CN101805338B - 噁二唑基哌嗪衍生物及其用途 - Google Patents
噁二唑基哌嗪衍生物及其用途 Download PDFInfo
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- CN101805338B CN101805338B CN201010139255.8A CN201010139255A CN101805338B CN 101805338 B CN101805338 B CN 101805338B CN 201010139255 A CN201010139255 A CN 201010139255A CN 101805338 B CN101805338 B CN 101805338B
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- Prior art keywords
- methyl
- phenyl
- hydroxy
- oxadiazol
- acethydrazide
- Prior art date
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- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000004885 piperazines Chemical class 0.000 title 1
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical class C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 claims abstract description 85
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- 201000011510 cancer Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- -1 phenylmethoxy Chemical group 0.000 claims description 184
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000001639 phenylmethylene group Chemical group [H]C(=*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 24
- 125000005605 benzo group Chemical group 0.000 claims description 23
- 238000006467 substitution reaction Methods 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000005394 methallyl group Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
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- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
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- 201000007983 brain glioma Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
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- 238000011321 prophylaxis Methods 0.000 claims description 2
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 5
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 22
- 239000012453 solvate Substances 0.000 abstract description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract description 8
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- 239000000203 mixture Substances 0.000 abstract description 7
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- 125000001424 substituent group Chemical group 0.000 abstract description 3
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- 206010020718 hyperplasia Diseases 0.000 abstract 1
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
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- 125000000217 alkyl group Chemical group 0.000 description 25
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- 125000003118 aryl group Chemical group 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 16
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 125000003545 alkoxy group Chemical group 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 150000002431 hydrogen Chemical class 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 125000003342 alkenyl group Chemical group 0.000 description 12
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- 125000005530 alkylenedioxy group Chemical group 0.000 description 11
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000004414 alkyl thio group Chemical group 0.000 description 9
- 125000000304 alkynyl group Chemical group 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- IUNJCFABHJZSKB-UHFFFAOYSA-N 2,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(O)=C1 IUNJCFABHJZSKB-UHFFFAOYSA-N 0.000 description 8
- 125000004849 alkoxymethyl group Chemical group 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- LOQLDQJTSMKBJU-UHFFFAOYSA-N 4-(chloromethyl)benzonitrile Chemical compound ClCC1=CC=C(C#N)C=C1 LOQLDQJTSMKBJU-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
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- 239000002552 dosage form Substances 0.000 description 4
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- INLWEXRRMUMHKB-UHFFFAOYSA-N 2-hydroxy-3-prop-2-enylbenzaldehyde Chemical compound OC1=C(CC=C)C=CC=C1C=O INLWEXRRMUMHKB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
