唑
(a)N-羟基-5-硝基呋喃-2-甲脒。1H NMR(DMSO-d6):10.31(s,1H),7.74(dd,1H,J=3.9和1.2Hz),7.12(dd,1H,J=3.8和1.3Hz),6.06(brs,2H)。
(b)5-(3-氯噻吩-2-基)-3-(5-硝基呋喃-2-基)-[1,2,4]噁二唑。1H NMR(CDCl3):7.67(d,1H,J=5.5Hz),7.45(d,1H,J=3.9Hz),7.36(d,1H,J=3.9Hz),7.16(d,1H,J=5.2Hz)。
实施例46
3-(4-氯-2-氟-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑
(a)4-氯-2-氟-N-羟基-苄脒。1H NMR(DMSO-d6):9.73(s,1H),7.55-7.46(m,2H),7.33-7.29(m,1H),5.86(brs,2H)。
(b)3-(4-氯-2-氟-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑。1H NMR(CDCl3):8.14-8.09(m,1H),7.62(d,1H,J=5.2Hz),7.32(t,1H,J=2.2Hz),7.30-7.28(m,1H),7.14(d,1H,J=5.2Hz)。
实施例47
5-(3-氯噻吩-2-基)-3-(3-甲基-吡啶-2-基)-[1,2,4]噁二唑
(a)N-羟基-3-甲基-吡啶-2-甲脒。1H NMR(DMSO-d6):9.84(d,1H,J=1.4Hz),8.43(d,1H,J=4.7Hz),7.67(d,1H,J 7.4Hz),7.31(dd,1H,J=7.7和4.7Hz),5.79(brs,2H),3.33(s,3H)。
(b)5-(3-氯噻吩-2-基)-3-(3-甲基-吡啶-2-基)-[1,2,4]噁二唑。1H NMR(CDCl3):8.70(dd,1H,J=4.3和1.2Hz),7.71-7.68(m,1H),7.62(dd,1H,J=5.5和0.6Hz),7.35(dd,1H,J=7.8和4.5Hz),7.13(dd,1H,J=5.5和0.6Hz),2.69(s,3H)。
实施例48
3-(4-氯-3-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑
(a)4-氯-N-羟基-3-甲基-苄脒。1H NMR(DMSO-d6):9.68(s,1H),7.65(d,1H,J=1.9Hz),7.51(dd,1H,J=8.2和1.9Hz),7.40(d,1H,J=8.5Hz),5.83(s,2H),2.34(s,3H)。
(b)3-(4-氯-3-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑。1H NMR(CDCl3):8.03(d,1H,J=1.6Hz),7.93(m,1H,J=8.2和1.6Hz),7.61(d,1H,J=5.5Hz),7.43(d,1H,J=8.2Hz),7.13(d,1H,J=5.5Hz),2.47(s,3H)。
实施例49
5-(3-溴呋喃-2-基)-3-(4-氯-2-甲基-苯基)-[1,2,4]噁二唑
以类似于实施例18b的方法制备标题化合物。由4-氯-N-羟基-2-甲基-苄脒(0.100g,0.542mmol)、3-溴呋喃-2-碳酰氯(0.113g,0.542mmol)和吡啶(1.4mL)得到0.044g(24%)标题化合物的棕色固体。1HNMR(CDCl3):8.07(d,1H,J=8.2Hz),7.67(dd,1H,J=1.9和0.6Hz),7.35-7.30(m,2H),6.75(dd,1H,J=1.9和0.6Hz),2.68(s,3H)。
实施例50
5-(3-溴呋喃-2-基)-3-(5-氯-3-甲基-吡啶-2-基)-[1,2,4]噁二唑
(a)3-甲基-5-硝基-吡啶-2-腈。在0℃下,在2-氰基-3-甲基吡啶(6.08g,51.5mmol)、四丁基铵硝酸盐(21.0g,69.0mmol)的叔-丁基甲基醚(150mL)白色悬浮液中缓慢加入三氟乙酸酐(9.6mmol,69.0mmol)。在0℃下,将白色悬浮液搅拌2小时,然后平衡到室温并搅拌过夜。所得黄色溶液倾入3M NaOH(300mL)中,CH2Cl2提取(300mL),Na2SO4干燥,然后蒸发除去溶剂。残渣通过闪式柱色谱纯化(硅胶,EtOAc∶己烷,1∶3.5洗脱)得到1.65g(19%)标题化合物的白色固体。1H NMR(CDCl3):9.33(d,1H,J=2.4Hz),8.50(d,1H,J=2.4Hz),2.74(s,3H)。
(b)5-氨基-3-甲基-吡啶-2-腈。在氢化烧瓶中加入3-甲基-5-硝基-吡啶-2-腈(1.65g,10.1mmol)、EtOH(37mL)、EtOAc(125mL)和5%Pd/C(1.10g,0.67%重量比)。所得黑色悬浮液在45psi压力下H2(g)中振摇3.5小时。然后经包含硅藻土(宽2英寸×高1.5英寸)的垂容玻璃漏斗过滤黑色悬浮液,用另外的EtOAc(250mL)洗涤。通过旋转蒸发除去溶剂得到1.34g(100%)标题化合物的棕色固体。1HNMR(丙酮-d6):7.94(d,1H,J=2.5Hz),6.94-6.93(m,1H),5.75(brs,2H),2.35(s,3H)。
(c)5-氯-3-甲基-吡啶-2-腈。在0℃下,向5-氨基-3-甲基-吡啶-2-腈(1.35g,10.1mmol)、氯化铜(I)(2.11g,21.3mmol)和12NHCl(3.6mL)的棕色乳液中缓慢加入亚硝酸钠(0.770g,11.1mmol)的水(3.3mL)透明溶液。在0℃下将所得绿色悬浮液再搅拌10分钟,然后平衡到室温。乙醚提取绿色悬浮液(4×200mL),Na2SO4干燥,蒸发除去溶剂。残渣通过闪式柱色谱纯化(硅胶,EtOAc∶己烷,1∶5洗脱),得到0.913g(59%)标题化合物的白色固体。1H NMR(CDCl3):8.50(d,1H,J=2.2Hz),7.68(d,1H,J=2.2Hz),2.57(s,3H)。
(d)5-氯-N-羟基-3-甲基-吡啶-2-甲脒。按类似于实施例18a的方法制备标题化合物。5-氯-3-甲基-吡啶-2-腈(0.913g,5.98mmol)、THF(42mL)和羟基胺(0.74mL,12mmol,50%wt/水)得到1.07g(96%)标题化合物的白色固体。1H NMR(DMSO-d6):9.95(s,1H),8.48-8.47(m,1H),7.88-7.87(m,1H),5.81(brs,2H),2.49(s,3H)。
(e)5-(3-溴呋喃-2-基)-3-(5-氯-3-甲基-吡啶-2-基)-[1,2,4]-噁二唑。按类似于实施例18b的方法制备标题化合物。由5-氯-N-羟基-3-甲基-吡啶-2-甲脒(1.05g,5.65mmol)、3-溴呋喃-2-碳酰氯(0.800g,6.65mmol)和吡啶(18.8mL)得到0.287g(14%)标题化合物的白色固体。1H NMR(CDCl3):8.63(d,1H,J=2.2Hz),7.70(d,1H,J=2.2Hz),7.67(dd,1H,J=1.9 and 1.1Hz),6.75(dd,1H,J=1.9 and 1.1Hz),2.69(s,3H)。
实施例51
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基氨基}-乙酸乙酯
在安装有磁搅拌棒的10mL微波反应烧瓶反应器中加入2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯胺(0.100g,0.320mmol)、无水乙醇(1.3mL)、溴乙酸乙酯(0.241g,1.44mmol)和三乙胺(67μL,0.48mmol)。悬浮液在120℃下反应15分钟,微波设在70瓦。所得黄色悬浮液用乙酸乙酯(50mL)稀释,然后用H2O(2×15mL)、盐酸(10mL)洗涤有机层,MgSO4干燥,并蒸发除去溶剂。白色固体通过闪式柱色谱进行纯化(硅胶,EtOAc∶己烷,1∶5洗脱)得到0.119g(94%)白色固体的标题化合物。1H NMR(CDCl3):7.59(dd,1H,J=5.2和1.4Hz),7.47(dd,1H,J=8.3和1.7Hz),7.38(dd,1H,J=8.3和1.1Hz),7.27(d,1H,J=1.7Hz),7.10(dd,1H,J=5.2和1.4Hz),5.11(t,1H,J=5.0Hz),4.29(q,2H,J=7.1Hz),4.05(d,2H,J=5.2Hz),1.33(t,3H,J=7.1Hz)。
通过类似于实施例51的方法制备实施例52-53的化合物。
实施例52
N′-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-N,N-二乙基-乙-1,2-二胺
由2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯胺(0.100g,0.320mmol)、无水EtOH(1.3mL)、2-溴-N,N-二乙基乙胺·HBr(0.334g,1.28mmol)和Et3N(0.230mL,1.60mmol)得到0.006g(5%)白色固体的标题化合物。1H NMR(丙酮-d6):8.08(d,1H,J=5.5Hz),7.48-7.37(m,3H),7.34(d,1H,J=5.2Hz),2.82-2.80(m,4H),2.62-2.58(m,4H),1.07(t,6H,J=7.0Hz)。
实施例53
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-(2-吗啉-4-基-乙基)-胺
