WO2021017795A1 - α,β-UNSATURATED KETONE DERIVATIVE, PREPARATION METHOD AND USE AS MEDICINE - Google Patents

α,β-UNSATURATED KETONE DERIVATIVE, PREPARATION METHOD AND USE AS MEDICINE Download PDF

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WO2021017795A1
WO2021017795A1 PCT/CN2020/101590 CN2020101590W WO2021017795A1 WO 2021017795 A1 WO2021017795 A1 WO 2021017795A1 CN 2020101590 W CN2020101590 W CN 2020101590W WO 2021017795 A1 WO2021017795 A1 WO 2021017795A1
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methyl
trimethoxyphenyl
indol
prop
acid
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French (fr)
Chinese (zh)
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庄春林
石英
从慧
***
黄嘉璇
余建强
徐丽娟
曲卓
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宁夏医科大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the technical field of medicine, in particular to an ⁇ , ⁇ -unsaturated ketone derivative, a preparation method and use as a medicine.
  • Microtubule targeted preparations have become an important part of anti-tumor drug development.
  • Microtubules are dynamic cytoskeletons composed of ⁇ and ⁇ tubulins. They play an important role in various cell functions, including mitosis. Microtubules exhibit different dynamic behaviors at different stages of the cell cycle, inhibiting microtubule dynamics, blocking the cell cycle, and inducing apoptosis, which are important therapeutic targets in tumor cells.
  • Tubulin inhibitors such as paclitaxel and vinblastine have been widely used to treat a variety of cancers. However, they showed a narrow therapeutic window, poor selectivity, and problems with multidrug resistance, usually due to high expression of p-glycoprotein or multidrug resistance-related proteins. Therefore, there is still a great need to develop a new type of small molecule that targets microtubules, has good selectivity and low toxicity (PharmRes (2012) 29: 2943-2971).
  • Chalcone derivatives are an important class of flavonoids.
  • the molecular structure is simple, with 1,3-diphenylpropenone as the basic skeleton. It has a wide range of biological activities, such as anti-tumor, antibacterial, anti-inflammatory, and Tuberculosis etc.
  • the novel indole chalcone is a new type of chalcone derivative discovered by the inventor in the previous study, which can significantly improve its anti-tumor activity and further study the mechanism of anti-tumor action.
  • this type of chalcone derivative acts on ⁇ -tubulin can effectively induce tumor cell apoptosis and block the tumor cell cycle in G2/M phase; among them, indochalcone, which represents the compound ⁇ -methyl substituted, shows excellent inhibition of parental tumor cells and multiple drugs Growth activity of drug-resistant tumor cells (Mol. Pharmaceutics 2018, 15, 3892-3900).
  • the third object of the invention is to provide the use of such ⁇ , ⁇ -unsaturated ketone derivatives as medicines.
  • the present invention provides a prodrug of an ⁇ , ⁇ -unsaturated ketone derivative and its isomer, salt or solvate.
  • the structure of the ⁇ , ⁇ -unsaturated ketone derivative is shown in general formula I:
  • a and B are independently selected from saturated ring, aromatic ring, aromatic heterocyclic ring, saturated ring or aromatic ring and aromatic heterocyclic ring;
  • R 1 is selected from hydrogen, 1-7 identical or different C1-C10 alkoxy groups
  • R 2 is selected from hydrogen, 1 to 7 identical or different C1-C10 alkyl groups, halogens, substituents composed of nitrogen and hydrogen, substituents composed of carbon, hydrogen and oxygen, or substituents composed of nitrogen and oxygen;
  • the substituent composed of oxygen element includes C1-C10 alkoxy;
  • the number of C1-C10 alkoxy groups in R 1 is 1 to 5.
  • the R 1 is selected from -OCH 2 COOCH 2 CH 3 .
  • said A and B are respectively selected from saturated ring, aromatic ring, aromatic heterocyclic ring, saturated ring and aromatic ring combined, saturated ring and aromatic heterocyclic ring or aromatic ring and aromatic heterocyclic ring;
  • the R 1 is selected from the group consisting of hydrogen, trimethoxy, dimethoxy, monomethoxy, substituted at different positions on the A,
  • the R 2 is selected from hydrogen, methoxy, methyl, fluorine, chlorine, bromine, nitro, amine, carboxyl or mono-substituted at different positions on the B
  • said A is selected from
  • the B is selected from
  • the R 1 is selected from the group consisting of hydrogen, trimethoxy, dimethoxy, monomethoxy, substituted at different positions on A,
  • the R 2 is selected from hydrogen, methoxy, methyl, fluorine, chlorine, bromine, nitro, amine, carboxyl or mono-substituted at different positions on B
  • the R 3 is selected from hydrogen, methyl, ethyl, or -CH 2 CH 2 -which forms a six-membered ring with A.
  • the pharmaceutically acceptable salt of the compound represented by the general formula I includes the acid addition salt formed by the compound of the general formula I and the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene Sulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.
  • hydrochloric acid hydrobromic acid
  • sulfuric acid sulfuric acid
  • phosphoric acid methanesulfonic acid
  • benzene Sulfonic acid p-toluenesulfonic acid
  • naphthalenesulfonic acid citric acid, tartaric acid, lactic acid, pyruvic acid
  • acetic acid maleic acid, succinic
  • the ⁇ , ⁇ -unsaturated ketone derivative is selected from one of the following structures:
  • the present invention provides the application of the prodrug of the ⁇ , ⁇ -unsaturated ketone derivative, isomer, salt or solvate described in the above technical scheme in preparing microtubule inhibitors.
  • the present invention provides the application of the prodrugs of ⁇ , ⁇ -unsaturated ketone derivatives, isomers, salts or solvates in the treatment of tumors, including the killing effect on tumor cells or in the treatment of tumor cells.
  • the tumor is colon cancer, lung cancer or leukemia.
  • Figure 1 is a graph showing the activity of compound 7 in a nude mouse model of HCT-116/L drug-resistant cell xenograft tumor, where A is the volume change of transplanted tumor in nude mice, B is the comparison of terminal tumor volumes, and C is the weight change of nude mice , D is the comparison of isolated tumors in the treatment group and the control group;
  • Figure 2 is a graph showing the drug-time curve of different doses of compound 7 administered to mice intraperitoneally.
  • the present invention provides a prodrug of an ⁇ , ⁇ -unsaturated ketone derivative and its isomer, salt or solvate.
  • the structure of the ⁇ , ⁇ -unsaturated ketone derivative is shown in general formula I:
  • a and B are independently selected from a saturated ring, an aromatic ring, an aromatic heterocyclic ring, a fused ring of a saturated ring and an aromatic ring, a fused ring of a saturated ring and an aromatic heterocyclic ring, or a fused ring of an aromatic ring and an aromatic heterocyclic ring;
  • R 1 is selected from hydrogen, 1 to 5 identical or different C1-C10 alkoxy groups, -OCH 2 COOCH 2 CH 3 ;
  • R 2 is selected from hydrogen, 1 to 7 identical or different C1-C10 alkyl groups, halogens, substituents composed of nitrogen and hydrogen, substituents composed of carbon, hydrogen and oxygen, or substituents composed of nitrogen and oxygen;
  • the substituent composed of oxygen element includes C1-C10 alkoxy;
  • the A and B are respectively selected from saturated ring, aromatic ring, aromatic heterocyclic ring, saturated ring or aromatic ring and aromatic heterocyclic ring.
  • said A is selected from
  • said B is selected from
  • the saturated ring or the aromatic ring and the aromatic heterocyclic ring are preferably a saturated ring and an aromatic ring, a saturated ring and an aromatic heterocyclic ring, or an aromatic ring and an aromatic heterocyclic ring.
  • the R 1 is selected from hydrogen, 1 to 7 identical or different C1-C10 alkoxy groups.
  • the number of the same or different C1-C10 alkoxy groups is more preferably 1-5, more preferably 3-5, and most preferably 4.
  • the C1-C10 alkoxy group is preferably a C2-C9 alkoxy group, more preferably a C3-C8 alkoxy group, and most preferably a C4-C6 alkoxy group.
  • the R 1 is further preferably selected from hydrogen, trimethoxy, dimethoxy, monomethoxy, and trimethoxy substituted at different positions on the A
  • the R 1 is also preferably selected from -OCH 2 COOCH 2 CH 3 .
  • the R 2 is selected from hydrogen, 1-7 identical or different C1-C10 alkyl groups, halogens, substituents composed of nitrogen and hydrogen, substituents composed of carbon, hydrogen and oxygen, or those composed of nitrogen and oxygen.
  • substituents; the substituents composed of the hydrocarbon elements include C1-C10 alkoxy groups.
  • the number of 1 to 7 is more preferably 2 to 6, more preferably 3 to 5, and most preferably 4.
  • the number of carbons in the C1-C10 alkyl group and C1-C10 alkoxy group is preferably C2-C9, more preferably C3-C8, and most preferably C4-C6.
  • the R 2 is further preferably selected from hydrogen, mono-substituted methoxy at different positions on the B, methyl, fluorine, chlorine, bromine, nitro, amine, carboxy or
  • the C1-C10 alkyl group is preferably a C2-C9 alkyl group, more preferably a C3-C8 alkyl group, and most preferably a C4-C6 alkyl group.
  • n is more preferably 2-9, more preferably 3-8, and most preferably 4-6.
  • halogen refers to fluorine, chlorine, bromine or iodine
  • alkyl refers to straight-chain or branched alkyl
  • aryl hetero refers to containing one or more selected from N, O, S-heteroatom monocyclic or polycyclic ring system, the ring system is aromatic, such as pyrrolyl, pyrazolyl, imidazolyl, indolyl, quinolinyl, benzothienyl, pyrrolopyridyl Etc.
  • Heterocyclyl refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, such as piperazinyl, piperidinyl, pyrrolidinyl, pyrazolidine Base etc.
  • the isomer is preferably a trans isomer.
  • the salt is preferably a pharmaceutically acceptable salt, more preferably an acid addition salt formed by the compound of formula I and an acid;
  • the acid preferably includes hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid .
  • the solvate preferably includes hydrate and non-hydrate.
  • the ⁇ , ⁇ -unsaturated ketone derivative is selected from one of the following structures: (E)-2-methyl-3-(4-methyl-1H-indole-3- Group)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (1), (E)-2-methyl-3-(5-methyl-1H- Indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one(2), (E)-2-methyl-3-(6- Methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (3), (E)-2-methyl- 3-(7-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (4), (E)- 3-(Benzo(b)thiophen-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1
  • the second aspect of the present invention provides a preparation method of the ⁇ , ⁇ -unsaturated ketone derivative and its isomer, salt or solvate prodrug.
  • the preparation method of the ⁇ , ⁇ -unsaturated ketone derivative and its isomers includes the following steps: 3,4,5-trimethoxybenzaldehyde (2g, 10.19 mmol) was added to the reaction vessel, THF (20mL) and ethylmagnesium bromide (15mL) were added after vacuum treatment, reacted for 4h under anaerobic conditions, monitored by TLC, diluted with water and ethyl acetate, and washed with saturated sodium chloride solution , Dried with anhydrous sodium sulfate, filtered, and spin-dried the organic phase.
  • the third aspect of the present invention provides the application of the prodrug of the ⁇ , ⁇ -unsaturated ketone derivative, isomer, salt or solvate in the treatment of tumor diseases.
  • the application in the treatment of tumors preferably includes the killing effect on tumor cells or the application in the treatment of tumor diseases with multidrug resistance.
  • the present invention provides the application of the prodrug of the ⁇ , ⁇ -unsaturated ketone derivative, isomer, salt or solvate in the preparation of microtubule inhibitors.
  • the application preferably includes the killing effect of antitumor drugs as a microtubule inhibitor on tumor cells.
  • the tumor preferably includes colon cancer, lung cancer or leukemia; the colon cancer preferably includes HCT-116 (colon cancer cell), HCT-116/OXA (drug-resistant colon cancer cell).
  • HCT-116 colon cancer cell
  • HCT-116/OXA drug-resistant colon cancer cell
  • the ⁇ , ⁇ -unsaturated ketone derivative and the prodrug of its isomer, salt or solvate of the present invention has good activity of inhibiting the proliferation of tumor cells, and can effectively inhibit common tumors such as colon cancer, lung cancer, leukemia, etc. Proliferation of cells and drug-resistant tumor cells; the invention is simple to synthesize, does not involve complicated steps, and has low synthesis cost.
  • Step a Synthesis of 1-(3,4,5-trimethoxyphenyl)propan-1-ol.
  • Step b Synthesis of 1-(3,4,5-trimethoxyphenyl)propan-1-one.
  • Step c (E)-2-methyl-3-(4-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene Synthesis of -1-one.
  • Example 22 Prepared according to the method of Example 22, the difference from Example 22 is that "1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde” is replaced with "1H-pyrrolo[3,2-c]pyridine -3-Formaldehyde".
  • Example 22 Prepared according to the method of Example 22, the difference from Example 22 is that "1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde” is replaced with "1H-pyrrolo[3,2-b]pyridine” -3-Formaldehyde".
  • Example 22 Prepared according to the method of Example 22, the difference from Example 22 is that "1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde” is replaced with "1H-pyrrolo[2,3-c]pyridine -3-Formaldehyde".
  • Example 12 Prepared according to the method of Example 12. The difference from Example 12 is that "6-methoxy-1H-indole-3-carbaldehyde" is replaced with "3-formyl-1H-indole-6-carboxylic acid Methyl ester".
  • Example 28 Prepared according to the method of Example 28, the difference from Example 28 is that "1-(7-methoxybenzo[d][1,3]dioxol-5-yl)propan-1 -Ketone" is replaced with "1-(3,4,5-trimethoxyphenyl)-1-propanone", and "1,8a dihydroimidazo[1,2-a]pyridine-3-carbaldehyde" Replace with "pyrazolo[1,5-a]pyridine-3-carbaldehyde".
  • Example 12 Prepared according to the method of Example 12, the difference from Example 12 is that "6-methoxy-1H-indole-3-carbaldehyde” is replaced with "3-formyl-1H-indole-6-carboxylic acid" ".
  • Step a Synthesis of 4-((tert-butyldimethylsilyl)oxy)-3,5-dimethoxybenzaldehyde.
  • Steps b and c refer to steps a and b in Example 1.
  • Step d Synthesis of 1-(4-hydroxy-3,5-dimethoxyphenyl)propan-1-one.
  • Step e Synthesis of ethyl 2-(2,6-dimethoxy-4-propionylphenoxy)acetate.
  • Step f Synthesis of (E)-2-(4-(3-(1H-indol-3-yl)-2-methacryloyl)-2,6-dimethylphenoxy) ethyl acetate .
  • Example 16 Prepared according to the method of Example 16, the difference from Example 16 is that "(E)-2-methyl-3-(6-nitro-1H-indol-3-yl)-1-(3, 4,5-Trimethoxyphenyl)prop-2-en-1-one" is replaced with "(E)-2-methyl-3-(7-nitro-1H-indol-3-yl)- 1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one".
  • Example 16 Prepared according to the method of Example 16, the difference from Example 16 is that "(E)-2-methyl-3-(6-nitro-1H-indol-3-yl)-1-(3, 4,5-Trimethoxyphenyl)prop-2-en-1-one" is replaced with "(E)-2-methyl-3-(5-nitro-1H-indol-3-yl)- 1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one".
  • the CellTiter-Blue method was used to test the in vitro anti-tumor activity of synthetic compounds 1 to 38 and some intermediates of the present invention.
  • HCT-116 colon cancer cell
  • HCT-116/OXA drug resistant colon cancer cell
  • Sample solution preparation Dissolve the compound or intermediate in DMSO to prepare a mother solution with a concentration of 50 ⁇ M. Then it is diluted with a medium containing 1% DMSO (three-fold or five-fold dilution), and finally a series of gradient concentration solutions are prepared.
  • the compound of the present invention is subjected to in vitro anti-tumor activity research:
  • HCT-116 colon cancer cells
  • HCT-116/OXA drug-resistant colon cancer cells
  • the CellTiter-Blue method was selected for activity testing, and the results showed that the compound showed good anti-tumor activity against colon cancer and its drug-resistant cell lines, especially against drug-resistant leukemia cells.
  • the activity of compounds without methoxy substitution on the benzene ring is significantly reduced, such as compounds 20 and 21; after bromine substitution and carboxyl substitution on the indole ring, the activity is also significantly reduced, such as compounds 9, 31.
  • Table 1 IC 50 values of target compounds on colon cancer (HCT-116) and drug-resistant colon cancer (HCT-116/OXA) cells
  • Select compound 7 (in vivo experiment number FC116) for in vivo anti-tumor activity experiment; select HCT-116/OXA drug-resistant cell xenograft nude mouse model to investigate its anti-tumor activity in vivo.
  • FC116 6 mg/mL FC116 (Compound 7): Dissolve 6 mg FC116 in 300 ⁇ L Tween 80, 100 ⁇ L castor oil, and 9.6 mL 0.5% CMC-Na, vortex and ultrasonically mix.
  • 10mg/mLOXA Dissolve 10mg FC116 in 300 ⁇ L Tween 80, 100 ⁇ L castor oil and 9.6mL0.5% CMC-Na by vortexing and sonicating.
  • mice Twenty-four healthy nude mice were divided into 4 groups evenly. They were injected intraperitoneally for 3 weeks and weighed every three days on average to measure the tumor volume. Animal treatment: Take tumors and organs.
  • mice 18 healthy adult ICR mice, the mice weighing 21-25g before the start of administration, were divided into 2 groups evenly, and the mice were injected intraperitoneally.
  • FC116 i.p.: Dissolve 0.15 mg FC116 in 300 ⁇ L Tween 80, 100 ⁇ L castor oil and 9.6 mL 0.5% CMC-Na by vortexing and sonicating.
  • FC116 i.p.: Dissolve 0.30 mg FC116 in 300 ⁇ L Tween 80, 100 ⁇ L castor oil and 9.6 mL 0.5% CMC-Na by vortexing and sonicating.
