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CN-121990982-A - Cyclic amine compound with aryl substitution as well as preparation method and application thereof

CN121990982ACN 121990982 ACN121990982 ACN 121990982ACN-121990982-A

Abstract

The invention discloses a cyclic amine compound with aryl substitution, a preparation method and application thereof. The invention provides application of a substance Z or a pharmaceutical composition containing the substance Z in preparation of serotonin 5-HT 2A receptor agonist, wherein the substance Z is a compound shown in a formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof or a stereoisomer thereof, and the pharmaceutical composition also contains a pharmaceutically acceptable carrier. The compounds of the present invention are useful for the prevention and treatment of depression, anxiety, cluster headache, or neurodegenerative diseases.

Inventors

  • CHENG JIANJUN
  • WANG SHENG
  • LI HUIQIONG
  • TANG LINGJIE
  • YAN HAOHAN

Assignees

  • 上海科技大学
  • 中国科学院分子细胞科学卓越创新中心

Dates

Publication Date
20260508
Application Date
20251105
Priority Date
20241106

Claims (14)

  1. 1. Use of substance Z, which is a compound of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, or a pharmaceutical composition comprising substance Z for the preparation of a serotonin 5-HT 2A receptor agonist; ; represents a single bond or a double bond; R 1 is H or C 1 -C 4 alkyl; R 2 is H, halogen, hydroxy, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or ; R 3 is H, halogen or C 1 -C 4 alkyl; r 4 is H, halogen or C 1 -C 4 alkyl; R 5 is H, halogen or C 1 -C 4 alkyl; R 6 is C 1 -C 4 alkyl; q is a C 6 -C 10 aromatic ring, a 4-8 membered carbocycle or a 4-8 membered heterocycle, wherein hetero atoms of the 4-8 membered heterocycle are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; m and n are independently 0,1,2 or 3.
  2. 2. Use according to claim 1, characterized in that it fulfils one or more of the following conditions: (1) In R 1 , the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (2) In R 2 , the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (3) In R 2 , the C 1-4 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (4) In R 2 , the halogen is fluorine, chlorine, bromine or iodine; (5) In R 3 , the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (6) In R 4 , the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (7) In R 5 , the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (8) In R 6 , the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (9) In Q, the C 6 -C 10 aromatic ring is a benzene ring or naphthalene ring, such as a benzene ring; (10) In Q, the 4-8 membered carbocycle is a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 7-membered carbocycle, or an 8-membered carbocycle; (11) In Q, the heteroatom of the 4-8 membered heterocycle is O or N; (12) In Q, the number of the 4-8 membered heterocyclic ring is 1; And (13) Q, the heteroatom of the 4-8 membered heterocyclic ring is a heteroatom of a 5-7 membered heterocyclic ring, for example 、 、 、 Or (b) 。
  3. 3. Use according to claim 1, characterized in that it fulfils one or more of the following conditions: (1) R 1 is H or C 1 -C 4 alkyl; (2) R 2 is H, halogen, hydroxy or amino; (3) Q is a benzene ring, a 4-8 membered carbocycle or a 4-8 membered heterocycle, wherein the heteroatom of the 4-8 membered heterocycle is N or O, and the number of the heteroatom is 1, preferably the heteroatom of the 4-8 membered heterocycle is O; and (4) m and n are independently 1 or 2.
