CN108358841B - 一类4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物及其制备方法与应用 - Google Patents
一类4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物及其制备方法与应用 Download PDFInfo
- Publication number
- CN108358841B CN108358841B CN201810253238.3A CN201810253238A CN108358841B CN 108358841 B CN108358841 B CN 108358841B CN 201810253238 A CN201810253238 A CN 201810253238A CN 108358841 B CN108358841 B CN 108358841B
- Authority
- CN
- China
- Prior art keywords
- substituted
- amino
- benzoyl hydrazine
- quinolin
- quinoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- -1 4- ((2-substituted quinoline-4-yl) amino) benzoyl hydrazine Chemical class 0.000 title claims abstract description 89
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 102100022679 Nuclear receptor subfamily 4 group A member 1 Human genes 0.000 claims abstract description 21
- 101100405118 Mus musculus Nr4a1 gene Proteins 0.000 claims abstract description 20
- 101100405120 Xenopus laevis nr4a1 gene Proteins 0.000 claims abstract description 20
- 201000011510 cancer Diseases 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 241000282414 Homo sapiens Species 0.000 claims abstract description 10
- 206010061218 Inflammation Diseases 0.000 claims abstract description 8
- 230000004054 inflammatory process Effects 0.000 claims abstract description 8
- 241001465754 Metazoa Species 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 239000007787 solid Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 8
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 230000019491 signal transduction Effects 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical class CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 11
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical class NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 abstract description 7
- 230000004936 stimulating effect Effects 0.000 abstract description 7
- 230000006907 apoptotic process Effects 0.000 abstract description 6
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 230000004663 cell proliferation Effects 0.000 abstract description 2
- 108091006146 Channels Proteins 0.000 abstract 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 42
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 12
- 230000003595 spectral effect Effects 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- DAAZHNSCAXBZRB-UHFFFAOYSA-N 4-(quinolin-4-ylamino)benzohydrazide Chemical compound N1=CC=C(C2=CC=CC=C12)NC1=CC=C(C(=O)NN)C=C1 DAAZHNSCAXBZRB-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 108020002144 NR4 subfamily Proteins 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 102000006255 nuclear receptors Human genes 0.000 description 4
