CN114524776A - 一种四氮唑类化合物及其应用 - Google Patents
一种四氮唑类化合物及其应用 Download PDFInfo
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- CN114524776A CN114524776A CN202210177099.7A CN202210177099A CN114524776A CN 114524776 A CN114524776 A CN 114524776A CN 202210177099 A CN202210177099 A CN 202210177099A CN 114524776 A CN114524776 A CN 114524776A
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- compound
- substituted
- tetrazole compound
- arh
- tetrazole
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- -1 Tetrazole compound Chemical class 0.000 title claims abstract description 44
- 108010080146 androgen receptors Proteins 0.000 claims abstract description 25
- 102000001307 androgen receptors Human genes 0.000 claims abstract description 25
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 18
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 18
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract 6
- 150000001875 compounds Chemical class 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 13
- 239000003112 inhibitor Substances 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims 3
- 230000000694 effects Effects 0.000 abstract description 14
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 84
- 238000000034 method Methods 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 238000012512 characterization method Methods 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- KQNBRMUBPRGXSL-UHFFFAOYSA-N 1-(bromomethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1 KQNBRMUBPRGXSL-UHFFFAOYSA-N 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 17
- 150000003536 tetrazoles Chemical class 0.000 description 14
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- YJQCIRAPWYWUSZ-UHFFFAOYSA-N 5-(4-chlorophenyl)-1-hydroxytetrazole Chemical compound ON1N=NN=C1C1=CC=C(Cl)C=C1 YJQCIRAPWYWUSZ-UHFFFAOYSA-N 0.000 description 5
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- IOOWNWLVCOUUEX-WPRPVWTQSA-N 2-[(3r,6s)-2-hydroxy-3-[(2-thiophen-2-ylacetyl)amino]oxaborinan-6-yl]acetic acid Chemical compound OB1O[C@H](CC(O)=O)CC[C@@H]1NC(=O)CC1=CC=CS1 IOOWNWLVCOUUEX-WPRPVWTQSA-N 0.000 description 2
- DNTVJEMGHBIUMW-IBGZPJMESA-N 3-[[4-[(1s)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)pyrazol-1-yl]ethyl]benzoyl]amino]propanoic acid Chemical compound C1([C@H](C)N2N=C(C=C2C2=CC3=CC=C(C=C3C=C2)OC)C=2C=C(Cl)C=C(Cl)C=2)=CC=C(C(=O)NCCC(O)=O)C=C1 DNTVJEMGHBIUMW-IBGZPJMESA-N 0.000 description 2
- XLWSBDFQAJXCQX-UHFFFAOYSA-N 4-(bromomethyl)-1,2-dichlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1Cl XLWSBDFQAJXCQX-UHFFFAOYSA-N 0.000 description 2
- WCDLCPLAAKUJNY-UHFFFAOYSA-N 4-[4-[3-(1h-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl]phenyl]morpholine Chemical compound C1COCCN1C1=CC=C(C2=CN3N=CC(=C3N=C2)C2=CNN=C2)C=C1 WCDLCPLAAKUJNY-UHFFFAOYSA-N 0.000 description 2
