CN115368331B - Dihydro-pyrone compound and preparation method and application thereof - Google Patents
Dihydro-pyrone compound and preparation method and application thereof Download PDFInfo
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- CN115368331B CN115368331B CN202110537228.4A CN202110537228A CN115368331B CN 115368331 B CN115368331 B CN 115368331B CN 202110537228 A CN202110537228 A CN 202110537228A CN 115368331 B CN115368331 B CN 115368331B
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- -1 Dihydro-pyrone compound Chemical class 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 239000007810 chemical reaction solvent Substances 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 26
- 239000003153 chemical reaction reagent Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 8
- 239000012634 fragment Substances 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- OKIJSNGRQAOIGZ-UHFFFAOYSA-N Butopyronoxyl Chemical class CCCCOC(=O)C1=CC(=O)CC(C)(C)O1 OKIJSNGRQAOIGZ-UHFFFAOYSA-N 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical group [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical group OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000006238 prop-1-en-1-yl group Chemical group [H]\C(*)=C(/[H])C([H])([H])[H] 0.000 claims description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 2
- GRNOZCCBOFGDCL-UHFFFAOYSA-N 2,2,2-trichloroacetyl isocyanate Chemical group ClC(Cl)(Cl)C(=O)N=C=O GRNOZCCBOFGDCL-UHFFFAOYSA-N 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 2
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- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical group [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 claims description 2
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- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 2
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 claims description 2
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 claims description 2
- VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 claims 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 102000004243 Tubulin Human genes 0.000 abstract description 8
- 108090000704 Tubulin Proteins 0.000 abstract description 8
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- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- 239000005457 ice water Substances 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 10
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- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 7
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 238000004321 preservation Methods 0.000 description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
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- IEKGSKLKBICCHQ-BDOJOPHNSA-N plocabulin Chemical compound COC1=CC[C@@H]([C@@H](C)\C=C(/C)\C=C/C=C\C(=O)N[C@H](C(=O)N\C=C/C[C@H](C\C=C/C)OC(N)=O)C(C)(C)C)OC1=O IEKGSKLKBICCHQ-BDOJOPHNSA-N 0.000 description 4
- 229950007088 plocabulin Drugs 0.000 description 4
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- SFJMFSWCBVEHBA-UHFFFAOYSA-M copper(i)-thiophene-2-carboxylate Chemical compound [Cu+].[O-]C(=O)C1=CC=CS1 SFJMFSWCBVEHBA-UHFFFAOYSA-M 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
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Abstract
The invention belongs to the technical field of medicine synthesis, and relates to a novel dihydropyrone compound, a preparation method and application thereof. The chemical formula of the dihydropyrone compound is shown in the following formula I. The biological experiment results show that the dihydropyrone compound can be used for preparing medicines for preventing and treating diseases related to tubulin, in particular medicines for preventing and treating cancers related to tubulin; the invention also comprises a chemical synthesis method for preparing the compound and application of the compound in preparing a medicine for preventing and treating tumors.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and relates to novel dihydropyrone compounds, a preparation method and application thereof, a medicine composition containing the compounds as active ingredients and application thereof in preparing medicines for treating diseases related to tubulin, in particular to cancers related to tubulin.
Background
The literature describes cancer as one of the major diseases threatening human health. In recent years, about 1800 tens of thousands of new cancer cases are increased annually worldwide, resulting in about 1000 tens of thousands of deaths. The incidence of cancer is high and is believed to be closely related to the aging of society and unhealthy lifestyle. Studies have shown that carcinogenic causes are both external factors, such as tobacco, chemicals, radiation, and infectious organisms, and also intrinsic factors, such as genetic susceptibility, immune status, and the like. The incidence of cancer has been continuously increasing with changes in modern living environments and lifestyles. Tumor cells grow rapidly and are easily changed, so that multi-drug resistance is generated, and chemotherapy fails. According to the statistics, more than 90% of chemotherapy failures are related to multi-drug resistance of tumor cells, the conventional treatment has large side effects, the treatment effect is poor, and the phenomena of tumor prognosis recurrence, metastasis and the like are urgent to need new treatment technologies to solve the bottleneck effects. The international medical community regards molecular-based personalized chemotherapy and targeted therapy as hopes to break through the current bottleneck of lung cancer treatment.
Studies have shown that microtubes (microtubule) are a hollow tubular structure (about 15nm inside diameter, about 24-26nm outside diameter, about 5nm wall thickness) that is widely found in a variety of eukaryotic cells. The basic constituent unit is a heterodimer (heterodimer) formed by combining alpha and beta tubulin (tubulin). Microtubules have a variety of important biological functions as a component of eukaryotic cells.
It has been demonstrated by studies of microtubules involved in signal transduction that microtubules are involved in ehog, JNK, wnt and in ERK protein kinase signal transduction pathways, and that signal molecules can interact with microtubules either directly or through motor proteins or through some scaffold proteins. The signal transduction function of the microtubule has important biological effects, and is related to polarization of cells, unstable dynamic behaviors of the microtubule, stability change of the microtubule, directionality of the microtubule and the position of the tissue center of the microtubule, and .(Nogales E.Annu.Rev.BioPhyS.Biomol.Struct.,2001,30：397-420,PhiliP E.T.,Clinical Cancer Research 2004,10(2)：415-427,Wittmann T.,Hyman A.,Nat.CellBiof.2001,3(1)：28-34,Gurdersen G.G.,Cook T.,Cell Biol.,1999,11(1)：81-94) plays a very key role in the growth and development of tumor cells, so that the microtubule becomes an ideal target point for anti-tumor drug research.
Plocabulin is a novel polyketide extracted from sponge Lithoplocamia lithistoides collected from the motor gas sea area by Spanish PHARMAMAR company in 2013, has sub-nanomolar proliferation inhibition activity on various tumor cells, can overcome P-gp mediated tumor resistance, and has an antitumor mechanism of playing a role in microtubule destabilization through combination with tubulin. The clinical research .(María J.M et al.,J.Am.Chem.Soc.2013,135,10164-10171,P.Aviles et al.,Eur.J.Cancer,2013,49,A888,M.Hidalgo et al.,Eur.J.Cancer,2013,49,A889)Plocabulin molecules currently undergoing various tumor treatments have 4 chiral centers and a complex skeleton structure such as polyene, and according to the prior published patent, plocabulin chemical total synthesis requires 18 steps (30 steps in total), which greatly increases the application development cost (WO 2007144423A1, WO2014191578A 1).
Based on the basis and the current situation of the prior art, the application aims to provide novel dihydropyrone compounds, and a preparation method and application thereof. According to the application, plocabulin is subjected to structure-activity relationship research and chemical structure transformation to obtain the compound with stronger anti-tumor activity.