- 108020004017 nuclear receptors Proteins 0.000 description 4
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- UCTUXUGXIFRVGX-UHFFFAOYSA-N 2,3,4-trimethoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(OC)=C1OC UCTUXUGXIFRVGX-UHFFFAOYSA-N 0.000 description 2
- KNDOFJFSHZCKGT-UHFFFAOYSA-N 4-chloroquinoline Chemical compound C1=CC=C2C(Cl)=CC=NC2=C1 KNDOFJFSHZCKGT-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 description 2
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 2
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- CBOQJANXLMLOSS-UHFFFAOYSA-N ethyl vanillin Chemical compound CCOC1=CC(C=O)=CC=C1O CBOQJANXLMLOSS-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- ZSKGQVFRTSEPJT-UHFFFAOYSA-N pyrrole-2-carboxaldehyde Chemical compound O=CC1=CC=CN1 ZSKGQVFRTSEPJT-UHFFFAOYSA-N 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
- MOEFFSWKSMRFRQ-UHFFFAOYSA-N 2-ethoxyphenol Chemical compound CCOC1=CC=CC=C1O MOEFFSWKSMRFRQ-UHFFFAOYSA-N 0.000 description 1
- MRLGCTNJRREZHZ-UHFFFAOYSA-N 3-phenoxybenzaldehyde Chemical compound O=CC1=CC=CC(OC=2C=CC=CC=2)=C1 MRLGCTNJRREZHZ-UHFFFAOYSA-N 0.000 description 1
- 101100405117 Homo sapiens NR4A1 gene Proteins 0.000 description 1
- 101001109700 Homo sapiens Nuclear receptor subfamily 4 group A member 1 Proteins 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 102000016978 Orphan receptors Human genes 0.000 description 1
- 108070000031 Orphan receptors Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 101001109695 Rattus norvegicus Nuclear receptor subfamily 4 group A member 1 Proteins 0.000 description 1
- 101100186386 Schizosaccharomyces pombe (strain 972 / ATCC 24843) nak1 gene Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000000728 Thymus Neoplasms Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000007159 enucleation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical group O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 201000009377 thymus cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- DKZBBWMURDFHNE-UHFFFAOYSA-N trans-coniferylaldehyde Natural products COC1=CC(C=CC=O)=CC=C1O DKZBBWMURDFHNE-UHFFFAOYSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- 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