由2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯胺(0.100g,0.320mmol)、无水EtOH(1.3mL)、4-(2-氯乙基)吗啉·HCl(0.238g,1.28mmol),Et3N(0.360mL,2.56mmol)和碘化钠(0.384g,2.56mmol)得到0.083g(61%)白色固体的标题化合物。1HNMR(丙酮-d6):8.09(d,1H,J=5.5Hz),7.48-7.38(m,3H),7.34(d,1H,J=5.2Hz),3.67(t,4H,J =4.7Hz),2.84(d,2H,J=9.9Hz),2.74(t,2H,J=6.0Hz),2.54-2.52(m,4H)。
实施例54
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸乙酯
在(2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基氨基)-乙酸乙酯(0.360g,0.903mmol)、低聚甲醛(0.271g,9.03mmol)和冰醋酸(4.5mL)的黄色混合物中5分钟内分小份加入氰基硼氢化钠(0.284g,4.51mmol)。黄色混合物变成白色悬浮液并在室温下搅拌过夜。将白色悬浮液加入到0℃的25%NaOH(水)溶液中。水层用二氯甲烷(50mL)提取,用盐水洗涤(15mL),MgSO4干燥,过滤并真空浓缩。透明油状物通过闪式柱色谱纯化(硅胶,EtOAc∶己烷,1∶5洗脱)得到0.362g(96%)白色固体的标题化合物。1H NMR(CDCl3):7.94(d,1H,J=1.7Hz),7.73(td,1H,J=8.2,1.9和1.7Hz),7.61(dd,1H,J=5.5,5.2,1.6和1.4Hz),7.45(dd,1H,J=8.5和1.4Hz),7.13(dd,1H,J=5.5,5.2,1.6和1.4Hz),4.18(q,2H,J=7.1Hz),4.04(s,2H),3.07(s,3H),1.26(t,3H,J=7.1Hz)。
实施例55
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸
向({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸乙酯(0.362g,0.880mmol)和EtOH∶H2O溶液(4∶1,13.4mL)的白色悬浮液中加入1M NaOH(0.033mL,0.84mmol)。另外加入等份的1M NaOH(1.98mL,50.34mmol)、乙醇(8mL)和THF(10mL)并将混合物搅拌2天直到通过TLC检测反应完成。通过加入1M HCl中和反应悬浮液并浓缩为白色固体。过滤白色固体并用H2O和乙醚洗涤得到0.142g(44%)黄色固体的标题化合物。1H NMR(DMSO-d6):8.19(dd,1H,J=5.2和0.8Hz),7.79(s,1H),7.52(dd,2H,J=8.2和6.3Hz),7.41(dd,1H,J=5.5Hz),3.77(s,2H),2.97(s,3H)。
实施例56
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸N-羟基琥珀酰亚胺基酯
向({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸(0.090g,0.23mmol)在无水二氯甲烷(2.3mL)中的白色悬浮液中加入N-羟基琥珀酰亚胺(0.027g,0.23mmol)和DCC(0.048g,0.23mmol)并搅拌4小时。在混合物加入无水DMF(1.4mL)并将白色悬浮液搅拌1小时,经垂容玻璃漏斗过滤并真空浓缩。白色固体通过闪式柱色谱层析纯化(硅胶,EtOAc∶己烷,1∶1洗脱)得到0.011g(10%)白色固体的标题化合物。1H NMR(CDCl3):07.97(d,1H,J=2.1Hz),7.79-7.76(m,1H,J=8.1,2.4,0.9和0.6Hz),7.61(dd,1H,J=5.1和0.9Hz),7.49(d,1H,J=8.1Hz),7.13(dd,1H,J=5.4和0.6Hz),4.38(s,2H),3.12(s,3H),2.83(s,4H)。
实施例57
5-(3-溴呋喃-2-基)-3-(3-甲基-吡啶-2-基)-[1,2,4]噁二唑
以类似于实施例18b的方法制备标题化合物。由N-羟基-3-甲基-吡啶-2-甲脒(0.100g,0.661mmol)、3-溴呋喃-2-碳酰氯(0.138g,0.661mmol)和吡啶(1.7mL)得到0.098g(48%)棕色固体的标题化合物。1H NMR(CDCl3):8.68(dd,1H,J=4.7和0.6Hz),7.71-7.68(m,1H),7.66(dd,1H,J=1.9和1.1Hz),7.36(d,1H,J=8.0和4.7Hz),6.75(dd,1H,J=1.9和1.1Hz),2.68(s,3H)。
实施例58
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸甲酯
(a)4-氧代-丁酸甲酯。将4,4-二甲氧基-丁酸甲酯(5.00g,30.8mmol)、乙醚(25.0mL)和1.2NHCl(12.0mL)的溶液在室温下搅拌1小时。反应物用水(50mL)稀释,二氯甲烷(3×60mL)提取,Na2SO4干燥并通过旋转蒸发除去溶剂得到4.00g(99%)油状标题化合物,用于进行下一步反应。
(b)4-(2-氯-5-氰基-苯基氨基)-丁酸甲酯。向搅拌的3-氨基-4-氯-苄腈(1.19g,7.83mmol)、冰醋酸(1.8mL,31mmol)、4-氧代-丁酸甲酯(4.00g,31mmol)和二氯乙烷(150mL)的溶液中加入三乙酰氧基硼氢化钠(6.74g,31.8mmol)并将反应混合物在室温下搅拌15小时。通过旋转蒸发除去溶剂,残渣用EtOAc(100mL)和水(50mL)稀释。加入饱和NaHCO3直到水层被中和,然后收集有机层,Na2SO4干燥,通过旋转蒸发除去溶剂。残渣通过闪式柱色谱层析纯化(硅胶,EtOAc∶己烷,1∶3.5洗脱),得到2.21g(>100%)标题化合物的混合物。1H NMR(CDCl3):7.32(d,1H,J=8.0Hz),6.90(dd,1H,J=8.0和1.9Hz),4.64(br s,1H),3.71(s,3H),3.25(q,2H,J=7.0Hz),2.47(t,2H,J=7.0Hz),2.04(q,2H,J=7.0Hz)。
(c)4-[(2-氯-5-氰基-苯基)-甲基-氨基]-丁酸甲酯。向4-(2-氯-5-氰基-苯基氨基)-丁酸甲酯(2.21g,8.74mmol)、低聚甲醛(2.34g,78.1mmol)和冰醋酸(80.0mL)的溶液中加入氰基硼氢化钠(2.70g,43.0mmol),搅拌所得到的溶液17小时。溶液用EtOAc(700mL)稀释,用饱和NaHCO3(1200mL)洗涤,过滤有机层,Na2SO4干燥,通过旋转蒸发除去溶剂。残渣通过闪式柱色谱层析纯化(硅胶,EtOAc∶己烷,1∶5洗脱),得到1.82g(最后两部的87%)无色油状标题化合物的。1H NMR(CDCl3):7.43(d,1H,J=8.2Hz),7.29(d,1H,J=1.6Hz),7.21(dd,1H,J=8.2和1.9Hz),3.68(s,3H),3.08(t,2H,J=7.4Hz),2.80(s,3H),2.39(t,2H,J=7.3Hz),1.98-1.88(m,2H,J=7.4Hz)。
(d)4-{[2-氯-5-(N-羟基氨基亚胺羰基)-苯基]-甲基-氨基}-丁酸甲酯。按类似于实施例18a的方法制备标题化合物。由4-[(2-氯-5-氰基-苯基)-甲基-氨基]-丁酸甲酯(1.81g,6.79mmol)和羟基胺(3×0.420mL,20.6mmol,50%wt/water)得到1.66g(81%)无色油状标题化合物。1H NMR(DMSO-d6):9.69(s,1H),7.46(d,1H,J=1.7Hz),7.38(d,1H,J=8.2Hz),7.30(dd,1H,J=8.2和1.9Hz),3.57(s,3H),2.99(t,2H,J=7.1Hz),2.69(s,3H),2.35(t,2H,J=7.3Hz),1.81-1.71(m,2H)。
(e)4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸甲酯。以类似于实施例18b的方法制备标题化合物。由在吡啶中的4-{[2-氯-5-(N-羟基氨基亚胺羰基)-苯基]-甲基-氨基}-丁酸甲酯(1.65g,5.49mmol)和3-氯噻吩-2-碳酰氯(0.995g,5.49mmol)(13.0mL)得到2.16g(93%)透明油状标题化合物。1HNMR(CDCl3):7.84(d,1H,J=1.9Hz),7.74(dd,1H,J=8.2和1.9Hz),7.61(d,1H,J=5.2Hz),7.48(d,1H,J=8.2Hz),7.13(d,1H,J=5.5Hz),3.68(s,3H),3.13(t,2H,J=7.3Hz),2.85(s,3H),2.42(t,2H,J=7.4Hz),2.00-1.91(m,2H)。
实施例59
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸
在0℃下,将LiOH(0.280g,6.66mmol)在H2O(6.0mL)中的溶液经历1分钟加入到的4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸甲酯(2.03g,4.76mmol)的THF(55.0mL)溶液。除去冰浴并允许溶液平衡到室温,此时加入THF(20.0mL)。将所得悬浮液搅拌21小时,加入EtOH(10mL)并搅拌溶液10.5小时。然后用3M NaOH(1.05mL)和EtOH(3.0mL)稀释反应溶液并搅拌30分钟。溶液用二氯甲烷(100mL)稀释、用NaHCO3水溶液(50mL)洗涤,通过旋转蒸发除去溶剂。残渣通过闪式柱色谱纯化(硅胶,使用二氯甲烷,然后EtOAc梯度洗脱)得到1.65g(84%)白色固体标题化合物。1H NMR(CDCl3):7.86(d,1H,J=1.9Hz),7.76(dd,1H,J=8.2和1.9Hz),7.60(d,1H,J=5.2Hz),7.49(d,1H,J=8.2Hz),7.14(d,1H,J=5.5Hz),3.16(t,2H,J=7.0Hz),2.85(s,3H),2.48(t,3H,J=7.3Hz),2.02-1.92(m,2H)。
实施例60
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸N-羟基琥珀酰亚胺基酯
以类似于实施例54的方法制备标题化合物。由4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸(1.64g,3.97mmol)、N-羟基琥珀酰亚胺(0.688g,5.98mmol)、DCC(1.21g,5.89mmol)和二氯甲烷(60.0mL)的溶液得到1.85g(91%)白色固体标题化合物的。1H NMR(CDCl3):7.86(d,1H,J=1.9Hz),7.76(dd,1H,J=8.2和1.9Hz),7.60(d,1H,J=5.2Hz),7.49(d,1H,J=8.2Hz),7.14(d,1H,J=5.5Hz),3.20(t,2H,J=7.1Hz),2.86(s,3H),2.84(br s,4H),2.77(t,2H,J=7.3Hz),2.12-2.02(m,2H)。
实施例61
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-1-(4-甲基-哌嗪1-基)-丁-1-酮
将4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸N-羟基琥珀酰亚胺基酯(0.128g,0.252mmol)、1-甲基哌嗪(0.035mL,0.32mmol)和二氯甲烷(5.0mL)的溶液在室温下搅拌25分钟,然后通过旋转蒸发除去溶剂。残渣通过闪式柱色谱层析纯化(硅胶,使用EtOAc,然后EtOAc∶MeOH∶Et3N,90∶5∶5梯度洗脱),得到0.119g(95%)无色油状标题化合物。1H NMR(CDCl3):7.85(d,1H,J=1.9Hz),7.74(dd,1H,J=8.2和1.9Hz),7.62(d,1H,J=5.2Hz),7.47(d,1H,J=8.2Hz),7.14(d,1H,J=5.2Hz),3.63(t,2H,J=5.1Hz),3.46(t,2H,J=5.1Hz),3.16(t,2H,J=6.9Hz),2.85(s,3H),2.43(t,2H,J=7.4Hz),2.37-2.35(m,4H),2.29(s,3H),2.01-1.92(m,2H)。
实施例62
N-丁基-4({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酰胺
以类似于实施例61的方法制备标题化合物。由4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸N-羟基琥珀酰亚胺基酯(0.0558g,0.109mmol)、正丁胺(0.011mL,0.11mmol)和二氯甲烷(6.0mL)的溶液得到0.082g(75%)油状标题化合物。1H NMR(CDCl3):7.86(d,1H,J=1.9Hz),7.76(dd,1H,J=8.2和2.2Hz),7.62(d,1H,J=5.2Hz),7.49(d,1H,J=8.2Hz),7.14(d,1H,J=5.2Hz),5.64(br s,1H),3.23-3.19(m,2H),3.14(t,2H,J=7.1Hz),2.82(s,3H),2.24(t,2H,J=7.1Hz),2.00-1.92(m,2H),1.43-1.24(m,4H),0.87(t,3H,J=7.1Hz)。
实施例63
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸辛酯
在175℃下,将4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸N-羟基琥珀酰亚胺基酯(0.0463g,0.0909mmol)、正丁醇(2.00mL,12.6mmol)和二氯甲烷(2.0mL)的溶液加热40分钟,冷却至室温,然后通过旋转蒸发除去溶剂。残渣通过闪式柱色谱层析纯化(硅胶,洗脱液EtOAc∶己烷,1∶5),并进行第二次柱层析(洗脱液EtOAc∶己烷,1∶5),然后共沸蒸发(4x丙酮),得到0.074g(82%)无色油状标题化合物。1H NMR(CDCl3):7.84(d,1H,J=1.9Hz),7.74(dd,1H,J=8.2和1.9Hz),7.61(dd,1H,J=5.2和0.8Hz),7.47(d,1H,J=8.2Hz),7.14(dd,1H,J=5.3和0.7Hz),4.06(t,2H,J=6.7Hz),3.13(t,2H,J=7.1Hz),2.86(s,3H),2.41(t,2H,J=7.4Hz),2.00-1.91(m,2H),1.62-1.57(m,2H),1.30-1.25(m,10H),0.90-0.85(m,3H)。
实施例64
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-乙胺
向搅拌的2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯胺(0.121g,0.386mmol)、(二甲基氨基)乙醛二乙缩醛(0.720mL,3.94mmol)、冰醋酸(24.0mL)和水(0.100mL,5.55mmol)溶液中加入氰基硼氢化钠(0.140g,2.22mmol)。将溶液在60℃下加热5天,然后在室温下搅拌溶液直到沉淀形成。过滤悬浮液,滤饼用EtOAc(10mL)洗涤,然后通过旋转蒸发浓缩滤液。残渣经闪式柱色谱层析纯化(硅胶,洗脱液EtOAc∶己烷,1∶3.5),获得0.027g(20%)标题化合物的白色固体。1H NMR(CDCl3):7.60(d,1H,J=5.2Hz),7.44-7.35(m,3H),7.13(d,1H,J=5.2Hz),4.33(brs,1H),3.37-3.28(m,2H),1.36(t,3H,J=7.1Hz)。
实施例65
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-乙酰胺
在实施例64反应期间,作为副产品得到标题化合物并获得24%产率的白色固体产物。1H NMR(CDCl3):9.14(brs,1H),7.85(dd,1H,J=8.5和1.9Hz),7.64(brs,1H),7.61(d,1H,J=5.2Hz),7.51(d,1H,J=8.2Hz),7.12(d,1H,J=5.2Hz),2.29(s,3H)。
实施例66
3-(3-溴甲基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑
在80℃下,将3-(4-氯-3-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑(1.45g,4.66mmol)、NBS(0.923g,5.19mmol)、AIBN(0.844g,5.14mmol)和CCl4(300mL)的溶液回流2小时。将溶液冷却至室温并另外加入NBS(0.913g,5.13mmol)和AIBN(0.218g,1.33mmol)再将溶液溶液回流1小时。将溶液冷却至室温并搅拌17小时。TLC表明并未发生反应,所以加入溴(0.240mL,4.67mmol),然后将溶液回流。回流的同时,用UV灯(254nm,18.4瓦)照射溶液2小时。将溶液冷却至室温、过滤并和通过旋转蒸发除去溶剂。残渣通过闪式柱色谱层析纯化(硅胶,己烷∶二氯甲烷,8∶3),得到0.808g(44%)白色固体的标题化合物。1H NMR(CDCl3):8.24(d,1H,J=2.2Hz),8.06(dd,1H,J=8.5和2.2Hz),7.63(d,1H,J=5.2Hz),7.54(d,1H,J=8.3Hz),7.14(d,1H,J=5.2Hz),4.66(s,2H)。
实施例67
3-(2-溴甲基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑
以类似于实施例66的方法,制备标题化合物。从3-(4-氯-2-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑(0.117g,0.377mmol)、NBS(0.070g,0.40mmol)、AIBN(0.037g,0.22mmol)、溴(0.021mL,0.41mmol)和CCl4(12.0mL)的溶液得到0.090g(61%)白色固体的标题化合物。1H NMR(CDCl3):8.12(d,1H,J=8.5Hz),7.63(d,1H,J=5.2Hz),7.57(d,1H,J=2.2Hz),7.44(dd,1H,J=8.5和2.2Hz),7.15(d,1H,J=5.2Hz),5.04(s,2H)。
实施例68
