CN116514780A - Indazole micromolecular tubulin inhibitor and preparation method and application thereof - Google Patents
Indazole micromolecular tubulin inhibitor and preparation method and application thereof Download PDFInfo
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- CN116514780A CN116514780A CN202310463202.9A CN202310463202A CN116514780A CN 116514780 A CN116514780 A CN 116514780A CN 202310463202 A CN202310463202 A CN 202310463202A CN 116514780 A CN116514780 A CN 116514780A
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- indazole
- bromo
- compound
- trimethoxyphenyl
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- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 229940122429 Tubulin inhibitor Drugs 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 201000007270 liver cancer Diseases 0.000 claims abstract description 5
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 4
- -1 indazole small molecule Chemical class 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- WMKDUJVLNZANRN-UHFFFAOYSA-N 6-bromo-1h-indazole Chemical compound BrC1=CC=C2C=NNC2=C1 WMKDUJVLNZANRN-UHFFFAOYSA-N 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 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 8
- UPCARQPLANFGQJ-UHFFFAOYSA-N 4-bromo-2-fluorobenzaldehyde Chemical compound FC1=CC(Br)=CC=C1C=O UPCARQPLANFGQJ-UHFFFAOYSA-N 0.000 claims description 8
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- 235000011056 potassium acetate Nutrition 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- RULQUTYJXDLRFL-UHFFFAOYSA-N (3,4,5-trimethoxyphenyl)boronic acid Chemical compound COC1=CC(B(O)O)=CC(OC)=C1OC RULQUTYJXDLRFL-UHFFFAOYSA-N 0.000 claims description 7
- MZUSCPDSQJSBSY-UHFFFAOYSA-N (6-methylpyridin-3-yl)boronic acid Chemical compound CC1=CC=C(B(O)O)C=N1 MZUSCPDSQJSBSY-UHFFFAOYSA-N 0.000 claims description 7
- 238000004440 column chromatography Methods 0.000 claims description 7
- HXITXNWTGFUOAU-UHFFFAOYSA-N dihydroxy-phenylborane Natural products OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 7
- 239000003744 tubulin modulator Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
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- 229940041181 antineoplastic drug Drugs 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
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- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
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- 239000008107 starch Substances 0.000 claims description 2
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- 239000000454 talc Substances 0.000 claims description 2
- 235000012222 talc Nutrition 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 6
- 230000000259 anti-tumor effect Effects 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 10
- 102000004243 Tubulin Human genes 0.000 abstract description 9
- 108090000704 Tubulin Proteins 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 238000006116 polymerization reaction Methods 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 4
- 230000002588 toxic effect Effects 0.000 abstract description 4
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- 230000002708 enhancing effect Effects 0.000 abstract description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 abstract description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 abstract description 3
- 201000005112 urinary bladder cancer Diseases 0.000 abstract description 3
- 230000007246 mechanism Effects 0.000 abstract description 2
- 230000035755 proliferation Effects 0.000 abstract description 2
- 150000002473 indoazoles Chemical class 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 13
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 7
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- 238000003556 assay Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 231100000782 microtubule inhibitor Toxicity 0.000 description 4
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- 241000699660 Mus musculus Species 0.000 description 3
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- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- USJUQEVUEBCLLR-UHFFFAOYSA-N 1h-indol-4-ylboronic acid Chemical compound OB(O)C1=CC=CC2=C1C=CN2 USJUQEVUEBCLLR-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 2
- 229940122255 Microtubule inhibitor Drugs 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
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- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
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- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07D401/04—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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an indazole type small molecular microtubulin inhibitor, a preparation method and application thereof, and also discloses a preparation method of the indazole type compound or a medicinal salt thereof. The compound of the invention is an indazole micromolecular tubulin inhibitor with novel structure, has strong proliferation inhibition activity on human liver cancer Huh-7 cells, human non-small cell lung cancer A549 cells and human bladder cancer T24 cells, and has the action mechanism similar to CA-4Can inhibit the polymerization of tubulin, and has important significance for enhancing the specificity and effectiveness of the medicament, reducing toxic and side effects, preventing medicament resistance and the like.
Description
Technical Field
The invention relates to an indazole micromolecular tubulin inhibitor, and a preparation method and application thereof, and belongs to the technical field of chemistry.