  4. 4. Use according to claim 1, characterized in that it is any of the following: Scheme 1: represents a single bond or a double bond; R 1 is H or C 1 -C 4 alkyl; r 2 is H, halogen, hydroxy or amino; R 3 is H; r 4 is H; r 5 is H; Q is benzene ring, 4-8 membered carbocycle or 4-8 membered heterocycle, wherein the hetero atom of the 4-8 membered heterocycle is N or O, and the number of the hetero atom is 1; m and n are independently 1 or 2; Scheme 2:R 1 is H or C 1 -C 4 alkyl; R 2 is H, hydroxy or amino; R 3 is H; r 4 is H; r 5 is H; m and n are each independently 1,2 or 3; When Q is a 4-8 membered heterocyclic ring, R 1 is C 1 -C 4 alkyl, Represents a double bond; When Q is a 4-8 membered carbocycle, R 1 is C 1 -C 4 alkyl, R 2 is H, Represents a single bond; when Q is a 4-8 membered carbocyclic ring, R 1 is H, R 2 is H, n is 1; Scheme 3R 1 is H or C 1 -C 4 alkyl; r 2 is H, halogen or hydroxy; R 3 is H; r 4 is H; r 5 is H; q is a C 6 -C 10 aromatic ring, a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, the 4-8 membered heterocyclic ring being 、 、 Or (b) ; M and n are each independently 1,2 or 3; When R 2 is halogen, m is 1; scheme 4R 1 is H or C 1 -C 4 alkyl; r 2 is H, halogen, hydroxy or amino; R 3 is H; r 4 is H; r 5 is H; m and n are each independently 1,2 or 3; When R 2 is OH, Q is a C 6 -C 10 aromatic ring, a 6-8 membered carbocyclic ring, or a 6-8 membered heterocyclic ring; When Q is a 6-8 membered heterocycle, R 2 is OH, R 1 is H, n is 2, Represents a single bond; Scheme 5:R 1 is H or C 1 -C 4 alkyl; r 2 is H, halogen, hydroxy or amino; R 3 is H; r 4 is H; r 5 is H; m and n are each independently 1,2 or 3; when Q is a 4-8 membered heterocyclic ring, m is 1, n is 2, R 2 is hydroxy, Represents a single bond; When m is 1, n is 2, Represents a single bond, and when R 2 is hydroxy, Q is a 7-8 membered carbocycle, a 4-8 membered heterocycle or a C 6 -C 10 aromatic ring; When m is 1, n is 2, Represents a double bond, and when R 2 is hydroxy, Q is a 6-8 membered carbocycle, a 6-8 membered heterocycle or a C 6 -C 10 aromatic ring; When m and n are 1, R 2 is hydroxy, Q is a 6-8 membered carbocyclic ring, a 6-8 membered heterocyclic ring, or a C 6 -C 10 aromatic ring.
  5. 5. Use according to claim 1, characterized in that it fulfils one or both of the following conditions: (1) Is that 、 、 、 、 、 Or (b) ; And (2) Is that 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  6. 6. The use according to claim 1, wherein the compound of formula I is: ; ; ; ; ; ; ; 。
  7. 7. Use of a substance Z according to any one of claims 1 to 6 or a pharmaceutical composition comprising a substance Z according to any one of claims 1 to 6 for the preparation of a medicament for the treatment and/or prophylaxis of antidepressant, anxiety, cluster headache or neurodegenerative disorders.
  8. 8. Use of a substance Z according to any one of claims 1 to 6 or a pharmaceutical composition comprising a substance Z according to any one of claims 1 to 6 for the manufacture of a medicament for serotonin 5-HT 2A receptor related treatment of depression, anxiety, cluster headache or neurodegenerative diseases, of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof or a stereoisomer thereof.
  9. 9. A compound of formula II, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterate thereof, or a stereoisomer thereof: ; represents a single bond or a double bond; R 1 is H or C 1 -C 4 alkyl; R 2 is H, halogen, hydroxy, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or ; R 3 is H, halogen or C 1 -C 4 alkyl; r 4 is H, halogen or C 1 -C 4 alkyl; R 5 is H, halogen or C 1 -C 4 alkyl; R 6 is C 1 -C 4 alkyl; Q is 7-8 membered carbocycle or 7-8 membered heterocycle, wherein the heteroatom of the 7-8 membered heterocycle is selected from one or more of N, O and S, and the number of the heteroatom is 1,2 or 3; m and n are independently 0,1,2 or 3.
