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CN-121990986-A - Disubstituted phenyl acrylamide/ester compound and preparation method and application thereof

CN121990986ACN 121990986 ACN121990986 ACN 121990986ACN-121990986-A

Abstract

The invention provides a disubstituted phenyl acrylamide/ester compound, a preparation method and application thereof, wherein the structural formula of the compound is shown as formula (I) or formula (II). The compound provided by the invention can be used as a covalent inhibitor of DHHC family proteins, and can inhibit proliferation, migration and invasion of tumor cells by inhibiting DHHC palmitoyl transferase activity and blocking palmitoyl modification process of substrate proteins, so that an anti-tumor effect is exerted. Experimental results show that the disubstituted phenyl acrylamide/ester compound has remarkable antiproliferative activity on various tumor cells, has an inhibition effect superior to that of a positive control drug 2-BP, and has the potential of being further developed into a new-generation high-efficiency low-toxicity antitumor drug.

Inventors

  • SONG YALI
  • LI JISEN
  • WANG XIAOFANG
  • LIU QINGXIN
  • WANG YIBO
  • YANG KAN
  • YOU ZHIHAO
  • JIA YOUCHAO

Assignees

  • 河北大学

Dates

Publication Date
20260508
Application Date
20260331

Claims (10)

  1. 1. A disubstituted phenyl acrylamide/ester compound or pharmaceutically acceptable salt thereof is characterized in that the structural general formula of the compound is shown as formula (I) or (II): (I) (II) Wherein X is oxygen atom or nitrogen atom, R 1 is any one of hydrogen atom, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, R 2 is any one of substituted or unsubstituted aliphatic, substituted or unsubstituted alicyclic, substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic and amino protecting group, and the carbon-carbon double bond is in a trans configuration.
  2. 2. The disubstituted phenylacrylamide/ester compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X is oxygen atom or nitrogen atom, R 1 is any one of hydrogen atom, benzene ring, 3-pyridine ring and 4-pyridine ring, R 2 is any one of phenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-methylphenyl, o-fluorophenyl, 2-thienyl, 2-furyl, cyclohexyl, tert-butoxy, n-propyl, isobutyl, n-butyl, 2, 6-dichlorophenyl or 3-pyridyl, and carbon-carbon double bond is trans-configuration.
  3. 3. The disubstituted phenylacrylamide/ester compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X is nitrogen atom, R 1 is any one of hydrogen atom, benzene ring, 3-pyridine ring and 4-pyridine ring, R 2 is any one of phenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-methylphenyl, o-fluorophenyl, 2-thienyl, 2-furyl, cyclohexyl, tert-butoxy, n-propyl, isobutyl, n-butyl, 2, 6-dichlorophenyl or 3-pyridyl, and carbon-carbon double bond is trans-configuration.
  4. 4. A process for the preparation of a compound of formula (I) characterized in that, When X is a nitrogen atom and R 1 is a hydrogen atom, the synthetic route is as follows: ; When X is nitrogen atom and R 1 is benzene ring, the synthetic route is as follows: ; when X is a nitrogen atom, R 1 is 3-pyridine or 4-pyridine, the synthetic route is as follows: ; when X is an oxygen atom and R 1 is a benzene ring, the synthetic route is as follows: ; wherein R 2 is as defined in claim 1.
  5. 5. A preparation method of a compound shown in a formula (II) is characterized in that the synthetic route is as follows: 。
  6. 6. the process according to claim 4, wherein, Step i, reacting a compound A with N-vinylformamide in the presence of triethylamine and 4-dimethylaminopyridine to generate a compound B; Step ii, carrying out boration reaction on the compound B and 9-borabicyclo [3.3.1] nonane, and then carrying out coupling reaction on the compound B and tertiary butyl (4-bromophenyl ethyl) carbamate under the catalysis of tetra (triphenylphosphine) palladium to generate a compound C; Step iii, deprotecting the compound C to obtain a compound D; Step iv, carrying out substitution reaction on the compound D and the acryloyl chloride in the presence of triethylamine to generate a product E; Step v, carrying out substitution reaction on cinnamoyl chloride and 4-bromophenylethylamine in the presence of triethylamine to generate a compound G; Step vi, carrying out boration reaction on the compound B and 9-borabicyclo [3.3.1] nonane, and then carrying out coupling reaction on the compound B and the compound G under the catalysis of tetra (triphenylphosphine) palladium to obtain a compound H; Step vii, carrying out substitution reaction on 3- (pyridine-3-yl) acrylic acid and 4-bromophenylethylamine under the catalysis of N, N' -carbonyl diimidazole to generate a compound J; Step viii, carrying out boration reaction on the compound B and 9-borabicyclo [3.3.1] nonane, and then carrying out coupling reaction on the compound B and the compound J under the catalysis of tetra (triphenylphosphine) palladium to obtain a compound K; step ix, carrying out substitution reaction on cinnamoyl chloride and 4-bromophenyl ethanol under the catalysis of triethylamine to generate a compound L; Step x, carrying out boration reaction on the compound B and 9-borabicyclo [3.3.1] nonane, and then carrying out coupling reaction on the compound B and the compound L under the catalysis of tetra (triphenylphosphine) palladium to obtain a compound M.
  7. 7. The preparation method according to claim 6, wherein, In step i, the molar ratio of N-vinylformamide, compound A, 4-dimethylaminopyridine to triethylamine is 1:1.2:0.05:1.2; in step ii, the molar ratio of compound B, 9-borobicyclo [3.3.1] nonane, tert-butyl (4-bromophenyl ethyl) carbamate, to tetrakis (triphenylphosphine) palladium is 1:3:0.6:0.06; in step iv, the molar ratio of compound D to acryloyl chloride and triethylamine is 1:1.5:1.5; in the step v, the molar ratio of the cinnamoyl chloride to the 4-bromophenylethylamine to the triethylamine is 1:1:1.2; In step vi, the molar ratio of compound B, 9-borobicyclo [3.3.1] nonane, compound G, to tetrakis (triphenylphosphine) palladium is 1:3:0.6:0.06; in step vii, the molar ratio of (E) -3- (pyridin-3-yl) acrylic acid, 4-bromophenylethylamine and N, N' -carbonyldiimidazole is 1:1:1.2; in step viii, the molar ratio of compound B, 9-borobicyclo [3.3.1] nonane, compound J, to tetrakis (triphenylphosphine) palladium is 1:3:0.6:0.06; in the step ix, the molar ratio of the cinnamoyl chloride to the 4-bromophenyl ethanol to the triethylamine is 1:1:1.2; in step x, the molar ratio of compound B, 9-borobicyclo [3.3.1] nonane, compound L, and tetrakis (triphenylphosphine) palladium is 1:3:0.6:0.06.
  8. 8. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the manufacture of an anti-tumour medicament.
  9. 9. The use according to claim 8, wherein the tumour is breast cancer, liver cancer, colon cancer or lymphoma.
  10. 10. A palmitoyl transferase inhibitor comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers or excipients.

