CN-122010914-A - Quinazoline-coumarin compound and preparation method and application thereof

CN122010914ACN 122010914 ACN122010914 ACN 122010914ACN-122010914-A

Abstract

The invention belongs to the field of pharmaceutical chemistry, and discloses a quinazoline-coumarin compound, and a preparation method and application thereof. It has the following structural general formula, wherein R 1 and R 2 are defined in the specification. Preliminary pharmacological experiments show that the compounds have the activity of inhibiting tumor cells such as gastric cancer, prostatic cancer, lung cancer and the like, and can be used for research and development of anti-tumor medicaments or development of inhibitors such as PI3K and the like.

Inventors

SHI XIUFANG
Du Luge
LU JUNRU
WU XIAOJUN
WANG YINGHAO
TANG NANA
HE WEICHENG

Assignees

郑州大学
郑州原理生物科技有限公司

Dates

Publication Date: 20260512
Application Date: 20260320

Claims (7)

1. A quinazoline-coumarin compound is characterized by having a structure shown in a general formula I, Wherein: R 1 is selected from a hydrogen atom, methyl, 4-methylphenyl, 2-methoxyphenyl, 3, 4-dimethoxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl or 4-bromophenyl; R 2 is selected from a hydrogen atom, a chlorine atom, a phenyl group, a 4-methoxyphenyl group, a 4-methylphenyl group, a thiophene or a furan.
2. Quinazoline-coumarin compound according to claim 1, characterized in that it is a compound selected from the following substituents: 。
3.a process for the preparation of a quinazolin-coumarin compound according to claim 1, characterized in that it is effected by the following process: ; The synthesis of the compound M takes resorcinol as a raw material, takes Friedel-crafts acylation reaction with acids containing different substituents to obtain a compound B, takes methylation reaction of the compound B to obtain a compound C, and takes cyclization under alkaline conditions to generate the compound M; the synthesis of the compound N takes o-aminobenzamide as a raw material, the compound E is obtained through hydrolysis, and then nucleophilic substitution, cyclization, amidation and chlorination reactions are sequentially carried out to obtain the compound N; nucleophilic substitution of compound M with compound N results in the formation of the target compound I.
4. A process for the preparation of a quinazoline-coumarin compound according to claim 3, wherein the synthesis of compound M is effected by: (1) In an organic solvent, carrying out Friedel-crafts acylation reaction on resorcinol and phenylacetic acid containing different substituents under the catalysis of Lewis acid to obtain a compound B; The Lewis acid is one or two of aluminum trichloride, ferric trichloride, zinc chloride, trifluoromethanesulfonic anhydride, boron trifluoride diethyl ether, titanium tetrachloride and stannic tetrachloride, and the organic solvent is one or two of toluene, xylene, ethylbenzene, propylbenzene, isopropylbenzene, butylbenzene, isobutylbenzene, tert-butylbenzene, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, 1, 4-dioxane, butyl acetate, N-dimethylformamide and 2, 2-trifluoroethanol; (2) In an organic solvent, performing nucleophilic substitution reaction on the compound B and a methylation reagent under the action of an acid binding agent to obtain a compound C; the methylating agent is one of methyl iodide, dimethyl carbonate, dimethyl sulfate, methyl p-toluenesulfonate and methyl triflate, the acid binding agent is one of potassium carbonate, sodium carbonate, cesium carbonate, pyridine, triethylamine, sodium hydride, sodium borohydride and N, N-diisopropylethylamine, and the organic solvent is one of acetone, acetonitrile, butanone, N-methylpyrrolidone, N-dimethylformamide and tetrahydrofuran; (3) In an organic solvent, the compound C is mixed with a carbonic diester solvent under the action of alkali, and the cyclization reaction is carried out to obtain a compound M; The alkali is one or more of sodium hydride, sodium borohydride, potassium tert-butoxide, sodium methoxide and sodium ethoxide, and the organic solvent is one or more of dimethyl carbonate, diethyl carbonate, dipropyl carbonate, methylethyl carbonate and ethylene carbonate.