Background
Microtubules are present in almost all eukaryotic cells and are one of the three major cytoskeletal components in eukaryotic cells. Microtubules are polymerized from alpha-tubulin heterodimers and beta-tubulin heterodimers in a head-to-tail fashion. The dynamics of continuous polymerization and depolymerization of microtubules plays a very important role in maintaining the physiological processes of cell morphology, cell signaling, cell mitosis, cell mass transport and the like.
Anti-microtubule drugs have become a main type of chemotherapy drugs and are widely used in the treatment of various clinical tumors. Tubulin inhibitors affect and interfere with the kinetics of polymerization and depolymerization of tubulin by binding to specific sites on tubulin, thereby blocking the formation of the M-phase spindle and arresting tumor cell growth in the G2/M phase. Currently, microtubule inhibitors used clinically mainly include drugs for inhibiting tubulin depolymerization typified by paclitaxel and drugs for inhibiting microtubule polymerization typified by vinca alkaloids. However, the problems of large toxic and side effects, easy generation of drug resistance, poor water solubility, complex structure, large synthesis difficulty and the like of the drugs are solved, and the search for novel, efficient and low-toxicity microtubule inhibitors has become a hotspot in the research of the current antitumor drugs.
Therefore, the design and synthesis of the small molecular microtubulin inhibitor with novel structure has important significance for enhancing the specificity and effectiveness of the medicament, reducing toxic and side effects, increasing bioavailability, preventing medicament resistance and the like.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides an indazole micromolecular tubulin inhibitor, a preparation method thereof and application thereof in preparing antitumor drugs.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
an indazole small molecule tubulin inhibitor having the structure shown in formula I:
wherein R is 1H-indol-4-yl or 6-methylpyridin-3-yl, and n is 0 or 1.
The second object of the invention is to provide a preparation method of the indazole type small molecule tubulin inhibitor.
The preparation method of the indazole type small molecular microtubule inhibitor comprises the steps of taking 4-bromo-2-fluorobenzaldehyde as an initial raw material, carrying out cyclization reaction with hydrazine hydrate to obtain 6-bromo-1H-indazole, carrying out a suzuki coupling reaction on the 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole and 3,4, 5-trimethoxyphenyl) -1H-indazole under the action of copper acetate and pyridine to obtain the indazole type small molecular microtubule inhibitor, wherein the 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole carries out a suzuki coupling reaction with indole-4-boric acid or 2-methyl-5-pyridineboronic acid under the catalysis of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride.
The preparation method of the indazole type small molecule tubulin inhibitor comprises the following specific synthesis steps:
(1) Dissolving 4-bromo-2-fluorobenzaldehyde in dimethyl sulfoxide, adding hydrazine hydrate, heating for reaction, adding water, and filtering to obtain 6-bromo-1H-indazole;
(2) Dissolving 6-bromo-1H-indazole in dichloromethane, adding 3,4, 5-trimethoxyphenylboronic acid, anhydrous copper acetate and pyridine, reacting at room temperature, spin-drying the solvent, and performing column chromatography to obtain 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole;
(3) Dissolving 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole in 1, 4-dioxane and water to obtain a mixed solution, sequentially adding potassium acetate, indole-4-boric acid or 2-methyl-5-pyridineboronic acid, exhausting, adding [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, heating for reaction, adding water and ethyl acetate for extraction, performing column chromatography to obtain a compound a or a compound b, adding the compound b into a mixed solution of acetyl chloride and ethanol, performing room temperature reaction, and performing suction filtration to obtain a compound c, wherein the compound a and the compound c are indazole micromolecular tubulin inhibitors.
According to a preferred embodiment of the invention, compound a is 6- (1H-indol-4-yl) -1- (3, 4, 5-trimethoxyphenyl) -1H-indazole, compound b is 6- (6-methylpyridin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) -1H-indazole, and compound c is 6- (6-methylpyridin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) -1H-indazole hydrochloride.
According to the invention, in the step (1), the mass volume ratio of the 4-bromo-2-fluorobenzaldehyde to the hydrazine hydrate is (200-400): (0.5-1), mg/mL.
According to the invention, in step (1), the heating reaction is carried out at 120-130℃for 15-20 hours.
