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CN-115353489-B - Deuterated amide derivative and application thereof

CN115353489BCN 115353489 BCN115353489 BCN 115353489BCN-115353489-B

Abstract

The invention belongs to the field of medicines, and particularly relates to a deuterated amide derivative and application thereof, in particular to a compound shown in a general formula I shown in the specification or pharmaceutically acceptable salt thereof and application thereof in preparing a medicament for treating neuropsychiatric diseases;

Inventors

  • ZHANG LING
  • JIANG YU
  • CHEN SHUAI
  • ZHOU JUN
  • LUO HUAN
  • JIN XUEMEI

Assignees

  • 苏州恩华生物医药科技有限公司

Dates

Publication Date
20260512
Application Date
20220511
Priority Date
20210517

Claims (13)

  1. 1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, Wherein n is 0;R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 each independently selected from H or D, provided that they are not simultaneously H, and R 15 is selected from halogen.
  2. 2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein at least one of R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 is D and R 15 is selected from fluorine, chlorine, bromine, iodine.
  3. 3. The compound according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein at least one of R 1 、R 2 、R 3 、R 7 、R 8 is D and R 15 is selected from fluorine, chlorine, bromine, iodine.
  4. 4. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein at least one of R 11 、R 12 、R 13 、R 14 is D and R 15 is selected from fluorine, chlorine, bromine, iodine.
  5. 5. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein R 1 、R 2 、R 3 is selected from D and R 15 is selected from fluorine, chlorine, bromine, iodine.
  6. 6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein the compound is selected from one of the following structures: 。
  7. 7. A pharmaceutical composition comprising a compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, mixture thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
  8. 8. An intermediate for the preparation of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof, having a structure according to formula III: Wherein n is 0;R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 as defined in any one of claims 1 to 6.
  9. 9. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, mixture thereof, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment of neuropsychiatric diseases.
  10. 10. The use according to claim 9, wherein the neuropsychiatric disease is selected from pain, schizophrenia, depression, anxiety, sleep disorders, neurodegenerative disorders, bipolar disorders, post-traumatic stress syndrome, addictive disorders, withdrawal syndrome or attention deficit.
  11. 11. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, mixture thereof, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for modulating NMDAR receptors, wherein the medicament optionally further comprises one or more additional agents that modulate the nervous system or ameliorate neuropsychiatric diseases in a mammal.
  12. 12. A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture thereof, comprising the steps of: , Reacting a compound shown in a general formula IV with a compound shown in a general formula SM-B under the action of a Grignard reagent to obtain a compound shown in a general formula III, reacting the compound shown in the general formula III with methanesulfonyl chloride under the conditions of organic base and organic solvent to obtain a methanesulfonyl ester compound, reacting the methanesulfonyl ester compound with phthalimide and inorganic base in the organic solvent to obtain a compound shown in a general formula II, and performing deprotection reaction on the compound shown in the general formula II to obtain a compound shown in a general formula I; Wherein n is 0;R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 as defined in any one of claims 1 to 6.
  13. 13. The method of claim 12, wherein the compound of formula IV is prepared by: Reacting a compound shown in a general formula V with paraformaldehyde or deuterated paraformaldehyde under the action of Eaton's reagent to prepare a compound shown in a general formula IV; orthesecondmethodcomprisesthestepsofreactingacompoundshowninageneralformulaVIIIwithacompoundshowninageneralformulaSM-AtoobtainacompoundshowninageneralformulaVII,reactingthecompoundshowninthegeneralformulaVIIwithchloroacetylchloridetoobtainacompoundshowninageneralformulaVI,andreactingthecompoundshowninthegeneralformulaVIwithFriedel-craftsreactiontoobtainacompoundshowninageneralformulaIV; Wherein n is 0;R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 as defined in any one of claims 1 to 6 and X is halogen.