Disclosure of Invention
The invention aims to provide a dihydropyrone compound with a structure shown in a general formula I, in particular to a dihydropyrone compound containing benzene rings or pyridine, which has sub-nanomolar proliferation inhibition activity on various tumor cells, thereby playing a role in preventing and treating cancers.
Wherein, when X is NH, R 1 is tert-butyl, R 2 is H, R 3 is H, R 4 is H, CONH 2, phthaloyl, trityl or benzyloxycarbonyl and other common protecting groups;
When X is O, R 1 is tertiary butyl, R 2 is CH 3,R3, R 4 is H, CONH 2, tertiary butyl dimethyl silicon base or tertiary butyl diphenyl silicon base and other common protecting groups;
When X is O, R 1 is benzyl containing heteroatom substituent, R 2 is H or CH 3,R3 is H or CH 2-CH＝CH-CH3,R4 is H, CONH 2, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.
In particular, the invention provides dihydropyrone compounds having the structure of formula I.
Wherein, when X is NH, R 1 is tert-butyl, R 2 is H, R 3 is H, R 4 is H, CONH 2, phthaloyl, trityl or benzyloxycarbonyl and other common protecting groups;
When X is O, R 1 is tertiary butyl, R 2 is CH 3,R3, R 4 is H, CONH 2, tertiary butyl dimethyl silicon base or tertiary butyl diphenyl silicon base and other common protecting groups;
When X is O, R 1 is benzyl containing heteroatom substituent, R 2 is H or CH 3,R3 is H or CH 2-CH＝CH-CH3,R4 is H, CONH 2, tert-butyldimethylsilyl or tert-butyldiphenylsilyl and other common protecting groups;
More specifically, the invention provides a compound, wherein preferred compounds are:
in a second aspect, the present invention provides a process for preparing said compound, said process comprising the steps of:
(1) Intermediate B is subjected to Boc protecting group removal under the condition of a proper reaction solvent and temperature to prepare intermediate C, wherein the reaction solvent is ethylene glycol or ethylene glycol dimethyl ether and the like, and the reaction temperature is 0-250 ℃;
(2) The intermediate C is subjected to condensation reaction under the conditions of a proper reaction solvent, a proper temperature and a proper condensing agent to prepare a fragment D, wherein the reaction solvent is common solvents such as dichloromethane, dichloroethane, tetrahydrofuran or N, N-dimethylformamide, the condensing agent is common reagents such as 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1-ethyl-3 (3-dimethylpropylamine) carbodiimide, and the reaction temperature is 0-50 ℃;
(3) The method comprises the steps of (1) performing coupling reaction on a fragment D and a fragment A under the conditions of a proper reaction solvent, a proper reaction temperature and a proper catalyst to prepare an intermediate E, wherein the reaction solvent is tetrahydrofuran, N-dimethylformamide or N-methylpyrrolidone and other common solvents, the catalyst is bis (acetonitrile) palladium (II) dichloride or thiophene-2-cuprous formate and other reagents, and the reaction temperature is 0-50 ℃;
(4) When X is NH, carrying out deprotection reaction on a proper intermediate E under proper reaction solvent, temperature and reagent conditions to prepare a corresponding intermediate F; the reaction solvent is tetrahydrofuran, methanol, ethanol or dichloromethane and other common solvents, the reagent is hydrazine hydrate, anhydrous hydrazine or methylamine and other reagents, and the reaction temperature is-30-50 ℃;
Or when X is O, carrying out deprotection reaction on a proper intermediate E under proper reaction solvent, temperature and reagent conditions to prepare a corresponding intermediate F; the reaction solvent is tetrahydrofuran, methanol, ethanol, methylene dichloride or water and other common solvents, the reagent is tetrabutylammonium fluoride, hydrogen fluoride, pyridine hydrogen fluoride or triethylamine hydrogen fluoride and other reagents, and the reaction temperature is-30-100 ℃;
(5) When X is NH, performing functional group conversion on a proper intermediate F under proper reaction solvent, temperature and reagent conditions to prepare a compound shown in a general formula II, wherein the reaction solvent is common solvents such as methanol, ethanol or water, the reagent is potassium cyanate or sodium cyanate, and the reaction temperature is 0-100 ℃;
When X is O, converting a proper intermediate F into a compound shown in a general formula II through proper reagent treatment functional groups under proper reaction solvent and temperature conditions, wherein the reaction solvent is a common solvent such as dichloromethane, dichloroethane or tetrahydrofuran, the reagent is trichloroacetyl isocyanate or aluminum oxide, and the reaction temperature is-30-50 ℃;
In a third aspect, the invention provides application of the compound in preparing a medicament for preventing and treating tumors.
The invention takes the compound 1-1 as an example, but is not limited to the compound 1-1, and the molecular structure is as follows:
The preparation process is as follows:
Removing the Boc protecting group from the intermediate B-1 to obtain an intermediate C-1; and then condensing with carboxylic acid to obtain an intermediate D-1. Performing Stille coupling reaction on the intermediate A and the intermediate D-1 to obtain an intermediate E-1; and removing the phthaloyl protecting group on the intermediate E-1 to obtain the intermediate F-1. Finally, F-1 reacts with potassium cyanate under the acidic condition to prepare the final product 1-1.
The compounds of the present invention were tested for their inhibition of proliferation in vitro on human lung cancer cell A549, human colon cancer cell HT-29, human hepatoma cell HepG2 and human breast cancer cell MDA-MB-231, and the pharmacodynamic assay methods employed were well known to those skilled in the art. The results show that the compound of the invention has better cancer cell proliferation inhibition effect, and can further develop novel tubulin inhibitors and antitumor drugs.
In the present invention, the pharmaceutical composition contains a therapeutically effective amount of a compound according to any one of claims 1 to 3.
In the invention, the compound accounts for 20-99% of the total weight of the pharmaceutical composition.
Because the microtubulin has extremely important effect in cell division, and inhibiting the microtubulin can inhibit proliferation of various malignant tumors, the novel dihydropyrone compound can be used for preparing a microtubulin inhibitor or an anti-tumor drug, and can be used for treating various malignant tumors such as lung cancer, gastric cancer, esophageal cancer, breast cancer, ovarian cancer, head and neck tumor and the like.