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- CGDASUSRZFBWRX-UHFFFAOYSA-N oxadiazole piperazine Chemical class c1conn1.C1CNCCN1 CGDASUSRZFBWRX-UHFFFAOYSA-N 0.000 description 3
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- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 3
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- CJXBHFANXQMZBF-UHFFFAOYSA-N 2-phenylethanethioamide Chemical compound NC(=S)CC1=CC=CC=C1 CJXBHFANXQMZBF-UHFFFAOYSA-N 0.000 description 2
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract
本发明属于医药技术领域,涉及通式I所示的含噁二唑基哌嗪乙酰肼衍生物、其几何异构体、及其药学上可接受的盐、水合物或溶剂化物,其中取代基Ar1和R1具有在说明书中给出的含义。本发明还涉及制备式I化合物的方法、含有上述化合物的药用组合物以及上述化合物用于制备治疗和/或预防癌症和其它增生性疾病的药物中的用途。
Description
技术领域
本发明属于医药技术领域,涉及噁二唑基哌嗪衍生物及其用途,具体涉及噁二唑基哌嗪衍生物、其药物组合物,及其在制备细胞增殖抑制剂,用于治疗和/或预防各种癌症的药物中的用途。
背景技术
肿瘤是一种严重威胁人类生命健康的疾病,近年来,肿瘤的发生率和死亡率呈逐年上升的趋势。细胞毒性药物能够杀死肿瘤细胞,但对癌细胞与正常细胞缺乏选择性,因此具有较强的毒副作用。
寻找能够选择性地杀死癌细胞,对正常增殖细胞无影响的靶向性抗肿瘤药物已成为新型抗肿瘤药物研发的重要方向。细胞凋亡又称细胞程序性死亡,在肿瘤的发生和发展过程中起着重要作用。近年来人们在细胞内发现了一类重要的蛋白质半胱天冬酶-3酶原蛋白(procaspase-3),procaspase-3在体内可被活化为半胱天冬酶-3(caspase-3),进而诱导细胞的凋亡。但在癌变细胞中,procaspase-3形成caspase-3的过程被破坏,因此造成肿瘤组织的生长。
2006年,Alan G Porter在Nature Chemical Biology上公开了一个能够选择性激活procaspase-3的化合物PAC-1(其结构式如下),并且进一步阐明了caspase-3在诱导细胞凋亡过程中的作用机理,研究表明,能够活化procaspase-3的化合物可以作为靶向分子从而诱导癌细胞的凋亡。由于procaspase-3在正常细胞中含量较低,因此健康细胞对PAC-1并不敏感,通过对同一个肿瘤患者的正常细胞与肿瘤细胞进行化验表明,癌变细胞对PAC-1的敏感程度要高2000倍。
PAC-1结构式
发明内容
本发明所解决的技术问题是合成一系列含有噁二唑基哌嗪的化合物,并进行了体外抗肿瘤活性筛选,结果表明具有较好的抗肿瘤活性。
本发明涉及通式Ⅰ所示的含噁二唑基的哌嗪乙酰肼类衍生物,及其几何异构体或其药学上可接受的盐、水合物或溶剂化物,
其中,
Ar1为芳基,芳基(C1-C4)烷基,且Ar1任选1-3个R2取代;
R2为氢,卤素,三氟甲基,三氟甲氧基,氨基,硝基,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,(C1-C4)烷氧基,(C1-C4)烷硫基,烯丙基,(2-甲基)烯丙基,(3-甲基)烯丙基,(C1-C4)烷 氧基甲基,(C1-C3)亚烷基二氧基;
R1为芳基,萘基,5-10元杂芳基,5-10元杂芳基(C1-C4)烷基,5-10元饱和或部分饱和的杂环基,5-10元饱和或部分饱和的杂环基(C1-C4)烷基,所述杂芳基和杂环基含有1-3个选自O、N和S的杂原子,且R1任选1-3个R3取代;
R3为氢,卤素,羟基,三氟甲基,三氟甲氧基,氨基,硝基,巯基,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,(C1-C4)烷氧基,(C1-C4)烷硫基,羟基(C1-C4)烷基,烯丙基,(2-甲基)烯丙基,(C1-C4)烷氧基甲基,(C1-C3)亚烷基二氧基,芳基(C1-C4)烷基,芳基(C1-C4)烷氧基,5-10元杂芳基(C0-C4)烷基,5-10元杂芳基(C0-C4)烷氧基,5-10元饱和或部分饱和的杂环基(C0-C4)烷基,5-10元饱和或部分饱和的杂环基(C0-C4)烷氧基,所述杂芳基和杂环基含有1-3个选自O、N和S的杂原子,且所述芳基、杂芳基和杂环基任选1-3个R4取代;
R4为氢,卤素,羟基,三氟甲基,三氟甲氧基,氨基,硝基,巯基,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,(C1-C4)烷氧基,(C1-C4)烷硫基,羟基(C1-C4)烷基,烯丙基,(2-甲基)烯丙基,(C1-C4)烷氧基甲基,(C1-C3)亚烷基二氧基,芳基(C1-C4)烷基,芳基(C1-C4)烷氧基,5-10元杂芳基(C1-C4)烷基,5-10元杂芳基(C1-C4)烷氧基,5-10元饱和或部分饱和的杂环基C1-C4烷基,5-10元饱和或部分饱和的杂环基C1-C4烷氧基,所述杂芳基和杂环基含有1-3个选自O、N和S的杂原子。
本发明优选涉及定义如下的通式Ⅰ衍生物,及其几何异构体或其药学上可接受的盐、水合物或溶剂化物,
其中,
Ar1为苯基,苯基C1-C4烷基,且Ar1任选1-3个R2取代;
R2为氢,卤素,三氟甲基,三氟甲氧基,氨基,硝基,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,(C1-C4)烷氧基,(C1-C4)烷硫基,烯丙基,(2-甲基)烯丙基,(3-甲基)烯丙基,(C1-C4)烷氧基甲基,(C1-C3)亚烷基二氧基;
R1为芳基,萘基,5-10元杂芳基,5-10元饱和或部分饱和的杂环基,所述杂芳基和杂环基含有1-3个选自O、N和S的杂原子,且R1任选1-3个R3取代;
R3为氢,卤素,羟基,三氟甲基,三氟甲氧基,氨基,硝基,巯基,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,(C1-C4)烷氧基,(C1-C4)烷硫基,羟基(C1-C4)烷基,烯丙基,(2-甲基)烯丙基,(C1-C4)烷氧基甲基,(C1-C3)亚烷基二氧基,芳基(C1-C2)烷基,芳基甲氧基,5-10元杂芳基(C0-C2)烷基,5-10元杂芳基甲氧基,5-10元饱和或部分饱和的杂环基(C0-C2)烷基,5-10元饱和或部分饱和的杂环基甲氧基,所述杂芳基和杂环基含有1-3个选自O、N和S的杂原子,且所述芳基、杂芳基和杂环基任选1-3个R4取代;
R4为氢,卤素,羟基,三氟甲基,三氟甲氧基,氨基,硝基,巯基,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,(C1-C4)烷氧基,(C1-C4)烷硫基,羟基(C1-C4)烷基,烯丙基,(2-甲基)烯丙基,(C1-C4)烷氧基甲基,(C1-C3)亚烷基二氧基,芳基(C1-C2)烷基,5-10元杂芳基(C1-C2)烷基,5-10元饱和或部分饱和的杂环基(C1-C2)烷基,所述杂芳基和杂环基含有1-3个选自O、N和S的杂原子。
本发明还优选涉及定义如下的通式Ⅰ衍生物,及其几何异构体或其药学上可接受的盐、水合物或溶剂化物,
其中,
Ar1为苯基,苯甲基,且Ar1任选1-3个R2取代;
R2为氢,卤素,三氟甲基,三氟甲氧基,氨基,硝基,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,(C1-C4)烷氧基,(C1-C4)烷硫基,烯丙基,(2-甲基)烯丙基,(3-甲基)烯丙基,(C1-C4)烷氧基甲基,(C1-C3)亚烷基二氧基;
R1为苯基,萘基,5-10元杂芳基,5-10元饱和或部分饱和的杂环基,所述杂芳基和杂环基含有1-3个选自O、N和S的杂原子,且R1任选1-3个R3取代;
R3为氢,卤素,羟基,三氟甲基,三氟甲氧基,氨基,硝基,巯基,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)烷氧基,(C1-C4)烷硫基,羟基(C1-C4)烷基,烯丙基,(2-甲基)烯丙基,(C1-C4)烷氧基甲基,(C1-C3)亚烷基二氧基,芳基(C1-C2)烷基,芳基甲氧基,5-10元杂芳基(C0-C2)烷基,5-10元杂芳基甲氧基,5-10元饱和或部分饱和的杂环基(C0-C2)烷基,5-10元饱和或部分饱和的杂环基甲氧基,所述杂芳基和杂环基含有1-3个选自O、N和S的杂原子,且所述芳基、杂芳基和杂环基任选1-3个R4取代;
R4为氢,卤素,羟基,三氟甲基,三氟甲氧基,氨基,硝基,巯基,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,(C1-C4)烷氧基,(C1-C4)烷硫基,羟基(C1-C4)烷基,烯丙基,(2-甲基)烯丙基,(C1-C4)烷氧基甲基,(C1-C3)亚烷基二氧基,苯甲基,3,4-二氧亚甲基苯甲基。
