CN102947268B - 吲哚基或吲哚啉基羟肟酸化合物 - Google Patents
吲哚基或吲哚啉基羟肟酸化合物 Download PDFInfo
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- CN102947268B CN102947268B CN201180017334.4A CN201180017334A CN102947268B CN 102947268 B CN102947268 B CN 102947268B CN 201180017334 A CN201180017334 A CN 201180017334A CN 102947268 B CN102947268 B CN 102947268B
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- indole
- benzenesulfonyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 64
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 title abstract 2
- 125000001041 indolyl group Chemical group 0.000 title abstract 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 20
- 201000011510 cancer Diseases 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims description 48
- -1 imidazole radicals Chemical class 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000003368 amide group Chemical group 0.000 claims description 14
- VDWLCYCWLIKWBV-UHFFFAOYSA-N 1-(benzenesulfonyl)indole Chemical compound C1=CC2=CC=CC=C2N1S(=O)(=O)C1=CC=CC=C1 VDWLCYCWLIKWBV-UHFFFAOYSA-N 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- AVIIJCYFOVAPRK-UHFFFAOYSA-N 1-(benzenesulfonyl)-2,3-dihydroindole Chemical compound C1CC2=CC=CC=C2N1S(=O)(=O)C1=CC=CC=C1 AVIIJCYFOVAPRK-UHFFFAOYSA-N 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
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Abstract
这里描述的是吲哚基或吲哚啉基羟肟酸化合物和包含它们的医药组合物,它们显示组蛋白去乙酰酶(HDAC)抑制活性。这里还描述了一种用这些化合物治疗癌症的方法。
Description
相关申请
本申请要求美国临时申请61/318,715的优先权。该在先申请的内
容作为参考并入本发明中。
背景技术
组蛋白去乙酰酶(HDACs)为一类可调控组蛋白乙酰化且因此调控基因表现的酶。HDAC抑制剂已知可诱发肿瘤细胞的细胞生长停滞、分化以及细胞凋亡,因为其为强力的抗癌药剂而备受关注,参见Lu et al.,J.Med.Chem.2005,48,5530-5535;Kulp et al.,Clin.Cancer Res.2006,12,5199-5206;及Ryan et al.,J.Clin.Onclo.2005,23,3912-3922。
发明内容
本发明基于意料不到的发现某些吲哚基或吲哚啉基羟肟酸化合物为HDAC抑制剂且具有强力的抗癌活性。因此,本发明关于吲哚基或吲哚啉基羟肟酸化合物及其癌症治疗的用途。
在一方面,本发明特征为如式(I)吲哚基或吲哚啉基羟肟酸化合物:
在该式中,为单键或双键;n为0、1或2;R1为H、选择性经芳基及杂芳基所取代的烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、C(O)Ra、或SO2Ra,其中Ra为H、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基;且各个R2、R3、R4、R5及R6独立为H、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、卤基、氰基、硝基、ORb、SRb、S(O)Rb、CH=CH-C(O)Rb、CH=CH-C(O)NRcRd、NHC(O)-CH=CH-C(O)Rb、NHC(O)-CH=CH-C(O)NRcRd、SO2NRcRd、OC(O)Rb、C(O)Rb、C(O)ORb、C(O)NRcRd、NRcRd、NHC(O)Rb、NHC(O)NRcRd、或NHC(S)Rc,其中各Rb、Rc及Rd独立为H、羟基、烷氧基、芳氧基、杂芳氧基、烷基、烯基、炔基、芳基、杂芳基、环烷基、环烯基、杂环烷基、或杂环烯基;且当R1为SO2Ra,至少一个R2、R3、R5及R6为CH=CH-C(O)NRcRd、NHC(O)-CH=CH-C(O)Rb或NHC(O)-CH=CH-C(O)NRcRd,或R4为CH=CH-C(O)Rb、CH=CH-C(O)NRcRd、NHC(O)-CH=CH-C(O)Rb、或NHC(O)-CH=CH-C(O)NRcRd,且当R1为芳基,R4为CH=CH-C(O)NHRc。
上述的吲哚基或吲哚啉基羟肟酸化合物的一子集包含那些R4为CH=CH-C(O)Rb、CH=CH-C(O)NRcRd、NHC(O)-CH=CH-C(O)Rb、或NHC(O)-CH=CH-C(O)NRcRd的化合物。在这些化合物中,R4可为C(O)NHOH、CH=CH-C(O)OH、CH=CH-C(O)NHOH、NHC(O)-CH=CH-C(O)OH、或NHC(O)-CH=CH-C(O)NHOH;R1可为SO2Ra,Ra为芳基或杂芳基(如选择性经卤基、羟基、烷氧基、胺基、氰基、或硝基取代的苯基);或至少一个R2、R3、R5及R6为CH=CH-C(O)NRcRd、NHC(O)-CH=CH-C(O)Rb、或NHC(O)-CH=CH-C(O)NRcRd(如CH=CH-C(O)NHOH、NHC(O)-CH=CH-C(O)OH、或NHC(O)-CH=CH-C(O)NHOH)。
上述的吲哚基或吲哚啉基羟肟酸化合物的另一子集包含那些至少一个R2、R3、R5及R6为CH=CH-C(O)NRcRd、NHC(O)-CH=CH-C(O)Rb、或NHC(O)-CH=CH-C(O)NRcRd的化合物。在这些化合物中,至少一个R2、R3、R5及R6可为CH=CH-C(O)NHOH、NHC(O)-CH=CH-C(O)OH、或NHC(O)-CH=CH-C(O)NHOH。R1可为SO2Ra,Ra为芳基或杂芳基(如选择性经卤基、羟基、烷氧基、胺基、氰基、或硝基取代的苯基)。
仍为上述的吲哚基或吲哚啉基羟肟酸化合物的又一子集为那些R1为SO2Ra且Ra为芳基或杂芳基的化合物。Ra可为选择性经卤基、羟基、烷氧基、胺基、氰基、或硝基取代的苯基。
术语「烷基」意指直链或支链单价烃,除非另有说明,否则其含有1-20个碳原子(如C1-C10)。烷基的例子包含但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、及叔丁基。术语「烯基」意指含有2-20个碳原子(如C2-C10)的直链或支链单价烃且有一或多个双键。烯基的例子包含但不限于乙烯、丙烯、烯丙基及1,4-丁二烯基。术语「炔基」意指含有2-20个碳原子(如C2-C10)的直链或支链单价烃且有一或多个三键。炔基的例子包含但不限于乙炔、1-丙炔、1-及2-丁炔及1-甲基-2-丁炔。术语「烷氧基」意指-O-烷基基,烷氧基的例子包含但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异-丁氧基、仲-丁氧基及叔-丁氧基。术语「胺基」意指NH2、烷基胺基或芳基胺基。术语「烷基胺基」代表-N(R)-烷基,其中R可为H、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基或杂芳基。
术语「环烷基」代表具有3至30个碳原子(如C3-C12)的单价饱和烃环系统,环烷基的实例包含但不限于环丙基、环丁基、环戊基、环己基、1,4-亚环己基、环庚基、环辛基及金刚烷基。术语「环烯基」代表具有3至30个碳原子(如C3-C12)及一或多个双键的单价非芳烃环系统,其例子包括环戊烯基、环己烯基和环庚烯基。术语「杂环烷基」代表带有一或多个杂原子(如O、N、S或Se)的单价非芳香族5-8员单环、8-12员双环或11-14员三环系统,杂环烷基基团的例子包含但不限于哌嗪基、吡咯啶基、二氧杂环己基、吗啉基及四氢呋喃。术语「杂环烯基」代表带有一或多个杂原子(如O、N、S或Se)及1或多个双键的单价非芳香族5-8员单环、8-12员双环或11-14员三环系统。