3-(4-氯-3-吡咯烷-1-基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑
在室温下,将3-(3-溴甲基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑(0.030g,0.077mmol)、吡咯烷(0.013mL,0.16mmol)、Et3N(0.054mL,0.39mmol)和二氯甲烷(8.0mL)的溶液搅拌20小时。溶液用二氯甲烷(30mL)稀释、用10%Na2CO3(25mL)洗涤、Na2SO4干燥并浓缩。产物与二氯甲烷(3×5mL)和己烷(2×5mL)共沸得到0.028g(96%)白色固体的标题化合物。1H NMR(CDCl3):8.27(d,1H,J=1.7Hz),7.98(dd,1H,J=8.2和1.9Hz),7.61(d,1H,J=5.2Hz),7.49(d,1H,J=8.5Hz),7.13(d,1H,J=5.2Hz),3.85(s,2H),2.67(brs,4H),1.84(brs,4H)。
通过类似于实施例68的方法,由相应的溴化物和胺来制备实施例69-71的化合物。
实施例69
3-(4-氯-3-二甲基氨基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑
1H NMR(CDCl3):8.21(d,1H,J=1.9Hz),7.99(dd,1H,J=8.2和1.6Hz),7.61(d,1H,J=5.2Hz),7.50(d,1H,J=8.2Hz),7.13(d,1H,J=5.2Hz),3.61(s,2H),2.34(s,6H)。
实施例70
3-(4-氯-2-吡咯烷-1-基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑
1H NMR(CDCl3):7.98(d,1H,J=8.2Hz),7.72(d,1H,J=2.0Hz),7.61(d,1H,J=5.5Hz),7.35(dd,1H,J=8.4和2.0Hz),7.14(d,1H,J=5.2Hz),4.05(s,2H),2.58(s,4H),1.77(s,4H)。
实施例71
3-(4-氯-2-二甲基氨基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑
1H NMR(CDCl3):7.99(d,1H,J=8.2Hz),7.66(d,1H,J=1.9Hz),7.61(d,1H,J=5.2Hz),7.37(dd,1H,J=8.5和2.2Hz),7.13(d,1H,J=5.5Hz),3.84(s,2H),2.27(s,6H)。
实施例72
3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑及类似物在固体肿瘤细胞作为半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋
亡诱导物的鉴定
人乳腺癌细胞系T-47D和ZR-75-1按照美国典型物保藏中心指定的培养基成分混合物+10%FCS(Invitrogen Corporation)在5%CO2-95%湿度的培养箱于37℃下进行生长。T-47D和ZR-75-1细胞被维持在50到80%融合和0.1到0.6×106细胞/mL的细胞密度。在600xg下离心来收获细胞并以0.65×106细胞/mL悬浮在适当的培养基+10%FCS中。将45μl细胞的等份试样加到96-孔微滴定板的孔中,其中含有2.5μl的10%DMSO的RPMI-1640培养基溶液,并含有0.16到100μM的3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑或其它试验化合物(0.016到10μM,最终浓度)。将22.5μL的细胞等份试样加入到384-孔微滴定板的孔中,其中含有2.5μl的10%DMSO的RPMI-1640培养基溶液但不含有试验化合物作为对照样品。通过搅拌混合样品然后在5%CO2-95%湿度的培养箱于37℃下培养48小时。培养后,从培养箱中取出样品并加入25μL含有14μM N-(Ac-DEVD)-N′-乙氧基羰基-R110(SEQ ID No.:1)荧光底物(Maxim,Inc.;W099/18856)、20%蔗糖(Sigma)、20mM DTT(Sigma)、200mM NaCl(Sigma)、40mM Na PIPES缓冲液pH7.2(Sigma)和500ug/mL溶血卵磷脂(Calbiochem)的溶液。搅拌混合样品并在室温下培养。使用荧光板读数仪(Model SpectraMaxGemini,Molecular Devices),加入底物溶液后大约1-2分钟为起始读数(T=0),在485nm处激发并且在530nm处发射,以确定对照样品的本底荧光。培养3小时后,如上读出样品的荧光度(T=3h)。
计算:
使用相对荧光度单位值(RFU)如下计算样品读数:
RFU(T-3h)-对照RFU(T-O)=实际RFU(T-3h)
通过3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-yl)-[1,2,4]-噁二唑或其它试验化合物的实际RFU值与对照样品的比值确定半胱氨酸天冬氨酸蛋白酶级联激活活性。通过S形量效计算法(Prism 2.0,GraphPad Software Inc.)确定EC50(nM)。半胱氨酸天冬氨酸蛋白酶活性(比值)和强度(EC50)汇总在表I中:
表I.半胱氨酸天冬氨酸蛋白酶活性和强度
实施例 | T-47D | |
比值 | EC50(nM) | |
1 | 11.9 | 1982 |
2 | 15.1 | 1523 |
4 | 11.9 | 1854 |
7 | 3.4 | 3995 |
9 | 9.0 | 3272 |
10 | 9.9 | 3749 |
13 | 4.4 | 5548 |
18 | 2.8 | 5035 |
22 | 5.4 | 3321 |
43 | 7.9 | 818 |
47 | 4.5 | 2440 |
49 | 11.9 | 1007 |
50 | 5.9 | 797 |
57 | 6.4 | 846 |
因此,确定3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑(实施例1)其类似物在固体肿瘤细胞中为半胱氨酸天冬氨酸蛋白酶级联激活剂和细胞凋亡诱导物。
实施例73
3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑
及类似物作为抑制细胞增殖(GI50)的抗肿瘤化合物的鉴定
按实施例72的方法来培养和收获T-47D和SKBr-3细胞。将90μl细胞(2.2×104细胞/mL)的等份试样加到96-孔微滴定板的孔中,其中含有10μl的10%DMSO的RPMI-1640培养基溶液,并含有1nM到100μM的3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑或其它试验(0.1nM到10μM,最终浓度)。将90μL的细胞等份试样加入到96-孔微滴定板的孔中,其中含有10μl的10%DMSO的RPMI-1640培养基溶液但不含有化合物,作为最大细胞增殖的对照样品(AMaX)。通过搅拌混合样品然后在5%CO2-95%湿度的培养箱于37℃下培养48小时。培养后,从培养箱中取出样品并加入20μL CellTiter 96 AQUEOUS OneSolution Cell ProliferationTM试剂(Promega)。搅拌混合样品并在5%CO2-95%湿度的培养箱于37℃下培养2-4小时。使用吸收度板读数仪(Model 1420 Wallac Instruments),加入溶液后大约1-2分钟为起始读数(T=0),测定在490nm处的吸收度。确定试验化合物可能有的本底吸收度。在490nm处未发现3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑有吸收度。培养2-4小时后,如上读出样品的吸收度(ATest)。
通过将90μL细胞或90μL培养基分别加到含有10μl 10%DMSO的RPMI-1640培养基溶液的96-孔微滴定板的孔中来测定起始细胞数目GI50(50%细胞增殖抑制作用的剂量)的基线值。通过搅拌混合样品然后在5%CO2-95%湿度的培养箱于37℃下培养0.5小时。培养后,从培养箱中取出样品并加入20μL CellTiter 96 AQUEOUS One Solution CellProliferationTM试剂(Promega)。搅拌混合样品并在5%CO2-95%湿度的培养箱于37℃下培养2-4小时。如上读取吸收度,将(Astart)定义为用作GI50测定基线的起始细胞数目的吸收度。
计算:
GI50(50%细胞增殖抑制作用的剂量)是[(ATest-Astart)/(AMax-Astart)]=0.5的浓度。
将GI50(nM)汇总在表II中:
表II.癌症细胞中的GI50
细胞系 | GI50(nM) | |||
实施例1 | 实施例2 | 实施例4 | 实施例9 | |
T-47D | 894 | 360 | 415 | 514 |
MX1 | 7000 | 5000 | 210 | 899 |
因此,确定3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑(实施例1)及其似物为抑制细胞增殖的抗肿瘤化合物。
现已充分描述了本发明,但本领域普通技术人员会理解在不影响本发明的范围或其任何实施方案的前提下可以在宽的和等同的条件、配制方法和其它参数之下实施本发明。本文中引用的所有专利、专利申请和公开文献的全部内容都充分地引入本文供参考。