Detailed Description
EXAMPLE 1 preparation of dihydropyranones
(S, 2Z,4Z, 6E) -N- ((S) -3, 3-dimethyl-1-oxo-1- ((Z) -4-ureido-1-yl) amino) butan-2-yl) -8- ((S) -5-methoxy-6-oxo-3, 6-dihydro-2H-pyran-2-yl) -6-methylnon-2, 4, 6-triamide (1-1)
(S, Z) -2-amino-N- (4- (1, 3-dioxoisoindol-2-yl) butyl-1-en-1-yl) -3, 3-dimethylbutyramide (C-1)
Intermediate B-1 (600 mg,1.40 mmol) was suspended in ethylene glycol (30 mL), the oil bath was set at 200deg.C, and after the target temperature was reached, the reaction solution was placed in the oil bath and stirred at constant temperature for 15 minutes. Immediately after the time, the reaction system was removed from the oil bath and cooled to room temperature with cold water. Ethyl acetate (300 mL) was added and the organic phase was washed with water (3 x 150 mL). Concentrating the organic phase, and performing column chromatography to obtain 380mg of intermediate C-1 as yellow oily liquid with yield 83％.1H NMR(600MHz,CDCl3)δ：8.79(d,1H,J＝11.4Hz),7.84(dd,2H,J＝5.4,3.0Hz),7.72(dd,2H,J＝5.4,3.0Hz),6.77(m,1H),4.77(dt,1H,J＝8.4,7.8Hz),3.75(t,1H,J＝7.8Hz),3.18(s,1H),2.49-2.41(m,2H),0.99(s,9H).13C NMR(150MHz,CDCl3)δ：171.27,168.42,134.07,131.95,123.30,106.15,64.18,37.11,34.35,26.65,24.97.HRMS(m/z)：330.1821[M+1]+(Calcd.for C18H23N3O3 330.1812).
(S) -N- ((Z) -4- (1, 3-dioxoisoindol-2-yl) butyl-1-en-1-yl) -3, 3-dimethyl-2- ((Z) -3- (tributylstannyl) acrylamido) butylamine (D-1)
Intermediate C-1 (380 mg,1.15mmol,1.0 eq.) was dissolved in DCM (32 mL) and DMF (8 mL), the reaction was placed in an ice-water bath and (Z) -3- (tributyl) acrylic acid (500 mg,1.39mmol,1.2 eq.) was added sequentially at 0-10℃to the reaction mixture, DIPEA (302. Mu.L, 1.73mmol,1.5 eq.), HOAT (173 mg,1.27mmol,1.1 eq.) and HATU (570 mg,1.50mmol,1.3 eq.) with stirring for 30 min. The reaction was quenched by adding a half saturated aqueous ammonium chloride solution (50 mL) at 0-10deg.C, stirred for 5 min, and MTBE (100 mL) was added. After stirring and separation, the organic phase was washed with water (50 mL), concentrated to give 497mg of intermediate D-1 as a colorless oily liquid by column chromatography, yield 64％.1H NMR(600MHz,CDCl3)δ：7.86(dd,2H,J＝5.4,3.0Hz),7.81(d,1H,J＝10.8Hz),7.73(dd,2H,J＝5.4,3.0Hz),7.01(d,1H,J＝12.0Hz),6.81-6.74(m,2H),6.34(d,1H,J＝9.6Hz),4.83(dt,1H,J＝8.4,7.8Hz),4.49(d,1H,J＝9.6Hz),3.74(t,1H,J＝7.2Hz),2.55-2.36(m,2H),1.53-1.39(m,6H),1.31-1.21(m,6H),1.01(s,9H),0.95-0.82(m,15H).13C NMR(150MHz,CDCl3)δ：168.50,168.22,166.18,153.53,136.19,134.15,131.91,123.43,123.28,107.06,60.71,37.07,35.26,29.24,27.41,26.56,24.88,13.77,11.52.HRMS(m/z)：696.2788[M+Na]+(Calcd.for C33H51N3O4Sn 696.2794).
(S, 2Z,4Z, 6E) -N- ((S) -1- ((Z) -4- (1, 3-dioxoisoindol-2-yl) butyl-1-en-1-yl) amine-O) -3, 3-dimethyl-1-oxobutan-2-yl) -8- ((S) -5-methoxy-6-oxo-3, 6-dihydro-2H-pyran-2-yl) -6-methylnon-2, 4, 6-triamide (E-1)
Intermediate D-1 (274 mg,0.407mmol,1.0 eq.) and A (170 mg, 0.188 mmol,1.2 eq.) were dissolved in NMP (20 mL), the reaction was placed in an ice-water bath, cuTC (116 mg,0.611mmol,1.5 eq.) was added at 0-10deg.C, and the mixture was stirred for 45 minutes with heat preservation. The reaction was removed from the ice-water bath, allowed to warm to room temperature naturally, and stirred at room temperature overnight, and the spot-on-plate showed complete reaction. The filter residue was washed with MTBE: ea=1:1 mixed solvent (75 mL) after the filter was filled with neutral alumina and filtered. The organic phases were combined and washed three times with 0.5M dilute hydrochloric acid (75, 2X 45 mL) and twice with water (2X 45 mL). Concentrating the organic phase, purifying with preparative plate, and purifying with semi-preparative chromatography to obtain 140mg intermediate E-1 as white solid in yield 57％.[α]20 D+33.0(c＝0.1,CHCl3).1H NMR(600MHz,CDCl3)δ：8.17(d,1H,J＝10.8Hz),7.87(dd,2H,J＝5.4,3.0Hz),7.73(dd,2H,J＝5.4,3.0Hz),7.30(dd,1H,J＝12.0,11.4Hz),6.88(dd,1H,J＝11.4,11.4Hz),6.79(dd,1H,J＝10.2,9.6Hz),6.38(d,1H,J＝9.6Hz),6.16(d,1H,J＝11.4Hz),5.69(d,1H,J＝11.4Hz),5.62(dd,1H,J＝6.6,3.6Hz),5.28(d,1H,J＝10.2Hz),4.84(dt,1H,J＝8.4,7.8Hz),4.53(d,1H,J＝9.6Hz),4.21(ddd,1H,J＝12.0,7.8,4.8Hz),3.72(t,2H,J＝7.8Hz),3.66(s,3H),2.85(m,1H),2.50-2.33(m,4H),1.84(s,3H),1.15(d,3H,J＝6.6Hz),1.04(s,9H).13C NMR(150MHz,CDCl3)δ：168.58,168.47,166.11,161.57,145.26,140.07,137.33,134.19,134.12,131.92,124.25,123.50,120.84,108.15,106.95,81.83,60.51,55.45,37.34,37.13,35.03,26.67,26.31,24.88,17.19,16.74.HRMS(m/z)：626.2845[M+Na]+(Calcd.for C34H41N3O7 626.2837).