术语「芳基」代表单价6-碳单环、10-碳双环、14-碳三环芳香环系统,芳基的实例包含但不限于苯基、萘基、蒽基。术语「杂芳基」代表具有一或多个杂原子(如O、N、S或Se)的单价芳香族5-8员单环、8-12员双环或11-14员三环环状系统,杂芳基实例包含吡啶基、呋喃基、咪唑基、苯并咪唑基、嘧啶基、噻吩基、喹啉基、吲哚基、四唑基及噻唑基。
上述的烷基、烯基、炔基、环烷基、杂环烷基、环烯基、杂环烯基、胺基、芳基及杂芳基可包含取代或未经取代的官能基。在胺基、环烷基、杂环烷基、环烯基、杂环烯基、芳基及杂芳基上的可能取代基包含但不限于C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C10烷氧基、芳基、芳氧基、杂芳基、杂芳氧基、胺基、C1-C10烷基胺基、芳基胺基、羟基、卤基、侧氧基(O=)、硫酮基(S=)、硫基、硅烷基、C1-C10烷硫基、芳硫基、C1-C10烷基磺酰基、芳基磺酰基、酰基胺基、胺基酰基、胺基硫酰基、甲脒基、巯基、酰胺基、硫脲基、氰硫基、磺酰胺基、胍基、酰脲基、氰基、氮基、酰基、硫代酰基、酰基氧基、脲基、胺甲酰基(-C(O)NH2)、羧基(-COOH)及羧酸酯。另一方面,烷基、烯基或炔基上可能的取代基为除了C1-C10烷基外的上述所有取代基。
环烷基、环烯基、杂环烷基、杂环烯基、芳基及杂芳基亦可彼此稠合。
本文中描述的吲哚基或吲哚啉基羟肟酸化合物包含化合物本身以及若可实施下的其盐、其溶剂化物及其前药。盐类,举例而言,可经由阴离子及吲哚基或吲哚啉基羟肟酸化合物上的正电荷基团(如胺基)间作用而形成。适当的阴离子包含氯离子、溴离子、碘离子、硫酸根离子、硫酸氢根离子(bisulfate)、胺基磺酸根离子、硝酸根离子、磷酸根离子、柠檬酸根离子、甲磺酸根离子、三氟乙酸根、麸胺酸根、葡萄糖醛酸根、戊二酸根、苹果酸根、马来酸根、琥珀酸根、富马酸根、酒石酸根、对甲苯磺酸根、水杨酸根、乳酸根、萘磺酸根及醋酸根。同样地,盐类也可经阳离子及吲哚基或吲哚啉基羟肟酸化合物上的负电荷基团(如羧酸)间作用而形成。合适的阳离子包括钠离子、钾离子、镁离子、钙离子及铵阳离子如四甲胺离子。吲哚基或吲哚啉基羟肟酸化合物亦可包含含有四级氮原子的盐类。前药的实例包含酯和其它医药上可接受的衍生物,当其施予个体后,可以提供具活性的吲哚基或吲哚啉基羟肟酸化合物。
在另一方面,本发明关于一种抑制HDAC活性的方法,其透过将细胞与有效量的上述吲哚基或吲哚啉基羟肟酸化合物接触。
又在另一方面,本发明关于一种治疗癌症的方法,其透过施予有需要的个体有效量的上述吲哚基或吲哚啉基羟肟酸化合物。
含有一或多种上述的吲哚基或吲哚啉基羟肟酸化合物而可用于治疗癌症的医药组合物、及其治疗用途以及化合物用于制备治疗癌症的药剂的用途也在本发明之范畴中。
本发明的一个或多个实施例的细节将详述于下,发明的其它特点、标的及优点将可由发明说明书及权利要求书中明显得知。
下方为本文所述的例示化合物:
本文中所述的吲哚基或吲哚啉基羟肟酸化合物可利用传统化学转化法(包含保护基方式)制备,如描述于R.Larock,Comprehensive Organic Transformations,VCH出版(1989);T.W.Greene及P.G.M.Wuts,Protective Groups in Organic Synthesis,第3版.,John Wiley 及Sons(1999);L.Fieser及M.Fieser,Fieser及Fieser′s Reagents forOrganic Synthesis,John Wiley及Sons(1994);及L.Paquette,ed.,Encyclopedia ofReagents for Organic Synthesis,John Wiley及Sons (1995)以及后续版本。
吲哚基或吲哚啉基羟肟酸化合物合成后,可进一步透过快速管柱色层分析法、高效液相色层分析、结晶或任何合适的方法纯化。
本文的吲哚基或吲哚啉基羟肟酸化合物可包含非芳香双键和一个或多个不对称中心,因此,其可产生外消旋及消旋混合物、单一对掌异构物、个别非镜像异构物、非镜像异构物混合物及顺或反异构物形式。所有异构物皆有可能产生。
(1)一种医药组合物,其含有效量的至少一种本发明的吲哚基或吲哚啉基羟肟酸化合物及医药上可接受的载体,及(2)一种治疗癌症的方法,其透过施予有需要的个体有效量的吲哚基或吲哚啉基羟肟酸化合物,亦在本发明之范畴中。
本文中术语「治疗」意指将吲哚基或吲哚啉基羟肟酸化合物投予患有癌症、具有癌症症状或有其癌症倾向的个体,其目的是为了治疗、疗愈、减轻、缓解、改善、医治、改善、增进、影响、或降低疾病的风险及相关癌症的症状或癌症的倾向。术语「有效量」指赋予个体预期的治疗效果的活性药物剂的量。有效量可能因为本技术领域技术人员的认知、根据给药途径、赋形剂的使用及与其它药剂共同使用的可能性而有所不同。
本发明方法可治疗的癌症包含各种器官的实体或血液肿瘤。实体肿瘤的实例包括胰脏癌;膀胱癌;大肠癌;乳癌,包括转移性乳癌;前列腺癌,包括雄性素依赖性和雄性素非依赖性前列腺癌;肾癌,包括如转移性肾细胞癌;肝细胞癌;肺癌,包括非小细胞肺癌(NSCLC),细支气管肺泡癌(BAC)及肺部恶性腺癌;卵巢癌,包括渐进性上皮或原发性腹膜癌;子宫颈癌;胃癌;食道癌;头颈癌,包括如头颈部鳞状细胞癌;黑色素瘤;神经内分泌癌,包括转移性神经内分泌肿瘤;脑肿瘤,包括神经胶质瘤,退行性寡树突胶质细胞瘤,成人多形性胶质母细胞瘤及成人退行性星状细胞瘤;骨癌;及软组织肉瘤。恶性血液疾病包括急性骨髓性白血病(AML);慢性骨髓性白血病(CML),包括加速期CML及CML急性芽球期(CML-BP);急性淋巴性白血病(ALL);慢性淋巴性白血病(CLL);霍奇金症(HD);非霍奇金淋巴瘤(NHL),包括滤泡性淋巴瘤及被套细胞淋巴瘤;B-细胞淋巴瘤;T-细胞淋巴瘤;多发性骨髓瘤(MM);巨大球蛋白血症(Waldenstrom′s macroglobulinemia);骨髓造血不良症候群(MDS),包括顽固性贫血(RA),带有环状铁芽球的顽固性贫血(RARS)(带有过量芽球的顽固性贫血(RAEB)),及转变中的RAEB(RAEB-T);及骨髓增生症候群。
为了实践本发明的方法,上述的医药组合物可以口服、非经肠、吸入喷剂、外用(局部)、经直肠、经鼻、经颊、经阴道或透过植入储存囊的方式投药。术语「非经肠」用于本文指包括经皮下、皮内、静脉内、肌肉内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内或颅内注射或输注的方式。
无菌注射组合物,例如,无菌注射液或油性悬浮液可根据技术领域中习知的技术,使用合适的分散剂或湿润剂(如Tween 80)来调配。无菌注射制剂亦可为在无毒性肠外可接受的稀释剂或溶剂的无菌注射溶液或悬浮液,举例而言,为在1,3-丁二醇中的溶液。在可接受的媒液及溶剂中,可采用甘露醇、水、林格式液及等渗氯化钠溶液。此外,无菌固定油也是传统上做为溶剂或悬浮液(如合成单-或双酸甘油酯)。脂肪酸,如油酸及其双酸甘油酯衍生物对于制备注射剂中有其效用,其为天然的医药上可接受的油类,如橄榄油或蓖麻油,特别是其聚氧乙烯化形式(polyoxyehylated version)。这些油溶液或悬浮液还可包含长链乙醇稀释剂或分散剂,或羧甲基纤维素(carboxymethyl cellulose)或类似的分散剂。其它常用的表面活性剂,如Tweens或Spans或其它类似的乳化剂或医药上常用于制备固体、液体或其它剂型的生物利用促进剂也可被用在所欲之调配物中。
用于经口投药的组合物可为任何口服可接受的剂型,其包含但不限于胶囊、锭剂、乳剂、水溶性悬浮液、分散液或溶液。在用于口服的锭剂中,常使用包含乳糖及玉米淀粉的载体。润滑剂,如硬脂酸镁亦为典型的添加物。用于口服的胶囊剂型中,常使用的稀释剂包括乳糖和干燥的玉米淀粉。当水溶液悬浮液或乳剂为经口投药时,活性成分可悬浮或溶解在结合乳化或悬浮剂的油相中。若有需要,可添加某些甜味剂、矫味剂或着色剂。鼻腔喷剂或吸入组合物可使用技术领域中习知的医药调配技术制备。含有吲哚基或吲哚啉基羟肟酸化合物亦可以肛门栓剂的形式经直肠投药。
医药组合物中的载体必须与调配物中的活性成分兼容(且较佳地,具有稳定活性成分的能力),且对于受治疗的个体不会有害。一或多种可溶性剂(如环糊精),其可与活性吲哚基或吲哚啉基羟肟酸化合物形成更易溶解的复合物,可被用于做为传递活性化合物的医药上载体。其它载体的实例包括含胶状的二氧化硅、硬脂酸镁、硫酸月桂酸钠及十号黄色色素(D&C Yellow #10)。
适宜的体外试验可做为初步评估吲哚基或吲哚啉基羟肟酸化合物抗癌活性的功效,如抑制癌细胞生长。而化合物可进一步检视其治疗癌症的功效。例如,化合物可投予至患癌症的动物体内(如小鼠模型中),接着评估该化合物的治疗功效。根据该结果,可决定合适的剂量及投药途径。