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- RINSMVSYCNNAGC-UHFFFAOYSA-N [bromo(difluoro)methyl]benzene Chemical compound FC(F)(Br)C1=CC=CC=C1 RINSMVSYCNNAGC-UHFFFAOYSA-N 0.000 description 1
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 1
- 229960000853 abiraterone Drugs 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- FWNJUSYYKZFUQB-UHFFFAOYSA-M bis(4-chlorophenyl)iodanium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.C1=CC(Cl)=CC=C1[I+]C1=CC=C(Cl)C=C1 FWNJUSYYKZFUQB-UHFFFAOYSA-M 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000005773 cancer-related death Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N hydroxylamine hydrochloride Substances Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- IIXGBDGCPUYARL-UHFFFAOYSA-N hydroxysulfamic acid Chemical compound ONS(O)(=O)=O IIXGBDGCPUYARL-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- MLZHFIUNOLFOTK-UHFFFAOYSA-N n-(5-chloropyridin-2-yl)quinoxaline-6-carboxamide Chemical compound N1=CC(Cl)=CC=C1NC(=O)C1=CC=C(N=CC=N2)C2=C1 MLZHFIUNOLFOTK-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MRIAQLRQZPPODS-UHFFFAOYSA-N nobiletin Chemical compound C1=C(OC)C(OC)=CC=C1C1=CC(=O)C2=C(OC)C(OC)=C(OC)C(OC)=C2O1 MRIAQLRQZPPODS-UHFFFAOYSA-N 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明提供了一种四氮唑类化合物及其应用,所述四氮唑类化合物的结构式I所示:其中Ar1选自取代或未取代的苯环、取代或未取代的杂环,Y选自C、O或N中任意一种,Z选自卤素;环A选自取代或未取代的苯环、取代或未取代的杂环、取代或未取代的C3‑C7脂肪环。本发明提供的四氮唑类化合物能够有效抑制雄激素受体,抑制效果好,具备潜在的前列腺癌治疗效果。
Description
技术领域
本发明属于药化领域,具体涉及一种四氮唑类化合物及其应用,尤其涉及一种活性高的四氮唑类化合物及其应用。
背景技术
前列腺癌(PCa)是男性癌症相关死亡的主要原因。雄激素受体(AR)是核受体家族的成员,在PCa的发展中起着关键作用。PCa是一种涉及雄激素过多和AR介导的信号通路过度表达的病症,PCa细胞的增殖和存活严重依赖于AR信号。因此,AR已成为治疗PCa的主要治疗靶点,手术或化学阉割的雄激素剥夺疗法是标准治疗方法,大多数患者会得到缓解。不幸的是,这种疾病通常会发展到无法治愈的阶段,称为去势抵抗性前列腺癌(CRPC),而AR持续或重新激活的信号通路加重了病情发展。大多数患者最初受益于第二代疗法,如恩杂鲁胺、阿帕鲁胺和达洛鲁胺,但最终会对它们产生二次耐药。因此,需要新的治疗策略来对抗AR信号通路。
CN111655249A公开了一种雄激素受体信号传导途径的抑制剂和p38抑制剂的药物组合,其用于治疗个体中的前列腺癌,其中前列腺肿瘤细胞表达AR-V7变体雄激素受体蛋白,或用于预防在通过雄激素受体信号传导途径的抑制剂治疗的患有前列腺癌的患者中抵抗性的发生。该发明进一步涉及一种药物组合物,其包含恩杂鲁胺、阿比特龙或阿帕鲁胺和选自LY2228820和ARRY-614的p38抑制剂,以及至少一种药学上可接受的赋形剂。该发明还涉及p38抑制剂用于恢复在用雄激素受体信号传导途径的抑制剂治疗后已获得对雄激素剥夺疗法(ADT)的抵抗性的患有前列腺癌的患者的对雄激素剥夺疗法(ADT)的敏感性的用途,其中前列腺肿瘤细胞表达AR-V7变体雄激素受体蛋白。
CN110327465A公开了一种复方抗前列腺癌药物,所述的药物由多甲氧基黄酮类药物和雄激素受体抑制剂药物组成。多甲氧基黄酮类药物和雄激素受体抑制剂药物的质量比为1:1。其中,所述的多甲氧基黄酮类药物为川陈皮素,所述的雄激素受体抑制剂药物为比卡鲁胺。本发明提供通过将多甲氧基黄酮类药物和雄激素受体抑制剂类抗癌药联合使用,药效明显优于单独用药,对抑制前列腺癌和阻止前列腺癌向恶性发展具有良好的抑制效果;本发明提供的药物使用剂量低,降低单独用药的浓度,从而减少药物的毒副作用,减少对人体的伤害;通过混合使用进一步减小了患者的经济负担,并起到比单独使用更好的效果。
由于目前患者接受第二代疗法后最终导致二次耐药,影响后续治疗。因此,如何提供一种全新的AR信号通路抑制剂,成为了亟待解决的问题。
发明内容
针对现有技术的不足,本发明的目的在于提供一种四氮唑类化合物及其应用,尤其提供一种活性高的四氮唑类化合物及其应用。本发明提供的四氮唑类化合物能够有效抑制雄激素受体,抑制效果好,具备潜在的前列腺癌治疗效果。
为达到此发明目的,本发明采用以下技术方案:
第一方面,本发明提供了一种四氮唑类化合物,所述四氮唑类化合物的结构如式I所示:
Y选自C、O或N中任意一种,Z选自卤素。
环A选自取代或未取代的苯环、取代或未取代的C4-C7的杂环、取代或未取代的C3-C7脂肪环。
所述卤素选自氟、氯、溴或碘中任意一种。