(S, 2Z,4Z, 6E) -N- ((S) -1- (((Z) -4-amino-1-en-1-yl) amino) -3, 3-dimethyl-1-oxobutan-2-yl) -8- ((S) -5-methoxy-6-oxo-3, 6-dihydro-2H-pyran-2-yl) -6-methyl-2, 4, 6-trienamide (F-1)
Intermediate E-1 (106 mg,0.176mmol,1.0 eq.) was dissolved in THF (8 mL) and the reaction was placed in an ice-water bath, 80% aqueous hydrazine hydrate solution (132 mg,2.11mmol,12.0 eq.) was added at 0-5℃and the reaction was stirred for 12 hours with heat preservation. Purification by preparative plate gave 20mg of crude F-1 as a pale yellow solid in 24% yield. HRMS (m/z): 496.2783[ M+Na ] +(Calcd.for C26H39N3O5 496.2782).
(S, 2Z,4Z, 6E) -N- ((S) -3, 3-dimethyl-1-oxo-1- ((Z) -4-ureido-1-yl) amine-O) butan-2-yl) -8- ((S) -5-methoxy-6-oxo-3, 6-dihydro-2H-pyran-2-yl) -6-methyl-non-2, 4, 6-trienamide (1-1)
Intermediate F-1 (20 mg,0.042mmol,1.0 eq.) and potassium cyanate (5 mg,0.063mmol,1.5 eq.) were dissolved in a mixed solution of methanol (5 mL), water (5 mL) and hydrochloric acid (1M, 5 mL), the reaction system was placed in an oil bath at 45℃and stirred overnight with heat preservation, and the spot plate showed complete reaction. Directly concentrating, purifying the residue with semi-prepared liquid phase to obtain 3mg of compound 1-1 as white solid with yield 14％.[α]20 D-9.0(c＝0.1,CHCl3).1H NMR(600MHz,CDCl3)δ：9.25(d,1H,J＝10.8Hz),7.24(dd,1H,J＝12.0,11.4Hz),6.97(d,1H,J＝6.0Hz),6.88(dd,1H,J＝12.0,11.4Hz),6.75(dd,1H,J＝10.2,9.6Hz),6.14(d,1H,J＝12.0Hz),5.73(d,1H,J＝11.4Hz),5.65(dd,1H,J＝6.6,3.0Hz),5.46(t,1H,J＝5.4Hz),5.33(d,1H,J＝9.6Hz),4.78(dt,1H,J＝9.0,7.2Hz),4.52(d,1H,J＝9.6Hz),4.27(ddd,1H,J＝11.4,6.6,3.6Hz),3.66(s,3H),3.21(m,1H),3.02(m,1H),2.83(m,1H),2.47(m,1H),2.40(m,1H),2.31(m,1H),2.24(m,1H),1.83(s,3H),1.16(d,3H,J＝6.6Hz),1.06(s,9H).13C NMR(150MHz,CDCl3)δ：168.94,166.84,161.81,160.32,145.16,140.05,137.13,134.24,133.79,124.19,123.55,120.97,108.87,108.38,81.77,60.99,55.48,40.34,37.12,34.83,26.77,26.58,26.19,17.15,16.34.HRMS(m/z)：539.2844[M+Na]+(Calcd.for C27H40N4O6 539.2840).
EXAMPLE 2 preparation of dihydropyranones
(Z) -4- ((S) -2- ((S, 2Z,4Z, 6E) -8- ((S) -5-methoxy-6-oxo-3, 6-dihydro-2H-pyran-2-yl) -6-methylnon-2, 4, 6-triamino) -3, 3-dimethylbutylamino) -3-methyl-3-en-1-ylcarbamate (2-1)
(S, Z) -2-amino-N- (4- ((tert-butyldimethylsilyl) oxy) -2-methyl-1-en-1-yl) -3, 3-dimethylbutyramide (C-2)
Intermediate B-2 (622 mg,1.45 mmol) was suspended in ethylene glycol (35 mL), the oil bath was set at 200deg.C, and after the target temperature was reached, the reaction solution was placed in the oil bath and stirred at an elevated temperature for 15 minutes. Immediately after the time, the reaction system was removed from the oil bath and cooled to room temperature with cold water. Ethyl acetate (350 mL) was added and the organic phase was washed with water (3 x 175 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain 363mg of intermediate C-2 as a yellow oily liquid which was used in the next step without purification in 76% yield.
(S) -N- ((Z) -4- ((tert-Butyldimethylsilanyloxy) -2-methyl-1-en-1-yl) -3, 3-dimethyl-2- ((Z) -3- (tributyl-trialkyl) acrylamido) butylamine (D-2)
Intermediate C-2 (362 mg,1.10mmol,1.0 eq.) was dissolved in DCM (12 mL) and DMF (3 mL), the reaction was placed in an ice-water bath and (Z) -3- (tributyl) acrylic acid (477 mg,1.32mmol,1.2 eq.) was added sequentially at 0-10℃to the reaction mixture, DIPEA (288. Mu.L, 1.65mmol,1.5 eq.), HOAT (165 mg,1.21mmol,1.1 eq.) and HATU (545 mg,1.43mmol,1.3 eq.) with stirring for 30 minutes and the plates indicated complete reaction. The reaction was quenched by adding a half saturated aqueous ammonium chloride solution (50 mL) at a temperature of 0-10deg.C, stirred for 5 minutes, MTBE (100 mL) was added to the reaction mixture, stirred and then separated into layers, and the organic phase was washed with water (50 mL). Concentrating the organic phase, and performing column chromatography to obtain 549mg of intermediate D-2 as colorless oily liquid with yield 74％.1H NMR(600MHz,CDCl3)δ：8.03(d,1H,J＝9.6Hz),6.98(d,1H,J＝12.0Hz),6.75(d,1H,J＝12.0Hz),6.54(d,1H,J＝9.0Hz),6.24(d,1H,J＝9.0Hz),4.35(d,1H,J＝9.6Hz),3.79(m,1H),3.71(m,1H),2.33(ddd,1H,J＝13.8,8.4,4.2Hz),2.13(ddd,1H,J＝14.4,5.4,3.6Hz),1.72(d,3H,J＝1.2Hz),1.52-1.41(m,6H),1.32-1.21(m,6H),1.00(s,9H),0.91(s,9H),0.91-0.83(m,15H),0.11(s,3H),0.09(s,3H).13C NMR(150MHz,CDCl3)δ：167.88,165.78,153.17,136.17,119.76,118.66,62.13,60.54,35.34,35.03,29.29,27.43,26.64,26.06,21.03,18.64,13.77,11.68,-5.20,-5.27.HRMS(m/z)：695.3603[M+Na]+(Calcd.for C32H64N2O3SiSn 695.3600).