不须进一步的详细阐述,相信以上的发明内容足以使本发明实施。下面的实施例仅做为解说性的实例,且无论如何不受限于其余以任何形式公开的情事。所有在本文中引用的刊物全文以参考方式并入本文。
【实施方式】
实施例1:合成1-苯磺酰基-1H-吲哚-5-羧酸羟酰胺(化合物1)
化合物1透过如上的流程1显示的方式合成(试剂及状态:a)氯化苯或氯化苯磺酰基、t-BuOK、KI、DMF;b)1M LiOH(aq)、二氧六环;c)(i)NH2OTHP、PyBOP、NEt3、DMF,rt;(ii)TFA、MeOH,rt)。
1-苯磺酰基-1H-吲哚-5-羧酸甲基酯(2):将甲基吲哚-5-羧酸酯(1)(0.30g,1.71mmol)、TBAHS(0.19g,0.26mmol)及KOH(0.19g,3.42mmol)悬浮于CH2Cl2(15mL)中搅拌20分钟,加入氯化苯磺酰基(0.32ml,2.57mmol)。反应混合物于室温下搅拌过夜,接着以水淬火,并以CH2Cl2(20mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩以得到黄色的残留物。
1-苯磺酰基-1H-吲哚-5-羧酸(3):1M LiOH水溶液(3.87ml,3.87mmol)加入溶于二氧陆圜(15mL)中之粗萃物2溶液中,混合物于40℃下搅拌过夜,接着于减压下浓缩。残留物溶于水中,接着将浓缩HCl加入溶液中使pH<7而得到沉淀物,以真空干燥后得到白色固体3(0.38g),产率为74%。1H NMR(500MHz,CD3OD):δ6.83(d,J=3.70Hz,1H),7.51-7.54(m,2H),7.60-7.63(m,1H),7.75(d,J=3.72Hz,1H),7.95(d,J=7.63H z,2H),7.97(dd,J=8.83,1.49Hz,1H),8.03(d,J=8.86Hz,1H),8.25(d,J=0.82Hz,1H)。
1-苯磺酰基-1H-吲哚-5-羧酸羟酰胺(化合物1):NH2OTHP(0.08g,0.72mmol)加入溶有3(0.18g,0.60mmol)、PyBOP(0.33g,0.63mmol)及三乙基胺(0.20ml,1.43mmol)之D MF(1.5mL)溶液中。反应混合物于室温下搅拌两小时,接着以水中止反应(quenched withwater),并以EtOAc(15mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩。残留物以硅胶管柱层析(CH2Cl2∶CH3OH=30∶1∶1%NH3(aq))纯化以得到白色固体,并在CH3OH(31mL)的存在下以TFA(1.70ml,22.89mmol)处理。反应混合物于室温下搅拌过夜,并于减压下浓缩得到白色残留物。该残留物以CH3OH再结晶以得到化合物1(0.10g)。1H NMR(500MHz,CD3OD):δ6.80(d,J=3.65Hz,1H),7.49-7.52(m,2H),7.59-7.62(m,1H),7.68(d,J=8.53Hz,1H),7.75(d,J=3.72Hz,1H),7.93(d,J=7.52Hz,2H),7.94-7.97(m,1H),8.04(d,J=8.53Hz,1H);C15H12N2O4S(M+)之HRMS(EI):估计值(calcd),316.0518;实际值(found),316.0518。Mp:65-67℃。
实施例2:合成1-苯甲基-1H-吲哚-5-羧酸羟酰胺(化合物2)
化合物2以类似实施例1的方式制备。
1H NMR(500MHz,CD3OD):δ5.40(s,2H),6.60(d,J=3.1Hz,1H),7.11(d,J=7.2Hz,2H),7.21-7.28(m,3H),7.36-7.38(m,2H),7.50(dd,J=8.5,1.7Hz,1H),8.02(d,J=1.1Hz,1H)。MS(EI)m/z:266。C16H14N2O2(M+)之HRMS(EI):估计值(calcd),266.1055;实际值(found),266.1057。Mp:132-135℃。
实施例3:合成3-(1-苯磺酰基-1H-吲哚-5-基)-N-羟基-丙烯酰胺(化合物3)
化合物3通过如上的流程2显示的方式合成(试剂及状态:a)氯化苯、苯甲酰氯、氯化苯磺酰基、4-甲氧基苯磺酰基氯、4-氟苯磺酰基氯或4-硝基苯磺酰基氯、t-BuOK、KI、DMF;b)4-碘化苯、K2CO3、CuO、DMF;c)Ph3P=CH-COOCH3、CH2Cl2;d)1MLiOH(aq)、二氧六环;e)(i)NH2OTHP、PyBOP、NEt3、DMF;(ii)TFA、MeOH;f)Fe、NH4Cl,异丙醇,H2O)。
1-苯磺酰基-1H-吲哚-5-羰醛(5):将甲基吲哚-5-羧酸酯(4)(1.00g,6.89mmol)、四丁基铵重硫酸盐(0.35g,1.03mmol)及KOH(0.77g,13.78mmol)悬浮于CH2Cl2(30mL)后搅拌20分钟,加入氯化苯磺酰基(1.32ml,10.33mmol)。反应混合物于室温下搅拌过夜,接着以水中止反应,并以CH2Cl2(20Ml×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩以得到黄色的残留物,并以硅胶管柱层析(EtOAc∶n-己烷=1∶2)纯化以得到白色固体5(1.79g)。1H NMR(500MHz,CDCl3):δ6.78(d,J=3.6Hz,1H),7.45-7.48(m,2H),7.55-7.58(m,1H),7.67(d,J=3.7Hz,1H),7.85-7.87(m,1H),7.89(d,J=7.6Hz,2H),8.06(s,1H),8.11(d,J=8.6Hz,1H),10.03(s,1H)。
3-(1-苯磺酰基-1H-吲哚-5-基)-丙烯酸甲基酯(7):甲基(三苯基磷)乙酸酯(methyl(triphenylpho sphoranylidene)acetate)(2.52g,7.53mmol)加入溶有5(1.79g,6.27mmol)的C H2Cl2(25mL)溶液中。反应混合物于室温下搅拌过夜,接着以水中止反应,并以CH2Cl2(25mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩以得到黄色的残留物,并以硅胶管柱层析(EtOAc∶n-己烷=1∶2)纯化以得到白色固体7(2.08g)。
3-(1-苯磺酰基-1H-吲哚-5-基)-丙烯酸(8):1M LiOH水溶液(11.72ml,11.72mmol)加入溶有7(2.00g,5.86mmol)的二氧陆圜(20mL),混合物于40℃下搅拌过夜,接着于减压下浓缩。残留物溶于水中,接着将浓缩HCl加入溶液中使成为酸性p H而得到沉淀物,以真空干燥后得到白色固体8(1.72g)。1H NMR(500MHz,CDC13):δ6.39(d,J=16.1Hz,1H),6.71(d,J=3.6Hz,1H),7.45-7.48(m,2H),7.52(dd,J=8.7,1.4Hz,1H),7.55-7.58(m,1H),7.61(d,J=3.7Hz,1H),7.67-7.72(m,2H),7.89(d,J=8.9Hz,2H),7.96(d,J=8.7Hz,1H)。
3-(1-苯磺酰基-1H-吲哚-5-基)-N-羟基-丙烯酰胺(化合物3):NH2OTHP(0.43g,3.67mmol)加入溶有8(1.00g,3.05mmol)、PyBOP(1.69g,3.24mmol)及三乙胺(1.02ml,7.33mmol)的DMF(1.5mL)溶液中。反应混合物在室温下搅拌3小时,接着以水淬火,并以EtOAc(20mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩,残留物以硅胶管柱层析(CH2Cl2∶CH3OH=30∶1∶1%NH3(aq))纯化以得到白色固体,并在CH3OH(140mL)的存在下以TFA(6.90ml,92.90mmol)处理。反应混合物于室温下搅拌过夜,并于减压下浓缩得到白色残留物。该残留物以CH3OH再结晶以得到红色固体之化合物3(0.85g);mp158-162℃。1H NMR(500MHz,CDCl3):δ6.42(d,J=15.8Hz,1H),6.75(d,J=3.5Hz,1H),7.49-7.54(m,3H),7.59-7.62(m,1H),7.61(d,J=15.5Hz,1H),7.68(d,J=3.6Hz,1H),7.72(s,1H),7.93(d,J=7.7Hz,2H),7.98(d,J=8.6Hz,1H)。MS(EI)m/z:327(100%),342(M+,3%)。C17H14N2O4S(M+)之HRMS(EI):估计值(calcd),342.0674;实际值(found),342.0673。
实施例4:合成N-羟基-3-[1-(4-甲氧基-苯磺酰基)-1H-吲哚-5-基]-丙烯酰胺(化合物4)
化合物4以类似实施例3中描述的方式制备。
