Search

CN-122010865-A - 1,4, 11-Trioxo-10, 14-diazaspirocyclic sunflower ketone and synthesis method and application thereof

CN122010865ACN 122010865 ACN122010865 ACN 122010865ACN-122010865-A

Abstract

The invention discloses 1,4, 11-trioxo-10, 14-diazaspiro-sunflower ketone and a synthesis method and application thereof, and belongs to the technical field of medicines. The test result of the applicant shows that the compound disclosed by the invention has a good inhibition effect on NO release by lipopolysaccharide-induced mouse macrophage RAW 264.7, shows good anti-inflammatory activity, and can be used for preparing medicines for treating inflammation.

Inventors

  • MO DONGLIANG
  • LUO YAN
  • LU YANJIAO
  • ZHAO YU

Assignees

  • 广西师范大学

Dates

Publication Date
20260512
Application Date
20240124

Claims (8)

  1. 1.1, 4, 11-Trioxo-10, 14-diazaspirocyclic sunflower ketone having the structure represented by the following formula (I): Wherein: R 1 phenyl; R 2 represents styryl; R 3 +R 4 =spirocyclic; r 5 represents a hydrogen atom; r 6 represents methyl; R 7 represents methyl; R 8 represents benzyl.
  2. 2. The method for synthesizing 1,4, 11-trioxo-10, 14-diazaspirocyclic ketone according to claim 1, characterized in that a compound represented by the following formula (II) and a compound represented by the formula (III) are placed in an organic solvent, an alkaline substance and a catalyst are added, and the reaction is performed under the condition of heating or non-heating to obtain a crude product of a target compound; Wherein: R 1 phenyl; R 2 represents styryl; R 3 +R 4 =spirocyclic; r 5 represents a hydrogen atom; r 6 represents methyl; R 7 represents methyl; r 8 represents benzyl; X represents a bromine atom.
  3. 3. The synthetic method according to claim 2, wherein the reaction is carried out under an inert atmosphere.
  4. 4. A synthetic method according to claim 2 or 3, characterized in that the reaction is carried out at a temperature of less than 100 ℃.
  5. 5. A synthesis method according to claim 2 or 3, wherein, The organic solvent is one or more than two selected from benzene, toluene, cyclohexane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, dichloromethane, acetone, chloroform, n-hexane and dioxane; The alkaline substance is one or more than two selected from tripotassium phosphate, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, pyridine, triethylamine and N, N-diisopropylethylamine; the catalyst is one or the combination of more than two of copper salt, ytterbium salt and scandium salt.
  6. 6. A synthetic method according to claim 2 or 3, further comprising the step of purifying the crude target compound.
  7. 7. Use of a 1,4, 11-trioxo-10, 14-diazaspirocyclic decanone or a pharmaceutically acceptable salt thereof according to claim 1, in the manufacture of a medicament for the treatment of inflammation.
  8. 8. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of the 1,4, 11-trioxo-10, 14-diazaspirocyclic sunflower ketone of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Description