According to a preferred embodiment of the present invention, in step (2), the mass ratio of 6-bromo-1H-indazole to 3,4, 5-trimethoxyphenylboronic acid is (300-350): (500-550).
According to the invention, in the step (2), the mass-volume ratio of the 6-bromo-1H-indazole to the pyridine is (300-350): (350-450), mg/. Mu.L.
According to the invention, in the step (2), the mass ratio of the 6-bromo-1H-indazole to the anhydrous copper acetate is (300-350): (400-480).
According to the invention, in the step (2), the reaction is carried out at room temperature for 10 to 20 hours.
According to a preferred aspect of the present invention, in step (3), the mass ratio of 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole, potassium acetate, indole-4-boronic acid, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride is (40-60): (30-50): (20-30): (5-20).
According to a preferred embodiment of the present invention, in step (3), the mass ratio of 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole, potassium acetate, 2-methyl-5-pyridineboronic acid, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride is (40-60): (30-50): (20-30): (5-20).
According to the invention, in the step (3), the volume ratio of the 1, 4-dioxane to the water in the mixed solution of the 1, 4-dioxane and the water is 1:1.
According to the invention, in the step (3), the mass volume ratio of the mixed solution of 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole, 1, 4-dioxane and water is (40-60): 4, mg/mL.
According to the invention, in step (3), the heating reaction is carried out at 80 to 100℃for 10 to 20 hours.
According to a preferred embodiment of the present invention, in the step (3), the structural formula of the compound a is represented by formula a:
according to a preferred embodiment of the present invention, in step (3), compound c has the structural formula shown in formula c:
the preparation method of the indazole micromolecular tubulin inhibitor comprises the following synthetic route:
a third object of the present invention is to provide the use of indazole small molecule tubulin inhibitors.
The indazole type small molecular microtubulin inhibitor is applied to the preparation of antitumor drugs, wherein tumors are lung cancer, liver cancer, prostatic cancer, cervical cancer, breast cancer and leukemia.
Comprises an effective amount of indazole small molecule tubulin inhibitors having the structure of formula I.
The pharmaceutical preparation can be prepared into oral preparation and parenteral preparation with one or more pharmaceutically acceptable carriers and/or excipients, and can be tablet, pill, capsule or injection.
The carrier includes, for example, physiological saline, buffered saline, dextrose, water, glycerol, ethanol or combinations thereof; the excipient may be selected from calcium phosphate, magnesium stearate, talc, dextrin, starch, gelatin cellulose, methyl cellulose, sodium carboxymethyl cellulose or polyvinylpyrrolidone.
The invention has the beneficial effects that:
1. the microtubulin inhibitor has novel structure and has important significance for enhancing the specificity and effectiveness of the medicament, reducing toxic and side effects, preventing medicament resistance and the like.
2. The compound disclosed by the invention is an indazole micromolecular tubulin inhibitor with a novel structure, has strong proliferation inhibition activity on human liver cancer Huh7 cells and human non-small cell lung cancer A549 cells and human bladder cancer T24 cells, has an action mechanism similar to colchicine, and can inhibit tubulin polymerization.
Drawings
FIG. 1 shows the results of a tubulin polymerization assay for the compound of example 1;
FIG. 2 shows the results of a tubulin polymerization assay for the compound of example 2;
FIG. 3 shows the results of a tubulin polymerization assay for a compound of CA-4;
FIG. 4 shows HE staining results of liver, kidney and spleen of mice.
Detailed Description
The present invention will be further described with reference to examples, but it should be understood that the following description is only for the purpose of illustrating the invention and is not to be construed as limiting the invention.