(S, 2Z,4Z, 6E) -N- ((S) -1- ((Z) -4- ((tert-butyldimethylsilyloxy) -2-methyl-1-en-1-yl) amino) -3, 3-dimethyl-1-oxobutan-2-yl) -8- ((S) -5-methoxy-6-oxo-3, 6-dihydro-2H-pyran-2-yl) -6-methylnon-2, 4, 6-triamide (E-2)
Intermediate D-2 (94 mg,0.140mmol,1.0 eq.) and A (58 mg,0.168mmol,1.2 eq.) were dissolved in NMP (10 mL) and the reaction was placed in an ice-water bath and CuTC (40 mg,0.210mmol,1.5 eq.) was added at 0-10deg.C with stirring for 45 minutes. The reaction was then removed from the ice-water bath, allowed to warm to room temperature naturally, and stirred at room temperature overnight, with a spot plate indicating complete reaction. The filter residue was washed with MTBE: ea=1:1 mixed solvent (75 mL) after the filter was filled with neutral alumina and filtered. The organic phases were combined and washed three times with 0.5M dilute hydrochloric acid (75, 2X 45 mL) and twice with water (2X 45 mL). Concentrating the organic phase, preparing and purifying to obtain 63mg of intermediate E-2 as colorless oily liquid with yield 75％.[α]20 D-34.8(c＝0.5,CHCl3).1H NMR(600MHz,CDCl3)δ：8.02(d,1H,J＝9.0Hz),7.24(dd,1H,J＝12.0,11.4Hz),6.87(dd,1H,J＝11.4,11.4Hz),6.53(d,1H,J＝9.0Hz),6.33(d,1H,J＝9.0Hz),6.15(d,1H,J＝11.4Hz),5.68(d,1H,J＝11.4Hz),5.63(dd,1H,J＝6.0,3.6Hz),5.28(d,1H,J＝10.2Hz),4.31(d,1H,J＝9.6Hz),4.21(ddd,1H,J＝12.6,7.8,4.8Hz),3.79(m,1H),3.71(m,1H),3.66(s,3H),2.86(m,1H),2.46-2.36(m,2H),2.32(ddd,1H,J＝13.8,7.8,4.2Hz),2.16(ddd,1H,J＝14.4,6.0,4.2Hz),1.85(d,3H,J＝1.2Hz),1.73(d,3H,J＝1.2Hz),1.16(d,3H,J＝6.6Hz),1.03(s,9H),0.91(s,9H),0.12(s,3H),0.10(s,3H).13C NMR(150MHz,CDCl3)δ：168.10,165.89,161.61,145.42,139.85,136.82,134.28,134.04,124.39,121.49,120.00,118.74,108.27,81.96,62.15,60.54,55.55,37.49,35.26,35.07,26.86,26.48,26.18,21.11,18.74,17.30,16.90,-5.06,-5.12.HRMS(m/z)：625.3643[M+Na]+(Calcd.for C33H54N2O6Si 625.3643).
(S, 2Z,4Z, 6E) -N- ((S) -1- (((Z) -4-hydroxy-2-methyl-1-en-1-yl) amino) -3, 3-dimethyl-1-oxobutan-2-yl) -8- ((S) -5-methoxy-6-oxo-3, 6-dihydro-2H-pyran-2-yl) -6-methylnon-2, 4, 6-triamide (F-2)
Intermediate E-2 (63 mg,0.104mmol,1.0 eq.) was dissolved in THF (20 mL) and the reaction was placed in an ice-water bath, TBAF in THF (1.0M, 416. Mu.L, 0.416mmol,4.0 eq.) was added at 0-10deg.C, and the addition was incubated for 10 minutes. The reaction was then removed from the ice-water bath, allowed to warm to room temperature naturally, and stirred at room temperature for 1 hour, with a dot-plate indicating complete reaction. The reaction system was again placed in an ice-water bath, and the reaction temperature was controlled to 0-10℃and quenched by adding saturated aqueous ammonium chloride (5 mL), followed by stirring for 5 minutes and dilution by adding water (20 mL). Ethyl acetate (50 mL) was added for extraction and the aqueous phase was again extracted with ethyl acetate (20 mL). The combined organic phases were concentrated and purified by semi-prep liquid phase after rapid column chromatography to give 28mg of intermediate F-2 as a white solid in yield 55％.[α]20 D-33.0(c＝0.1,MeOH).1H NMR(600MHz,CDCl3)δ：8.66(d,1H,J＝9.6Hz),7.27(dd,1H,J＝11.4,11.4Hz),6.89(ddd,1H,J＝11.4,11.4,0.6Hz),6.59(d,1H,J＝9.0Hz),6.47(d,1H,J＝9.0Hz),6.17(d,1H,J＝11.4Hz),5.70(d,1H,J＝11.4Hz),5.64(dd,1H,J＝6.0,3.0Hz),5.30(d,1H,J＝9.6Hz),4.35(d,1H,J＝9.0Hz),4.23(ddd,1H,J＝12.0,7.8,4.8Hz),3.79(t,2H,J＝5.4Hz),3.68(s,3H),2.86(m,1H),2.67(br s,1H),2.48-2.37(m,2H),2.27(t,2H,J＝5.4Hz),1.86(d,3H,J＝0.6Hz),1.75(d,3H,J＝1.2Hz),1.18(d,3H,J＝6.6Hz),1.05(s,9H).13C NMR(150MHz,CDCl3)δ：168.05,166.33,161.60,145.24,140.08,137.21,134.18,134.08,124.12,120.93,119.31,118.95,108.15,81.82,61.30,60.71,55.45,37.35,34.87,34.47,26.71,26.33,21.32,17.20,16.74.HRMS(m/z)：489.2961[M+1]+(Calcd.for C27H40N2O6 489.2959).