1,4, 11-Trioxo-10, 14-diazaspirocyclic sunflower ketone and synthesis method and application thereof The application relates to a 1-oxygen-2, 8-diazacyclic ketone derivative, a synthesis method and application thereof, which are filed in the name of 202410099899.0, wherein the application date of the filed application is 2024, 1 month and 24 days, and the name of the filed application is 1-oxygen-2, 8-diazacyclic ketone derivative, the synthesis method and application thereof. Technical Field The invention relates to a 1-oxygen-2, 8-diazacyclic sunflower ketone derivative, and a synthetic method and application thereof, belonging to the technical field of medicines. Background Medium-sized (8-12) nitrogen heterocycles are an extremely important class of compounds that exist in a range of natural and non-natural products, and these compounds also exhibit great potential in drug discovery, where the backbones of nitrogen-containing heterodecatomic rings exist in many different natural products and biologically significant compound molecules, for example muramine, protopine and dysazecine are a class of alkaloids found in plants of the genus corydaline that possess a benzoquinolizine structural backbone. At present, a great deal of literature researches report that the pharmacological activity of the compound can be used for inhibiting neuron excitability (Phytochemistry 2018,150,85-92), has a certain inhibition effect on gastric acid secretion, has antibacterial, antiviral, anti-inflammatory and other activities (Chin.J.Vet.Sci.2008,12,1098–1101&Journal of Animal Science and Veterinary Medicine,2013,32,3-5.).Picraphylline, is alkaloid in Rauvolfia plants, has good pharmacological activity, and can be used for resisting malaria, inflammation, cytotoxicity, antioxidants, ulcers and other pharmacological effects (Asian Pac.J. trop.Med.2014,7, 1-8). However, efficient construction of such backbones remains a significant challenge due to unfavorable inter-ring interactions and entropy effects of the mesocyclic compounds. Therefore, the development of new strategies to construct nitrogen-containing heterodecacyclic compounds is of great importance. Disclosure of Invention The invention aims to provide a series of 1-oxo-2, 8-diazacyclic sunflower ketone derivatives with novel structure and better anti-inflammatory activity, and a synthesis method and application thereof. In order to solve the technical problems, the invention adopts the following technical scheme: the 1-oxygen-2, 8-diazacyclic sunflower ketone derivative is a compound with a structure shown in the following formula (I) or pharmaceutically acceptable salt thereof: Wherein: R 1 represents unsubstituted or monosubstituted phenyl or unsubstituted thienyl, wherein the substituents are C 1～6 alkyl, alkoxy or halogen atoms; R 2 represents a hydrogen atom, or an unsubstituted or monosubstituted phenyl group, or an unsubstituted or monosubstituted styryl group, wherein the substituent is a C 1～6 alkyl group, an alkoxy group or a halogen atom; R 3 represents a hydrogen atom, a methyl group, an ethyl group, an n-butyl group or a halogen atom, or is a substituted C 1～6 alkyl group; R 4 represents a hydrogen atom or a phenyl group, or an unsubstituted or monosubstituted C 1～4 alkyl group, or an unsubstituted or monosubstituted C 1～4 alkoxy group; r 5 represents a hydrogen atom; R 6 represents methyl, ethyl or phenyl; r 7 represents a hydrogen atom or a methyl group; R 8 represents methyl, allyl or phenylpropargyl, or is unsubstituted or monosubstituted benzyl. Further, the 1-oxo-2, 8-diazacyclohexanone derivative of the invention may specifically be any one of the following compounds 3aa to 3 al: 3aa：R1＝Ph,R2＝CH2-CH2-Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3ba：R1＝4-OMe-Ph,R2＝CH2-CH2-4-OMe-Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3ca：R1＝4-Me-Ph,R2＝CH2-CH2-4-Me-Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3da：R1＝4-Cl-Ph,R2＝CH2-CH2-4-Cl-Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3ea：R1＝4-CF3-Ph,R2＝CH2-CH2-4-CF3-Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3fa：R1＝3-Br-Ph,R2＝CH2-CH2-3-Br-Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3ga：R1＝2-Br-Ph,R2＝CH2-CH2-2-Br-Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3ha：R1＝Ph,R2＝Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3ia：R1＝Ph,R2＝4-OMe-Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3ja：R1＝Ph,R2＝4-F-Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3ka：R1＝Ph,R2＝2-Br-Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3la：R1＝4-Br-Ph,R2＝Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3ma：R1＝4-CF3-Ph,R2＝Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3na：R1＝2-thienyl,R2＝Ph,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3oa：R1＝Ph,R2＝H,R3＝Me,R4＝Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3pa：R1＝Ph,R2＝CH2-CH2-Ph,R3＝H,R4＝n-Bu,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3qa：R1＝Ph,R2＝CH2-CH2-Ph,R3＝Ph,R4＝Et,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3ra：R1＝Ph,R2＝CH2-CH2-Ph,R3＝Ph,R4＝H,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3sa：R1＝Ph,R2＝CH2-CH2-Ph,R3＝H,R4＝(CH2)4Cl,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3ta：R1＝Ph,R2＝CH2-CH2-Ph,R3＝H,R4＝(CH2)3CO2Me,R5＝H,R6＝Me,R7＝Me,R8＝Bn; 3ua：R1＝Ph,R2＝CH2-CH2-Ph,R3+R4＝Cyclopentane,R5