WO2021017795A1 - 一种α,β-不饱和酮衍生物、制备方法及作为药物的用途 - Google Patents

一种α,β-不饱和酮衍生物、制备方法及作为药物的用途 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)
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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

涉及医药技术领域，提出一种ɑ,β-不饱和酮衍生物及其制备方法和应用。所提供的α,β-不饱和酮衍生物结构如通式Ⅰ所示，各取代基定义见说明书，所述化合物可以靶向微管蛋白，对多种肿瘤亲代和耐药株均有较强的抑制作用，可以制备用于治疗恶性肿瘤及与分化增殖相关疾病的药物。

Description

一种α,β-不饱和酮衍生物、制备方法及作为药物的用途
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。
技术领域
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。
背景技术
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。
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)。
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)。
发明内容
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。
为了解决上述技术问题，本发明采用的技术方案是：
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：
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；
R 1选自氢、1～7个相同或不同C1-C10烷氧基；
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 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。
优选的，所述R 1中C1-C10烷氧基的个数为1～5个。
优选的，所述R 1选自-OCH 2COOCH 2CH 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；
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
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
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。
优选的，所述A选自
Figure PCTCN2020101590-appb-000005
所述B选自
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
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
所述R 3选自氢、甲基、乙基或与A组成六元环的-CH 2CH 2-。
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。
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：
(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。
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。
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。
优选的，所述肿瘤为结肠癌、肺癌或白血病。
说明书附图
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；
图2为小鼠腹腔给予不同剂量的化合物7的药-时曲线图。
具体实施方式
下面结合实施例对本发明进一步说明。
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：
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；
R 1选自氢、1～5个相同或不同C1-C10烷氧基、-OCH 2COOCH 2CH 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 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
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。
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。
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。
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。
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
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。
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。
在本发明中，所述异构体优选为反式异构体。
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。
在本发明中，所述溶剂合物优选包括水合物和非水合物。
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)。
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。
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。
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。
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。
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。
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)。
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。
实施例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
Figure PCTCN2020101590-appb-000017
步骤a：1-(3,4,5-三甲氧基苯基)丙-1-醇的合成。
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％。
步骤b：1-(3,4,5-三甲氧基苯基)丙-1-酮的合成。
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％。
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。
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。
实施例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
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”。
实施例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
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”。
实施例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
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”。
实施例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
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。
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.
实施例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
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。
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。
实施例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
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”。
实施例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
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”。
实施例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
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。
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)。
实施例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
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。
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。
实施例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
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。
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。
实施例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
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。
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。
实施例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
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。
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。
实施例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
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”。
实施例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
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”。
实施例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
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。
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。
实施例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
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。
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。
实施例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
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。
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。
实施例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
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。
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。
实施例20
(E)-3-(1H-吲哚-3-基)-2-甲基-1-苯基丙-2-烯-1-酮(20)的制备
Figure PCTCN2020101590-appb-000029
参照实施例1制备中间体苯丙酮。
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。
实施例21
(E)-3-(1H-吲哚-3-基)-1-苯基丙-2-烯-1-酮(21)的制备
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。
实施例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
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。
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％。
实施例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
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”。
实施例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
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”。
实施例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
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”。
实施例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
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”。
实施例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
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。
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。
实施例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
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。
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。
实施例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
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”。
实施例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
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。
实施例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
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”。
实施例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
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。
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)。
实施例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
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。
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)。
实施例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
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。
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。
实施例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
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。
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)。
实施例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：
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。
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％。
步骤b、c参照实施例1中的步骤a、b。
步骤d：1-(4-羟基-3,5-二甲氧基苯基)丙-1-酮的合成。
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％。
步骤e：2-(2,6-二甲氧基-4-丙酰基苯氧基)乙酸乙酯的合成。
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％。
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。
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)。
实施例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
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”。
实施例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)
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”。
实施例39
本发明化合物的体外抗肿瘤活性测试
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。
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。
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。
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。
使用GraphPadPrism软件分析处理数据，最终测得化合物IC 50值。
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：
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。
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
Figure PCTCN2020101590-appb-000040
Figure PCTCN2020101590-appb-000041
实施例40
本发明制备的化合物的体内抗肿瘤活性测试
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。
实验方法：
1、动物：选取4周龄雄性裸鼠；
2、受试物给药
给药剂量：1.5mg/kg，3mg/kg，10mg/kg(OXA)
给药途径：腹腔注射(i.p.)
给药体积：200μL
3、受试物配制
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。
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。
4、试验过程
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。
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。
实施例41
本发明制备的化合物7的药代动力学性质研究
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。
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。
0.30mg/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。
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。
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。
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。
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
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。
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。
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。

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：
    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；
    R 1选自氢、1～7个相同或不同C1-C10烷氧基；
    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 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。
  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：
    所述R 1中C1-C10烷氧基的个数为1～5个。
  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：
    所述R 1选自-OCH 2COOCH 2CH 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：
    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；
    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
    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
    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。
  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：
    所述A选自
    Figure PCTCN2020101590-appb-100005
    所述B选自
    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
    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
    所述R 3选自氢、甲基、乙基或与A组成六元环的-CH 2CH 2-。
  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。
  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：
    (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。
  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。
  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。
  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。
PCT/CN2020/101590 2019-07-26 2020-07-13 一种α,β-不饱和酮衍生物、制备方法及作为药物的用途 WO2021017795A1 (zh)

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