Example 1: preparation of 6- (1H-indol-4-yl) -1- (3, 4, 5-trimethoxyphenyl) -1H-indazole
(1) 4-bromo-2-fluorobenzaldehyde (300 mg, 1.178 mmol) was dissolved in dimethyl sulfoxide (12 ml), 80% hydrazine hydrate (0.72 ml,11.8 mmol) was added, and reacted at 125℃for 16H, water was added, stirred for 30min, suction filtered, and dried to give 6-bromo-1H-indazole (240 mg), yield 83%; melting point: 182-183 ℃. MS (ESI) calcd.for C 7 H 5 BrN 2 [M+H] + :196.96,found:196.98。
(2) 6-bromo-1H-indazole (320 mg,1.63 mmol) was dissolved in dichloromethane, 3,4, 5-trimethoxyphenylboronic acid (518 mg,2.45 mmol) and pyridine (394. Mu.L) were added sequentially, then anhydrous copper acetate (442.5 mg,2.45 mmol) was added, reacted at room temperature for 12H, filtered, and column chromatography (EA: PE=1:12) was performed to give 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole (455 mg) in 77% yield. Melting point: 126-127 ℃. MS (ESI) calcd.for C 16 H 15 BrN 2 O 3 [M+H] + :363.03,found:363.10。
(3) 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole (50 mg,0.14 mmol) and indole-4-boronic acid (26.6 mg,0.165 mmol) were added to a mixed solvent of water (2 mL) and 1, 4-dioxane (2 mL), followed by potassium acetate (40.5 mg, 0.41)mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (10 mg,0.014 mmol), air-vented, reacted at 90℃for 14H, after TLC monitoring the reaction completion, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatographed to give 6- (1H-indol-4-yl) -1- (3, 4, 5-trimethoxyphenyl) -1H-indazole (40 mg) in 73% yield. Melting point: 214-216 ℃. HRMS (ESI) calcd for C 24 H 21 N 3 O 3 [M+H] + ：400.1656found:400.1663。 1 H NMR(600MHz,DMSO-d 6 )δ11.29(s,1H),8.38(s 1H),8.03(s,1H),7.97(d,J＝8.3Hz,1H),7.57(dd,J＝8.3,1.2Hz,1H),7.48–7.37(m,2H),7.25–7.15(m,2H),7.10(s,2H),6.78–6.66(m,1H),3.86(s,6H),3.71(s,3H)。
Example 2: preparation of 6- (1H-indol-4-yl) -1- (3, 4, 5-trimethoxyphenyl) -1H-indazole hydrochloride
(1) 4-bromo-2-fluorobenzaldehyde (300 mg, 1.178 mmol) was dissolved in dimethyl sulfoxide (12 ml), 80% hydrazine hydrate (0.72 ml,11.8 mmol) was added, and reacted at 125℃for 16H, water was added, stirred for 30min, suction filtered, and dried to give 6-bromo-1H-indazole (240 mg) in 83% yield. Melting point: 182-183 ℃. MS (ESI) calcd.for C 7 H 5 BrN 2 [M+H] + :196.96,found:196.98。
(2) 6-bromo-1H-indazole (320 mg,1.63 mmol) was dissolved in dichloromethane, 3,4, 5-trimethoxyphenylboronic acid (518 mg,2.45 mmol) and pyridine (394. Mu.L) were added sequentially, then anhydrous copper acetate (442.5 mg,2.45 mmol) was added, reacted at room temperature for 12H, filtered, and column chromatography (EA: PE=1:12) was performed to give 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole (455 mg) in 77% yield. Melting point: 126-127 ℃. MS (ESI) calcd.for C 16 H 15 BrN 2 O 3 [M+H] + :363.03,found:363.10。
(3) 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole (50 mg,0.14 mmol) and 6-methyl-3-pyridineboronic acid (22.6 mg,0.165 mmol) were added to a mixed solvent of water (2 mL) and 1, 4-dioxane (2 mL), followed by potassium acetate (40.5 mg,0.41 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (10 mg,0.014 mmol) and air were vented, after completion of the reaction at 90℃for 16H, the TLC was monitored by water quenching, ethyl acetate extraction, washing with saturated brine, drying over anhydrous sodium sulfate, column chromatography gave 6- (1H-indol-4-yl) -1- (3, 4, 5-trimethoxyphenyl) -1H-indazole (37 mg) in 71% yield.
