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CN-121990967-A - N-propyl-4-phenylindole derivative and preparation method and application thereof

CN121990967ACN 121990967 ACN121990967 ACN 121990967ACN-121990967-A

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an N-propyl-4-phenylindole derivative, and a preparation method and application thereof. The structure of the N-propyl-4-phenylindole derivative is shown as follows, the compound takes an indole ring as a mother nucleus, a phenyl substituent is introduced into the 4-position of the mother nucleus, a flexible N-propyl connecting chain is connected to the 1-position, the hydrophobic interaction with a receptor is enhanced through 4-phenyl, the physical and chemical properties of the whole molecule are adjusted, and then the N-propyl chain is flexibly connected with various alkaline amino fragments to obtain the N-propyl-4-phenylindole derivative. The unique structure realizes the strong H 3 receptor antagonistic activity and anticonvulsant effect, has good safety and central nervous system penetrability, and is hopeful to be developed into a new generation of high-efficiency low-toxicity antiepileptic drugs.

Inventors

  • DENG XIANQING
  • ZHENG YING
  • ZHU YINGNA
  • SONG MINGXIA
  • LIU SIMING
  • HUA YI

Assignees

  • 井冈山大学

Dates

Publication Date
20260508
Application Date
20260325

Claims (10)

  1. 1. An N-propyl-4-phenylindole derivative, characterized in that the N-propyl-4-phenylindole derivative has the following chemical structural formula: ; Wherein R 1 is H or halogen, and R 2 is selected from any one of the following groups: 。
  2. 2. the N-propyl-4-phenylindole derivative according to claim 1, wherein the N-propyl-4-phenylindole derivative is selected from one of the following compounds: 。
  3. 3. A process for the preparation of an N-propyl-4-phenylindole derivative according to claim 1 or 2, characterized by comprising the steps of: carrying out Suzuki coupling reaction on 4-bromo-1H-indole and phenylboronic acid compounds to obtain an intermediate 2; the intermediate 2 and chloropropylamine reagent are subjected to N-alkylation reaction to obtain the N-propyl-4-phenylindole derivative, wherein the synthetic route is as follows: 。
  4. 4. The method for producing an N-propyl-4-phenylindole derivative according to claim 3, wherein the phenylboronic acid compound is phenylboronic acid, 2-phenylboronic acid, 3-phenylboronic acid or 4-phenylboronic acid; The chloropropylamine reagent is N- (3-chloropropyl) piperidine hydrochloride, 4- (3-chloropropyl) morpholine, 3-chloro-N, N-diethylpropan-1-amine, N- (3-chloropropyl) dibutylamine or 1- (3-chloropropyl) -4-phenylpiperidine.
  5. 5. A process for the preparation of an N-propyl-4-phenylindole derivative according to claim 3, characterised in that the specific preparation of intermediate 2 is: dissolving 4-bromo-1H-indole, phenylboronic acid compound, alkali and palladium catalyst in a solvent to perform Suzuki coupling reaction to obtain an intermediate 2.
  6. 6. The method for producing an N-propyl-4-phenylindole derivative according to claim 5, wherein the molar ratio of the 4-bromo-1H-indole, phenylboronic acid compound and the base is 1:1.1 to 1.3:2 to 4, and the molar ratio of the 4-bromo-1H-indole and the palladium catalyst is 1:0.02 to 0.1.
  7. 7. The method for producing an N-propyl-4-phenylindole derivative according to claim 3, wherein the molar ratio of the intermediate 2 to the chloropropylamine reagent is 1:1 to 1.2.
  8. 8. The method for producing an N-propyl-4-phenylindole derivative according to claim 3, wherein the temperature of the Suzuki coupling reaction is 60 to 70℃and the temperature of the N-alkylation reaction is 80 to 90 ℃.
  9. 9. The process for producing an N-propyl-4-phenylindole derivative according to claim 3, wherein the solvent is 1, 4-dioxane and water in a volume ratio of 1, 4-dioxane to water of 3:1, and the base is potassium carbonate.
  10. 10. Use of an N-propyl-4-phenylindole derivative for the preparation of a medicament against an epileptic condition, characterized in that the N-propyl-4-phenylindole derivative is an N-propyl-4-phenylindole derivative according to claim 1 or 2.