- C07D401/12—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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
一类4‑((2‑取代喹啉‑4‑基)氨基)苯甲酰肼类衍生物及其制备方法与应用,涉及N'‑取代亚甲基‑4‑((2‑取代喹啉‑4‑基)氨基)苯甲酰肼类衍生物。所述一类N'‑取代亚甲基‑4‑((2‑取代喹啉‑4‑基)氨基)苯甲酰肼类衍生物可在制备抗肿瘤药物中应用。提供一类新颖的激动Nur77信号通路的衍生物,它们可以通过激动Nur77相关信号通路活性,阻断肿瘤细胞增殖,诱导细胞凋亡,从而可以用于人和动物的多种疾病如恶性肿瘤、炎症等的治疗和预防。所述激动Nur77信号通路的衍生物可在制备用于人和动物的多种疾病药物中应用,所述疾病包括恶性肿瘤、炎症等。
Description
技术领域
本发明涉及N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物,尤其是涉及一类4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物及其制备方法与应用。
背景技术
恶性肿瘤依旧是严重影响人类生命安全的主要疾病之一,现有的治疗恶性肿瘤的小分子药物虽然具有一定的疗效,但依然存在着较为严重的毒副作用。因此,越来越多的研究者将目标从传统的的细胞毒性药物转移到具有靶向性的新型抗肿瘤药物方向。
核受体(Nuclear Receptors,NRs)超家族是真核细胞生物体内广泛分布一大类功能蛋白,其对机体生长发育、新陈代谢、细胞分化及各种病理生理过程均有重要的调节作用,被视为潜在的治疗恶性肿瘤的重要靶点之一。Nur77(又名TR3,NGFI-B和NAK1)是由立早基因NR4A1编码的孤儿受体,属于核受体超家族的一员。近年来的研究表明,Nur77在细胞凋亡过程中具有重要作用([1]Gronemeyer H,Gustafsson J,Laudet V.Principles formodulation of the nuclear receptor superfamily.Nature Reviews Drug Discovery,2004,3(11):950-64)。其出核与细胞凋亡之间的相互关系已在肺癌、卵巢癌、肠癌、前列腺癌、胃癌、胸腺癌等多种肿瘤细胞中被证实。因此,Nur77被视为一个很有前景的新型治疗恶性肿瘤的潜在靶点([2]Hazel T G,Nathans D,Lau L F.Hazel TG,Nathans D,Lau LF.Agene inducible by serum growth factors encodes a member of the steroid andthyroid hormone receptor superfamily.Proc Natl AcadSci USA 85:8444-8448[J].Proceedings of the NationalAcademy of Sciences of the United States ofAmerica,1988,85(22):8444-8。同时,近年来研究证明,Nur77和炎症相关,所以,Nur77可视为一个潜在的抗炎靶点([3]Hu M,Luo Q,Alitongbieke G,et al.Celastrol-InducedNur77Interaction with TRAF2 Alleviates Inflammation by PromotingMitochondrial Ubiquitination and Autophagy.Molecular Cell,2017,66(1):141)。
发明内容
本发明的第一目的在于提供一类具有新颖结构的N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物及其制备方法。
本发明的第二目的在于提供一类N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物在制备抗肿瘤药物的应用。
本发明的第三目的在于提供一类新颖的激动Nur77信号通路的衍生物。它们可以通过激动Nur77相关信号通路活性,阻断肿瘤细胞增殖,诱导细胞凋亡,从而可以用于人和动物的多种疾病如恶性肿瘤、炎症等的治疗和预防。
所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的结构式为:
其中,R1代表H或甲基;R2代表取代或未取代的芳香基团,优选为2-萘基、1-萘基、2,3,4-三甲氧基苯基、4-羟基-3-甲氧基苯基、1-氢吡咯-2-基、3-苯氧基苯基、4-羟基-3-乙氧基苯基、4-甲氧基苯基、吡啶-3-基、吡啶-4-基、2-甲基-5-甲氧基吲哚-3-基等中的一种。
所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的制备方法包括以下步骤:
1)以苯胺(1)和取代乙酰乙酸乙酯为原料,多聚磷酸为溶剂,加热反应,得白色固体2-取代喹啉-4-醇(2);
2)2-取代喹啉-4-醇(2)在三氯氧磷溶剂中反应,得白色中间体4-氯-2-取代喹啉(3);
3)4-氯-2-取代喹啉(3)与对氨基苯甲酸乙酯反应得4-((2-取代喹啉-4-基)氨基)苯甲酸乙酯(4),再将(4)与水合肼反应得4-((2-取代喹啉-4-基)氨基)苯甲酰肼(5),最后(5)与不同的醛或酮缩合得目标化合物N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼。
在步骤1)中,所述搅拌的温度可为110℃;所述苯胺(1)的结构式为:
其中,R1代表H或CH3。
所述2-取代喹啉-4-醇(2)的结构式为:
其中,R1代表H或CH3。
在步骤2)中,所述反应的温度可为130℃;所述4-氯-2-取代喹啉(3)的结构式为:
其中,R1代表H或CH3。
在步骤3)中,所述4-((2-取代喹啉-4-基)氨基)苯甲酸乙酯(4)的结构式为:
其中,R1代表H或CH3;
所述4-((2-取代喹啉-4-基)氨基)苯甲酰肼(5)的结构式为:
其中,R1代表H或CH3。
所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的反应路线为:
其中,R1代表H或CH3;R2代表取代或未取代的芳香基团,优选为2-萘基、1-萘基、2,3,4-三甲氧基苯基、4-羟基-3-甲氧基苯基、1-氢吡咯-2-基、3-苯氧基苯基、4-羟基-3-乙氧基苯基、4-甲氧基苯基、吡啶-3-基、吡啶-4-基、2-甲基-5-甲氧基吲哚-3-基。
所述一类N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物可在制备抗肿瘤药物中应用。
本发明提供一类新颖的激动Nur77信号通路的衍生物,它们可以通过激动Nur77相关信号通路活性,阻断肿瘤细胞增殖,诱导细胞凋亡,从而可以用于人和动物的多种疾病如恶性肿瘤、炎症等的治疗和预防。
所述激动Nur77信号通路的衍生物可在制备用于人和动物的多种疾病药物中应用,所述疾病包括恶性肿瘤、炎症等。
本发明涉及了一类N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物,该类衍生物在结构上具有创造性。
本发明涉及了一类具有新结构的N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的制备,其反应条件温和,产率高,成本低廉,反应过程简单易控制,适用于工业化生产。本发明涉及的N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物具有抗肿瘤活性,可用于制备抗肿瘤药物。对上述衍生物进行了激动Nur77信号通路的相关活性测试,发现其抗肿瘤活性与其激动Nur77信号通路的活性呈正相关,上述的衍生物可用于预防和治疗Nur77信号通路受扰有关的疾病,如恶性肿瘤和炎症等。
附图说明
图1为HepG2、QGY-7703细胞经不同浓度的F21(1.5μM,2.0μM,3.0μM,4.0μM,4.5μM,6.0μM)处理24h后,PARP、Bcl-2、Nur77的免疫印迹分析结果。
具体实施方式
为了便于理解本发明,现结合具体实施方式对本发明作进一步说明,以进一步诠释本发明,但不构成对本发明的任何方式的限制。
以下给出本发明化合物的体外抗肿瘤增殖活性及其代表化合物对Nur77相关信号通路活性激动的研究。
体外抗肿瘤增殖活性测试实验:利用MTT法测定合成化合物对HepG2、QGY-7703、SMMC-7721等人癌细胞系和人正常细胞系Lo2生长抑制活性。表1列举了本发明部分化合物对各测试细胞系的IC50值,由此说明该系列化合物具有明显的抗肿瘤活性,但对正常细胞Lo2也具有较强的毒性。
表1本发明部分化合物对体外细胞的生长抑制活性
本发明代表化合物F21对Nur77相关信号通路活性激动的研究:图1显示了HepG2、QGY-7703细胞经不同浓度的F21(1.5μM,2.0μM,3.0μM,4.0μM,4.5μM,6.0μM)处理24h后,PARP、Bcl-2、Nur77的免疫印迹分析结果。结果显示,F21能上调Nur77、下调促生存蛋白Bcl-2的表达,这表明F21可以通过促进Nur77-Bcl-2的相关信号通路,抑制肿瘤细胞增殖,促进肿瘤细胞凋亡。因此,本发明所述化合物可用于Nur77-Bcl-2信号通路相关疾病的预防和治疗,如用于人和动物的恶性肿瘤治疗和预防。
以下给出具体实施例。
实施例1:N'-((萘-2-基)亚甲基)-4-((喹啉-4-基)氨基)苯肼酰肼的制备:
4-((喹啉-4-基)氨基)苯甲酸乙酯的制备:
在干燥密封的100mL反应瓶中加入4-羟基喹啉(2.90g,0.020mol),三氯氧磷(30mL),搅拌反应,密封加热至120℃继续反应3h后,TLC检测反应已完全,停止反应。反应液冷却至室温,减压浓缩除去溶剂,加入50mL冰水,活性炭脱色,抽滤,收集滤液,冰浴下用10%NaOH调pH为8~9,蒸馏,得到无色液体4-氯喹啉2.80g,收率87%。
在干燥的100mL圆底烧瓶中依次加入4-氯喹啉(1.60g,0.010mol),对氨基苯甲酸乙酯(1.70g,0.010mol),正丁醇(35mL),2滴浓盐酸,回流反应15h。TLC检测反应已完全。反应液充分冷却,有固体析出,抽滤,收集滤饼,烘干得白色固体4-((喹啉-4-基)氨基)苯甲酸乙酯2.36g,收率81%。
N'-((萘-2-基)亚甲基)-4-((喹啉-4-基)氨基)苯肼酰肼的制备:
在干燥的50mL圆底烧瓶中依次加入4-((喹啉-4-基)氨基)苯甲酸乙酯(2.90g,0.010mol),乙醇(5mL),水合肼(20mL),回流反应24h。TLC检测反应已完全。反应液充分冷却,抽滤,收集滤饼,烘干得白色固体4-((喹啉-4-基)氨基)苯甲酰肼2.20g,收率78%。
在干燥的10mL圆底烧瓶中依次加入4-((喹啉-4-基)氨基)苯甲酰肼(27.8mg,0.10mmol),2-萘甲醛(17.1mg,0.11mmol),乙醇(5mL),1滴三氟乙酸,回流反应12h,TLC反应已完全。加压浓缩除去溶剂,得粗产物,硅胶柱层析分离(洗脱剂为二氯甲烷︰甲醇=10︰1v/v),得到固体20.0mg,收率50%,其中所述的4-((喹啉-4-基)氨基)苯甲酰肼,2-萘甲醛的摩尔配比为1︰1.1。波谱数据:1H NMR(600MHz,DMSO-d6):12.13(s,1H),10.96(br.s.,1H),8.74(d,J=8.4Hz,1H),8.63~8.69(m,2H),8.15~8.20(m,3H),7.95~8.13(m,6H),7.86(ddd,J=2.8,5.6,8.4Hz,1H),7.69(d,J=8.4Hz,2H),7.56~7.64(m,2H),7.05(d,J=7.0Hz,1H);13C NMR(151MHz,DMSO-d6):162.8,158.8,158.6,154.8,148.4,144.0,141.0,139.1,134.5,134.2,133.3,132.5,132.1,131.5,129.9,129.3,129.0,128.8,128.3,127.8,127.7,127.3,123.9,123.1,121.2,118.0,101.0;ESI-MS(+):[M+H]+,405.5。