  • mice were taken before and after 15min, 30min, 1h, 2h, 4h, 8h, 24h, 32h, 48h and 72h respectively.
  • the satellite blood sampling method was used to collect 0.1mL of whole blood and add heparin. Sodium anticoagulation, centrifugation at 4°C for 5min to separate plasma, store at -80°C for testing, and collect 3 animals at each time point.
  • the LC-MS/MS method was used to determine the original drug concentration in the plasma of mice at different points after administration.
  • Standard curve Take 25 ⁇ L of blank mouse plasma, add 25 ⁇ L of FC116 standard series solution and 250 ⁇ L of methanol, vortex for 2min, centrifuge at 4°C, 3200rpm for 20min, take the supernatant for LC-MS/MS analysis.
  • Unknown sample Take 25 ⁇ L of each mouse plasma sample, add 275 ⁇ L of methanol, vortex for 2min, centrifuge at 4°C, 3200rpm for 20min, take the supernatant for LC-MS/MS analysis.
  • FC116 can reach the highest plasma drug concentration of 69.2 ng/mL within 0.5 h (Table 2), complete metabolism at 4 h ( Figure 2), and higher concentration (3 mg/kg). kg) FC116 can reach the highest blood concentration of 118ng/mL in 0.25h, and the metabolism is complete in 8h, and there is no accumulation in the body.
  • the compounds and their salts prepared in the present invention can be used to prepare anti-tumor drugs.

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Abstract

The present application relates to the technical field of medicine, and provides an α,β-unsaturated ketone derivative, a preparation method and a use thereof. The structure of the provided α,β-unsaturated ketone derivative is as shown in the general formula I, the definition of each substituent is shown in the description, the compound can target tubulin, has stronger inhibitory effects on a plurality of tumor parental generations and drug-resistant strains, and can be used to prepare medicines for treating malignant tumors and diseases associated with differentiation and proliferation.

Description

一种α,β-不饱和酮衍生物、制备方法及作为药物的用途An α, β-unsaturated ketone derivative, preparation method and use as medicine
本申请要求于2019年07月26日提交中国专利局、申请号为CN201910679937.9、发明名称为“一种α,β-不饱和酮衍生物、制备方法及作为药物的用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application requires that it be submitted to the Chinese Patent Office on July 26, 2019. The application number is CN201910679937.9 and the invention title is "an α, β-unsaturated ketone derivative, preparation method and use as a medicine". The priority of, the entire content of which is incorporated in this application by reference.
技术领域Technical field
本发明涉及医药技术领域，尤其涉及一种α,β-不饱和酮衍生物、制备方法及作为药物的用途。The present invention relates to the technical field of medicine, in particular to an α,β-unsaturated ketone derivative, a preparation method and use as a medicine.
背景技术Background technique
当前，癌症已经成为一种严重威胁人类健康生命的疾病。目前临床上治疗恶性肿瘤仍主要采用化疗的方法，但一半以上的肿瘤对传统化疗药物已产生显著耐药。据美国癌症协会估计，90％以上肿瘤患者死于不同程度的耐药，肿瘤耐药已经成为临床化疗失败的主要原因。因此，开发一种选择性靶向多药耐药的新型抗肿瘤化疗药物已经成为迫切需要。Currently, cancer has become a serious threat to human health and life. At present, the clinical treatment of malignant tumors still mainly uses chemotherapy, but more than half of the tumors have developed significant resistance to traditional chemotherapy drugs. According to estimates by the American Cancer Society, more than 90% of cancer patients die of different degrees of drug resistance, and tumor drug resistance has become the main reason for the failure of clinical chemotherapy. Therefore, it has become an urgent need to develop a new type of anti-tumor chemotherapeutic drug that selectively targets multidrug resistance.
近年来，微管靶向制剂已经成为抗肿瘤药物研发的一个重要部分。微管是由α,β微管蛋白组成的动态细胞骨架，它们在各种细胞功能中起着重要作用，包括有丝***。微管在细胞周期的不同阶段表现出不同的动态行为，抑制微管动力学，阻滞细胞周期，诱导细胞凋亡，是肿瘤细胞中的重要治疗靶标。紫杉醇、长春碱等微管蛋白抑制剂已广泛用于治疗多种癌症。然而，他们显示出治疗窗窄、选择性差以及多药耐药性问题，通常是由于p-糖蛋白或多药耐药相关蛋白的高表达。因此，开发一种新型靶向微管、选择性好、低毒的小分子仍有很大需求(PharmRes(2012)29:2943-2971)。In recent years, microtubule targeted preparations have become an important part of anti-tumor drug development. Microtubules are dynamic cytoskeletons composed of α and β tubulins. They play an important role in various cell functions, including mitosis. Microtubules exhibit different dynamic behaviors at different stages of the cell cycle, inhibiting microtubule dynamics, blocking the cell cycle, and inducing apoptosis, which are important therapeutic targets in tumor cells. Tubulin inhibitors such as paclitaxel and vinblastine have been widely used to treat a variety of cancers. However, they showed a narrow therapeutic window, poor selectivity, and problems with multidrug resistance, usually due to high expression of p-glycoprotein or multidrug resistance-related proteins. Therefore, there is still a great need to develop a new type of small molecule that targets microtubules, has good selectivity and low toxicity (PharmRes (2012) 29: 2943-2971).
查尔酮衍生物是类黄酮中一类重要的化合物，分子结构简单，以1,3-二苯基丙烯酮为基本骨架，具有广泛的生物学活性，如抗肿瘤、抗菌、抗炎、抗结核等。新型吲哚查尔酮是本发明人前期研究发现的一类新型查尔酮衍生物，可使其抗肿瘤活性显著提高，进一步地对抗肿瘤作用机制研究，发现该类查尔酮衍生物作用于β-微管蛋白，有效诱导肿瘤细胞凋亡，阻滞肿瘤细胞周期于G2/M期；其中，代表化合物α-甲基取代的吲哚查尔酮表现出优异的抑制亲代肿瘤细胞和多药耐药肿瘤细胞生长活性(Mol.Pharmaceutics2018,15,3892-3900)。Chalcone derivatives are an important class of flavonoids. The molecular structure is simple, with 1,3-diphenylpropenone as the basic skeleton. It has a wide range of biological activities, such as anti-tumor, antibacterial, anti-inflammatory, and Tuberculosis etc. The novel indole chalcone is a new type of chalcone derivative discovered by the inventor in the previous study, which can significantly improve its anti-tumor activity and further study the mechanism of anti-tumor action. It is found that this type of chalcone derivative acts on β-tubulin can effectively induce tumor cell apoptosis and block the tumor cell cycle in G2/M phase; among them, indochalcone, which represents the compound α-methyl substituted, shows excellent inhibition of parental tumor cells and multiple drugs Growth activity of drug-resistant tumor cells (Mol. Pharmaceutics 2018, 15, 3892-3900).
发明内容Summary of the invention
本发明的目的在于提供一类微管靶向抗肿瘤活性的α,β-不饱和酮衍生物；本发明的另一目的是提供该类α,β-不饱和酮衍生物的制备方法；本发明的第三目的是提供该类α,β-不饱和酮衍生物作为药物的应用。The object of the present invention is to provide a type of α,β-unsaturated ketone derivatives with microtubule-targeting anti-tumor activity; another object of the present invention is to provide a method for preparing such α,β-unsaturated ketone derivatives; The third object of the invention is to provide the use of such α,β-unsaturated ketone derivatives as medicines.
为了解决上述技术问题，本发明采用的技术方案是：In order to solve the above technical problems, the technical solutions adopted by the present invention are:
本发明提出一种α,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物，α,β-不饱和酮衍生物的结构如通式I所示：The present invention provides a prodrug of an α, β-unsaturated ketone derivative and its isomer, salt or solvate. The structure of the α, β-unsaturated ketone derivative is shown in general formula I:
Figure PCTCN2020101590-appb-000001
Figure PCTCN2020101590-appb-000001
其中，A和B独立地选自饱和环、芳环、芳杂环、饱和环或芳环及芳杂环并环；Wherein, A and B are independently selected from saturated ring, aromatic ring, aromatic heterocyclic ring, saturated ring or aromatic ring and aromatic heterocyclic ring;
R 1选自氢、1～7个相同或不同C1-C10烷氧基； R 1 is selected from hydrogen, 1-7 identical or different C1-C10 alkoxy groups;
R 2选自氢、1～7个相同或不同C1-C10烷基、卤素、氮氢元素组成的取代基、碳氢氧元素组成的取代基或氮氧元素组成的取代基；所述碳氢氧元素组成的取代基包括C1-C10烷氧基； R 2 is selected from hydrogen, 1 to 7 identical or different C1-C10 alkyl groups, halogens, substituents composed of nitrogen and hydrogen, substituents composed of carbon, hydrogen and oxygen, or substituents composed of nitrogen and oxygen; The substituent composed of oxygen element includes C1-C10 alkoxy;
R 3选自氢、C1-C10烷基或与A组成多元环的-(CH 2) n-，其中，n＝1～10。 R 3 is selected from hydrogen, C1-C10 alkyl, or -(CH 2 ) n -which forms a polycyclic ring with A, wherein n=1-10.
优选的，所述R 1中C1-C10烷氧基的个数为1～5个。 Preferably, the number of C1-C10 alkoxy groups in R 1 is 1 to 5.
优选的，所述R 1选自-OCH 2COOCH 2CH 3。 Preferably, the R 1 is selected from -OCH 2 COOCH 2 CH 3 .
优选的，所述A和B分别选自饱和环、芳环、芳杂环、饱和环与芳环的并环、饱和环与芳杂环的并环或芳环与芳杂环的并环；Preferably, said A and B are respectively selected from saturated ring, aromatic ring, aromatic heterocyclic ring, saturated ring and aromatic ring combined, saturated ring and aromatic heterocyclic ring or aromatic ring and aromatic heterocyclic ring;
所述R 1选自氢、所述A上不同位置取代的三甲氧基、二甲氧基、单甲氧基、
Figure PCTCN2020101590-appb-000002
Figure PCTCN2020101590-appb-000003
The R 1 is selected from the group consisting of hydrogen, trimethoxy, dimethoxy, monomethoxy, substituted at different positions on the A,
Figure PCTCN2020101590-appb-000002
Figure PCTCN2020101590-appb-000003
所述R 2选自氢、所述B上不同位置单取代的甲氧基、甲基、氟、氯、溴、硝基、胺基、羧基或
Figure PCTCN2020101590-appb-000004
The R 2 is selected from hydrogen, methoxy, methyl, fluorine, chlorine, bromine, nitro, amine, carboxyl or mono-substituted at different positions on the B
Figure PCTCN2020101590-appb-000004
所述R 3选自氢、甲基、乙基或与所述A组成多元环的-(CH 2) n-，其中，n＝1～10。 The R 3 is selected from hydrogen, methyl, ethyl or -(CH 2 ) n -which forms a polycyclic ring with the A, where n=1-10.
优选的，所述A选自
Figure PCTCN2020101590-appb-000005
Preferably, said A is selected from
Figure PCTCN2020101590-appb-000005
所述B选自
Figure PCTCN2020101590-appb-000006
Figure PCTCN2020101590-appb-000007
The B is selected from
Figure PCTCN2020101590-appb-000006
Figure PCTCN2020101590-appb-000007
所述R 1选自氢、A上不同位置取代的三甲氧基、二甲氧基、单甲氧基、
Figure PCTCN2020101590-appb-000008
Figure PCTCN2020101590-appb-000009
The R 1 is selected from the group consisting of hydrogen, trimethoxy, dimethoxy, monomethoxy, substituted at different positions on A,
Figure PCTCN2020101590-appb-000008
Figure PCTCN2020101590-appb-000009
所述R 2选自氢、B上不同位置单取代的甲氧基、甲基、氟、氯、溴、硝基、胺基、羧基或
Figure PCTCN2020101590-appb-000010
The R 2 is selected from hydrogen, methoxy, methyl, fluorine, chlorine, bromine, nitro, amine, carboxyl or mono-substituted at different positions on B
Figure PCTCN2020101590-appb-000010
所述R 3选自氢、甲基、乙基或与A组成六元环的-CH 2CH 2-。 The R 3 is selected from hydrogen, methyl, ethyl, or -CH 2 CH 2 -which forms a six-membered ring with A.
优选的，所述结构通式I所示化合物，其药学上可接受的盐包括通式I化合物与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。Preferably, the pharmaceutically acceptable salt of the compound represented by the general formula I includes the acid addition salt formed by the compound of the general formula I and the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene Sulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.
优选的，所述的α,β-不饱和酮衍生物选自以下结构中的一种：Preferably, the α,β-unsaturated ketone derivative is selected from one of the following structures:
(E)-2-甲基-3-(4-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(5-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(6-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(7-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(苯并[b]噻吩-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(5-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(6-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(5-氯-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(5-溴-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-1-(3,5-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮、(E)-3-(1H-吲哚-3-基)-1-(5-甲氧基吡啶-3-基)-2-甲基丙-2-烯-1-酮、(E)-3-(6-甲氧基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(5-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(6-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(7-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(6-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-((1H-吲哚-3-基)亚甲基)-1-(3,4,5-三甲氧基苯基)丁-1-酮、(E)-1-(3,4-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮、(E)-3-(1H-吲哚-3-基)-1-(3-甲氧基苯基)-2-甲基丙-2-烯-1-酮、(E)-3-(1H-吲哚-3-基)-2-甲基-1-苯基丙-2-烯-1-酮、(E)-3-(1H-吲哚-3-基)-1-苯基丙-2-烯-1-酮、(E)-2-甲基-3-(1H-吡咯并[2,3-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(1H-吡咯并[3,2-c]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(1H-吡咯并[3,2-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(1H-吡咯并[2,3-c]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(2-甲基-3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)-1H-吲哚-6-羧酸甲酯、(E)-3-(1H-吲哚-3-基)-1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)-2-甲基丙-2-烯-1-酮、(E)-3-(咪唑并[1,2-a]吡啶-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(吡唑并[1,5-a]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-((1H-吲哚-3-基)亚甲基)-5-甲氧基-3,4-二氢萘-1(2H)-酮、(E)-3-(2-甲基-3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)-1H-吲哚-6-羧酸、(E)-2-甲基-3-(1H-吡唑-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(1H-吡咯-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(喹啉-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(1H-吲哚-2-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-(4-(3-(1H-吲哚-3-基)-2-甲基丙烯酰基)-2,6-二甲基苯氧基)乙酸乙酯、(E)-3-(7-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮或(E)-3-(5-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮。(E)-2-Methyl-3-(4-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1- Ketone, (E)-2-methyl-3-(5-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene- 1-ketone, (E)-2-methyl-3-(6-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)propan-2- En-1-one, (E)-2-methyl-3-(7-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop- 2-en-1-one, (E)-3-(benzo(b)thiophen-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2 -En-1-one, (E)-3-(5-fluoro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop- 2-en-1-one, (E)-3-(6-fluoro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)propane -2-En-1-one, (E)-3-(5-chloro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl) Prop-2-en-1-one, (E)-3-(5-bromo-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl) )Prop-2-en-1-one, (E)-1-(3,5-dimethoxyphenyl)-3-(1H-indol-3-yl)-2-methylpropan-2 -En-1-one, (E)-3-(1H-indol-3-yl)-1-(5-methoxypyridin-3-yl)-2-methylprop-2-ene-1 -Ketone, (E)-3-(6-methoxy-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)propan-2- En-1-one, (E)-2-methyl-3-(5-nitro-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop- 2-en-1-one, (E)-2-methyl-3-(6-nitro-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl) Prop-2-en-1-one, (E)-2-methyl-3-(7-nitro-1H-indol-3-yl)-1-(3,4,5-trimethoxybenzene Yl)prop-2-en-1-one, (E)-3-(6-amino-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxy Phenyl) prop-2-en-1-one, (E)-2-((1H-indol-3-yl)methylene)-1-(3,4,5-trimethoxyphenyl) Butan-1-one, (E)-1-(3,4-dimethoxyphenyl)-3-(1H-indol-3-yl)-2-methylprop-2-ene-1- Ketone, (E)-3-(1H-indol-3-yl)-1-(3-methoxyphenyl)-2-methylprop-2-en-1-one, (E)-3 -(1H-indol-3-yl)-2 -Methyl-1-phenylprop-2-en-1-one, (E)-3-(1H-indol-3-yl)-1-phenylprop-2-en-1-one, ( E)-2-Methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene- 1-ketone, (E)-2-methyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)propane -2-En-1-one, (E)-2-methyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(3,4,5-trimethoxy Phenyl)prop-2-en-1-one, (E)-2-methyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-1-(3,4 ,5-Trimethoxyphenyl)prop-2-en-1-one, (E)-3-(2-methyl-3-oxo-3-(3,4,5-trimethoxyphenyl) )Prop-1-en-1-yl)-1H-indole-6-carboxylic acid methyl ester, (E)-3-(1H-indol-3-yl)-1-(7-methoxybenzene And [d][1,3]dioxol-5-yl)-2-methylprop-2-en-1-one, (E)-3-(imidazo[1,2-a )Pyridin-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, (E)-2-methyl-3-( Pyrazolo[1,5-a]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, (E)-2-(( 1H-indol-3-yl)methylene)-5-methoxy-3,4-dihydronaphthalene-1(2H)-one, (E)-3-(2-methyl-3-oxy Generation-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-1H-indole-6-carboxylic acid, (E)-2-methyl-3-( 1H-pyrazol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, (E)-2-methyl-3-(1H-pyrrole -3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, (E)-2-methyl-3-(quinolin-3-yl) -1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, (E)-3-(1H-indol-2-yl)-2-methyl-1- (3,4,5-Trimethoxyphenyl)prop-2-en-1-one, (E)-2-(4-(3-(1H-indol-3-yl)-2-methyl Acryloyl)-2,6-dimethylphenoxy)ethyl acetate, (E)-3-(7-amino-1H-indol-3-yl)-2-methyl-1-(3, 4,5-Trimethoxyphenyl)prop-2-en-1-one or (E)-3-(5-amino-1H-indol-3-yl)-2-methyl-1-(3 ,4,5-Trimethoxyphenyl)prop-2-en-1-one.