所述杂环选自噻吩、吡啶或吡唑中任意一种。
所述C3-C7脂肪环选自环丙烷、环丁烷、环戊烷、环己烷或环庚烷中任意一种。
所述C4-C7的杂环选自哒嗪、吡啶或噻吩中任意一种。
上述特定结构的化合物能够有效抑制雄激素受体,具有显著的抑制效果。
优选地,所述取代的取代基选自卤素、卤素取代或未取代的C1-C6烷基、卤素取代或未取代的C1-C6烷氧基中任意一种。
所述C1-C6烷基例如可以是甲基、乙基、丙基、异丙基、正丁基、正戊基或正己基等,C1-C6烷氧基例如可以是甲氧基、乙氧基、丙氧基或异丙氧基等。
优选地,所述取代的取代基选自卤素。
优选地,所述Ar1选自取代或未取代的苯环。
优选地,所述Ar1选自取代的苯环。
优选地,所述Y选择O。
当Y选自O时,所述四氮唑类化合物可以示例性的由包括以下步骤的方法制备得到:将化合物与HONH2盐酸盐反应,得到化合物之后在盐酸条件下于乙腈溶液中与N-氯代丁二酰亚胺反应,得到化合物接着在苯中与NaN3反应得到化合物之后与CH3COCl在苯中反应得到中间体最后将中间体分别与 反应,得到所述四氮唑类化合物。
其中Ar1、Z、环A具有与如上所述相同的范围。
第二方面,本发明提供了如上所述的四氮唑类化合物在制备雄激素受体抑制剂中的应用。
第三方面,本发明还提供了如上所述的四氮唑类化合物在制备前列腺癌治疗药物中的应用。
与现有技术相比,本发明具有如下有益效果:
本发明提供了一种特定结构的四氮唑类化合物,其对于雄激素受体具有显著的抑制效果,能够用于制备雄激素受体抑制剂以及前列腺癌治疗药物。
具体实施方式
为更进一步阐述本发明所采取的技术手段及其效果,以下结合本发明的优选实施例来进一步说明本发明的技术方案,但本发明并非局限在实施例范围内。
实施例1
本实施例提供了一种四氮唑类化合物1,具体结构如下:
制备步骤如下:
(1)取盐酸羟胺(10.42g,150mmol)加入到搅拌着的4-氯苯甲醛(7.0g,50mmol)、乙酸钠(24.6g,150mmol)和无水乙醇(300mL)混合物中,然后回流加热2小时。减压除去溶剂,将残余物倒入水中,用乙酸乙酯萃取。有机相用无水硫酸钠干燥。减压除去溶剂,得到(E)-4-氯苯甲醛肟(7.7g,49.5mmol,99%);
(2)在搅拌的(E)-4-氯苯甲醛肟(7.7g,49.5mmol)的40mL乙腈(含有5滴浓盐酸)混合溶液中,以保持在每次后续添加之前蓝绿色褪色的速率,分批加入N-氯代琥珀酰亚胺,将溶液静置30分钟。加入80mL水,用苯(2×40mL)萃取。将合并的有机相干燥、过滤,得到alpha-4-二氯苯甲醛肟;
(3)叠氮化钠(6.5g,0.1mol)溶于水(35mL)中,缓慢加入到在冰浴下搅拌的alpha-4-二氯苯甲醛肟的苯溶液中。混合物在室温下搅拌48小时。将有机相用水洗涤(2×100mL),用硫酸钠干燥并迅速用于下一步反应(得到alpha-叠氮基-4-氯苯甲醛肟);
(4)将含有alpha-叠氮基-4-氯苯甲醛肟的苯溶液缓慢加入到在冰浴下搅拌的含过量乙酰氯(20mL)的苯(20mL)溶液中。添加完成后,将反应混合物缓慢升温至室温并静置48小时。将混合物部分蒸发(至30mL),用水(10mL)小心稀释,并在60℃下搅拌2小时。将所得混合物冷却至室温,加入冰水(100mL)稀释,用乙醚(100mL)萃取。将有机相用水洗涤,然后用饱和碳酸氢钠(2×100mL)萃取。合并碳酸氢钠萃取液,用浓盐酸酸化至pH=1。过滤得固体,滤饼用水洗涤并干燥,得到5-(4-氯苯基)-1-羟基四氮唑;
(5)将5-(4-氯苯基)-1-羟基四氮唑(500mg,2.55mmol)、1-(溴甲基)-4-氯苯(498mg,2.42mmol)、碳酸钾(769mg,5.86mol)加入到乙腈(10mL)中,在室温下搅拌过夜。旋干溶剂,向残余物中加入水(20mL),用乙酸乙酯(3×50mL)萃取。合并有机相,用饱和食盐水(20mL)洗涤,干燥并蒸发。将粗物质通过色谱法在硅胶上提纯,接着用DCM和石油醚重结晶,得到化合物1,产率82%。
表征数据如下:
M.p.216℃。
1HNMR(400MHz,CDCl-d6)7.18(2H,d,J 8.44Hz,ArH),7.44(2H,d,J 8.6Hz,ArH),7.18(2H,d,J 8.4Hz,ArH),7.06–7.23(2H,d,J 8.48,ArH),5.39(2H,benzylic CH2)。13CNMR(150MHz,DMSO-d6)155.09,151.60,141.04,137.16,133.06,129.29,128.50,126.83,123.88,123.33,119.36,113.16,53.83,44.10,42.10,35.95,13.09,11.55。HRMS(ESI):m/zcalcd for C20H24N5O2 32S:398.1651[M+H]+;found:398.1657。
实施例2
本实施例提供了一种四氮唑类化合物2,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-(溴甲基)-3-氯苯外,其余与实施例1一致。
最终得到化合物2,产率88%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.81-7.74(2H,m,ArH),7.48-7.41(2H,m,ArH),7.31-7.25(1H,m,ArH),7.19-7.12(2H,m,ArH),6.98-6.99(1H,m,ArH),5.39(2H,s)。13C NMR(150MHz,CDCl3)146.76,138.26,134.91,132.81,130.51,130.35,130.24,129.44,129.33,128.23,120.38,82.63。HRMS(ESI):m/z calcd for C14H10Cl2N4O:320.0232[M+H]+;found:321.17。
实施例3
本实施例提供了一种四氮唑类化合物9a,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-(溴甲基)-4-氟苯外,其余与实施例1一致。