实施例2:4-((喹啉-4-基)氨基)-N'-((2,3,4-三甲氧基苯基)亚甲基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成2,3,4-三甲氧基苯甲醛(21.6mg,0.11mmol),最后分离得到淡黄色固体状产物24.6mg,收率54%。波谱数据:1H NMR(600MHz,DMSO-d6):11.96(s,1H),10.96(br.s.,1H),8.73(d,J=8.4Hz,1H),8.68(s,1H),8.64(d,J=6.8Hz,1H),8.13(d,J=8.6Hz,2H),8.04~8.07(m,2H),7.85(ddd,J=2.3,6.0,8.4Hz,1H),7.61~7.69(m,3H),7.04(d,J=7.0Hz,1H),6.96(d,J=9.0Hz,1H),3.87(d,J=3.95Hz,6H),3.79(s,3H);13C NMR(151MHz,DMSO-d6):162.4,159.1,158.8,158.6,155.7,154.8,153.1,144.0,143.9,142.0,140.9,139.0,134.5,132.2,129.8,127.8,125.0,123.9,121.1,121.0,120.8,118.0,116.7,109.2,101.0,62.3,61.0,56.5;ESI-MS(+):[M+H]+,457.5。
实施例3:N'-((4-羟基-3-甲氧基苯基)亚甲基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成4-羟基-3甲氧基苯甲醛(16.7mg,0.11mmol),最后分离得到黄白色固体状产物23.0mg,收率56%。波谱数据:1H NMR(600MHz,DMSO-d6):11.88(s,1H),10.99(br.s.,1H),9.70(br.s.,1H),8.74(d,J=8.4Hz,1H),8.64(d,J=7.0Hz,1H),8.39(s,1H),8.13(d,J=8.4Hz,2H),8.05~8.08(m,2H),7.86(ddd,J=2.3,5.9,8.3Hz,1H),7.67(d,J=8.4Hz,2H),7.36(d,J=1.5Hz,1H),7.11(dd,J=1.7,8.1Hz,1H),7.04(d,J=7.0Hz,1H),6.9(d,J=8.07Hz,1H),3.85(s,3H);ESI-MS(+):[M+H]+,413.4。
实施例4:N'-((萘-1-基)亚甲基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成1-萘甲醛(17.1mg,0.11mmol),最后分离得到白色固体状产物21.2mg,收率51%。波谱数据:1H NMR(600MHz,DMSO-d6):12.14(s,1H),10.98(br.s.,1H),9.18(s,1H),8.91(d,J=8.6Hz,1H),8.75(d,J=8.4Hz,1H),8.65(d,J=6.8Hz,1H),8.20(d,J=8.4Hz,2H),8.02~8.09(m,4H),7.97(d,J=7.0Hz,1H),7.82~7.91(m,1H),7.67~7.76(m,3H),7.60~7.67(m,2H),7.07(d,J=6.8Hz,1H);13C NMR(151MHz,DMSO-d6:162.7,158.9,158.7,154.8,148.4,144.0,141.1,139.1,134.5,134.0,132.0,131.1,130.7,130.0,129.9,129.3,128.3,127.8,127.8,126.8,126.1,125.1,124.7,123.9,121.1,118.0,101.0;ESI-MS(+):[M+H]+,417.5。
实施例5:N'-(3-苯氧基亚苄基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成3-苯氧基苯甲醛(21.8mg,0.11mmol),最后分离得到淡黄色固体状产物24.3mg,收率53%。波谱数据:1H NMR(600MHz,DMSO-d6):11.96(br.s.,1H),8.61(d,J=5.87Hz,1H),8.57(d,J=8.25Hz,1H),8.48(s,1H),8.05(d,J=7.89Hz,2H),8.00(d,J=8.44Hz,1H),7.91(t,J=7.52Hz,1H),7.69~7.78(m,1H),7.58(d,J=7.89Hz,2H),7.47~7.53(m,2H),7.41~7.47(m,3H),7.35~7.40(m,1H),7.16~7.24(m,1H),7.07~7.14(m,4H);ESI-MS(+):[M+H]+,459.5。
