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CN-122010924-A - Aminothiazole heterocyclic compound containing pyridone and synthesis and application thereof

CN122010924ACN 122010924 ACN122010924 ACN 122010924ACN-122010924-A

Abstract

The invention provides an aminothiazole heterocyclic compound containing pyridone, synthesis and application thereof, wherein the aminothiazole heterocyclic compound has a structure shown in a general formula I or a general formula II or pharmaceutically acceptable salt or isotopic labeled compound thereof. The invention also discloses a preparation method of the derivative and the like. Experiments prove that the aminothiazole heterocyclic compound containing the pyridone can effectively inhibit the replication of herpes simplex virus in Vero cells, has a non-nucleoside structure, has better inhibition activity than that of acyclovir which is a first-line clinical medicine, and can be used for preparing active medicines for resisting the herpes simplex virus. The general formula I or II is as follows: 。

Inventors

  • CHEN WENTENG
  • PAN DONGLI
  • LI WEIYING
  • CHEN SHANSHAN
  • ZHU QI
  • FU HUI
  • YU YONGPING

Assignees

  • 浙江大学
  • 浙江大学金华研究院

Dates

Publication Date
20260512
Application Date
20260130

Claims (7)

  1. 1. An aminothiazole heterocyclic compound containing pyridone is characterized by having a structure shown in a general formula I or a general formula II or pharmaceutically acceptable salts thereof or isotopically labeled compounds thereof, Wherein the method comprises the steps of R 1 is selected from halogen, benzene ring, substituted benzene ring, unsubstituted aromatic heterocycle or substituted aromatic heterocycle; R 2 is selected from C1-C4 alkane or aralkyl.
  2. 2. The pyridone-containing aminothiazole heterocyclic compound according to claim 1, wherein R 1 is preferably selected from one of the following structures: 。
  3. 3. The pyridone-containing aminothiazole heterocyclic compound according to claim 1, wherein R 2 is preferably selected from methyl or benzyl.
  4. 4. The aminothiazole heterocyclic compound containing a pyridone according to claim 1, wherein said pharmaceutically acceptable isotopic label is in a form wherein one or more atoms of said compound are replaced by isotopic atoms thereof, said isotopic atoms being deuterium ( 2 H) or tritium ( 3 H).
  5. 5. The aminothiazole heterocyclic compound containing pyridone according to any one of claims 1 to 4, wherein the compound is selected from any one of the following: 2- (4-bromo-2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-1), N-methyl-2- (2-oxo-4-p-tolyl-1, 2-dihydropyridin-1-yl) -N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-2), 2- (4- (2, 5-Difluorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-3), 2- (4- (3-Chlorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-4), 2- (4- (4-Methoxyphenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-5), 2- (4- ([ 1,1' -Biphenyl ] -4-yl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-6), N-methyl-2- (2-oxo-4-phenyl-1, 2-dihydropyridin-1-yl) -N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-7), 2- (4- (4-Fluorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-8), 2- (2-Methoxy-2 '-oxo- [3,4' -bipyridyl ] -1 '(2' H) -yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-9), 2- (4- (Benzo [ d ] [1,3] dioxol-5-yl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-10), 2- (4- (4-Chlorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-11), N-methyl-2- (2-oxo-4- (4- (trifluoromethyl) phenyl) -1, 2-dihydropyridin-1-yl) -N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-12), 2- (4- (3-Methoxyphenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-13), 2- (4- (2-Chlorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-14), 2- (4- (Furan-3-yl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-15), 2- (4- (Furan-2-yl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-16), 2- (4- (3-Fluorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-17), 2- (4- (2-Fluorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-18), N-methyl-2- (4- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) -N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-II-1), 2- (4- (1-Benzyl-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-II-2).
  6. 6. The synthesis method of the aminothiazole heterocyclic compound containing pyridone according to any one of claims 1 to 5, wherein the synthesis method is realized by the following steps: The compound I-1 is reacted with ethyl bromoacetate under the action of H 2 SO 4 and NaNO 2 to obtain an intermediate I-2, the intermediate I-2 is reacted with ethyl bromoacetate under the existence of K 2 CO 3 to obtain an intermediate I-3, ; The compound II-1 and pinacol biborate undergo a Suzuki coupling reaction in the presence of KOAc and PdCl 2 (dppf) to obtain an intermediate II-2, ; Under the existence of K 2 CO 3 and PdCl 2 (dppf), respectively carrying out Suzuki coupling reaction with boric acid compounds or boric acid ester compounds with different structures to obtain an intermediate I-2-1~I-18-1, carrying out alkaline hydrolysis on the intermediate I-3 or the intermediate I-2-1~I-18-1 under the action of LiOH H 2 O to obtain an intermediate I-1-1 or I-2-2~I-18-2, respectively carrying out amide condensation reaction on the intermediate I-1-1 or I-2-2~I-18-2 and the intermediate 1-4 under the action of HOBt and EDCI to obtain L-I-1-L-I-18, ; Or the intermediate I-2 is respectively subjected to substitution reaction with halogenated hydrocarbon with different structures in the presence of alkali such as NaH or K 2 CO 3 to obtain an intermediate II-1-1 or II-2-1, the intermediate II-1 or II-2-1 is respectively subjected to Suzuki coupling reaction with the intermediate II-2 in the presence of KOAc and PdCl 2 (dppf) to obtain an intermediate II-1-2 or II-2-2, the intermediate II-1-2 or II-2-2 is subjected to alkali hydrolysis under the action of LiOH H 2 O to obtain an intermediate II-1-3 or II-2-3, the intermediate II-1-3 or II-2-3 is respectively subjected to amide condensation reaction with the intermediate 1-4 under the action of HOBt and EDCI to obtain L-II-1 or L-II-2, 。
  7. 7. The use of a pyridone-containing aminothiazole heterocyclic compound or a pharmaceutically acceptable salt thereof or an isotopically labeled compound thereof according to any one of claims 1 to 5 in the preparation of a medicament having anti-herpesvirus activity.