1H NMR(500MHz,CD3OD):δ3.79(s,3H),6.43(d,J=15.8Hz,1H),6.73(d,J=3.5Hz,1H),6.99(d,J=9.1Hz,2H),7.52(d,J=8.7Hz,1H),7.62(d,J=15.7Hz,1H),7.65(d,J=3.6Hz,1H),7.71(s,1H),7.86(d,J=8.9Hz,2H),7.97(d,J=8.6Hz,1H)。LC/MS m/z:373(M+)。C18H16N2O5(M+)之HRMS(EI):估计值(calcd),372.0780;实际值(found),372.0779。
实施例5:合成3-[1-(4-氟基-苯磺酰基)-1H-吲哚-5-基]-N-羟基-丙烯酰胺(化合物5)
化合物5以类似实施例3中描述的方式制备。
1H NMR(500MHz,CD3OD):δ6.45(d,J=15.9Hz,1H),6.77(d,J=3.5Hz,1H),7.54(d,J=8.6Hz,2H),7.61(d,J=15.4Hz,1H),7.67(d,J=3.7Hz,1H),7.73(s,1H),7.98-8.02(m,3H)。LC/MSm/z:361(M+)。C17H13FN2O4S(M+)之HRMS(EI):估计值(calcd),360.0580;实际值(found),360.0580。Mp:137-141℃。
实施例6:合成N-羟基-3-[1-(4-硝基-苯磺酰基)-1H-吲哚-5-基]-丙烯酰胺(化合物6)
化合物6以类似实施例3中描述的方式制备。
1H NMR(500MHz,CD3OD):δ6.44(d,J=15.7Hz,1H),6.81(d,J=3.1Hz,1H),7.56(d,J=8.6Hz,1H),7.61(d,J=15.7Hz,1H),7.72(d,J=3.5Hz,1H),7.74(s,1H),8.01(d,J=8.5Hz,1H),8.18(d,J=8.6Hz,2H),8.33(d,J=8.6Hz,2H)。C17H13N3O 6S(M+)之HRMS(EI):估计值(calcd),387.0525;实际值(found),387.0523。Mp:75-84℃。
实施例7:合成3-[1-(4-胺基-苯磺酰基)-1H-吲哚-5-基]-N-羟基-丙烯酰胺(化合物7)
化合物7以实施例3中的流程2途径合成。化合物6(0.10g,0.26mmol),铁粉(0.05g,0.77mmol)及氯化铵(0.03g,0.52mmol)悬浮于异丙醇(5ml)及水(1ml)并回流4小时。反应混合物于室温下搅拌过夜,接着以水淬火,并以CH2Cl2萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩,反应混合物以硅胶管柱层析(CH2Cl2∶CH3OH=10∶1∶1%NH3(aq))纯化以得到化合物7(0.06g)。
1H NMR(500MHz,CD3OD):δ6.57(d,J=8.9Hz,2H),6.60(d,J=15.8Hz,1H),6.69(d,J=3.5Hz,1H),7.53(dd,J=8.5,1.4Hz,1H),7.58(d,J=9.0Hz,2H),7.60(d,J=8.3Hz,1H),7.62(d,J=3.8Hz,1H),7.73(s,1H),7.94(d,J=8.6Hz,1H)。C17H15N3O4S(M+)之HRMS(EI):估计值(calcd),357.0783;实际值(found),357.0785。
实施例8:合成3-[1-(3,4-二甲氧基-苯磺酰基)-1H-吲哚-5-基]-N-羟基-丙烯酰胺(化合物8)
化合物8以类似实施例3中描述的方式制备。
1H NMR(500MHz,CD3OD):δ3.78(s,3H),3.81(s,3H),6.42(d,J=15.78Hz,1H),6.73(d,J=3.57Hz,1H),7.00(d,J=8.61Hz,1H),7.33(d,J=1.99Hz,1H),7.52-7.56(m,2H),7.60(d,J=15.75Hz,1H),7.68(d,J=3.65Hz,1H),7.72(s,1H),7.99(d,J=8.66Hz,1H)。
实施例9:合成3-(1-苯甲基-1H-吲哚-5-基)-N-羟基-丙烯酰胺(化合物9)
化合物9以类似实施例3中描述的方式制备。
1H NMR(500MHz,CD3OD):δ5.32(s,2H),6.57(d,J=3.1Hz,1H),7.10(d,J=7.1Hz,2H),7.14(d,J=3.1Hz,1H),7.25-7.32(m,5H),7.37(d,J=8.3Hz,1H),7.80(s,1H),7.85(d,J=15.4Hz,1H。LC/MS m/z:293(M+)。C18H16N2O2(M+)之HRMS(EI):估计值(calcd),292.1212;实际值(found),292.1213。Mp:133-136℃。
实施例10:合成3-(1-苯甲酰基-1H-吲哚-5-基)-N-羟基-丙烯酰胺(化合物10)
化合物10以类似实施例3中描述的方式制备。
1H NMR(500MHz,DMSO):δ6.48(d,J=15.8Hz,1H),6.78(d,J=3.6Hz,1H),7.42(d,J=3.6Hz,1H),7.54-7.61(m,4H),7.67-7.70(m,1H),7.75(d,J=7.3Hz,2H),7.86(s,1H),8.24(d,J=8.6Hz,1H),9.00(s,1H),10.73(s,1H)。MS(EI) m/z:306。C18H14N2O3(M+)之HRMS(EI):估计值(calcd),306.1004;实际值(found),306.1006。Mp:146-149℃。
实施例11:合成N-羟基-3-(1-苯基-1H-吲哚-5-基)-丙烯酰胺(化合物11)
1-苯基-1H-吲哚-5-羰醛(6):甲基吲哚-5-羧酸酯(4)(0.70g,4.82mmol)、4-碘化苯(0.65mL,5.79mmol)、K2CO3(0.93g,6.75mmol)、CuO(0.04g,0.48mmol)悬浮于DMF(2mL)中回流2天。反应混合物以水淬火,并以EtOAc(20mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩得到黄色残留物,并以硅胶管柱层析(EtOAc∶n-己烷=1∶4)纯化以得到6(0.30g)。1H NMR(500MHz,CD3OD):δ6.83(d,J=3.2Hz,1H),7.431-7.44(m,1H),7.42(d,J=3.1Hz,1H),7.49-7.51(m,2H),7.54-7.60(m,3H),7.77(dd,J=8.7,1.1Hz,1H),10.06(s,1H)。
化合物11以类似实施例3中描述的方式制备,使用6取代5。
1H NMR(500MHz,CD3OD):δ7.18(d,J=15.7Hz,1H),7.49(d,J=3.1Hz,1H),8.15-8.20(m,1H),8.30-8.38(m,8H),8.59(s,1H)。MS(EI)m/z:278。C17H14N2O2(M+)之HRMS(EI):估计值(calcd),278.1055;实际值(found),278.1055。Mp:96-110℃。
实施例12:合成3-(1-苯磺酰基-2,3-二氢-1H-吲哚-5-基)-N-羟基-丙烯酰胺(化合物12)
化合物12透过如上方流程3的途径合成(试剂及状态:a)NaBH3CN、AcOH;b)氯化苯磺酰基、4-甲氧基苯磺酰基氯或3,4-二甲氧基苯磺酰基氯、4-氟苯磺酰基氯或4-硝基苯磺酰基氯、吡啶;c)LiAlH4、THF;(d)PDC、MS、CH2Cl2;f)Ph3P=CHCOOCH3、CH2Cl2;(g)1M LiOH(aq)、二氧六环;(h)(i)NH2OTHP、PyBOP、NEt3、DMF;(ii)TFA、MeOH;(i)Fe、NH4Cl、异丙醇、水。
2,3-二氢-1H-吲哚e-5-羧酸甲基酯(10):氰基硼氢化钠(0.16g,2.57mmol)在0℃下加入溶于AcOH(2mL)的甲基吲哚-5-羧酸酯(9)(0.30g,1.71mmol)溶液中,反应混合物加热至室温,并搅拌2小时后,在0℃下以水淬火。加入浓缩NaOH使pH=10,水层以CH2Cl2(15mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩以得到黄色残留物,并以硅胶管柱层析(EtOAc∶n-己烷=1∶2)纯化以得到10(0.28g)。1H NMR(500MHz,CD3OD):δ3.06(t,J=8.5Hz,2H),3.65(t,J=8.5Hz,2H),3.84(s,3H),6.53-6.55(m,1H),7.75-7.76(m,2H)。
1-苯磺酰基-2,3-二氢-1H-吲哚-5-羧酸甲基酯(11):将氯化苯磺酰基(0.40ml,3.16mmol)加入溶有10(0.28g,1.58mmol)的吡啶(2mL)溶液中。反应混合物回流过夜,反应物接着以硅胶管柱层析(EtOAc∶n-己烷=1∶3)纯化以到11(0.40g)。1H NMR(500MHz,CDCl3):δ2.99(t,J=8.6Hz,2H),3.87(s,3H),3.97(t,J=8.6Hz,2H),7.45-7.48(m,2H),7.56-7.59(m,1H),7.66(d,J=8.5Hz,1H),7.75(s,1H),7.82(d,J=7.7Hz,2H),7.90(d,J=7.9Hz,1H)。