本发明提供了上述技术方案所述的α,β-不饱和酮衍生物、异构体、盐或溶剂合物的前体药物在制备微管抑制剂中的应用。The present invention provides the application of the prodrug of the α,β-unsaturated ketone derivative, isomer, salt or solvate described in the above technical scheme in preparing microtubule inhibitors.
本发明提供了上述技术方案所述的α,β-不饱和酮衍生物、异构体、盐或溶剂合物的前体药物在***中的应用，包括对肿瘤细胞的杀伤作用或在治疗具有多药耐药的肿瘤疾病中的应用。The present invention provides the application of the prodrugs of α, β-unsaturated ketone derivatives, isomers, salts or solvates in the treatment of tumors, including the killing effect on tumor cells or in the treatment of tumor cells. Application in tumor diseases with multidrug resistance.
优选的，所述肿瘤为结肠癌、肺癌或白血病。Preferably, the tumor is colon cancer, lung cancer or leukemia.
说明书附图Description and drawings
图1为化合物7在HCT-116/L耐药细胞移植瘤裸鼠模型的活性图，其中，A为裸鼠移植瘤体积变化，B为终末瘤体积间的比较，C为裸鼠体重变化，D为给药组离体肿瘤与对照组肿瘤的比较；Figure 1 is a graph showing the activity of compound 7 in a nude mouse model of HCT-116/L drug-resistant cell xenograft tumor, where A is the volume change of transplanted tumor in nude mice, B is the comparison of terminal tumor volumes, and C is the weight change of nude mice , D is the comparison of isolated tumors in the treatment group and the control group;
图2为小鼠腹腔给予不同剂量的化合物7的药-时曲线图。Figure 2 is a graph showing the drug-time curve of different doses of compound 7 administered to mice intraperitoneally.
具体实施方式Detailed ways
下面结合实施例对本发明进一步说明。In the following, the present invention will be further described in conjunction with embodiments.
本发明提出一种α,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物，α,β-不饱和酮衍生物的结构如通式I所示：The present invention provides a prodrug of an α, β-unsaturated ketone derivative and its isomer, salt or solvate. The structure of the α, β-unsaturated ketone derivative is shown in general formula I:
Figure PCTCN2020101590-appb-000011
Figure PCTCN2020101590-appb-000011
其中，A和B独立地选自饱和环、芳环、芳杂环、饱和环与芳环的并环、饱和环与芳杂环的并环或芳环与芳杂环的并环；Wherein, A and B are independently selected from a saturated ring, an aromatic ring, an aromatic heterocyclic ring, a fused ring of a saturated ring and an aromatic ring, a fused ring of a saturated ring and an aromatic heterocyclic ring, or a fused ring of an aromatic ring and an aromatic heterocyclic ring;
R 1选自氢、1～5个相同或不同C1-C10烷氧基、-OCH 2COOCH 2CH 3； R 1 is selected from hydrogen, 1 to 5 identical or different C1-C10 alkoxy groups, -OCH 2 COOCH 2 CH 3 ;
R 2选自氢、1～7个相同或不同C1-C10烷基、卤素、氮氢元素组成的取代基、碳氢氧元素组成的取代基或氮氧元素组成的取代基；所述碳氢氧元素组成的取代基包括C1-C10烷氧基； R 2 is selected from hydrogen, 1 to 7 identical or different C1-C10 alkyl groups, halogens, substituents composed of nitrogen and hydrogen, substituents composed of carbon, hydrogen and oxygen, or substituents composed of nitrogen and oxygen; The substituent composed of oxygen element includes C1-C10 alkoxy;
R 3选自氢、C1-C10烷基或与A组成多元环的-(CH 2) n-，其中，n＝1～10。 R 3 is selected from hydrogen, C1-C10 alkyl, or -(CH 2 ) n -which forms a polycyclic ring with A, wherein n=1-10.
在本发明中，所述A和B分别选自饱和环、芳环、芳杂环、饱和环或芳环及芳杂环并环。在本发明中，所述A选自
Figure PCTCN2020101590-appb-000012
在本发明中，所述B选自
Figure PCTCN2020101590-appb-000013
Figure PCTCN2020101590-appb-000014
In the present invention, the A and B are respectively selected from saturated ring, aromatic ring, aromatic heterocyclic ring, saturated ring or aromatic ring and aromatic heterocyclic ring. In the present invention, said A is selected from
Figure PCTCN2020101590-appb-000012
In the present invention, said B is selected from
Figure PCTCN2020101590-appb-000013
Figure PCTCN2020101590-appb-000014
在本发明中，所述饱和环或芳环及芳杂环并环优选为饱和环与芳环的并环、饱和环与芳杂环的并环或芳环与芳杂环的并环。In the present invention, the saturated ring or the aromatic ring and the aromatic heterocyclic ring are preferably a saturated ring and an aromatic ring, a saturated ring and an aromatic heterocyclic ring, or an aromatic ring and an aromatic heterocyclic ring.
在本发明中，所述R 1选自氢、1～7个相同或不同C1-C10烷氧基。在本发明中，所述相同或不同C1-C10烷氧基的个数进一步优选为1～5，更优选为3～5，最优选为4。在本发明中，所述C1-C10烷氧基优选为C2-C9烷氧基，更优选为C3-C8烷氧基，最优选为C4-C6烷氧基。 In the present invention, the R 1 is selected from hydrogen, 1 to 7 identical or different C1-C10 alkoxy groups. In the present invention, the number of the same or different C1-C10 alkoxy groups is more preferably 1-5, more preferably 3-5, and most preferably 4. In the present invention, the C1-C10 alkoxy group is preferably a C2-C9 alkoxy group, more preferably a C3-C8 alkoxy group, and most preferably a C4-C6 alkoxy group.
在本发明中，所述R 1进一步优选选自氢、所述A上不同位置取代的三甲氧基、二甲氧基、单甲氧基、
Figure PCTCN2020101590-appb-000015
在本发明中，所述R 1还优选选自-OCH 2COOCH 2CH 3。 In the present invention, the R 1 is further preferably selected from hydrogen, trimethoxy, dimethoxy, monomethoxy, and trimethoxy substituted at different positions on the A
Figure PCTCN2020101590-appb-000015
In the present invention, the R 1 is also preferably selected from -OCH 2 COOCH 2 CH 3 .
在本发明中，所述R 2选自氢、1～7个相同或不同C1-C10烷基、卤素、氮氢元素组成的取代基、碳氢氧元素组成的取代基或氮氧元素组成的取代基；所述碳氢氧元素组成的取代基包括C1-C10烷氧基。在本发明中，所述1～7个进一步优选为2～6个，更优选为3～5个，最优选为4个。在本发明中，所述C1-C10烷基和C1-C10烷氧基 中碳的个数优选为C2-C9，更优选为C3-C8，最优选为C4-C6。 In the present invention, the R 2 is selected from hydrogen, 1-7 identical or different C1-C10 alkyl groups, halogens, substituents composed of nitrogen and hydrogen, substituents composed of carbon, hydrogen and oxygen, or those composed of nitrogen and oxygen. Substituents; the substituents composed of the hydrocarbon elements include C1-C10 alkoxy groups. In the present invention, the number of 1 to 7 is more preferably 2 to 6, more preferably 3 to 5, and most preferably 4. In the present invention, the number of carbons in the C1-C10 alkyl group and C1-C10 alkoxy group is preferably C2-C9, more preferably C3-C8, and most preferably C4-C6.
在本发明中，所述R 2进一步优选选自氢、所述B上不同位置单取代的甲氧基、甲基、氟、氯、溴、硝基、胺基、羧基或
Figure PCTCN2020101590-appb-000016
In the present invention, the R 2 is further preferably selected from hydrogen, mono-substituted methoxy at different positions on the B, methyl, fluorine, chlorine, bromine, nitro, amine, carboxy or
Figure PCTCN2020101590-appb-000016
在本发明中，所述R 3选自氢、C1-C10烷基或与A组成多元环的-(CH 2) n-，其中，n＝1～10。在本发明中，所述C1-C10烷基优选为C2-C9烷基，更优选为C3-C8烷基，最优选为C4-C6烷基。在本发明中，n进一步优选为2～9，更优选为3～8，最优选为4～6。 In the present invention, the R 3 is selected from hydrogen, a C1-C10 alkyl group, or -(CH 2 ) n -which forms a polycyclic ring with A, where n=1-10. In the present invention, the C1-C10 alkyl group is preferably a C2-C9 alkyl group, more preferably a C3-C8 alkyl group, and most preferably a C4-C6 alkyl group. In the present invention, n is more preferably 2-9, more preferably 3-8, and most preferably 4-6.
本发明中，“卤素”是指氟、氯、溴或碘；“烷基”是指直链或支链的烷基；“芳杂基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系，环状体系是芳香性的，如吡咯基、吡唑基、咪唑基、吲哚基、喹啉基、苯并噻吩基、吡咯并吡啶基等；“杂环基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系，如哌嗪基、哌啶基、吡咯烷基、吡唑烷基等。In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodine; "alkyl" refers to straight-chain or branched alkyl; and "aryl hetero" refers to containing one or more selected from N, O, S-heteroatom monocyclic or polycyclic ring system, the ring system is aromatic, such as pyrrolyl, pyrazolyl, imidazolyl, indolyl, quinolinyl, benzothienyl, pyrrolopyridyl Etc.; "Heterocyclyl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, such as piperazinyl, piperidinyl, pyrrolidinyl, pyrazolidine Base etc.
在本发明中，所述异构体优选为反式异构体。In the present invention, the isomer is preferably a trans isomer.
在本发明中，所述盐优选为药学上可接受的盐，更优选为所述通式I化合物与酸形成的酸加成盐；所述酸优选包括盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。In the present invention, the salt is preferably a pharmaceutically acceptable salt, more preferably an acid addition salt formed by the compound of formula I and an acid; the acid preferably includes hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid .
在本发明中，所述溶剂合物优选包括水合物和非水合物。In the present invention, the solvate preferably includes hydrate and non-hydrate.
在本发明中，所述的α,β-不饱和酮衍生物选自以下结构中的一种：(E)-2-甲基-3-(4-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(1)、(E)-2-甲基-3-(5-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(2)、(E)-2-甲基-3-(6-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(3)、(E)-2-甲基-3-(7-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(4)、(E)-3-(苯并[b]噻吩-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(5)、(E)-3-(5-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(6)、(E)-3-(6-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(7)、(E)-3-(5-氯-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(8)、(E)-3-(5-溴-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(9)、(E)-1-(3,5-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮(10)、(E)-3-(1H-吲哚-3-基)-1-(5-甲氧基吡啶-3-基)-2-甲基丙-2-烯-1-酮(11)、(E)-3-(6-甲氧基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(12)、(E)-2-甲基-3-(5-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(13)、(E)-2-甲基-3-(6-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(14)、(E)-2-甲基-3-(7-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(15)、(E)-3-(6-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(16)、(E)-2-((1H-吲哚-3-基)亚甲基)-1-(3,4,5-三甲氧基苯基)丁-1-酮(17)、(E)-1-(3,4-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮(18)、(E)-3-(1H-吲哚-3-基)-1-(3-甲氧基苯基)-2-甲基丙-2-烯-1-酮(19)、(E)-3-(1H-吲哚-3-基)-2-甲基-1-苯基丙-2-烯-1-酮(20)、(E)-3-(1H-吲哚-3-基)-1-苯基丙-2-烯-1-酮(21)、(E)-2-甲基-3-(1H-吡咯并[2,3-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(22)、(E)-2-甲基-3-(1H-吡咯并[3,2-c]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(23)、(E)-2-甲基-3-(1H-吡咯并[3,2-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(24)、(E)-2-甲基-3-(1H-吡咯并[2,3-c]吡啶-3-基)-1-(3,4,5-三甲氧基苯基) 丙-2-烯-1-酮(25)、(E)-3-(2-甲基-3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)-1H-吲哚-6-羧酸甲酯(26)、(E)-3-(1H-吲哚-3-基)-1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)-2-甲基丙-2-烯-1-酮(27)、(E)-3-(咪唑并[1,2-a]吡啶-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(28)、(E)-2-甲基-3-(吡唑并[1,5-a]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(29)、(E)-2-((1H-吲哚-3-基)亚甲基)-5-甲氧基-3,4-二氢萘-1(2H)-酮(30)、(E)-3-(2-甲基-3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)-1H-吲哚-6-羧酸(31)、(E)-2-甲基-3-(1H-吡唑-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(32)、(E)-2-甲基-3-(1H-吡咯-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(33)、(E)-2-甲基-3-(喹啉-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(34)、(E)-3-(1H-吲哚-2-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(35)、(E)-2-(4-(3-(1H-吲哚-3-基)-2-甲基丙烯酰基)-2,6-二甲基苯氧基)乙酸乙酯(36)、(E)-3-(7-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(37)或(E)-3-(5-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(38)。In the present invention, the α, β-unsaturated ketone derivative is selected from one of the following structures: (E)-2-methyl-3-(4-methyl-1H-indole-3- Group)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (1), (E)-2-methyl-3-(5-methyl-1H- Indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one(2), (E)-2-methyl-3-(6- Methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (3), (E)-2-methyl- 3-(7-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (4), (E)- 3-(Benzo(b)thiophen-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one(5), (E )-3-(5-Fluoro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (6 ), (E)-3-(6-fluoro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1 -Ketone (7), (E)-3-(5-chloro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)propan-2 -En-1-one (8), (E)-3-(5-bromo-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl) ) Prop-2-en-1-one (9), (E)-1-(3,5-dimethoxyphenyl)-3-(1H-indol-3-yl)-2-methyl Prop-2-en-1-one (10), (E)-3-(1H-indol-3-yl)-1-(5-methoxypyridin-3-yl)-2-methylpropane -2-En-1-one (11), (E)-3-(6-methoxy-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethyl Oxyphenyl)prop-2-en-1-one (12), (E)-2-methyl-3-(5-nitro-1H-indol-3-yl)-1-(3, 4,5-Trimethoxyphenyl)prop-2-en-1-one (13), (E)-2-methyl-3-(6-nitro-1H-indol-3-yl)- 1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (14), (E)-2-methyl-3-(7-nitro-1H-indole- 3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (15), (E)-3-(6-amino-1H-indole-3 -Yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (16), (E)-2-((1H-indole- 3-yl)methylene)-1-(3,4,5-trimethoxyphenyl)butan-1-one (17), (E)-1-(3,4-dimethoxyphenyl) )-3 -(1H-indol-3-yl)-2-methylprop-2-en-1-one (18), (E)-3-(1H-indol-3-yl)-1-(3 -Methoxyphenyl)-2-methylprop-2-en-1-one (19), (E)-3-(1H-indol-3-yl)-2-methyl-1-benzene Prop-2-en-1-one (20), (E)-3-(1H-indol-3-yl)-1-phenylprop-2-en-1-one (21), (E )-2-Methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1 -Ketone (22), (E)-2-methyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl )Prop-2-en-1-one (23), (E)-2-methyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(3,4 ,5-Trimethoxyphenyl)prop-2-en-1-one (24), (E)-2-methyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl )-1-(3,4,5-trimethoxyphenyl) prop-2-en-1-one (25), (E)-3-(2-methyl-3-oxo-3-( 3,4,5-Trimethoxyphenyl)prop-1-en-1-yl)-1H-indole-6-carboxylic acid methyl ester (26), (E)-3-(1H-indole- 3-yl)-1-(7-methoxybenzo[d][1,3]dioxol-5-yl)-2-methylprop-2-en-1-one (27 ), (E)-3-(imidazo[1,2-a]pyridin-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-ene -1-one (28), (E)-2-methyl-3-(pyrazolo[1,5-a]pyridin-3-yl)-1-(3,4,5-trimethoxybenzene Yl)prop-2-en-1-one (29), (E)-2-((1H-indol-3-yl)methylene)-5-methoxy-3,4-dihydronaphthalene -1(2H)-ketone (30), (E)-3-(2-methyl-3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-ene-1 -Yl)-1H-indole-6-carboxylic acid (31), (E)-2-methyl-3-(1H-pyrazol-3-yl)-1-(3,4,5-trimethoxy Phenyl)prop-2-en-1-one (32), (E)-2-methyl-3-(1H-pyrrol-3-yl)-1-(3,4,5-trimethoxy Phenyl) prop-2-en-1-one (33), (E)-2-methyl-3-(quinolin-3-yl)-1-(3,4,5-trimethoxyphenyl ) Prop-2-en-1-one (34), (E)-3-(1H-indol-2-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl) )Prop-2-en-1-one (35), (E)-2-(4-(3-(1H-indol-3-yl)-2-methyl Acryloyl)-2,6-dimethylphenoxy)ethyl acetate (36), (E)-3-(7-amino-1H-indol-3-yl)-2-methyl-1 -(3,4,5-Trimethoxyphenyl)prop-2-en-1-one (37) or (E)-3-(5-amino-1H-indol-3-yl)-2- Methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (38).
本发明的第二个方面提供了所述α,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物的制备方法。The second aspect of the present invention provides a preparation method of the α,β-unsaturated ketone derivative and its isomer, salt or solvate prodrug.