本发明特别优选定义如下的通式Ⅰ化合物,及其几何异构体或其药学上可接受的盐、水合物或溶剂化物,
其中,
Ar1为苯基,苯甲基,且Ar1任选1-3个R2取代;
R2为氢,卤素,三氟甲基,烯丙基,(2-甲基)烯丙基;
R1为苯基,萘基,5-10元杂芳基,5-10元饱和或部分饱和的杂环基,所述杂芳基和杂环基含有1-3个选自O、N和S的杂原子,且R1任选1-3个R3取代;
R3为氢,卤素,羟基,(C1-C4)烷基,(C1-C4)烯基,烯丙基,(2-甲基)烯丙基,(3-甲基)烯丙基,(C1-C3)亚烷基二氧基,芳基甲氧基,5-10元杂芳基(C0-C2)烷基,5-10元杂芳基甲氧基,所述杂芳基含有1-3个选自O、N和S的杂原子,且所述芳基和杂芳基任选1-3个R4取代;
R4为氢,卤素,羟基,三氟甲基,三氟甲氧基,(C1-C4)烷基,(C1-C4)烯基,(C1-C4)炔基,(C1-C4)烷氧基,烯丙基,(2-甲基)烯丙基,(C1-C3)亚烷基二氧基,苯甲基,3,4-二氧亚甲基苯甲基。
本发明还特别优选定义如下的通式Ⅰ化合物,及其几何异构体或其药学上可接受的盐、水合物或溶剂化物,
其中,
Ar1为苯基,且Ar1任选1-3个R2取代;
R2为卤素,三氟甲基;
R1为苯基,萘基,且R1任选1-3个R3取代;
R3为氢,卤素,羟基,(C1-C4)烷基,(C1-C4)烯基,烯丙基,(2-甲基)烯丙基,(3-甲基)烯丙基,苯基甲氧基,4-噻唑基,4-噻唑基甲氧基,且所述苯基和噻唑基任选1-3个R4取代;
R4为氢,卤素,羟基,三氟甲基,(C1-C4)烷基,(C1-C3)亚烷基二氧基,苯甲基,3,4-二氧亚甲基苯甲基。
本发明通式I化合物,及其几何异构体或其药学上可接受的盐、水合物或溶剂化物优选以下化合物,但这些化合物并不意味着对本发明的任何限制:
N/-(2-羟基-4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)苯基亚甲基)-2-((4-((3-(4-((2-三氟甲基)苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-苄氧基苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(2,4-二氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(3-三氟甲基苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(4-叔丁基苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(2,4-二氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(4-叔丁基苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-苄氧基苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(4-氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(2,4-二氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯基亚甲基)-2-((4-((3-(4-(3-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-(2-甲基烯丙基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-(2-甲基烯丙基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(4-叔丁基苄氧基)苯基亚甲基)-2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯亚甲基)-2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(3-甲基-2-羟基-6-异丙基苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(3-氟苄氧基)苯基亚甲基)-2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(3-氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-苄氧基苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(4-氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(2-苄基噻唑-4-基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(2-苄基噻唑-4-基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
本发明特别优选以下化合物:
N/-(2-羟基-3-烯丙基苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-苄氧基苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(4-氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯基亚甲基)-2-((4-((3-(4-(3-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-(2-甲基烯丙基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-(2-甲基烯丙基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(4-叔丁基苄氧基)苯基亚甲基)-2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯亚甲基)-2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(3-甲基-2-羟基-6-异丙基苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-苄氧基苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(4-氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑 -5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(2-苄基噻唑-4-基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(2-苄基噻唑-4-基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
而且,按照本发明所属领域的一些通常方法,本发明中上式I的衍生物可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐,与下列酸加成的盐是特别优选的:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
此外,本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式I的衍生物,它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明中“卤素”是指氟、氯、溴或碘代;“烷基”是指直链或支链的烷基;“亚烷基”是指直链或支链的亚烷基;“芳基”是指无取代基或连有取代基的苯基;“杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系,环状体系是芳香性的,如噻唑基,咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、呋喃基、噻吩基、吡咯基,苯并噻唑基,噁唑基,异噁唑基,萘基,喹啉基,异喹啉基,苯并咪唑基,苯并噁唑基等;“饱和或部分饱和的杂环基”是指含有一个或多个选自N、O、S的杂原子的单环或多环的环状体系,如2H-1-苯并吡喃-2-酮基、吡咯烷基、吗啉基、哌嗪基、哌啶基、吡唑烷基、咪唑烷基和噻唑啉基等。
本发明可以含有上式I的衍生物,及其药学上可接受的盐、水合物或溶剂化物作为活性成份,与药学上可接受的载体或赋型剂混合制备成组合物,并制备成临床上可接受的剂型,上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用,只要它们不产生其他不利的作用,例如过敏反应。
本发明的药用组合物可配制成若干种剂型,其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型,包括:粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下不稳定的,可将其配制成肠衣片剂。