(1-苯磺酰基-2,3-二氢-1H-吲哚-5-基)-甲醇(12):将LAH(0.10g,2.52mmol)在0℃下加入溶有11(0.40g,1.26mmol)的THF(10mL)溶液中。反应混合物加热至室温,并搅拌2小时后,以水停止反应,并以CH2Cl2(15mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩,反应混合物以硅胶管柱层析(EtOAc∶n-己烷=1∶1)纯化以得到12(0.24g)。1HNMR(500MHz,CDCl3):δ2.83(t,J=8.4Hz,2H),3.92(t,J=8.5Hz,2H),4.49(s,2H),7.09(s,1H),7.16(d,J=8.2Hz,1H),7.46-7.49(m,2H),7.53(d,J=8.2Hz,1H),7.60(t,J=7.5Hz,1H),7.76(d,J=7.7Hz,2H)。
1-苯磺酰基-2,3-二氢-1H-吲哚-5-羰醛(13):将分子筛(0.63g)加入溶有12(0.24g,0.83mmol)之CH2Cl2(10mL)、PDC(0.63g,1.66mmol)溶液中。混合物在室温下搅拌过夜后,以硅藻土过滤。有机层在减压下浓缩,接着以硅胶管柱层析(EtOAc∶n-己烷=1∶2)纯化以得到13(0.19g)。1H NMR(500MHz,CDCl3):δ3.05(t,J=8.6Hz,2H),4.01(t,J=8.7Hz,2H),7.46-7,49(m,2H),7.58-7.62(m,2H),7.71(d,J=8.3H z,1H),7.75(d,J=8.3Hz,1H),7.84(d,J=7.8Hz,2H),9.85(s,1H)。
3-(1-苯磺酰基-2,3-二氢-1H-吲哚-5-基)-丙烯酸甲基酯(14):将甲基
(三苯基磷)乙酸酯(0.27g,0.79mmol)加入溶有13(0.19g,0.66mmol)之CH2Cl2(10mL)溶液中。混合物在室温下搅拌3小时后,以水停止反应,并以CH2Cl2(15mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩,并于减压下浓缩以得到黄色残留物,并以硅胶管柱层析(EtOAc∶n-己烷=1∶3)纯化以得到14(0.20g)。
3-(1-苯磺酰基-2,3-二氢-1H-吲哚-5-基)-丙烯酸(15):将1M LiOH水溶液(1.16ml,1.16mmol)加入溶有14(0.20g,0.58mmol)之二氧陆圜(15mL)溶液。反应混合物在40℃下搅拌过夜,并在减压下浓缩。残留物溶于水中,加入浓缩HCl以成为酸性pH而产生沉淀物,并以真空干燥以获得15(0.16g)。1H NMR(500MHz,CD3OD):δ2.92(t,J=8.5Hz,2H),3.96(t,J=8.5Hz,2H),6.33(d,J=15.9Hz,1H),7.38(s,1H),107.41(d,J=8.5Hz,1H),7.50-7.53(m,2H),7.55(d,J=16.1Hz,1H),7.58-7.64(m,2H),7.82(d,J=7.6Hz,2H)。
3-(1-苯磺酰基-2,3-二氢-1H-吲哚-5-基)-N-羟基-丙烯酰胺(化合物12):将NH2OTHP(0.05g,0.44mmol)加入溶有15(0.12g,0.37mmol),PyBOP(0.20g,0.39mmol),三乙基胺(0.12ml,0.88mmol)之DMF(1.5mL)溶液中。反应混合物于室温下搅拌一小时,接着以水停止反应,并以EtOAc(15mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩。残留物以硅胶管柱层析(CH2Cl2∶CH3OH=30∶1∶1%NH3(aq))纯化以得到白色固体,并在CH3OH(25mL)的存在下以TFA(1.13ml,15.21mmol)处理并于室温下搅拌过夜。反应混合物于减压下浓缩得到白色残留物,并以CH3OH再结晶以得到化合物12(0.12g)。Mp:131-132℃。1H NMR(500MHz,CD3OD):δ2.91(t,J=8.5Hz,2H),3.96(t,J=8.4Hz,2H),6.32(d,J=15.8Hz,1H),7.32(s,1H),7.37-7.39(m,1H),7.46(d,J=15.7Hz,1H),7.50-7.53(m,2H),7.58-7.64(m,2H),7.82(d,J=7.8Hz,2H)。MS(EI)m/z:170(100%),344(M+,3.21%)。C17H16N2O4S(M+)之HRMS(EI):估计值(calcd),344.0831;实际值(found),344.0829。
实施例13:合成N-羟基-3-[1-(4-甲氧基-苯磺酰基)-2,3-二氢-1H-吲哚-5-基]-丙烯酰胺(化合物13)
化合物13以类似实施例12中描述的方式制备。
1H NMR(500MHz,CD3OD):δ2.91(t,J=8.46Hz,2H),3.81(s,3H),3.92(t,J=8.49Hz,2H),6.31(d,J=15.78Hz,1H),7.00(d,J=8.85Hz,2H),7.32(s,1H),7.37(d,J=8.77H z,1H),7.46(d,J=15.78Hz,1H),7.56(d,J=8.36Hz,1H),7.74(d,J=8.80Hz,2H)。Mp:159-160℃。
实施例14:合成3-[1-(4-氟基-苯磺酰基)-2,3-二氢-1H-吲哚-5-基]-N-羟基丙烯酰胺(化合物14)
化合物14以类似实施例12中描述的方式制备。
1H NMR(500MHz,CD3OD):δ2.93(t,J=8.41Hz,2H),3.95(t,J=8.42Hz,2H),6.80(d,J=15.40Hz,1H),7.25(t,J=8.67H z,2H),7.33(s,1H),7.37-7.43(m,2H),7.56(d,J=8.17Hz,1H),7.86-7.89(m,2H)。
实施例15:合成N-羟基-3-[1-(4-硝基-苯磺酰基)-2,3-二氢-1H-吲哚-5-基]-丙烯酰胺(化合物15)
化合物15以类似实施例12中描述的方式制备。
1H NMR(500MHz,CD3OD):δ2.96(t,J=8.38Hz,2H),4.02(t,J=8.47Hz,2H),6.32(d,J=15.78Hz,1H),7.34(s,1H),7.40(d,J=8.29Hz,1H),7.45(d,J=15.71Hz,1H),7.59(d,J=8.34Hz,1H),8.06(d,J=8.73Hz,2H),8.34(d,J=8.82Hz,2H)。
实施例16:合成3-[1-(4-胺基-苯磺酰基)-2,3-二氢-1H-吲哚-5-基]-N-羟基丙烯酰胺(化合物16)
化合物16以类似实施例7中描述的方式制备,起始化合物为化合物15。
1H NMR(500MHz,CD3OD):δ2.91(t,J=8.41Hz,2H),3.87(t,J=8.52Hz,2H),6.48(d,J=15.75Hz,1H),6.58(d,J=8.80Hz,2H),7.34(s,1H),7.37(d,J=8.21Hz,1H),7.44(d,J=15.78Hz,1H),7.45(d,J=8.85Hz,2H),7.53(d,J=8.37Hz,1H)。
实施例17:合成3-[1-(3,4-二甲氧基-苯磺酰基)-2,3-二氢-1H-吲哚-5-基]-N羟基-丙烯酰胺(化合物17)
化合物17以类似实施例12中描述的方式制备。
1H NMR(500MHz,CD3OD):δ2.90(t,J=8.39Hz,2H),3.72(s,3H),3.85(s,3H),3.93(t,J=8.45Hz,2H),6.33(d,J=15.73Hz,1H),7.06(d,J=8.54Hz,1H),7.19(d,J=1.82Hz,1H),7.36(s,1H),7.41-7.50(m,3H),7.61(d,J=8.37Hz,1H)。
实施例18:合成1-苯磺酰基-2,3-二氢-1H-吲哚e-5-羧酸羟酰胺(化合物18)
化合物18以实施例12中流程3的途径制备。
1-苯磺酰基-2,3-二氢-1H-吲哚-5-羧酸(16):1M LiOH水溶液(2.4ml,2.40mmol)加入溶有11(0.38g,1.20mmol)的二氧陆圜(15mL)溶液中。反应混合物在40℃下搅拌过夜接着在减压下浓缩。残留物溶于水中,加入浓缩HCl以成为酸性p H而产生沉淀物,并以真空干燥以获得16(0.34g)。1H NMR(500MHz,CD3OD):δ2.97(t,J=8.6Hz,2H),3.99(t,J=8.6Hz,2H),7.51-7.54(m,2H),7.61-7.64(m,2H),7.74(s,1H),7.84-7.88(m,3H)。
1-苯磺酰基-2,3-二氢-1H-吲哚-5-羧酸羟酰胺(化合物18)