Claims (31)
1、一种治疗动物患有的对诱导细胞凋亡有反应的疾病的方法,它包括给与需要所述治疗的动物有效量的具有式IV的化合物:
或其可药用盐或前药或互变异构体,其中:R1-R3独立地为氢、卤代、卤代烷基、芳基、稠芳基、碳环基、杂环基、杂芳基、烷基、链烯基、炔基、芳烷基、芳基链烯基、芳基炔基、杂芳基链烷基、杂芳烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、硝基、氨基、氰基、酰基氨基、羟基、巯基、酰氧基、叠氮基、烷氧基、芳氧基、杂芳氧基、芳基烷氧基、杂芳基烷氧基、卤代烷氧基、羧基、羰基酰氨基或烷基巯基,各基团为未取代的或取代的;Q为S、O或NR9,其中R9为氢、未取代的或取代的烷基、未取代的或取代的环烷基或未取代的或取代的芳基;并且环A为未取代的或取代的杂环或碳环。
2、权利要求1的方法,其中所述动物为哺乳动物。
3、权利要求1的方法,其中Q为O或S。
4、权利要求1的方法,其中R3不为氢。
5、权利要求1的方法,其中环A为未取代的或取代的吗啉基、哌嗪基、哌啶基或环己基。
6、权利要求1的方法,其中所述化合物选自:
5-(3-氯噻吩-2-基)-3-(1-哌啶基)-[1,2,4]-噁二唑;和
5-(3-氯噻吩-2-基)-3-(4-吗啉基)-[1,2,4]-噁二唑;
或其可药用盐或其前药。
7、一种治疗动物患有的对诱导细胞凋亡有反应的疾病的方法,它包括给与需要所述治疗的动物有效量的化合物,所述化合物选自:
3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(3-二甲基氨基-4-氯-苯基)-[1,2,4]-噁二唑;
3-(3-氨基-4-氯-苯基)-5-(3-溴呋喃-2-基)-[1,2,4]-噁二唑;
5-(3-溴呋喃-2-基)-3-(3-二甲基氨基-4-氯-苯基)-[1,2,4]-噁二唑;
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯基}-2-(4-甲基-哌嗪1-基)-乙酰胺;
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯基}-琥珀酰胺酸乙酯;
5-(3-氯噻吩-2-基)-3-(4-氯-3-氰基-苯基)-[1,2,4]-噁二唑;
3-(4-氯-苄氧基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(4-氯-3-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(4-氯-3-硝基-苯基)-[1,2,4]-噁二唑;
3-(5-氯-吡啶-2-基)-5-(3-甲氧基-噻吩-2-基)-[1,2,4]-噁二唑;
3-(5-氯-吡啶-2-基)-5-(3-甲基-3H-咪唑-4-基)-[1,2,4]-噁二唑;
3-[2-(4-氯-苯基)-乙烯基]-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-1H-吡咯-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(3-氯-1H-吡咯-2-基)-[1,2,4]-噁二唑;
5-(3-氯-1-甲基-1H-吡咯-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;和
5-[3-氯-1-(2-二甲基氨基乙基)-1H-吡咯-2-基]-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(吗啉-4-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(吡咯烷-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(4-甲基哌啶-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(2-甲基哌啶-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(4-三氟甲基哌啶-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(4-甲基哌嗪-1-基)-[1,2,4]噁二唑;
4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸苄酯;
4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯;
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-氨基甲酸叔丁酯;
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-乙酸乙酯;
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-3-基}-乙酸乙酯;
5-(3-氯噻吩-2-基)-2-(哌啶-1-基)-[1,3,4]噁二唑;
5-(3-氯噻吩-2-基)-2-(吗啉-4-基)-[1,3,4]噁二唑;
5-(3-氯噻吩-2-基)-2-(4-甲基哌嗪-1-基)-[1,3,4]噁二唑;
4-[5-(3-溴呋喃-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸苄酯;
4-[5-(3-溴呋喃-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯;
5-(3-氯噻吩-2-基)-2-(哌嗪1-基)-[1,3,4]噁二唑三氟乙酸盐;
5-(3-溴呋喃-2-基)-2-(哌嗪1-基)-[1,3,4]噁二唑三氟乙酸盐;
5-(3-氯噻吩-2-基)-3-(4-氨基哌啶-1-基)-[1,2,4]噁二唑三氟乙酸盐;
5-(3-氯噻吩-2-基)-3-(噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(1H-吡咯-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(呋喃-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-y1)-3-(呋喃-3-基)-[1,2,4]噁二唑;
3-(4-氯-2-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(5-甲基呋喃-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(5-硝基呋喃-2-基)-[1,2,4]噁二唑;
3-(4-氯-2-氟-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(3-甲基-吡啶-2-基)-[1,2,4]噁二唑;
3-(4-氯-3-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-溴呋喃-2-基)-3-(4-氯-2-甲基-苯基)-[1,2,4]噁二唑;
5-(3-溴呋喃-2-基)-3-(5-氯-3-甲基-吡啶-2-基)-[1,2,4]噁二唑;
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基氨基}-乙酸乙酯;
N′-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-N,N-二乙基-乙-1,2-二胺;
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-(2-吗啉-4-基-乙基)-胺;
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸乙酯;
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸;
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸N-羟基琥珀酰亚胺基酯;
5-(3-溴呋喃-2-基)-3-(3-甲基-吡啶-2-基)-[1,2,4]噁二唑;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸甲酯;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸N-羟基琥珀酰亚胺基酯;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-1-(4-甲基-哌嗪1-基)-丁-1-酮;
N-丁基-4({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酰胺;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸辛酯;
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-乙胺;
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-乙酰胺;