体外抗肿瘤活性试验表明,本发明的通式Ⅰ的衍生物具有抗肿瘤活性,因此本发明化合物可以用于制备治疗和/或预防各种癌症的药物,如乳腺、肺、肝脏、肾脏、结肠、直肠、胃、前列腺、膀胱、子宫、胰腺、骨髓、睾丸、卵巢、淋巴、软组织、头颈、甲状腺、食道的癌和白血病、成神经细胞瘤等。特别用于制备治疗和/或预防白血病的药物。
本发明的活性化合物或其可药用盐及其溶剂化物可作为唯一的抗肿瘤药物单独使用,或者可以与现已上市的抗肿瘤药物(如铂类药物顺铂、喜树碱类药物伊立替康、长春花碱类药物诺维本、脱氧胞昔类药物吉西他滨、足叶乙甙、紫杉醇等)联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线1描述了本发明的式I衍生物的制备,所有的原料都是通过这些示意图中描述的方式、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终衍生物都是通过这些示意图中描述的方法或通过与其类似的方法制备的,这些方法是有机化学领域普通技术人员熟知的。这些示意图中应用的全部可变因数如权利要求中的定义。
合成路线1
按照本发明的式Ⅰ衍生物,可按照路线1的方法,以4-氯甲基苯腈为起始原料,首先与化合物A-I进行取代反应得中间体A-II,与盐酸羟胺加成得中间体A-III,之后与氯乙酰氯环合得含1,2,4-噁二唑结构的中间体A-IV,再与哌嗪发生取代反应后与氯乙酸乙酯反应得中间体A-VI,之后与水合肼反应得中间体A-VII,最后与相应的醛经缩合,制得式I化合物。其中相应的醛可以通过有机化学领域普通技术人员熟知的方法制备或者可商购。
本发明首次合成了一系列含有噁二唑基哌嗪的化合物,其制备方法简单,重现性好,制备的化合物纯度高,收率高,且具有较好的抗肿瘤活性。
具体实施方式:
实施例旨在阐述而不是限制本发明的范围。衍生物的核磁共振氢谱用Bruker ARX-600测定,质谱用Agilent1100LC/MSD测定;所用试剂均为分析纯或化学纯。
表1实施例1~28的结构式
实施例1:N/-(2-羟基-4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)苯基亚甲基)-2-(4-((3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
步骤A4-((2-(三氟甲基)苯氧基)甲基)苯腈的制备
将10g(0.066mol)4-氯甲基苯腈,9.7g(0.060mol)2-(三氟甲基)苯酚与12g(0.087mol)碳酸钾溶于50mL的DMF中,60℃反应2h,向反应溶液中加入250mL水,搅拌,静置,抽滤,水洗滤饼至中性,干燥,得白色固体17g,收率93%,MS[MH+](m/z):277。
步骤B4-((2-(三氟甲基)苯氧基)甲基)-N/-羟基苯甲脒的制备
将86g(0.31mol)4-((2-(三氟甲基)苯氧基)甲基)苯腈,24g(0.34mol)盐酸羟胺,15g(0.375mol)氢氧化钠于200mL乙醇中回流4h,减压蒸干溶剂,残余物加水,析出固体,抽滤,干燥,得白色固体79g,收率82%,MS[MH+](m/z):311。
步骤C3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-5-(氯甲基)-1,2,4-噁二唑的制备
将8.5g(0.027mol)4-((2-(三氟甲基)苯氧基)甲基)-N/-羟基苯甲脒溶于100mL甲苯中,室温滴加1.5g(0.014mol)氯乙酰氯的甲苯溶液25mL,滴毕,再加入30mL甲苯,回流2h,反应毕,将反应液冷却,析出固体,抽滤,弃去滤饼。将滤液蒸干,得白色固体,收率56%,MS[MH+](m/z):369。
步骤D1-((3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-5-(氯甲基)-1,2,4-噁二唑-5-基)甲基)哌嗪
将9.5g(0.0258mol)3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-5-(氯甲基)-1,2,4-噁二唑与40g(0.206mol)哌嗪溶于150ml乙醇中,室温反应4h,反应毕,将溶剂蒸干,氯仿溶解,水洗,有机层干燥,减压浓缩,得白色固体8g,收率62%,MS[MH+](m/z):418。
步骤E2-(4-((3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-5-(氯甲基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酸乙酯
将8g(0.02mol)1-((3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-5-(氯甲基)-1,2,4-噁二唑-5-基)甲基)哌嗪,2.6g(0.021mol)氯乙酸乙酯与2.4g(0.028mol)碳酸氢钠溶于60ml乙醇,60℃反应6h,反应毕,减压浓缩,残余物倒入水中,析出固体,抽滤,干燥,得白色固体5.4g,收率56%,MS[MH+](m/z):505。
步骤F2-(4-((3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-5-(氯甲基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼
将2g(0.004mol)2-(4-((3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-5-(氯甲基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酸乙酯与2g(0.04mol)水合肼在乙醇中回流5h,反应毕,自然冷却,有固体析出,抽滤,干燥,得白色固体1.5g,收率77%,MS[MH+](m/z):490。
步骤G4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)-2-羟基苯甲醛的制备
首先用化合物B-I与硫氢化钠反应,得到中间体B-II,再与1,3-二氯丙酮环合得到中间体B-III,最后与2,4-二羟基苯甲醛反应,制得4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)-2-羟基苯甲醛,如合成路线2所示。
合成路线2
具体制备方法如下:
步骤G-12-(苯并[d][1,3]二氧戊环-5-基)硫代乙酰胺的制备
将14g(0.25mol)硫氢化钠、25.4g(0.125mol)MgCl2.6H2O、16.1g(0.1mol)2-(苯并[d][1,3]二氧戊环-5-基)乙腈依次加入DMF和水的混合溶剂中,室温反应15h,反应毕,将反应液倒入冰水中,用盐酸调PH值4~5,有大量乳白色的固体析出,抽滤,干燥,得白色固体10.3g,收率53%,MS[MH+](m/z):195。
步骤G-22-((苯并[d][1,3]二氧戊环-5-基)甲基)-4-(氯甲基)噻唑的制备
将10.3g(0.05mol)2-(苯并[d][1,3]二氧戊环-5-基)硫代乙酰胺与7g(0.05mol)1,3-二氯丙酮溶于乙腈,50℃反应4h,反应毕,析出固体,抽滤,水洗滤饼,得浅黄色固体8.7g,收率61%,MS[MH+](m/z):268。
步骤G-34-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)-2-羟基苯甲醛的制备
将8.7g(0.03mol)2-((苯并[d][1,3]二氧戊环-5-基)甲基)-4-(氯甲基)噻唑,4.5g(0.03mol)2,4-二羟基苯甲醛,3.2g(0.035mol)碳酸氢钠与1g碘化钾加入乙腈中,80℃反应2h,反应毕,减压浓缩,残余物加入甲醇加热溶解,活性碳脱色,抽滤,滤液自然冷却,有棕黄色固体析出,抽滤,干燥,得固体7.6g,收率64%,MS[MH+](m/z):369。
步骤H N/-(4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)-2-羟基苯亚甲基)-2-(4-((3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐的制备
将2g(0.004mol)2-(4-((3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-5-(氯甲基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼与1.5g(0.004mol)4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)-2-羟基苯甲醛在乙醇中回流10h,反应毕,有固体析出,抽滤,干燥。将所得固体溶于氯仿,滴加饱和盐酸乙醇溶液,析出白色固体,抽滤,干燥,得白色固体1.7g,收率48%。
MS[MH+](m/z):842;1H NMR(DMSO-d6):δ8.42(s,1H),8.26(d,2H),7.61(m,6H),7.31(d,1H),7.09(t,1H),6.86(m,3H),6.56(m,2H),5.96(s,2H),5.51(br,1H),5.35(s,2H),5.06(d,2H),4.52(s,1H),4.21(s,5H),3.55~2.91(m,8H).