Description

Disubstituted phenyl acrylamide/ester compound and preparation method and application thereof Technical Field The invention relates to the field of preparation of antitumor compounds, in particular to a disubstituted phenyl acrylamide/ester compound, and a preparation method and application thereof. Background The DHHC enzyme (Asp-His-His-Cys protein), also known as palmitoyltransferase (palmitoyltransferase), is a key enzyme involved in the modification of the protein S-palmitoylation (S-acylation). Studies have shown that DHHC enzyme overexpression is present in most tumor cells, and inhibitors thereof have an inhibitory effect on tumor growth. DHHC inhibitors refer to compounds capable of inhibiting DHHC enzymatic activity, thereby blocking protein palmitoylation. The types of DHHC inhibitors reported at present are limited, 2-BP (2-bromopalmitic acid) is relatively widely studied, and CMA (N-cyanomethyl-N-cinnamamide), cerulomycin and tunicamycin are also included. However, the inhibitor has the defects of low activity, poor specificity and the like, and limits the basic research and clinical application prospect. Therefore, there is an urgent need to develop novel highly potent, highly selective DHHC inhibitors. Disclosure of Invention The invention aims to provide a disubstituted phenyl acrylamide/ester compound or pharmaceutically acceptable salt thereof, which solves the problems of low activity, poor specificity and rare variety of the existing DHHC inhibitor. It is another object of the present invention to provide a process for the preparation of the above compounds and pharmaceutically acceptable salts thereof. It is a further object of the present invention to provide the use of the above compounds and pharmaceutically acceptable salts thereof in the preparation of antitumor drugs. In order to achieve the above purpose, the technical scheme of the invention is as follows: A disubstituted phenyl acrylamide/ester compound or pharmaceutically acceptable salt thereof, wherein the structural general formula of the compound is shown as formula (I) or (II): 、 Wherein X is an oxygen atom or a nitrogen atom, R 1 is selected from a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, R 2 is selected from a hydrogen atom, a substituted or unsubstituted aliphatic substituent, a substituted or unsubstituted alicyclic substituent, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group and an amino protecting group, and the carbon-carbon double bond is in a trans configuration (E type). Preferably, X is an oxygen atom or a nitrogen atom, R 1 is a hydrogen atom, a benzene ring, a 3-pyridine ring or a 4-pyridine ring, R 2 is a hydrogen atom, a phenyl group, an o-chlorophenyl group, a m-chlorophenyl group, a p-chlorophenyl group, an o-methylphenyl group, an o-fluorophenyl group, a 2-thienyl group, a 2-furyl group, a cyclohexyl group, a t-butoxy group, an n-propyl group, an isobutyl group, an n-butyl group, a2, 6-dichlorophenyl group or a 3-pyridyl group, and the carbon-carbon double bond is in a trans configuration (E type). More preferably, X is an oxygen atom or a nitrogen atom, R 1 is a hydrogen atom, a benzene ring or a 3-pyridine ring, R 2 is phenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-methylphenyl, o-fluorophenyl, 2-thienyl, 2-furyl, cyclohexyl, t-butoxy, n-propyl, isobutyl, n-butyl, 2, 6-dichlorophenyl or 3-pyridyl, and the carbon-carbon double bond is in a trans configuration (E-type). More preferably, the compound is selected from one of the following structures: 、、、、、、、、、、、、、。 Pharmaceutically acceptable salts of the compounds include, but are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, citrate, fumarate, hydrochloride, hydrobromide, maleate, methanesulfonate, and the like. The invention also provides a preparation method of the compound, and the synthetic route and the steps are as follows. When X is a nitrogen atom and R 1 is a hydrogen atom, the synthetic route of the compound shown in the formula (I) is as follows: 。 the method comprises the following specific steps: Step i, carrying out substitution reaction on acyl chloride (compound A) with R 2 substituent and N-vinylformamide to generate compound B; Step ii, the compound B and tertiary butyl (4-bromophenyl ethyl) carbamate are subjected to a coupling reaction to generate a compound C; step iii, removing BOC from the compound C to obtain a compound D; step iv, the compound D and the acryloyl chloride undergo substitution reaction to generate a product E. Specifically, in the step i, the compound A, N-vinylformamide, 4-dimethylaminopyridine and triethylamine react in anhydrous tetrahydrofuran under the protection of nitrogen gas for 24: 24 h, and then NaOH solution is dropwise added at 0 ℃ to obtain the compound B. The mol ratio of the N-vinylformamide, the compound A, the 4-dimethylaminopyridine, the triethylamine and the N