将NH2OTHP(0.12g,0.99mmol)加入溶有16(0.25g,0.82mmol),PyBOP(0.46g,0.87mmol),三乙基胺(0.28ml,1.98mmol)之DMF(2mL)溶液中。反应混合物于室温下搅拌1.5小时,接着以水停止反应,并以EtOAc(15mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩。残留物以硅胶管柱层析(CH2Cl2∶CH3OH=30∶1∶1%NH3(aq))纯化以得到白色固体,并在CH3OH(52mL)的存在下以TFA(2.7ml,36.35mmol)处理并于室温下搅拌过夜。反应混合物于减压下浓缩得到白色残留物,并以CH3OH再结晶以得到化合物18(0.25g)。1H NMR(500MHz,CD3OD):δ2.95(d,J=8.49Hz,2H),3.97(d,J=8.52Hz,2H),7.48-7.52(m,3H),7.57-7.63(m,3H),7.82(d,J=7.71Hz,2H)。C15H14N2O4S(M+)之HRMS(EI):估计值(calcd),318.0674;实际值(found),318.0672。Mp:130-132℃。
实施例19:合成3-(1-苯磺酰基-1H-吲哚-3-y1)-N-羟基-丙烯酰胺(化合物19)
化合物19透过如上方流程4的途径合成(试剂及状态:a)NH2OTHP、PyBOP、NEt3、DMF;b)氯化苯磺酰基、KOH、四-n-丁基胺重硫酸盐、CH2Cl2;c)TFA、MeOH。
3-(1H-吲哚-3-基)-N-(四氢-哌喃-2-基氧基)-丙烯酰胺(18)
将NH2OTHP(0.38g,3.21mmol)加入溶有反-3-吲哚丙烯酸(17)(0.50g,2.67mmol),PyBOP(1.47g,2.83mmol),三乙基胺(0.74ml,6.41mmol)之THF(25mL)溶液中。反应混合物于室温下搅拌2小时并于减压下浓缩,残留物溶于EtOAc并以水停止反应,接着以EtOAc(20mL×3)萃取。合并的有机层以无水MgSO4干燥。残留物以硅胶管柱层析(EtOAc∶n-己烷=1∶1.5∶1%NH3(aq))纯化以得到18。1H NMR(500MHz,CD3OD):δ1.58-1.70(m,3H),1.79-1.90(m,3H),3.63-3.65(m,1H),4.03-4.08(m,1H),4.97-4.98(m,1H),6.47(d,J=14.9Hz,1H),7.15-7.21(m,2H),7.41(d,J=7.8Hz,1H),7.59(s,1H),7.84-7.87(m,2H)。
3-(1-苯磺酰基-1H-吲哚-3-基)-N-(四氢-哌喃-2-基氧基)-丙烯酰胺(19):
悬浮于CH2Cl2(15mL)中的18(0.52g,1.82mmol)、四-n-丁基胺重硫酸盐(0.09g,0.27mmol)及KOH(0.20g,3.63mmol)搅拌20分钟,加入氯化苯磺酰基(0.35ml,2.72mmol)并在室温下搅拌过夜。反应混合物以水停止反应后,以CH2Cl2(20mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩以得到黄色残留物,并以硅胶管柱层析(EtOAc∶n-己烷=1∶1.5)纯化以得到19(0.42g)。
3-(1-苯磺酰基-1H-吲哚-3-基)-N-羟基-丙烯酰胺(化合物19):
溶有粗萃19的甲醇(50ml)溶液以TFA(2.2ml,29.8mmol)处理。反应混合物在室温下搅拌过夜,反应混合物接着于减压下浓缩以得到黄色残留物,并以CH3OH再结晶以得到化合物19(0.1g)。1HNMR(500MHz,CD3OD):δ6.61(d,J=16.0Hz,1H),7.35-7.43(m,2H),7.55-7.58(m,2H),7.65-7.68(m,1H),6.69(d,J=16.0Hz,1H),7.85(d,J=7.8Hz,1H),8.00-8.05(m,3H),8.27(s,1H)。MS(EI)m/z:342。C17H14N2O4S(M+)之HRMS(EI):估计值(calcd),342.0674;实际值(found),342.0673。Mp:199-200℃。
实施例20:合成3-(1-苯磺酰基-1H-吲哚-6-基)-N-羟基-丙烯酰胺(化合物20)
化合物20以类似实施例3中描述的方式制备。
1H NMR(500MHz,CD3OD):δ6.50(d,J=15.8Hz,1H),6.74(d,J=3.6Hz,1H),7.43(d,J=8.1Hz,1H),7.50-7.54(m,3H),7.59(t,J=7.4Hz,1H),8.65(d,J=15.8Hz,1H),7.71(d,J=3.6Hz,1H),7.93(d,J=1.1Hz,1H),7.94(s,1H),8.13(s,1H)。MS(EI)m/z:342;Mp:166-168℃。
实施例21:合成3-(1-苯磺酰基-1H-吲哚-4-基)-N-羟基-丙烯酰胺(化合物21)
化合物21以类似实施例3中描述的方式制备。
1H NMR(500MHz,CD3OD):δ6.54(d,J=15.8Hz,1H),7.03(d,J=3.6Hz,1H),7.33(t,J=7.9Hz,1H),7.49(d,J=8.1Hz,2H),7.55(s,1H),7.60(t,J=7.5Hz,1H),7.78(d,J=3.8Hz,1H),7.88(d,J=15.8Hz,1H),7.92(d,J=7.7Hz,2H),8.01(d,J=8.4Hz,1H)。MS(EI)m/z:342。C17H14N2O4S(M+)之HRMS(EI):估计值(calcd),342.0674;实际值(found),342.0674。Mp:108-110℃。
实施例22:合成3-(1-苯磺酰基-1H-吲哚-7-基)-N-羟基-丙烯酰胺(化合物22)
化合物22以类似实施例3中描述的方式制备。
1H NMR(500MHz,CD3OD):δ5.87(d,J=15.1Hz,1H),6.62(d,J=3.7Hz,1H),7.07-7.10(m,1H),7.15-7.16(m,1H),7.26-7.30(m,2H),7.39-7.43(m,2H),7.61(d,J=7.9Hz,2H),7.70(d,J=3.7Hz,1H),8.34(d,J=15.2Hz,1H)。MS(EI)m/z:342。C17H14N2O4S(M+)之HRMS(EI):估计值(calcd),342.0672;实际值(found),342.0674。Mp:175-176℃。
实施例23:合成N-羟基-3-(1H-吲哚-4-基)-丙烯酰胺(化合物23)化合物23以类似实施例3中描述的方式制备。
1H NMR(500MH z,CD3OD):δ6.67(d,J=15.6Hz,1H),6.77(d,J=2.9Hz,1H),7.11-7.14(m,1H),7.27(d,J=7.3Hz,1H),7.35(d,J=3.1Hz,1H),7.43(d,J=8.0Hz,1H),8.0(d,J=15.8Hz,1H)。LC/MS m/z:203(M++1)。C11H10N2O2(M+)之HRM S(EI):估计值(calcd),202.0742;实际值(found),202.0742。Mp:188-190℃。
实施例24:合成3-(3-苯磺酰基-1H-吲哚-6-基)-N-羟基-丙烯酰胺(化合物24)
化合物24以上方流程5所示的途径合成,(试剂及状态:(a)Ph3P=CH-CO2CH3、CH2Cl2;(b)NaH、Ph-S-S-Ph、DMF;(c)MCPBA、CH2Cl2;(d)LiOH、MeOH、H2O;(e)(i)NH2OTHP、PyBOP、NEt3、DMF;(ii)TFA、MeOH)。
3-(1H-吲哚-6-基)-丙烯酸甲基酯(21):甲基(三苯基磷)乙酸酯(1.38g,4.13mmol)加入溶有20(0.5g,3.44mmol)之CH2Cl2(15mL)溶液中。反应混合物于室温下搅拌过夜后,以水淬火,并以CH2Cl2(20mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩以得到黄色残留物,接着以硅胶管柱层析(EtOAc∶n-己烷=1∶4)纯化以得到21(0.63g)。1H NMR(500MHz,CD3OD):δ3.81(s,3H),6.43(d,J=15.8Hz,1H),6.57(m,1H),7.30(t,J=2.7Hz,1H),7.35(dd,J=8.2,1.0Hz,1H),7.55(s,1H),7.62(d,J=8.3Hz,1H),7.80(d,J=15.9Hz,1H),8.30(s,1H)。
3-(3-苯基磺酰基-1H-吲哚-6-基)-丙烯酸甲基酯(22):将21(0.63g,3.13mmol)于0℃下加入悬浮于DMF(6mL)之NaH(0.11g,4.70mmol)。反应混合物接着加热至室温。在搅拌2小时后加入苯二硫苯(0.75g,3.44mmol),反应混合物搅拌过夜后,于0℃下以水淬火,并以EtOAc(15mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩以得到黄色残留物,接着以硅胶管柱层析(EtOAc∶n-己烷=1∶3)纯化以得到22(0.61g)。1H NMR(500MHz,CD3OD):δ3.81(s,3H),6.44(d,J=15.8Hz,1H),7.03-7.18(m,5H),7.37-7.39(m,1H),7.56-7.60(m,3H),7.80(d,J=15.9Hz,1H),8.53(s,1H)。