按照实施例1的方法,首先以4-氯甲基苯腈和适合的取代苯酚为起始原料,经六步反应,制备得到噁二唑基哌嗪乙酰肼类衍生物A-VII;之后再与按照步骤G的方法制备得到的适合的醛反应,制备得到实施例2和3的化合物。
实施例2:N/-(2-羟基-4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)苯基亚甲基)-2-(4-((3-(4-((4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):808;1H NMR(DMSO-d6):δ8.27(s,1H),8.06(d,2H),7.64(d,3H),7.58(s,1H),7.34(d,2H),7.05(d,2H),6.91(s,1H),6.87(d,1H),6.81(d,1H),6.57(m,2H),6.00(s,2H),5.21(s,2H),5.09(s,2H),4.54(s,1H),4.23(s,2H),4.13(s,3H),3.55(m,2H),3.27(m,2H),3.08(m,2H),2.80(m,2H).
实施例3:N/-(4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)-2-羟基苯亚甲基)-2-(4-((3-(4-((4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):792;1H NMR(DMSO-d6):δ8.30(s,1H),8.08(d,2H),7.67(d,3H),7.59(s,1H),7.18(m,2H),7.05(m,2H),6.93(m,3H),6.58(s,2H),6.01(s,2H),5.21(s,2H),5.11(d,2H),4.55(s,1H),4.25(s,2H),4.16(d,3H),3.59(m,2H),3.29(m,2H),3.13(m,2H),2.86(m,2H).
实施例4:N/-(2-羟基-4-苄氧基苯基亚甲基)-2-(4-((3-(4-((4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
步骤I:2-羟基-4-苄氧基苯甲醛的制备
合成路线3
将2,4-二羟基苯甲醛与氯苄反应,即可得到2-羟基-4-苄氧基苯甲醛,如合成路线3所示,具体制备方法如下:
将50g(0.362mol)2,4-二羟基苯甲醛,59.3g(0.471mol)氯苄,34.7g(0.413mol)碳酸氢钠,12g(0.0724mol)碘化钾加入乙腈中,回流反应30h。反应毕,将反应液倒入水中,析出固体,抽滤,水洗滤饼,干燥。用甲醇重结晶,得白色固体54g,收率66%,MS[MH+](m/z):228。
再按照实施例1的方法制备得到实施例4化合物。
MS[MH+](m/z):667;1H NMR(DMSO-d6):δ8.27(s,1H),8.04(d,2H),7.63(d,3H),7.33(m,7H),7.07(d,2H),6.55(m,2H),5.21(s,2H),5.08(d,2H),4.53(s,1H),4.13(s,3H),3.52(m,2H),3.28(m,2H),3.06(m,2H),2.84(m,2H).
按照实施例1的方法,首先以4-氯甲基苯腈和适合的取代苯酚为起始原料,经六步反应,制备得到噁二唑基哌嗪乙酰肼类衍生物A-VII;之后再与按照步骤I的方法制备得到的适合的醛反应,制备得到实施例5~17的化合物。
实施例5:N/-(2-羟基-4-(2,4-二氯苄氧基)-苯基亚甲基)-2-(4-((3-(4-((4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):720;1H NMR(DMSO-d6):δ8.29(s,1H),8.04(d,2H),7.59(m,5H),7.47(t,1H),7.11(t,2H),7.02(m,2H),6.55(m,2H),5.18(m,4H),4.54(s,1H),4.19(s,3H),3.56(m,2H),3.31(m,2H),3.12(m,2H),2.88(m,2H).
实施例6:N/-(2-羟基-4-(3-三氟甲基苄氧基)苯基亚甲基)-2-(4-((3-(4-((4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):718;1H NMR(DMSO-d6):δ8.29(s,1H),8.04(d,2H),7.80(m,2H),7.63(m,5H),7.13(t,2H),7.06(m,2H),6.60(m,2H),5.19(s,4H),4.54(s,1H),4.20(s,3H),3.56(m,2H),3.31(m,2H),3.13(m,2H),2.89(m,2H).
实施例7:N/-(2-羟基-4-(4-叔丁基苄氧基)苯基亚甲基)-2-(4-((3-(4-((4-氯苯氧基)甲基)苯 基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):723;1H NMR(DMSO-d6):δ8.27(s,1H),8.04(d,2H),7.63(d,2H),7.34(m,6H),7.04(d,2H),6.56(m,2H),5.21(s,2H),5.04(d,2H),4.52(s,1H),4.13(s,3H),3.53(m,2H),3.34(m,2H),3.06(m,2H),2.80(m,2H),1.28(s,9H).
实施例8:N/-(2-羟基-4-(2,4-二氯苄氧基)苯基亚甲基)-2-(4-((3-(4-((4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):736.
实施例9:N/-(2-羟基-4-(4-叔丁基苄氧基)苯基亚甲基)-2-(4-((3-(4-((4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):706.
实施例10:N/-(2-羟基-4-苄氧基苯基亚甲基)-2-(4-((3-(4-((3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):669;1H NMR(DMSO-d6):δ8.41(s,1H),8.03(d,2H),7.62(d,2H),7.33(m,7H),7.15(m,1H),6.85(d,1H),6.50(m,2H),5.20(s,2H),5.11(s,2H),3.99(s,2H),3.31(s,1H),3.09(s,1H),2.62(m,8H).
实施例11:N/-(2-羟基-4-(4-氯苄氧基)苯基亚甲基)-2-(4-((3-(4-((3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):703;1H NMR(DMSO-d6):δ8.28(s,1H),8.04(d,2H),7.66(d,3H),7.46-7.32(m,5H),7.15(m,1H),6.87(m,1H),6.54(m,2H),5.21(s,2H),5.08(d,2H),4.53(s,1H),4.15(s,3H),3.54(m,2H),3.27(m,2H),3.11(m,2H),2.81(m,2H).
实施例12:N/-(2-羟基-4-(2,4-二氯苄氧基)苯基亚甲基)-2-(4-((3-(4-((3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):738.