5. A process for the preparation of a quinazoline-coumarin compound according to claim 3, wherein the synthesis of compound N is effected by: (1) In a solvent, the compound D undergoes hydrolysis reaction under the action of alkali to obtain a compound E; The alkali is one or two of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, and the solvent is one or two of methanol, ethanol, isopropanol, n-butanol, propylene glycol, water, ethylene glycol and acetonitrile; (2) Adding a condensing agent into an organic solvent, and carrying out nucleophilic substitution reaction on the compound E and acyl chloride or carboxylic acid containing different substituents under the action of Lewis base to obtain a compound F; The Lewis base is selected from triethylamine, N, N-diisopropylethylamine, ethylenediamine, N, N ' -dimethylethylenediamine, N, N, N ', N ' -tetramethylethylenediamine, pyridine, triethanolamine, triethylenediamine, N-methylmorpholine, 4-dimethylaminopyridine, pyrrolidinylpyridine, 1, 5-diazabicyclo, 1, 8-diazabicyclo [5.4.0] undec-7-ene, tetramethylguanidine, 1,5, 7-triazabicyclo [4, 0] deca-5-ene, 7-methyl-1, 5, 7-triazabicyclo [4, 0] deca-5-ene, or one or two of sodium carbonate, sodium acetate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, calcium hydride, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, N-butyllithium, tert-butyllithium, hexamethyldisilylamido potassium, hexamethyldisilylamido sodium, diisopropylamino lithium, 2, 6-tetramethylpiperidine; the condensing agent is selected from 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, benzotriazole-N, N, N ', N ' -tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1, 3-tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, N-hydroxysuccinimide, N-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, N-hydroxyphthalimide, one or two of O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, O-benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate, O- (N-succinimidyl) -1, 3-tetramethylurea tetrafluoroborate, 2- (5-norbornene-2, 3-dicarboximido) -1, 3-tetramethylurea tetrafluoroborate quaternary ammonium salt, 1H-benzotriazol-1-yl oxy tripyrrolidinyl hexafluorophosphate and benzotriazol-1-yl oxy tris (dimethylamino) phosphonium hexafluorophosphate, wherein the organic solvent is one or two of dichloromethane, diethyl ether, tetrahydrofuran, chloroform, ethyl acetate and acetonitrile; (3) In an organic solvent, carrying out intramolecular dehydration cyclization on the compound F and a nucleophilic reagent or a condensing agent to obtain a compound G; The nucleophilic reagent is selected from one of acetic anhydride, propionic anhydride, butyric anhydride, thionyl chloride, acetyl chloride, aromatic aldehyde, phosphorus pentoxide, phosphorus oxychloride, oxalyl chloride, polyphosphoric acid, etc.; the condensing agent used is selected from 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate, 6-chlorobenzotriazol-1, 3-tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, N-hydroxysuccinimide, N-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, N-hydroxyphthalimide, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, O-benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate, O- (N-succinimidyl) -1, 3-tetramethylurea tetrafluoroborate, 2- (5-norbornene-2, 3-dicarboximido) -1, 3-tetramethylurea tetrafluoroborate, 1-benzotriazol-N, N ', N' -tetramethylurea hexafluorophosphate, O-benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate, O- (N-succinimido) -1, 3-tetramethylurea tetrafluoro-1-triazol-1-phosphate, 1-triazol-2-hydroxy-7-azobenzo-benzotriazol-1-yl phosphate; the organic solvent is selected from dichloromethane, tetrahydrofuran, toluene, xylene, ethylbenzene, one or two of dioxane, pyridine, picoline and N, N-dimethyl formamide, or the nucleophilic reagent is used as solvent; (4) In an organic solvent, heating and refluxing the compound G in a reagent for providing a nitrogen source to obtain a compound H; The reagent containing nitrogen source is one or more of formamide, acetamide, urea, ammonium acetate and ammonium formate, and the organic solvent is selected from one or two of toluene, xylene, N-dimethylformamide, N-dimethylacetamide, ethylene glycol and N-methylpyrrolidone, or the reagent containing nitrogen source is used as a solvent; (5) Heating and refluxing the compound H in an organic solvent in a chlorinating agent to obtain a compound N; the chlorinating agent is one or more of phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride and oxalyl chloride, and the organic solvent is selected from one or two of toluene, ethylbenzene, chlorobenzene, acetonitrile, xylene and 1, 2-dichloroethane, or the chlorinating agent is used as a solvent.
6. The method for preparing a quinazoline-coumarin compound according to claim 3, wherein the synthesis of the target compound I is obtained by reacting the compound M with the compound N in an organic solvent under the action of a base catalyst; The base catalyst is one or two of 4-pyrrolidinyl pyridine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylamine, N-diisopropylethylamine, potassium carbonate, cesium carbonate and triethylamine, and the organic solvent is one of toluene, ethylbenzene, xylene, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide.
7. Use of a quinazoline-coumarin compound according to claim 1 or 2 in the preparation of a medicament, wherein the compound is used as an active ingredient or is mixed with pharmaceutically acceptable auxiliary ingredients in the form of a salt thereof to prepare a PI3K inhibitor for use in an antitumor medicament for gastric cancer, prostate cancer, lung cancer or breast cancer.