在本发明中，所述α,β-不饱和酮衍生物及其异构体的制备方法，包括以下步骤：在0℃下，将3,4,5-三甲氧基苯甲醛(2g,10.19mmol)加入反应容器内，真空处理后加入THF(20mL)和乙基溴化镁(15mL)，在无氧条件下反应4h，TLC监测，用水和乙酸乙酯稀释，并用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，旋干有机相，剩余粗品通过硅胶柱色谱纯化(洗脱剂：乙酸乙酯/正己烷＝1:4)，得中间体1-(3,4,5-三甲氧基苯基)丙-1-醇。在室温下，将其中间体(746.6mg,3.30mmol)溶于CH 2Cl 2(10mL),加入PCC(1068mg,4.96mmol),N 2保护下反应，TLC点板监测，然后用水稀释，CH 2Cl 2萃取，并用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，旋干有机相，剩余粗品通过硅胶柱色谱纯化(洗脱剂：石油醚/乙酸乙酯＝5:1)得化合物1-(3,4,5-三甲氧基苯基)丙-1-酮，将其中间体(448mg,2mmol)溶于哌啶(0.1mL)的甲苯(6mL)溶液中，加入1H-吲哚-3-甲醛(156.8mg,0.8mmol)，130℃反应4h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物。 In the present invention, the preparation method of the α, β-unsaturated ketone derivative and its isomers includes the following steps: 3,4,5-trimethoxybenzaldehyde (2g, 10.19 mmol) was added to the reaction vessel, THF (20mL) and ethylmagnesium bromide (15mL) were added after vacuum treatment, reacted for 4h under anaerobic conditions, monitored by TLC, diluted with water and ethyl acetate, and washed with saturated sodium chloride solution , Dried with anhydrous sodium sulfate, filtered, and spin-dried the organic phase. The remaining crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1:4) to obtain intermediate 1-(3,4,5- Trimethoxyphenyl)prop-1-ol. Dissolve its intermediate (746.6 mg, 3.30 mmol) in CH 2 Cl 2 (10 mL) at room temperature, add PCC (1068 mg, 4.96 mmol), and react under N 2 protection. TLC spot plate monitoring, then dilute with water, CH 2 Cl 2 was extracted, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the organic phase was spin-dried. The remaining crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5:1). Compound 1-(3,4,5-trimethoxyphenyl)-1-propanone, the intermediate (448mg, 2mmol) was dissolved in piperidine (0.1mL) in toluene (6mL), and 1H- Indole-3-carbaldehyde (156.8mg, 0.8mmol) was reacted at 130°C for 4h, the organic phase was spin-dried, and the remaining crude product was recrystallized from ethanol to obtain the target compound.
本发明的第三个方面提供了所述α,β-不饱和酮衍生物、异构体、盐或溶剂合物的前体药物在***疾病中的应用。The third aspect of the present invention provides the application of the prodrug of the α,β-unsaturated ketone derivative, isomer, salt or solvate in the treatment of tumor diseases.
在本发明中，所述在***中的应用优选包括对肿瘤细胞的杀伤作用或在治疗具有多药耐药的肿瘤疾病中的应用。In the present invention, the application in the treatment of tumors preferably includes the killing effect on tumor cells or the application in the treatment of tumor diseases with multidrug resistance.
本发明提供了所述α,β-不饱和酮衍生物、异构体、盐或溶剂合物的前体药物在制备微管抑制剂中的应用。在本发明中，所述应用优选包括作为微管抑制剂抗肿瘤药物对肿瘤细胞的杀伤作用。The present invention provides the application of the prodrug of the α,β-unsaturated ketone derivative, isomer, salt or solvate in the preparation of microtubule inhibitors. In the present invention, the application preferably includes the killing effect of antitumor drugs as a microtubule inhibitor on tumor cells.
在本发明中，所述肿瘤优选包括结肠癌、肺癌或白血病；所述结肠癌优选包括HCT-116(结肠癌细胞)、HCT-116/OXA(耐药结肠癌细胞)。In the present invention, the tumor preferably includes colon cancer, lung cancer or leukemia; the colon cancer preferably includes HCT-116 (colon cancer cell), HCT-116/OXA (drug-resistant colon cancer cell).
本发明的α,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物具有较好的抑制肿瘤细胞增殖的活性，可以有效抑制结肠癌、肺癌、白血病等常见肿瘤细胞以及耐药肿瘤细胞的增殖；本发明合成简单，未涉及繁琐步骤，合成成本低。The α, β-unsaturated ketone derivative and the prodrug of its isomer, salt or solvate of the present invention has good activity of inhibiting the proliferation of tumor cells, and can effectively inhibit common tumors such as colon cancer, lung cancer, leukemia, etc. Proliferation of cells and drug-resistant tumor cells; the invention is simple to synthesize, does not involve complicated steps, and has low synthesis cost.
实施例1Example 1
(E)-2-甲基-3-(4-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(1)的制备(E)-2-Methyl-3-(4-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1- Preparation of ketone (1)
Figure PCTCN2020101590-appb-000017
Figure PCTCN2020101590-appb-000017
步骤a：1-(3,4,5-三甲氧基苯基)丙-1-醇的合成。Step a: Synthesis of 1-(3,4,5-trimethoxyphenyl)propan-1-ol.
在0℃下，将3,4,5-三甲氧基苯甲醛(2g,10.19mmol)加入反应容器内，真空处理后加入THF(20mL)和乙基溴化镁(15mL)，在无氧条件下反应4h，TLC监测，用水和乙酸乙酯稀释，并用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，旋干有机相，剩余粗品通过硅胶柱色谱纯化(洗脱剂：乙酸乙酯/正己烷＝1:4)，得化合物1-(3,4,5-三甲氧基苯基)丙-1-醇2.13g，收率94％。At 0℃, add 3,4,5-trimethoxybenzaldehyde (2g, 10.19mmol) into the reaction vessel, add THF (20mL) and ethylmagnesium bromide (15mL) after vacuum treatment. The reaction was carried out for 4 hours, monitored by TLC, diluted with water and ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried. The remaining crude product was purified by silica gel column chromatography (eluent: ethyl acetate /N-hexane=1:4) to obtain 2.13 g of compound 1-(3,4,5-trimethoxyphenyl)-1-propanol, with a yield of 94%.
步骤b：1-(3,4,5-三甲氧基苯基)丙-1-酮的合成。Step b: Synthesis of 1-(3,4,5-trimethoxyphenyl)propan-1-one.
在室温下，将1-(3,4,5-三甲氧基苯基)丙-1-醇(746.6mg,3.30mmol)溶于CH 2Cl 2(10mL)，加入PCC(1068mg,4.96mmol)，N 2保护下反应，TLC点板监测，然后用水稀释，CH 2Cl 2萃取，并用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，旋干有机相，剩余粗品通过硅胶柱色谱纯化(洗脱剂：石油醚/乙酸乙酯＝5:1)得化合物1-(3,4,5-三甲氧基苯基)丙-1-酮690mg，收率93.2％。 At room temperature, 1-(3,4,5-trimethoxyphenyl)-1-propanol (746.6 mg, 3.30 mmol) was dissolved in CH 2 Cl 2 (10 mL), and PCC (1068 mg, 4.96 mmol) was added The reaction under the protection of N 2 was monitored by TLC spot plate, then diluted with water, extracted with CH 2 Cl 2 and washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and spin-dried the organic phase. The remaining crude product was purified by silica gel column chromatography (Eluent: petroleum ether/ethyl acetate=5:1) 690 mg of compound 1-(3,4,5-trimethoxyphenyl)-1-propanone was obtained, with a yield of 93.2%.
步骤c：(E)-2-甲基-3-(4-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮的合成。Step c: (E)-2-methyl-3-(4-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene Synthesis of -1-one.
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(448mg,2mmol)溶于哌啶(0.1mL)的甲苯(6mL)溶液中，加入4-甲基-1H-吲哚-3-甲醛(156.8mg,0.8mmol)，130℃反应4h,旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-2-甲基-3-(4-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(1)230mg,收率51.3％。 1H NMR(300MHz,CDCl 3)δ8.69(s,1H),7.97(s,1H),7.60(d,1H,J＝1.2Hz),7.26-7.29(m,1H),7.10-7.16(m,1H),6.89-6.95(m,3H),3.89-3.91(m,9H),2.47(s,3H),2.29(s,3H).MS(ESI):m/z[M+H] +:366.17。 Intermediate 1-(3,4,5-trimethoxyphenyl)-1-propanone (448mg, 2mmol) was dissolved in a toluene (6mL) solution of piperidine (0.1mL), and 4-methyl- 1H-Indole-3-carbaldehyde (156.8mg, 0.8mmol), react at 130℃ for 4h, spin off the organic phase, and recrystallize the remaining crude product with ethanol to obtain the target compound (E)-2-methyl-3-(4-methyl) Yl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (1) 230 mg, yield 51.3%. 1 H NMR (300MHz, CDCl 3 ) δ8.69 (s, 1H), 7.97 (s, 1H), 7.60 (d, 1H, J = 1.2Hz), 7.26-7.29 (m, 1H), 7.10-7.16 ( m,1H),6.89-6.95(m,3H),3.89-3.91(m,9H),2.47(s,3H),2.29(s,3H).MS(ESI):m/z(M+H) + :366.17.
实施例2Example 2
(E)-2-甲基-3-(5-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(2)的制备(E)-2-Methyl-3-(5-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1- Preparation of ketone (2)
按照实施例1的方法制备，与实施例1的区别在于，在步骤c中将“4-甲基-1H-吲哚-3-甲醛”替换为“5-甲基-1H-吲哚-3-甲醛”。Prepared according to the method of Example 1, the difference from Example 1 is that in step c, "4-methyl-1H-indole-3-carbaldehyde" is replaced with "5-methyl-1H-indole-3 -formaldehyde".
实施例3Example 3
(E)-2-甲基-3-(6-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(3)的制备(E)-2-Methyl-3-(6-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1- Preparation of ketone (3)
按照实施例1的方法制备，与实施例1的区别在于，在步骤c中将“4-甲基-1H-吲哚-3-甲醛”替换为“6-甲基-1H-吲哚-3-甲醛”。Prepared according to the method of Example 1, the difference from Example 1 is that in step c, "4-methyl-1H-indole-3-carbaldehyde" is replaced with "6-methyl-1H-indole-3 -formaldehyde".
实施例4Example 4
(E)-2-甲基-3-(7-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(4)的制备(E)-2-Methyl-3-(7-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1- Preparation of ketone (4)
按照实施例1的方法制备，与实施例1的区别在于，在步骤c中将“4-甲基-1H-吲哚-3-甲醛”替换为“7-甲基-1H-吲哚-3-甲醛”。Prepared according to the method of Example 1, the difference from Example 1 is that in step c, "4-methyl-1H-indole-3-carbaldehyde" is replaced with "7-methyl-1H-indole-3 -formaldehyde".
实施例5Example 5
(E)-3-(苯并[b]噻吩-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(5)的制备(E)-3-(Benzo(b)thiophen-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (5 ) Preparation
Figure PCTCN2020101590-appb-000018
Figure PCTCN2020101590-appb-000018
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3,4,5-trimethoxyphenyl)propan-1-one was prepared.
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(448mg,2mmol)与苯并[b]噻吩-3-甲醛(162.2mg,1mmol)溶于乙醇(8mL)溶液中，室温搅拌30min，然后加入氢氧化钠(3mL)至反应完全，用CH 2Cl 2萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-3-(苯并[b]噻吩-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮206.1mg,收率56％。 1H NMR(300MHz,CDCl 3)δ7.91(s,1H),7.70(d,2H,J＝13.2Hz),7.44(d,3H,J＝14.1Hz),7.09(s,2H),3.91-3.96(m,9H),2.35(s,3H).MS(ESI):m/z[M+H] +:369.12. The intermediate 1-(3,4,5-trimethoxyphenyl)-1-propanone (448mg, 2mmol) and benzo(b)thiophene-3-carbaldehyde (162.2mg, 1mmol) were dissolved in ethanol (8mL ) In the solution, stirred at room temperature for 30 minutes, then added sodium hydroxide (3mL) until the reaction is complete, extracted with CH 2 Cl 2 , washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, spin-dried the organic phase, the remaining crude product Recrystallize from ethanol to obtain the target compound (E)-3-(benzo(b)thiophen-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-ene -1-one 206.1mg, the yield is 56%. 1 H NMR(300MHz, CDCl 3 )δ7.91(s,1H), 7.70(d,2H,J=13.2Hz), 7.44(d,3H,J=14.1Hz), 7.09(s,2H), 3.91 -3.96(m,9H),2.35(s,3H).MS(ESI):m/z[M+H] + :369.12.
实施例6Example 6
(E)-3-(5-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(6)的制备(E)-3-(5-Fluoro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (6) Preparation
Figure PCTCN2020101590-appb-000019
Figure PCTCN2020101590-appb-000019
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3,4,5-trimethoxyphenyl)propan-1-one was prepared.
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(336mg,1.5mmol)与5-氟-1H-吲哚-3-甲醛(81.6mg,0.5mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-3-(5-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮94.1mg，产率51％ 1H NMR(300MHz,CDCl 3)δ8.62(s,1H),7.67(s,1H),7.54(s,1H),7.36(dd,1H,J＝4.5,8.7Hz),7.20-7.26(m,1H),7.02(s,3H),3.90-3.96(m,9H),2.31(s,3H).MS(ESI):m/z[M+H] +:370.14。 The intermediate 1-(3,4,5-trimethoxyphenyl)-1-propanone (336mg, 1.5mmol) was dissolved with 5-fluoro-1H-indole-3-carbaldehyde (81.6mg, 0.5mmol) Add piperidine (0.3mL) to ethanol (5mL) solution, stir at 95℃ for 48h, spin dry the organic phase, and recrystallize the remaining crude product from ethanol to obtain the target compound (E)-3-(5-fluoro-1H-indole) -3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 94.1mg, yield 51% 1 H NMR (300MHz, CDCl 3 )δ8.62(s,1H), 7.67(s,1H), 7.54(s,1H), 7.36(dd,1H,J=4.5,8.7Hz), 7.20-7.26(m,1H), 7.02(s , 3H), 3.90-3.96 (m, 9H), 2.31 (s, 3H). MS (ESI): m/z[M+H] + : 370.14.
实施例7Example 7
(E)-3-(6-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(7)的制备(E)-3-(6-Fluoro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (7) Preparation
按照实施例6的方法制备，与实施例6的区别在于，将“5-氟-1H-吲哚-3-甲醛”替换为“6-氟-1H-吲哚-3-甲醛”。It is prepared according to the method of Example 6, and the difference from Example 6 is that "5-fluoro-1H-indole-3-carbaldehyde" is replaced with "6-fluoro-1H-indole-3-carbaldehyde".
实施例8Example 8
(E)-3-(5-氯-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(8)的制备(E)-3-(5-chloro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (8) Preparation
按照实施例6的方法制备，与实施例6的区别在于，将“5-氟-1H-吲哚-3-甲醛”替换为“5-氯-1H-吲哚-3-甲醛”。It is prepared according to the method of Example 6, and the difference from Example 6 is that "5-fluoro-1H-indole-3-carbaldehyde" is replaced with "5-chloro-1H-indole-3-carbaldehyde".
实施例9Example 9
(E)-3-(5-溴-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(9)的制备(E)-3-(5-Bromo-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (9) Preparation
Figure PCTCN2020101590-appb-000020
Figure PCTCN2020101590-appb-000020
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3,4,5-trimethoxyphenyl)propan-1-one was prepared.
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(448mg,2mmol)溶于PhCH 3(6mL)、哌啶(0.12mL)中，加入5-溴-1H-吲哚-3-甲醛(149.2mg,0.66mmol)，110℃反应 4h,旋干有机相，剩余粗品经乙醇重结晶得化合物(E)-3-(5-溴-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮154.7mg，收率为54％。 1H NMR(300MHz,CDCl 3)δ8.61(s,1H),7.70(s,1H),7.62(s,1H),7.53(s,1H),7.33-7.38(m,2H),7.03(s,2H),3.91-3.97(m,9H),2.30(s,3H)。 Intermediate 1-(3,4,5-trimethoxyphenyl)-1-propanone (448mg, 2mmol) was dissolved in PhCH 3 (6mL), piperidine (0.12mL), and 5-bromo-1H was added -Indole-3-carbaldehyde (149.2mg, 0.66mmol), react at 110℃ for 4h, spin off the organic phase, and recrystallize the remaining crude product with ethanol to obtain compound (E)-3-(5-bromo-1H-indole-3 -Yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 154.7 mg, the yield was 54%. 1 H NMR (300MHz, CDCl 3 ) δ8.61 (s, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 7.33-7.38 (m, 2H), 7.03 ( s, 2H), 3.91-3.97 (m, 9H), 2.30 (s, 3H).
实施例10Example 10
(E)-1-(3,5-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮(10)的制备(E)-1-(3,5-Dimethoxyphenyl)-3-(1H-indol-3-yl)-2-methylprop-2-en-1-one (10)
Figure PCTCN2020101590-appb-000021
Figure PCTCN2020101590-appb-000021
参照实施例1制备中间体1-(3,5-二甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3,5-dimethoxyphenyl)propan-1-one was prepared.
将中间体1-(3,5-二甲氧基苯基)丙-1-酮(200mg,1.03mmol)与1H-吲哚-3-甲醛(49.8mg,0.323mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-1-(3,5-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮56.1mg，产率51％。 1H NMR(300MHz,CDCl 3)δ8.73(s,1H),7.70(s,1H),7.63(s,1H),7.56(d,1H,J＝7.8Hz),7.43(d,1H,J＝7.8Hz),7.16-7.21(m,1H,),6.86(s,3H),6.64(s,1H),3.83(s,6H),2.31(s,3H).MS(ESI):m/z[M+H] +:322.14。 The intermediate 1-(3,5-dimethoxyphenyl)-1-propanone (200mg, 1.03mmol) and 1H-indole-3-carbaldehyde (49.8mg, 0.323mmol) were dissolved in ethanol (5mL) Add piperidine (0.3mL) to the solution, stir at 95°C for 48h, spin dry the organic phase, and recrystallize the remaining crude product from ethanol to obtain the target compound (E)-1-(3,5-dimethoxyphenyl)-3 -(1H-indol-3-yl)-2-methylprop-2-en-1-one 56.1 mg, yield 51%. 1 H NMR(300MHz,CDCl 3 )δ8.73(s,1H), 7.70(s,1H), 7.63(s,1H), 7.56(d,1H,J=7.8Hz), 7.43(d,1H, J=7.8Hz),7.16-7.21(m,1H,),6.86(s,3H),6.64(s,1H),3.83(s,6H),2.31(s,3H).MS(ESI):m /z[M+H] + :322.14.