实施例13:N/-(2-羟基-4-(4-叔丁基苄氧基)苯基亚甲基)-2-(4-((3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):757;1H NMR(DMSO-d6):δ8.28(s,1H),8.06(d,2H),7.62(m,5H),7.34(m,5H),7.10(t,1H),6.53(m,2H),5.38(s,2H),5.03(d,2H),4.54(s,1H),4.18(s,3H),3.55(m,2H),3.39(m,2H),3.30(m,2H),3.10(m,2H),1.27(s,9H).
实施例14:N/-(2-羟基-4-(3-氟苄氧基)苯基亚甲基)-2-(4-((3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):718.
实施例15:N/-(2-羟基-5-(3-氯苄氧基)苯基亚甲基)-2-(4-((3-(4-((4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):702.
实施例16:N/-(2-羟基-5-苄氧基苯基亚甲基)-2-(4-((3-(4-((3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):669;1H NMR(DMSO-d6):δ8.45(s,1H),8.03(t,2H),7.61(t,2H),7.41(m,2H),7.36(m,3H),7.30(m,1H),7.20(m,1H),7.19(d,1H),6.97(m,3H),5.19(s,2H),5.03(s,2H),3.97(d,2H),3.09(s,1H),2.94(s,1H),2.60(m,8H).
实施例17:N/-(2-羟基-5-(4-氯苄氧基)苯基亚甲基)-2-(4-((3-(4-((4-氯苯氧基)甲基)苯基)-1,2,4- 噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):702;1H NMR(DMSO-d6):δ8.44(s,1H),8.01(t,2H),7.60(t,2H),7.46(d,1H),7.35(m,3H),7.32(d,2H),7.16(d,1H),7.12(d,2H),7.03(d,1H),6.81(d,1H),5.19(s,2H),5.04(s,2H),3.98(d,2H),3.33(s,1H),3.08(s,1H),2.59(m,8H).
实施例18:N/-(2-羟基-3-烯丙基苯基亚甲基)-2-(4-((3-(4-((4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
步骤J:2-羟基-3-烯丙基苯甲醛的制备
首先将邻羟基苯甲醛与3-溴丙烯反应,得到中间体J-A,再于高温条件下进行重排反应,得到2-羟基-3-烯丙基苯甲醛,如合成路线4所示,具体制备方法如下:
合成路线4
将290g(2.38mol)邻羟基苯甲醛溶于DMF中,加入493g(3.57mol)K2CO3,之后滴加346g(2.86mol)3-溴丙烯,60℃反应15h,滤去不溶物,滤液倒入500ml CH2Cl2中,有机相依次用5%NaOH水溶液、饱和食盐水和水洗,无水Na2SO4干燥,减压浓缩,得黄色油状物317g,收率82.3%。将317g(1.96mol)2-烯丙氧基苯甲醛于200℃反应4小时,反应完毕,减压蒸馏得黄色油状物3-烯丙基-2-羟基苯甲醛200g,收率63%,MS[MH+](m/z):162。
再按照实施例1的方法制备得到实施例18化合物。
MS[MH+](m/z):601;1H NMR(DMSO-d6):δ8.50(s,1H),8.05(d,2H),7.64(d,2H),7.35(m,3H),7.19(d,1H),7.06(d,2H),6.90(m,1H),5.95(m,1H),5.22(s,2H),5.02(m,2H),4.11(m,3H),3.43(m,3H),3.39-2.85(m,8H).
按照实施例1的方法,首先以4-氯甲基苯腈和适合的取代苯酚为起始原料,经六步反应,制备得到噁二唑基哌嗪乙酰肼类衍生物A-VII;之后再与按照步骤J的方法制备得到的适合的醛反应,制备得到实施例19~23的化合物。
实施例19:N/-(2-羟基-3-烯丙基苯基亚甲基)-2-(4-((3-(4-((4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):585;1H NMR(DMSO-d6):δ8.47(s,1H),8.01(m,2H),7.62(d,2H),7.23(d,1H),7.11(m,3H),7.02(m,2H),6.87(t,1H),5.92(m,1H),5.18(s,2H),5.00(m,2H),4.00(s,2H),3.37(m,2H),3.13(s,2H),2.64(m,8H).
实施例20:N/-(2-羟基-3-烯丙基苯基亚甲基)-2-(4-((3-(4-((3-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):601;1H NMR(DMSO-d6):δ8.48(s,1H),8.05(d,2H),7.64(d,2H),7.30(t,2H),7.19(m,1H),7.13(d,1H),7.00(d,2H),6.87(t,1H),5.95(m,1H),5.24(s,2H),5.02(m,2H),4.61(s,1H),4.17(s,3H),3.54-2.87(m,10H).
实施例21:N/-(2-羟基-3-烯丙基苯基亚甲基)-2-(4-((3-(4-((2-(三氟甲基)苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):635;1H NMR(DMSO-d6):δ8.48(s,1H),8.04(d,2H),7.60(m,5H),7.31(m,1H),7.17(m,1H),7.08(m,1H),6.85(m,1H),5.88(m,1H),5.36(s,2H),5.00(m,2H),4.60(s,1H),4.16(d,3H),3.54-2.91(m,10H).
实施例22:N/-(2-羟基-3-(2-甲基烯丙基)苯基亚甲基)-2-(4-((3-(4-((4-氟苯氧基)甲基)苯 基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):599;1H NMR(DMSO-d6):δ8.50(s,1H),8.04(d,2H),7.63(d,2H),7.16-7.02(m,6H),6.90(m,1H),5.19(s,2H),4.75(m,1H),4.56(m,2H),4.17(d,3H),3.54-2.88(m,10H),1.67(s,3H).
实施例23:N/-(2-羟基-3-(2-甲基烯丙基)苯基亚甲基)-2-(4-((3-(4-((3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
MS[MH+](m/z):617;1H NMR(DMSO-d6):δ8.52(s,1H),8.04(d,2H),7.63(d,2H),7.32(m,2H),7.15(m,2H),6.86(m,2H),5.64(br,1H),5.20(s,2H),4.75(m,1H),4.55(d,2H),4.18(d,3H),3.57-3.03(m,10H),1.678(s,3H).