3-(3-溴甲基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(2-溴甲基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(4-氯-3-吡咯烷-1-基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(4-氯-3-二甲基氨基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(4-氯-2-吡咯烷-1-基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;和
3-(4-氯-2-二甲基氨基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
或其可药用盐或前药。
8、权利要求1或7的方法,其中所述疾病为癌症。
9、权利要求8的方法,其中所述癌症为何杰金病、非何杰金性淋巴瘤、急性或慢性淋巴性白血病、多发性骨髓瘤、成神经细胞瘤、乳腺癌、卵巢癌、肺癌、维尔姆斯瘤、宫颈癌、睾丸癌、软组织肉瘤、慢性淋巴性白血病、原发性巨球蛋白血症、膀胱癌、慢性粒细胞性白血病、原发性脑癌、恶性黑色素瘤、小细胞肺癌、胃癌、结肠癌、恶性胰腺胰岛瘤、恶性类癌、恶性黑色素瘤、绒毛癌、蕈样霉菌病、头颈癌、骨源性肉瘤、胰腺癌、急性粒细胞性白血病、毛细胞性白血病、成神经细胞瘤、横纹肌肉瘤、卡波济肉瘤、泌尿生殖器癌、甲状腺癌、食道癌、恶性高钙血症、宫颈增生、肾细胞癌、子宫内膜癌、真性红细胞增多症、特发性血小板增多症、肾上腺皮质癌、皮肤癌或前列腺癌。
10、权利要求8的方法,其中所述癌症为耐药癌。
11、权利要求8的方法,进一步包括给与至少一种已知的癌症化疗药,或所述药物的可药用盐。
12、权利要求8的方法,其中所述化合物与至少一种下列化合物一起给与,所述化合物选自白消安、顺铂、丝裂霉素C、卡铂、秋水酰碱、长春碱、紫杉醇、多西他赛、喜树碱、拓扑替康、阿霉素、依托泊甙、5-氮杂胞苷、5-氟尿嘧啶、甲氨蝶呤、5-氟-2′-脱氧-尿苷、ara-C、羟基脲、硫鸟嘌呤、美法仑、苯丁酸氮芥、环磷酰胺、异环磷酰胺、长春新碱、米托胍腙、表柔比星、阿柔比星、博来霉素、米托蒽醌、羟吡咔唑、氟达拉滨、奥曲肽、视黄酸、他莫西芬、赫赛汀、Rituxan、三氧化砷、gamcitabine、多沙唑嗪、特拉唑嗪、坦索罗辛、CB-64D、CB-184、氟哌啶醇、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、Cerivastatin、安普那韦、阿巴卡韦、CGP-73547、CGP-61755、DMP-450、印地那韦、那非那韦、替普拉那韦、利托那韦、沙奎那韦、ABT-378、AG 1776、BMS-232,632、bexarotene、维甲酸、13-顺式-视黄酸、9-顺式-视黄酸、α-二氟甲基鸟氨酸、ILX23-7553、芬维A胺、N-4羧基苯基retinamide、乳胱氨酸、MG-132、PS-341、Gleevec、ZD1839(Iressa)、SH268、染料木黄酮、CEP2563、SU6668、SU11248、EMD121974、R115777、SCH66336、L-778,123、BAL9611、TAN-1813、黄酮吡啶酚、UCN-01、Roscovitine、olomoucine、赛来昔布、valecoxib、罗非昔布和阿拉诺新。
13、权利要求8的方法,进一步包括用放射性治疗来治疗所述动物。
14、权利要求8的方法,其中所述化合物在手术治疗所述动物的所述癌症后给与。
15、权利要求1或7的方法,其中所述疾病为自身免疫性疾病。
16、权利要求1或7的方法,其中所述疾病为有传染性的病毒性疾病。
17、权利要求1或7的方法,其中所述疾病为类风湿性关节炎。
18、权利要求1或7的方法,其中所述疾病为炎性疾病。
19、权利要求1或7的方法,其中所述疾病为皮肤病。
20、权利要求1或7的方法,其中所述疾病为牛皮癣。
21.一种药物制剂,它含有可药用载体和具有式IV的化合物:
或其可药用盐,前药或互变异构体,其中:R1-R3独立地为氢、卤代、卤代烷基、芳基、稠芳基、碳环基、杂环基、杂芳基、烷基、链烯基、炔基、芳烷基、芳基链烯基、芳基炔基、杂芳烷基、杂芳基链烯基、杂芳基炔基、碳环烷基、杂环烷基、羟基烷基、硝基、氨基、氰基、酰基氨基、羟基、巯基、酰氧基、叠氮基、烷氧基、芳氧基、杂芳氧基、芳基烷氧基、杂芳基烷氧基、卤代烷氧基、羧基、羰基酰氨基或烷基巯基,各基团为未取代的或取代的;Q为S、O或NR9,其中R9为氢、未取代的或取代的烷基、未取代的或取代的环烷基或未取代的或取代的芳基;并且环A为未取代的或取代的杂环或碳环。
22、权利要求21的制剂,其中所述化合物选自:
5-(3-氯噻吩-2-基)-3-(1-哌啶基)-[1,2,4]-噁二唑;和
5-(3-氯噻吩-2-基)-3-(4-吗啉基)-[1,2,4]-噁二唑;
或其可药用盐或其前药。
23、一种药物制剂,它含有可药用载体和选自下列的化合物:
3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(3-二甲基氨基-4-氯-苯基)-[1,2,4]-噁二唑;
3-(3-氨基-4-氯-苯基)-5-(3-溴呋喃-2-基)-[1,2,4]-噁二唑;
5-(3-溴呋喃-2-基)-3-(3-二甲基氨基-4-氯-苯基)-[1,2,4]-噁二唑;
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯基}-2-(4-甲基-哌嗪1-基)-乙酰胺;
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯基}-琥珀酰胺酸乙酯;
5-(3-氯噻吩-2-基)-3-(4-氯-3-氰基-苯基)-[1,2,4]-噁二唑;
3-(4-氯-苄氧基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(4-氯-3-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(4-氯-3-硝基-苯基)-[1,2,4]-噁二唑;
3-(5-氯-吡啶-2-基)-5-(3-甲氧基-噻吩-2-基)-[1,2,4]-噁二唑;
3-(5-氯-吡啶-2-基)-5-(3-甲基-3H-咪唑-4-基)-[1,2,4]-噁二唑;
3-[2-(4-氯-苯基)-乙烯基]-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-1H-吡咯-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(3-氯-1H-吡咯-2-基)-[1,2,4]-噁二唑;
5-(3-氯-1-甲基-1H-吡咯-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;和
5-[3-氯-1-(2-二甲基氨基乙基)-1H-吡咯-2-基]-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(吗啉-4-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(吡咯烷-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(4-甲基哌啶-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(2-甲基哌啶-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(4-三氟甲基哌啶-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(4-甲基哌嗪-1-基)-[1,2,4]噁二唑;
4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸苄酯;
4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯;
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-氨基甲酸叔丁酯;
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-乙酸乙酯;
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-3-基}-乙酸乙酯;
5-(3-氯噻吩-2-基)-2-(哌啶-1-基)-[1,3,4]噁二唑;
5-(3-氯噻吩-2-基)-2-(吗啉-4-基)-[1,3,4]噁二唑;
5-(3-氯噻吩-2-基)-2-(4-甲基哌嗪-1-基)-[1,3,4]噁二唑;
4-[5-(3-溴呋喃-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸苄酯;
4-[5-(3-溴呋喃-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯;
5-(3-氯噻吩-2-基)-2-(哌嗪1-基)-[1,3,4]噁二唑三氟乙酸盐;
5-(3-溴呋喃-2-基)-2-(哌嗪1-基)-[1,3,4]噁二唑三氟乙酸盐;
5-(3-氯噻吩-2-基)-3-(4-氨基哌啶-1-基)-[1,2,4]噁二唑三氟乙酸盐;
5-(3-氯噻吩-2-基)-3-(噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(1H-吡咯-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(呋喃-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(呋喃-3-基)-[1,2,4]噁二唑;