(Z) -4- ((S) -2- ((S, 2Z,4Z, 6E) -8- ((S) -5-methoxy-6-oxo-3, 6-dihydro-2H-pyran-2-yl) -6-methylnon-2, 4, 6-triamino) -3, 3-dimethylbutylamino) -3-methyl-3-en-1-ylcarbamate (2-1)
Intermediate F-2 (25 mg,0.051mmol,1.0 eq.) was dissolved in DCM (5 mL) and the reaction was placed in an ice-water bath and TCAI (10. Mu.L, 0.084mmol,1.6 eq.) was added at 0-10deg.C, and the reaction was stirred for 30min with heat preservation and indicated by a dot plate. The reaction was then removed from the ice-water bath, allowed to warm to room temperature, neutral alumina (125 mg) was added, and after stirring for 30 minutes the reaction was complete by spotting. The funnel was filled with neutral alumina and the filter residue was washed with DCM: meoh=50:1 mixed solvent (30 mL). The combined organic phases were concentrated and purified by semi-preparative liquid phase after rapid column chromatography to give 12mg of compound 2-1 as a white solid in yield 44％.[α]20 D-45.0(c＝0.1,CHCl3).1H NMR(600MHz,CDCl3)δ：8.17(d,1H,J＝10.2Hz),7.21(dd,1H,J＝12.0,11.4Hz),6.89(ddd,1H,J＝11.4,11.4,1.2Hz),6.63(d,1H,J＝10.2,1.2Hz),6.37(d,1H,J＝9.6Hz),6.16(d,1H,J＝12.0Hz),5.67(d,1H,J＝11.4Hz),5.63(dd,1H,J＝6.0,2.4Hz),5.29(d,1H,J＝9.6Hz),4.31(d,1H,J＝9.6Hz),4.23(ddd,1H,J＝12.0,7.8,4.2Hz),4.14(m,1H),4.07(m,1H),3.66(s,3H),2.86(m,1H),2.53(m,1H),2.48-2.35(m,2H),2.22(m,1H),1.84(d,3H,J＝1.2Hz),1.74(d,3H,J＝1.2Hz),1.16(d,3H,J＝6.6Hz),1.05(s,9H).13C NMR(150MHz,CDCl3)δ：167.75,166.46,161.60,157.63,145.23,140.30,137.57,134.29,133.93,124.13,120.63,119.21,116.18,108.15,81.82,63.45,60.85,55.46,37.26,34.45,31.15,26.61,26.23,20.95,17.16,16.60.HRMS(m/z)：532.3002[M+1]+(Calcd.for C28H41N3O7 532.3017).
EXAMPLE preparation of dihydropyranones
(S, 1Z, 6Z) -1- ((S) -3- (4-chlorophenyl) -2- ((S, 2Z,4Z, 6E) -8- ((S) -5-methoxy-6-oxo-3, 6-dihydro-2H-pyran-2-yl) -6-methylnon-2, 4, 6-triamino) propanamide) oct-1, 6-dien-4-ylcarbamate (3-1)
(S) -2-amino-N- ((S, 1Z, 6Z) -4- ((tert-butyldiphenylsilicon) oxy) oct-1, 6-dien-1-yl) -3- (4-chlorophenyl) propanamine (C-3)
Intermediate B-3 (567 mg,0.857 mmol) was suspended in ethylene glycol (35 mL), the oil bath was set to 200℃and after the target temperature was reached, the reaction solution was placed in the oil bath and stirred for 15 minutes with heat preservation. Immediately after the time, the reaction system was removed from the oil bath and cooled to room temperature with cold water. Ethyl acetate (350 mL) was added and the organic phase was washed with water (3 x 175 mL). Concentrating the organic phase, and performing column chromatography to obtain 388mg of intermediate C-3 as yellow oily liquid with yield 81％.1H NMR(600MHz,CDCl3)δ：8.99(d,1H,J＝10.8Hz),7.72-7.63(m,4H),7.45-7.33(m,6H),7.31-7.33(m,6H),7.29(d,2H,J＝8.4Hz),7.13(d,2H,J＝8.4Hz),6.72(dd,1H,J＝10.2,10.2Hz),5.44(m,1H),5.31(m,1H),4.83(dt,1H,J＝8.4,7.8Hz),3.85(m,1H),3.55(m,1H),3.22(m,1H),2.67(m,1H),2.24-2.05(m,4H),1.41(d,3H,J＝6.6Hz),1.05(s,9H).13C NMR(150MHz,CDCl3)δ：171.06,136.14,135.91,134.22,132.82,130.60,129.61,128.91,127.53,126.12,125.88,121.92,108.30,72.43,56.13,39.96,33.89,32.51,27.02,19.36,12.91.HRMS(m/z)：561.2704[M+1]+(Calcd.for C33H41ClN2O2Si 561.2699).
(Z) -N- ((S) -1- ((S, 1Z, 6Z) -4- ((tert-butyldiphenylsiloxy) oct-1, 6-dien-1-yl) amino) -3- (4-chlorophenyl) -1-oxopropan-2-yl) -3- (tributyl) acrylamide (D-3)
Intermediate C-3 (3838 mg,0.691mmol,1.0 eq.) was dissolved in DCM (20 mL) and DMF (5 mL), the reaction was placed in an ice-water bath, the temperature of the reaction solution was controlled to 0-10℃and (Z) -3- (tributyl) acrylic acid (300 mg,0.831mmol,1.2 eq.), DIPEA (181. Mu.L, 1.04mmol,1.5 eq.), HOAT (104 mg,0.764mmol,1.1 eq.) and HATU (349mg, 0.899mmol,1.3 eq.) were added in sequence, and the reaction was stirred for 30 minutes with heat preservation and spotted plates showed complete reaction. The reaction was quenched by adding a half saturated aqueous ammonium chloride solution (50 mL) at 0-10deg.C, stirred for 5 min, MTBE (100 mL) was added, stirred and then separated, and the organic phase was washed with water (50 mL). Concentrating the organic phase, and performing column chromatography to obtain 535mg of intermediate D-3 as colorless oily liquid with yield 86％.1H NMR(600MHz,CDCl3)：δ：7.70-7.62(m,4H),7.46-7.34(m,6H),7.25(d,1H,J＝10.2Hz),7.22(d,2H,J＝8.4Hz),7.08(d,2H,J＝8.4Hz),7.03(d,1H,J＝12.0Hz),6.67(d,1H,J＝12.6Hz),6.61(dd,1H,J＝10.8,9.0Hz),6.23(d,1H,J＝8.4Hz),5.45(m,1H),5.26(m,1H),4.83(m,1H),4.63(m,1H),3.81(m,1H),3.04-2.91(m,2H),2.20-2.09(m,2H),2.02(m,1H),1.83(m,1H),1.54-1.43(m,6H),1.38(d,3H,J＝7.8Hz),1.30-1.24(m,6H),1.04(s,9H),0.99-0.83(m,15H).13C NMR(150MHz,CDCl3)δ：167.79,166.18,154.46,135.85,135.63,135.54,134.80,134.15,134.00,132.99,130.61,129.74,129.72,128.81,127.64,127.58,126.43,126.35,125.82,121.52,109.24,72.31,54.40,37.73,33.79,32.17,29.30,29.23,29.17,27.84,27.37,27.00,26.85,19.31,17.52,13.81,13.62,12.90,11.57.HRMS(m/z)：905.3868[M+1]+(Calcd.for C48H69ClN2O3SiSn 905.3861).