实施例24:N/-(2-羟基-(5-(2-苄基噻唑-4-基)苯基亚甲基)-2-(4-((3-(4-((3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
步骤K:2-羟基-5-(2-苄基-噻唑-4-基)苯甲醛的制备
合成路线5
首先将苯乙腈与硫氢化钠反应,得到中间体K-A;再将邻羟基苯甲醛与氯乙酰氯反应,得到中间体K-B;最后将K-A与K-B反应,得到2-羟基-5-(2-苄基-噻唑-4-基)苯甲醛,如合成路线5所示,具体制备方法如下:
步骤K-1:2-苯基硫代乙酰胺的制备
将6g(0.1070mol)硫氢化钠,溶于水中,加入100ml的DMF和10.8g(0.0530mol)六水氯化镁,室温搅拌10分钟,加入10g(0.085mol)苯乙腈,室温反应0.5h。反应液倒入冰水中,析出黄色固体,抽滤,盐酸水溶液和水分别洗滤饼,干燥,得淡黄色固体8.2g,收率64%,MS[MH+](m/z):151。
步骤K-2:2-羟基-5-(2-氯乙酰基)苯甲醛的制备
首先将三氯化铝加入二氯甲烷中,之后滴加11.3g(0.1mol)乙酰氯,回流0.5h,分批向反应液中加入12.2g(0.1mol)水杨醛,继续回流16h,冷却,将反应液倒入冰水中,二氯甲烷萃取,水洗有机层,无水硫酸钠干燥,减压浓缩,得固体产品10.5g,收率53%,MS[MH+](m/z):199。
步骤K-3:2-羟基-5-(2-苄基-噻唑-4-基)苯甲醛的制备
将10.5g(0.05mol)2-羟基-5-(2-苄基-噻唑-4-基)苯甲醛和7.5g(0.05mol)2-苯基硫代乙酰胺溶于乙腈中,回流反应4h,有固体析出,冷却后抽滤,水洗滤饼,得淡黄色固体9.7g,收率69%MS[MH+](m/z):282。
再按照实施例1的方法制备得到实施例24化合物。
MS[MH+](m/z):736;1H NMR(DMSO-d6):δ8.42(s,1H),8.22(dd,1H),8.05(m,2H),7.84(dd,1H),7.79(d,1H),7.63(t,2H),7.34(m,5H),7.26(m,1H),7.17(m,1H),7.00(m,1H),6.87(d, 1H),5.21(s,2H),4.63(s,1H),4.38(d,2H),4.15(s,3H),3.58(m,2H),3.31(m,2H),3.10(m,2H),2.80(m,2H).
实施例25:N/-(2-羟基-(5-(2-苄基噻唑-4-基)苯基亚甲基)-2-(4-((3-(4-((4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
按照实施例24的方法,制备得到实施例25化合物。
MS[MH+](m/z):734;1H NMR(DMSO-d6):δ8.39(s,1H),8.23(s,1H),8.02(d,2H),7.77(m,2H),7.61(d,2H),7.33(m,5H),7.26(s,1H),7.03(d,2H),6.98(m,1H),5.19(s,2H),4.62(s,1H),4.36(d,2H),4.14(d,2H),3.56(m,2H),3.29(m,2H),3.11(m,2H),2.79(m,2H).
实施例26:N/-(2-羟基-1-萘基亚甲基)-2-(4-((3-(4-((4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
按照实施例1的方法,选用商购的2-羟基-1-萘甲醛,制备得到实施例26化合物。
MS[MH+](m/z):611.
实施例27:N/-((2-羟基-3-甲基-6-异丙基)苯基亚甲基)-2-(4-((3-(4-((3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
步骤L:2-羟基-3-甲基-6-异丙基苯甲醛的制备
将2g(0.013mol)2-甲基-5-异丙基苯酚、2.5g(0.026mol)氯化镁、1.2g(0.04mol)多聚甲醛和3.7ml(0.026mol)三乙胺加入乙腈中回流8h,反应毕稍冷,将反应液倒入水中,稀盐酸调pH至2~3,乙醚萃取,无水硫酸钠干燥,减压蒸干,得白色固体1.3g,收率58%,MS[MH+](m/z):175。
再按照实施例1的方法制备得到实施例27化合物。
MS[MH+](m/z):619;1H NMR(DMSO-d6):δ8.95(s,1H),8.05(d,2H),7.64(d,2H),7.33(m,1H),7.17(m,2H),6.87(m,1H),6.76(m,1H),5.21(s,2H),4.60(s,1H),4.16(m,3H),3.55(m,2H),3.32(m,2H),3.19(m,1H),3.11(m,2H),2.85(m,2H),2.12(d,3H),1.19(t,6H).
实施例28:N/-((4-甲基-7-羟基-2-氧代-2H-色烯-6-基)亚甲基)-2-(4-((3-(4-((3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼盐酸盐
步骤M:4-甲基-7-羟基-2-氧代-2H-色烯-6-甲醛的制备
将17.6g(0.1mol)4-甲基-7-羟基-2H-色烯-2-酮、42g(0.3mol)乌洛托品依次加入10ml三氟乙酸中,100℃反应3h,反应毕,冷却后将反应液倒入水中,乙醚萃取。有机层用氯化钠饱和溶液洗2-3次,无水硫酸镁干燥,减压浓缩。残余物溶物50%甲醇,之后加入13.8g(0.1mol)碳酸钾,室温继续反应1h,用稀盐酸调pH2-3,乙酸乙酯萃取,有机层用氯化钠饱和溶液洗2-3次,无水硫酸镁干燥,减压浓缩,得白色固体9.8g,收率48%,MS[MH+](m/z):204。
再按照实施例1的方法制备得到实施例28化合物。MS[MH+](m/z):645.