实施例11Example 11
(E)-3-(1H-吲哚-3-基)-1-(5-甲氧基吡啶-3-基)-2-甲基丙-2-烯-1-酮(11)的制备(E)-3-(1H-Indol-3-yl)-1-(5-methoxypyridin-3-yl)-2-methylprop-2-en-1-one (11)
Figure PCTCN2020101590-appb-000022
Figure PCTCN2020101590-appb-000022
参照实施例1制备中间体1-(5-甲氧基吡啶-3-基)丙-1-酮。Referring to Example 1, the intermediate 1-(5-methoxypyridin-3-yl)propan-1-one was prepared.
将中间体1-(5-甲氧基吡啶-3-基)丙-1-酮(200mg,1.21mmol)与1H-吲哚-3-甲醛(58.5mg,0.403mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-3-(1H-吲哚-3-基)-1-(5-甲氧基吡啶-3-基)-2-甲基丙-2-烯-1-酮54.3mg，产率46％。 1H NMR(300MHz,CDCl 3)δ8.93(s,1H),8.51(d,2H,J＝18.0Hz),7.67(s,2H),7.53(d,2H,J＝9.0Hz),7.44(d,1H,J＝9.0Hz),7.30(s,1H),7.15-7.20(m,1H),3.93(s,3H),2.32(s,3H).MS(ESI):m/z[M+H] +:293.13。 Intermediate 1-(5-methoxypyridin-3-yl)-1-propanone (200mg, 1.21mmol) and 1H-indole-3-carbaldehyde (58.5mg, 0.403mmol) were dissolved in ethanol (5mL) Add piperidine (0.3mL) to the solution, stir at 95°C for 48h, spin dry the organic phase, and recrystallize the remaining crude product from ethanol to obtain the target compound (E)-3-(1H-indol-3-yl)-1-( 5-Methoxypyridin-3-yl)-2-methylprop-2-en-1-one 54.3 mg, yield 46%. 1 H NMR(300MHz,CDCl 3 )δ8.93(s,1H),8.51(d,2H,J=18.0Hz),7.67(s,2H),7.53(d,2H,J=9.0Hz),7.44 (d,1H,J=9.0Hz),7.30(s,1H),7.15-7.20(m,1H),3.93(s,3H),2.32(s,3H).MS(ESI):m/z[ M+H] + :293.13.
实施例12Example 12
(E)-3-(6-甲氧基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(12)的制备(E)-3-(6-Methoxy-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1 -Preparation of ketone (12)
Figure PCTCN2020101590-appb-000023
Figure PCTCN2020101590-appb-000023
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3,4,5-trimethoxyphenyl)propan-1-one was prepared.
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(336mg,1.5mmol)与6-甲氧基-1H-吲哚-3-甲醛(87.5mg,0.5mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-3-(6-甲氧基-1H- 吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮120mg，产率63％。 1H NMR(600MHz,CDCl 3)δ8.47(s,1H),7.62(s,1H),7.52(d,1H,J＝2.4Hz),7.45(s,1H),7.43(s,1H),7.02(s,1H),6.91(d,1H,J＝2.4Hz),6.85-6.86(dd,1H,J＝2.4,9.0Hz),3.95(s,3H),3.89(s,6H),3.86(s,3H),2.30(d,3H,J＝0.6Hz).MS(ESI):m/z[M+H] +:382.16。 Intermediate 1-(3,4,5-trimethoxyphenyl)-1-propanone (336mg, 1.5mmol) and 6-methoxy-1H-indole-3-carbaldehyde (87.5mg, 0.5mmol) ) Was dissolved in ethanol (5mL) solution, piperidine (0.3mL) was added, stirred at 95°C for 48h, and the organic phase was spin-dried. The remaining crude product was recrystallized from ethanol to obtain the target compound (E)-3-(6-methoxy- 120 mg of 1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, the yield is 63%. 1 H NMR(600MHz, CDCl 3 )δ8.47(s,1H), 7.62(s,1H), 7.52(d,1H,J=2.4Hz), 7.45(s,1H),7.43(s,1H) ,7.02(s,1H),6.91(d,1H,J=2.4Hz),6.85-6.86(dd,1H,J=2.4,9.0Hz),3.95(s,3H),3.89(s,6H), 3.86 (s, 3H), 2.30 (d, 3H, J = 0.6 Hz). MS (ESI): m/z [M+H] + : 382.16.
实施例13Example 13
(E)-2-甲基-3-(5-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(13)的制备(E)-2-Methyl-3-(5-nitro-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1- Preparation of ketone (13)
Figure PCTCN2020101590-appb-000024
Figure PCTCN2020101590-appb-000024
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3,4,5-trimethoxyphenyl)propan-1-one was prepared.
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(336mg,1.5mmol)与5-硝基-1H-吲哚-3-甲醛(102.9mg,0.5mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-2-甲基-3-(5-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮84.5mg，产率41％。 1H NMR(300MHz,DMSO -d6)δ12.50(s,1H),8.49(s,1H),8.07-8.13(d,2H),7.65(d,2H,J＝9.0Hz),7.04(s,2H),3.78-3.84(m,9H),2.23(s,3H). 13C NMR(150MHz,DMSO -d6)δ162.66,159.45,156.50,149.49,146.64,138.11,137.52,134.69,133.86,128.68,128.47,128.24,123.98,121.33,120.19,117.82,116.06,114.97,74.44,67.77,46.02.MS(ESI):m/z[M+H] +:367.17。 The intermediate 1-(3,4,5-trimethoxyphenyl)-1-propanone (336mg, 1.5mmol) and 5-nitro-1H-indole-3-carbaldehyde (102.9mg, 0.5mmol) Dissolve in ethanol (5mL) solution, add piperidine (0.3mL), stir at 95℃ for 48h, spin dry the organic phase, and recrystallize the remaining crude product from ethanol to obtain the target compound (E)-2-methyl-3-(5- Nitro-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 84.5 mg, the yield was 41%. 1 H NMR (300MHz, DMSO -d6 ) δ12.50 (s, 1H), 8.49 (s, 1H), 8.07-8.13 (d, 2H), 7.65 (d, 2H, J = 9.0Hz), 7.04 (s , 2H), 3.78-3.84 (m, 9H), 2.23 (s, 3H). 13 C NMR (150MHz, DMSO -d6) δ162.66,159.45,156.50,149.49,146.64,138.11,137.52,134.69,133.86,128.68, 128.47, 128.24, 123.98, 121.33, 120.19, 117.82, 116.06, 114.97, 74.44, 67.77, 46.02. MS (ESI): m/z[M+H] + : 367.17.
实施例14Example 14
(E)-2-甲基-3-(6-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(14)的制备(E)-2-Methyl-3-(6-nitro-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1- Preparation of ketone (14)
按照实施例13的方法制备，与实施例13的区别在于，将“5-硝基-1H-吲哚-3-甲醛”替换为“6-硝基-1H-吲哚-3-甲醛”。It is prepared according to the method of Example 13, and the difference from Example 13 is that "5-nitro-1H-indole-3-carbaldehyde" is replaced with "6-nitro-1H-indole-3-carbaldehyde".
实施例15Example 15
(E)-2-甲基-3-(7-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(15)的制备(E)-2-Methyl-3-(7-nitro-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1- Preparation of ketone (15)
按照实施例13的方法制备，与实施例13的区别在于，将“5-硝基-1H-吲哚-3-甲醛”替换为“7-硝基-1H-吲哚-3-甲醛”。It was prepared according to the method of Example 13, and the difference from Example 13 was that "5-nitro-1H-indole-3-carbaldehyde" was replaced with "7-nitro-1H-indole-3-carbaldehyde".
实施例16Example 16
(E)-3-(6-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(16)的制备(E)-3-(6-Amino-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (16) Preparation
Figure PCTCN2020101590-appb-000025
Figure PCTCN2020101590-appb-000025
参照实施例13制备(E)-2-甲基-3-(6-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮。Refer to Example 13 to prepare (E)-2-methyl-3-(6-nitro-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)propan-2 -En-1-one.
将(E)-2-甲基-3-(6-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(100mg,0.25mmol)溶于乙醇/水(5：1)中，加入NH 4Cl(53.9mg,1mmol)，搅拌下加 入铁粉(56mg,1mmol)，升温至55℃，TLC点板监测至反应完全。用硅藻土过滤，CH 2Cl 2萃取，并用饱和氯化钠洗涤，无水硫酸钠干燥，过滤，旋干有机相，得到目标化合物(E)-3-(6-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮56.6mg，收率62％。 1H NMR(300MHz,CDCl 3)δ11.35(s,1H),7.54(s,2H),7.08(d,1H,J＝3.0Hz),6.92(s,2H),6.60(d,2H,J＝3.0Hz),6.47-6.48(m,1H),4.89(s,1H),3.77-3.80(m,9H),2.16(s,3H).MS(ESI):m/z[M+H] +:367.16。 (E)-2-Methyl-3-(6-nitro-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1 -Ketone (100mg, 0.25mmol) is dissolved in ethanol/water (5:1), NH 4 Cl (53.9mg, 1mmol) is added, iron powder (56mg, 1mmol) is added while stirring, the temperature is raised to 55°C, and TLC clicks the plate Monitor until the reaction is complete. Filtered with celite, extracted with CH 2 Cl 2 , washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried the organic phase to obtain the target compound (E)-3-(6-amino-1H-indole -3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 56.6 mg, yield 62%. 1 H NMR (300MHz, CDCl 3 ) δ 11.35 (s, 1H), 7.54 (s, 2H), 7.08 (d, 1H, J = 3.0 Hz), 6.92 (s, 2H), 6.60 (d, 2H, J=3.0Hz),6.47-6.48(m,1H),4.89(s,1H),3.77-3.80(m,9H),2.16(s,3H).MS(ESI):m/z[M+H ] + :367.16.
实施例17Example 17
(E)-2-((1H-吲哚-3-基)亚甲基)-1-(3,4,5-三甲氧基苯基)丁-1-酮(17)的制备(E)-2-((1H-Indol-3-yl)methylene)-1-(3,4,5-trimethoxyphenyl)butan-1-one (17)
Figure PCTCN2020101590-appb-000026
Figure PCTCN2020101590-appb-000026
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丁-1-酮。Referring to Example 1, the intermediate 1-(3,4,5-trimethoxyphenyl)butan-1-one was prepared.
将中间体1-(3,4,5-三甲氧基苯基)丁-1-酮(200mg,0.84mmol)与1H-吲哚-3-甲醛(40.6mg,0.28mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-2-((1H-吲哚-3-基)亚甲基)-1-(3,4,5-三甲氧基苯基)丁-1-酮43.9mg，产率43％。 1H NMR(300MHz,CDCl 3)δ8.60(s,1H),7.64(s,1H),7.54-7.57(m,2H),7.44(d,1H,J＝8.1Hz),7.30(s,1H),7.16-7.21(m,1H),7.03(s,2H),3.89-3.95(m,9H),2.83(d,2H,J＝7.5Hz),1.59(s,3H).MS(ESI):m/z[M+H]+:366.17。 The intermediate 1-(3,4,5-trimethoxyphenyl)butan-1-one (200mg, 0.84mmol) and 1H-indole-3-carbaldehyde (40.6mg, 0.28mmol) were dissolved in ethanol (5mL ), add piperidine (0.3mL) to the solution, stir at 95℃ for 48h, spin dry the organic phase, and recrystallize the remaining crude product with ethanol to obtain the target compound (E)-2-((1H-indol-3-yl)methylene Yl)-1-(3,4,5-trimethoxyphenyl)butan-1-one 43.9 mg, the yield was 43%. 1 H NMR(300MHz,CDCl 3 )δ8.60(s,1H),7.64(s,1H),7.54-7.57(m,2H),7.44(d,1H,J=8.1Hz), 7.30(s, 1H),7.16-7.21(m,1H),7.03(s,2H),3.89-3.95(m,9H),2.83(d,2H,J=7.5Hz),1.59(s,3H).MS(ESI ): m/z[M+H]+: 366.17.
实施例18Example 18
(E)-1-(3,4-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮(18)的制备(E)-1-(3,4-Dimethoxyphenyl)-3-(1H-indol-3-yl)-2-methylprop-2-en-1-one (18)
Figure PCTCN2020101590-appb-000027
Figure PCTCN2020101590-appb-000027
参照实施例1制备中间体1-(3,4-二甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3,4-dimethoxyphenyl)propan-1-one was prepared.
将中间体1-(3,4-二甲氧基苯基)丙-1-酮(200mg,1.03mmol)与1H-吲哚-3-甲醛(49.82mg,0.34mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-1-(3,4-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮57.4mg，产率52％。 1H NMR(300MHz,CDCl 3)δ8.72(s,1H),7.57-7.62(m,3H),7.40-7.45(m,3H),7.30(s,1H),7.16-7.21(m,1H),6.93(d,1H,J＝8.1Hz),3.96(d,6H,J＝13.2Hz),2.32(s,3H).MS(ESI):m/z[M+H]+:322.14。 The intermediate 1-(3,4-dimethoxyphenyl)-1-propanone (200mg, 1.03mmol) and 1H-indole-3-carbaldehyde (49.82mg, 0.34mmol) were dissolved in ethanol (5mL) Add piperidine (0.3mL) to the solution, stir at 95°C for 48h, spin dry the organic phase, and recrystallize the remaining crude product from ethanol to obtain the target compound (E)-1-(3,4-dimethoxyphenyl)-3 -(1H-indol-3-yl)-2-methylprop-2-en-1-one 57.4 mg, yield 52%. 1 H NMR (300MHz, CDCl 3 ) δ8.72 (s, 1H), 7.57-7.62 (m, 3H), 7.40-7.45 (m, 3H), 7.30 (s, 1H), 7.16-7.21 (m, 1H) ), 6.93 (d, 1H, J = 8.1 Hz), 3.96 (d, 6H, J = 13.2 Hz), 2.32 (s, 3H). MS (ESI): m/z[M+H]+: 322.14.
实施例19Example 19
(E)-3-(1H-吲哚-3-基)-1-(3-甲氧基苯基)-2-甲基丙-2-烯-1-酮(19)的制备Preparation of (E)-3-(1H-indol-3-yl)-1-(3-methoxyphenyl)-2-methylprop-2-en-1-one (19)
Figure PCTCN2020101590-appb-000028
Figure PCTCN2020101590-appb-000028
参照实施例1制备中间体1-(3-甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3-methoxyphenyl)propan-1-one was prepared.
将中间体1-(3-甲氧基苯基)丙-1-酮(200mg,1.22mmol)与1H-吲哚-3-甲醛(58.94mg,0.41mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-1-(E)-3-(1H-吲哚-3-基)-1-(3-甲氧基苯基)-2-甲基丙-2-烯-1-酮54.4mg，产率46％。 1H NMR(300MHz,CDCl 3)δ8.72 (s,1H),7.65(d,2H,J＝12.3Hz),7.53(d,1H,J＝7.8Hz),7.36-7.44(m,2H),7.26-7.31(m,3H,J＝15.0Hz),7.08-7.20(m,2H),3.86(s,3H),2.31(s,3H).MS(ESI):m/z[M+H]+:292.13。 The intermediate 1-(3-methoxyphenyl)propan-1-one (200mg, 1.22mmol) and 1H-indole-3-carbaldehyde (58.94mg, 0.41mmol) were dissolved in ethanol (5mL) solution, Add piperidine (0.3mL), stir at 95°C for 48h, spin dry the organic phase, and recrystallize the remaining crude product with ethanol to obtain the target compound (E)-1-(E)-3-(1H-indol-3-yl)- 1-(3-Methoxyphenyl)-2-methylprop-2-en-1-one is 54.4 mg, and the yield is 46%. 1 H NMR (300MHz, CDCl 3 )δ8.72 (s, 1H), 7.65 (d, 2H, J = 12.3 Hz), 7.53 (d, 1H, J = 7.8 Hz), 7.36-7.44 (m, 2H) ,7.26-7.31(m,3H,J=15.0Hz),7.08-7.20(m,2H),3.86(s,3H),2.31(s,3H).MS(ESI):m/z[M+H ]+:292.13.
实施例20Example 20
(E)-3-(1H-吲哚-3-基)-2-甲基-1-苯基丙-2-烯-1-酮(20)的制备Preparation of (E)-3-(1H-indol-3-yl)-2-methyl-1-phenylprop-2-en-1-one (20)
Figure PCTCN2020101590-appb-000029
Figure PCTCN2020101590-appb-000029
参照实施例1制备中间体苯丙酮。Refer to Example 1 to prepare intermediate phenylacetone.
将中间体苯丙酮(200mg,1.49mmol)与1H-吲哚-3-甲醛(72.12mg,0.50mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-3-(1H-吲哚-3-基)-2-甲基-1-苯基丙-2-烯-1-酮74.0mg，产率57％。 1H NMR(600MHz,CDCl 3)δ8.76(s,1H),7.73-7.75(m,2H),7.62-7.64(m,2H),7.55-7.57(m,1H),7.47-7.52(m,3H),7.42(d,1H,J＝7.8Hz),7.25-7.28(m,1H),7.15-7.18(m,1H),2.33(s,3H).MS(ESI):m/z[M+H]+:262.12。 The intermediate phenylacetone (200mg, 1.49mmol) and 1H-indole-3-carbaldehyde (72.12mg, 0.50mmol) were dissolved in ethanol (5mL) solution, piperidine (0.3mL) was added, and stirred at 95°C for 48h. Dry organic phase, and the remaining crude product was recrystallized from ethanol to obtain the target compound (E)-3-(1H-indol-3-yl)-2-methyl-1-phenylprop-2-en-1-one 74.0mg , The yield is 57%. 1 H NMR (600MHz, CDCl 3 ) δ8.76 (s, 1H), 7.73-7.75 (m, 2H), 7.62-7.64 (m, 2H), 7.55-7.57 (m, 1H), 7.47-7.52 (m ,3H),7.42(d,1H,J=7.8Hz),7.25-7.28(m,1H),7.15-7.18(m,1H),2.33(s,3H).MS(ESI):m/z[ M+H]+: 262.12.