3-(3-苯磺酰基-1H-吲哚-6-基)-丙烯酸甲基酯(23):于0℃下将3-氯过氧苯甲酸(0.77g,4.44mmol)加入溶有22(0.61g,1.97mmol)之CH2Cl2(40mL)溶液中。反应混合物移至室温下且搅拌过夜。之后以饱合NaHCO3(aq)在0℃下淬火,接着以CH2Cl2(25mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩以得到绿色残留物,接着以硅胶管柱层析(EtOAc∶n-己烷=1∶1)纯化以得到23(0.36g)。1H NMR(500MHz,CD3OD):δ3.81(s,3H),6.43(d,J=16.0Hz,1H),7.03-7.18(m,5H),7.73(d,J=16.0Hz,1H),7.56-7.60(m,4H)。8.85(s,1H)。
3-(3-苯磺酰基-1H-吲哚-6-基)-丙烯酸(24):将氢氧化锂(0.05g,2.11mmol)加入溶有23(0.36g,1.05)的MeOH(10mL)及水(2ml)之溶液中。反应混合物回流6小时,接着在减压下浓缩获得残留物。将残留物溶于水,加入3N HCl直至成为酸性pH后,混合物以EtOAc(20mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩以得到棕色残留物,并以EtO H再结晶以得到24(0.2g)。1H NMR(500MHz,CD3OD):δ6.46(d,J=15.8Hz,1H),7.62-7.69(m,4H),7.81(s,1H),7.81(d,J=16.0Hz,1H),7.95(d,J=8.4Hz,1H),8.12(d,J=7.3Hz,2H),8.21(s,1H)。
3-(3-苯磺酰基-1H-吲哚-6-基)-N-羟基-丙烯酰胺(化合物24):将NH2OTHP(0.04g,0.37mmol)加入溶有24(0.10g,0.31mmol)、PyBOP(0.17g,100.33mmol)、三乙基胺(0.1ml,0.74mmol)之DMF(1mL)溶液中。反应混合物在室温下搅拌1小时,以水停止反应,接着以EtOAc(15mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩,残留物以硅胶管柱层析(CH2Cl2∶CH3OH=30∶1∶1%NH3(aq))纯化以得到白色固体,并在CH3OH(15mL)的存在下以TFA(0.70ml,9.44mmol)处理且于室温下搅拌过夜。反应混合物于减压下浓缩得到白色残留物。该残留物以CH3OH再结晶以得到化合物24(0.08g)。1H NMR(500MHz,CD3OD):δ6.45(d,J=15.8Hz,1H),7.45(d,J=8.4Hz,1H),7.50-7.65(m,5H),7.81(d,J=8.4Hz,1H),7.98-8.00(m,2H),8.04(s,1H)。MS(EI)m/z:342。C17H14N2O4S(M+)之HRMS(EI):估计值(calcd),342.0674;实际值(found),342.0674。
实施例25:合成3-(3-苯磺酰基-1H-吲哚-5-基)-N-羟基-丙烯酰胺(化合物25)
化合物25以类似实施例24中描述的方式制备。
1H NMR(500MHz,CD3OD):δ6.48(d,J=16.2Hz,1H),7.52(s,2H),7.56(d,J=7.7Hz,2H),7.55-7.59(m,1H),7.67(d,J=15.9Hz,1H),8.01(s,1H),8.03(d,J=6.9Hz,2H),8.07(s,1H)。MS(EI)m/z:342。Mp:182-184℃。
实施例26:合成3-(3-苯磺酰基-1H-吲哚-7-基)-N-羟基-丙烯酰胺(化合物26)
化合物26以类似实施例24中描述的方式制备。
1H NMR(500MHz,DMSO):δ6.58(d,J=15.5Hz,1H),7.26(t,J=7.7Hz,1H),7.52-7.58(m,4H),7.86(d,J=7.9Hz,1H),8.01-8.07(m,4H)。MS(EI)m/z:342。C17H14N2O4S(M+)之HRMS(EI):估计值(calcd),342.0674;实际值(found),342.0673。Mp:249-251℃。
实施例27:合成丁-2-烯二酸(1-苯磺酰基-1H-吲哚-5-基)-酰胺羟酰胺(化合物27)
化合物27以上方流程6所示的途径合成,(试剂及状态:(a)氯化苯磺酰基、KOH、TBAHS、CH2Cl2;(b)Fe、NH4Cl、IPA、H2O;(c)(i)反丁烯二酰氯、THF(ii)NH2OH-HC,sat.NaHCO3(aq),THF)。
1-苯磺酰基-5-硝基-1H-吲哚(26):将5-硝基吲哚(25)(1.00g,6.17mmol)、四丁基铵重硫酸盐(0.32g,0.93mmol)及KOH(0.69g,12.33mmol)悬浮于CH2Cl2(20mL)后搅拌30分钟,加入氯化苯磺酰基(1.18ml,9.25mmol)。反应混合物于室温下搅拌过夜,接着以水停止反应,并以CH2Cl2(20mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩以得到黄色的残留物,并以硅胶管柱层析(EtOAc∶n-己烷=1∶4)纯化以得到26(1.72g)。1H NMR(500MHz,CD3OD):δ6.81(d,J=3.6Hz,1H),7.48-7.51(m,2H),7.58-7.61(m,1H),7.73(d,J=3.69Hz,1H),7.90(d,J=7.64Hz,2H),8.09(d,J=9.0Hz,1H),8.21(dd,J=9.0,2.0Hz,1H),8.47(d,J=2.0Hz,1H)。
1-苯磺酰基-1H-吲哚-5-基胺(27):将铁(0.64g,11.51mmol)及氯化铵(0.41g,7.67mmol)加入悬浮于I PA(38mL)及水(9mL)的2(1.16g,3.84mmol)中,回流过夜。反应以硅藻土过滤后,溶剂在减压下浓缩以得到棕色残留物,并将其溶于CH2Cl2并以水淬火,接着以CH2Cl2(20mL×3)萃取。合并的有机层以无水MgSO4干燥并于减压下浓缩以得到棕色的残留物,并以硅胶管柱层析(EtOAc∶n-己烷=1∶2∶1%NH3(aq))以得到27(0.86g)。1H NMR(500MHz,CD3OD):δ3.60(s,2H),6.48(d,J=3.6H z,1H),6.69(dd,J=8.7,2.1Hz,1H),6.76(d,J=1.8Hz,1H),7.39-7.42(m,2H),7.44(d,J=3.5H z,1H),7.49-7.51(m,1H),7.77(d,J=8.7Hz,1H),7.82(d,J=7.9Hz,2H)。
丁-2-烯二酸(1-苯磺酰基-1H-吲哚-5-基)-胺羟酰胺(化合物27):将溶有27(0.20g,0.73mmol)之THF(2mL)溶液以滴落方式加入溶有反丁烯二酰氯(0.08mL,0.73mmole)之THF(1mL)溶液。混合物在室温下搅拌10分钟后,接着以真空干燥以得到残留物。该残留物接着溶于THF(mL)中。在另一容器中,将s at.NaHCO3溶液(3ml)加入悬浮于THF(4mL)之盐酸羟胺(0.26g,3.77mmole)中,反应混合物于室温下搅拌10分钟。两个容器中的内容物混合并于室温下搅拌1小时。混合物以EtOAc(15mL×3)及水分层,合并的有机层以无水MgSO4干燥并于减压下浓缩以得到黄色的残留物,并以硅胶管柱层析(CH2Cl2∶CH3OH=10∶1∶1%AcOH)以得到化合物27(0.12g)。1H NMR(500MHz,CD3OD):δ7.70(d,J=3.3Hz,1H),6.86(d,J=15.0Hz,1H),7.10(d,J=15.0Hz,1H),7.46-7.51(m,3H),7.58-7.61(m,1H),7.65(d,J=3.4Hz,1H),7.90-7.97(m,4H)。C18H15N3O5S(M+)之HRMS(EI):估计值(calcd),385.0732;实际值(found),385.0732。Mp:193-194℃。
实施例28:合成N-羟基-3-[1-(4-甲氧基-苯磺酰基)-1H-吲哚-7-基]-丙烯酰胺(化合物28)
化合物28以类似实施例3中描述的方式制备。
实施例29:合成3-(1-苯磺酰基-1H-吲哚-5-基)-丙烯酸(化合物29)
化合物29以类似实施例3中描述的方式制备。