3-(4-氯-2-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(5-甲基呋喃-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(5-硝基呋喃-2-基)-[1,2,4]噁二唑;
3-(4-氯-2-氟-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(3-甲基-吡啶-2-基)-[1,2,4]噁二唑;
3-(4-氯-3-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-溴呋喃-2-基)-3-(4-氯-2-甲基-苯基)-[1,2,4]噁二唑;
5-(3-溴呋喃-2-基)-3-(5-氯-3-甲基-吡啶-2-基)-[1,2,4]噁二唑;
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基氨基}-乙酸乙酯;
N′-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-N,N-二乙基-乙-1,2-二胺;
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-(2-吗啉-4-基-乙基)-胺;
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸乙酯;
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸;({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸N-羟基琥珀酰亚胺基酯;
5-(3-溴呋喃-2-基)-3-(3-甲基-吡啶-2-基)-[1,2,4]噁二唑;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸甲酯;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸N-羟基琥珀酰亚胺基酯;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-1-(4-甲基-哌嗪1-基)-丁-1-酮;
N-丁基-4({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酰胺;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸辛酯;
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-乙胺;
N-2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-乙酰胺;
3-(3-溴甲基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(2-溴甲基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(4-氯-3-吡咯烷-1-基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(4-氯-3-二甲基氨基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(4-氯-2-吡咯烷-1-基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;和
3-(4-氯-2-二甲基氨基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
或其可药用盐或前药。
24、权利要求21或23的药物组合物,它进一步包含至少一种已知的癌症化疗药,或所述药物的可药用盐。
25、权利要求21或23的药物组合物,它进一步包含至少一种选自下列的化合物:白消安、顺铂、丝裂霉素C、卡铂、秋水酰碱、长春碱、紫杉醇、多西他赛、喜树碱,拓扑替康、阿霉素、依托泊甙、5-氮杂胞苷、5-氟尿嘧啶、甲氨蝶呤、5-氟-2′-脱氧-尿苷、ara-C、羟基脲、硫鸟嘌呤、美法仑、苯丁酸氮芥、环磷酰胺、异环磷酰胺、长春新碱、米托胍腙、表柔比星、阿柔比星、博来霉素、米托蒽醌、羟吡咔唑、氟达拉滨、奥曲肽、视黄酸、他莫西芬、赫赛汀、Rituxan、三氧化砷、gamcitabine、多沙唑嗪、特拉唑嗪、坦索罗辛、CB-64D、CB-184、氟哌啶醇、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、Cerivastatin、安普那韦、阿巴卡韦、CGP-73547、CGP-61755、DMP-450、印地那韦、那非那韦、替普拉那韦、利托那韦、沙奎那韦、ABT-378、AG 1776、BMS-232,632、bexarotene、维甲酸、13-顺式-视黄酸、9顺式-视黄酸、α-二氟甲基鸟氨酸、ILX23-7553、芬维A胺、N-4羧基苯基retinamide、乳胱氨酸、MG-132,PS-341、Gleevec、ZD1839(Iressa)、SH268、染料木黄酮、CEP2563、SU6668、SU11248、EMD121974、R115777、SCH66336、L-778,123、BAL9611、TAN-1813、黄酮吡啶酚、UCN-01、Roscovitine、olomoucine、赛来昔布、valecoxib、罗非昔布和阿拉诺新。
27、权利要求26的化合物,其中Q为O或S。
28、权利要求26的化合物,其中R3不为氢。
29、权利要求26的化合物,其中环A为未取代的或取代的吗啉基、哌嗪基、哌啶基或环己基。
30、权利要求26的化合物,其中所述化合物选自:
5-(3-氯噻吩-2-基)-3-(1-哌啶基)-[1,2,4]-噁二唑;和
5-(3-氯噻吩-2-基)-3-(4-吗啉基)-[1,2,4]-噁二唑;
或其可药用盐或前药。
31、一种化合物,选自:
3-(3-氨基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(3-二甲基氨基-4-氯-苯基)-[1,2,4]-噁二唑;
3-(3-氨基-4-氯-苯基)-5-(3-溴呋喃-2-基)-[1,2,4]-噁二唑;
5-(3-溴呋喃-2-基)-3-(3-二甲基氨基-4-氯-苯基)-[1,2,4]-噁二唑;
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯基}-2-(4-甲基-哌嗪1-基)-乙酰胺;
N-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑-3-基]-苯基}-琥珀酰胺酸乙酯;
5-(3-氯噻吩-2-基)-3-(4-氯-3-氰基-苯基)-[1,2,4]-噁二唑;
3-(4-氯-苄氧基)-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(4-氯-3-氟-苯基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(4-氯-3-硝基-苯基)-[1,2,4]-噁二唑;
3-(5-氯-吡啶-2-基)-5-(3-甲氧基-噻吩-2-基)-[1,2,4]-噁二唑;
3-(5-氯-吡啶-2-基)-5-(3-甲基-3H-咪唑-4-基)-[1,2,4]-噁二唑;
3-[2-(4-氯-苯基)-乙烯基]-5-(3-氯噻吩-2-基)-[1,2,4]-噁二唑;
5-(3-氯-1H-吡咯-2-基)-3-(5-氯-吡啶-2-基)-[1,2,4]-噁二唑;
3-(4-氯-苯基)-5-(3-氯-1H-吡咯-2-基)-[1,2,4]-噁二唑;
5-(3-氯-1-甲基-1H-吡咯-2-基)-3-(4-氯-苯基)-[1,2,4]-噁二唑;和
5-[3-氯-1-(2-二甲基氨基乙基)-1H-吡咯-2-基]-3-(4-氯-苯基)-[1,2,4]-噁二唑;
5-(3-氯噻吩-2-基)-3-(吗啉-4-基)-[1,2,4]噁二唑;5-(3-氯噻吩-2-基)-3-(吡咯烷-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(4-甲基哌啶-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(2-甲基哌啶-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(4-三氟甲基哌啶-1-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(4-甲基哌嗪-1-基)-[1,2,4]噁二唑;
4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸苄酯;
4-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯;
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-氨基甲酸叔丁酯;
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-4-基}-乙酸乙酯;
{1-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-哌啶-3-基}-乙酸乙酯;
5-(3-氯噻吩-2-基)-2-(哌啶-1-基)-[1,3,4]噁二唑;