(S, 2Z,4Z, 6E) -N- ((S) -1- ((S, 1Z, 6Z) -4- ((tert-butyldiphenylsiloxy) oct-1, 6-dien-1-yl) amino) -3- (4-chlorophenyl) -1-oxopropan-2-yl) -8- ((S) -5-methoxy-6-oxo-3, 6-dihydro-2H-pyran-2-yl) -6-methylnon-2, 4, 6-triamide (E-3)
Intermediate D-3 (120 mg,0.133mmol,1.0 eq.) and A (55 mg,0.15 mmol,1.2 eq.) were dissolved in NMP (10 mL) and the reaction was placed in an ice-water bath and CuTC (38 mg,0.200mmol,1.5 eq.) was added at 0-10deg.C with stirring for 45 minutes. The reaction was then removed from the ice-water bath, allowed to warm to room temperature naturally, and stirred at room temperature overnight, with a spot plate indicating complete reaction. The filter residue was washed with MTBE: ea=1:1 mixed solvent (75 mL) after the filter was filled with neutral alumina and filtered. The organic phases were combined and washed three times with 0.5M dilute hydrochloric acid (75, 2X 45 mL) and twice with water (2X 45 mL). Concentrating the organic phase, preparing and purifying the plate to obtain 79mg of intermediate E-3 as colorless oily liquid with yield 71％.1H NMR(600MHz,CDCl3)δ：7.70-7.62(m,4H),7.49-7.35(m,7H),7.19-7.26(m,3H),7.13(d,2H,J＝7.8Hz),6.90(dd,1H,J＝12.0,11.4Hz),6.61(dd,1H,J＝10.2,9.6Hz),6.21(d,1H,J＝7.8Hz),6.16(d,1H,J＝11.4Hz),5.61(dd,1H,J＝6.6,3.0Hz),5.61(dd,1H,J＝11.4,4.2Hz),5.44(m,1H),5.28(d,1H,J＝9.6Hz),5.24(m,1H),4.80(m,1H),4.60(m,1H),4.20(m,1H),3.80(m,1H),3.65(s,3H),3.13-2.97(m,2H),2.86(m,1H),2.46-2.31(m,2H),2.27-1.96(m,4H),1.84(s,3H),1.39(d,3H,J＝6.6Hz),1.16(d,3H,J＝7.2Hz),1.04(s,9H).13C NMR(150MHz,CDCl3)δ：167.83,166.27,161.52,145.27,140.69,138.05,135.89,135.02,134.36,134.19,134.07,133.01,130.64,129.70,128.90,127.61,127.56,126.29,125.90,123.97,121.58,119.97,109.25,108.08,81.77,72.34,55.45,54.38,37.31,33.94,32.25,27.02,26.25,19.32,17.17,16.68,12.92.HRMS(m/z)：857.3735[M+Na]+(Calcd.for C49H59ClN2O6Si 857.3723).
(S, 2Z,4Z, 6E) -N- ((S) -3- (4-chlorophenyl) -1- ((S, 1Z, 6Z) -4-hydroxyocta-1, 6-dien-1-yl) amino) -1-oxopropan-2-yl) -8- ((S) -5-methoxy-6-oxo-3, 6-dihydro-2H-pyran-2-yl) -6-methylnon-2, 4, 6-triamide (F-3)
Intermediate E-3 (79 mg,0.095mmol,1.0 eq.) was dissolved in THF (20 mL) and the reaction was placed in an ice-water bath, TBAF in THF (1.0M, 378. Mu.L, 0.378mmol,4.0 eq.) was added at 0-10deg.C and the addition was allowed to stand for 10 minutes. The reaction was removed from the ice-water bath, allowed to warm to room temperature naturally, and stirred at room temperature for 1 hour, with a spot plate indicating complete reaction. The reaction system was placed in an ice-water bath, a saturated aqueous ammonium chloride solution (5 mL) was added to quench the reaction at a temperature of 0-10℃and water (20 mL) was added to dilute the reaction system after stirring for 5 minutes. Ethyl acetate (50 mL) was added for extraction, and the aqueous phase was extracted again with ethyl acetate (20 mL) after separation. The combined organic phases were concentrated and purified by semi-prep liquid phase after rapid column chromatography to give 29mg of intermediate F-3 as a white solid in yield 52％.[α]20 D-45.0(c＝0.1,CHCl3).1H NMR(600MHz,CDCl3)δ：8.74(d,1H,J＝10.2Hz),7.27(d,2H,J＝7.8Hz),7.21(dd,1H,J＝12.0,11.4Hz),7.17(d,2H,J＝8.4Hz),6.89(dd,1H,J＝11.4,11.4Hz),6.70(dd,1H,J＝9.6,9.6Hz),6.41(d,1H,J＝7.2Hz),6.17(d,1H,J＝12.0Hz),5.70-5.56(m,3H),5.36(m,1H),5.29(d,1H,J＝9.6Hz),4.86(dt,1H,J＝8.4,7.8Hz),4.70(m,1H),4.22(m,1H),3.66(s,3H),3.65(m,1H),3.11(m,1H),3.05(m,1H),2.86(m,1H),2.48-2.32(m,2H),2.27-2.05(m,4H),1.84(s,3H),1.64(d,3H,J＝7.2Hz),1.16(d,3H,J＝6.6Hz).13C NMR(150MHz,CDCl3)δ：168.16,166.25,161.57,145.25,140.56,137.87,135.12,134.37,134.06,132.89,130.80,128.81,127.84,125.50,123.98,123.42,120.19,109.08,108.14,81.79,71.86,55.46,54.60,37.84,37.30,34.61,32.68,26.26,17.17,16.66,13.09.HRMS(m/z)：597.2713[M+1]+(Calcd.for C33H41ClN2O6597.2726).