最终得到化合物9a,产率51%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.81-7.79(2H,m,ArH),7.49-7.42(2H,m,ArH),7.19-7.11(2H,m,ArH),6.91-6.85(2H,m,ArH),5.41(2H,s)。13C NMR(150MHz,CDCl3)164.95,162.96,146.83,138.21,132.58,132.51,129.44,129.36,127.00,126.98,120.62,116.21,116.21,116.04,82.80。19F NMR spectrum for 9a(376MHz;CDCl3)109.49。HRMS(ESI):m/z calcdfor C14H10ClFN4O:304.0527[M+H]+;found:305.18。
实施例4
本实施例提供了一种四氮唑类化合物9b,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-(溴甲基)-3-氟苯外,其余与实施例1一致。
最终得到化合物9b,产率27%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.89-7.81(2H,m,ArH),7.49-7.43(2H,m,ArH),7.29-7.21(1H,m,ArH),7.05-6.97(1H,m,ArH),6.96-6.85(2H,m,ArH),5.43(2H,s)。13C NMR(150MHz,CDCl3)163.74,161.76,146.67,138.30,133.28,133.23,130.78,130.71,129.51,129.36,125.87,125.85,120.51,117.60,117.43,117.22,117.04,82.63。19F NMR spectrum for 9a(376MHz;CDCl3)111.38。HRMS(ESI):m/z calcd for C14H10ClFN4O:304.0527[M+H]+;found:305.19。
实施例5
本实施例提供了一种四氮唑类化合物9c,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-(溴甲基)-4-溴苯外,其余与实施例1一致。
最终得到化合物9c,产率43%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.79-7.75(2H,m,ArH),7.41-7.45(2H,m,ArH),7.38-7.31(2H,m,ArH),7.02-6.97(2H,m,ArH),5.39(2H,s)。13C NMR(150MHz,CDCl3)146.83,138.25,132.24,131.89,129.92,129.43,129.39,125.12,120.55,82.78。HRMS(ESI):m/z calcdfor C14H10BrClN4O:363.9727[M+H]+;found:367.14。
实施例6
本实施例提供了一种四氮唑类化合物9d,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-(溴甲基)-3-溴苯外,其余与实施例1一致。
最终得到化合物9d,产率46%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.75-7.85(2H,m,ArH),7.49-7.42(3H,m,ArH),7.34-7.31(1H,m,ArH),7.12-7.08(1H,m,ArH),7.07-7.01(1H,m,ArH),5.39(2H,s)。13C NMR(150MHz,CDCl3)146.89,138.38,133.54,133.39,133.06,130.51,129.53,129.40,128.74,123.01,120.43,82.65。HRMS(ESI):m/z calcd for C14H10BrClN4O:363.9727[M+H]+;found:367.13。
实施例7
本实施例提供了一种四氮唑类化合物9e,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-(溴甲基)-3,4-二氯苯外,其余与实施例1一致。
最终得到化合物9e,产率70%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.83-7.79(2H,m,ArH),7.51-7.47(2H,m,ArH),7.37-7.31(1H,m,ArH),7.30-7.29(2H,m,ArH),6.99-6.95(1H,m,ArH),5.39(2H,s)。13C NMR(150MHz,CDCl3)146.87,138.49,135.04,133.37,132.21,131.03,130.99,129.51,129.37,129.27,120.31,81.96。HRMS(ESI):m/z calcd for C14H9ClN4O:353.9842[M+H]+;found:357.13。
实施例8
本实施例提供了一种四氮唑类化合物9f,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-溴甲苯外,其余与实施例1一致。
最终得到化合物9f,产率58%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.87(2H),7.43(2H),7.25(2H),7.15(2H),5.41(2H)。13CNMR(125MHz,CDCl3)146.79,138.02,130.94,130.47,130.40,129.37,129.35,128.98,120.66,83.75,77.41,77.16,76.91。HRMS(ESI):m/z calcd for C14H11ClN4O:287.0721[M+H]+;found:287.22。
实施例9
本实施例提供了一种四氮唑类化合物9g,具体结构如下:
制备步骤中除将步骤(1)中的4-氯苯甲醛替换为等量的4-氟苯甲醛外,其余与实施例1一致。
最终得到化合物9g,产率75%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.88(2H),7.15(4H),7.06(2H),5.41(2H)。13C NMR(125MHz,CDCl3)166.65,166.63,146.79,136.64,131.64,130.42,130.35,129.48,129.14,118.30,118.27,116.43,116.25,82.59。HRMS(ESI):m/z calcd for C14H10ClFN4O:304.0527[M+H]+;found:305.17.