实施例21Example 21
(E)-3-(1H-吲哚-3-基)-1-苯基丙-2-烯-1-酮(21)的制备Preparation of (E)-3-(1H-indol-3-yl)-1-phenylprop-2-en-1-one (21)
Figure PCTCN2020101590-appb-000030
Figure PCTCN2020101590-appb-000030
将苯乙酮(200mg,1.66mmol)与1H-吲哚-3-甲醛(72.12mg,0.55mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-3-(1H-吲哚-3-基)-1-苯基丙-2-烯-1-酮75.5mg，产率55％。 1H NMR(300MHz,CDCl 3)δ8.54(s,1H),8.03-8.14(m,4H),7.45-7.63(m,6H),7.31-7.34(m,2H).MS(ESI):m/z[M+H]+:248.11。 Dissolve acetophenone (200mg, 1.66mmol) and 1H-indole-3-carbaldehyde (72.12mg, 0.55mmol) in ethanol (5mL) solution, add piperidine (0.3mL), stir at 95℃ for 48h, spin dry In the organic phase, the remaining crude product was recrystallized from ethanol to obtain 75.5 mg of the target compound (E)-3-(1H-indol-3-yl)-1-phenylprop-2-en-1-one with a yield of 55%. 1 H NMR (300MHz, CDCl 3 ) δ8.54 (s, 1H), 8.03-8.14 (m, 4H), 7.45-7.63 (m, 6H), 7.31-7.34 (m, 2H).MS (ESI): m/z[M+H]+: 248.11.
实施例22Example 22
(E)-2-甲基-3-(1H-吡咯并[2,3-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(22)的制备(E)-2-Methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene Preparation of -1-one (22)
Figure PCTCN2020101590-appb-000031
Figure PCTCN2020101590-appb-000031
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3,4,5-trimethoxyphenyl)propan-1-one was prepared.
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(448mg,2mmol)溶于甲苯(6mL)、哌啶(0.12mL)中，加入1H-吡咯并[2,3-b]吡啶-3-甲醛(97.32mg,0.66mmol)，110℃反应4h，过滤，经乙醇重结晶得化合物(E)-2-甲基-3-(1H-吡咯并[2,3-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮96.2mg，收率为41％。Intermediate 1-(3,4,5-trimethoxyphenyl)-1-propanone (448mg, 2mmol) was dissolved in toluene (6mL), piperidine (0.12mL), and 1H-pyrrolo[2 ,3-b]pyridine-3-carbaldehyde (97.32mg, 0.66mmol), reacted at 110°C for 4h, filtered, and recrystallized from ethanol to obtain compound (E)-2-methyl-3-(1H-pyrrolo[2, 3-b]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 96.2 mg, the yield was 41%.
实施例23Example 23
(E)-2-甲基-3-(1H-吡咯并[3,2-c]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(23)的制备(E)-2-Methyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene Preparation of -1-one (23)
按照实施例22的方法制备，与实施例22的区别在于，将“1H-吡咯并[2,3-b]吡啶-3-甲醛”替换为“1H-吡咯并[3,2-c]吡啶-3-甲醛”。Prepared according to the method of Example 22, the difference from Example 22 is that "1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde" is replaced with "1H-pyrrolo[3,2-c]pyridine -3-Formaldehyde".
实施例24Example 24
(E)-2-甲基-3-(1H-吡咯并[3,2-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(24)的制备(E)-2-Methyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene Preparation of -1-one (24)
按照实施例22的方法制备，与实施例22的区别在于，将“1H-吡咯并[2,3-b]吡啶-3-甲醛”替换为“1H-吡咯并[3,2-b]吡啶-3-甲醛”。Prepared according to the method of Example 22, the difference from Example 22 is that "1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde" is replaced with "1H-pyrrolo[3,2-b]pyridine" -3-Formaldehyde".
实施例25Example 25
(E)-2-甲基-3-(1H-吡咯并[2,3-c]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(25)的制备(E)-2-Methyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene Preparation of -1-one (25)
按照实施例22的方法制备，与实施例22的区别在于，将“1H-吡咯并[2,3-b]吡啶-3-甲醛”替换为“1H-吡咯并[2,3-c]吡啶-3-甲醛”。Prepared according to the method of Example 22, the difference from Example 22 is that "1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde" is replaced with "1H-pyrrolo[2,3-c]pyridine -3-Formaldehyde".
实施例26Example 26
(E)-3-(2-甲基-3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)-1H-吲哚-6-羧酸甲酯(26)的制备(E)-3-(2-Methyl-3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-1H-indole-6- Preparation of methyl carboxylate (26)
按照实施例12的方法制备，与实施例12的区别在于，将“6-甲氧基-1H-吲哚-3-甲醛”替换为“3-甲酰基-1H-吲哚-6-羧酸甲酯”。Prepared according to the method of Example 12. The difference from Example 12 is that "6-methoxy-1H-indole-3-carbaldehyde" is replaced with "3-formyl-1H-indole-6-carboxylic acid Methyl ester".
实施例27Example 27
(E)-3-(1H-吲哚-3-基)-1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)-2-甲基丙-2-烯-1-酮(27)的制备(E)-3-(1H-indol-3-yl)-1-(7-methoxybenzo[d][1,3]dioxol-5-yl)-2-methyl Preparation of propyl-2-en-1-one (27)
Figure PCTCN2020101590-appb-000032
Figure PCTCN2020101590-appb-000032
参照实施例1制备中间体1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)丙-1-酮。Referring to Example 1, the intermediate 1-(7-methoxybenzo[d][1,3]dioxol-5-yl)propan-1-one was prepared.
将中间体1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)丙-1-酮(200mg,0.96mmol)与1H-吲哚-3-甲醛(46.48mg,0.32mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-3-(1H-吲哚-3-基)-1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)-2-甲基丙-2-烯-1-酮54.8mg，产率51％。 1H NMR(300MHz,CDCl 3)δ8.66(s,1H),7.59-7.62(m,3H),7.44(d,1H,J＝7.8Hz),7.28-7.31(m,1H),7.17-7.22(m,1H),7.06(s,1H),6.99(s,1H),6.09(s,2H),3.93(s,3H),2.30(s,3H).MS(ESI):m/z[M+H]+:336.12。 Intermediate 1-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1-propanone (200mg, 0.96mmol) and 1H-indole-3 -Formaldehyde (46.48mg, 0.32mmol) was dissolved in ethanol (5mL) solution, piperidine (0.3mL) was added, stirred at 95°C for 48h, the organic phase was spin-dried, and the remaining crude product was recrystallized from ethanol to obtain the target compound (E)-3 -(1H-indol-3-yl)-1-(7-methoxybenzo[d][1,3]dioxol-5-yl)-2-methylpropan-2- En-1-one is 54.8 mg, and the yield is 51%. 1 H NMR(300MHz, CDCl 3 )δ8.66(s,1H), 7.59-7.62(m,3H), 7.44(d,1H,J=7.8Hz), 7.28-7.31(m,1H), 7.17- 7.22 (m, 1H), 7.06 (s, 1H), 6.99 (s, 1H), 6.09 (s, 2H), 3.93 (s, 3H), 2.30 (s, 3H).MS (ESI): m/z [M+H]+:336.12.
实施例28Example 28
(E)-3-(咪唑并[1,2-a]吡啶-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(28)的制备(E)-3-(imidazo[1,2-a]pyridin-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1 -Preparation of ketone (28)
Figure PCTCN2020101590-appb-000033
Figure PCTCN2020101590-appb-000033
参照实施例1制备中间体1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)丙-1-酮。Referring to Example 1, the intermediate 1-(7-methoxybenzo[d][1,3]dioxol-5-yl)propan-1-one was prepared.
将中间体1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)丙-1-酮(200mg,0.89mmol)与1,8a二氢咪唑并[1,2-a]吡啶-3-甲醛(44.05mg,0.30mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-3-(咪唑并[1,2-a]吡啶-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮53.7mg，产率51％。 1H NMR(300MHz,CDCl 3)δ8.09(s,1H),7.99(d,1H,J＝6.6Hz),7.74(d,1H,J＝9.0Hz),7.32-7.38(m,2H),7.26(s,1H),6.93-6.99(m,2H), 3.89-3.95(m,9H),2.39(s,3H).MS(ESI):m/z[M+H]+:353.15。 The intermediate 1-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1-propanone (200mg, 0.89mmol) and 1,8a dihydroimidazole And [1,2-a]pyridine-3-carbaldehyde (44.05mg, 0.30mmol) was dissolved in ethanol (5mL) solution, piperidine (0.3mL) was added, stirred at 95℃ for 48h, and the organic phase was spin-dried to dry the remaining crude product. Ethanol was recrystallized to obtain the target compound (E)-3-(imidazo[1,2-a]pyridin-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)propane The -2-en-1-one is 53.7 mg, and the yield is 51%. 1 H NMR(300MHz,CDCl 3 )δ8.09(s,1H),7.99(d,1H,J=6.6Hz),7.74(d,1H,J=9.0Hz),7.32-7.38(m,2H) , 7.26 (s, 1H), 6.93-6.99 (m, 2H), 3.89-3.95 (m, 9H), 2.39 (s, 3H). MS (ESI): m/z [M+H]+: 353.15.
实施例29Example 29
(E)-2-甲基-3-(吡唑并[1,5-a]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(29)的制备(E)-2-Methyl-3-(pyrazolo[1,5-a]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene- Preparation of 1-ketone (29)
按照实施例28的方法制备，与实施例28的区别在于，将“1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)丙-1-酮”替换为“1-(3,4,5-三甲氧基苯基)丙-1-酮”，将“1,8a二氢咪唑并[1,2-a]吡啶-3-甲醛”替换为“吡唑并[1,5-a]吡啶-3-甲醛”。Prepared according to the method of Example 28, the difference from Example 28 is that "1-(7-methoxybenzo[d][1,3]dioxol-5-yl)propan-1 -Ketone" is replaced with "1-(3,4,5-trimethoxyphenyl)-1-propanone", and "1,8a dihydroimidazo[1,2-a]pyridine-3-carbaldehyde" Replace with "pyrazolo[1,5-a]pyridine-3-carbaldehyde".
实施例30Example 30
(E)-2-((1H-吲哚-3-基)亚甲基)-5-甲氧基-3,4-二氢萘-1(2H)-酮(30)的制备(E)-2-((1H-Indol-3-yl)methylene)-5-methoxy-3,4-dihydronaphthalene-1(2H)-one (30)
Figure PCTCN2020101590-appb-000034
Figure PCTCN2020101590-appb-000034
将5-甲氧基-3,4-二氢萘-1(2H)-酮(200mg,1.13mmol)与1H-吲哚-3-甲醛(54.92mg,0.38mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-2-((1H-吲哚-3-基)亚甲基)-5-甲氧基-3,4-二氢萘-1(2H)-酮(30)59.7mg，产率52％。 1H NMR(300MHz,CDCl 3)δ8.55(s,1H),8.25(s,1H),7.89(d,1H,J＝7.5Hz),7.78(d,1H,J＝7.8Hz),7.55(s,1H),7.43(d,2H,J＝7.5Hz),7.30-7.35(m,2H),7.04(d,1H,J＝8.1Hz),3.89(s,3H)2.97-3.13(m,4H).MS(ESI):m/z[M+H]+:304.13。 Dissolve 5-methoxy-3,4-dihydronaphthalene-1(2H)-one (200mg, 1.13mmol) and 1H-indole-3-carbaldehyde (54.92mg, 0.38mmol) in ethanol (5mL) Add piperidine (0.3mL), stir at 95℃ for 48h, spin dry the organic phase, and recrystallize the remaining crude product from ethanol to obtain the target compound (E)-2-((1H-indol-3-yl)methylene) -5-Methoxy-3,4-dihydronaphthalene-1(2H)-one (30) 59.7mg, yield 52%. 1 H NMR(300MHz, CDCl 3 )δ8.55(s,1H), 8.25(s,1H), 7.89(d,1H,J=7.5Hz), 7.78(d,1H,J=7.8Hz), 7.55 (s, 1H), 7.43 (d, 2H, J = 7.5 Hz), 7.30-7.35 (m, 2H), 7.04 (d, 1H, J = 8.1 Hz), 3.89 (s, 3H) 2.97-3.13 (m ,4H).MS(ESI): m/z[M+H]+: 304.13.
实施例31Example 31
(E)-3-(2-甲基-3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)-1H-吲哚-6-羧酸(31)的制备(E)-3-(2-Methyl-3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-1H-indole-6- Preparation of carboxylic acid (31)
按照实施例12的方法制备，与实施例12的区别在于，将“6-甲氧基-1H-吲哚-3-甲醛”替换为“3-甲酰基-1H-吲哚-6-羧酸”。Prepared according to the method of Example 12, the difference from Example 12 is that "6-methoxy-1H-indole-3-carbaldehyde" is replaced with "3-formyl-1H-indole-6-carboxylic acid" ".
实施例32Example 32
(E)-2-甲基-3-(1H-吡唑-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(32)的制备(E)-2-Methyl-3-(1H-pyrazol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (32) preparation
Figure PCTCN2020101590-appb-000035
Figure PCTCN2020101590-appb-000035
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3,4,5-trimethoxyphenyl)propan-1-one was prepared.
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(336mg,1.5mmol)与1H-吡唑-3-甲醛(48.0mg,0.5mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干，经乙醇重结晶得到目标化合物(E)-2-甲基-3-(1H-吡唑-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮66.4mg，产率44％。 1H NMR(300MHz,CDCl 3)δ8.11(s,1H),7.66(s,1H),7.18(s,1H),6.98(s,2H),6.63(s,1H),3.88-3.92(m,9H),2.34(s,3H)。 Intermediate 1-(3,4,5-trimethoxyphenyl)-1-propanone (336mg, 1.5mmol) and 1H-pyrazole-3-carbaldehyde (48.0mg, 0.5mmol) were dissolved in ethanol (5mL ) Add piperidine (0.3mL) to the solution, stir at 95°C for 48h, spin dry, and recrystallize from ethanol to obtain the target compound (E)-2-methyl-3-(1H-pyrazol-3-yl)-1 -(3,4,5-trimethoxyphenyl)prop-2-en-1-one 66.4mg, yield 44%. 1 H NMR (300MHz, CDCl 3 ) δ 8.11 (s, 1H), 7.66 (s, 1H), 7.18 (s, 1H), 6.98 (s, 2H), 6.63 (s, 1H), 3.88-3.92 ( m, 9H), 2.34 (s, 3H).
实施例33Example 33
(E)-2-甲基-3-(1H-吡咯-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(33)的制备Preparation of (E)-2-methyl-3-(1H-pyrrol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (33)
Figure PCTCN2020101590-appb-000036
Figure PCTCN2020101590-appb-000036
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3,4,5-trimethoxyphenyl)propan-1-one was prepared.
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(336mg,1.5mmol)与1H-吡咯-3-甲醛(47.5mg,0.5mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干，经乙醇重结晶得到目标化合物(E)-2-甲基-3-(1H-吡咯-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮64.5mg，产率43％。 1H NMR(300MHz,CDCl 3)δ8.56(s,1H),7.23(s,1H),7.09(s,1H),6.88-6.92(m,3H),6.52(s,1H),3.88-3.96(m,9H),2.25(s,3H)。 Intermediate 1-(3,4,5-trimethoxyphenyl)-1-propanone (336mg, 1.5mmol) and 1H-pyrrole-3-carbaldehyde (47.5mg, 0.5mmol) were dissolved in ethanol (5mL) Add piperidine (0.3mL) to the solution, stir at 95°C for 48h, spin dry, and recrystallize from ethanol to obtain the target compound (E)-2-methyl-3-(1H-pyrrol-3-yl)-1-( 3,4,5-trimethoxyphenyl)prop-2-en-1-one 64.5mg, the yield was 43%. 1 H NMR(300MHz, CDCl 3 )δ8.56(s,1H), 7.23(s,1H), 7.09(s,1H), 6.88-6.92(m,3H), 6.52(s,1H), 3.88- 3.96 (m, 9H), 2.25 (s, 3H).
实施例34Example 34
(E)-2-甲基-3-(喹啉-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(34)的制备(E)-2-Methyl-3-(quinolin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (34)
Figure PCTCN2020101590-appb-000037
Figure PCTCN2020101590-appb-000037
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3,4,5-trimethoxyphenyl)propan-1-one was prepared.
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(448mg，2mmol)与喹啉-3-甲醛(47.5mg，1mmol)溶于乙醇(8mL)中，室温搅拌30min，然后加入氢氧化钠(3mL)至反应完全，用CH 2Cl 2萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，旋干有机相，经乙醇重结晶得到目标化合物(E)-2-甲基-3-(喹啉-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮85.1mg,收率47％。 1H NMR(300MHz,CDCl 3)δ8.97(s,1H),8.29(s,1H),8.18-8.21(m,1H),7.90(d,1H,J＝8.1Hz),7.78-7.83(m,1H,),7.61-7.66(m,1H),7.28(s,1H),7.07(s,2H),3.91-3.95(m,9H),2.38(s,3H).MS(ESI):m/z[M+H] +:364.15。 Intermediate 1-(3,4,5-trimethoxyphenyl)-1-propanone (448mg, 2mmol) and quinoline-3-carbaldehyde (47.5mg, 1mmol) were dissolved in ethanol (8mL) at room temperature Stir for 30min, then add sodium hydroxide (3mL) until the reaction is complete, extract with CH 2 Cl 2 , wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, spin dry the organic phase, and recrystallize from ethanol to obtain the target compound ( E)-2-Methyl-3-(quinolin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 85.1mg, yield 47% . 1 H NMR(300MHz, CDCl 3 )δ8.97(s,1H), 8.29(s,1H), 8.18-8.21(m,1H), 7.90(d,1H,J=8.1Hz), 7.78-7.83( m,1H,),7.61-7.66(m,1H),7.28(s,1H),7.07(s,2H),3.91-3.95(m,9H),2.38(s,3H).MS(ESI): m/z[M+H] + :364.15.