实施例6:N’-((1-氢-吡咯-2-基)亚甲基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成2-吡咯甲醛(10.5mg,0.11mmol),最后分离得到白色固体状产物19.9mg,收率56%。波谱数据:1H NMR(600MHz,DMSO-d6):11.66(s,1H),11.57(br.s.,1H),10.92(br.s.,1H),8.73(d,J=8.4Hz,1H),8.63(d,J=7.0Hz,1H),8.33(s,1H),8.11(d,J=8.4Hz,2H),8.03~8.07(m,2H),7.85(ddd,J=1.9,6.4,8.3Hz,1H),7.65(d,J=8.4Hz,2H),7.01(d,J=7.0Hz,1H),6.89~6.96(m,1H),6.52(br.s.,1H),6.11~6.19(m,1H);13C NMR(151MHz,DMSO-d6):162.2,158.7,158.5,154.8,144.0,141.6,140.7,139.1,134.5,132.5,129.8,127.7,127.5,125.0,123.9,123.1,121.2,118.0,113.9,109.8,101.0;ESI-MS(+):[M+H]+,356.4。
实施例7:N’-(4-甲氧基苯亚苄基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成4-甲氧基苯甲醛(15.0mg,0.11mmol),最后分离得到白色固体状产物20.2mg,收率51%。波谱数据:1H NMR(600MHz,DMSO-d6):11.90(s,1H),8.74(d,J=8.44Hz,1H),8.64(d,J=6.97Hz,1H),8.45(s,1H),8.13(d,J=8.44Hz,2H),8.06~8.08(m,2H),7.85(ddd,J=3.39,4.86,8.44Hz,1H),7.70(d,J=8.62Hz,2H),7.67(d,J=8.44Hz,2H),7.01~7.08(m,3H),3.83(s,3H);13C NMR(151MHz,DMSO-d6):162.5,161.4,158.9,158.7,154.8,148.4,143.9,140.9,139.0,134.5,132.2,129.8,129.2,127.7,127.3,125.0,123.9,121.1,118.0,114.8,101.0,55.8;ESI-MS(+):[M+H]+,397.4。
实施例8:N'-((3-乙氧基-4-羟基苯)亚苄基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成3-乙氧基-4-羟基苯甲醛(18.3mg,0.11mmol),最后分离得到白色固体状产物22.2mg,收率52%。波谱数据:1H NMR(600MHz,DMSO-d6):11.84(s,1H),10.96(br.s.,1H),9.57(br.s.,1H),8.74(d,J=8.4Hz,1H),8.64(d,J=7.0Hz,1H),8.38(s,1H),8.12(d,J=8.4Hz,2H),8.05~8.08(m,2H),7.85(ddd,J=3.0,5.2,8.5Hz,1H),7.66(d,J=8.4Hz,2H),7.29~7.35(m,1H),7.08~7.13(m,1H),7.03(d,J=6.8Hz,1H),6.88(d,J=8.1Hz,1H),4.08(q,J=7.0Hz,2H),1.38(t,J=7.0Hz,3H);13C NMR(151MHz,DMSO-d6):162.5,158.9,158.7,154.8,149.8,149.1,147.7,143.9,140.8,139.0,134.5,132.3,129.8,127.7,126.1,125.0,123.9,122.6,121.1,118.0,116.0,110.8,101.0,64.3,15.2;ESI-MS(+):[M+H]+,427.5。
实施例9:N’-(吡啶-4-基亚甲基)-4-(喹啉-4-基氨基)苯甲酰肼:
反应步骤同实施例1的合成,将2-萘甲醛换成吡啶-4-甲醛(11.8mg,0.11mol),最后分离得到白色固体状产物20.1mg,收率55%。波谱数据:1H NMR(600MHz,DMSO-d6):12.23(br.s.,1H),8.68(br.s.,2H),8.63(d,J=6.2Hz,1H),8.61(d,J=8.4Hz,1H),8.50(br.s.,1H),8.06~8.12(m,2H),7.99~8.04(m,1H),7.92~7.98(m,1H),7.76(t,J=7.6Hz,1H),7.69(br.s.,2H),7.62(d,J=8.6Hz,2H),7.13(d,J=6.2Hz,1H);13C NMR(151MHz,DMSO-d6):163.1,158.8,158.6,151.6,150.8,146.7,145.7,142.9,142.0,132.8,129.9,129.8,126.9,124.4,123.5,123.0,121.5,119.2,116.8,102.4;ESI-MS(+):[M+H]+,368.4。
实施例10:N’-(吡啶-3-基亚甲基)-4-((喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,收2-萘甲醛换成吡啶-3-甲醛(11.8mg,0.11mmol),最后分离得到白色固体状产物20.1mg,收率55%。波谱数据:1H NMR(600MHZ,SMSO-d6):12.17(s,1H),8.89(br.s.,1H),8.71(d,J=8.4Hz,1H),8.64(d,J=6.60Hz,2H),8.56(s,1H),8.18(d,J=7.5Hz,1H),8.11~8.15(m,2H),8.02~8.07(m,2H),7.84(ddd,J=3.0,5.3,8.4Hz,1H),7.63~7.70(m,2H),7.49~7.55(m,1H),7.07(d,J=6.6Hz,1H);13C NMR(151MHz,DMSO-d6):166.7,162.9,153.8,151.2,150.7,149.2,145.7,144.6,141.5,137.4,134.1,134.0,130.7,129.9,127.6,124.6,124.5,123.8,121.9,118.3,101.4;ESI-MS(+):[M+H]+,368.4。