实施例10
本实施例提供了一种四氮唑类化合物9h,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-(溴甲基)-3-氯苯外,其余与实施例9一致。
最终得到化合物9h,产率74%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.89(2H),7.28(1H),7.18(4H),7.03(1H),7.01(2H),5.48(2H)。13C NMR(125MHz,CDCl3)165.71,163.69,146.81,134.93,132.90,130.53,130.48,130.41,130.36,130.24,128.25,118.21,118.18,116.55,116.38,82.58。HRMS(ESI):m/zcalcd for C14H10ClFN4O:304.0527[M+H]+;found:304.92。
实施例11
本实施例提供了一种四氮唑类化合物9i,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-(溴甲基)-3,4-二氯苯外,其余与实施例9一致。
最终得到化合物9i,产率70%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.86(2H),7.31(1H),7.27(1H),7.15(2H),6.92(1H),5.48(2H)。13C NMR(125MHz,CDCl3)165.79,163.77,146.87,134.98,133.32,132.19,131.11,130.97,130.49,130.42,129.27,118.12,118.18,118.09,116.60,116.42,81.88。HRMS(ESI):m/z calcd for C14H9Cl2FN4O:338.0137[M+H]+;found:339.15。
实施例12
本实施例提供了一种四氮唑类化合物9j,具体结构如下:
制备步骤中除将步骤(1)中的4-氯苯甲醛替换为等量的3-氯苯甲醛外,其余与实施例1一致。
最终得到化合物9j,产率32%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.84(1H),7.75(1H),7.52(1H),7.46(1H),7.21(2H),7.11(2H),5.48(2H)。13C NMR(125MHz,CDCl3)146.56,136.83,135.14,131.80,131.74,130.38,129.35,129.24,127.96,126.24,123.68,82.85。HRMS(ESI):m/z calcd for C14H10Cl2N4O:320.0232[M+H]+;found:321.16。
实施例13
本实施例提供了一种四氮唑类化合物9k,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-(溴甲基)-3-氯苯外,其余与实施例12一致。
最终得到化合物9k,产率47%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.85(1H),7.76(1H),7.52(1H),7.46(1H),7.30(1H),7.18(2H),7.03(1H),5.48(2H)。13C NMR(125MHz,CDCl3)146.58,135.17,135.00,132.75,131.93,130.61,130.45,130.41,130.26,128.35,128.00,126.18,123.53,82.80。HRMS(ESI):m/z calcd for C14H10Cl2N4O:320.0232[M+H]+;found:321.10。
实施例14
本实施例提供了一种四氮唑类化合物9m,具体结构如下:
制备步骤中除将步骤(1)中的4-氯苯甲醛替换为等量的2,4-二氯苯甲醛、步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-(溴甲基)-3-氯苯外,其余与实施例1一致。
最终得到化合物9m,产率68%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.55(1H),7.30(2H),7.18(1H),7.03(2H),6.88(1H),5.48(2H)。13C NMR(125MHz,CDCl3)146.29,138.62,135.07,134.82,133.11,132.33,130.52,130.36,130.29,130.01,128.15,127.50,120.23,82.37。HRMS(ESI):m/z calcd forC14H9Cl3N4O:353.9842[M+H]+;found:355.07。
实施例15
本实施例提供了一种四氮唑类化合物9n,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-(溴甲基)-3-三氟甲基苯外,其余与实施例1一致。
最终得到化合物9n,产率45%。
表征数据如下:
1H NMR(400MHz,CDCl3)8.25(1H),7.86(2H),7.51(3H),7.27(2H),5.48(2H)。13CNMR(125MHz,CDCl3)146.73,138.41,133.43,132.02,131.96,131.70,131.44,131.18,129.66,129.51,129.40,129.26,127.20,127.04,126.72 124.56,122.39,120.31,120.23,82.57。HRMS(ESI):m/z calcd for C15H10ClF3N4O:354.0495[M+H]+;found:355.15。
实施例16
本实施例提供了一种四氮唑类化合物9q,具体结构如下:
制备步骤中除将步骤(1)中的4-氯苯甲醛替换为等量的4-甲氧基苯甲醛外,其余与实施例1一致。