Description

N-propyl-4-phenylindole derivative and preparation method and application thereof Technical Field The invention belongs to the technical field of antiepileptic drugs, and particularly relates to an N-propyl-4-phenylindole derivative, a preparation method and application thereof. Background Epilepsy is a type of chronic neurological disease caused by abnormal synchronous discharge of brain neurons, and is clinically manifested mainly as recurrent and transient motor, sensory or conscious disturbance. At present, most of the clinically commonly used antiepileptic drugs play a role by regulating ion channels or neurotransmitter receptors, but have drug resistance, and adverse reactions such as cognitive function decline and liver and kidney function injury are easily caused by long-term administration, so that compounds with new structural characteristics and new action mechanisms are needed for improving treatment effects and eliminating or reducing side reactions. The histamine-able nervous system plays an important role in the regulation of epilepsy. Intra-brain histamine acts as an inhibitory neurotransmitter and can regulate its own and other neurotransmitter release (e.g., glutamate, gamma-aminobutyric acid, acetylcholine and dopamine) through presynaptic H 3 receptor negative feedback. Antagonizing the H 3 receptor can increase the concentration of inhibitory neurotransmitters in the synaptic cleft, thereby helping to suppress neuronal hyperexcitations. Thus, the development of highly selective histamine H 3 receptor antagonists has become one of the new strategies for antiepileptic drug development. In the antiepileptic field, a number of H 3 receptor antagonists have been reported to have anticonvulsant activity. For example, document 1 https:// doi.org/10.3389/fphar.2024.1364353. The compound DL76 reported in the document 1 shows a dose-dependent protective effect in a Maximum Electric Shock (MES) model, can obviously shorten hindlimb rigidity time of an electric stimulation mouse at 60mg/kg, and other non-imidazole derivatives such as E159, E169 and the like also show anticonvulsant effects in an animal epileptic model. Despite the advances in research described above, there are still some disadvantages to the current H 3 receptor antagonists that enter clinical studies or pre-clinical development. Most compounds still have the defects of insufficient H 3 R selectivity, poor blood brain barrier penetrating capability and low in vivo activity, so that the clinical development of the compounds is hindered. Disclosure of Invention In order to solve the problems, the invention provides a novel N-propyl-4-phenylindole derivative which has novel action mechanism and has anti-epileptic drug development potential, and a preparation method and application thereof. The derivatives act on a histamine H 3 receptor, negatively feed back and regulate the release of histamine and other neurotransmitters, and participate in the regulation of nerve signals of epileptic seizures. According to the invention, an indole ring is used as a parent nucleus, a phenyl substituent is introduced into the 4-position of the parent nucleus, and the 1-position is connected with a flexible n-propyl connecting chain. The introduction of phenyl increases the overall rigidity and hydrophobicity of the molecule, optimizes the binding capacity of the molecule and a transmembrane hydrophobic region of an H 3 receptor, thereby improving the affinity and antagonistic activity of the receptor, and adjusts the lipophilicity of the whole molecule so as to improve the capacity of the whole molecule to penetrate the blood brain barrier. Meanwhile, different amine groups are introduced into the n-propyl connecting chain. By utilizing proper length and flexibility of the propyl chain, the terminal alkaline amino group can be accurately combined with a receptor to form an effective ionic bond or hydrogen bond with a key amino acid residue, and meanwhile, the influence of an alkaline center on H 3 receptor antagonistic activity, subtype selectivity and brain penetrability is studied by changing the structure of an R 2 group (comprising cyclic amine, open chain amine and different substitution modes), so that a molecule with both strong antagonistic activity and excellent pharmacokinetic property is preferred. The invention provides an N-propyl-4-phenylindole derivative, which has the following chemical structural formula: ; Wherein R 1 is H or halogen, and R 2 is selected from any one of the following groups: 。 Preferably, the N-propyl-4-phenylindole derivative is selected from one of the following compounds: 。 Preferably, the N-propyl-4-phenylindole derivative is an addition salt of a compound shown in a structural general formula and a pharmaceutically acceptable acid, wherein the pharmaceutically acceptable acid is any one of hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, methanesulfonic acid and maleic acid. Th