实施例35Example 35
(E)-3-(1H-吲哚-2-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(35)的制备(E)-3-(1H-indol-2-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (35) preparation
Figure PCTCN2020101590-appb-000038
Figure PCTCN2020101590-appb-000038
参照实施例1制备中间体1-(3,4,5-三甲氧基苯基)丙-1-酮。Referring to Example 1, the intermediate 1-(3,4,5-trimethoxyphenyl)propan-1-one was prepared.
将中间体1-(3,4,5-三甲氧基苯基)丙-1-酮(336mg，1.5mmol)与1H-吲哚-2-甲醛(72.5mg，0.5mmol)溶于乙醇(5mL)溶液中，加入哌啶(0.3mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-3-(1H-吲哚-2-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮82.5mg，产率47％。 1H NMR(300MHz,CDCl 3)δ8.30(s,1H),7.66(d,1H,J＝7.2Hz),7.38(s,2H),7.20(s,2H),6.97(s,2H),6.89(s,1H),3.89-3.94(m,9H),2.43(s,3H)。 The intermediate 1-(3,4,5-trimethoxyphenyl)-1-propanone (336mg, 1.5mmol) and 1H-indole-2-carbaldehyde (72.5mg, 0.5mmol) were dissolved in ethanol (5mL ) Add piperidine (0.3mL) to the solution, stir at 95°C for 48h, spin dry the organic phase, and recrystallize the remaining crude product with ethanol to obtain the target compound (E)-3-(1H-indol-2-yl)-2- Methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 82.5mg, the yield was 47%. 1 H NMR(300MHz,CDCl 3 )δ8.30(s,1H), 7.66(d,1H,J=7.2Hz), 7.38(s,2H), 7.20(s,2H), 6.97(s,2H) , 6.89 (s, 1H), 3.89-3.94 (m, 9H), 2.43 (s, 3H).
实施例36Example 36
(E)-2-(4-(3-(1H-吲哚-3-基)-2-甲基丙烯酰基)-2,6-二甲基苯氧基)乙酸乙酯(36)的制备，合成路线如下：Preparation of (E)-2-(4-(3-(1H-indol-3-yl)-2-methacryloyl)-2,6-dimethylphenoxy) ethyl acetate (36) , The synthetic route is as follows:
Figure PCTCN2020101590-appb-000039
Figure PCTCN2020101590-appb-000039
步骤a：4-((叔丁基二甲基硅烷基)氧基)-3,5-二甲氧基苯甲醛的合成。Step a: Synthesis of 4-((tert-butyldimethylsilyl)oxy)-3,5-dimethoxybenzaldehyde.
将4-羟基-3,5-二甲氧基苯甲醛(10g，54.89mmol)和咪唑(14.95g，219.6mmol)溶于DMF(100mL)中，在0℃下加入TBSCl(16.55g,109.8mmol),TLC监测至反应完全，用水猝灭，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，旋干有机相，剩余粗品通过硅胶柱色谱纯化(洗脱剂：石油醚/乙酸乙酯＝10：1)，得化合物4-((叔丁基二甲基硅烷基)氧基)-3,5-二甲氧基苯甲醛11.37g，收率70％。Dissolve 4-hydroxy-3,5-dimethoxybenzaldehyde (10g, 54.89mmol) and imidazole (14.95g, 219.6mmol) in DMF (100mL), add TBSCl (16.55g, 109.8mmol) at 0°C ), TLC monitored until the reaction was complete, quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and spin-dried the organic phase. The remaining crude product was purified by silica gel column chromatography (eluent: petroleum Ether/ethyl acetate=10:1) to obtain 11.37 g of compound 4-((tert-butyldimethylsilyl)oxy)-3,5-dimethoxybenzaldehyde, with a yield of 70%.
步骤b、c参照实施例1中的步骤a、b。Steps b and c refer to steps a and b in Example 1.
步骤d：1-(4-羟基-3,5-二甲氧基苯基)丙-1-酮的合成。Step d: Synthesis of 1-(4-hydroxy-3,5-dimethoxyphenyl)propan-1-one.
将1-(4-((叔丁基二甲基硅烷基)氧基)-3,5-二甲氧基苯基)丙-1-酮(2.32g，7.15mmol)溶于THF(30mL)，在0℃下加入TBAF(7.5mL)，N 2保护下反应2h，TLC监测至反应完全，用水猝灭，乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，旋干有机相，剩余粗品通过硅胶柱色谱纯化(洗脱剂：石油醚/乙酸乙酯＝1：1)，得化合物1-(4-羟基-3,5-二甲氧基苯基)丙-1-酮1.34g，收率89％。 Dissolve 1-(4-((tert-butyldimethylsilyl)oxy)-3,5-dimethoxyphenyl)-1-propanone (2.32g, 7.15mmol) in THF (30mL) TBAF (7.5mL) was added at 0°C and reacted for 2h under N 2 protection. TLC monitored until the reaction was complete, quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and rotated Dry organic phase, and the remaining crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1:1) to obtain compound 1-(4-hydroxy-3,5-dimethoxyphenyl) propyl- 1.34g of 1-ketone, yield 89%.
步骤e：2-(2,6-二甲氧基-4-丙酰基苯氧基)乙酸乙酯的合成。Step e: Synthesis of ethyl 2-(2,6-dimethoxy-4-propionylphenoxy)acetate.
将1-(4-羟基-3,5-二甲氧基苯基)丙-1-酮(266mg,1.27mmol)、碳酸钾(351.9mg,2.55mmol)、2-溴乙酸乙酯(425.1mg,2.55mmol)溶于DMF(6mL)中，TLC监测至反应完全，用水猝灭，乙酸乙酯萃取，氯化钠洗涤，无水硫酸钠干燥，通过硅胶柱色谱纯化(洗脱剂：石油醚/乙酸乙酯＝10：1)，得化合物2-(2,6-二甲氧基-4-丙酰基苯氧基)乙酸乙酯296.2mg，收率79％。Combine 1-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone (266mg, 1.27mmol), potassium carbonate (351.9mg, 2.55mmol), ethyl 2-bromoacetate (425.1mg , 2.55mmol) was dissolved in DMF (6mL), TLC monitored until the reaction was complete, quenched with water, extracted with ethyl acetate, washed with sodium chloride, dried with anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: petroleum ether /Ethyl acetate=10:1) to obtain 296.2 mg of compound 2-(2,6-dimethoxy-4-propionylphenoxy) ethyl acetate with a yield of 79%.
步骤f：(E)-2-(4-(3-(1H-吲哚-3-基)-2-甲基丙烯酰基)-2,6-二甲基苯氧基)乙酸乙酯的合成。Step f: Synthesis of (E)-2-(4-(3-(1H-indol-3-yl)-2-methacryloyl)-2,6-dimethylphenoxy) ethyl acetate .
将中间体2-(2,6-二甲氧基-4-丙酰基苯氧基)乙酸乙酯(460mg,1.55mmol)与1H-吲哚-3-甲醛(75.1mg,0.5mmol)溶于乙醇(10mL)溶液中，加入哌啶(0.6mL)，95℃搅拌48h，旋干有机相，剩余粗品经乙醇重结晶得到目标化合物(E)-2-(4-(3-(1H-吲哚-3-基)-2-甲基丙烯酰基)-2,6-二甲基苯氧基)乙酸乙酯100.7mg，收率46％。 1H NMR(300MHz,CDCl 3)δ8.61(s,1H),7.66(s,2H),7.57(s,1H),7.43(s,1H),7.21(s,2H),7.01(s,1H),4.70-4.74(m,2H),4.30(d,2H,J＝7.2Hz),3.87-3.90(m,6H),2.31(s,3H),1.25(s,3H)。 The intermediate 2-(2,6-dimethoxy-4-propionylphenoxy) ethyl acetate (460mg, 1.55mmol) and 1H-indole-3-carbaldehyde (75.1mg, 0.5mmol) were dissolved in Add piperidine (0.6mL) to ethanol (10mL) solution, stir at 95°C for 48h, spin dry the organic phase, and recrystallize the remaining crude product from ethanol to obtain the target compound (E)-2-(4-(3-(1H-indole) Dol-3-yl)-2-methacryloyl)-2,6-dimethylphenoxy) ethyl acetate 100.7 mg, yield 46%. 1 H NMR(300MHz,CDCl 3 )δ8.61(s,1H),7.66(s,2H),7.57(s,1H),7.43(s,1H),7.21(s,2H),7.01(s, 1H), 4.70-4.74 (m, 2H), 4.30 (d, 2H, J=7.2 Hz), 3.87-3.90 (m, 6H), 2.31 (s, 3H), 1.25 (s, 3H).
实施例37Example 37
(E)-3-(7-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(37)的制备(E)-3-(7-amino-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (37) Preparation
按照实施例16的方法制备，与实施例16的区别在于，将“(E)-2-甲基-3-(6-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮”替换为“(E)-2-甲基-3-(7-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮”。Prepared according to the method of Example 16, the difference from Example 16 is that "(E)-2-methyl-3-(6-nitro-1H-indol-3-yl)-1-(3, 4,5-Trimethoxyphenyl)prop-2-en-1-one" is replaced with "(E)-2-methyl-3-(7-nitro-1H-indol-3-yl)- 1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one".
实施例38Example 38
(E)-3-(5-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮(38)(E)-3-(5-amino-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (38)
按照实施例16的方法制备，与实施例16的区别在于，将“(E)-2-甲基-3-(6-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮”替换为“(E)-2-甲基-3-(5-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮”。Prepared according to the method of Example 16, the difference from Example 16 is that "(E)-2-methyl-3-(6-nitro-1H-indol-3-yl)-1-(3, 4,5-Trimethoxyphenyl)prop-2-en-1-one" is replaced with "(E)-2-methyl-3-(5-nitro-1H-indol-3-yl)- 1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one".
实施例39Example 39
本发明化合物的体外抗肿瘤活性测试In vitro anti-tumor activity test of the compounds of the invention
采用了CellTiter-Blue法，测试了本发明合成化合物1～38和部分中间体的体外抗肿瘤活性。The CellTiter-Blue method was used to test the in vitro anti-tumor activity of synthetic compounds 1 to 38 and some intermediates of the present invention.
实验方法：HCT-116(结肠癌细胞)、HCT-116/OXA(耐药结肠癌细胞)，用RPMI+10％FBS+1％双抗培养。Experimental method: HCT-116 (colon cancer cell), HCT-116/OXA (drug resistant colon cancer cell), cultured with RPMI+10% FBS+1% double antibody.
样品液配制：用DMSO溶解化合物或中间体，配成浓度为50μM的母液。然后用含1％DMSO的培养基稀释(三倍或五倍稀释)，最终配成系列梯度浓度溶液。Sample solution preparation: Dissolve the compound or intermediate in DMSO to prepare a mother solution with a concentration of 50μM. Then it is diluted with a medium containing 1% DMSO (three-fold or five-fold dilution), and finally a series of gradient concentration solutions are prepared.
96孔板每孔加4000～8000个细胞，置于37℃、5％CO 2培养箱内孵育24小时后，分别加入样品液和对照品液，200μL/孔，37℃作用72小时。每孔加入的CellTiter-Blue(荧光蓝细胞活性试剂盒)溶液20μL，作用0.5～1小时后用全自动酶标仪(生产厂商LabsystemsDragon)测570/590nmOD值，计算半数抑制浓度IC 50。 Add 4000 to 8000 cells per well in a 96-well plate. After incubating for 24 hours in a 37°C, 5% CO 2 incubator, add sample solution and reference solution, 200μL/well, at 37°C for 72 hours. Add 20 μL of CellTiter-Blue (fluorescent blue cell activity kit) solution to each well, measure the 570/590nm OD value with an automatic microplate reader (manufacturer LabsystemsDragon) after 0.5 to 1 hour, and calculate the IC 50 of the half inhibitory concentration.
使用GraphPadPrism软件分析处理数据，最终测得化合物IC 50值。 GraphPad Prism software was used to analyze and process the data, and finally the IC 50 value of the compound was measured.
根据以上的体外抗肿瘤活性测试方法对本发明的化合物进行体外抗肿瘤活性研究：According to the above in vitro anti-tumor activity test method, the compound of the present invention is subjected to in vitro anti-tumor activity research:
选取了2种肿瘤细胞株研究目标化合物的体外抗肿瘤活性：HCT-116(结肠癌细胞)、HCT-116/OXA(耐药结肠癌细胞)。选用CellTiter-Blue法进行活性测试，结果显示，化合物对结肠癌及其耐药细胞株均表现出较好的抗肿瘤活性，尤其对耐药白血病细胞表现出更好的抗肿瘤活性。其中活性最好的衍生物主要有2个：化合物6和7，IC 50值都在10nM以下。但是苯环上无甲氧基取代的化合物活性显著降低，如化合物20和21；吲哚环上的溴取代、羧基取代后，活性也显著降低，如化合物9、31。 Two tumor cell lines were selected to study the in vitro anti-tumor activity of the target compounds: HCT-116 (colon cancer cells) and HCT-116/OXA (drug-resistant colon cancer cells). The CellTiter-Blue method was selected for activity testing, and the results showed that the compound showed good anti-tumor activity against colon cancer and its drug-resistant cell lines, especially against drug-resistant leukemia cells. Among them, there are mainly 2 derivatives with the best activity: compounds 6 and 7, with IC 50 values below 10 nM. However, the activity of compounds without methoxy substitution on the benzene ring is significantly reduced, such as compounds 20 and 21; after bromine substitution and carboxyl substitution on the indole ring, the activity is also significantly reduced, such as compounds 9, 31.
表1目标化合物对结肠癌(HCT-116)及耐药结肠癌(HCT-116/OXA)细胞的IC 50值 Table 1 IC 50 values of target compounds on colon cancer (HCT-116) and drug-resistant colon cancer (HCT-116/OXA) cells
Figure PCTCN2020101590-appb-000040
Figure PCTCN2020101590-appb-000040
Figure PCTCN2020101590-appb-000041
Figure PCTCN2020101590-appb-000041
实施例40Example 40
本发明制备的化合物的体内抗肿瘤活性测试In vivo anti-tumor activity test of the compound prepared by the present invention
选取化合物7(体内实验编号为FC116)进行体内抗肿瘤活性实验；选取了HCT-116/OXA耐药细胞移植瘤裸鼠模型考察了其体内抑瘤活性。Select compound 7 (in vivo experiment number FC116) for in vivo anti-tumor activity experiment; select HCT-116/OXA drug-resistant cell xenograft nude mouse model to investigate its anti-tumor activity in vivo.
实验方法：experimental method:
1、动物：选取4周龄雄性裸鼠；1. Animals: select 4-week-old male nude mice;
2、受试物给药2. Administration of test substance
给药剂量：1.5mg/kg，3mg/kg，10mg/kg(OXA)Dosage: 1.5mg/kg, 3mg/kg, 10mg/kg (OXA)
给药途径：腹腔注射(i.p.)Route of administration: intraperitoneal injection (i.p.)
给药体积：200μLDosing volume: 200μL
3、受试物配制3. Preparation of test substance
6mg/mLFC116(化合物7)：将6mgFC116溶于300μL吐温80、100μL蓖麻油和9.6mL0.5％CMC-Na中涡旋超声混匀。6 mg/mL FC116 (Compound 7): Dissolve 6 mg FC116 in 300 μL Tween 80, 100 μL castor oil, and 9.6 mL 0.5% CMC-Na, vortex and ultrasonically mix.
10mg/mLOXA：将10mgFC116溶于300μL吐温80、100μL蓖麻油和9.6mL0.5％CMC-Na中涡旋超声混匀。10mg/mLOXA: Dissolve 10mg FC116 in 300μL Tween 80, 100μL castor oil and 9.6mL0.5% CMC-Na by vortexing and sonicating.
4、试验过程4. Test process
健康裸鼠24只，平均分成4组，腹腔注射给药，连续给药3周，平均每三天称重，测肿瘤体积。动物处理：取瘤子和器官。Twenty-four healthy nude mice were divided into 4 groups evenly. They were injected intraperitoneally for 3 weeks and weighed every three days on average to measure the tumor volume. Animal treatment: Take tumors and organs.
结果如图1所示，其中，A为裸鼠移植瘤体积变化，B为终末瘤体积间的比较，C为裸鼠体重变化，D为给药组离体肿瘤与对照组肿瘤的比较。由图1可知，奥沙利铂(Oxaliplatin，OXA)的抑制率40％，FC116(1.5mg/kg/d，i.p.)与奥沙利铂相当，抑瘤率45％；当FC116(化合物7)剂量提高到3mg/kg/d，i.p.具有明显体内抗肿瘤活性，抑瘤率为78％，且毒性相对较低。The results are shown in Figure 1, where A is the volume change of transplanted tumors in nude mice, B is the comparison of terminal tumor volumes, C is the weight changes of nude mice, and D is the comparison of the tumors in the administration group and the control group. It can be seen from Figure 1 that the inhibition rate of oxaliplatin (OXA) is 40%, FC116 (1.5mg/kg/d, ip) is equivalent to oxaliplatin, and the tumor inhibition rate is 45%; when FC116 (compound 7) When the dose is increased to 3mg/kg/d, ip has obvious anti-tumor activity in vivo, with 78% tumor inhibition rate and relatively low toxicity.
实施例41Example 41
本发明制备的化合物7的药代动力学性质研究Study on the pharmacokinetic properties of compound 7 prepared by the invention
健康成年ICR小鼠18只，给药开始前小鼠体重为21～25g，平均分成2组，小鼠的腹腔注射给药。18 healthy adult ICR mice, the mice weighing 21-25g before the start of administration, were divided into 2 groups evenly, and the mice were injected intraperitoneally.
0.15mg/mLFC116(i.p.)：将0.15mgFC116溶于300μL吐温80、100μL蓖麻油和9.6mL0.5％CMC-Na中涡旋超声混匀。0.15 mg/mL FC116 (i.p.): Dissolve 0.15 mg FC116 in 300 μL Tween 80, 100 μL castor oil and 9.6 mL 0.5% CMC-Na by vortexing and sonicating.