最终得到化合物9q,产率39%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.98(2H),7.26(1H),7.18(2H),7.02(2H),5.40(2H),3.91(2H)。13C NMR(125MHz,CDCl3)162.33,147.25,136.52,131.62,129.77,129.17,114.52,114.32,82.34,77.41,77.16,76.90,55.62。HRMS(ESI):m/z calcd for C15H13ClN4O2:316.0727[M+H]+;found:317.20。
实施例17
本实施例提供了一种四氮唑类化合物9r,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的1-(溴甲基)-3-氯苯外,其余与实施例16一致。
最终得到化合物9r,产率30%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.89(2H),7.35(1H),7.29(1H),7.11(1H),7.01(2H),5.49(2H),3.91(2H)。13C NMR(125MHz,CDCl3)162.33,147.19,134.82,133.15,130.38,130.18,129.74,128.18,114.57,114.13,82.26,77.41,77.16,76.90,55.58。HRMS(ESI):m/z calcdfor C15H13ClN4O2:317.0827[M+H]+;found:317.20。
实施例18
本实施例提供了一种四氮唑类化合物9t,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的2-(溴甲基)-5-氯噻吩外,其余与实施例1一致。
最终得到化合物9t,产率53%。
表征数据如下:
1H NMR(400MHz,CDCl3)7.82(2H),7.49(2H),6.18(1H),6.14(1H),5.51(2H)。13CNMR(125MHz,CDCl3)147.18,138.25,134.99,131.55,130.97,129.46,129.42,126.63,120.38,77.42,77.16,76.91,76.59。HRMS(ESI):m/z calcd for C12H8Cl2N4O2S:326.9896[M+H]+;found:327.10。
实施例19
本实施例提供了一种四氮唑类化合物9v,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的3-(溴甲基)-6-氯吡啶外,其余与实施例1一致。
最终得到化合物9v,产率49%。
表征数据如下:
1H NMR(500MHz,CDCl3)8.25(1H),7.86(2H),7.50(3H),7.25(1H),5.51(2H)。13CNMR(125MHz,CDCl3)153.68,150.93,146.43,140.19,138.57,129.68,129.24,126.01,124.68,120.22,79.66,77.41,77.16,76.91。HRMS(ESI):m/z calcd for C13H9Cl2N5O:322.0284[M+H]+;found:322.08。
实施例20
本实施例提供了一种四氮唑类化合物9w,具体结构如下:
制备步骤中除将步骤(5)中的1-(溴甲基)-4-氯苯替换为等量的4-(溴甲基)-2-氯吡啶外,其余与实施例1一致。
最终得到化合物9w,产率30%。
表征数据如下:
1H NMR(400MHz,CDCl3)8.41(1H),7.91(2H),7.56(2H),7.29(1H),7.11(1H),5.51(2H)。13C NMR(125MHz,CDCl3)152.27,150.43,146.20,143.06,138.62,129.73,129.23,124.10,121.95,120.02,80.14,77.42,77.16,76.91。HRMS(ESI):m/z calcd forC13H9Cl2N5O:322.1490[M+H]+;found:322.18。
实施例21
本实施例提供了一种四氮唑类化合物11,具体结构如下:
制备方法如下:
(1)将甲基溴化镁(3.0M乙醚溶液,12.05mL,37.5mmol)装入配备有磁力搅拌器的干燥和氮气保护的圆底烧瓶中。加入无水乙醚(10mL),并将搅拌的混合物在冰水浴中冷却至0℃。将4-氯苯乙酮(2.63g,17.0mmol)的乙醚(10mL)溶液通过滴液漏斗逐滴加入。添加完成后,将反应混合物缓慢升温至室温。混合物搅拌过夜,用饱和氯化铵水溶液(30mL)和冰(5mL)淬灭。水相用乙醚(3×50mL)萃取。合并的有机相用硫酸钠干燥,旋干溶剂,得到2-(4-氯苯基)-2-丙醇(2.5g,86%),为无色油状物,无需进一步纯化即可使用;
(2)通过注射器将TFA(0.3mL)滴加至装有5-(4-氯苯基)-1-羟基四氮唑(495mg,2.52mmol,参考实施例1方法制得)和2-(4-氯苯基)-2-丙醇(430mg,2.52mmol)在无水1,2-二氯乙烷(12mL)混合溶液的玻璃封管。用聚四氟乙烯帽密封,并将反应物加热至80℃,搅拌16小时。将混合物转移至分液漏斗,用DCM冲洗,并用碳酸钠水溶液洗涤。收集有机相,用MgSO4干燥,旋干。残余物通过硅胶柱纯化,得到化合物11(123mg,14%),为白色固体。
表征数据如下:
1H NMR(500MHz,CDCl-d6)8.43(2H,d,J 8.6Hz,ArH),7.50(2H,d,J 8.6Hz,ArH),7.35(2H,d,J 8.7Hz,ArH),7.25(2H,d,J 8.7,ArH),2.16(6H,s,2CH3)。
实施例22
本实施例提供了一种四氮唑类化合物12a,具体结构如下:
制备步骤中除步骤(5)为:在0℃下,氮气保护,将5-(4-氯苯基)-1-羟基四氮唑(150mg,,0.84mmol)溶于无水DMF(3mL)中,加入到搅拌的NaH(47mg,1.2mmol)的无水DMF(3mL)悬浮液中。一旦添加完成,将反应混合物缓慢升温至室温。将反应混合物在室温下搅拌15分钟并在冰水浴中重新冷却至0℃。逐滴加入溴二氟甲基苯(207mg,1mmol)的无水DMF(2mL)溶液。反应混合物在室温下搅拌过夜。加入饱和氯化铵水溶液(8mL)并用乙醚(40mL)萃取整个溶液。用水(2×10mL)洗涤有机层,经无水硫酸钠干燥,并在减压下蒸发。残余物通过硅胶色谱纯化,得到白色固体状化合物12a(产率35%)外,其余与实施例1一致。
表征数据如下:
1H NMR(400MHz,CDCl3)7.97-7.94(2H,m,ArH),7.68-7.64(3H,m,ArH),7.59-7.55(4H,m,ArH)。
实施例23
本实施例提供了一种四氮唑类化合物13a,具体结构如下:
制备步骤中除步骤(5)为:5-(4-氯苯基)-1-羟基四氮唑(150mg,0.83mmol)、t-BuOK(1M乙醚溶液,1.9mL,1.9mmol)和乙腈(10mL)的混合物在室温下搅拌5分钟。添加双(4-氯苯基)碘鎓三氟甲磺酸盐(665mg,1.9mmol)并将反应混合物在室温下搅拌过夜。减压蒸发溶剂。粗物质通过硅胶色谱法纯化(3%,乙酸乙酯在石油醚中),得到化合物13a为浅棕色固体(产率18%)外,其余与实施例1一致。
表征数据如下:
1H NMR(500MHz,CDCl3)8.05-8.94(2H,m,ArH),7.55-7.53(2H,m,ArH),7.38-7.35(2H,m,ArH),6.92-6.89(2H,m,ArH)。
实施例24
本实施例提供了一种四氮唑类化合物20,具体结构如下:
制备步骤如下:
(1)将5-苯基四氮唑(500mg,3.42mmol)溶解在70℃碳酸钠水溶液(7.5%,150mL)中,并在剧烈搅拌下,分批加入羟胺-O-磺酸(1.16g,10.3mmol)。将反应混合物在70℃搅拌4小时。将反应混合物冷却至室温,并用EA(3×70mL)萃取。合并有机相,干燥并旋干。残余物通过硅胶色谱纯化,得到1-氨基-5-苯基四氮唑(65mg,12%)为白色固体;
(2)将1-氨基-5-苯基四氮唑(60mg,0.37mmol)、4-氯苯甲酰氯(65.5mg,0.37mmol)和吡啶(1.0mL)加入到密封管中,在120℃下加热6小时。将反应液冷却至室温,减压除去吡啶。残余物通过硅胶色谱纯化,得到化合物20(20mg,18%),为白色固体。
表征数据如下:
1H NMR(500MHz,MeOD)7.96(2H,d,J 8.05Hz,ArH),7.90(2H,d,J 7.3Hz,ArH),7.63-7.56(5H,m,ArH)。
抑制效果研究:
测试实施例1-24化合物对具有ARV7的CRPC细胞(22RV1)(来自中科院上海细胞库)的生物活性。首先消化并铺板22rv1细胞于384孔板内,每孔细胞数1500个,体积20μL,在细胞培养箱培养。24h后加入化合物与细胞共同孵育。化合物母液浓度为10mM,3倍梯度稀释,10个浓度,对照组加入DMSO。细胞培养箱培养72h后检测。检测时,384孔板中每孔加入CellTiter-Glo试剂(普洛麦格),震板10min后在化学发光仪中检测读数。使用GraphpadPrism8软件计算拟合化合物增殖抑制曲线,计算IC50值,结果如下:
以上结果显示本发明提供的化合物对于22RV1具有有效的生长抑制效果,显示出对于雄激素受体的抑制效果,同时比较结果也可以发现,在本发明优选的结构范围内,抑制效果更加明显,IC50能够达到nm级别。
申请人声明,本发明通过上述实施例来说明本发明的四氮唑类化合物及其应用,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
Claims (10)
2.根据权利要求1所述的四氮唑类化合物,其特征在于,所述Ar1选自取代或未取代的苯环。
3.根据权利要求2所述的四氮唑类化合物,其特征在于,所述Ar1选自取代的苯环。
4.根据权利要求1-3中任一项所述的四氮唑类化合物,其特征在于,所述Y选择O。
6.根据权利要求1-5中任一项所述的四氮唑类化合物,其特征在于,所述取代的取代基选自卤素、卤素取代或未取代的C1-C6烷基、卤素取代或未取代的C1-C6烷氧基中任意一种。
7.根据权利要求1-5中任一项所述的四氮唑类化合物,其特征在于,所述取代的取代基选自卤素。
9.一种根据权利要求1-8中任一项所述的四氮唑类化合物在制备雄激素受体抑制剂中的应用。
10.一种根据权利要求1-8中任一项所述的四氮唑类化合物在制备前列腺癌治疗药物中的应用。
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB787582A (en) * | 1953-09-28 | 1957-12-11 | Hoechst Ag | Manufacture of water-insoluble monoazo-dyestuffs of the tetrazole series |
WO1998039309A1 (en) * | 1997-03-06 | 1998-09-11 | Dunlena Pty. Limited | Heterocyclic herbicides |
WO2008042399A2 (en) * | 2006-10-03 | 2008-04-10 | The Trustees Of The University Of Pennsylvania | Method for treatment of macular degeneration |
WO2008080455A1 (de) * | 2006-12-21 | 2008-07-10 | Merck Patent Gmbh | Tetrahydrobenzoisoxazole- und tetrahydroindazole-derivate als modulatoren der mitotische motor-protein |