5-(3-氯噻吩-2-基)-2-(吗啉-4-基)-[1,3,4]噁二唑;
5-(3-氯噻吩-2-基)-2-(4-甲基哌嗪-1-基)-[1,3,4]噁二唑;
4-[5-(3-溴呋喃-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸苄酯;
4-[5-(3-溴呋喃-2-基)-[1,2,4]噁二唑-3-基]-哌嗪-1-羧酸叔丁酯;
5-(3-氯噻吩-2-基)-2-(哌嗪1-基)-[1,3,4]噁二唑三氟乙酸盐;
5-(3-溴呋喃-2-基)-2-(哌嗪1-基)-[1,3,4]噁二唑三氟乙酸盐;
5-(3-氯噻吩-2-基)-3-(4-氨基哌啶-1-基)-[1,2,4]噁二唑三氟乙酸盐;
5-(3-氯噻吩-2-基)-3-(噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(1H-吡咯-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(呋喃-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(呋喃-3-基)-[1,2,4]噁二唑;
3-(4-氯-2-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(5-甲基呋喃-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(5-硝基呋喃-2-基)-[1,2,4]噁二唑;
3-(4-氯-2-氟-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(5-硝基呋喃-2-基)-[1,2,4]噁二唑;
3-(4-氯-2-氟-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-氯噻吩-2-基)-3-(3-甲基-吡啶-2-基)-[1,2,4]噁二唑;
3-(4-氯-3-甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
5-(3-溴呋喃-2-基)-3-(4-氯-2-甲基-苯基)-[1,2,4]噁二唑;
5-(3-溴呋喃-2-基)-3-(5-氯-3-甲基-吡啶-2-基)-[1,2,4]噁二唑;
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基氨基}-乙酸乙酯;
N′-{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-N,N-二乙基-乙-1,2-二胺;
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-(2-吗啉-4-基-乙基)-胺;
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸乙酯;
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸;
({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基氨基)-乙酸N-羟基琥珀酰亚胺基酯;
5-(3-溴呋喃-2-基)-3-(3-甲基-吡啶-2-基)-[1,2,4]噁二唑;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸甲酯;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-丁酸N-羟基琥珀酰亚胺基酯;
4-({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-甲基-氨基)-1-(4-甲基-哌嗪1-基)-丁-1-酮;
N-丁基-4({2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基}-甲基-氨基)-丁酸辛酯;
{2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-乙胺;
N-2-氯-5-[5-(3-氯噻吩-2-基)-[1,2,4]噁二唑-3-基]-苯基}-乙酰胺;
3-(3-溴甲基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(2-溴甲基-4-氯-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(4-氯-3-吡咯烷-1-基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(4-氯-3-二甲基氨基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
3-(4-氯-2-吡咯烷-1-基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;和
3-(4-氟-2-二甲基氨基甲基-苯基)-5-(3-氯噻吩-2-基)-[1,2,4]噁二唑;
或其可药用盐或前药。
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US43395302P | 2002-12-18 | 2002-12-18 | |
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US (2) | US7144876B2 (zh) |
EP (1) | EP1581213A4 (zh) |
JP (1) | JP2006516250A (zh) |
CN (1) | CN100364531C (zh) |
AU (1) | AU2003303373B8 (zh) |
CA (1) | CA2509224A1 (zh) |
WO (1) | WO2004058253A1 (zh) |
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-
2003
- 2003-12-18 US US10/737,865 patent/US7144876B2/en not_active Expired - Fee Related
- 2003-12-18 CN CNB2003801064405A patent/CN100364531C/zh not_active Expired - Fee Related
- 2003-12-18 EP EP03808469A patent/EP1581213A4/en not_active Withdrawn
- 2003-12-18 WO PCT/US2003/040308 patent/WO2004058253A1/en active Search and Examination
- 2003-12-18 JP JP2004563731A patent/JP2006516250A/ja active Pending
- 2003-12-18 CA CA002509224A patent/CA2509224A1/en not_active Abandoned
- 2003-12-18 AU AU2003303373A patent/AU2003303373B8/en not_active Ceased
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101838260A (zh) * | 2010-03-31 | 2010-09-22 | 华南理工大学 | 二氢吡咯酮衍生物作为Caspase-3抑制剂 |
CN101838260B (zh) * | 2010-03-31 | 2013-08-14 | 华南理工大学 | 二氢吡咯酮衍生物作为Caspase-3抑制剂 |
CN103408477A (zh) * | 2013-08-22 | 2013-11-27 | 陈鹏飞 | 一种含砷配位化合物及其制备方法 |
CN103408477B (zh) * | 2013-08-22 | 2015-06-10 | 陈鹏飞 | 一种含砷配位化合物及其制备方法 |
Also Published As
Publication number | Publication date |
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EP1581213A4 (en) | 2008-11-19 |
AU2003303373B2 (en) | 2010-02-11 |
US20070112003A1 (en) | 2007-05-17 |
AU2003303373A1 (en) | 2004-07-22 |
CN100364531C (zh) | 2008-01-30 |
JP2006516250A (ja) | 2006-06-29 |
US20040127521A1 (en) | 2004-07-01 |
AU2003303373B8 (en) | 2010-06-10 |
CA2509224A1 (en) | 2004-07-15 |
US7144876B2 (en) | 2006-12-05 |
EP1581213A1 (en) | 2005-10-05 |
US7317029B2 (en) | 2008-01-08 |
WO2004058253A1 (en) | 2004-07-15 |
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