0.30mg/mLFC116(i.p.)：将0.30mgFC116溶于300μL吐温80、100μL蓖麻油和9.6mL0.5％CMC-Na中涡旋超声混匀。0.30 mg/mL FC116 (i.p.): Dissolve 0.30 mg FC116 in 300 μL Tween 80, 100 μL castor oil and 9.6 mL 0.5% CMC-Na by vortexing and sonicating.
样品采集和处理：两组小鼠分别于给药前及给药后15min、30min、1h、2h、4h、8h、24h、32h、48h和72h，采用卫星采血法采集全血0.1mL，加入肝素钠抗凝，在4℃条件下离心5min以分离血浆，于-80℃保存待测，每个时间点采集3只动物。Sample collection and processing: The two groups of mice were taken before and after 15min, 30min, 1h, 2h, 4h, 8h, 24h, 32h, 48h and 72h respectively. The satellite blood sampling method was used to collect 0.1mL of whole blood and add heparin. Sodium anticoagulation, centrifugation at 4°C for 5min to separate plasma, store at -80°C for testing, and collect 3 animals at each time point.
LC-MS/MS法测定小鼠给药后不同点血浆中的原形药物浓度。标准曲线：取空白小鼠血浆25μL，分别加入FC116标准系列溶液各25μL和甲醇250μL，涡旋混合2min，在4℃、3200rpm条件下离心20min，取上清液用于LC-MS/MS分析。未知样品：取小鼠血浆样品各25μL，加入甲醇275μL，涡旋混合2min，在4℃、3200rpm条件下离心20min，取上清液用于LC-MS/MS分析。The LC-MS/MS method was used to determine the original drug concentration in the plasma of mice at different points after administration. Standard curve: Take 25μL of blank mouse plasma, add 25μL of FC116 standard series solution and 250μL of methanol, vortex for 2min, centrifuge at 4℃, 3200rpm for 20min, take the supernatant for LC-MS/MS analysis. Unknown sample: Take 25μL of each mouse plasma sample, add 275μL of methanol, vortex for 2min, centrifuge at 4℃, 3200rpm for 20min, take the supernatant for LC-MS/MS analysis.
小鼠单次腹腔注射给予FC116的血药浓度-时间曲线如图2所示，相应药代动力学参数如表2所示。The blood concentration-time curve of a single intraperitoneal injection of FC116 in mice is shown in Figure 2, and the corresponding pharmacokinetic parameters are shown in Table 2.
表2 ICR小鼠腹腔注射给予1.5mg/kg，3mg/kg的化合物7(FC116)血浆药物浓度Table 2 Plasma drug concentration of compound 7 (FC116) given by intraperitoneal injection of 1.5 mg/kg and 3 mg/kg in ICR mice
Figure PCTCN2020101590-appb-000042
Figure PCTCN2020101590-appb-000042
由图2和表2可知，1.5mg/kg的FC116血浆药物浓度在0.5h即可达到最高血药浓度69.2ng/mL(表2),4h代谢完全(图2)，更高浓度(3mg/kg)的FC116在0.25h即可达到最高血药浓度118ng/mL，且8h代谢完全，均无体内蓄积。From Figure 2 and Table 2, it can be seen that the plasma drug concentration of FC116 at 1.5 mg/kg can reach the highest plasma drug concentration of 69.2 ng/mL within 0.5 h (Table 2), complete metabolism at 4 h (Figure 2), and higher concentration (3 mg/kg). kg) FC116 can reach the highest blood concentration of 118ng/mL in 0.25h, and the metabolism is complete in 8h, and there is no accumulation in the body.
综上所述，本发明制备的化合物及其盐类可以用于制备抗抗肿瘤药物。In summary, the compounds and their salts prepared in the present invention can be used to prepare anti-tumor drugs.
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。对这些实施例的多种修改对本领域的专业技术人员来说是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。The description of the above embodiments is only used to help understand the method and core idea of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention. Various modifications to these embodiments are obvious to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown in this document, but should conform to the widest scope consistent with the principles and novel features disclosed in this document.

Claims (10)

  1. 一类α,β-不饱和酮衍生物、异构体、盐或溶剂合物的前体药物，其特征在于，α,β-不饱和酮衍生物的结构如通式Ⅰ所示：A class of α, β-unsaturated ketone derivatives, isomers, salts or prodrugs of solvates, characterized in that the structure of α, β-unsaturated ketone derivatives is shown in general formula I:
    Figure PCTCN2020101590-appb-100001
    Figure PCTCN2020101590-appb-100001
    其中，A和B分别选自饱和环、芳环、芳杂环、饱和环或芳环及芳杂环并环；Wherein, A and B are respectively selected from saturated ring, aromatic ring, aromatic heterocyclic ring, saturated ring or aromatic ring and aromatic heterocyclic ring;
    R 1选自氢、1～7个相同或不同C1-C10烷氧基； R 1 is selected from hydrogen, 1-7 identical or different C1-C10 alkoxy groups;
    R 2选自氢、1～7个相同或不同C1-C10烷基、卤素、氮氢元素组成的取代基、碳氢氧元素组成的取代基或氮氧元素组成的取代基；所述碳氢氧元素组成的取代基包括C1-C10烷氧基； R 2 is selected from hydrogen, 1 to 7 identical or different C1-C10 alkyl groups, halogens, substituents composed of nitrogen and hydrogen, substituents composed of carbon, hydrogen and oxygen, or substituents composed of nitrogen and oxygen; The substituent composed of oxygen element includes C1-C10 alkoxy;
    R 3选自氢、C1-C10烷基或与A组成多元环的-(CH 2) n-，其中，n＝1～10。 R 3 is selected from hydrogen, C1-C10 alkyl, or -(CH 2 ) n -which forms a polycyclic ring with A, wherein n=1-10.
  2. 如权利要求1所述的α,β-不饱和酮衍生物、异构体、盐或溶剂合物的前体药物，其特征在于：The α,β-unsaturated ketone derivative, isomer, salt or solvate prodrug of claim 1, wherein:
    所述R 1中C1-C10烷氧基的个数为1～5个。 The number of C1-C10 alkoxy groups in R 1 is 1 to 5.
  3. 如权利要求1所述的α,β-不饱和酮衍生物、异构体、盐或溶剂合物的前体药物，其特征在于：The α,β-unsaturated ketone derivative, isomer, salt or solvate prodrug of claim 1, wherein:
    所述R 1选自-OCH 2COOCH 2CH 3。 The R 1 is selected from -OCH 2 COOCH 2 CH 3 .
  4. 如权利要求1～3任一项所述的α,β-不饱和酮衍生物、异构体、盐或溶剂合物的前体药物，其特征在于：The α, β-unsaturated ketone derivative, isomer, salt or solvate prodrug according to any one of claims 1 to 3, characterized in that:
    所述A和B分别选自饱和环、芳环、芳杂环、饱和环或芳环及芳杂环并环；Said A and B are respectively selected from saturated ring, aromatic ring, aromatic heterocyclic ring, saturated ring or aromatic ring and aromatic heterocyclic ring;
    所述R 1选自氢、所述A上不同位置取代的三甲氧基、二甲氧基、单甲氧基、
    Figure PCTCN2020101590-appb-100002
    Figure PCTCN2020101590-appb-100003
    The R 1 is selected from the group consisting of hydrogen, trimethoxy, dimethoxy, monomethoxy, substituted at different positions on the A,
    Figure PCTCN2020101590-appb-100002
    Figure PCTCN2020101590-appb-100003
    所述R 2选自氢、所述B上不同位置单取代的甲氧基、甲基、氟、氯、溴、硝基、胺基、羧基或
    Figure PCTCN2020101590-appb-100004
    The R 2 is selected from hydrogen, methoxy, methyl, fluorine, chlorine, bromine, nitro, amine, carboxyl or mono-substituted at different positions on the B
    Figure PCTCN2020101590-appb-100004
    所述R 3选自氢、甲基、乙基或与所述A组成多元环的-(CH 2) n-，其中，n＝1～10。 The R 3 is selected from hydrogen, methyl, ethyl or -(CH 2 ) n -which forms a polycyclic ring with the A, where n=1-10.
  5. 如权利要求1～3任一项所述的α,β-不饱和酮衍生物、异构体、盐或溶剂合物的前体药物，其特征在于：The α, β-unsaturated ketone derivative, isomer, salt or solvate prodrug according to any one of claims 1 to 3, characterized in that:
    所述A选自
    Figure PCTCN2020101590-appb-100005
    The A is selected from
    Figure PCTCN2020101590-appb-100005
    所述B选自
    Figure PCTCN2020101590-appb-100006
    Figure PCTCN2020101590-appb-100007
    The B is selected from
    Figure PCTCN2020101590-appb-100006
    Figure PCTCN2020101590-appb-100007
    所述R 1选自氢、A上不同位置取代的三甲氧基、二甲氧基、单甲氧基、
    Figure PCTCN2020101590-appb-100008
    Figure PCTCN2020101590-appb-100009
    The R 1 is selected from the group consisting of hydrogen, trimethoxy, dimethoxy, monomethoxy, substituted at different positions on A,
    Figure PCTCN2020101590-appb-100008
    Figure PCTCN2020101590-appb-100009
    所述R 2选自氢、B上不同位置单取代的甲氧基、甲基、氟、氯、溴、硝基、胺基、羧基或
    Figure PCTCN2020101590-appb-100010
    The R 2 is selected from hydrogen, mono-substituted methoxy, methyl, fluorine, chlorine, bromine, nitro, amine, carboxyl or
    Figure PCTCN2020101590-appb-100010
    所述R 3选自氢、甲基、乙基或与A组成六元环的-CH 2CH 2-。 The R 3 is selected from hydrogen, methyl, ethyl, or -CH 2 CH 2 -which forms a six-membered ring with A.
  6. 如权利要求1～3任一项所述的α,β-不饱和酮衍生物、异构体、盐或溶剂合物的前体药物，其特征在于：所述结构通式I所示化合物，其药学上可接受的盐包括通式I化合物与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。The α,β-unsaturated ketone derivative, isomer, salt or solvate prodrug according to any one of claims 1 to 3, wherein the compound represented by the general structural formula I, The pharmaceutically acceptable salts thereof include acid addition salts formed by compounds of general formula I with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, lemon Acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.
  7. 根据权利要求1～3所述的α,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物，其特征在于：所述的α,β-不饱和酮衍生物选自以下结构中的一种：The α, β-unsaturated ketone derivative and its isomer, salt or solvate prodrug according to claims 1 to 3, characterized in that: the α, β-unsaturated ketone derivative One of the following structures:
    (E)-2-甲基-3-(4-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(5-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(6-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(7-甲基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(苯并[b]噻吩-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(5-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(6-氟-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(5-氯-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(5-溴-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-1-(3,5-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮、(E)-3-(1H-吲哚-3-基)-1-(5-甲氧基吡啶-3-基)-2-甲基丙-2-烯-1-酮、(E)-3-(6-甲氧基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(5-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(6-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(7-硝基-1H-吲哚-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(6-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-((1H-吲哚-3-基)亚甲基)-1-(3,4,5-三甲氧基苯基)丁-1-酮、(E)-1-(3,4-二甲氧基苯基)-3-(1H-吲哚-3-基)-2-甲基丙-2-烯-1-酮、(E)-3-(1H-吲哚-3-基)-1-(3-甲氧基苯基)-2-甲基丙-2-烯-1-酮、(E)-3-(1H-吲哚-3-基)-2-甲基-1-苯基丙-2-烯-1-酮、(E)-3-(1H-吲哚-3-基)-1-苯基丙-2-烯 -1-酮、(E)-2-甲基-3-(1H-吡咯并[2,3-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(1H-吡咯并[3,2-c]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(1H-吡咯并[3,2-b]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(1H-吡咯并[2,3-c]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(2-甲基-3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)-1H-吲哚-6-羧酸甲酯、(E)-3-(1H-吲哚-3-基)-1-(7-甲氧基苯并[d][1,3]二氧杂环戊烯-5-基)-2-甲基丙-2-烯-1-酮、(E)-3-(咪唑并[1,2-a]吡啶-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(吡唑并[1,5-a]吡啶-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-((1H-吲哚-3-基)亚甲基)-5-甲氧基-3,4-二氢萘-1(2H)-酮、(E)-3-(2-甲基-3-氧代-3-(3,4,5-三甲氧基苯基)丙-1-烯-1-基)-1H-吲哚-6-羧酸、(E)-2-甲基-3-(1H-吡唑-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(1H-吡咯-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-甲基-3-(喹啉-3-基)-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-3-(1H-吲哚-2-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮、(E)-2-(4-(3-(1H-吲哚-3-基)-2-甲基丙烯酰基)-2,6-二甲基苯氧基)乙酸乙酯、(E)-3-(7-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮或(E)-3-(5-氨基-1H-吲哚-3-基)-2-甲基-1-(3,4,5-三甲氧基苯基)丙-2-烯-1-酮。(E)-2-Methyl-3-(4-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene-1- Ketone, (E)-2-methyl-3-(5-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene- 1-ketone, (E)-2-methyl-3-(6-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)propan-2- En-1-one, (E)-2-methyl-3-(7-methyl-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop- 2-en-1-one, (E)-3-(benzo(b)thiophen-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2 -En-1-one, (E)-3-(5-fluoro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop- 2-en-1-one, (E)-3-(6-fluoro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)propane -2-En-1-one, (E)-3-(5-chloro-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl) Prop-2-en-1-one, (E)-3-(5-bromo-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl) )Prop-2-en-1-one, (E)-1-(3,5-dimethoxyphenyl)-3-(1H-indol-3-yl)-2-methylpropan-2 -En-1-one, (E)-3-(1H-indol-3-yl)-1-(5-methoxypyridin-3-yl)-2-methylprop-2-ene-1 -Ketone, (E)-3-(6-methoxy-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)propan-2- En-1-one, (E)-2-methyl-3-(5-nitro-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop- 2-en-1-one, (E)-2-methyl-3-(6-nitro-1H-indol-3-yl)-1-(3,4,5-trimethoxyphenyl) Prop-2-en-1-one, (E)-2-methyl-3-(7-nitro-1H-indol-3-yl)-1-(3,4,5-trimethoxybenzene Yl)prop-2-en-1-one, (E)-3-(6-amino-1H-indol-3-yl)-2-methyl-1-(3,4,5-trimethoxy Phenyl) prop-2-en-1-one, (E)-2-((1H-indol-3-yl)methylene)-1-(3,4,5-trimethoxyphenyl) Butan-1-one, (E)-1-(3,4-dimethoxyphenyl)-3-(1H-indol-3-yl)-2-methylprop-2-ene-1- Ketone, (E)-3-(1H-indol-3-yl)-1-(3-methoxyphenyl)-2-methylprop-2-en-1-one, (E)-3 -(1H-indol-3-yl)-2 -Methyl-1-phenylprop-2-en-1-one, (E)-3-(1H-indol-3-yl)-1-phenylprop-2-en-1-one, ( E)-2-Methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-ene- 1-ketone, (E)-2-methyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)propane -2-En-1-one, (E)-2-methyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(3,4,5-trimethoxy Phenyl)prop-2-en-1-one, (E)-2-methyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-1-(3,4 ,5-Trimethoxyphenyl)prop-2-en-1-one, (E)-3-(2-methyl-3-oxo-3-(3,4,5-trimethoxyphenyl) )Prop-1-en-1-yl)-1H-indole-6-carboxylic acid methyl ester, (E)-3-(1H-indol-3-yl)-1-(7-methoxybenzene And [d][1,3]dioxol-5-yl)-2-methylprop-2-en-1-one, (E)-3-(imidazo[1,2-a )Pyridin-3-yl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, (E)-2-methyl-3-( Pyrazolo[1,5-a]pyridin-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, (E)-2-(( 1H-indol-3-yl)methylene)-5-methoxy-3,4-dihydronaphthalene-1(2H)-one, (E)-3-(2-methyl-3-oxy Generation-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-1H-indole-6-carboxylic acid, (E)-2-methyl-3-( 1H-pyrazol-3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, (E)-2-methyl-3-(1H-pyrrole -3-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, (E)-2-methyl-3-(quinolin-3-yl) -1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, (E)-3-(1H-indol-2-yl)-2-methyl-1- (3,4,5-Trimethoxyphenyl)prop-2-en-1-one, (E)-2-(4-(3-(1H-indol-3-yl)-2-methyl Acryloyl)-2,6-dimethylphenoxy)ethyl acetate, (E)-3-(7-amino-1H-indol-3-yl)-2-methyl-1-(3, 4,5-Trimethoxyphenyl)prop-2-en-1-one or (E)-3-(5-amino-1H-indol-3-yl)-2-methyl-1-(3 ,4,5-Trimethoxyphenyl)prop-2-en-1-one.
  8. 如权利要求1～7任一项所述的α,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物在制备微管抑制剂中的应用。The use of the α,β-unsaturated ketone derivative and its isomer, salt or solvate prodrug according to any one of claims 1 to 7 in the preparation of microtubule inhibitors.
  9. 如权利要求1～7任一项所述的α,β-不饱和酮衍生物及其异构体、盐或溶剂合物的前体药物在***中的应用，包括对肿瘤细胞的杀伤作用或在治疗具有多药耐药的肿瘤疾病中的应用。The use of the α,β-unsaturated ketone derivative and its isomer, salt or solvate prodrug in the treatment of tumors according to any one of claims 1 to 7, including the killing effect on tumor cells Or in the treatment of multi-drug resistance tumor diseases.
  10. 如权利要求9所述的应用，其特征在于，所述肿瘤为结肠癌、肺癌或白血病。The application according to claim 9, wherein the tumor is colon cancer, lung cancer or leukemia.
PCT/CN2020/101590 2019-07-26 2020-07-13 α,β-UNSATURATED KETONE DERIVATIVE, PREPARATION METHOD AND USE AS MEDICINE WO2021017795A1 (en)

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