本发明产物的药理研究
对按照本发明的上式Ⅰ的化合物进行了体外抑制人白血病细胞株HL-60,人前列腺癌细胞DU145,人肺腺癌细胞A549,人结肠癌细胞Colon205,人肺癌细胞NCI-H226,人肝癌细胞Hep3B,人胃癌细胞HGC-27,人肝癌细胞HepG2,人乳腺癌细胞MCF-7,人脑胶质瘤细胞U87活性筛选,对照品N/-((2-羟基-3-烯丙基)苯基亚甲基)-2-(4-苄基哌嗪-1-基)乙酰肼(PAC-1)按照专利WO2006128173所述方法制备得到。
(1)细胞复苏并传代2-3次稳定后,用胰蛋白酶溶液(0.25%)使其从培养瓶底部消化下来。将细胞消化液倒入离心管中后,之后加入培养液以终止消化。将离心管在800r/min下 离心10min,弃去上清液后加入5mL培养液,吹打混匀细胞,吸取10μL细胞混悬液加入细胞计数板中计数,调整细胞浓度为104个/孔。96孔板中除A1孔为空白孔不加细胞外,其余皆加入100μL细胞混悬液。将96孔板放入培养箱中培养24h。
(2)用50μL二甲基亚砜溶解受试样品,然后加入适量培养液,使样品溶解成2mg/mL药液,然后在24孔板中将样品稀释为20,4,0.8,0.16,0.032μg/mL。
每个浓度加入3孔,其中周围两行两列细胞长势受环境影响较大,只作为空白细胞孔使用。将96孔板放入培养箱中培养72h。
(3)将96孔板中带药培养液弃去,用磷酸缓冲溶液(PBS)将细胞冲洗两遍,在每孔中加入MTT(四氮唑)(0.5mg/mL)100μL放入培养箱中4h后,弃去MTT溶液,加入二甲基亚砜100μL。在磁力振荡器上振荡使存活细胞与MTT反应产物甲臜充分溶解,放入酶标仪中测定结果。通过Bliss法可求出药物IC50值。
化合物的抑制多种肿瘤细胞株活性结果见表2。
表2实施例化合物体外抗肿瘤活性
从上述试验结果可以清楚地看出,本发明所要保护的通式Ⅰ的化合物,具有良好的体外抗肿瘤活性,因此本发明的化合物具有很好的工业应用前景。
Claims (7)
1.通式Ⅰ的化合物,及其几何异构体或其药学上可接受的盐,
其中,
Ar1为苯基,苯甲基,且Ar1任选1-3个R2取代;
R2为氢,卤素,三氟甲基,烯丙基,2-甲基烯丙基;
R1为苯基,萘基,,且R1任选1-3个R3取代;
R3为氢,羟基,C1-C4烷基,C1-C4烯基,苯基甲氧基,5-10元杂芳基C0-C2烷基,5-10元杂芳基甲氧基,所述杂芳基含有1-3个选自O、N和S的杂原子,且所述苯基和杂芳基任选1-3个R4取代;
R4为氢,卤素,三氟甲基,C1-C4烷基,C1-C3亚烷基二氧基,苯甲基。
2.权利要求1的通式Ⅰ化合物,及其几何异构体或其药学上可接受的盐,
其中,
Ar1为苯基,且Ar1任选1-3个R2取代;
R2为卤素,三氟甲基;
R1为苯基,萘基,,且R1任选1-3个R3取代;
R3为氢,羟基,C1-C4烷基,烯丙基,2-甲基烯丙基,苯基甲氧基,4-噻唑基,4-噻唑基甲氧基,且所述苯基和噻唑基任选1-3个R4取代;
R4为氢,卤素,三氟甲基,C1-C4烷基,C1-C3亚烷基二氧基,苯甲基。
3.噁二唑基哌嗪衍生物选自:
N/-(2-羟基-4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)苯基亚甲基)-2-((4-((3-(4-((2-三氟甲基)苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-苄氧基苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(2,4-二氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(3-三氟甲基苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(4-叔丁基苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(2,4-二氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(4-叔丁基苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-苄氧基苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(4-氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(2,4-二氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯基亚甲基)-2-((4-((3-(4-(3-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-(2-甲基烯丙基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-(2-甲基烯丙基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(4-叔丁基苄氧基)苯基亚甲基)-2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯亚甲基)-2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(3-甲基-2-羟基-6-异丙基苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(3-氟苄氧基)苯基亚甲基)-2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(3-氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-苄氧基苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(4-氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(2-苄基噻唑-4-基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(2-苄基噻唑-4-基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼。
4.噁二唑基哌嗪衍生物选自:
N/-(2-羟基-3-烯丙基苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-((2-((苯并[d][1,3]二氧戊环-5-基)甲基)噻唑-4-基)甲氧基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-苄氧基苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(4-氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯基亚甲基)-2-((4-((3-(4-(3-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-(2-甲基烯丙基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-(2-甲基烯丙基)苯基亚甲基)-2-((4-((3-(4-(4-氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-4-(4-叔丁基苄氧基)苯基亚甲基)-2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-3-烯丙基苯亚甲基)-2-((4-((3-(4-(2-三氟甲基苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(3-甲基-2-羟基-6-异丙基苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-苄氧基苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(4-氯苄氧基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(2-苄基噻唑-4-基)苯基亚甲基)-2-((4-((3-(4-(4-氯苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼;
N/-(2-羟基-5-(2-苄基噻唑-4-基)苯基亚甲基)-2-((4-((3-(4-(3,4-二氟苯氧基)甲基)苯基)-1,2,4-噁二唑-5-基)甲基)哌嗪-1-基)乙酰肼。
5.一种药用组合物,包含权利要求1-4中任何一项的化合物,及其几何异构体或其药学上可接受的盐作为活性成分以及药学上可接受的赋型剂。
6.权利要求1-4中任何一项的化合物,及其几何异构体或其药学上可接受的盐在制备治疗和/或预防各种癌症疾病的药物中的应用。
7.权利要求6所述的应用,其特征在于:所述的癌症选自白血病、肺癌、肝癌、前列腺癌、结肠癌、胃癌、乳腺癌、脑胶质瘤。
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CN102643252B (zh) * | 2012-04-17 | 2014-06-25 | 沈阳药科大学 | 含哌嗪乙酰肼的双芳基脲类衍生物及其应用 |
CN103864797A (zh) * | 2012-12-10 | 2014-06-18 | 韩冰 | 一类具有神经保护作用的化合物及其用途 |
CN103622965B (zh) * | 2013-12-10 | 2016-03-16 | 沈阳药科大学 | 噁二唑基哌嗪化合物在制备抗血管新生药物中的用途 |
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