Description

Quinazoline-coumarin compound and preparation method and application thereof Technical Field The invention belongs to the field of pharmaceutical chemistry, and relates to a quinazoline-coumarin compound, a preparation method thereof and application of the quinazoline-coumarin compound serving as a pharmaceutical active ingredient of a PI3K inhibitor in development of antitumor drugs such as gastric cancer, prostatic cancer, lung cancer and breast cancer. Background Phosphatidylinositol 3-kinase (PI 3K) is a class of lipid kinases that catalyze the transfer of the gamma-phosphate group of ATP to the hydroxyl group at the D3 position of the inositol ring of Phosphatidylinositol (PI) and its derivatives, activating the downstream protein kinase B/rapamycin target protein (AKT/mTOR) signaling pathway, and thus regulating various cellular processes such as cell proliferation, metabolism, survival, autophagy, etc., which are critical for maintaining cellular homeostasis. Abnormal activation of PI3K is an important driving factor for the occurrence and development of diseases such as tumors, and has high-frequency abnormality in malignant tumors such as lung cancer, colorectal cancer, breast cancer, gastric cancer, and prostate cancer, and plays a key role in the occurrence and progress of various cancers. Specifically, p110 alpha subunit encoding gene PIK3CA high-frequency mutation, regulatory subunit abnormality and PTEN deletion of class I PI3K can cause abnormal accumulation of phosphatidylinositol-3, 4, 5-triphosphate (PIP 3), initiate continuous activation of AKT/mTORC1 pathway and promote malignant proliferation, drug resistance and metastasis of cells. Therefore, the PI3K becomes an important target point for tumor targeted therapy, and the development of the high-efficiency and high-selectivity PI3K inhibitor has important clinical value and application prospect. At present, various PI3K inhibitors enter clinical researches or application stages, but the existing PI3K inhibitors still have a plurality of defects, such as poor subtype selectivity, easy generation of drug resistance, stronger toxic and side effects and the like, and limit the clinical curative effect. Coumarin is a natural compound with benzopyrone ring, and researches show that the coumarin compound has broad-spectrum bioactivity, such as anti-tumor, antibacterial, drug-resistant, antihypertensive and the like, and has low toxicity and good biocompatibility. The quinazoline compound is a classical kinase inhibitor skeleton, the planar structure of the quinazoline compound is easy to adapt to an ATP binding pocket of PI3K, and the quinazoline compound can play a role in inhibiting by targeting a binding kinase active site. Therefore, the invention takes quinazoline parent nucleus as skeleton, introduces coumarin ring, designs novel quinazoline-coumarin compound, and aims to develop PI3K inhibitor with strong inhibition activity, high selectivity and small toxic and side effect, thereby providing new candidate medicine for tumor treatment. Disclosure of Invention The first object of the invention is to provide a novel quinazoline-coumarin compound, which takes quinazoline as a mother nucleus and introduces a coumarin ring to construct a double-ring framework so as to solve the problems of poor subtype selectivity, drug resistance, strong toxicity to normal cells and the like of the existing PI3K inhibitor. A second object of the present invention is to provide a process for the preparation of the quinazoline-coumarin compound. It is a third object of the invention to provide the use of the quinazoline-coumarin compounds. The quinazoline-coumarin compound is a compound with a structural general formula I or pharmaceutically acceptable salt of the compound shown in the structural general formula I: Wherein, the R 1 is selected from hydrogen atom, C1-5 chain alkyl, mono-substituted or poly-substituted phenyl, and the substituent is selected from C1-5 chain alkyl, methoxy and halogen. R 1 is preferably a hydrogen atom, methyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3, 4-dimethoxyphenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 4-chlorophenyl group or 4-bromophenyl group; R 2 is selected from hydrogen atom, halogen, mono-or polysubstituted phenyl or heterocyclic compound containing sulfur and oxygen, and the substituent is selected from C1-5 chain alkyl, methoxy and halogen. R 2 is preferably a hydrogen atom, a chlorine atom, a phenyl group, a 4-methoxyphenyl group, a 4-methylphenyl group, a thiophene or a furan. The quinazoline-coumarin backbone-containing compound based on the general formula I is preferably a compound with the following substituent: The quinazoline-coumarin compound is realized by the following synthetic route and can be divided into three parts, namely the synthesis of a compound M (coumarin ring), the synthesis of a compound N (quinazoline ring) and the synthesis of a target compou