(4) Acetyl chloride was added to ethanol, stirred for 15min, and then added to 6- (1H-indol-4-yl) -1- (3, 4, 5-trimethoxyphenyl) -1H-indazole (30 mg) for 20min. After standing for 40min, suction filtration gave 6- (1H-indol-4-yl) -1- (3, 4, 5-trimethoxyphenyl) -1H-indazole hydrochloride (25 mg). Yield: 76%. Melting point: 220-222 ℃. HRMS (ESI) calcd for C 22 H 21 N 3 O 3 [M+H] + ：376.1656,found:363.1659。 1 H NMR(600MHz,DMSO-d 6 )δ9.18(d,J＝1.5Hz,1H),8.82(dd,J＝8.4,1.5Hz,1H),8.43(s,1H),8.24(s,1H),8.05(d,J＝8.4Hz,1H),7.95(d,J＝8.4Hz,1H),7.69(d,J＝8.4Hz,1H),7.07(s,2H),3.87(s,6H),3.73(s,3H),2.78(s,3H)。
Experimental example 1: antiproliferative assays
1. The test method comprises the following steps:
the human liver cancer Huh7 cells, the human bladder cancer T24 cells, the human non-small cell lung cancer A549 cells and the taxol resistant A549/Tax cells are all purchased from American ATCC cell bank, the compound of example 1 and the compound of example 2 are respectively administered at different concentrations, the blank control group is added with the same volume of DMS0 (without the compound 1 and the compound 2) at 37 ℃ and 5 percent CO 2 The inhibition of tumor cells by the compounds was determined by tetramethyl azoazole (MTT) colorimetry for 72h incubation in the incubator of (2), and the results are shown in Table 1.
2. Test results:
TABLE 1 antiproliferative Activity of the inventive compounds against different tumor cells
Experimental example 2: tubulin polymerization experiments
1. Experimental drugs: the compound prepared in example 1 (designated YJ-1), the compound prepared in example 2 (designated YJ-2), CA-4 and dimethyl sulfoxide (DMSO).
2. The experimental method comprises the following steps:
extracting and purifying fresh pig brain to obtain tubulin. In PEM buffer (100 mM PIPES, 1mM MgCl) containing 1mM GTP and 5% glycerol 2 And 1mM EGTA), tubulin was mixed with different concentrations of the compound at 37 ℃. The microtubule polymerization process was monitored using a SPECTRA MAX 190 (Molecular Device) spectrophotometer, with absorbance values read at 340nM, 1 reading every 1min, and plotted. IC (integrated circuit) 50 The value is the concentration of the compound at which the inhibition rate on tubulin assembly is 50% after 20min incubation.
3. The results of the experiments are shown in FIGS. 1 and 2, respectively, and it can be seen from FIGS. 1 and 2 that both the compound prepared in example 1 and the compound prepared in example 2 inhibit tubulin polymerization, similar to the CA-4 effect (FIG. 3). Compound YJ-1 and compound YJ-2 inhibit tubulin polymerization IC 50 1.75. Mu.M and 3.00. Mu.M, respectively.
Experimental example 3: in vivo safety analysis
1. Experimental drugs: the compound prepared in example 1 (designated YJ-1), the compound prepared in example 2 (designated YJ-2) and 0.5% sodium carboxymethylcellulose (0.5% CMC).
2. The experimental method comprises the following steps:
the nude mice were given a week of environmental adaptation under sterile conditions prior to the experiment. 200. Mu.L of PBS solution containing A549 cells was inoculated on the right side underarm of nude mice (1X 10) 7 Individual cells/mL), when the tumor volume reaches 90mm 3 At this time, the nude mice were randomly grouped, 5 per group. Compounds to be tested YJ-1 (25 mg/kg) and YJ-2 (25 mg/kg) were administered once daily by gavage with vehicle and observed for 21 consecutive days. Collecting organs (liver, kidney, spleen), processing into paraffin, and treating with hematoxylin and eosin (H)&E) Staining, further evaluating the in vivo safety of the test compounds.
3. The experimental results are shown in FIG. 4, and the compound prepared in example 1 and the compound prepared in example 2 have no obvious damage to the liver, kidney and spleen of mice at a dose of 25 mg/kg. These results indicate that the compound prepared in example 1 and the compound prepared in example 2 have good safety in mice.
Claims (10)
1. An indazole small molecule tubulin inhibitor having the structure shown in formula I:
wherein R is 1H-indol-4-yl or 6-methylpyridin-3-yl, and n is 0 or 1.