Description

Deuterated amide derivative and application thereof The application claims priority of prior application of 'deuterated amide derivative and application thereof' of patent application number CN202110532496.7 submitted to China national intellectual property agency on the 17 th year of 2021. The entire contents of said prior application are incorporated by reference into the present application. Technical Field The invention belongs to the field of medicines, and particularly relates to a deuterated amide derivative and application thereof. Background NMDAR (N-methyl-D-aspartate receptor) is a glutamate ionotropic receptor, is predominantly permeable to Ca 2+ ions, can be activated upon binding to glycine and glutamate, and plays an important role in excitatory synaptic plasticity. Physiologically, they activate and trigger the opening of ion channels and produce input currents that deactivate only slowly. Can lead to the excessive activation of NMDAR in pathological conditions, and is an important pathogenesis of receptor excitotoxicity. The physiological activity of NMDAR is essential for normal neurological function, excessive activation of NMDAR is involved in acute neurological diseases such as stroke or craniocerebral injury, and in chronic stress conditions such as neurodegenerative diseases, many pathologies are thought to be associated with NMDAR hyperactivity and thus potentially sensitive to NMDAR antagonists ([ J ]. Journal of neurochemistry,2006,97 (6): 1611-1626.). There is growing evidence that NMDAR is important in inducing and maintaining central sensitization in painful conditions. Furthermore NMDAR may also mediate peripheral sensitization and visceral pain ([ J ]. Nature,2005,438 (7071):1162.). A large amount of preclinical data supports the potential for NMDAR antagonists to treat opioid-induced incurable pain, postoperative pain, cancer pain. Additional studies have shown that typical antidepressants alter the affinity of the glycine site at the NMDA receptor, that reduced NMDAR function contributes to the anti-depressive response, that administration of a single intoxicated dose of ketamine via the intravenous route significantly improves the condition of patients with refractory depression, and that the anti-depressive effect obtained lasts for one week ([ J ]. Arches of GENERAL PSYCHIATRY,2006, 63 (8): 856-864.), current S-ketamine nasal spraysBatches have been marketed in the united states at 3 months 2019 for adjuvant therapy to treat resistant depression. Depending on the site of action of NMDAR, they can be broadly classified into three classes, including non-competitive (or allosteric) antagonists (ATD sites), such as ifenprodil, RGH-896, evt101, competitive antagonists (LBD sites), such as GLYX-13, NRX-1074, non-competitive antagonists, channel hole blockers (TMD sites) including ketamine, dextromethorphan, memantine, and the like. However, there are a number of side effects that remain common in the currently marketed NMDAR antagonists, such as hallucinations, confusion, personality disorders, nightmares, agitation, attention deficit, mood changes, convulsions, sedation, etc. (J. Biochemical pharmacology,2003,66 (6): 877-886.), thus limiting their use. The higher the affinity for NMDAR channel Kong Jie antibody, the slower its binding to NMDAR, resulting in a sustained influx of Ca 2+, requiring a high drug concentration to achieve complete binding to the receptor, such as MK-801, which dissociates slowly from NMDAR, resulting in greater psychomimetic side effects. There have been studies to date that high affinity non-competitive NMDA receptor antagonists like MK-801, while capable of preventing activation of NMDAR, preventing Ca 2+ from flowing, have limited their use due to significant psychomimetic adverse effects. In contrast, low affinity, non-competitive NMDAR antagonists (e.g., memantine) may reduce toxicity due to the faster rate of blocking and leaving NMDAR by memantine (J. European journal of pharmacology,1996,317 (2-3): 377-381). Additional studies have shown that memantine has been found to have better inhibitory recovery kinetics in the treatment of alzheimer's disease due to its moderate affinity for the NMDA receptor channel and its rapid dissociation from NMDAR ([ J ]. Neuropharmacology,2009,56 (5): 866-875.), and that memantine (dizocilpine) is believed to be the major determinant of better clinical tolerability of memantine ([ J ]. ACS CHEMICAL neuroscience,2018,9 (11): 2722-2730.). The ability to rapidly dissociate from NMDAR is therefore one of the keys to the development of NMDAR antagonists. CN106957285A discloses an aminocyclobutane derivative, an NMDAR antagonist, for potential treatment of depression and chronic pain, the structure of which is shown below: At present, although NMDAR inhibitors with a channel hole blocker (TMD site) are marketed, the effect of rapidly dissociating from NMDAR and reducing the mental side effects cannot be achieved, so