实施例11:N’-((5-甲氧基-2-甲基-1-氢吲哚-3-基)亚甲基)-4-((2-甲基喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将4-(喹啉-4-基氨基)苯甲酰肼换成4-((2-甲基喹啉-4-基氨基)氨基)苯甲酰肼(29.2mg,0.10mmol),将2-萘甲醛换成2-甲基-5-甲氧基-1-氢吲哚-3-甲醛(20.8mg,0.11mmol),最后分离得到淡黄色固体状产物23.6mg,收率51%。波谱数据:1H NMR(600MHz,DMSO-d6):11.64(s,1H),11.43(s,1H),10.85(br.s.,1H),8.75~8.82(m,2H),8.15(d,J=8.4Hz,2H),8.09(d,J=8.3Hz,1H),8.00(t,J=7.7Hz,1H),7.82(d,J=2.6Hz,1H),7.77(t,J=7.7Hz,1H),7.65(d,J=8.3Hz,2H),7.24(d,J=8.6Hz,1H),6.93(s,1H),6.78(dd,J=2.6,8.8Hz,1H),3.80(s,3H),3.39(br.s.,3H),2.62~2.68(m,3H);13CNMR(151MHz,DMSO-d6):161.7,155.6,154.8,153.9,145.2,141.0,140.8,139.4,134.0,132.4,131.2,129.5,127.0,126.5,124.8,124.0,117.1,111.8,111.1,107.9,104.7,101.3,55.8,20.6,12.0;ESI-MS(+):[M+H]+,464.5。
实施例12:N'-((5-甲氧基-2-甲基-1-氢吲哚-3-基)亚甲基)-4-((2-甲基喹啉-4-基)氨基)苯甲酰肼:
反应步骤同实施例1的合成,将4-(喹啉-4-基氨基)苯甲酰肼换成4-(2-甲基喹啉-4-基氨基)苯甲酰肼(29.2mg,0.10mmol),将2-萘甲醛换成2,3,4-三甲氧基苯甲醛(21.6mg,0.11mmol),最后分离得到白色固体状产物22.5mg,收率49%。波谱数据:1H NMR(600MHz,DMSO-d6):11.96(s,1H),10.79(br.s.,1H),8.66~8.70(m,2H),8.13(d,J=8.4Hz,2H),8.00~8.05(m,1H),7.96~8.00(m,1H),7.78~7.83(m,1H),7.65(d,J=8.6Hz,3H),6.94~6.98(m,2H),3.87(s,3H),3.87(s,3H),3.79(s,3H),2.66(s,3H);13C NMR(151MHz,DMSO-d6):162.5,155.7,155.6,154.2,153.1,144.0,142.0,141.0,139.0,134.3,131.9,129.8,127.3,124.9,123.7,121.0,120.8,120.4,116.9,109.2,101.3,62.3,61.0,56.4,20.5;ESI-MS(+):[M+H]+,471.5。
Claims (7)
2.如权利要求1所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的制备方法,其特征在于包括以下步骤:
1)以苯胺(1)和取代乙酰乙酸乙酯为原料,多聚磷酸为溶剂,加热反应,得白色固体2-取代喹啉-4-醇(2);
所述苯胺(1)的结构式为:
所述2-取代喹啉-4-醇(2)的结构式为:
其中,R1代表H或CH3;
2)2-取代喹啉-4-醇(2)在三氯氧磷溶剂中反应,得白色中间体4-氯-2-取代喹啉(3);
所述4-氯-2-取代喹啉(3)的结构式为:
其中,R1代表H或CH3;
3)4-氯-2-取代喹啉(3)与对氨基苯甲酸乙酯反应得4-((2-取代喹啉-4-基)氨基)苯甲酸乙酯(4),再将(4)与水合肼反应得4-((2-取代喹啉-4-基)氨基)苯甲酰肼(5),最后(5)与不同的醛或酮缩合,得目标化合物N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼;
所述4-((2-取代喹啉-4-基)氨基)苯甲酸乙酯(4)的结构式为:
其中,R1代表H或CH3;
所述4-((2-取代喹啉-4-基)氨基)苯甲酰肼(5)的结构式为:
其中,R1代表H或CH3。
3.如权利要求2所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的制备方法,其特征在于在步骤1)中,所述搅拌的温度为110℃。
4.如权利要求2所述N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物的制备方法,其特征在于在步骤2)中,所述反应的温度为130℃。
6.如权利要求1所述一类N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物在制备抗肿瘤药物中应用。