(S, 1Z, 6Z) -1- ((S) -3- (4-chlorophenyl) -2- ((S, 2Z,4Z, 6E) -8- ((S) -5-methoxy-6-oxo-3, 6-dihydro-2H-pyran-2-yl) -6-methylnon-2, 4, 6-triamino) propanamide) oct-1, 6-dien-4-ylcarbamate (3-1)
Intermediate F-3 (25 mg,0.042mmol,1.0 eq.) was dissolved in DCM (10 mL), the reaction was placed in an ice-water bath, TCAI (10. Mu.L, 0.084mmol,2.0 eq.) was added at 0-10deg.C, and the addition was incubated for 30 min with stirring and the plates indicated complete reaction. The reaction system was removed from the ice-water bath, naturally warmed to room temperature, neutral alumina (125 mg) was added to the reaction solution, and after stirring for 30 minutes, the reaction was completed by spotting on a plate. The funnel was filled with neutral alumina and the filter residue was washed with DCM: meoh=50:1 mixed solvent (30 mL). The organic phases were combined and concentrated, and after rapid column passage, the positive compound 3-1 was purified using a semi-preparative liquid phase as a white solid. Quality 14mg, yield 52％.[α]20 D-63.0(c＝0.1,CHCl3).1H NMR(600MHz,CDCl3)δ：8.70(d,1H,J＝10.8Hz),7.25(m,1H),7.24(d,2H,J＝8.4Hz),7.13(d,2H,J＝8.4Hz),6.91(dd,1H,J＝12.0,11.4Hz),6.76(dd,1H,J＝9.6,9.6Hz),6.63(d,1H,J＝8.4Hz),6.16(d,1H,J＝11.4Hz),5.70-5.57(m,3H),5.37(m,1H),5.31(m,1H),4.90-4.76(m,2H),4.36-4.14(m,2H),3.66(s,3H),3.18-3.04(m,2H),2.86(m,1H),2.47(m,1H),2.38(m,1H),2.20(m,1H),2.05(m,1H),1.82(s,3H),1.62(d,3H,J＝6.6Hz),1.15(d,3H,J＝6.6Hz).13C NMR(150MHz,CDCl3)δ：168.38,166.18,161.66,157.73,145.18,140.42,137.80,134.78,134.21,133.75,132.83,130.90,128.56,127.06,124.90,124.36,124.02,120.36,108.28,106.46,81.87,75.56,55.46,54.11,38.14,37.03,31.25,30.63,26.05,17.10,16.26,13.00.HRMS(m/z)：640.2788[M+1]+(Calcd.for C34H42ClN3O7 640.2784).
Example 4: in vitro tumor cell proliferation inhibition activity assay
The test method comprises the following steps:
Growth inhibition of A549, HT-29, hepG2 and MDA-MB-231 tumor cells was examined using the CCK-8 method. The method comprises the following specific steps: cells in the logarithmic growth phase are inoculated into 96-well culture plates according to proper density, 90 mu L of each well is cultured overnight, medicines with different concentrations are added for 72 hours, three compound wells are arranged at each concentration, and solvent control and cell-free zeroing wells with corresponding concentrations are arranged. After completion of the reaction, 10. Mu.L of CCK-8 was added to each well, and after incubation in an incubator for 4 hours, the optical density (OD value) at a wavelength of 450nm was measured by a SpectraMax 190 microplate reader.
The IC 50 value is obtained by adopting a random software of an enzyme label instrument through regression by a four-parameter method.
The results show (as shown in Table 1) that the compounds of the present invention show better tumor cell proliferation inhibitory activity, and that the IC 50 value of each of the compounds 1-1 and 2-1 for cell proliferation inhibitory activity is less than 10nM.
Table 1: target compound for inhibiting proliferation activity of tumor cells
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Claims (7)
1. Dihydropyranone compounds having a structure represented by formula I:
Wherein when X is NH, R1 is tert-butyl, R2 is H, R3 is H, and R4 is H, CONH, phthalyl, trityl or benzyloxycarbonyl;
when X is 0, R1 is tert-butyl, R2 is CH3, R3 is H, and R4 is H, CONH, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;
When X is 0, R1 is benzyl, R2 is H or CH3, R3 is H or ch2—ch=ch—ch3, and R4 is H, CONH2, t-butyldimethylsilyl or t-butyldiphenylsilyl.
2. Dihydropyrone compounds with a structure shown in a general formula II,
Wherein, when X is NH, R1 is tert-butyl, R2 is H, and R3 is H;
When X is 0, R1 is tert-butyl, R2 is CH3, and R3 is H;
When X is 0, R1 is p-chlorobenzyl, R2 is H or CH3, and R3 is H or CH 2-CH＝CH-CH3.
3. The dihydropyrone compound according to claim 2, wherein the preferred compound is a compound of the structure:
4. The method for preparing the dihydropyrone compound according to claim 1, comprising the steps of:
(1) Intermediate B is subjected to Boc protecting group removal under the conditions of a reaction solvent and a temperature to prepare an intermediate C, wherein the reaction solvent is ethylene glycol or ethylene glycol dimethyl ether, and the reaction temperature is 0-250 ℃:
(2) The intermediate C is subjected to condensation reaction under the conditions of a reaction solvent, a temperature and a condensing agent to prepare a fragment D, wherein the reaction solvent is dichloromethane, dichloroethane, tetrahydrofuran or N, N-dimethylformamide, the condensing agent is 2- (7-azabenzotriazol) -N, N, N', N-tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1-ethyl-3 (3-dimethylpropylamine) carbodiimide, and the reaction temperature is 0-50 ℃;
(3) The method comprises the steps of (1) performing a coupling reaction on a fragment D and a fragment A under the conditions of a reaction solvent, a temperature and a catalyst to prepare an intermediate E, wherein the reaction solvent is tetrahydrofuran, N-dimethylformamide or N-methylpyrrolidone, the catalyst is bis (acetonitrile) palladium (II) dichloride or thiophene-2-cuprous formate reagent, and the reaction temperature is 0-50 ℃;
(4) When X is NH, carrying out deprotection reaction on the intermediate E under the conditions of a reaction solvent, temperature and a reagent to prepare a corresponding intermediate F; the reaction solvent is tetrahydrofuran, methanol, ethanol or dichloromethane, the reagent is hydrazine hydrate, anhydrous hydrazine or methylamine reagent, and the reaction temperature is-30-50 ℃; or when X is 0, carrying out deprotection reaction on the intermediate E under the conditions of reaction solvent, temperature and reagent to prepare a corresponding intermediate F; the reaction solvent is tetrahydrofuran, methanol, ethanol, methylene dichloride or water, the reagent is tetrabutylammonium fluoride, hydrogen fluoride, pyridine hydrogen fluoride or triethylamine hydrogen fluoride reagent, and the reaction temperature is-30-100 ℃;
(5) When X is NH, performing functional group conversion on the intermediate F under the conditions of a reaction solvent, temperature and a reagent to prepare a compound shown in a general formula II, wherein the reaction solvent is methanol, ethanol or water, the reagent is potassium cyanate or sodium cyanate, and the reaction temperature is 0-100 ℃;
When X is 0, the intermediate F is subjected to functional group conversion under the conditions of a reaction solvent and temperature, wherein the reaction solvent is dichloromethane, dichloroethane or tetrahydrofuran, the reagent is trichloroacetyl isocyanate or aluminum oxide reagent, and the reaction temperature is-30-50 ℃.
5. Use of the dihydropyrone compounds as defined in claims 1 to 3 for the preparation of medicaments for the prophylaxis and therapy of tumors; the tumors are human lung cancer cells A549, human colon cancer cells HT-29, human liver cancer cells HepG2 and human breast cancer cells MDA-MB-231.
6. The use according to claim 5, wherein the medicament comprises a therapeutically effective amount of a compound according to any one of claims 1 to 3.
7. The use according to claim 5, wherein said compound comprises 20% to 99% of the total weight of said medicament.
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