2. The method for preparing the indazole type micro-molecular tubulin inhibitor, which takes 4-bromo-2-fluorobenzaldehyde as an initial raw material, performs cyclization reaction with hydrazine hydrate to obtain 6-bromo-1H-indazole, the 6-bromo-1H-indazole reacts with 3,4, 5-trimethoxyphenylboronic acid under the action of copper acetate and pyridine to obtain 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole, and the 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole performs suzuki coupling reaction with indole-4-boric acid or 2-methyl-5-pyridineboronic acid under the catalysis of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride to obtain the indazole type micro-molecular tubulin inhibitor.
3. The method for preparing indazole type small molecule tubulin inhibitors according to claim 1, which comprises the following specific synthesis steps:
(1) Dissolving 4-bromo-2-fluorobenzaldehyde in dimethyl sulfoxide, adding hydrazine hydrate, heating for reaction, adding water, and filtering to obtain 6-bromo-1H-indazole;
(2) Dissolving 6-bromo-1H-indazole in dichloromethane, adding 3,4, 5-trimethoxyphenylboronic acid, anhydrous copper acetate and pyridine, reacting at room temperature, spin-drying the solvent, and performing column chromatography to obtain 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole;
(3) Dissolving 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole in 1, 4-dioxane and water to obtain a mixed solution, sequentially adding potassium acetate, indole-4-boric acid or 2-methyl-5-pyridineboronic acid, exhausting, adding [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, heating for reaction, adding water and ethyl acetate for extraction, performing column chromatography to obtain a compound a or a compound b, adding the compound b into a mixed solution of acetyl chloride and ethanol, performing room temperature reaction, and performing suction filtration to obtain a compound c, wherein the compound a and the compound c are indazole micromolecular tubulin inhibitors.
4. A process according to claim 3, wherein in step (1), the mass to volume ratio of 4-bromo-2-fluorobenzaldehyde to hydrazine hydrate is (200-400): (0.5-1), mg/mL, heating to react at 120-130 ℃ for 15-20h.
5. The method according to claim 3, wherein in the step (2), the mass ratio of 6-bromo-1H-indazole to 3,4, 5-trimethoxyphenylboronic acid is (300-350): (500-550), the mass volume ratio of the 6-bromo-1H-indazole to the pyridine is (300-350): (350-450), the mass ratio of the 6-bromo-1H-indazole to the anhydrous copper acetate is (300-350): (400-480), and the room temperature reaction is 10-20h at room temperature.
6. The preparation method according to claim 3, wherein in the step (3), the mass ratio of 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole, potassium acetate, indole-4-boric acid, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride is (40-60): (30-50): (20-30): (5-20);
the mass ratio of the 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole, potassium acetate and 2-methyl-5-pyridineboronic acid, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride is (40-60): (30-50): (20-30): (5-20).
7. The process according to claim 3, wherein in the step (3), the volume ratio of 1, 4-dioxane to water in the mixed solution of 1, 4-dioxane and water is 1:1,
the mass volume ratio of the mixed solution of the 6-bromo-1- (3, 4, 5-trimethoxyphenyl) -1H-indazole, the 1, 4-dioxane and water is (40-60): 4, mg-the volume of the solution is in the range of mL,
the heating reaction is carried out for 10-20h at 80-100 ℃.
8. A process according to claim 3, wherein in step (3), compound a has the formula a:
the structural formula of the compound c is shown as formula c:
9. the use of an indazole type small molecule tubulin inhibitor according to claim 1, for the preparation of an antitumor drug, wherein said tumor is lung cancer, liver cancer, prostate cancer, cervical cancer, breast cancer and leukemia.
10. An antitumor pharmaceutical formulation comprising an effective amount of an indazole-type small molecule tubulin inhibitor having the structure of formula I according to claim 1; the pharmaceutical preparation can be prepared into oral preparation and parenteral administration preparation by one or more pharmaceutically acceptable carriers and/or excipients, and can be tablet, pill, capsule or injection;
the carrier includes, for example, physiological saline, buffered saline, dextrose, water, glycerol, ethanol or combinations thereof; the excipient may be selected from calcium phosphate, magnesium stearate, talc, dextrin, starch, gelatin cellulose, methyl cellulose, sodium carboxymethyl cellulose or polyvinylpyrrolidone.
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