7.如权利要求1所述一类N'-取代亚甲基-4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物在制备激动Nur77信号通路的药物中的应用,所述激动Nur77信号通路的药物在制备用于人和动物的多种疾病药物中应用,所述疾病为恶性肿瘤和炎症。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810253238.3A CN108358841B (zh) | 2018-03-26 | 2018-03-26 | 一类4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物及其制备方法与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810253238.3A CN108358841B (zh) | 2018-03-26 | 2018-03-26 | 一类4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物及其制备方法与应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108358841A CN108358841A (zh) | 2018-08-03 |
CN108358841B true CN108358841B (zh) | 2020-11-10 |
Family
ID=63001088
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810253238.3A Expired - Fee Related CN108358841B (zh) | 2018-03-26 | 2018-03-26 | 一类4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物及其制备方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108358841B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109734708B (zh) * | 2019-02-01 | 2021-04-09 | 厦门大学 | 嘧啶吲哚类Nur77受体调控剂及其制备方法和应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103204808B (zh) * | 2012-12-21 | 2016-04-20 | 中山大学 | 一种双喹啉衍生物及其制备方法和在制备抗癌药物中的应用 |
-
2018
- 2018-03-26 CN CN201810253238.3A patent/CN108358841B/zh not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN108358841A (zh) | 2018-08-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106220641B (zh) | 含愈创兰烃薁结构的吲哚螺环类化合物及其制备方法与应用 | |
CN109734708B (zh) | 嘧啶吲哚类Nur77受体调控剂及其制备方法和应用 | |
CN113024508A (zh) | 一类含氮杂环衍生物及其制法和用途 | |
CN111704646B (zh) | 甾体类化合物及其制备方法和用途 | |
CN109336866A (zh) | 一种多取代吡啶环类化合物其制备方法及应用 | |
CN107573327B (zh) | 吲唑-甲酰胺-吡啶酮衍生物及其制备方法和用途 | |
CN102164905B (zh) | 作为体内缺氧模拟剂的化合物,组合物,及其应用 | |
CN108358841B (zh) | 一类4-((2-取代喹啉-4-基)氨基)苯甲酰肼类衍生物及其制备方法与应用 | |
CN110240598B (zh) | 甲酰胺衍生物的制备方法及其中间体化合物 | |
CN110669038B (zh) | 一种嘧啶类fgfr4v550l抑制剂及其制备方法和应用 | |
CN107573318A (zh) | 一种具抗肿瘤活性的新型棉酚席夫碱类衍生物及其合成方法 | |
CN108997341B (zh) | 酰胺-朝格尔碱衍生物及其合成方法与应用 | |
CN110746402B (zh) | 一种2-n-芳基-4-n-芳基-5-氟嘧啶类化合物及其制备方法和应用 | |
CN111892608A (zh) | 一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用 | |
CN110078706B (zh) | 一种伊马替尼衍生物及其制备方法和用途 | |
CN112679409B (zh) | 一种4-吲哚-取代硫半脲衍生物及其制备方法和应用 | |
CN108864110B (zh) | 萘醌并吡喃衍生物及其合成方法与应用 | |
WO2018133159A1 (zh) | 一类喹啉类新化合物制备方法 | |
CN110156672B (zh) | 一种氨基脲化合物制备方法以及制得化合物的应用 | |
CN110759961B (zh) | 一类熊果酸吲哚醌酰胺衍生物及其制备方法和应用 | |
CN115490689A (zh) | 不可逆krasg12c抑制剂的制备及其应用 | |
CN109020883B (zh) | 一种3-氰基-2-氨基吡啶类衍生物及其制备方法与应用 | |
CN105348170B (zh) | 1-(2-(碳酰肼取代基团)-1h-吲哚-5-基)-3-取代脲衍生物及制备方法 | |
CN115572247B (zh) | 一类维生素k3衍生物及其医药用途 | |
CN110862396A (zh) | 一种吡咯并[3,4-c]咔唑-1,3(2H,6H)-二酮类化合物的合成方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20201110 |
|
CF01 | Termination of patent right due to non-payment of annual fee |