Description

Aminothiazole heterocyclic compound containing pyridone and synthesis and application thereof Technical Field The invention belongs to the field of pharmaceutical chemistry, and in particular relates to an aminothiazole heterocyclic compound containing pyridone, and synthesis and application thereof. Background Herpes Simplex Virus (HSV) is widely spread in the global population, and diseases caused by infection mainly comprise herpes labialis, gingivitis, keratitis, pharyngitis, HSV related infectious encephalitis and the like. Currently, clinically used anti-HSV first-line drugs are mainly nucleoside DNA polymerase inhibitors represented by Acyclovir (ACV). However, the medicines have the problems that (1) the herpes simplex virus generates drug resistance to ACV after long-term and excessive use, and (2) the ACV has serious side effects including neurotoxicity, renal injury and the like. The problem of side effects of the parent nucleus cannot be solved based on structural transformation and modification of acyclovir, and the problem of drug resistance is difficult to avoid. Therefore, development of an anti-herpes simplex virus drug having a novel structural type is expected to solve the above-described problems. Disclosure of Invention The invention provides an aminothiazole heterocyclic compound containing pyridone, in particular to a structure shown in a general formula I or a general formula II or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable isotope labeled compound thereof, Wherein the method comprises the steps of R 1 is selected from halogen, benzene ring, substituted benzene ring, unsubstituted aromatic heterocycle, or substituted aromatic heterocycle, R 2 is selected from C1-C4 alkane or aralkyl; The pyridone-containing aminothiazole heterocyclic compound, R 1, is preferably selected from one of the following structures: ; The aminothiazole heterocyclic compound containing pyridone preferably has R 2 selected from methyl or benzyl. The aminothiazole heterocyclic compound containing pyridone is selected from any one of the following compounds: 2- (4-bromo-2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-1) N-methyl-2- (2-oxo-4-p-tolyl-1, 2-dihydropyridin-1-yl) -N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-2) 2- (4- (2, 5-Difluorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-3) 2- (4- (3-Chlorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-4) 2- (4- (4-Methoxyphenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-5) 2- (4- ([ 1,1' -Biphenyl ] -4-yl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-6) N-methyl-2- (2-oxo-4-phenyl-1, 2-dihydropyridin-1-yl) -N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-7) 2- (4- (4-Fluorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-8) 2- (2-Methoxy-2 '-oxo- [3,4' -bipyridyl ] -1 '(2' H) -yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-9) 2- (4- (Benzo [ d ] [1,3] dioxol-5-yl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-10) 2- (4- (4-Chlorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-11) N-methyl-2- (2-oxo-4- (4- (trifluoromethyl) phenyl) -1, 2-dihydropyridin-1-yl) -N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-12) 2- (4- (3-Methoxyphenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-13) 2- (4- (2-Chlorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-14) 2- (4- (Furan-3-yl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-15) 2- (4- (Furan-2-yl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-16) 2- (4- (3-Fluorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-17) 2- (4- (2-Fluorophenyl) -2-oxo-1, 2-dihydropyridin-1-yl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-I-18) N-methyl-2- (4- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) -N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-II-1) 2- (4- (1-Benzyl-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) -N-methyl-N- (4-methyl-5-sulfamoylthiazol-2-yl) acetamide (L-II-2). The compound of the invention is pharmaceutically acceptable salt, and the pharmaceutically acceptable salt is formed by reacting the compound with inorganic acid and organic acid. The pharmaceutically acceptable salt is hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, oxalate, tartrate, methanesulfonate, p-toluenesulfonate, fumarate, taurine, ci