  10. 10. A compound of formula II, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof according to claim 9, which satisfies one or more of the following conditions: (1) In R 1 , the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (2) In R 2 , the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (3) In R 2 , the C 1-4 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (4) In R 2 , the halogen is fluorine, chlorine, bromine or iodine; (5) In R 3 , the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (6) In R 4 , the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (7) In R 5 , the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (8) In R 6 , the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (9) In Q, the 7-8 membered carbocycle is a 7-membered carbocycle; (10) In Q, the heteroatom of the 7-8 membered heterocycle is O or N; (11) In Q, the number of the 7-8 membered heterocyclic ring is 1; and (12) Q, the heteroatom of the 7-8 membered heterocyclic ring is a heteroatom of a 7-membered heterocyclic ring, for example 、 Or (b) 。
  11. 11. The compound of formula II, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof according to claim 9, which is any one of the following schemes: Scheme 1: represents a single bond or a double bond; R 1 is H or C 1 -C 4 alkyl; r 2 is hydroxy; R 3 is H; r 4 is H; r 5 is H; q is a 7-membered carbocycle or 7-membered heterocycle, wherein the heteroatom of the 7-membered heterocycle is N or O, and the number of the heteroatom is 1; m and n are independently 1 or 2; Scheme 2:R 1 is H or C 1 -C 4 alkyl; R 2 is H or hydroxy; R 3 is H; r 4 is H; r 5 is H; m and n are independently 1,2 or 3; When Q is a 7-8 membered heterocyclic ring, R 1 is C 1 -C 4 alkyl, Represents a double bond; scheme 3:R 1 is H or C 1 -C 4 alkyl; R 2 is H or hydroxy; R 3 is H; r 4 is H; r 5 is H; m and n are independently 1,2 or 3; When Q is a 7-8 membered heterocyclic ring, the 7-8 membered heterocyclic ring is Or (b) ; Scheme 4:R 1 is H or C 1 -C 4 alkyl; R 2 is H or hydroxy; R 3 is H; r 4 is H; r 5 is H; m and n are independently 1,2 or 3; When Q is a 7-8 membered heterocycle, R 2 is OH, R 1 is H, n is 2, Represents a single bond; Scheme 5:R 1 is H or C 1 -C 4 alkyl; R 2 is H or hydroxy; R 3 is H; r 4 is H; r 5 is H; m and n are independently 1,2 or 3; When Q is a 7-8 membered heterocyclic ring, m is 1, n is 2, R 2 is OH, Representing a single bond.
  12. 12. A compound of formula II, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof according to claim 9, wherein it satisfies one or both of the following conditions: (1) Is that 、 、 、 、 Or (b) ; And (2) Q is a 7-membered carbocyclic ring or 7-membered heterocyclic ring, the heteroatom of the 7-membered heterocyclic ring is N or O, the number of heteroatoms is 1, preferably the heteroatom of the 7-membered heterocyclic ring is O, preferably, Is that 、 、 Or (b) 。
  13. 13. The compound of formula II, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof according to claim 9, wherein the compound of formula II is any one of the following: ; ; ; ; ; ; 。
  14. 14. A pharmaceutical composition comprising (i) a compound of formula II according to any one of claims 9 to 13, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuteride thereof, or a stereoisomer thereof, and (II) a pharmaceutically acceptable carrier.