CN107778262A (zh) * | 2016-08-24 | 2018-03-09 | 尹玉新 | 1,5‑双取代四氮唑类化合物及其制备方法和应用 |
CN109942547A (zh) * | 2019-05-06 | 2019-06-28 | 河南师范大学 | 具有生物活性的新型喹啉取代三氮唑类化合物及其合成方法和应用 |
CN110746398A (zh) * | 2019-10-18 | 2020-02-04 | 刘沛友 | 4-杂环取代喹唑啉类衍生物及其制备方法和用途 |
CN111655249A (zh) * | 2017-11-14 | 2020-09-11 | 蒙彼利埃地区癌症研究所 | 用于治疗前列腺癌的活性物的组合 |
CN113402473A (zh) * | 2021-06-22 | 2021-09-17 | 四川省医学科学院·四川省人民医院 | 硫代三氮唑类化合物、其制备方法及其应用 |
-
2022
- 2022-02-25 CN CN202210177099.7A patent/CN114524776A/zh active Pending
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB787582A (en) * | 1953-09-28 | 1957-12-11 | Hoechst Ag | Manufacture of water-insoluble monoazo-dyestuffs of the tetrazole series |
WO1998039309A1 (en) * | 1997-03-06 | 1998-09-11 | Dunlena Pty. Limited | Heterocyclic herbicides |
WO2008042399A2 (en) * | 2006-10-03 | 2008-04-10 | The Trustees Of The University Of Pennsylvania | Method for treatment of macular degeneration |
US20090247483A1 (en) * | 2006-10-03 | 2009-10-01 | Claire Mitchell | Method for Treatment of Macular Degeneration |
WO2008080455A1 (de) * | 2006-12-21 | 2008-07-10 | Merck Patent Gmbh | Tetrahydrobenzoisoxazole- und tetrahydroindazole-derivate als modulatoren der mitotische motor-protein |
CN107778262A (zh) * | 2016-08-24 | 2018-03-09 | 尹玉新 | 1,5‑双取代四氮唑类化合物及其制备方法和应用 |
CN111655249A (zh) * | 2017-11-14 | 2020-09-11 | 蒙彼利埃地区癌症研究所 | 用于治疗前列腺癌的活性物的组合 |
CN109942547A (zh) * | 2019-05-06 | 2019-06-28 | 河南师范大学 | 具有生物活性的新型喹啉取代三氮唑类化合物及其合成方法和应用 |
CN110746398A (zh) * | 2019-10-18 | 2020-02-04 | 刘沛友 | 4-杂环取代喹唑啉类衍生物及其制备方法和用途 |
CN113402473A (zh) * | 2021-06-22 | 2021-09-17 | 四川省医学科学院·四川省人民医院 | 硫代三氮唑类化合物、其制备方法及其应用 |
Non-Patent Citations (8)
Title |
---|
BURGESS, J. M.,等: "Reaction of w-hydrazinobenzaldehyde arylhydrazones with nitrous acid", 《TETRAHEDRON》, vol. 18, pages 1001 - 1004 * |
CAS: "RN: 2752557-90-5", RN: 2752557-90-5, pages 2752557 - 90 * |
CAS: "RN: 2759703-29-0", RN: 2759703-29-0, pages 2759703 - 29 * |
CAS: "RN:2752716-73-5", RN:2752716-73-5, pages 2752716 - 73 * |
CAS: "RN:2759443-97-3", RN:2759443-97-3, pages 2759443 - 97 * |
MODERHACK, DIETRICH,等: "Tetrazolium N-aminides: complementary studies on synthesis and properties", 《HETEROCYCLES》, vol. 78, no. 10, 31 December 2009 (2009-12-31), pages 2509 - 2522 * |
PLENKIEWICZ, J.,等: "The rearrangement of 1-alkoxy-5-aryltetrazoles to 3-alkyl-5-aryltetrazole-1-oxides", 《POLISH JOURNAL OF CHEMISTRY》, vol. 67, no. 10, 31 December 1993 (1993-12-31), pages 1767 - 1778 * |
郭广柱: "3-(4-氟苯基)-1H-吡唑类雄激素受体拮抗剂的合成及其活性评价", 《山东大学硕士学位论文》 * |
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