1H NMR(500MHz,CDCl3):δ6.39(d,J=16.1Hz,1H),6.71(d,J=3.6Hz,1H),7.45-7.48(m,2H),7.52(dd,J=8.7,1.4Hz,1H),7.55-7.58(m,1H),7.61(d,J=3.7Hz,1H),7.67-7.72(m,2H),7.89(d,J=8.9Hz,2H),7.96(d,J=8.7Hz,1H)。
实施例30:细胞存活试验
i)MTT试验
人类白血病细胞株K562(带有BCR/ABL转位)、NB4(表现PML/RAR阿法融合蛋白)、MV4-11(带有FLT-3ITD突变)、HL60(带有p53单倍数突变)、Kasumi-1(8;21染色体易位,表现c-kit)及U937(似巨噬细胞)做为研究人类白血病细胞的使用模型。细胞悬浮于含有10%FBS之RPMI 1640(Life Technologies)中,每孔以104个细胞接种于带有或不带有测试化合物之96孔盘中,不同浓度的化合物亦受测试。在不同浓度化合物之细胞存活率在经处理48小时或72小时后使用3-(4,5-二甲基噻唑-2-基)-2,5-溴化二苯基四氮唑(MTT)试验(Sigma,工作浓度0.5mg/ml)测定之。MTT试验为良好的细胞毒性检测方法,该方法可定量地检测细胞粒线体对3-(4,5-二甲基噻唑-2-基)-2,5-溴化二苯基四氮唑的还原活性而产生一种深蓝色的甲臜(formazan)产物。每个试验化合物的LC50及GI50分别依此检测。GI50系指相较于控制组细胞中,可减少净细胞增生达50%时之化合物浓度。50%之生长抑制定义为[(Ti-Tz)/(C-Tz)]×100=50,其中,Tz代表时间为零时的细胞浓度(此时没有细胞增加),C代表控制组细胞的细胞浓度(没有加入测试化合物),且Ti代表在GI50下以测试化合物处理之群组其细胞浓度。药物浓度导致总量生长抑制(TGI)则定为Ti=Tz。LC50系指在药物处理最终时导致净细胞相较于起始时损失50%的化合物浓度,在处理后的细胞凈损失定义为[(Ti-Tz)/Tz]×100=-50。
细胞接种于96孔的平底盘中(每孔2,500至3,000个细胞),细胞培育于37℃下含5%CO2,外加10%FBS之RPMI 1640培养基中以测试化合物(化合物3、化合物12、Ara-C及SAHA)在不同的浓度下(即0、5、10、15及20μM)处理48或72小时,培养基接着由每孔中移除,并加入含150μL之0.5mg/mL MTT之RPMI 1640培养基,在37℃下培育2小时后,将上清液移除并加入200μL/well之DMSO以溶解残存之MTT染剂。使用读盘机检验每孔在570nm的吸光值,每个化合物浓度进行6重复试验,MTT试验得到的结果如下表1所示。
ii)SRB试验
人类癌症A549(非小细胞肺癌)、MDA-MB-231(雌激素依赖性乳癌)、Hep 3B(肝癌)及HA22T(肝癌)细胞接种于96孔盘中培育于含有5%FBS的培养基。24小时后,细胞以10%三氯醋酸(TCA)固定以代表化合物加入时(T0)的细胞群体。在额外以DMSO或测试化合物培育48小时后,细胞以10%TCA固定且加入在1%醋酸的浓度4%(w/v)SRB来将细胞染色。未结合的SRB以1%醋酸洗去,而SRB结合细胞则以10mM三苯甲基碱(Trizma base)溶出。于波长515nm下测量吸光值,使用量测到零时点(T0)、控制组(C)及有化合物存在的细胞生长(Ti)的吸光值来计算每个化合物浓度的生长百分比,50%之生长抑制定义为[(Ti-T0)/(C-T0)]×100=50,且GI50定义为在化合物培育时,相较于控制组细胞,可减少导致净蛋白质增加(如SRB染色所测定)达50%时的化合物浓度。结果如表2所示。
表2
实施例31:西方墨点分析
PC-3细胞于外加10%FBS的RPMI 1640中以浓度1、2.5、或5μM浓度的测试化合物处理48小时。将细胞收集并以超音波处理。得到的细胞残余物中的蛋白质浓度以布拉德福(bradford)蛋白质试验套组(Bio-Rad,Hercules,CA)测试。含有一样浓度蛋白质的蛋白质残余物进行10%SDS-聚丙烯酰胺凝(10%)胶电泳,胶上的蛋白质接着于半干式转渍槽中转移至免疫硝化纤维膜(Millipore,Bellerica,MA)上。该转渍的纤维膜以含有0.1%Tween20之三羟甲基氨基甲烷缓冲食盐水(TBST)清洗两次。以含有5%脱脂奶粉的TBST阻滞(block)40分钟后,转渍膜在4℃、含1%脱脂奶粉的TBST下,以抗乙酰化-H 3(抗体购自Upstate Biotechnology,Inc,Lake Placid,NY)、H3(Upstate Biotechnology)、乙酰化-α-微管蛋白(Sigma-Aldrich,St.Louis,MO)、磷酸化-Akt(丝胺酸473)(Cell SignalingTechnologies,Danvers,MA)、Akt(Cell Signaling Technologies)、乙酰化-p53(SantaCruz Biotechnology,Santa Cruz,CA)、p53(Santa Cruz Biotechnology)、p21(SantaCruz Biotechnology,Santa Cruz,CA)、或α-微管蛋白(Sigma-Aldrich,St.Louis,MO)(1∶3000稀释)的初级抗体培育过夜。膜接着以TBST清洗三次共15分钟,并以与辣根共轭的山羊抗兔或抗鼠Ig-G抗体(1∶3000稀释)于室温下培育1小时。在以清洗TBST至少三次后,测试每个蛋白条带的讯息强度。
SAHA、化合物13及12受到测试,结果显示,化合物3及12和SAHA一样,可抑制组织蛋白的去乙酰化且向上调控H3表现及微管蛋白的乙酰化。
其它实施例
本说明书中之所有特征可以任意组合。揭示于此说明书中的每个特征可以任合具有相同、相等或类似目的的另一种特征替代,因此,除非有特别说明,否则揭示于此的每个特征仅为相同或相似的同属性系列的1个实例。
由上方的说明,本领域技术人员可轻易的确认本发明的实质特征,且在不偏离本发明的精神及范围下,可对本发明做不同的变化及修饰,以适应不同的用途及状态。因此,其它的实施例亦在本发明权利要求范围的范畴之中。
Claims (17)
1.一种如式(I)的化合物:
其中
为单键或双键;
n为0、1或2;
R1为SO2Ra,其中Ra为选自由苯基、萘基和蒽基所组成的群组的芳基或选自由吡啶基、呋喃基、咪唑基、苯并咪唑基、嘧啶基、噻吩基、喹啉基、吲哚基、四唑基和噻唑基所组成的群组的杂芳基,其选择性经卤基、羟基、烷氧基、胺基、氰基或硝基取代;
R2为H、C1-C10烷基、NHC(O)-CH=CH-C(O)NRcRd或C(O)NRcRd,其中各Rc及Rd独立为H或羟基;
各个R3、R4、R5及R6独立为H、C1-C10烷基、CH=CH-C(O)NRcRd、NHC(O)-CH=CH-C(O)NRcRd或C(O)NRcRd,其中各Rc及Rd独立为H或羟基;
且其限制条件为一个或多个R2、R3、R4、R5及R6具有以下定义:R2为NHC(O)-CH=CH-C(O)NRcRd;或各个R3、R4、R5及R6独立为CH=CH-C(O)NRcRd或NHC(O)-CH=CH-C(O)NRcRd。
2.如权利要求1所述的化合物,其中R4为CH=CH-C(O)NRcRd或NHC(O)-CH=CH-C(O)NRcRd。
3.如权利要求1所述的化合物,其中R4为C(O)NHOH、CH=CH-C(O)NHOH或NHC(O)-CH=CH-C(O)NHOH。
4.如权利要求3所述的化合物,其中R4为CH=CH-C(O)NHOH。
5.如权利要求4所述的化合物,其中Ra为选择性经卤基、羟基、烷氧基、胺基、氰基、或硝基取代的苯基。
6.如权利要求1所述的化合物,其中各个R3、R5及R6独立为CH=CH-C(O)NRcRd或NHC(O)-CH=CH-C(O)NRcRd。
7.如权利要求6所述的化合物,其中各个R3、R5及R6独立为CH=CH-C(O)NHOH或NHC(O)-CH=CH-C(O)NHOH。
8.如权利要求7所述的化合物,其中Ra为选择性受卤基、羟基、烷氧基、胺基、氰基、或硝基取代的苯基。
9.如权利要求1所述的化合物,其中Ra为选择性受卤基、羟基、烷氧基、胺基、氰基、或硝基取代的苯基。
10.如权利要求1所述的化合物,其中该化合物为以下化合物1、3-8、12-18、20-22、27和28中的一种:
11.如权利要求10所述的化合物,其中该化合物为3-(1-苯磺酰基-1H-吲哚-5-基)-N-羟基-丙烯酰胺或3-(1-苯磺酰基-2,3-二氢-1H-吲哚-5-基)-N-羟基-丙烯酰胺。
12.一种如权利要求1所述的化合物的用途,其用于制备治疗癌症的药剂。
13.一种如权利要求2所述的化合物的用途,其用于制备治疗癌症之药剂。
14.一种如权利要求10所述的化合物的用途,其用于制备治疗癌症的药剂。
15.一种医药组合物,其包含如权利要求1所述的化合物及医药上可接受的载体。
16.一种医药组合物,其包含如权利要求2所述的化合物及医药上可接受的载体。
17.一种医药组合物,其包含如权利要求10所述的化合物及医药上可接受的载体。
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