Description

Cyclic amine compound with aryl substitution as well as preparation method and application thereof Technical Field The invention relates to a cyclic amine compound with aryl substitution, a preparation method and application thereof. Background Depression is a common mental disorder with major symptoms including low mood, loss of interest in daily activities, feelings of guilt, sleep disorders, etc., and a higher proportion of patients develop suicidal ideation or behavior. The number of people worldwide suffering from depression has been counted to exceed 3 billion. Depression symptoms usually continue to occur or recur, severely affecting the quality of life of the patient, and creating a tremendous social burden. The pathogenesis of depression is complex, and is related to genetics, environment and the like. Currently, the hypothesis for the pathogenesis of depression is monoamine hypothesis, neuroplasticity hypothesis, and neurotrophic imbalance hypothesis. The monoamine hypothesis provides important theoretical support for antidepressant drug development and neuroscience research. This hypothesis suggests that a decrease in the concentration or activity of monoamine neurotransmitters such as serotonin in the brain is responsible for the symptoms of depression. The most commonly prescribed antidepressant drugs are currently used mainly to increase monoamine neurotransmitter levels. Tricyclic antidepressants (imipramine, amitriptyline, etc.), selective serotonin reuptake inhibitors (fluoxetine, paroxetine, citalopram, sertraline, etc.), and the like have important roles in the clinical treatment of depression. However, these drugs have obvious disadvantages such as slow onset of action, inability to meet the need for rapid symptomatic relief in patients with clinical depression, and numerous side effects such as weight gain, nausea, dry mouth, increased risk of suicidal ideation after withdrawal, etc. Therefore, searching for new drug targets, developing new antidepressants is urgent. Recent studies have found that hallucinogens have great potential in the treatment of mental disorders such as depression. Hallucinogens such as galectin (siroccin) exhibit rapid, sustained antidepressant effects in clinical secondary trials (Duan et al, chem Rev 2024, 124, 124-163; carharharris et al, N Engl J Med 2021, 384:1402-1411). Hallucinogens produce pharmacological effects primarily through activation of serotonin 5-HT 2A receptors in the brain. Known hallucinogens are largely classified into three classes, depending on the chemical structure type, as tryptamines (e.g. stropharin), ergotamines (e.g. lysergic acid diethylamine/LSD) and phenethylamines (e.g. maskanin) (Duan et al Chem Rev 2024, 124, 124-163). Most known hallucinogens have the problem of poor selectivity except for activation of the serotonin 5-HT 2A receptor (Duan et al, chem Rev 2024, 124, 124-163). For example, both galectin and LSD activate the 5-HT 2B receptor (Rouaud et al, J Psychopharmacol 2024,38,217-224.). The 5-HT 2B receptor is highly expressed on heart valves and activation of this receptor has been found to cause heart valve disease (Roth, N Engl J Med 2007, 356,6-9; dumotier et al J Pharmacol Toxicol Methods 2024, 128,107542). Thus, the U.S. FDA published guidelines for the study of hallucinogens in 2023, indicating that attention is paid to the possible toxic side effects of this class of substances on activation of the 5-HT 2B receptor (Harris, JAMA 2023, 25; 330 (4), 307). In addition, studies have shown that few non-fanciful 5-HT 2A receptor agonists have antidepressant potential in addition to hallucinogens (Duan et al, chem Rev 2024, 124, 124-163). For example, TBG (Tabernanthalog) (Cameron et al, nature 2021, 589, 474-479) modified with the fantasy drug Ibugine and IHCH-7086 (Cao et al, science 2022, 375, 403-411) modified with the anti-schizophrenia drug Lu Meipai (Lumateperone) are both antidepressant without causing fantasy, and compound (R) -69 obtained by screening the modified tetrahydropyridine compound library is likewise antidepressant without causing fantasy (Kaplan et al, nature 2022, 610, 582-591). These results all show great potential of the 5-HT 2A receptor as a novel antidepressant target. Meanwhile, the substance has great potential in the aspect of treating other neuropsychiatric diseases, such as anxiety disorder, cluster headache, neurodegenerative diseases and the like. However, the currently known 5-HT 2A agonists are of a lesser class, and the selectivity of known compounds for the 5-HT 2B receptor is also generally poor. Thus, there is a need to develop novel 5-HT 2A receptor agonists. Disclosure of Invention In order to solve the problem of less 5-HT 2A receptor agonist types in the prior art, the invention provides a cyclic amine compound with aryl substitution, and a preparation method and application thereof. The compounds of the present invention are useful for the prevention and treatment of depressi